Francois Haddad

All Publications

• Blood pressure in athletic preparticipation evaluation and the implication for cardiac remodelling. Heart (British Cardiac Society) Hedman, K., Moneghetti, K. J., Christle, J. W., Bagherzadeh, S. P., Amsallem, M., Ashley, E., Froelicher, V., Haddad, F. 2019

  Abstract

  OBJECTIVES: To explore blood pressure (BP) in athletes at preparticipation evaluation (PPE) in the context of recently updated US and European hypertension guidelines, and to determine the relationship between BP and left ventricular (LV) remodelling.METHODS: In this retrospective study, athletes aged 13-35 years who underwent PPE facilitated by the Stanford Sports Cardiology programme were considered. Resting BP was measured in both arms; repeated once if ≥140/90mm Hg. Athletes with abnormal ECGs or known hypertension were excluded. BP was categorised per US/European hypertension guidelines. In a separate cohort of athletes undergoing routine PPE echocardiography, we explored the relationship between BP and LV remodelling (LV mass, mass/volume ratio, sphericity index) and LV function.RESULTS: In cohort 1 (n=2733, 65.5% male), 34.3% of athletes exceeded US hypertension thresholds. Male sex (B=3.17, p<0.001), body mass index (BMI) (B=0.80, p<0.001) and height (B=0.25, p<0.001) were the strongest independent correlates of systolic BP. In the second cohort (n=304, ages 17-26), systolic BP was an independent correlate of LV mass/volume ratio (B=0.002, p=0.001). LV longitudinal strain was similar across BP categories, while higher BP was associated with slower early diastolic relaxation.CONCLUSION: In a large contemporary cohort of athletes, one-third presented with BP levels above the current US guidelines' thresholds for hypertension, highlighting that lowering the BP thresholds at PPE warrants careful consideration as well as efforts to standardise measurements. Higher systolic BP was associated with male sex, BMI and height and with LV remodelling and diastolic function, suggesting elevated BP in athletes during PPE may signify a clinically relevant condition.

  View details for DOI 10.1136/heartjnl-2019-314815

  View details for PubMedID 31142598

• A longitudinal big data approach for precision health NATURE MEDICINE Rose, S., Contrepois, K., Moneghetti, K. J., Zhou, W., Mishra, T., Mataraso, S., Dagan-Rosenfeld, O., Ganz, A. B., Dunn, J., Hornburg, D., Rego, S., Perelman, D., Ahadi, S., Sailani, M., Zhou, Y., Leopold, S. R., Chen, J., Ashland, M., Christle, J. W., Avina, M., Limcaoco, P., Ruiz, C., Tan, M., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E., McLaughlin, T. L., Haddad, F., Snyder, M. P. 2019; 25 (5): 792-+

  View details for DOI 10.1038/s41591-019-0414-6

  View details for Web of Science ID 000468247800023

• Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension. The Journal of thoracic and cardiovascular surgery Noly, P., Piquereau, J., Coblence, M., Ataam, J. A., Guihaire, J., Rucker-Martin, C., Decante, B., Haddad, F., Fadel, E., Mercier, O. 2019

  Abstract

  OBJECTIVE: We aimed to assess the mitochondrial respiratory capacities in the right ventricle in the setting of ventricular remodeling induced by pressure overload.METHODS: Chronic thromboembolic pulmonary hypertension was induced in 8 piglets over a 12-week period (chronic thromboembolic pulmonary hypertension model). Right ventricular remodeling, right ventricular function, and mitochondrial respiratory function were assessed at 3, 6, and 12weeks after induction of pulmonary hypertension and were compared with sham animals (n=5). Right ventricular cardiomyocytes and mitochondrial structure were studied in transmission electronic microscopy after 12weeks.RESULTS: As of 3weeks, chronic pressure overload induced right ventricular dilatation, right ventricular hypertrophy, and right ventricular dysfunction. Maladaptive remodeling in the chronic thromboembolic pulmonary hypertension model was confirmed by the decrease of right ventricular pulmonary artery coupling and right fractional area change. Mitochondrial functional assays in permeabilized right ventricular myocardial fibers revealed that oxidative phosphorylation capacities (complex I, complex II, and IV of the mitochondrial respiratory chain) were degraded. Furthermore, no change in substrate preference of mitochondria was found in the overloaded right ventricle. There was a good correlation between maximal mitochondrial oxygen consumption rate and right ventricular pulmonary artery coupling (Pearson coefficient r=0.83). Transmission electronic microscopy analysis showed that the composition of cardiomyocytes was no different between the chronic thromboembolic pulmonary hypertension group and the sham group. However, mitochondrial structure anomalies were significantly increased in the chronic thromboembolic pulmonary hypertension group.CONCLUSIONS: Mitochondrial respiratory function impairment is involved early in the development of right ventricular dysfunction in a piglet model of chronic thromboembolic pulmonary hypertension. Underlying mechanisms remain to be elucidated.

  View details for PubMedID 30979421

• Circulating Biomarkers Predicting Longitudinal Changes in Left Ventricular Structure and Function in a General Population. Journal of the American Heart Association Cauwenberghs, N., Ravassa, S., Thijs, L., Haddad, F., Yang, W., Wei, F., Lopez, B., Gonzalez, A., Diez, J., Staessen, J. A., Kuznetsova, T. 2019; 8 (2): e010430

  Abstract

  Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C-terminal telopeptide, matrix metalloproteinase-1) and high-sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (-14.2%) and increase in E/e' ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, -14.2%; C-terminal telopeptide, -16.4%; P≤0.029). An increase in E/e' ratio over time was borderline associated with lower matrix metalloproteinase-1 (+9.8%) and lower matrix metalloproteinase-1/tissue inhibitor of metalloproteinase-1 ratio (+11.9%; P≤0.041). Higher high-sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow-up ( P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation.

  View details for PubMedID 30638123

• Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension. Circulation research Sweatt, A. J., Hedlin, H. K., Balasubramanian, V., Hsi, A., Blum, L. K., Robinson, W. H., Haddad, F., Hickey, P. M., Condliffe, R. A., Lawrie, A., Nicolls, M. R., Rabinovitch, M., Khatri, P., Zamanian, R. T. 2019

  Abstract

  Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, though it remains unknown if distinct immune phenotypes exist.Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles.In a prospective observational study of Group 1 PAH patients evaluated at Stanford University (discovery cohort, n=281) and University of Sheffield (validation cohort, n=104) between 2008-2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks- cluster 1 (n=58)(TRAIL, CCL5, CCL7, CCL4, MIF), cluster 3 (n=77)(IL-12, IL-17, IL-10, IL-7, VEGF), and cluster 4 (n=37)(IL-8, IL-4, PDGF-β, IL-6, CCL11). Demographics, PAH etiologies, comorbidities, and medications were similar across clusters. Non-invasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%, CI 35.4-64.1%) and favorable for cluster 3 (82.4%, CI 72.0-94.3%)(across-cluster p<0.001). Findings were replicated in the validation cohort, where machine learning classified four immune clusters with comparable proteomic, clinical, and prognostic features.Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization Group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity.

  View details for PubMedID 30661465

• Pathophysiology of the right ventricle andof the pulmonary circulation in pulmonary hypertension: an update. The European respiratory journal Vonk Noordegraaf, A., Chin, K. M., Haddad, F., Hassoun, P. M., Hemnes, A. R., Hopkins, S. R., Kawut, S. M., Langleben, D., Lumens, J., Naeije, R. 2018

  Abstract

  The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.

  View details for PubMedID 30545976

• The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation. Journal of cardiac failure Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y. J., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823–32

  Abstract

  BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.METHODS AND RESULTS: From 2009 to 2015, 158 patients who underwent implantation of continuous-flow devices who had complete echocardiographic and hemodynamic data were included. Quantitative RV parameters included RV end-diastolic (RVEDAI) and end-systolic area index, RV free-wall longitudinal strain (RVLS), fractional area change, tricuspid annular plane systolic excursion, and right atrial area and pressure. Independent correlates of early RHF (<30 days) were determined with the use of logistic regression analysis. Mean age was 56 ± 13 years, with 79% male; 49% had INTERMACS profiles ≤2. RHF occurred in 60 patients (38%), with 20 (13%) requiring right ventricular assist device. On multivariate analysis, INTERMACS profiles (adjusted odds ratio 2.38 [95% confidence interval [CI] 1.47-3.85]), RVEDAI (1.61 [1.08-2.32]), and RVLS (2.72 [1.65-4.51]) were independent correlates of RHF (all P < .05). Both RVLS and RVEDAI were incremental to validated risk scores (including the EUROMACS score) for early RHF after LVAD (all P < .01).CONCLUSIONS: RV end-diastolic and strain are complementary prognostic markers of RHF after LVAD implantation.

  View details for PubMedID 30539717

• Forgotten No More: A Focused Update on the Right Ventricle in CardiovascularDisease. JACC. Heart failure Amsallem, M., Mercier, O., Kobayashi, Y., Moneghetti, K., Haddad, F. 2018

  Abstract

  In the last decade, there has been renewed interest in the study of the right ventricle. It is now well established that right ventricular function is a strong predictor of mortality, not only in heart failure but also in pulmonary hypertension, congenital heart disease, and cardiothoracic surgery. The right ventricle is part of a cardiopulmonary unit with connections to the pulmonary circulation, venous return, atria, and left ventricle. In this context, ventriculoarterial coupling, interventricular interactions, and pericardial constraint become important to understand right ventricular adaptation to injury or abnormal loading conditions. This state-of-the-art review summarizes major advances that occurred in the field of right ventricular research over the last decade. The first section focuses on right ventricular physiology and pulmonary circulation. The second section discusses the emerging data on right ventricular phenotyping, highlighting the importance of myocardial deformation (strain) imaging and assessment of end-systolic dimensions. The third section reviews recent clinical trials involving patients at risk for or with established right ventricular failure, focusing on beta blockade, phosphodiesterase inhibition, and mechanical support of the failing right heart. The final section presents a perspective on active areas of research that are most likely to translate in clinical practice in the next decade.

  View details for PubMedID 30316939

• Right ventricular load adaptability metrics in patients undergoing left ventricular assist device implantation. The Journal of thoracic and cardiovascular surgery Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. 2018

  Abstract

  OBJECTIVE: Several right load adaptability metrics have been proposed as predictors of right heart failure (RHF) following left ventricular assist device implantation. This study sought to validate and compare the prognostic value of these indices.METHODS: This retrospective study included 194 patients undergoing continuous-flow left ventricular assist device implantation. The primary end point was unplanned right atrial assist device (RVAD) need within 30days after left ventricular assist device implantation; the secondary end points included clinical RHF syndrome without RVAD need and the composite of RHF or RVAD need. Load adaptability indices or interventricular ratios were divided into surrogates of ventriculoarterial coupling (RV area change:end-systolic area), indices reflecting adaptation proportionality (Dandel's index=tricuspid regurgitation velocity-time integral normalized for average RV radius in diastole or systole), and simple ratios (eg, pulse pressure:right atrial pressure or right arterial pressure:pulmonary arterial wedge pressure).RESULTS: Mean age was 55±13years with 77% of men. RHF occurred in 75 patients with 30 patients requiring RVAD implantation. Among right heart metrics, right arterial pressure (normalized odd ratio, 1.62; 95% confidence interval, 1.15-2.38), right arterial pressure:pulmonary arterial wedge pressure (normalized odds ratio, 1.59; 95% confidence interval, 1.08-2.32) and pulse pressure:right arterial pressure<2.0 (normalized odds ratio, 2.56; 95% confidence interval, 1.16-5.56) were associated with RVAD need (all P values<.02). These 3 metrics significantly added incremental prognostic value to the Interagency Registry for Mechanically Assisted Circulatory Support classification score in a similar range, whereas only RAP was incremental to the Michigan score. Correlates of RHF not requiring RVAD included RV end-systolic area index and the Dandel indices, which provided similar incremental value to the Interagency Registry for Mechanically Assisted Circulatory Support, Michigan, and European Registry for Patients with Mechanical Circulatory Support scores.CONCLUSIONS: Although associated with outcome, right load adaptability indices do not appear to provide strong incremental value when compared with simple metrics.

  View details for PubMedID 30482529

• Optimizing right ventricular focused four-chamber views using three-dimensional imaging, a comparative magnetic resonance based study. The international journal of cardiovascular imaging Amsallem, M., Lu, H., Tang, X., Do Couto Francisco, N. L., Kobayashi, Y., Moneghetti, K., Shiran, H., Rogers, I., Schnittger, I., Liang, D., Haddad, F. 2018

  Abstract

  Obtaining focused right ventricular (RV) apical view remains challenging using conventional two-dimensional (2D) echocardiography. This study main objective was to determine whether measurements from RV focused views derived from three-dimensional (3D) echocardiography (3D-RV-focused) are closely related to measurements from magnetic resonance (CMR). A first cohort of 47 patients underwent 3D echocardiography and CMR imaging within 2h of each other. A second cohort of 25 patients had repeat 3D echocardiography to determine the test-retest characteristics; and evaluate the bias associated with unfocused RV views. Tomographic views were extracted from the 3D dataset: RV focused views were obtained using the maximal RV diameter in the transverse plane, and unfocused views from a smaller transverse diameter enabling visualization of the tricuspid valve opening. Measures derived using the 3D-RV-focused view were strongly associated with CMR measurements. Among functional metrics, the strongest association was between RV fractional area change (RVFAC) and ejection fraction (RVEF) (r=0.92) while tricuspid annular plane systolic excursion moderately correlated with RVEF (r=0.47), all p<0.001. Among RV size measures, the strongest association was found between RV end-systolic area (RVESA) and volume (r=0.87, p<0.001). RV unfocused views led on average to 10% underestimation of RVESA. The 3D-RV-focused method had acceptable test-retest characteristics with a coefficient of variation of 10% for RVESA and 11% for RVFAC. Deriving standardized RV focused views using 3D echocardiography strongly relates to CMR-derived measures and may improve reproducibility in RV 2D measurements.

  View details for PubMedID 29654480

• Long-term prognostic value of invasive and non-invasive measures early after heart transplantation. International journal of cardiology Kobayashi, Y., Kobayashi, Y., Yang, H. M., Bouajila, S., Luikart, H., Nishi, T., Choi, D. H., Schnittger, I., Valantine, H. A., Khush, K. K., Yeung, A. C., Haddad, F., Fearon, W. F. 2018; 260: 31–35

  Abstract

  Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting.A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year.The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 ± 0.06, 21.3 ± 17.3, 60.4 ± 5.4%, and 14.2 ± 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 ± 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively).Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation.

  View details for PubMedID 29622448

• Early Development of Right Ventricular Ischemic Lesions in a Novel Large Animal Model of Acute Right Heart Failure in Chronic Thromboembolic Pulmonary Hypertension. Journal of cardiac failure Boulate, D., Arthur Ataam, J., Connolly, A. J., Giraldeau, G., Amsallem, M., Decante, B., Lamrani, L., Fadel, E., Dorfmuller, P., Perros, F., Haddad, F., Mercier, O. 2017

  Abstract

  Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration.We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n = 9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n = 5) and control (n = 5) groups.We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration.

  View details for PubMedID 28801076

• Noninvasive Imaging in the Assessment of the Cardiopulmonary Vascular Unit CIRCULATION Noordegraaf, A. V., Haddad, F., Bogaard, H. J., Hassoun, P. M. 2015; 131 (10): 899-913

  View details for DOI 10.1161/CIRCULATI0NAHA.114.006972

  View details for Web of Science ID 000350771700013

• Experimental Models of Right Heart Failure: A Window for Translational Research in Pulmonary Hypertension SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Guihaire, J., Bogaard, H. J., Flecher, E., Noly, P., Mercier, O., Haddad, F., Fadel, E. 2013; 34 (5): 689-699

  Abstract

  The right ventricle (RV) faces major changes in loading conditions associated with cardiovascular and pulmonary vascular disorders. Despite major pharmacological advances since the last decade, pulmonary arterial hypertension remains a deadly disease mainly secondary to the development of right ventricular failure (RVF). Several experimental models of RVF have been developed over the past three decades providing a particular insight in RV pathophysiology. Mechanisms involved in the transition from RV adaptive hypertrophy to maladaptive remodeling and failure in conditions of chronic RV pressure or volume overload are of a great interest but not yet completely understood. Further investigations are needed to find new therapeutic approaches for RVF. Current animal models and emerging concepts of translational RV research will be detailed in this review.

  View details for DOI 10.1055/s-0033-1355444

  View details for Web of Science ID 000324401900013

  View details for PubMedID 24037635

• Effects of Intracoronary CD34(+) Stem Cell Transplantation in Nonischemic Dilated Cardiomyopathy Patients 5-Year Follow-Up CIRCULATION RESEARCH Vrtovec, B., Poglajen, G., Lezaic, L., Sever, M., Domanovic, D., Cernelc, P., Socan, A., Schrepfer, S., Torre-Amione, G., Haddad, F., Wu, J. C. 2013; 112 (1): 165-173

  Abstract

  CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance.We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response.Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs. 18%; P=0.03), but not of sudden cardiac death (9% vs. 16%; P=0.39).Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.

  View details for DOI 10.1161/CIRCRESAHA.112.276519

  View details for Web of Science ID 000313053000021

  View details for PubMedID 23065358

• Sudden death in myotonic dystrophy NEW ENGLAND JOURNAL OF MEDICINE Vrtovec, B., Haddad, F. 2008; 359 (15): 1628-1628

  View details for Web of Science ID 000259903100022

  View details for PubMedID 18846683

• Twenty-year survivors of heart transplantation at Stanford University AMERICAN JOURNAL OF TRANSPLANTATION Deuse, T., Haddad, F., Pham, M., Hunt, S., Valantine, H., BATES, M. J., Mallidi, H. R., Oyer, P. E., Robbins, R. C., Reitz, B. A. 2008; 8 (9): 1769-1774

  Abstract

  Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between January 1968 and December 2007 with an increase of 1-year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty-year survivors had a mean age at transplant of 29.4 +/- 13.6 years. Rejection-free and infection-free 1-year survivals were 14.3% and 18.8%, respectively. At their last follow-up, 86.7% of long-term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half-life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 +/- 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty-year survival was achieved in 12.5% of patients transplanted before 1988. Although still associated with considerable morbidity, long-term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade.

  View details for DOI 10.1111/j.1600-6143.2008.02310.x

  View details for Web of Science ID 000258401700004

  View details for PubMedID 18557718

• The changing face of heart transplantation JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hunt, S. A., Haddad, F. 2008; 52 (8): 587-598

  Abstract

  It has been 40 years since the first human-to-human heart transplant performed in South Africa by Christiaan Barnard in December 1967. This achievement did not come as a surprise to the medical community but was the result of many years of early pioneering experimental work by Alexis Carrel, Frank Mann, Norman Shumway, and Richard Lower. Since then, refinement of donor and recipient selection methods, better donor heart management, and advances in immunosuppression have significantly improved survival. In this article, we hope to give a perspective on the changing face of heart transplantation. Topics that will be covered in this review include the changing patient population as well as recent advances in transplantation immunology, organ preservation, allograft vasculopathy, and immune tolerance.

  View details for DOI 10.1016/j.jacc.2008.05.020

  View details for Web of Science ID 000258394000001

  View details for PubMedID 18702960

• Right ventricular function in cardiovascular disease, Part II - Pathophysiology, clinical importance, and management of right ventricular failure CIRCULATION Haddad, F., Doyle, R., Murphy, D. J., Hunt, S. A. 2008; 117 (13): 1717-1731

  View details for DOI 10.1161/CIRCULATIONAHA.107.653584

  View details for Web of Science ID 000254576500013

  View details for PubMedID 18378625

• Right ventricular function in cardiovascular disease, part I - Anatomy, physiology, aging, and functional assessment of the right ventricle CIRCULATION Haddad, F., Hunt, S. A., Rosenthal, D. N., Murphy, D. J. 2008; 117 (11): 1436-1448

  View details for DOI 10.1161/CIRCULATIONAHA.107.653576

  View details for Web of Science ID 000254065200011

  View details for PubMedID 18347220

• Right ventricular myocardial performance index predicts perioperative mortality or circulatory failure in high-risk valvular surgery JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Haddad, F., Denault, A. Y., Couture, P., Cartier, R., Pellerin, M., Levesque, S., Lambert, J., Tardif, J. 2007; 20 (9): 1065-1072

  Abstract

  The prognostic value of right ventricular myocardial performance index (RVMPI) and right ventricular fractional area change (RVFAC) in mitral or aortic valve surgery has not been well described. The main objective of this study is to assess the prognostic value of RVMPI and RVFAC in predicting postoperative mortality or circulatory failure.RVMPI and RVFAC were prospectively measured after induction of anesthesia using transesophageal echocardiography in 50 consecutive patients undergoing corrective mitral or aortic valve surgery. Univariate and multivariate analyses were performed for the primary clinical end point of in-hospital mortality or circulatory failure.In the study population, the mean age was 67 +/- 9 years. The primary end point occurred in 17 patients (34%); three patients died, and 14 patients presented signs of circulatory failure. Multivariate regression analysis identified RVMPI and RVFAC as variables of prognostic significance.Preoperative RVMPI and RVFAC could have an incremental value in predicting postoperative mortality and morbidity in valvular heart surgery. Future studies are needed to validate these results in a larger population.

  View details for DOI 10.1016/j.echo.2007.02.017

  View details for Web of Science ID 000249454900006

  View details for PubMedID 17566702

• Applying Cardiopulmonary Exercise Testing to the Evaluation of Left Ventricular Function for Patients Ventricular Assist Device Therapy American College of Sports Medicine Christle, J. W., Moneghetti , K. J., Haddad, F., Banerjee, D., Myers, J., : 533

  View details for DOI 10.1249/01.mss.0000518376.31161.d1

• The Impact of Prescribed Fire versus Wildfire on the Immune and Cardiovascular Systems of Children. Allergy Prunicki, M., Kelsey, R., Lee, J., Zhou, X., Smith, E., Haddad, F., Wu, J., Nadeau, K. 2019

  View details for PubMedID 31002401

• COMPARISON OF UNITED STATES AND EUROPEAN CRITERIA FOR HYPERTENSION IN A LARGE COHORT OF COMPETITIVE ATHLETES EXAMINED AS PART OF PRE-PARTICIPATION EVALUATION Hedman, K., Moneghetti, K., Christle, J. W., Bagherzadeh, S. P., Haddad, F., Ashley, E. A., Froelicher, V. ELSEVIER SCIENCE INC. 2019: 446

  View details for Web of Science ID 000460565900446

• THE EFFECTS OF CD34+CELL THERAPY ON FUNCTIONAL MITRAL REGURGITATION IN PATIENTS WITH NON-ISCHEMIC DILATED CARDIOMYOPATHY Frljak, S., Zemljic, G., Poglajen, G., Cerar, A., Jaklic, M., Haddad, F., Vrtovec, B. ELSEVIER SCIENCE INC. 2019: 1010

  View details for Web of Science ID 000460565901023

• INDEPENDENT PROGNOSTIC VALUES OF CLINICAL RISK SCORES, RIGHT VENTRICULAR SYSTOLIC PRESSURE, AND N-TERMINAL PRO-B-TYPE PEPTIDE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION: INSIGHTS FROM SUPERVISED AND UNSUPERVISED MODELS Tremblay-Gravel, M., Kobayashi, Y., Boralkar, K., Li, X., Bouajila, S., Nishi, T., Amsallem, M., Moneghetti, K., Selej, M., Ozen, M., Demirci, U., Ashley, E. A., Wheeler, M., Knowlton, K., Kouznetsova, T., Haddad, F. ELSEVIER SCIENCE INC. 2019: 718

  View details for Web of Science ID 000460565900718

• RESTING BLOOD PRESSURE IN 2881 ATHLETES AGED 9-35 YEARS OF AGE AND THE RELATION TO SEX, AGE, BODY SIZE, AND AFRO-AMERICAN DESCENT Bagherzadeh, S. P., Hedman, K., Christle, J. W., Moneghetti, K., Ashley, E. A., Haddad, F., Froelicher, V. ELSEVIER SCIENCE INC. 2019: 447

  View details for Web of Science ID 000460565900447

• REPLY: Increasingly Recognized Role of Right Ventricle Assessment in Cardiac Amyloidosis JACC-HEART FAILURE Amsallem, M., Witteles, R., Haddad, F. 2019; 7 (3): 279–80

  View details for DOI 10.1016/j.jchf.2018.12.010

  View details for Web of Science ID 000460037600017

  View details for PubMedID 30819389

• STRONG-D: Strength training regimen for normal weight diabetics: Rationale and design. Contemporary clinical trials Faroqi, L., Bonde, S., Goni, D. T., Wong, C. W., Wong, M., Walai, K., Araya, S., Azamey, S., Schreiner, G., Bandy, M., Raghuram, S. S., Mittal, A., Mukherji, A., Wangdak, T., Talamoa, R., Vera, K., Nacif-Coelho, C., Cde, L. G., Christensen, M., Johannsen, N., Haddad, F., Moharir, M., Palaniappan, L. 2019

  Abstract

  BACKGROUND: Currently, there is a lack of data on effective lifestyle recommendations for normal-weight diabetics (NWD), who can represent up to 1 in 5 individuals with Type II Diabetes Mellitus (T2DM). NWD is especially prevalent in Asian populations and the elderly. Specific exercise treatment recommendations are needed for patients with normal-weight diabetes (NWD), as those in this category face higher mortality rates than overweight and obese diabetics. Standard T2DM treatment recommends aerobic training; however, performing aerobic training alone may not be appropriate for NWD and strength training may be a more effective treatment recommendation.OBJECTIVE: While it is known that strength and aerobic training are beneficial in obese diabetics, there is currently insufficient evidence to recommend this regimen in NWD. The Strength Training Regimen for Normal Weight Diabetics (STRONG-D) study aims to determine the best exercise regimen for NWD and address the current lack of appropriate physical activity recommendations for this population. The primary goal of this study is to determine whether strength training aids glycemic control better than aerobic training in NWD.STUDY DESIGN: STRONG-D is a three-arm randomized controlled trial designed to compare the clinical effectiveness of structured strength training only, aerobic training only, and combination (strength + aerobic) training sessions, modeled after the intervention in the Health Benefits of Aerobic and Resistance Training in T2DM patients (HART-D) study. Potential participants meeting eligibility criteria of HbA1c values of 6.5% to 13.0% and BMI of 18.5 kg/m2 to 25 kg/m2 will be enrolled. After randomization, participants will begin a 9-month exercise intervention. The primary outcomes will be HbA1c levels. The secondary endpoints will include physical fitness, body composition measured by Dual X-Ray Absorptiometry (DXA) scans, and leg strength and endurance measured by Biodex testing. Initial follow-up visits will occur at 3 months, 6 months, and 9 months. To determine the long-term effects of the exercise intervention, passive follow-up will continue via electronic health records (EHR) until a 24-month follow-up visit. A total of 282 participants will be randomized into the three study arms determine the clinically significant differences between strength-only, aerobic-only and combination regimens.

  View details for PubMedID 30625372

• Temporal changes in left ventricular longitudinal strain in general population: Clinical correlates and impact on cardiac remodeling. Echocardiography (Mount Kisco, N.Y.) Kuznetsova, T., Nijs, E., Cauwenberghs, N., Knez, J., Thijs, L., Haddad, F., Yang, W., Kerkhof, P. L., Voigt, J., Staessen, J. A. 2019

  Abstract

  BACKGROUND: Recent studies in patients and general population have reported the role of left ventricular (LV) longitudinal strain (LS) as an independent predictor of outcome. However, there are few data on changes in LS over time. We therefore investigated in a general population clinical correlates of temporal changes in LS. We also explored the potential correlation between temporal changes in LV volumes and LS.METHODS AND RESULTS: We measured LV end-systolic (ESV) and end-diastolic (EDV) volumes by conventional echocardiography and LS by 2D speckle tracking in 627 participants (mean age 50.6years, 51.4% women; 41.3% hypertensives) at baseline and after 4.7years. For statistical analysis, we used the absolute values of LS. In stepwise regression, the magnitude of the decrease in all LV LS indexes over time was greater in men than in women (P<0.0001). Higher baseline mean arterial pressure (MAP), a larger longitudinal increase in MAP, and stopping diuretic treatment during follow-up were related to larger decreases in LS indexes. In multivariable-adjusted analysis, we observed an inverse correlation between baseline ESV and LV LS (P≤0.0017). Similarly, lower baseline LS and a larger decrease in LS over time were correlated with a lesser longitudinal decrease in ESV (P≤0.0004).CONCLUSIONS: A significant decrease in LS over time was associated with male sex, higher baseline MAP, ∆MAP, and alteration in antihypertensive treatment. We suggested an interaction between a longitudinal decrease in LV deformation and adverse cardiac remodeling, while underscoring the importance of deformation analysis based on LS assessment in patients at risk.

  View details for PubMedID 30609050

• A longitudinal big data approach for precision health. Nature medicine Schüssler-Fiorenza Rose, S. M., Contrepois, K., Moneghetti, K. J., Zhou, W., Mishra, T., Mataraso, S., Dagan-Rosenfeld, O., Ganz, A. B., Dunn, J., Hornburg, D., Rego, S., Perelman, D., Ahadi, S., Sailani, M. R., Zhou, Y., Leopold, S. R., Chen, J., Ashland, M., Christle, J. W., Avina, M., Limcaoco, P., Ruiz, C., Tan, M., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E., McLaughlin, T. L., Haddad, F., Snyder, M. P. 2019; 25 (5): 792–804

  Abstract

  Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

  View details for PubMedID 31068711

• Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z., Giraldeau, G., Finocchiaro, G., Kobayashi, Y., Wheeler, M., Perez, M., Moneghetti, K., Oxborough, D., George, K. P., Myers, J., Ashley, E., Haddad, F. 2019; 29 (3): 224–31

  Abstract

  There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

  View details for PubMedID 31033616

• Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement. International journal of cardiology Kim, J. B., Kobayashi, Y., Kuznetsova, T., Moneghetti, K. J., Brenner, D. A., O'Malley, R., Dao, C., Wu, J. C., Fischbein, M., Craig Miller, D., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. 2018; 270: 83–88

  Abstract

  OBJECTIVE: Previous studies have suggested that cytokines and growth factors may predict ventricular recovery following aortic valve replacement (AVR). The primary objective of this study was to identify cytokines that predict ventricular recovery following transcatheter AVR (TAVR).METHODS: We prospectively enrolled 121 consecutive patients who underwent TAVR. Standard echocardiographic assessment at baseline, 1-month and 1-year after TAVR included left ventricular (LV) mass index (LVMI) and global longitudinal strain (GLS). Blood samples were obtained at the time of the procedure to measure cytokines using a 63-plex Luminex platform. Partial least squares-discriminant analysis was performed to identify cytokines associated with ventricular remodeling and function at baseline as well as 1 year after TAVR.RESULTS: The mean age was 84 ± 9 years, with a majority of male subjects (59%), a mean LVMI of 120.4 ± 45.1 g/m2 and LVGLS of -13.0 ± 3.2%. On average, LV mass decreased by 8.1% and GLS improved by 20.3% at 1 year following TAVR. Among cytokines assayed, elevated hepatocyte growth factor (HGF) emerged as a common factor significantly associated with worse baseline LVMI and GLS as well as reduced ventricular recovery (p < 0.005). Other factors associated with ventricular recovery included a select group of vascular growth factors, inflammatory mediators and tumor necrosis factors, including VEGF-D, ICAM-1, TNFbeta, and IL1beta.CONCLUSION: We identified a network of cytokines, including HGF, that are significantly correlated with baseline LVMI and GLS, and ventricular recovery following TAVR.

  View details for PubMedID 30219541

• Effects of acute increases in right ventricular preload and afterload on pulmonary artery pulse pressure in a chronic thromboembolic hypertension model Boulate, D., Chemla, D., Loisel, F., Decante, B., Herve, P., Haddad, F., Fadel, E., Mercier, O. EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2018

  View details for DOI 10.1183/13993003.congress-2018.PA3074

  View details for Web of Science ID 000455567104106

• Evaluating the clinical implementation of structured exercise: A randomized controlled trial among non-insulin dependent type II diabetics. Contemporary clinical trials Dpm, L. F., Wong, M., Bonde, S., Wong, C. W., Walai, K., West, W., Goni, D. T., Araya, S., Azamey, S., Nacif-Coelho, C., Raghuram, S. S., Vera, K., Mittal, A., Cde, L. G., Christensen, M., Johannsen, N., Haddad, F., Moharir, M., Palaniappan, L. 2018

  Abstract

  BACKGROUND: The American Diabetes Association (ADA) currently recommends 150 min of moderate-intensity aerobic exercise per week and resistance exercise at least twice per week in individuals with type 2 diabetes (T2DM) to improve overall health.1 However, approximately 38% of patients with T2DM do not exercise at recommended levels and 31% do not exercise at all.2 The efficacy of structured exercise interventions has been proven effective in reducing glycosylated hemoglobin A1c (HbA1c) levels in patients, but practical approaches are needed to translate these findings into the clinical setting.3-7 OBJECTIVE: The Initiate and Maintain Physical Activity in Clinics (IMPACT) Study aims to compare structured group exercise within the clinic to usual care in T2DM patients. The main purpose of the study is to determine the optimal and feasible level and weekly frequency of structured contact in a clinical setting needed to initiate and maintain physical activity recommendations long-term.STUDY DESIGN: IMPACT is a longitudinal, randomized-controlled study designed to track study participants over 30 months. Once study participants have met eligibility and enrollment criteria, they are randomized and enrolled into one of three arms: 1* per week exercise, 3* per week exercise, or the usual care control group. After randomization, participants begin Phase 1: Initiate lasting 6 months. Over the course of Phase 1, participants in the exercise groups will attend instructor led group training at a Stanford approved physical fitness facility. At the end of 6 months, participants enter Phase 2: Maintain lasting 24 months. Over the course of Phase 2, participants in all three arms will attend periodic follow-up visits for clinical measurements and survey administration for their final two years of participation. These findings will enable the clinical implementation of a structured exercise regimen designed to specifically address the aerobic and resistance training recommendations for patients with T2DM.

  View details for PubMedID 30205182

• Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Bouajila, S., Stolfo, D., Finocchiaro, G., Kuznetsova, T., Liang, D., Schnittger, I., Ashley, E., Wheeler, M., Haddad, F. 2018

  Abstract

  Aims: The myocardial performance index (MPI) is a time-based index of global myocardial performance. In this study, we sought to compare the prognostic value of the MPI with other strain and remodelling indices in hypertrophic cardiomyopathy (HCM).Methods and results: We enrolled 126 patients with HCM and 50 age- and sex-matched controls. Along with traditional echocardiographic assessment, MPI, left ventricular global longitudinal strain (LVGLS), E/e' ratio, and total left atrial (LA) global strain (LAS) were also measured. Time-based MPI was calculated from flow or tissue-based pulse wave Doppler (PWD and TDI) as the (isovolumic-relaxation and contraction time)/systolic-time. We used hierarchical clustering and network analysis to better visualize the relationship between parameters. The primary endpoint was the composite of all-cause death, heart transplantation, left ventricular assist device implantation, and clinical worsening. Left ventricular outflow tract (LVOT) obstruction was present in 56% of patients. Compared with controls, patients with HCM had worse LVGLS (-14.0±3.4% vs. -19.6±1.5%), higher E/e' (12.9±7.2 vs. 6.1±1.5), LA volume index (LAVI) (36.4±13.8ml/m2 vs. 25.6±6.7ml/m2), and MPI (0.55±0.17 vs. 0.40±0.11 for PWD and 0.59±0.22 vs. 0.46±0.09 for TDI) (all P<0.001). During a median follow-up of 55months, 47 endpoints occurred. PWD or TDI-based MPI was not associated with outcome, while LAVI, LAS, LVGLS, and E/e' were (all P<0.01). On multivariable analysis, LVOT obstruction (P<0.001), LAS (P<0.001), and E/e' (P=0.02) were retained as independent associates. They were in different clusters suggesting complemental relationship between them.Conclusion: Time-based index is less predictive of outcome than strain or tissue Doppler indices. LAS may be a promising prognostic marker in HCM.

  View details for PubMedID 30060097

• Applying current normative data to prognosis in heart failure: The Fitness Registry and the Importance of Exercise National Database (FRIEND) INTERNATIONAL JOURNAL OF CARDIOLOGY Moneghetti, K. J., Hock, J., Kaminsky, L., Arena, R., Lui, G. K., Haddad, F., Wheeler, M., Froelicher, V., Ashley, E., Myers, J., Christle, J. W. 2018; 263: 75–79

  Abstract

  Percent of predicted peak VO2 (ppVO2) is considered a standard measure for establishing disease severity, however, there are known limitations to traditional normative values. This study sought to compare ppVO2 from the newly derived "Fitness Registry and the Importance of Exercise: a National Database" (FRIEND) registry equation to conventional prediction equations in a clinical cohort of patients undergoing cardiopulmonary exercise testing (CPX).We selected 1094 patients referred for evaluation of heart failure (HF) symptoms who underwent CPX. ppVO2 was calculated using the FRIEND, Wasserman/Hansen and Jones equations. Participants were followed for a median of 4.5 years [Interquartile range 3.5-6.0] for the composite endpoint of death, advanced HF therapy, or acute decompensated HF requiring hospital admission. Mean age was 48 ± 15 years and 62% were female. The FRIEND registry equation predicted the lowest ppVO2 (measured/predicted; 71 ± 31%), compared to the Wasserman/Hansen (74 ± 29%) and Jones equations (83 ± 33%) (p < 0.001). All expressions of peak VO2 were significant as univariate predictors of outcome with no significant differences between equations on pairwise analysis of receiver operating characteristic curves. When compared at a similar threshold of ppVO2 the event rate was significantly lower in the FRIEND registry equation versus the currently used Wasserman and Jones equations.The use of the newly derived FRIEND registry equation predicts HF outcomes; however, it appears to predict a higher predicted VO2; the clinical implication being a lower threshold of percent predicted peak VO2 should be considered when risk stratifying patients with HF.

  View details for PubMedID 29525067

• Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation Ma, N., Zhang, J., Itzhaki, I., Zhang, S. L., Chen, H., Haddad, F., Kitani, T., Wilson, K. D., Tian, L., Shrestha, R., Wu, H., Lam, C. K., Sayed, N., Wu, J. C. 2018

  Abstract

  Background -The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. Methods -To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM_000258.2:c.170C>A, NP_000249.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Humaninduced pluripotent stem cells (iPSCs) were derived from the heterozygous VUSMYL3(170C>A) carrier, and their genome was edited using CRISPR/Cas9 to generate 4 isogenic iPSC lines: (1) corrected "healthy" control; (2) homozygous VUSMYL3(170C>A); (3) heterozygous frameshift mutation MYL3(170C>A/fs); and (4) known heterozygous MYL3 pathogenic mutation (NM_000258.2:c.170C>G), at the same nucleotide position as VUSMYL3(170C>A), lines. Extensive assays including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic iPSC-derived cardiomyocytes (iPSC-CMs). Results -The heterozygous VUSMYL3(170C>A)-iPSC-CMs did not show an HCM phenotype at the gene expression, morphology, or functional levels. Furthermore, genome-edited homozygous VUSMYL3(170C>A)- and frameshift mutation MYL3(170C>A/fs)-iPSC-CMs lines were also asymptomatic, supporting a benign assessment for this particular MYL3 variant. Further assessment of the pathogenic nature of a genome-edited isogenic line carrying a known pathogenic MYL3 mutation, MYL3(170C>G), and a carrier-specific iPSC-CMs line, carrying a MYBPC3(961G>A) HCM variant, demonstrated the ability of this combined platform to provide both pathogenic and benign assessments. Conclusions -Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrierspecific manner in a dish. As such, this platform represents a promising VUS riskassessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field.

  View details for PubMedID 29914921

• Effects of Repetitive Transendocardial CD34+ Cell Transplantation in Patients with Non-Ischemic Dilated Cardiomyopathy. Circulation research Vrtovec, B., Poglajen, G., Sever, M., Zemljic, G., Frljak, S., Cerar, A., Cukjati, M., Jaklic, M., Cernelc, P., Haddad, F., Wu, J. C. 2018

  Abstract

  Rationale: Preclinical data in heart failure models suggest that repetitive stem cell therapy may be superior to single-dose cell administration. Objective: We investigated whether repetitive administration of CD34+ cells is superior to single dose administration in patients with non-ischemic dilated cardiomyopathy (DCM). Methods and Results: Of 66 patients with DCM, NYHA functional class III, and left ventricular ejection fraction (LVEF)< 40% enrolled in the study, 60 were randomly allocated to repetitive cell therapy (Group A, N=30), or single cell therapy (Group B, N=30). Patients received granulocyte-colony stimulating factor (G-CSF) for 5 days and 80 million CD34+ cells were collected by apheresis and injected transendocardially. In Group A, cell therapy was repeated at 6 months. All patients were followed for 1 year, and the primary end-point was the difference in change in LVEF between the groups. At baseline, the groups did not differ in age, sex, LVEF, NT-proBNP, or 6-minute walk test distance. When directly comparing groups A and B at 1 year, there was no significant difference in change in LVEF (from 32.2±9.3% to 41.2±6.5% in Group A and from 30.0±7.0% to 37.9±5.3% in Group B, P=0.40). From baseline to 6 months, both groups improved in LVEF (+6.9±3.3% in Group A, P=0.001 and +7.1±3.5% in Group B, P=0.001), NT-proBNP (-578±211 pg/ml, P=0.02 and -633±305 pg/ml, P=0.01) and 6MWT (+87±21 m, P=0.03 and +92±25 m, P=0.02). In contrast, we observed no significant changes between 6 months and 1 year (LVEF: +2.1±2.3% in Group A, P=0.19 and +0.8±3.1% in Group B, P=0.56; NT-proBNP: -215±125 pg/ml, P=0.26 and -33±205 pg/ml, P=0.77; 6MWT: +27±11 m, P=0.2 and +12±18 m, P=0.42). Conclusions: In patients with DCM, repetitive CD34+ cell administration does not appear to be associated with superior improvements in LVEF, NT-proBNP, or 6MWT when compared to single dose cell therapy. Clinical Trial: NCT02248532.

  View details for PubMedID 29880546

• Impact of the initiation of balloon pulmonary angioplasty program on referral of patients with chronic thromboembolic pulmonary hypertension to surgery. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Amsallem, M., Guihaire, J., Arthur Ataam, J., Lamrani, L., Boulate, D., Mussot, S., Fabre, D., Taniguchi, Y., Haddad, F., Sitbon, O., Jais, X., Humbert, M., Simonneau, G., Mercier, O., Brenot, P., Fadel, E. 2018

  Abstract

  BACKGROUND: Balloon pulmonary angioplasty (BPA) is a technique proposed for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study we aimed to determine whether initiation of the BPA program has modified the characteristics and outcome of patients undergoing pulmonary endarterectomy (PEA), and compared the characteristics of patients undergoing one or the other procedure.METHODS: This prospective registry study included all patients with CTEPH who underwent PEA in the French National Reference Center before (2012 to 2013) and after (2015 to 2016) BPA program initiation (February 2014). Pre-operative clinical and hemodynamics profiles, peri-operative (Jamieson classification, surgery duration, need of assistance) characteristics of both groups, and all-cause mortality were compared using the t-test or chi-square test. Characteristics of patients subjected to surgery or BPA since February 2014 were also compared.RESULTS: The total number of patients referred to the CTEPH team increased in the BPA era (n = 291vs n = 484). The pre-operative characteristics of patients from the pre-BPA era (n = 240) were similar to those from the BPA era (n = 246). Despite more Jamieson Type 3 cases (29%) in the second period, 30- and 90-day mortality remained stable (both p > 0.30). Patients subjected to BPA (n = 177) were older than those subjected to PEA (n = 364) (64 ± 14vs 60 ± 14years, respectively), and had higher rates of splenectomy (10% vs 1%) or implantable port (9% vs 3%), lower total pulmonary resistance, better cardiac index, and better renal function (all p < 0.01).CONCLUSIONS: This study shows the influence of the initiation of the BPA program on the profile of patients with CTEPH undergoing PEA.

  View details for PubMedID 30037729

• Right Ventricular Structure and Function in the Veteran Ultramarathon Runner: Is There Evidence for Chronic Maladaptation? JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Rothwell, O., George, K., Somauroo, J., Lord, R., Stembridge, M., Shave, R., Hoffman, M. D., Wilson, M., Ashley, E., Haddad, F., Eijsvogels, T. H., Oxborough, D. 2018; 31 (5): 598-+

  Abstract

  It has been proposed that chronic exposure to prolonged strenuous exercise may result in maladaptation of the right ventricle (RV). The aim of this study was to establish RV structure and function, including septal insertion points, using conventional echocardiography and myocardial strain (ε) imaging in a veteran population of ultramarathon runners (UR) and age- and sex-matched controls.A retrospective study design provided 40 UR (>35 years old; mean ± SD training experience, 18 ± 12 years) and 24 sedentary controls who had previously undergone conventional two-dimensional, tissue Doppler and speckle-tracking echocardiography to measure RV size and function. Peak RV ε and strain rate (SR) were assessed from the base, mid, and apical lateral wall. SR were assessed during systole (SRs'), early diastole (SRe') and late diastole (SRa'). Regional assessment of RV insertion points was made at the basal inferoseptum and apical septum using left ventricular (LV) longitudinal ε and at the anteroseptum and inferoseptum using LV circumferential and radial ε.All structural indices of RV size were significantly larger in UR. RV regional and global peak ε were not different between groups, whereas basal RV SR was significantly lower in UR. UR had significantly higher peak LV circumferential ε (anteroseptum, -26% ± 8% vs -21% ± 6%; inferoseptum, -25% ± 6% vs -16% ± 9%) and higher peak LV longitudinal ε (apical septum, -28% ± 7% vs -22% ± 4%) compared with controls. There was regional heterogeneity in UR that was not observed in controls with significantly lower longitudinal ε at the basal inferoseptal insertion point when compared with the global ε (-19% ± 2% vs -22% ± 4%).Myocardial ε imaging highlights no overt maladaptation in this cohort of veteran UR, although lower insertion point ε, compared with global ε, in UR may warrant further investigation.

  View details for PubMedID 29305036

• Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes. Heart (British Cardiac Society) Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018

  Abstract

  OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+Swave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69mV vs 0.21±0.17mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (rho=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

  View details for PubMedID 29680808

• Relation of Insulin Resistance to Longitudinal Changes in Left Ventricular Structure and Function in a General Population JOURNAL OF THE AMERICAN HEART ASSOCIATION Cauwenberghs, N., Knez, J., Thijs, L., Haddad, F., Vanassche, T., Yang, W., Wei, F., Staessen, J. A., Kuznetsova, T. 2018; 7 (7)

  Abstract

  Population data on the longitudinal changes of left ventricular (LV) structure and function in relation to insulin resistance are sparse. Therefore, we assessed in a general population whether hyperinsulinemia predicts longitudinal changes in LV and arterial characteristics.In 627 participants (mean age 50.7 years, 51.4% women), we assessed echocardiographic indexes of LV structure and function and carotid-femoral pulse wave velocity by applanation tonometry at baseline and after 4.7 years. We regressed longitudinal changes in these indexes on baseline insulin and its change during follow-up, and reported standardized effect sizes as a percentage of the SD of LV changes associated with a doubling of insulin. After adjustment, higher baseline insulin predicted a greater temporal increase in LV mass index (effect size: +15.1%) and E/e' ratio (+22.1%), and a greater decrease in e' peak and longitudinal strain (-11.2% to -17.1%). A greater increase in insulin during follow-up related to a greater increase in LV mass index (+10.7%) and decline in ejection fraction and longitudinal strain (-11.4% to -15.7%). Participants who became or remained insulin resistant during follow-up experienced worse changes in longitudinal strain, E/e', and LV mass index as compared with participants who did not develop or had improved insulin resistance over time (P≤0.033). Moreover, multivariable-adjusted increase in pulse wave velocity was higher in participants with diabetes mellitus than in participants without diabetes mellitus (+1.46 m/s versus +0.71 m/s; P=0.039).Hyperinsulinemia at baseline and during follow-up predicted worsening of LV function and remodeling over time. Our findings underline the importance of management of insulin resistance.

  View details for DOI 10.1161/JAHA.117.008315

  View details for Web of Science ID 000430009000011

  View details for PubMedID 29574459

  View details for PubMedCentralID PMC5907600

• PREDICTING MORTALITY WITH AORTOMITRAL CALCIFICATIONS IN 317 TAVR PATIENTS Willemink, M., Maret, E., Moneghetti, K., Kim, J., Haddad, F., Kobayashi, Y., Higashigaito, K., Yeung, A., Lee, A., Miller, D., Fischbein, M., Fearon, W., Fleischmann, D. ELSEVIER SCIENCE INC. 2018: 1591

  View details for DOI 10.1016/S0735-1097(18)32132-6

  View details for Web of Science ID 000429659703241

• RIGHT HEART MALADAPTIVE PHENOTYPES AND PREDICTION OF RIGHT HEART FAILURE FOLLOWING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Aymami, M., Haddad, F., Amsallem, M., Wheeler, M., Moneghetti, K., Adams, J., Verhoye, J., Sallam, K., Woo, Y., Ha, R., Banerjee, D. ELSEVIER SCIENCE INC. 2018: 652

  View details for DOI 10.1016/S0735-1097(18)31193-8

  View details for Web of Science ID 000429659701502

• RIGHT VENTRICULAR LOAD ADAPTABILITY IN PATIENTS UNDERGOING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Wheeler, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1624

  View details for DOI 10.1016/S0735-1097(18)32165-X

  View details for Web of Science ID 000429659703274

• SUBCLINICAL LEFT VENTRICULAR DYSFUNCTION IN WOMEN WITH ANGINA IN THE ABSENCE OF OBSTRUCTIVE CORONARY ARTERY DISEASE: A COMPREHENSIVE INVASIVE AND ECHOCARDIOGRAPHIC STUDY Bouajila, S., Pargaonkar, V., Kobayashi, Y., Kobayashi, Y., Haddad, F., Tremmel, J. ELSEVIER SCIENCE INC. 2018: 132

  View details for DOI 10.1016/S0735-1097(18)30673-9

  View details for Web of Science ID 000429659700133

• INTEGRATING CORRELATION BASED NETWORKS INTO RISK PROGNOSTICATION OF CARDIOMYOPATHY Moneghetti, K., Kim, J., Kobayashi, Y., Boralkar, K., Wheeler, M., Ashley, E., Haddad, F. ELSEVIER SCIENCE INC. 2018: 837

  View details for DOI 10.1016/S0735-1097(18)31378-0

  View details for Web of Science ID 000429659702087

• IMMUNE PROFILE OF HEALTHY CARDIOVASCULAR AGING: INSIGHTS FROM A POPULATION-BASED STUDY AND NETWORK MODELING Bouajila, S., Moneghetti, K., Kobayashi, Y., Gomari, F. A., Abbasi, F., Davis, M. M., Wu, J. C., Kuznetsova, T., Sayed, N., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1657

  View details for Web of Science ID 000429659703307

• THE PROGNOSTIC VALUE OF COMPUTED TOMOGRAPHY FRAILTY MEASURES FOR PROLONGED HOSPITAL STAY AFTER TAVR IN 429 PATIENTS Maret, E., Willemink, M., Moneghetti, K., Kim, J., Haddad, F., Kobayashi, Y., Miller, C., Yeung, A., Fishbein, M., Fearon, W., Fleischmann, D. ELSEVIER SCIENCE INC. 2018: 1414

  View details for DOI 10.1016/S0735-1097(18)31955-7

  View details for Web of Science ID 000429659703064

• THE COMPLEMENTARY VALUE OF THE GET WITH THE GUIDELINES: HEART FAILURE RISK SCORE AND LABORATORY MARKERS AT DISCHARGE IN PREDICTING MORTALITY IN PATIENTS HOSPITALIZED WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION Boralkar, K., Kobayashi, Y., Pargaonkar, V., Moneghetti, K., Tuzovic, M., Krishnan, G., Amsallem, M., Kouznetsova, T., Horne, B., Knowlton, K., Heidenreich, P., Haddad, F. ELSEVIER SCIENCE INC. 2018: 839

  View details for DOI 10.1016/S0735-1097(18)31380-9

  View details for Web of Science ID 000429659702089

• Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? PULMONARY CIRCULATION Loisel, F., Provost, B., Haddad, F., Guihaire, J., Amsallem, M., Vrtovec, B., Fadel, E., Uzan, G., Mercier, O. 2018; 8 (2): 2045893218755979

  Abstract

  Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients.

  View details for PubMedID 29480154

  View details for PubMedCentralID PMC5844533

• Circulating Biomarkers to Identify Responders in Cardiac Cell therapy (vol 7, 4419, 2017) SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2018; 8: 4257

  Abstract

  A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

  View details for PubMedID 29511207

• EXPRESS: Non-invasive Right Ventricular Load Adaptability Indices in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension. Pulmonary circulation French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R., Haddad, F., Chung, L. 2018: 2045894018788268

  View details for PubMedID 29938590

• Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI insight Rockson, S. G., Tian, W., Jiang, X., Kuznetsova, T., Haddad, F., Zampell, J., Mehrara, B., Sampson, J. P., Roche, L., Kim, J., Nicolls, M. R. 2018; 3 (20)

  Abstract

  Lymphedema is a common condition affecting millions around the world that still lacks approved medical therapy. Because ketoprofen, an NSAID, has been therapeutic in experimental lymphedema, we evaluated its efficacy in humans.We first performed an exploratory open-label trial. Patients with either primary or secondary lymphedema received ketoprofen 75 mg by mouth 3 times daily for 4 months. Subjects were evaluated for changes in histopathology, with skin thickness, limb volume, and tissue bioimpedance changes serving as secondary endpoints. Based on our encouraging findings, we next conducted a placebo-controlled trial, with the primary outcome defined as a change in skin thickness, as measured by skin calipers. Secondary endpoints for this second study included histopathology, limb volume, bioimpedance, and systemic inflammatory mediators.We enrolled 21 lymphedema patients in the open-label trial, from November 2010 to July 2011. Histopathology and skin thickness were significantly improved at 4 months compared with baseline. In the follow-up, double-blind, placebo-controlled trial, we enrolled 34 patients from August 2011 to October 2015, with 16 ketoprofen recipients and 18 placebo-treated subjects. No serious adverse events occurred. The ketoprofen recipients demonstrated reduced skin thickness, as well as improved composite measures of histopathology and decreased plasma granulocyte CSF (G-CSF) expression.These 2 exploratory studies together support the utility of targeted antiinflammatory therapy with ketoprofen in patients with lymphedema. Our results highlight the promise of such approaches to help restore a failing lymphatic circulation.ClinicalTrials.gov NCT02257970.

  View details for PubMedID 30333315

• Current Knowledge and Recent Advances of Right Ventricular Molecular Biology and Metabolism from Congenital Heart Disease to Chronic Pulmonary Hypertension BIOMED RESEARCH INTERNATIONAL Guimaron, S., Guihaire, J., Amsallem, M., Haddad, F., Fadel, E., Mercier, O. 2018: 1981568

  Abstract

  Studies about pulmonary hypertension and congenital heart diseases have introduced the concept of right ventricular remodeling leading these pathologies to a similar outcome: right ventricular failure. However right ventricular remodeling is also a physiological process that enables the normal fetal right ventricle to adapt at birth and gain its adult phenotype. The healthy mature right ventricle is exposed to low pulmonary vascular resistances and is compliant. However, in the setting of chronic pressure overload, as in pulmonary hypertension, or volume overload, as in congenital heart diseases, the right ventricle reverts back to a fetal phenotype to sustain its function. Mechanisms include angiogenic changes and concomitant increased metabolic activity to maintain energy production. Eventually, the remodeled right ventricle cannot resist the increased afterload, leading to right ventricular failure. After comparing the fetal and adult healthy right ventricles, we sought to review the main metabolic and cellular changes occurring in the setting of PH and CHD. Their association with RV function and potential impact on clinical practice will also be discussed.

  View details for PubMedID 29581963

  View details for PubMedCentralID PMC5822779

• Exercise testing in heart failure: a contemporary discussion in an era of novel diagnostic techniques and biomarkers. Current opinion in cardiology Moneghetti, K. J., Christle, J. W., Myers, J., Haddad, F. 2018; 33 (2): 217–24

  Abstract

  The purpose of this review is to highlight recent advances in the field of exercise testing for patients with heart failure.The importance of assessment of cardiorespiratory fitness (CRF) and exercise testing in heart failure is highlighted in the consensus recommendation of the American Heart Association. Contemporary studies have validated the independent and incremental strength of CRF metrics in patients with heart failure and coronary artery disease. The use of respiratory gas analysis and imaging or hemodynamics during physical exercise is feasible and results in high prognostic utility across the continuum of heart failure. Understanding how CRF metrics complement existing and novel biomarkers and risk scores is an emerging subject of scientific inquiry.In the current era of personalized medicine, integrating CRF, imaging and circulating biomarkers will allow us to further develop individualized strategies for improving outcome in patients with heart failure.

  View details for PubMedID 29227300

• Athletic Remodeling in Female College Athletes, the "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z., Giraldeau, G., Finocchiaro, G., Kobayashi, Y., Wheeler, M., Perez, M., Moneghetti, K., Oxborough, D., George, K. P., Myers, J., Ashley, E., Haddad, F. 2018

  Abstract

  There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

  View details for PubMedID 29369833

• Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scientific reports Moneghetti, K. J., Skhiri, M., Contrepois, K., Kobayashi, Y., Maecker, H., Davis, M., Snyder, M., Haddad, F., Montoya, J. G. 2018; 8 (1): 2779

  Abstract

  Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS. Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups. Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

  View details for PubMedID 29426834

• Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension EUROPEAN RESPIRATORY JOURNAL Spiekerkoetter, E., Sung, Y. K., Sudheendra, D., Scott, V., Del Rosario, P., Bill, M., Haddad, F., Long-Boyle, J., Hedlin, H., Zamanian, R. T. 2017; 50 (3)

  Abstract

  Pulmonary arterial hypertension (PAH) is a devastating disease characterised by occlusive pulmonary vasculopathy. Activation of bone morphogenetic protein receptor 2 (BMPR2) signalling by FK506 (tacrolimus) reverses occlusive vasculopathy in rodent PAH models. Here, we determined the safety and tolerability of low-level FK506 therapy in stable PAH patients.We performed a randomised, double-blind, placebo-controlled, 16-week, single-centre, phase IIa trial in PAH patients with New York Heart Association functional class II/III symptoms using three FK506 target levels (<2, 2-3 and 3-5 ng·mL-1). 23 patients were randomised and 20 patients completed the trial.FK506 was generally well tolerated, with nausea/diarrhoea being the most commonly reported adverse event and no observation of line infections in patients on intravenous prostacyclin therapy. PAH patients had significantly lower BMPR2 expression in peripheral blood mononuclear cells versus healthy controls (n=13; p=0.005), which improved after FK506 treatment. While we observed that some patients responded with a pronounced increase in BMPR2 expression as well as improvement in 6-min walk distance, and serological and echocardiographic parameters of heart failure, these changes were not significant.Low-level FK506 is well tolerated and increases BMPR2 in subsets of PAH patients. These results support the study of FK506 in a phase IIb efficacy trial.

  View details for PubMedID 28893866

• Circulating Biomarkers to Identify Responders in Cardiac Cell therapy SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2017; 7: 4419

  Abstract

  Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76-94% elevated) than non-responders. Several biomarkers had values that differed significantly (P < 0.05) between responders and non-responders including stem cell factor, platelet-derived growth factor, and interleukin-15. We then used these lead candidates for ROC analysis and found multiple biomarkers with values areas under the curve >0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers.

  View details for PubMedID 28667255

• Cell Transplantation on Diastolic Parameters in Patients with Nonischemic Dilated Cardiomyopathy. Stem cells translational medicine Bervar, M., Kozelj, M., Poglajen, G., Sever, M., Zemljic, G., Frljak, S., Cukjati, M., Cernelc, P., Haddad, F., Vrtovec, B. 2017; 6 (6): 1515-1521

  Abstract

  We sought to evaluate the physiological background and the effects of CD34(+) cell transplantation on diastolic parameters in nonischemic dilated cardiomyopathy patients (DCM). We enrolled 38 DCM patients with NYHA class III and LVEF < 40% who underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially in the areas of myocardial hibernation. Patients were followed for 1 year. At baseline, estimated filling pressures were significantly elevated (E/e' ≥ 15) in 18 patients (Group A), and moderately elevated (E/e '< 15) in 20 patients (Group B). The groups did not differ in age (54 ± 9 years vs. 52 ± 10 years; p = .62), gender (male: 85% vs. 78%; p = .57), or LVEF (31 ± 7% vs. 34 ± 6%; p = .37). When compared to Group B patients in Group A had more segments with myocardial scar (4.9 ± 2.7 vs. 2.7 ± 2.9; p = .03), myocardial hibernation (2.2 ± 1.6 vs. 0.9 ± 1.1; p = .02), and longer average local relaxation time on electroanatomical mapping (378 ± 41 ms vs. 333 ± 34 ms, p = .01). During follow-up there was an improvement in diastolic parameters in Group A (E/e': from 24.3 ± 12.1 to 16.3 ± 8.0; p = .005), but not in Group B (E/e': from 10.2 ± 3.7 to 13.2 ± 9.1; p = .19). Accordingly, in Group A, we found an increase in 6-minute walk distance (from 463 ± 83 m to 546 ± 91 m; p = .03), and a decrease in NT-proBNP (from 2140 ± 1743 pg/ml to 863 ± 836 pg/ml; p = .02). In nonischemic DCM, diastolic dysfunction appears to correlate with areas of myocardial scar and hibernation. Transendocardial CD34(+) cell transplantation may improve diastolic parameters in this patient cohort. Stem Cells Translational Medicine 2017;6:1515-1521.

  View details for DOI 10.1002/sctm.16-0331

  View details for PubMedID 28296283

• Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension: Comparison With Validated Models. Circulation. Cardiovascular imaging Amsallem, M., Sweatt, A. J., Aymami, M. C., Kuznetsova, T., Selej, M., Lu, H., Mercier, O., Fadel, E., Schnittger, I., McConnell, M. V., Rabinovitch, M., Zamanian, R. T., Haddad, F. 2017; 10 (6)

  Abstract

  Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension.From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49±14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ≥III, and mean pulmonary vascular resistance was 11.2±6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9±2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (χ(2), 62.2; P<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics.RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension.

  View details for DOI 10.1161/CIRCIMAGING.116.005771

  View details for PubMedID 28592589

• Dynamic changes in aortic impedance after transcatheter aortic valve replacement and its impact on exploratory outcome. international journal of cardiovascular imaging Kobayashi, Y., Kim, J. B., Moneghetti, K. J., Kobayashi, Y., Zhang, R., Brenner, D. A., O'Malley, R., Schnittger, I., Fischbein, M., Miller, D. C., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. 2017

  Abstract

  Valvulo-arterial impedance (Zva) has been shown to predict worse outcome in medically managed aortic stenosis (AS) patients. We aimed to investigate the association between Zva and left ventricular (LV) adaptation and to explore the predictive value of Zva for cardiac functional recovery and outcome after transcatheter aortic valve replacement (TAVR). We prospectively enrolled 128 patients with AS who underwent TAVR. Zva was calculated as: (systolic blood pressure + mean transaortic gradient)/stroke volume index). Echocardiographic assessment occurred at baseline, 1-month and 1-year after TAVR. The primary endpoints were to investigate associations between Zva and global longitudinal strain (GLS) at baseline as well as GLS change after TAVR. The secondary was to compare all-cause mortality after TAVR between patients with pre-defined Zva (=5 mmHg m(2)/ml), stroke volume index (=35 ml/m(2)), and GLS (=-15%) cutoffs. The mean GLS was reduced (-13.0 ± 3.2%). The mean Zva was 5.2 ± 1.6 mmHg*m(2)/ml with 55% of values ≥5.0 mmHg*m(2)/ml, considered to be abnormally high. Higher Zva correlated with worse GLS (r = -0.33, p < 0.001). After TAVR, Zva decreased significantly (5.1 ± 1.6 vs. 4.5 ± 1.6 mmHg*m(2)/ml, p = 0.001). A reduction of Zva at 1-month was associated with GLS improvement at 1-month (r = -0.31, p = 0.001) and at 1-year (r = -0.36 and p = 0.001). By Kaplan-Meier analysis, patients with higher Zva at baseline had higher mortality (Log-rank p = 0.046), while stroke volume index and GLS did not differentiate outcome (Log-rank p = 0.09 and 0.25, respectively). As a conclusion, Zva is correlated with GLS in AS as well as GLS improvement after TAVR. Furthermore, a high baseline Zva may have an additional impact to traditional parameters on predicting worse mortality after TAVR.

  View details for DOI 10.1007/s10554-017-1155-6

  View details for PubMedID 28516313

• Left atrial function and phenotypes in asymmetric hypertrophic cardiomyopathy. Echocardiography (Mount Kisco, N.Y.) Kobayashi, Y., Wheeler, M., Finocchiaro, G., Ariyama, M., Kobayashi, Y., Perez, M. V., Liang, D., Kuznetsova, T., Schnittger, I., Ashley, E., Haddad, F. 2017

  Abstract

  Few studies have analyzed changes in left atrial (LA) function associated with different phenotypes of asymmetric hypertrophic cardiomyopathy (HCM). We sought to demonstrate the association of impairments in LA function with disease phenotype in patients with obstructive and nonobstructive HCM.From Stanford Cardiomyopathy Registry, we randomly selected 50 age-/sex-matched healthy controls, 35 patients with nonobstructive HCM (HCM 1), 35 patients with obstructive HCM (HCM 2), and 35 patients with obstructive HCM requiring septal reduction therapy (HCM 3). Echocardiography was performed to evaluate left ventricular (LV) strain as well as LA function including LA emptying fraction and LA strain.The mean age was 51±14 years and 57% were male. LA volume index differed among all four predefined groups (25.6±6.7 mL/m(2) in controls, 32.2±13.3 mL/m(2) in HCM 1, 42.0±12.9 mL/m(2) in HCM 2, 52.4±15.2 mL/m(2) for HCM 3, and P<.05 all between groups). All measurement of LA function was impaired in patients with HCM than controls. Total and passive LA function was further impaired in HCM 2 or 3 compared with HCM 1, while active LA function was not different among the three groups. Among LV strains, only septal longitudinal strain differed among all groups (-18.5±1.9% in controls, -14.5±1.9% in HCM 1, -13.3±1.8% in HCM 2, -11.6±2.3% in HCM 3, and P<.05 all between groups).LA function was impaired in patients with HCM even in minimally symptomatic nonobstructive phenotype. Total and passive LA function was further impaired in patients with obstructive HCM.

  View details for DOI 10.1111/echo.13533

  View details for PubMedID 28370331

• Left Atrium Maximal Axial Cross-Sectional Area is a Specific Computed Tomographic Imaging Biomarker of World Health Organization Group 2 Pulmonary Hypertension. Journal of thoracic imaging Jivraj, K., Bedayat, A., Sung, Y. K., Zamanian, R. T., Haddad, F., Leung, A. N., Rosenberg, J., Guo, H. H. 2017; 32 (2): 121-126

  Abstract

  Left heart disease is associated with left atrial enlargement and is a common cause of pulmonary hypertension (PH). We investigated the relationship between left atrium maximal axial cross-sectional area (LA-MACSA), as measured on chest computed tomography (CT), and PH due to left heart disease (World Health Organization group 2) in patients with right heart catheterization-proven PH.A total of 165 patients with PH who had undergone right heart catheterization with pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP) measurements and nongated chest CTs were included. LA-MACSA, LA anterior-posterior, and LA transverse measurements were independently obtained using the hand-drawn region-of-interest and distance measurement tools on standard PACS by 2 blinded cardiothoracic radiologists. Nonparametric statistical analyses and receiver operating characteristic curve were performed.Forty-three patients had group 2 PH (PCWP>15 mm Hg), and 122 had nongroup 2 PH (PCWP≤15 mm Hg). Median LA-MACSA was significantly different between the group 2 PH and nongroup 2 PH patients (2312 vs. 1762 mm, P<0.001). Interobserver concordance correlation for LA-MACSA was high at 0.91 (P<0.001). At a threshold of 2400 mm, LA-MACSA demonstrated 93% specificity for classifying group 2 PH (area under the curve, 0.73; P<0.001).LA-MACSA is a readily obtainable and reproducible measurement of left atrial enlargement on CT and can distinguish between group 2 and nongroup 2 PH with high specificity.

  View details for DOI 10.1097/RTI.0000000000000252

  View details for PubMedID 28009778

• Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states NATURE MEDICINE Furman, D., Chang, J., Lartigue, L., Bolen, C. R., Haddad, F., Gaudilliere, B., Ganio, E. A., Fragiadakis, G. K., Spitzer, M. H., Douchet, I., Daburon, S., Moreau, J., Nolan, G. P., Blanco, P., Dechanet-Merville, J., Dekker, C. L., Jojic, V., Kuo, C. J., Davis, M. M., Faustin, B. 2017; 23 (2): 174-184

  Abstract

  Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N(4)-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.

  View details for DOI 10.1038/nm.4267

  View details for Web of Science ID 000393729000009

  View details for PubMedID 28092664

• Electroanatomic Properties of the Myocardium Predict Response to CD34+Cell Therapy in Patients With Ischemic and Nonischemic Heart Failure JOURNAL OF CARDIAC FAILURE Zemljic, G., Poglajen, G., Sever, M., Cukjati, M., Frljak, S., Androcec, V., Cernelc, P., Haddad, F., Vrtovec, B. 2017; 23 (2): 153-160

  Abstract

  We investigated a correlation between electromechanical properties of the myocardium and response to CD34+ cell therapy in patients with chronic heart failure.We enrolled 40 patients with ischemic cardiomyopathy (ICM) and 40 with nonischemic dilated cardiomyopathy (DCM). All patients were in New York Heart Association functional class III and had a left ventricular ejection fraction (LVEF) <40%. CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Electroanatomic mapping was performed to define areas of myocardial scar and hibernation, and CD34+ cells were injected transendocardially in the hibernating areas. Patient were followed for 6 months; responders were defined as patients with LVEF increase of >5%. At baseline, the groups did not differ in sex, LVEF, creatinine, N-terminal pro-B-type natriuretic peptide or electroanatomic parameters (scar area: 53 ± 18% in ICM vs 55 ± 23% in DCM [P = .83]; hibernating area: 23 ± 13% vs 22 ± 12% [P = .56]). At 6 months we found similar rates of responders in both groups (60% in ICM vs 65% in DCM [P = .95]). When compared with nonresponders, responders had less myocardial scar (47 ± 17% vs 58 ± 15% [P = .003]).In patients with chronic heart failure due to ICM and DCM we observed similar electroanatomic properties of the myocardium. In both groups, lower myocardial scar burden was associated with better clinical response to CD34+ cell therapy.

  View details for DOI 10.1016/j.cardfail.2016.08.002

  View details for Web of Science ID 000393535300010

  View details for PubMedID 27523610

• Investigating the value of right heart echocardiographic metrics for detection of pulmonary hypertension in patients with advanced lung disease. The international journal of cardiovascular imaging Amsallem, M., Boulate, D., Kooreman, Z., Zamanian, R. T., Fadel, G., Schnittger, I., Fadel, E., McConnell, M. V., Dhillon, G., Mercier, O., Haddad, F. 2017

  Abstract

  This study determined whether novel right heart echocardiography metrics help to detect pulmonary hypertension (PH) in patients with advanced lung disease (ALD). We reviewed echocardiography and catheterization data of 192 patients from the Stanford ALD registry and echocardiograms of 50 healthy controls. Accuracy of echocardiographic right heart metrics to detect PH was assessed using logistic regression and area under the ROC curves (AUC) analysis. Patients were divided into a derivation (n = 92) and validation cohort (n = 100). Experimental validation was assessed in a piglet model of mild PH followed longitudinally. Tricuspid regurgitation (TR) was not interpretable in 52% of patients. In the derivation cohort, right atrial maximal volume index (RAVI), ventricular end-systolic area index (RVESAI), free-wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) differentiated patients with and without PH; 20% of patients without PH had moderate to severe RV enlargement by RVESAI. On multivariate analysis, RAVI and TAPSE were independently associated with PH (AUC = 0.77, p < 0.001), which was confirmed in the validation cohort (0.78, p < 0.001). Presence of right heart metrics abnormalities did not improve detection of PH in patients with interpretable TR (p > 0.05) and provided moderate detection value in patients without TR. Only two patients with more severe PH (mean pulmonary pressure 35 and 36 mmHg) were missed. The animal model confirmed that right heart enlargement discriminated best pigs with PH from shams. This study highlights the frequency of right heart enlargement and dysfunction in ALD irrespectively from presence of PH, therefore limiting their use for detection of PH.

  View details for DOI 10.1007/s10554-017-1069-3

  View details for PubMedID 28120156

• The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload. The Journal of thoracic and cardiovascular surgery Noly, P. E., Haddad, F., Arthur-Ataam, J., Langer, N., Dorfmüller, P., Loisel, F., Guihaire, J., Decante, B., Lamrani, L., Fadel, E., Mercier, O. 2017; 154 (6): 2070–79

  Abstract

  Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling.We induced RV chronic pressure overload over a 20-week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression.Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 ± 99 vs 1213 ± 74 cap/mm2; P < .01), lower CD to stroke work ratio (0.29 ± 0.07 vs 0.82 ± 0.16; P = .02), higher myocardial fibrosis (15.4% ± 3.8% vs 8.0% ± 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression.The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms.

  View details for PubMedID 28712579

• Load Adaptability in Patients With Pulmonary Arterial Hypertension. The American journal of cardiology Amsallem, M., Boulate, D., Aymami, M., Guihaire, J., Selej, M., Huo, J., Denault, A. Y., McConnell, M. V., Schnittger, I., Fadel, E., Mercier, O., Zamanian, R. T., Haddad, F. 2017; 120 (5): 874–82

  Abstract

  Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n = 85) and a validation cohort (n = 200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44 ± 11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24 ± 11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2 = 0.53, p < 0.001) and RV end-systolic area indexed to body surface area right ventricular end-systolic area index (RVESAI) (R2 = 0.29, p < 0.001), allowing the derivation of simple ratiometric load-specific indices of RV adaptation. In right heart parameters, RVESAI was the strongest predictor of outcomes (hazard ratio per SD = 1.93, 95% confidence interval 1.37 to 2.75, p < 0.001). Although RVESAI/PVRI0.35 provided small incremental discrimination on multivariate modeling, none of the load-adaptability indices provided stronger discrimination of outcome than simple RV adaptation metrics in either the derivation or the validation cohort. In conclusion, allometric modeling enables quantification of the proportionality of RV load adaptation but offers small incremental prognostic value to RV end-systolic dimension in PAH.

  View details for PubMedID 28705377

• Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy. European heart journal cardiovascular Imaging Moneghetti, K. J., Giraldeau, G., Wheeler, M. T., Kobayashi, Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashley, E., Haddad, F. 2017

  Abstract

  Risk stratification in heart failure (HF) relies on several established clinical risk scores, however, myocardial deformation, right heart metrics, and exercise performance have not usually been considered. This study sought to assess the incremental value of advanced echocardiographic and cardiopulmonary exercise testing (CPX) parameters to validated risk scores in HF.The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) and Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI) scores were applied to 208 ambulatory patients with dilated cardiomyopathy (DCM) who completed echocardiography in conjunction with CPX as part of the Stanford Exercise Testing registry. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation, and hospitalization for acute HF. Mean age, left ventricular ejection fraction (LVEF), and left ventricular global longitudinal strain (LVGLS) were 47 ± 13 years, 33 ± 13%, and -10.6 ± 4.4%, respectively, while right ventricular free-wall longitudinal strain was -18.8 ± 5.5%. Partial correlation mapping identified strong correlations between LVEF, LVGLS, and LV systolic strain rate, with a moderate correlation between these metrics and peak VO2. Over a median follow up of 5.3 years, the composite end point occurred in 60 patients. Cox proportional hazards identified MAGGIC score [hazard ratio (HR) (2.04 [1.39-3.01], P < 0.01], peak VO2 HR (0.52 [0.28-0.97], P = 0.04), and right atrial volume indexed (RAVI) HR (1.31 [1.07-1.61], P < 0.01) as independent correlates of outcome. RAVI remained an independent correlate when combined with the MECKI score (2.21 [1.59-3.07]), P < 0.01, RAVI, 1.33 [1.06-1.67], P = 0.01).Our study demonstrates that RAVI is complementary to well-validated HF risk scores and highlights the importance of exercise performance in DCM.

  View details for PubMedID 28977353

• Value of Strain Imaging and Maximal Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy. The American journal of cardiology Moneghetti, K. J., Stolfo, D., Christle, J. W., Kobayashi, Y., Finocchiaro, G., Sinagra, G., Myers, J., Ashley, E. A., Haddad, F., Wheeler, M. T. 2017; 120 (7): 1203–8

  Abstract

  Longitudinal strain (LS) has been shown to be predictive of outcome in hypertrophic cardiomyopathy (HC). Percent predicted peak oxygen uptake (ppVO2), among other cardiopulmonary exercise testing (CPX) metrics, is a strong predictor of prognosis in HC. However, there has been limited investigation into the combination of LS and CPX metrics. This study sought to determine how LS and parameters of exercise performance contribute to prognosis in HC. One hundred and thirty-one consecutive patients with HC who underwent CPX and stress echocardiography were included. Global, septal, and lateral LS were assessed at rest and stress. Eighty matched individuals were used as controls. Patients were followed for the composite end point of death and worsening heart failure. All absolute LS components were lower in patients with HC than in controls (global 14.3 ± 4.0% vs 18.8 ± 2.2%, p <0.001; septal 11.9 ± 4.9% vs 17.9 ± 2.7%, p <0.001; lateral 16.0 ± 4.7% vs 19.4 ± 3.1%, p = 0.001). Global strain reserve was also reduced in patients with HC (13 ± 5% vs 19 ± 8%, p = 0.002). Over a median follow-up of 56 months (interquartile range 14 to 69), the composite end point occurred in 53 patients. Global LS was predictive of outcome on univariate analysis (0.55 [0.41 to 0.74], p <0.001). When combined with CPX metrics, lateral LS was the only strain variable predictive of outcome along with indexed left atrial volume (LAVI) and ppVO2. The worst outcomes were observed for patients with lateral LS <16.1%, LAVI >52 ml/m2, and ppVO2 <80%. The combination of lateral LS, LAVI, and ppVO2 presents a simple model for outcome prediction.

  View details for PubMedID 28802509

• Autoantibody profiling on a plasmonic nano-gold chip for the early detection of hypertensive heart disease. Proceedings of the National Academy of Sciences of the United States of America Li, X., Kuznetsova, T., Cauwenberghs, N., Wheeler, M., Maecker, H., Wu, J. C., Haddad, F., Dai, H. 2017; 114 (27): 7089–94

  Abstract

  The role of autoimmunity in cardiovascular (CV) diseases has been increasingly recognized. Autoimmunity is most commonly examined by the levels of circulating autoantibodies in clinical practices. Measurement of autoantibodies remains, however, challenging because of the deficiency of reproducible, sensitive, and standardized assays. The lack of multiplexed assays also limits the potential to identify a CV-specific autoantibody profile. To overcome these challenges, we developed a nanotechnology-based plasmonic gold chip for autoantibody profiling. This approach allowed simultaneous detection of 10 CV autoantibodies targeting the structural myocardial proteins, the neurohormonal regulatory proteins, the vascular proteins, and the proteins associated with apoptosis and coagulation. Autoantibodies were measured in four groups of participants across the continuum of hypertensive heart diseases. We observed higher levels of all 10 CV autoantibodies in hypertensive subjects (n= 77) compared with healthy participants (n= 30), and the autoantibodies investigated were related to each other, forming a highly linked network. In addition, we established that autoantibodies to troponin I, annexin-A5, and beta 1-adrenegic receptor best discriminated hypertensive subjects with adverse left ventricular (LV) remodeling or dysfunction (n= 49) from hypertensive subjects with normal LV structure and function (n= 28). By further linking these three significant CV autoantibodies to the innate and growth factors, we revealed a positive but weak association between autoantibodies to troponin I and proinflammatory cytokine IL-18. Overall, we demonstrated that this platform can be used to evaluate autoantibody profiles in hypertensive subjects at risk for heart failure.

  View details for PubMedID 28630342

• Report from the Annual Conference of the British Society of Echocardiography, November 2016, Queen Elizabeth II Conference Centre, London. Echo research and practice Steeds, R. P., Cowie, M. R., Rana, B. S., Chambers, J. B., Ray, S., Srinivasan, J., Schwarz, K., Neil, C. J., Scally, C., Horowitz, J. D., Frenneaux, M. P., Pislaru, C., Dawson, D. K., Rothwell, O. J., George, K., Somauroo, J. D., Lord, R., Stembridge, M., Shave, R., Hoffman, M., Ashley, E. A., Haddad, F., Eijsvogels, T. M., Oxborough, D., Hampson, R., Kinsey, C. D., Gurunathan, S., Vamvakidou, A., Karogiannis, N., Senior, R., Ahmadvazir, S., Shah, B. N., Zacharias, K., Bowen, D., Robinson, S., Ihekwaba, U., Parker, K., Boyd, J., Densem, C. G., Atkinson, C., Hinton, J., Gaisie, E. B., Rakhit, D. J., Yue, A. M., Roberts, P. R., Thomas, D., Phen, P., Sibley, J., Fergey, S., Russhard, P. 2017; 4 (3): M1

  View details for PubMedID 30390608

• Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Amsallem, M. 2017; 10 (10 Pt B): 1278–80

  View details for PubMedID 29025578

• Load Adaptability in Patients With Pulmonary Arterial Hypertension. Am J Cardiol Amsallem, M., et al 2017: 874–82

  Abstract

  Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n = 85) and a validation cohort (n = 200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44 ± 11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24 ± 11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2 = 0.53, p < 0.001) and RV end-systolic area indexed to body surface area right ventricular end-systolic area index (RVESAI) (R2 = 0.29, p < 0.001), allowing the derivation of simple ratiometric load-specific indices of RV adaptation. In right heart parameters, RVESAI was the strongest predictor of outcomes (hazard ratio per SD = 1.93, 95% confidence interval 1.37 to 2.75, p < 0.001). Although RVESAI/PVRI0.35 provided small incremental discrimination on multivariate modeling, none of the load-adaptability indices provided stronger discrimination of outcome than simple RV adaptation metrics in either the derivation or the validation cohort. In conclusion, allometric modeling enables quantification of the proportionality of RV load adaptation but offers small incremental prognostic value to RV end-systolic dimension in PAH.

  View details for DOI 10.1016/j.amjcard.2017.05.053

• Myocardial bridging is associated with exercise-induced ventricular arrhythmia and increases in QT dispersion. Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc Nishikii-Tachibana, M., Pargaonkar, V. S., Schnittger, I., Haddad, F., Rogers, I. S., Tremmel, J. A., Wang, P. J. 2017

  Abstract

  A myocardial bridge (MB) has been associated with ventricular arrhythmia and sudden death during exercise. QT dispersion (QTd) is a measure of abnormal repolarization and may predict ventricular arrhythmia. We investigated the frequency of ventricular arrhythmias during exercise and the QTd at rest and after exercise, in patients with an MB compared to a normal cohort.We studied the rest and stress ECG tracings of patients with an MB suspected by focal septal buckling on exercise echocardiography (EE) (Echo-MB group, N = 510), those with an MB confirmed by another examination (MB group, N = 110), and healthy controls (Control group, N = 198).The frequency of exercise-induced premature ventricular contractions (PVCs) was significantly higher in the Echo-MB and MB groups compared with the Control group (both p < .001). In all, 25 patients (4.9%) in the Echo-MB group, seven patients (6.4%) in the MB group and no patients in the Control group had exercise-induced non-sustained ventricular tachycardia (NSVT). There was no difference in the baseline QTd between the groups. In the Echo-MB and MB groups, QTd postexercise increased significantly when compared with baseline (both p < .001). Patients with NSVT had a higher frequency of male gender and an even greater increase in QTd with exercise compared with the non-NSVT group.There is an increased frequency of exercise-induced PVCs and NSVT in patients with MBs. Exercise significantly increases QTd in MB patients, with an even greater increase in QTd in MB patients with NSVT. Exercise in MB patients results in ventricular arrhythmias and abnormalities in repolarization.

  View details for PubMedID 28921787

• GDF-15 (Growth Differentiation Factor 15) Is Associated With Lack of Ventricular Recovery and Mortality After Transcatheter Aortic Valve Replacement. Circulation. Cardiovascular interventions Kim, J. B., Kobayashi, Y., Moneghetti, K. J., Brenner, D. A., O'Malley, R., Schnittger, I., Wu, J. C., Murtagh, G., Beshiri, A., Fischbein, M., Miller, D. C., Liang, D., Yeung, A. C., Haddad, F., Fearon, W. F. 2017; 10 (12)

  Abstract

  Recent data suggest that circulating biomarkers may predict outcome in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the association between inflammatory, myocardial, and renal biomarkers and their role in ventricular recovery and outcome after TAVR.A total of 112 subjects undergoing TAVR were included in the prospective registry. Plasma levels of B-type natriuretic peptide, hs-TnI (high-sensitivity troponin I), CRP (C-reactive protein), GDF-15 (growth differentiation factor 15), GAL-3 (galectin-3), and Cys-C (cystatin-C) were assessed before TAVR and in 100 sex-matched healthy controls. Among echocardiographic parameters, we measured global longitudinal strain, indexed left ventricular mass, and indexed left atrial volume. The TAVR group included 59% male, with an average age of 84 years, and 1-year mortality of 18%. Among biomarkers, we found GDF-15 and CRP to be strongly associated with all-cause mortality (P<0.001). Inclusion of GDF-15 and CRP to the Society of Thoracic Surgeons score significantly improved C index (0.65-0.79; P<0.05) and provided a category-free net reclassification improvement of 106% at 2 years (P=0.01). Among survivors, functional recovery in global longitudinal strain (>15% improvement) and indexed left ventricular mass (>20% decrease) at 1 year occurred in 48% and 22%, respectively. On multivariate logistic regression, lower baseline GDF-15 was associated with improved global longitudinal strain at 1 year (hazard ratio=0.29; P<0.001). Furthermore, improvement in global longitudinal strain at 1 month correlated with lower overall mortality (hazard ratio=0.45; P=0.03).Elevated GDF-15 correlates with lack of reverse remodeling and increased mortality after TAVR and improves risk prediction of mortality when added to the Society of Thoracic Surgeons score.

  View details for PubMedID 29222133

• Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M., Kobayashi, Y., Wheeler, M., Barrett, C., Liedtke, M., Lafayette, R., Schrier, S., Haddad, F., Witteles, R. 2017; 120 (8): 1381–86

  Abstract

  Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

  View details for PubMedID 28844519

• Incremental Value of Deformation Imaging and Hemodynamics Following Heart Transplantation: Insights From Graft Function Profiling. JACC. Heart failure Kobayashi, Y., Sudini, N. L., Rhee, J. W., Aymami, M., Moneghetti, K. J., Bouajila, S., Kobayashi, Y., Kim, J. B., Schnittger, I., Teuteberg, J. J., Khush, K. K., Fearon, W. F., Haddad, F. 2017; 5 (12): 930–39

  Abstract

  This study investigated to define graft dysfunction and to determine its incremental association with long-term outcome after heart transplantation (HT).Although graft failure is an established cause of late mortality after HT, few studies have analyzed the prognostic value of graft dysfunction at 1- and 5-year follow-up of HT.Patients who underwent HT and completed their first annual evaluation with right heart catheterization and echocardiography at Stanford University between January 1999 and December 2011 were included in the study. Hierarchical clustering was used to identify modules to capture independent features of graft dysfunction at 1 year. The primary endpoint for analysis consisted of the composite of cardiovascular mortality, re-transplantation, or heart failure hospitalization within 5 years of HT. The study further explored whether changes in graft dysfunction between 1 and 5 years were associated with 10-year all-cause mortality.A total of 215 HT recipients were included in the study. Using hierarchical clustering, 3 functional modules were identified; among them, left ventricular global longitudinal strain (LVGLS), stroke volume index, and right atrial pressure (RAP) or pulmonary capillary wedge pressure (PCWP) captured key features of graft function. Graft dysfunction based on pre defined LVGLS in absolute value <14%, stroke volume index <35 ml/m2, RAP >10 mm Hg, or PCWP >15 mm Hg were present in 41%, 36%, and 27%, respectively. The primary endpoint at 5 years occurred in 52 patients (24%), whereas 10-year all-cause mortality occurred in 30 (27%) of 110 patients alive at 5 years. On multivariate analysis, RAP (standardized hazard ratio: 1.63), LVGLS (standardized hazard ratio: 1.39), and a history of hemodynamically compromising rejection within 1 year (hazard ratio: 2.18) were independent predictors of 5-year outcome. RAP at 5 years, as well as change in RAP from 1 to 5 years, was predictive of 10-year all-cause mortality.RAP and LVGLS at the first annual evaluation provide complementary prognostic information in predicting 5-year outcome after HT.

  View details for PubMedID 29191301

• Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension. Circulation Saito, T., Miyagawa, K., Chen, S. Y., Tamosiuniene, R., Wang, L., Sharp, O., Samayoa, E., Harada, D., Moonen, J. A., Cao, A., Chen, P. I., Hennigs, J. K., Gu, M., Li, C. G., Leib, R. D., Li, D., Adams, C. M., Del Rosario, P. A., Bill, M. A., Haddad, F., Montoya, J. G., Robinson, W., Fantl, W. J., Nolan, G. P., Zamanian, R. T., Nicolls, M. R., Chiu, C. Y., Ariza, M. E., Rabinovitch, M. 2017

  Abstract

  Background -Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. Methods -Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat. Results -SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6. Conclusions -Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

  View details for PubMedID 28935667

• Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy European Heart Journal - Cardiovascular Imaging Moneghetti , K. J., Giraldeau, G., Wheeler, M. T., Kobayashi , Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashely, E., Haddad , F. 2017

  View details for DOI 10.1093/ehjci/jex187

• Contractile reserve and cardiopulmonary exercise parameters in patients with dilated cardiomyopathy, the two dimensions of exercise testing. Echocardiography (Mount Kisco, N.Y.) Moneghetti, K. J., Kobayashi, Y., Christle, J. W., Ariyama, M., Vrtovec, B., Kouznetsova, T., Wilson, A., Ashley, E., Wheeler, M. T., Myers, J., Haddad, F. 2017

  Abstract

  Left ventricular (LV) contractile reserve assessed using imaging and cardiopulmonary exercise testing (CPX) has been shown to predict outcome in patients with dilated cardiomyopathy (DCM). Few clinical studies have, however, analyzed the relationship between them.A cohort of 75 ambulatory patients with DCM underwent stress treadmill echocardiography with CPX. LV contractile reserve was calculated as absolute change (ΔLVEF=LVEFpeak -LVEFrest ) and percent change (%LVEF=[(LVEFpeak -LVEFrest )/LVEFpeak) ]×100) in LVEF, circumferential and longitudinal strain (LS). Exercise capacity was measured as peak oxygen uptake (peak VO2 ) and ventilatory efficiency as the slope of minute ventilation to CO2 production (VE/VCO2 slope). Values of contractile reserve were compared to matched controls. We also explored which metric of ventricular response (absolute or percent change) was less dependent on baseline LV function.Patients with DCM had a mean age, rest and peak LVEF of 44±10 years, 42±10% and 50±12%, respectively. Among parameters of contractile reserve, peak cardiac output was the strongest parameter associated with peak VO2 (r=.63, P<.001). Along with age, sex, and BMI, it explained more than 70% of the variance in peak VO2 . In contrast, LVEF and LS were only weakly related to peak VO2 . With regard to ventilatory efficiency, the strongest parameter that emerged was right atrial volume index (r=.36, P<.001). Percent change in LVEF was more independent of baseline function than absolute change.Echocardiographic contractile reserve and CPX provide complementary information. Percent change in contractile reserve was most independent of baseline function, therefore may be preferred when analyzing the ventricular response to exercise.

  View details for PubMedID 28681553

• Exploratory insights from the right-sided electrocardiogram following prolonged endurance exercise. European journal of sport science Lord, R., George, K., Somauroo, J., Jain, N., Reese, K., Hoffman, M. D., Haddad, F., Ashley, E., Jones, H., Oxborough, D. 2016; 16 (8): 1014-1022

  Abstract

  Prolonged strenuous exercise has a profound effect on cardiac function. The right heart may be more susceptible to this imposition; yet, right-sided chest leads have not been utilised in this setting.Thirty highly trained athletes at the 2014 Western States 100-mile Endurance Run from Squaw Valley to Auburn, California (body mass 68 ± 12 kg, age 45 ± 10 years, 57 ± 15 miles per week) were recruited for the study. Pre- and post-race, a right-sided 12-lead ECG was obtained and data were extracted for P, R and S waves, J point, ST segment and T wave amplitude. Data were compared using Students T-test and statistical significance set as P < .05.There was a significant increase in P wave amplitude (29%) and QTc interval (4%) pre- to post-race from standard 12-lead ECG. From the right-sided12-lead ECG, a 23% (P = .01) and 38% (P = .03) increase in J point amplitude in V1R and V2R and a 22% (P = .05) increase in ST segment integral in V2R and V3R were evident. T wave inversion was evident in leads V2R-V6R in 50-90% of athletes, respectively. Close examination revealed marked heterogeneity in individual ECGs.Completion of a 100-mile ultra-marathon resulted in significant changes in the right-sided ECG alongside more marked responses in specific individuals. P wave, ST segment and T wave changes post-race are indicative of acute exercise-induced right heart electrical adaptation.

  View details for DOI 10.1080/17461391.2016.1165292

  View details for PubMedID 27027796

• A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE Denault, A. Y., Bussieres, J. S., Arellano, R., Finegan, B., Gavra, P., Haddad, F., Nguyen, A. Q., Varin, F., Fortier, A., Levesque, S., Shi, Y., Elmi-Sarabi, M., Tardif, J., Perrault, L. P., Lambert, J. 2016; 63 (10): 1140-1153

  Abstract

  Inhaled milrinone (iMil) has been used for the treatment of pulmonary hypertension (PH) but its efficacy, safety, and prophylactic effects in facilitating separation from cardiopulmonary bypass (CPB) and preventing right ventricular (RV) dysfunction have not yet been evaluated in a clinical trial. The purpose of this study was to investigate if iMil administered before CPB would be superior to placebo in facilitating separation from CPB.High-risk cardiac surgical patients with PH were randomized to receive iMil or placebo after the induction of anesthesia and before CPB. Hemodynamic parameters and RV function were evaluated by means of pulmonary artery catheterization and transesophageal echocardiography. The groups were compared for the primary outcome of the level of difficulty in weaning from CPB. Among the secondary outcomes examined were the reduction in the severity of PH, the incidence of RV failure, and mortality.Of the 124 patients randomized, the mean (standard deviation [SD]) EuroSCORE II was 8.0 (2.6), and the baseline mean (SD) systolic pulmonary artery pressure (SPAP) was 53 (9) mmHg. The use of iMil was associated with increases in cardiac output (P = 0.03) and a reduction in SPAP (P = 0.04) with no systemic hypotension. Nevertheless, there was no difference in the combined incidence of difficult or complex separation from CPB between the iMil and control groups (30% vs 28%, respectively; absolute difference, 2%; 95% confidence interval [CI], -14 to 18; P = 0.78). There was also no difference in RV failure between the iMil and control groups (15% vs 14%, respectively; difference, 1%; 95% CI, -13 to 12; P = 0.94). Mortality was increased in patients with RV failure vs those without (22% vs 2%, respectively; P < 0.001).In high-risk cardiac surgery patients with PH, the prophylactic use of iMil was associated with favourable hemodynamic effects that did not translate into improvement of clinically relevant endpoints. This trial was registered at ClinicalTrials.gov; identifier: NCT00819377.

  View details for DOI 10.1007/s12630-016-0709-8

  View details for Web of Science ID 000383592000004

  View details for PubMedID 27470232

• Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Boralkar, K., Amsallem, M., Tuzovic, M., Liang, D., Yang, P. C., Narayan, S., Kuznetsova, T., Wu, J. C., Schnittger, I., Haddad, F. 2016

  Abstract

  Left ventricular (LV) strain provides incremental values to LV ejection fraction (LVEF) in predicting outcome. We sought to investigate if similar relationship is observed between left atrial (LA) emptying fraction and LA strain.In this study, we selected 50 healthy subjects, 50 patients with dilated, 50 hypertrophic, and 50 infiltrative (light-chain (AL) amyloidosis) cardiomyopathy (CMP). Echocardiographic measures included LVEF and LA emptying fraction as well as LV and LA longitudinal strain (LVLS and LALS). After regression analysis, comparison of least square means of LA strain among aetiologies was performed. Intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used in the assessment of variability and reproducibility of LV and LA metrics. The mean LVLS and all LA metrics were impaired in patients with all CMP compared with healthy subjects. In contrast to the moderate relationship between LVEF and LVLS (r = -0.51, P < 0.001), there was a strong linear relationship between LA emptying fraction and LA strain (r = 0.87, P < 0.001). In multiple regression analysis, total LA strain was associated with LVLS (β = -0.48, P < 0.001), lateral E/e' (β = -0.24, P < 0.001), age (β = -0.21, P < 0.001), and heart rate (β = -0.14, P = 0.02). The least square mean of LA strain adjusted for the parameters was not different among aetiologies (ANOVA P = 0.82). The ICC (>0.77) and COV (<13) were acceptable.In contrast to LV measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium irrespective of CMP aetiology. Either LA emptying fraction or LA strain could be used as an important parameter in predictive models.

  View details for PubMedID 27638850

• [OP.4B.04] LONGITUDINAL CHANGES IN LEFT VENTRICULAR STRUCTURE AND DIASTOLIC FUNCTION IN RELATION TO ARTERIAL PROPERTIES IN A GENERAL POPULATION. Journal of hypertension Cauwenberghs, N., Knez, J., D'hooge, J., Thijs, L., Yang, W. Y., Haddad, F., Staessen, J. A., Kuznetsova, T. 2016; 34: e44-5

  Abstract

  Serial imaging studies are needed to clarify the relation of change in left ventricular (LV) structure and function with arterial stiffness. In this longitudinal population study, we assessed in continuous and categorical analyses to what extent arterial properties predict alterations in echocardiographic indexes reflecting LV structure and function.In 607 participants (50.7% women; mean age, 50.7 years), using conventional echocardiography and tissue Doppler imaging, we measured LV dimensions, transmitral blood flow and mitral annular tissue Doppler velocities at baseline and after 4.7 years. Using applanation tonometry, we assessed augmentation pressure (AP), central pulse pressure (cPP) and carotid-femoral pulse wave velocity (PWV) at baseline. Standardized effect size was expressed as percent of changes in standard deviation (SD) of δ echocardiographic indexes associated with 1-SD increase in baseline arterial indexes.The clinical correlates of δLV indexes included baseline LV index, age, sex, body mass index, mean blood pressure, pulse rate and changes over time in these co-variables. After full adjustment, longitudinal increase in LV septal (standardized effect size: +14.6%; P = 0.0017) and posterior wall (+13.3%; P = 0.0015) thickness was significantly associated with higher PWV at baseline, whereas LV internal diameter (-12.2%; P = 0.014) decreased with PWV. Consequently, a greater increase in relative wall thickness was associated with baseline PWV (+17.2%; P < 0.0001). We observed similar longitudinal increase in LV wall thickness in relation to higher baseline PWV in men and women. In adjusted logistic analysis, higher baseline PWV was associated with a 156% increase in the odds of developing LV concentric remodeling during follow-up as compared to participants who improved LV geometry (P = 0.0088). Furthermore, in women, a higher baseline cPP predicted a greater increase in LV mass (+18.1%, P = 0.018) and E/e' ratio (+25.8%, P = 0.0064).The key finding of this study is that longitudinal increase in LV relative wall thickness was associated with higher baseline PWV, measure of arterial stiffness. Moreover, in women, a higher cPP predicted worsening of LV diastolic function. Our study demonstrated the importance of arterial properties as a mediator of LV concentric remodeling in men and women, and diastolic dysfunction in women.

  View details for DOI 10.1097/01.hjh.0000491450.97368.ae

  View details for PubMedID 27508699

• Alterations in Cardiac Mechanics Following Ultra-Endurance Exercise: Insights from Left and Right Ventricular Area-Deformation Loops. Journal of the American Society of Echocardiography Lord, R., George, K., Somauroo, J., Stembridge, M., Jain, N., Hoffman, M. D., Shave, R., Haddad, F., Ashley, E., Jones, H., Oxborough, D. 2016; 29 (9): 879-887 e1

  Abstract

  The aim of this study was to use novel area-deformation (ε) loops to interrogate the interaction between the right ventricular (RV) and left ventricular (LV) mechanics following a 100-mile endurance run.Fifteen participants (mean body mass, 70.1 ± 8.8 kg; mean age, 40 ± 8 years) were recruited for the study. Echocardiography was performed before the race, after the race, and 6 hours into recovery. RV and LV area and longitudinal ε were assessed using standard and speckle-tracking echocardiography. Following cubic spline interpolation, these variables were obtained across the same cardiac cycle and used to derive area-ε loops.The RV area-ε loop demonstrated a rightward shift after the race, with increased RV area (from 26.0 to 27.1 cm(2)) and reduced peak RV ε (from -28.6% to -25.8%). The recovery RV area-ε loop was similar to the postrace loop. A leftward shift was observed in the LV area-ε loop after the race, secondary to reduced LV area (from 35.8 to 32.5 cm(2)) and reduced peak ε (from -18.3% to -16.6%). In recovery, LV ε values returned toward baseline.A 100-mile ultramarathon resulted in a rightward shift in the RV area-ε loop as a result of RV dilatation. There was a concomitant leftward shift in the LV area-ε loop as a result of underfilling of the left ventricle. At 6 hours after exercise, there was a partial recovery of the left ventricle, while RV function remained depressed. It appears that changes in RV function do not have a serial impact on the left ventricle during recovery from ultra-endurance activity.

  View details for DOI 10.1016/j.echo.2016.05.004

  View details for PubMedID 27373587

• Right heart imaging in patients with heart failure: a tale of two ventricles. Current opinion in cardiology Amsallem, M., Kuznetsova, T., Hanneman, K., Denault, A., Haddad, F. 2016; 31 (5): 469-482

  Abstract

  The purpose is to describe the recent advances made in imaging of the right heart, including deformation imaging, tissue, and flow characterization by MRI, and molecular imaging.Recent developments have been made in the field of deformation imaging of the right heart, which may improve risk stratification of patients with heart failure and pulmonary hypertension. In addition, more attention has been given to load adaptability metrics of the right heart; these simplified indices, however, still face challenges from a conceptual point of view. The emergence of novel MRI sequences, such as native T1 mapping, allows better detection and quantification of myocardial fibrosis and could allow better prediction of postsurgical recovery of the right heart. Other advances in MRI include four-dimensional flow imaging, which may be particularly useful in congenital heart disease or for the detection of early stages of pulmonary vascular disease.The review will place the recent developments in right heart imaging in the context of clinical care and research.

  View details for DOI 10.1097/HCO.0000000000000315

  View details for PubMedID 27467173

• Extracorporeal Life Support After Pulmonary Endarterectomy as a Bridge to Recovery or Transplantation: Lessons From 31 Consecutive Patients ANNALS OF THORACIC SURGERY Boulate, D., Mercier, O., Mussot, S., Fabre, D., Stephan, F., Haddad, F., Jais, X., Dartevelle, P., Fadel, E. 2016; 102 (1): 260-268

  Abstract

  Extracorporeal life support (ECLS) can be used to sustain patients having cardiorespiratory failure after pulmonary endarterectomy (PEA). We aimed to assess outcomes and to identify factors associated with short-term survival among patients who required ECLS after PEA.We reviewed the charts of consecutive patients who required ECLS after PEA between 2005 and 2013 at our institution. Patients with failed PEA were scheduled for heart-lung transplantation, and patients with potentially reversible hemodynamic or respiratory failure were given appropriate supportive care until recovery.Of the 829 patients who underwent PEA, 31 (3.7%) required postoperative ECLS. Of these, 23 continued to receive support, and 8 were listed for heart-lung transplantation during ECLS. Overall inhospital survival was 48.4% (15 of 31). Of patients listed for transplantation, 2 died while on support; 4 of the 6 patients undergoing transplantation lived to hospital discharge. Of the 23 supportive care patients, 11 (47.8%) were alive at hospital discharge. The factors associated with survival were younger age (p = 0.02), larger post-PEA decrease in mean pulmonary artery pressure (p = 0.020), lower post-PEA total pulmonary resistance (p = 0.008), and pure respiratory failure related to reperfusion edema or airway bleeding (p = 0.003).Extracorporeal life support may be useful to support patients with complications after PEA either to recovery or to salvage transplantation.

  View details for DOI 10.1016/j.athoracsur.2016.01.103

  View details for Web of Science ID 000378634400063

  View details for PubMedID 27112656

• Additive Prognostic Value of Left Ventricular Systolic Dysfunction in a Population-Based Cohort CIRCULATION-CARDIOVASCULAR IMAGING Kuznetsova, T., Cauwenberghs, N., Knez, J., Yang, W., Herbots, L., D'hooge, J., Haddad, F., Thijs, L., Voigt, J., Staessen, J. A. 2016; 9 (7)

  Abstract

  Techniques of 2-dimensional speckle tracking enable the measurement of myocardial deformation (strain) during systole. Recent clinical studies explored the prognostic role of left ventricular global longitudinal strain (GLS). However, there are few data on the association between cardiovascular outcome and GLS in the community. Therefore, we hypothesized that GLS contains additive prognostic information over and beyond traditional cardiovascular risk factors in a large, population-based cohort.We measured GLS by 2-dimensional speckle tracking in the apical 4-chamber view in 791 participants (mean age 50.9 years). We calculated multivariable adjusted hazard ratios for midwall, endocardial, and epicardial GLS, while accounting for family cluster and cardiovascular risk factors. Median follow-up was 7.9 years (5th to 95th percentile, 3.7-9.6). In continuous analysis, with adjustments applied for covariables, midwall, endocardial, and epicardial GLS were significant predictors of fatal and nonfatal cardiovascular (n=96; P<0.0001) and cardiac events (n=68; P≤0.001). In the sex-specific low quartile of midwall GLS (<18.8% in women and <17.4% in men), the risk was significantly higher than the average population risk for cardiovascular (128%, P<0.0001) and cardiac (94%, P=0.0007) events. We also noticed that the risk for cardiovascular events increased with increasing number of left ventricular abnormalities, such as low GLS, diastolic dysfunction, and hypertrophy (log-rank P<0.0001).Low GLS measured by 2-dimensional speckle tracking predicts future cardiovascular events independent of conventional risk factors. Left ventricular midwall strain represents a simple echocardiographic measure, which might be used for assessing cardiovascular risk in a population-based cohort.

  View details for DOI 10.1161/CIRCIMAGING.116.004661

  View details for Web of Science ID 000380608900007

  View details for PubMedID 27329778

• Heart rate-guided, but not dose-guided titration of beta blockers stabilizes ventricular repolarization in patients with chronic heart failure JOURNAL OF ELECTROCARDIOLOGY Fister, M., Mikuz, U., Starc, V., Vrtovec, B., Haddad, F. 2016; 49 (4): 579-586

  Abstract

  We compared the effects of heart rate-guided and dose-guided beta-blocker titration strategies on QT variability in patients with chronic heart failure (CHF).In a prospective study we recorded 5-minute resting high-resolution ECGs (HRECG) in 100 patients with CHF and measured heart rate (HR) and ventricular repolarization by QT variability index (QTVI). In a subgroup of patients not reaching target HR (<70bpm) we uptitrated beta blockers and repeated HRECG measurements 3months thereafter.Target HR was present in 46 patients (group A), and in 54 patients HR was above target (group B). The groups did not differ in age, gender, NYHA class, NT pro-BNP, creatinine, or beta blocker dose. Patients in group A displayed significantly lower QTVI than patients in group B (-1.25±0.55 vs. -1.52±0.42, P=0.013). When uptitrating beta-blockers we found a decrease in HR (from 91±15bpm to 71±15bpm, P<0.001), NTpro BNP levels (from 4474±3878pg/ml to 3042±2566pg/ml, P=0.024), and NYHA class (from 3.0±0.8 to 2.5±0.7, P=0.006). With beta-blocker uptitration QTVI decreased in 10 of 24 patients (42%). In these patients HR decreased more than in the remaining cohort (-25±20bpm vs. -15±17bpm, P=0.017). On multivariate analysis, the presence of target HR was a predictor of QTVI decrease (P=0.017), but beta-blocker dose was not.In patients with CHF treated by beta-blockers, changes in QT variability appear to occur in parallel with changes of heart rate. This suggests that heart rate-guided titration of beta-blockers may be associated with decreased risk of sudden cardiac death.

  View details for DOI 10.1016/j.jelectrocard.2016.01.002

  View details for Web of Science ID 000378981900018

  View details for PubMedID 26875428

• Impact and pitfalls of scaling of left ventricular and atrial structure in population-based studies JOURNAL OF HYPERTENSION Kuznetsova, T., Haddad, F., Tikhonoff, V., Kloch-Badelek, M., Ryabikov, A., Knez, J., Malyutina, S., Stolarz-Skrzypek, K., Thijs, L., Schnittger, I., Wu, J. C., Casiglia, E., Narkiewicz, K., Kawecka-Jaszcz, K., Staessen, J. A. 2016; 34 (6): 1186-1194

  Abstract

  Several allometric methods for indexing cardiac structures to body size have been proposed but the optimal way for normalization of cardiac structures is still controversial. We aimed to estimate the allometric exponents that best describe the relationships between cardiac dimensions and body size, propose normative values, and analyze how the different scaling metrics influence the prevalence of left ventricular hypertrophy (LVH) and chambers enlargement as well as predictive models for cardiovascular outcome in the community.We measured left ventricular end-diastolic dimension, end-diastolic volume, left ventricular mass, and left atrial volume in randomly recruited population cohorts (n = 1509; 52.8% women; mean age, 47.8 years).In a healthy subgroup (n = 656), the allometric exponents that described the relationships between left ventricular end-diastolic dimension and body size were 1, 0.5, and 0.33 for body height, body surface area (BSA), and estimated lean body mass, respectively. With regard to left ventricular end-diastolic volume, left ventricular mass, and left atrial volume the allometric exponents for body height were 2.9, 2.7, and 2.0, respectively; for BSA, they ranged from 1.7 to 1.8; for estimated lean body mass all exponents were around 1. These exponents were used to appropriately scale the cardiac dimensions to body size and derived sex-specific cut-off limits for different indexed cardiac dimensions. The hazard ratios of cardiovascular outcome were highest for LVH defined by left ventricular mass/height.Our study resulted in a proposal for thresholds for various indexed cardiac dimensions. Left ventricular mass indexed to height was sensitive in detection of LVH associated with obesity and slightly better predicted outcome.

  View details for DOI 10.1097/HJH.0000000000000922

  View details for Web of Science ID 000375146000024

  View details for PubMedID 27035735

• Efficacy of CD34(+) Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Is Absent in Patients With Diabetes but Preserved in Patients With Insulin Resistance STEM CELLS TRANSLATIONAL MEDICINE Vrtovec, B., Sever, M., Jensterle, M., Poglajen, G., Janez, A., Kravos, N., Zemljic, G., Cukjati, M., Cernelc, P., Haddad, F., Wu, J. C., Jorde, U. P. 2016; 5 (5): 632-638

  Abstract

  : We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). A total of 45 outpatients with DCM received granulocyte colony-stimulating factor for 5 days. CD34(+) cells were then collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no-IR group). After stimulation, we found higher numbers of CD34(+) cells in the IR group (94 ± 73 × 10(6) cells per liter) than in the no-IR group (54 ± 35 × 10(6) cells per liter) or DM group (31 ± 20 × 10(6) cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34(+) cells in the IR group (IR group, 216 ± 110 × 10(6) cells; no-IR group, 127 ± 82 × 10(6) cells; DM group, 77 ± 83 × 10(6) cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6% ± 6.9%) and the no-IR group (+4.4% ± 7.2%) but not in the DM group (-0.9% ± 5.4%; p = .035). The N-terminal pro-brain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DM group (-606 ± 850 pg/ml; -698 ± 1,105 pg/ml; and +238 ± 963 pg/ml, respectively; p = .034). Transendocardial CD34(+) cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34(+) stem cell mobilization and a preserved clinical response to cell therapy.The present study is the first clinical study directly evaluating the effects of altered glucose metabolism on the efficacy of CD34(+) stem cell therapy in patients with nonischemic dilated cardiomyopathy. The results offer critical insights into the physiology of stem cell mobilization in heart failure and possibly an explanation for the often conflicting results obtained with stem cell therapy for heart failure. These results demonstrate that patients with dilated cardiomyopathy and diabetes do not benefit from autologous CD34(+) cell therapy. This finding could serve as a useful tool when selecting heart failure patients for future clinical studies in the field of stem cell therapy.

  View details for DOI 10.5966/sctm.2015-0172

  View details for Web of Science ID 000375176200013

  View details for PubMedID 27025690

  View details for PubMedCentralID PMC4835245

• Impact of Septal Reduction on Left Atrial Size and Diastole in Hypertrophic Cardiomyopathy ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Finocchiaro, G., Haddad, F., Kobayashi, Y., Lee, D., Pavlovic, A., Schnittger, I., Sinagra, G., Magavern, E., Myers, J., Froelicher, V., Knowles, J. W., Ashley, E. 2016; 33 (5): 686-694

  Abstract

  Both myectomy and alcohol septal ablation (ASA) can substantially reduce left ventricular (LV) outflow obstruction, relieve symptoms, and improve outcomes in hypertrophic cardiomyopathy (HCM). It is unclear whether septal reduction decreases left atrial (LA) size and improves diastolic function. The aim of this study was to analyze the consequences of septal reduction on LA size and diastolic function in a cohort of patients with HCM.Forty patients (mean age: 50 ± 14, male sex 64%) with HCM who underwent septal reduction (myectomy or alcohol septal ablation) were studied. Retrospective analyses of echocardiograms preprocedure, postprocedure, and at 1 year of follow-up were performed.Thirty-one patients had septal myectomy and 9 ASA. The degree of reduction in rest peak LV outflow tract gradient was significant (57 ± 32 vs. 23 ± 20 mmHg at 1 year, P < 0.001). Maximal interventricular septal thickness decreased from 22 ± 6 mm preprocedure to 19 ± 4 mm postprocedure (P < 0.001); moderate-to-severe mitral regurgitation (MR) was initially present in 34% of the sample and only 2% after the procedure. Average LA volume index (LAVI) decreased from 63 ± 20 to 55 ± 20 mL/m(2) at the 1-year follow-up (P < 0.001). We did not observe a significant improvement in diastolic function at Doppler (E/A 1.2 ± 0.4 vs. 1.1 ± 0.5, P = 0.07; E' 7.6 ± 3.6 vs. 6.9 ± 3.0, P = 0.4) pre- and postprocedure, respectively). At 1 year, only 5% of the patients were severely symptomatic (NYHA III). On multivariate analysis, a significant change in the LVOT gradient during stress (Δ gradient ≥30 mmHg) was the only variable independently associated with LAVI reverse remodeling >10 mL/m(2) [OR = 6.4 (CI 95% 1.12-36.44), P = 0.04].Septal reduction is effective in the relief of LV obstruction and symptoms in patients with HCM. The hemodynamic changes result in a significant LA reverse remodeling, but not in an improvement of diastolic function in these patients.

  View details for DOI 10.1111/echo.13158

  View details for PubMedID 26926154

• Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population JOURNAL OF HYPERTENSION Cauwenberghs, N., Knez, J., Tikhonoff, V., D'hooge, J., Kloch-Badelek, M., Thijs, L., Stolarz-Skrzypek, K., Haddad, F., Wojciechowska, W., Swierblewska, E., Casiglia, E., Kawecka-Jaszcz, K., Narkiewicz, K., Staessen, J. A., Kuznetsova, T. 2016; 34 (4): 762-771

  Abstract

  Late-systolic loading of the left ventricular (LV) is determined by arterial wave reflections and central vascular stiffening. We, therefore, investigated the relationship between various Doppler indexes reflecting LV systolic and diastolic function and arterial stiffness in the framework of a large population study of randomly recruited study participants.In 1233 study participants (51.7% women; mean age, 48 years; 41.5% hypertensive), using conventional and tissue Doppler imaging, we measured: the transmitral early (E) and late (A) diastolic velocities; tissue Doppler imaging systolic and early (e') and late diastolic mitral annular velocities; and end-systolic longitudinal and radial strain. Using applanation tonometry, we assessed central pulse pressure (cPP), augmentation pressure and carotid-femoral pulse wave velocity.After full adjustment, transmitral E and A peaks increased with augmentation pressure and cPP (P less than 0.0001) and e' was positively associated with cPP (P = 0.013). The E/e' ratio increased significantly with augmentation pressure (P less than 0.0001), cPP (P less than 0.0001) and pulse wave velocity (P = 0.048). Although accounting for covariables, all arterial indexes were on average significantly higher in the diastolic dysfunction group with elevated filling pressure (n = 171) when compared to participants with normal diastolic function (n = 961; P ≤ 0.0004) or with impaired relaxation (n = 101; P ≤ 0.008). Longitudinal strain decreased independently with mean arterial pressure (P = 0.03). The correlation between radial strain and the arterial indexes shifted from positive at middle age (50-60 years) to negative at older (P less than 0.0001 for interaction).Our study underscored the importance of arterial characteristics as a mediator of LV systolic and diastolic dysfunction. We demonstrated an age-dependent relationship between radial strain and indexes of arterial stiffness.

  View details for DOI 10.1097/HJH.0000000000000854

  View details for Web of Science ID 000371856900024

  View details for PubMedID 26828786

• De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS genetics Priest, J. R., Osoegawa, K., Mohammed, N., Nanda, V., Kundu, R., Schultz, K., Lammer, E. J., Girirajan, S., Scheetz, T., Waggott, D., Haddad, F., Reddy, S., Bernstein, D., Burns, T., Steimle, J. D., Yang, X. H., Moskowitz, I. P., Hurles, M., Lifton, R. P., Nickerson, D., Bamshad, M., Eichler, E. E., Mital, S., Sheffield, V., Quertermous, T., Gelb, B. D., Portman, M., Ashley, E. A. 2016; 12 (4)

  Abstract

  Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

  View details for DOI 10.1371/journal.pgen.1005963

  View details for PubMedID 27058611

• Regional right ventricular dysfunction in acute pulmonary embolism: relationship with clot burden and biomarker profile INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Tuzovic, M., Adigopula, S., Amsallem, M., Kobayashi, Y., Kadoch, M., Boulate, D., Krishnan, G., Liang, D., Schnittger, I., Fleischmann, D., McConnell, M. V., Haddad, F. 2016; 32 (3): 389-398

  Abstract

  Regional right ventricular (RV) dysfunction (RRVD) is an echocardiographic feature in acute pulmonary embolism (PE), primarily reported in patients with moderate-to-severe RV dysfunction. This study investigated the clinical importance of RRVD by assessing its relationship with clot burden and biomarkers. We identified consecutive patients admitted to the emergency department between 1999 and 2014 who underwent computed tomographic angiography, echocardiography, and biomarker testing (troponin and NT-proBNP) for suspected acute PE. RRVD was defined as normal excursion of the apex contrasting with hypokinesis of the mid-free wall segment. RV assessment included measurements of ventricular dimensions, fractional area change, free-wall longitudinal strain and tricuspid annular plane systolic excursion. Clot burden was assessed using the modified Miller score. Of 82 patients identified, 51 had acute PE (mean age 66 ± 17 years, 43 % male). No patient had RV myocardial infarction. RRVD was present in 41 % of PEs and absent in all patients without PE. Among patients with PE, 86 % of patients with RRVD had central or multi-lobar PE. Patients with RRVD had higher prevalence of moderate-to-severe RV dilation (81 vs. 30 %, p < 0.01) and dysfunction (86 vs. 23 %, p < 0.01). There was a strong trend for higher troponin level in PE patients with RRVD (38 vs. 13 % in PE patients without RRVD, p = 0.08), while there was no significant difference for NT-proBNP (67 vs. 73 %, p = 0.88). RRVD showed good concordance between readers (87 %). RRVD is associated with an increased clot burden in acute PE and is more prevalent among patients with moderate-to-severe RV enlargement and dysfunction.

  View details for DOI 10.1007/s10554-015-0780-1

  View details for PubMedID 26428674

• Comparison of left ventricular manual versus automated derived longitudinal strain: implications for clinical practice and research INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Kobayashi, Y., Ariyama, M., Kobayashi, Y., Giraldeau, G., Fleischman, D., Kozelj, M., Vrtovec, B., Ashley, E., Kuznetsova, T., Schnittger, I., Liang, D., Haddad, F. 2016; 32 (3): 429-437

  Abstract

  Systolic global longitudinal strain (GLS) is emerging as a useful metric of ventricular function in heart failure and usually assessed using post-processing software. The purpose of this study was to investigate whether longitudinal strain (LS) derived using manual-tracings of ventricular lengths (manual-LS) can be reliable and time efficient when compared to LS obtained by post-processing software (software-LS). Apical 4-chamber view images were retrospectively examined in 50 healthy controls, 100 patients with dilated cardiomyopathy (DCM), and 100 with hypertrophic cardiomyopathy (HCM). We measured endocardial and mid-wall manual-LS and software-LS, using peak of average regional curve [software-LS(a)] and global ventricular lengths [software-LS(l)] according to definition of Lagragian strain. We compared manual-LS and software-LS by using Bland-Altman plot and coefficient of variation (COV). In addition, test-retest was also performed for further assessment of variability in measurements. While manual-LS was obtained in all subjects, software-LS could be obtained in 238 subjects (95 %). The time spent for obtaining manual-LS was significantly shorter than for the software-LS (94 ± 39 s vs. 141 ± 79 s, P < 0.001). Overall, manual-LS had an excellent correlation with both software-LS (a) (R(2) = 0.93, P < 0.001) and software-LS(l) (R(2) = 0.84, P < 0.001). The bias (95 %CI) between endocardial manual-LS and software-LS(a) was 0.4 % [-2.8, 3.6 %] in absolute and 3.5 % [-17.0, 24.0 %] in relative difference while it was 0.4 % [-2.5, 3.3 %] and 3.4 % [-16.2, 23.1 %], respectively with software-LS(l). Mid-wall manual-LS and mid-wall software-LS(a) also had good agreement [a bias (95 % CI) for absolute value of 0.1 % [-2.1, 2.5 %] in HCM, and 0.2 % [-2.2, 2.6 %] in controls]. The COV for manual and software derived LS were below 6 %. Test-retest showed good variability for both methods (COVs were 5.8 and 4.7 for endocardial and mid-wall manual-LS, and 4.6 and 4.9 for endocardial and mid-wall software-LS(a), respectively. Manual-LS appears to be as reproducible as software-LS; this may be of value especially when global strain is the metric of interest.

  View details for DOI 10.1007/s10554-015-0804-x

  View details for Web of Science ID 000370166100008

  View details for PubMedID 26578468

• Pearls and pitfalls in managing right heart failure in cardiac surgery CURRENT OPINION IN ANESTHESIOLOGY Haddad, F., Elmi-Sarabi, M., Fadel, E., Mercier, O., Denault, A. Y. 2016; 29 (1): 68-79

  Abstract

  To review the recent insights in the evaluation and management of perioperative (RHF).Recent studies highlight the potential role of myocardial deformation imaging in the evaluation of patients at risk of postoperative RHF. There is also a growing interest to study the value of load-adaptation indices of the right heart in the setting of pulmonary hypertension or left ventricular assist device implantation. Finally, the field of temporary extracorporeal life support devices for RHF is rapidly evolving and new strategies are emerging.An integrated approach for assessing the cardiopulmonary axis combining imaging, hemodynamic and tissue perfusion monitoring is emerging, as particularly helpful in the field. Several developments in the field of temporary right heart support including the pumpless interventional lung assist membrane ventilator are offering new opportunities to support the right-heart pulmonary circulation. Future multicenter studies are needed to develop more effective preventive and therapeutic strategies for RHF.

  View details for DOI 10.1097/ACO.0000000000000284

  View details for Web of Science ID 000369423600011

  View details for PubMedID 26658183

• Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2016; 29 (2): 93-102

  Abstract

  There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5 days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2) = 0.95, P < .001), with mean pulmonary artery pressure = 0.60 × systolic pulmonary artery pressure + 2.1 mm Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5 days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > .05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

  View details for DOI 10.1016/j.echo.2015.11.001

  View details for Web of Science ID 000369168700003

• Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction. Journal of the American Society of Hypertension Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984 e3

  Abstract

  There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

  View details for DOI 10.1016/j.jash.2015.10.003

  View details for PubMedID 26565110

• Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984

  Abstract

  There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

  View details for DOI 10.1016/j.jash.2015.10.003

  View details for Web of Science ID 000367214500014

  View details for PubMedID 26565110

• Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension CLINICAL TRANSPLANTATION Hill, C., Maxwell, B., Boulate, D., Haddad, F., Ha, R., Afshar, K., Weill, D., Dhillon, G. S. 2015; 29 (12): 1067-1075

  Abstract

  Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically-ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT versus DLT. All adult IPAH patients (>18 years) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the sub-groups as defined by the recipients' hospitalization status. 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall the adjusted survivals after HLT or DLT were similar. The recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically-ill IPAH patients admitted to the ICU at time of transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.12628

  View details for Web of Science ID 000367825400004

• Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension. Clinical transplantation Hill, C., Maxwell, B., Boulate, D., Haddad, F., Ha, R., Afshar, K., Weill, D., Dhillon, G. S. 2015; 29 (12): 1067-1075

  Abstract

  Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically-ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT versus DLT. All adult IPAH patients (>18 years) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the sub-groups as defined by the recipients' hospitalization status. 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall the adjusted survivals after HLT or DLT were similar. The recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically-ill IPAH patients admitted to the ICU at time of transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.12628

  View details for PubMedID 26358537

• Gender Differences in Ventricular Remodeling and Function in College Athletes, Insights from Lean Body Mass Scaling and Deformation Imaging AMERICAN JOURNAL OF CARDIOLOGY Giraldeau, G., Kobayashi, Y., Finocchiaro, G., Wheeler, M., Perez, M., Kuznetsova, T., Lord, R., George, K. P., Oxborough, D., Schnittger, T., Froelicher, V., Liang, D., Ashley, E., Haddad, F. 2015; 116 (10): 1610-1616

  Abstract

  Several studies suggest gender differences in ventricular dimensions in athletes. Few studies have, however, made comparisons of data indexed for lean body mass (LBM) using allometry. Ninety Caucasian college athletes (mixed sports) who were matched for age, ethnicity, and sport total cardiovascular demands underwent dual-energy x-ray absorptiometry scan for quantification of LBM. Athletes underwent comprehensive assessment of left and right ventricular and atrial structure and function using 2-dimensional echocardiography and deformation imaging using the TomTec analysis system. The mean age of the study population was 18.9 ± 1.9 years. Female athletes (n = 45) had a greater fat free percentage (19.4 ± 3.7%) compared to male athletes (11.5 ± 3.7%). When scaled to body surface area, male had on average 19 ± 3% (p <0.001) greater left ventricular (LV) mass; in contrast, when scaled to LBM, there was no significant difference in indexed LV mass -1.4 ± 3.0% (p = 0.63). Similarly, when allometrically scaled to LBM, there was no significant gender-based difference in LV or left atrial volumes. Although female athletes had mildly higher LV ejection fraction and LV global longitudinal strain in absolute value, systolic strain rate and allometrically indexed stroke volume were not different between genders (1.5 ± 3.6% [p = 0.63] and 0.0 ± 3.7% [p = 0.93], respectively). There were no differences in any of the functional atrial indexes including strain or strain rate parameters. In conclusion, gender-related differences in ventricular dimensions or function (stroke volume) appear less marked, if not absent, when indexing using LBM allometrically.

  View details for DOI 10.1016/j.amjcard.2015.08.026

  View details for PubMedID 26456207

• Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study. Journal of the American Heart Association Kobayashi, Y., Tremmel, J. A., Kobayashi, Y., Amsallem, M., Tanaka, S., Yamada, R., Rogers, I. S., Haddad, F., Schnittger, I. 2015; 4 (11)

  Abstract

  Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established.We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5±16.0 years. Fifty-five patients had a diastolic fractional flow reserve ≤0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0±1.8% for patients with MB versus 19.2±1.5% for control, P=0.53) and lateral LS (20.1±2.0% versus 20.0±1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9±2.6% versus 21.7±1.6%, P<0.001) and lower absolute (-0.1±2.1% versus 2.5±1.3%, P<0.001) and relative change (-0.6±11.2% versus 13.1±7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS.Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

  View details for DOI 10.1161/JAHA.115.002496

  View details for PubMedID 26581225

• Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study JOURNAL OF THE AMERICAN HEART ASSOCIATION Kobayashi, Y., Tremmel, J. A., Kobayashi, Y., Amsallem, M., Tanaka, S., Yamada, R., Rogers, I. S., Haddad, F., Schnittger, I. 2015; 4 (11)

  Abstract

  Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established.We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5±16.0 years. Fifty-five patients had a diastolic fractional flow reserve ≤0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0±1.8% for patients with MB versus 19.2±1.5% for control, P=0.53) and lateral LS (20.1±2.0% versus 20.0±1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9±2.6% versus 21.7±1.6%, P<0.001) and lower absolute (-0.1±2.1% versus 2.5±1.3%, P<0.001) and relative change (-0.6±11.2% versus 13.1±7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS.Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

  View details for DOI 10.1161/JAHA.115.002496

  View details for Web of Science ID 000366615600020

  View details for PubMedID 26581225

• Increased red cell distribution width is associated with poor stem cell mobilization in patients with advanced chronic heart failure BIOMARKERS Poglajen, G., Sever, M., Cernelc, P., Haddad, F., Vrtovec, B. 2015; 20 (6-7): 365-370

  View details for DOI 10.3109/1354750X.2015.1094137

  View details for PubMedID 26472500

• Prognostic utility of right atrial emptying fractions in pulmonary arterial hypertension. Pulmonary circulation Brunner, N. W., Haddad, F., Kobayashi, Y., Hsi, A., Swiston, J. R., Gin, K. G., Zamanian, R. T. 2015; 5 (3): 473-480

  Abstract

  Although left atrial function has been extensively studied in patients with heart failure, the determinants and clinical correlates of impaired right atrial (RA) function have been poorly studied. We investigated measures of RA function in pulmonary arterial hypertension (PAH). We identified all treatment-naive patients with World Health Organization category 1 PAH seen at our center during 2000-2011 who had right heart catheterization and 6-minute walk test (6MWT) within 1 month of initial echocardiographic examination. Atrial size was measured using the monoplane area-length method, and atrial function was quantified using total, passive, and active RA emptying fractions (RAEFs). We compared measures of RAEF with known prognostic clinical, echocardiographic, and hemodynamic parameters. For the subset of patients with follow-up echocardiographic examination/6MWT within 6-18 months, we investigated the change in RAEF. In an exploratory analysis, we investigated the association between RAEF and mortality. Our population consisted of 39 patients with treatment-naive (incident) PAH, 30 of whom had follow-up testing. The mean total, passive, and active RAEFs were 24.4% ± 15.1%, 8.5% ± 6.9%, and 17.6% ± 13.9%, respectively. Total and active RAEFs correlated with tricuspid annular plane systolic excursion (P = 0.004 and P = 0.005) and cardiac output (P = 0.02 and P = 0.01). The change in active RAEF correlated with change in 6-minute walk distance (P = 0.02). In our Cox regression analysis, low active and total RAEF were associated with mortality, with hazard ratios of 5.6 (95% confidence interval [CI], 1.2-26.2; P = 0.03) and 4.2 (95% CI, 1.1-15.5; P = 0.03), respectively. Passive RAEF was poorly reproducible and not associated with outcome. Measures of RAEF appear to have prognostic importance in PAH and warrant further study.

  View details for DOI 10.1086/682218

  View details for PubMedID 26401248

• Acute intraoperative effect of intravenous amiodarone on right ventricular function in patients undergoing valvular surgery. European heart journal. Acute cardiovascular care Denault, A. Y., Beaulieu, Y., Couture, P., Haddad, F., Shi, Y., Pagé, P., Levesque, S., Tardif, J., Lambert, J. 2015; 4 (4): 316-325

  Abstract

  Amiodarone is commonly used in the acute care setting. However the acute hemodynamic and echocardiographic effect of intravenous amiodarone administered intraoperatively on right ventricular (RV) systolic and diastolic function using transesophageal echocardiography (TEE) has not been described.The study design was a randomized controlled trial in elective cardiac surgical patients undergoing valvular surgery. Patients received an intravenous loading dose of 300 mg of either amiodarone or placebo in the operating room, followed by an infusion of 15 mg/kg for two days. Hemodynamic profiles, echocardiographic measurement of RV and left ventricular (LV) dimensions, Doppler interrogation of tricuspid and mitral valve, hepatic and pulmonary venous flow combined with tissue Doppler imaging of the tricuspid and mitral valve annulus were obtained before and after bolus.Although more patients in the placebo group had chronic obstructive lung disease (14 vs 6, p=0.05) and diabetes (14 vs 5; p=0.0244), there was no difference in terms of baseline hemodynamic, 2D and Doppler variables. After bolus, a significant increase in pulmonary artery pressure, central venous pressure and pulmonary vascular resistance index (p<0.05) was observed in the amiodarone group with reduction in systolic to diastolic (S/D) ratio of the hepatic (p=0.0247) and pulmonary venous (p=0.0052) velocity.Acute administration of amiodarone is associated with alteration in RV diastolic properties and has minimal negative inotropic effect on RV systolic function in cardiac surgical patients with valvular disease.

  View details for DOI 10.1177/2048872614549102

  View details for PubMedID 25178692

• Right Ventricular Depression After Cardiopulmonary Bypass for Valvular Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Denault, A. Y., Couture, P., Beaulieu, Y., Haddad, F., Deschamps, A., Nozza, A., Page, P., Tardif, J., Lambert, J. 2015; 29 (4): 836-844

  View details for DOI 10.1053/j.jvca.2015.01.011

  View details for Web of Science ID 000359825600003

• Immunologic Network and Response to Intramyocardial CD34(+) Stem Cell Therapy in Patients With Dilated Cardiomyopathy JOURNAL OF CARDIAC FAILURE Haddad, F., Sever, M., Poglajen, G., Lezaic, L., Yang, P., Maecker, H., Davis, M., Kuznetsova, T., Wu, J. C., Vrtovec, B. 2015; 21 (7): 572-582

  Abstract

  Although stem cell therapy (SCT) is emerging as a potential treatment for patients with dilated cardiomyopathy (DCM), clinical response remains variable. Our objective was to determine whether baseline differences in circulating immunologic and nonimmunologic biomarkers may help to identify patients more likely to respond to intramyocardial injection of CD34(+)-based SCT.We enrolled from January 3, 2011 to March 5, 2012 37 patients with longstanding DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral CD34(+) stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) and collection by means of apheresis. CD34(+) cells were labeled with (99m)Tc-hexamethylpropyleneamine oxime to allow assessment of stem cell retention at 18 hours. Response to SCT was predefined as an increase in LVEF of ≥5% at 3 months. The majority (84%) of patients were male with an overall mean LVEF of 27 ± 7% and a median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 2,774 pg/mL. Nineteen patients (51%) were responders to SCT. There was no significant difference between responders and nonresponders regarding to age, sex, baseline LVEF, NT-proBNP levels, or 6-minute walking distance. With the use of a partial least squares (PLS) predictive model, we identified 9 baseline factors that were associated with both stem cell response and stem cell retention (mechanistic validation). Among the baseline factors positively associated with both clinical response and stem cell retention were G-CSF, SDF-1, LIF, MCP-1, and MCP-3. Among baseline factors negatively associated with both clinical response and retention were IL-12p70, FASL, ICAM-1, and GGT. A decrease in G-CSF at 3-month follow-up was also observed in responders compared with nonresponders (P = .02).If further validated, baseline immunologic and nonimmunologic biomarkers may help to identify patients with DCM who are more likely to respond to CD34(+)-based SCT.

  View details for DOI 10.1016/j.cardfail.2015.03.011

  View details for Web of Science ID 000358105900007

  View details for PubMedID 25863169

• Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology Bent, R. E., Wheeler, M. T., Hadley, D., Knowles, J. W., Pavlovic, A., Finocchiaro, G., Haddad, F., Salisbury, H., Race, S., Shmargad, Y., Matheson, G. O., Kumar, N., Saini, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 65 (22): 2462-2463

  View details for DOI 10.1016/j.jacc.2015.03.559

  View details for PubMedID 26046742

• Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Spruijt, O. A., Denault, A. Y., Mercier, O., Brunner, N., Furman, D., Fadel, E., Bogaard, H. J., Schnittger, I., Vrtovec, B., Wu, J. C., de Jesus Perez, V., Vonk-Noordegraaf, A., Zamanian, R. T. 2015; 8 (6): 627-638

  Abstract

  This study sought to determine whether a simple score combining indexes of right ventricular (RV) function and right atrial (RA) size would offer good discrimination of outcome in patients with pulmonary arterial hypertension (PAH).Identifying a simple score of outcome could simplify risk stratification of patients with PAH and potentially lead to improved tailored monitoring or therapy.We recruited patients from both Stanford University (derivation cohort) and VU University Medical Center (validation cohort). The composite endpoint for the study was death or lung transplantation. A Cox proportional hazard with bootstrap CI adjustment model was used to determine independent correlates of death or transplantation. A predictive score was developed using the beta coefficients of the multivariable models.For the derivation cohort (n = 95), the majority of patients were female (79%), average age was 43 ± 11 years, mean pulmonary arterial pressure was 54 ± 14 mm Hg, and pulmonary vascular resistance index was 25 ± 12 Wood units m(2). Over an average follow-up of 5 years, the composite endpoint occurred in 34 patients, including 26 deaths and 8 patients requiring lung transplant. On multivariable analysis, RV systolic dysfunction grade (hazard ratio [HR]: 3.4 per grade; 95% confidence interval [CI]: 2.0 to 7.8; p < 0.001), severe RA enlargement (HR: 3.0; 95% CI: 1.3 to 8.1; p = 0.009), and systemic blood pressure <110 mm Hg (HR: 3.3; 95% CI: 1.5 to 9.4; p < 0.001) were independently associated with outcome. A right heart (RH) score constructed on the basis of these 3 parameters compared favorably with the National Institutes of Health survival equation (0.88; 95% CI: 0.79 to 0.94 vs. 0.60; 95% CI: 0.49 to 0.71; p < 0.001) but was not statistically different than the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) score c-statistic of 0.80 (95% CI: 0.69 to 0.88) with p = 0.097. In the validation cohort (n = 87), the RH score remained the strongest independent correlate of outcome.In patients with prevalent PAH, a simple RH score may offer good discrimination of long-term outcome.

  View details for DOI 10.1016/j.jcmg.2014.12.029

  View details for PubMedID 25981508

• 8A.02: THE ASSOCIATION OF LEFT VENTRICULAR AND ATRIAL STRUCTURE WITH BODY COMPOSITION: IMPACT AND PITFALLS OF SCALING IN POPULATION BASED STUDIES. Journal of hypertension Kuznetsova, T., Haddad, F., Thijs, L., Tikhonoff, V., Kloch-Badelek, M., Sakiewicz, W., Ryabikov, A., Knez, J., Malyutina, S., Stolarz-Skrzypek, K., Casiglia, E., Narkiewicz, K., Kawecka-Jaszcz, K., Staessen, J. A. 2015; 33

  Abstract

  Several allometric methods for indexing cardiac structures to body size have been proposed but the optimal way for normalization of cardiac structures is still controversial. We aimed to estimate the allometric exponents that best describe the relationships between cardiac dimensions and body size and propose normative values. We also explored how different scaling metrics influence the associations of left heart size with cardiovascular risk factors and outcome in the general population.We measured left ventricular end-diastolic dimension (LVEDD), end-diastolic volume (LVEDV), left ventricular mass (LVM) and left atrial volume (LAV) in randomly recruited population cohorts (n = 1509; 52.8% women; mean age, 47.8 years). After determining optimal scaling metrics in a healthy reference population (n = 656) and proposing normative values, we analyzed how the different scaling metrics influence predictive models for left ventricular hypertrophy (LVH) and left atrial enlargement (LAE) as well as cardiovascular outcome.The allometric exponents that described the relationships between LVEDD and body size were 1, 0.5 and 0.33 for body height (BH), body surface area (BSA) and estimated lean body mass (eLBM), respectively. With regards to LVEDV, LVM and LAV the allometric exponents for BH were 2.9, 2.7 and 2.0, respectively; for BSA they ranged from 1.7 to 1.8; for eLBM all exponents were around 1. These exponents were used to appropriately scale the cardiac dimensions to body size and derived sex-specific cut-off limits for different indexed cardiac dimensions. Indexation of LVM to height2.7 better detected LVH in overweight and obese subjects. The hazard ratios of cardiovascular outcome were highest for LVH defined by LVM/height2.7.Our current study resulted in a proposal for thresholds for various indexed cardiac dimensions. LVM indexed to height has the advantage of being more sensitive in detection of LVH associated with obesity and slightly better for prediction of outcome.

  View details for DOI 10.1097/01.hjh.0000467631.86257.8b

  View details for PubMedID 26102661

• Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension JACC-CARDIOVASCULAR IMAGING Haddad, F., Spruijt, O. A., Denault, A. Y., Mercier, O., Brunner, N., Furman, D., Fadel, E., Bogaard, H. J., Schnittger, I., Vrtovec, B., Wu, J. C., Perez, V. D., Vonk-Noordegraaf, A., Zamanian, R. T. 2015; 8 (6): 627-638

  View details for DOI 10.1016/j.jcmg.2014.12.029

  View details for Web of Science ID 000356560600001

  View details for PubMedID 25981508

• Prevalence and Prognostic Role of Right Ventricular Involvement in Stress-Induced Cardiomyopathy JOURNAL OF CARDIAC FAILURE Finocchiaro, G., Kobayashi, Y., Magavern, E., Zhou, J. Q., Ashley, E., Sinagra, G., Schnittger, I., Knowles, J. W., Fearon, W. F., Haddad, F., Tremmel, J. A. 2015; 21 (5): 419-425

  Abstract

  Stress-induced cardiomyopathy (SCM) is a reversible cardiomyopathy observed in patients without significant coronary disease. The aim of this study was to assess the incidence and clinical significance of right ventricular (RV) involvement in SCM.We retrospectively analyzed echocardiograms from 40 consecutive patients who presented with SCM at Stanford University Medical Center from September 2000 to November 2010. The primary end point was overall mortality. RV involvement was observed in 20 patients (50%; global RV hypokinesia in 15 patients and focal RV apical akinesia in 5 patients). The independent correlates of RV involvement were older age (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.7two, P = .01) and LVEF (per 10% decrease: OR 3.60, CI 1.77-7.32; P = .02). At a mean follow-up of 44 ± 32 months, 12 patients (30%) died (in-hospital death in 3 patients). At multivariate analysis, the presence of an RV fractional area change <35% emerged as an independent predictor of death (OR 3.6, CI 1.06-12.41; P = .04).RV involvement is a common finding in SCM, and may present as either global or focal RV apical involvement. Both older age and lower LVEF are associated with a higher risk of RV involvement, which appears to be a major predictor of death.

  View details for DOI 10.1016/j.cardfail.2015.02.001

  View details for PubMedID 25704104

• Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment. JACC. Heart failure Finocchiaro, G., Haddad, F., Knowles, J. W., Caleshu, C., Pavlovic, A., Homburger, J., Shmargad, Y., Sinagra, G., Magavern, E., Wong, M., Perez, M., Schnittger, I., Myers, J., Froelicher, V., Ashley, E. A. 2015; 3 (5): 408-418

  Abstract

  This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.

  View details for DOI 10.1016/j.jchf.2014.11.011

  View details for PubMedID 25863972

• 3A. Personal History: Have You Ever Had Excessive Shortness of Breath or Fatigue with Exercise beyond What Is Expected for Your Level of Fitness? CURRENT SPORTS MEDICINE REPORTS Haddad, F., Finocchiaro, G., Myers, J. 2015; 14 (3): 257-259

  View details for Web of Science ID 000354551400028

  View details for PubMedID 25968867

• Right ventricular reserve in a piglet model of chronic pulmonary hypertension EUROPEAN RESPIRATORY JOURNAL Guihaire, J., Haddad, F., Noly, P., Boulate, D., Decante, B., Dartevelle, P., Humbert, M., Verhoye, J., Mercier, O., Fadel, E. 2015; 45 (3): 709-717

  Abstract

  Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular-arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure-volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean ± sd pulmonary artery pressure (34 ± 9 versus 14 ± 2 mmHg; p<0.01) and in a lower ventricular-arterial coupling efficiency (0.66 ± 0.18 versus 1.24 ± 0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean ± SD 47 ± 5% versus 20 ± 5%, p<0.01, and 81 ± 37% versus 32 ± 14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular-arterial coupling (R(2)=0.74; p<0.01). RV reserve was associated with ventricular-arterial coupling in a porcine model of chronic pressure overload.

  View details for DOI 10.1183/09031936.00081314

  View details for Web of Science ID 000350701200020

  View details for PubMedID 25504996

• Intracoronary Transplantation of CD34(+) Cells Is Associated With Improved Myocardial Perfusion in Patients With Nonischemic Dilated Cardiomyopathy. Journal of cardiac failure Lezaic, L., Socan, A., Poglajen, G., Peitl, P. K., Sever, M., Cukjati, M., Cernelc, P., Wu, J. C., Haddad, F., Vrtovec, B. 2015; 21 (2): 145-152

  Abstract

  We investigated the effects of intracoronary transplantation of CD34(+) cells on myocardial perfusion in patients with nonischemic dilated cardiomyopathy (DCM).We enrolled 21 patients with DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral stem cell mobilization with granulocyte-colony stimulating factor (G-CSF). CD34(+) cells were collected by means of apheresis. Patients underwent myocardial perfusion imaging, and CD34(+) cells were injected in the coronary artery supplying viable segments with reduced myocardial perfusion and regional dysfunction. Myocardial perfusion imaging was repeated 6 months later. Clinical response to stem cell therapy was predefined as a change in LVEF >5%. The majority of patients were men (81%) with an overall mean age 53 ± 9 years, LVEF 25 ± 5%, and 6-minute walking distance 354 ± 71 m. Myocardial perfusion defects at rest were observed in 86% of patients and were more common in the left anterior descending territory (50%). At 6 months' follow-up, there was a significant improvement in rest myocardial perfusion scores (6.3 ± 5.8 vs 3.1 ± 4.3; P < .001), LVEF (25 ± 7% vs 29 ± 8%; P = .005), and 6-minute walking distance (354 ± 71 m vs 404 ± 91 m; P < .001). Responders to stem cell therapy had lower summed rest perfusion score at both baseline (3.2 ± 3.0 vs 9.1 ± 6.3; P = .015) and follow-up (1.0 ± 1.5 vs 5.0 ± 5.1; P = .028).CD34(+) cell transplantation may lead to improved myocardial perfusion in patients with nonischemic DCM. Patients with less severe myocardial perfusion defects at baseline may have an increased likelihood to respond to intracoronary CD34(+) cell transplantation.

  View details for DOI 10.1016/j.cardfail.2014.11.005

  View details for PubMedID 25459687

• Right Ventricular Depression After Cardiopulmonary Bypass for Valvular Surgery. Journal of cardiothoracic and vascular anesthesia Denault, A. Y., Couture, P., Beaulieu, Y., Haddad, F., Deschamps, A., Nozza, A., Pagé, P., Tardif, J. C., Lambert, J. 2015; 29 (4): 836–44

  Abstract

  To assess if right ventricular (RV) dysfunction is associated with increased mortality after cardiac surgery.Post-hoc analysis of a single-center double-blind randomized controlled trial.University hospital.A total of 120 patients undergoing simple or complex valvular surgery.Patients were randomized to receive intravenous amiodarone or placebo intraoperatively. As secondary analysis, patients were divided into those requiring or not requiring postoperative inotropic agents.After cardiopulmonary bypass (CPB), there were significant increases in heart rate, cardiac index, systolic and mean arterial pressures, central venous pressure and pulmonary capillary wedge pressure with reduction in systemic vascular resistance (p<0.05). Right ventricular end-systolic area became larger in those without inotropes and tricuspid annular plane systolic excursion was reduced in all patients; mitral annular systolic velocities were higher in patients receiving inotropes. Both right- and left-sided Doppler signals were altered significantly after CPB, which may be attributed to increased filling pressure. Inotropic agents were required in 56 patients after CPB (47%). The use of inotropic agents was associated with increased left and right atrial velocities (p<0.05). There were no differences in postoperative complications between groups; however, the number of deaths at 6 years was increased in patients who received inotropes after CPB (p = 0.0247).The increases in right-sided dimensions after CPB are associated with reduction in RV function and increased biventricular filling pressure, suggesting worsening biventricular function and interventricular dependence. Inotropic medications were associated with unaltered RV dimensions and increased biatrial activity.

  View details for PubMedID 25976606

• Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2015

  Abstract

  There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5 days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2) = 0.95, P < .001), with mean pulmonary artery pressure = 0.60 × systolic pulmonary artery pressure + 2.1 mm Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5 days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > .05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

  View details for PubMedID 26691401

• The right ventricle following ultra-endurance exercise: insights from novel echocardiography and 12-lead electrocardiography EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY Lord, R., Somauroo, J., Stembridge, M., Jain, N., Hoffman, M. D., George, K., Jones, H., Shave, R., Haddad, F., Ashley, E., Oxborough, D. 2015; 115 (1): 71-80

  Abstract

  There is contradictory evidence related to the impact of ultra-marathon running on right ventricular (RV) structure and function. Consequently, the aims of this study were to: (1) comprehensively assess RV structure and function before and immediately following a 100-mile ultra-marathon in highly trained runners, (2) determine the nature of RV recovery 6 h post-race, and (3) document 12-lead electrocardiogram (ECG) changes post-exercise.Echocardiography and 12-lead ECG were assessed in 15 competitors in a repeated measures design before and immediately after completion of the 2013 Western States Endurance Race. A subset of nine was reassessed 6 h into recovery. Standard echocardiography was used to determine RV size, function and wall stress. Myocardial speckle tracking (MST) provided peak, time to peak and temporal indices for RV longitudinal strain and strain rates (ε and SR).RV size was increased post-race (inflow tract 14 %, outflow tract 11 %, P = 0.004 and 0.002). RV wall stress was elevated by 11 % post-race. Peak RV ε was reduced by 10 % (P = 0.007) and significantly delayed post-race (P = 0.008). Most changes in RV function persisted at the 6-h assessment. Post-race there was an increase in the prevalence of right-sided ECG changes.Completion of a 100-mile ultra-marathon resulted in acute changes in RV structure and function that persisted 6 h into recovery and are consistent with sustained exposure to an elevated RV wall stress. These findings were supported by right-sided changes to the 12-lead ECG.

  View details for DOI 10.1007/s00421-014-2995-6

  View details for Web of Science ID 000347293500004

  View details for PubMedID 25204280

• Noninvasive imaging in the assessment of the cardiopulmonary vascular unit. Circulation Vonk Noordegraaf, A., Haddad, F., Bogaard, H. J., Hassoun, P. M. 2015; 131 (10): 899–913

  View details for PubMedID 25753343

• The Presence of Electromechanical Mismatch In Nonischemic Dilated Cardiomyopathy Is Associated With Ventricular Repolarization Instability JOURNAL OF CARDIAC FAILURE Mikuz, U., Poglajen, G., Fister, M., Starc, V., Wu, J. C., Hsia, H., Haddad, F., Vrtovec, B. 2014; 20 (12): 891-898

  Abstract

  We analyzed electromechanical mismatch (EMM) and its relationship to ventricular repolarization in patients with non-ischemic dilated cardiomyopathy (DCM).In 39 DCM patients with LVEF<40% and NHYA class ≥III, electroanatomical mapping was used to quantify areas of EMM. High resolution ECG was used to measure heart rate variability (HRV) and QT variability (QTVI). EMM was present in 22 patients (56%, Group 1), whereas 17 patients presented no mismatched segments (44%, Group 2). The groups did not differ in age (56±10 years in Group 1 vs. 57±7 years in Group 2, P=0.82), sex (male: 82% vs. 94%, P=0.40), LVEF (27±8% vs. 25±6%, P=0.18), or NT-proBNP (2350 pg/ml vs. 2831 pg/ml, P=0.32). Although heart rate and HRV were similar in both groups (rate: 80±20 bpm in Group 1 vs. 74±19 bpm in Group 2, P=0.47; SDNN: 106±79 vs. 88±115, P=0.61), we found significantly higher QTVI values in patients from Group 1 (-1.15±0.46 vs. -1.62±0.51 in Group 2, P=0.005). In patients with ICDs, ventricular arrhythmias recorded within 1 year prior enrollment were more frequent in Group 1 than Group 2 (58% vs. 13%, P=0.02).EMM is present in majority of patients with DCM and is associated with ventricular repolarization instability.clinicaltrials.gov: NCT01350310.

  View details for DOI 10.1016/j.cardfail.2014.10.002

  View details for Web of Science ID 000346229300004

  View details for PubMedID 25305502

• Biventricular VAD versus LVAD for right heart failure. Annals of cardiothoracic surgery Boulate, D., Marques, M. A., Ha, R., Banerjee, D., Haddad, F. 2014; 3 (6): 585-588

  View details for DOI 10.3978/j.issn.2225-319X.2014.08.08

  View details for PubMedID 25512899

  View details for PubMedCentralID PMC4250556

• Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of autism and developmental disorders Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for PubMedID 24849255

• Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for Web of Science ID 000343724000027

• The effects of levosimendan on renal function early after heart transplantation: results from a pilot randomized trial CLINICAL TRANSPLANTATION Knezevic, I., Poglajen, G., Hrovat, E., Oman, A., Pintar, T., Wu, J. C., Vrtovec, B., Haddad, F. 2014; 28 (10): 1105-1111

  Abstract

  We evaluated the effects of a levosimendan (LS)-based strategy compared with standard inotropic therapy on renal function in heart transplantation.Using a randomized study design, 94 patients were assigned to LS-based therapy or standard inotropic support. At the time of transplantation, the groups did not differ in age, gender, heart failure etiology, hemodynamic profile, LVEF, or comorbidities. While there were no differences in serum creatinine (sCr) or eGFR between groups at baseline, patients in the LS group had a greater increase in their relative eGFR (62% vs. 12%, p = 0.002) and a lower incidence of acute kidney injury (AKI) (28% vs. 6%, p = 0.01) during the first post-transplant week. On logistic regression analysis, correlates of AKI were randomization to LS therapy (OR = 0.21 [0.09-0.62], p = 0.01), baseline renal dysfunction (OR = 3.9 [1.1-13.6], p = 0.032), and diabetes mellitus (OR = 4.2 [1.1-16.5], p = 0.038). However, LS was associated with a greater need for additional norepinephrine therapy (40 [85%] vs. 15 [31%], p < 0.001) and a trend toward longer intensive care unit stay (9.5 ± 9.0 d vs. 7.0 ± 6.0 d, p = 0.13).In patients undergoing heart transplantation, levosimendan-based strategy may be associated with better renal function when compared to standard therapy.

  View details for DOI 10.1111/ctr.12424

  View details for Web of Science ID 000344186200007

  View details for PubMedID 25053182

• [Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology]. Türk Kardiyoloji Dernegi arsivi : Türk Kardiyoloji Derneginin yayin organidir Vonk-Noordegraaf, A., Haddad, F., Chin, K. M., Forfia, P. R., Kawut, S. M., Lumens, J., Naeije, R., Newman, J., Oudiz, R. J., Provencher, S., Torbicki, A., Voelkel, N. F., Hassoun, P. M. 2014; 42: 29-44

  Abstract

  Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the uderlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22-33) a 2013 by the American College of Cardiology Foundation).

  View details for PubMedID 25697032

• Effects of Transendocardial CD34(+) Cell Transplantation in Patients With Ischemic Cardiomyopathy CIRCULATION-CARDIOVASCULAR INTERVENTIONS Poglajen, G., Sever, M., Cukjati, M., Cernelc, P., Knezevic, I., Zemljic, G., Haddad, F., Wu, J. C., Vrtovec, B. 2014; 7 (4): 552-559

  Abstract

  We investigated the effects of transendocardial CD34(+) cell transplantation in patients with ischemic cardiomyopathy.In a prospective crossover study, we enrolled 33 patients with ischemic cardiomyopathy with New York Heart Association class III and left ventricular ejection fraction <40%. In phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by granulocyte colony stimulating factor, collected via apheresis, and injected transendocardially in the areas of hibernating myocardium. Patients were followed up for 6 months after the procedure (phase 2). Two patients died during phase 1 and none during phase 2. The remaining 31 patients were 85% men, aged 57±6 years. In phase 1, we found no change in left ventricular ejection fraction (from 25.2±6.2% to 27.1±6.6%; P=0.23), N-terminal pro B-type natriuretic peptide (from 3322±3411 to 3672±5165 pg/mL; P=0.75) or 6-minute walk distance (from 373±68 to 411±116 m; P=0.17). In contrast, in phase 2 there was an improvement in left ventricular ejection fraction (from 27.1±6.6% to 34.9±10.9%; P=0.001), increase in 6-minute walk distance (from 411±116 to 496±113 m; P=0.001), and a decrease in N-terminal pro B-type natriuretic peptide (from 3672±5165 to 1488±1847 pg/mL; P=0.04). The average number of injected CD34(+) cells was 90.6±7.5×10(6). Higher doses of CD34(+) cells and a more diffuse distribution of transendocardial cell injections were associated with better clinical response.Transendocardial CD34(+) cell transplantation may be associated with improved left ventricular function, decreased N-terminal pro B-type natriuretic peptide levels, and better exercise capacity in patients with ischemic cardiomyopathy. These effects seem to be particularly pronounced in patients receiving diffusely distributed cell injections and high-dose cell therapy.http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

  View details for DOI 10.1161/CIRCINTERVENTIONS.114.001436

  View details for Web of Science ID 000341205500019

  View details for PubMedID 25097199

• Pulmonary hypertension in patients with advanced heart failure is associated with increased levels of interleukin-6 BIOMARKERS Dolenc, J., Sebestjen, M., Vrtovec, B., Kozelj, M., Haddad, F. 2014; 19 (5): 385-390

  Abstract

  Inflammatory, endothelial and neurohormonal biomarkers are involved in heart failure (HF) and pulmonary hypertension (PH) pathogenesis.To study these biomarkers in PH due to advanced HF.Thirty adults with HF were included. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), endothelin-1 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured in peripheral vein and pulmonary artery during right heart catheterisation.IL-6, TNF-α, hsCRP and NT-proBNP correlated with pulmonary pressures independent of ventricular function, HF etiology and vascular bed. IL-6 was independent predictor of systolic pulmonary artery pressure (sPAP).Inflammatory biomarkers correlate to PH severity. IL-6 predicts sPAP in advanced HF.

  View details for DOI 10.3109/1354750X.2014.918654

  View details for Web of Science ID 000340430100005

  View details for PubMedID 24831174

• Septal curvature is marker of hemodynamic, anatomical, and electromechanical ventricular interdependence in patients with pulmonary arterial hypertension. Echocardiography (Mount Kisco, N.Y.) Haddad, F., Guihaire, J., Skhiri, M., Denault, A. Y., Mercier, O., Al-Halabi, S., Vrtovec, B., Fadel, E., Zamanian, R. T., Schnittger, I. 2014; 31 (6): 699-707

  Abstract

  The objective of this study was to determine the factors independently associated with septal curvature in patients with pulmonary arterial hypertension (PAH).Eighty-five consecutive patients with PAH who had an echocardiogram and a right heart catheterization within 24 hours of each others were included in the study. Septal curvature was assessed at the mid-papillary level using the eccentricity index (EI). Marked early systolic septal anterior motion was defined as a change in EI > 0.2 between end-diastole and early systole. Inter-ventricular mechanical delay was calculated as the percent time difference between right ventricular (RV) to left ventricular (LV) end-ejection time normalized for the RR interval.Average age was 45 ± 11 years and the majority of patients were women (75%). Mean right atrial pressure was 11 ± 7 mmHg, mean PAP was 52 ± 13 mmHg, relative RV area 1.8 ± 0.9, and RV fractional area change 24 ± 8%. End-diastolic EI was 1.6 ± 0.4 and systolic EI was 2.5 ± 0.8. On multivariate analysis relative pulmonary pressure, relative RV area, and inter-ventricular mechanical delay were independently associated with systolic EI (R(2)  = 0.72, P < 0.001). Independent determinants of diastolic EI included relative RV area and mean PAP (R(2)  = 0.69, P < 0.001). A systolic EI >1.08 differentiated patients with PAH from healthy controls with an AUC = 0.99. Patients with early systolic septal anterior motion (44% of subjects) had lower exercise capacity, more extensive ventricular remodeling, and worst ventricular function.Septal curvature is a useful marker of structural, hemodynamic, and electromechanical ventricular interdependence in PAH.

  View details for DOI 10.1111/echo.12468

  View details for PubMedID 24372843

• Impact of insulin resistance on ventricular function in pulmonary arterial hypertension. journal of heart and lung transplantation Brunner, N. W., Skhiri, M., Fortenko, O., Hsi, A., Haddad, F., Khazeni, N., Zamanian, R. T. 2014; 33 (7): 721-726

  Abstract

  Insulin resistance (IR) is an independent prognostic marker in pulmonary arterial hypertension (PAH), although the mechanism by which it engenders risk is unknown. We prospectively investigated the clinical, laboratory, hemodynamic, and echocardiographic characteristics of insulin-sensitive (IS) and IR patients with PAH.This was a prospective cohort study including well-phenotyped patients with PAH proven at cardiac catheterization. Patients were classified as IS or IR on the basis of the well-validated triglyceride/high-density lipoprotein-cholesterol ratio. Clinical, laboratory, and hemodynamic characteristics were compared between cohorts. Distance walked on the 6-minute walk test (6MWT) and echocardiograms were compared between IS and IR for the sub-set of patients that had these tests within 1 month of cardiac catheterization.Of the 111 PAH patients enrolled, 59 were IS, 25 were IR, and 27 were classified as indeterminate. Mean age was 45.8 ± 15.0 years. IR was associated with worse New York Heart Association class (p = 0.02). There were no differences in hemodynamics, biomarkers, 6MWT distance, or parameters of right ventricular function (i.e., tricuspid annular plane systolic excursion, myocardial performance index, and fractional area change) between groups. Despite similar systemic vascular resistance, parameters of left ventricular diastolic function were more favorable for IS vs IR, including mitral inflow E wave velocity (82 ± 17 vs 64 ± 19 msec, p = 0.02), E/A ratio (1.2 ± 0.4 vs 0.8 ± 0.2, p = 0.01), and lateral mitral valve E' velocity (13.9 ± 3.5 vs 10.4 ± 2.2 msec, p = 0.01).IR is associated with worse functional class and diastology compared with IS in PAH, although other prognostic parameters are similar.

  View details for DOI 10.1016/j.healun.2014.02.016

  View details for PubMedID 24819985

• Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature Deuse, T., Hua, X., Wang, D., Maegdefessel, L., Heeren, J., Scheja, L., Bolaños, J. P., Rakovic, A., Spin, J. M., Stubbendorff, M., Ikeno, F., Länger, F., Zeller, T., Schulte-Uentrop, L., Stoehr, A., Itagaki, R., Haddad, F., Eschenhagen, T., Blankenberg, S., Kiefmann, R., Reichenspurner, H., Velden, J., Klein, C., Yeung, A., Robbins, R. C., Tsao, P. S., Schrepfer, S. 2014; 509 (7502): 641-644

  Abstract

  Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

  View details for DOI 10.1038/nature13232

  View details for PubMedID 24747400

• Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature Deuse, T., Hua, X., Wang, D., Maegdefessel, L., Heeren, J., Scheja, L., Bolaños, J. P., Rakovic, A., Spin, J. M., Stubbendorff, M., Ikeno, F., Länger, F., Zeller, T., Schulte-Uentrop, L., Stoehr, A., Itagaki, R., Haddad, F., Eschenhagen, T., Blankenberg, S., Kiefmann, R., Reichenspurner, H., Velden, J., Klein, C., Yeung, A., Robbins, R. C., Tsao, P. S., Schrepfer, S. 2014; 509 (7502): 641-644

  Abstract

  Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

  View details for DOI 10.1038/nature13232

  View details for PubMedID 24747400

• Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy. Journal of cardiac failure Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Schnittger, I., Knowles, J. W., Perez, M., Magavern, E., Myers, J., Ashley, E. 2014; 20 (4): 236-243

  Abstract

  Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.

  View details for DOI 10.1016/j.cardfail.2014.01.014

  View details for PubMedID 24486928

• Relationship between Echocardiographic and Magnetic Resonance Derived Measures of Right Ventricular Size and Function in Patients with Pulmonary Hypertension. Journal of the American Society of Echocardiography Shiran, H., Zamanian, R. T., McConnell, M. V., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Wu, J. C., Haddad, F., Yang, P. C. 2014; 27 (4): 405-412

  Abstract

  Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared.The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2) = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2) = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2) = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18 cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

  View details for DOI 10.1016/j.echo.2013.12.011

  View details for PubMedID 24444659

• Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery. Pulmonary circulation Brunner, N., de Jesus Perez, V. A., Richter, A., Haddad, F., Denault, A., Rojas, V., Yuan, K., Orcholski, M., Liao, X. 2014; 4 (1): 10-24

  Abstract

  Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

  View details for DOI 10.1086/674885

  View details for PubMedID 25006417

• Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery PULMONARY CIRCULATION Brunner, N., Perez, V. A., Richter, A., Haddad, F., Denault, A., Rojas, V., Yuan, K., Orcholski, M., Liao, X. 2014; 4 (1): 10-24

  View details for DOI 10.1086/674885

  View details for Web of Science ID 000209982100003

• Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

  Abstract

  In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.

  View details for DOI 10.1111/echo.12467

  View details for PubMedID 24299065

• Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

  View details for DOI 10.1111/echo.12467

  View details for PubMedID 24299065

• Right ventricular plasticity in a porcine model of chronic pressure overload. journal of heart and lung transplantation Guihaire, J., Haddad, F., Boulate, D., Capderou, A., Decante, B., Flécher, E., Eddahibi, S., Dorfmüller, P., Hervé, P., Humbert, M., Verhoye, J., Dartevelle, P., Mercier, O., Fadel, E. 2014; 33 (2): 194-202

  Abstract

  Ventricular-arterial coupling is a measure of the relationship between ventricular contractility and afterload. We sought to determine the relationship between ventricular-arterial coupling and right ventricular (RV) remodeling in a novel porcine model of progressive pulmonary hypertension (PH).Chronic PH was induced in pigs by ligation of the left pulmonary artery (PA) followed by 5 weekly injections of cyanoacrylate to progressively obstruct the right lower lobe arteries (PH group, n = 10). At 6 weeks, 5 PH animals underwent reperfusion of the left lung through conduit anastomosis to decrease RV afterload, whereas 5 other animals received no treatment. Five sham-operated piglets were used as controls. RV function was assessed using echocardiography and conductance catheterization. RV gene expression of beta-myosin heavy chain (β-MHC) and B-type natriuretic peptide (BNP) were quantified by polymerase chain reaction.At 6 weeks, compared with controls, the PH group had higher mean PA pressure (32 ± 6 vs 14 ± 2 mm Hg, p < 0.01). The increase in RV elastance was insufficient to compensate for the increase in pulmonary arterial elastance in the PH group and altered ventricular-arterial coupling occurred (0.65 ± 0.16 vs 1.28 ± 0.14, p < 0.01). The degree of ventricular-arterial uncoupling was related to RV enlargement and systolic dysfunction. Ventricular-arterial uncoupling and increased RV mass index were associated with up-regulation of β-MHC and BNP expression.Ventricular-arterial coupling is closely associated with ventricular remodeling and systolic function as well as contractile and BNP gene expression. Dynamic changes in myosin expression may determine RV work efficiency in PH.

  View details for DOI 10.1016/j.healun.2013.10.026

  View details for PubMedID 24290166

• Prevalence and clinical correlates of right ventricular dysfunction in patients with hypertrophic cardiomyopathy. American journal of cardiology Finocchiaro, G., Knowles, J. W., Pavlovic, A., Perez, M., Magavern, E., Sinagra, G., Haddad, F., Ashley, E. A. 2014; 113 (2): 361-367

  Abstract

  Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.

  View details for DOI 10.1016/j.amjcard.2013.09.045

  View details for PubMedID 24230980

• Cardiac metastases and tumor embolization: A rare sequelae of primary undifferentiated liver sarcoma. International journal of surgery case reports Dua, M. M., Cloyd, J. M., Haddad, F., Beygui, R. E., Norton, J. A., Visser, B. C. 2014; 5 (12): 927-931

  Abstract

  Primary hepatic sarcomas are uncommon malignant neoplasms; prognostic features, natural history, and optimal management of these tumors are not well characterized.This report describes the management of a 51-year-old patient that underwent a right trisectionectomy for a large hepatic mass found to be a liver sarcoma on pathology. He subsequently developed tumor emboli to his lungs and was discovered to have cardiac intracavitary metastases from his primary tumor. The patient underwent cardiopulmonary bypass and resection of the right-sided heart metastases to prevent further pulmonary sequela of tumor embolization.The lack of distinguishing symptoms or imaging characteristics that clearly define hepatic sarcomas makes it challenging to achieve a diagnosis prior to pathologic examination. Metastatic spread is frequently to the lung or pleura, but very rarely seen within the heart. Failure to recognize cardiac metastatic disease will ultimately lead to progressive tumor embolization and cardiac failure if left untreated.The most effective therapy for primary liver sarcomas is surgery; radical resection should be performed if possible given the aggressive nature of these tumors to progress and metastasize.

  View details for DOI 10.1016/j.ijscr.2014.10.004

  View details for PubMedID 25460438

• How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

  View details for DOI 10.1136/bmjopen-2014-004814

  View details for PubMedID 24928584

• How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

  Abstract

  It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.Tertiary referral centre from Stanford, California, USA.383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Echocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).Reverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E'<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E' was similarly elevated (E/E': 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m(2) was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m(2) (OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E'>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E'<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.In HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.

  View details for DOI 10.1136/bmjopen-2014-004814

  View details for PubMedID 24928584

  View details for PubMedCentralID PMC4067898

• RV dysfunction after lung transplantation: a new prognostic marker or mainly a correlate of lung allograft function? JACC. Cardiovascular imaging Haddad, F., Fadel, E. 2014; 7 (11): 1095–97

  View details for PubMedID 25459590

• Right Heart Adaptation to Pulmonary Arterial Hypertension Physiology and Pathobiology JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vonk-Noordegraaf, A., Haddad, F., Chin, K. M., Forfia, P. R., Kawut, S. M., Lumens, J., Naeije, R., Newman, J., Oudiz, R. J., Provencher, S., Torbicki, A., Voelkel, N. F., Hassoun, P. M. 2013; 62 (25): D22-D33

  Abstract

  Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

  View details for DOI 10.1016/j.jacc.2013.10.027

  View details for Web of Science ID 000329459400004

  View details for PubMedID 24355638

• Non-invasive indices of right ventricular function are markers of ventriculararterial coupling rather than ventricular contractility: insights from a porcine model of chronic pressure overload EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Guihaire, J., Haddad, F., Boulate, D., Decante, B., Denault, A. Y., Wu, J., Herve, P., Humbert, M., Dartevelle, P., Verhoye, J., Mercier, O., Fadel, E. 2013; 14 (12): 1140-1149

  Abstract

  To investigate the physiological correlates of indices of RV function in a model of chronic pressure overload.Chronic pulmonary hypertension (PH) was induced in piglets by ligation of the left pulmonary artery (PA) followed by weekly embolization of right lower lobe arteries for 5 weeks (the PH group, n = 11). These animals were compared with sham-operated animals (controls, n = 6). At 6 weeks, a subgroup of five PH pigs underwent surgical reperfusion of the left lung and four others were followed until 12 weeks without treatment. Right ventricular function was assessed using echocardiography and conductance catheter measurements. At 6 weeks, mean PA pressure was higher in PH group compared with controls (35 ± 9 vs. 14 ± 2 mmHg, P < 0.01). Although RV elastance (Ees) increased at 6 weeks in the PH group (0.55 ± 0.09 vs. 0.38 ± 0.05 mmHg/mL, P < 0.001), ventricular-arterial coupling measured by the ratio of Ees on PA elastance (Ea) was decreased (0.68 ± 0.17 vs. 1.18 ± 0.18, P < 0.001). There was a strong direct relationship between Ees/Ea and indices of RV function, while relationship between Ees and indices of RV function was moderate. Changes in indices of RV function with time and after left lung reperfusion were associated with changes in Ees/Ea.Usual indices of RV function are associated with ventricular-arterial coupling rather than with ventricular contractility in a model of chronic pressure overload.

  View details for DOI 10.1093/ehjci/jet092

  View details for Web of Science ID 000326966100004

  View details for PubMedID 23677917

• CD34(+) Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Patients. Clinical pharmacology & therapeutics Vrtovec, B., Poglajen, G., Sever, M., Lezaic, L., Socan, A., Haddad, F., Wu, J. C. 2013; 94 (4): 452-458

  Abstract

  Recent trends indicate that patients with nonischemic dilated cardiomyopathy represent the largest subpopulation of heart failure patients with a significant need for alternative treatment modalities. Similar to patients with ischemic cardiomyopathy, patients with nonischemic dilated cardiomyopathy have been found to have myocardial regions with flow abnormalities, which may represent targets for neoangiogenic therapies. CD34(+) stem cells might contribute to the formation of new blood vessels from existing vascular structures in ischemic tissues by the direct incorporation of injected cells into the newly developing vasculature or by the production and secretion of angiogenic cytokines. This review summarizes the long-term clinical effects and potential underlying mechanisms of CD34(+) cell therapy in patients with nonischemic dilated cardiomyopathy.Clinical Pharmacology & Therapeutics (2013); 94 4, 452-458. doi:10.1038/clpt.2013.134.

  View details for DOI 10.1038/clpt.2013.134

  View details for PubMedID 23903668

• Imaging cardiac stem cell transplantation using radionuclide labeling techniques: clinical applications and future directions. Methodist DeBakey cardiovascular journal Lezaic, L., Haddad, F., Vrtovec, B., Wu, J. C. 2013; 9 (4): 218-222

  Abstract

  Stem cell therapy is emerging as a potential new therapy for patients with advanced heart failure. In recent years, advances in molecular imaging have allowed monitoring of stem cell homing and survival. In this review article, we will discuss the clinical application and future directions of stem cell imaging in advanced heart failure.

  View details for PubMedID 24298314

• Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation Vrtovec, B., Poglajen, G., Lezaic, L., Sever, M., Socan, A., Domanovic, D., Cernelc, P., Torre-Amione, G., Haddad, F., Wu, J. C. 2013; 128 (11): S42-9

  Abstract

  In an open-label blinded study, we compared intracoronary and transendocardial CD34(+) cell transplantation in patients with nonischemic dilated cardiomyopathy.Of the 40 patients with dilated cardiomyopathy, 20 were randomized to receive intracoronary injection and 20 received transendocardial CD34(+) cell delivery. In both groups, CD34(+) cells were mobilized by filgrastim, collected via apheresis, and labeled with technetium-99m radioisotope for single-photon emission computed tomographic imaging. In the intracoronary group, cells were injected intracoronarily in the artery supplying segments of greater perfusion defect on myocardial perfusion scintigraphy. In the transendocardial group, electroanatomic mapping was used to identify viable but dysfunctional myocardium, and transendocardial cell injections were performed. Nuclear single-photon emission computed tomographic imaging for quantification of myocardial retention was performed 18 hours thereafter. At baseline, groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide levels. The number of CD34(+) cells was also comparable (105 ± 31 × 10(6) in the transendocardial group versus 103 ± 27 × 10(6) in the intracoronary group, P=0.62). At 18 hours after procedure, myocardial retention was higher in the transendocardial group (19.2 ± 4.8%) than in the intracoronary group (4.4 ± 1.2%, P<0.01). At 6 months, left ventricular ejection fraction improved more in the transendocardial group (+8.1 ± 4.3%) than in the intracoronary group (+4.2 ± 2.3%, P=0.03). The same pattern was observed for the 6-minute walk test distance (+125 ± 33 m in the transendocardial group versus +86 ± 13 m in the intracoronary group, P=0.03) and N-terminal pro-brain natriuretic peptide (-628 ± 211 versus -315 ± 133 pg/mL, P=0.04).In patients with dilated cardiomyopathy, transendocardial CD34(+) cell transplantation is associated with higher myocardial retention rates and greater improvement in ventricular function, N-terminal pro-brain natriuretic peptide, and exercise capacity compared with intracoronary route.http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000230

  View details for PubMedID 24030420

• Race differences in ventricular remodeling and function among college football players. American journal of cardiology Haddad, F., Peter, S., Hulme, O., Liang, D., Schnittger, I., Puryear, J., Gomari, F. A., Finocchiaro, G., Myers, J., Froelicher, V., Garza, D., Ashley, E. A. 2013; 112 (1): 128-134

  Abstract

  Athletic training is associated with increases in ventricular mass and volume. Recent studies have shown that left ventricular mass increases proportionally in white athletes with a mass/volume ratio approaching unity. The objective of this study was to compare the proportionality in ventricular remodeling and ventricular function in black versus white National Collegiate Athletic Association Division I football players. From 2008 to 2011, football players at Stanford University underwent cardiovascular screening with a 12-point history and physical examination, electrocardiography, and focused echocardiography. Compared with white players, black players had on average higher left ventricular mass indexes (77 ± 11 vs 71 ± 11 g/m(2), p = 0.009), higher mass/volume ratios (1.18 ± 0.16 vs 1.06 ± 0.09 g/ml, p <0.001), and higher QRS vector magnitudes (3.2 ± 0.7 vs 2.7 ± 0.8, p = 0.002). Black race had an odds ratio of 14 (95% confidence interval 5 to 42, p <0.001) for a mass/volume ratio >1.2. Mass/volume ratio was inversely related to early diastolic tissue Doppler velocity e' (r = -0.50, p <0.001) but not to QRS vector magnitude (r = 0.065, p = 0.034). With regard to systolic indexes, there was no significant difference in the left ventricular ejection fraction, velocity of circumferential shortening, and isovolumic acceleration. In conclusion, black college football players exhibit more concentric ventricular remodeling, lower early diastolic annular velocities, and increased ventricular voltage compared with white players. Ventricular mass increases proportionally to volume in white players but not in black players.

  View details for DOI 10.1016/j.amjcard.2013.02.065

  View details for PubMedID 23602691

• Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients. Transplantation proceedings Vrtovec, B., Haddad, F., Pham, M., Deuse, T., Fearon, W. F., Schrepfer, S., Leon, S., Vu, T., Valantine, H., Hunt, S. A. 2013; 45 (6): 2406-2409

  Abstract

  We evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients.Of 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10(9)cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence.At baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67-37.2] and OR = 0.09 [0.02-0.52], respectively).G-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.

  View details for DOI 10.1016/j.transproceed.2013.01.106

  View details for PubMedID 23953556

• Clinical and Echocardiographic Presentation of Rejection Episodes Following Heart Transplantation 33rd Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation Sudini, N. L., Huo, J., Pan, S., Montoya, J., Leon, S., Vu, T., Beygui, R. E., Vrtovec, B., Wu, J. C., Pham, M., KUSH, K., Berry, G., Hunt, S., Haddad, F. ELSEVIER SCIENCE INC. 2013: S254–S254

  View details for Web of Science ID 000316712100696

• Relation of B-Type Natriuretic Peptide Level in Heart Failure to Sudden Cardiac Death in Patients With and Without QT Interval Prolongation AMERICAN JOURNAL OF CARDIOLOGY Vrtovec, B., Knezevic, I., Poglajen, G., Sebestjen, M., Olcrajsek, R., Haddad, F. 2013; 111 (6): 886-890

  Abstract

  Increased levels of B-type natriuretic peptide (BNP) are associated with prolongation of the action potential in ventricular myocardium. We investigated the relation of a BNP increase, QT interval, and sudden cardiac death (SCD) in the presence of heart failure (HF). We enrolled 398 patients with HF, New York Heart Association class III or IV, and left ventricular ejection fraction <40%. At baseline and after 3 months, we measured BNP and the QT interval. A BNP increase was defined as a change in BNP of ≥+10%. The QTc interval was calculated using the Bazett formula. QTc interval prolongation was defined as a change in QTc of ≥+10%. The patients were followed up for 1 year. During a 3-month period, BNP increased significantly in 53% of the patients (group 1) and did not in 47% (group 2). During the same period, the QTc interval was more prolonged in group 1 (+44 ± 12 ms) than in group 2 (+7 ± 6 ms; p = 0.01). During 1 year of follow-up, 20 patients died suddenly (SCD), 16 from pump failure. Although the SCD rates did not differ between the 2 groups (5.7% in group 1 vs 4.2% in group 2, p = 0.53), they were significantly greater in the patients in group 1 with QTc interval prolongation ≥+10% (13.8%, p <0.001). The Kaplan-Meier-derived SCD-free survival rates were 2.9 times greater in patients without QTc interval prolongation than in those with prolonged QTc (p <0.001). QTc interval prolongation was an independent correlate of SCD (p = 0.006), but BNP increase was not (p = 0.32). In conclusion, a BNP increase in patients with HF was associated with an increased risk of SCD only in patients with QTc interval prolongation.

  View details for DOI 10.1016/j.amjcard.2012.11.041

  View details for Web of Science ID 000316537700019

• IMPROVEMENT IN RIGHT ATRIAL FUNCTION IS ASSOCIATED WITH IMPROVED FUNCTIONAL CAPACITY IN PULMONARY ARTERIAL HYPERTENSION 62nd Annual Scientific Session of the American-College-of-Cardiology Brunner, N. W., Haddad, F., Swiston, J. R., Gin, K., Tsang, T. S., Zamanian, R. T. ELSEVIER SCIENCE INC. 2013: E1246–E1246

  View details for Web of Science ID 000316555201351

• RIGHT ATRIAL EMPTYING FRACTIONS ARE ASSOCIATED WITH SURVIVAL IN PULMONARY ARTERIAL HYPERTENSION 62nd Annual Scientific Session of the American-College-of-Cardiology Brunner, N. W., Haddad, F., Swiston, J. R., Gin, K., Tsang, T. S., Zamanian, R. T. ELSEVIER SCIENCE INC. 2013: E896–E896

  View details for Web of Science ID 000316555201001

• ST-Elevation Myocardial Infarction Following Heart Transplantation as an Unusual Presentation of Coronary Allograft Vasculopathy: A Case Report TRANSPLANTATION PROCEEDINGS Peter, S., HULME, O., Deuse, T., Vrtovec, B., Fearon, W. F., Hunt, S., Haddad, F. 2013; 45 (2): 787-791

  Abstract

  The presentation, mechanisms, and incidence of ST elevation myocardial infarction (STEMI) in heart transplant recipients have been characterized only to a limited degree in the current literature. Herein, we present a unique case of STEMI years after heart transplantation with a focus on the salient features of its diagnosis and interventions. We also provide a review of the epidemiology of this phenomenon.A 33-year-old woman who was status post cardiac transplantation for dilated cardiomyopathy presented to the clinic with mild nonspecific fatigue and concern after having noticed relative bradycardia compared with her posttransplantation baseline heart rate. Electrocardiogram (ECG) showed junctional rhythm and inferior ST elevations, likely reflecting nodal ischemia. Troponins were grossly positive and echocardiogram showed marked right ventricular dysfunction.Successful percutaneous coronary intervention (PCI) with aspiration thrombectomy and drug-eluting stent placement was emergently performed. The heart's rhythm soon returned to sinus tachycardia. Right ventricular wall-motion abnormalities resolved. The patient suffered no clinical sequelae of her STEMI.This case illustrated that "classic" symptoms of STEMI may not occur at all in the setting of heart transplantation. To our knowledge, this is the first case of posttransplantation STEMI presenting as asymptomatic bradycardia, and highlights the importance of maintaining high clinical suspicion for ischemia in transplant recipients with subtle changes. In reviewing the epidemiology of this case, we locate and bundle different types of studies that have directly or indirectly looked at STEMI in heart transplantation. For a variety of putative pathophysiological reasons, STEMI is indeed a rare manifestation of the common transplant phenomenon of coronary artery vasculopathy (CAV).

  View details for DOI 10.1016/j.transproceed.2012.08.021

  View details for PubMedID 23498821

• Perioperative right ventricular dysfunction CURRENT OPINION IN ANESTHESIOLOGY Denault, A. Y., Haddad, F., Jacobsohn, E., Deschamps, A. 2013; 26 (1): 71-81

  Abstract

  To evaluate new information on the importance of right ventricular function, diagnosis and management in cardiac surgical patients.There is growing evidence that right ventricular function is a key determinant in survival in cardiac surgery, particularly in patients with pulmonary hypertension. The diagnosis of this condition is helped by the use of specific hemodynamic parameters and echocardiography. In that regard, international consensus guidelines on the echocardiographic assessment of right ventricular function have been recently published. New monitoring modalities in cardiac surgery such as regional near-infrared spectroscopy can also assist management. Management of right ventricular failure will be influenced by the presence or absence of myocardial ischemia and left ventricular dysfunction. The differential diagnosis and management will be facilitated using a systematic approach.The use of right ventricular pressure monitoring and the publications of guidelines for the echocardiographic assessment of right ventricular anatomy and function allow the early identification of right ventricular failure. The treatment success will be associated by optimization of the hemodynamic, echocardiographic and near-infrared spectroscopy parameters.

  View details for DOI 10.1097/ACO.0b013e32835b8be2

  View details for Web of Science ID 000312953900012

  View details for PubMedID 23235519

• Stem cell therapy in patients with heart failure. Methodist DeBakey cardiovascular journal Vrtovec, B., Poglajen, G., Haddad, F. 2013; 9 (1): 6-10

  Abstract

  Heart failure results from injury to the myocardium from a variety of causes, including ischemic and nonischemic etiologies. Severe heart failure carries a 50% 5-year mortality rate and is responsible for more than one-third of cardiovascular deaths in the United States.1 Heart failure progression is accompanied by activation of neurohormonal and cytokine systems as well as a series of adaptive changes within the myocardium, collectively referred to as left ventricular remodelling. The unfavorable alterations may be categorized broadly into changes that occur in the cardiac myocytes and changes that occur in the volume and composition of the extracellular matrix.2 Since remodelling in heart failure is progressive and eventually becomes detrimental, the majority of treatment strategies are aimed at stopping or reversing this process. Although medical management, cardiac resychronization therapy, and long-term or destination mechanical circulatory support have been successful in this regard, a considerable number of patients still progress to end-stage heart failure with limited therapeutic options. For these patients, stem cell therapies are being investigated as a safe treatment strategy for decreasing cardiac remodelling on top of conventional medical and device treatment.

  View details for PubMedID 23518819

• Right-ventricular failure following left ventricle assist device implantation CURRENT OPINION IN CARDIOLOGY Patlolla, B., Beygui, R., Haddad, F. 2013; 28 (2): 223-233

  Abstract

  To review recent insights on right-ventricular failure (RVF) following left-ventricular assist device (LVAD) implantation.Even with the availability of new generation continuous mechanical assist devices, RVF after implantation of LVAD is still associated with high morbidity and mortality. Recent studies have tried to better define the risk of RVF using combined clinical scores and measures of right-ventricular function or strain. Small exploratory studies have also investigated the role of pulmonary vasodilators and phosphodiesterase inhibitors in selected patients receiving LVAD implantation.Measure of right-ventricular function could improve the risk stratification of RVF following LVAD implantation. Future multicenter studies are needed to validate right-ventricular risk scores and to develop evidence-guided preventive and therapeutic strategies.

  View details for DOI 10.1097/HCO.0b013e32835dd12c

  View details for Web of Science ID 000314811800018

  View details for PubMedID 23337895

• Comparison of Aortic Root Diameter to Left Ventricular Outflow Diameter Versus Body Surface Area in Patients With Marfan Syndrome AMERICAN JOURNAL OF CARDIOLOGY Shiran, H., Haddad, F., Miller, D. C., Liang, D. 2012; 110 (10): 1518-1522

  Abstract

  Aortic root dilation is important in the diagnosis of familial aortic syndromes, such as Marfan syndrome, and an important risk factor for aortic complications, such as dissection or rupture. Transthoracic echocardiography reliably measures the absolute aortic root size; however, the degree of abnormality of the measurement requires correction for the expected normal aortic root size for each patient. The expected normal size is currently predicted according to the body surface area (BSA) and age. However, the correlation between root size and BSA is imperfect, particularly for older patients. A potential exists to improve the diagnosis and treatment of patients with aortic disease, with an improved estimation of normal aortic root size. A reference size derived from within the cardiovascular system has been hypothesized to provide a more direct correlation with the aortic root size. Images from the Stanford echocardiography database were reviewed, and measurements of the aortic root and internal dimensions were performed in a control cohort (n = 150). The measurements were repeated in adult patients with Marfan syndrome (n = 70) on serial echocardiograms (145 total studies reviewed). Of the 150 control patients, excellent correlation was found between the aortic root and left ventricular outflow tract diameters, r(2) = 0.67, and r(2) = 0.34 with BSA (p <0.0001, for both). More importantly, using the left ventricular outflow tract to predict the normal aortic root size, instead of the BSA and age, improved the diagnostic accuracy of aortic root measurements for diagnosing Marfan syndrome. In conclusion, an internal cardiovascular reference, the left ventricular outflow tract diameter, can improve the diagnosis of aortic disease and might provide a better reference for the degree of abnormality.

  View details for DOI 10.1016/j.amjcard.2012.06.062

  View details for Web of Science ID 000311523900021

  View details for PubMedID 22858189

• Clinical and Functional Correlates of Early Microvascular Dysfunction After Heart Transplantation CIRCULATION-HEART FAILURE Haddad, F., Khazanie, P., Deuse, T., Weisshaar, D., Zhou, J., Nam, C. W., Vu, T. A., Gomari, F. A., Skhiri, M., Simos, A., Schnittger, I., Vrotvec, B., Hunt, S. A., Fearon, W. F. 2012; 5 (6): 759-768

  Abstract

  Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients.Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3-12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1±0.7 versus 3.5±0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54±0.09 versus 0.43±0.09; P<0.01] and [0.47±0.14 versus 0.32±0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91]).A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes.

  View details for DOI 10.1161/CIRCHEARTFAILURE.111.962787

  View details for PubMedID 22933526

• Pulmonary Hypertension A Stage for Ventricular Interdependence? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hsia, H. H., Haddad, F. 2012; 59 (24): 2203-2205

  View details for DOI 10.1016/j.jacc.2011.12.049

  View details for Web of Science ID 000304932500011

  View details for PubMedID 22676941

• The Intersection of Genes and Environment Development of Pulmonary Arterial Hypertension in a Patient With Hereditary Hemorrhagic Telangiectasia and Stimulant Exposure CHEST Ayala, E., Kudelko, K. T., Haddad, F., Zamanian, R. T., Perez, V. d. 2012; 141 (6): 1598-1600

  Abstract

  Pulmonary arterial hypertension (PAH) is a rare complication of hereditary hemorrhagic telangiectasia (HHT). The triggers that promote the development of PAH in HHT remain poorly understood. We present the case of a 45-year-old woman with decompensated right-sided heart failure secondary to newly diagnosed PAH. The clinical diagnosis of HHT was confirmed on the basis of recurrent spontaneous epistaxis, multiple typical mucocutaneous telangiectasia, and the presence of pulmonary arteriovenous malformation. There was also a suggestive family history. The patient was discovered to have active and extensive stimulant abuse in addition to HHT. We concluded that there may be a temporal relationship between exposure to stimulants and development of PAH in a host with underlying gene mutation. This case highlights the paradigm of PAH development after environmental exposure in a genetically susceptible host.

  View details for DOI 10.1378/chest.11-1402

  View details for Web of Science ID 000305039300054

  View details for PubMedID 22670022

  View details for PubMedCentralID PMC3367481

• Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction. Pulmonary circulation Perez, V. A., Haddad, F., Zamanian, R. T. 2012; 2 (2): 163-169

  Abstract

  Pulmonary hypertension (PH) is commonly seen in patients who present with left ventricular diastolic dysfunction (LVDD) and is considered a marker of poor prognosis. While PH in this setting is thought to result from pulmonary venous congestion, there is a subset of patients in which pulmonary pressures fail to improve with appropriate management of diastolic heart failure and go on to develop a clinical picture similar to that of patients with pulmonary arterial hypertension (PAH). Despite the utility of Doppler echocardiography and exercise testing in the initial evaluation of patients with suspected PH-LVDD, the diagnosis can only be confirmed using right heart catheterization. Management of PH-LVDD centers on both optimizing fluid management and afterload reduction to reducing left ventricular diastolic pressures and also increase pulmonary venous return. To date, there is no clear evidence that addition of PH-specific drugs can improve clinical outcomes, and their use should only be considered in the setting of clinical trials. In conclusion, PH-LVDD remains a challenging clinical entity that complicates the management of left ventricular dysfunction and significantly contributes to its morbidity and mortality. Determination of the optimal diagnostic and treatment strategies for this form of PH should be the goal of future studies.

  View details for DOI 10.4103/2045-8932.97598

  View details for PubMedID 22837857

• Cardiac Paraganglioma: Diagnostic and Surgical Challenges JOURNAL OF CARDIAC SURGERY Huo, J. L., Choi, J. C., DeLuna, A., Lee, D., Fleischmann, D., Berry, G. J., Deuse, T., Haddad, F. 2012; 27 (2): 178-182

  Abstract

  Primary cardiac paragangliomas are rare extra-adrenal tumors. Though they account for less than 1% of all primary cardiac tumors, they are considerable sources of morbidity and mortality. In this case review, we discuss the challenges associated with the diagnosis and management of cardiac paragangliomas.

  View details for DOI 10.1111/j.1540-8191.2011.01378.x

  View details for Web of Science ID 000302172800009

  View details for PubMedID 22273468

• Endothelial progenitor cells in cardiovascular disease and chronic inflammation: from biomarker to therapeutic agent BIOMARKERS IN MEDICINE Grisar, J. C., Haddad, F., Gomari, F. A., Wu, J. C. 2011; 5 (6): 731-744

  Abstract

  The discovery of endothelial progenitor cells in the 1990s challenged the paradigm of angiogenesis by showing that cells derived from hematopoietic stem cells are capable of forming new blood vessels even in the absence of a pre-existing vessel network, a process termed vasculogenesis. Since then, the majority of studies in the field have found a strong association between circulating endothelial progenitor cells and cardiovascular risk. Several studies have also reported that inflammation influences the mobilization and differentiation of endothelial progenitor cells. In this review, we discuss the emerging role of endothelial progenitor cells as biomarkers of cardiovascular disease as well as the interplay between inflammation and endothelial progenitor cell biology. We will also review the challenges in the field of endothelial progenitor cell-based therapy.

  View details for DOI 10.2217/BMM.11.92

  View details for Web of Science ID 000298488200005

  View details for PubMedID 22103609

  View details for PubMedCentralID PMC3285378

• Quantitative Comparison of Microcirculatory Dysfunction in Patients With Stress Cardiomyopathy and ST-Segment Elevation Myocardial Infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kim, H., Tremmel, J. A., Nam, C., Zhou, J., Haddad, F., Vagelos, R. H., Lee, D. P., Yeung, A. C., Fearon, W. F. 2011; 58 (23): 2430-2431

  View details for DOI 10.1016/j.jacc.2011.08.046

  View details for Web of Science ID 000297319700016

  View details for PubMedID 22115653

• Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

  Abstract

  Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

  View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

  View details for PubMedID 21908586

• Pulmonary Hypertension Associated With Left Heart Disease: Characteristics, Emerging Concepts, and Treatment Strategies PROGRESS IN CARDIOVASCULAR DISEASES Haddad, F., Kudelko, K., Mercier, O., Vrtovec, B., Zamanian, R. T., Perez, V. D. 2011; 54 (2): 154-167

  Abstract

  Left heart disease (LHD) represents the most common causes of pulmonary hypertension (PH). Whether caused by systolic or diastolic dysfunction or valvular heart disease, a hallmark of PH associated with LHD is elevated left atrial pressure. In all cases, the increase in left atrial pressure causes a passive increase in pulmonary pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in pulmonary arterial pressure. When present, PH is associated with a worse prognosis in patients with LHD. In addition to local abnormalities in nitric oxide and endothelin production, gene modifiers such as serotonin polymorphisms may be associated with the pathogenesis of PH in LHD. Optimizing heart failure regimens and corrective valve surgery represent the cornerstone of the treatment of PH in LHD. Recent studies suggest that sildenafil, a phosphodiesterase-5 inhibitor, is a promising agent in the treatment of PH in LHD. Unloading the left ventricle with circulatory support may also reverse severe PH in patients with end-stage heart failure allowing candidacy to heart transplantation.

  View details for DOI 10.1016/j.pcad.2011.06.003

  View details for Web of Science ID 000294880400009

  View details for PubMedID 21875514

• Incidence, Correlates, and Consequences of Acute Kidney Injury in Patients With Pulmonary Arterial Hypertension Hospitalized With Acute Right-Side Heart Failure JOURNAL OF CARDIAC FAILURE Haddad, F., Fuh, E., Peterson, T., Skhiri, M., Kudelko, K. T., Perez, V. D., Winkelmayer, W. C., Doyle, R. L., Chertow, G. M., Zamanian, R. T. 2011; 17 (7): 533-539

  Abstract

  Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH).We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2).AKI is relatively common in patients with PAH and associated with a short-term risk of death.

  View details for DOI 10.1016/j.cardfail.2011.03.003

  View details for PubMedID 21703524

• Effects of Intracoronary Stem Cell Transplantation in Patients With Dilated Cardiomyopathy JOURNAL OF CARDIAC FAILURE Vrtovec, B., Poglajen, G., Sever, M., Lezaic, L., Domanovic, D., Cernelc, P., Haddad, F., Torre-Amione, G. 2011; 17 (4): 272-281

  Abstract

  We investigated clinical effects of intracoronary transplantation of CD34+ cells in patients with dilated cardiomyopathy (DCM).Of 55 patients with DCM, 28 were randomized to CD34+ transplantation (SC group), and 27 patients did not receive stem cell therapy (controls). In the SC group, peripheral blood CD34+ cells were mobilized by granulocyte-colony stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and CD34+ cells were injected in the coronary artery supplying the segments with reduced viability.At baseline, the 2 groups did not differ in age, gender, left ventricular ejection fraction (LVEF), or NT-proBNP levels. At 1 year, stem cell therapy was associated with an increase in LVEF (from 25.5 ± 7.5% to 30.1 ± 6.7%; P = .03), an increase in 6-minute walk distance (from 359 ± 104 m to 485 ± 127 m; P = .001), and a decrease in NT-proBNP (from 2069 ± 1996 pg/mL to 1037 ± 950 pg/mL; P = .01). The secondary endpoint of 1-year mortality or heart transplantation was lower in patients receiving SC therapy (2/28, 7%) than in controls (8/27, 30%) (P = .03), and SC therapy was the only independent predictor of outcome on multivariable analysis (P = .04).Intracoronary stem cell transplantation could lead to improved ventricular remodeling, better exercise tolerance and potentially improved survival in patients with DCM.

  View details for DOI 10.1016/j.cardfail.2010.11.007

  View details for Web of Science ID 000289318500002

  View details for PubMedID 21440864

• Stress-induced cardiomyopathy associated with a transfusion reaction: A case of potential crosstalk between the histaminic and adrenergic systems EXPERIMENTAL & CLINICAL CARDIOLOGY Zhou, J. Q., Choe, E., Ang, L., Schnittger, I., Rockson, S. G., Tremmel, J. A., Haddad, F. 2011; 16 (1): 30-32

  Abstract

  The adrenergic and histaminergic systems have been reported to have analogous effects on the heart. A case of transient ventricular dysfunction with echocardiographic findings characteristic of stress-induced cardiomyopathy (also known as takotsubo cardiomyopathy) in a patient who had an urticarial transfusion reaction is described. The effect of histamine on ventricular function and its interaction with the adrenergic system are discussed.

  View details for Web of Science ID 000300518800008

  View details for PubMedID 21523205

  View details for PubMedCentralID PMC3076164

• The concept of ventricular reserve in heart failure and pulmonary hypertension: an old metric that brings us one step closer in our quest for prediction CURRENT OPINION IN CARDIOLOGY Haddad, F., Vrtovec, B., Ashley, E. A., Deschamps, A., Haddad, H., Denault, A. Y. 2011; 26 (2): 123-131

  Abstract

  Ventricular reserve is emerging a strong predictor of outcome in heart failure and cardiovascular disease. Ventricular reserve is the term used to describe the extent of increase or change in ventricular function that occurs during exercise or pharmacological stress (typically with dobutamine).The interest in ventricular reserve lies in its ability to assess viability in coronary artery disease, to predict clinical outcome and response to therapy in patients with heart failure and to screen patients for early cardiovascular disease.In this paper, we will review the emerging role of ventricular reserve in heart failure and pulmonary hypertension. We will also explore the mechanisms involved in the pathophysiology of impaired ventricular reserve and discuss future directions of research in the field.

  View details for DOI 10.1097/HCO.0b013e3283437485

  View details for Web of Science ID 000287189400008

  View details for PubMedID 21297465

• Right ventricular failure: a novel era of targeted therapy. Current heart failure reports Banerjee, D., Haddad, F., Zamanian, R. T., Nagendran, J. 2010; 7 (4): 202-211

  Abstract

  There now is strong evidence to recognize the pivotal role of the right ventricle (RV) in heart disease and to establish it as a unique and separate entity than the left ventricle (LV). Here, we summarize the differences between the two ventricles, the diagnosis of RV failure, and the management of acute and chronic RV failure. We review the indices derived by echocardiography used to measure RV function, and novel biomarkers that may play a role diagnosing and prognosticating in RV-specific disease. There are new novel therapies that specifically target the RV in disease. For example, phosphodiesterase type 5 inhibitors improve contractility of the hypertrophied RV while sparing the normal LV in pulmonary arterial hypertension. The metabolism of the hypertrophied RV is another area for therapeutic exploitation by metabolic modulation. We also suggest future potential molecular targets that may be unique to the RV because they are upregulated in RV hypertrophy greater than in LV hypertrophy.

  View details for DOI 10.1007/s11897-010-0031-7

  View details for PubMedID 20890792

• Cardiac myosin heavy chain gene regulation by thyroid hormone involves altered histone modifications AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Haddad, F., Jiang, W., Bodell, P. W., Qin, A. X., Baldwin, K. M. 2010; 299 (6): H1968-H1980

  Abstract

  The antithetical regulation of cardiac α- and β-myosin heavy chain (MHC) genes by thyroid hormone (T(3)) is not well understood but appears to involve thyroid hormone interaction with its nuclear receptor and MHC promoters as well as cis-acting noncoding regulatory RNA (ncRNA). Both of these phenomena involve epigenetic regulations. This study investigated the extent that altered thyroid state induces histone modifications in the chromatin associated with the cardiac MHC genes. We hypothesized that specific epigenetic events could be identified and linked to cardiac MHC gene switching in response to a hypothyroid or hyperthyroid state. A hypothyroid state was induced in rats by propylthiouracil treatment (PTU), whereas a hyperthyroid (T(3)) was induced by T(3) treatment. The left ventricle was analyzed after 7 days for MHC pre-mRNA expression, and the chromatin was assessed for enrichment in specific histone modifications using chromatin immunoprecipitation quantitative PCR assays. At both the α-MHC promoter and the intergenic region, the enrichment in acetyl histone H3 at K9/14 (H3K9/14ac) and trimethyl histone H3 at K4 (H3K4me3) changed in a similar fashion. They were both decreased with PTU treatment but did not change under T(3), except at a location situated 5' to the antisense intergenic transcription start site. These same marks varied differently on the β-MHC promoter. For example, H3K4me3 enrichment correlated with the β-promoter activity in PTU and T(3) groups, whereas H3K9/14ac was repressed in the T(3) group but did not change under PTU. Histone H3K9me was enriched in chromatin of both the intergenic and α-MHC promoters in the PTU group, whereas histone H4K20me1 was enriched in chromatin of β-MHC promoter in the normal control and T(3) groups. Collectively, these findings provide evidence that specific epigenetic phenomena modulate MHC gene expression in altered thyroid states.

  View details for DOI 10.1152/ajpheart.00644.2010

  View details for Web of Science ID 000284936600027

  View details for PubMedID 20833952

• Improved Screening for Aortic Root Dilation by Transthoracic Echocardiography Shiran, H., Haddad, F., Liang, D. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231602191

• Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. journal of heart and lung transplantation Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., de Jesus Perez, V. 2010; 29 (9): 1071-1075

  Abstract

  We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

  View details for DOI 10.1016/j.healun.2010.04.023

  View details for PubMedID 20627625

  View details for PubMedCentralID PMC2926193

• Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay JOURNAL OF HEART AND LUNG TRANSPLANTATION Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., Perez, V. D. 2010; 29 (9): 1071-1075

  Abstract

  We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

  View details for DOI 10.1016/j.healun.2010.04.023

  View details for Web of Science ID 000281494800016

  View details for PubMedCentralID PMC2926193

• Review of Heart-Lung Transplantation at Stanford ANNALS OF THORACIC SURGERY Deuse, T., Sista, R., Weill, D., Tyan, D., Haddad, F., Dhillon, G., Robbins, R. C., Reitz, B. A. 2010; 90 (1): 329-337

  Abstract

  Long-term survival after heart-lung transplantation was first achieved in 1981 at Stanford and a total of 217 heart-lung transplantations had been performed by June 2008. This review summarizes Stanford's cumulative experience with heart-lung transplantation, demonstrates the progress that has been made, and discusses past and persistent problems. Diagnostic tools and treatment options for infectious diseases and rejection have changed and patient survival markedly improved over the almost three decades. Eight patients lived longer than 20 years. Further options to treat infections and strategies to control bronchiolitis obliterans syndrome, the main causes of early and long-term mortality, respectively, are required to achieve routine long-term survival.

  View details for DOI 10.1016/j.athoracsur.2010.01.023

  View details for PubMedID 20609821

• Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Field REVISTA ESPANOLA DE CARDIOLOGIA Skhiri, M., Hunt, S. A., Denault, A. Y., Haddad, F. 2010; 63 (4): 451-471

  Abstract

  In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension or left heart failure. Our understanding of right heart failure has improved considerably over the last two decades. In this review article, our objective was to provide a critical summary of the evidence underlying the management of right heart failure. A systematic review of the literature was performed using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials to identify studies conducted between January 1975 and January 2010. The literature search encompassed observational studies, randomized controlled trials and meta-analyses. The evidence underlying the use of beta-blockade, angiotensin-converting enzyme inhibitors, inhaled nitric oxide, hydralazine, warfarin, and resynchronization therapy in right heart failure was systematically reviewed. Emerging new therapies, such as metabolic modulators, and the pearls and pitfalls of managing right heart failure are also discussed in the article.

  View details for Web of Science ID 000276217300011

  View details for PubMedID 20334811

• [Tratamiento basado en la evidencia de la insuficiencia cardiaca derecha: una revisión sistemática de un campo empírico]. Revista española de cardiología (English ed.) Skhiri, M., Hunt, S. A., Denault, A. Y., Haddad, F. 2010; 63 (4): 451-471

  Abstract

  In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension or left heart failure. Our understanding of right heart failure has improved considerably over the last two decades. In this review article, our objective was to provide a critical summary of the evidence underlying the management of right heart failure. A systematic review of the literature was performed using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials to identify studies conducted between January 1975 and January 2010. The literature search encompassed observational studies, randomized controlled trials and meta-analyses. The evidence underlying the use of beta-blockade, angiotensinconverting enzyme inhibitors, inhaled nitric oxide, hydralazine, warfarin, and resynchronization therapy in right heart failure was systematically reviewed. Emerging new therapies, such as metabolic modulators, and the perils and pitfalls of managing right heart failure are also discussed in the article.

  View details for DOI 10.1016/S1885-5857(10)70094-3

  View details for PubMedID 24776472

• Risk Factors Predictive of Right Ventricular Failure After Left Ventricular Assist Device Implantation AMERICAN JOURNAL OF CARDIOLOGY Drakos, S. G., Janicki, L., Horne, B. D., Kfoury, A. G., Reid, B. B., Clayson, S., Horton, K., Haddad, F., Li, D. Y., Renlund, D. G., Fisher, P. W. 2010; 105 (7): 1030-1035

  Abstract

  Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for >/=48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the beta coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation.

  View details for DOI 10.1016/j.amjcard.2009.11.026

  View details for Web of Science ID 000276576200023

  View details for PubMedID 20346326

• Changing trends in infectious disease in heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Deuse, T., Pham, M., Khazanie, P., Rosso, F., Luikart, H., Valantine, H., Leon, S., Vu, T. A., Hunt, S. A., Oyer, P., Montoya, J. G. 2010; 29 (3): 306-315

  Abstract

  During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation.Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978-1980), (2) 72 in the early cyclosporine era (1982-1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988-1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002-2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil.The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 +/- 77 days, pre-cyclosporine era; 304 +/- 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred.The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.

  View details for DOI 10.1016/j.healun.2009.08.018

  View details for PubMedID 19853478

• New insights for the diagnosis and management of right ventricular failure, from molecular imaging to targeted right ventricular therapy CURRENT OPINION IN CARDIOLOGY Haddad, F., Ashley, E., Michelakis, E. D. 2010; 25 (2): 131-140

  Abstract

  Despite the recognition of a critical role of the right ventricle (RV) in many aspects of cardiovascular medicine, there has been surprisingly little interest in right ventricular-targeted imaging and therapeutic approaches. Compared with the left ventricle, the RV has a different embryologic origin, undergoes a dramatic change during the transition from the fetal to the adult circulation and normally operates in a low resistance or impedance arterial system. Here, we review new insights on the pathophysiology, assessment and management of right ventricular failure.Our understanding of the mechanisms underlying right ventricular failure has improved. As in the left ventricle, decrease in alpha-myosin heavy chain and a switch towards glycolysis from fatty acid oxidation is observed in the stressed RV, but the key question remains unanswered: why is the RV so much more vulnerable to failure upon afterload increase compared with the left ventricle? In assessing the RV, it is becoming increasingly important to consider the RV and pulmonary artery as a unit. New therapies that could specifically target the RV, such as metabolic modulators and phosphodiesterase type 5 inhibitors, are now being considered.A better understanding of the molecular mechanisms of right ventricular failure will lead to the development of new strategies for the diagnosis and management of right ventricular failure. Right ventricular-targeted therapies are needed in a number of diseases in which only the RV fails.

  View details for DOI 10.1097/HCO.0b013e328335febd

  View details for Web of Science ID 000274797100010

  View details for PubMedID 20130456

• Calcineurin plays a modulatory role in loading-induced regulation of type I myosin heavy chain gene expression in slow skeletal muscle AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Pandorf, C. E., Jiang, W. H., Qin, A. X., Bodell, P. W., Baldwin, K. M., Haddad, F. 2009; 297 (4): R1037-R1048

  Abstract

  The role of calcineurin (Cn) in skeletal muscle fiber-type expression has been a subject of great interest because of reports indicating that it controls the slow muscle phenotype. To delineate the role of Cn in phenotype remodeling, particularly its role in driving expression of the type I myosin heavy chain (MHC) gene, we used a novel strategy whereby a profound transition from fast to slow fiber type is induced and examined in the absence and presence of cyclosporin A (CsA), a Cn inhibitor. To induce the fast-to-slow transition, we first subjected rats to 7 days of hindlimb suspension (HS) + thyroid hormone [triiodothyronine (T(3))] to suppress nearly all expression of type I MHC mRNA in the soleus muscle. HS + T(3) was then withdrawn, and rats resumed normal ambulation and thyroid state, during which vehicle or CsA (30 mg x kg(-1) x day(-1)) was administered for 7 or 14 days. The findings demonstrate that, despite significant inhibition of Cn, pre-mRNA, mRNA, and protein abundance of type I MHC increased markedly during reloading relative to HS + T(3) (P < 0.05). Type I MHC expression was, however, attenuated by CsA compared with vehicle treatment. In addition, type IIa and IIx MHC pre-mRNA, mRNA, and relative protein levels were increased in Cn-treated compared with vehicle-treated rats. These findings indicate that Cn has a modulatory role in MHC transcription, rather than a role as a primary regulator of slow MHC gene expression.

  View details for DOI 10.1152/ajpregu.00349.2009

  View details for Web of Science ID 000270184100014

  View details for PubMedID 19657098

• The Efficacy of Implantable Cardioverter-Defibrillators in Heart Transplant Recipients Results From a Multicenter Registry CIRCULATION-HEART FAILURE Tsai, V. W., Cooper, J., Garan, H., Natale, A., Ptaszek, L. M., Ellinor, P. T., Hickey, K., Downey, R., Zei, P., Hsia, H., Wang, P., Hunt, S., Haddad, F., Al-Ahmad, A. 2009; 2 (3): 197-201

  Abstract

  Sudden cardiac death among orthotopic heart transplant recipients is an important mechanism of death after cardiac transplantation. The role for implantable cardioverter-defibrillators (ICDs) in this population is not well established. This study sought to determine whether ICDs are effective in preventing sudden cardiac death in high-risk heart transplant recipients.We retrospectively analyzed the records of all orthotopic heart transplant patients who had ICD implantation between January 1995 and December 2005 at 5 heart transplant centers. Thirty-six patients were considered high risk for sudden cardiac death. The mean age at orthotopic heart transplant was 44+/-14 years, the majority being male (n=29). The mean age at ICD implantation was 52+/-14 years, whereas the average time from orthotopic heart transplant to ICD implant was 8 years +/-6 years. The main indications for ICD implantation were severe allograft vasculopathy (n=12), unexplained syncope (n=9), history of cardiac arrest (n=8), and severe left ventricular dysfunction (n=7). Twenty-two shocks were delivered to 10 patients (28%), of whom 8 (80%) received 12 appropriate shocks for either rapid ventricular tachycardia or ventricular fibrillation. The shocks were effective in terminating the ventricular arrhythmias in all cases. Three (8%) patients received 10 inappropriate shocks. Underlying allograft vasculopathy was present in 100% (8 of 8) of patients who received appropriate ICD therapy.Use of ICDs after heart transplantation may be appropriate in selected high-risk patients. Further studies are needed to establish an appropriate prevention strategy in this population.

  View details for DOI 10.1161/CIRCHEARTFAILURE.108.814525

  View details for Web of Science ID 000269161600007

  View details for PubMedID 19808340

• Angina Associated With Left Main Coronary Artery Compression in Pulmonary Hypertension JOURNAL OF HEART AND LUNG TRANSPLANTATION Perez, V. A., Haddad, F., Vagelos, R. H., Fearon, W., Feinstein, J., Zamanian, R. T. 2009; 28 (5): 527-530

  Abstract

  Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.

  View details for DOI 10.1016/j.healun.2008.12.008

  View details for PubMedID 19416787

• A Novel Non-Invasive Method of Estimating Pulmonary Vascular Resistance in Patients With Pulmonary Arterial Hypertension JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Haddad, F., Zamanian, R., Beraud, A., Schnittger, I., Feinstein, J., Peterson, T., Yang, P., Doyle, R., Rosenthal, D. 2009; 22 (5): 523-529

  Abstract

  The assessment of pulmonary vascular resistance (PVR) plays an important role in the diagnosis and management of pulmonary arterial hypertension (PAH). The main objective of this study was to determine whether the noninvasive index of systolic pulmonary arterial pressure (SPAP) to heart rate (HR) times the right ventricular outflow tract time-velocity integral (TVI(RVOT)) (SPAP/[HR x TVI(RVOT)]) provides clinically useful estimations of PVR in PAH.Doppler echocardiography and right-heart catheterization were performed in 51 consecutive patients with established PAH. The ratio of SPAP/(HR x TVI(RVOT)) was then correlated with invasive indexed PVR (PVRI) using regression and Bland-Altman analysis. Using receiver operating characteristic curve analysis, a cutoff value for the Doppler equation was generated to identify patients with PVRI > or = 15 Wood units (WU)/m2.The mean pulmonary arterial pressure was 52 +/- 15 mm Hg, the mean cardiac index was 2.2 +/- 0.6 L/min/m2, and the mean PVRI was 20.5 +/- 9.6 WU/m2. The ratio of SPAP/(HR x TVI(RVOT)) correlated very well with invasive PVRI measurements (r = 0.860; 95% confidence interval, 0.759-0.920). A cutoff value of 0.076 provided well-balanced sensitivity (86%) and specificity (82%) to determine PVRI > 15 WU/m2. A cutoff value of 0.057 increased sensitivity to 97% and decreased specificity to 65%.The novel index of SPAP/(HR x TVI(RVOT)) provides useful estimations of PVRI in patients with PAH.

  View details for DOI 10.1016/j.echo.2009.01.021

  View details for PubMedID 19307098

• Right Ventricular Dysfunction Predicts Poor Outcome Following Hemodynamically Compromising Rejection JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Fisher, P., Pham, M., Berry, G., Weisshaar, D., Kuppahally, S., Vrtovec, B., Deuse, T., Virani, S., Fearon, W., Valantine, H., Hunt, S. 2009; 28 (4): 312-319

  Abstract

  Hemodynamically compromising rejection (HCR) is a major cause of mortality and morbidity after heart transplantation. Right ventricular (RV) function is a strong predictor of outcome in patients with heart failure and myocarditis. The objective of the current study is to determine whether RV dysfunction predicts event-free survival in patients with HCR.Medical records of 548 heart transplant patients followed at Stanford University between January 1998 and January 2007 were reviewed. HCR was defined as a rejection episode requiring hospitalization for heart failure. Univariate and multivariate analyses were performed to identify risk factors for death or retransplantation at 1 year.HCR occurred in 71 patients (12.9%). Death or retransplantation at 1 year occurred in 28 patients (39%). Univariate analysis identified non-cellular rejection (odds ratio [OR] = 3.20, p = 0.021), the need for inotropic support (OR = 4.80, p = 0.007), RV dysfunction (OR = 4.63, p = 0.006), left ventricular ejection fraction (OR = 0.941, p = 0.031) and acute renal failure (OR = 3.82, p = 0.010) as predictors of death or retransplantation at 1 year. Multivariate analysis identified RV dysfunction (OR = 4.80, p = 0.007) and the need for inotropic support (OR = 5.00, p = 0.009) as predictors of death or retransplantation at 1 year.In the modern era of immunosuppression, HCR remains a major complication after heart transplantation. RV dysfunction was identified as a novel risk factor for death or retransplantation following HCR.

  View details for DOI 10.1016/j.healun.2008.12.023

  View details for PubMedID 19332256

• Microvascular Dysfunction and Suboptimal Glycemic Control Predicts Poor Outcome Following Heart Transplantation 58th Annual Scientific Session of the American-College-of-Cardiology Khazanie, P., Haddad, F., Simos, A. M., Pham, M., Weisshaar, D. M., Desai, S. V., Shah, M. G., McLaughlin, T. L., Hunt, S. A., Valantine, H. A., Fearon, W. ELSEVIER SCIENCE INC. 2009: A182–A182

  View details for Web of Science ID 000263864200760

• Diabetes Does Not Affect Ventricular Repolarization and Sudden Cardiac Death Risk in Patients with Dilated Cardiomyopathy PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Vrtovec, B., Fister, M., Poglajen, G., Starc, V., Haddad, F. 2009; 32: S146-S150

  Abstract

  We studied the effects of diabetes on ventricular repolarization parameters and sudden cardiac death in patients with dilated cardiomyopathy (DCM).We enrolled 132 consecutive patients in New York Heart Association (NYHA) heart failure functional classes II or III and left ventricular ejection fraction <40% without evidence of coronary artery disease. In 45 patients (34%), diabetes was diagnosed according to standard criteria (study group), and the remaining 87 (66%) had no diabetes (controls). All patients underwent a 5-minute high-resolution electrocardiogram recording for determination of QT variability (QTV) index and were followed for 1 year thereafter.At baseline, the two groups did not differ in age, gender, left ventricular ejection fraction, NYHA functional class, or plasma brain natriuretic peptide levels. Similarly, QTV index did not differ between the study group (-0.51 +/- 0.55) and controls (-0.48 +/- 0.51; P = 0.48). During follow-up, 18 patients (14%) died of cardiac causes. Of the 18 deaths, eight were attributed to heart failure, and 10 to sudden cardiac death. Mortality was higher in the study group (10/45, 20%) than in controls (8/87, 10%) (P = 0.03). The same was true of the heart failure mortality (6/45 [13%] vs 2/87 [2%], P = 0.01), but not of the sudden cardiac death rate (3/45 [7%] vs 7/87 [8%], P = 0.78). By multiple variable analyses, diabetes predicted total and heart failure mortality, and a high QTV predicted sudden cardiac death.Diabetes appears to increase the risk of heart failure in patients with DCM without affecting ventricular repolarization parameters and sudden cardiac death risk.

  View details for Web of Science ID 000266562900034

  View details for PubMedID 19250080

• The Right Ventricle in Cardiac Surgery, a Perioperative Perspective: II. Pathophysiology, Clinical Importance, and Management ANESTHESIA AND ANALGESIA Haddad, F., Couture, P., Tousignant, C., Denault, A. Y. 2009; 108 (2): 422-433

  Abstract

  The importance of right ventricular (RV) function in cardiovascular disease and cardiac surgery has been recognized for several years. RV dysfunction has been shown to be a significant prognostic factor in cardiac surgery and heart transplantation. In the first article of this review, key features of RV anatomy, physiology, and assessment were presented. In this second part, we review the pathophysiology, clinical importance, and management of RV failure in cardiac surgery.

  View details for DOI 10.1213/ane.0b013e31818d8b92

  View details for Web of Science ID 000262590000005

  View details for PubMedID 19151265

• Microvascular Drysfunction and Suboptimal Glycemic Control Predicts Poor Outcome Following Heart Transplantation 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation Khazanie, P., Haddad, F., Simos, A. M., Weissbaar, D. M., Desai, S. V., Pham, M., McLaugblin, T. L., Shah, M. G., Hunt, S. A., Valantine, H. A., Fearon, W. ELSEVIER SCIENCE INC. 2009: S228–S228

  View details for Web of Science ID 000263539800464

• Changing Trends in Infectious Complications among Heart Transplant Recipients 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation Haddad, F., Deuse, T., Rosso, P., Pham, M., Khazanie, P., Luikart, H., Valantine, H. A., Hunt, S. A., Vu, T., Oyer, P. E., Robbins, R. C., Montoya, J. G. ELSEVIER SCIENCE INC. 2009: S237–S238

  View details for Web of Science ID 000263539800490

• The Right Ventricle in Cardiac Surgery, a Perioperative Perspective: I. Anatomy, Physiology, and Assessment ANESTHESIA AND ANALGESIA Haddad, F., Couture, P., Tousignant, C., Denault, A. Y. 2009; 108 (2): 407-421

  Abstract

  The importance of right ventricular (RV) function in cardiovascular disease and cardiac surgery has been recognized for several years. RV dysfunction has been shown to be a significant prognostic factor in heart failure, congenital heart disease, valvular disease, and cardiac surgery. In the first of our two articles, we will review key features of RV anatomy, physiology, and assessment. In the first article, the main discussion will be centered on the echographic assessment of RV structure and function. In the second review article, pathophysiology, clinical importance, and management of RV failure in cardiac surgery will be discussed.

  View details for DOI 10.1213/ane.0b013e31818f8623

  View details for Web of Science ID 000262590000004

  View details for PubMedID 19151264

• Intergenic transcription and developmental regulation of cardiac myosin heavy chain genes AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Haddad, F., Qin, A. X., Bodell, P. W., Jiang, W., Giger, J. M., Baldwin, K. M. 2008; 294 (1): H29-H40

  Abstract

  Cardiac myosin heavy chain (MHC) gene expression undergoes a rapid transition from beta- to alpha-MHC during early rodent neonatal development (0-21 days of age). Thyroid hormone (3,5,3'-triiodothyronine, T(3)) is a major player in this developmental shift; however, the exact mechanism underlying this transition is poorly understood. The goal of this study was to conduct a more thorough analysis of transcriptional activity of the cardiac MHC gene locus during the early postnatal period in the rodent, in order to gain further insight on the regulation of cardiac MHC genes. We analyzed the expression of alpha- and beta-MHC at protein, mRNA, and pre-mRNA levels at birth and 7, 10, 15, and 21 days after birth in euthyroid and hypothyroid rodents. Using novel technology, we also analyzed RNA expression across the cardiac gene locus, and we discovered that the intergenic (IG) region between the two cardiac genes possesses bidirectional transcriptional activity. This IG transcription results in an antisense RNA product as described previously, which is thought to exert an inhibitory effect on beta-MHC gene transcription. On the second half of the IG region, sense transcription occurs, resulting in expression of a sense IG RNA that merges with the alpha-MHC pre-mRNA. This sense IG RNA transcription was detected in the alpha-MHC gene promoter, approximately -1.8 kb relative to the alpha-MHC transcription start site. Both sense and antisense IG RNAs were developmentally regulated and responsive to a hypothyroid state (11, 14). This novel observation provides more complexity to the cooperative regulation of the two genes, suggesting the involvement of epigenetic processes in the regulation of cardiac MHC gene locus.

  View details for DOI 10.1152/ajpheart.01125.2007

  View details for Web of Science ID 000252261200007

  View details for PubMedID 17982008

• Outcome in cardiac recipients of donor hearts with increased left ventricular wall thickness AMERICAN JOURNAL OF TRANSPLANTATION Kuppahally, S. S., Valantine, H. A., Weisshaar, D., Parekh, H., Hung, Y. Y., Haddad, F., Fowler, M., Vagelos, R., Perlroth, M. G., Robbins, R. C., Hunt, S. A. 2007; 7 (10): 2388-2395

  Abstract

  The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

  View details for DOI 10.1111/j.1600-6143.2007.01930.x

  View details for Web of Science ID 000249167000022

  View details for PubMedID 17845572

• Management strategies for patients with pulmonary hypertension in the intensive care unit CRITICAL CARE MEDICINE Zamanian, R. T., Haddad, F., Doyle, R. L., Weinacker, A. B. 2007; 35 (9): 2037-2050

  Abstract

  Pulmonary hypertension may be encountered in the intensive care unit in patients with critical illnesses such as acute respiratory distress syndrome, left ventricular dysfunction, and pulmonary embolism, as well as after cardiothoracic surgery. Pulmonary hypertension also may be encountered in patients with preexisting pulmonary vascular, lung, liver, or cardiac diseases. The intensive care unit management of patients can prove extremely challenging, particularly when they become hemodynamically unstable. The objective of this review is to discuss the pathogenesis and physiology of pulmonary hypertension and the utility of various diagnostic tools, and to provide recommendations regarding the use of vasopressors and pulmonary vasodilators in intensive care.We undertook a comprehensive review of the literature regarding the management of pulmonary hypertension in the setting of critical illness. We performed a MEDLINE search of articles published from January 1970 to March 2007. Medical subject headings and keywords searched and cross-referenced with each other were: pulmonary hypertension, vasopressor agents, therapeutics, critical illness, intensive care, right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil, dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both human and animal studies related to pulmonary hypertension were reviewed.Pulmonary hypertension presents a particular challenge in critically ill patients, because typical therapies such as volume resuscitation and mechanical ventilation may worsen hemodynamics in patients with pulmonary hypertension and right ventricular failure. Patients with decompensated pulmonary hypertension, including those with pulmonary hypertension associated with cardiothoracic surgery, require therapy for right ventricular failure. Very few human studies have addressed the use of vasopressors and pulmonary vasodilators in these patients, but the use of dobutamine, milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest support in the literature. Treatment of pulmonary hypertension resulting from critical illness or chronic lung diseases should address the primary cause of hemodynamic deterioration, and pulmonary vasodilators usually are not necessary.

  View details for DOI 10.1097/01.CCM.0000280433.74246.9E

  View details for PubMedID 17855818

• Active bacterial myocarditis: A case report and review of the literature JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Berry, G., Doyle, R. L., Martineau, P., Leung, T., Racine, N. 2007; 26 (7): 745-749

  Abstract

  Bacterial myocarditis (BM) is an uncommon cause of infectious myocarditis. BM is usually seen in the context of overwhelming sepsis or as part of a specific bacterial syndrome. The definitive diagnosis of bacterial myocarditis requires biopsy or morphologically proven active myocarditis with evidence of bacterial invasion or positive tissue cultures. The management of bacterial myocarditis consists of aggressive and early antibiotic or anti-toxin treatment, appropriate hemodynamic support, and treatment of arrhythmias or mechanical complications. We present a case of acute Listeria monocytogenes myocarditis in an immunocompetent patient and highlight the challenges in the diagnosis and treatment of bacterial myocarditis.

  View details for DOI 10.1016/j.healun.2007.04.010

  View details for Web of Science ID 000248195700014

  View details for PubMedID 17613408

• Long term outcomes in adult heart transplant recipients treated with OKT3 versus daclizumab induction therapy. 7th American Transplant Congress Virani, S. A., Ransohoff, K., Haddad, F., Valantine, H. A., Chin, C. WILEY-BLACKWELL. 2007: 424–424

  View details for Web of Science ID 000246370201514

• Pulmonary nocardiosis in a heart transplant patient: Case report and review of the literature JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Hunt, S. A., Perlroth, M., Valantine, H., Doyle, R., Montoya, J. 2007; 26 (1): 93-97

  Abstract

  Pulmonary infection with Nocardia is an uncommon but serious infection found in immunocompromised patients. We describe a rapidly progressive pulmonary nocardiosis in a heart transplant patient. We then review the common clinical features of Nocardia infection in transplant recipients, outlining the challenges in its diagnosis and management. We also review the differences between Pneumocystis jiroveci prophylaxis regimens with respect to concomitant prophylaxis of Nocardia and other opportunistic infections.

  View details for DOI 10.1016/j.healun.2006.11.002

  View details for PubMedID 17234524

• Inhaled milrinone: a new alternative in cardiac surgery? Seminars in cardiothoracic and vascular anesthesia Denault, A. Y., Lamarche, Y., Couture, P., Haddad, F., Lambert, J., Tardif, J., Perrault, L. P. 2006; 10 (4): 346-360

  Abstract

  The administration of milrinone through inhalation has been studied in only a few animal and human studies. Compared to the intravenous administration, inhaled milrinone has been shown to reduce pulmonary artery pressure without systemic hypotension. Therefore, this approach could represent an alternative to nitric oxide. This current state of knowledge of intravenous and inhaled milrinone is presented and summarized.

  View details for PubMedID 17200091

• Giant coronary aneurysms in heart transplantation: an unusual presentation of cardiac allograft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Perez, M., Fleischmann, D., Valantine, H., Hunt, S. A. 2006; 25 (11): 1367-1370

  Abstract

  Cardiac allograft vasculopathy is a leading cause of death during long-term follow-up of heart transplant recipients. We report 2 cases of cardiac allograft vasculopathy associated with giant coronary aneurysms. To our knowledge, these are the first reported cases of spontaneous giant coronary aneurysms in heart transplant recipients.

  View details for DOI 10.1016/j.healun.2006.07.006

  View details for Web of Science ID 000242222100015

  View details for PubMedID 17097503

• Left and right ventricular diastolic dysfunction as predictors of difficult separation from cardiopulmonary bypass CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Denault, A. Y., Couture, P., Buithieu, J., Haddad, F., Carrier, M., Babin, D., Levesque, S., Tardif, J. 2006; 53 (10): 1020-1029

  Abstract

  As the evaluation of diastolic function can be complex in the setting of a busy cardiac operating room, its assessment may benefit from an algorithmic approach using transesophageal echocardiography. We developed a diagnostic algorithm which was then applied in a series of cardiac surgery patients to determine whether moderate to severe left ventricular diastolic dysfunction (LVDD) and right ventricular diastolic dysfunction (RVDD) can predict difficult separation from cardiopulmonary bypass (DSB).An algorithm using pulsed-wave Doppler interrogation of the mitral and tricuspid valve, the pulmonary and hepatic venous flow, and tissue Doppler interrogation of the mitral and tricuspid annulus was developed. The study was divided in two phases involving two groups of patients undergoing cardiac surgery. In phase I, echocardiographic evaluations of patients (n = 74) were used to test the reproducibility of the algorithm and to evaluate inter-observer variability using Cohen's kappa values which were calculated in three specific periods. In phase II, the algorithm was applied to a second group of patients (validation group, n = 179) to explore its prognostic significance. The primary end-point in phase II was DSB.In phase I, the kappa coefficients for LVDD and RVDD algorithms were 0.77 and 0.82, respectively. In phase II, moderate or severe degrees of LVDD were observed in 29 patients (16%) and moderate to severe RVDD was observed in 18 patients (10%) before cardiac surgery. Both moderate and severe LVDD (P = 0.017) and RVDD (P = 0.049) before surgery were observed more frequently in patients with DSB.Moderate and severe LVDD and RVDD can be identified with very good reproducibility, and both degrees of diastolic dysfunction are associated with DSB.

  View details for Web of Science ID 000241350900012

  View details for PubMedID 16987858

• Dynamic right ventricular outflow tract obstruction in cardiac surgery JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Denault, A. Y., Chaput, M., Couture, P., Hebert, Y., Haddad, F., Tardif, J. 2006; 132 (1): 43-49

  Abstract

  Right ventricular outflow tract obstruction can be a cause of hemodynamic instability but it has not been described in non-congenital cardiac surgery.The prevalence of right ventricular outflow tract obstruction was retrospectively studied in 670 consecutive patients undergoing cardiac surgery. Significant right ventricular outflow tract obstruction was diagnosed if the right ventricular systolic to pulmonary artery peak gradient was more than 25 mm Hg. The diagnosis was based on measurement of the right ventricular and pulmonary artery systolic pressure through the paceport and distal opening of the pulmonary artery catheter. To further validate the prevalence and the importance of right ventricular outflow tract obstruction, 130 patients were prospectively studied over a 12-month period.In the retrospective cohort, 6 patients (1%) undergoing various types of cardiac surgical procedures were found to have significant dynamic right ventricular outflow tract obstruction with a mean gradient of 31 +/- 4 mm Hg (26 to 35 mm Hg). In the prospective study significant dynamic right ventricular outflow tract obstruction was identified in 5 patients (4%) (average peak: 37 +/- 15 mm Hg; range: 27 to 60 mm Hg). The typical transesophageal echocardiography finding was end-systolic obliteration of the right ventricular outflow tract. In patients with significant dynamic right ventricular outflow tract obstruction, hemodynamic instability was present in 10/11 patients (91%).Right ventricular outflow tract obstruction is easily diagnosed using the paceport of the pulmonary artery catheter and should be considered as a potential cause of hemodynamic instability especially when transesophageal echocardiography reveals systolic right ventricular cavity obliteration.

  View details for DOI 10.1016/j.jtcvs.2006.03.014

  View details for Web of Science ID 000238522000011

  View details for PubMedID 16798301