Kiran Kaur Khush, MD, MAS

All Publications

• Current opinions in organ allocation AMERICAN JOURNAL OF TRANSPLANTATION Achille, M., Agarwal, G., Albert, M., Amarelli, C., Baran, D. A., Blosser, C., Brown, K., Bucuvalas, J., Butler, C. R., Caicedo, J. C., Caulfield, T., Cendales, L. C., Chadban, S., Cooper, M., Dalal, P., Danovitch, G., Delos Santos, R., Denu, R. A., Devuni, D., Foley, D. P., Formica, R. N., Forsythe, J., Fortin, M., Foster, B. J., Fowler, K. J., Friedewald, J., Friedman, B., Gentry, S., Gill, J. S., Gill, J., Glazier, A., Goldberg, D., Golebiewska, J. E., Gordon, E. J., Greenwald, M. A., Gross, J., Halazun, K. J., Hammel, L., Hays, R. A., Heimbach, J., Hippen, B., Hsu, E. K., Husain, S., Jadlowiec, C. C., Jevnikar, A., Jhajj, G., Johnson, M., Kamoun, M., Kapnadak, S. G., Karp, S. J., Kayler, L., Khush, K. K., Kinkhabwala, M., Kulkarni, S., Kute, V., Kwong, A. J., La Muraglia Ii, G., Lai, J. C., Lavee, J., Lentine, K., Levitsky, J., Lynch, R., Mahdavi-Mazdeh, M., Manonelles, A., Mansard, M., Mathur, A. K., McEvoy, C., McIntosh, C. M., Mohan, S., Muller, E., Mulvihill, M. S., Newell, K., Ogdon, J., Orlowski, J., Parajuli, S., Patel, J. K., Patzer, R., Peradejordi, M., Rahmel, A., Riella, L., Roll, G. R., Ruff, S. F., Samuel, U., Sawinski, D., Schaffer, R. L., Schmidt, L., Schold, J., Shaffer, A. A., Shah, R. A., Sharma, P., Shawar, S., Sholkamy, A., Snyder, J., Solez, K., Sosa, R. A., Stehlik, J., Sweet, S., Taner, T., Thomas, A. G., Treleaven, D., Webster, A. C., West, S. C., Westphal, S. G., White, D. M., Witkowski, P., Wojciechowski, D., Woodle, E., Yabu, J. M., Amer Journal Transplantation 2018; 18 (11): 2625–34

  Abstract

  Existing methods of academic publication provide limited opportunity to obtain stakeholder input on issues of broad interest. This article reports the results of an experiment to produce a collaborative, crowdsourced article examining a current controversial issue in transplant medicine (hereby referred to as the "C4 Article"). The editorial team as a whole selected the topic of organ allocation, then divided into six sections, each supported by an individual editorial team. Widely promoted by the American Journal of Transplantation, the C4 Article was open for public comment for 1 month. The nonblinded editorial teams reviewed the contributions daily and interacted with contributors in near-real time to clarify and expand on the content received. Draft summaries of each section were posted and subsequently revised as new contributions were received. One hundred ninety-four individuals viewed the manuscript, and 107 individuals contributed to the manuscript during the submission period. The article engaged the international transplant community in producing a contemporary delineation of issues of agreement and controversy related to organ allocation and identified opportunities for new policy development. This initial experience successfully demonstrated the potential of a crowdsourced academic manuscript to advance a broad-based understanding of a complex issue.

  View details for DOI 10.1111/ajt.15094

  View details for Web of Science ID 000449512400007

  View details for PubMedID 30303603

• Increasing complexity of thoracic transplantation and the rise of multiorgan transplantation around the world: Insights from the International Society for Heart and Lung Transplantation Registry. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Stehlik, J., Chambers, D. C., Zuckermann, A., Mehra, M. R., Khush, K. K. 2018; 37 (10): 1145–54

  View details for DOI 10.1016/j.healun.2018.07.016

  View details for PubMedID 30293611

• Longitudinal Changes in Kidney Function Following Heart Transplantation: Stanford Experience. Clinical transplantation Taiwo, A., Khush, K., Stedman, M. R., Zheng, Y., Tan, J. C. 2018: e13414

  Abstract

  Many heart transplant recipients experience declining kidney function following transplantation. We aimed toquantify change in kidney function in heart transplant recipients stratified by pre-transplant kidney function. 230 adult heart transplant recipients between May 1, 2008 and December 31, 2014 were evaluated for up to 5 years post-transplant (median 1 year). Using 19,398 total eGFR assessments, we evaluated trends in estimated glomerular filtration rate (eGFR) in recipients with normal/near normal (eGFR >45 mL/min/1.73m2 ) versus impaired (eGFR <45 mL/min/1.73m2 ) kidney function and the likelihood of reaching an eGFR of 20 mL/min/1.73m2 after heart transplant. Baseline characteristics were similar. Immediately following heart transplant, the impaired pre-transplant kidney function group showed a mean eGFR gain of 9.5mL/min/1.73m2 (n=193) versus a mean decline of 4.9 mL/min/1.73m2 (n=37) in the normal/near normal group. Subsequent rates of eGFR decline were 2.2 mL/min/1.73m2 /yrversus2.9 mL/min/1.73m2 /yr, respectively. The probability of reaching an eGFR of 20 mL/min/1.73m2 or less at 1, 5, and 10 years following heart transplant was 1%, 4% and 30% in the impaired group, and <1%, <1%, and 10% in the normal/near normal group. Estimates of expected recovery in kidney function and its decline over time will help inform decision making about kidney care after heart transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13414

  View details for PubMedID 30240515

• Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Moayedi, Y., Foroutan, F., Miller, R. J., Fan, C. S., Posada, J. G., Alhussein, M., Tremblay-Gravel, M., Oro, G., Luikart, H. I., Yee, J., Shullo, M. A., Khush, K. K., Ross, H. J., Teuteberg, J. J. 2018

  Abstract

  BACKGROUND: Gene expression profiling (GEP) was developed for non-invasive surveillance of acute cellular rejection. Despite its widespread use, there has been a paucity in outcome data for patients managed with GEP outside of clinical trials.METHODS: The Outcomes AlloMap Registry (OAR) is an observational, prospective, multicenter study including patients aged ≥ 15 years and ≥ 55 days post-cardiac transplant. Primary outcome was death and a composite outcome of hemodynamically significant rejection, graft dysfunction, retransplantation, or death. Secondary outcomes included readmission rates and development of coronary allograft vasculopathy and malignancies.RESULTS: The study included 1,504 patients, who were predominantly Caucasian (69%), male (74%), and aged 54.1 ± 12.9 years. The prevalence of moderate to severe acute cellular rejection (≥2R) was 2.0% from 2 to 6 months and 2.2% after 6 months. In the OAR there was no association between higher GEP scores and coronary allograft vasculopathy (p = 0.25), cancer (p = 0.16), or non-cytomegalovirus infection (p = 0.10). Survival at 1, 2, and 5 years post-transplant was 99%, 98%, and 94%, respectively. The composite outcome occurred in 103 patients during the follow-up period. GEP scores in dual-organ recipients (heart-kidney and heart-liver) were comparable to heart-alone recipients.CONCLUSIONS: This registry comprises the largest contemporary cohort of patients undergoing GEP for surveillance. Among patients selected for GEP surveillance, survival is excellent, and rates of acute rejection, graft dysfunction, readmission, and death are low.

  View details for DOI 10.1016/j.healun.2018.09.004

  View details for PubMedID 30352779

• Transplant phenomapping: A move toward personalized immunosuppression. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Khush, K. K. 2018; 37 (8): 943–44

  View details for DOI 10.1016/j.healun.2018.05.005

  View details for PubMedID 30055812

• Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Jackson, A. M., Tunc, I., Berry, G. J., Cochrane, A., Grimm, D., Davis, A., Shah, P., Brown, A. W., Wang, Y., Timofte, I., Shah, P., Gorham, S., Wylie, J., Goodwin, N., Jang, M., Marishta, A., Bhatti, K., Fideli, U., Yang, Y., Luikart, H., Cao, Z., Pirooznia, M., Zhu, J., Marboe, C., Iacono, A., Nathan, S. D., Orens, J., Valantine, H. A., Khush, K. 2018; 37 (7): 925–32

  Abstract

  Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs.Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

  View details for DOI 10.1016/j.healun.2018.01.1305

  View details for Web of Science ID 000438014300015

  View details for PubMedID 29500138

• Accepting hepatitis C virus infected donor hearts for transplantation: Multi-step consent, unrealized opportunity, and the Stanford experience. Clinical transplantation Moayedi, Y., Gulamhusein, A. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2018: e13308

  Abstract

  The current mismatch between supply of and demand for donor organs has prompted transplant clinicians to consider innovative solutions to broaden the donor pool. Despite a 10% increase in the number of organ donors available from 2015 to 2016, wait times remain unacceptable for the 4,000 patients listed for heart transplantation in the United States (US). (1) Many hearts that would otherwise be acceptable go unused because the donors have hepatitis C virus (HCV). Advancements and availability of highly efficacious and safe direct acting antiviral (DAA) therapy for chronic HCV allows consideration of use of organs from viremic, nucleic acid testing (NAT) positive donors in HCV negative recipients. We describe Stanford's experience with using organs from HCV infected donors for heart transplantation and the associated ethical implications and programmatic planning required, as put forth in the recent American Society of Transplantation (AST) meeting report (May 2017).(2) This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13308

  View details for PubMedID 29869354

• New Horizons on the 50th Anniversary of Heart Transplantation in Canada: "Where There Is Death, There Is Hope" CANADIAN JOURNAL OF CARDIOLOGY Moayedi, Y., Alhussein, M., Posada, J., Kozuszko, S., Khush, K. K., Teuteberg, J. J., Badiwala, M. V., Ross, H. J. 2018; 34 (6): 694–95

  View details for DOI 10.1016/j.cjca.2018.02.002

  View details for Web of Science ID 000433209800002

  View details for PubMedID 29703422

• Disclosure of infectious risk to heart transplant candidates: Shared decision-making is here to stay JOURNAL OF HEART AND LUNG TRANSPLANTATION Moayedi, Y., Ross, H. J., Khush, K. K. 2018; 37 (5): 564–67

  Abstract

  The Public Health Service has defined 12 criteria of increased-risk (PHS-IR) for transmissible viral infections in potential organ donors where clinicians are required to document informed consent. Over the last decade, there has been a near tripling of PHS-IR donor organs in the United States. In light of the paucity in guidelines and consensus statements to guide clinicians on how to provide informed consent to potential recipients, using a typical case, we provide an overview including: how to effectively communicate infectious risk, whether clinicians should decline PHS-IR organs, the need to standardize disclosure practice across centers and finally how much information about the donor should be communicated to the transplant candidate. Many patients can be empowered by involving them in shared decision making to understand the minimal risk associated with the use of PHS-IR organs; an important step in improving donor utilization.

  View details for DOI 10.1016/j.healun.2017.12.014

  View details for Web of Science ID 000432164900003

  View details for PubMedID 29395752

• IMPACT OF ENDOTHELIN-1 ON CARDIAC ALLOGRAFT VASCULOPATHY, LATE MORTALITY AND RE-TRANSPLANTATION FOLLOWING HEART TRANSPLANTATION Parikh, R., Khush, K., Luikart, H., Grimm, D., Yu, M., Yeung, A., Valantine, H., Fearon, W. ELSEVIER SCIENCE INC. 2018: 2667

  View details for DOI 10.1016/S0735-1097(18)33208-X

  View details for Web of Science ID 000429659705117

• Throwing out the good with the bad: Declining potential donor hearts with left ventricular dysfunction JOURNAL OF HEART AND LUNG TRANSPLANTATION Moayedi, Y., Khush, K. K. 2018; 37 (3): 321–22

  View details for DOI 10.1016/j.healun.2017.09.009

  View details for Web of Science ID 000427400800004

  View details for PubMedID 29029801

• Change in lymphocyte to neutrophil ratio predicts acute rejection after heart transplantation. International journal of cardiology Choi, D. H., Kobayashi, Y., Nishi, T., Luikart, H., Dimbil, S., Kobashigawa, J., Khush, K., Fearon, W. F. 2018; 251: 58–64

  Abstract

  Most immunosuppressive drugs provide targeted immunosuppression by selective inhibition of lymphocyte activation and proliferation. This study evaluated whether a change in the lymphocyte to neutrophil ratio (LNR) is related to acute rejection.In 74 cardiac transplant recipients peripheral blood lymphocyte and neutrophil counts were measured soon after (baseline) and three, six, and 12months after heart transplantation. The primary endpoint was the incidence of acute rejection.Significant acute rejection after heart transplantation occurred in 20 patients (27%) during a median follow-up of 49.4 [IQR 37.4-61.1] months. LNR significantly increased over time (0.1149±0.1354 at baseline, 0.2330±0.2266 at 3months, 0.2961±0.2849 at 6months, and 0.3521±0.2383 at 12months; P<0.001), especially during the first 3months in the group without acute rejection. The area under the curve of the change in LNR during the first three months (ΔLNR) for acute rejection was 0.565 (95% CI 0.420 to 0.710, P=0.380) on ROC curve analysis. The best cutoff value of Δ LNR to differentiate those with and without acute rejection was ≤0.046 by ROC curve analysis. Kaplan-Meier analysis revealed that the low ΔLNR group (≤0.046) had a significantly higher rate of acute rejection than the high ΔLNR group (>0.046) (37.5% vs. 19.0%, log-rank: P=0.0358). The low ΔLNR for the first 3months was an independent predictor of clinically significant acute rejection after adjusting for cytomegalovirus donor seropositive and recipient seronegative.The results of this study suggest that ΔLNR over the first 3months after heart transplantation is a strong and independent predictor of acute rejection after heart transplantation. ΔLNR can be used as an early biomarker for predicting of acute rejection after heart transplantation.

  View details for DOI 10.1016/j.ijcard.2017.10.060

  View details for PubMedID 29074043

• Donor selection in the modern era ANNALS OF CARDIOTHORACIC SURGERY Khush, K. K. 2018; 7 (1): 126–34

  Abstract

  The growing disparity between the supply of donor hearts for transplantation and the demand for such organs has led to liberalization of the criteria for donor heart acceptance over the past few decades. The upper age limit and size restrictions for donor heart acceptance continue to be revised and hearts are being routinely used from donors with left ventricular dysfunction, left ventricular hypertrophy (LVH), cocaine use, multiple medical co-morbidities and after cardiopulmonary resuscitation. This article reviews recent data for use of such "expanded criteria" donor hearts and suggests ways to further increase the donor pool, including use of hearts from donors with hepatitis C and after circulatory determination of death. Donor biomarkers and risk scores may eventually aid in heart acceptance decisions, while ethical issues surrounding information sharing with transplant recipients remain a topic of great debate.

  View details for DOI 10.21037/acs.2017.09.09

  View details for Web of Science ID 000425924700015

  View details for PubMedID 29492390

  View details for PubMedCentralID PMC5827134

• 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 DOI 10.1016/j.ijcard.2018.01.070

  View details for PubMedID 29622448

• Molecular Diagnostic Testing in Cardiac Transplantation CURRENT CARDIOLOGY REPORTS Khush, K., Zarafshar, S. 2017; 19 (11): 118

  Abstract

  Acute rejection is one of the most feared complications of cardiac transplantation. Developing non-invasive methods for detection and surveillance of acute rejection have long been a goal for post-transplant care.Here, we will review molecular diagnostic tests that are currently in use or under development to diagnose acute cellular rejection after cardiac transplantation. Gene expression, microRNA, molecular microscope, and cell-free DNA assays offer non-invasive alternatives to the endomyocardial biopsy for acute rejection surveillance.

  View details for DOI 10.1007/s11886-017-0915-1

  View details for Web of Science ID 000413208200002

  View details for PubMedID 29030720

• The Conundrum of Equitable Organ Allocation in Heart Transplantation: The Moving Target of Candidate Risk Score. Transplantation Potena, L., Khush, K. K. 2017

  View details for DOI 10.1097/TP.0000000000001841

  View details for PubMedID 28590947

• Report from the American society of transplantation conference on donor heart selection in adult cardiac transplantation in the U.S. American journal of transplantation Kobashigawa, J., Khush, K., Colvin, M., Acker, M., Van Bakel, A., Eisen, H., Naka, Y., Patel, J., Baran, D. A., Daun, T., Luu, M., Olymbios, M., Rogers, J., Jeevanandam, V., Esmailian, F., Pagani, F. D., Lima, B., Stehlik, J. 2017

  Abstract

  Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less-than-optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

  View details for DOI 10.1111/ajt.14354

  View details for PubMedID 28510318

• Combined heart lung transplantation: an updated review of the current literature. Transplantation Pasupneti, S., Dhillon, G., Reitz, B., Khush, K. 2017

  Abstract

  Heart lung transplantation is a viable treatment option for patients with many end stage heart and lung pathologies. However, given the complex nature of the procedure, it is imperative that patients are selected appropriately and the clinician is aware of the many unique aspects in management of this population. This review seeks to describe updated organ selection policies, peri and postoperative management strategies, monitoring of graft function, and clinical outcomes for patients following combined heart-lung transplantation in the current era.

  View details for DOI 10.1097/TP.0000000000001820

  View details for PubMedID 28505026

• Personalized treatment in heart transplantation. Current opinion in organ transplantation Khush, K. K. 2017

  Abstract

  We are entering the era of personalized medicine, in which pharmacogenomics and biomarker-based assays can be used to tailor diagnostic tests and drug therapies to individual patients. This new approach to patient-specific care offers the potential to maximize the efficacy of available medical treatments while reducing the incidence of adverse side effects. Here, we present approaches to personalize the care of heart transplant recipients.Four strategies for personalized posttransplant care are described, including use of pharmacogenomic data to individualize the use of immunosuppressive drugs, immune monitoring to prevent acute rejection while reducing the long-term consequences of over immunosuppression, noninvasive surveillance for acute rejection, and targeted prophylaxis against opportunistic infections.The long-term survival of heart transplant recipients is limited by side effects of immunosuppressive drugs, including infectious complications, renal dysfunction, and malignancy. We discuss strategies to maximize the benefits of immunosuppressive and prophylactic therapies while minimizing their long-term toxicities.

  View details for DOI 10.1097/MOT.0000000000000406

  View details for PubMedID 28266942

• The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Choi, D. H., Chmura, S. A., Ramachandran, V., Dionis-Petersen, K. Y., Kobayashi, Y., Nishi, T., Luikart, H., Dimbil, S., Kobashigawa, J., Khush, K., Lewis, D. B., Fearon, W. F. 2017

  Abstract

  The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection.Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%).Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection.A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection.

  View details for DOI 10.1016/j.healun.2017.10.012

  View details for PubMedID 29198869

• 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 DOI 10.1016/j.jchf.2017.10.011

  View details for PubMedID 29191301

• Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy. Journal of the American College of Cardiology Okada, K., Fearon, W. F., Luikart, H., Kitahara, H., Otagiri, K., Tanaka, S., Kimura, T., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Honda, Y. 2016; 68 (4): 382-392

  Abstract

  Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events.This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation.In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation.At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality.ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

  View details for DOI 10.1016/j.jacc.2016.05.028

  View details for PubMedID 27443435

  View details for PubMedCentralID PMC4959008

• Assessment of Heart Transplant Waitlist Time and Pre- and Post-transplant Failure A Mixed Methods Approach EPIDEMIOLOGY Goldstein, B. A., Thomas, L., Zaroff, J. G., John Nguyen, J., Menza, R., Khush, K. K. 2016; 27 (4): 469-476

  View details for DOI 10.1097/EDE.0000000000000472

  View details for Web of Science ID 000379847600007

• Single-stranded DNA library preparation uncovers the origin and diversity of ultrashort cell-free DNA in plasma SCIENTIFIC REPORTS Burnham, P., Kim, M. S., Agbor-Enoh, S., Luikart, H., Valantine, H. A., Khush, K. K., De Vlaminck, I. 2016; 6

  Abstract

  Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100 bp nuclear genomic cfDNA (p 10(-5), Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p 10(-5)) and microbial cfDNA (71.3x, p 10(-5)). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods.

  View details for DOI 10.1038/srep27859

  View details for Web of Science ID 000377827700001

  View details for PubMedID 27297799

  View details for PubMedCentralID PMC4906518

• Association of periarterial neovascularization with progression of cardiac allograft vasculopathy and long-term clinical outcomes in heart transplant recipients JOURNAL OF HEART AND LUNG TRANSPLANTATION Kitahara, H., Okada, K., Tanaka, S., Yang, H., Miki, K., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P. G., Yeung, A. C., Fitzgerald, P. J., Khush, K. K., Fearon, W. F., Honda, Y. 2016; 35 (6): 752-759

  Abstract

  This study investigated the relationship between periarterial neovascularization, development of cardiac allograft vasculopathy (CAV), and long-term clinical outcomes after heart transplantation. Proliferation of the vasa vasorum is associated with arterial inflammation. The contribution of angiogenesis to the development of CAV has been suggested.Serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in 102 heart transplant recipients. Periarterial small vessels (PSV) were defined as echolucent luminal structures <1 mm in diameter, located ≤2 mm outside of the external elastic membrane. The signal void structures were excluded when they connected to the coronary lumen (considered as side branches) or could not be followed in ≥3 contiguous frames. The number of PSV was counted at 1-mm intervals throughout the first 50 mm of the left anterior descending artery, and the PSV score was calculated as the sum of cross-sectional values. Patients with a PSV score increase of ≥ 4 between baseline and 1-year post-transplant were classified as the "proliferative" group. Maximum intimal thickness was measured for the entire analysis segment.During the first year post-transplant, the proliferative group showed a greater increase in maximum intimal thickness (0.33 ± 0.36 mm vs 0.10 ± 0.28 mm, p < 0.001) and had a higher incidence of acute cellular rejection (50.0% vs 23.9%, p = 0.025) than the non-proliferative group. On Kaplan-Meier analysis, cardiac death-free survival rate over a median of 4.7 years was significantly lower in the proliferative group than in the non-proliferative group (hazard ratio, 3.10; p = 0.036).The increase in PSV, potentially representing an angioproliferative response around the coronary arteries, was associated with early CAV progression and reduced survival after heart transplantation.

  View details for DOI 10.1016/j.healun.2016.02.002

  View details for Web of Science ID 000379367700008

  View details for PubMedID 27068036

• Invasive Assessment of Coronary Physiology Predicts Late Mortality After Heart Transplantation CIRCULATION Yang, H., Khush, K., Luikart, H., Okada, K., Lim, H., Kobayashi, Y., Honda, Y., Yeung, A. C., Valantine, H., Fearon, W. F. 2016; 133 (20): 1945-1950

  Abstract

  -The aim of this study is to determine the prognostic value of invasively assessing coronary physiology early after heart transplantation.-Seventy-four cardiac transplant recipients had fractional flow reserve (FFR), coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and intravascular ultrasound (IVUS) performed down the left anterior descending coronary artery soon after (baseline) and 1 year after heart transplantation. The primary endpoint was the cumulative survival free of death or retransplantation at a mean follow-up of 4.5±3.5 years. The cumulative event-free survival was significantly lower in patients with an FFR<0.90 at baseline (42 vs 79%, p=0.01) or an IMR≥20 measured one year after heart transplantation (39 vs. 69%, p=0.03). Patients in whom IMR decreased or did not change from baseline to 1 year had higher event-free survival compared to those patients with an increase in IMR (66 vs. 36%, p=0.03). FFR<0.90 at baseline (hazards ratio [HR] 0.13, 95% confidence interval [CI] 0.02-0.81, p=0.03), IMR ≥20 at 1 year (HR 3.93, 95% CI 1.08-14.27, p=0.04) and rejection during the first year (HR 6.00, 95% CI 1.56-23.09, p=0.009) were independent predictors of death/retransplantation, while IVUS parameters were not.-Invasive measures of coronary physiology (FFR and IMR) determined early after heart transplantation are significant predictors of late death or retransplantation.

  View details for DOI 10.1161/CIRCULATIONAHA.115.018741

  View details for Web of Science ID 000376618600009

  View details for PubMedID 27143679

• Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation JACC-HEART FAILURE Okada, K., Kitahara, H., Yang, H., Tanaka, S., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P. G., Yeung, A. C., Valantine, H. A., Fitzgerald, P. J., Khush, K. K., Honda, Y., Fearon, W. F. 2015; 3 (12): 942-952

  Abstract

  This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

  View details for DOI 10.1016/j.jchf.2015.07.013

  View details for Web of Science ID 000366949300002

• Design and Implementation of the International Genetics and Translational Research in Transplantation Network TRANSPLANTATION Keating, B. J., van Setten, J., Jacobson, P. A., Holmes, M. V., Verma, S. S., Chandrupatla, H. R., Nair, N., Gao, H., Li, Y. R., Chang, B., Wong, C., Phillips, R., Cole, B. S., Mukhtar, E., Zhang, W., Cao, H., Mohebnasab, M., Hou, C., Lee, T., Steel, L., Shaked, O., Garifallou, J., Miller, M. B., Karczewski, K. J., Akdere, A., Gonzalez, A., Lloyd, K. M., McGinn, D., Michaud, Z., Colasacco, A., Lek, M., Fu, Y., Pawashe, M., Guettouche, T., Himes, A., Perez, L., Guan, W., Wu, B., Schladt, D., Menon, M., Zhang, Z., Tragante, V., de Jonge, N., Otten, H. G., de Weger, R. A., van de Graaf, E. A., Baan, C. C., Manintveld, O. C., De Vlaminck, I., Piening, B. D., Strehl, C., Shaw, M., Snieder, H., Klintmalm, G. B., O'Leary, J. G., Amaral, S., Goldfarb, S., Rand, E., Rossano, J. W., Kohli, U., Heeger, P., Stahl, E., Christie, J. D., Fuentes, M. H., Levine, J. E., Aplenc, R., Schadt, E. E., Stranger, B. E., Kluin, J., Potena, L., Zuckermann, A., Khush, K., Alzahrani, A. J., Al-Muhanna, F. A., Al-Ali, A. K., Al-Ali, R., Al-Rubaish, A. M., Al-Mueilo, S., Byrne, E. M., Miller, D., Alexander, S. I., Onengut-Gumuscu, S., Rich, S. S., Suthanthiran, M., Tedesco, H., Saw, C. L., Ragoussis, J., Kfoury, A. G., Horne, B., Carlquist, J., Gerstein, M. B., Reindl-Schwaighofer, R., Oberbauer, R., Wijmenga, C., Palmer, S., Pereira, A. C., Segovia, J., Alonso-Pulpon, L. A., Comez-Bueno, M., Vilches, C., Jaramillo, N., de Borst, M. H., Naesens, M., Hao, K., MacArthur, D., Balasubramanian, S., Conlon, P. J., Lord, G. M., Ritchie, M. D., Snyder, M., Olthoff, K. M., Moore, J. H., Petersdorf, E. W., Kamoun, M., Wang, J., Monos, D. S., de Bakker, P. I., Hakonarson, H., Murphy, B., Lankree, M. B., Garcia-Pavia, P., Oetting, W. S., Birdwell, K. A., Bakker, S. J., Israni, A. K., Shaked, A., Asselbergs, F. W. 2015; 99 (11): 2401-2412

  Abstract

  Genetic association studies of transplantation outcomes have been hampered by small samples and highly complex multifactorial phenotypes, hindering investigations of the genetic architecture of a range of comorbidities which significantly impact graft and recipient life expectancy. We describe here the rationale and design of the International Genetics & Translational Research in Transplantation Network. The network comprises 22 studies to date, including 16494 transplant recipients and 11669 donors, of whom more than 5000 are of non-European ancestry, all of whom have existing genomewide genotype data sets.We describe the rich genetic and phenotypic information available in this consortium comprising heart, kidney, liver, and lung transplant cohorts.We demonstrate significant power in International Genetics & Translational Research in Transplantation Network to detect main effect association signals across regions such as the MHC region as well as genomewide for transplant outcomes that span all solid organs, such as graft survival, acute rejection, new onset of diabetes after transplantation, and for delayed graft function in kidney only.This consortium is designed and statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies. The study design allows a spectrum of analyses to be performed including recipient-only analyses, donor-recipient HLA mismatches with focus on loss-of-function variants and nonsynonymous single nucleotide polymorphisms.

  View details for DOI 10.1097/TP.0000000000000913

  View details for Web of Science ID 000369087800037

  View details for PubMedCentralID PMC4623847

• Noninvasive monitoring of infection and rejection after lung transplantation. Proceedings of the National Academy of Sciences of the United States of America De Vlaminck, I., Martin, L., Kertesz, M., Patel, K., Kowarsky, M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Nicolls, M. R., Cornfield, D., Weill, D., Valantine, H., Khush, K. K., Quake, S. R. 2015; 112 (43): 13336-13341

  Abstract

  The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

  View details for DOI 10.1073/pnas.1517494112

  View details for PubMedID 26460048

• Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study PLOS MEDICINE Vollmers, C., De Vlaminck, I., Valantine, H. A., Penland, L., Luikart, H., Strehl, C., Cohen, G., Khush, K. K., Quake, S. R. 2015; 12 (10)

  View details for DOI 10.1371/journal.pmed.1001890

  View details for Web of Science ID 000364466600008

  View details for PubMedID 26466143

• Gene expression profiling to study racial differences after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Pham, M. X., Teuteberg, J. J., Kfoury, A. G., Deng, M. C., Kao, A., Anderson, A. S., Cotts, W. G., Ewald, G. A., Baran, D. A., Hiller, D., Yee, J., Valantine, H. A. 2015; 34 (7): 970-977

  Abstract

  The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores.We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race.In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels.African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.

  View details for DOI 10.1016/j.healun.2015.01.987

  View details for Web of Science ID 000356998800014

  View details for PubMedID 25840504

  View details for PubMedCentralID PMC4475410

• National decline in donor heart utilization with regional variability: 1995-2010. American journal of transplantation Khush, K. K., Zaroff, J. G., Nguyen, J., Menza, R., Goldstein, B. A. 2015; 15 (3): 642-649

  Abstract

  The severe shortage of donor hearts limits the availability of transplantation for the growing population of patients with end-stage heart disease. We examined national trends in donor heart acceptance for transplant. OPTN data were analyzed for all potential adult cardiac organ donors between 1995 and 2010. Donor heart disposition was categorized as transplanted, declined for transplant or other. We studied changes in the probability of donor heart acceptance according to demographic and clinical characteristics, nationwide and by UNOS region. Of 82 053 potential donor hearts, 34% were accepted and 48% were declined (18% used for other purposes). There was a significant decrease in donor heart acceptance from 44% in 1995 to 29% in 2006, and subsequent increase to 32% in 2010. Older donor age, female sex and medical co-morbidities predicted non-acceptance. Donor age and co-morbidities increased during the study period, with a concomitant decrease in acceptance of hearts from donors with undesirable characteristics. Overall, predictors of heart non-use were similar across UNOS regions, although utilization varied between regions. Regional variation suggests a potential to improve heart acceptance rates in under-performing regions, and supports research and policy efforts aimed at establishing evidence-based criteria for donor heart evaluation and acceptance for transplantation.

  View details for DOI 10.1111/ajt.13055

  View details for PubMedID 25676093

• Reliability of echocardiographic measurements of left ventricular systolic function in potential pediatric heart transplant donors. journal of heart and lung transplantation Chen, S., Selamet Tierney, E. S., Khush, K. K., Nguyen, J., Goldstein, B. A., May, L. J., Hollander, S. A., Kaufman, B. D., Rosenthal, D. N. 2015; 34 (1): 100-106

  Abstract

  Echocardiogram reports, but not images, are usually available for the evaluation of potential donor hearts. To assess the reliability of local reports of potential pediatric heart donors, we compared echocardiographic measurements of left ventricular (LV) systolic function between local hospitals and a central echocardiography laboratory.We identified all potential donors aged <18 years managed by the California Transplant Donor Network from 2009 to 2013. Echocardiograms and reports were obtained from local hospitals. All studies were reviewed in a central laboratory by an experienced pediatric cardiologist blinded to local reports. Local and central measurements of fractional shortening (FS) were compared using the Bland-Altman method (mean difference ± 2 standard deviations). LV function was categorized based on FS as normal or mild, moderately, or severely depressed.There were 70 studies from 59 donors with local and central measurements of FS. The mean difference between local and central FS was 3.9 ± 9.0. The limits of agreement ranged from -14.2 to 22. Twenty-five studies had discordant measurements of LV function, with 17 discordant by 1 category and 8 by 2 or more categories. Of 55 studies categorized as normal by local measurement, 6 were moderately to severely depressed by central review. Of 15 studies categorized as depressed by local measurement, 3 were normal by central review.Local and central measurements of LV systolic function were discordant in 36% of studies. Given such discordance, efforts to obtain and view actual echocardiographic images should be part of the standard evaluation of potential pediatric heart donors.

  View details for DOI 10.1016/j.healun.2014.08.019

  View details for PubMedID 25307622

  View details for PubMedCentralID PMC4278954

• Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection SCIENCE TRANSLATIONAL MEDICINE De Vlaminck, I., Valantine, H. A., Snyder, T. M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Bernstein, D., Weisshaar, D., Quake, S. R., Khush, K. K. 2014; 6 (241)

  Abstract

  Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

  View details for DOI 10.1126/scitranslmed.3007803

  View details for Web of Science ID 000338711700003

• Identification of Common Blood Gene Signatures for the Diagnosis of Renal and Cardiac Acute Allograft Rejection PLOS ONE Li, L., Khush, K., Hsieh, S., Ying, L., Luikart, H., Sigdel, T., Roedder, S., Yang, A., Valantine, H., Sarwal, M. M. 2013; 8 (12)

  Abstract

  To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

  View details for DOI 10.1371/journal.pone.0082153

  View details for Web of Science ID 000328735700038

  View details for PubMedID 24358149

  View details for PubMedCentralID PMC3864873

• Temporal response of the human virome to immunosuppression and antiviral therapy. Cell De Vlaminck, I., Khush, K. K., Strehl, C., Kohli, B., Luikart, H., Neff, N. F., Okamoto, J., Snyder, T. M., Cornfield, D. N., Nicolls, M. R., Weill, D., Bernstein, D., Valantine, H. A., Quake, S. R. 2013; 155 (5): 1178-1187

  Abstract

  There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.

  View details for DOI 10.1016/j.cell.2013.10.034

  View details for PubMedID 24267896

• Donor Predictors of Allograft Use and Recipient Outcomes After Heart Transplantation CIRCULATION-HEART FAILURE Khush, K. K., Menza, R., John Nguyen, J., Zaroff, J. G., Goldstein, B. A. 2013; 6 (2): 300-309

  View details for DOI 10.1161/CIRCHEARTFAILURE.112.000165

  View details for Web of Science ID 000331381200026

• Pregnancy-Related Human Leukocyte Antigen Sensitization Leading to Cardiac Allograft Vasculopathy and Graft Failure in a Heart Transplant Recipient: A Case Report TRANSPLANTATION PROCEEDINGS Ginwalla, M., Pando, M. J., Khush, K. K. 2013; 45 (2): 800-802

  Abstract

  In this report, we present a heart transplant recipient who developed cross-reactive paternal and donor-specific human leukocyte antigen (HLA) class II antibodies during pregnancy, leading to accelerated cardiac allograft vasculopathy and severe allograft dysfunction 17 years after transplantation. This resulted in acute heart failure and ventricular arrhythmias requiring repeat heart transplantation.

  View details for DOI 10.1016/j.transproceed.2012.10.038

  View details for Web of Science ID 000316772500058

  View details for PubMedID 23498823

• Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection. PloS one Li, L., Khush, K., Hsieh, S., Ying, L., Luikart, H., Sigdel, T., Roedder, S., Yang, A., Valantine, H., Sarwal, M. M. 2013; 8 (12)

  Abstract

  To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

  View details for DOI 10.1371/journal.pone.0082153

  View details for PubMedID 24358149

  View details for PubMedCentralID PMC3864873

• Beta-Adrenergic Receptor Polymorphisms and Cardiac Graft Function in Potential Organ Donors AMERICAN JOURNAL OF TRANSPLANTATION Khush, K. K., Pawlikowska, L., Menza, R. L., Goldstein, B. A., Hayden, V., Nguyen, J., Kim, H., Poon, A., Sapru, A., Matthay, M. A., Kwok, P. Y., Young, W. L., Baxter-Lowe, L. A., Zaroff, J. G. 2012; 12 (12): 3377-3386

  Abstract

  Prior studies have demonstrated associations between beta-adrenergic receptor (βAR) polymorphisms and left ventricular dysfunction-an important cause of allograft nonutilization for transplantation. We hypothesized that βAR polymorphisms predispose donor hearts to LV dysfunction after brain death. A total of 1043 organ donors managed from 2001-2006 were initially studied. The following βAR single nucleotide polymorphisms were genotyped: β1AR 1165C/G (Arg389Gly), β1AR 145A/G (Ser49Gly), β2AR 46G/A (Gly16Arg) and β2AR 79C/G (Gln27Glu). In multivariable regression analyses, the β2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fraction <50%. The β1AR1165 and β2AR46 SNPs were associated with higher dopamine requirement during the donor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 μg/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between βAR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. βAR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts.

  View details for DOI 10.1111/j.1600-6143.2012.04266.x

  View details for Web of Science ID 000311854800022

  View details for PubMedID 22994654

  View details for PubMedCentralID PMC3513582

• The 4G/4G Genotype of the PAI-1 (Serpine-1) 4G/5G Polymorphism Is Associated With Decreased Lung Allograft Utilization AMERICAN JOURNAL OF TRANSPLANTATION Sapru, A., Zaroff, J. G., Pawlikowska, L., Liu, K. D., Khush, K. K., Baxter-Lowe, L. A., Hayden, V., Menza, R. L., Convery, M., Lo, V., Poon, A., Kim, H., Young, W. L., Kukreja, J., Matthay, M. A. 2012; 12 (7): 1848-1854

  Abstract

  Widespread thrombi are found among donor lungs rejected for transplantation. The 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1) gene impacts transcription and the 4G allele is associated with increased PAI-1 levels. We hypothesized that the 4G/4G genotype would be associated with decreased lung graft utilization, potentially because of worse oxygenation in the donor. We genotyped donors managed by the California Transplant Donor Network from 2001 to 2008 for the 4G/5G polymorphism in the PAI-1 gene. Non-Hispanic donors from 2001 to 2005 defined the discovery cohort (n = 519), whereas donors from 2006 to 2008 defined the validation cohort (n = 369). We found, that the odds of successful lung utilization among Non-Hispanic white donors were lower among donors with the 4G/4G genotype compared to those without this genotype in both the discovery (OR = 0.55, 95% CI = 0.3-0.9, p = 0.02) and validation (OR = 0.5, 95% CI = 0.3-0.9, p = 0.03) cohorts. This relationship was independent of age, gender, cause of death, drug use and history of smoking. Donors with the 4G/4G genotype also had a lower PaO2/FiO2 ratio (p = 0.03) and fewer donors with the 4G/4G genotype achieved the threshold PaO2/FiO2 ratio ≥ 300 (p = 0.05). These findings suggest a role for impaired fibrinolysis resulting in worse gas exchange and decreased donor utilization.

  View details for DOI 10.1111/j.1600-6143.2012.03996.x

  View details for Web of Science ID 000305789400023

  View details for PubMedID 22390401

• Electrocardiographic Characteristics of Potential Organ Donors and Associations With Cardiac Allograft Use CIRCULATION-HEART FAILURE Khush, K. K., Menza, R., Nguyen, J., Goldstein, B. A., Zaroff, J. G., Drew, B. J. 2012; 5 (4): 475-483

  Abstract

  Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.A single experienced reviewer interpreted the first ECG obtained after brain stem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft use for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities). Fifty-seven percent of potential cardiac allografts in this cohort were accepted for transplantation. Left ventricular hypertrophy on ECG was a strong predictor of allograft nonuse. No significant associations were seen among corrected QT interval prolongation, repolarization changes, and allograft use for transplantation after adjusting for donor clinical variables and echocardiographic findings.We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brain stem herniation and are not associated with allograft use for transplantation.

  View details for DOI 10.1161/CIRCHEARTFAILURE.112.968388

  View details for Web of Science ID 000313578100018

  View details for PubMedID 22615333

• Relation of Improvement in Estimated Glomerular Filtration Rate With Atorvastatin to Reductions in Hospitalizations for Heart Failure (from the Treating to New Targets [TNT] Study) AMERICAN JOURNAL OF CARDIOLOGY Ho, J. E., Waters, D. D., Kean, A., Wilson, D. J., DeMicco, D. A., Breazna, A., Wun, C., Deedwania, P. C., Khush, K. K. 2012; 109 (12): 1761-1766

  Abstract

  Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.

  View details for DOI 10.1016/j.amjcard.2012.02.019

  View details for Web of Science ID 000305729200014

  View details for PubMedID 22459310

• Influence of donor and recipient sex mismatch on heart transplant outcomes: Analysis of the International Society for Heart and Lung Transplantation Registry JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Kubo, J. T., Desai, M. 2012; 31 (5): 459-466

  Abstract

  Prior studies have presented contradictory results after analyzing associations between donor and recipient sex on survival after heart transplantation and causes of death such as acute rejection (AR) and cardiac allograft vasculopathy (CAV). We used the International Society for Heart and Lung Transplantation (ISHLT) Registry, the largest repository of heart transplant outcomes worldwide, to comprehensively address these questions.We studied 60,584 adult recipients of heart transplants performed between 1990 and 2008. Outcomes of interest were overall survival, death-censored allograft survival, AR, and CAV, which were studied using regression models. To assess whether donor/recipient sex mismatch affected outcomes, the experience of male recipients with female vs male donors was compared with that of female recipients with female vs male donors through inclusion of an interaction term between donor and recipient sex.Significant differences were observed between male and female recipients in overall survival and death-censored allograft survival for female vs male donors. Male recipients of female allografts had a 10% increase in adjusted mortality relative to male recipients of male allografts, whereas female recipients of female allografts had a 10% decrease in adjusted mortality relative to female recipients of male allografts (p < 0.0001). Findings were similar for death-censored allograft survival. Differences in the effect of donor sex on AR or CAV between male and female recipients were not significant.Analysis of the ISHLT data set has demonstrated a strong association between donor/recipient sex mismatch and reduced survival after heart transplantation.

  View details for DOI 10.1016/j.healun.2012.02.005

  View details for Web of Science ID 000302756700005

  View details for PubMedID 22418079

• Universal noninvasive detection of solid organ transplant rejection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Snyder, T. M., Khush, K. K., Valantine, H. A., Quake, S. R. 2011; 108 (15): 6229-6234

  Abstract

  It is challenging to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. Because transplanted organs have genomes that are distinct from the recipient's genome, we used high throughput shotgun sequencing to develop a universal noninvasive approach to monitoring organ health. We analyzed cell-free DNA circulating in the blood of heart transplant recipients and observed significantly increased levels of cell-free DNA from the donor genome at times when an endomyocardial biopsy independently established the presence of acute cellular rejection in these heart transplant recipients. Our results demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection, and this measurement can be made on any combination of donor and recipient. This noninvasive test holds promise for replacing the endomyocardial biopsy in heart transplant recipients and may be applicable to other solid organ transplants.

  View details for DOI 10.1073/pnas.1013924108

  View details for Web of Science ID 000289413600060

  View details for PubMedID 21444804

• Single-nucleotide polymorphisms in the beta-adrenergic receptor genes are associated with lung allograft utilization JOURNAL OF HEART AND LUNG TRANSPLANTATION Sapru, A., Pawlikowska, L., Liu, K. D., Khush, K. K., Ann-Baxter-Lowe, L., Hayden, V., Menza, R. L., Convery, M., Poon, A., Landeck, M., Zaroff, J. G., Matthay, M. A. 2011; 30 (2): 211-217

  Abstract

  Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of β-adrenergic receptors (βARs). Single-nucleotide polymorphisms (SNPs) in βAR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in βAR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.Nine hundred fifty-one organ donors were genotyped for 4 amino-acid-coding SNPs in the βAR genes. Lung allograft utilization was compared among donors stratified by genotypes.Utilization of donor lung allografts was 55% vs 35% (p = 0.02) among donors with GG vs AA/AG genotypes of the Ser49Gly SNP, 39% vs 32% (p = 0.04) with GG vs AA/AG genotype of Gly16Arg SNP and 37% vs 32% (p = 0.1) with CC vs GC/GG genotype of the Arg389Gly SNP. In the combined analysis, donors carrying 0 or 1 associated genotype had a utilization rate of 33%, whereas donors carrying 2 or 3 associated genotypes had utilization rates of 44% and 58%, respectively (p = 0.008). There was a stepwise decrease in chest radiograph infiltrates and an increase in partial pressure of oxygen/fraction of inspired oxygen (PaO(2)/FIO(2)) with an increasing number of these associated genotypes.Genetic variants in the βAR genes among organ donors are associated with higher rates of lung allograft utilization. The increased utilization may be related to increased clearance of pulmonary edema and improved oxygenation in donors with favorable genotypes and suggests that βAR agonists may have a role in donor management.

  View details for DOI 10.1016/j.healun.2010.08.011

  View details for Web of Science ID 000286545200015

  View details for PubMedID 20869266

  View details for PubMedCentralID PMC3019270

• Differentially Expressed RNA from Public Microarray Data Identifies Serum Protein Biomarkers for Cross-Organ Transplant Rejection and Other Conditions PLOS COMPUTATIONAL BIOLOGY Chen, R., Sigdel, T. K., Li, L., Kambham, N., Dudley, J. T., Hsieh, S., Klassen, R. B., Chen, A., Caohuu, T., Morgan, A. A., Valantine, H. A., Khush, K. K., Sarwal, M. M., Butte, A. J. 2010; 6 (9)

  Abstract

  Serum proteins are routinely used to diagnose diseases, but are hard to find due to low sensitivity in screening the serum proteome. Public repositories of microarray data, such as the Gene Expression Omnibus (GEO), contain RNA expression profiles for more than 16,000 biological conditions, covering more than 30% of United States mortality. We hypothesized that genes coding for serum- and urine-detectable proteins, and showing differential expression of RNA in disease-damaged tissues would make ideal diagnostic protein biomarkers for those diseases. We showed that predicted protein biomarkers are significantly enriched for known diagnostic protein biomarkers in 22 diseases, with enrichment significantly higher in diseases for which at least three datasets are available. We then used this strategy to search for new biomarkers indicating acute rejection (AR) across different types of transplanted solid organs. We integrated three biopsy-based microarray studies of AR from pediatric renal, adult renal and adult cardiac transplantation and identified 45 genes upregulated in all three. From this set, we chose 10 proteins for serum ELISA assays in 39 renal transplant patients, and discovered three that were significantly higher in AR. Interestingly, all three proteins were also significantly higher during AR in the 63 cardiac transplant recipients studied. Our best marker, serum PECAM1, identified renal AR with 89% sensitivity and 75% specificity, and also showed increased expression in AR by immunohistochemistry in renal, hepatic and cardiac transplant biopsies. Our results demonstrate that integrating gene expression microarray measurements from disease samples and even publicly-available data sets can be a powerful, fast, and cost-effective strategy for the discovery of new diagnostic serum protein biomarkers.

  View details for DOI 10.1371/journal.pcbi.1000940

  View details for Web of Science ID 000282372600010

  View details for PubMedID 20885780

  View details for PubMedCentralID PMC2944782

• Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: Analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database AMERICAN HEART JOURNAL Khush, K. K., Tasissa, G., Butler, J., McGlothlin, D., De Marco, T. 2009; 157 (6): 1026-1034

  Abstract

  Pulmonary hypertension has been shown to predict hospitalizations and mortality in patients with heart failure. We aimed to define the prevalence of mixed pulmonary hypertension (MPH; mean pulmonary artery pressure > or = 25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > or = 3 Wood units), identify clinical predictors of MPH, and determine whether MPH predicts adverse outcomes in patients hospitalized with severe heart failure.This is a subgroup analysis of patients assigned to pulmonary artery catheter placement in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Patients with and without MPH were compared with respect to baseline characteristics and clinical outcomes, including NYHA class, 6-minute walk distance, quality of life, days hospitalized, and 6-month mortality.Of the 171 patients studied, 80 (47%) had MPH. Older age was the only significant predictor of MPH. MPH patients had lower cardiac index (1.8 +/- 0.5 L/min vs 2.1 +/- 0.5 L/min, P = .001) and higher systemic vascular resistance index (3,179 +/- 1,454 vs 2,550 +/- 927 dynes x s/cm5 x m2, P < .001) compared to those without MPH. Importantly, right ventricular function was relatively preserved (median RVSWI 8.7 gm-m/m2/beat) in MPH patients. There were no significant differences in clinical outcomes between the two groups.Mixed pulmonary hypertension is common in patients hospitalized with advanced heart failure and is not associated with adverse short-term clinical outcomes over and above the poor prognosis of ADHF patients without MPH.

  View details for DOI 10.1016/j.ahj.2009.02.022

  View details for Web of Science ID 000266669500010

  View details for PubMedID 19464413

• New developments in immunosuppressive therapy for heart transplantation EXPERT OPINION ON EMERGING DRUGS Khush, K. K., Valantine, H. A. 2009; 14 (1): 1-21

  Abstract

  Heart transplantation is a well-established therapeutic option for many patients with end-stage heart disease. A major challenge in heart transplantation today is providing effective immunosuppression to prevent graft rejection while minimizing the many adverse effects of currently available therapies.To systematically review current immunosuppressive treatment strategies after heart transplantation and to review emerging drugs in various stages of development.A comprehensive literature review was performed using the online PubMed and Pharmaprojects databases.This article gives an overview of the immunosuppressive agents in current use, with a detailed review of emerging drugs with novel therapeutic targets.

  View details for DOI 10.1517/14728210902791605

  View details for Web of Science ID 000264685900001

  View details for PubMedID 19265486

• Association of African American race with elevated pulmonary artery Diastolic pressure: Data from the heart and soul study JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Kush, K. K., Shah, S. J., Ristow, B., De Marco, T., Whooley, M. A., Schiller, N. B. 2007; 20 (11): 1307-1313

  Abstract

  Whether increased severity of heart failure in African Americans is a result of differences in cardiac physiology is uncertain. The end-diastolic pulmonary regurgitation (EDPR) gradient is associated with abnormal cardiac physiology. We hypothesized that African American race is associated with an elevated EDPR gradient that may partially predispose African Americans to heart failure.The Heart and Soul Study prospectively assessed the EDPR gradient in 480 patients with coronary disease. We used multivariable linear regression to investigate the independent association of African American race with EDPR gradient.Compared with 393 non-African Americans, the 87 African Americans had similar indices of left ventricular systolic and diastolic function, left ventricular mass index, mitral regurgitation, peak tricuspid regurgitation gradient, and pulmonary velocity time integral. However, the EDPR gradient was significantly higher in African Americans (4.2 +/- 3.3 mm Hg) than in Caucasians (3.1 +/- 2.5 mm Hg) or other racial groups (3.5 +/- 2.7 mm Hg) (P = .008). In a multivariable model, African American race was a significant predictor of elevated EDPR gradient (beta coefficient 0.75, P = .03).African American race is independently associated with an elevated EDPR gradient in patients with coronary artery disease.

  View details for DOI 10.1016/j.ccho.2007.03.011

  View details for Web of Science ID 000251062300012

  View details for PubMedID 17588717

• Donor cardiac troponin I levels do not predict recipient survival after cardiac transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Menza, R. L., Babcock, W. D., Zaroff, J. G. 2007; 26 (10): 1048-1053

  Abstract

  Serum levels of cardiac troponin I (cTnI) are frequently measured in the evaluation of potential heart donors. However, the utility of cTnI levels for predicting recipient outcomes remains controversial. This study was performed to determine whether donor cardiac cTnI levels exceeding 1.0 microg/liter are associated with adverse recipient outcomes.All donors managed by the California Transplant Donor Network between January 2001 and July 2002 with consent for donor evaluation and at least 1 measured cTnI level were included in the study if 1-year recipient mortality data were available. Each study subject was classified as having elevated cTnI if any level exceeded 1.0 microg/liter. Donor variables, recipient risk of 30-day and 1-year mortality, and recipient need for mechanical circulatory support were compared between the 2 groups.A total of 263 potential donors were evaluated, and 98 had elevated cTnI levels. Of these potential donors, 139 were accepted for transplantation. The cTnI levels were normal in 96 and elevated in 43. Most donors (77%) with elevated cTnI levels had levels of less than 10 microg/liter. Donor cardiopulmonary resuscitation was associated with cTnI elevations. Donors with elevated cTnI levels did not require higher doses of inotropic drugs before transplantation and had similar hemodynamic profiles compared with donors with normal cTnI levels. Although there was a trend towards longer post-transplant hospitalization in recipients of grafts from donors with elevated cTnI levels (17 days vs 15 days, p = 0.044), there was no significant difference in the recipient need for mechanical circulatory support or 30-day and 1-year mortality between the 2 groups.In this study, a modestly elevated donor cTnI was not associated with a higher risk of recipient mortality or need for post-transplant mechanical circulatory support. A potential donor heart should not be discarded solely because the troponin level is elevated.

  View details for DOI 10.1016/j.healun.2007.07.026

  View details for Web of Science ID 000250268900013

  View details for PubMedID 17919626

• Effect of high-dose atorvastatin on hospitalizations for heart failure - Subgroup analysis of the treating to new targets (TNT) study 78th Annual Scientific Session of the American-Heart-Association Khush, K. K., Waters, D. D., Bittner, V., Deedwania, P. C., Kastelein, J. J., Lewis, S. J., Wenger, N. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: 576–83

  Abstract

  Statins reduce the rate of major cardiovascular events in high-risk patients, but their potential benefit as treatment for heart failure (HF) is less clear.Patients (n=10,001) with stable coronary disease were randomized to treatment with atorvastatin 80 or 10 mg/d and followed up for a median of 4.9 years. A history of HF was present in 7.8% of patients. A known ejection fraction <30% and advanced HF were exclusion criteria for the study. A predefined secondary end point of the study was hospitalization for HF. The incidence of hospitalization for HF was 2.4% in the 80-mg arm and 3.3% in the 10-mg arm (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). The treatment effect of the higher dose was more marked in patients with a history of HF: 17.3% versus 10.6% in the 10- and 80-mg arms, respectively (hazard ratio, 0.59; 95% confidence interval, 0.4 to 0.88; P=0.009). Among patients without a history of HF, the rates of hospitalization for HF were much lower: 1.8% in the 80-mg group and 2.0% in the 10-mg group (hazard ratio, 0.87; 95% confidence interval, 0.64 to 1.16; P=0.34). Only one third of patients hospitalized for HF had evidence of preceding angina or myocardial infarction during the study period. Blood pressure was almost identical during follow-up in the treatment groups.Compared with a lower dose, intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces hospitalizations for HF. In a post hoc analysis, this benefit was observed only in patients with a history of HF. The mechanism accounting for this benefit is unlikely to be due primarily to a reduction in interim coronary events or differences in blood pressure.

  View details for DOI 10.1161/CIRCULATIONAHA.106.625574

  View details for Web of Science ID 000244000800009

  View details for PubMedID 17261662

• Effects of statin therapy on the development and progression of heart failure: Mechanisms and clinical trials JOURNAL OF CARDIAC FAILURE Khush, K. K., Waters, D. D. 2006; 12 (8): 664-674

  Abstract

  Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure-a physiologic state characterized by systemic inflammation and endothelial dysfunction.This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF.Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.

  View details for DOI 10.1016/j.cardfail.2006.05.003

  View details for Web of Science ID 000241534400013

  View details for PubMedID 17045188

• Nesiritide acutely increases pulmonary and systemic levels of nitric oxide in patients with pulmonary hypertension JOURNAL OF CARDIAC FAILURE Khush, K. K., De Marco, T., Vakharia, K. T., Harmon, C., Fineman, J. R., Chatterjee, K., Michaels, A. D. 2006; 12 (7): 507-513

  Abstract

  Pulmonary hypertension (PH) is characterized by decreased pulmonary vascular expression of nitric oxide (NOx), a vasodilator that increases levels of smooth muscle cyclic guanosine monophosphate (cGMP). This study investigated mechanisms by which the vasodilator B-type natriuretic peptide (BNP) affects the systemic and pulmonary vasculature in PH patients.Twenty PH patients with mean pulmonary artery (PA) pressure > 25 mm Hg were enrolled. Ten had precapillary (pulmonary capillary wedge pressure [PCWP] < or = 15 mm Hg) and 10 had postcapillary (PCWP > 15 mm Hg) PH. Right heart catheterization was performed before and 30 minutes after intravenous nesiritide infusion. NOx and cGMP levels from the PA and systemic (AO) arteries were obtained before and after nesiritide infusion. The postcapillary PH patients demonstrated significantly reduced pulmonary vascular resistance after nesiritide; there was no change in the precapillary PH cohort. NOx levels increased significantly in both AO (P < .0001) and PA (P = .0093), as did cGMP levels (P < .0001). There was a higher increase in NOx levels from the pulmonary arteries in precapillary PH patients compared to postcapillary PH patients (P = .020).In PH patients, nesiritide infusion significantly increases NOx levels, suggesting a novel mechanism for its vasodilatory effects. These responses may differ between pre- and postcapillary PH patients.

  View details for DOI 10.1016/j.cardfail.2006.05.004

  View details for Web of Science ID 000240708700003

  View details for PubMedID 16952783

• Obese patients have lower B-type and atrial natriuretic peptide levels compared with nonobese. Congestive heart failure (Greenwich, Conn.) Khush, K. K., Gerber, I. L., Mckeown, B., Marcus, G., Vessey, J., Foster, E., Chatterjee, K., Michaels, A. D. 2006; 12 (2): 85-90

  Abstract

  Obesity is a risk factor for the development of heart failure, but the causal mechanism remains unclear. Impaired production or enhanced clearance of natriuretic peptides, which regulate sodium balance and sympathetic activation, may play an important role. The authors investigated the relationship of plasma B-type natriuretic peptide and atrial natriuretic peptide levels to body mass index in 100 patients referred for left heart catheterization. Hemodynamic and echocardiographic data were obtained for all study participants. Atrial natriuretic peptide and B-type natriuretic peptide levels were compared in obese (body mass index > or = 30 kg/m2) and nonobese (body mass index < 30 kg/m2) subjects. Multivariate regression analyses were performed, adjusting for clinical and hemodynamic covariates. Obese patients had significantly lower B-type natriuretic peptide (p = 0.03) and atrial natriuretic peptide (p = 0.04) levels compared with nonobese. Multivariate analysis revealed lower B-type natriuretic peptide (p = 0.095) and atrial natriuretic peptide (p = 0.007) levels in obese patients while controlling for age, sex, left ventricular end-diastolic pressure, and left ventricular ejection fraction. Low levels of circulating natriuretic peptides are thus associated with obesity and may contribute to the development of heart failure.

  View details for PubMedID 16596042

• The history of the coronary care unit 58th Annual Meeting of the Canadian-Cardiovascular-Society Khush, K. K., Rapaport, E., Waters, D. PULSUS GROUP INC. 2005: 1041–45

  Abstract

  The first coronary care units were established in the early 1960s in an attempt to reduce mortality from acute myocardial infarction. Pioneering cardiologists recognized the threat of death due to malignant arrhythmias in the postinfarction setting, and developed techniques for successful external defibrillation. The ability to abort sudden death led to continuous monitoring of the cardiac rhythm and an organized system of cardiopulmonary resuscitation, incorporating external defibrillation with cardiac drugs and specialized equipment. Arrhythmia monitoring and cardiopulmonary resuscitation could be performed by trained nursing staff, which eliminated delays in treatment and significantly reduced mortality. These early triumphs in aborting sudden death led to the development of techniques to treat cardiogenic shock, limit infarct size and initiate prehospital coronary care, all of which laid the foundation for the current era of interventional cardiology.

  View details for Web of Science ID 000232871000009

  View details for PubMedID 16234887

• A full house: complications from an uncorrected patent ductus arteriosus. Current cardiology reports Khush, K. K., Randhawa, R., Israel, E. 2005; 7 (4): 310-313

  Abstract

  True aneurysms of the pulmonary artery are rare, and are most often due to pulmonary hypertension arising from congenital heart defects. We report the case of a 40-year-old man with an uncorrected patent ductus arteriosus who presented with pulmonary infarction and pneumonia, and subsequently died of cardiac arrest. Autopsy revealed a large pulmonary artery aneurysm, in situ pulmonary artery thrombosis complicated by pulmonary infarction, pulmonary artery dissection, and cardiac tamponade. Although each of these complications is rare in and of itself, this case demonstrates the entire spectrum of complications from a single uncorrected congenital cardiac anomaly.

  View details for PubMedID 15987630

• Age and aneurysm position predict patterns of left ventricular dysfunction after subarachnoid hemorrhage JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Khush, K., Kopelnik, A., Tung, P., Banki, N., Dae, M., Lawton, M., Smith, W., Drew, B., Foster, E., Zaroff, J. 2005; 18 (2): 168-174

  Abstract

  Cardiac injury, including left ventricular dysfunction, frequently occurs in patients with subarachnoid hemorrhage. Patterns of left ventricular dysfunction often do not follow coronary artery distributions, and may correlate with myocardial sympathetic innervation. Left ventricular dysfunction of the anterior and anteroseptal walls that spares the apex is unusual for patients with myocardial infarction and may represent a neurally mediated pattern of injury. We performed serial echocardiography on 225 patients with subarachnoid hemorrhage and classified those with regional wall-motion abnormalities as following either an apex-sparing (AS) or apex-affected (AA) pattern. Wall-motion abnormalities were found in 61 of 225 patients studied (27%). The AS pattern was found in 49% of these patients. Younger age and anterior aneurysm position were independent predictors of this AS pattern. Both patterns of wall-motion abnormalities appear to be transient, reversible phenomena. The AS pattern may represent a unique form of neurally mediated cardiac injury.

  View details for DOI 10.1016/j.echo.2004.08.045

  View details for Web of Science ID 000226972000011

  View details for PubMedID 15682055

• Lessons prom the PROVE-IT trial - Higher dose of potent statin better for high-risk patients CLEVELAND CLINIC JOURNAL OF MEDICINE Khush, K. K., Waters, D. 2004; 71 (8): 609-616

  Abstract

  The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE-IT/TIMI-22) showed that in patients with acute coronary syndromes, aggressive lipid-lowering using atorvastatin 80 mg/day provided greater protection against death or major cardiovascular events than did moderate lipid-lowering using pravastatin 40 mg/day. Lowering the low-density lipoprotein cholesterol level to approximately 62 mg/dL with atorvastatin resulted in a 16% reduction in cardiovascular end points.

  View details for Web of Science ID 000223379600003

  View details for PubMedID 15449756