Yasuhiro Shudo

All Publications

• Gene expression profiling of acute type A aortic dissection combined with in vitroassessment†. European journal of cardio-thoracic surgery Kimura, N., Futamura, K., Arakawa, M., Okada, N., Emrich, F., Okamura, H., Sato, T., Shudo, Y., Koyano, T. K., Yamaguchi, A., Adachi, H., Matsuda, A., Kawahito, K., Matsumoto, K., Fischbein, M. P. 2017

  Abstract

  The mechanisms underlying aortic dissection remain to be fully elucidated. We aimed to identify key molecules driving dissection through gene expression profiling achieved by microarray analysis and subsequent in vitro experiments using human aortic endothelial cells (HAECs) and aortic vascular smooth muscle cells (AoSMCs).Total RNA, including microRNA (miRNA), was isolated from the intima-media layer of dissected ascending aorta obtained intraoperatively from acute type A aortic dissection (ATAAD) patients without familial thoracic aortic disease ( n  = 8) and that of non-dissected ascending aorta obtained from transplant donors ( n  = 9). Gene expression profiling was performed with mRNA and miRNA microarrays, and results were confirmed by quantitative polymerase chain reaction (qPCR). Target genes and miRNA were identified by gene ontology analysis and a literature search. To reproduce the in silico results, HAECs and AoSMCs were stimulated in vitro by upstream cytokines, and expression of target genes was assessed by qPCR.Microarray analysis revealed 1536 genes (3.6%, 1536/42 545 probes) and 41 miRNAs (3.0%, 41/1368 probes) that were differentially expressed in the ATAAD group (versus donor group). The top 15 related pathways included regulation of inflammatory response, growth factor activity and extracellular matrix. Gene ontology analysis identified JAK2 (regulation of inflammatory response), PDGFA, TGFB1, VEGFA (growth factor activity) and TIMP3 , TIMP4, SERPINE1 (extracellular matrix) as the target genes and miR-21-5p, a TIMP3 repressor, as target miRNA that interacts with the target genes. Validation qPCR confirmed the altered expression of all 7 target genes and miR-21-5p in dissected aorta specimens (all genes, P  < 0.05). Ingenuity pathway analysis showed TNF-α and TGF-β to be upstream cytokines for the target genes. In vitro experiments showed these cytokines inhibit TIMP3 expression ( P  < 0.05) and enhance VEGFA expression ( P  < 0.01) in AoSMCs but not HAECs. miR-21-5p expression increases in AoSMCs under TNF-α and TGF-β stimulation (fold change: 1.36; P  = 0.011).Results of our novel approach, integrating in vitro assessment into gene expression profiling, implicated chronic inflammation characterized by MMP-TIMP dysregulation, increased VEGFA expression, and TGF-β signalling in the development of dissection. Further investigation may reveal novel diagnostic biomarkers and uncover the mechanism(s) underlying ATAAD.

  View details for DOI 10.1093/ejcts/ezx095

  View details for PubMedID 28402522

• Current status of domino heart transplantation. Journal of cardiac surgery Shudo, Y., Ma, M., Boyd, J. H., Woo, Y. J. 2017; 32 (3): 229-232

  Abstract

  Domino heart transplant, wherein the explanted heart from the recipient of an en-bloc heart-lung is utilized for a second recipient, represents a unique surgical strategy for patients with end-stage heart failure. With a better understanding of the potential advantages and disadvantages of this procedure, its selective use in the current era can improve and maximize organ allocation in the United States. In this report, we reviewed the current status of domino heart transplantation.

  View details for DOI 10.1111/jocs.13104

  View details for PubMedID 28219115

• Adipose tissue-derived multi-lineage progenitor cells improve left ventricular dysfunction in porcine ischemic cardiomyopathy model JOURNAL OF HEART AND LUNG TRANSPLANTATION Shudo, Y., Miyagawa, S., Ohkura, H., Fukushima, S., Saito, A., Kawaguchi, N., Matsuura, N., Toda, K., Sakaguchi, T., Nishi, H., Yoshikawa, Y., Shimizu, T., Okano, T., Matsuyama, A., Sawa, Y. 2017; 36 (2): 237-239

  View details for DOI 10.1016/j.healun.2016.11.012

  View details for Web of Science ID 000393532500016

  View details for PubMedID 28159019

• Successful use of donor lungs after repairing severely injured pulmonary vein of donor lungs. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery Shudo, Y., Miller, S. L., Boyd, J. H., Woo, Y. J. 2017

  View details for DOI 10.1093/ejcts/ezx392

  View details for PubMedID 29186381

• An innovative biologic system for photon-powered myocardium in the ischemic heart. Science advances Cohen, J. E., Goldstone, A. B., Paulsen, M. J., Shudo, Y., Steele, A. N., Edwards, B. B., Patel, J. B., MacArthur, J. W., Hopkins, M. S., Burnett, C. E., Jaatinen, K. J., Thakore, A. D., Farry, J. M., Truong, V. N., Bourdillon, A. T., Stapleton, L. M., Eskandari, A., Fairman, A. S., Hiesinger, W., Esipova, T. V., Patrick, W. L., Ji, K., Shizuru, J. A., Woo, Y. J. 2017; 3 (6): e1603078

  Abstract

  Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.

  View details for DOI 10.1126/sciadv.1603078

  View details for PubMedID 28630913

  View details for PubMedCentralID PMC5470824

• Layered smooth muscle cell-endothelial progenitor cell sheets derived from the bone marrow augment postinfarction ventricular function. The Journal of thoracic and cardiovascular surgery Shudo, Y., Goldstone, A. B., Cohen, J. E., Patel, J. B., Hopkins, M. S., Steele, A. N., Edwards, B. B., Kawamura, M., Miyagawa, S., Sawa, Y., Woo, Y. J. 2017; 154 (3): 955–63

  Abstract

  The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of their natural biologic foundation, namely smooth muscle pericytes. We hypothesized that joint delivery of EPCs and smooth muscle cells (SMCs) in a novel, totally bone marrow-derived cell sheet will mimic the native architecture of a mature blood vessel and act as an angiogenic construct to limit post infarction ventricular remodeling.Primary EPCs and mesenchymal stem cells were isolated from bone marrow of Wistar rats. Mesenchymal stem cells were transdifferentiated into SMCs by culture on fibronectin-coated culture dishes. Confluent SMCs topped with confluent EPCs were detached from an Upcell dish to create a SMC-EPC bi-level cell sheet. A rodent model of ischemic cardiomyopathy was then created by ligating the left anterior descending artery. Rats were randomized into 3 groups: cell sheet transplantation (n = 9), no treatment (n = 12), or sham surgery control (n = 7).Four weeks postinfarction, mature vessel density tended to increase in cell sheet-treated animals compared with controls. Cell sheet therapy significantly attenuated the extent of cardiac fibrosis compared with that of the untreated group (untreated vs cell sheet, 198 degrees [interquartile range (IQR), 151-246 degrees] vs 103 degrees [IQR, 92-113 degrees], P = .04). Furthermore, EPC-SMC cell sheet transplantation attenuated myocardial dysfunction, as evidenced by an increase in left ventricular ejection fraction (untreated vs cell sheet vs sham, 33.5% [IQR, 27.8%-35.7%] vs 45.9% [IQR, 43.6%-48.4%] vs 59.3% [IQR, 58.8%-63.5%], P = .001) and decreases in left ventricular dimensions.The bone marrow-derived, spatially arranged SMC-EPC bi-level cell sheet is a novel, multilineage cellular therapy obtained from a translationally practical source. Interactions between SMCs and EPCs augment mature neovascularization, limit adverse remodeling, and improve ventricular function after myocardial infarction.

  View details for DOI 10.1016/j.jtcvs.2017.04.081

  View details for PubMedID 28651946

• Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy. Cardiovascular diabetology Kawamura, M., Paulsen, M. J., Goldstone, A. B., Shudo, Y., Wang, H., Steele, A. N., Stapleton, L. M., Edwards, B. B., Eskandari, A., Truong, V. N., Jaatinen, K. J., Ingason, A. B., Miyagawa, S., Sawa, Y., Woo, Y. J. 2017; 16 (1): 142

  Abstract

  Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM.Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle).SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group.Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.

  View details for DOI 10.1186/s12933-017-0625-4

  View details for PubMedID 29096622

• Percutaneous, minimally invasive approach to implantable left ventricular assist device deactivation. The Journal of thoracic and cardiovascular surgery Kidambi, S., Shudo, Y., Dake, M. D., Woo, Y. J., Ha, R. V. 2017

  View details for DOI 10.1016/j.jtcvs.2017.08.120

  View details for PubMedID 29102456

• Operative technique and pitfalls in donor heart procurement. Asian cardiovascular & thoracic annals Shudo, Y., Hiesinger, W., Oyer, P. E., Woo, Y. J. 2017; 25 (1): 80-82

  Abstract

  We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program.

  View details for DOI 10.1177/0218492316678716

  View details for PubMedID 28074702

• A modified explant technique of HeartWare ventricular assist device for bridge to recovery. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery Shudo, Y., Choi, C. W., Woo, Y. J., Ha, R. V. 2017

  Abstract

  The HeartWare left ventricular assist device is a miniaturized, continuous centrifugal-flow pump. The implantation technique is well described and relatively standardized across different institutions. However, there still exists a technical concern about handling the inflow cannula at the time of device explant. Specifically, the removal of the sewing ring and plicating the apical defect en masse may distort the geometry of the left ventricle and impart myocardial dysfunction. Additionally, a prefabricated repair mechanism by the manufacturer is not readily available in all countries (i.e. USA). Here, we describe a technique to address the apical core defect, using a tailor-made plug and leaving the sewing ring in situ, at the time of the HeartWare left ventricular assist device explant.

  View details for DOI 10.1093/ejcts/ezx270

  View details for PubMedID 28950296

• A modified technique for orthotopic heart transplantation to minimize warm ischaemic time. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery Shudo, Y., Wang, H., Woo, Y. J. 2017

  Abstract

  Prolonged allograft ischaemic time in heart transplantation adversely impacts the performance of the donor heart in the immediate postoperative period and ultimately results in decreased post-transplant survival. Therefore, optimal surgical technique for heart transplantation should aim to minimize allograft ischaemic time. Here, we report a case of successful orthotopic heart transplantation using a modified technique to reduce allograft ischaemic time and warm ischaemic time.

  View details for DOI 10.1093/ejcts/ezx411

  View details for PubMedID 29186382

• A modified implantation technique of left ventricular assist device: optimal outflow tract positioning. International journal of cardiology Shudo, Y., Choi, C. W., Woo, Y. J., Ha, R. V. 2016; 223: 776-778

  View details for DOI 10.1016/j.ijcard.2016.08.209

  View details for PubMedID 27573606

• Isolation and trans-differentiation of mesenchymal stromal cells into smooth muscle cells: Utility and applicability for cell-sheet engineering. Cytotherapy Shudo, Y., Cohen, J. E., Goldstone, A. B., MacArthur, J. W., Patel, J., Edwards, B. B., Hopkins, M. S., Steele, A. N., Joubert, L., Miyagawa, S., Sawa, Y., Woo, Y. J. 2016; 18 (4): 510-517

  Abstract

  Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) have shown potential to differentiate into various cell types, including smooth muscle cells (SMCs). The extracellular matrix (ECM) represents an appealing and readily available source of SMCs for use in tissue engineering. In this study, we hypothesized that the ECM could be used to induce MSC differentiation to SMCs for engineered cell-sheet construction.Primary MSCs were isolated from the BM of Wistar rats, transferred and cultured on dishes coated with 3 different types of ECM: collagen type IV (Col IV), fibronectin (FN), and laminin (LM). Primary MSCs were also included as a control. The proportions of SMC (a smooth muscle actin [aSMA] and SM22a) and MSC markers were examined with flow cytometry and Western blotting, and cell proliferation rates were also quantified.Both FN and LM groups were able to induce differentiation of MSCs toward smooth muscle-like cell types, as evidenced by an increase in the proportion of SMC markers (aSMA; Col IV 42.3 ± 6.9%, FN 65.1 ± 6.5%, LM 59.3 ± 7.0%, Control 39.9 ± 3.1%; P = 0.02, SM22; Col IV 56.0 ± 7.7%, FN 74.2 ± 6.7%, LM 60.4 ± 8.7%, Control 44.9 ± 3.6%) and a decrease in that of MSC markers (CD105: Col IV 64.0 ± 5.2%, FN 57.6 ± 4.0%, LM 60.3 ± 7.0%, Control 85.3 ± 4.2%; P = 0.03). The LM group showed a decrease in overall cell proliferation, whereas FN and Col IV groups remained similar to control MSCs (Col IV, 9.0 ± 2.3%; FN, 9.8 ± 2.5%; LM, 4.3 ± 1.3%; Control, 9.8 ± 2.8%).Our findings indicate that ECM selection can guide differentiation of MSCs into the SMC lineage. Fibronectin preserved cellular proliferative capacity while yielding the highest proportion of differentiated SMCs, suggesting that FN-coated materials may be facilitate smooth muscle tissue engineering.

  View details for DOI 10.1016/j.jcyt.2016.01.012

  View details for PubMedID 26971679

• B-type natriuretic peptide response and reverse left ventricular remodeling after surgical correction of functional mitral regurgitation in patients with advanced cardiomyopathy. Journal of cardiology Kainuma, S., Taniguchi, K., Toda, K., Shudo, Y., Takeda, K., Funatsu, T., Miyagawa, S., Kondoh, H., Nishi, H., Yoshikawa, Y., Fukushima, S., Hamada, S., Kubo, K., Daimon, T., Sawa, Y. 2015; 66 (4): 279-285

  Abstract

  Restrictive mitral annuloplasty (RMA) can reverse left ventricular (LV) remodeling and reduce plasma B-type natriuretic peptide (BNP), a surrogate biomarker of heart failure. However, the relationship between reverse LV remodeling and plasma BNP changes after RMA is poorly defined. We explored the main hemodynamic factors contributing to change in plasma BNP after RMA in patients with functional mitral regurgitation (MR).Twenty-four patients with moderate to severe functional MR secondary to LV systolic dysfunction [ejection fraction (EF) <40%] underwent 64-row multidetector computed tomography (MDCT) before and 1.4 months after RMA. LV end-diastolic volume index (EDVI), end-systolic volume index (ESVI), LVEF, and regional and global end-systolic wall stress (ESS) were calculated from 3-dimensional MDCT images, with blood samples for plasma BNP measurement collected the same day.After RMA, LV volumes and global ESS were decreased, while LVEF improved (all p<0.01). There were significant correlations between changes in LVEDVI and LVESVI (r=0.90, p<0.0001), LVESVI and global ESS (r=0.54, p=0.006), and global ESS and LVEF (r=-0.60, p=0.002). The median value for the plasma BNP also decreased from 597 pg/ml [interquartile range (IQR), 360-934 pg/ml] to 207 pg/ml (IQR, 124-271 pg/ml), in association with changes in LVEDVI (r=0.47, p=0.019), LVESVI (r=0.56, p=0.004), LVEF (r=-0.60, p=0.002), and global ESS (r=0.74, p<0.0001). Multivariate regression analysis showed that global ESS change was the strongest contributor to change in natural-log-transformed plasma BNP (standardized partial regression coefficient=0.59, p=0.004), indicating a strong association between decrease in LV afterload and reduction in plasma BNP level after RMA.There may be a significant association between LV reverse remodeling and plasma BNP change after RMA. Furthermore, LV end-systolic myocardial stress may be the key mechanical stimulus influencing plasma BNP after surgical correction for functional MR. Whether these favorable BNP responses and reverse remodeling can predict improved survival requires further study.

  View details for DOI 10.1016/j.jjcc.2015.02.015

  View details for PubMedID 25851471

• A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy TISSUE ENGINEERING PART A Shudo, Y., Cohen, J. E., MacArthur, J. W., Goldstone, A. B., Otsuru, S., Trubelja, A., Patel, J., Edwards, B. B., Hung, G., Fairman, A. S., Brusalis, C., Hiesinger, W., Atluri, P., Hiraoka, A., Miyagawa, S., Sawa, Y., Woo, Y. J. 2015; 21 (19-20): 2515-2525

  Abstract

  There exists a substantial body of work describing cardiac support devices to mechanically support the left ventricle (LV); however, these devices lack biological effects. To remedy this, we implemented a cell sheet engineering approach utilizing chondrocytes, which in their natural environment produce a relatively elastic extracellular matrix (ECM) for a cushioning effect. Therefore, we hypothesized that a chondrocyte cell sheet applied to infarcted and borderzone myocardium will biologically enhance the ventricular ECM and increase elasticity to augment cardiac function in a model of ischemic cardiomyopathy (ICM). Primary articular cartilage chondrocytes of Wistar rats were isolated and cultured on temperature-responsive culture dishes to generate cell sheets. A rodent ICM model was created by ligating the left anterior descending coronary artery. Rats were divided into two groups: cell sheet transplantation (1.0 × 10(7) cells/dish) and no treatment. The cell sheet was placed onto the surface of the heart covering the infarct and borderzone areas. At 4 weeks following treatment, the decreased fibrotic extension and increased elastic microfiber networks in the infarct and borderzone areas correlated with this technology's potential to stimulate ECM formation. The enhanced ventricular elasticity was further confirmed by the axial stretch test, which revealed that the cell sheet tended to attenuate tensile modulus, a parameter of stiffness. This translated to increased wall thickness in the infarct area, decreased LV volume, wall stress, mass, and improvement of LV function. Thus, the chondrocyte cell sheet strengthens the ventricular biomechanical properties by inducing the formation of elastic microfiber networks in ICM, resulting in attenuated myocardial stiffness and improved myocardial function.

  View details for DOI 10.1089/ten.tea.2014.0155

  View details for Web of Science ID 000362546100006

  View details for PubMedID 26154752

  View details for PubMedCentralID PMC4605354

• Evaluation of late aortic insufficiency with continuous flow left ventricular assist device†. European journal of cardio-thoracic surgery Hiraoka, A., Cohen, J. E., Shudo, Y., Macarthur, J. W., Howard, J. L., Fairman, A. S., Atluri, P., Kirkpatrick, J. N., Woo, Y. J. 2015; 48 (3): 400-406

  Abstract

  The aim of this study was to evaluate late development of aortic insufficiency (AI) with continuous flow left ventricular assist device (CLVAD). Development of AI is an increasingly recognized important complication in CLVAD therapy, but there are still few reports about this topic.We analysed data from 99 patients who underwent CLVAD implantation. De novo AI was defined as the development of mild or greater AI in patients with none or trace preoperative AI. Anatomic and functional correlates of de novo AI were investigated.Among the 17 patients with preoperative mild AI, no improvements were observed in mitral regurgitation or LV end-systolic dimension. Of the remaining 82 patients, de novo AI was identified in 43 patients (52%), on the most recent follow-up echocardiography, and did not influence survival nor improvement of LV geometry. Rate of freedom from de novo AI at 1 year after CLVAD implantation was 35.9%. Development of significantly greater AI was observed in patients without valve opening (AI grade 1.3 ± 1.0 vs 0.7 ± 0.9; P = 0.005). By multivariate Cox hazard model, smaller body surface area (BSA) [hazard ratio: 0.83 [95% confidence interval (CI): 0.72-0.97], P = 0.018], larger aortic root diameter (AOD) [hazard ratio: 1.11 (95% CI: 1.02-1.22), P = 0.012] and higher pulmonary artery systolic pressure (PASP) [hazard ratio: 1.24 (95% CI: 1.10-1.41), P < 0.001] were identified as the independent preoperative risk factors for de novo AI. In a subset of patients with speed adjustments, increase of CLVAD speed worsened AI and led to insufficient LV unloading in patients with aortic dilatation (AOD ≥ 3.5 cm).Any significant mortality difference related to preoperative or development of postimplant AI was not found. AI was associated with changes in LV size, and there appears to be an interaction between BSA, preoperative PASP, time since implant, aortic valve opening, aortic size and development of AI. Longitudinal clinical management in CLVAD patients, particularly in terms of CLVAD speed optimization, should include careful assessment.

  View details for DOI 10.1093/ejcts/ezu507

  View details for PubMedID 25653250

• Non-resectional leaflet remodeling mitral valve repair preserves leaflet mobility: A quantitative echocardiographic analysis of mitral valve configuration INTERNATIONAL JOURNAL OF CARDIOLOGY Shudo, Y., Cohen, J. E., MacArthur, J. W., Goldstone, A. B., Hiraoka, A., Howard, J., Fairman, A. S., Patel, J., Edwards, B. B., Atluri, P., Woo, Y. J. 2015; 186: 16-18

  View details for DOI 10.1016/j.ijcard.2015.03.239

  View details for Web of Science ID 000354337200007

  View details for PubMedID 25804458

• Bioengineered Stromal Cell- Derived Factor-1 alpha Analogue Delivered as an Angiogenic Therapy Significantly Restores Viscoelastic Material Properties of Infarcted Cardiac Muscle JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Trubelja, A., MacArthur, J. W., Sarver, J. J., Cohen, J. E., Hung, G., Shudo, Y., Fairman, A. S., Patel, J., Edwards, B. B., Damrauer, S. M., Hiesinger, W., Atluri, P., Woo, Y. J. 2014; 136 (8)

  Abstract

  Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

  View details for DOI 10.1115/1.4027731

  View details for Web of Science ID 000338507000012

• A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circulation. Heart failure Cohen, J. E., Purcell, B. P., Macarthur, J. W., Mu, A., Shudo, Y., Patel, J. B., Brusalis, C. M., Trubelja, A., Fairman, A. S., Edwards, B. B., Davis, M. S., Hung, G., Hiesinger, W., Atluri, P., Margulies, K. B., Burdick, J. A., Woo, Y. J. 2014; 7 (4): 619-626

  Abstract

  Neuregulin-1β (NRG) is a member of the epidermal growth factor family possessing a critical role in cardiomyocyte development and proliferation. Systemic administration of NRG demonstrated efficacy in cardiomyopathy animal models, leading to clinical trials using daily NRG infusions. This approach is hindered by requiring daily infusions and off-target exposure. Therefore, this study aimed to encapsulate NRG in a hydrogel to be directly delivered to the myocardium, accomplishing sustained localized NRG delivery.NRG was encapsulated in hydrogel, and release over 14 days was confirmed by ELISA in vitro. Sprague-Dawley rats were used for cardiomyocyte isolation. Cells were stimulated by PBS, NRG, hydrogel, or NRG-hydrogel (NRG-HG) and evaluated for proliferation. Cardiomyocytes demonstrated EdU (5-ethynyl-2'-deoxyuridine) and phosphorylated histone H3 positivity in the NRG-HG group only. For in vivo studies, 2-month-old mice (n=60) underwent left anterior descending coronary artery ligation and were randomized to the 4 treatment groups mentioned. Only NRG-HG-treated mice demonstrated phosphorylated histone H3 and Ki67 positivity along with decreased caspase-3 activity compared with all controls. NRG was detected in myocardium 6 days after injection without evidence of off-target exposure in NRG-HG animals. At 2 weeks, the NRG-HG group exhibited enhanced left ventricular ejection fraction, decreased left ventricular area, and augmented borderzone thickness.Targeted and sustained delivery of NRG directly to the myocardial borderzone augments cardiomyocyte mitotic activity, decreases apoptosis, and greatly enhances left ventricular function in a model of ischemic cardiomyopathy. This novel approach to NRG administration avoids off-target exposure and represents a clinically translatable strategy in myocardial regenerative therapeutics.

  View details for DOI 10.1161/CIRCHEARTFAILURE.113.001273

  View details for PubMedID 24902740

• Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1a analog in a translational ovine myocardial infarction model. Circulation research Macarthur, J. W., Cohen, J. E., McGarvey, J. R., Shudo, Y., Patel, J. B., Trubelja, A., Fairman, A. S., Edwards, B. B., Hung, G., Hiesinger, W., Goldstone, A. B., Atluri, P., Wilensky, R. L., Pilla, J. J., Gorman, J. H., Gorman, R. C., Woo, Y. J. 2014; 114 (4): 650-659

  Abstract

  After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

  View details for DOI 10.1161/CIRCRESAHA.114.302884

  View details for PubMedID 24366171

  View details for PubMedCentralID PMC4137973

• Addition of Mesenchymal Stem Cells Enhances the Therapeutic Effects of Skeletal Myoblast Cell-Sheet Transplantation in a Rat Ischemic Cardiomyopathy Model TISSUE ENGINEERING PART A Shudo, Y., Miyagawa, S., Ohkura, H., Fukushima, S., Saito, A., Shiozaki, M., Kawaguchi, N., Matsuura, N., Shimizu, T., Okano, T., Matsuyama, A., Sawa, Y. 2014; 20 (3-4): 728-739

  Abstract

  Functional skeletal myoblasts (SMBs) are transplanted into the heart effectively and safely as cell sheets, which induce functional recovery in myocardial infarction (MI) patients without lethal arrhythmia. However, their therapeutic effect is limited by ischemia. Mesenchymal stem cells (MSCs) have prosurvival/proliferation and antiapoptotic effects on co-cultured cells in vitro. We hypothesized that adding MSCs to the SMB cell sheets might enhance SMB survival post-transplantation and improve their therapeutic effects.Cell sheets of primary SMBs of male Lewis rats (r-SMBs), primary MSCs of human female fat tissues (h-MSCs), and their co-cultures were generated using temperature-responsive dishes. The levels of candidate paracrine factors, rat hepatocyte growth factor and vascular endothelial growth factor, in vitro were significantly greater in the h-MSC/r-SMB co-cultures than in those containing r-SMBs only, by real-time PCR and enzyme-linked immunosorbent assay (ELISA). MI was generated by left-coronary artery occlusion in female athymic nude rats. Two weeks later, co-cultured r-SMB or h-MSC cell sheets were implanted or no treatment was performed (n=10 each). Eight weeks later, systolic and diastolic function parameters were improved in all three treatment groups compared to no treatment, with the greatest improvement in the co-cultured cell sheet transplantation group. Consistent results were found for capillary density, collagen accumulation, myocyte hypertrophy, Akt-signaling, STAT3 signaling, and survival of transplanted cells of rat origin, and were related to poly (ADP-ribose) polymerase-dependent signal transduction.Adding MSCs to SMB cell sheets enhanced the sheets' angiogenesis-related paracrine mechanics and, consequently, functional recovery in a rat MI model, suggesting a possible strategy for clinical applications.

  View details for Web of Science ID 000331208800027

  View details for PubMedID 24164292

  View details for PubMedCentralID PMC3926175

• Continuous Flow Left Ventricular Assist Device Implant Significantly Improves Pulmonary Hypertension, Right Ventricular Contractility, and Tricuspid Valve Competence JOURNAL OF CARDIAC SURGERY Atluri, P., Fairman, A. S., MacArthur, J. W., Goldstone, A. B., Cohen, J. E., Howard, J. L., Zalewski, C. M., Shudo, Y., Woo, Y. J. 2013; 28 (6): 770-775

  Abstract

  Continuous flow left ventricular assist devices (CF LVAD) are being implanted with increasing frequency for end-stage heart failure. At the time of LVAD implant, a large proportion of patients have pulmonary hypertension, right ventricular (RV) dysfunction, and tricuspid regurgitation (TR). RV dysfunction and TR can exacerbate renal dysfunction, hepatic dysfunction, coagulopathy, edema, and even prohibit isolated LVAD implant. Repairing TR mandates increased cardiopulmonary bypass time and bicaval cannulation, which should be reserved for the time of orthotopic heart transplantation. We hypothesized that CF LVAD implant would improve pulmonary artery pressures, enhance RV function, and minimize TR, obviating need for surgical tricuspid repair.One hundred fourteen continuous flow LVADs implanted from 2005 through 2011 at a single center, with medical management of functional TR, were retrospectively analyzed. Pulmonary artery pressures were measured immediately prior to and following LVAD implant. RV function and TR were graded according to standard echocardiographic criteria, prior to, immediately following, and long-term following LVAD.There was a significant improvement in post-VAD mean pulmonary arterial pressures (26.6 ± 4.9 vs. 30.2 ± 7.4 mmHg, p = 0.008) with equivalent loading pressures (CVP = 12.0 ± 4.0 vs. 12.1 ± 5.1 p = NS). RV function significantly improved, as noted by right ventricular stroke work index (7.04 ± 2.60 vs. 6.05 ± 2.54, p = 0.02). There was an immediate improvement in TR grade and RV function following LVAD implant, which was sustained long term.Continuous flow LVAD implant improves pulmonary hypertension, RV function, and tricuspid regurgitation. TR may be managed nonoperatively during CF LVAD implant.

  View details for DOI 10.1111/jocs.12214

  View details for Web of Science ID 000326894300051

  View details for PubMedID 24118109

• Sustained release of engineered stromal cell-derived factor 1-a from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation Macarthur, J. W., Purcell, B. P., Shudo, Y., Cohen, J. E., Fairman, A., Trubelja, A., Patel, J., Hsiao, P., Yang, E., Lloyd, K., Hiesinger, W., Atluri, P., Burdick, J. A., Woo, Y. J. 2013; 128 (11): S79-86

  Abstract

  Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000343

  View details for PubMedID 24030424

• Spatially oriented, temporally sequential smooth muscle cell-endothelial progenitor cell bi-level cell sheet neovascularizes ischemic myocardium. Circulation Shudo, Y., Cohen, J. E., MacArthur, J. W., Atluri, P., Hsiao, P. F., Yang, E. C., Fairman, A. S., Trubelja, A., Patel, J., Miyagawa, S., Sawa, Y., Woo, Y. J. 2013; 128 (11): S59-68

  Abstract

  Endothelial progenitor cells (EPCs) possess robust therapeutic angiogenic potential, yet may be limited in the capacity to develop into fully mature vasculature. This problem might be exacerbated by the absence of a neovascular foundation, namely pericytes, with simple EPC injection. We hypothesized that coculturing EPCs with smooth muscle cells (SMCs), components of the surrounding vascular wall, in a cell sheet will mimic the native spatial orientation and interaction between EPCs and SMCs to create a supratherapeutic angiogenic construct in a model of ischemic cardiomyopathy.Primary EPCs and SMCs were isolated from Wistar rats. Confluent SMCs topped with confluent EPCs were spontaneously detached from the Upcell dish to create an SMC-EPC bi-level cell sheet. A rodent ischemic cardiomyopathy model was created by ligating the left anterior descending coronary artery. Rats were then immediately divided into 3 groups: cell-sheet transplantation (n=14), cell injection (n=12), and no treatment (n=13). Cocultured EPCs and SMCs stimulated an abundant release of multiple cytokines in vitro. Increased capillary density and improved blood perfusion in the borderzone elucidated the significant in vivo angiogenic potential of this technology. Most interestingly, however, cell fate-tracking experiments demonstrated that the cell-sheet EPCs and SMCs directly migrated into the myocardium and differentiated into elements of newly formed functional vasculature. The robust angiogenic effect of this cell sheet translated to enhanced ventricular function as demonstrated by echocardiography.Spatially arranged EPC-SMC bi-level cell-sheet technology facilitated the natural interaction between EPCs and SMCs, thereby creating structurally mature, functional microvasculature in a rodent ischemic cardiomyopathy model, leading to improved myocardial function.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000293

  View details for PubMedID 24030422

• Normalization of postinfarct biomechanics using a novel tissue-engineered angiogenic construct. Circulation Atluri, P., Trubelja, A., Fairman, A. S., Hsiao, P., MacArthur, J. W., Cohen, J. E., Shudo, Y., Frederick, J. R., Woo, Y. J. 2013; 128 (11): S95-104

  Abstract

  Cell-mediated angiogenic therapy for ischemic heart disease has had disappointing results. The lack of clinical translatability may be secondary to cell death and systemic dispersion with cell injection. We propose a novel tissue-engineered therapy, whereby extracellular matrix scaffold seeded with endothelial progenitor cells (EPCs) can overcome these limitations using an environment in which the cells can thrive, enabling an insult-free myocardial cell delivery to normalize myocardial biomechanics.EPCs were isolated from the long bones of Wistar rat bone marrow. The cells were cultured for 7 days in media or seeded at a density of 5 × 10(6) cells/cm(2) on a collagen/vitronectin matrix. Seeded EPCs underwent ex vivo modification with stromal cell-derived factor-1α (100 ng/mL) to potentiate angiogenic properties and enhance paracrine qualities before construct formation. Scanning electron microscopy and confocal imaging confirmed EPC-matrix adhesion. In vitro vasculogenic potential was assessed by quantifying EPC cell migration and vascular differentiation. There was a marked increase in vasculogenesis in vitro as measured by angiogenesis assay (8 versus 0 vessels/hpf; P=0.004). The construct was then implanted onto ischemic myocardium in a rat model of acute myocardial infarction. Confocal microscopy demonstrated a significant migration of EPCs from the construct to the myocardium, suggesting a direct angiogenic effect. Myocardial biomechanical properties were uniaxially quantified by elastic modulus at 5% to 20% strain. Myocardial elasticity normalized after implant of our tissue-engineered construct (239 kPa versus normal=193, P=0.1; versus infarct=304 kPa, P=0.01).We demonstrate restoration and normalization of post-myocardial infarction ventricular biomechanics after therapy with an angiogenic tissue-engineered EPC construct.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000368

  View details for PubMedID 24030426

• Predicting Right Ventricular Failure in the Modern, Continuous Flow Left Ventricular Assist Device Era 59th Annual Meeting of the Southern-Thoracic-Surgical-Association (STSA) Atluri, P., Goldstone, A. B., Fairman, A. S., MacArthur, J. W., Shudo, Y., Cohen, J. E., Acker, A. L., Hiesinger, W., Howard, J. L., Acker, M. A., Woo, Y. J. ELSEVIER SCIENCE INC. 2013: 857–64

  Abstract

  In the era of destination continuous flow left ventricular assist devices (LVAD), the decision of whether a patient will tolerate isolated LVAD support or will need biventricular support (BIVAD) can be challenging. Incorrect decision making with delayed right ventricular (RV) assist device implantation results in increased morbidity and mortality. Continuous flow LVADs have been shown to decrease pulmonary hypertension and improve RV function. We undertook this study to determine predictors in the continuous flow LVAD era that identify patients who are candidates for isolated LVAD therapy as opposed to biventricular support.We reviewed demographic, hemodynamic, laboratory, and echocardiographic variables for 218 patients who underwent VAD implant from 2003 through 2011 (LVAD=167, BIVAD=51), during the era of continuous flow LVADs.Fifty preoperative risk factors were compared between patients who were successfully managed with an LVAD and those who required a BIVAD. Seventeen variables demonstrated statistical significance by univariate analysis. Multivariable logistic regression analysis identified central venous pressure>15 mmHg (OR 2.0, "C"), severe RV dysfunction (OR 3.7, "R"), preoperative intubation (OR 4.3, "I"), severe tricuspid regurgitation (OR 4.1, "T"), heart rate>100 (OR 2.0, Tachycardia-"T")-CRITT as the major criteria predictive of the need for biventricular support. Utilizing these data, a highly sensitive and easy to use risk score for determining RV failure was generated that outperformed other established risk stratification tools.We present a preoperative risk calculator to determine suitability of a patient for isolated LVAD support in the current continuous flow ventricular assist device era.

  View details for DOI 10.1016/j.athoracsur.2013.03.099

  View details for Web of Science ID 000323940200026

  View details for PubMedID 23791165

• Myocardial Layer-Specific Effect of Myoblast Cell-Sheet Implantation Evaluated by Tissue Strain Imaging CIRCULATION JOURNAL Shudo, Y., Miyagawa, S., Nakatani, S., Fukushima, S., Sakaguchi, T., Saito, A., Asanuma, T., Kawaguchi, N., Matsuura, N., Shimizu, T., Okano, T., Sawa, Y. 2013; 77 (4): 1063-1072

  View details for DOI 10.1253/circj.CJ-12-0615

  View details for Web of Science ID 000318203200035

  View details for PubMedID 23291995

• Mathematically engineered stromal cell-derived factor-1 alpha stem cell cytokine analog enhances mechanical properties of infarcted myocardium JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY MacArthur, J. W., Trubelja, A., Shudo, Y., Hsiao, P., Fairman, A. S., Yang, E., Hiesinger, W., Sarver, J. J., Atluri, P., Woo, Y. J. 2013; 145 (1): 278-284

  Abstract

  The biomechanical response to a myocardial infarction consists of ventricular remodeling that leads to dilatation, loss of contractile function, abnormal stress patterns, and ultimately heart failure. We hypothesized that intramyocardial injection of our previously designed pro-angiogenic chemokine, an engineered stromal cell-derived factor-1α analog (ESA), improves mechanical properties of the heart after infarction.Male rats (n = 54) underwent either sham surgery (n = 17) with no coronary artery ligation or ligation of the left anterior descending artery (n = 37). The rats in the myocardial infarction group were then randomized to receive either saline (0.1 mL, n = 18) or ESA (6 μg/kg, n = 19) injected into the myocardium at 4 predetermined spots around the border zone. Echocardiograms were performed preoperatively and before the terminal surgery. After 4 weeks, the hearts were explanted and longitudinally sectioned. Uniaxial tensile testing was completed using an Instron 5543 Microtester. Optical strain was evaluated using custom image acquisition software, Digi-Velpo, and analyzed in MATLAB.Compared with the saline control group at 4 weeks, the ESA-injected hearts had a greater ejection fraction (71.8% ± 9.0% vs 55.3% ± 12.6%, P = .0004), smaller end-diastolic left ventricular internal dimension (0.686 ± 0.110 cm vs 0.763 ± 0.160 cm, P = .04), greater cardiac output (36 ± 11.6 mL/min vs 26.9 ± 7.3 mL/min, P = .05), and a lower tensile modulus (251 ± 56 kPa vs 301 ± 81 kPa, P = .04). The tensile modulus for the sham group was 195 ± 56 kPa, indicating ESA injection results in a less stiff ventricle.Direct injection of ESA alters the biomechanical response to myocardial infarction, improving the mechanical properties in the postinfarct heart.

  View details for DOI 10.1016/j.jtcvs.2012.09.080

  View details for Web of Science ID 000312386300047

  View details for PubMedID 23244259

• Mitral Valve Repair for Medically Refractory Functional Mitral Regurgitation in Patients With End-Stage Renal Disease and Advanced Heart Failure CIRCULATION Kainuma, S., Taniguchi, K., Daimon, T., Sakaguchi, T., Funatsu, T., Miyagawa, S., Kondoh, H., Takeda, K., Shudo, Y., Masai, T., Ohishi, M., Sawa, Y. 2012; 126 (11): S205-S213

  Abstract

  Information regarding patient selection for mitral valve repair for chronic kidney disease or end-stage renal disease (ESRD) with severe heart failure (HF) as well as outcome is limited.We classified 208 patients with advanced HF symptoms (Stage C/D) undergoing mitral valve repair for functional mitral regurgitation into 3 groups: estimated glomerular filtration rate ≥30 mL/min/1.73 m(2) (control group, n=144); estimated glomerular filtration rate <30 mL/min/1.73 m(2), not dependent on hemodialysis (late chronic kidney disease group, n=45), and ESRD on hemodialysis (ESRD group, n=19; preoperative hemodialysis duration 83 ± 92 months). Follow-up was completed with a mean duration of 49 ± 25 months. Postoperative (1-month) cardiac catheterization showed that left ventricular end-systolic volume index decreased from 109 ± 38 to 79 ± 41, 103 ± 31 to 81 ± 31, and 123 ± 40 to 76 ± 34 mL/m(2), in the control, late chronic kidney disease, and ESRD groups, respectively. Left ventricular end-diastolic pressure decreased, whereas cardiac index increased in all groups with no intergroup differences for those postoperative values. Freedom from mortality and HF readmission at 5 years was 18% ± 7% in late chronic kidney disease (P<0.0001 versus control, P=0.01 versus ESRD), and 64% ± 12% in ESRD (P=1 versus control) as compared with 52% ± 5% in the control group (median event-free survival, 26, 67, and 63 months, respectively).Mitral valve repair for medically refractory functional mitral regurgitation in patients with advanced HF yielded improvements in left ventricular function and hemodynamics irrespective of preoperative renal function status. Patients with ESRD showed favorable late outcome in terms of freedom from mortality and readmission for HF as compared with those with late chronic kidney disease. Further studies are needed to assess the survival benefits of mitral valve repair in patients with ESRD and advanced HF.

  View details for DOI 10.1161/CIRCULATIONAHA.111.077768

  View details for Web of Science ID 000314150200029

  View details for PubMedID 22965985

• Serial multidetector computed tomography assessment of left ventricular reverse remodeling, mass, and regional wall stress after restrictive mitral annuloplasty in dilated cardiomyopathy JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Shudo, Y., Taniguchi, K., Takeda, K., Sakaguchi, T., Funatsu, T., Kondoh, H., Sawa, Y. 2012; 143 (4): S43-S47

  Abstract

  To evaluate serial data on left ventricular and myocardial reverse remodeling after restrictive mitral annuloplasty.Thirteen patients (age, 64 ± 6 years) with functional mitral regurgitation associated with dilated cardiomyopathy (ejection fraction, ≤ 35%) were examined before (baseline), soon (1.7 ± 1.5 months), and more than 1 year (16 ± 8 months) after restrictive mitral annuloplasty using multidetector computed tomography. The left ventricular end-diastolic and end-systolic volume indexes, left ventricular ejection fraction, left ventricular mass index, and end-systolic wall stress were estimated.In the period soon after restrictive mitral annuloplasty, significant reverse left ventricular remodeling was present, with decreases in the left ventricular end-diastolic volume index (149 ± 42 to 119 ± 41 mL/m(2), P = .04) and left ventricular end-systolic volume index (114 ± 44 to 78 ± 43 mL/m(2), P = .02), and an increase in left ventricular ejection fraction (25% ± 10% to 37% ± 14%, P = .01). Additional changes in these parameters were seen in the later period (103 ± 29 mL/m(2), 61 ± 23 mL/m(2), and 42% ± 9%, respectively; all P < .05 vs baseline). In the early postrestrictive mitral annuloplasty period, the left ventricular mass index did not change significantly (104 ± 22 to 104 ± 18 g/m(2), P = NS), but significant regression occurred in the later period (90 ± 17 g/m(2), P < .05 vs baseline). The end-systolic wall stress was significantly decreased in the early period (P < .05) and was sustained in the late period. Furthermore, the increase in left ventricular ejection fraction in the late period correlated significantly with the magnitude of the end-systolic wall stress reduction (r = -0.67, P = .01).Our findings indicate that ventricular reverse remodeling occurs soon after restrictive mitral annuloplasty. In contrast, myocardial reverse remodeling (ie, regression of myocardial hypertrophy) occurs over time between the early and late postoperative periods. Our data also suggest that the late improvement in left ventricular systolic performance might be attributable to a decrease in the left ventricular afterload.

  View details for DOI 10.1016/j.jtcvs.2011.11.013

  View details for Web of Science ID 000301598700011

  View details for PubMedID 22169453

• Left Ventricular Mechanics Following Restrictive Mitral Annuloplasty for Functional Mitral Regurgitation: Two-Dimensional Speckle Tracking Echocardiographic Study ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Shudo, Y., Nakatani, S., Sakaguchi, T., Miyagawa, S., Yoshikawa, Y., Takeda, K., Saito, S., Takeda, Y., Sakata, Y., Yamamoto, K., Sawa, Y. 2012; 29 (4): 445-450

  Abstract

  Restrictive mitral annuloplasty (RMA) is widely employed for patients with functional mitral regurgitation (MR). Its improvement of left ventricular (LV) function has been demonstrated by only a gradual increase in LV ejection fraction (EF) in the chronic phase. However, the detailed evaluation of changes in LV function has not been fully elucidated in functional MR patients before and after RMA. Therefore, we performed two-dimensional speckle tracking echocardiography (2D-STE), which enables accurate evaluation of myocardial deformation and rotation that are undetectable by conventional echocardiography.We studied 13 patients (mean age 61 ± 10 years) with functional MR associated with cardiomyopathy undergoing RMA. In addition to conventional echocardiographic measurements, 2D-STE was performed to measure peak systolic radial (RS), circumferential (CS), and longitudinal (LS) strains and twist before and 4 ± 2 weeks after surgery. LV twist was defined as the difference between the apical and basal rotations.After RMA, EF and LS remained unchanged, but RS and CS were significantly improved at the mid-LV (RS, 20.6 ± 10.8 vs 24.5 ± 11.6%; CS, -9.6 ± 5.2 vs -12.8 ± 5.6%) and at the apex (RS, 15.0 ± 12.2 vs 18.7 ± 8.6%; CS, -4.4 ± 3.0 vs -7.8 ± 4.8%). RS and CS were unchanged at the base. The apical and basal rotations changed significantly, from 3.5°± 0.7° to 9.2°± 2.1°, and -2.1°± 0.7° to -3.8°± 1.0°, respectively. Consequently, the LV twist increased significantly, from 5.6°± 1.0° to 13.0°± 1.9°.Radial and circumferential strains and LV twist increased significantly in the early postoperative period in functional MR patients after RMA and concomitant procedures.

  View details for DOI 10.1111/j.1540-8175.2011.01607.x

  View details for Web of Science ID 000302540700019

  View details for PubMedID 22486374

• The extent of early left ventricular reverse remodelling is related to midterm outcomes after restrictive mitral annuloplasty in patients with non-ischaemic dilated cardiomyopathy and functional mitral regurgitation EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Takeda, K., Sakaguchi, T., Miyagawa, S., Shudo, Y., Kainuma, S., Masai, T., Taniguchi, K., Sawa, Y. 2012; 41 (3): 506-511

  Abstract

  Restrictive mitral annuloplasty (RMA) can often improve heart failure symptoms and induce left ventricular (LV) reverse remodelling in patients with non-ischaemic dilated cardiomyopathy (DCM) and functional mitral regurgitation. However, it is unknown whether the observed LV reverse remodelling translates into better outcomes or not.Fifty patients with advanced non-ischaemic DCM (age, 64 ± 10 years, 74% men) underwent RMA and were followed up with a mean of 2 years. Preoperatively, all had 3 to 4+ functional mitral regurgitation (MR), an ejection fraction (EF) of 26 ± 8.6 %, an indexed LV end-systolic volume (LVESVI) of 112 ± 47 ml/m(2). All patients received complete semi-rigid undersized ring annuloplasty. Correlations between early reduction in LVESVI at 1 month after the operation and mid-term clinical outcomes were analysed.There was no 30-day mortality. LVESVI significantly decreased to 96 ± 53 ml/m(2) and LVEF improved to 31 ± 15%. During follow-up, 16 (32%) recurred heart failure, of whom 7 (14%) died. The receiver operating characteristic (ROC) curve found that a reduction in LVESVI >8.3% had a sensitivity of 80% and a specificity of 78% in predicting all adverse events. With this cut-off value, there were 30 (60%) responders to reverse remodelling. Responders had significantly better survival (96.4 versus 68.7%, P = 0.007) and freedom from heart failure rate (85.4 versus 31.8%, P = 0.0003) than non-responders at 3 years. In a 1-year follow-up echocardiographic study, non-responders had shown no significant LV reverse remodelling with greater degree of residual MR than responders.The extent of early LV reverse remodelling is related to mid-term mortality, heart failure events and late reverse remodelling and repair durability after RMA for non-ischaemic DCM.

  View details for DOI 10.1093/ejcts/ezr004

  View details for Web of Science ID 000300507400017

  View details for PubMedID 22011774

• Novel regenerative therapy using cell-sheet covered with omentum flap delivers a huge number of cells in a porcine myocardial infarction model JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Shudo, Y., Miyagawa, S., Fukushima, S., Saito, A., Shimizu, T., Okano, T., Sawa, Y. 2011; 142 (5): 1188-1196

  Abstract

  A key challenge to applying cell transplantation to treat severely damaged myocardium is in delivering large numbers of cells with minimum cell loss. We developed a new implantation method using skeletal myoblast (SMB) sheets, wrapped with an omentum flap as a blood supply to deliver huge numbers of SMBs to the damaged heart. We examined whether this method could be used to deliver a large amount of cells to deteriorated porcine myocardium.Cell sheets were obtained by culturing mini-pig autologous SMB cells on temperature-responsive culture dishes. Myocardial infarction was induced by placing an ameroid constrictor around the left anterior descending artery. The mini-pigs were divided into 4 treatment groups (n = 6 in each): cell sheets with omentum, cell sheets only, omentum only, and sham operation. Each animal implant consisted of 30 cell sheets (1.5 × 10(7) cells per sheet). Six 5-layer constructs were each placed on a different area, immediately adjacent to but not overlapping one another, to cover the infarct and border regions.The new regenerative cell delivery system using SMB sheets covered and wrapped with omentum resulted in (1) a significantly reduced infarct size causing, at least in part, a thin scar with thick well-vascularized cardiac tissue; (2) increased angiogenesis, as determined by a significantly higher vascular density; and (3) improved cardiac function, as determined by echocardiography, compared with the conventional method (SMB sheet implantation).This cell delivery system shows potential for repairing the severely failed heart.

  View details for DOI 10.1016/j.jtcvs.2011.07.002

  View details for Web of Science ID 000296337500035

  View details for PubMedID 21924436

• Establishing New Porcine Ischemic Cardiomyopathy Model by Transcatheter Ischemia-Reperfusion of the Entire Left Coronary Artery System for Preclinical Experimental Studies TRANSPLANTATION Shudo, Y., Miyagawa, S., Fukushima, S., Saito, A., Kawaguchi, N., Matsuura, N., Sawa, Y. 2011; 92 (7): E34-E35

  View details for DOI 10.1097/TP.0b013e31822d875c

  View details for Web of Science ID 000295319500003

  View details for PubMedID 21952307

• Restrictive Mitral Annuloplasty With or Without Surgical Ventricular Restoration in Ischemic Dilated Cardiomyopathy With Severe Mitral Regurgitation CIRCULATION Shudo, Y., Taniguchi, K., Takeda, K., Sakaguchi, T., Funatsu, T., Matsue, H., Miyagawa, S., Kondoh, H., Kainuma, S., Kubo, K., Hamada, S., Izutani, H., Sawa, Y. 2011; 124 (11): S107-S114

  Abstract

  We assessed changes in left ventricular (LV) volume and function and in regional myocardial wall stress in noninfarcted segments after restrictive mitral annuloplasty (RMA) with or without surgical ventricular restoration (SVR).Thirty-nine patients with ischemic cardiomyopathy (ejection fraction ≤ 0.35) and severe mitral regurgitation (≥ 3) were studied before and 2.8 months after surgery with cine-angiographic multidetector computed tomography (cine-MDCT). Eighteen underwent RMA alone (RMA group) and 21 underwent RMA and SVR (RMA+SVR group). In addition to measuring conventional parameters (LV end-diastolic volume index [LVEDVI], LV end-systolic volume index [LVESVI], and LV ejection fraction), we evaluated the regional circumferential end-systolic wall stress and mean circumferential fiber shortening in both the basal and mid-LV regions using 3-dimensional cine-MDCT images. LV end-diastolic and end-systolic volume indexes were significantly greater in the RMA+SVR group than in the RMA group preoperatively, but these values did not differ significantly postoperatively. LV end-diastolic and end-systolic volume indexes decreased significantly, by 21% and 27% after RMA and by 35% and 42% after RMA and SVR, and the percent reductions in LV end-diastolic and end-systolic volume indexes were significantly larger in the RMA+SVR group. Regional end-systolic wall stress decreased and circumferential fiber shortening increased significantly in the noninfarcted regions after RMA with or without SVR.RMA plus SVR showed a potentially greater reduction of LV end-diastolic and end-systolic volume indexes than RMA alone. In selected patients with more advanced LV remodeling, concomitant SVR may favorably affect the LV reverse-remodeling process induced by RMA.

  View details for DOI 10.1161/CIRCULATIONAHA.110.010330

  View details for Web of Science ID 000294782800013

  View details for PubMedID 21911799

• Does Stringent Restrictive Annuloplasty for Functional Mitral Regurgitation Cause Functional Mitral Stenosis and Pulmonary Hypertension? CIRCULATION Kainuma, S., Taniguchi, K., Daimon, T., Sakaguchi, T., Funatsu, T., Kondoh, H., Miyagawa, S., Takeda, K., Shudo, Y., Masai, T., Fujita, S., Nishino, M., Sawa, Y. 2011; 124 (11): S97-S106

  Abstract

  It remains controversial whether restrictive mitral annuloplasty (RMA) for functional mitral regurgitation (MR) can induce functional mitral stenosis (MS) that may cause postoperative residual pulmonary hypertension (PH).One hundred eight patients with left ventricular (LV) dysfunction and severe MR underwent RMA with stringent downsizing of the mitral annulus. Systolic pulmonary artery pressure (PAP) and mitral valve performance variables were determined by Doppler echocardiography prospectively and 1 month after RMA. Fifty-eight patients underwent postoperative hemodynamic measurements. Postoperative echocardiography showed a mean pressure half-time of 92 ± 14 ms, a transmitral mean gradient of 2.9 ± 1.1 mm Hg, and a mitral valve effective orifice area of 2.4 ± 0.4 cm(2), consistent with functional MS. Doppler-derived systolic PAP was 32 ± 8 mm Hg, which correlated weakly with the transmitral mean gradient (ρ=0.23, P=0.02). Postoperative cardiac catheterization also showed significant improvements in LV volume and systolic function, pulmonary capillary wedge pressure, cardiac index, and systolic PAP; the latter was associated with LV end-diastolic pressure [standardized partial regression coefficient (SPRC)=0.51], pulmonary vascular resistance (SPRC=0.47), cardiac index (SPRC=0.37), and transmitral pressure gradient (SPRC=0.20). In a multivariate Cox proportional hazard model, postoperative PH (systolic PAP >40 mm Hg), but not mitral valve performance variables, was strongly associated with adverse cardiac events.RMA for functional MR resulted in varying degrees of functional MS. However, our data were more consistent with the residual PH being caused by LV dysfunction and pulmonary vascular disease than by the functional MS. The residual PH, not functional MS, was the major predictor of post-RMA adverse cardiac events.

  View details for DOI 10.1161/CIRCULATIONAHA.110.013037

  View details for Web of Science ID 000294782800012

  View details for PubMedID 21911824

• Novel software package for quantifying local circumferential myocardial stress INTERNATIONAL JOURNAL OF CARDIOLOGY Shudo, Y., Matsumiya, G., Takeda, K., Matsue, H., Taniguchi, K., Sawa, Y. 2011; 147 (1): 134-136

  Abstract

  Local myocardial stress is an important index of ventricular loading conditions. We developed a novel software package to provide estimation of local circumferential stress in the entire left ventricle (LV) based on Janz's method using contemporary LV imaging techniques. The aim of this study was to confirm the validity of our novel software by comparing local circumferential stress (local σ) with global equatorial stress (global σ) values. We acquired 30° right anterior oblique LVG images in 74 patients (aortic regurgitation; n = 48, aortic stenosis; n = 26) and 26 healthy subjects, then analyzed them using Janz's method to elucidate local σ in segment #12 (mid-anterolateral) based on AHA/ASE segmentation criteria. Global σ was obtained using Mirsky's formula. A highly significant correlation was found between local σ and global σ (r = 0.99, p < 0.001). Bland-Altman analysis also showed good agreement between the two methods (mean bias 2.4 kdyn/cm(2), limits of agreement 9.3 kdyn/cm(2)/-4.6 kdyn/cm(2)). There were good correlations for both intra-observer and inter-observer agreement. Our novel software package was shown useful to assess local circumferential stress with contemporary cardiovascular imaging techniques.

  View details for DOI 10.1016/j.ijcard.2009.05.026

  View details for Web of Science ID 000287443300027

  View details for PubMedID 20064671

• Resection of advanced stage malignant retroperitoneal neoplasms with tumor thrombus extending into the right atrium: Report of four cases SURGERY TODAY Shudo, Y., Matsumiya, G., Sakaguchi, T., Fujita, T., Yamauchi, T., Sawa, Y. 2011; 41 (2): 262-265

  Abstract

  Surgery for retroperitoneal neoplasms with a tumor thrombus extension into the right atrium is challenging. This study reviewed four surgical cases of advanced stage malignant neoplasms with the tumor thrombus extending into the right atrium. The malignant neoplasms involved the kidney in two patients, and the liver and adrenal gland in one each. The tumor thrombus was removed through a longitudinal cavotomy and right atriotomy in all cases. The inferior vena cava reconstruction was performed by directly closing it in one patient and by pericardial patch suturing in another. Cardiopulmonary bypass was used for all procedures and a Pringle maneuver was used to reduce bleeding from the liver in three. There was no perioperative or hospital death. Two of the four with renal cell carcinoma were alive 7 and 13 months after the surgery. One with hepatocellular carcinoma died of recurrent malignancy after 4 months, while the patient with an adrenal carcinoma remained disease free after surgery. These cases indicate the safety of the present procedure. Although the long-term results are still unknown, there were favorable early results and a lack of perioperative complications. Surgical challenges in resecting an intracardiac extension of retroperitoneal malignancy require close cooperation among the attending urologist, and both gastrointestinal and cardiovascular surgeons.

  View details for DOI 10.1007/s00595-009-4231-2

  View details for Web of Science ID 000286600400018

  View details for PubMedID 21264766

• Mechanism of Beneficial Effects of Restrictive Mitral Annuloplasty in Patients With Dilated Cardiomyopathy and Functional Mitral Regurgitation CIRCULATION Takeda, K., Taniguchi, K., Shudo, Y., Kainuma, S., Hamada, S., Matsue, H., Matsumiya, G., Sawa, Y. 2010; 122 (11): S3-S9

  Abstract

  Restrictive mitral annuloplasty (RMA) often leads to reverse left ventricular (LV) remodeling in patients with advanced cardiomyopathy and functional mitral regurgitation. However, the mechanism responsible for its favorable effects on LV ejection performance has been poorly understood. We evaluated systolic wall stress using cineangiographic multidetector computed tomography (MDCT) and our developed software system to assess stress-shortening relations before and after RMA.Twenty-four patients with dilated cardiomyopathy underwent 64-row MDCT before and 2 months after RMA. All patients underwent stringent downsizing annuloplasty with a semirigid complete ring. Reconstructed images were used to calculate LV end-diastolic index (EDVI) and end-systolic volume index (ESVI), LV ejection fraction, and regional and global end-systolic wall stress (ESS). After RMA, LVEDVI and LVESVI decreased from 151±52 to 131±53 mL/m(2) (P=0.0001) and from 114±48 to 92±50 mL/m(2) (P=0.0001), respectively. Global ESS decreased from 157±43 to 139±50 kdyne/cm(2) (P=0.01), and LV ejection fraction improved from 27±8.0 to 33±13% (P=0.0007). There were significant correlations between change in LVEDVI and LVESVI (r=0.88, P<0.0001) and change in LVESVI and global ESS (r=0.68, P=0.0002). Moreover, the magnitude of increase in LV ejection fraction significantly correlated with the degree of reduction in global ESS (r=-0.61, P=0.002). Patients without significant reverse LV remodeling had significantly higher preoperative and postoperative global ESS than those with it.Our study suggests that decrease in afterload after reduction in volume overload was responsible for postoperative reverse LV remodeling process after RMA.

  View details for DOI 10.1161/CIRCULATIONAHA.109.927855

  View details for Web of Science ID 000282294800001

  View details for PubMedID 20837922

• Assessment of Changes in Mitral Valve Configuration With Multidetector Computed Tomography Impact of Papillary Muscle Imbrication and Ring Annuloplasty CIRCULATION Shudo, Y., Matsumiya, G., Sakaguchi, T., Miyagawa, S., Yoshikawa, Y., Yamauchi, T., Takeda, K., Saito, S., Nakatani, S., Taniguchi, K., Izutani, H., Sawa, Y. 2010; 122 (11): S29-S36

  Abstract

  The optimal surgical procedures in functional mitral regurgitation remain controversial. We applied papillary muscle imbrication (PMI) combined with undersized mitral annuloplasty (UMAP). Multidetector computed tomography (MDCT) provides images of different phases of the cardiac cycle, allowing an assessment of the geometry. In the present study, we evaluated the mitral valve configuration and subvalvular apparatus before and after UMAP and/or PMI using MDCT imaging.We studied 26 patients with functional mitral regurgitation (3+ to 4+) with an ejection fraction ≥35% who underwent diagnostic MDCT examinations before and early after the operation. Of these, 15 underwent UMAP and PMI (UMAP+PMI group) and 11 underwent UMAP (UMAP group). The annular anteroposterior diameter, tenting height, tenting area, and interpapillary muscle distance at end-systole were quantified. The annular anteroposterior diameter, tenting height, and tenting area were significantly decreased after the operation in both groups. Whereas the average change in annular anteroposterior diameter, tenting area, and interpapillary muscle distance did not differ between the 2 groups, the average change in tenting height was greater in the UMAP+PMI group than in the UMAP group (5.1±1.3 versus 3.8±2.3 mm, P=0.036). There was a significant correlation between the change in interpapillary muscle distance and the change in tenting height in the UMAP+PMI group (r=0.788, P=0.0005).Our results examined with MDCT indicated that UMAP combined with PMI improved leaflet tethering compared with UMAP, reflecting differences in the effects of the surgical procedures used, and suggested that concomitant PMI might be beneficial in some cases.

  View details for DOI 10.1161/CIRCULATIONAHA.109.928002

  View details for Web of Science ID 000282294800005

  View details for PubMedID 20837921

• A Simplified Echocardiographic Measurements of Direct Effects of Restrictive Annuloplasty on Mitral Valve Geometry ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Shudo, Y., Matsue, H., Toda, K., Hata, H., Fujita, S., Taniguchi, K., Sawa, Y. 2010; 27 (8): 931-936

  Abstract

  The purpose of this study was to evaluate the direct effects of restrictive mitral annuloplasty on mitral valve geometry.We studied 23 patients (mean age: 63 ± 5 years) with functional mitral regurgitation (moderate to severe) and advanced cardiomyopathy (ejection fraction: 25 ± 8%) with ischemic (n = 15) or nonischemic (n = 8) conditions, who underwent restrictive annuloplasty. We determined annular septal-lateral diameter, tenting height, tenting area, vertical length of coaptation of the mitral leaflets (coaptation length), and ratio of coaptation length to septal-lateral diameter (coaptation length index) at end-systole, before and after surgery, using transthoracic echocardiography.Annular septal-lateral diameter, tenting height, and tenting area were significantly decreased (34 ± 7 to 20 ± 5 mm, P < 0.05; 9 ± 4 to 5 ± 2 mm, P < 0.05; 210 ± 120 to 80 ± 50 mm(2) , P < 0.05, respectively), whereas coaptation length and coaptation length index were significantly increased (3.4 ± 1.3 to 6.5 ± 2.9 mm, P < 0.05; 0.11 ± 0.06 to 0.33 ± 0.15, P < 0.05, respectively). Spearman's rank correlation analysis revealed that these five variables had a statistically significant correlation with the degree of mitral regurgitation. Furthermore, stepwise regression analysis showed that coaptation length index, in contrast to coaptation length, was the most important correlate with the degree of mitral regurgitation.Our simplified parameters were useful for quantitative and geometrical descriptions of mitral valve geometry, and may also provide important information for developing a surgical strategy for functional mitral regurgitation.

  View details for DOI 10.1111/j.1540-8175.2010.01182.x

  View details for Web of Science ID 000281900100012

  View details for PubMedID 20849480

• Impact of surgical ventricular reconstruction for ischemic dilated cardiomyopathy on restrictive filling pattern. General thoracic and cardiovascular surgery Shudo, Y., Matsumiya, G., Sakaguchi, T., Miyagawa, S., Yamauchi, T., Takeda, K., Saito, S., Taniguchi, K., Sawa, Y. 2010; 58 (8): 399-404

  Abstract

  Little information related to the effects of surgical ventricular reconstruction on left ventricular diastolic function is available. The aims of this study were to examine the effects of surgical ventricular reconstruction on left ventricular diastolic function and assess the predictive significance of that function on clinical outcome in patients with ischemic cardiomyopathy due to broad anteroseptal myocardial infarction undergoing surgical ventricular reconstruction.We studied 21 patients undergoing surgical ventricular reconstruction and combined surgery for ischemic cardiomyopathy with a low ejection fraction (mean ejection fraction 23% +/- 6%). Doppler echocardiography was performed before and 6 +/- 4 months after the operation.There were no deaths within 30 days. Of the 21 patients, 6 reached the clinical endpoint (cardiac death or hospitalization due to congestive heart failure). The Doppler-derived restrictive filling pattern--defined as the deceleration time (DcT) <140 ms and the mitral peak early/mitral late diastolic filling velocity (E/A) ratio >1.5--was significantly related to reaching the clinical endpoint (P < 0.01). Furthermore, stepwise multivariate analysis showed that a preoperative restrictive filling pattern was the only independent predictor of reaching the clinical endpoint (P < 0.005, F = 11.2).In patients with ischemic cardiomyopathy undergoing surgical ventricular reconstruction and combined surgery, surgical ventricular reconstruction did not change the restrictive filling pattern, and the preoperative restrictive filling pattern was an important marker of postoperative clinical outcome.

  View details for DOI 10.1007/s11748-010-0597-8

  View details for PubMedID 20703860

• Assessment of regional myocardial wall stress before and after surgical correction of functional ischaemic mitral regurgitation using multidetector computed tomography and novel software system EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Shudo, Y., Taniguchi, K., Takeda, K., Sakaguchi, T., Matsue, H., Izutani, H., Matsumiya, G., Sawa, Y. 2010; 38 (2): 163-169

  Abstract

  The objective of this study was to assess changes in left ventricular (LV) volume, function and regional myocardial wall stress in non-infarcted segments following restrictive mitral annuloplasty (RMA) in patients with ischaemic cardiomyopathy (ICM) and severe functional mitral regurgitation (MR).Twenty-two patients with ICM (ejection fraction <35%) and severe MR were investigated before and 3 months after RMA using cine-angiographic multidetector row computed tomography (cine-MDCT). For comparative purposes, 38 normal subjects were also studied. Cine-MDCT LV images were reconstructed in a cardiac cycle and regional circumferential wall stress (end-systolic stress (ESS)) was evaluated from the LV end-systolic image using Janz's method. The ESS was determined in six basal and six mid-LV segments of the ventricle based on AHA/ASE criteria. Five apical infarcted segments were not analysed. Mean circumferential fibre shortening (CFS) in both basal and mid-LV regions was determined as a parameter of regional systolic performance.Left ventricular end-diastolic volume (index) (LVEDVI) and left ventricular end-systolic volume (index) (LVESVI) decreased significantly and left ventricular ejection fraction (LVEF) increased after surgery. Neither end-systolic nor end-diastolic sphericity index changed significantly after surgery. Regional ESS significantly decreased in both basal and mid-LV regions after surgery. There was a significant inverse correlation between the change in average value of regional ESS and magnitude of increase in mean CFS of the mid-LV region (r=-0.67, p=0.0018). Postoperative reduction in ESS in the mid-LV region was also correlated with improvement in global EF (r=-0.72, p<0.01).The present cine-MDCT may be useful for assessing regional myocardial stress in patients with ICM. We found that RMA could reduce both end-diastolic and end-systolic volume leading to reduction in regional systolic wall stress, which resulted in improved ejection performance of non-infarcted myocardium in patients with functional MR and ICM.

  View details for DOI 10.1016/j.ejcts.2010.01.029

  View details for Web of Science ID 000280941200010

  View details for PubMedID 20619218

• Cardiomyoblast-like Cells Differentiated from Human Adipose Tissue-Derived Mesenchymal Stem Cells Improve Left Ventricular Dysfunction and Survival in a Rat Myocardial Infarction Model TISSUE ENGINEERING PART C-METHODS Okura, H., Matsuyama, A., Lee, C., Saga, A., Kakuta-Yamamoto, A., Nagao, A., Sougawa, N., Sekiya, N., Takekita, K., Shudo, Y., Miyagawa, S., Komoda, H., Okano, T., Sawa, Y. 2010; 16 (3): 417-425

  Abstract

  Adipose tissue-derived mesenchymal stem cells (ADMSCs) are multipotent cells. Here we examined whether human ADMSCs (hADMSCs) could differentiate into cardiomyoblast-like cells (CLCs) by induction with dimethylsulfoxide and whether the cells would be utilized to treat cardiac dysfunction. Dimethylsulfoxide induced the expression of various cardiac markers in hADMSCs, such as alpha-cardiac actin, cardiac myosin light chain, and myosin heavy chain; none of which were detected in noncommitted hADMSCs. The induced cells were thus designated as hADMSC-derived CLCs (hCLCs). To confirm their beneficial effect on cardiac function, hCLC patches were transplanted onto the Nude rat myocardial infarction model, and compared with noncommitted hADMSC patch transplants and sham operations. Echocardiography demonstrated significant short-term improvement of cardiac function in both the patch-transplanted groups. However, long-term follow-up showed rescue and maintenance of cardiac function in the hCLC patch-transplanted group only, but not in the noncommitted hADMSC patch-transplanted animals. The hCLCs, but not the hADMSCs, engrafted into the scarred myocardium and differentiated into human cardiac troponin I-positive cells, and thus regarded as cardiomyocytes. Transplantation of the hCLC patches also resulted in recovery of cardiac function and improvement of long-term survival rate. Thus, transplantation of hCLC patches is a potentially effective therapeutic strategy for future cardiac tissue regeneration.

  View details for DOI 10.1089/ten.tec.2009.0362

  View details for Web of Science ID 000278083900010

  View details for PubMedID 19624256

• Impact of untreated mild-to-moderate mitral regurgitation at the time of isolated aortic valve replacement on late adverse outcomes EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Takeda, K., Matsumiya, G., Sakaguchi, T., Miyagawa, S., Yamauchi, T., Shudo, Y., Izutani, H., Sawa, Y. 2010; 37 (5): 1033-1038

  Abstract

  The impact of untreated mild-to-moderate mitral regurgitation (MR) on patients undergoing isolated aortic valve replacement (AVR) is uncertain. The aim of this study is to investigate its long-term effects on outcomes.We retrospectively reviewed 193 consecutive patients undergoing isolated AVR between 1993 and 2007. The mean age of the study group was 64+/-12 years, 59% were male and the mean preoperative ejection fraction was 59+/-12%. The pathologic aetiology and degree of MR was determined on preoperative echocardiogram. Patients were stratified into preoperative no/trivial MR (group I; n=134) versus mild-to-moderate MR (group II; n=59). The aetiology of MR in group II was either organic (n=35, 60%) or functional (n=24, 41%). Survival and functional outcome were compared between the two groups and analyses for predictors of adverse events were performed by the Cox proportional hazard model.Operative mortality was 2.6% (n=5). In group II, mean degree of MR significantly decreased from 2.1+/-0.3 to 1.6+/-0.8 during the late period (p=0.003). The improvement in MR grade was more obvious in patients with functional aetiology. Although the actuarial survival was not significantly different between groups, freedom from re-admission for heart failure at 10 years was significantly lower in group II than in group I (23% vs 83%; p=0.002). Multivariate analysis demonstrated that independent predictors of heart failure were presence of mild-to-moderate MR (p=0.012, odds ratio (OR) 3.8) and left ventricular ejection fraction (p=0.004, OR 0.95).Despite the significant reduction after isolated AVR, preoperative mild-to-moderate MR is an independent risk factor impacting long-term functional outcome. Our results suggested that the concomitant mitral valve surgery for mild-to-moderate MR is warranted, especially in patients with reduced left ventricular function.

  View details for DOI 10.1016/j.ejcts.2009.11.046

  View details for Web of Science ID 000278614000008

  View details for PubMedID 20362456

• Redo Arch Aneurysm Repair for New-Onset Aortic Arch Dissection Following Ascending Aortic Surgery: Long Elephant Trunk Technique Combined With Trifurcate-Branched Graft ANNALS OF VASCULAR SURGERY Shudo, Y., Toda, K., Matsue, H., Hata, H., Yoshida, K., Taniguchi, K. 2010; 24 (3)

  Abstract

  Reoperative surgical intervention for a new-onset aortic arch dissection following a Bentall procedure or graft replacement for the ascending aorta is often difficult, especially in elderly patients. Herein, we report a re-do arch replacement method using a trifurcate-branched graft and long elephant trunk anastomosis at the composite root graft on the ascending aorta. The present technique is feasible as an alternative for new-onset or residual aortic arch aneurysm, as well as dissection following an operation for the ascending aorta.

  View details for DOI 10.1016/j.avsg.2009.05.017

  View details for Web of Science ID 000275516100021

  View details for PubMedID 20053528

• Repair for acute type A aortic dissection with a long elephant trunk technique JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hata, H., Toda, K., Shudo, Y., Kainuma, S., Yoshida, K., Yamamoto, K., Taniguchi, K. 2009; 137 (3): 777-778

  View details for DOI 10.1016/j.jtcvs.2008.07.058

  View details for Web of Science ID 000263791500052

  View details for PubMedID 19258117

• Elephant trunk anastomosis proximal to origin of innominate artery in total arch replacement ANNALS OF THORACIC SURGERY Taniguchi, K., Toda, K., Hata, H., Shudo, Y., Matsue, H., Takahashi, T., Kuki, S. 2007; 84 (5): 1729-1734

  Abstract

  The purpose of this study was to describe our current technique for aortic arch replacement using a four-branched arch graft and a long elephant trunk.Using our method, the ascending aorta is replaced with a four-branched Hemashield arch graft (Hemashield Platinum, Woven Double Velour [Boston Scientific Corp, Wayne, NJ]) while cooling the patient. When 25 degrees C is reached, selective cerebral perfusion is started and the elephant trunk is inserted under open distal conditions into the descending aorta using a catching catheter introduced through a femoral artery. A distal aortic anastomosis is then performed between the four-branched graft and distal aorta incorporating the elephant trunk at the base of the innominate artery. Arch vessels are reconstructed separately during rewarming.Between October 1998 and December 2005, we performed the present technique in 52 patients with no operative deaths within 30 days after the procedure. The mean duration of hypothermic circulatory arrest was 24 +/- 5 minutes, whereas that of selective cerebral perfusion was 86 +/- 9 minutes.The technique described herein requires a shorter circulatory arrest time and is uniformly applicable to patients with extensive thoracic aortic aneurysms.

  View details for DOI 10.1016/j.athoracsur.2007.05.087

  View details for Web of Science ID 000250782500045

  View details for PubMedID 17954096

• Detection of novel serotype K Streptococcus mutans in infective endocarditis patients JOURNAL OF MEDICAL MICROBIOLOGY Nakano, K., Nomura, R., Nemoto, H., Murai, T., Yoshioka, H., Shudo, Y., Hata, H., Toda, K., Taniguchi, K., Amano, A., Ooshima, T. 2007; 56 (10): 1413-1415

  View details for Web of Science ID 000250538100026

  View details for PubMedID 17893184

• Left ventricular mass: impact on left ventricular contractile function and its reversibility in patients undergoing aortic valve replacement EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Taniguchi, K., Takahashi, T., Toda, K., Matsue, H., Shudo, Y., Shintani, H., Mitsuno, M., Sawa, Y. 2007; 32 (4): 588-595

  Abstract

  We examined the relationships of left ventricular (LV) contractile state with LV geometry and hypertrophy in patients with aortic valve disease, and investigated the reversibility of LV hypertrophy and contractility following aortic valve replacement.Preoperative data from quantitative cineangiography and pressure measurements in 132 patients with chronic aortic valve disease, of whom 82 aortic regurgitation (AR), 41 aortic stenosis (AS), and 9 had mixed stenosis and regurgitation (AS-AR), were reviewed. Late after surgery, 59 of the patients (39 with AR, 20 with AS) were studied to elucidate the postoperative reversibility of LV performance and regression of LV hypertrophy.Preoperatively, multiple comparison tests found significant changes in the variables of LV volumes and dimensions in relation to LV contractile state. In stepwise regression analysis, the LV mass index was initially incorporated into a multivariate regression model as an important correlate of LV contractile state. LV geometric variables showed either no or a poor correlation with contractile state. Following aortic valve replacement, improvement of LV contractile dysfunction and regression of LV hypertrophy were limited in many of the patients who had severe preoperative hypertrophy (LV mass index 200% of normal or greater). Further, a close association between LV hypertrophy and LV contractility persisted postoperatively.Our results suggest that the development of LV hypertrophy in terms of an increase in LV mass index, in contrast to changes in geometric patterns, is significantly associated with deterioration in contractile function. LV hypertrophy may become irreversible and pathological at equivalent degrees of hypertrophy (LV mass index >/=200% of normal), regardless of the type of aortic valve lesion.

  View details for DOI 10.1016/j.ejcts.2007.07.003

  View details for Web of Science ID 000250253600007

  View details for PubMedID 17689973

• Successful total arch replacement with long elephant trunk for chronic aortic dissection (DeBakey IIIb) ANNALS OF THORACIC SURGERY Shudo, Y., Taniguchi, K., Matsue, H., Takahashi, T., Toda, K., Hata, H., Sawa, Y. 2007; 84 (2): 659-661

  Abstract

  A 68-year-old man presenting with abdominal distention was found on enhanced computed tomography to have a dilated ascending aorta and aortic dissection (DeBakey IIIb). Through a median sternotomy, we performed a total arch replacement using a four-branched Hemashield graft (Meadox Medical, Oakland, NJ) and a long elephant trunk anastomosis at the base of the innominate artery. Postoperatively, a pseudolumen of the descending aorta was effectively thrombo-excluded to the T12 level. Visceral blood flow was preserved, and the patient's postoperative course was uneventful.

  View details for DOI 10.1016/j.athoracsur.2006.12.013

  View details for Web of Science ID 000248192400053

  View details for PubMedID 17643660

• Hypertrophic cardiomyopathy in China AMERICAN JOURNAL OF CARDIOLOGY Maron, B. J. 2007; 100 (1): 145-146

  View details for DOI 10.1016/j.amjcard.2007.02.069

  View details for Web of Science ID 000247921800028

  View details for PubMedID 17599458

• Radical operation for invasive thymoma with intracaval, intracardiac, and lung invasion JOURNAL OF CARDIAC SURGERY Shudo, Y., Takahashi, T., Ohta, M., Ikeda, N., Matsue, H., Taniguchi, K. 2007; 22 (4): 330-332

  Abstract

  We report a rare case of invasive type AB thymoma (WHO classification system) with intracaval and intracardiac extension into the right atrium. A cardiopulmonary bypass facilitated an en bloc excision of the tumor with a lobectomy, along with a combined resection of the right atrium and reconstruction of the bilateral brachiocephalic veins and right atrium. Aggressive surgical intervention should be considered in such cases, as long-term prognosis is primarily dependent on a complete resection of the extended thymoma.

  View details for DOI 10.1111/j.1540-8191.2007.00417.x

  View details for Web of Science ID 000247943500011

  View details for PubMedID 17661777

• Serotype distribution of Streptococcus mutans a pathogen of dental caries in cardiovascular specimens from Japanese patients JOURNAL OF MEDICAL MICROBIOLOGY Nakano, K., Nemoto, H., Nomura, R., Homma, H., Yoshioka, H., Shudo, Y., Hata, H., Toda, K., Taniguchi, K., Amano, A., Ooshima, T. 2007; 56 (4): 551-556

  Abstract

  The involvement of oral bacteria in the pathogenesis of cardiovascular disease has been studied, with Streptococcus mutans, a pathogen of dental caries, detected in cardiovascular lesions at a high frequency. However, no information is available regarding the properties of S. mutans detected in those lesions. Heart valve specimens were collected from 52 patients and atheromatous plaque specimens from 50 patients, all of whom underwent cardiovascular operations, and dental plaque specimens were taken from 41 of those subjects prior to surgery. Furthermore, saliva samples were taken from 73 sets of healthy mothers (n=73) and their healthy children (n=78). Bacterial DNA was extracted from all specimens, then analysed by PCR with S. mutans-specific and serotype-specific primer sets. The detection rates of S. mutans in the heart valve and atheromatous plaque specimens were 63 and 64 %, respectively. Non-c serotypes were identified with a significantly higher frequency in both cardiovascular and dental plaque samples from the subjects who underwent surgery as compared to serotype c, which was detected in 70-75 % of the samples from the healthy subjects. The serotype distribution in cardiovascular patients was significantly different from that in healthy subjects, suggesting that S. mutans serotype may be related to cardiovascular disease.

  View details for DOI 10.1099/jmm.0.47051-0

  View details for Web of Science ID 000245795600018

  View details for PubMedID 17374899

• Simple and easy method for chordal reconstruction during mitral valve repair ANNALS OF THORACIC SURGERY Shudo, Y., Taniguchi, K., Takahashi, T., Matsue, H. 2006; 82 (1): 348-349

  Abstract

  We describe a simple reproducible method for chordal replacement using expanded polytetrafluoroethylene sutures during a mitral valve repair. With this technique, fine length adjustments of the new chordae are easy to make and it is possible to tie the two ends of the suture securely without slippage.

  View details for DOI 10.1016/j.athorscur.2005.05.087

  View details for Web of Science ID 000238521600071

  View details for PubMedID 16798256