John W. MacArthur

All Publications

• Beating Heart Transplantation: How to Do It. Innovations (Philadelphia, Pa.) Krishnan, A., Guenthart, B. A., Ruengesri, C., Elde, S., Zhu, Y., MacArthur, J. W., Woo, Y. J. 2024: 15569845231220678

  Abstract

  Heart transplantation utilizing deceased after circulatory death (DCD) donors has expanded the donor pool through the use of ex vivo normothermic perfusion. Compared with brain death donation, the conventional method of performing DCD heart transplantation includes an additional period of warm and cold ischemia. We have developed a beating heart implantation technique that obliviates the need for a second cardioplegic arrest and the associated reperfusion injury. We hypothesize this reproducible method may improve short-term and long-term outcomes to mirror results seen in brain death donors and provide details on how to perform beating heart transplantation.

  View details for DOI 10.1177/15569845231220678

  View details for PubMedID 38258625

• Reconstruction of the aorta and pulmonary artery during heart-liver transplantation in an adult congenital patient. JTCVS techniques Mullis, D. M., Limbu, L., Bonham, C. A., MacArthur, J. W. 2023; 21: 129-131

  View details for DOI 10.1016/j.xjtc.2023.06.011

  View details for PubMedID 37854833

  View details for PubMedCentralID PMC10580035

• Blood transfusion in cardiac surgeries - Toward a personalized protocol. American journal of surgery Min, Y., Dalal, A. R., Pedroza, A. J., Pham, T. D., Panigrahi, A. K., Goldstone, A. B., MacArthur, J. W., Woo, Y. J., Baiocchi, M., Fischbein, M. P. 2023

  View details for DOI 10.1016/j.amjsurg.2023.07.035

  View details for PubMedID 37558518

• Successful Heart Transplants from Over 2,000 Miles Away. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Weininger, G., Choi, A. Y., Joseph Woo, Y., MacArthur, J. W. 2023

  View details for DOI 10.1016/j.healun.2023.07.005

  View details for PubMedID 37479048

• Percutaneous Bailout Technique for Trapping an Embolized Valve During Valve-in-Valve TAVR. The Journal of invasive cardiology Stathogiannis, K. E., MacArthur, J. W., Lee, J. T., Sharma, R. P. 2023; 35 (3): E160

  Abstract

  A complex 15-year treatment history of a 75-year-old man with New York Heart Association class III symptoms is presented via images and video. His treatment history was noteworthy of bicuspid aortic valve (AV) and a ventricular septal defect (VSD), for which he had an AV replacement and VSD closure in 2005. In 2015, he underwent redo AV replacement and root reconstruction. Echocardiography demonstrated severe bioprosthetic AV stenosis and moderate AV regurgitation. Valve-in-valve transcatheter aortic valve replacement with a Sentinel cerebral protection device was recommended. Pre-operative computed tomography scan showed dilated aortic root and descending aorta with evidence of pseudocoarcta- tion. This case highlights the need for multidisciplinary team approach and the in-depth knowledge of various devices and techniques available.

  View details for PubMedID 36884365

• Strategies for Transcatheter Aortic Valve Replacement in Patients With a Right Aortic Arch. Structural heart : the journal of the Heart Team Wang, H., Akanbi, O., MacArthur, J. W., Sharma, R. P. 2023; 7 (2): 100099

  View details for DOI 10.1016/j.shj.2022.100099

  View details for PubMedID 37275589

  View details for PubMedCentralID PMC10236863

• Blood transfusion in aortic root surgery impairs midterm survival. JTCVS open Dalal, A. R., Pedroza, A. J., Krishnan, A., Min, Y., Tognozzi, E., Yokoyama, N., Nakamura, K., Mitchel, O. R., Baiocchi, M., Woo, Y. J., MacArthur, J. W., Fischbein, M. P. 2023; 13: 9-19

  Abstract

  To evaluate the effect of perioperative allogeneic packed red blood cell (RBC) transfusion during aortic root replacement.We reviewed patients undergoing aortic root replacement at our institution between March 2014 and April 2020. In total, 760 patients underwent aortic root replacement, of whom 442 (58%) received a perioperative RBC transfusion. Propensity score matching was used to account for baseline and operative differences resulting in 159 matched pairs. All-cause mortality was assessed with Kaplan-Meier curves. Data were obtained from our institutional Society of Thoracic Surgeons database and chart review.After propensity score matching, the RBC-transfused and -nontransfused groups were similar for all preoperative characteristics. Cardiopulmonary bypass time, crossclamp time, and lowest operative temperature were similar between the transfused and nontransfused groups (standardized mean difference <0.05). RBC transfusion was associated with more frequent postoperative ventilation greater than 24 hours (36/159 [23%] vs 19/159 [12%]; P = .01), postoperative hemodialysis (9/159 [5.7%] vs 0/159 [0%]; P = .003), reoperation for mediastinal hemorrhage (9/159 [5.7%] vs 0/159 [0%]; P = .003), and longer intensive care unit and hospital length of stay (3 vs 2 days and 8 vs 6 days respectively; P < .001). Thirty-day operative mortality after propensity score matching was similar between the cohorts (1.9%; 3/159 vs 0%; P = .2), and 5-year survival was reduced in the RBC transfusion cohort (90.2% [95% confidence interval, 84.1%-96.7%] vs 97.1% [95% confidence interval, 92.3%-100%] P = .035).Aortic root replacement frequently requires RBC transfusion during and after the operation, but even after matching for observed preoperative and operative characteristics, RBC transfusion is associated with more frequent postoperative complications and reduced midterm survival.

  View details for DOI 10.1016/j.xjon.2023.01.006

  View details for PubMedID 37063152

  View details for PubMedCentralID PMC10091283

• Outcomes after concomitant arch replacement at the time of aortic root surgery. JTCVS open Krishnan, A., Dalal, A. R., Pedroza, A. J., Nakamura, K., Yokoyama, N., Tognozzi, E., Woo, Y. J., Fischbein, M., MacArthur, J. W. 2023; 13: 1-8

  Abstract

  Contemporary series of aortic arch replacement at the time of aortic root surgery are limited in number of patients and mostly address hemiarch replacement. We describe outcomes after aortic root and concomitant arch replacement, including total arch replacement.This single-institution retrospective review studied 1196 consecutive patients from May 2004 to September 2020 who underwent first-time aortic root replacement. Patients undergoing surgery for endocarditis were excluded (n = 68, 5.7%). Patients undergoing concomitant root and arch replacement were propensity matched with patients undergoing isolated root surgery based on indication, clinical and operative characteristics, demographics, medical history including connective tissue disorders, and urgency. Multivariable Cox proportional hazards and logistic regression modeling were used to assess the primary outcome of all-cause mortality and the secondary outcomes of prolonged ventilator use, postoperative blood transfusion, and debilitating stroke, adjusted for patient and operative characteristics.Among the 1128 patients who underwent aortic root intervention during the study period, 471 (41.8%) underwent concomitant aortic arch replacement. Most underwent hemiarch replacement (n = 411, 87.4%); 59 patients (12.6%) underwent total arch replacement (with elephant trunk: n = 23, 4.9%; without elephant trunk: n = 36, 7.7%). The mean follow-up time was 4.6 years postprocedure. Operative mortality was 2.2%, and total mortality over the entire study period was 9.2%. Propensity matching generated 348 matches (295 concomitant hemiarch, 53 concomitant total arch). Concomitant hemiarch (hazard ratio, 1.00; 95% confidence interval, 0.54-1.86, P = .99) and total arch replacement (hazard ratio, 1.60, 95% confidence interval, 0.72-3.57, P = .24) were not significantly associated with increased mortality. Rates of stroke were not significantly different among each group: isolated root (n = 11/348, 3.7%), root + hemiarch (n = 17/295, 5.8%), and root + total arch (n = 3/53, 5.7%) replacement (P = .50), nor was the adjusted risk of stroke. Both concomitant arch interventions were associated with prolonged ventilator use and use of postoperative blood transfusions.Hemiarch and total arch replacement are safe to perform at the time of aortic root intervention, with no significant differences in survival or stroke rates, but increased ventilator and blood product use.

  View details for DOI 10.1016/j.xjon.2022.12.014

  View details for PubMedID 37063158

  View details for PubMedCentralID PMC10091289

• Outcomes of Reoperative Aortic Root Replacement After Previous Acute Type A Dissection Repair. Seminars in thoracic and cardiovascular surgery Pedroza, A. J., Dalal, A. R., Krishnan, A., Yokoyama, N., Nakamura, K., Tognozzi, E., Woo, Y. J., Macarthur, J. W., Fischbein, M. P. 2023

  Abstract

  Limited aortic root repair for acute type A dissection is associated with greater risk of proximal reoperations compared to full aortic root replacement. Surgical outcomes for patients undergoing reoperative root replacement after previous dissection repair are unknown. This study seeks to determine outcomes for these patients to further inform the debate surrounding optimal upfront management of the aortic root in acute dissection. Retrospective record review of all patients who underwent full aortic root replacement after a previous type A dissection repair operation at a tertiary academic referral center from 2004-2020 was performed. Among 57 cases of reoperative root replacement after type A repair, 35 cases included concomitant aortic arch replacements, and 21 cases involved coronary reconstruction (unilateral or bilateral modified Cabrol grafts). There were 3 acute post-operative strokes and 4 operative mortalities (composite 30-day and in-hospital deaths, 7.0%) . Mid-term outcomes were equivalent for patients who required arch replacement compared to isolated proximal repairs (81.8% vs. 80.6% estimated 5-year survival, median follow-up 5.53 years. Reoperative root replacement after index type A dissection repairs, including those with concomitant aortic arch replacement and/or coronary reconstruction is achievable with acceptable outcomes at an experienced aortic center.

  View details for DOI 10.1053/j.semtcvs.2023.02.001

  View details for PubMedID 36758660

• Surgical management of severe mitral annular calcification. Asian cardiovascular & thoracic annals Elde, S., Zhu, Y., MacArthur, J. W., Woo, Y. J. 2022: 2184923221136935

  Abstract

  BACKGROUND: Surgical management of severe mitral annular calcification (MAC) presents a challenging problem for even the most experienced surgeons. Preoperative planning is the most effective strategy to mitigate risk in these scenarios. MAC alone should not disqualify a patient from consideration for mitral valve repair, although the presence of concurrent greater than moderate stenosis warrants consideration of mitral valve replacement.METHODS: While repair and replacement techniques for mitral regurgitation in the setting of MAC overlap with those used to repair a non-calcified mitral apparatus, there are unique considerations to the surgical conduct of these procedures. Specifically, this article describes techniques that may be employed when the severity of MAC precludes typical repair or replacement strategies.RESULTS: Between 2014 and 2021, 77 patients were operated on by a single surgeon for mitral valve disease complicated by severe MAC. Using the systematic approach described herein, 1-year mortality was 7.8% and overall mortality over a follow-up period extending 1 to 8 years was 9.1%.CONCLUSIONS: Despite the inherent challenges of mitral valve repair or replacement in the setting of severe MAC, a systematic approach beginning with preoperative planning, modification of annular suture placement, and techniques to mitigate severe complications have, in our experience, resulting in a reliable methodology for managing severe MAC with excellent outcomes.

  View details for DOI 10.1177/02184923221136935

  View details for PubMedID 36537728

• Resection of a synovial cell sarcoma by cardiac autotransplantation: A case report. JTCVS techniques Mullis, D. M., Zhu, Y., Guenthart, B. A., Bonham, S. A., Trope, W. L., Berry, G. J., Woo, Y. J., MacArthur, J. W. 2022; 16: 123-127

  View details for DOI 10.1016/j.xjtc.2022.09.009

  View details for PubMedID 36510550

  View details for PubMedCentralID PMC9735421

• Intraoperative Considerations in a Patient on Intravenous Epoprostenol Undergoing Minimally Invasive Cardiac Surgery. Journal of cardiothoracic and vascular anesthesia Tull, C. M., Abraham, A. M., MacArthur, J. W., Vanneman, M. W., Feng, T. R. 2022

  View details for DOI 10.1053/j.jvca.2022.04.021

  View details for PubMedID 35644744

• Extracorporeal membrane oxygenator as a bridge to heart-liver en bloc transplant in a patient with Fontan circulation. JTCVS techniques Kim, J. L., Vaikunth, S. S., Haeffele, C., MacArthur, J. W. 2022; 12: 171-174

  View details for DOI 10.1016/j.xjtc.2022.01.018

  View details for PubMedID 35403048

• Continuous Serratus Anterior Plane Block: A Team Approach JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Kim, R. K., Brodt, J., MacArthur, J. W., Tsui, B. H. 2022; 36 (4): 1217-+

  View details for DOI 10.1053/j.jvca.2021.09.014

  View details for Web of Science ID 000767605200043

• Applications of Tissue Decellularization Techniques in Ventricular Myocardial Biofabrication. Frontiers in bioengineering and biotechnology Krishnan, A., Wang, H., MacArthur, J. W. 2022; 10: 802283

  Abstract

  Ischemic heart disease is the leading cause of death around the world, and though the advent of coronary revascularization has revolutionized its treatment, many patients who sustain ischemic injury to the heart will go on to develop heart failure. Biofabrication of ventricular myocardium for replacement of irreversibly damaged ischemic myocardium is sought after as a potential therapy for ischemic heart failure, though challenges in reliably producing this biomaterial have limited its clinical application. One method that shows promise for generation of functional myocardium is the use of tissue decellularization to serve as a scaffold for biofabrication. This review outlines the methods, materials, challenges, and prospects of tissue decellularization techniques for ventricular myocardium biofabrication. Decellularization aims to preserve the architecture and composition of the extracellular matrix of the tissue it is applied to, allowing for the subsequent implantation of stem cells of the desired cell type. Decellularization can be achieved with multiple reagents, most of which have detergent properties. A variety of cell types can be implanted in the resulting scaffold, including cardiac progenitor cells, and embryonic or induced pluripotent stem cells to generate a range of tissue, from patches to beating myocardium. The future of this biofabrication method will likely emphasize patient specific tissue engineering to generate complex 3-dimensional constructs that can replace dysfunctional cardiac structures.

  View details for DOI 10.3389/fbioe.2022.802283

  View details for PubMedID 35265593

• Post-Transplant Extracorporeal Membrane Oxygenation for Severe Primary Graft Dysfunction to Support the Use of Marginal Donor Hearts. Transplant international : official journal of the European Society for Organ Transplantation Shudo, Y., Alassar, A., Wang, H., Lingala, B., He, H., Zhu, Y., Hiesinger, W., MacArthur, J. W., Boyd, J. H., Lee, A. M., Currie, M., Woo, Y. J. 2022; 35: 10176

  Abstract

  Severe primary graft dysfunction (PGD) is the leading cause of early postoperative mortality following orthotopic heart transplantation (OHT). Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used as salvage therapy. This study aimed to evaluate the outcomes in adult OHT recipients who underwent VA-ECMO for severe PGD. We retrospectively reviewed 899 adult (≥18years) patients who underwent primary OHT at our institution between 1997 and 2017. Recipients treated with VA-ECMO (19, 2.1%) exhibited a higher incidence of previous cardiac surgery (p = .0220), chronic obstructive pulmonary disease (p = .0352), and treatment with a calcium channel blocker (p = .0018) and amiodarone (p = .0148). Cardiopulmonary bypass (p = .0410) and aortic cross-clamp times (p = .0477) were longer in the VA-ECMO cohort and they were more likely to have received postoperative transfusion (p = .0013); intra-aortic balloon pump (IABP, p < .0001), and reoperation for bleeding or tamponade (p < .0001). The 30-day, 1-year, and overall survival after transplantation of non-ECMO patients were 95.9, 88.8, and 67.4%, respectively, compared to 73.7, 57.9, and 47.4%, respectively in the ECMO cohort. Fourteen (73.7%) of the ECMO patients were weaned after a median of 7days following OHT (range: 1-12days). Following OHT, VA-ECMO may be a useful salvage therapy for severe PGD and can potentially support the usage of marginal donor hearts.

  View details for DOI 10.3389/ti.2022.10176

  View details for PubMedID 35340846

• Analysis of the revised heart allocation policy and the influence of increased mechanical circulatory support on survival. The Journal of thoracic and cardiovascular surgery Elde, S., He, H., Lingala, B., Baiocchi, M., Wang, H., Hiesinger, W., MacArthur, J. W., Shudo, Y., Woo, Y. J. 1800

  Abstract

  OBJECTIVES: In 2018, the new United Network for Organ Sharing heart allocation policy took effect. This study evaluated waitlist mortality, mechanical circulatory support utilization, and its influence on posttransplant survival.METHODS: Two 12-month cohorts matched for time of year before and after the policy change were defined by inclusion criteria of first-time transplant recipients aged 18years or older who were listed and underwent transplant during the same era. Student t test and Wilcoxon rank-sum test were used for mean and median differences, respectively. Categorical variables were compared using chi2 or Fisher exact test. Kaplan-Meier curves were used to characterize survival, including time-to-event analysis with the log-rank test. Fine-Gray modeling was used to characterize waitlist mortality. Cox proportional-hazard models were used for multivariate analysis.RESULTS: Waitlist mortality in the new era is significantly improved based on a competing-risks model (Gray test P=.0064). Unadjusted 180-day posttransplant mortality increased from 5.8% during the old era to 8.0% during the new (P=.0134). However, time-to-event analysis showed similar 180-day survival in both eras. After risk adjustment, the hazard ratio for posttransplant 180-day mortality during the new era was 1.18 (95% CI, 0.85-1.64; P=.333). The posttransplant 180-day mortality of the extracorporeal membrane oxygenation bridge-to-transplant subgroup improved from 28.6% in the old era to 8.4% in the new era (P=.0103; log-rank P=.0021). Patients with an intra-aortic balloon pump at the time of transplant had similar 180-day posttransplant mortality between eras (5.4% vs 7.0%; P=.4831).CONCLUSIONS: The United Network for Organ Sharing policy change is associated with reduced waitlist mortality and similar risk adjusted posttransplant 180-day mortality. The new era is also associated with improved 180-day survival in patientsundergoing bridge to transplant with extracorporeal membrane oxygenation.

  View details for DOI 10.1016/j.jtcvs.2021.11.076

  View details for PubMedID 35027214

• Biomechanical engineering comparison of four leaflet repair techniques for mitral regurgitation using a novel 3-dimensional-printed left heart simulator JTCVS TECHNIQUES Paulsen, M. J., Cuartas, M., Imbrie-Moore, A., Wang, H., Wilkerson, R., Farry, J., Zhu, Y., Ma, M., MacArthur, J. W., Woo, Y. 2021; 10: 244-251

  View details for DOI 10.1016/j.xjtc.2021.09.040

  View details for Web of Science ID 000732665100001

• Extended Static Hypothermic Preservation In Cardiac Transplantation: A Case Report. Transplantation proceedings Guenthart, B. A., Krishnan, A., Koyano, T., La Francessca, S., Chan, J., Alassar, A., Macarthur, J. W., Shudo, Y., Hiesinger, W., Woo, Y. J. 2021

  Abstract

  BACKGROUND: The donor shortage poses a major limitation to use of heart transplantation. Novel strategies such as use of expanded-criteria donors with prolonged ischemia times are being employed to address this need. Recent developments in static hypothermia have allowed for the safe use of cardiac allografts with prolonged ischemic times.CASE REPORT: We present the case of a 68-year-old woman with valvular cardiomyopathy refractory to medical therapy who underwent orthotopic heart transplantation with a cardiac allograft exposed to elevated ischemic times. This was achieved through use of the federally approved SherpaPak Cardiac Transport System for transportation of the allograft. This method of static hypothermic organ preservation allowed for a 330-minute total ischemic time, including 283 minutes of storage within the preservation system. The patient tolerated the procedure well and was discharged on postoperative day 10, with excellent graft function and no evidence of rejection 3 months postoperatively.CONCLUSIONS: Though traditionally ischemic times of 240 minutes or less are recommended for cardiac allografts, we demonstrate, to our knowledge, the longest reported ischemic time of 330 minutes via use of a novel method of static hypothermia for organ preservation. The recipient had an excellent outcome postoperatively, demonstrating the potential for this new organ preservation system to expand the donor pool and improve access and use of heart transplantation.

  View details for DOI 10.1016/j.transproceed.2021.08.021

  View details for PubMedID 34521542

• Resection of a Giant Epithelioid Hemangioendothelioma Arising from the Superior Vena Cava. The Annals of thoracic surgery Elliott, I. A., Kasinpila, P., Guenthart, B. A., MacArthur, J. W., Berry, M. F. 2021

  Abstract

  Epithelioid hemangioendothelioma is a rare malignant vascular sarcoma. Here we present a patient with a very large tumor arising from the superior vena cava (SVC), in whom a resection with negative margins was accomplished using veno-venous bypass and bovine pericardial patch reconstruction of the SVC.

  View details for DOI 10.1016/j.athoracsur.2021.01.034

  View details for PubMedID 33529605

• Operative Technique of Donor Organ Procurement for En Bloc Heart-Liver Transplantation. Transplantation Elde, S. n., Brubaker, A. L., Than, P. A., Rinewalt, D. n., MacArthur, J. W., Alassar, A. n., Bonham, C. A., Esquivel, C. O., Shudo, Y. n., Concepcion, W. n., Woo, Y. J. 2021

  Abstract

  Combined heart-liver transplant is an emerging option for patients with indications for heart transplantation and otherwise prohibitive hepatic dysfunction. Heart-liver transplantation is particularly relevant for patients with single ventricle physiology who often develop Fontan-associated liver disease and fibrosis. While only performed at a limited number of centers, several approaches to combined heart-liver transplantation have been described. The en bloc technique offers several potential advantages over the traditional sequential technique. Specifically, en bloc heart-liver transplantation may allow improved hemodynamics, decreased bleeding, reduced liver allograft ischemic time, and may result in reduced rates of graft dysfunction. Here we describe our center's en bloc heart-liver procurement technique in detail, with the aim of allowing broader use and standardization of this technique. Supplemental Visual Abstract; http://links.lww.com/TP/C147.

  View details for DOI 10.1097/TP.0000000000003697

  View details for PubMedID 33606485

• First lung and kidney multi-organ transplant following COVID-19 Infection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Guenthart, B. A., Krishnan, A., Alassar, A., Madhok, J., Kakol, M., Miller, S., Cole, S. P., Rao, V. K., Acero, N. M., Hill, C. C., Cheung, C., Jackson, E. C., Feinstein, I., Tsai, A. H., Mooney, J. J., Pham, T., Elliott, I. A., Liou, D. Z., La Francesca, S., Shudo, Y., Hiesinger, W., MacArthur, J. W., Brar, N., Berry, G. J., McCarra, M. B., Desai, T. J., Dhillon, G. S., Woo, Y. J. 2021

  Abstract

  As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

  View details for DOI 10.1016/j.healun.2021.02.015

  View details for PubMedID 34059432

• Intracardiac paragangliomas: surgical approach and perioperative management. General thoracic and cardiovascular surgery Guenthart, B. A., Trope, W., Keeyapaj, W., Weiel, J. J., Edmonson, A., MacArthur, J. W., Annes, J. P., Woo, Y. J., Lui, N. S. 2020

  Abstract

  Intracardiac paragangliomas most commonly arise from the left atrium and are often infiltrative and densely adherent to surrounding structures. Given their rarity, only scattered reports exist in the literature and standardized perioperative and surgical management is not well established. We describe a case of a 60-year-old woman with a mildly functioning intracardiac paraganglioma in which division of the superior vena cava improved exposure and enabled a complex limited resection. Further, we provide an overview of the diagnostic workup, perioperative medical management, surgical approach, and surveillance strategy in patients with these challenging tumors.

  View details for DOI 10.1007/s11748-020-01503-2

  View details for PubMedID 33074472

• Ex Vivo Analysis of a Porcine Bicuspid Aortic Valve and Aneurysm Disease Model. The Annals of thoracic surgery Zhu, Y., Imbrie-Moore, A. M., Park, M. H., Paulsen, M. J., Wang, H., MacArthur, J. W., Woo, Y. J. 2020

  Abstract

  We identified an extremely rare congenital porcine type 0 lateral bicuspid aortic valve (BAV) from a fresh porcine heart. Using a 3D-printed ex vivo left heart simulator, we analyzed valvular hemodynamics at baseline, in an aortic aneurysm disease model, and after valve-sparing root replacement (VSRR). We showed that BAV regurgitation due to aortic aneurysm can be successfully repaired without significant hemodynamic impairment with the VSRR technique in an individualized approach. Our results provide direct hemodynamic evidence supporting the use of VSRR for patients with BAV regurgitation.

  View details for DOI 10.1016/j.athoracsur.2020.05.086

  View details for PubMedID 32663472

• Donors after circulatory death heart trial. Future cardiology Shudo, Y., Benjamin-Addy, R., Koyano, T. K., Hiesinger, W., MacArthur, J. W., Woo, Y. J. 2020

  Abstract

  Orthotopic heart transplantation is the gold standard treatment for end-stage heart failure. However, the persistent shortage of available donor organs has resulted in an ever-increasing waitlist and longer waiting periods for transplantation. On the contrary, increasing the number of heart transplants by preserving extended criteria donors and donation after circulatory deathhearts with the Organ Care System (OCS) Heart System has the potential to provide the goldstandard, life-saving treatment to patients with end-stage heart failure. The objective of the Donation After Circulatory Death Heart Trial is to evaluate the effectiveness of the OCS Heart System to preserve and assess hearts donated after circulatory death for transplantation to increase the pool of donor hearts available for transplantation, which can potentially provide patients with end-stage heart failure with the life-saving treatment. Clinical Trial Registration: NCT03831048 (ClinicalTrials.gov).

  View details for DOI 10.2217/fca-2020-0070

  View details for PubMedID 32628044

• Relation of Length of Survival After Orthotopic Heart Transplantation to Age of the Donor. The American journal of cardiology Shudo, Y., Guenther, S. P., Lingala, B., He, H., Hiesinger, W., MacArthur, J. W., Currie, M. E., Lee, A. M., Boyd, J. H., Woo, Y. J. 2020

  Abstract

  We aim to evaluate the impact of donor age on the outcomes in orthotropic heart transplantation recipients. The United Network for Organ Sharing database was queried for adult patients (age; ≥60) underwent first-time orthotropic heart transplantation between 1987 and 2019 (n = 18,447). We stratified the cohort by donor age; 1,702 patients (9.2%) received a heart from a donor age of <17 years; 11,307 patients (61.3%) from a donor age of 17 ≥, < 40; 3,525 patients (19.1%) from a donor age of 40 ≥, < 50); and 1,913 patients (10.4%) from a donor age of ≥50. There was a significant difference in the survival likelihood (p < 0.0001) based on donor's age-based categorized cohort, however, the median survival was 10.5 years in the cohort in whom the donor was <17, 10.3 years in whom the donor was 17 ≥, < 40, 9.4 years in whom the donor was 40 ≥, < 50, and 9.0 years in whom the donor was ≥ 50. Additionally, there was no significant difference in the episode of acute rejection (p = 0.19) nor primary graft failure (p = 0.24). In conclusion, this study demonstrated that patients receiving hearts from the donor age of ≥50 years old showed slight inferior survival likelihood, but appeared to be equivalent median survival.

  View details for DOI 10.1016/j.amjcard.2020.06.036

  View details for PubMedID 32736794

• A novel cross-species model of Barlow's disease to biomechanically analyze repair techniques in an exvivo left heart simulator. The Journal of thoracic and cardiovascular surgery Imbrie-Moore, A. M., Paulsen, M. J., Zhu, Y., Wang, H., Lucian, H. J., Farry, J. M., MacArthur, J. W., Ma, M., Woo, Y. J. 2020

  Abstract

  OBJECTIVE: Barlow's disease remains challenging to repair, given the complex valvular morphology and lack of quantitative data to compare techniques. Although there have been recent strides in exvivo evaluation of cardiac mechanics, to our knowledge, there is no disease model that accurately simulates the morphology and pathophysiology of Barlow's disease. The purpose of this study was to design such a model.METHODS: To simulate Barlow's disease, a cross-species exvivo model was developed. Bovine mitral valves (n=4) were sewn into a porcine annulus mount to create excess leaflet tissue and elongated chordae. A heart simulator generated physiologic conditions while hemodynamic data, high-speed videography, and chordal force measurements were collected. The regurgitant valves were repaired using nonresectional repair techniques such as neochord placement.RESULTS: The model successfully imitated the complexities of Barlow's disease, including redundant, billowing bileaflet tissues with notable regurgitation. After repair, hemodynamic data confirmed reduction of mitral leakage volume (25.9±2.9 vs 2.1±1.8mL, P<.001) and strain gauge analysis revealed lower primary chordae forces (0.51±0.17 vs 0.10±0.05N, P<.001). In addition, the maximum rate of change of force was significantly lower postrepair for both primary (30.80±11.38 vs 8.59±4.83N/s, P<.001) and secondary chordae (33.52±10.59 vs 19.07±7.00N/s, P=.006).CONCLUSIONS: This study provides insight into the biomechanics of Barlow's disease, including sharply fluctuating force profiles experienced by elongated chordae prerepair, as well as restoration of primary chordae forces postrepair. Our disease model facilitates further in-depth analyses to optimize the repair of Barlow's disease.

  View details for DOI 10.1016/j.jtcvs.2020.01.086

  View details for PubMedID 32249088

• Comprehensive Ex Vivo Comparison of 5 Clinically Used Conduit Configurations for Valve-Sparing Aortic Root Replacement Using a 3-Dimensional-Printed Heart Simulator. Circulation Paulsen, M. J., Imbrie-Moore, A. M., Baiocchi, M. n., Wang, H. n., Hironaka, C. E., Lucian, H. J., Farry, J. M., Thakore, A. D., Zhu, Y. n., Ma, M. n., MacArthur, J. W., Woo, Y. J. 2020; 142 (14): 1361–73

  Abstract

  Many graft configurations are clinically used for valve-sparing aortic root replacement, some specifically focused on recapitulating neosinus geometry. However, the specific impact of such neosinuses on valvular and root biomechanics and the potential influence on long-term durability are unknown.Using a custom 3-dimenstional-printed heart simulator with porcine aortic roots (n=5), the anticommissural plication, Stanford modification, straight graft (SG), Uni-Graft, and Valsalva graft configurations were tested in series using an incomplete counterbalanced measures design, with the native root as a control, to mitigate ordering effects. Hemodynamic and videometric data were analyzed using linear models with conduit as the fixed effect of interest and valve as a fixed nuisance effect with post hoc pairwise testing using Tukey's correction.Hemodynamics were clinically similar between grafts and control aortic roots. Regurgitant fraction varied between grafts, with SG and Uni-Graft groups having the lowest regurgitant fractions and anticommissural plication having the highest. Root distensibility was significantly lower in SG versus both control roots and all other grafts aside from the Stanford modification (P≤0.01 for each). All grafts except SG had significantly higher cusp opening velocities versus native roots (P<0.01 for each). Relative cusp opening forces were similar between SG, Uni-Graft, and control groups, whereas anticommissural plication, Stanford modification, and Valsalva grafts had significantly higher opening forces versus controls (P<0.01). Cusp closing velocities were similar between native roots and the SG group, and were significantly lower than observed in the other conduits (P≤0.01 for each). Only SG and Uni-Graft groups experienced relative cusp closing forces approaching that of the native root, whereas relative forces were >5-fold higher in the anticommissural plication, Stanford modification, and Valsalva graft groups.In this ex vivo modeling system, clinically used valve-sparing aortic root replacement conduit configurations have comparable hemodynamics but differ in biomechanical performance, with the straight graft most closely recapitulating native aortic root biomechanics.

  View details for DOI 10.1161/CIRCULATIONAHA.120.046612

  View details for PubMedID 33017215

• Operative Techniques and Pitfalls in Donor Bilateral Lung Procurement. Transplantation proceedings Dalal, A. R., Rinewalt, D. E., MacArthur, J. W., Shudo, Y. n., Woo, Y. J. 2020

  Abstract

  Demand for lung transplant continues to grow nationally, and the number of donation after brain death and donation after circulatory death lung procurements increases each year.We describe the Stanford technique for bilateral lung procurement for donation after brain death and donation after circulatory death and highlight the pitfalls and common mistakes to standardize the procurement process and ensure proper harvesting to prevent organ loss.Damage to the lung graft during bilateral en bloc procurement most commonly results from either poor preservation or injury to a pulmonary vein during division of the left atrial cuff.En bloc bilateral lung procurement should be standardized to ensure reproducible graft harvesting and preservation while teaching new generations of transplant surgeons.

  View details for DOI 10.1016/j.transproceed.2020.01.023

  View details for PubMedID 32139275

• Impact of Surgical Approach in Double Lung Transplantation: Median Sternotomy vs Clamshell Thoracotomy. Transplantation proceedings Shudo, Y. n., Rinewalt, D. n., Lingala, B. n., Kim, F. Y., He, H. n., Boyd, J. H., Lee, A. M., Hiesinger, W. n., Currie, M. E., MacArthur, J. W., Woo, Y. J. 2020

  Abstract

  Double lung transplantation (DLT) remains the gold standard for end-stage lung disease. Although DLT was historically performed via clamshell thoracotomy, recently the median sternotomy has emerged as a viable alternative. As the ideal surgical approach remains unclear, the aim of our study was to compare the short- and long-term outcomes of these 2 surgical approaches in DLT.We retrospectively reviewed 192 consecutive adult patients who underwent primary DLT at our institution between 2012 and 2017 (sternotomy, n = 147; clamshell, n = 45). The impact of each surgical approach on post-transplant morbidity was investigated, and the overall survival probability analyses were performed.There were no significant differences in recipients' baseline and donors' characteristics and bilateral allograft ischemic time. Freedom from primary graft dysfunction, acute rejection episodes, postoperative prolonged ventilator support, tracheostomy, postoperative stroke, and airway dehiscence were comparable between these 2 groups. The duration of cardiopulmonary bypass and operative time were significantly longer in the clamshell thoracotomy group. Postoperative extracorporeal membrane oxygenation usage tended to be more frequent in the clamshell thoracotomy group than the median sternotomy group, despite no statistical significance. Length of hospital and intensive care unit stay were not influenced by the type of incision. There was no significant difference in overall survival between these 2 procedure groups (P = .61, log-rank test).The median sternotomy approach in DLT decreases operative time and more importantly leads to a shorter duration of cardiopulmonary bypass. The type of surgical approach did not show any statistically significant impact on adult DLT recipients' morbidity and survival.

  View details for DOI 10.1016/j.transproceed.2019.10.018

  View details for PubMedID 31911057

• A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model. Journal of cardiovascular development and disease Cohen, J. E., Goldstone, A. B., Wang, H. n., Purcell, B. P., Shudo, Y. n., MacArthur, J. W., Steele, A. N., Paulsen, M. J., Edwards, B. B., Aribeana, C. N., Cheung, N. C., Burdick, J. A., Woo, Y. J. 2020; 7 (4)

  Abstract

  The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy's potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure-volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure-volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

  View details for DOI 10.3390/jcdd7040053

  View details for PubMedID 33212844

• Three-Dimensional Multi-layered Microstructure using Laser Direct-Writing System. Tissue engineering. Part A Shudo, Y. n., MacArthur, J. W., Kunitomi, Y. n., Joubert, L. M., Kawamura, M. n., Ono, J. n., Thakore, A. D., Jaatinen, K. J., Eskandari, A. n., Hironaka, C. E., Shin, H. S., Woo, Y. J. 2020

  Abstract

  Tissue engineering is an essential component of developing effective regenerative therapies. Here, we introduce a promising method to create scaffold-free three dimensional (3D) tissue engineered multi-layered microstructures from cultured cells using the "3D tissue fabrication system" (Regenova®, Cyfuse, Japan). This technique utilizes the adhesive nature of cells. When cells are cultured in non-adhesive wells, they tend to aggregateand form a spheroidal structure. The advantage of this approach is that cellular components can be mixed into one spheroid, thereby promoting the formation of extracellular matrices, such as collagen and elastin. This system enables one to create a pre-designed 3D structure composed of cultured cells. We found the advantages of this system to be: (1) the length, size, and shape of the structure were designable and highly reproducible because of the computer controlled robotics system, (2) the graftable structure could be created within a reasonable period (8 days), and (3) the constructed tissue did not contain any foreign material, which may avoid the potential issues ofcontamination, biotoxicity, and allergy. The utilization of this robotic system enabled thecreation of a 3D multi-layered microstructure made of cell based spheres with a satisfactory mechanical properties and abundant extracellular matrix during a short period of time. These results suggest that this new technology will represent a promising, attractive, and practical strategy in the field of tissue engineering.

  View details for DOI 10.1089/ten.TEA.2019.0313

  View details for PubMedID 32085692

• Signalosome-Regulated SRF Phosphorylation Determining Myocyte Growth in Width versus Length as a Therapeutic Target for Heart Failure. Circulation Li, J. n., Tan, Y. n., Passariello, C. L., Martinez, E. C., Kritzer, M. D., Li, X. n., Li, X. n., Li, Y. n., Yu, Q. n., Ohgi, K. n., Thakur, H. n., MacArthur, J. W., Ivey, J. R., Woo, Y. J., Emter, C. A., Dodge-Kafka, K. n., Rosenfeld, M. G., Kapiloff, M. S. 2020

  Abstract

  Background: Concentric and eccentric cardiac hypertrophy are associated with pressure and volume overload, respectively, in cardiovascular disease both conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetric growth of the cardiac myocyte in mainly width or length, respectively. The molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood. Identification of the mechanisms governing asymmetric myocyte growth could provide new therapeutic targets for the prevention or treatment of heart failure. Methods: Primary adult rat ventricular myocytes, adeno-associated virus (AAV)-mediated gene delivery in mice, and human tissue samples are used to define a regulatory pathway controlling pathological myocyte hypertrophy. Chromatin Immunoprecipitation Assays with Sequencing (ChIP-seq) and Precision Nuclear Run-On Sequencing (PRO-seq) are used to define a transcriptional mechanism. Results: Here we report that asymmetric cardiac myocyte hypertrophy is modulated by serum response factor (SRF) phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes in vitro and in vivo. SRF Ser103 phosphorylation is bidirectionally regulated by p90 ribosomal S6 kinase type 3 (RSK3) and protein phosphatase 2A (PP2A) at signalosomes organized by the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ), such that increased SRF phosphorylation activates Activator Protein 1 (AP1)-dependent enhancers that direct myocyte growth in width. AAV are used to express in vivo mAKAPβ-derived RSK3 and PP2A anchoring disruptor peptides that block the association of the enzymes with the mAKAPβ scaffold. Inhibition of RSK3 signaling prevents concentric cardiac remodeling due to pressure overload, while inhibition of PP2A signaling prevents eccentric cardiac remodeling induced by myocardial infarction, in each case improving cardiac function. SRF Ser103 phosphorylation is significantly decreased in dilated human hearts, supporting the notion that modulation of the mAKAPβ-SRF signalosome could be a new therapeutic approach for human heart failure. Conclusions: We have identified a new molecular switch, namely mAKAPβ signalosome-regulated SRF phosphorylation, that controls a transcriptional program responsible for modulating changes in cardiac myocyte morphology that occur secondary to pathological stressors. Complementary AAV-based gene therapies constitute rationally-designed strategies for a new translational modality for heart failure.

  View details for DOI 10.1161/CIRCULATIONAHA.119.044805

  View details for PubMedID 32933333

• Mitral chordae tendineae force profile characterization using a posterior ventricular anchoring neochordal repair model for mitral regurgitation in a three-dimensional-printed ex vivo left heart simulator. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery Paulsen, M. J., Imbrie-Moore, A. M., Wang, H., Bae, J. H., Hironaka, C. E., Farry, J. M., Lucian, H. J., Thakore, A. D., MacArthur, J. W., Cutkosky, M. R., Woo, Y. J. 2019

  Abstract

  OBJECTIVES: Posterior ventricular anchoring neochordal (PVAN) repair is a non-resectional technique for correcting mitral regurgitation (MR) due to posterior leaflet prolapse, utilizing a single suture anchored in the myocardium behind the leaflet. This technique has demonstrated clinical efficacy, although a theoretical limitation is stability of the anchoring suture. We hypothesize that the PVAN suture positions the leaflet for coaptation, after which forces are distributed evenly with low repair suture forces.METHODS: Porcine mitral valves were mounted in a 3-dimensional-printed heart simulator and chordal forces, haemodynamics and echocardiography were collected at baseline, after inducing MR by severing chordae, and after PVAN repair. Repair suture forces were measured with a force-sensing post positioned to mimic in vivo suture placement. Forces required to pull the myocardial suture free were also determined.RESULTS: Relative primary and secondary chordae forces on both leaflets were elevated during prolapse (P<0.05). PVAN repair eliminated MR in all valves and normalized chordae forces to baseline levels on anterior primary (0.37±0.23 to 0.22±0.09 N, P<0.05), posterior primary (0.62±0.37 to 0.14±0.05 N, P=0.001), anterior secondary (1.48±0.52 to 0.85±0.43 N, P<0.001) and posterior secondary chordae (1.42±0.69 to 0.59±0.17 N, P=0.005). Repair suture forces were minimal, even compared to normal primary chordae forces (0.08±0.04 vs 0.19±0.08 N, P=0.002), and were 90 times smaller than maximum forces tolerated by the myocardium (0.08±0.04 vs 6.9±1.3 N, P<0.001).DISCUSSION: PVAN repair eliminates MR by positioning the posterior leaflet for coaptation, distributing forces throughout the valve. Given extremely low measured forces, the strength of the repair suture and the myocardium is not a limitation.

  View details for DOI 10.1093/ejcts/ezz258

  View details for PubMedID 31638697

• Heart-lung transplantation with concomitant aortic arch reconstruction for Eisenmenger syndrome and type B interrupted aortic arch. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Wang, H., Shudo, Y., MacArthur, J. W., Woo, Y. J. 2019

  View details for DOI 10.1016/j.healun.2019.09.002

  View details for PubMedID 31570290

• A modified implantation technique for temporary right ventricular assist device: Enabling ambulation and less invasive decannulation. Journal of cardiac surgery Rinewalt, D., Shudo, Y., MacArthur, J. W., Woo, Y. J., Hiesinger, W. 2019

  Abstract

  This report describes our unique temporary right ventricular assist device (RVAD) implantation technique, which enables early mobilization even during biventricular support and subsequent less invasive RVAD removal without needing resternotomy upon recovery.

  View details for DOI 10.1111/jocs.14193

  View details for PubMedID 31389624

• Bioengineered analog of stromal cell-derived factor 1 alpha preserves the biaxial mechanical properties of native myocardium after infarction JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS Wang, H., Wisneski, A., Paulsen, M. J., Imbrie-Moore, A., Wang, Z., Xuan, Y., Hernandez, H., Lucian, H. J., Eskandari, A., Thakore, A. D., Parry, J. M., Hironaka, C. E., von Bornstaedt, D., Steele, A. N., Stapleton, L. M., Williams, K. M., Wu, M. A., MacArthur, J. W., Woo, Y. 2019; 96: 165–71

  View details for DOI 10.1016/j.jmbbm.2019.04.014

  View details for Web of Science ID 000472243400018

• Surgical Management for Aortoesophageal Fistula After Endovascular Aortic Repair. The Annals of thoracic surgery Zhu, Y. n., MacArthur, J. W., Lui, N. n., Lee, A. M. 2019

  Abstract

  This case demonstrates successful surgical management of a 6 cm-long aortoesophageal fistula from an infected stent graft. A 69-year-old woman with a penetrating descending thoracic aortic ulcer underwent endovascular aortic repair. Two weeks later, she presented with nausea and melena, and was found to have an infected stent graft on imaging. She underwent a two-stage procedure encompassing aortic arch debranching and extra-anatomic aortic bypass in stage one, and stent graft resection, primary esophageal repair, intercostal and omental flap and jejunostomy tube placement in stage two. She was discharged one month later and is doing well 1.5 years after the operation.

  View details for DOI 10.1016/j.athoracsur.2019.08.076

  View details for PubMedID 31586613

• Surgical excision of a free floating ascending aortic thrombus. Journal of cardiac surgery Dalal, A. R., Kabirpour, A. n., MacArthur, J. W. 2019

  Abstract

  A 73-year-old female presented with leg claudication and chest pain. A mobile mass in the ascending aorta was found.The mass was removed through a transverse aortotomy on circulatory arrest via sternotomy.Free-floating ascending aortic thrombus is a rare source of peripheral embolization. We advocate for emergent surgical resection to prevent further embolization and stroke.

  View details for DOI 10.1111/jocs.14396

  View details for PubMedID 31830328

• Bioengineered analog of stromal cell-derived factor 1α preserves the biaxial mechanical properties of native myocardium after infarction. Journal of the mechanical behavior of biomedical materials Wang, H. n., Wisneski, A. n., Paulsen, M. J., Imbrie-Moore, A. n., Wang, Z. n., Xuan, Y. n., Hernandez, H. L., Lucian, H. J., Eskandari, A. n., Thakore, A. D., Farry, J. M., Hironaka, C. E., von Bornstaedt, D. n., Steele, A. N., Stapleton, L. M., Williams, K. M., Wu, M. A., MacArthur, J. W., Woo, Y. J. 2019; 96: 165–71

  Abstract

  Adverse remodeling of the left ventricle (LV) after myocardial infarction (MI) results in abnormal tissue biomechanics and impaired cardiac function, often leading to heart failure. We hypothesized that intramyocardial delivery of engineered stromal cell-derived factor 1α analog (ESA), our previously-developed supra-efficient pro-angiogenic chemokine, preserves biaxial LV mechanical properties after MI. Male Wistar rats (n = 45) underwent sham surgery (n = 15) or permanent left anterior descending coronary artery ligation. Rats sustaining MI were randomized for intramyocardial injections of either saline (100 μL, n = 15) or ESA (6 μg/kg, n = 15), delivered at four standardized borderzone sites. After 4 weeks, echocardiography was performed, and the hearts were explanted. Tensile testing of the anterolateral LV wall was performed using a displacement-controlled biaxial load frame, and modulus was determined after constitutive modeling. At 4 weeks post-MI, compared to saline controls, ESA-treated hearts had greater wall thickness (1.68 ± 0.05 mm vs 1.42 ± 0.08 mm, p = 0.008), smaller end-diastolic LV internal dimension (6.88 ± 0.29 mm vs 7.69 ± 0.22 mm, p = 0.044), and improved ejection fraction (62.8 ± 3.0% vs 49.4 ± 4.5%, p = 0.014). Histologic analysis revealed significantly reduced infarct size for ESA-treated hearts compared to saline controls (29.4 ± 2.9% vs 41.6 ± 3.1%, p = 0.021). Infarcted hearts treated with ESA exhibited decreased modulus compared to those treated with saline in both the circumferential (211.5 ± 6.9 kPa vs 264.3 ± 12.5 kPa, p = 0.001) and longitudinal axes (194.5 ± 6.5 kPa vs 258.1 ± 14.4 kPa, p < 0.001). In both principal directions, ESA-treated infarcted hearts possessed similar tissue compliance as sham non-infarcted hearts. Overall, intramyocardial ESA therapy improves post-MI ventricular remodeling and function, reduces infarct size, and preserves native LV biaxial mechanical properties.

  View details for PubMedID 31035067

• A 3D Printed Ex Vivo Left Heart Simulator Quantifies and Validates Posterior Ventricular Anchoring Neochordoplasty Paulsen, M. J., Bae, J., Imbrie-Moore, A. M., Wang, H., Farry, J. M., Lin, M. A., Hironaka, C. E., Lucian, H. J., Edwards, B. B., Thankore, A. D., MacArthur, J. W., Steele, A. N., Stapleton, L., Williams, K. M., Deschamps, D., Kulkarni, R., Cutkosky, M. R., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619407215

• Computationally-Engineered Analog of Stromal Cell-Derived Factor 1[alpha] Preserves the Mechanical Properties of Infarcted Myocardium Under Planar Biaxial Tension Wang, H., Wisneski, A., Paulsen, M. J., Wang, Z., Hernandez, L., Xuan, Y., von Bornstaedt, D., Steele, A. N., Stapleton, L. M., Lucian, H. J., Anahita, E., Thakore, A. D., Farry, J. M., Hironaka, C. E., Williams, K. M., Wu, M., MacArthur, J. W., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619407263

• SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Goldstone, A. B., Burnett, C. E., Cohen, J. E., Paulsen, M. J., Eskandari, A., Edwards, B. E., Ingason, A. B., Steele, A. N., Patel, J. B., MacArthur, J. W., Shizuru, J. A., Woo, Y. 2018; 11 (4): 274–84

  View details for DOI 10.1007/s12265-017-9772-y

  View details for Web of Science ID 000443418700002

• SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells. Journal of cardiovascular translational research Goldstone, A. B., Burnett, C. E., Cohen, J. E., Paulsen, M. J., Eskandari, A., Edwards, B. E., Ingason, A. B., Steele, A. N., Patel, J. B., MacArthur, J. W., Shizuru, J. A., Woo, Y. J. 2018

  Abstract

  Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.

  View details for PubMedID 29468554

• The tip of the iceberg: Evaluating the mechanism behind dehiscence of mitral annuloplasty rings. The Journal of thoracic and cardiovascular surgery MacArthur, J. W., Boyd, J. 2017

  View details for PubMedID 28947191

• Stem Cell Therapy: Healing or Hype? Why Stem Cell Delivery Doesn't Work CIRCULATION RESEARCH Steele, A. N., MacArthur, J. W., Woo, Y. 2017; 120 (12): 1868–70

  View details for PubMedID 28596172

• Injectable Bioengineered Hydrogel Therapy in the Treatment of Ischemic Cardiomyopathy. Current treatment options in cardiovascular medicine MacArthur, J. W., Steele, A. N., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. J. 2017; 19 (4): 30-?

  Abstract

  Over the past two decades, the field of cardiovascular medicine has seen the rapid development of multiple different modalities for the treatment of ischemic myocardial disease. Most research efforts have focused on strategies aimed at coronary revascularization, with significant technological advances made in percutaneous coronary interventions as well as coronary artery bypass graft surgery. However, recent research efforts have shifted towards ways to address the downstream effects of myocardial infarction on both cellular and molecular levels. To this end, the broad application of injectable hydrogel therapy after myocardial infarction has stimulated tremendous interest. In this article, we will review what hydrogels are, how they can be bioengineered in unique ways to optimize therapeutic potential, and how they can be used as part of a treatment strategy after myocardial infarction.

  View details for DOI 10.1007/s11936-017-0530-x

  View details for PubMedID 28337717

• 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. n., 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. n., Fairman, A. S., Hiesinger, W. n., Esipova, T. V., Patrick, W. L., Ji, K. n., 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 PubMedID 28630913

• Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb. Journal of vascular surgery Edwards, B. B., Fairman, A. S., Cohen, J. E., Macarthur, J. W., Goldstone, A. B., Woo, J. B., Hiesinger, W., Woo, Y. J. 2016; 64 (4): 1093-1099

  Abstract

  Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion.Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 μL injection of saline (n = 9) or 6 μg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 μg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers.Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03).Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.

  View details for DOI 10.1016/j.jvs.2015.06.140

  View details for PubMedID 26372192

• Cell transplantation in heart failure: where do we stand in 2016? EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY MacArthur, J. W., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. 2016; 50 (3): 396–99

  View details for PubMedID 27587719

• 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

• 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 PubMedID 26154752

• 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

• A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement ANNALS OF THORACIC SURGERY Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., MacArthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1991

  Abstract

  We examined the feasibility and efficacy of a "repair-all" strategy applied in all patients with degenerative mitral regurgitation, regardless of valve complexity, risk profile, and surgical approach.Between 2002 and 2011, 4,241 patients underwent mitral operations at our institution. Analysis was limited to 525 consecutive patients with mitral regurgitation due to leaflet prolapse (posterior, 75%; anterior, 5%; bileaflet, 20%) who underwent isolated mitral operations. A right minithoracotomy was used in 46% of procedures. Propensity scores identified 153 well-matched patient pairs for evaluation of the effect of surgical approach on valve reparability.Mitral repair was successful in 99% (520 of 525) of patients. The location of the leaflet prolapse did not significantly influence the repair rate or the need for intraoperative revision of the initial repair. The repair rate and the need for intraoperative repair revision also did not significantly differ by surgical approach. Intraoperative revision did not confer a greater risk of perioperative morbidity or longer length of stay. At 8 years, freedom from severe mitral regurgitation was 97% ± 2%. Development of residual mitral regurgitation did not differ by location of the leaflet prolapse, need for repair revision, or surgical approach. After discharge, the survival trend did not differ between patients who did and did not require intraoperative repair revision.In experienced centers, a "repair-all" strategy for degenerative mitral regurgitation can be used with nearly 100% repair rates and excellent outcomes, regardless of valve complexity. When necessary, intraoperative revision of the initial repair may be performed in most patients without a significant incremental risk, thereby further enhancing repair rates.

  View details for DOI 10.1016/j.athoracsur.2014.12.076

  View details for Web of Science ID 000357521600028

  View details for PubMedID 25865766

• A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement. Annals of thoracic surgery Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., Macarthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1990

  Abstract

  We examined the feasibility and efficacy of a "repair-all" strategy applied in all patients with degenerative mitral regurgitation, regardless of valve complexity, risk profile, and surgical approach.Between 2002 and 2011, 4,241 patients underwent mitral operations at our institution. Analysis was limited to 525 consecutive patients with mitral regurgitation due to leaflet prolapse (posterior, 75%; anterior, 5%; bileaflet, 20%) who underwent isolated mitral operations. A right minithoracotomy was used in 46% of procedures. Propensity scores identified 153 well-matched patient pairs for evaluation of the effect of surgical approach on valve reparability.Mitral repair was successful in 99% (520 of 525) of patients. The location of the leaflet prolapse did not significantly influence the repair rate or the need for intraoperative revision of the initial repair. The repair rate and the need for intraoperative repair revision also did not significantly differ by surgical approach. Intraoperative revision did not confer a greater risk of perioperative morbidity or longer length of stay. At 8 years, freedom from severe mitral regurgitation was 97% ± 2%. Development of residual mitral regurgitation did not differ by location of the leaflet prolapse, need for repair revision, or surgical approach. After discharge, the survival trend did not differ between patients who did and did not require intraoperative repair revision.In experienced centers, a "repair-all" strategy for degenerative mitral regurgitation can be used with nearly 100% repair rates and excellent outcomes, regardless of valve complexity. When necessary, intraoperative revision of the initial repair may be performed in most patients without a significant incremental risk, thereby further enhancing repair rates.

  View details for DOI 10.1016/j.athoracsur.2014.12.076

  View details for PubMedID 25865766

• 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 PubMedID 25804458

• Shear-Thinning Supramolecular Hydrogels with Secondary Autonomous Covalent Crosslinking to Modulate Viscoelastic Properties In Vivo ADVANCED FUNCTIONAL MATERIALS Rodell, C. B., MacArthur, J. W., Dorsey, S. M., Wade, R. J., Wang, L. L., Woo, Y. J., Burdick, J. A. 2015; 25 (4): 636-644

  Abstract

  Clinical percutaneous delivery of synthetically engineered hydrogels remains limited due to challenges posed by crosslinking kinetics - too fast leads to delivery failure, too slow limits material retention. To overcome this challenge, we exploit supramolecular assembly to localize hydrogels at the injection site and introduce subsequent covalent crosslinking to control final material properties. Supramolecular gels were designed through the separate pendant modifications of hyaluronic acid (HA) by the guest-host pair cyclodextrin and adamantane, enabling shear-thinning injection and high target site retention (>98%). Secondary covalent crosslinking occurred via addition of thiols and Michael-acceptors (i.e., methacrylates, acrylates, vinyl sulfones) on HA and increased hydrogel moduli (E=25.0±4.5kPa) and stability (>3.5 fold in vivo at 28 days). Application of the dual-crosslinking hydrogel to a myocardial infarct model showed improved outcomes relative to untreated and supramolecular hydrogel alone controls, demonstrating its potential in a range of applications where the precise delivery of hydrogels with tunable properties is desired.

  View details for DOI 10.1002/adfm.201403550

  View details for Web of Science ID 000348856500015

  View details for PubMedCentralID PMC4624407

• Shear-Thinning Supramolecular Hydrogels with Secondary Autonomous Covalent Crosslinking to Modulate Viscoelastic Properties In Vivo. Advanced functional materials Rodell, C. B., MacArthur, J. W., Dorsey, S. M., Wade, R. J., Wang, L. L., Woo, Y. J., Burdick, J. A. 2015; 25 (4): 636-644

  Abstract

  Clinical percutaneous delivery of synthetically engineered hydrogels remains limited due to challenges posed by crosslinking kinetics - too fast leads to delivery failure, too slow limits material retention. To overcome this challenge, we exploit supramolecular assembly to localize hydrogels at the injection site and introduce subsequent covalent crosslinking to control final material properties. Supramolecular gels were designed through the separate pendant modifications of hyaluronic acid (HA) by the guest-host pair cyclodextrin and adamantane, enabling shear-thinning injection and high target site retention (>98%). Secondary covalent crosslinking occurred via addition of thiols and Michael-acceptors (i.e., methacrylates, acrylates, vinyl sulfones) on HA and increased hydrogel moduli (E=25.0±4.5kPa) and stability (>3.5 fold in vivo at 28 days). Application of the dual-crosslinking hydrogel to a myocardial infarct model showed improved outcomes relative to untreated and supramolecular hydrogel alone controls, demonstrating its potential in a range of applications where the precise delivery of hydrogels with tunable properties is desired.

  View details for DOI 10.1002/adfm.201403550

  View details for PubMedID 26526097

  View details for PubMedCentralID PMC4624407

• Natural history of coexistent tricuspid regurgitation in patients with degenerative mitral valve disease: Implications for future guidelines JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Goldstone, A. B., Howard, J. L., Cohen, J. E., MacArthur, J. W., Atluri, P., Kirkpatrick, J. N., Woo, Y. J. 2014; 148 (6): 2802-2809

  Abstract

  The management of coexistent tricuspid regurgitation in patients with mitral regurgitation remains controversial. We sought to define the incidence and natural history of coexistent tricuspid regurgitation in patients undergoing isolated mitral surgery for degenerative mitral regurgitation, as well as the effect of late secondary tricuspid regurgitation on cardiovascular symptom burden and survival.To minimize confounding, analysis was limited to 495 consecutive patients who underwent isolated mitral surgery for degenerative mitral valve disease between 2002 and 2011. Patients with coexistent severe tricuspid regurgitation were excluded because such patients typically undergo concomitant tricuspid intervention.Grade 1 to 3 coexistent tricuspid regurgitation was present in 215 patients (43%) preoperatively. Actuarial freedom from grade 3 to 4 tricuspid regurgitation 1, 5, and 9 years after surgery was 100% ± 0%, 90% ± 2%, and 64% ± 7%, respectively. Older age (P < .001) and grade of preoperative tricuspid regurgitation (P = .006) independently predicted postoperative progression of tricuspid regurgitation on multivariable analysis. However, when limited to patients with mild or absent tricuspid regurgitation, indexed tricuspid annular diameter was the only significant risk factor for late tricuspid regurgitation (P = .04). New York Heart Association functional class and long-term survival did not worsen with development of late secondary tricuspid regurgitation (P = .4 and P = .6, respectively). However, right ventricular dysfunction was significantly more common in patients with more severe late tricuspid regurgitation (P = .007).Despite durable correction of degenerative mitral regurgitation, less than severe tricuspid regurgitation is likely to progress after surgery if uncorrected. Given the low incremental risk of tricuspid annuloplasty, a more aggressive strategy of concomitant tricuspid repair may be warranted.

  View details for DOI 10.1016/j.jtcvs.2014.08.001

  View details for PubMedID 25218532

• Tissue-engineered, hydrogel-based endothelial progenitor cell therapy robustly revascularizes ischemic myocardium and preserves ventricular function. journal of thoracic and cardiovascular surgery Atluri, P., Miller, J. S., Emery, R. J., Hung, G., Trubelja, A., Cohen, J. E., Lloyd, K., Han, J., Gaffey, A. C., MacArthur, J. W., Chen, C. S., Woo, Y. J. 2014; 148 (3): 1090-1098

  Abstract

  Cell-based angiogenic therapy for ischemic heart failure has had limited clinical impact, likely related to low cell retention (<1%) and dispersion. We developed a novel, tissue-engineered, hydrogel-based cell-delivery strategy to overcome these limitations and provide prolonged regional retention of myocardial endothelial progenitor cells at high cell dosage.Endothelial progenitor cells were isolated from Wistar rats and encapsulated in fibrin gels. In vitro viability was quantified using a fluorescent live-dead stain of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells. Endothelial progenitor cell-laden constructs were implanted onto ischemic rat myocardium in a model of acute myocardial infarction (left anterior descending ligation) for 4 weeks. Intramyocardial cell injection (2 × 10(6) endothelial progenitor cells), empty fibrin, and isolated left anterior descending ligation groups served as controls. Hemodynamics were quantified using echocardiography, Doppler flow analysis, and intraventricular pressure-volume analysis. Vasculogenesis and ventricular geometry were quantified. Endothelial progenitor cell migration was analyzed by using endothelial progenitor cells from transgenic enhanced green fluorescent protein(+) rodents.Endothelial progenitor cells demonstrated an overall 88.7% viability for all matrix and cell conditions investigated after 48 hours. Histologic assessment of 1-week implants demonstrated significant migration of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells from the fibrin matrix to the infarcted myocardium compared with intramyocardial cell injection (28 ± 12.3 cells/high power field vs 2.4 ± 2.1 cells/high power field, P = .0001). We also observed a marked increase in vasculogenesis at the implant site. Significant improvements in ventricular hemodynamics and geometry were present after endothelial progenitor cell-hydrogel therapy compared with control.We present a tissue-engineered, hydrogel-based endothelial progenitor cell-mediated therapy to enhance cell delivery, cell retention, vasculogenesis, and preservation of myocardial structure and function.

  View details for DOI 10.1016/j.jtcvs.2014.06.038

  View details for PubMedID 25129603

• Combined heart and liver transplantation can be safely performed with excellent short- and long-term results. Annals of thoracic surgery Atluri, P., Gaffey, A., Howard, J., Phillips, E., Goldstone, A. B., Hornsby, N., MacArthur, J. W., Cohen, J. E., Gutsche, J., Woo, Y. J. 2014; 98 (3): 858-862

  Abstract

  Heart transplant has become the gold standard therapy for end-stage heart failure. Short- and long-term outcomes after orthotopic heart transplant have been excellent. Many patients with heart failure manifest hepatic failure as a result of a chronically elevated central venous pressure. Concomitant hepatic failure has been a contraindication to heart transplant in most centers. A few select institutions are currently performing combined heart-liver transplantation to treat dual organ failure. The outcomes after dual organ transplant are largely unknown, with limited data from a few select centers. We undertook this study to analyze our large experience with combined heart-liver transplant and determine the short-term and long-term outcomes associated with this procedure.We have performed 1,050 heart transplants at our center to date. Of these patients, 26 underwent combined heart and liver transplant (largest single-center experience). We reviewed demographic, perioperative, and short- and long-term outcomes after this combined procedure.All 26 patients underwent successful dual organ transplant, without any episodes of primary graft dysfunction. Average length of intensive care unit stay was 10 ± 5 days, and average hospital stay was 25 ± 11 days. Kaplan-Meier analysis demonstrated excellent short-term survival (1 year, 87% ± 7%) and long-term survival (5 years, 83% ± 8%). Interestingly, only 3 patients (11%) demonstrated any evidence of rejection long-term by myocardial biopsy, suggesting that concomitant hepatic transplantation may provide immunologic protection for the cardiac allograft.We present the largest single-center series of combined heart and liver transplant. This dual organ strategy is highly feasible, with excellent long-term survival. Concomitant liver transplant may confer immunologic protection for the cardiac allograft.

  View details for DOI 10.1016/j.athoracsur.2014.04.100

  View details for PubMedID 25069688

• 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