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Kadosh BS, Patel SS, Sidhu SK, Massie AB, Golob S, Goldberg RI, Reyentovich A, Moazami N. Waitlist mortality for patients with cardiac allograft vasculopathy under the 2018 OPTN donor heart allocation system. J Heart Lung Transplant 2025; 44:378-385. [PMID: 39603482 DOI: 10.1016/j.healun.2024.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/09/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND In the 2018 Organ Procurement and Transplantation Network donor heart allocation system, patients listed for re-transplantation due to cardiac allograft vasculopathy (CAV) are assigned to Status 4 unless hemodynamic criteria are met. We aim to examine waitlist outcomes of CAV patients among adult heart transplant candidates. METHODS We examined waitlist mortality stratified by CAV and waitlist status among adult heart transplant candidates using Scientific Registry of Transplant Recipients data from 10/1/2018-11/1/2023. We analyzed waitlist mortality using Kaplan-Meier curves and doubly-robust Cox regressions adjusted for age, gender, sex, race, and dialysis. We compared CAV to non-CAV patients by initial waitlist status, first status of interest, and time-dependent status. RESULTS Of 21,586 listed patients, 368 were listed for CAV. CAV patients were most often listed at Status 4 with lower proportions at Status 3/2/1 compared with non-CAV patients. Status 4 and Status 3 CAV candidates demonstrated higher than expected waitlist mortality compared to non-CAV counterparts (Status 4: HR 0.51, 95% CI 0.31-0.84; p < 0.01; Status 3: HR 0.61, 95% CI 0.23-1.64; p = 0.33) with similar mortality to non-CAV patients in Status 3 and 2, respectively (Status 4: HR 0.80, 95% CI 0.48-1.35; p = 0.4; Status 3: HR 1.07, 95% CI 0.40-2.86; p = 0.89). When stratifying by status tier, CAV waitlist patients ever listed at Status 4 and 3 had a higher probability of death compared to their non-CAV counterparts (Status 4: HR 1.99, 95% CI 1.20-3.31, p < 0.01; Status 3: HR 3.06, 95% CI 1.06-8.87, p = 0.04). CONCLUSIONS After 2018, CAV patients had a higher risk of waitlist mortality at Status 4 and 3 compared to non-CAV patients. These results suggest that CAV patients are underprioritized in the current allocation system.
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Affiliation(s)
- Bernard S Kadosh
- Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY.
| | - Suhani S Patel
- Department of Surgery, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
| | - Sharnendra K Sidhu
- Department of Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
| | - Allan B Massie
- Department of Surgery, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
| | - Stephanie Golob
- Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
| | - Randal I Goldberg
- Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
| | - Alex Reyentovich
- Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
| | - Nader Moazami
- Department of Cardiothoracic Surgery, New York University Grossman School of Medicine, NYU Langone Health, New York, NY
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Wu Y, Gao L, Lazo J, Martinez B, Grewal S, Yurkova I, Galeota J, Nash C, Cutler M, Tarango N, Prasad P, Cheng R, Motiwala S, De Marco T. Care of Adult Heart Transplant Recipients by the Primary Care Provider: A Practical Roadmap. J Clin Med 2025; 14:1346. [PMID: 40004875 PMCID: PMC11856219 DOI: 10.3390/jcm14041346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/05/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Heart transplantation has significantly improved survival and enhanced the quality of life of patients with end-stage heart failure. Successful long-term outcomes are predicated on a collaborative effort among patients, transplant teams, and primary care providers (PCPs). Notably, PCPs are increasingly pivotal in post-transplant care, engaging in annual assessments, early recognition of complications, and referral, thus minimizing morbidity and mortality. This article highlights key considerations for PCPs, including indications for heart transplant, immunosuppressive therapy and infection prophylaxis, management of post-transplant complications, psychosocial and lifestyle adjustment, and family planning. This roadmap aims to empower PCPs to deliver optimal care and improve long-term outcomes for heart transplant recipients.
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Affiliation(s)
- Yu Wu
- Department of Surgery, Division of Cardiothoracic Surgery, Section of Mechanical Circulatory Support, University of California San Francisco Health, San Francisco, CA 94143, USA
| | - Lina Gao
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Jose Lazo
- Department of Pharmacy, University of California San Francisco Health, San Francisco, CA 94143, USA; (J.L.)
| | - Brandon Martinez
- Department of Pharmacy, University of California San Francisco Health, San Francisco, CA 94143, USA; (J.L.)
| | - Simran Grewal
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Irina Yurkova
- Department of Surgery, Division of Cardiothoracic Surgery, Section of Mechanical Circulatory Support, University of California San Francisco Health, San Francisco, CA 94143, USA
| | - Julia Galeota
- Department of Social Work, University of California San Francisco Health, San Francisco, CA 94143, USA
| | - Catherine Nash
- Department of Social Work, University of California San Francisco Health, San Francisco, CA 94143, USA
| | - Meghan Cutler
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Nimaljeet Tarango
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Pooja Prasad
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Richard Cheng
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Shweta Motiwala
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
| | - Teresa De Marco
- Department of Medicine, Division of Cardiology, Section of Advanced Heart Failure and Heart Transplant, University of California San Francisco Health, San Francisco, CA 94143, USA (M.C.)
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Kang M, Park HK, Kim KS, Choi D. Animal models for transplant immunology: bridging bench to bedside. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:354-376. [PMID: 39233453 PMCID: PMC11732767 DOI: 10.4285/ctr.24.0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/05/2024] [Accepted: 07/07/2024] [Indexed: 09/06/2024]
Abstract
The progress of transplantation has been propelled forward by animal experiments. Animal models have not only provided opportunities to understand complex immune mechanisms in transplantation but also served as a platform to assess therapeutic interventions. While small animals have been instrumental in uncovering new therapeutic concepts related to immunosuppression and immune tolerance, the progression to human trials has largely been driven by studies in large animals. Recent research has begun to explore the potential of porcine organs to address the shortage of available organs. The consistent progress in transplant immunology research can be attributed to a thorough understanding of animal models. This review provides a comprehensive overview of the available animal models, detailing their modifications, strengths, and weaknesses, as well as their historical applications, to aid researchers in selecting the most suitable model for their specific research needs.
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Affiliation(s)
- Minseok Kang
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Hwon Kyum Park
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Kyeong Sik Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Korea
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Yu F, Ribeiro R, Rosales R, Hauck L, Grothe D, Alvarez J, Adamson M, Rao V, Badiwala M, Billia F. Dialysis preserves heart function during ex situ heart perfusion. JHLT OPEN 2024; 4:100074. [PMID: 40144237 PMCID: PMC11935421 DOI: 10.1016/j.jhlto.2024.100074] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background Ex situ heart perfusion (ESHP) has been used to optimize donor organs before heart transplantation. However, cardiac function often deteriorates with the development of myocardial edema. The use of dialysis during ESHP could assist in cardiac preservation. Methods Male Yorkshire pig hearts were subjected to ESHP for 8 hours with or without dialysis. Hearts were supported during nonworking mode and working mode, and pressure-volume loops and coronary vasomotor function were evaluated. Finally, tissue biopsies were assessed for mitochondrial function, oxidative stress, and inflammation. Results Adding dialysis to ESHP significantly enhanced cardiac function, with improved preload recruitable stroke work at 4 hours (64.09 ± 20.13 vs 35.08 ± 13.52, p = 0.010) and 8 hours (64.31 ± 9.08 vs 23.30 ± 19.25, p = 0.0002), maximal elastance at 8 hours (24.67 ± 10.75 vs 10.62 ± 8.471, p = 0.0477), and end diastolic pressure volume relationship at 8 hours (644.7 ± 566.68 vs 86.63 ± 72.05, p = 0.0187). Coronary vasomotor function improved in the dialysis group in endothelium dependent (LogIC50 -7.39 ± 0.25 vs -2.22 ± 0.76, p < 0.0001) and independent (LogIC50 -6.11 ± 0.19 vs -4.79 ± 0.11, p < 0.0001) vasorelaxation. Dialyzed hearts also had reduced sensitivity to endothelin-1 (LogEC50 -7.94 ± 0.5 vs -8.54 ± 0.06, p = 0.0449) and significant changes in endothelin receptor-related protein expression related and oxidative stress. Conclusions The combination of dialysis with ESHP improves myocardial and coronary vasomotor preservation and may allow for longer perfusion times.
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Affiliation(s)
- Frank Yu
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Roberto Ribeiro
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Roizar Rosales
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Ludger Hauck
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Daniela Grothe
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Juglans Alvarez
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Division of Cardiovascular Surgery, Peter Munk Cardiac Center, Toronto Ontario, Canada
- Ajmera Transplant Center, University Health Network, Toronto Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Mitchell Adamson
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Vivek Rao
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Division of Cardiovascular Surgery, Peter Munk Cardiac Center, Toronto Ontario, Canada
- Ajmera Transplant Center, University Health Network, Toronto Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Mitesh Badiwala
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Heart, Vascular and Thoracic Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Filio Billia
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Ajmera Transplant Center, University Health Network, Toronto Ontario, Canada
- Ted Rogers Center for Heart Research, University Health Network, Toronto Ontario, Canada
- Division of Cardiology, Peter Munk Cardiac Center, Toronto Ontario, Canada
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Kuczaj A, Pawlak S, Głowacki J, Antończyk R, Śliwka J, Przybyłowski P, Hrapkowicz T. Utility of 64-Slice Coronary Computed Tomography Angiography in Heart Transplant Recipients. Transplant Proc 2024; 56:836-840. [PMID: 38729834 DOI: 10.1016/j.transproceed.2024.03.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 03/29/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Graft vasculopathy is a leading cause of death after heart transplantation (HTx). Diagnosing cardiac allograft vasculopathy (CAV) within this patient group poses significant challenges. This study aimed to evaluate the safety and efficacy of coronary computed tomographic angiography (CCTA) in patients after HTx. METHODS We enrolled 107 consecutive HTx recipients (26 women, mean age 50 ± 17 years); all were ≥3 years post-HTx with minimal or no evidence of CAV in a prior coronary angiography performed a minimum of 2 years before the current examination. The inclusion criteria comprised an estimated glomerular filtration rate (eGFR) of ≥30, absence of new heart failure symptoms, and no contraindications to iodine contrast or CT scans. All patients underwent a 64-slice CCTA. In cases of minimal or no changes, noninvasive follow-up examinations were conducted. Significant changes in CT prompted additional coronary angiography. RESULTS Of the enrolled participants, 9 exhibited minimal changes; 98 displayed no changes in coronary angiography. The median time since transplant was 7 years, with IQR of 4 to 11.25 years. Significant changes were excluded in 98 patients. Among the 9 patients with suspected significant CAV, significant changes were confirmed in 8 patients, resulting in percutaneous transluminal coronary angioplasty (PTCA) performed in 6. One patient from this group died shortly after PTCA. No cardiovascular incidents were observed within the remaining group. The median follow-up period was 539 (IQR = 289-654 days). The mean left ventricular ejection fraction at follow-up was 58% ± 5% compared with 58% ± 4% at baseline. At follow-up, the mean eGFR was 64 ± 18 mL/kg/1.73 m2 compared with the baseline value of 67.2 mL/kg/1.73 m2. CONCLUSIONS CCTA appears to offer a secure and efficient means of assessment in HTx recipients.
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Affiliation(s)
- Agnieszka Kuczaj
- Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland; Silesian Center for Heart Diseases, Zabrze, Poland.
| | - Szymon Pawlak
- Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland; Silesian Center for Heart Diseases, Zabrze, Poland
| | - Jan Głowacki
- Silesian Center for Heart Diseases, Zabrze, Poland; Department of Radiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Remigiusz Antończyk
- Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland; Silesian Center for Heart Diseases, Zabrze, Poland
| | - Joanna Śliwka
- Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland; Silesian Center for Heart Diseases, Zabrze, Poland
| | - Piotr Przybyłowski
- Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland; Silesian Center for Heart Diseases, Zabrze, Poland
| | - Tomasz Hrapkowicz
- Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland; Silesian Center for Heart Diseases, Zabrze, Poland
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Lee KS, Kim H, Lee SH, Choi DJ, Yoon M, Jeon ES, Choi JO, Kang J, Lee HY, Jung SH, Oh J, Kang SM, Lee SY, Ju MH, Kim JJ, Kim MS, Cho HJ. Impact of Everolimus Initiation and Corticosteroid Weaning During Acute Phase After Heart Transplantation on Clinical Outcome: Data from the Korean Organ Transplant Registry (KOTRY). Transpl Int 2024; 37:11878. [PMID: 38644935 PMCID: PMC11028401 DOI: 10.3389/ti.2024.11878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 03/21/2024] [Indexed: 04/23/2024]
Abstract
The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56 years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9 years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.
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Affiliation(s)
- Kyu-Sun Lee
- Department of Internal Medicine and Division of Cardiology, Eulji University Hospital and Eulji University School of Medicine, Daejeon, Republic of Korea
- Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyungseop Kim
- Division of Cardiology, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Sun Hwa Lee
- Division of Cardiology, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Dong-Ju Choi
- Cardiovascular Center, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Minjae Yoon
- Cardiovascular Center, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Eun-Seok Jeon
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea
| | - Jin-Oh Choi
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea
| | - Jeehoon Kang
- Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hae-Young Lee
- Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung-Ho Jung
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaewon Oh
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seok-Min Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Yong Lee
- Division of Cardiology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Min Ho Ju
- Department of Thoracic and Cardiovascular Surgery, Pusan National University Yangsan Hospital, Medical Research Institute, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Jae-Joong Kim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine Seoul, Seoul, Republic of Korea
| | - Myoung Soo Kim
- Deparment of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea
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Kopecky BJ, Lavine KJ. Cardiac macrophage metabolism in health and disease. Trends Endocrinol Metab 2024; 35:249-262. [PMID: 37993313 PMCID: PMC10949041 DOI: 10.1016/j.tem.2023.10.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/24/2023]
Abstract
Cardiac macrophages are essential mediators of cardiac development, tissue homeostasis, and response to injury. Cell-intrinsic shifts in metabolism and availability of metabolites regulate macrophage function. The human and mouse heart contain a heterogeneous compilation of cardiac macrophages that are derived from at least two distinct lineages. In this review, we detail the unique functional roles and metabolic profiles of tissue-resident and monocyte-derived cardiac macrophages during embryonic development and adult tissue homeostasis and in response to pathologic and physiologic stressors. We discuss the metabolic preferences of each macrophage lineage and how metabolism influences monocyte fate specification. Finally, we highlight the contribution of cardiac macrophages and derived metabolites on cell-cell communication, metabolic health, and disease pathogenesis.
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Affiliation(s)
- Benjamin J Kopecky
- Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Kory J Lavine
- Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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Zhou X, Xu Q, Li W, Dong N, Stomberski C, Narla G, Lin Z. Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice. Transplantation 2024; 108:e36-e48. [PMID: 38126420 PMCID: PMC10922415 DOI: 10.1097/tp.0000000000004832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
BACKGROUND Although heart transplantation is the definitive treatment for heart failure in eligible patients, both acute and chronic transplant rejection frequently occur. Protein phosphatase 2A (PP2A) activity is critical in maintaining tissue and organ homeostasis. In this study, we evaluated the effect of a novel class of small molecule activators of PP2A (SMAPs) on allograft rejection in a mouse heterotopic heart transplantation model. METHODS Recipient mice were administered with DT-061 (a pharmaceutically optimized SMAP) or vehicle by oral gavage beginning 1 d after transplantation. Histological and immunofluorescence analyses were performed to examine allograft rejection. Regulatory T cells (Treg) from recipient spleens were subjected to flow cytometry and RNA sequencing analysis. Finally, the effect of DT-061 on smooth muscle cells (SMCs) migration and proliferation was assessed. RESULTS DT-061 treatment prolonged cardiac allograft survival. SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNA sequencing data derived from Treg of treated splenic tissues. Importantly, SMAPs extended immunosuppressive agent cytotoxic T lymphocyte-associated antigen-4-Ig-induced cardiac transplantation tolerance and allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and SMC proliferation. Finally, our in vitro studies implicate suppression of MEK/ERK pathways as a unifying mechanism for the effect of PP2A modulation in Treg and SMCs. CONCLUSIONS PP2A activation prevents cardiac rejection and prolongs allograft survival in a murine model. Our findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation.
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Affiliation(s)
- Xianming Zhou
- Cardiology Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Xu
- Cardiology Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Department of Cardiovascular Surgery, Xiangya Hospital of Central South University, Changsha, China
| | - Wangzi Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nianguo Dong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Colin Stomberski
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Goutham Narla
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Zhiyong Lin
- Cardiology Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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9
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Cecere A, Kerkhof PLM, Civieri G, Angelini A, Gambino A, Fraiese A, Bottio T, Osto E, Famoso G, Fedrigo M, Giacomin E, Toscano G, Montisci R, Iliceto S, Gerosa G, Tona F. Coronary Flow Evaluation in Heart Transplant Patients Compared to Healthy Controls Documents the Superiority of Coronary Flow Velocity Reserve Companion as Diagnostic and Prognostic Tool. Front Cardiovasc Med 2022; 9:887370. [PMID: 35811712 PMCID: PMC9263115 DOI: 10.3389/fcvm.2022.887370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundDistinct contributions by functional or structural alterations of coronary microcirculation in heart transplantation (HT) and their prognostic role have not been fully elucidated. We aimed to identify the mechanisms of coronary microvascular dysfunction (CMD) in HT and their prognostic implications.Methods134 patients, surviving at least 5 years after HT, without evidence of angiographic vasculopathy or symptoms/signs of rejection were included. 50 healthy volunteers served as controls. All underwent the assessment of rest and hyperemic coronary diastolic peak flow velocity (DPVr and DPVh) and coronary flow velocity reserve (CFVR) and its inherent companion that is based on the adjusted quadratic mean: CCFVR = √{(DPVr)2 + (DPVh)2}. Additionally, basal and hyperemic coronary microvascular resistance (BMR and HMR) were estimated.ResultsBased on CFVR and DPVh, HT patients can be assigned to four endotypes: endotype 1, discordant with preserved CFVR (3.1 ± 0.4); endotype 2, concordant with preserved CFVR (3.4 ± 0.5); endotype 3, concordant with impaired CFVR (1.8 ± 0.3) and endotype 4, discordant with impaired CFVR (2.0 ± 0.2). Intriguingly, endotype 1 showed lower DPVr (p < 0.0001) and lower DPVh (p < 0.0001) than controls with lower CFVR (p < 0.0001) and lower CCFVR (p < 0.0001) than controls. Moreover, both BMR and HMR were higher in endotype 1 than in controls (p = 0.001 and p < 0.0001, respectively), suggesting structural microvascular remodeling. Conversely, endotype 2 was comparable to controls. A 13/32 (41%) patients in endotype 1 died in a follow up of 28 years and mortality rate was comparable to endotype 3 (14/31, 45%). However, CCFVR was < 80 cm/s in all 13 deaths of endotype 1 (characterized by preserved CFVR). At multivariable analysis, CMD, DPVh < 75 cm/s and CCFVR < 80 cm/s were independent predictors of mortality. The inclusion of CCFVR < 80 cm/s to models with clinical indicators of mortality better predicted survival, compared to only adding CMD or DPVh < 75 cm/s (p < 0.0001 and p = 0.03, respectively).ConclusionA normal CFVR could hide detection of microvasculopathy with high flow resistance and low flow velocities at rest. This microvasculopathy seems to be secondary to factors unrelated to HT (less rejections and more often diabetes). The combined use of CFVR and CCFVR provides more complete clinical and prognostic information on coronary microvasculopathy in HT.
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Affiliation(s)
- Annagrazia Cecere
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Peter L. M. Kerkhof
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Giovanni Civieri
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Annalisa Angelini
- Cardiovascular Pathology Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Antonio Gambino
- Division of Cardiac Surgery, University of Padua, Padua, Italy
| | - Angela Fraiese
- Division of Cardiac Surgery, University of Padua, Padua, Italy
| | - Tomaso Bottio
- Division of Cardiac Surgery, University of Padua, Padua, Italy
| | - Elena Osto
- Cardiology, University Heart Center, University Hospital of Zürich, Zurich, Switzerland
- Institute of Clinical Chemistry, University of Zurich, University Hospital of Zürich, Zurich, Switzerland
| | - Giulia Famoso
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Marny Fedrigo
- Cardiovascular Pathology Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Enrico Giacomin
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | | | - Roberta Montisci
- Clinical Cardiology, AOU Cagliari, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
| | - Sabino Iliceto
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Gino Gerosa
- Division of Cardiac Surgery, University of Padua, Padua, Italy
| | - Francesco Tona
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
- *Correspondence: Francesco Tona,
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10
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Singh S, Patlolla SH, Sundaragiri PR, Gurumurthy G, Cheungpasitporn W, Vallabhajosyula S. Acute myocardial infarction in heart transplant recipients: An 18-year national study. AMERICAN HEART JOURNAL PLUS : CARDIOLOGY RESEARCH AND PRACTICE 2022; 17:100167. [PMID: 38559875 PMCID: PMC10978363 DOI: 10.1016/j.ahjo.2022.100167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/29/2022] [Accepted: 05/29/2022] [Indexed: 04/04/2024]
Abstract
Among 11,622,528 acute myocardial infarction (AMI) hospitalizations, 892 had a history of heart transplantation (HT). In comparison to AMI admissions without HT, those with prior HT were more frequently complicated with cardiac arrest (8.3 % vs 5.0 %, p < 0.001), acute non-cardiac organ failure (17.4 % vs 9.4 %) (p < 0.001), lower rates of coronary angiography (55.4 % vs 63.6 %, p < 0.001), comparable rates of percutaneous coronary intervention (38.8 % vs 41.5 %, p = 0.10), higher rates of pulmonary artery catheterization (2.7 % vs 1.1 %, p < 0.001), invasive mechanical ventilation and acute hemodialysis compared to AMI admissions without HT. Compared to AMI admissions without HT, prior HT recipients had higher in-hospital mortality (11.8 % vs 6.2 %, adjusted odds ratio 2.87 [95 % CI 2.23-3.70]; p < 0.001).
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Affiliation(s)
- Sohrab Singh
- Department of Medicine, The Brooklyn Hospital, Brooklyn, NY, United States of America
| | - Sri Harsha Patlolla
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, United States of America
| | - Pranathi R. Sundaragiri
- Section of Primary Care Internal Medicine, Wake Forest Baptist Health, High Point, NC, United States of America
| | - Gayathri Gurumurthy
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Saraschandra Vallabhajosyula
- Section of Cardiovascular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America
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11
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Geographic Variation in Heart Transplant Extended Criteria Donors in the United States. Ann Thorac Surg 2022; 114:1629-1635. [PMID: 35364052 DOI: 10.1016/j.athoracsur.2022.03.039] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 03/05/2022] [Accepted: 03/14/2022] [Indexed: 11/20/2022]
Abstract
BACKGROUND Recent research has explored the use of higher risk extended criteria donors (ECDs) as a means of expanding the donor pool for heart transplantation. Here we sought to explore the current geographic distribution and survival outcomes of ECD utilization in various regions across the United States. METHODS The United Network for Organ Sharing database was retrospectively queried for adult primary heart transplantation from 2000 to 2019. The EXPAND trial definition of ECD was used: ischemic time ≥ 4 hours, ejection fraction < 50%, age > 55 years, and history of coronary artery disease. Geographic data and 2019 population estimates were obtained from the US Census Bureau. RESULTS Of the 42 642 transplants included in our analysis, 11 750 (27.6%) used ECDs. Region utilization of ECDs ranged from 18.4% to 46.5% of transplants. Region 6 had the highest utilization rate at 46.5%; this was primarily driven by the number of transplants with ischemic time ≥ 4 hours. Region 6 encompasses the largest total area (1.08 million square miles) and smallest population density (15.6 people per square mile). Region 8 had the lowest marginal donor utilization rate at 18.4%. Regions with high utilization of low ejection fractions, older donors, and donors with coronary artery disease (ie, regions 1 and 2) were able to maintain an average utilization rate of ECDs by maintaining short ischemic times. CONCLUSIONS Large discrepancies in the use of ECDs exist across the different United Network for Organ Sharing regions. This is primarily driven by longer ischemic times, likely guided by variance in population densities between different regions.
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12
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Rodriguez ER, Santos-Martins C, Tan CD. Pathology of cardiac transplantation. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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13
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Pober JS, Chih S, Kobashigawa J, Madsen JC, Tellides G. Cardiac allograft vasculopathy: current review and future research directions. Cardiovasc Res 2021; 117:2624-2638. [PMID: 34343276 PMCID: PMC8783389 DOI: 10.1093/cvr/cvab259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/02/2021] [Accepted: 07/29/2021] [Indexed: 12/25/2022] Open
Abstract
Cardiac allograft vasculopathy (CAV) is a pathologic immune-mediated remodelling of the vasculature in transplanted hearts and, by impairing perfusion, is the major cause of late graft loss. Although best understood following cardiac transplantation, similar forms of allograft vasculopathy occur in other vascularized organ grafts and some features of CAV may be shared with other immune-mediated vasculopathies. Here, we describe the incidence and diagnosis, the nature of the vascular remodelling, immune and non-immune contributions to pathogenesis, current therapies, and future areas of research in CAV.
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MESH Headings
- Adaptive Immunity
- Animals
- Coronary Artery Disease/epidemiology
- Coronary Artery Disease/immunology
- Coronary Artery Disease/metabolism
- Coronary Artery Disease/pathology
- Coronary Vessels/immunology
- Coronary Vessels/metabolism
- Coronary Vessels/pathology
- Endothelial Cells/immunology
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Graft Rejection/epidemiology
- Graft Rejection/immunology
- Graft Rejection/metabolism
- Graft Rejection/pathology
- Graft Survival
- Heart Transplantation/adverse effects
- Humans
- Immunity, Innate
- Muscle, Smooth, Vascular/immunology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/immunology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Risk Factors
- Signal Transduction
- Treatment Outcome
- Vascular Remodeling
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Affiliation(s)
- Jordan S Pober
- Department of Immunobiology, Pathology and Dermatology, Yale School of Medicine, 10 Amistad Street, New Haven CT 06520-8089, USA
| | - Sharon Chih
- Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada
| | - Jon Kobashigawa
- Department of Medicine, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
| | - Joren C Madsen
- Division of Cardiac Surgery and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - George Tellides
- Department of Surgery (Cardiac Surgery), Yale School of Medicine, New Haven, CT, USA
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14
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SARS-CoV-2 vaccination in cardiothoracic organ transplant recipients: effective strategies wanted. Clin Res Cardiol 2021; 110:1139-1141. [PMID: 34241675 PMCID: PMC8267762 DOI: 10.1007/s00392-021-01876-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 11/25/2022]
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15
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(Cardiac allograft vasculopathy nowadays). COR ET VASA 2021. [DOI: 10.33678/cor.2020.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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16
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Ram E, Klempfner R, Peled A, Kassif Y, Sternik L, Lavee J, Peled Y. Weight gain post-heart transplantation is associated with an increased risk for allograft vasculopathy and rejection. Clin Transplant 2020; 35:e14187. [PMID: 33314309 DOI: 10.1111/ctr.14187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/24/2020] [Accepted: 12/07/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Obesity and overweight are associated with an increased risk for cardiovascular disease. Since fat mass (FM) and fat-free mass (FFM) both contribute to total body weight (TBW), we characterized the post-heart transplantation (HT) change in TBW and its implications for outcomes. METHODS Post-HT changes in TBW, FM, and FFM were reviewed for 211 HT patients assessed during 1997-2017. Endpoints included cardiac allograft vasculopathy (CAV) and rejection. RESULTS Median TBW increased by 7.3% at 1 year, with a significant rise in the obese category (28% vs. 13%, p < 0.001) and with FM versus FFM making the main contribution (23% vs. 3%, p < 0.001). When patients were divided according to median TBW change ("high" vs. "low"), Kaplan-Meier analysis showed that 10-year freedom from CAV (log-rank p < 0.005) and rejection (log-rank p < 0.01) was significantly higher for the "low" TBW change group. Consistently, multivariable analyses showed that the "high" group was independently associated with significant 3.5-fold and 4.2-fold increased risks for CAV (95% CI 1.4-8.7, p = 0.01) and rejection (95% CI 1.2-15.4, p = 0.03), respectively. CONCLUSIONS Weight gain, contributed mostly by FM, is independently associated with an increased risk for CAV and rejection. Follow-up emphasis should be placed on weight gain and preventative measures.
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Affiliation(s)
- Eilon Ram
- Heart Transplantation Unit, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, Israel.,Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Robert Klempfner
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Israeli Association for Cardiovascular Trials, Ramat Gan, Israel
| | - Amir Peled
- Clalit Health Services, Central Region, Israel
| | - Yigal Kassif
- Heart Transplantation Unit, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, Israel.,Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Leonid Sternik
- Heart Transplantation Unit, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, Israel.,Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jacob Lavee
- Heart Transplantation Unit, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, Israel.,Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Peled
- Heart Transplantation Unit, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, Israel.,Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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17
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Lu M, Xue R, Wang P, Wang X, Tian X, Liu Y, Wang S, Cui A, Xie J, Le L, Zhao M, Quan J, Li N, Meng D, Wang X, Sun N, Chen AF, Xiang M, Chen S. Induced pluripotent stem cells attenuate chronic allogeneic vasculopathy in an integrin beta-1-dependent manner. Am J Transplant 2020; 20:2755-2767. [PMID: 32277602 DOI: 10.1111/ajt.15900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 01/25/2023]
Abstract
This study aimed to determine the mechanism of isogeneic-induced pluripotent stem cells (iPSCs) homing to vascular transplants and their therapeutic effect on chronic allogeneic vasculopathy. We found that integrin β1 (Intgβ1) was the dominant integrin β unit in iPSCs that mediates the adhesion of circulatory and endothelial cells (ECs). Intgβ1 knockout or Intgβ1-siRNAs inhibit iPSC adhesion and migration across activated endothelial monolayers. The therapeutic effects of the following were examined: iPSCs, Intgβ1-knockout iPSCs, iPSCs transfected with Intgβ1-siRNAs or nontargeting siRNAs, iPSC-derived ECs, iPSC-derived ECs simultaneously overexpressing Intgα4 and Intgβ1, iPSCs precultured in endothelial medium for 3 days (endothelial-prone stem cells), primary aortic ECs, mouse embryonic fibroblasts, and phosphate-buffered saline (control). The cells were administered every 3 days for a period of 8 weeks. iPSCs, iPSCs transfected with nontargeting siRNAs, and endothelial-prone stem cells selectively homed on the luminal surface of the allografts, differentiated into ECs, and decreased neointimal proliferation. Through a single administration, we found that iPSCs trafficked to allograft lesions, differentiated into ECs within 1 week, and survived for 4-8 weeks. The therapeutic effect of a single administration was moderate. Thus, Intgβ1 and pluripotency are essential for iPSCs to treat allogeneic vasculopathy.
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Affiliation(s)
- Meng Lu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Rong Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Pingping Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaokai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaoyu Tian
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yingying Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Shun Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Anfeng Cui
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jingxin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lili Le
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Meng Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jing Quan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ning Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Dan Meng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xinhong Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ning Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Alex F Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Meng Xiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Sifeng Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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18
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MicroRNA-142-5p is Up-regulated on Allogeneic Immune Responses and Up-regulates MHC Class II Expression in Human Umbilical Vein Endothelial Cells. Transplant Proc 2020; 53:408-416. [PMID: 32616346 DOI: 10.1016/j.transproceed.2020.05.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/12/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE MicroRNA could be biomarker and therapeutic target for rejection. The aim of this study was to investigate the role of miR-142-5p in allogeneic immune responses using in vitro and in vivo models. MATERIALS AND METHODS Primary and immortalized human umbilical vein endothelial cells (HUVECs) were cultured with unrelated blood mononuclear cells to induce allogeneic immune responses. Syngeneic and allogeneic skin graft was performed in mice. Flow cytometry, quantitative reverse transcription-polymerase chain reaction, and Western blotting was performed to understand the underlying mechanisms. RESULTS miR-142-5p was up-regulated in primary HUVEC and a HUVEC line when allogeneic immune responses were elicited. miR-142-5p was also up-regulated in the murine allogeneic skin graft. Overexpression of miR-142-5p in HUVEC increased the expression of HLA-ABC and HLA-DR additively to allogeneic immune responses, suggesting a possible increase in alloantigen presentation. Inhibition of miR-142-5p reduced the expression of HLA-DR. ZEB1, a putative target gene of miR-142-5p, was down-regulated in HUVEC on allogeneic immune response as well as in murine allogeneic skin graft. CONCLUSION These results suggest that the up-regulation of miR-142-5p on allogeneic immune response might facilitate endothelial activation to exacerbate rejection.
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19
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Mallah SI, Atallah B, Moustafa F, Naguib M, El Hajj S, Bader F, Mehra MR. Evidence-based pharmacotherapy for prevention and management of cardiac allograft vasculopathy. Prog Cardiovasc Dis 2020; 63:194-209. [DOI: 10.1016/j.pcad.2020.03.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 03/17/2020] [Indexed: 01/08/2023]
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20
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Grubić Rotkvić P, Cigrovski Berković M, Rotkvić L, Bulj N. Prevention of cardiac allograft vasculopathy - A new possible indication for SGLT-2 inhibitors? Med Hypotheses 2020; 137:109594. [PMID: 32006921 DOI: 10.1016/j.mehy.2020.109594] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 01/15/2020] [Accepted: 01/22/2020] [Indexed: 10/25/2022]
Abstract
One of the main risk factors influencing patient survival after heart transplantation is cardiac allograft vasculopathy, the leading cause of death after the first year of transplantation. It is an entity of multifactorial origin including both humoral and cellular alloimmune responses as well as immunologic-independent factors such as graft injury, ischaemia-reperfusion injury, oxidative stress, cytomegalovirus infection, hyperlipidaemia, diabetes mellitus and hypertension. A fundamental characteristic of cardiac allograft vasculopathy is vascular remodelling, initially driven by the injury and apoptosis of endothelial cells, then by the migration of smooth muscle cells leading to intimal thickening and ultimately allograft vessel occlusion. Since cardiac allograft vasculopathy occurs within the first year of transplantation, prevention strategies should be implemented early. The disease could be partially prevented with overall cardiovascular risk reduction, mainly by controlling diabetes, hyperlipidemia and hypertension that can be related to the recipient but also induced or augmented by immunosuppressive drugs used. Current therapeutic options are only partially effective in postponing the development of vascular lesions. Diabetes is an important issue in the management of patients following cardiac transplantation. Although it is highly prevalent among heart transplant recipients (23% at 1 year increasing to 37% at 5 years after the procedure), no specific therapeutic protocols have been recommended yet. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs that produce glycosuric and natriuretic effects by inhibiting glucose and sodium reabsorption from the renal proximal tubules and have already shown benefits in cardiovascular outcome trials. Our hypothesis is that SGLT-2 inhibitors could prevent or delay the development of cardiac allograft vasculopathy targeting various mechanisms underpinning its pathogenesis due to their antidiabetic, antihypertensive, anti-inflammatory, antifibrotic, antioxidative and antiapoptotic effects, as well as through amelioration of endothelial dysfunction, ischaemia-reperfusion injury and modification of neurohumoral system. All the segments of the proposed theory that could interfere with evolution of vasculopathy are discussed separately within the main text. The implications for the science if the hypothesis were to be confirmed are as follows: prolongation of lifespan in heart transplant patients with diabetes, reduction of polypragmasia in posttransplant patients while targeting several mechanisms with one drug, and the possibility of spreading the indications even to patients without diabetes.
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Affiliation(s)
- Petra Grubić Rotkvić
- Department of Cardiology, University Hospital "Sveti Duh", Sveti Duh 64, 10 000 Zagreb, Croatia.
| | - Maja Cigrovski Berković
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital Centre "Sestre Milosrdnice", Zagreb, Croatia; Department for Medicine of Sports and Exercise, Faculty of Kinesiology, University of Zagreb, Zagreb, Croatia
| | - Luka Rotkvić
- Department of Cardiology, Magdalena Clinic for Cardiovascular Disease, Krapinske Toplice, Croatia
| | - Nikola Bulj
- Department of Cardiology, University Hospital Centre "Sestre Milosrdnice", Zagreb, Croatia; School of Medicine, University of Zagreb, Zagreb, Croatia
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21
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Grupper A, Gewirtz H, Kushwaha S. Reinnervation post-heart transplantation. Eur Heart J 2019; 39:1799-1806. [PMID: 28087606 DOI: 10.1093/eurheartj/ehw604] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/25/2016] [Indexed: 12/11/2022] Open
Abstract
Heart transplantation results in complete denervation of the donor heart with loss of afferent and efferent nerve connections. The majority of patients remain completely denervated during the first 6-12 months following transplantation. Evidence of reinnervation is usually found during the second year after transplantation and involve the myocardial muscle, sinoatrial node, and coronary vessels, but remains incomplete and regionally limited many years post-transplant. Restoration of cardiac innervation can improve exercise capacity as well as blood flow regulation in the coronary arteries, and hence improve quality of life. As yet, there is no evidence that the reinnervation process is associated with the occurrence of allograft-related events or survival.
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Affiliation(s)
- Avishay Grupper
- Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | | | - Sudhir Kushwaha
- Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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22
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See Hoe LE, Bartnikowski N, Wells MA, Suen JY, Fraser JF. Hurdles to Cardioprotection in the Critically Ill. Int J Mol Sci 2019; 20:E3823. [PMID: 31387264 PMCID: PMC6695809 DOI: 10.3390/ijms20153823] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/26/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation (HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) technology has unveiled additional therapeutic options for refractory cardiac disease. Unfortunately, despite both MCS and HTx being quintessential treatments for significant cardiac impairment, associated morbidity and mortality remain high. MCS technology continues to evolve, but is associated with numerous disturbances to cardiac function (e.g., oxidative damage, arrhythmias). Following MCS intervention, HTx is frequently the destination option for survival of critically ill cardiac patients. While effective, donor hearts are scarce, thus limiting HTx to few qualifying patients, and HTx remains correlated with substantial post-HTx complications. While MCS and HTx are vital to survival of critically ill cardiac patients, cardioprotective strategies to improve outcomes from these treatments are highly desirable. Accordingly, this review summarizes the current status of MCS and HTx in the clinic, and the associated cardiac complications inherent to these treatments. Furthermore, we detail current research being undertaken to improve cardiac outcomes following MCS/HTx, and important considerations for reducing the significant morbidity and mortality associated with these necessary treatment strategies.
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Affiliation(s)
- Louise E See Hoe
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia.
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia.
| | - Nicole Bartnikowski
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Science and Engineering Faculty, Queensland University of Technology, Chermside 4032, Australia
| | - Matthew A Wells
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- School of Medical Science, Griffith University, Southport 4222, Australia
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia
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23
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Langstraat M, Musters KJS, Manintveld O, Masetti M, Potena L. Coronary artery disease in heart transplantation: new concepts for an old disease. Transpl Int 2018; 31:787-827. [DOI: 10.1111/tri.13141] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
| | | | | | - Marco Masetti
- Heart and Lung Transplant Program; Bologna University Hospital; Bologna Italy
| | - Luciano Potena
- Heart and Lung Transplant Program; Bologna University Hospital; Bologna Italy
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24
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Abstract
PURPOSE OF REVIEW Despite the improvement in medical therapy for heart failure and the advancements in mechanical circulatory support, heart transplantation (HT) still remains the best therapeutic option to improve survival and quality of life in patients with advanced heart failure. Nevertheless, HT recipients are exposed to the risk of several potential complications that may impair their outcomes. In this article, we aim to provide a practical and scholarly framework for clinicians approaching heart transplant medicine, as well as a concise update for the experienced readers on the most relevant post-HT complications. RECENT FINDINGS While recognizing that most of the treatments herein discussed are based more on experience than on solid scientific evidence, significant step forward has been made in particular in the recognition and management of primary graft dysfunction, antibody-mediated rejection, and renal dysfunction. Complications after HT may vary according to the time from surgery and can be related to graft function and pathology or to diseases and dysfunctions occurring in other organs or systems, mainly as side effects of immunosuppressive drugs and progression of pre-existing conditions. Future research needs to focus on improving precision diagnostics of causes of graft dysfunction and on reaching an optimal and customized balance between efficacy and toxicities of immunosuppressive strategies.
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Affiliation(s)
- Luciano Potena
- Heart Transplant Program, Bologna Academic Hospital, Policlinico S. Orsola-Malpighi, Building 25, Via Massarenti, 9, 40138, Bologna, Italy.
| | - Andreas Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Francesco Barberini
- Heart Transplant Program, Bologna Academic Hospital, Policlinico S. Orsola-Malpighi, Building 25, Via Massarenti, 9, 40138, Bologna, Italy
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Extended distance cardiac allograft can successfully be utilized without impacting long-term survival. J Heart Lung Transplant 2017; 36:968-972. [DOI: 10.1016/j.healun.2017.04.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 02/14/2017] [Accepted: 04/12/2017] [Indexed: 11/21/2022] Open
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Yuan X, Teng X, Wang Y, Yao Y. Recipient treatment with acetylcholinesterase inhibitor donepezil attenuates primary graft failure in rats through inhibiting post-transplantational donor heart ischaemia/reperfusion injury. Eur J Cardiothorac Surg 2017; 53:400-408. [DOI: 10.1093/ejcts/ezx289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 07/13/2017] [Accepted: 07/18/2017] [Indexed: 01/05/2023] Open
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Ma S, Jiang Y, Huang W, Li X, Li S. Role of Transient Receptor Potential Channels in Heart Transplantation: A Potential Novel Therapeutic Target for Cardiac Allograft Vasculopathy. Med Sci Monit 2017; 23:2340-2347. [PMID: 28516902 PMCID: PMC5444344 DOI: 10.12659/msm.901920] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Heart transplantation has evolved as the criterion standard therapy for end-stage heart failure, but its efficacy is limited by the development of cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients. Here, we briefly review the key processes in the development of CAV during heart transplantation and highlight the roles of transient receptor potential (TRP) channels in these processes during heart transplantation. Understanding the roles of TRP channels in contributing to the key procedures for the development of CAV during heart transplantation could provide basic scientific knowledge for the development of new preventive and therapeutic approaches to manage patients with CAV after heart transplantation.
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Affiliation(s)
- Shuo Ma
- Department of Physiology, Dalian Medical University, Dalian, Liaoning, China (mainland).,The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Yue Jiang
- Department of Physiology, Dalian Medical University, Dalian, Liaoning, China (mainland).,The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Weiting Huang
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Xintao Li
- Department of Physiology, Dalian Medical University, Dalian, Liaoning, China (mainland).,The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Shuzhuang Li
- Department of Physiology, Dalian Medical University, Dalian, China (mainland)
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Freystaetter K, Andreas M, Bilban M, Perkmann T, Kaider A, Masetti M, Kocher A, Wolzt M, Zuckermann A. The recipient's heme oxygenase-1 promoter region polymorphism is associated with cardiac allograft vasculopathy. Transpl Int 2017; 30:510-518. [DOI: 10.1111/tri.12935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 11/25/2016] [Accepted: 01/31/2017] [Indexed: 01/18/2023]
Affiliation(s)
| | - Martin Andreas
- Division of Cardiac Surgery; Medical University of Vienna; Vienna Austria
| | - Martin Bilban
- Department of Laboratory Medicine; Medical University of Vienna; Vienna Austria
| | - Thomas Perkmann
- Department of Laboratory Medicine; Medical University of Vienna; Vienna Austria
| | - Alexandra Kaider
- Section for Clinical Biometrics; Center for Medical Statistics Informatics and Intelligent Systems; Medical University of Vienna; Vienna Austria
| | - Marco Masetti
- Department of Cardiology; Bologna University Hospital; Bologna Italy
| | - Alfred Kocher
- Division of Cardiac Surgery; Medical University of Vienna; Vienna Austria
| | - Michael Wolzt
- Department of Clinical Pharmacology; Medical University of Vienna; Vienna Austria
| | - Andreas Zuckermann
- Division of Cardiac Surgery; Medical University of Vienna; Vienna Austria
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He S, Zhong W, Yin L, Wang Y, Qiu Z, Song G. High expression of ubiquitin-specific peptidase 39 is associated with the development of vascular remodeling. Mol Med Rep 2017; 15:2567-2573. [PMID: 28447728 PMCID: PMC5428656 DOI: 10.3892/mmr.2017.6297] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 01/15/2016] [Indexed: 01/27/2023] Open
Abstract
Vascular remodeling is the primary cause underlying the failure of angioplasty surgeries, including vascular stenting, transplant vasculopathy and vein grafts. Multiple restenosis‑associated proteins and genes have been identified to account for this. In the present study, the functions of ubiquitin‑specific peptidase 39 (USP39) were investigated in the context of two vascular remodeling models (a mouse common carotid artery ligation and a pig bilateral saphenous vein‑carotid artery interposition graft). USP39 has previously been observed to be upregulated in ligated arteries, and this result was confirmed in the pig vein graft model. In addition, Transwell assay results demonstrated that vascular smooth muscle cell (VSMC) migration was suppressed by lentiviral vector‑mediated downregulation of USP39 and enhanced by upregulation of USP39. Furthermore, knockdown of USP39 inhibited VSMC cell proliferation and the expression of cyclin D1 and cyclin‑dependent kinase 4, as analyzed via cell counting, MTT assay and western blotting. These results suggest that USP39 may represent a novel therapeutic target for treating vascular injury and preventing vein-graft failure.
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Affiliation(s)
- Shuai He
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Wei Zhong
- Cancer Research Center, Medical College of Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Li Yin
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Yifei Wang
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Zhibing Qiu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Gang Song
- Cancer Research Center, Medical College of Xiamen University, Xiamen, Fujian 361102, P.R. China
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Relationship between markers of plaque vulnerability in optical coherence tomography and atherosclerotic progression in adult patients with heart transplantation. J Heart Lung Transplant 2017; 36:185-192. [DOI: 10.1016/j.healun.2016.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 05/05/2016] [Accepted: 06/01/2016] [Indexed: 02/03/2023] Open
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Immune Responses to Tissue-Restricted Nonmajor Histocompatibility Complex Antigens in Allograft Rejection. J Immunol Res 2017; 2017:6312514. [PMID: 28164137 PMCID: PMC5253484 DOI: 10.1155/2017/6312514] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 12/06/2016] [Indexed: 01/02/2023] Open
Abstract
Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs. Therefore, chronic diseases can activate self-reactive lymphocytes, inducing tissue-restricted autoimmunity. During organ transplantation, donor lymphocytes are tested against recipient serum (i.e., cross-matching) to detect antibodies (Abs) against donor human leukocyte antigens, which has been shown to reduce Ab-mediated hyperacute rejection. However, primary allograft dysfunction and rejection still occur frequently. Because donor lymphocytes do not express tissue-restricted SAgs, preexisting Abs against SAgs are undetectable during conventional cross-matching. Preexisting and de novo immune responses to tissue-restricted SAgs (i.e., autoimmunity) play a major role in rejection. In this review, we discuss the evidence that supports autoimmunity as a contributor to rejection. Testing for preexisting and de novo immune responses to tissue-restricted SAgs and treatment based on immune responses after organ transplantation may improve short- and long-term outcomes after transplantation.
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Natural killer cells in inflammatory heart disease. Clin Immunol 2016; 175:26-33. [PMID: 27894980 DOI: 10.1016/j.clim.2016.11.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 10/09/2016] [Accepted: 11/20/2016] [Indexed: 02/07/2023]
Abstract
Despite of a multitude of excellent studies, the regulatory role of natural killer (NK) cells in the pathogenesis of inflammatory cardiac disease is greatly underappreciated. Clinical abnormalities in the numbers and functions of NK cells are observed in myocarditis and inflammatory dilated cardiomyopathy (DCMi) as well as in cardiac transplant rejection [1-6]. Because treatment of these disorders remains largely symptomatic in nature, patients have little options for targeted therapies [7,8]. However, blockade of NK cells and their receptors can protect against inflammation and damage in animal models of cardiac injury and inflammation. In these models, NK cells suppress the maturation and trafficking of inflammatory cells, alter the local cytokine and chemokine environments, and induce apoptosis in nearby resident and hematopoietic cells [1,9,10]. This review will dissect each protective mechanism employed by NK cells and explore how their properties might be exploited for their therapeutic potential.
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Baron O, Fabre S, Haloun A, Treilhaud M, al Habasch O, Duveau D, Michaud JL, Despins P. Retrospective Clinical Comparison of Celsior Solution to Modified Blood Wallwork Solution in Lung Transplantation for Cystic Fibrosis. Prog Transplant 2016; 12:176-80. [PMID: 12371042 DOI: 10.1177/152692480201200304] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Objective To compare the preservative effects of Celsior solution and modified blood Wallwork solution in lung transplantation. Methods From 1989 to 2000, 44 lung transplantations for cystic fibrosis were performed: 26 grafts were preserved with modified blood Wallwork solution and 18 with Celsior solution. Results Preoperative status of the 2 groups was similar. The ratio of arterial oxygen to fraction of inspired oxygen and the pulmonary vascular resistance on the first postoperative day did not differ significantly between the 2 groups. Early death was 4% (SD, 20%) in the Wallwork group versus 11% (SD, 32%) in the Celsior group (not significant). No death was related to graft failure. The forced expiratory volume in 1 second during the first month after transplantation was 63% (SD, 19%) in the Wallwork group versus 63% (SD, 16%) in the Celsior group (not significant). Conclusion Because the solution does not need to be prepared on site and does not require blood from the donor, Celsior seems better than Wallwork solution for preserving lung grafts.
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Affiliation(s)
- O Baron
- Thoracic Transplantation Unit, Cardiovascular Surgery Department, Laennec Hospital, Nantes, France
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Iannaccone M, Meynet I, Omedè P, D'Ascenzo F, Taha S, Bertaina M, Colaci C, Marangoni L, Ribezzo M, Boffini M, Rinaldi M, Moretti C, Gaita F. Relationship between ventricular pressure and coronary artery disease in asymptomatic adult heart transplant recipients. J Cardiovasc Med (Hagerstown) 2016; 18:410-414. [PMID: 26999619 DOI: 10.2459/jcm.0000000000000320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The association between data of right heart catheterization and cardiac allograft vasculopathy (CAV) in adult heart transplant (HTx) recipients remains to be determined. METHODS AND RESULTS This is an observational, retrospective study, including all consecutive asymptomatic HTx patients undergoing routine right and left catheterization. The independent predictive power of pulmonary capillary wedge pressure (PCWP) to predict CAV (classified according to working formulation of a standardized nomenclature for CAV-2010) was the primary end point. Seventy-one patients were included, with a mean time from HTx to procedure of 19 ± 25 months. At coronary angiography first degree of CAV was found in eight patients (11.2%), second degree of CAV in two patients (2.8%), and third in two (2.8%). PCWP values were significantly higher in patients with CAV compared with patients without CAV (17.5 ± 7.5 vs. 10.4 ± 5.6, P < 0.001) and values of 15 mmHg or greater had an AUC of 0.71 (0.48-0.92), with a sensitivity of 71% and a specificity of 73% in predicting CAV, with an independent relationship confirmed at logistic regression analysis (odds ratio 1.28, IC 1.06-1.53; P = 0.008). CONCLUSION A significantly elevated PCWP at the time of the diagnosis of transplant coronary artery disease may be considered as an early marker of CAV, especially in asymptomatic HTx recipients.
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Affiliation(s)
- Mario Iannaccone
- Division of Cardiology, 'Città della Salute e della Scienza', Ospedale S.G. Battista -- Molinette, University of Turin, Turin, Italy
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Adiputra Y, Chen SL. Clinical Relevance of Coronary Fractional Flow Reserve: Art-of-state. Chin Med J (Engl) 2016; 128:1399-406. [PMID: 25963364 PMCID: PMC4830323 DOI: 10.4103/0366-6999.156805] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Objective: The objective was to delineate the current knowledge of fractional flow reserve (FFR) in terms of definition, features, clinical applications, and pitfalls of measurement of FFR. Data Sources: We searched database for primary studies published in English. The database of National Library of Medicine (NLM), MEDLINE, and PubMed up to July 2014 was used to conduct a search using the keyword term “FFR”. Study Selection: The articles about the definition, features, clinical application, and pitfalls of measurement of FFR were identified, retrieved, and reviewed. Results: Coronary pressure-derived FFR rapidly assesses the hemodynamic significance of individual coronary artery lesions and can readily be performed in the catheterization laboratory. The use of FFR has been shown to effectively guide coronary revascularization procedures leading to improved patient outcomes. Conclusions: FFR is a valuable tool to determine the functional significance of coronary stenosis. It combines physiological and anatomical information, and can be followed immediately by percutaneous coronary intervention (PCI) if necessary. The technique of FFR measurement can be performed easily, rapidly, and safely in the catheterization laboratory. By systematic use of FFR in dubious stenosis and multi-vessel disease, PCI can be made an even more effective and better treatment than it is currently. The current clinical evidence for FFR should encourage cardiologists to use this tool in the catheterization laboratory.
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Affiliation(s)
| | - Shao-Liang Chen
- Department of Cardiology, Nanjing First Hospital of Nanjing Medical University, Nanjing, Jiangsu 210006, China
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Tan C, Halushka M, Rodriguez E. Pathology of Cardiac Transplantation. Cardiovasc Pathol 2016. [DOI: 10.1016/b978-0-12-420219-1.00016-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Park KH, Kwon TG, Matsuzawa Y, Sun T, Liu Z, Lennon RJ, Lerman LO, Kushwaha SS, Lerman A. Association between the vasa vasorum and the atherosclerotic changes in cardiac allograft vasculopathy: volumetric analysis. Eur Heart J Cardiovasc Imaging 2015; 17:272-9. [PMID: 26657475 DOI: 10.1093/ehjci/jev285] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 10/04/2015] [Indexed: 12/14/2022] Open
Abstract
AIMS The current study was designed to test that vasa vasorum (VV) plays a role in the progression of cardiac allograft vasculopathy (CAV) in patients with heart transplantation (HTX). METHODS AND RESULTS Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) were performed in the left anterior descending artery in 19 segments of 19 HTX patients (median 2.1 years from HTX). Each segment is composed of both the continuous lesions: (i) CAV area: intimal thickness >0.5 mm with 5 mm length and (ii) VV area: intimal thickness ≤0.5 mm with 5 mm length. The per cent VV volume (VV volume/vessel volume × 100, %VV) was evaluated in the VV area with OCT (in CAV area VV cannot be assessed because of limited penetration power of OCT). A year later, the association between the baseline %VV and the change in per cent plaque volume (plaque volume/vessel volume × 100, %PV) was evaluated with IVUS. To a normal distribution, Δ%PV (follow-up %PV-initial %PV) was undergone square root transformation. The correlations between the %VV at baseline study and square root-Δ%PV were significant both in the CAV area and in the VV area (r = 0.787, P < 0.001 and r = 0.701, P < 0.001, respectively). In multivariable analysis, only the %VV was significantly correlated with square root-Δ%PV in both areas. CONCLUSION The current study demonstrated a significant association between the VV volume and the progression of plaque volume in both the CAV area and the VV area. Thus, VV may be a potential predictor and possible therapeutic target to attenuate CAV.
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Affiliation(s)
- Kyoung-Ha Park
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA Division of Cardiovascular Disease, Hallym University Medical Center, Anyang, Korea
| | - Taek-Geun Kwon
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Yasushi Matsuzawa
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Tao Sun
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Zhi Liu
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Ryan J Lennon
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Sudhir S Kushwaha
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Amir Lerman
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
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Franz M, Doll F, Grün K, Richter P, Köse N, Ziffels B, Schubert H, Figulla HR, Jung C, Gummert J, Renner A, Neri D, Berndt A. Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin. Int J Cardiol 2015; 195:311-22. [PMID: 26056964 DOI: 10.1016/j.ijcard.2015.05.144] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Revised: 05/13/2015] [Accepted: 05/26/2015] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND AIMS Management of chronic rejection is challenging since there are not sufficient preventive or therapeutic strategies. The rejection process leads to overexpression of ED-A(+) fibronectin (ED-A(+) Fn). The human antibody F8, specific to ED-A(+) Fn, may serve as a vehicle for targeted delivery of bioactive payloads, e.g. interleukin 10 (IL-10). The aim of this study was to investigate the therapeutic effects of the fusion protein F8-interleukin-10 (F8-IL10) in the process of chronic rejection development. METHODS A heterotopic rat heart transplantation model was used to induce chronic rejection. For therapeutic interventions, the immunocytokines F8-humanIL10 (DEKAVIL), F8-ratIL10 as well as KSF-humanIL10 (irrelevant antigen-specificity) were used. Treatment was performed weekly for 10 weeks starting at day 7 after transplantation (1mg/animal). RESULTS In the cardiac allografts, treatment with F8-huIL10 or F8-ratIL10 was associated with increased heart weights, a higher grade of chronic rejection, increased CIF, higher protein expression levels of alpha-smooth muscle actin (α-SMA), an augmented infiltration with inflammatory cells (CD4+, CD8+ and CD68+ cells) and higher serum levels of brain natriuretic peptide (BNP) compared to the control groups. CONCLUSIONS All observed treatment effects are transplantation-specific since the F8 antibody is specific to ED-A(+) Fn that is not expressed in healthy hearts. A clear targeting effect of F8-huIL10 as well as F8-ratIL10 could be proven. Against that background, a further study is needed to address the question, if F8-IL10 treatment is capable to reduce CAV and CIF starting at a time point when chronic rejection has fully developed (therapeutic approach).
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Affiliation(s)
- Marcus Franz
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
| | - Fabia Doll
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland
| | - Katja Grün
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany
| | - Petra Richter
- Institute of Pathology, Jena University Hospital, Jena, Germany
| | - Nilay Köse
- Institute of Pathology, Jena University Hospital, Jena, Germany
| | - Barbara Ziffels
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany
| | - Harald Schubert
- Institute of Laboratory Animal Science and Welfare, Jena University Hospital, Jena, Germany
| | - Hans R Figulla
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany
| | - Christian Jung
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany
| | - Jan Gummert
- Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr-University of Bochum, Bad Oeynhausen, Germany
| | - André Renner
- Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr-University of Bochum, Bad Oeynhausen, Germany
| | - Dario Neri
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland
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Barge-Caballero G, Barge-Caballero E, Marzoa-Rivas R, Paniagua-Martín MJ, Barrio-Rodríguez A, Naya-Leira C, Blanco-Canosa P, Grille-Cancela Z, Vázquez-Rodríguez JM, Crespo-Leiro MG. Clinical evaluation of rosuvastatin in heart transplant patients with hypercholesterolemia and therapeutic failure of other statin regimens: short-term and long-term efficacy and safety results. Transpl Int 2015; 28:1034-41. [DOI: 10.1111/tri.12585] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 11/26/2014] [Accepted: 04/07/2015] [Indexed: 11/26/2022]
Affiliation(s)
- Gonzalo Barge-Caballero
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - Eduardo Barge-Caballero
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - Raquel Marzoa-Rivas
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - María J. Paniagua-Martín
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - Alfredo Barrio-Rodríguez
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - Carmen Naya-Leira
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - Paula Blanco-Canosa
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - Zulaika Grille-Cancela
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - José Manuel Vázquez-Rodríguez
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
| | - María G. Crespo-Leiro
- Servicio de Cardiología; Complejo Hospitalario Universitario de A Coruña; A Coruña Spain
- Instituto de Investigación Biomédica de A Coruña (INIBIC); A Coruña Spain
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Lopez-Fernandez S, Manito-Lorite N, Gómez-Hospital JA, Roca J, Fontanillas C, Melgares-Moreno R, Azpitarte-Almagro J, Cequier-Fillat A. Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation. Clin Transplant 2014; 28:1393-401. [DOI: 10.1111/ctr.12470] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2014] [Indexed: 01/28/2023]
Affiliation(s)
- Silvia Lopez-Fernandez
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
- Department of Cardiology; Virgen de las Nieves University Hospital; FIBAO; Granada Spain
| | - Nicolas Manito-Lorite
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Joan Antoni Gómez-Hospital
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Josep Roca
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Carles Fontanillas
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Rafael Melgares-Moreno
- Department of Cardiology; Virgen de las Nieves University Hospital; FIBAO; Granada Spain
| | - José Azpitarte-Almagro
- Department of Cardiology; Virgen de las Nieves University Hospital; FIBAO; Granada Spain
| | - Angel Cequier-Fillat
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
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Guddeti RR, Matsuo Y, Matsuzawa Y, Aoki T, Lennon RJ, Lerman LO, Kushwaha SS, Lerman A. Ischemic cardiomyopathy is associated with coronary plaque progression and higher event rate in patients after cardiac transplantation. J Am Heart Assoc 2014; 3:jah3634. [PMID: 25095871 PMCID: PMC4310404 DOI: 10.1161/jaha.114.001091] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Background Cardiac allograft vasculopathy is the leading cause of graft failure and death in heart transplant (HTx) recipients; however, the association between the etiology of heart failure (ischemic cardiomyopathy [ICM] or non‐ICM) that led to HTx and progression of cardiac allograft vasculopathy, and adverse events after HTx has not been explored. Methods and Results We retrospectively included 165 HTx patients, who were followed‐up with at least 2 virtual histology–intravascular ultrasound examinations after HTx, and grouped them as ICM (n=46) or non‐ICM (n=119). Coronary artery plaque volume was analyzed using virtual histology–intravascular ultrasound, and cardiovascular event data—a composite of myocardial infarction, hospitalization for heart failure and arrhythmia, revascularization, retransplantation, and death including cardiovascular death—were collected from the medical records of all study subjects. ICM patients had significantly higher plaque volume at both first (P=0.040) and follow‐up (P=0.015) intravascular ultrasound examinations. After multivariate adjustment for traditional coronary risk factors, ICM was significantly associated with plaque progression (odds ratio 3.10; CI 1.17 to 9.36; P=0.023). Ten‐year cardiovascular event‐free survival was 50% in ICM patients compared with 84% in non‐ICM patients (log‐rank test P=0.003). In multivariate Cox proportional hazard analysis, ICM was significantly associated with a higher event rate after HTx (hazard ratio 2.02; 95% CI 1.01 to 4.00; P=0.048). Conclusion Our study demonstrates that ischemic etiology of cardiomyopathy prior to HTx may be independently associated with plaque progression and higher event rate after HTx.
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Affiliation(s)
- Raviteja R Guddeti
- Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN (R.R.G., Y.M., Y.M., T.A., S.S.K., A.L.)
| | - Yoshiki Matsuo
- Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN (R.R.G., Y.M., Y.M., T.A., S.S.K., A.L.)
| | - Yasushi Matsuzawa
- Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN (R.R.G., Y.M., Y.M., T.A., S.S.K., A.L.)
| | - Tatsuo Aoki
- Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN (R.R.G., Y.M., Y.M., T.A., S.S.K., A.L.)
| | - Ryan J Lennon
- Division of Biomedical Statistics and Informatics, Mayo College of Medicine, Rochester, MN (R.J.L.)
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (L.O.L.)
| | - Sudhir S Kushwaha
- Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN (R.R.G., Y.M., Y.M., T.A., S.S.K., A.L.)
| | - Amir Lerman
- Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN (R.R.G., Y.M., Y.M., T.A., S.S.K., A.L.)
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Coronary cardiac allograft vasculopathy versus native atherosclerosis: difficulties in classification. Virchows Arch 2014; 464:627-35. [PMID: 24807733 DOI: 10.1007/s00428-014-1586-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 04/14/2014] [Accepted: 04/24/2014] [Indexed: 02/01/2023]
Abstract
Cardiac allograft vasculopathy is regarded as a progressive and diffuse intimal hyperplastic lesion of arteries and veins that leads to insidious vessel narrowing and to allograft ischemic disease, such as acute myocardial infarction or sudden cardiac death. The coronary lesions in transplanted hearts are considered as a particular type of arteriosclerosis with many similarities but also significant differences compared to native coronary atherosclerosis. It is particularly difficult for pathologists to systematically classify the lesions and to elucidate their origins, since over time, the allograft immune responses cause vascular pathology characterized by not only the onset of de novo fibrocellular lesions but also remodeling of already-existing native atherosclerotic lesions in the donor heart. Intraplaque hemorrhages, which result from newly formed leaky microvessels, may cause rapid increase of stenosis and generate a substrate for plaque destabilization. Comparing cardiac allograft vasculopathy from explanted hearts at autopsy with native coronary atherosclerosis from hearts removed at transplantation has revealed that ongoing intraplaque hemorrhages are also an important feature of cardiac allograft vasculopathy and may be important factors in the rapid progression of cardiac allograft vasculopathy.
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Nytrøen K, Gullestad L. Exercise after heart transplantation: An overview. World J Transplant 2013; 3:78-90. [PMID: 24392312 PMCID: PMC3879527 DOI: 10.5500/wjt.v3.i4.78] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 07/15/2013] [Accepted: 07/25/2013] [Indexed: 02/05/2023] Open
Abstract
While life expectancy is greatly improved after a heart transplant, survival is still limited, and compared to the general population, the exercise capacity and health-related quality of life of heart transplant recipients are reduced. Increased exercise capacity is associated with a better prognosis. However, although several studies have documented positive effects of exercise after heart transplantation (HTx), little is known about the type, frequency and intensity of exercise that provides the greatest health benefits. Moreover, the long-term effects of exercise on co-morbidities and survival are also unclear. Exercise restrictions apply to patients with a denervated heart, and for decades, it was believed that the transplanted heart remained denervated. This has since been largely disproved, but despite the new knowledge, the exercise restrictions have largely remained, and up-to-date guidelines on exercise prescription after HTx do not exist. High-intensity, interval based aerobic exercise has repeatedly been documented to have superior positive effects and health benefits compared to moderate exercise. This applies to both healthy subjects as well as in several patient groups, such as patients with metabolic syndrome, coronary artery disease or heart failure. However, whether the effects of this type of exercise are also applicable to heart transplant populations has not yet been fully established. The purpose of this article is to give an overview of the current knowledge about the exercise capacity and effect of exercise among heart transplant recipients and to discuss future exercise strategies.
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Chen H, Xia J, Zhang L, Jin X, Yang M, Li J, Zhao Y. NKG2D blockade attenuated cardiac allograft vasculopathy in a mouse model of cardiac transplantation. Clin Exp Immunol 2013; 173:544-52. [PMID: 23638995 DOI: 10.1111/cei.12128] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2013] [Indexed: 12/27/2022] Open
Abstract
A previous paper has reported that blockade of NKG2D was effective in protecting allograft in murine models of cardiac transplantation, but the mechanism of NKG2D blockade on attenuated cardiac allograft vasculopathy (CAV) was still unknown. In our current study, we found that wild-type recipients treated with anti-NKG2D monoclonal antibody (mAb) plus cytotoxic T lymphocyte antigen (CTLA)-4-immunoglobulin (I)g showed prolonged allograft survivals (>90 days, P < 0·001) significantly and attenuated CAV. These in-vivo results correlated with reduced alloantibody production, low expression of interleukin (IL)-17 and IL-6, while infiltration of regulatory T cells increased. IL-6 administration induced shorter allograft survival and higher CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients, whereas IL-17 had no significant effect on allograft survival and CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients. Furthermore, the prolonged allograft survival induced by NKG2D blockade was abrogated partially with depletion of regulatory T cells. In conclusion, blockade of NKG2D combined with CTLA-4-Ig attenuated CAV and this effect was associated with lower alloantibody production, inhibited IL-6 expression and enhanced expansion of regulatory T cells.
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Affiliation(s)
- H Chen
- Emergency Centre, Zhongnan Hospital, Wuhan University, Wuhan, China
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Nytrøen K, Rustad LA, Erikstad I, Aukrust P, Ueland T, Lekva T, Gude E, Wilhelmsen N, Hervold A, Aakhus S, Gullestad L, Arora S. Effect of high-intensity interval training on progression of cardiac allograft vasculopathy. J Heart Lung Transplant 2013; 32:1073-80. [PMID: 23906899 DOI: 10.1016/j.healun.2013.06.023] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 06/25/2013] [Accepted: 06/25/2013] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is a progressive form of atherosclerosis occurring in heart transplant (HTx) recipients, leading to increased morbidity and mortality. Given the atheroprotective effect of exercise on traditional atherosclerosis, we hypothesized that high-intensity interval training (HIIT) would reduce the progression of CAV among HTx recipients. METHODS Forty-three cardiac allograft recipients (mean ± SD age 51 ± 16 years; 67% men; time post-HTx 4.0 ± 2.2 years), all clinically stable and >18 years old, were randomized to either a HIIT group or control group (standard care) for 1 year. The effect of training on CAV progression was assessed by intravascular ultrasound (IVUS). RESULTS IVUS analysis revealed a significantly smaller mean increase [95% CI] in atheroma volume (PAV) of 0.9% [95% CI -;0.3% to 1.9%] in the HIIT group as compared with the control group, 2.5% [1.6% to 3.5%] (p = 0.021). Similarly, the mean increase in total atheroma volume (TAV) was 0.3 [0.0 to 0.6] mm(3)/mm in the HIT group vs 1.1 [0.6 to 1.7] mm(3)/mm in the control group (p = 0.020), and mean increase in maximal intimal thickness (MIT) was 0.02-0.01 to 0.04] mm in the HIIT group vs 0.05 [0.03 to 0.08] mm in the control group (p = 0.054). Qualitative plaque progression (virtual histology parameters) and inflammatory activity (biomarkers) were similar between the 2 groups during the study period. CONCLUSIONS HIIT among maintenance HTx recipients resulted in a significantly impaired rate of CAV progression. Future larger studies should address whether exercise rehabilitation strategies should be included in CAV management protocols.
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Affiliation(s)
- Kari Nytrøen
- Department of Cardiology, Oslo University Hospital HF Rikshospitalet, Oslo.
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Angaswamy N, Tiriveedhi V, Sarma NJ, Subramanian V, Klein C, Wellen J, Shenoy S, Chapman WC, Mohanakumar T. Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection. Hum Immunol 2013; 74:1478-85. [PMID: 23876679 DOI: 10.1016/j.humimm.2013.07.002] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 07/09/2013] [Accepted: 07/09/2013] [Indexed: 01/02/2023]
Abstract
Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.
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Affiliation(s)
- Nataraju Angaswamy
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
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Zhu H, Li J, Wang S, Liu K, Wang L, Huang L. γδ T Cell Receptor Deficiency Attenuated Cardiac Allograft Vasculopathy and Promoted Regulatory T cell Expansion. Scand J Immunol 2013; 78:44-9. [PMID: 23659436 DOI: 10.1111/sji.12064] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 04/15/2013] [Indexed: 12/28/2022]
Affiliation(s)
- H. Zhu
- Department of Anesthesiology and The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education; School & Hospital of Stomatology; Wuhan University; Wuhan; China
| | - J. Li
- Department of Oncology; Wuhan Central Hospital; Wuhan; China
| | - S. Wang
- Department of Cardiovascular Surgery; Union Hospital; Huazhong University of Science and Technology; Wuhan; China
| | - K. Liu
- Department of Anesthesiology and The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education; School & Hospital of Stomatology; Wuhan University; Wuhan; China
| | - L. Wang
- Department of Anesthesiology and The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education; School & Hospital of Stomatology; Wuhan University; Wuhan; China
| | - L. Huang
- Department of Anesthesiology and The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education; School & Hospital of Stomatology; Wuhan University; Wuhan; China
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