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Inglis SS, Abbas M, Asleh R, Garmany A, Smith BH, Kushwaha S, Pereira N, Clavell AL, Villavicencio MA, Spencer PJ, Daly RC, Behfar A, Rosenbaum AN. Incidence and risk factors for rejection after conversion from calcineurin inhibitor to sirolimus-based immunosuppression in orthotopic heart transplant recipients. J Heart Lung Transplant 2025; 44:975-983. [PMID: 39743050 DOI: 10.1016/j.healun.2024.12.014] [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: 09/01/2024] [Revised: 12/11/2024] [Accepted: 12/14/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Although recommended in International Society for Heart and Lung Transplantation (ISHLT) guidelines, transition to mammalian targets of rapamycin (mTOR) inhibitors in heart transplant recipients is not routinely performed, in part due to perceived risk of rejection. This study sought to evaluate the incidence and risk factors for biopsy-proven, clinically relevant rejection following conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) immunosuppression. METHODS A single center retrospective study was conducted of all consecutive adult patients who underwent orthotopic heart transplantation (OHT) and CNI-free SRL conversion from January 1999 to January 2023. All post-OHT biopsy data were obtained and graded per ISHLT criteria (antibody-mediated rejection [pAMR] or acute cellular rejection [ACR]). The primary endpoint was early rejection, defined as grade 2R ACR, pAMR 1, or greater, within 6 months after conversion. RESULTS Three hundred and seventeen patients (72% male, mean age 51.5±12.6 years) were included. Median time to SRL conversion following OHT was 0.76 years (IQR 0.49, 1.42). Median time from conversion to rejection was 0.51 years (IQR 0.31, 1.05). Thirty eight patients (12%) experienced early rejection. Following multivariate analysis, both timing to SRL conversion following OHT (OR 0.94 per month, 95% CI: 0.89-0.99, p-value=0.0054) and age at transplantation (OR 0.96, 95% CI: 0.93-0.99, p-value=0.0071) were independently associated with early rejection. Rejection following SRL conversion was not associated with increased risk of cardiac allograft vasculopathy (CAV) grade 2-3. CONCLUSIONS In a CNI-free SRL conversion protocol, both earlier SRL conversion following OHT and younger age at transplant are independently associated with early rejection, but rejection is not associated with a net increased risk of prognostically important CAV. Individualization of transition is necessary to mitigate risk, and these findings may aid in improvement of future conversion protocols.
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Affiliation(s)
- Sara S Inglis
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, Minnesota; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Mohsin Abbas
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, Minnesota; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Rabea Asleh
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Armin Garmany
- Graduate School of Biomedical Sciences, Alix School of Medicine, Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota
| | - Byron H Smith
- Department of Biostatistics, Mayo Clinic, Rochester, Minnesota
| | - Sudhir Kushwaha
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Naveen Pereira
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alfredo L Clavell
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Philip J Spencer
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
| | - Richard C Daly
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
| | - Atta Behfar
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, Minnesota; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Andrew N Rosenbaum
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, Minnesota; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.
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Barghash M, Pinney SP. Targeting long-term benefit by tailoring calcineurin inhibitor-free regimens early after adult heart transplant. J Heart Lung Transplant 2025; 44:984-985. [PMID: 39848552 DOI: 10.1016/j.healun.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 01/25/2025] Open
Affiliation(s)
- Maya Barghash
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sean P Pinney
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, New York.
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Stomberski CT, Colvin MM. Cardiac Allograft Vasculopathy: A Focus on Advances in Diagnosis and Management. Methodist Debakey Cardiovasc J 2025; 21:58-71. [PMID: 40384732 PMCID: PMC12082475 DOI: 10.14797/mdcvj.1580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/12/2025] [Indexed: 05/20/2025] Open
Abstract
Cardiac allograft vasculopathy (CAV) is a type of coronary artery disease unique to heart transplant recipients that can result from chronic rejection of the transplanted heart. CAV is a major cause of morbidity and mortality after the first year of transplantation. Both immune and nonimmune mechanisms contribute to the initiation and progression of CAV and result in intimal thickening, fibrosis with luminal stenosis, chronic myocardial ischemia and eventual graft failure. Recent advances in imaging modalities-including invasive intracoronary imaging and noninvasive imaging with cardiac positron emission tomography-have improved the early detection of CAV and may allow for optimization of CAV-targeted therapies to reduce CAV progression and ultimately preserve graft function.
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Thorp EB, Ananthakrishnan A, Lantz CW. Decoding immune cell interactions during cardiac allograft vasculopathy: insights derived from bioinformatic strategies. Front Cardiovasc Med 2025; 12:1568528. [PMID: 40342971 PMCID: PMC12058854 DOI: 10.3389/fcvm.2025.1568528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/04/2025] [Indexed: 05/11/2025] Open
Abstract
Chronic allograft vasculopathy (CAV) is a major cause of late graft failure in heart transplant recipients, characterized by progressive intimal thickening and diffuse narrowing of the coronary arteries. Unlike atherosclerosis, CAV exhibits a distinct cellular composition and lesion distribution, yet its pathogenesis remains incompletely understood. A major challenge in CAV research has been the limited application of advanced "-omics" technologies, which have revolutionized the study of other vascular diseases. Recent advancements in single-cell and spatial transcriptomics, proteomics, and metabolomics have begun to uncover the complex immune-endothelial-stromal interactions driving CAV progression. Notably, single-cell RNA sequencing has identified previously unrecognized immune cell populations and signaling pathways implicated in endothelial injury and vascular remodeling after heart transplantation. Despite these breakthroughs, studies applying these technologies to CAV remain sparse, limiting the translation of these insights into clinical practice. This review aims to bridge this gap by summarizing recent findings from single-cell and multi-omic approaches, highlighting key discoveries, and discussing their implications for understanding CAV pathogenesis.
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Affiliation(s)
- Edward B. Thorp
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Aparnaa Ananthakrishnan
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Connor W. Lantz
- Department of Surgery, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Alnsasra H, Asleh R, Khalil F, Akiki E, Briasoulis A, Dean PG, Bentall AJ, Kushwaha SS. Treatment With mTOR Inhibitors as Primary Immunosuppression After Combined Heart and Kidney Transplantation. J Card Fail 2024:S1071-9164(24)00959-X. [PMID: 39653323 DOI: 10.1016/j.cardfail.2024.10.451] [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: 03/27/2024] [Revised: 10/20/2024] [Accepted: 10/28/2024] [Indexed: 01/13/2025]
Abstract
INTRODUCTION Sirolimus (SRL) mitigates cardiac allograft vasculopathy (CAV) progression and confers renal protection after heart transplantation (HT). However, its safety and efficacy in patients undergoing combined heart and kidney transplantation (HKT) are unclear. This study aimed to investigate the impact of conversion from calcineurin inhibitors (CNIs) to SRL on CAV progression, renal function, and outcomes in HKT compared with isolated HT. METHODS A cohort of 302 patients who underwent either HT only (n = 262) or HKT (n = 40) was analyzed. CAV progression was assessed by measuring the delta (Δ) annual change in plaque volume (PV) and plaque index (PI) using coronary intravenous ultrasound (IVUS). Clinical adverse outcomes included all-cause death and CAV-associated events. Overall, 217 (72%) patients were converted from CNI to SRL as primary immunosuppression. HT recipients were more likely to be converted to SRL than HKT recipients (74% vs. 55%, P = .01). RESULTS HKT was associated with higher Δ PV (P = .01) and a trend toward higher ΔPI (P = .06) than HT only, but this association was attenuated after adjustment to SRL conversion. HKT was associated with similar risk of death (HR, 0.98; 95% CI 0.39-2.5, P = 0.97) and CAV-related events (HR, 1.6; 95% CI 0.91-2.8, P = .10). Conversion to SRL was associated with decreased risk of death and CAV-related events in the overall cohort. This association was not modified by the type of organ transplantation and without a significant effect on estimated glomerular filtration rate or proteinuria. CONCLUSION Conversion to sirolimus as a primary immunosuppressant could be effective for either HT-only or HKT recipients.
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Affiliation(s)
- Hilmi Alnsasra
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota; Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel; Department of Cardiology, Soroka University Medical Center, Beersheva, Israel
| | - Rabea Asleh
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota; Heart Institute, Faculty of Medicine, Hadassah University Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Fouad Khalil
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Elias Akiki
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Alexandros Briasoulis
- Department of Cardiovascular Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa; National Kapodistrian University of Athens, Greece
| | - Patrick G Dean
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Andrew J Bentall
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Sudhir S Kushwaha
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.
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Weis M, Weis M. Transplant Vasculopathy Versus Native Atherosclerosis: Similarities and Differences. Transplantation 2024; 108:1342-1349. [PMID: 37899386 DOI: 10.1097/tp.0000000000004853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Cardiac allograft vasculopathy (CAV) is one of the leading causes of graft failure and death after heart transplantation. Alloimmune-dependent and -independent factors trigger the pathogenesis of CAV through activation of the recipients' (and to a lesser extent donor-derived) immune system. Early diagnosis of CAV is complicated by the lack of clinical symptoms for ischemia in the denervated heart, by the impact of early functional coronary alterations, by the insensitivity of coronary angiography, and by the involvement of small intramyocardial vessels. CAV in general is a panarterial disease confined to the allograft and characterized by diffuse concentric longitudinal intimal hyperplasia in the epicardial coronary arteries and concentric medial disease in the microvasculature. Plaque composition in CAV may include early fibrous and fibrofatty tissue and late atheromatous calcification. In contrast, native coronary atherosclerosis usually develops over decades, is focal, noncircumferential, and typically diminishes proximal parts of the epicardial vessels. The rapid and early development of CAV has an adverse prognostic impact, and current prevention and treatment strategies are of limited efficacy compared with established strategies in native atherosclerosis. Following acute coronary syndromes, patients after heart transplantation were more likely to have accompanying cardiogenic shock and higher mortality compared with acute coronary syndromes patients with native hearts.
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Affiliation(s)
- Michael Weis
- Department of Internal Medicine I, Krankenhaus Neuwittelsbach, Munich, Germany
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Rodenas-Alesina E, Aleksova N, Stubbs M, Foroutan F, Kozuszko S, Posada JD, McDonald M, Moayedi Y, Ross H, Dipchand A. Cardiac allograft vasculopathy and survival in pediatric heart transplant recipients transitioned to adult care. J Heart Lung Transplant 2024; 43:229-237. [PMID: 37704160 DOI: 10.1016/j.healun.2023.09.005] [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: 03/06/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is an important cause of mortality after pediatric heart transplantation (HT) but there is a paucity of data regarding its incidence and impact on survival in pediatric recipients transitioned to adult care. METHODS We conducted a retrospective review of consecutive pediatric HT patients from 1989 to 2017 at the Hospital for Sick Children who transitioned to adult care at ≥18 years at Toronto General Hospital. We evaluated the incidence of International Society of Heart and Lung Transplantation CAV grade ≥1 using competing risk models. We assessed the association between all-cause mortality and CAV using Cox proportional hazards and used Kaplan Meier methods to evaluate all-cause mortality stratified by CAV and transplant era (1989-2001, 2002-2017). RESULTS Ninety-six patients were transitioned to adult care by January 2022, of which 53 underwent repeat coronary angiography as adults. CAV was newly diagnosed in 49% patients after transition to adult care. The overall incidence of CAV was 3.9 cases per 100 person-years. There was no difference in the adjusted incidence of CAV according to transplant era (subdistribution hazard ratios = 1.17, 95% confidence interval (CI) 0.54-2.66). CAV was associated with a higher risk of death in the early era (hazard ratio (HR) 10.29, 95% CI 2.16-49.96), but not in the recent era (HR 1.61, 95% 0.35-7.47). CONCLUSIONS There is a role for continued CAV surveillance after the transition to adult care. The implications of diagnosing CAV after the transition to adult care require further study, particularly because the risk of death in pediatric HT recipients diagnosed with CAV in the more recent era may be attenuated compared to the earlier HT era.
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Affiliation(s)
| | - Natasha Aleksova
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Women's College Hospital, Toronto, Ontario, Canada.
| | - Michael Stubbs
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Farid Foroutan
- Ted Rogers Centre for Heart Research, University Health Network, Toronto, Ontario, Canada
| | - Stella Kozuszko
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Juan Duero Posada
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Michael McDonald
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Yasbanoo Moayedi
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Heather Ross
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Anne Dipchand
- Hospital for Sick Children, Toronto, Ontario, Canada
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8
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Lopez-Schenk R, Collins NL, Schenk NA, Beard DA. Integrated Functions of Cardiac Energetics, Mechanics, and Purine Nucleotide Metabolism. Compr Physiol 2023; 14:5345-5369. [PMID: 38158366 PMCID: PMC10956446 DOI: 10.1002/cphy.c230011] [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: 01/03/2024]
Abstract
Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.
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Affiliation(s)
- Rachel Lopez-Schenk
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Nicole L Collins
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Noah A Schenk
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Daniel A Beard
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
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Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, Dixon DL, Fearon WF, Hess B, Johnson HM, Kazi DS, Kolte D, Kumbhani DJ, LoFaso J, Mahtta D, Mark DB, Minissian M, Navar AM, Patel AR, Piano MR, Rodriguez F, Talbot AW, Taqueti VR, Thomas RJ, van Diepen S, Wiggins B, Williams MS. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 2023; 148:e9-e119. [PMID: 37471501 DOI: 10.1161/cir.0000000000001168] [Citation(s) in RCA: 482] [Impact Index Per Article: 241.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Abstract
AIM The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.
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Affiliation(s)
| | | | | | | | | | | | - Dave L Dixon
- Former Joint Committee on Clinical Practice Guideline member; current member during the writing effort
| | - William F Fearon
- Society for Cardiovascular Angiography and Interventions representative
| | | | | | | | - Dhaval Kolte
- AHA/ACC Joint Committee on Clinical Data Standards
| | | | | | | | - Daniel B Mark
- Former Joint Committee on Clinical Practice Guideline member; current member during the writing effort
| | | | | | | | - Mariann R Piano
- Former Joint Committee on Clinical Practice Guideline member; current member during the writing effort
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10
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Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, Dixon DL, Fearon WF, Hess B, Johnson HM, Kazi DS, Kolte D, Kumbhani DJ, LoFaso J, Mahtta D, Mark DB, Minissian M, Navar AM, Patel AR, Piano MR, Rodriguez F, Talbot AW, Taqueti VR, Thomas RJ, van Diepen S, Wiggins B, Williams MS. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2023; 82:833-955. [PMID: 37480922 DOI: 10.1016/j.jacc.2023.04.003] [Citation(s) in RCA: 163] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
AIM The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.
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11
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Mylonas KS, Soukouli I, Avgerinos DV, Boletis JN. Current immunosuppression strategies in pediatric heart transplant. Immunotherapy 2022; 14:663-667. [PMID: 35510326 DOI: 10.2217/imt-2021-0352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
| | - Ioanna Soukouli
- Department of Nephrology & Renal Transplantation, Laiko General Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | | | - John N Boletis
- Department of Nephrology & Renal Transplantation, Laiko General Hospital, National & Kapodistrian University of Athens, Athens, Greece
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12
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Du Y, Duan C, Yang Y, Yuan G, Zhou Y, Zhu X, Wei N, Hu Y. Heart Transplantation: A Bibliometric Review From 1990-2021. Curr Probl Cardiol 2022; 47:101176. [PMID: 35341797 DOI: 10.1016/j.cpcardiol.2022.101176] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/22/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND As the rapidly aging population and the rising incidence of end-stage heart failure (HF), extensive research has been conducted on heart transplantation (HTx). Bibliometrics harbors the function for describing the relationships of knowledge structures in different research fields and predicting the growth trend . METHODS The publications were searched and filtered based on the WOS core database. The target literature was visualized and analyzed by CiteSpace or VOSviewer . RESULTS In total, 19,998 published papers were obtained. There is a wave-like growth in HTx development. Most advanced research results are concentrated in a few developed countries, while the interactions with developing countries are still in infancy. The United States occupies a strong dominant position among active countries on HTx. Early research hotpots mostly focused on primary disease, survival risk factors, and complications. In recent years, the research frontiers have shifted steadily to clinical evaluation of immunosuppressants and diagnosis of acute rejection, cardiac re-injury with COVID-19, innovations in ventricular assist devices(VAD), and donation allocation strategies. The research directions of HTx are gradually shifting from observational studies to intervention research.
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Affiliation(s)
- Yihang Du
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China
| | - Chenglin Duan
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China; Beijing University of Chinese Medicine, Beijing, China
| | - Yihan Yang
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China; Beijing University of Chinese Medicine, Beijing, China
| | - Guozhen Yuan
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China
| | - Yan Zhou
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China; Beijing University of Chinese Medicine, Beijing, China
| | - Xueping Zhu
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China
| | - Namin Wei
- Beijing University of Chinese Medicine, Beijing, China
| | - Yuanhui Hu
- Cardiovascular department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine Sciences, Beijing, China.
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13
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Asleh R, Vucicevic D, Petterson TM, Kremers WK, Pereira NL, Daly RC, Edwards BS, Steidley DE, Scott RL, Kushwaha SS. Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study. J Clin Med 2022; 11:jcm11020322. [PMID: 35054016 PMCID: PMC8779206 DOI: 10.3390/jcm11020322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/03/2022] [Accepted: 01/07/2022] [Indexed: 02/01/2023] Open
Abstract
Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
- Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: or
| | - Darko Vucicevic
- Department of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Tanya M. Petterson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Walter K. Kremers
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Naveen L. Pereira
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - Richard C. Daly
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - Brooks S. Edwards
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - D. Eric Steidley
- Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ 85054, USA; (D.E.S.); (R.L.S.)
| | - Robert L. Scott
- Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ 85054, USA; (D.E.S.); (R.L.S.)
| | - Sudhir S. Kushwaha
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
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Konda P, Golamari R, Eisen HJ. Novel Immunosuppression in Solid Organ Transplantation. Handb Exp Pharmacol 2022; 272:267-285. [PMID: 35318509 DOI: 10.1007/164_2021_569] [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] [Indexed: 06/14/2023]
Abstract
Solid organ transplantation and survival has improved tremendously in the last few decades, much of the success has been attributed to the advancements in immunosuppression. While steroids are being replaced and much of the immunosuppressive strategies focus on steroid free regimens, novel agents have introduced in the induction, maintenance, and treatment of acute rejection phase. MTOR inhibitors have helped with the renal sparing side effect from the calcineurin inhibitors, newer agents such as rituximab have decreased the incidence of donor-specific antibodies which led to decreased incidence of acute rejection reactions. In this chapter we discuss the newer therapies directed specifically for solid organ transplantation.
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Affiliation(s)
- Prasad Konda
- Heart and Vascular Institute, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Reshma Golamari
- Department of Hospital Medicine, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Howard J Eisen
- Heart and Vascular Institute, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA.
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15
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Wang L, Wang F, Liu K, Long C, Chen Y, Li C, Li L, Liu F, Zhang X, Jing Y, Wang Y, Liang A, Yan H, Zhang H. αB-crystallin/HSPB2 is critical for hyperactive mTOR-induced cardiomyopathy. J Cell Physiol 2021; 236:8110-8121. [PMID: 34101831 DOI: 10.1002/jcp.30465] [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: 01/16/2021] [Revised: 04/24/2021] [Accepted: 05/26/2021] [Indexed: 11/09/2022]
Abstract
Even though aberrant mechanistic target of rapamycin (mTOR) signaling is known to cause cardiomyopathy, its underlying mechanism remains poorly understood. Because augmentation of αB-crystallin and hspB2 was presented in the cortical tubers and lymphangioleiomyomatosis of tuberous sclerosis complex patients, we deciphered the role of αB-crystallin and its adjacent duplicate gene, hspB2, in hyperactive mTOR-induced cardiomyopathy. Cardiac Tsc1 deletion (T1-hKO) caused mouse mTOR activation and cardiomyopathy. Overexpression of αB-crystallin and hspB2 was presented in the hearts of these mice. Knockout of αB-crystallin/hspB2 reversed deficient Tsc1-mediated fetal gene expression, mTOR activation, mitochondrial damage, cardiomyocyte vacuolar degeneration, cardiomyocyte size, and fibrosis of T1-hKO mice. These cardiac-Tsc1; αB-crystallin; hspB2 triple knockout (tKO) mice had improved cardiac function, smaller heart weight to body weight ratio, and reduced lethality compared with T1-hKO mice. Even though activated mTOR suppressed autophagy in T1-hKO mice, ablation of αB-crystallin and hspB2 failed to restore autophagy in tKO mice. mTOR inhibitors suppressed αB-crystallin expression in T1-hKO mice and rat cardiomyocyte line H9C2. Starvation of H9C2 cells activated autophagy and suppressed αB-crystallin expression. Since inhibition of autophagy restored αB-crystallin expression in starved H9C2 cells, autophagy is a negative regulator of αB-crystallin expression. mTOR thus stimulates αB-crystallin expression through suppression of autophagy. In conclusion, αB-crystallin and hspB2 play a pivotal role in Tsc1 knockout-related cardiomyopathy and are therapeutic targets of hyperactive mTOR-associated cardiomyopathy.
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Affiliation(s)
- Lianmei Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Safety Research Center of Injectable Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fang Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Kemei Liu
- Department of Cardiovascular Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Caifeng Long
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yi Chen
- Department of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunjia Li
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Li Li
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Fangming Liu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinyu Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yanling Jing
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yanan Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Aihua Liang
- Safety Research Center of Injectable Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hongbing Yan
- Department of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Coronary Heart Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China
| | - Hongbing Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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16
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Alnsasra H, Asleh R, Oh JK, Maleszewski JJ, Lerman A, Toya T, Chandrasekaran K, Bois MC, Kushwaha SS. Impact of Sirolimus as a Primary Immunosuppressant on Myocardial Fibrosis and Diastolic Function Following Heart Transplantation. J Am Heart Assoc 2020; 10:e018186. [PMID: 33325244 PMCID: PMC7955460 DOI: 10.1161/jaha.120.018186] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P=0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P=0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P=0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P=0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P=0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P=0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.
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Affiliation(s)
- Hilmi Alnsasra
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | - Rabea Asleh
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN.,Department of Cardiology Hadassah University Medical Center Jerusalem Israel
| | - Jae K Oh
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | | | - Amir Lerman
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | - Takumi Toya
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | | | - Melanie C Bois
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN
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17
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“Cardiac allograft vasculopathy: Pathogenesis, diagnosis and therapy”. Transplant Rev (Orlando) 2020; 34:100569. [DOI: 10.1016/j.trre.2020.100569] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/19/2020] [Indexed: 01/06/2023]
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18
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Habibi S, Ghaffarpasand E, Shojaei F, Alihashemi M, Kahe F, Zahedi Tajrishi F, Chi G. Prognostic Value of Biomarkers in Cardiac Allograft Vasculopathy following Heart Transplantation: A Literature Review. Cardiology 2020; 145:693-702. [PMID: 32892195 DOI: 10.1159/000509630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 06/23/2020] [Indexed: 11/19/2022]
Abstract
Cardiac allograft vasculopathy (CAV), also known as cardiac transplant vasculopathy, is a major determinant of long-term survival among cardiac transplantation recipients. Histologically, CAV is featured by diffuse, concentric thickening of the vascular wall, and primarily affects large and small epicardial coronary arteries, intramyocardial arteries, and veins. Owing to graft denervation, CAV typically follows an insidious course, and patients may not experience classic angina symptoms but instead present with progressive heart failure or ventricular arrhythmias. Recent studies on biomarkers have furthered the knowledge concerning the prediction and prognosis of CAV. Given its association with metabolic, thrombotic, inflammatory, and immunologic markers, CAV is likely to represent a complex multifactorial process that involves both immune-mediated and non-immune-mediated pathways. In order to identify the high-risk patients that would benefit from early intervention, future research is warranted to examine the usefulness of a biomarker panel in CAV risk stratification.
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Affiliation(s)
- Shaghayegh Habibi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Eiman Ghaffarpasand
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Fahimehalsadat Shojaei
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Mahda Alihashemi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Farima Kahe
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Gerald Chi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA,
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19
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Picão S, Oliveira-Santos M, Batista M, Prieto D, Antunes MJ, Pego M, Matos V, Gonçalves L, Jorge E. Cardiac allograft vasculopathy: Incidence and predictors in a single-center cohort. Rev Port Cardiol 2020; 39:205-212. [PMID: 32471665 DOI: 10.1016/j.repc.2019.10.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 10/08/2019] [Accepted: 10/27/2019] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION AND AIMS Cardiac allograft vasculopathy (CAV) is one of the most significant complications after orthotopic heart transplantation. We aimed to investigate the incidence and predictors of CAV in a large cohort of orthotopic heart transplantation patients. METHODS We conducted a retrospective analysis on a prospective cohort of 233 patients who underwent transplantation between November 2003 and May 2014. Baseline clinical data and invasive coronary angiograms (n=712) performed as part of the follow-up program were analyzed by two independent investigators. RESULTS We included 157 male and 45 female patients with a median age of 66 years. A third of patients had previous ischemic heart disease, 30% peripheral arterial disease, 37% hypertension and 47% dyslipidemia, and 17% were smokers. Acute moderate or severe rejection occurred in 42 patients during the first year. Over a median follow-up of 2920 days, 18% were diagnosed with CAV, with an incidence of 2.91 cases per 100 person-years. Predictors of CAV were previous ischemic heart disease (HR 2.32, 95% CI 1.21-4.45, p=0.01), carotid artery disease (HR 2.44, 95% CI 1.27-4.71, p<0.01), and donor age (HR 1.04, 95% CI 1.00-1.07, p=0.01). CONCLUSION In a single-center cohort of orthotopic heart transplantation patients, predictors of CAV were previous ischemic heart disease, carotid artery disease and donor age.
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Affiliation(s)
- Sofia Picão
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal.
| | | | - Manuel Batista
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal
| | - David Prieto
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal
| | | | - Mariano Pego
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal
| | - Vítor Matos
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal
| | - Lino Gonçalves
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal
| | - Elisabete Jorge
- Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal
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20
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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: 16] [Impact Index Per Article: 3.2] [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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21
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Picão S, Oliveira-Santos M, Batista M, Prieto D, Antunes MJ, Pego M, Matos V, Gonçalves L, Jorge E. Cardiac allograft vasculopathy: Incidence and predictors in a single-center cohort. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.repce.2019.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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22
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Lee F, Nair V, Chih S. Cardiac allograft vasculopathy: Insights on pathogenesis and therapy. Clin Transplant 2020; 34:e13794. [PMID: 31991002 DOI: 10.1111/ctr.13794] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 01/14/2020] [Accepted: 01/23/2020] [Indexed: 12/21/2022]
Abstract
Cardiac allograft vasculopathy (CAV) is a unique accelerated form of coronary vascular disease affecting heart transplant recipients. This complication is a significant contributor to medium- to long-term post-transplant morbidity and mortality. There is a high prevalence of CAV with approximately one in three patients developing CAV by 5 years post-transplant. Morphologically, CAV is characterized by concentric coronary intimal hyperplasia in both the epicardial arteries and intramural microvasculature. Although several immune and non-immune factors have been identified, their precise pathogenic mechanisms, interactions, and relative importance in the development of CAV are not well defined. The advent of improved imaging surveillance modalities has resulted in earlier detection during the disease process. However, overall management of CAV remains challenging due to paucity of treatment. This review aims to discuss key concepts on the pathogenesis of CAV and current management strategies, focusing on the use of mammalian target of rapamycin inhibitors.
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Affiliation(s)
- Felicity Lee
- Heart Failure and Transplantation, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada
| | - Vidhya Nair
- Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Sharon Chih
- Heart Failure and Transplantation, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada
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23
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Impaired Exercise Tolerance Early After Heart Transplantation Is Associated With Development of Cardiac Allograft Vasculopathy. Transplantation 2020; 104:2196-2203. [DOI: 10.1097/tp.0000000000003110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Bellumkonda L, Patel J. Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy. Clin Transplant 2019; 34:e13769. [DOI: 10.1111/ctr.13769] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Lavanya Bellumkonda
- Division of Cardiology Department of Medicine Yale School of Medicine New Haven CT USA
| | - Jignesh Patel
- Cedars‐Sinai Medical Center Smidt Heart Institute Los Angeles CA USA
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25
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Van Keer JM, Van Aelst LN, Rega F, Droogne W, Voros G, Meyns B, Vanhaecke J, Emonds MP, Janssens S, Naesens M, Van Cleemput J. Long-term outcome of cardiac allograft vasculopathy: Importance of the International Society for Heart and Lung Transplantation angiographic grading scale. J Heart Lung Transplant 2019; 38:1189-1196. [DOI: 10.1016/j.healun.2019.08.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/25/2019] [Accepted: 08/07/2019] [Indexed: 12/12/2022] Open
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26
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Hughes A, Okasha O, Farzaneh-Far A, Kazmirczak F, Nijjar PS, Velangi P, Akçakaya M, Martin CM, Shenoy C. Myocardial Fibrosis and Prognosis in Heart Transplant Recipients. Circ Cardiovasc Imaging 2019; 12:e009060. [PMID: 31610691 DOI: 10.1161/circimaging.119.009060] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Myocardial fibrosis is a well-described histopathologic feature in heart transplant recipients. Whether myocardial fibrosis in heart transplant recipients is independently associated with clinical outcomes is unclear. We sought to determine whether myocardial fibrosis on late gadolinium enhancement cardiovascular magnetic resonance imaging in heart transplant recipients was independently associated with all-cause death or major adverse cardiac outcomes in the long-term. METHODS Using a cohort of consecutive heart transplant recipients that had cardiovascular magnetic resonance imaging, we determined the prevalence and the patterns of myocardial fibrosis and analyzed associations between myocardial fibrosis and a composite end point of all-cause death or major adverse cardiac events: retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. RESULTS One hundred and fifty-two heart transplant recipients (age, 54±15 years; 29% women; 5.0±5.4 years after heart transplantation) were included. Myocardial fibrosis was present in 18% (37% infarct pattern, 41% noninfarct pattern, and 22% both). Its prevalence was positively associated with cardiac allograft vasculopathy grade. With a median follow-up of 2.6 years, myocardial fibrosis was independently associated with all-cause death or major adverse cardiac events (hazard ratio, 2.88; 95% CI, 1.59-5.23; P<0.001) after adjustment for cardiac allograft vasculopathy, history of rejection, time since transplantation, left ventricular ejection fraction, and indexed right ventricular end-diastolic volume. Every 1% increase in myocardial fibrosis was independently associated with a 6% higher hazard for all-cause death or major adverse cardiac events (hazard ratio, 1.06; 95% CI, 1.03-1.09; P<0.001). The addition of myocardial fibrosis variables to models with cardiac allograft vasculopathy, history of rejection, time since transplantation, left ventricular ejection fraction, and indexed right ventricular end-diastolic volume resulted in significant improvements in model fit, suggesting incremental prognostic value. CONCLUSIONS In heart transplant recipients, myocardial fibrosis is seen on late gadolinium enhancement cardiovascular magnetic resonance imaging in 18%. Both the presence and the extent of myocardial fibrosis are independently associated with the long-term risk of all-cause death or major adverse cardiac events.
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Affiliation(s)
- Andrew Hughes
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
| | - Osama Okasha
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
| | - Afshin Farzaneh-Far
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL (A.F.-F.)
| | - Felipe Kazmirczak
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
| | - Prabhjot S Nijjar
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
| | - Pratik Velangi
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
| | - Mehmet Akçakaya
- Department of Electrical and Computer Engineering and Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN (M.A.)
| | - Cindy M Martin
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
| | - Chetan Shenoy
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN (A.H., O.O., F.K., P.S.N., P.V., C.M.M., C.S.)
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Combined heart and kidney transplantation—Is there a protective effect against cardiac allograft vasculopathy using intravascular ultrasound? J Heart Lung Transplant 2019; 38:956-962. [DOI: 10.1016/j.healun.2019.06.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/14/2019] [Accepted: 06/16/2019] [Indexed: 11/20/2022] Open
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Asleh R, Briasoulis A, Kremers WK, Adigun R, Boilson BA, Pereira NL, Edwards BS, Clavell AL, Schirger JA, Rodeheffer RJ, Frantz RP, Joyce LD, Maltais S, Stulak JM, Daly RC, Tilford J, Choi WG, Lerman A, Kushwaha SS. Long-Term Sirolimus for Primary Immunosuppression in Heart Transplant Recipients. J Am Coll Cardiol 2019; 71:636-650. [PMID: 29420960 DOI: 10.1016/j.jacc.2017.12.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating cardiac allograft vasculopathy (CAV) after heart transplantation (HT). However, data on the long-term effect on CAV progression and clinical outcomes are lacking. OBJECTIVES The aim of this study was to test the long-term safety and efficacy of conversion from CNI to SRL as maintenance therapy on CAV progression and outcomes after HT. METHODS A cohort of 402 patients who underwent HT and were either treated with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression was analyzed. CAV progression was assessed using serial coronary intravascular ultrasound during treatment with CNI (n = 99) and after conversion to SRL (n = 235) in patients who underwent at least 2 intravascular ultrasound studies. RESULTS The progression in plaque volume (2.8 ± 2.3 mm3/mm vs. 0.46 ± 1.8 mm3/mm; p < 0.0001) and plaque index (plaque volume-to-vessel volume ratio) (12.2 ± 9.6% vs. 1.1 ± 7.9%; p < 0.0001) were significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up period of 8.9 years from time of HT, all-cause mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70; p = 0.0002), and CAV-related events were also less frequent during treatment with SRL (adjusted hazard ratio: 0.35; 95% confidence interval: 0.21 to 0.59; p < 0.0001). Further analyses suggested more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (≤2 years) compared with late conversion (>2 years) after HT. CONCLUSIONS Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Alexandros Briasoulis
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Walter K Kremers
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Rosalyn Adigun
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Barry A Boilson
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Naveen L Pereira
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Brooks S Edwards
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Alfredo L Clavell
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - John A Schirger
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Richard J Rodeheffer
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Robert P Frantz
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Lyle D Joyce
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Simon Maltais
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - John M Stulak
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Richard C Daly
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Jonella Tilford
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Woong-Gil Choi
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Amir Lerman
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Sudhir S Kushwaha
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.
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Eisen HJ, Hasni SF, Wang D. The Return of the mTOR Inhibitors: Getting it Right in Patients After Cardiac Transplantation. J Am Coll Cardiol 2019; 71:651-653. [PMID: 29420961 DOI: 10.1016/j.jacc.2017.12.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 12/19/2017] [Accepted: 12/21/2017] [Indexed: 10/18/2022]
Affiliation(s)
- Howard J Eisen
- Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
| | - S Farhan Hasni
- Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Denise Wang
- Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania
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Konerman MC, Lazarus JJ, Weinberg RL, Shah RV, Ghannam M, Hummel SL, Corbett JR, Ficaro EP, Aaronson KD, Colvin MM, Koelling TM, Murthy VL. Reduced Myocardial Flow Reserve by Positron Emission Tomography Predicts Cardiovascular Events After Cardiac Transplantation. Circ Heart Fail 2019; 11:e004473. [PMID: 29891737 DOI: 10.1161/circheartfailure.117.004473] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND We evaluated the diagnostic and prognostic value of quantification of myocardial flow reserve (MFR) with positron emission tomography (PET) in orthotopic heart transplant patients. METHODS AND RESULTS We retrospectively identified orthotopic heart transplant patients who underwent rubidium-82 cardiac PET imaging. The primary outcome was the composite of cardiovascular death, acute coronary syndrome, coronary revascularization, and heart failure hospitalization. Cox regression was used to evaluate the association of MFR with the primary outcome. The relationship of MFR and cardiac allograft vasculopathy severity in patients with angiography within 1 year of PET imaging was assessed using Spearman rank correlation and logistic regression. A total of 117 patients (median age, 60 years; 71% men) were identified. Twenty-one of 62 patients (34%) who underwent angiography before PET had cardiac allograft vasculopathy. The median time from orthotopic heart transplant to PET imaging was 6.4 years (median global MFR, 2.31). After a median of 1.4 years, 22 patients (19%) experienced the primary outcome. On an unadjusted basis, global MFR (hazard ratio, 0.22 per unit increase; 95% confidence interval, 0.09-0.50; P<0.001) and stress myocardial blood flow (hazard ratio, 0.48 per unit increase; 95% confidence interval, 0.29-0.79; P=0.004) were associated with the primary outcome. Decreased MFR independently predicted the primary outcome after adjustment for other variables. In 42 patients who underwent angiography within 12 months of PET, MFR and stress myocardial blood flow were associated with moderate-severe cardiac allograft vasculopathy (International Society of Heart and Lung Transplantation grade 2-3). CONCLUSIONS MFR assessed by cardiac rubidium-82 PET imaging is a predictor of cardiovascular events after orthotopic heart transplant and is associated with cardiac allograft vasculopathy severity.
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Affiliation(s)
- Matthew C Konerman
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - John J Lazarus
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Richard L Weinberg
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Ravi V Shah
- University of Michigan, Ann Arbor. Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston (R.V.S.)
| | | | - Scott L Hummel
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - James R Corbett
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.).,Division of Nuclear Medicine, Department of Radiology (J.R.C., E.P.F., V.L.M.)
| | - Edward P Ficaro
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.).,Division of Nuclear Medicine, Department of Radiology (J.R.C., E.P.F., V.L.M.)
| | - Keith D Aaronson
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Monica M Colvin
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Todd M Koelling
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Venkatesh L Murthy
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.).,Division of Nuclear Medicine, Department of Radiology (J.R.C., E.P.F., V.L.M.)
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Acharya D, Rajapreyar I. Myocardial perfusion imaging for cardiac allograft vasculopathy assessment: Evidence grows, but questions remain. J Nucl Cardiol 2019; 26:853-856. [PMID: 29116561 DOI: 10.1007/s12350-017-1116-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 10/23/2017] [Indexed: 01/06/2023]
Affiliation(s)
- Deepak Acharya
- Section of Advanced Heart Failure Transplantation, and Mechanical Circulatory Support, University of Alabama at Birmingham, 1900 University Blvd, THT 321, Birmingham, AL, 35294, USA.
| | - Indranee Rajapreyar
- Section of Advanced Heart Failure Transplantation, and Mechanical Circulatory Support, University of Alabama at Birmingham, 1900 University Blvd, THT 321, Birmingham, AL, 35294, USA
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The change of immunosuppressive regimen from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors and its effect on malignancy following heart transplantation. Int Immunopharmacol 2019; 69:150-158. [PMID: 30711744 DOI: 10.1016/j.intimp.2019.01.035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/11/2022]
Abstract
Malignancy is a significant cause of mortality after organ transplantation. There is an increased rate of malignancy following heart transplantation (HTx) compared to the general population and other organ transplant recipients. Post-HTx patients with a history of malignancy are also at a higher risk of developing new malignancies or exacerbation of their existing malignancies. Mammalian target of Rapamycin inhibitors (mTORIs) are newly introduced immunosuppressive drugs with a unique mechanism of action. By changing the immunosuppressive regimen from classic drugs, especially calcineurin inhibitors (CNIs) to mTORIs, the rate of developing de novo malignancies and the relapse of former malignancies is significantly reduced. However, issues like allograft function, total surveillance of patients, and post-transplantation complications should be considered during the conversion of drug regimens utilizing CNIs to drug regimens employing mTORIs. We reviewed different post-heart transplant maintenance immunosuppressive regimens and their effect on post-HTx malignancies with a focus on mTORIs, compared safety against effectiveness, and gathered conclusions based on our review of the literature, which may lead clinicians to make a better evidence-based decision regarding post-HTx maintenance immunosuppressive drug regimens. Overall, CNI to mTORI conversion in post-HTx maintenance immunosuppressive drug regimens was associated with a reduced rate of developing malignancy in post-HTx patients. Furthermore, nephrotoxicity decreased significantly while using mTORIs in combination with lower doses of CNIs and the rejection rate was equivalent to CNI-only regimens. In conclusion, mTORI-based maintenance immunosuppressive drug regimens seem to be safe and beneficial when considering efficacy vs. adverse effects, and all-cause mortality rates are significantly lower in patients switched to mTORIs when compared to CNI recipients.
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Warden BA, Duell PB. Management of dyslipidemia in adult solid organ transplant recipients. J Clin Lipidol 2019; 13:231-245. [PMID: 30928441 DOI: 10.1016/j.jacl.2019.01.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 02/07/2023]
Abstract
Solid organ transplantation (SOT) has revolutionized treatment of end-stage disease. Improvements in the SOT continuum of care have unmasked a significant burden of cardiovascular disease, manifesting as a leading cause of morbidity and mortality. Although several risk factors for development of post-transplant cardiovascular disease exist, dyslipidemia remains one of the most frequent and modifiable risks. An important contributor to dyslipidemia in SOT recipients is the off-target metabolic effects of immunosuppressive medications, which may alter lipoproteins and their metabolism. Dyslipidemia management is paramount as lipid-lowering therapy with statins has demonstrated reductions in graft vasculopathy, decreased rejection rates, and improved survival. Several nonstatin medication options are available, but data supporting their benefit in the SOT population are minimal, typically extrapolated from studies in the general population. Further compounding dyslipidemia management is the complex interplay of drug interactions between lipid-lowering and immunosuppressant medications, which can result in serious toxicity and/or therapeutic failure.
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Affiliation(s)
- Bruce A Warden
- Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA
| | - P Barton Duell
- Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
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34
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Witkowsky O, Teuteberg J, Althouse AD, Shullo M. Thrombotic events with proliferation signal inhibitor‒based immunosuppression in cardiac transplantation. J Heart Lung Transplant 2019; 38:619-626. [PMID: 30685236 DOI: 10.1016/j.healun.2019.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/02/2018] [Accepted: 01/03/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Some literature exists potentially linking proliferation signal inhibitors (PSIs) to venous thromboembolism (VTE). We sought to determine the impact of PSIs on development of VTE in heart transplant (HT) patients while controlling for other risk factors. METHODS The incidence and predisposing factors of VTE were analyzed in this retrospective review of patients >18 years who underwent HT January 2000 to October 2016. Re-transplants, multiorgan transplants, or patients that expired within 30 days post-HT were excluded. VTE incidence rates are reported as number of events per 100 person-years. Cox proportional hazards models were used to assess the relationship between PSI exposure (time-varying covariate) and VTE. RESULTS Of 561 HT recipients, 112 received PSIs, started a median of 1.5 years post-HT. There were 102 total VTE events: 78 in PSI-naive patients during 2,547 patient-years (3.0 events per 100 person-years) vs 24 in PSI-exposed patients during 544 patient-years (4.4 events per 100 person-years). Cox proportional hazards models with PSI exposure as a time-varying covariate indicated the increased risk was statistically significant (unadjusted hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.31 to 3.49, p = 0.002). A VTE history was significantly associated with increased risk of VTE post-HT (HR 1.58, 95% CI 1.07 to 2.35, p = 0.022); however, the risk remained significant when adjusting for potential confounders, including previous VTE (HR 2.0, 95% CI 1.18 to 3.38, p = 0.010). CONCLUSIONS Exposure to PSIs is associated with a significant increase in risk for VTE even when controlling for other risk factors. When considering the use of PSI-based immunosuppression after HT, the risk of VTE over time should be weighed against the potential benefit.
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Affiliation(s)
- Olya Witkowsky
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
| | | | - Andrew D Althouse
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Bertic M, Chue CD, Virani S, Davis MK, Ignaszewski A, Sedlak T. Coronary Vasospasm Following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy. Can J Cardiol 2018; 34:1687.e9-1687.e11. [PMID: 30527163 DOI: 10.1016/j.cjca.2018.08.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/14/2018] [Accepted: 08/14/2018] [Indexed: 11/16/2022] Open
Abstract
Coronary artery vasospasm (CVS) has been described in orthotopic heart transplant patients but is rare in the post-transplanted, denervated heart. Severe CVS has been associated with accelerated cardiac allograft vasculopathy (CAV) and allograft rejection. Allograft vasculopathy is the leading cause of decreased long-term survival in orthotopic heart transplant. The prognostic significance and relationship of the presence and severity of CVS with CAV are not well understood. We present a case of severe symptomatic CVS with rapid development of severe CAV. Our case emphasizes the need for close angiographic surveillance and intracoronary imaging for early detection of CAV in the presence of vasospasm.
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Affiliation(s)
- Mia Bertic
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Colin Dominic Chue
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sean Virani
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Margot K Davis
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrew Ignaszewski
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tara Sedlak
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada.
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Evans AS, Weiner M, Jain A, Patel PA, Jayaraman AL, Townsley MM, Shah R, Gutsche JT, Renew JR, Ha B, Martin AK, Linganna R, Leong R, Bhatt HV, Garcia H, Feduska E, Shaefi S, Feinman JW, Eden C, Weiss SJ, Silvay G, Augoustides JG, Ramakrishna H. The Year in Cardiothoracic and Vascular Anesthesia: Selected Highlights from 2018. J Cardiothorac Vasc Anesth 2018; 33:2-11. [PMID: 30472017 DOI: 10.1053/j.jvca.2018.10.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Indexed: 01/28/2023]
Affiliation(s)
- Adam S Evans
- Anesthesia Associates of Morristown, Morristown, NJ
| | - Menachem Weiner
- Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine, Mount Sinai Hospital, New York, NY
| | - Ankit Jain
- Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA
| | - Prakash A Patel
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Arun L Jayaraman
- Anesthesiology and Perioperative Medicine, Mayo Clinic, Scottsdale, AZ
| | - Mathew M Townsley
- Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama, Birmingham, AL
| | - Ronak Shah
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jacob T Gutsche
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - J Ross Renew
- Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL
| | - Bao Ha
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Archer K Martin
- Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL
| | - Regina Linganna
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Ron Leong
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Himani V Bhatt
- Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine, Mount Sinai Hospital, New York, NY
| | - Harry Garcia
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Eric Feduska
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Shahzad Shaefi
- Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Boston, MA
| | - Jared W Feinman
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Caroline Eden
- Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine, Mount Sinai Hospital, New York, NY
| | - Stuart J Weiss
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - George Silvay
- Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine, Mount Sinai Hospital, New York, NY
| | - John G Augoustides
- Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
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Asleh R, Briasoulis A, Pereira NL, Boilson BA, Edwards BS, Adigun R, Maltais S, Daly RC, Lerman A, Kushwaha SS. Timing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients. ESC Heart Fail 2018; 5:1118-1129. [PMID: 30019530 PMCID: PMC6300821 DOI: 10.1002/ehf2.12329] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 05/30/2018] [Accepted: 06/04/2018] [Indexed: 01/09/2023] Open
Abstract
Aims Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new‐generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long‐term CAV progression and clinical outcomes in a large contemporary HT cohort. Methods and results We analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow‐up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES (<2 years after HT) and the LS (>2 years after HT) groups. During a median follow‐up of 8.2 years, ES resulted in significantly lower change (Δ) of plaque index (+3.8% ± 1.7% vs. +8.2% ± 3.6%; P = 0.0008) and PV (+0.8 ± 0.3 vs. +1.9 ± 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV‐associated events (hazard ratio 0.48, 95% confidence interval: 0.27–0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all‐cause mortality and CAV‐associated events (hazard ratio 0.58, 95% confidence interval: 0.38–0.91; P = 0.019). Conclusions Early initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV‐related events and mortality.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | | | - Naveen L Pereira
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Barry A Boilson
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Brooks S Edwards
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Rosalyn Adigun
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Simon Maltais
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Richard C Daly
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Sudhir S Kushwaha
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
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Jennings DL, Lange N, Shullo M, Latif F, Restaino S, Topkara VK, Takeda K, Takayama H, Naka Y, Farr M, Colombo P, Baker WL. Outcomes associated with mammalian target of rapamycin (mTOR) inhibitors in heart transplant recipients: A meta-analysis. Int J Cardiol 2018; 265:71-76. [PMID: 29605470 DOI: 10.1016/j.ijcard.2018.03.111] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 03/19/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Data evaluating mTOR inhibitor use heart transplant (HT) patients comes from relatively small studies and controversy exists regarding their specific role. We performed a meta-analysis of randomized trials to evaluate the efficacy and safety of mTOR inhibitors in HT patients. METHODS We performed a systematic literature search of Medline and Embase through July 2017 identifying studies evaluating mTOR inhibitors in HT patients reporting effects on coronary allograft vasculopathy (CAV), renal function, acute cellular rejection (ACR), cytomegalovirus (CMV) infection, and discontinuation due to adverse drug events (ADE). Data were pooled using a random-effects model producing a mean difference (MD; for continuous data) or odds ratio (OR; for dichotomous data) and 95% confidence interval (CI). RESULTS 14 trials reported at least one outcome of interest. Change in mean maximal intimal thickness was significantly reduced with mTOR (-0.04 [-0.07 to -0.02]) compared to calcineurin inhibitor/mycophenolate mofetil (CNI/MMF). Rates of CMV infection were also significantly reduced (0.26; [0.2 to 0.32]) with mTOR regimens compared to CNI/MMF therapy. ACR was more frequent with CNI-sparing regimens 6.46 [1.55 to 26.95]). eGFR was significantly improved with CNI-sparing therapies (mean difference 12.09 mL/min [2.43 to 21.74]), but was similar between CNI/mTOR versus CNI/MMF regimens (p > 0.05). Rates of discontinuation due to ADE were higher in mTOR-containing regimens (OR 2.15 [1.28 to 3.60], p = 0.01), while mortality rates were similar (OR 0.91 [0.61 to 1.37], p = 0.62). CONCLUSIONS mTOR-containing regimens can attenuate CAV and CMV risk in HT recipients. A mTOR/MMF combination preserves renal function but increases the risk of ACR.
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Affiliation(s)
- Douglas L Jennings
- Department of Pharmacy, Columbia University Medical Center, New York, NY, United States.
| | - Nicholas Lange
- Department of Pharmacy, Columbia University Medical Center, New York, NY, United States
| | - Michael Shullo
- WVU Medicine, West Virginia Health System, Morgantown, WV, United States
| | - Farhana Latif
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Susan Restaino
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Veli K Topkara
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Koji Takeda
- Division of Cardiovascular Surgery, Department of Surgery, Columbia University Medical Center, New York, NY, United States
| | - Hiroo Takayama
- Division of Cardiovascular Surgery, Department of Surgery, Columbia University Medical Center, New York, NY, United States
| | - Yoshifumi Naka
- Division of Cardiovascular Surgery, Department of Surgery, Columbia University Medical Center, New York, NY, United States
| | - Maryjane Farr
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Paolo Colombo
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - William L Baker
- Department of Pharmacy Practice, University of Connecticut, Storrs, CT, United States
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Roos JCP, Daniels MJ, Morris E, Hyry HI, Cox TM. Heterogeneity in a large pedigree with Danon disease: Implications for pathogenesis and management. Mol Genet Metab 2018; 123:177-183. [PMID: 28822614 PMCID: PMC6588538 DOI: 10.1016/j.ymgme.2017.06.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 06/13/2017] [Accepted: 06/14/2017] [Indexed: 11/17/2022]
Abstract
BACKGROUND Danon disease is an X-linked disturbance of autophagy manifesting with cognitive impairment and disordered heart and skeletal muscle. After a period of relative stability, patients deteriorate rapidly and may quickly become ineligible for elective heart transplantation - the only life-saving therapy. METHODS We report a large pedigree with diverse manifestations of Danon disease in hemizygotes and female heterozygotes. RESULTS Malignant cardiac arrhythmias requiring amiodarone treatment induced thyroid disease in two patients; intractable thyrotoxicosis, which enhances autophagy, caused the death of a 21year-old man. Our patients also had striking elevation of serum troponin I during the accelerated phase of their illness (p<0.01) and rising concentrations heralded cardiac decompensation. We argue for changes to cardiac transplantation eligibility criteria. CONCLUSION Danon disease causes hypertrophic cardiomyopathy - here we propose a common pathophysiological basis for the metabolic and structural effects of this descriptive class of heart disorders. We also contend that troponin I may have prognostic value and merits exploration for clinical decision-making including health warning bracelets. Rapamycin (Sirolimus®), an approved immunosuppressant which also influences autophagy, may prove beneficial. In the interim, while new treatments are developed, a revaluation of cardiac transplantation eligibility criteria is warranted.
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Affiliation(s)
| | | | | | - Hanna I Hyry
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Timothy M Cox
- Department of Medicine, University of Cambridge, Cambridge, UK.
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Floré V, Brown AJ, Pettit SJ, West NEJ, Lewis C, Parameshwar J, Hoole SP. Intravascular ultrasound of the proximal left anterior descending artery is sufficient to detect early cardiac allograft vasculopathy. Clin Transplant 2017; 32. [DOI: 10.1111/ctr.13167] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2017] [Indexed: 11/27/2022]
Affiliation(s)
- Vincent Floré
- Department of Interventional Cardiology; Papworth Hospital; Cambridge UK
- Hartcentrum AZ Maria Middelares; Gent Belgium
| | - Adam J. Brown
- Department of Interventional Cardiology; Papworth Hospital; Cambridge UK
| | | | - Nick E. J. West
- Department of Interventional Cardiology; Papworth Hospital; Cambridge UK
| | - Clive Lewis
- Department of Transplantation; Papworth Hospital; Cambridge UK
| | | | - Stephen P. Hoole
- Department of Interventional Cardiology; Papworth Hospital; Cambridge UK
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Changes in Outcomes of Cardiac Allograft Vasculopathy Over 30 Years Following Heart Transplantation. JACC-HEART FAILURE 2017; 5:891-901. [DOI: 10.1016/j.jchf.2017.09.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/04/2017] [Accepted: 09/13/2017] [Indexed: 11/18/2022]
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Cheng R, Kransdorf EP, Wei J, Patel JK, Kobashigawa JA, Azarbal B. Angiogenesis on coronary angiography is a marker for accelerated cardiac allograft vasculopathy as assessed by intravascular ultrasound. Clin Transplant 2017; 31. [PMID: 28786501 DOI: 10.1111/ctr.13069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Errant neovascularization and coronary artery fistulae (CAF) are frequently observed after cardiac transplantation. The relationship between angiographic neovascularization/CAF and coronary plaque progression is unknown. METHODS Angiography and intravascular ultrasound were routinely performed at 4-6 weeks and 1-year post-transplant. Pts were divided into three groups: no angiographic angiogenesis (Group 1), neovascularization only (Group 2), and CAF (Group 3). First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), and percent atheroma volume (PAV) were compared between groups. RESULTS The 106 pts were included, 40/106 in Group 1, 42/106 in Group 2, and 24/106 in Group 3. Respectively, first-year ΔMIT was 0.14 ± 0.13 mm, 0.32 ± 0.26 mm, and 0.50 ± 0.34 mm, P < .001. ΔMIA was 0.6 ± 0.6 mm2 , 1.7 ± 1.8 mm2 , and 3.0 ± 2.6 mm2 , P < .001. ΔPAV was 2.3 ± 2.5%, 6.0 ± 5.1%, and 9.6 ± 9.0%, P < .001. Rapid plaque progression occurred in 1/40 (2.5%) pts in Group 1, 12/42 (28.6%) in Group 2, and 12/24 (50%) in Group 3, P < .001. Multivariate analysis identified both antithymocyte globulin and presence of CAF as independently associated with rapid plaque progression: OR 0.29 (P = .038) and 4.04 (P = .014). CONCLUSION Neovascularization and CAF are commonly present on surveillance angiography after cardiac transplantation and may signify amplified angiogenesis. Their presence is associated with accelerated coronary plaque progression by IVUS.
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Affiliation(s)
| | | | - Janet Wei
- Cedars-Sinai Heart Institute, Los Angeles, CA, USA
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Kransdorf EP, Loghmanpour NA, Kanwar MK, Temkit MH, Stehlik J. Prediction model for cardiac allograft vasculopathy: Comparison of three multivariable methods. Clin Transplant 2017; 31. [DOI: 10.1111/ctr.12925] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2017] [Indexed: 11/28/2022]
Affiliation(s)
- Evan P. Kransdorf
- Cedars-Sinai Heart Institute; Cedars-Sinai Medical Center; Los Angeles CA USA
| | | | - Manreet K. Kanwar
- Cardiovascular Institute; Allegheny General Hospital; Pittsburgh PA USA
| | - M'hamed H. Temkit
- Division of Health Sciences Research; Mayo Clinic Arizona; Scottsdale AZ USA
| | - Josef Stehlik
- Division of Cardiovascular Medicine; University of Utah School of Medicine; Salt Lake City UT USA
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Simha V, Qin S, Shah P, Smith BH, Kremers WK, Kushwaha S, Wang L, Pereira NL. Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients. J Cardiovasc Transl Res 2016; 10:9-15. [PMID: 28028691 DOI: 10.1007/s12265-016-9719-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 11/08/2016] [Indexed: 11/24/2022]
Abstract
Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2-3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia.
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Affiliation(s)
- Vinaya Simha
- Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Sisi Qin
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA
| | - Pankaj Shah
- Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Byron H Smith
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Walter K Kremers
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Sudhir Kushwaha
- Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Naveen L Pereira
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA. .,Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Recent Advances in Mammalian Target of Rapamycin Inhibitor Use in Heart and Lung Transplantation. Transplantation 2016; 100:2558-2568. [DOI: 10.1097/tp.0000000000001432] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Sex Related Differences in the Risk of Antibody-Mediated Rejection and Subsequent Allograft Vasculopathy Post-Heart Transplantation: A Single-Center Experience. Transplant Direct 2016; 2:e106. [PMID: 27795988 PMCID: PMC5068197 DOI: 10.1097/txd.0000000000000616] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 07/08/2016] [Indexed: 11/26/2022] Open
Abstract
Background Pregnancies may result in antibodies against HLA, a risk factor for antibody-mediated rejection (AMR) and subsequent cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). The aim of this study was to evaluate sex differences in the incidence of AMR events and subsequent risk of CAV among HTx recipients. Methods The study comprised 160 patients (51 [32%] women) who underwent HTx in 2008 to 2014. The cumulative effect of AMR events was calculated by AMR score (sum of myocardial biopsy grading divided by number of biopsies taken during 3 years post-HTx). Results Females had higher levels of anti-HLA I antibodies pre-HTx compared to males which was associated with a history of pregnancies, total number of children and with a higher AMR score at 6 months post-HTx (P < 0.05). Women demonstrated a significant increase in the total incidence of AMR events (27 vs. 7%, P = 0.001) and in AMR scores at 6, 12, 24 and 36 months post-HTx compared to men (P < 0.05). There were no differences in cellular rejection between the groups. A history of AMR events was associated with a significantly increased risk of severe CAV onset (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.012). Conclusions Women are at higher risk for AMR post-HTx which subsequently increases their risk for CAV. Females recipients may benefit from closer surveillance to identify AMR at an earlier stage post-HTx, and targeted immunosuppressive therapy to attenuate the development of CAV.
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Mason JC. Cytoprotective pathways in the vascular endothelium. Do they represent a viable therapeutic target? Vascul Pharmacol 2016; 86:41-52. [PMID: 27520362 DOI: 10.1016/j.vph.2016.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/08/2016] [Indexed: 12/28/2022]
Abstract
The vascular endothelium is a critical interface, which separates the organs from the blood and its contents. The endothelium has a wide variety of functions and maintenance of endothelial homeostasis is a multi-dimensional active process, disruption of which has potentially deleterious consequences if not reversed. Vascular injury predisposes to endothelial apoptosis, dysfunction and development of atherosclerosis. Endothelial dysfunction is an end-point, a central feature of which is increased ROS generation, a reduction in endothelial nitric oxide synthase and increased nitric oxide consumption. A dysfunctional endothelium is a common feature of diseases including rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus and chronic renal impairment. The endothelium is endowed with a variety of constitutive and inducible mechanisms that act to minimise injury and facilitate repair. Endothelial cytoprotection can be enhanced by exogenous factors such as vascular endothelial growth factor, prostacyclin and laminar shear stress. Target genes include endothelial nitric oxide synthase, heme oxygenase-1, A20 and anti-apoptotic members of the B cell lymphoma protein-2 family. In light of the importance of endothelial function, and the link between its disruption and the risk of atherothrombosis, interest has focused on therapeutic conditioning and reversal of endothelial dysfunction. A detailed understanding of cytoprotective signalling pathways, their regulation and target genes is now required to identify novel therapeutic targets. The ultimate aim is to add vasculoprotection to current therapeutic strategies for systemic inflammatory diseases, in an attempt to reduce vascular injury and prevent or retard atherogenesis.
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Affiliation(s)
- Justin C Mason
- Vascular Science, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.
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Elevated immune monitoring as measured by increased adenosine triphosphate production in activated lymphocytes is associated with accelerated development of cardiac allograft vasculopathy after cardiac transplantation. J Heart Lung Transplant 2016; 35:1018-23. [PMID: 27138702 DOI: 10.1016/j.healun.2016.03.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 02/26/2016] [Accepted: 03/21/2016] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Elevated immune monitoring (IM), as measured by adenosine triphosphate (ATP) release from activated lymphocytes, has been suggested to represent an under-immunosuppressed state. Its association with the development of angiographic cardiac allograft vasculopathy (CAV) is unknown. METHODS Patients transplanted between January 2007 and December 2011 with annual angiograms and at least 1 IM assay were included in the analysis. Peak IM scores were determined for each patient. Patients with peak IM in the highest quartile (Group 2) were compared with those with scores in the lower quartiles (Group 1). Mild disease was scored as Grade 1 (CAV1) and moderate or severe disease was scored as Grades 2 or 3 (CAV2/3). RESULTS Two hundred forty patients were included. The mean age at transplant was 54.2 ± 12.1 years. Time to peak IM assay was 105.9 ± 44.1 days and average number of assays obtained per patient was 3.1 ± 1.8. Patients in the highest quartile (Group 2) had peak IM ≥446 ng ATP/ml. Mean clinical follow-up was 4.6 ± 1.7 years. CAV1 was observed in 86 of 180 (47.8%) patients in Group 1 and 39 of 60 (65.0%) in Group 2. Freedom from CAV1 was significantly lower in patients in Group 2 (log rank, p = 0.012). CAV2/3 occurred in 7 of 180 (3.7%) patients in Group 1 and 9 of 60 (15.0%) patients in Group 2. Freedom from CAV2/3 was significantly lower in patients in Group 2 (p = 0.003). In multivariate analysis elevated peak IM assay was still found to be associated with angiographic CAV (hazard ratio 1.647, confidence interval 1.020 to 2.661, p = 0.041). CONCLUSION Elevated peak IM, as measured by increased ATP production, in activated lymphocytes is associated with decreased freedom from angiographic CAV.
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