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Simonenko M, Hansen D, Niebauer J, Volterrani M, Adamopoulos S, Amarelli C, Ambrosetti M, Anker SD, Bayes-Genis A, Gal TB, Bowen TS, Cacciatore F, Caminiti G, Cavarretta E, Chioncel O, Coats AJS, Cohen-Solal A, D'Ascenzi F, de Pablo Zarzosa C, Gevaert AB, Gustafsson F, Kemps H, Hill L, Jaarsma T, Jankowska E, Joyce E, Krankel N, Lainscak M, Lund LH, Moura B, Nytrøen K, Osto E, Piepoli M, Potena L, Rakisheva A, Rosano G, Savarese G, Seferovic PM, Thompson DR, Thum T, Van Craenenbroeck EM. Prevention and rehabilitation after heart transplantation: A clinical consensus statement of the European Association of Preventive Cardiology, Heart Failure Association of the ESC, and the European Cardio Thoracic Transplant Association, a section of ESOT. Eur J Prev Cardiol 2024; 31:1385-1399. [PMID: 38894688 DOI: 10.1093/eurjpc/zwae179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 01/20/2024] [Accepted: 02/21/2024] [Indexed: 06/21/2024]
Abstract
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus.
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Affiliation(s)
- Maria Simonenko
- Cardiopulmonary Exercise Test Research Department, Heart Transplantation Outpatient Department, V.A. Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Dominique Hansen
- REVAL and BIOMED Rehabilitation Research Center, Hasselt University, Hasselt, Belgium
- Heart Centre Hasselt, Jessa Hospital, Hasselt, Belgium
| | - Josef Niebauer
- University Institute of Sports Medicine, Prevention and Rehabilitation, Paracelsus Medical University, Salzburg, Austria
| | | | - Stamatis Adamopoulos
- Heart Failure and Heart Transplantation Unit, Onassis Cardiac Surgery Center, Athens, Greece
| | - Cristiano Amarelli
- Department of Cardiac Surgery and Transplants, Monaldi Hospital, Azienda dei Colli, Naples, Italy
| | - Marco Ambrosetti
- Cardiovascular Rehabilitation Unit, ASST Crema, Santa Marta Hospital, Rivolta d'Adda (CR), Italy
| | - Stefan D Anker
- Department of Cardiology (CVK), Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Tuvia Ben Gal
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Petah Tikva and Sackler, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - T Scott Bowen
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK
| | - Francesco Cacciatore
- Department of Translational Medicine, University of Naples 'Federico II', Naples, Italy
| | | | - Elena Cavarretta
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', Bucharest, Romania
- University of Medicine Carol Davila, Bucharest, Romania
| | | | - Alain Cohen-Solal
- Cardiology Department, University of Paris, INSERM UMRS-942, Hopital Lariboisiere, AP-HP, Paris, France
| | - Flavio D'Ascenzi
- Division of Cardiology, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | | | - Andreas B Gevaert
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Edegem, Belgium
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Hareld Kemps
- Department of Cardiology, Maxima Medical Centre, Eindhoven, The Netherlands
- Department of Industrial Design, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Loreena Hill
- School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK
| | - Tiny Jaarsma
- Department of Health, Medicine and Caring Science, Linköping University, Linköping, Sweden
- Julius Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Emer Joyce
- Department of Cardiology, Mater University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Nicolle Krankel
- Universitätsmedizin Berlin Campus Benjamin Franklin Klinik für Kardiologie Charite, Berlin, Germany
| | | | - Lars H Lund
- Department of Medicine, Karolinska Institutet and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Brenda Moura
- Armed Forces Hospital, Porto, Portugal
- Centre for Health Technologies and Services Research, Faculty of Medicine of University of Porto, Porto, Portugal
| | - Kari Nytrøen
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Elena Osto
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
- Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Massimo Piepoli
- Dipartimento Scienze Biomediche per la Salute, Universita' Degli Studi di Milan, Milan, Italy
- Cardiologia Universitaria, IRCCS Policlinico San Donato, Milan, Italy
| | | | - Amina Rakisheva
- Department of Cardiology, Scientific Institution of Cardiology and Internal Diseases, Almaty, Kazakhstan
- Department of Cardiology, Kapshagai City Hospital, Almaty, Kazakhstan
| | - Giuseppe Rosano
- St. George's Hospital NHS Trust University of London, London, UK
| | - Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Petar M Seferovic
- Faculty of Medicine and Heart Failure Center, University of Belgrade, Belgrade University Medical Center, Belgrade, Serbia
| | - David R Thompson
- School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School and Fraunhofer Institute for Toxicology and Experimental Research, Hannover, Germany
| | - Emeline M Van Craenenbroeck
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Edegem, Belgium
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Simonenko M, Hansen D, Niebauer J, Volterrani M, Adamopoulos S, Amarelli C, Ambrosetti M, Anker SD, Bayes-Genis A, Ben Gal T, Bowen TS, Cacciatore F, Caminiti G, Cavarretta E, Chioncel O, Coats AJS, Cohen-Solal A, D’Ascenzi F, de Pablo Zarzosa C, Gevaert AB, Gustafsson F, Kemps H, Hill L, Jaarsma T, Jankowska E, Joyce E, Krankel N, Lainscak M, Lund LH, Moura B, Nytrøen K, Osto E, Piepoli M, Potena L, Rakisheva A, Rosano G, Savarese G, Seferovic PM, Thompson DR, Thum T, Van Craenenbroeck EM. Prevention and Rehabilitation After Heart Transplantation: A Clinical Consensus Statement of the European Association of Preventive Cardiology, Heart Failure Association of the ESC, and the European Cardio Thoracic Transplant Association, a Section of ESOT. Transpl Int 2024; 37:13191. [PMID: 39015154 PMCID: PMC11250379 DOI: 10.3389/ti.2024.13191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 05/30/2024] [Indexed: 07/18/2024]
Abstract
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
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Affiliation(s)
- Maria Simonenko
- Cardiopulmonary Exercise Test Research Department, Heart Transplantation Outpatient Department, V. A. Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Dominique Hansen
- REVAL and BIOMED Rehabilitation Research Center, Hasselt University, Hasselt, Belgium
- Heart Centre Hasselt, Jessa Hospital, Hasselt, Belgium
| | - Josef Niebauer
- University Institute of Sports Medicine, Prevention and Rehabilitation, Paracelsus Medical University, Salzburg, Austria
| | | | - Stamatis Adamopoulos
- Heart Failure and Heart Transplantation Unit, Onassis Cardiac Surgery Center, Athens, Greece
| | - Cristiano Amarelli
- Department of Cardiac Surgery and Transplants, Monaldi Hospital, Azienda dei Colli, Naples, Italy
| | - Marco Ambrosetti
- Cardiovascular Rehabilitation Unit, ASST Crema, Santa Marta Hospital, Rivolta D’Adda, Italy
| | - Stefan D. Anker
- Department of Cardiology (CVK), Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) Partner Site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Tuvia Ben Gal
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Petah Tikva and Sackler, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - T. Scott Bowen
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Francesco Cacciatore
- Department of Translational Medicine, University of Naples “Federico II”, Naples, Italy
| | | | - Elena Cavarretta
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases “Prof. C. C. Iliescu”, Bucharest, Romania
- University of Medicine Carol Davila, Bucharest, Romania
| | | | - Alain Cohen-Solal
- Cardiology Department, University of Paris, INSERM UMRS-942, Hopital Lariboisiere, AP-HP, Paris, France
| | - Flavio D’Ascenzi
- Division of Cardiology, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | | | - Andreas B. Gevaert
- Research Group Cardiovascular Diseases, Genetics, Pharmacology and Physiopathology of Heart, Blood Vessels and Skeleton (GENCOR) Department, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Edegem, Belgium
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Hareld Kemps
- Department of Cardiology, Maxima Medical Centre, Eindhoven, Netherlands
- Department of Industrial Design, Eindhoven University of Technology, Eindhoven, Netherlands
| | - Loreena Hill
- School of Nursing and Midwifery, Queen’s University Belfast, Belfast, United Kingdom
| | - Tiny Jaarsma
- Department of Health, Medicine and Caring Science, Linköping University, Linköping, Sweden
- Julius Center, University Medical Center Utrecht, Utrecht, Netherlands
| | - Ewa Jankowska
- Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Emer Joyce
- Department of Cardiology, Mater University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Nicolle Krankel
- Universitätsmedizin Berlin Campus Benjamin Franklin Klinik für Kardiologie Charite, Berlin, Germany
| | | | - Lars H. Lund
- Department of Medicine, Karolinska Institutet and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Brenda Moura
- Armed Forces Hospital, Porto, Portugal
- Centre for Health Technologies and Services Research, Faculty of Medicine of University of Porto, Porto, Portugal
| | - Kari Nytrøen
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Elena Osto
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
- Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Massimo Piepoli
- Dipartimento Scienze Biomediche per la Salute, Universita’ Degli Studi di Milan, Milan, Italy
- Cardiologia Universitaria, IRCCS Policlinico San Donato, Milan, Italy
| | | | - Amina Rakisheva
- Department of Cardiology, Scientific Institution of Cardiology and Internal Diseases, Almaty, Kazakhstan
- Department of Cardiology, Kapshagai City Hospital, Almaty, Kazakhstan
| | - Giuseppe Rosano
- St. George’s Hospital NHS Trust University of London, London, United Kingdom
| | - Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Petar M. Seferovic
- Faculty of Medicine and Heart Failure Center, University of Belgrade, Belgrade University Medical Center, Belgrade, Serbia
| | - David R. Thompson
- School of Nursing and Midwifery, Queen’s University Belfast, Belfast, United Kingdom
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School and Fraunhofer Institute for Toxicology and Experimental Research, Hannover, Germany
| | - Emeline M. Van Craenenbroeck
- Research Group Cardiovascular Diseases, Genetics, Pharmacology and Physiopathology of Heart, Blood Vessels and Skeleton (GENCOR) Department, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Edegem, Belgium
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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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Park HW, Ozcan I, Toya T, Ahmad A, Kanaji Y, Kushwaha SS, Lerman LO, Lerman A. Invasive aortic pulse pressure is linked to cardiac allograft vasculopathy after heart transplantation. Int J Cardiol 2023; 370:167-174. [PMID: 36346255 DOI: 10.1016/j.ijcard.2022.10.159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 10/20/2022] [Accepted: 10/25/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Pulse pressure (PP) has been linked to an increased risk of extent of coronary atherosclerosis and cardiovascular events. This study aimed to investigate the contribution of aortic PP on cardiac allograft vasculopathy (CAV) progression, and cardiovascular events after heart transplantation (HTx). METHODS A total of 330 HTx patients (mean age 49 ± 25 years, 70.0% male) undergoing routine serial coronary intravascular ultrasound (IVUS) studies and had invasive aortic PP were enrolled. The median time from HTx to first IVUS was 13.6 months. CAV progression was assessed by IVUS as the changes (Δ) in plaque volume divided by the segment length (PV/SL), adjusted for the time between IVUS (median, 3.99 years; interquartile range, 1.99-7.20 years), and was defined as ΔPV/SL ≥0.50 mm3/mm/year. Major adverse cardiovascular event (MACE) was defined as any incidence of mortality, myocardial infarction, coronary revascularization, heart failure hospitalization, or re-transplantation. RESULTS Recipient age, recipient sex, and renal dysfunction were independent determinant of high aortic PP (≥ 50 mmHg). High aortic PP was an independent determinant of CAV progression [odds ratio, 1.72; 95% confidence interval (CI), 1.01-2.93; p = 0.045]. Both high aortic PP (HR 1.46, 95% CI 1.01-2.11, p = 0.044) and high baseline CAV grade on angiogram (≥1, HR 1.50, 95% CI 1.03-2.21, p = 0.037) were independently associated with MACEs over 12 years. CONCLUSION In post-HTx patients, high aortic PP was significantly associated with plaque progression. Both aortic PP and CAV grade are independently associated with MACE during long-term follow-up. These findings suggest that arterial stiffness and CAV can be important predictors of MACEs.
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Affiliation(s)
- Hyun Woong Park
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; Department of Cardiology in Internal Medicine, Chungnam National University Sejong Hospital, Chungnam National University College of Medicine, Sejong, South Korea
| | - Ilke Ozcan
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Takumi Toya
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine, Saint Luis University School of Medicine, Saint Louis, MO, USA
| | - Ali Ahmad
- Division of Cardiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yoshihisa Kanaji
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; Division of Cardiovascular Medicine, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Sudhir S Kushwaha
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
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Nelson LM, Christensen TE, Rossing K, Hasbak P, Gustafsson F. Prognostic value of myocardial flow reserve obtained by 82-rubidium positron emission tomography in long-term follow-up after heart transplantation. J Nucl Cardiol 2022; 29:2555-2567. [PMID: 34414554 DOI: 10.1007/s12350-021-02742-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/25/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is a leading cause of death following heart transplantation (HTx) and non-invasive prognostic methods in long-term CAV surveillance are needed. We evaluated the prognostic value of myocardial flow reserve (MFR) obtained by 82-rubidium (82Rb) positron emission tomography (PET). METHODS Recipients undergoing dynamic rest-stress 82Rb PET between April 2013 and June 2017 were retrospectively evaluated in a single-center study. Evaluation by PET included quantitative myocardial blood flow and semiquantitative myocardial perfusion imaging. Patients were grouped by MFR (MFR ≤ 2.0 vs MFR > 2.0) and the primary outcome was all-cause mortality. RESULTS A total of 50 patients (68% men, median age 57 [IQR: 43 to 68]) were included. Median time from HTx to PET was 10.0 (6.7 to 16.0) years. In 58% of patients CAV was documented prior to PET. During a median follow-up of 3.6 (2.3 to 4.3) years 12 events occurred. Survival probability by Kaplan-Meier method was significantly higher in the high-MFR group (log-rank P = .02). Revascularization (n = 1), new CAV diagnosis (n = 1), and graft failure (n = 4) were more frequent in low-MFR patients. No retransplantation occurred. CONCLUSIONS Myocardial flow reserve appears to offer prognostic value in selected long-term HTx recipients and holds promise as a non-invasive method for CAV surveillance possibly guiding management strategy.
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Affiliation(s)
- Lærke Marie Nelson
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
| | - Thomas Emil Christensen
- Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Medicine, Holbæk Hospital, Holbæk, Region Zealand, Denmark
| | - Kasper Rossing
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Philip Hasbak
- Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Ozcan I, Toya T, Cohen-Shelly M, Park HW, Ahmad A, Ozcan A, Noseworthy PA, Kapa S, Lerman LO, Attia ZI, Kushwaha SS, Friedman PA, Lerman A. Artificial intelligence-derived cardiac ageing is associated with cardiac events post-heart transplantation. EUROPEAN HEART JOURNAL. DIGITAL HEALTH 2022; 3:516-524. [PMID: 36710906 PMCID: PMC9779895 DOI: 10.1093/ehjdh/ztac051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 09/08/2022] [Indexed: 02/01/2023]
Abstract
Aims An artificial intelligence algorithm detecting age from 12-lead electrocardiogram (ECG) has been suggested to reflect 'physiological age'. An increased physiological age has been associated with a higher risk of cardiac mortality in the non-transplant population. We aimed to investigate the utility of this algorithm in patients who underwent heart transplantation (HTx). Methods and results A total of 540 patients were studied. The average ECG ages within 1 year before and after HTx were used to represent pre- and post-HTx ECG ages. Major adverse cardiovascular event (MACE) was defined as any coronary revascularization, heart failure hospitalization, re-transplantation, and mortality. Recipient pre-transplant ECG age (mean 63 ± 11 years) correlated significantly with recipient chronological age (mean 49 ± 14 years, R = 0.63, P < 0.0001), while post-transplant ECG age (mean 54 ± 10 years) correlated with both the donor (mean 32 ± 13 years, R = 0.45, P < 0.0001) and the recipient ages (R = 0.38, P < 0.0001). During a median follow-up of 8.8 years, 307 patients experienced MACE. Patients with an increase in ECG age post-transplant showed an increased risk of MACE [hazard ratio (HR): 1.58, 95% confidence interval (CI): (1.24, 2.01), P = 0.0002], even after adjusting for potential confounders [HR: 1.58, 95% CI: (1.19, 2.10), P = 0.002]. Conclusion Electrocardiogram age-derived cardiac ageing after transplantation is associated with a higher risk of MACE. This study suggests that physiological age change of the heart might be an important determinant of MACE risk post-HTx.
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Affiliation(s)
- Ilke Ozcan
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Takumi Toya
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA,Division of Cardiology, National Defense Medical College, Tokorozawa, Namiki, 3 Chome−2 Saitama, Japan
| | - Michal Cohen-Shelly
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Hyun Woong Park
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA,Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsangnam-do, 52727, South Korea
| | - Ali Ahmad
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA,Department of Internal Medicine, Saint Louis University School of Medicine, 1402 S Grand Blvd, St. Louis, MO 63104, USA
| | - Alp Ozcan
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Peter A Noseworthy
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Suraj Kapa
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Lilach O Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA,Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Zachi I Attia
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Sudhir S Kushwaha
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Paul A Friedman
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Amir Lerman
- Corresponding author. Tel: +1 507 255 4152, Fax: +1 507 255 7798,
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Paediatric heart transplantation recipients ≥7 years of age receiving donors with pre-existing coronary atherosclerosis showed progressive coronary artery disease. Cardiol Young 2022; 32:1104-1111. [PMID: 34565492 DOI: 10.1017/s1047951121003784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND This study aimed to determine the effect of donor-transmitted atherosclerosis on the late aggravation of cardiac allograft vasculopathy in paediatric heart recipients aged ≥7 years. METHODS In total, 48 patients were included and 23 had donor-transmitted atherosclerosis (baseline maximal intimal thickness of >0.5 mm on intravascular ultrasonography). Logistic regression analyses were performed to identify risk factors for donor-transmitted atherosclerosis. Rates of survival free from the late aggravation of cardiac allograft vasculopathy (new or worsening cardiac allograft vasculopathy on following angiograms, starting 1 year after transplantation) in each patient group were estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of the results of intravascular ultrasonography at 1 year after transplantation on the late aggravation of cardiac allograft vasculopathy, correcting for possible covariates including donor-transmitted atherosclerosis, was examined using the Cox proportional hazards model. RESULTS The mean follow-up duration after transplantation was 5.97 ± 3.58 years. The log-rank test showed that patients with donor-transmitted atherosclerosis had worse survival outcomes than those without (p = 0.008). Per the multivariate model considering the difference of maximal intimal thickness between baseline and 1 year following transplantation (hazard ratio, 22.985; 95% confidence interval, 1.948-271.250; p = 0.013), donor-transmitted atherosclerosis was a significant covariate (hazard ratio, 4.013; 95% confidence interval, 1.047-15.376; p = 0.043). CONCLUSION Paediatric heart transplantation recipients with donor-transmitted atherosclerosis aged ≥7 years had worse late cardiac allograft vasculopathy aggravation-free survival outcomes.
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8
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Schaefer AK, Kiss A, Oszwald A, Nagel F, Acar E, Aliabadi-Zuckermann A, Hackl M, Zuckermann A, Kain R, Jakubowski A, Ferdinandy P, Hallström S, Podesser BK. Single Donor Infusion of S-Nitroso-Human-Serum-Albumin Attenuates Cardiac Isograft Fibrosis and Preserves Myocardial Micro-RNA-126-3p in a Murine Heterotopic Heart Transplant Model. Transpl Int 2022; 35:10057. [PMID: 35497886 PMCID: PMC9045410 DOI: 10.3389/ti.2022.10057] [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: 09/24/2021] [Accepted: 03/17/2022] [Indexed: 11/17/2022]
Abstract
Objectives: Cold ischemia and subsequent reperfusion injury are non-immunologic cornerstones in the development of graft injury after heart transplantation. The nitric oxide donor S-nitroso-human-serum-albumin (S-NO-HSA) is known to attenuate myocardial ischemia-reperfusion (I/R)-injury. We assessed whether donor preservation with S-NO-HSA affects isograft injury and myocardial expression of GATA2 as well as miR-126-3p, which are considered protective against vascular and endothelial injury. Methods: Donor C57BL/6 mice received intravenous (0.1 μmol/kg/h) S-NO-HSA (n = 12), or 0.9% saline (control, n = 11) for 20 min. Donor hearts were stored in cold histidine-tryptophan-α-ketoglutarate-N solution for 12 h and underwent heterotopic, isogenic transplantation, except 5 hearts of each group, which were analysed immediately after preservation. Fibrosis was quantified and expression of GATA2 and miR-126-3p assessed by RT-qPCR after 60 days or immediately after preservation. Results: Fibrosis was significantly reduced in the S-NO-HSA group (6.47% ± 1.76 vs. 11.52% ± 2.16; p = 0.0023; 12 h-S-NO-HSA-hHTX vs. 12 h-control-hHTX). Expression of miR-126-3p was downregulated in all hearts after ischemia compared to native myocardium, but the effect was significantly attenuated when donors received S-NO-HSA (1 ± 0.27 vs. 0.33 ± 0.31; p = 0.0187; 12 h-S-NO-HSA-hHTX vs. 12 h-control-hHTX; normalized expression to U6 snRNA). Conclusion: Donor pre-treatment with S-NO-HSA lead to reduced fibrosis and preservation of myocardial miR-126-3p and GATA2 levels in murine cardiac isografts 60 days after transplantation.
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Affiliation(s)
- Anne-Kristin Schaefer
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria.,Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - André Oszwald
- Department of Pathology, Medical University of Vienna, Vienna, Austria.,Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Felix Nagel
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Eylem Acar
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | | | | | - Andreas Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, Vienna, Austria.,Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Andrzej Jakubowski
- Department of Pharmacology, Jagiellonian University Medical College, Kraków, Poland.,Department of Anesthesiology and Intensive Care, Małopolska Orthopedic and Rehabilitation Hospital, Kraków, Poland
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Seth Hallström
- Division of Physiological Chemistry, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
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9
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Wiefels C, Almufleh A, Yao J, deKemp RA, Chong AY, Mielniczuk LM, Stadnick E, Davies RA, Beanlands RS, Chih S. Prognostic utility of longitudinal quantification of PET myocardial blood flow early post heart transplantation. J Nucl Cardiol 2022; 29:712-723. [PMID: 32918246 DOI: 10.1007/s12350-020-02342-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 07/19/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Myocardial blood flow (MBF) quantification by Rubidium-82 positron emission tomography (PET) has shown promise for cardiac allograft vasculopathy (CAV) surveillance and risk stratification post heart transplantation. The objective was to determine the prognostic value of serial PET performed early post transplantation. METHODS AND RESULT Heart transplant (HT) recipients at the University of Ottawa Heart Institute with 2 PET examinations (PET1 = baseline, PET2 = follow-up) within 6 years of transplant were included in the study. Evaluation of PET flow quantification included stress MBF, coronary vascular resistance (CVR), and myocardial flow reserve (MFR). The primary composite outcome was all-cause death, re-transplant, myocardial infarction, revascularization, allograft dysfunction, cardiac allograft vasculopathy (CAV), or heart failure hospitalization. A total of 121 patients were evaluated (79% male, mean age 56 ± 11 years) with consecutive scans performed at mean 1.4 ± 0.7 and 2.6 ± 1.0 years post HT for PET1 and PET2, respectively. Over a mean follow-up of 3.0 (IQR 1.8, 4.6) years, 26 (22%) patients developed the primary outcome: 1 death, 11 new or progressive angiographic CAV, 2 percutaneous coronary interventions, 12 allograft dysfunction. Unadjusted Cox analysis showed a significant reduction in event-free survival in patients with PET1 stress MBF < 2.1 (HR: 2.43, 95% CI 1.11-5.29 P = 0.047) and persistent abnormal PET1 to PET2 CVR > 76 (HR: 2.19, 95% CI 0.87-5.51 P = 0.045). There was no association between MFR and outcomes. CONCLUSION Low-stress MBF and persistent increased CVR on serial PET imaging early post HT are associated with adverse cardiovascular outcomes. Early post-transplant and longitudinal assessment by PET may identify at-risk patients for increased surveillance post HT.
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Affiliation(s)
- Christiane Wiefels
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
- Pós-graduação em Ciências Cardiovasculares, Universidade Federal Fluminense, Niterói, Brazil
| | - Aws Almufleh
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
- Cardiac Sciences Department, King Saud University, Riyadh, Saudi Arabia
| | - Jason Yao
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Robert A deKemp
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Aun-Yeong Chong
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Lisa Marie Mielniczuk
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Ellamae Stadnick
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Ross A Davies
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Rob S Beanlands
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
| | - Sharon Chih
- Cardiology, University of Ottawa Heart Institute, 40, Ruskin Street, Ottawa, ON, K1Y 4W7, Canada.
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10
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Mohiuddin MM, Goerlich CE, Singh AK, Zhang T, Tatarov I, Lewis B, Sentz F, Hershfeld A, Braileanu G, Odonkor P, Strauss E, Williams B, Burke A, Hittman J, Bhutta A, Tabatabai A, Gupta A, Vaught T, Sorrells L, Kuravi K, Dandro A, Eyestone W, Kaczorowski DJ, Ayares D, Griffith BP. Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months. Xenotransplantation 2022; 29:e12744. [PMID: 35357044 DOI: 10.1111/xen.12744] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 01/04/2023]
Abstract
We report orthotopic (life-supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti-CD40 monoclonal antibody-based immunosuppression. In this current study, life-supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti-inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective "multi-gene" xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective "multi-gene" modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans.
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Affiliation(s)
- Muhammad M Mohiuddin
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Corbin E Goerlich
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA.,Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Avneesh K Singh
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Tianshu Zhang
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Ivan Tatarov
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Billeta Lewis
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Faith Sentz
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Alena Hershfeld
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Gheorghe Braileanu
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Patrick Odonkor
- Department of Anesthesiology, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Erik Strauss
- Department of Anesthesiology, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Brittney Williams
- Department of Anesthesiology, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Allen Burke
- Department of Pathology, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Jamie Hittman
- Department of Pathology, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Adnan Bhutta
- Department of Pediatrics, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Ali Tabatabai
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Anuj Gupta
- Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | | | | | - Amy Dandro
- Revivicor, Inc., Blacksburg, Virginia, USA
| | | | - David J Kaczorowski
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | - Bartley P Griffith
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
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11
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Alfonso F, Rivero F, Segovia-Cubero J. Early diagnosis of cardiac allograft vasculopathy: biopsy, liquid biopsy, non-invasive imaging, coronary imaging, or coronary physiology? Eur Heart J 2021; 42:4930-4933. [PMID: 34665226 DOI: 10.1093/eurheartj/ehab722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Affiliation(s)
- Fernando Alfonso
- Department of Cardiology, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, IIS-IP, CIBERCV, Madrid, Spain
| | - Fernando Rivero
- Department of Cardiology, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, IIS-IP, CIBERCV, Madrid, Spain
| | - Javier Segovia-Cubero
- Department of Cardiology, Hospital Universitario Puerta de Hierro, Majadahonda, Universidad Autónoma de Madrid, CIVERCV, Madrid, Spain
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12
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Pober JS, Chih S, Kobashigawa J, Madsen JC, Tellides G. Cardiac allograft vasculopathy: current review and future research directions. Cardiovasc Res 2021; 117:2624-2638. [PMID: 34343276 PMCID: PMC8783389 DOI: 10.1093/cvr/cvab259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/02/2021] [Accepted: 07/29/2021] [Indexed: 12/25/2022] Open
Abstract
Cardiac allograft vasculopathy (CAV) is a pathologic immune-mediated remodelling of the vasculature in transplanted hearts and, by impairing perfusion, is the major cause of late graft loss. Although best understood following cardiac transplantation, similar forms of allograft vasculopathy occur in other vascularized organ grafts and some features of CAV may be shared with other immune-mediated vasculopathies. Here, we describe the incidence and diagnosis, the nature of the vascular remodelling, immune and non-immune contributions to pathogenesis, current therapies, and future areas of research in CAV.
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MESH Headings
- Adaptive Immunity
- Animals
- Coronary Artery Disease/epidemiology
- Coronary Artery Disease/immunology
- Coronary Artery Disease/metabolism
- Coronary Artery Disease/pathology
- Coronary Vessels/immunology
- Coronary Vessels/metabolism
- Coronary Vessels/pathology
- Endothelial Cells/immunology
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Graft Rejection/epidemiology
- Graft Rejection/immunology
- Graft Rejection/metabolism
- Graft Rejection/pathology
- Graft Survival
- Heart Transplantation/adverse effects
- Humans
- Immunity, Innate
- Muscle, Smooth, Vascular/immunology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/immunology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Risk Factors
- Signal Transduction
- Treatment Outcome
- Vascular Remodeling
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Affiliation(s)
- Jordan S Pober
- Department of Immunobiology, Pathology and Dermatology, Yale School of Medicine, 10 Amistad Street, New Haven CT 06520-8089, USA
| | - Sharon Chih
- Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada
| | - Jon Kobashigawa
- Department of Medicine, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
| | - Joren C Madsen
- Division of Cardiac Surgery and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - George Tellides
- Department of Surgery (Cardiac Surgery), Yale School of Medicine, New Haven, CT, USA
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13
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Ozcan I, Toya T, Corban MT, Ahmad A, Lerman LO, Kushwaha SS, Lerman A. Peripheral microvascular dysfunction is associated with plaque progression and adverse long-term outcomes in heart transplant patients. ESC Heart Fail 2021; 8:5266-5274. [PMID: 34510802 PMCID: PMC8712915 DOI: 10.1002/ehf2.13610] [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: 04/21/2021] [Revised: 08/17/2021] [Accepted: 09/01/2021] [Indexed: 11/21/2022] Open
Abstract
Aims Cardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non‐heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation. Methods and results We included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index < 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re‐transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm3/mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow‐up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high‐density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03). Conclusions Peripheral endothelial dysfunction is associated with increased plaque progression and adverse long‐term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.
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Affiliation(s)
- Ilke Ozcan
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
| | - Takumi Toya
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA.,Division of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Michel T Corban
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
| | - Ali Ahmad
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Sudhir S Kushwaha
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
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14
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Ozcan I, Toya T, Corban MT, Ahmad A, Loeffler D, Morse D, Lerman LO, Kushwaha SS, Lerman A. Circulating Progenitor Cells Are Associated With Plaque Progression And Long-Term Outcomes In Heart Transplant Patients. Cardiovasc Res 2021; 118:1703-1712. [PMID: 34132771 DOI: 10.1093/cvr/cvab203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/10/2021] [Accepted: 06/14/2021] [Indexed: 11/13/2022] Open
Abstract
AIMS Circulating progenitor cells (CPCs) play a role in vascular repair and plaque stability, while osteocalcin (OC) expressing CPCs have been linked to unstable plaque and adverse cardiovascular outcomes. However, their role in cardiac allograft vasculopathy (CAV) has not been elucidated. This cohort study aimed to investigate the contribution of CPCs on CAV progression and cardiovascular events after heart transplantation. METHODS AND RESULTS A total of 80 heart transplant patients (mean age 55 ± 14 years, 72% male) undergoing annual intravascular ultrasound (IVUS) had fresh CPCs marked by CD34, CD133, and OC counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. CAV progression was assessed by IVUS as the change (Δ) in plaque volume divided by segment length (PV/SL), adjusted for the time between IVUS measurements (median 3.0, interquartile range (IQR) [2.8, 3.1] years), and was defined as ΔPV/SL that is above the median ΔPV/SL of study population. Major adverse cardiac events (MACE) was defined as any incident of revascularization, myocardial infarction, heart failure admission, re-transplantation, stroke and death. Patients with higher CD34+CD133+ CPCs had a decreased risk of CAV progression (odds ratio 0.58, 95% confidence interval [CI] [0.37, 0.92], p = 0.01) and MACE (hazard ratio [HR] 0.79, 95% CI [0.66, 0.99], p = 0.05) during a median (IQR) follow up of 8.0 years (7.2, 8.3). Contrarily, higher OC+ cell counts were associated with an increased risk of MACE (HR 1.26, 95% CI [1.03, 1.57], p = 0.02). CONCLUSIONS Lower levels of CD34+CD133+ CPCs are associated with plaque progression and adverse long-term outcomes in patients who underwent allograft heart transplantation. In contrast, higher circulating OC+ levels are associated with adverse long term outcomes. Thus, CPCs might play a role in amelioration of transplant vasculopathy, while OC expression by these cells might play a role in progression. TRANSLATIONAL PERSPECTIVE The results of the current study suggest lower levels of circulating CD34+CD133+ cell levels are associated with cardiac allograft vasculopathy progression and future adverse cardiovascular events, while higher OC+ cell levels are associated with a greater risk of future cardiovascular events. Further studies confirming our findings might elucidate the role of circulating progenitor cells in the pathophysiology of CAV. Moreover, our findings might support the use of circulating progenitors as biomarkers, as well as the notion of cell therapy as potential treatment option for CAV, a disease with severe burden and limited treatment options.
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Affiliation(s)
- Ilke Ozcan
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Takumi Toya
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.,Division of Cardiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Michel T Corban
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Ali Ahmad
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Darrell Loeffler
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - David Morse
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Sudhir S Kushwaha
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
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15
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Nikolova AP, Kobashigawa JA. Cardiac Allograft Vasculopathy: The Enduring Enemy of Cardiac Transplantation. Transplantation 2019; 103:1338-1348. [PMID: 31241553 DOI: 10.1097/tp.0000000000002704] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cardiac allograft vasculopathy remains a major limiting factor in the long-term survival of the heart transplant recipient. Our understanding of its pathogenesis is continuously evolving as advances in imaging modalities have allowed a direct window into the natural history of the disease. Innovation in diagnostic modalities has spurred the proliferation of prognostic tools and biomarkers. And in parallel, pharmacological advances have emerged that have helped ameliorate the disease's progressive course.
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Affiliation(s)
- Andriana P Nikolova
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Jon A Kobashigawa
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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16
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Lee JH, Okada K, Khush K, Kobayashi Y, Sinha S, Luikart H, Valantine H, Yeung AC, Honda Y, Fearon WF. Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation 2018; 135:1093-1095. [PMID: 28289008 DOI: 10.1161/circulationaha.116.025268] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Jang Hoon Lee
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Kozo Okada
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Kiran Khush
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Yuhei Kobayashi
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Seema Sinha
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Helen Luikart
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Hannah Valantine
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Alan C Yeung
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - Yasuhiro Honda
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.)
| | - William F Fearon
- From Stanford University Medical Center, CA (J.H.L., K.O., K.K., Y.K., H.L. H.V., A.C.Y., Y.H., W.F.F.); Kyunpook National University Hospital, Daegu, Republic of Korea (J.H.L.); and Menlo Medical Clinic, Menlo Park, CA (S.S.).
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17
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Chih S, Chong AY, Erthal F, deKemp RA, Davies RA, Stadnick E, So DY, Overgaard C, Wells G, Mielniczuk LM, Beanlands RS. PET Assessment of Epicardial Intimal Disease and Microvascular Dysfunction in Cardiac Allograft Vasculopathy. J Am Coll Cardiol 2018; 71:1444-1456. [DOI: 10.1016/j.jacc.2018.01.062] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 12/30/2017] [Accepted: 01/19/2018] [Indexed: 11/17/2022]
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18
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Payne GA, Hage FG, Acharya D. Transplant allograft vasculopathy: Role of multimodality imaging in surveillance and diagnosis. J Nucl Cardiol 2016; 23:713-27. [PMID: 26711101 DOI: 10.1007/s12350-015-0373-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 11/27/2015] [Indexed: 01/22/2023]
Abstract
Cardiac allograft vasculopathy (CAV) is a challenging long-term complication of cardiac transplantation and remains a leading long-term cause of graft failure, re-transplantation, and death. CAV is an inflammatory vasculopathy distinct from traditional atherosclerotic coronary artery disease. Historically, the surveillance and diagnosis of CAV has been dependent on serial invasive coronary angiography with intravascular imaging. Although commonly practiced, angiography is not without significant limitations. Technological advances have provided sophisticated imaging techniques for CAV assessment. It is now possible to assess the vascular lumen, vessel wall characteristics, absolute blood flow, perfusion reserve, myocardial contractile function, and myocardial metabolism and injury in a noninvasive, expeditious manner with little risk. The current article will review key imaging modalities for the surveillance, diagnosis, and prognosis of CAV and discuss coronary physiology of transplanted hearts with emphasis on the clinical implications for provocative and vasodilator stress testing.
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Affiliation(s)
- Gregory A Payne
- Division of Cardiovascular Disease, University of Alabama at Birmingham School of Medicine, Tinsley Harrison Tower, Room 321, Birmingham, AL, 35294-006, USA
| | - Fadi G Hage
- Division of Cardiovascular Disease, University of Alabama at Birmingham School of Medicine, Tinsley Harrison Tower, Room 321, Birmingham, AL, 35294-006, USA
- Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Deepak Acharya
- Division of Cardiovascular Disease, University of Alabama at Birmingham School of Medicine, Tinsley Harrison Tower, Room 321, Birmingham, AL, 35294-006, USA.
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19
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Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord 2015; 15:130. [PMID: 26481314 PMCID: PMC4617895 DOI: 10.1186/s12872-015-0124-z] [Citation(s) in RCA: 459] [Impact Index Per Article: 45.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 10/09/2015] [Indexed: 02/07/2023] Open
Abstract
Hemostasis encompasses a set of tightly regulated processes that govern blood clotting, platelet activation, and vascular repair. Upon vascular injury, the hemostatic system initiates a series of vascular events and activates extravascular receptors that act in concert to seal off the damage. Blood clotting is subsequently attenuated by a plethora of inhibitors that prevent excessive clot formation and eventual thrombosis. The endothelium which resides at the interface between the blood and surrounding tissues, serves an integral role in the hemostatic system. Depending on specific tissue needs and local stresses, endothelial cells are capable of evoking either antithrombotic or prothrombotic events. Healthy endothelial cells express antiplatelet and anticoagulant agents that prevent platelet aggregation and fibrin formation, respectively. In the face of endothelial dysfunction, endothelial cells trigger fibrin formation, as well as platelet adhesion and aggregation. Finally, endothelial cells release pro-fibrinolytic agents that initiate fibrinolysis to degrade the clot. Taken together, a functional endothelium is essential to maintain hemostasis and prevent thrombosis. Thus, a greater understanding into the role of the endothelium can provide new avenues for exploration and novel therapies for the management of thromboembolisms.
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Affiliation(s)
- Jonathan W Yau
- Division of Cardiac Surgery, St. Michael's Hospital, Suite 8-003, Bond Wing, 30 Bond St., Toronto, ON, M5B 1W8, Canada.
| | - Hwee Teoh
- Division of Cardiac Surgery, St. Michael's Hospital, Suite 8-003, Bond Wing, 30 Bond St., Toronto, ON, M5B 1W8, Canada. .,Divisions of Endocrinology & Metabolism, Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, ON, Canada.
| | - Subodh Verma
- Division of Cardiac Surgery, St. Michael's Hospital, Suite 8-003, Bond Wing, 30 Bond St., Toronto, ON, M5B 1W8, Canada. .,Department of Surgery, University of Toronto, Toronto, ON, Canada.
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20
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Wilson RF. Coronary Angiography. Coron Artery Dis 2015. [DOI: 10.1007/978-1-4471-2828-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Vecchiati A, Tellatin S, Angelini A, Iliceto S, Tona F. Coronary microvasculopathy in heart transplantation: Consequences and therapeutic implications. World J Transplant 2014; 4:93-101. [PMID: 25032098 PMCID: PMC4094955 DOI: 10.5500/wjt.v4.i2.93] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 01/11/2014] [Accepted: 03/12/2014] [Indexed: 02/05/2023] Open
Abstract
Despite the progress made in the prevention and treatment of rejection of the transplanted heart, cardiac allograft vasculopathy (CAV) remains the main cause of death in late survival transplanted patients. CAV consists of a progressive diffuse intimal hyperplasia and the proliferation of vascular smooth muscle cells, ending in wall thickening of epicardial vessels, intramyocardial arteries (50-20 μm), arterioles (20-10 μm), and capillaries (< 10 μm). The etiology of CAV remains unclear; both immunologic and non-immunologic mechanisms contribute to endothelial damage with a sustained inflammatory response. The immunological factors involved are Human Leukocyte Antigen compatibility between donor and recipient, alloreactive T cells and the humoral immune system. The non-immunological factors are older donor age, ischemia-reperfusion time, hyperlipidemia and CMV infections. Diagnostic techniques that are able to assess microvascular function are lacking. Intravascular ultrasound and fractional flow reserve, when performed during coronary angiography, are able to detect epicardial coronary artery disease but are not sensitive enough to assess microvascular changes. Some authors have proposed an index of microcirculatory resistance during maximal hyperemia, which is calculated by dividing pressure by flow (distal pressure multiplied by the hyperemic mean transit time). Non-invasive methods to assess coronary physiology are stress echocardiography, coronary flow reserve by transthoracic Doppler echocardiography, single photon emission computed tomography, and perfusion cardiac magnetic resonance. In this review, we intend to analyze the mechanisms, consequences and therapeutic implications of microvascular dysfunction, including an extended citation of relevant literature data.
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22
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Som R, Morris PJ, Knight SR. Graft Vessel Disease Following Heart Transplantation: A Systematic Review of the Role of Statin Therapy. World J Surg 2014; 38:2324-34. [DOI: 10.1007/s00268-014-2543-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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23
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Using advanced noninvasive imaging techniques to probe the links between regional coronary artery endothelial dysfunction and atherosclerosis. Trends Cardiovasc Med 2013; 24:149-56. [PMID: 24296299 DOI: 10.1016/j.tcm.2013.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/07/2013] [Accepted: 10/09/2013] [Indexed: 01/09/2023]
Abstract
Cardiovascular disease remains the number one cause of death in the US annually. The development in recent years of imaging strategies that can identify coronary endothelial dysfunction noninvasively provides new information about the early presence and local spatial heterogeneity of endothelial function in patients with, and those at risk for, coronary artery disease. In this article, we will briefly review the mechanisms relating endothelial function and atherosclerosis, contemporary imaging strategies now able to quantify coronary endothelial function noninvasively, and recent insights on human coronary endothelial function.
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Gutiérrez E, Flammer AJ, Lerman LO, Elízaga J, Lerman A, Fernández-Avilés F. Endothelial dysfunction over the course of coronary artery disease. Eur Heart J 2013; 34:3175-81. [PMID: 24014385 DOI: 10.1093/eurheartj/eht351] [Citation(s) in RCA: 231] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The vascular endothelium regulates blood flow in response to physiological needs. Endothelial dysfunction is closely related to atherosclerosis and its risk factors, and it constitutes an intermediate step on the progression to adverse events throughout the natural history of coronary artery disease (CAD), often affecting clinical outcomes. Understanding the relation of endothelial function with CAD provides an important pathophysiological insight, which can be useful both in clinical and research management. In this review, we summarize the current knowledge on endothelial dysfunction and its prognostic influence throughout the natural history of CAD, from early atherosclerosis to post-transplant management.
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Affiliation(s)
- Enrique Gutiérrez
- Servicio de Cardiología, Instituto de Investigación Sanitaria, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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Colvin-Adams M, Harcourt N, Duprez D. Endothelial dysfunction and cardiac allograft vasculopathy. J Cardiovasc Transl Res 2012; 6:263-77. [PMID: 23135991 DOI: 10.1007/s12265-012-9414-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Accepted: 10/02/2012] [Indexed: 12/19/2022]
Abstract
Cardiac allograft vasculopathy remains a major challenge to long-term survival after heart transplantation. Endothelial injury and dysfunction, as a result of multifactorial immunologic and nonimmunologic insults in the donor and the recipient, are prevalent early after transplant and may be precursors to overt cardiac allograft vasculopathy. Current strategies for managing cardiac allograft vasculopathy, however, rely on the identification and treatment of established disease. Improved understanding of mechanisms leading to endothelial dysfunction in heart transplant recipients may provide the foundation for the development of sensitive screening techniques and preventive therapies.
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Affiliation(s)
- Monica Colvin-Adams
- Cardiovascular Division, University of Minnesota, Minneapolis, MN 55455, USA.
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Calé R, Rebocho MJ, Aguiar C, Almeida M, Queiroz e Melo J, Silva JA. Diagnosis, prevention and treatment of cardiac allograft vasculopathy. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2012. [DOI: 10.1016/j.repce.2012.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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27
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Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation 2012; 126:753-67. [PMID: 22869857 DOI: 10.1161/circulationaha.112.093245] [Citation(s) in RCA: 884] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Andreas J Flammer
- Division of Cardiovascular Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
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Calé R, Rebocho MJ, Aguiar C, Almeida M, Queiroz E Melo J, Silva JA. [Diagnosis, prevention and treatment of cardiac allograft vasculopathy]. Rev Port Cardiol 2012; 31:721-30. [PMID: 22999223 DOI: 10.1016/j.repc.2012.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Accepted: 06/14/2012] [Indexed: 10/27/2022] Open
Abstract
The major limitation of long-term survival after cardiac transplantation is allograft vasculopathy, which consists of concentric and diffuse intimal hyperplasia. The disease still has a significant incidence, estimated at 30% five years after cardiac transplantation. It is a clinically silent disease and so diagnosis is a challenge. Coronary angiography supplemented by intravascular ultrasound is the most sensitive diagnostic method. However, new non-invasive diagnostic techniques are likely to be clinically relevant in the future. The earliest possible diagnosis is essential to prevent progression of the disease and to improve its prognosis. A new nomenclature for allograft vasculopathy has been published in July 2010, developed by the International Society for Heart and Lung Transplantation (ISHLT), establishing a standardized definition. Simultaneously, the ISHLT published new guidelines standardizing the diagnosis and management of cardiac transplant patients. This paper reviews contemporary concepts in the pathophysiology, diagnosis, prevention and treatment of allograft vasculopathy, highlighting areas that are the subject of ongoing research.
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Affiliation(s)
- Rita Calé
- Departamento de Cardiologia e Cirurgia Cardiotorácica, Hospital Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.
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29
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Goligorsky MS. Microvascular rarefaction: the decline and fall of blood vessels. Organogenesis 2012; 6:1-10. [PMID: 20592859 DOI: 10.4161/org.6.1.10427] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2009] [Accepted: 10/26/2009] [Indexed: 12/31/2022] Open
Abstract
The goals of this presentation are two-fold: (1) to briefly sketch the field of vascular rarefaction as a key component of various fibrotic diseases and (2) to illustrate it with four vignettes depicting diverse mechanisms of microvascular rarefaction. Specifically, I shall describe migratory and angiogenic incompetence of endothelial cells under conditions of reduced bioavailability of nitric oxide, role of endothelial-to-mesenchymal cell and mesenchymal stem cell-to-endothelial reprogramming, and potential role of antiangiogenic peptides in the development of graft vascular disease as exemplified by chronic allograft nephropathy.
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Affiliation(s)
- Michael S Goligorsky
- Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY, USA.
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30
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Tavares AC, Bocchi EA, Guimarães GV. Endothelial function in pre-pubertal children at risk of developing cardiomyopathy: a new frontier. Clinics (Sao Paulo) 2012; 67:273-8. [PMID: 22473410 PMCID: PMC3297038 DOI: 10.6061/clinics/2012(03)12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Revised: 11/03/2011] [Accepted: 11/22/2011] [Indexed: 01/22/2023] Open
Abstract
Although it is known that obesity, diabetes, and Kawasaki's disease play important roles in systemic inflammation and in the development of both endothelial dysfunction and cardiomyopathy, there is a lack of data regarding the endothelial function of pre-pubertal children suffering from cardiomyopathy. In this study, we performed a systematic review of the literature on pre-pubertal children at risk of developing cardiomyopathy to assess the endothelial function of pre-pubertal children at risk of developing cardiomyopathy. We searched the published literature indexed in PubMed, Bireme and SciELO using the keywords 'endothelial', 'children', 'pediatric' and 'infant' and then compiled a systematic review. The end points were age, the pubertal stage, sex differences, the method used for the endothelial evaluation and the endothelial values themselves. No studies on children with cardiomyopathy were found. Only 11 papers were selected for our complete analysis, where these included reports on the flow-mediated percentage dilatation, the values of which were 9.80±1.80, 5.90±1.29, 4.50±0.70, and 7.10±1.27 for healthy, obese, diabetic and pre-pubertal children with Kawasaki's disease, respectively. There was no significant difference in the dilatation, independent of the endothelium, either among the groups or between the genders for both of the measurements in children; similar results have been found in adolescents and adults. The endothelial function in cardiomyopathic children remains unclear because of the lack of data; nevertheless, the known dysfunctions in children with obesity, type 1 diabetes and Kawasaki's disease may influence the severity of the cardiovascular symptoms, the prognosis, and the mortality rate. The results of this study encourage future research into the consequences of endothelial dysfunction in pre-pubertal children.
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Affiliation(s)
- Aline Cristina Tavares
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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31
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Impact of Donor-Transmitted Atherosclerosis on Early Cardiac Allograft Vasculopathy: New Findings by Three-Dimensional Intravascular Ultrasound Analysis. Transplantation 2011; 91:1406-11. [DOI: 10.1097/tp.0b013e31821ab91b] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Wildhirt S, Weis M, Schulze C, Conrad N, Rieder G, Enders G, Hoepp C, Scheidt W, Reichart B. An association between microvascular endothelial dysfunction, transcardiac nitric oxide production and pro-inflammatory cytokines after heart transplantation in humans. Transpl Int 2011. [DOI: 10.1111/j.1432-2277.2000.tb02025.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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33
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Wildhirt S, Weis M, Schulze C, Conrad N, Rieder G, Enders G, Ihnken K, Scheidt W, Reichart B. Effects of Celsior and University of Wisconsin preservation solutions on hemodynamics and endothelial function after cardiac transplantation in humans: a single-center, prospective, randomized trial. Transpl Int 2011. [DOI: 10.1111/j.1432-2277.2000.tb02021.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Nath DS, Ilias Basha H, Tiriveedhi V, Alur C, Phelan D, Ewald GA, Moazami N, Mohanakumar T. Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy. J Heart Lung Transplant 2010; 29:1277-85. [PMID: 20615726 DOI: 10.1016/j.healun.2010.05.025] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Revised: 05/13/2010] [Accepted: 05/26/2010] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx). METHODS One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-γ, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays. RESULTS AMR patients were more likely DSA positive (AMR-: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR-: 144 ± 115 μg/ml; AMR+: 285 ± 70 μg/ml; p = 0.033) and VIM (AMR-: 37 ± 19 μg/ml; AMR+: 103 ± 43 μg/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 ± 0.9 fold, p = 0.003) and VIM (7.3 ± 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 ± 0.4-fold, p = 0.009) and VIM (1.7 ± 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV-): 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV-: 191 ± 120 μg/ml; CAV+: 550 ± 98 μg/ml; p = 0.025) and VIM (CAV-: 55 ± 25 μg/ml; CAV+: 255 ± 49 μg/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 ± 7.3-fold, p = 0.002) and VIM (7.0 ± 3.9-fold, p = 0.003). CONCLUSIONS The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively.
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Affiliation(s)
- Dilip S Nath
- Division of Cardiothoracic Surgery, Barnes-Jewish Hospital, St. Louis, Missouri, USA
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Adenovirus-mediated overexpression of glutathione-s-transferase mitigates transplant arteriosclerosis in rabbit carotid allografts. Transplantation 2010; 89:409-16. [PMID: 20177342 DOI: 10.1097/tp.0b013e3181c69838] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cardiac transplant arteriosclerosis or cardiac allograft vasculopathy remains the leading cause of graft failure and patient death in heart transplant recipients. Endothelial cell injury is crucial in the development of human atherosclerosis and may play a role in allograft vasculopathy. Glutathione-S-transferase (GST) is known to protect endothelial cells from damage by oxidants and toxins. However, the contribution of human GST A4-4 (hGSTA4-4) to vascular cell injury and consequent transplant arteriosclerosis is unknown. METHODS A recombinant adenoviral vector containing hGSTA4-4 gene was constructed and delivered to vascular endothelial cells in an in vivo rabbit carotid artery transplant model. Forty-five days after transplantation, allografts were harvested (n=28). Blood flow was measured by ultrasonography. In addition, grafts were analyzed by histology, morphometry, immunostaining, and western blot. RESULTS The severity of arteriosclerosis in hGSTA4-4 transduced allografts was compared with control by measuring degree of stenosis by neointima. Decrease in blood flow in hGSTA4-4 transduced allografts was significantly less than control allografts, which also developed greater intimal thickening and stenosis than hGSTA4-4 transduced allografts in the proximal and distal regions of the graft. Leukocyte and macrophage infiltration was reduced in hGSTA4-4 transduced carotid arteries. CONCLUSION Our data indicate that hGSTA4-4 overexpression protects the integrity of vessel wall from oxidative injury, and attenuates transplant arteriosclerosis.
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37
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Ganz P, Ho JE, Hsue PY. Structural and functional manifestations of human atherosclerosis: do they run in parallel? Eur Heart J 2009; 30:1556-8. [DOI: 10.1093/eurheartj/ehp238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Lavi S, Bae JH, Rihal CS, Prasad A, Barsness GW, Lennon RJ, Holmes DR, Lerman A. Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques. Heart 2009; 95:1525-30. [PMID: 19497916 DOI: 10.1136/hrt.2009.166017] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND/OBJECTIVE Endothelial dysfunction and atherosclerosis are systemic disorders, but are often characterised by segmental involvement and complications. A potential mechanism for local involvement early in the disease process may be related to plaque composition. This study was designed to test the hypothesis that in patients with minimal coronary atherosclerosis, coronary artery segments with abnormal endothelial function have specific plaque characteristics. METHODS Intravascular ultrasound (IVUS) images were obtained from 30 patients who underwent coronary endothelial function assessment. Spectral analysis of the IVUS radiofrequency data was used for assessment of plaque composition. IVUS findings of the coronary sections were compared according to the corresponding endothelial response to acetylcholine. RESULTS Sections with a decrease epicardial coronary arterial diameter in response to acetylcholine had smaller baseline lumen (7.5 (2.4) mm(2) vs 8.8 (3.3) mm(2), p = 0.006) but larger plaque burden (37.1% (9.4%) vs 31% (7%), p = 0.003) than sections with normal endothelial response. Sections with endothelial dysfunction had larger necrotic core plaques: 0.13 (0.03-0.33) mm(2) vs 0.0 (0.0-0.07), p<0.001 and more dense calcium: 0.03 (IQR 0.0-0.13) mm(2) vs 0.0 (0.0-0.10) mm(2), p<0.01), than those with normal endothelial response. Only necrotic core area was associated with endothelial dysfunction (p<0.001) after adjusting for other measures. CONCLUSIONS This study suggests that local coronary endothelial dysfunction in patients with minimal coronary atherosclerosis is associated with plaque characteristics that are typical of vulnerable plaques.
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Affiliation(s)
- S Lavi
- Division of Cardiovascular Diseases and the Center for Coronary Physiology and Imaging, Mayo Clinic, Rochester, MN 55905, USA
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Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 2009; 157:527-36. [PMID: 19630832 PMCID: PMC2707964 DOI: 10.1111/j.1476-5381.2009.00240.x] [Citation(s) in RCA: 185] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Revised: 01/20/2009] [Accepted: 02/05/2009] [Indexed: 12/14/2022] Open
Abstract
The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent antiatherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide (NO) as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions, such as hypertension, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium-derived contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension. However, cyclooxygenase-dependent EDCFs production is characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.
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Affiliation(s)
- Daniele Versari
- Department of Internal Medicine, University of Pisa, Pisa, Italy
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Raichlin E, Prasad A, Kremers WK, Edwards BS, Rihal CS, Lerman A, Kushwaha SS. Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients. Eur Heart J 2009; 30:1356-63. [PMID: 19383734 DOI: 10.1093/eurheartj/ehp123] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
AIMS The aim of this study was to evaluate coronary vasomotor function in cardiac transplant recipients maintained on sirolimus (SRL)- or cyclosporin (CyA)-based immunosuppression. METHODS AND RESULTS Endothelium-independent response to intracoronary nitroglycerin and adenosine and endothelium-dependent response to intracoronary acetylcholine (Ach) were assessed in 15 SRL- and 21 CyA- treated subjects with angiographically normal coronary arteries. Baseline mean blood pressure was lower in the SRL group (85.6 +/- 10.3 vs. 105.2 +/- 8.7 mmHg, P = 0.002). There was no difference between the groups in coronary flow reserve after adenosine administration in multivariable analysis (P = 0.34). Nitroglycerin administration resulted in increase in coronary artery diameter in the SRL compared with the CyA groups (2.79 +/- 0.54 vs. 2.57 +/- 0.61, P = 0.0036). In 13 SRL-treated subjects without evidence of cardiac allograft vasculopathy (CAV), Ach administration resulted in less epicardial vasoconstriction compared with CyA-treated subjects (2.7 +/- 17.7 vs. -15.6 +/- 17.2%, P = 0.005). Two SRL-treated subjects with three-dimensional intravascular ultrasound evidence of CAV developed coronary spasm in response to Ach 10(-4). Microvascular endothelial function did not differ between the groups. CONCLUSION Sirolimus immunosuppression is associated with less pronounced coronary epicardial endothelial dysfunction compared with CyA immunosuppression. Improvement of coronary vasomotor function with SRL may be an important mechanism for the prevention of CAV.
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Affiliation(s)
- Eugenia Raichlin
- William J. von Liebig Transplant Center and the Division of Cardiovascular Diseases, Mayo Clinic (Go 5-469), 200 First Street, SW, Rochester, MN 55905, USA
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Features of cardiac allograft coronary endothelial dysfunction. Am J Cardiol 2009; 103:1154-8. [PMID: 19361606 DOI: 10.1016/j.amjcard.2008.12.039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Revised: 12/21/2008] [Accepted: 12/21/2008] [Indexed: 11/22/2022]
Abstract
The aim of the study was to evaluate the features and mechanism of cardiac allograft coronary endothelial dysfunction. Coronary blood flow and epicardial coronary artery diameter response to intracoronary acetylcholine and N(G)-monomethyl-l-arginine were assessed in 19 cyclosporine-treated heart transplant recipients with normal coronary angiograms (3.8 +/- 2.3 years after transplantation) and compared with 19 age-, gender-, and cardiovascular risk factor-matched nontransplantation control patients with normal coronary angiograms. Heart transplant recipients had more epicardial vasoconstriction in response to intracoronary acetylcholine (mean -16 +/- 19% [SD] vs 4 +/- 10%; p = 0.036). Microvascular endothelial function was similar between groups. Coronary flow reserve in response to adenosine was higher in the transplant group (3.6 +/- 0.8 vs 3.1 +/- 0.7; p = 0.04). The effect of N(G)-monomethyl-l-arginine (64 micromol/min) on coronary blood flow (-16 +/- 21% vs -37 +/- 19%; p = 0.018), coronary artery diameter (-10 +/- 13% vs -21 +/- 11%; p = 0.04), and coronary vascular resistance (34 +/- 40% vs 73 +/- 63%; p = 0.047) was significantly attenuated in the transplant group compared with controls. In conclusion, cardiac allograft epicardial coronary endothelial function was abnormal and may be related to an impaired endogenous NO synthetase pathway and reduced endothelial nitric oxide production in transplant recipients.
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Albumin Augmentation Improves Condition of Guinea Pig Hearts After 4 hr of Cold Ischemia. Transplantation 2009; 87:956-65. [DOI: 10.1097/tp.0b013e31819c83b5] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Mitchell RN. Graft Vascular Disease: Immune Response Meets the Vessel Wall. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2009; 4:19-47. [DOI: 10.1146/annurev.pathol.3.121806.151449] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Richard N. Mitchell
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School Health Sciences and Technology, Boston, Massachusetts 02115;
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Ganz P, Hsue PY. Individualized Approach to the Management of Coronary Heart Disease. J Am Coll Cardiol 2009; 53:331-3. [DOI: 10.1016/j.jacc.2008.10.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2008] [Revised: 10/09/2008] [Accepted: 10/14/2008] [Indexed: 11/28/2022]
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Late Onset Antibody-Mediated Rejection and Endothelial Localization of Vascular Endothelial Growth Factor Are Associated With Development of Cardiac Allograft Vasculopathy. Transplantation 2008; 86:991-7. [DOI: 10.1097/tp.0b013e318186d734] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Schubert S, Abdul-Khaliq H, Wellnhofer E, Hiemann NE, Ewert P, Lehmkuhl HB, Meyer R, Miera O, Peters B, Hetzer R, Berger F. Coronary flow reserve measurement detects transplant coronary artery disease in pediatric heart transplant patients. J Heart Lung Transplant 2008; 27:514-21. [PMID: 18442717 DOI: 10.1016/j.healun.2008.02.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2007] [Revised: 01/31/2008] [Accepted: 02/06/2008] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) in patients who have undergone heart transplantation leads to graft dysfunction and is still the major concern for long-term survival. Evaluation of coronary flow velocity reserve (CFR) has been established for diagnosis of CAV. Systemic application of adenosine vs intracoronary testing for CFR has been validated in adults; however, its accuracy in pediatric patients has not yet been proven. METHODS CFR was prospectively measured in 33 clinically asymptomatic pediatric heart transplant recipients. CFR measurements were made in the left anterior descending (LAD) artery using a 0.014-inch Doppler FloWire (Cardiometrics). CFR was defined as the ratio of hyperemic (after adenosine injection) to basal (before adenosine) average peak velocity (APV). Adenosine (Adrekar) was administered by intracoronary (15 or 30 mug bolus) and systemic (0.1 mg/kg) injection in each patient. Epicardial CAV was evaluated in coronary angiograms (Stanford criteria) and microvasculopathy was diagnosed in endomyocardial biopsies (evidence of luminal stenosis) blinded to clinical data. RESULTS Thirty-three patients were included in this study. Their median age (range) was 11.9 (1.4 to 17) years and median post-transplant time 4.3 (1 to 11.7) years. Seventeen of the 33 patients had epicardial CAV (mainly peripheral obliterations or B1 and B2 lesions) and microvascular CAV. Epicardial CAV only was found in 4 patients and microvasculopathy only was present in only 1 patient. CFR was significantly reduced in patients with epicardial CAV and microvasculopathy when compared with patients without any signs of CAV: 206 +/- 53 vs 276 +/- 39 (p < 0.001) for the systemic application and 213 +/- 50 vs 271 +/- 45 (p = 0.004) for the intracoronary application. CONCLUSIONS CFR and coronary vasoreactivity to adenosine are decreased in pediatric patients with CAV and correlate with histopathologic and angiographic evidence of microvascular disease. Measurement of CFR with intracoronary and systemic application of adenosine is comparable, while systemic application is necessary for non-invasive measurement of CFR in pediatric patients.
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Affiliation(s)
- Stephan Schubert
- Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany.
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McManus CA, Rose ML, Dunn MJ. Diagnostic Markers for Monitoring Heart Transplant Rejection. Clin Proteomics 2008. [DOI: 10.1002/9783527622153.ch14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Bayliss J, Maguire JA, Bailey M, Leet A, Kaye D, Richardson M, Bergin PJ, Dowling J, Thomson NM, Stein AN. Increased vascular endothelial growth factor mRNA in endomyocardial biopsies from allografts demonstrating severe acute rejection: A longitudinal study. Transpl Immunol 2008; 18:264-74. [DOI: 10.1016/j.trim.2007.07.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Revised: 07/16/2007] [Accepted: 07/31/2007] [Indexed: 01/08/2023]
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Vallbracht-Israng KB, Morguet A, Schwimmbeck PL. Correlation of epicardial and systemic flow-mediated vasodilation in patients with atypical angina but no evidence of atherosclerotic disease. Can J Cardiol 2007; 23:1054-60. [PMID: 17985007 DOI: 10.1016/s0828-282x(07)70873-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Atypical angina represents a diagnostic challenge and can be observed in the absence of significant coronary atherosclerosis. Endothelial dysfunction is a relevant marker of prognosis, considering cardiovascular events. The aim of the present study was to compare flow-mediated vasodilation (FMD) in systemic peripheral and epicardial coronary arteries. If noninvasive measurements of FMD in systemic arteries correlated with invasive measurements of coronary FMD, this may facilitate diagnostic approaches and determination of prognosis in patients with atypical angina in the future. Patients with atherosclerosis were excluded, because structural changes of coronary vessels may impair adequate comparison. METHODS Endothelial function (ENF) of epicardial and systemic arteries was examined in 61 consecutive patients with atypical angina in whom significant atherosclerosis was excluded by coronary angiography. ENF of the epicardial arteries was examined during heart catheterization, measuring diameter changes of the proximal left anterior descending coronary artery (LAD) in response to reactive hyperemia, induced by locally administered adenosine via infusion catheter to the mid-segment of the LAD (coronary FMD [FMDc]). ENF of the radial artery was examined with high-resolution ultrasound, measuring peripheral FMD (FMDp) in response to reactive hyperemia induced by distal cuff occlusion. Endothelium-independent vasoreactivity to glycerol trinitrate was assessed. RESULTS In patients with atypical angina in the absence of atherosclerosis, there was a significant correlation in ENF between coronary and systemic arteries (r=0.437; P=0.001). The underlying disease was myocardial inflammation (Inf) in 48 patients, in whom the mean (+/- SD) ENF of epicardial (FMDc-Inf 3.40+/-5.55%) and systemic (FMDp-Inf 3.69+/-2.93%) arteries was significantly impaired (P<0.001), compared with 13 control (Co) patients who had normal myocardial biopsies (FMDc-Co 14.51+/-8.62%; FMDp-Co 7.69+/-3.42%). FMD of coronary (r=-0.353; P=0.005) and systemic (r=-0.542; P<0.001) arteries correlated significantly with myocardial inflammation and endothelial activation. CONCLUSIONS There was a significant correlation in FMD between coronary and systemic arteries in patients with atypical angina but without significant atherosclerosis. Inflammatory processes are associated with endothelial dysfunction of both vascular regions.
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Vallbracht-Israng KB, Kazak I, Schwimmbeck PL. Association of cytokines with endothelium dependent flow mediated vasodilation (FMD) of systemic arteries in patients with non-ischemic cardiomyopathy. Cardiovasc Ultrasound 2007; 5:49. [PMID: 18070342 PMCID: PMC2231343 DOI: 10.1186/1476-7120-5-49] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Accepted: 12/10/2007] [Indexed: 01/14/2023] Open
Abstract
Background Aim of this study was to elucidate the relation between localised inflammatory heart disease and endothelial dysfunction in the peripheral circulation, considering circulating cytokines as a potential link. Methods In 38 patients with non-ischemic heart disease, myocardial biopsies were examined for myocardial inflammation (immunohistology) and virus persistence (PCR). Cytokines (sIL-4, IFN-g, IFN-b, IFN-a, sIL-12p7, TNF-a) were measured by ELISA in venous serum. Endothelial function of the radial artery was examined by ultrasound, measuring diameter changes in response to reactive hyperemia (FMD), compared to glyceroltrinitrate (GTN-MD). Patients with EF < 35% were excluded. Results Age 44 ± 14 years, 19 male, 19 female, EF 63.5[16]%. FMD 4.38 [4.82]%. 30 patients had myocardial inflammation (8 not), 23 virus persistence (15 not). FMD correlated significantly with sIL-12p7 (p = 0.024, r = -0.365), but not with other cytokines. sIL-12p7 levels were significantly higher in patients with severely impaired FMD (n = 17), compared with normal FMD (n = 21): 10.70 [10.72] vs. 4.33 [7.81] pg/ml (p = 0.002). Endothelium independent vasodilation (GTN-MD 23.67 [8.21]%) was not impaired. Conclusion Endothelial dysfunction of peripheral arteries in patients with non-ischemic cardiomyopathy is associated with elevated serum concentrations of sIL-12p7, but not of other cytokines. Circulating sIL-12p7 may partly explain, that endothelial dysfunction is not restricted to the coronary circulation, but involves systemic arteries.
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Affiliation(s)
- Katja B Vallbracht-Israng
- Department of Cardiology, Campus Virchow Hospital, Charité Medical University, Augustenburger Platz 1, 13353 Berlin, Germany.
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