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Abadie B, Elghoul Y, Prakash SS, Besir B, Ziada K, Jacob M, Bhattacharya S, Bhat P, Starling RC, Tang WHW, Jaber W. Coronary microvascular dysfunction by positron emission tomography and outcomes in patients after cardiac transplantation without epicardial allograft vasculopathy. Eur Heart J Cardiovasc Imaging 2025:jeaf042. [PMID: 39919052 DOI: 10.1093/ehjci/jeaf042] [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: 11/05/2024] [Revised: 01/08/2025] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) affects both epicardial and microvascular coronary arteries, however few studies have characterized microvascular dysfunction in this population. Several prior studies have shown positron emission tomography/computed tomography (PET/CT) can be used to screen for epicardial CAV, however the clinical implications of abnormal blood flow in the absence of epicardial CAV is unknown. OBJECTIVE Our study sought to assess the prognostic implications of microvascular dysfunction and its sub-types, endogen/functional and classical/structural, using PET/CT in cardiac transplant patients without epicardial CAV. METHODS Transplant patients with no prior history of CAV and normal myocardial perfusion imaging were included. Patients were then classified by the presence of microvascular dysfunction (CMD) (MFR <2.0); patients with CMD were further subcategorized into endogen/functional (stress myocardial blood flow ≥1.7 mL/min/g) and classical/structural (stress myocardial blood flow <1.7 mL/min/g). The primary outcomes were all-cause mortality and a composite of all-cause mortality, heart failure hospitalization, acute coronary syndrome, revascularization, and re-transplantation. RESULTS 356 patients met the inclusion criteria. CMD was present in 141 (39.6%) patients, of which 112 (31.4%) had endogen/functional CMD and 29 (8.1%) had classical/structural CMD. After multivariable adjustment, endogen/functional CMD was associated with a higher rate of the composite outcome (HR 2.39, 95%CI 1.32-4.29, p = 0.004) and all-cause mortality (HR 2.98, 95%CI 1.34-6.64, p = 0.008). Classical/structural CMD was not associated with the primary composite outcome (HR 0.92, 95%CI 0.27-3.17, p = 0.893) or all-cause mortality (HR 1.22, 95%CI 0.263-5.69, p = 0.797). CONCLUSIONS In cardiac transplant patients with no history of CAV and normal myocardial perfusion, an endogen/functional pattern of CMD is associated with higher rate of adverse events and death. This association was not present in patients with a classical/structural CMD pattern. Incorporating endogen/microvascular dysfunction assessment in PET/CT reporting may identify a higher risk group hereto now considered low risk.
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Affiliation(s)
- Bryan Abadie
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Yasmine Elghoul
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Sakthi Surya Prakash
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Besir Besir
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Khaled Ziada
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Miriam Jacob
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Sanjeeb Bhattacharya
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Pavan Bhat
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Randall C Starling
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - W H Wilson Tang
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | - Wael Jaber
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
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de Souza JAF, Catai AM, de Moura-Tonello SCG, Araújo BTS, Barros AEVR, de Aguiar MIR, Campos SL, de Andrade AD, Brandão DC. Correlation between peripheral endothelial function, oxygen consumption and ventilatory efficiency in heart transplantation recipients. Heart Lung 2024; 64:208-213. [PMID: 38092582 DOI: 10.1016/j.hrtlng.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 03/18/2024]
Abstract
BACKGROUND Endothelial dysfunction and peak oxygen uptake (VO2peak) are also predictors of increased risk of cardiovascular events in heart transplantation (HTx) recipients. The preservation of endothelial function may contribute to exercise tolerance. OBJECTIVE To investigate the correlation between peripheral endothelial function and exercise tolerance through VO2peak and ventilation to carbon dioxide production slope (VE / VCO2 slope) in HTx recipients. METHODS A pilot cross-sectional study was conducted with adult individuals aged 18-65 years, HTx ≥ six months after surgery, who had a stable medical condition and no changes over the last three months of immunosuppressive treatment. The patients underwent an assessment of endothelial function through PAT (EndoPAT-2000®) and performed a cardiopulmonary exercise test (CPET). RESULTS A total of 41% of the studied population presented endothelial dysfunction. The individuals were divided into two groups: the endothelial dysfunction (GED; n=9) group and the normal endothelial function (GNEF; n=13) group according to the logarithm of the reactive hyperemia index (LnRHI). There was a positive and moderate correlation between the LnRHI and VO2 peak (r=0.659, p=0.013) and a negative and moderate correlation between the LnRHI and VE/VCO2 slope (r= -0.686, p= 0.009) in the GNEF. However, no significant correlations were found in the GED. CONCLUSION The results showed that the preservation of peripheral endothelial function is significantly correlated with an increase in exercise tolerance in individuals after HTx. These findings bring important considerations for cardiovascular risk prevention and emphasize that therapeutic strategies with physical training programs must be implemented early.
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Affiliation(s)
| | - Aparecida Maria Catai
- Physiotherapy Department, Federal University of Sao Carlos (UFSCAR), São Carlos, Brazil
| | | | - Bruna T S Araújo
- Physiotherapy Department, Federal University of Pernambuco (UFPE), Recife, Brazil
| | | | | | - Shirley Lima Campos
- Physiotherapy Department, Federal University of Pernambuco (UFPE), Recife, Brazil
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Otunla AA, Shanmugarajah K, Davies AH, Lucia Madariaga M, Shalhoub J. The Biological Parallels Between Atherosclerosis and Cardiac Allograft Vasculopathy: Implications for Solid Organ Chronic Rejection. Cardiol Rev 2024; 32:2-11. [PMID: 38051983 DOI: 10.1097/crd.0000000000000437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Atherosclerosis and solid organ chronic rejection are pervasive chronic disease states that account for significant morbidity and mortality in developed countries. Recently, a series of shared molecular pathways have emerged, revealing biological parallels from early stages of development up to the advanced forms of pathology. These shared mechanistic processes are inflammatory in nature, reflecting the importance of inflammation in both disorders. Vascular inflammation triggers endothelial dysfunction and disease initiation through aberrant vasomotor control and shared patterns of endothelial activation. Endothelial dysfunction leads to the recruitment of immune cells and the perpetuation of the inflammatory response. This drives lesion formation through the release of key cytokines such as IFN-y, TNF-alpha, and IL-2. Continued interplay between the adaptive and innate immune response (represented by T lymphocytes and macrophages, respectively) promotes lesion instability and thrombotic complications; hallmarks of advanced disease in both atherosclerosis and solid organ chronic rejection. The aim of this study is to identify areas of overlap between atherosclerosis and chronic rejection. We then discuss new approaches to improve current understanding of the pathophysiology of both disorders, and eventually design novel therapeutics.
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Affiliation(s)
- Afolarin A Otunla
- From the Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | | | - Alun H Davies
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
| | | | - Joseph Shalhoub
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
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Ahn Y, Koo HJ, Hyun J, Lee SE, Jung SH, Park DW, Ahn JM, Kang DY, Park SJ, Hwang HS, Kang JW, Yang DH, Kim JJ. CT Coronary Angiography and Dynamic CT Myocardial Perfusion for Detection of Cardiac Allograft Vasculopathy. JACC Cardiovasc Imaging 2023; 16:934-947. [PMID: 37407125 DOI: 10.1016/j.jcmg.2022.12.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 12/23/2022] [Indexed: 07/07/2023]
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is a major obstacle limiting long-term graft survival. Effective noninvasive surveillance modalities reflecting both coronary artery and microvascular components of CAV are needed. OBJECTIVES The authors evaluated the diagnostic performance of dynamic computed tomography-myocardial perfusion imaging (CT-MPI) and coronary computed tomography angiography (CCTA) for CAV. METHODS A total of 63 heart transplantation patients underwent combined CT-MPI and CCTA plus invasive coronary angiography (ICA) with intravascular ultrasonography (IVUS) between December 2018 and October 2021. The median interval between CT-MPI and heart transplantation was 4.3 years. Peak myocardial blood flow (MBF) of the whole myocardium (MBFglobal) and minimum MBF (MBFmin) among the 16 segments according to the American Heart Association model, except the left ventricular apex, were calculated from CT-MPI. CCTA was assessed qualitatively, and the degree of coronary artery stenosis was recorded. CAV was diagnosed based on both ICA (ISHLT criteria) and IVUS. Patients were followed up for a median time of 2.3 years after CT-MPI and a median time of 5.7 years after transplantation. RESULTS Among the 63 recipients, 35 (55.6%) had diagnoses of CAV. The median MBFglobal and MBFmin were significantly lower in patients with CAV (128.7 vs 150.4 mL/100 mL/min; P = 0.014; and 96.9 vs 122.8 mL/100 mL/min; P < 0.001, respectively). The combined use of coronary artery stenosis on CCTA and MBFmin showed the highest diagnostic performance with an area under the curve of 0.886 (sensitivity: 74.3%, specificity: 96.4%, positive predictive value: 96.3%, and negative predictive value: 75.0%). CONCLUSIONS The combination of CT-MPI and CCTA demonstrated excellent diagnostic performance for the detection of CAV. One-stop evaluation of the coronary artery and microvascular components involved in CAV using combined CCTA and CT-MPI may be a potent noninvasive screening method for early detection of CAV.
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Affiliation(s)
- Yura Ahn
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Hyun Jung Koo
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
| | - Junho Hyun
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sang Eun Lee
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sung Ho Jung
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Duk-Woo Park
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jung-Min Ahn
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Do-Yoon Kang
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seung-Jung Park
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Hee Sang Hwang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joon-Won Kang
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Dong Hyun Yang
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jae-Joong Kim
- Division of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Iwańczyk S, Woźniak P, Smukowska-Gorynia A, Araszkiewicz A, Nowak A, Jankowski M, Konwerska A, Urbanowicz T, Lesiak M. Microcirculatory Disease in Patients after Heart Transplantation. J Clin Med 2023; 12:jcm12113838. [PMID: 37298033 DOI: 10.3390/jcm12113838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/25/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Although the treatment and prognosis of patients after heart transplantation have significantly improved, late graft dysfunction remains a critical problem. Two main subtypes of late graft dysfunction are currently described: acute allograft rejection and cardiac allograft vasculopathy, and microvascular dysfunction appears to be the first stage of both. Studies revealed that coronary microcirculation dysfunction, assessed by invasive methods in the early post-transplant period, correlates with a higher risk of late graft dysfunction and death during long-term follow-up. The index of microcirculatory resistance, measured early after heart transplantation, might identify the patients at higher risk of acute cellular rejection and major adverse cardiovascular events. It may also allow optimization and enhancement of post-transplantation management. Moreover, cardiac allograft vasculopathy is an independent prognostic factor for transplant rejection and survival rate. The studies showed that the index of microcirculatory resistance correlates with anatomic changes and reflects the deteriorating physiology of the epicardial arteries. In conclusion, invasive assessment of the coronary microcirculation, including the measurement of the microcirculatory resistance index, is a promising approach to predict graft dysfunction, especially the acute allograft rejection subtype, during the first year after heart transplantation. However, further advanced studies are needed to fully grasp the importance of microcirculatory dysfunction in patients after heart transplantation.
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Affiliation(s)
- Sylwia Iwańczyk
- 1st Department of Cardiology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | - Patrycja Woźniak
- 1st Department of Cardiology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | - Anna Smukowska-Gorynia
- 1st Department of Cardiology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | | | - Alicja Nowak
- 1st Department of Cardiology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | - Maurycy Jankowski
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-701 Poznań, Poland
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | - Aneta Konwerska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | - Tomasz Urbanowicz
- Cardiac Surgery and Transplantology Department, Poznan University of Medical Sciences, 60-701 Poznań, Poland
| | - Maciej Lesiak
- 1st Department of Cardiology, Poznan University of Medical Sciences, 60-701 Poznań, Poland
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Civieri G, Masiero G, Osto E, Gambino A, Angelini A, Fraiese A, Fedrigo M, Toscano G, Bottio T, Perazzolo Marra M, Iliceto S, Gerosa G, Tona F. Coronary Collateral Circulation: A New Predictor of Mortality in Heart Transplant Recipients With Allograft Vasculopathy. Transplant Direct 2023; 9:e1470. [PMID: 37090121 PMCID: PMC10118324 DOI: 10.1097/txd.0000000000001470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 04/25/2023] Open
Abstract
Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT.
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Affiliation(s)
- Giovanni Civieri
- Cardiology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Giulia Masiero
- Cardiology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Elena Osto
- Department of Cardiology, Heart Center, University Hospital Zurich and University of Zürich, Zurich, Switzerland
- Institute for Clinical Chemistry, University Hospital Zurich and University of Zürich, Zurich, Switzerland
| | - Antonio Gambino
- Division of Cardiac Surgery, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Annalisa Angelini
- Cardiac Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Angela Fraiese
- Department of Cardiology, Heart Center, University Hospital Zurich and University of Zürich, Zurich, Switzerland
| | - Marny Fedrigo
- Cardiac Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Giuseppe Toscano
- Department of Cardiology, Heart Center, University Hospital Zurich and University of Zürich, Zurich, Switzerland
| | - Tomaso Bottio
- Department of Cardiology, Heart Center, University Hospital Zurich and University of Zürich, Zurich, Switzerland
| | - Martina Perazzolo Marra
- Cardiology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Sabino Iliceto
- Cardiology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Gino Gerosa
- Department of Cardiology, Heart Center, University Hospital Zurich and University of Zürich, Zurich, Switzerland
| | - Francesco Tona
- Cardiology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
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Ding Q, Loganathan S, Zhou P, Sayour AA, Brlecic P, Radovits T, Domain R, Korkmaz B, Karck M, Szabó G, Korkmaz-Icöz S. Alpha-1-Antitrypsin Protects Vascular Grafts of Brain-Dead Rats Against Ischemia/Reperfusion Injury. J Surg Res 2023; 283:953-964. [PMID: 36915024 DOI: 10.1016/j.jss.2022.11.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/04/2022] [Accepted: 11/20/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Endothelial dysfunction is a potential side effect of brain death (BD). Ischemia/reperfusion (IR) injury during heart transplantation may lead to further endothelial damage. Protective effects of alpha-1-antitrypsin (AAT), a human neutrophil serine protease inhibitor, have been demonstrated against IR injury. We hypothesized that AAT protects brain-dead rats' vascular grafts from IR injury. METHODS Donor rats were subjected to BD by inflation of a subdural balloon. After 5.5 h, aortic rings were immediately mounted in organ baths (BD, n = 6 rats) or preserved in saline, supplemented either with vehicle (BD-IR, n = 8 rats) or AAT (BD-IR + AAT, n = 14 rats) for 24 h. During organ bath experiment, rings from both IR groups were exposed to hypochlorite to simulate warm reperfusion-associated endothelial injury. Endothelial function was measured ex vivo. Immunohistochemical staining for caspases was carried out and DNA-strand breaks were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Data are presented as median (interquartile range). RESULTS AAT improved IR-induced decreased maximum endothelium-dependent vasorelaxation to acetylcholine in the BD-IR + AAT aortas compared to the BD-IR group (BD: 83 (9-28) % versus BD-IR: 49 (39-60) % versus BD-IR + AAT: 64 (24-42) %, P < 0.05). Additionally, an increase in the rings' sensitivity to acetylcholine was noted after AAT (pD2-value: BD-IR + AAT: 7.35 (7.06-7.89) versus BD-IR: 6.96 (6.65-7.21), P < 0.05). Caspase-3, -8, -9, and -12 immunoreactivity and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were significantly decreased by AAT. CONCLUSIONS AAT alleviates endothelial dysfunction, prevents increased caspase-3, -8, -9, and -12 levels, and decreases apoptotic DNA breakage due to BD and IR injury. This suggests that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular damage.
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Affiliation(s)
- Qingwei Ding
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Sivakkanan Loganathan
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany; Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, Germany
| | - Pengyu Zhou
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Alex Ali Sayour
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany; Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Paige Brlecic
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Roxane Domain
- INSERM UMR-1100, "Research Center for Respiratory Diseases" and University of Tours, Tours, France
| | - Brice Korkmaz
- INSERM UMR-1100, "Research Center for Respiratory Diseases" and University of Tours, Tours, France
| | - Matthias Karck
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Gábor Szabó
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany; Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, Germany
| | - Sevil Korkmaz-Icöz
- Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany; Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, Germany.
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Bockus L, Kim F. Coronary endothelial dysfunction: from pathogenesis to clinical implications. Open Heart 2022; 9:e002200. [PMID: 36600608 PMCID: PMC9743399 DOI: 10.1136/openhrt-2022-002200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 11/14/2022] [Indexed: 12/13/2022] Open
Abstract
Endothelial dysfunction (ED) has a substantial role in the pathogenesis of atherosclerosis and other vascular diseases. Multiple risk factors, including smoking, hyperlipiadaemia and diabetes, can have associated ED, which is correlated with cardiac events. Measurement of coronary artery endothelial function requires the use of invasive techniques to assess both epicardial coronary artery and microvascular beds. Peripheral vascular techniques and endothelial biomarkers can be used to indirectly assess coronary ED. In this review of coronary artery ED, we discuss the current state of the field, the techniques used to measure ED and its clinical implications.
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Affiliation(s)
- Lee Bockus
- Deparment of Medicine, University of Washington, Seattle, Washington, USA
| | - Francis Kim
- Deparment of Medicine, University of Washington, Seattle, Washington, 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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11
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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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12
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Makkeyah SM, Elseedawy ME, Abdel-Kader HM, Mokhtar GM, Ragab IA. Vascular endothelial growth factor response with propranolol therapy in patients with infantile hemangioma. Pediatr Hematol Oncol 2022; 39:215-224. [PMID: 34477031 DOI: 10.1080/08880018.2021.1961956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Vascular endothelial growth factor-A (VEGF-A) is a master regulator of angiogenesis, with higher levels in infantile hemangioma (IH). The effects of propranolol on IH are not fully understood and may involve vasoconstriction, angiogenesis inhibition, and apoptosis induction. Therefore, we examined the effects of propranolol therapy on levels of VEGF-A in patients with IH in the proliferative phase and compared the VEGF-A levels to those in untreated patients in the involuting or involuted phases, as well as studied the consistency between the clinical and VEGF responses in patients receiving treatment. In a prospective study, we compared 24 patients with IH in the proliferative phase to 9 patients with IH in the involuting or involuted phase, assessing clinical responses to therapy and changes in VEGF-A levels after 3 months. The median VEGF level before treatment was 275 pg/ml; however, after 3 months, the level significantly decreased to 100 pg/ml (P = 0.007). Median VEGF was significantly higher in patients in the proliferative phase after 3 months of treatment (100 pg/ml) as compared to those in the involuting phase (50 pg/ml). We found no significant correlation between VEGF level and IH size reduction. Propranolol therapy induced a significant decline in VEGF levels at the 3-month evaluation in patients in the proliferative phase; however, this did not reach the levels of IH in the involuting phase. VEGF response was not translated to a clinical response in some patients with IH. These results put in uncertainty the clinical benefit of targeting VEGF pathway in IH.
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Affiliation(s)
- S M Makkeyah
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - M E Elseedawy
- bDepartment of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - H M Abdel-Kader
- bDepartment of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - G M Mokhtar
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - I A Ragab
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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13
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Wei D, Trenson S, Van Keer JM, Melgarejo J, Cutsforth E, Thijs L, He T, Latosinska A, Ciarka A, Vanassche T, Van Aelst L, Janssens S, Van Cleemput J, Mischak H, Staessen JA, Verhamme P, Zhang ZY. The novel proteomic signature for cardiac allograft vasculopathy. ESC Heart Fail 2022; 9:1216-1227. [PMID: 35005846 PMCID: PMC8934921 DOI: 10.1002/ehf2.13796] [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: 09/10/2021] [Revised: 11/24/2021] [Accepted: 12/17/2021] [Indexed: 01/01/2023] Open
Abstract
AIMS Cardiac allograft vasculopathy (CAV) is the major long-term complication after heart transplantation, leading to mortality and re-transplantation. As available non-invasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV. METHODS AND RESULTS We measured urinary proteome by capillary electrophoresis coupled with mass spectrometry in 217 heart transplantation recipients (mean age: 55.0 ± 14.4 years; women: 23.5%), including 76 (35.0%) patients with CAV diagnosed by coronary angiography. We randomly and evenly grouped participants into the derivation cohort (n = 108, mean age: 56.4 ± 13.8 years; women: 22.2%; CAV: n = 38) and the validation cohort (n = 109, mean age: 56.4 ± 13.8 years; women: 24.8%, CAV: n = 38), stratified by CAV. Using the decision tree-based machine learning methods (extreme gradient boost), we constructed a proteomic signature for CAV discrimination in the derivation cohort and verified its performance in the validation cohort. The proteomic signature that consisted of 27 peptides yielded areas under the curve of 0.83 [95% confidence interval (CI): 0.75-0.91, P < 0.001] and 0.71 (95% CI: 0.60-0.81, P = 0.001) for CAV discrimination in the derivation and validation cohort, respectively. With the optimized threshold of 0.484, the sensitivity, specificity, and accuracy for CAV differentiation in the validation cohort were 68.4%, 73.2%, and 71.6%, respectively. With adjustment of potential clinical confounders, the signature was significantly associated with CAV [adjusted odds ratio: 1.31 (95% CI: 1.07-1.64) for per 0.1% increment in the predicted probability, P = 0.012]. Diagnostic accuracy significantly improved by adding the signature to the logistic model that already included multiple clinical risk factors, suggested by the integrated discrimination improvement of 9.1% (95% CI: 2.5-15.3, P = 0.005) and net reclassification improvement of 83.3% (95% CI: 46.7-119.5, P < 0.001). Of the 27 peptides, the majority were the fragments of collagen I (44.4%), collagen III (18.5%), collagen II (3.7%), collagen XI (3.7%), mucin-1 (3.7%), xylosyltransferase 1 (3.7%), and protocadherin-12 (3.7%). Pathway analysis performed in Reactome Pathway Database revealed that the multiple pathways involved by the signature were related to the pathogenesis of CAV, such as collagen turnover, platelet aggregation and coagulation, cell adhesion, and motility. CONCLUSIONS This pilot study identified and validated a urinary proteomic signature that provided a potential approach for the surveillance of CAV. These proteins might provide insights into CAV pathological processes and call for further investigation into personalized treatment targets.
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Affiliation(s)
- Dongmei Wei
- Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 7, Box 7001, Leuven, BE-3000, Belgium
| | - Sander Trenson
- Department of Cardiology, Sint-Jan Hospital Bruges, Bruges, Belgium
| | - Jan M Van Keer
- Division of Cardiology, University Hospitals Leuven, Leuven, Belgium
| | - Jesus Melgarejo
- Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 7, Box 7001, Leuven, BE-3000, Belgium
| | - Ella Cutsforth
- Biomedical Sciences Group, Faculty of Medicine, University of Leuven, Leuven, Belgium
| | - Lutgarde Thijs
- Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 7, Box 7001, Leuven, BE-3000, Belgium
| | - Tianlin He
- Mosaiques Diagnostics GmbH, Hannover, Germany
| | | | - Agnieszka Ciarka
- Division of Cardiology, University Hospitals Leuven, Leuven, Belgium.,Faculty of Medicine, University of Information Technology and Management in Rzeszow, Rzeszow, Poland
| | - Thomas Vanassche
- Centre for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Lucas Van Aelst
- Division of Cardiology, University Hospitals Leuven, Leuven, Belgium
| | - Stefan Janssens
- Division of Cardiology, University Hospitals Leuven, Leuven, Belgium
| | | | - Harald Mischak
- Mosaiques Diagnostics GmbH, Hannover, Germany.,BHF Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Jan A Staessen
- Biomedical Sciences Group, Faculty of Medicine, University of Leuven, Leuven, Belgium.,Non-Profit Research Institute Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium
| | - Peter Verhamme
- Centre for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Zhen-Yu Zhang
- Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 7, Box 7001, Leuven, BE-3000, Belgium
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14
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Impact of Exercise Modalities on Peripheral and Central Components of Cardiorespiratory Capacity in Heart Transplantation Patients: A Systematic Review and Meta-Analysis. Medicina (B Aires) 2021; 58:medicina58010032. [PMID: 35056339 PMCID: PMC8779927 DOI: 10.3390/medicina58010032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/10/2021] [Accepted: 12/24/2021] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives: To analyze the effects of aerobic, resistance, and combined training on peripheral and central components related to cardiorespiratory capacity after HTx. Materials and Methods: No time restriction was applied for study inclusion. MEDLINE/PubMed; EMBASE, CENTRAL, and PEDro databases were investigated. Studies reporting heart transplanted patients older than 19 years following aerobic, resistance, and combined training according. The outcomes included: V′O2 peak, VE/V’CO2 slope, heart rate (HR peak), systolic and diastolic blood pressure (SBP and DBP peak), maximum repetition test(1RM), sit-to-stand test, and flow-mediated dilation (FMD). The studies were selected by consensus. Four hundred ninety-two studies initially met the selection criteria. Cochrane handbook was used for abstracting data and assessing data quality and validity. Independent extraction by two observers was applied. Results: Isolated aerobic training leads to a greater increase in V′O2 peak than combined training compared to the control group (p < 0.001, I2 = 0%). However, no significant differences were found in the subgroup comparison (p = 0.19, I2 = 42.1%). HR peak increased similarly after aerobic and combined training. High-intensity interval training (HIIT) was better than moderate continuous intensity to increase the V′O2 after long term in HTx. Still, there is scarce evidence of HIIT on muscle strength and FMD. No change on VE/V’CO2 slope, FMD, and SBP, DBP peak. 1RM and the sit-to-stand test increased after resistance training (p < 0.001, I2 = 70%) and CT (p < 0.001, I2 = 0%) when compared to control. Conclusions: Aerobic and combined training effectively improve VO2 peak and muscle strength, respectively. HIIT seems the better choice for cardiorespiratory capacity improvements. More studies are needed to examine the impact of training modalities on VE/V’CO2 slope and FMD.
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15
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Korkmaz-Icöz S, Zhou P, Guo Y, Loganathan S, Brlecic P, Radovits T, Sayour AA, Ruppert M, Veres G, Karck M, Szabó G. Mesenchymal stem cell-derived conditioned medium protects vascular grafts of brain-dead rats against in vitro ischemia/reperfusion injury. Stem Cell Res Ther 2021; 12:144. [PMID: 33627181 PMCID: PMC7905634 DOI: 10.1186/s13287-021-02166-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Brain death (BD) has been suggested to induce coronary endothelial dysfunction. Ischemia/reperfusion (IR) injury during heart transplantation may lead to further damage of the endothelium. Previous studies have shown protective effects of conditioned medium (CM) from bone marrow-derived mesenchymal stem cells (MSCs) against IR injury. We hypothesized that physiological saline-supplemented CM protects BD rats' vascular grafts from IR injury. METHODS The CM from rat MSCs, used for conservation purposes, indicates the presence of 23 factors involved in apoptosis, inflammation, and oxidative stress. BD was induced by an intracranial-balloon. Controls were subjected to a sham operation. After 5.5 h, arterial pressures were measured in vivo. Aortic rings from BD rats were harvested and immediately mounted in organ bath chambers (BD group, n = 7) or preserved for 24 h in 4 °C saline-supplemented either with a vehicle (BD-IR group, n = 8) or CM (BD-IR+CM group, n = 8), prior to mounting. Vascular function was measured in vitro. Furthermore, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) have been performed. RESULTS BD in donors was associated with significantly impaired hemodynamic parameters and higher immunoreactivity of aortic myeloperoxidase (MPO), nitrotyrosine, caspase-3, caspase-8, caspase-9, and caspase-12 compared to sham-operated rats. In organ bath experiments, impaired endothelium-dependent vasorelaxation to acetylcholine in the BD-IR group compared to BD rats was significantly improved by CM (maximum relaxation to acetylcholine: BD 81 ± 2% vs. BD-IR 50 ± 3% vs. BD-IR + CM 72 ± 2%, p < 0.05). Additionally, the preservation of BD-IR aortic rings with CM significantly lowered MPO, caspase-3, caspase-8, and caspase-9 immunoreactivity compared with the BD-IR group. Furthermore, increased mRNA expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the aortas from the BD-IR rats compared to BD group were significantly decreased by CM. CONCLUSIONS The preservation of BD rats' vascular grafts with CM alleviates endothelial dysfunction following IR injury, in part, by reducing levels of inflammatory response and caspase-mediated apoptosis.
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Affiliation(s)
- Sevil Korkmaz-Icöz
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany.
| | - Pengyu Zhou
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany
| | - Yuxing Guo
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany
| | - Sivakkanan Loganathan
- Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, 06120, Germany
| | - Paige Brlecic
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, 1122, Hungary
| | - Alex Ali Sayour
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany.,Heart and Vascular Center, Semmelweis University, Budapest, 1122, Hungary
| | - Mihály Ruppert
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany.,Heart and Vascular Center, Semmelweis University, Budapest, 1122, Hungary
| | - Gábor Veres
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany.,Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, 06120, Germany
| | - Matthias Karck
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany
| | - Gábor Szabó
- Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University Hospital Heidelberg, INF 326, 69120, Heidelberg, Germany.,Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, 06120, Germany
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16
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Golbus JR, Adie S, Yosef M, Murthy VL, Aaronson KD, Konerman MC. Statin intensity and risk for cardiovascular events after heart transplantation. ESC Heart Fail 2020; 7:2074-2081. [PMID: 32578953 PMCID: PMC7524051 DOI: 10.1002/ehf2.12784] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/26/2020] [Accepted: 04/27/2020] [Indexed: 01/20/2023] Open
Abstract
AIMS Statins improve survival and reduce rejection and cardiac allograft vasculopathy after heart transplantation (HT). The impact of different statin intensities on clinical outcomes has never been assessed. We set out to determine the impact of statin exposure on cardiovascular outcomes after HT. METHODS AND RESULTS We performed a retrospective study of 346 adult patients who underwent HT from 2006 to 2018. Statin intensity was determined longitudinally after HT based on American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The primary outcome was the time to the first primary event defined as the composite of heart failure hospitalization, myocardial infarction, revascularization, and all-cause mortality. Secondary outcomes included time to significant rejection and time to moderate-severe cardiac allograft vasculopathy. Adverse events were evaluated for subjects on high-intensity statin therapy. A Cox proportional hazards model was used to evaluate the relationship between clinical variables, statin intensity, and outcomes. Most subjects were treated with low-intensity statin therapy although this declined from 89.9% of the population at 1month after HT to 42.8% at 5years after HT. History of ischaemic cardiomyopathy, significant acute rejection, older donor age, and lesser statin intensity (p ≤ 0.001) were associated with reduced time to the primary outcome in a multivariable Cox model. Greater intensity of statin therapy was most beneficial early after HT. There were no statin-related adverse events for the 14 subjects on high-intensity statin therapy. CONCLUSIONS Greater statin intensity was associated with a reduction in adverse cardiovascular outcomes after HT.
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Affiliation(s)
- Jessica R Golbus
- Department of Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - Sarah Adie
- University of Michigan Health System, Ann Arbor, MI, USA
| | - Matheos Yosef
- Michigan Institute of Clinical and Health Research, University of Michigan, Ann Arbor, MI, USA
| | - Venkatesh L Murthy
- Department of Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - Keith D Aaronson
- Department of Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - Matthew C Konerman
- Department of Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA
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17
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Aleksova N, So DY, Stadnick E, Mielniczuk LM, Chih S. Increased platelet reactivity after heart transplantation. TRANSPLANTATION REPORTS 2020. [DOI: 10.1016/j.tpr.2020.100044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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18
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Bellumkonda L, Patel J. Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy. Clin Transplant 2019; 34:e13769. [DOI: 10.1111/ctr.13769] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Lavanya Bellumkonda
- Division of Cardiology Department of Medicine Yale School of Medicine New Haven CT USA
| | - Jignesh Patel
- Cedars‐Sinai Medical Center Smidt Heart Institute Los Angeles CA USA
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19
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Konerman MC, Lazarus JJ, Weinberg RL, Shah RV, Ghannam M, Hummel SL, Corbett JR, Ficaro EP, Aaronson KD, Colvin MM, Koelling TM, Murthy VL. Reduced Myocardial Flow Reserve by Positron Emission Tomography Predicts Cardiovascular Events After Cardiac Transplantation. Circ Heart Fail 2019; 11:e004473. [PMID: 29891737 DOI: 10.1161/circheartfailure.117.004473] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND We evaluated the diagnostic and prognostic value of quantification of myocardial flow reserve (MFR) with positron emission tomography (PET) in orthotopic heart transplant patients. METHODS AND RESULTS We retrospectively identified orthotopic heart transplant patients who underwent rubidium-82 cardiac PET imaging. The primary outcome was the composite of cardiovascular death, acute coronary syndrome, coronary revascularization, and heart failure hospitalization. Cox regression was used to evaluate the association of MFR with the primary outcome. The relationship of MFR and cardiac allograft vasculopathy severity in patients with angiography within 1 year of PET imaging was assessed using Spearman rank correlation and logistic regression. A total of 117 patients (median age, 60 years; 71% men) were identified. Twenty-one of 62 patients (34%) who underwent angiography before PET had cardiac allograft vasculopathy. The median time from orthotopic heart transplant to PET imaging was 6.4 years (median global MFR, 2.31). After a median of 1.4 years, 22 patients (19%) experienced the primary outcome. On an unadjusted basis, global MFR (hazard ratio, 0.22 per unit increase; 95% confidence interval, 0.09-0.50; P<0.001) and stress myocardial blood flow (hazard ratio, 0.48 per unit increase; 95% confidence interval, 0.29-0.79; P=0.004) were associated with the primary outcome. Decreased MFR independently predicted the primary outcome after adjustment for other variables. In 42 patients who underwent angiography within 12 months of PET, MFR and stress myocardial blood flow were associated with moderate-severe cardiac allograft vasculopathy (International Society of Heart and Lung Transplantation grade 2-3). CONCLUSIONS MFR assessed by cardiac rubidium-82 PET imaging is a predictor of cardiovascular events after orthotopic heart transplant and is associated with cardiac allograft vasculopathy severity.
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Affiliation(s)
- Matthew C Konerman
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - John J Lazarus
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Richard L Weinberg
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Ravi V Shah
- University of Michigan, Ann Arbor. Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston (R.V.S.)
| | | | - Scott L Hummel
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - James R Corbett
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.).,Division of Nuclear Medicine, Department of Radiology (J.R.C., E.P.F., V.L.M.)
| | - Edward P Ficaro
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.).,Division of Nuclear Medicine, Department of Radiology (J.R.C., E.P.F., V.L.M.)
| | - Keith D Aaronson
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Monica M Colvin
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Todd M Koelling
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.)
| | - Venkatesh L Murthy
- Division of Cardiovascular Medicine, Department of Internal Medicine (M.C.K., J.J.L., R.L.W., M.G., S.L.H., J.R.C., K.D.A., M.M.C., T.M.K., V.L.M.).,Division of Nuclear Medicine, Department of Radiology (J.R.C., E.P.F., V.L.M.)
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20
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Cote AT, Hosking M, Voss C, Human DG, Sandor GGS, Harris KC. Coronary artery intimal thickening and ventricular dynamics in pediatric heart transplant recipients. CONGENIT HEART DIS 2018; 13:663-670. [DOI: 10.1111/chd.12629] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 05/18/2018] [Accepted: 05/21/2018] [Indexed: 11/26/2022]
Affiliation(s)
- Anita T. Cote
- Department of Pediatrics; University of British Columbia & British Columbia Children’s Hospital Research Institute; Vancouver Canada
- School of Human Kinetics; Trinity Western University; Langley Canada
| | - Martin Hosking
- British Columbia Children’s Hospital, Children’s Heart Centre; Vancouver Canada
| | - Christine Voss
- Department of Pediatrics; University of British Columbia & British Columbia Children’s Hospital Research Institute; Vancouver Canada
- British Columbia Children’s Hospital, Children’s Heart Centre; Vancouver Canada
| | - Derek G Human
- British Columbia Children’s Hospital, Children’s Heart Centre; Vancouver Canada
| | - George G. S. Sandor
- Department of Pediatrics; University of British Columbia & British Columbia Children’s Hospital Research Institute; Vancouver Canada
- British Columbia Children’s Hospital, Children’s Heart Centre; Vancouver Canada
| | - Kevin C. Harris
- Department of Pediatrics; University of British Columbia & British Columbia Children’s Hospital Research Institute; Vancouver Canada
- British Columbia Children’s Hospital, Children’s Heart Centre; Vancouver Canada
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21
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Assessment of myocardial blood flow and coronary flow reserve with positron emission tomography in ischemic heart disease: current state and future directions. Heart Fail Rev 2018; 22:441-453. [PMID: 28593557 DOI: 10.1007/s10741-017-9625-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Positron emission tomography (PET) is a versatile imaging technology that allows assessment of myocardial perfusion, both at a spatially relative scale and also in absolute terms, thereby enabling noninvasive evaluation of myocardial blood flow (MBF) and coronary flow reserve (CFR). Assessment of MBF using FDA-approved PET isotopes, such as 82Rb and 13N-ammonia, has been well validated, and several software packages are currently available, thereby allowing for MBF evaluation to be incorporated into routine workflow in contemporary nuclear laboratories. Incremental diagnostic and prognostic information provided with the knowledge of MBF has the potential for widespread applications. Improving the ability to identify the true burden of obstructive epicardial coronary stenoses and allowing for noninvasive assessment of coronary micro circulatory function can be achieved with MBF assessment. On the other hand, attenuated CFR has been shown to predict adverse cardiovascular prognosis in a variety of clinical settings and patient subgroups. With expanding applications of MBF, this tool promises to provide unique insight into the integrity of the entire coronary vascular bed beyond what is currently available with relative perfusion assessment. This review intends to provide an in-depth discussion of technical and clinical aspects of MBF assessment with PET as it relates to patients with ischemic heart disease.
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22
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Chernyavskiy AM, Doronin DV, Fomichev AV, Osipov DE, Shmyrev VA, Karaskov AM. 10-YEAR HEART TRANSPLANTATION EXPERIENCE IN NOVOSIBIRSK. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2018. [DOI: 10.15825/1995-1191-2018-1-23-31] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Aim:to show the analysis of 10-year heart transplantation experience, the main complications and problems of the heart transplantation evaluation. Materials and methods.66 orthotopic heart transplantations were performed in patients with terminal chronic heart failure in our clinic since 2008. The heart failure causes were dilated cardiomyopathy in 46 cases (70%), postinfarction cardiosclerosis in 20 cases (30%). The recipients were 59 men (89%) and 7 women (11%), the average age was 46 ± 10 years. All patients had a severe left heart dilatation and critical left ventricular systolic dysfunction (left ventricular EDV 283 ± 58 ml, left ventricular ejection fraction 17 ± 5%, cardiac index 1.5 ± 0.3 l/min/m2). In some recipients, heart transplantation is performed in the second stage after preliminary implantation of mechanical circulatory support systems (LVAD, BVAD). The fi rst heart transplantations were performed using the biatrial technique (8 cases (12%)), the others were performed using the bicaval technique (58 cases (88%)). After the operation, patients received a three-component immunosuppressive therapy: the inhibitors of calcineurin, mycophenolate and corticosteroids.Results.54 patients (82%) were discharged from the clinic after heart transplantation. The hospital mortality was 12 recipients (18%). The mortality in the long-term period was 10 recipients (15%). The hospital mortality cases were acute graft dysfunction in 5 cases (42%), infectious-septic complications in 4 cases (33%), massive intraoperative bleeding in 2 cases (17%), and total thrombosis of pulmonary artery in 1 case (8%). The death causes in the long-term period were acute transplant rejection in 4 cases (40%), coronary artery disease of the transplanted heart in 3 cases (30%), Kaposi’s sarcoma in 1 case (10%), lung cancer in 1 case (10%), and viral pneumonia in 1 case (10%).Conclusion.Over a 10-year period, we have gained a lot of experience in heart transplantation; the procedures complications have been studied; the stages of preservation, harvesting and transportation of the donor heart, operative technique and postoperative treatment of patients have been improved to avoid complications in the early and long-term postoperative period.
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Affiliation(s)
- A. M. Chernyavskiy
- Meshalkin National Medical Research Center, Ministry of Health of Russian Federation
| | - D. V. Doronin
- Meshalkin National Medical Research Center, Ministry of Health of Russian Federation
| | - A. V. Fomichev
- Meshalkin National Medical Research Center, Ministry of Health of Russian Federation
| | - D. E. Osipov
- Meshalkin National Medical Research Center, Ministry of Health of Russian Federation
| | - V. A. Shmyrev
- Meshalkin National Medical Research Center, Ministry of Health of Russian Federation
| | - A. M. Karaskov
- Meshalkin National Medical Research Center, Ministry of Health of Russian Federation
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23
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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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24
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Alba AC, Foroutan F, Ng Fat Hing NKV, Fan CPS, Manlhiot C, Ross HJ. Incidence and predictors of sudden cardiac death after heart transplantation: A systematic review and meta-analysis. Clin Transplant 2018; 32:e13206. [DOI: 10.1111/ctr.13206] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2018] [Indexed: 11/29/2022]
Affiliation(s)
- Ana C. Alba
- Heart Failure and Transplantation Program; Toronto General Hospital; University Health Network; Toronto ON Canada
| | - Farid Foroutan
- Heart Failure and Transplantation Program; Toronto General Hospital; University Health Network; Toronto ON Canada
| | | | - Chun-Po S. Fan
- The Hospital for Sick Children; University of Toronto; Toronto ON Canada
| | - Cedric Manlhiot
- The Hospital for Sick Children; University of Toronto; Toronto ON Canada
| | - Heather J. Ross
- Heart Failure and Transplantation Program; Toronto General Hospital; University Health Network; Toronto ON Canada
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25
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Peled Y, Lavee J, Raichlin E, Katz M, Arad M, Kassif Y, Peled A, Asher E, Elian D, Har-Zahav Y, Shlomo N, Freimark D, Goldenberg I, Klempfner R. Early aspirin initiation following heart transplantation is associated with reduced risk of allograft vasculopathy during long-term follow-up. Clin Transplant 2017; 31. [DOI: 10.1111/ctr.13133] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2017] [Indexed: 11/26/2022]
Affiliation(s)
- Yael Peled
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Jacob Lavee
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Eugenia Raichlin
- Cardiology Department; Loyola University Medical Center; Maywood IL USA
| | - Moshe Katz
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Michael Arad
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Yigal Kassif
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Amir Peled
- Clalit Health Services; Central Region; Tel Aviv Israel
| | - Elad Asher
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Dan Elian
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Yedael Har-Zahav
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
| | - Nir Shlomo
- Israeli Association for Cardiovascular Trials; Sheba Medical Center; Israel
| | - Dov Freimark
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
| | - Ilan Goldenberg
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
- Israeli Association for Cardiovascular Trials; Sheba Medical Center; Israel
| | - Robert Klempfner
- The Leviev Heart Center; Sheba Medical Center; Tel Hashomer Israel
- Sackler School of Medicine; Tel Aviv University; Tel Aviv Israel
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26
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van Geuns RJ, Sideris G, Van Royen N, El Mahmoud R, Diletti R, Bal Dit Sollier C, Garot J, Van Der Hoeven NW, Cortese B, Ding L, Lechthaler I, Deliargyris EN, Anthopoulos P, Drouet L. Bivalirudin infusion to reduce ventricular infarction: the open-label, randomised Bivalirudin Infusion for Ventricular InfArction Limitation (BIVAL) study. EUROINTERVENTION 2017; 13:e540-e548. [PMID: 28506937 DOI: 10.4244/eij-d-17-00307] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
AIMS The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI). METHODS AND RESULTS This multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0±19.7 g for bivalirudin vs. 27.1±20.7 g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8 g vs. 7.7±6.3 g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility. CONCLUSIONS This study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.
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27
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Pampaloni MH, Shrestha UM, Sciammarella M, Seo Y, Gullberg GT, Botvinick EH. Noninvasive PET quantitative myocardial blood flow with regadenoson for assessing cardiac allograft vasculopathy in orthotopic heart transplantation patients. J Nucl Cardiol 2017; 24:1134-1144. [PMID: 28138813 PMCID: PMC5534390 DOI: 10.1007/s12350-016-0761-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 08/22/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND Risk stratification and early detection of cardiac allograft vasculopathy (CAV) is essential in orthotopic heart transplantation (OHT) patients. This study assesses the changes in myocardial blood flow (MBF) noninvasively in OHT patients using quantitative cardiac PET with regadenoson. METHODS Twelve patients (Group 1) (8 males, 4 females, mean age 55 ± 7 years) with no history of post OHT myocardial ischemia were enrolled 5.4 ± 2.0 years after OHT. Fifteen patients (Group 2) (9 males, 6 females, mean age 71 ± 9 years) with intermediate pretest probability but not documented evidence for coronary artery disease (CAD) were also included to serve as control. Global and regional MBFs were assessed using dynamic 13N-NH3 PET at rest and during regadenoson-induced hyperemia. The coronary flow reserve (CFR) was also calculated as the ratio of hyperemic to resting MBF. RESULTS Mean regadenoson-induced rate-pressure products were similar in both groups, while there was an increase in resting rate-pressure product in Group 1 patients. Both mean and median values of resting MBF were higher in Group 1 than Group 2 patients (1.33 ± 0.31 and 1.01 ± 0.21 mL/min/g for Groups 1 and 2, respectively, P < .001), while mean hyperemic MBF values were similar in both Groups (2.68 ± 0.84 and 2.64 ± 0.94 mL/min/g, P = NS) but median hyperemic MBF values were lower in Group 1 than Group 2 patients (2.0 vs. 2.60 mL/min/g, P = .018). Both mean and median CFR values demonstrated a significant reduction for Group 1 compared to Group 2 patients (2.07 ± 0.74 vs 2.63 ± 0.48, P = .025). CONCLUSIONS This study suggests that the MBF in OHT patients may be abnormal at resting state with diminished CFR. This hints that the epicardial and microvascular coronary subsystem may be exacerbated after OHT leading to the gradual progression of CAV.
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Affiliation(s)
- Miguel Hernandez Pampaloni
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., Suite 350, San Francisco, CA, 94143-0946, USA
| | - Uttam M Shrestha
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., Suite 350, San Francisco, CA, 94143-0946, USA.
| | - Maria Sciammarella
- Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Youngho Seo
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., Suite 350, San Francisco, CA, 94143-0946, USA
| | - Grant T Gullberg
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., Suite 350, San Francisco, CA, 94143-0946, USA
| | - Elias H Botvinick
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., Suite 350, San Francisco, CA, 94143-0946, USA
- Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA
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Abstract
PURPOSE OF REVIEW Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival after heart transplantation. Innovative new techniques to diagnose CAV have been applied to detect disease. This review will examine the current diagnostic and treatment options available to clinicians for CAV. RECENT FINDINGS Diagnostic modalities addressing the pathophysiology underlying CAV (arterial wall thickening and decreased coronary blood flow) improve diagnostic sensitivity when compared to traditional (angiography and dobutamine stress echocardiography) techniques. SUMMARY Limited options are available to prevent and treat CAV; however, progress has been made in making an earlier and more accurate diagnosis. Future research is needed to identify the optimal time to modify immunosuppression and investigate novel treatments for CAV.
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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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Abstract
Although the number of available donor hearts severely limits the epidemiologic impact of heart transplantation on patients with heart failure, patients with end-stage heart failure unresponsive to medical management currently have no other viable alternatives. Destination therapy with a ventricular assist device is the closest toward approaching clinical reality but has been plagued with problems of infection and stroke. The purpose of this review is to summarize recent developments in the field that may broaden the clinical impact of heart transplantation. For example, novel methods of cardiac preservation are being designed to safely evaluate and utilize “extended criteria” donors. Surgical techniques and medical management have reduced the incidence of postoperative right heart failure, and immunosuppressive regimens promise to limit chronic graft vascular disease.
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Platelet-derived Growth Factor-B Protects Rat Cardiac Allografts From Ischemia-reperfusion Injury. Transplantation 2016; 100:303-13. [PMID: 26371596 DOI: 10.1097/tp.0000000000000909] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Microvascular dysfunction and cardiomyocyte injury are hallmarks of ischemia-reperfusion injury (IRI) after heart transplantation. Platelet-derived growth factors (PDGF) have an ambiguous role in this deleterious cascade. On one hand, PDGF may exert vascular stabilizing and antiapoptotic actions through endothelial-pericyte and endothelial-cardiomyocyte crosstalk in the heart; and on the other hand, PDGF signaling mediates neointimal formation and exacerbates chronic rejection in cardiac allografts. The balance between these potentially harmful and beneficial actions determines the final outcome of cardiac allografts. METHODS AND RESULTS We transplanted cardiac allografts from Dark Agouti rat and Balb mouse donors to fully major histocompatibility complex-mismatched Wistar Furth rat or C57 mouse recipients with a clinically relevant 2-hour cold ischemia and 1-hour warm ischemia. Ex vivo intracoronary delivery of adenovirus-mediated gene transfer of recombinant human PDGF-BB upregulated messenger RNA expression of anti-mesenchymal transition and survival factors BMP-7 and Bcl-2 and preserved capillary density in rat cardiac allografts at day 10. In mouse cardiac allografts PDGF receptor-β, but not -α intragraft messenger RNA levels were reduced and capillary protein localization was lost during IRI. The PDGF receptor tyrosine kinase inhibitor imatinib mesylate and a monoclonal antibody against PDGF receptor-α enhanced myocardial damage evidenced by serum cardiac troponin T release in the rat and mouse cardiac allografts 6 hours after reperfusion, respectively. Moreover, imatinib mesylate enhanced rat cardiac allograft vasculopathy, cardiac fibrosis, and late allograft loss at day 56. CONCLUSIONS Our results suggest that PDGF-B signaling may play a role in endothelial and cardiomyocyte recovery from IRI after heart transplantation.
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Roman MJ, Naqvi TZ, Gardin JM, Gerhard-Herman M, Jaff M, Mohler E. American Society of Echocardiography Report. Vasc Med 2016; 11:201-11. [PMID: 17288128 DOI: 10.1177/1358863x06070511] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Noninvasive measures of atherosclerosis have emerged as adjuncts to standard cardiovascular disease (CVD) risk factors in an attempt to refine risk stratification and the need for more aggressive preventive strategies. Two such approaches, carotid artery imaging and brachial artery reactivity testing (BART), are ultrasound based. Numerous carotid artery imaging protocols have been used, and methodologic aspects are described in detail in this review. The panel recommends that protocols: (1) use end-diastolic (minimum dimension) images for intimal-medial thickness (IMT) measurements; (2) provide separate categorization of plaque presence and IMT; (3) avoid use of a single upper limit of normal for IMT because the measure varies with age, sex, and race; and (4) incorporate lumen measurement, particularly when serial measurements are performed to account for changes in distending pressure. Protocols may vary in the number of segments wherein IMT is measured, whether near wall is measured in addition to far wall, and whether IMT measurements are derived from B-mode or M-mode images, depending on the application. BART is a technique that requires meticulous attention to patient preparation and methodologic detail. Its application is substantially more challenging than is carotid imaging and remains largely a research technique that is not readily translated into routine clinical practice.
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Affiliation(s)
- Mary J Roman
- Weill Medical College of Cornell University, New York, NY, USA.
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The index of microcirculatory resistance in the physiologic assessment of the coronary microcirculation. Coron Artery Dis 2016; 26 Suppl 1:e15-26. [PMID: 26247265 DOI: 10.1097/mca.0000000000000213] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The coronary microcirculation plays a critical role in normal cardiac physiology as well as in many disease states. However, methods to evaluate the function of the coronary microvessels have been limited by technical and theoretical issues. Recently, the index of microcirculatory resistance (IMR) has been proposed and validated as a simple and specific invasive method of assessing the coronary microcirculation. By relying on the thermodilution theory and using a pressure-temperature sensor guidewire, IMR provides a measurement of the minimum achievable microcirculatory resistance in a target coronary artery territory, enabling a quantitative assessment of the microvascular integrity. Unlike indices such as coronary flow reserve, IMR is highly reproducible and independent of hemodynamic changes. In ST-elevation myocardial infarction, IMR predicts myocardial recovery and long-term mortality, whereas in patients with stable coronary artery disease, preintervention IMR predicts the occurrence of periprocedural myocardial infarction. Increasingly, research has focused on IMR-guided interventions of the microcirculation, with the aim of preventing and/or treating the microcirculatory dysfunction that commonly accompanies the epicardial coronary disease. In the present review, we will discuss the theoretical and practical basis for IMR, the clinical studies supporting it, and the future lines of research using this novel tool.
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Abstract
Cardiac allograft vasculopathy (CAV) has a high prevalence among patients that have undergone heart transplantation. Cardiac allograft vasculopathy is a multifactorial process in which the immune system is the driving force. In this review, the data on the immunological and fibrotic processes that are involved in the development of CAV are summarized. Areas where a lack of knowledge exists and possible additional research can be completed are pinpointed. During the pathogenesis of CAV, cells from the innate and the adaptive immune system cooperate to reject the foreign heart. This inflammatory response results in dysfunction of the endothelium and migration and proliferation of smooth muscle cells (SMCs). Apoptosis and factors secreted by both the endothelium as well as the SMCs lead to fibrosis. The migration of SMCs together with fibrosis provoke concentric intimal thickening of the coronary arteries, which is the main characteristic of CAV.
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Erbel C, Mukhammadaminova N, Gleissner CA, Osman NF, Hofmann NP, Steuer C, Akhavanpoor M, Wangler S, Celik S, Doesch AO, Voss A, Buss SJ, Schnabel PA, Katus HA, Korosoglou G. Myocardial Perfusion Reserve and Strain-Encoded CMR for Evaluation of Cardiac Allograft Microvasculopathy. JACC Cardiovasc Imaging 2016; 9:255-66. [DOI: 10.1016/j.jcmg.2015.10.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 10/02/2015] [Accepted: 10/07/2015] [Indexed: 10/22/2022]
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Díez-delhoyo F, Gutiérrez-Ibañes E, Loughlin G, Sanz-Ruiz R, Vázquez-Álvarez ME, Sarnago-Cebada F, Angulo-Llanos R, Casado-Plasencia A, Elízaga J, Diáz FFA. Coronary physiology assessment in the catheterization laboratory. World J Cardiol 2015; 7:525-538. [PMID: 26413229 PMCID: PMC4577679 DOI: 10.4330/wjc.v7.i9.525] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/10/2015] [Accepted: 07/27/2015] [Indexed: 02/07/2023] Open
Abstract
Physicians cannot rely solely on the angiographic appearance of epicardial coronary artery stenosis when evaluating patients with myocardial ischemia. Instead, sound knowledge of coronary vascular physiology and of the methods currently available for its characterization can improve the diagnostic and prognostic accuracy of invasive assessment of the coronary circulation, and help improve clinical decision-making. In this article we summarize the current methods available for a thorough assessment of coronary physiology.
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Cardona A, Kondapally Seshasai SR, Davey J, Arrebola-Moreno AL, Ambrosio G, Kaski JC, Ray KK. A meta-analysis of published studies of endothelial dysfunction does not support its routine clinical use. Int J Clin Pract 2015; 69:649-58. [PMID: 25728053 DOI: 10.1111/ijcp.12630] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Endothelial dysfunction is a marker of future cardiovascular disease (CVD) risk, yet epidemiological studies have yielded inconsistent results. We therefore studied the association between endothelial dysfunction and CVD under diverse circumstances. METHODS AND RESULTS Literature-based meta-analysis of prospective observational studies with ≥ 12 months of follow-up published in Medline and having information on endothelial function and CVD outcomes. Tabular data on participant characteristics, endothelial function assessments and incident CVD outcomes were abstracted from individual studies. Random-effects meta-analysis was used to quantify pooled associations, and I(2) statistic to evaluate between-study heterogeneity. Potential sources of heterogeneity were explored by subgroup analyses and meta-regression. Thirty five studies involving 17,206 participants met the inclusion criteria. During more than 80,000 person-years of observation, up to 2755 CVD events were accrued, yielding a pooled relative risk (RR) of 1.25 (95% confidence interval 1.15-1.35) for CVD comparing top (i.e. more severe) vs. bottom (less severe) third of endothelial dysfunction. There was significant between-study heterogeneity and evidence of publication bias. RRs varied importantly according to the method used to ascertain endothelial function, and were higher among older individuals and among participants with risk factors for CVD or established CVD at baseline. CONCLUSIONS Although endothelial dysfunction is an important determinant of cardiovascular outcomes in people with pre-existing CVD, current evidence base does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD.
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Affiliation(s)
- A Cardona
- Cardiovascular and Cell Sciences Research Institute, St. George's, University of London, London, UK
- Division of Cardiology, University of Perugia School of Medicine, Perugia, Italy
| | - S R Kondapally Seshasai
- Cardiovascular and Cell Sciences Research Institute, St. George's, University of London, London, UK
| | - J Davey
- Cardiovascular and Cell Sciences Research Institute, St. George's, University of London, London, UK
| | - A L Arrebola-Moreno
- Cardiovascular and Cell Sciences Research Institute, St. George's, University of London, London, UK
- Division of Cardiology, University Hospital Virgen de Las Nieve, Granada, Spain
| | - G Ambrosio
- Division of Cardiology, University of Perugia School of Medicine, Perugia, Italy
| | - J C Kaski
- Cardiovascular and Cell Sciences Research Institute, St. George's, University of London, London, UK
| | - K K Ray
- Cardiovascular and Cell Sciences Research Institute, St. George's, University of London, London, UK
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Cardiac allograft vasculopathy: a donor or recipient induced pathology? J Cardiovasc Transl Res 2015; 8:106-16. [PMID: 25652948 PMCID: PMC4382530 DOI: 10.1007/s12265-015-9612-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 01/14/2015] [Indexed: 01/16/2023]
Abstract
Cardiac allograft vasculopathy (CAV) is one of the main causes of late-stage heart failure after heart transplantation. CAV is characterized by concentric luminal narrowing of the coronary arteries, but the exact pathogenesis of CAV is still not unraveled. Many researchers show evidence of an allogeneic immune response of the recipient, whereas others show contrasting results in which donor-derived cells induce an immune response against the graft. In addition, fibrosis of the neo-intima can be induced by recipient-derived circulating cells or donor-derived cells. In this review, both donor and recipient sides of the story are described to obtain better insight in the pathogenesis of CAV. Dual outcomes were found regarding the contribution of donor and recipient cells in the initiation of the immune response and the development of fibrosis during CAV. Future research could focus more on the potential synergistic interaction of donor and recipient cells leading to CAV.
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40
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von Rossum A, Laher I, Choy JC. Immune-mediated vascular injury and dysfunction in transplant arteriosclerosis. Front Immunol 2015; 5:684. [PMID: 25628623 PMCID: PMC4290675 DOI: 10.3389/fimmu.2014.00684] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 12/18/2014] [Indexed: 12/16/2022] Open
Abstract
Solid organ transplantation is the only treatment for end-stage organ failure but this life-saving procedure is limited by immune-mediated rejection of most grafts. Blood vessels within transplanted organs are targeted by the immune system and the resultant vascular damage is a main contributor to acute and chronic graft failure. The vasculature is a unique tissue with specific immunological properties. This review discusses the interactions of the immune system with blood vessels in transplanted organs and how these interactions lead to the development of transplant arteriosclerosis, a leading cause of heart transplant failure.
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Affiliation(s)
- Anna von Rossum
- Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, BC , Canada
| | - Ismail Laher
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, BC , Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, BC , Canada
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41
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Tousoulis D, Simopoulou C, Papageorgiou N, Oikonomou E, Hatzis G, Siasos G, Tsiamis E, Stefanadis C. Endothelial dysfunction in conduit arteries and in microcirculation. Novel therapeutic approaches. Pharmacol Ther 2014; 144:253-267. [PMID: 24928320 DOI: 10.1016/j.pharmthera.2014.06.003] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 05/28/2014] [Indexed: 11/22/2022]
Abstract
The vascular endothelium not only is a single monolayer of cells between the vessel lumen and the intimal wall, but also plays an important role by controlling vascular function and structure mainly via the production of nitric oxide (NO). The so called "cardiovascular risk factors" are associated with endothelial dysfunction, that reduces NO bioavailability, increases oxidative stress, and promotes inflammation contributing therefore to the development of atherosclerosis. The significant role of endothelial dysfunction in the development of atherosclerosis emphasizes the need for efficient therapeutic interventions. During the last years statins, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists, antioxidants, beta-blockers and insulin sensitizers have been evaluated for their ability to restore endothelial function (Briasoulis et al., 2012). As there is not a straightforward relationship between therapeutic interventions and improvement of endothelial function but rather a complicated interrelationship between multiple cellular and sub-cellular targets, research has been focused on the understanding of the underlying mechanisms. Moreover, the development of novel diagnostic invasive and non-invasive methods has allowed the early detection of endothelial dysfunction expanding the role of therapeutic interventions and our knowledge. In the current review we present the available data concerning the contribution of endothelial dysfunction to atherogenesis and review the methods that assess endothelial function with a view to understand the multiple targets of therapeutic interventions. Finally we focus on the classic and novel therapeutic approaches aiming to improve endothelial dysfunction and the underlying mechanisms.
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Affiliation(s)
- Dimitris Tousoulis
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece.
| | - Chryssa Simopoulou
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
| | - Nikos Papageorgiou
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
| | - Evangelos Oikonomou
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
| | - George Hatzis
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
| | - Gerasimos Siasos
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
| | - Eleftherios Tsiamis
- 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
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43
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Lopez-Fernandez S, Manito-Lorite N, Gómez-Hospital JA, Roca J, Fontanillas C, Melgares-Moreno R, Azpitarte-Almagro J, Cequier-Fillat A. Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation. Clin Transplant 2014; 28:1393-401. [DOI: 10.1111/ctr.12470] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2014] [Indexed: 01/28/2023]
Affiliation(s)
- Silvia Lopez-Fernandez
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
- Department of Cardiology; Virgen de las Nieves University Hospital; FIBAO; Granada Spain
| | - Nicolas Manito-Lorite
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Joan Antoni Gómez-Hospital
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Josep Roca
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Carles Fontanillas
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
| | - Rafael Melgares-Moreno
- Department of Cardiology; Virgen de las Nieves University Hospital; FIBAO; Granada Spain
| | - José Azpitarte-Almagro
- Department of Cardiology; Virgen de las Nieves University Hospital; FIBAO; Granada Spain
| | - Angel Cequier-Fillat
- Àrea de Malalties del Cor; Bellvitge University Hospital; IDIBELL; L′Hospitalet de Llobregat; Barcelona Spain
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44
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Le NT, Takei Y, Izawa-Ishizawa Y, Heo KS, Lee H, Smrcka AV, Miller BL, Ko KA, Ture S, Morrell C, Fujiwara K, Akaike M, Abe JI. Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. THE JOURNAL OF IMMUNOLOGY 2014; 193:3803-15. [PMID: 25187658 DOI: 10.4049/jimmunol.1400571] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Because ERK5 inhibits endothelial inflammation and dysfunction, activating ERK5 might be a novel approach to protecting vascular endothelial cells (ECs) against various pathological conditions of the blood vessel. We have identified small molecules that protect ECs via ERK5 activation and determined their contribution to preventing cardiac allograft rejection. Using high-throughput screening, we identified certain statins and antimalarial agents including chloroquine, hydroxychloroquine, and quinacrine as strong ERK5 activators. Pitavastatin enhanced ERK5 transcriptional activity and Kruppel-like factor-2 expression in cultured human and bovine ECs, but these effects were abolished by the depletion of ERK5. Chloroquine and hydroxychloroquine upregulated ERK5 kinase activity and inhibited VCAM-1 expression in an ERK5-dependent but MAPK/ERK kinase 5- and Kruppel-like factor 2/4-independent manner. Leukocyte rolling and vascular reactivity were used to evaluate endothelial function in vivo, and we found that EC-specific ERK5 knockout (ERK5-EKO) mice exhibited increased leukocyte rolling and impaired vascular reactivity, which could not be corrected by pitavastatin. The role of endothelial ERK5 in acute cardiac allograft rejection was also examined by heterotopic grafting of the heart obtained from either wild-type or ERK5-EKO mice into allomismatched recipient mice. A robust increase in both inflammatory gene expression and CD45-positive cell infiltration into the graft was observed. These tissue rejection responses were inhibited by pitavastatin in wild-type but not ERK5-EKO hearts. Our study has identified statins and antimalarial drugs as strong ERK5 activators and shown that ERK5 activation is preventive of endothelial inflammation and dysfunction and acute allograft rejection.
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Affiliation(s)
- Nhat-Tu Le
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Yuichiro Takei
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Yuki Izawa-Ishizawa
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Kyung-Sun Heo
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Hakjoo Lee
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Alan V Smrcka
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Benjamin L Miller
- Department of Dermatology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642; and
| | - Kyung Ae Ko
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Sara Ture
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Craig Morrell
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Keigi Fujiwara
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642
| | - Masashi Akaike
- Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 770-8503, Japan
| | - Jun-ichi Abe
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642;
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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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46
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Pober JS, Jane-wit D, Qin L, Tellides G. Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy. Arterioscler Thromb Vasc Biol 2014; 34:1609-14. [PMID: 24903097 DOI: 10.1161/atvbaha.114.302818] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cardiac allograft vasculopathy is the major cause of late graft loss in heart transplant recipients. Histological studies of characteristic end-stage lesions reveal arterial changes consisting of a diffuse, confluent, and concentric intimal expansion containing graft-derived cells expressing smooth muscle markers, extracellular matrix, penetrating microvessels, and a host mononuclear cell infiltrate concentrated subjacent to an intact graft-derived luminal endothelial cell lining with little evidence of acute injury. This intimal expansion combined with inadequate compensatory outward remodeling produces severe generalized stenosis extending throughout the epicardial and intramyocardial arterial tree that causes ischemic graft failure. Cardiac allograft vasculopathy lesions affect ≥50% of transplant recipients and are both progressive and refractory to treatment, resulting in ≈5% graft loss per year through the first 10 years after transplant. Lesions typically stop at the suture line, implicating alloimmunity as the primary driver, but pathogenesis may be multifactorial. Here, we will discuss 6 potential contributors to lesion formation (1) conventional risk factors of atherosclerosis; (2) pre- or peritransplant injuries; (3) infection; (4) innate immunity; (5) T-cell-mediated immunity; and (6) B-cell-mediated immunity through production of donor-specific antibody. Finally, we will consider how these various mechanisms may interact with each other.
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Affiliation(s)
- Jordan S Pober
- From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT.
| | - Dan Jane-wit
- From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT
| | - Lingfeng Qin
- From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT
| | - George Tellides
- From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT
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Syrjälä SO, Tuuminen R, Nykänen AI, Raissadati A, Dashkevich A, Keränen MAI, Arnaudova R, Krebs R, Leow CC, Saharinen P, Alitalo K, Lemström KB. Angiopoietin-2 inhibition prevents transplant ischemia-reperfusion injury and chronic rejection in rat cardiac allografts. Am J Transplant 2014; 14:1096-108. [PMID: 24708486 DOI: 10.1111/ajt.12672] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 12/30/2013] [Accepted: 01/22/2014] [Indexed: 01/25/2023]
Abstract
Transplant ischemia-reperfusion injury (Tx-IRI) and allograft dysfunction remain as two of the major clinical challenges after heart transplantation. We investigated the role of angiopoietin-2 (Ang2) in Tx-IRI and rejection using fully MHC-mismatched rat cardiac allografts. We report that plasma levels of Ang2 were significantly enhanced in the human and rat recipients of cardiac allografts, but not in the rat recipients of syngrafts, during IRI. Ex vivo intracoronary treatment of rat cardiac allografts with anti-Ang2 antibody before 4-h cold preservation prevented microvascular dysfunction, endothelial cell (EC) adhesion molecule expression and leukocyte infiltration, myocardial injury and the development of cardiac fibrosis and allograft vasculopathy. Recipient preoperative and postoperative treatment with anti-Ang2 antibody produced otherwise similar effects without effecting microvascular dysfunction, and in additional experiments prolonged allograft survival. Recipient preoperative treatment alone failed to produce these effects. Moreover, ex vivo intracoronary treatment of allografts with recombinant Ang2 enhanced Tx-IRI and, in an add-back experiment, abolished the beneficial effect of the antibody. We demonstrate that neutralization of Ang2 prevents EC activation, leukocyte infiltration, Tx-IRI and the development of chronic rejection in rat cardiac allografts. Our results suggest that blocking Ang2 pathway is a novel, clinically feasible, T cell-independent strategy to protect cardiac allografts.
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Affiliation(s)
- S O Syrjälä
- Transplantation Laboratory, Haartman Institute, University of Helsinki, and Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland
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48
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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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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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50
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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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