Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure. Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation. Angiotensin converting enzyme inhibitors are used in less than one half of transplant recipients. Preliminary data suggest that angiotensin converting enzyme inhibitors retard the atherosclerotic plaque development that is the hallmark of cardiac allograft vasculopathy. Moreover, this class of drug appears to increase circulating endothelial progenitor cell number and has anti-inflammatory properties, both of which improve endothelial dysfunction, the key precursor to the development of cardiac allograft vasculopathy. The objective of this project is to investigate the role of an angiotensin converting enzyme inhibitor, ramipril, in preventing the development of cardiac allograft vasculopathy. During the first month after cardiac transplantation subjects will undergo coronary angiography with intravascular ultrasound measurements of plaque volume in the left anterior descending coronary artery. Using a coronary pressure wire, epicardial artery and microvascular physiology will be assessed. Finally, endothelial function and mediators of endothelial function, including circulating endothelial progenitor cells, will be measured. Subjects will then be randomized in a double blind fashion to either ramipril or placebo. After 1 year, the above assessment will be repeated. The primary endpoint will be the development of cardiac allograft vasculopathy based on intravascular ultrasound-derived parameters.
The second aim will be to assess the effect of ramipril on endothelial dysfunction early after transplantation.
The final aim i s to determine the impact of ramipril on coronary physiology early after transplantation.

Public Health Relevance

Heart transplantation remains an important treatment option for patients with heart failure. Unfortunately, many patients who undergo heart transplantation suffer and die because of the development of narrowings in the arteries supplying blood to the transplanted heart. The goal of this project is to investigate the ability of a drug called ramipril to prevent this significant complication.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093475-04
Application #
8259175
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Shah, Monica R
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$329,353
Indirect Cost
$81,853
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Parikh, Rushi V; Khush, Kiran; Pargaonkar, Vedant S et al. (2018) Association of Endothelin-1 With Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation. J Card Fail :
Fearon, William F; Okada, Kozo; Kobashigawa, Jon A et al. (2017) Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. J Am Coll Cardiol 69:2832-2841
Lee, Jang Hoon; Okada, Kozo; Khush, Kiran et al. (2017) Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation 135:1093-1095
Yang, Hyoung-Mo; Khush, Kiran; Luikart, Helen et al. (2016) Invasive Assessment of Coronary Physiology Predicts Late Mortality After Heart Transplantation. Circulation 133:1945-50
Okada, Kozo; Fearon, William F; Luikart, Helen et al. (2016) Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy. J Am Coll Cardiol 68:382-92
Chiu, Peter; Fearon, William F; Raleigh, Lindsay A et al. (2016) Salvage Extracorporeal Membrane Oxygenation Prior to ""Bridge"" Transcatheter Aortic Valve Replacement. J Card Surg 31:403-5
Kitahara, Hideki; Okada, Kozo; Tanaka, Shigemitsu et al. (2016) Association of periarterial neovascularization with progression of cardiac allograft vasculopathy and long-term clinical outcomes in heart transplant recipients. J Heart Lung Transplant 35:752-9
Fearon, William F (2015) Invasive coronary physiology for assessing intermediate lesions. Circ Cardiovasc Interv 8:e001942
Okada, Kozo; Kitahara, Hideki; Yang, Hyoung-Mo et al. (2015) Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation. JACC Heart Fail 3:942-52
Fearon, William F (2014) Percutaneous coronary intervention should be guided by fractional flow reserve measurement. Circulation 129:1860-70

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