Angiotensin Converting Enzyme (ACE) Inhibition and Cardiac Allograft Vasculopathy

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 is to determine the impact of ramipril on coronary physiology early after transplantation.

During the first 4 years of this study, we plan to recruit patients within the first month after OHT. As has become routine at Stanford, study subjects will undergo baseline coronary angiography and IVUS assessment of their left anterior descending coronary artery. Coronary endothelial function will be assessed as well transmyocardial levels of ADMA and other mediators of endothelial function. Blood samples will be obtained for analyzing circulating EPC number and function. Epicardial and microvascular coronary physiology in the left anterior descending coronary artery will be determined by measuring FFR and IMR with a coronary pressure wire(in the adults only). Subjects will then be randomized to either the ACE I(Ramipril), or to placebo, in addition to their usual medications. During years 2 through 5 of this project, study subjects will undergo the above routine invasive assessments at 1 year after OHT. During the 5th year of this project, data analysis and manuscript preparation will occur. Table 2. Patient Flowchart Time post OHT Event 0-4 Weeks Recruitment and enrollment 4-6 Weeks Baseline angiogram, endothelial function, coronary physiology and IVUS studies 4-6 (at time of baseline)Weeks Baseline blood sampling for circulating EPC studies 4-6 Weeks Randomization to ramipril or placebo to begin one week after baseline studies 5-7 Weeks Titration up of ramipril or placebo Month 3 and month 6: blood sampling for EPC studies. 11-13 Months 1 year angiogram, endothelial function, coronary physiology and IVUS studies 11-13 Months 1 year blood sampling for circulating EPC studies The primary endpoint of the study will be change in plaque volume as determined by IVUS analysis at baseline and 1 year later, between those treated with ramipril compared to those treated with placebo. Secondary endpoints will include change in circulating EPC number and function, change in ADMA levels,change in coronary endothelium-dependent vasodilation, and change in coronary physiology (FFR and IMR)from baseline to 1 year. Although there are multiple potential mechanisms by which ACE I might reduce CAV, evaluating each of these is beyond the scope of this project. For this reason, we will focus on the likely common final pathway of endothelial dysfunction mediated by dysregulation of ADMA and NOS, as well as changes in EPCs. If this study shows a benefit to ACE I therapy in this population, the goal of future studies will be to determine the exact mechanism by which this occurs and to perform a large, multicenter study comparing ACE I to placebo with hard clinical endpoints. Study visits include two major time points 1) baseline angiogram and IVUS which include recording of angiographic data, lab data, clinical data. 2)assessment at the usual follow up periods post transplant, and these data points will also be collected for research purposes. after base line which usually occurs one month post transplant plus or minus 2 weeks. F/u = q 2 weeks until two months out from tx, then once per month until six months out from TX, then every two months until the patient is 12 months out from TX. Each routine f/u visit includes a physical exam,vital signs, echocardiogram, chest x-ray, a complete metabolic panel ( contains a Creatinine), Complete blood count, immunosuppressant drug blood levels, and a heart biopsy (at the same intervals described above).

Use of a ACE ( angiotension converting enzyme) inhibitors post heart Transplant for Blood pressure control.

Cardiac Allograft Vasculopathy(CAV) Defined as Change in IVUS-assessed Plaque Volume From Baseline to One Year

also called transplant coronary artery disease or cardiac transplant vasculopathy defined as coronary artery stenosis(narrowing) ranging from 30 to 70 percent by coronary angiography. Measured in this study as change in IVUS-assessed Plaque Volume from baseline to one year.

The percent change in diameter of the left anterior descending artery was measured by quantitative angiography after acetylcholine and compared to baseline angiography. The percentage of participants who had ≥20% coronary artery diameter reduction after acetylcholine at one year is presented.

asymmetric dimethylarginine (ADMA), is an inhibitor of endothelial nitric oxide synthase which is a primary regulator of endothelial function.

The Percentage of Endothelial Progenitor Cells ( EPC) in Peripheral Blood in Patients One Year After Transplant

The determination of the percentage of EPC in peripheral blood involved surface staining peripheral blood mononuclear cells (PBMCs) with appropriate fluorescently-labeled antibodies to delineate EPCs from other blood cells, followed by analysis by conventional flow cytometry.

FFR is a technique used in coronary catheterization to measure pressure differences across a coronary artery stenosis (narrowing, usually due to atherosclerosis) to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle (myocardial ischemia). It is defined as the ratio of the distal coronary pressure to the proximal coronary pressure.

The index of microcirculatory resistance (IMR) is a pressure-temperature sensor guidewire-based measurement, performed during cardiac catheterization, of the minimum microcirculatory resistance in a specific coronary artery. The IMR provides a quantitative measure of coronary microvasculature status.

Inclusion Criteria: Heart transplant recipient within the first month of transplant; 12 years of age or older; Must have a serum creatinine less than 2.0 mg/dl; Will provide written informed consent; Female patients of childbearing potential must have negative pregnancy test; For pediatric patient, parent(s) will provide consent and the child will sign assent. Exclusion Criteria: Less than 12 years of age; Have more than one solid organ transplant at time of heart transplant; Has serum creatinine greater than 2.0 mg/dl; Pregnancy.

Arashi H, Sato T, Kobashigawa J, Luikart H, Kobayashi Y, Okada K, Sinha S, Honda Y, Yeung AC, Khush K, Fearon WF. Long-term clinical outcomes with use of an angiotensin-converting enzyme inhibitor early after heart transplantation. Am Heart J. 2020 Apr;222:30-37. doi: 10.1016/j.ahj.2020.01.003. Epub 2020 Jan 9.

Fearon WF, Okada K, Kobashigawa JA, Kobayashi Y, Luikart H, Sana S, Daun T, Chmura SA, Sinha S, Cohen G, Honda Y, Pham M, Lewis DB, Bernstein D, Yeung AC, Valantine HA, Khush K. Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. J Am Coll Cardiol. 2017 Jun 13;69(23):2832-2841. doi: 10.1016/j.jacc.2017.03.598.

Lee JH, Okada K, Khush K, Kobayashi Y, Sinha S, Luikart H, Valantine H, Yeung AC, Honda Y, Fearon WF. Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation. 2017 Mar 14;135(11):1093-1095. doi: 10.1161/CIRCULATIONAHA.116.025268. No abstract available.