Allograft vasculopathy
Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation☆

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Abstract

Objective

Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used serial studies to evaluate changes in coronary endothelial function in patients with and without clinically evident CAV.

Background

In serial studies with intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening.

Methods

We studied 45 patients annually, beginning at transplantation until pre-specified end-points (angiographic CAV or cardiac death) were reached. At each study, we measured coronary endothelial function using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and Doppler velocities.

Results

Of the 45 patients studied, 9 reached end-points during the study (6 had CAV and 3 died). The mean annual change in area response to acetylcholine was −4.5% ± 3.0% in patients who reached end-points and −0.9% ± 1.5% in those who did not (p = 0.04). The mean annual decrement in flow response to acetylcholine was greater in patients who reached end-points (−31% ± 11% vs −5% ± 5%, p = 0.08). Responses to adenosine and nitroglycerin did not differ.

Conclusions

When serial responses were evaluated, patients with end-points had more rapid decreases in endothelial function. The rate of disease progression may be more important than the absolute degree of intimal thickening in early CAV. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function may provide important prognostic information about the development of CAV after heart transplantation.

Section snippets

Patient population

The study cohort consisted of heart transplant recipients who underwent post-transplant angiography at Rush–Presbyterian–St. Luke’s Medical Center. We excluded patients <18 years of age, patients with known angiographic evidence of coronary artery stenosis exceeding 50% of luminal diameter, and patients with evidence of acute rejection in endomyocardial biopsy specimens at the time of angiography. All patients gave informed consent according to the guidelines of the Rush–Presbyterian–St. Luke’s

Patient characteristics

The mean age of the 45 study patients was 48 ± 10 years (range, 18–64 years), and the mean donor age was 28 ± 13 years (range, 11–55 years). Forty-one were men, and 4 were women. The pre-transplant diagnosis was coronary artery disease in 21 (47%) and non-ischemic cardiomyopathy in 24 (53%). All patients received triple-immunosuppressive therapy (prednisone, cyclosporine, and azathioprine or mycophenolate mofetil) and pravastatin. Calcium-channel antagonists were not prescribed routinely to

Discussion

It stands to reason that the vascular endothelium would be involved in initiating chronic rejection after cardiac transplantation, because it is situated between circulating immune cells and the vessel wall. Endothelial damage leads to intimal proliferation, macrophage migration, and eventual smooth muscle hyperplasia.15 Other risk factors recognized to promote allograft vasculopathy, such as hyperlipidemia, hypertension, and hyperglycemia, also cause endothelial dysfunction, in part through

Conclusions

We performed serial studies using simultaneous IVUS and Doppler measurements to assess epicardial and microvascular endothelial function in heart transplant recipients. The study is the first to show that patients with cardiovascular end-points after heart transplantation had a more rapid decrease in endothelial function than did patients without end-points. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of

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    ☆

    This work was supported in part by a grant-in-aid from the Metropolitan Chicago American Heart Association and in part by a SmithKline Beecham Junior Faculty Development Award to Dr. Hollenberg.

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    Copyright © 2003 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.