BACKGROUND: Coronary flow reserve (CFR) is reduced in a majority of patients after heart transplantation (HTx). Pharmacological interventions, however, provide only limited information on CFR under physiological conditions. Thus, CFR during exercise was evaluated in the present study. METHODS AND RESULTS: Coronary angiography was performed at rest and during supine bicycle exercise in 35 patients early (2 to 3 months; n = 10) or late (1 to 6 years; mean, 2.5 years; n = 25) after HTx and in 8 controls (C). CFR was determined by parametric imaging after administration of 10 mg intracoronary papaverine, during exercise, and after 1.6 mg sublingual nitroglycerin. Epicardial coronary artery size was measured by quantitative coronary angiography. CFR after papaverine was normal early (3.6 +/- 0.5 versus C, 3.6 +/- 0.7; P = NS) and late (3.8 +/- 1.3 P = NS) after HTx. During exercise, CFR was normal early (3.1 +/- 0.6 versus C, 3.9 +/- 0.9; P = NS) but decreased late (2.3 +/- 0.6; P < .01) after HTx. The increase in coronary cross-sectional area during exercise was also diminished late after HTx (14 +/- 10% versus C, 22 +/- 10%; P < .05). Both exercise-induced CFR (r = -.39, P < .05) and coronary vasodilation (r = -.44, P < .01) were inversely correlated with time after HTx. CONCLUSIONS: CFR during exercise is normal early but reduced late after HTx, whereas CFR after papaverine administration is maintained. This difference between physiological and pharmacological vasodilation suggests progressive endothelial dysfunction after HTx.