To evaluate the hemodynamic response to upright exercise of heart transplant recipients, we had 10 patients aged 46 +/- 14 years undergo rest and exercise radionuclide ventriculography 6 to 26 (mean, 14) month after orthotopic heart transplantation. Results were compared with those obtained in 18 young subjects, aged 22 +/- 3 years, and 17 older subjects, aged 56 +/- 5 years. Radionuclide ventriculography was performed at rest and at three levels of exercise, representing 50%, 70%, and 90% of the maximal physical workload. At rest, heart rate was higher in transplant patients than in normal subjects, but during exercise, heart rate increased only 33% compared with a 142% increase in the young subjects and a 111% increase in the older group. During exercise, left ventricular ejection fraction increased in the three groups, but, as compared with the transplant group, the increase of ejection fraction was higher in the young group. End-diastolic volume increased both in transplant patients (+16%) and in older subjects (+13%), whereas it decreased (-20%) in the young subjects during exercise. End-systolic volume decreased in the young group and in the transplant group with exercise, and it did not change in the older group. Cardiac index increased throughout the three levels of exercise in the three groups of subjects, but cardiac index was higher during exercise in young and older normal subjects. With exercise, all three groups showed increases in peak filling rates, but young subjects had a significantly higher value compared with the transplant group. Filling fraction in the first third of diastole did not change with exercise in the transplant and the older group but increased in the young group. We conclude that in transplant patients, increase in cardiac index during upright exercise is mediated by an increase in end-diastolic index during submaximal exercise and by increased heart rate and augmented contractility at peak exercise. Early diastolic filling is altered in these patients, and this alteration is independent from the changes in heart rate and cardiac volumes. When compared with normal persons, this pattern of hemodynamic response to exercise is similar to older subjects but differs from young subjects in whom the increase in heart rate and reduction in end-systolic volume are the chief mechanisms of enhancing cardiac index during exercise.