To evaluate regional differences in thickness and systolic function of human myocardium perfused by angiographically normal coronary arteries in valvular and ischemic heart disease, we performed intraoperative epicardial M-mode mapping of ventriculographically normal wall regions (perfused by normal coronary arteries) in 22 subjects undergoing either coronary bypass surgery for stenoses in other vessels (n = 15) or mitral (n = 5) and/or aortic valve replacement (n = 4). In patients in whom both anterior and inferior walls were ventriculographically normal and normally perfused (n = 6), comparison of the two walls showed the anterior wall to be thicker at both end diastole and end systole, but there was no difference in the percentage of systolic thickening. Analysis of myocardium along the long axis revealed apical sites to be thinner than basal sites at both end diastole and end systole. Percentage of systolic thickening was also increased at apical sites. In patients in whom only the anterior wall was normal, a similar decrease in anterior wall thickness was noted at the apex. Thus systematic regional heterogeneity along both the left ventricular major and minor axes is found in the chronically diseased human heart as it is in the normal heart. Assessment of myocardial structure and function and of the effects of therapeutic interventions must take this heterogeneity into account.