Mechanical myocardial actuation during ventricular fibrillation improves tolerance to ischemia compared with cardiopulmonary bypass. Direct mechanical ventricular actuation (DMVA) is a unique non-blood-contacting biventricular assist device that provides circulatory support during ventricular fibrillation without demonstrating adverse effects on the myocardium. The purpose of this study was to assess the preservation of myocardial energy stores and myocardial responses to ischemia after circulatory support during ventricular fibrillation with direct mechanical ventricular actuation versus cardiopulmonary bypass. Twenty adult mongrel dogs were randomized to receive circulatory support with either cardiopulmonary bypass or direct mechanical ventricular actuation. After 4 hours of ventricular fibrillation, hearts were defibrillated and left ventricular transmural biopsies were obtained. Hearts were then excised and subjected to 90 minutes of normothermic total ischemia. Serial biopsies were obtained at 15-minute intervals to determine regional depletion of high energy phosphates. The time-to-peak ischemic contracture was recorded by using needle-tipped Millar catheters placed in the left ventricular endocardium, epicardium, septum, and right ventricle. Time-to-peak ischemic contracture of the endocardium (62.6 +/- 1.4 vs. 58.8 +/- 1.0 minutes, p less than 0.05) and septum (61.1 +/- 6.9 vs. 46.9 +/- 6.2 minutes, p less than 0.004) were significantly prolonged after direct mechanical ventricular actuation versus cardiopulmonary bypass, respectively. Similar trends were noted in the epicardium and right ventricular regions; however, these differences were not statistically significant. Left ventricular adenosine triphosphate (ATP) levels were better preserved after direct mechanical ventricular actuation (22 +/- 1.5 mumols/g dry wt) compared with cardiopulmonary bypass (17 +/- 1.9 mumols/g dry wt). The depletion of left ventricular endocardium ATP during normothermic ischemia was significantly delayed after direct mechanical ventricular actuation compared with cardiopulmonary bypass. 