Post-extrasystolic potentiation and the force-frequency relationship: differential augmentation of myocardial contractility in working myocardium from patients with end-stage heart failure

Abstract

We studied post-extrasystolic potentiation (PESP) and frequency potentiation (FP) of human working myocardium isolated from the ventricles of 10 patients with end-stage heart failure (CHF) and 17 non-failing controls (CTL). The contractility index was peak isometric tension developed in vitro by trabeculae carneae (CTL n = 34, CHF n = 31); programmed electrical stimulation was used to initiate as well as alter the timing relationship of the contractile events. While holding constant the total number of contractions per unit of time, we compared the augmentation of contractile performance that occurred upon doubling the stimulation frequency (FP) to that of changing the stimulation pattern (PESP). In the CTL group we found that FP and PESP differed in their ability to augment cardiac contractile performance, PESP being more effective; 105 +/- 13% for PESP vs. 34 +/- 11% (mean +/- S.E.M.) for FP. In the CHF group, the inotropic response to PESP was similar to CTL; in contrast, the relative efficacy of FP (3 +/- 3%) compared to PESP (81 +/- 14%) was markedly diminished. Studies with positive inotropic agents revealed that the percent change in contractility induced by FP and PESP depends upon the relative inotropic state of the heart; however, the contractile response to PESP always equaled or exceeded those produced by clinically relevant concentrations of inotropic agents, particularly in CHF muscles. Agents that increase intracellular levels of adenosine 3',5'-cyclic monophosphate reversed the FP abnormalities seen in the CHF group, suggesting that deficient production of this second messenger in heart failure may cause the abnormal force-frequency relationship in failing myocardium. We conclude that the differential responses of myopathic muscle to PESP and FP may be caused by abnormal restitution processes during diastole. Our results suggest that PESP may be an effective therapeutic modality for patients with severe heart failure who have failed to adequately respond to inotropic drugs, and may serve as a useful indicator of cardiac contractile reserve in these patients.