Abnormal frequency-dependent responses represent the pathophysiologic signature of contractile failure in human myocardium

Abstract

Background. – The normal increase in isometric developed force (DF) with faster pacing rates, known as the positive force–frequency response/relationship (FFR), is altered in failing myocardium, as shown by its negative response to increased pacing. The objective of this study was to determine if increasing Ca 2+ influx with L-type Ca 2+ channel (L-CaCh) agonists: BayK 8644 (BayK) and FPL 64176 (FPL) or increased extracellular Ca 2+ could increase contractility and normalize the FFR in failing myocardium. Methods. – Isometric DF was measured in right ventricular trabeculae from failing ( n = 28) and non-failing ( n = 12) human hearts at various stimulation frequencies (0.5–2.5 Hz) before and after bath application of BayK (250 nM), FPL (100 nM), or high Ca 2+ (7.0 mM). Post-rest (PR) experiments were also conducted on several trabeculae. Results. – In trabeculae from failing hearts, the DF decreased with an increase in pacing. Addition of L-CaCh agonists increased DF to similar levels in trabeculae from both failing and non-failing hearts at slow pacing rates, but did not alter the negative FFR in the failing group. During increased rest intervals, the amount of PR potentiation was diminished in trabeculae from failing hearts as compared to the non-failing preparations. Conclusion. – This study demonstrates that the abnormal FFR observed in trabeculae from failing hearts is a reliable physiologic signature of the cardiomyopathic state even when DF, at slow stimulation frequencies, is relatively high. These studies further demonstrate that the impaired FFR is not due to an inability to further increase contractility. Rather, our findings suggest that the abnormal FFR and blunted PR potentiation alike are a reflection of an altered functional balance between Ca 2+ re-uptake and Ca 2+ extrusion.