Levosimendan restores the positive force-frequency relation in heart failure

Abstract

Frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise. In heart failure (HF), this positive force-frequency relation is impaired, and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. A myofilament Ca2+ sensitizer, levosimendan, has been shown to improve exercise tolerance in HF. This may be due to its beneficial actions on the force-frequency relation and LV-arterial coupling (end-systolic elastance/arterial elastance, EES/ EA). We assessed the effects of therapeutic doses of levosimendan on the force-frequency relation and EES/ EA in nine conscious dogs after pacing-induced HF using pressure-volume analysis. Before HF, pacing tachycardia increased EES, shortened τ, and did not impair EES/ EA and mechanical efficiency (stroke work/pressure-volume area, SW/PVA). In contrast, after HF, pacing at 140, 160, 180, and 200 beat/min (bpm) produced smaller a increase of EES or less shortening of τ, whereas EES/ EA (from 0.56 at baseline to 0.42 at 200 bpm) and SW/PVA (from 0.52 at baseline to 0.43 at 200 bpm) progressively decreased. With levosimendan, basal EES increased 27% (6.2 mmHg/ml), τ decreased 11% (40.8 ms), EES/ EA increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, EES further increased by 23%, 37%, 68%, and 89%; τ decreased by 9%, 12%, 15%, and 17%; and EES/ EA was augmented by 11%, 16%, 31%, and 33%, incrementally, with pacing rate. SW/PVA was improved (0.61 to 0.64). In conclusion, in HF, treatment with levosimendan restores the normal positive LV systolic and diastolic force-frequency relation and prevents tachycardia-induced adverse effect on LV-arterial coupling and mechanical efficiency.