Levosimendan restores the positive force-frequency relation in heart failure

Abstract

Masutani S, Cheng HJ, Tachibana H, Little WC, Cheng CP. Levosimendan restores the positive force-frequency relation in heart failure. Am J Physiol Heart Circ Physiol 301: H488 -H496, 2011. First published May 13, 2011; doi:10.1152/ajpheart.01116.2010.-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 Ca 2ϩ 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 forcefrequency relation and EES/EA in nine conscious dogs after pacinginduced HF using pressure-volume analysis. Before HF, pacing tachycardia increased E ES, shortened , 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 , 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 E ES increased 27% (6.2 mmHg/ml), decreased 11% (40.8 ms), EES/EA increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, E ES further increased by 23%, 37%, 68%, and 89%; 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.drugs; contractility; diastole; heart rate UNDER NORMAL CONDITIONS, an increase in heart rate (HR) augments myocardial contractility and the rate of relaxation (15,39,44). This force-frequency behavior is determined by both calcium handling and myofilament properties (26). It has been shown that the integrated dynamic balance of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is the primary cellular mechanism responsible for the force-frequency relation (FFR) and is determined by sarcoplasmic reticulum (SR) Ca 2ϩ load and Ca 2ϩ flux through the sarcolemma via L-type Ca 2ϩ channels and the Na ϩ -Ca 2ϩ exchanger (13). The positive FFR and relaxation-frequency relation (RFR) enhance cardiac performance during stress or exercise (7,36,39,44,52). In heart failure (HF), the positive FFR and RFR are impaired (16,24,28,29,44), and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. This contributes to exercise intolerance in HF (44, 52). The altered responses of LV contraction and relaxation to HR in HF may at least partially ...

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