title: 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 Ca(2+) 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, E(ES)/E(A)). We assessed the effects of therapeutic doses of levosimendan on the force-frequency relation and E(ES)/E(A) in nine conscious dogs after pacing-induced HF using pressure-volume analysis. Before HF, pacing tachycardia increased E(ES), shortened τ, and did not impair E(ES)/E(A) 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 E(ES) or less shortening of τ, whereas E(ES)/E(A) (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), τ decreased 11% (40.8 ms), E(ES)/E(A) increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, E(ES) further increased by 23%, 37%, 68%, and 89%; τ decreased by 9%, 12%, 15%, and 17%; and E(ES)/E(A) 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.
authors.affiliation: Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Masutani
authors.forename: Heng-Jie
authors.initials: HJ
authors.lastname: Cheng
authors.forename: Hideo
authors.initials: H
authors.lastname: Tachibana
authors.forename: William C
authors.initials: WC
authors.lastname: Little
authors.forename: Che-Ping
authors.initials: CP
authors.lastname: Cheng
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D056966:Excitation Contraction Coupling / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D013318:Stroke Volume / Q000187:drug effects; D013610:Tachycardia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan