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(Circulation. 2007;115:1218-1224.)
© 2007 American Heart Association, Inc.

Heart Failure

Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction

Alteration of Force-Frequency and Relaxation-Frequency Relationships

Michael M. Givertz, MD; Costa Andreou, MD; Chester H. Conrad, MD, PhD; Wilson S. Colucci, MD

From the Cardiomyopathy Program and Cardiovascular Section (M.M.G., C.A., W.S.C.), Boston University Medical Center, Boston, Mass; and Cardiology Section (C.H.C.), VA Boston Healthcare System, Boston, Mass.

Correspondence to Michael M. Givertz, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mgivertz{at}partners.org

Received October 6, 2006; accepted January 2, 2007.

Background— Enthusiasm for the development of Ca²⁺ sensitizers as inotropic agents for heart failure has been tempered by reports of impaired relaxation. Levosimendan, which increases myofilament Ca²⁺ sensitivity via Ca²⁺-dependent binding to troponin C, exerts positive inotropic and lusitropic effects in failing human myocardium in vitro. We sought to determine the direct effects of levosimendan on failing human myocardium in vivo, and in particular whether levosimendan exerts heart rate–dependent effects on systolic or diastolic function.

Methods and Results— Ten patients with left ventricular dysfunction caused by nonischemic dilated cardiomyopathy (mean left ventricular ejection fraction, 27±2%) were instrumented with an infusion catheter in the left main coronary artery, a high-fidelity micromanometer-tipped catheter in the left ventricle, and a bipolar pacing wire in the right atrium. Inotropic (peak +dP/dt) and lusitropic (Tau) responses were assessed during continuous intracoronary drug infusion in sinus rhythm followed by atrial pacing at 20, 40, and 60 beats per minute above the sinus rate. Under control conditions (intracoronary 5% dextrose in water), atrial-pacing tachycardia decreased Tau by 13% (P<0.05), but did not increase +dP/dt. Intracoronary levosimendan (3.75 and 12.5 µg/min for 15 minutes each) increased +dP/dt dose-dependently and decreased Tau over a range of heart rates, but did not alter the slope of the force-frequency or relaxation-frequency relationship.

Conclusions— Myocardial calcium sensitization with levosimendan exerts mild inotropic and lusitropic effects in humans with left ventricular dysfunction, but does not alter the force-frequency or relaxation-frequency relationship.

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				F. Guarracino, L. Tritapepe, and A. Morelli Letter by Guarracino et al Regarding Article, "Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction: Alteration of Force-Frequency and Relaxation-Frequency Relationships" Circulation, September 11, 2007; 116(11): e346 - e346. [Full Text] [PDF]

				M. M. Givertz, C. Andreou, C. H. Conrad, and W. S. Colucci Response to Letter Regarding Article, "Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction: Alteration of Force-Frequency and Relaxation-Frequency Relationships" Circulation, September 11, 2007; 116(11): e347 - e347. [Full Text] [PDF]