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(Circulation. 2004;109:1674-1679.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Long-Term Heart Rate Reduction Induced by the Selective I_f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

Paul Mulder, PhD; Stephane Barbier, BS; Abdeslam Chagraoui, PhD; Vincent Richard, PhD; Jean Paul Henry; Françoise Lallemand; Sylvanie Renet; Guy Lerebours, MD, PhD; Florence Mahlberg-Gaudin, PhD; Christian Thuillez, MD, PhD

From INSERM U644 (IFRMP No. 23) (P.M., S.B., A.C., V.R., J.P.H., F.L., S.R., C.T.), UFR de Médecine et de Pharmacie, Rouen, France, and Institut de Recherches Internationales Servier (G.L., F.M.-G.), Courbevoie, France.

Correspondence to Prof C. Thuillez, INSERM U644, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France. E-mail Christian.Thuillez{at}chu-rouen.fr

Received March 31, 2003; de novo received July 15, 2003; revision received November 14, 2003; accepted November 17, 2003.

Background— Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O₂ supply, and reduces myocardial O₂ consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown.

Methods and Results— We assessed, in rats with CHF, the effects of long-term HRR induced by the selective I_f current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (–18% versus untreated at 10 mg · kg^–1 · d^–1), without modifying blood pressure, LV end-diastolic pressure, or dP/dt_max/min. Ivabradine significantly reduced LV end-systolic but not end-diastolic diameter, which resulted in preserved cardiac output due to increased stroke volume. In the Langendorff preparation, ivabradine shifted LV systolic but not end-diastolic pressure-volume relations to the left. Ivabradine decreased LV collagen density and increased LV capillary density without modifying LV weight. Three days after interruption of treatment, the effects of ivabradine on LV geometry, shortening, and stroke volume persisted despite normalization of heart rate.

Conclusions— In rats with CHF, long-term HRR induced by the selective I_f inhibitor ivabradine improves LV function and increases stroke volume, preserving cardiac output despite the HRR. The improvement of cardiac function is related not only to the HRR per se but also to modifications in the extracellular matrix and/or function of myocytes as a consequence of long-term HRR.

Key Words: heart failure • heart rate • drugs • pathology

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