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CARDIOVASCULAR

Effect of Long-Term Heart Rate Reduction by I_f Current Inhibition on Pressure Overload-Induced Heart Failure in Rats

Institut National de la Santé et de la Recherche Médicale U698, Groupe Hospitalier Bichat-Claude Bernard, Paris, France (V.C., M.H., L.L., J.-B.M., J.-J.M., D.L.); Institut National de la Santé et de la Recherche Médicale U689, Hôpital Lariboisière, Paris, France (C.H.); Institut National de la Santé et de la Recherche Médicale U769, Chatenay-Malabry, France (R.V.-C.); Pathology Department, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8149, Assistance Publique-Hôpitaux de Paris, Beaujon Hospital, Clichy, France (P.B.); Institut Nationale de la Sante et de la Recherche Médicale U772, Groupe Hospitalier Bichat-Claude Bernard, Paris, France (B.E.); Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Service de Physiologie-Explorations Fonctionnelles, Paris, France (B.E., J.-J.M.); and Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Cardiology Department, Paris, France (D.L.)

We investigated the effects of long-term heart rate reduction (HRR) on pressure overload-induced heart failure. Pressure overload of the left ventricle was induced in 21-day-old rats by banding the ascending aorta. HRR was induced for 3 months with ivabradine (n = 44), a selective I_f current inhibitor, at 10 mg/kg/day, starting 14 days after banding. Thirty-six control banded rats and 16 sham-operated rats received standard chow. Banding resulted in severe left ventricular (LV) hypertrophy (+55% versus shams; p < 0.001) and fibrosis, together with a 34% decrease (p < 0.01) in the LV shortening fraction. Heart rate decreased by 19% in ivabradine-treated rats (p < 0.005 versus controls). Stroke volume increased (by 17%; p < 0.01), whereas cardiac output did not change with HRR. In contrast, HRR resulted in 1) a marked increase in LV filling pressure (p < 0.01) and in atrial, lung, and right ventricular weights (38, 30, and 54%, respectively; p < 0.001); 2) a 50% increase in the incidence of pleural/abdominal effusion (p < 0.001); 3) 7 and 26% increases in LV hypertrophy and fibrosis, respectively (p < 0.05); and 4) a 53% increase in the atrial natriuretic peptide mRNA level compared with controls (p < 0.001). After 3 months of treatment, ivabradine withdrawal normalized the heart rate and reduced LV size and LV filling pressure (p < 0.05). In conclusion, pure longstanding HRR showed no beneficial effect on LV dysfunction in a rat model of pressure overload-induced LV hypertrophy, and it seemed to favor adverse LV remodeling and its congestive consequences.

Address correspondence to: Dr. Damien Logeart, Cardiology Department, Lariboisiere Hospital, 2 rue Ambroise Pare, 75010 Paris, France. E-mail: damien.logeart{at}lrb.aphp.fr

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