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

Abstract

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.