Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction

Abstract

The importance of heart rate for left ventricular remodeling and prognosis after myocardial infarction is not known. We examined the contribution of heart rate reduction by zatebradine, a direct sinus node inhibitor without negative inotropic effects on left ventricular function and dilatation, on mortality, energy metabolism, and neurohormonal changes in rats with experimental myocardial infarction (MI). Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was 33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was 36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant). Zatebradine reduced left and right ventricular norepinephrine and increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to-norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in rats with MI remained unchanged by zatebradine. Lowering heart rate per se reduces mortality and MI size in this model but induces adverse effects on left ventricular remodeling in rats with small MI.

Bradycardic Therapy Improves Left Ventricular Function and Remodeling in Dogs with Coronary Embolization-Induced Chronic Heart Failure

“…Most importantly, cilobradine therapy affected ventricular remodeling similar to metoprolol and prevented further increases in ventricular size compared with control animals after CHF. These results are in direct contrast to the effect of chronic zatebradine in rats (Hu et al, 2003), which produced a significant increase in ventricular dimensions after 8 weeks of therapy. Animals treated with metoprolol and high-dose cilobradine, as hypothesized, demonstrated the greatest improvements in ventricular function.…”

“…Although no change was found in prior experiment in sympathetic neurohormones after zatebradine therapy (Hu et al, 2003), serum neurohormonal analysis was not performed in the current study and could corroborate our functional improvements with biochemical data. A complete metabolic analysis, including myocardial enzymes, LDH isoenzymes, and creatinine, would also aid in understanding the effect of cilobradine on long-term markers of energy parameters.…”

“…The most extensively studied sinus node inhibitor, zatebradine, has been shown to reduce the incidence of ventricular fibrillation (Hu et al, 2003), reduce infarct size (Hu et al, 2003), and enhance arterial baroreflex sensitivity, implying higher central and peripheral vagal (autonomic) tone (Kruger et al, 2000). However, despite lowering early mortality and decreasing infarct size as reported by Hu et al (2003) in a rat model, zatebradine induced LV remodeling with concurrent increased neurohormonal turnover, suggestive of continued sympathetic stimulation. Likewise, zatebradine produced disappointing results in the treatment of stable angina in patients, failing to improve time to moderate angina in two separate double-blinded clinical trials (Frishman et al, 1995;Glasser et al, 1997).…”

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

“…Recently, Dedkov et al (2007) showed that a 25% ivabradine-induced HRR after myocardial infarction improved maximal myocardial perfusion and the coronary reserve, an effect that was related to reduced periarteriolar collagen content. Using an 8-week 25% zatebradine-mediated HRR, Hu et al (2004) observed mitigated results. In large myocardial infarctions, HRR enhanced LV performance with no change in LV remodeling.…”

Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart

“…For example, sinus node inhibitors (like zatebradine and ivabradine) reduce heart rate by 30% without major effects on cardiac output and contractility 24,25 .…”