INCREASED SURVIVAL AFTER LONG-TERM TREATMENT WITH MIBEFRADIL, A SELECTIVE T-CHANNEL CALCIUM-ANTAGONIST, IN HEART-FAILURE

Objectives. We sought to investigate the effects of mibefradil on surv ival, hemodynamic variables and cardiac remodeling in a rat model of c hronic heart failure (HF) and to compare these effects with those of t he angiotensin-converting enzyme (ACE) inhibitor cilazapril. Backgroun d. The use of calcium channel blocking agents in chronic HF has been d isappointing, Most studies have shown that these drugs have either no or even detrimental effects due in part to the negative inotropic effe cts they induce, Mibefradil is a calcium channel blocker that selectiv ely blocks T channels and displays moderately negative inotropic prope rties only at high doses, Because T channels are upregulated in the hy pertrophied heart and could mediate hypertrophic signals and increase ar rhythmogenicity, blockade of these channels might be beneficial in chronic HF. Methods. Rats were subjected to coronary artery ligation a nd 9 months of treatment with mibefradil (15 mg/kg body weight per day ) or cilazapril (10 mg/kg per day) or no treatment, Survival and systo lic blood pressure were assessed over the 9-month treatment period, af ter which cardiac hemodynamic variables and structure were determined. Results. Mibefradil increased survival rate to the same extent as cil azapril (71% for mibefradil vs. 75% for cilazapril and 44% for no trea tment), Mibefradil decreased systolic blood pressure, although to a le sser estent than cilazapril, Both treatments decreased left ventricula r (LV) end diastolic and central venous pressures, without any change in the first derivative of LV pressure over time or heart rate, Mibefr adil decreased LV weight (although less than cilazapril) without affec ting right ventricular weight. Finally, both drugs normalized LV colla gen density. Conclusions. Mibefradil in a rat model improved survival to the same extent as an ACE inhibitor, without impairing LV function, and was associated with a reduction in LV weight and fibrosis, Thus, mibefradil might be beneficial in the treatment of chronic HF. (C) 199 7 by the American College of Cardiology.