Abstract 3913: Nicorandil Inhibits Ventricular Remodeling and Arrhythmias in a Mouse Model of Chronic Heart Failure
Introduction: Beneficial hemodynamic effects of nicorandil, an ATP-sensitive K+ channel opener, in acute heart failure have been demonstrated. However, whether nicorandil has inhibitory effects on the development of chronic heart failure (CHF) remains unknown. Therefore, we examined the effects of chronic administration of nicorandil on ventricular function, the number of premature ventricular contractions (PVC), and electrical and structural ventricular remodeling in transgenic mice with transient cardiac expression of activated G protein alpha q (G alpha q-TG; a model of CHF).
Method and Results: Nicorandil (6 mg/kg/day) or vehicle was orally administered in 24 G alpha q-TG mice from 8 weeks to 32 weeks of age. Ventricular function was investigated at age in 32 weeks using two-dimensionally-directed M-mode echocardiography. The degree of fibrosis was also elucidated using digital microscopic images from left ventricular sections stained with Masson’s trichrome. Out of 12 vehicle-treated G alpha q-TG mice, 3 died before 32 weeks of age (25 %). In contrast, none of 12 nicorandil-treated G alpha q-TG mice died. Nicorandil improved ventricular dysfunction, determined by dilatation of left ventricular dimensions (left ventricular end-diastolic dimension= 2.8±0.16 vs. 3.4±0.12 mm, p<0.05) and reduction of LV fractional shortening (37.0±0.9 vs. 26.7±1.6 %, p<0.001) in G alpha q-TG mice. During 10 min of electrocardiogram (ECG) lead II monitoring, PVC was frequently (more than 20 beats/min) observed in 4 of 7 vehicle-treated G alpha q-TG mice but in none of 10 nicorandil-treated G alpha q-TG mice tested (p<0.05 by Fisher’s exact test). QT interval was significantly shorter in nicorandil-treated G alpha q-TG mice than in vehicle-treated G alpha q-TG mice (34±3 vs. 43±2 millisecond, p<0.05). Moreover, the degree of extensive interstitial fibrosis in the left ventricle was significantly less in nicorandil-treated G alpha q-TG mice than in vehicle-treated G alpha q-TG mice (reduced by approximately 45 %, p<0.05). These findings demonstrated that nicorandil inhibited ventricular electrical and structural remodeling and VT in a mouse model of CHF and suggest that nicorandil is useful for the treatment of CHF as well as acute heart failure.