Electrophysiological remodeling in post-myocardial infarcted rats: focus on f-current and heart rate.

Purpose: Ivabradine (IVA) is a specific heart-rate (HR) lowering drug blocking f-current in sinoatrial node cells. During remodeling, f-current is overexpressed in infarcted left ventricle (LV) and might exert a proarrhythmic role. The effect of ivabradine on If overexpression in the remodelled ventricular tissue is unknown. We tested whether a pure HR reduction with IVA in post-MI rats, could counteract electrophysiological remodeling and thus, f-current overexpression. Methods: Seven days after LAD ligation, MI rats were treated with 10 mg/kg/day IVA (MI+IVA) or vehicle (MI) (drinking water) for 90 days. SHAM rats were used as controls. At the end, HR was measured by echocardiography. Isolated LV myocytes were used for patch-clamp recording. The f-current was recorded in the whole-cell configuration (hyperpolarizing steps from -60 to -140 mV steps from holding potential of - 30 mV). mRNA HCN2 and HCN4 isoforms as well as mRNA ANP were measured by RT- PCR in LV samples. Results: HR was significantly reduced (-11%) in MI+IVA vs. MI or SHAM. Ventricle mRNA ANP, index of fetal gene re-expression during LV remodeling, not-detected (below detection limit) in SHAM, was markedly increased in MI (13 fold vs. SHAM). This up-regulation was attenuated by 50% in MI+IVA group (6.5 fold vs. SHAM). Maximal specific density f-current was increased in MI vs. SHAM and was partially prevented in MI+IVA (If density at -90mV was 3.0±1.0pS/pF, 7.5±2.0pS/pF, 3.9±1.3*pS/pF; at -130mV was 21.7±4.9pS/pF, 49.3±7.0**pS/pF, 37.0±4.6pS/pF; Sham, MI and MI+IVA respectively,* p<0.01 vs MI, **P<0.05 versus SHAM ; n=12). Activation curve of f-current was similar in all groups. mRNA HCN2 and HCN4 increased in MI while in MI+IVA, HCN overexpression was reduced for HCN4 and tends to decrease for HCN2(HCN2: 0.9±0.1 (n=6), 1.9±0.2** (n=5), 1.3±0.2 (n=5); HCN4: 1.0±0.1 (n=6), 5.9±1.2** (n=5), 2.0±0.5* (n=5); Sham, MI and MI+IVA respectively, values are expressed in arbitrary units). The HCN4/HCN2 ratio, being 1 in SHAM, rising to 3.1 in MI, was reverted to 1.5 in MI+IVA, thus suggesting a major contribution of the HCN4 isoforms to the overexpression of f-channels. Conclusions: Chronic HR reduction with ivabradine significantly decreases LV electrophysiological remodeling in MI rats by reducing the functional and molecular f-channel overexpression. These results support a potential anti-arrhythmic properties of IVA in post MI heart failure.