Long-term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization-activated cyclic nucleotide gated channel overexpression.

Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on If current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression. We investigated both the If current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the If current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the If current density (at -170 mV: TG, -39.6 ± 4.6 pA/pF; WT, -26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V1/2 : TG, -109.45 ± 1.35 mV; WT, -128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform If loss of function. Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01). IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as they partially counteract HCN overexpression and reverse electrophysiological cardiac remodeling by attenuating If gain-of-function.

Wang J ，Yang YM ，Li Y ，Zhu J ，Lian H ，Shao XH ，Zhang H ，Fu YC ，Zhang LF ... -  《-》

Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression.

Recent clinical data suggest beneficial effects of ivabradine, a specific heart rate (HR)-lowering drug, in heart failure patients. However, the mechanisms responsible for these effects have not been completely clarified. Thus, we investigated functional/molecular changes in I(f), the specific target of ivabradine, in the failing atrial and ventricular myocytes where this current is up-regulated as a consequence of maladaptive remodelling. We investigated the effects of ivabradine (IVA; 10 mg·kg(-1) ·day(-1) for 90 days) on electrophysiological remodelling in left atrial (LA), left ventricular (LV) and right ventricular (RV) myocytes from post-mycardial infarcted (MI) rats, with sham-operated (sham or sham + IVA) rats as controls. I(f) current was measured by patch-clamp; hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms and microRNA (miRNA-1 and miR-133) expression were evaluated by reverse transcription quantitative PCR. Maximal specific conductance of I(f) was increased in MI, versus sham, in LV (P < 0.01) and LA myocytes (P < 0.05). Ivabradine reduced HR in both MI and sham rats (P < 0.05). In MI + IVA, I(f) overexpression was attenuated and HCN4 transcription reduced by 66% and 54% in LV and RV tissue, respectively, versus MI rats (all P < 0.05). miR-1 and miR-133, which modulate post-transcriptional expression of HCN2 and HCN4 genes, were significantly increased in myocytes from MI + IVA. The beneficial effects of ivabradine may be due to the reversal of electrophysiological cardiac remodelling in post-MI rats by reduction of functional overexpression of HCN channels. This is attributable to transcriptional and post-transcriptional mechanisms.

Suffredini S ，Stillitano F ，Comini L ，Bouly M ，Brogioni S ，Ceconi C ，Ferrari R ，Mugelli A ，Cerbai E ... -  《-》

Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts.

Kuwabara Y ，Kuwahara K ，Takano M ，Kinoshita H ，Arai Y ，Yasuno S ，Nakagawa Y ，Igata S ，Usami S ，Minami T ，Yamada Y ，Nakao K ，Yamada C ，Shibata J ，Nishikimi T ，Ueshima K ，Nakao K ... -  《Journal of the American Heart Association》

Ivabradine prevents deleterious effects of dopamine therapy in heart failure: No role for HCN4 overexpression.

Exacerbations of chronic heart failure (CHF) are often treated with catecholamines to provide short term inotropic support, but this strategy is associated with long-term detrimental hemodynamic effects and increased ventricular arrhythmias (VA), possibly related to increased heart rate (HR). We hypothesized that ivabradine may prevent adverse effects of short-term dopamine treatment in CHF. Rats with post-myocardial infarction CHF received 2-week infusion of saline, dopamine(D), ivabradine(I) or D&I; cardiac function was assessed using echocardiography and pressure-volume loops while VA were assessed using telemetric ECG recording. Expression of HCN4, a potentially proarrhythmic channel blocked by ivabradine, was assessed in left ventricular (LV) myocardium. HCN4 expression was also assessed in human explanted normal and failing hearts and correlated with VA. Dopamine infusion had detrimental effects on hemodynamic parameters and LV remodeling and induced VA in CHF rats, while ivabradine completely prevented these effects. CHF rats demonstrated HCN4 overexpression in LV myocardium, and ivabradine and, unexpectedly, dopamine prevented this. Failing human hearts also exhibited HCN4 overexpression in LV myocardium that was unrelated to patient's sex, CHF etiology, VA severity or plasma NT-proBNP. HR reduction offered by ivabradine may be a feasible strategy to extract benefits of inotropic support in CHF exacerbations, avoiding detrimental effects on CHF biology or VA. Ivabradine may offer additional beneficial effects in this setting, going beyond pure HR reduction, however prevention of ventricular HCN4 overexpression is unlikely to play a major role.

Paterek A ，Sochanowicz B ，Oknińska M ，Śmigielski W ，Kruszewski M ，Mackiewicz U ，Mączewski M ，Leszek P ... -  《-》

Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under β-blockade.

Kawada T ，Yamamoto H ，Uemura K ，Hayama Y ，Nishikawa T ，Zheng C ，Li M ，Miyamoto T ，Sugimachi M ... -  《-》