Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR‐133a

Abstract

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

The effect of ivabradine therapy on dilated cardiomyopathy patients with congestive heart failure: a systematic review and meta-analysis

“…Furthermore, several studies have found that ivabradine can improve cardiac function through alternative mechanisms: ivabradine reduces adverse remodeling and injury in the heart by inhibiting calcium overload induced by increased I f current ( 31 ). Shuai et al ( 32 ) found that ivabradine ameliorated pressure overload-induced myocardial fibrosis and cardiac dysfunction by upregulating miR-133a in mice. Ivabradine may mediate the immunomodulatory and anti-inflammatory effects independent of heart rate reduction ( 33 , 34 ).…”

Non-coding RNAs in the pathophysiology of heart failure with preserved ejection fraction

“…It was shown that the target for miR-133a-3p was Igf1r, a component of the IGF1R/PI3K/AKT signaling pathway, which is important for cell survival (73). In contrast, cardiac miR-133a was reduced in TAC mouse model and an in vitro fibrosis model using neonatal rat primary ventricular fibroblasts treated with Ang-II (137), again indicating that miRNAs can be differently regulated in diastolic vs. systolic HF.…”

Drug Therapy for Acute and Chronic Heart Failure with Preserved Ejection Fraction with Hypertension: A State-of-the-Art Review

“…Ivabradine, a funny current ( I f ) inhibitor, reduces heart rate without reducing cardiac inotropy [ 129 ] and may have some positive effects on cardiac fibrosis via upregulation of microRNA-133a, which targets connective tissue growth factor and collagen 1 in cardiac fibroblasts [ 130 ]. To date, two randomized controlled trials [ 131 , 132 ] and one cross-over study [ 133 ] have been conducted to evaluate the usefulness of ivabradine in patients with HFpEF.…”