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

Shuai Shao,Qian Yang,Ya Suo,Guangping Li,Yue Zhang,Xinghua Wang,Ying Li,Meng Yuan,Mengqi Gong,Qiankun Bao,Ming Yuan,Susana Novella

doi:10.1155/2021/1257283

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.

Highlights

Heart failure (HF) is a difficult problem for cardiologists in clinical practice
We found upregulation of interventricular septal thickness at diastole (IVSTd), left ventricular posterior wall thickness at diastole (LVPWd), diastolic blood pressure (DBP), and systolic blood pressure (SBP) in mice from 4 to 17 weeks after transverse aortic constriction (TAC) surgery compared to sham-operated mice (Tables 1 and 2)
Immunofluorescence staining showed that the expression of α-SMA and Connective tissue growth factor (CTGF) was significantly upregulated from the eighth week (Figures 1(g), 1(i), and 1(j)), indicating the activation of fibroblasts

Summary

Introduction

Heart failure (HF) is a difficult problem for cardiologists in clinical practice. It has the characteristics of high incidence, high readmission rates, and high mortality, which seriously affect the quality of life of patients [1]. Based on the left ventricular function, HF could be further categorized as HF with reduced ejection fraction (HFrEF, known as systolic HF) and HF with preserved ejection fraction (HFpEF, known as diastolic HF). This differentiation is necessary for the clinic because of different underlying etiologies, demographics, comorbidities, and responses to therapies [2]. HFpEF implies a myocardial process impairing filling due to an increase in ventricular stiffness or a decrease in ventricular relaxation [3] In both HFpEF and HFrEF, the activation of cardiac fibroblasts and myofibroblast formation contribute to maladaptive remodeling and progressive cardiac functional decline [4]. An I(f) channel is a member of the hyperpolarizationactivated cyclic nucleotide-gated (HCN) channel family, and it is regulated by the autonomic nervous system [8, 9]

Methods

Results

Conclusion