Abstract
AbstractBradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, If, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of If, and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and If in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.
Funder
U.S. Department of Health & Human Services | National Institutes of Health
British Heart Foundation
Fondation Leducq
Publisher
Springer Science and Business Media LLC
Reference99 articles.
1. Ambrosy, A. P. et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J. Am. Coll. Cardiol. 63, 1123–1133 (2014).
2. Benes, J. et al. Resting heart rate and heart rate reserve in advanced heart failure have distinct pathophysiologic correlates and prognostic impact: a prospective pilot study. J. Am. Coll. Cardiol. Heart Fail. 1, 259–266 (2013).
3. Crespo-Leiro, M. G. et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur. J. Heart Fail. 18, 613–625 (2016).
4. Fox, K. et al. Resting heart rate in cardiovascular disease. J. Am. Coll. Cardiol. 50, 823–830 (2007).
5. Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376, 875–885 (2010).
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