In a mouse model of heart failure, treatment with antimiR-370-3p significantly improved survival (85% vs 35.3%, P=0.013) and blunted sinus bradycardia by restoring HCN4 expression.
Does silencing miR-370-3p with an antimiR rescue funny current, improve sinus node function, and reduce mortality in a mouse model of heart failure?
Silencing miR-370-3p represents a novel therapeutic approach to rescue sinus node dysfunction and bradycardia in heart failure by restoring the pacemaker funny current (If).
Absolute Event Rate: 85% vs 35.3%
p-value: p=0.013
Abstract Bradyarrhythmias 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, I f , in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of I f , 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 I f 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.
Yanni et al. (Thu,) conducted a other in Heart failure (n=56). antimiR-370-3p vs. PBS (vehicle) was evaluated on Survival at 60 days (p=0.013). In a mouse model of heart failure, treatment with antimiR-370-3p significantly improved survival (85% vs 35.3%, P=0.013) and blunted sinus bradycardia by restoring HCN4 expression.