Key result
Cardiomyocyte Piezo1 deletion boosts post-MI survival ~26 percentage points in mice, preserving LVEF.
Why the study?
The role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remained undefined.
Does cardiomyocyte-specific deletion of the mechanosensitive cation channel Piezo1 preserve cardiac function and prevent lethal ventricular arrhythmias after myocardial infarction in mice?
Does cardiomyocyte-specific deletion of the mechanosensitive cation channel Piezo1 preserve cardiac function and prevent lethal ventricular arrhythmias after myocardial infarction in mice?
Identifies the mechanosensitive channel Piezo1 as a key link between post-MI mechanical stress, CaMKII/RyR2-mediated calcium leak, and lethal ventricular arrhythmias, suggesting Piezo1 inhibition as a potential antiarrhythmic and cardioprotective target.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for Piezo1 inhibition post-MI; leaves open translation to human arrhythmia prevention.
Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1 Cko ) exhibited preserved cardiac function after MI. Piezo1 Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca 2+ overload and increasing the activation of Ca 2+ -modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca 2+ leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca 2+ handling, implying a promising therapeutic target in sudden cardiac death and heart failure.
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Su et al. (2023) studied Ventricular arrhythmogenesis following myocardial infarction (preclinical mouse and hiPSC-CM models) (n=28). Cardiomyocyte-specific Piezo1 knockout (Piezo1 Cko) and pharmacological Piezo1 modulation (Yoda1, Jedi1, Dooku1, GsMTx4) vs. Piezo1 fl/fl control littermates or vehicle (PBS) was evaluated on Survival at 6 weeks post-myocardial infarction (p=<0.05). Cardiomyocyte-specific Piezo1 deletion preserved LVEF (31.31% vs 18.64%) and improved 6-week post-MI survival (92.3% vs 66.7%, P<0.05) while reducing ventricular arrhythmia in mice.
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