R4496C RyR2 mutation impairs atrial and ventricular contractility

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cardiac Electrophysiology

Background:

• The ryanodine receptor type 2 (RyR2) is critical for cardiac excitation-contraction coupling, regulating calcium release from the sarcoplasmic reticulum.
• Dysfunctional RyR2 gating, leading to increased open probability (Po) and calcium leakage, is implicated in arrhythmias like catecholaminergic polymorphic ventricular tachycardia (CPVT).
• The specific impact of RyR2 mutations on myocardial contractility remains largely unknown.

Purpose of the Study:

• To investigate the effects of the CPVT-associated RyR2 R4496C mutation on atrial and ventricular myocardial contractility.
• To elucidate the underlying mechanisms of altered contractility in the presence of the R4496C RyR2 mutation.

Main Methods:

• Isometric twitch tension measurements in isolated cardiac trabeculae from wild-type and R4496C RyR2 mutant mice.
• Assessment of calcium transient amplitude and sarcoplasmic reticulum (SR) calcium content in single ventricular myocytes.
• Evaluation of responses to various inotropic stimuli including high stimulation frequency, isoproterenol, and elevated extracellular calcium.

Main Results:

• Baseline twitch force was comparable between wild-type and R4496C RyR2 mutant myocardium.
• R4496C trabeculae exhibited blunted positive inotropic responses to stimulation frequency, isoproterenol, and high extracellular calcium, along with reduced post-rest potentiation.
• Single R4496C myocytes showed normal baseline calcium transient amplitude despite reduced SR calcium content, but failed to increase SR calcium loading under inotropic challenge due to increased RyR2-mediated calcium leak.
• Faster recovery of force following premature stimuli in R4496C myocardium was observed, potentially due to faster inactivation recovery of mutant RyR2 channels.

Conclusions:

• The R4496C RyR2 mutation directly alters both ventricular and atrial myocardial contractility.
• Increased RyR2 open probability and fractional calcium release preserve baseline contractility but impair the heart's ability to augment force during physiological stress.
• RyR2 dysfunction contributes significantly to impaired cardiac contractility and may underlie the pathophysiology of CPVT.