Impact of RyR2 potentiation on myocardial function

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca²⁺ transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca²⁺ release, shifting the intracellular Ca²⁺ transient versus sarcoplasmic reticulum (SR) Ca²⁺ content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca²⁺ content, to enhance contractility if SR Ca²⁺ content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention.NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca²⁺ transient-sarcoplasmic reticulum (SR) Ca²⁺ content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca²⁺ content, or successfully counteract the effects of a negative inotropic action.