Increasing SR Ca uptake: a double-edged sword

Abstract

We read with great attention the recently published article by Sato et al. titled ‘Increasing SERCA function promotes initiation of calcium sparks and breakup of calcium waves’ (Sato et al. 2021). We believe that the opposing effects of increasing SR Ca uptake described in the paper is very significant, not only from the physiological point of view, but also because of the possible therapeutic consequences. It is very well known that different attempts have been made and are in course, to treat cardiac failure by improving SR Ca uptake and increasing systolic and diastolic function (Greenberg et al. 2014; Hulot et al. 2017; Lyon et al. 2020; Wasala et al. 2020). As is clear from Sato’s results, this constitutes a double-edged sword, because the increase in SR Ca content may also increase SR Ca leak and cardiac arrhythmias. However, if the increase in SR Ca uptake is high enough, SR Ca load and contractility may be improved, whereas SR Ca waves are aborted. Still, several questions remain to be discussed. One of them refers to the effects of a persistent and exacerbated increase in SR Ca leak. Although the increase in SR Ca uptake may be less arrhythmogenic because of Ca wave abortion, which is the consequence of the chronic exacerbated SR Ca leak?