Paper of the Month

November 2018

Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression. Science Translational Medicine. DZHK-Autoren: Mohamed, Hartmann, Tirilomis, Richter, Zeisberg, Didié, Lehnart, Luther, Voigt, Seidler, Sossalla, Hasenfuss, Toischer

Contractile impairment in heart failure (HF) is caused by reduced cardiomyocyte calcium (Ca2+) transients that is mainly due to a reduced sarcoplasmic reticulum (SR) Ca2+ content either be decreased uptake via SR Ca2+ ATPase (SERCA) or by increased efflux via ryanodine receptor (RyR2). Increased  SR Ca2+ leak via RyR2 has been suggested to have a mechanistic role in the development of HF and cardiac arrhythmias. DZHK scientist Karl Toischer and his colleagues (first author: Belal Mohamed) from Göttingen have increased the knowledge of the SR in HF by treating mice with a new and very selective RYR2 stabilizer (RYCAL, S36). S36 normalized the SR Ca2+ leak and improved survival in the pressure overload and myocardial infarction models. The development of HF, measured by echocardiography as well as molecular markers, showed no difference in S36- versus vehicle treated-mice, but the amount and severity of arrhythmias were reduced by S36.

This results were confirmed by dantrolene, a rycal-unrelated RyR2 stabilizer. Analysis of isolated cardiomyocytes from murine and human hearts showed a reduction of delayed afterdepolarizations, spontaneous and induced Ca2+ waves, and triggered activity in S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SERCA function and action potential durations were not influenced. Moreover, rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia (CPVT) could also rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, but reducing the SR Ca2+ leak attenuates arrhythmias and thereby improves mortality. Stabilization of RyR2 by newly generated rycals could therefore represent a promising target for treatment of fatal arrhythmias in HF and CPVT patients.