Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression

• Published in: Science translational medicine 2018-09, Vol.10 (458)
• Main Authors: Mohamed, Belal A, Hartmann, Nico, Tirilomis, Petros, Sekeres, Karolina, Li, Wener, Neef, Stefan, Richter, Claudia, Zeisberg, Elisabeth M, Kattner, Lars, Didié, Michael, Guan, Kaomei, Schmitto, Jan D, Lehnart, Stephan E, Luther, Stefan, Voigt, Niels, Seidler, Tim, Sossalla, Samuel, Hasenfuss, Gerd, Toischer, Karl
• Format: Article
• Language: English
• Subjects: Action potential; Adenosine; Adenosine triphosphatase; Arrhythmia; Calcium (reticular); Calcium signalling; Cardiac muscle; Cardiomyocytes; Echocardiography; Heart diseases; Leak channels; Muscle contraction; Myocardial infarction; Myocardium; Pluripotency; Ryanodine receptors; Sarcoplasmic reticulum; Stem cell transplantation; Stem cells; Tachycardia; Triphosphatase; Ventricle
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aan0724

Increased sarcoplasmic reticulum (SR) Ca leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36- versus placebo-treated mice. Reduction of SR Ca leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca leak-independent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca transient, SR Ca load, SR Ca adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.