| First Author | Mohamed BA | Year | 2018 |
| Journal | Sci Transl Med | Volume | 10 |
| Issue | 458 | PubMed ID | 30209242 |
| Mgi Jnum | J:266929 | Mgi Id | MGI:6200503 |
| Doi | 10.1126/scitranslmed.aan0724 | Citation | Mohamed BA, et al. (2018) Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression. Sci Transl Med 10(458) |
| abstractText | Increased sarcoplasmic reticulum (SR) Ca(2+) 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(2+) 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(2+) 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(2+) leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca(2+) 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(2+) waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca(2+) transient, SR Ca(2+) load, SR Ca(2+) 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(2+) leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice. |
