Format

Send to

Choose Destination
Sci Transl Med. 2018 Sep 12;10(458). pii: eaan0724. doi: 10.1126/scitranslmed.aan0724.

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

Author information

1
Department of Cardiology and Pneumology, Georg-August-University, 37075 Göttingen, Germany.
2
DZHK (German Centre for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany.
3
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura City 35516, Egypt.
4
Institute of Pharmacology and Toxicology, Technische Universität Dresden, 01307 Dresden, Germany.
5
Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany.
6
Research Group Biomedical Physics, Max Planck Institute for Dynamics and Self-Organization, 37077 Göttingen, Germany.
7
Endotherm Life Science Molecules, 66123 Saarbrücken, Germany.
8
Institute of Pharmacology and Toxicology, Georg-August-University, 37075 Göttingen, Germany.
9
Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.
10
Department of Cardiology and Pneumology, Georg-August-University, 37075 Göttingen, Germany. ktoischer@med.uni-goettingen.de.

Abstract

Increased sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ 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 Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ 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 Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center