Chronic dantrolene treatment attenuates cardiac dysfunction and reduces atrial fibrillation inducibility in a rat myocardial infarction heart failure model

Colleen Nofi; Kuo Zhang; Yi-Da Tang; Ying Li; Allan Migirov; Kaie Ojamaa; A Martin Gerdes; Youhua Zhang

doi:10.1016/j.hroo.2020.03.004

Chronic dantrolene treatment attenuates cardiac dysfunction and reduces atrial fibrillation inducibility in a rat myocardial infarction heart failure model

Heart Rhythm O2. 2020 Jun 15;1(2):126-135. doi: 10.1016/j.hroo.2020.03.004. eCollection 2020 Jun.

Authors

Colleen Nofi¹, Kuo Zhang^{1

2}, Yi-Da Tang², Ying Li¹, Allan Migirov¹, Kaie Ojamaa¹, A Martin Gerdes¹, Youhua Zhang¹

Affiliations

¹ Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York.
² Department of Internal Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Background: Cardiac ryanodine receptor 2 (RyR2) dysfunction and elevated diastolic Ca²⁺ leak have been linked to arrhythmogenesis not only in inherited arrhythmia syndromes but also in acquired forms of heart disease including heart failure (HF) and atrial fibrillation (AF). Thus, stabilizing RyR2 may exert therapeutic effects in these conditions.

Objective: The purpose of this study was to investigate the effects of stabilizing RyR2 with chronic dantrolene treatment on HF development and AF inducibility in a myocardial infarction (MI)-induced HF model in rats.

Methods: MI was induced in adult Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Two weeks after MI surgery, rats with large MI (≥40%) were randomly assigned to MI-vehicle (n = 14) or MI-dantrolene (10 mg/kg/d; n = 13) groups. Sham-surgery rats (n = 7) served as controls.

Results: Compared to the MI-vehicle group, 4-week dantrolene treatment significantly improved cardiac function, with increased left ventricular (LV) fractional shortening (19.48% ± 3.61% vs 15.43% ± 2.65%; P <.01), and decreased LV end-diastolic pressure (12.58 ± 8.52 mm Hg vs 21.91 ± 7.25 mm Hg; P <.01), left atrial diameter (4.97 ± 0.75 mm vs 6.09 ± 1.53 mm; P <.05), and fibrosis content (6.42% ± 0.78% vs 9.76% ± 2.25%; P <.001). Dantrolene significantly decreased AF inducibility (69% in MI-vehicle vs 23% in MI-dantrolene; P <.05). Dantrolene treatment was associated with reduced RyR2 phosphorylation and favorably altered gene expression involving ion channels, sympathetic signaling, oxidative stress, and inflammatory markers.

Conclusion: Chronic dantrolene treatment attenuated LV dysfunction and reduced AF inducibility, which was associated with decreased RyR2 phosphorylation and normalization of many adverse changes in gene expression. Thus, stabilizing RyR2 with chronic dantrolene treatment is a promising novel strategy for decreasing AF in HF.

Keywords: Atrial fibrillation; Cardiac ryanodine receptor; Dantrolene; Heart failure; Ryanodine receptor stabilizer.