Failing Hearts Are More Vulnerable to Sympathetic, but Not Vagal Stimulation–Induced, Atrial Fibrillation—Ameliorated with Dantrolene Treatment

Delfiner, Matthew S.; Nofi, Colleen; Li, Ying; Gerdes, A. Martin; Zhang, Youhua

doi:10.1016/j.cardfail.2018.05.008

Cited by 11 publications

(19 citation statements)

References 32 publications

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“…We previously demonstrated that, compared with normal hearts (which are more sensitive to vagal stimulation-induced AF), 29 failing hearts are more vulnerable to sympathetic stimulation-induced AF. 15 We further demonstrated that stabilizing RyR2 with acute dantrolene treatment could significantly attenuate sympathetic stimulation-enhanced AF inducibility in failing hearts. 15 To our knowledge, this was the first study to examine long-term dantrolene treatment on AF in HF.…”

Section: Dantrolene Treatment In Hf and Afmentioning

confidence: 68%

“…15 We further demonstrated that stabilizing RyR2 with acute dantrolene treatment could significantly attenuate sympathetic stimulation-enhanced AF inducibility in failing hearts. 15 To our knowledge, this was the first study to examine long-term dantrolene treatment on AF in HF. We found that chronic dantrolene treatment improved cardiac function, attenuated atrial remodeling, and significantly reduced AF inducibility and AF duration in this animal model.…”

Section: Dantrolene Treatment In Hf and Afmentioning

confidence: 68%

“…RyR2 dysfunction and its exacerbation by sympathetic activation could explain our finding that failing hearts are more vulnerable to sympathetic stimulation-induced AF compared to normal hearts. 15 Moreover, these results provide a mechanistic explanation that sympathetic inhibition with Figure 7 Expression of selected adrenergic, oxidative, inflammation, and collagen genes in left atrial tissue. Gene expression was normalized using cyclophilin A and Rplp1.…”

Section: Discussionmentioning

confidence: 95%

“…Atrial electrophysiology and AF inducibility tests were performed as previously described. 15,16 In brief, a Standard S1S2 pacing protocol was used for determination of atrial effective refractory periods. Burst pacing containing 200 impulses at 50 Hz was used to induce AF.…”

Section: Electrophysiology and Af Inducibility Testmentioning

confidence: 99%

“…We previously demonstrated that acute dantrolene treatment can significantly attenuate sympathetic stimulation-enhanced AF inducibility in a rat myocardial infarction (MI)–induced HF model. 15 Accordingly, we hypothesized that by stabilizing cardiac RyR2, chronic dantrolene treatment may be a therapeutic option for reducing AF in HF. This study was designed to investigate the effects of chronic dantrolene treatment on HF development and AF inducibility in a rat MI-HF model.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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BACKGROUND Cardiac ryanodine receptor 2 (RyR2) dysfunction and elevated diastolic Ca 21 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 MIvehicle (n 5 14) or MI-dantrolene (10 mg/kg/d; n 5 13) groups. Sham-surgery rats (n 5 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% 6 3.61% vs 15.43% 6 2.65%; P ,.01), and decreased LV end-diastolic pressure (12.58 6 8.52 mm Hg vs 21.91 6 7.25 mm Hg; P ,.01), left atrial diameter (4.97 6 0.75 mm vs 6.09 6 1.53 mm; P ,.05), and fibrosis content (6.42% 6 0.78% vs 9.76% 6 2.25%; P ,.001). Dantrolene significantly decreased AF inducibility (69% in MIvehicle 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.

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Section: Dantrolene Treatment In Hf and Afmentioning

confidence: 68%

Section: Dantrolene Treatment In Hf and Afmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 95%

Section: Electrophysiology and Af Inducibility Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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