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

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

doi:10.1016/j.hroo.2020.03.004

Cited by 22 publications

(24 citation statements)

References 32 publications

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“…Dantrolene inhibits sarcoplasmic calcium release in skeletal muscle cells, and it is indicated in malignant hyperthermia. A favorable anti-AF effect has been observed in various preclinical settings such as rat models of heart failure [ 162 ], hypertension [ 163 ], and autonomic nervous system imbalance [ 164 , 165 ]. A canine model of tachypaced AF further supports dantrolene’s antiarrhythmic potential, and RyR2 channel stabilization is the underlying antiarrhythmic mechanism [ 166 ].…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

et al. 2021

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The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

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Section: Therapeutic Perspectivesmentioning

confidence: 99%

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

et al. 2021

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“…The most critical pathologic event underneath heart dysfunction associates with an impairment in Ca 2+ handling, in particular, RYR2 dysregulated functionality. After coronary artery ligation, Nofi et al [286] electrically stimulated infarcted rat hearts in vivo with 200-bpm burst pacing at 50 Hz, successfully generating AF. In order to stabilize the arrhythmogenic hearts, dantrolene was administered, proving once again its efficacy in suppressing triggered arrhythmias in atrial and ventricular cardiomyocytes [287,288].…”

Section: Modeling Of Af-related Nppa Mutationsmentioning

confidence: 99%

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

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Iliceto

Civieri

et al. 2021

Cells

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Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

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“…For calcium transient duration (CaTD) analysis, 0 to 50% of repolarization (CaTD 50 ) and 0 to 80% of repolarization (CaTD 80 ) were analyzed, as described previously. 23,24 Calcium amplitude alternans ratio analysis Ca 21 amplitude alternans refers to the beat-to-beat difference of Ca 21 signal amplitudes during cardiac stimulation. A calcium amplitude alternans ratio (CaAAR) of 1 indicates similar amplitudes, whereas a ratio of 0.5 refers to a 50% difference between large and small Ca 21 amplitudes.…”

Section: Calcium Transient Duration Analysismentioning

confidence: 99%

“…26 Diastolic/spontaneous calcium leak The presence of spontaneous calcium elevation (SCaE) is the result of a leaky RyR2 receptor during diastole. This parameter is unitless and was measured from the Ca 21 wave and normalized to Ca 21 transient amplitude. The calcium signal fluorescence elevation between the final pacing beat and the first spontaneous beat was calculated as described previously.…”

Section: Calcium Transient Duration Analysismentioning

confidence: 99%

“…17 Alternatively, dantrolene (Dan), a ryanodine receptor (RyR) stabilizer, has been shown to improve sarcoplasmic calcium release as well as cardiac function in models of both acute and chronic cardiomyopathy. [18][19][20][21] Previously, we have shown that Dan infusion during cardiopulmonary resuscitation improved cardiac hemodynamics by normalizing cardiac calcium dynamics. 22 Thus, in the present study, we sought to investigate the role of dantrolene-mediated calcium regulation in the prevention of DICM using a murine model.…”

Section: Introductionmentioning

confidence: 99%

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Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

et al. 2021

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BACKGROUND Doxorubicin (Dox) is a potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. Intracellular calcium dysregulation has been reported to be involved in doxorubicin-induced cardiomyopathy (DICM). The cardioprotective role of RyR stabilizer dantrolene (Dan) on the calcium dynamics of DICM has not yet been explored. OBJECTIVE To evaluate the effects of dantrolene on intracellular calcium dysregulation and cardiac contractile function in a DICM model.METHODS Adult male C57BL/6 mice were randomized into 4 groups: (1) Control, (2) Dox Only, (3) Dan Only, and (4) Dan 1 Dox. Fractional shortening (FS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography. In addition, mice were sacrificed 2 weeks after doxorubicin injection for optical mapping of the heart in a Langendorff setup. RESULTSTreatment with Dox was associated with a reduction in both FS and LVEF at 2 weeks (P , .0001) and 4 weeks (P , .006). Dox treatment was also associated with prolongation of calcium transient durations CaTD 50 (P 5 .0005) and CaTD 80 (P , .0001) and reduction of calcium amplitude alternans ratio (P , .0001). Concomitant treatment with Dan prevented the Dox-induced decline in FS and LVEF (P , .002 at both 2 and 4 weeks). Dan also prevented Dox-induced prolongation of CaTD 50 and CaTD 80 and improved the CaT alternans ratio (P , .0001). Finally, calcium transient rise time was increased in the doxorubicin-treated group, indicating RyR2 dyssynchrony, and dantrolene prevented this prolongation (P 5 .02).CONCLUSION Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.

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

Cited by 22 publications

References 32 publications

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

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