Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

Mohammed Ali Azam, MBBS, PhD; Praloy Chakraborty, MD; Mahmoud M. Bokhari, MBBS; Keith Dadson, PhD; Beibei Du, MD, PhD; Stéphane Massé, MASc; Daoyuan Si, MD, PhD; Ahmed Niri, BEng; Arjun K. Aggarwal; Patrick F.H. Lai, MSc; Sheila Riazi, MD, MSc; Filio Billia, MD, PhD; Kumaraswamy Nanthakumar, MD

Heart Rhythm O2 (Dec 2021)

Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

Mohammed Ali Azam, MBBS, PhD,
Praloy Chakraborty, MD,
Mahmoud M. Bokhari, MBBS,
Keith Dadson, PhD,
Beibei Du, MD, PhD,
Stéphane Massé, MASc,
Daoyuan Si, MD, PhD,
Ahmed Niri, BEng,
Arjun K. Aggarwal,
Patrick F.H. Lai, MSc,
Sheila Riazi, MD, MSc,
Filio Billia, MD, PhD,
Kumaraswamy Nanthakumar, MD

Affiliations

Mohammed Ali Azam, MBBS, PhD: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Praloy Chakraborty, MD: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Mahmoud M. Bokhari, MBBS: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Keith Dadson, PhD: Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Beibei Du, MD, PhD: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Stéphane Massé, MASc: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Daoyuan Si, MD, PhD: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Ahmed Niri, BEng: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Arjun K. Aggarwal: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Patrick F.H. Lai, MSc: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada
Sheila Riazi, MD, MSc: Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, Canada
Filio Billia, MD, PhD: Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Kumaraswamy Nanthakumar, MD: The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada; Address reprint requests and correspondence: Dr Kumaraswamy Nanthakumar, Division of Cardiology, University Health Network, Toronto General Hospital, 150 Gerrard St W, GW3-526, Toronto, Ontario, Canada, M5G 2C4.

Journal volume & issue: Vol. 2, no. 6
pp. 733 – 741

Abstract

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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 + 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. Results: Treatment 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 CaTD50 (P = .0005) and CaTD80 (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 CaTD50 and CaTD80 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 = .02). Conclusion: Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.

Published in Heart Rhythm O2

ISSN: 2666-5018 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: https://www.journals.elsevier.com/heart-rhythm-o2

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