Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

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

doi:10.1016/j.hroo.2021.08.008

Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

Heart Rhythm O2. 2021 Dec 17;2(6Part B):733-741. doi: 10.1016/j.hroo.2021.08.008. eCollection 2021 Dec.

Authors

Affiliations

¹ The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada.
² Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada.
³ Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, Canada.

Abstract

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.

Keywords: Cardiac function; Cardiomyopathy; Dantrolene; Doxorubicin; Myocardial calcium transients.