Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

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 CaTD(50) (P = .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 = .02). CONCLUSION: Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.