Doxorubicin-induced sinus node dysfunction associated with mitochondria and nuclear impairment in a mouse model

Doxorubicin (DXB), an effective anti-cancer drug, is well documented for its cardiotoxicity in the ventricular myocardium. Although DXB-induced cardiomyopathy can cause arrhythmias, its impact on the cardiac conduction system remains unclear. We aimed to investigate whether DXB affects the function and subcellular structure of the sinus node, the primary pacemaking site. C57BL/6 N mice received intraperitoneal injections of DXB at a total dose of 20 mg/kg. DXB treatment resulted in a reduced intrinsic heart rate during both the acute and chronic phases. We also observed DXB-induced downregulation of genes encoding pacemaker channels in both phases and Ca 2+ regulators in the chronic phase. Ultrastructural analysis revealed increased mitochondrial fragmentation, chromatin condensation, and a small number of severely damaged cells within the sinus node. These findings suggest that DXB impairs sinus node function, structure, and transcriptional regulation, potentially through mitochondrial and nuclear damage, leading to loss of pacemaker cells. • Doxorubicin (DXB) reduces the intrinsic heart rate in mice. • DXB induces downregulation of genes encoding heart rate regulators. • DXB triggers mitochondrial and nuclear abnormalities in sinus node cells. • These findings may guide targeted therapies to improve patients’ cardiac outcomes.