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

## TL;DR

This study shows that doxorubicin harms the heart's pacemaker by damaging mitochondria and cell nuclei in mice.

## Contribution

The study reveals doxorubicin's impact on the sinus node's function and structure through mitochondrial and nuclear damage.

## Key findings

- Doxorubicin reduces intrinsic heart rate in mice during acute and chronic phases.
- Doxorubicin causes mitochondrial fragmentation and chromatin condensation in sinus node cells.
- Doxorubicin downregulates genes for pacemaker channels and calcium regulators in the sinus node.

## Abstract

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 Ca2 + 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.

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.