Key result
Doxorubicin alters cardiac sympathetic innervation density and topology, revealing a novel mechanism of chemotherapy-induced cardiotoxicity.
Why the study?
The mechanisms underlying doxorubicin-induced cardiotoxicity remain incompletely understood, and recent studies suggest doxorubicin may affect cardiac sympathetic neurons in addition to cardiomyocytes.
Does doxorubicin treatment cause alterations in cardiac sympathetic innervation in mice and human hearts?
Does doxorubicin treatment cause alterations in cardiac sympathetic innervation in mice and human hearts?
Doxorubicin cardiotoxicity includes direct neurotoxic effects on cardiac sympathetic neurons, unveiling a novel mechanism for chemotherapy-induced autonomic dysregulation.
May implicate autonomic dysregulation in doxorubicin cardiotoxicity; hypothesis-generating from animal data and requires clinical validation.
Doxorubicin (DOXO) remains amongst the most commonly used anti-cancer agents for the treatment of solid tumors, lymphomas, and leukemias. However, its clinical use is hampered by cardiotoxicity, characterized by heart failure and arrhythmias, which may require chemotherapy interruption, with devastating consequences on patient survival and quality of life. Although the adverse cardiac effects of DOXO are consolidated, the underlying mechanisms are still incompletely understood. It was previously shown that DOXO leads to proteotoxic cardiomyocyte (CM) death and myocardial fibrosis, both mechanisms leading to mechanical and electrical dysfunction. While several works focused on CMs as the culprits of DOXO-induced arrhythmias and heart failure, recent studies suggest that DOXO may also affect cardiac sympathetic neurons (cSNs), which would thus represent additional cells targeted in DOXO-cardiotoxicity. Confocal immunofluorescence and morphometric analyses revealed alterations in SN innervation density and topology in hearts from DOXO-treated mice, which was consistent with the reduced cardiotropic effect of adrenergic neurons in vivo. Ex vivo analyses suggested that DOXO-induced denervation may be linked to reduced neurotrophic input, which we have shown to rely on nerve growth factor, released from innervated CMs. Notably, similar alterations were observed in explanted hearts from DOXO-treated patients. Our data demonstrate that chemotherapy cardiotoxicity includes alterations in cardiac innervation, unveiling a previously unrecognized effect of DOXO on cardiac autonomic regulation, which is involved in both cardiac physiology and pathology, including heart failure and arrhythmias.
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Moro et al. (2022) studied Doxorubicin-induced cardiotoxicity. Doxorubicin was evaluated on Cardiac sympathetic neuron innervation density and topology. Doxorubicin treatment alters cardiac sympathetic neuron innervation density and topology in both mice and explanted human hearts, revealing a novel mechanism of chemotherapy-induced cardiotoxicity.
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