Anthracycline-induced cardiomyopathy: Is there a new light at the end of the tunnel?

Q: What is the clinical evidence from this study?

Study design: Editorial. Population: Anthracycline-induced cardiomyopathy. Intervention: Dantrolene. Primary outcome: Prevention of left ventricular ejection fraction impairment and improvement in calcium dynamics in a murine model.

Q: What does this research mean for the field?

Dantrolene protects against doxorubicin-induced impairment of left ventricular ejection fraction and improves calcium dynamics in preclinical models of anthracycline cardiotoxicity. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Michael G. Fradley; Brian Olshansky

doi:10.1016/j.hroo.2021.10.008

December 1, 2021Heart Rhythm O2Open Access

Anthracycline-induced cardiomyopathy: Is there a new light at the end of the tunnel?

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Why the study?

Does dantrolene prevent anthracycline-induced cardiac dysfunction and improve myocardial calcium dynamics?

Key Points

To review the ongoing challenges of anthracycline-induced cardiotoxicity and evaluate emerging evidence supporting ryanodine receptor stabilization with dantrolene as a potential cardioprotective strategy.
Editorial commentary synthesizing clinical evidence on anthracycline-induced heart failure and neurohormonal therapies from trials including PRADA and CECCY.
Evaluation of preclinical experimental findings from murine and Langendorff heart models assessing dantrolene administration during doxorubicin exposure.
Clinical neurohormonal blockade using beta-blockers or angiotensin receptor blockers failed to prevent long-term decline in left ventricular ejection fraction in trials such as PRADA and CECCY.
Preclinical findings demonstrated that dantrolene protected against doxorubicin-induced myocardial injury, preserved left ventricular ejection fraction, and improved calcium transient duration and amplitude alternans ratio without reducing spontaneous diastolic calcium leak.
Mechanisms of anthracycline-mediated cardiotoxicity involve reactive oxygen species, topoisomerase-II DNA damage, and calcium dysregulation, though translation to clinical application requires addressing concerns such as liver toxicity.

Structured PICO

Does dantrolene prevent anthracycline-induced cardiac dysfunction and improve myocardial calcium dynamics?

P

Population

Murine model of anthracycline-induced (doxorubicin) cardiac dysfunction (in vivo and in a Langendorff preparation), as well as broader discussion of cancer patients receiving anthracyclines

I

Intervention

Dantrolene (skeletal muscle relaxant and ryanodine receptor stabilizer)

O

Outcome

Prevention of impairment of left ventricular ejection fraction and improvement in calcium dynamics (calcium transient duration, calcium transient rise time, and calcium amplitude alternans ratio)surrogate

Limitations

The role of calcium dysregulation in the pathophysiology of anthracycline-induced cardiomyopathy has yet to be established definitively
Results from a preclinical mouse model may not translate to humans of both sexes
Concerns with potential adverse effects of dantrolene, including liver toxicity
Role of calcium dysregulation in the pathophysiology of anthracycline-induced cardiomyopathy is not definitively established
Preclinical mouse model results may not translate to humans of both sexes
Potential adverse effects of dantrolene including liver toxicity

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Implication

This editorial highlights preclinical evidence that dantrolene preserves left ventricular ejection fraction and improves calcium dynamics against doxorubicin cardiotoxicity, supporting future prospective clinical studies.

Abstract

Despite introduction of novel targeted therapies and immunotherapies, cytotoxic chemotherapy with anthracyclines remains an integral part of treatment regimens for many solid and hematologic malignancies. The potential for cardiovascular toxicity with anthracyclines is well established, with the first reports of dose-dependent heart failure published in the 1970s.1 Since then, significant effort has been spent to identify risk factors for anthracycline-induced cardiotoxicity and develop prevention strategies.

Discussion

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Cite This Study

Fradley et al. (2021) conducted an editorial in Anthracycline-induced cardiomyopathy. Dantrolene was evaluated on Prevention of left ventricular ejection fraction impairment and improvement in calcium dynamics in a murine model.

synapsesocial.com/papers/6a7ca5d5ea40b5a66a3f6b1d https://doi.org/10.1016/j.hroo.2021.10.008

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Anthracycline-induced cardiomyopathy: Is there a new light at the end of the tunnel?

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Anthracycline-induced cardiomyopathy: Is there a new light at the end of the tunnel?

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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