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  • Review Article
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Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine

Nature Reviews Cardiology volume 22, pages 183–198 (2025)Cite this article

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Abstract

Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. Despite improvements in the prognosis of patients with DCM in the past decade, this condition remains a leading cause of heart failure and premature death. Conventional treatment for DCM is based on the foundational therapies for heart failure with reduced ejection fraction. However, increasingly, attention is being directed towards individualized treatments and precision medicine. The ability to confirm genetic causality is gradually being complemented by an increased understanding of genotype–phenotype correlations. Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the ‘two-hit’ hypothesis). The roles of common genetic variants in the general population and of gene modifiers in disease onset and progression are also discussed. Finally, areas for future research are highlighted, particularly novel therapies, such as small molecules, RNA and gene therapy, and measures for the prevention of arrhythmic death.

Key points

  • Dilated cardiomyopathy (DCM) is a heterogeneous disease with multiple causes and high variability in phenotype presentation and outcomes.

  • Genetic testing has been recommended in guidelines as a fundamental step in the clinical decision-making process; the results can guide not only family screening but also aetiological characterization and risk stratification.

  • Genotype–phenotype correlations can aid clinicians in prioritizing genetic testing in patients with a higher likelihood of identifying a disease-causing variant, particularly for genes associated with major arrhythmic events.

  • A strong interaction exists between the genetic background and environmental exposures, which can lead to different phenotypic manifestations of the disease (that is, the two-hit hypothesis).

  • Advances in the management of DCM are moving towards a precision medicine approach to the diagnostic work-up and treatment.

  • Future research and resource allocation will focus on the identification of disease-modifying treatments for DCM, which include molecular targeted and gene therapies.

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Fig. 1: Complex interactions in the pathophysiology of dilated cardiomyopathy.
Fig. 2: Genotype–phenotype correlations in dilated cardiomyopathy.
Fig. 3: Life-threatening ventricular arrhythmias and HF-related events in DCM.
Fig. 4: Cascade screening in DCM.
Fig. 5: Simplified mechanisms of inflammation in dilated cardiomyopathy.

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Acknowledgements

M.R.G.T. and L.M. receive grant support from the National Institutes of Health (X01 HL139403, UL1 RR025870, R01HL164634 and R01HL147064).

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Authors and Affiliations

  1. Cardiothoracovascular Department, Centre for Diagnosis and Treatment of Cardiomyopathies, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI) and University of Trieste, Trieste, Italy

    Marta Gigli, Davide Stolfo, Marco Merlo & Gianfranco Sinagra

  2. Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

    Davide Stolfo

  3. Adult Medical Genetics Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Matthew R. G. Taylor

  4. Molecular Genetics Program, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Luisa Mestroni

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D.S. has received honoraria for lectures and fees for expert advice from AstraZeneca, Janssen, Merck, Novartis and Novo Nordisk. M.R.G.T. and L.M. receive grant support from Bristol Meyers Squibb, Greenstone Bioscience, Owkin, Pfizer and Tenaya Therapeutics. M.R.G.T also receives grant support from Rocket Pharmaceuticals and Spark Therapeutics. L.M. is member of the Scientific Advisory Board of Tenaya Therapeutics. The other authors declare no competing interests.

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Related links

ARVC Risk Calculator: https://arvcrisk.com/

ClinGen database: https://www.clinicalgenome.org/

DCM SHaRe registry: https://www.theshareregistry.org/

LMNA risk VTA Calculator: https://lmna-risk-vta.fr/

PLN 5-year VA Risk Calculator: https://plnriskcalculator.shinyapps.io/final_shiny/

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Gigli, M., Stolfo, D., Merlo, M. et al. Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine. Nat Rev Cardiol 22, 183–198 (2025). https://doi.org/10.1038/s41569-024-01074-2

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