John Mandrola, MD

Cardiogenetics

Secondary Cardiomyopathy Isn’t so Secondary After All

Secondary cardiomyopathies might not be caused by environmental factors after all, after a massive four-biobank study found that their development is a lot more dependent on which combination of genetic risks you already have.

• Secondary cardiomyopathies including peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) have traditionally been viewed as caused by environmental conditions.
• While rare single gene mutations linked to dilated cardiomyopathy (DCM) were known to be higher in these populations, the role of mult-gene expression was unclear until now.

The multi-biobank genetic analysis examined nearly 1.3M individuals identifying 3.4k people with secondary cardiomyopathies (70 PPCM, 2,281 ACM, 1,063 CCM). Upon looking at the combination of genes these patients had, researchers found some stunning gene architectures.

• People with the combination of genes that lead to DCM were also at far greater risk for all secondary cardiomyopathy types: PPCM (OR: 1.82 per SD), ACM (OR: 1.56), and CCM (OR: 1.64).
• In medically reviewed cases, monogenic variants were present in only 7 of 113 individuals, while 66 had high polygenic scores making them 3x more likely to develop CM.
• Most people with cardiomyopathy didn’t have prior risk factors, suggesting genetics rather than environmental exposure drives disease development.
• Researchers also found that while some people developed cardiomyopathy due to a single genetic mutation, far more developed CM due to multi-gene mutations.

Even with well-established environmental triggers like pregnancy, alcohol, and chemotherapy, the genetic data suggests these exposures act as magnifiers in people who are already genetically susceptible rather than primary causes.

• The shared genetic architecture between secondary cardiomyopathies and DCM implies these conditions may represent the same underlying disease process triggered by distinct environmental stressors.
• This reframes “secondary” cardiomyopathies as primarily genetic conditions with environmental magnifiers, rather than environmental conditions with genetic contributions.

The Takeaway

This landmark genetic study fundamentally challenges how we understand secondary cardiomyopathies, revealing that most cases reflect underlying genetic predisposition triggered by environmental factors rather than direct environmental causes. Future prevention strategies should focus on population-level genetic screening to identify at-risk individuals, potentially preventing thousands of cases currently classified as unavoidable environmental complications.

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