Gene group predicts arrhythmia in dilated cardiomyopathy, even with preserved ejection fraction

Design

International registry cohort analysis (SHaRe), observational

Population

2,660 genotyped adults with dilated cardiomyopathy; 16% high-arrhythmic-risk gene variants, 17% low-risk gene variants, 67% gene-elusive

Primary outcome

Major ventricular arrhythmia, atrial fibrillation, heart failure, death and their composite, adjusted for age, sex and ejection fraction

Effect

High-risk gene vs gene-elusive: major ventricular arrhythmia HR 3.25 (95% CI 2.63 to 4.01); with LVEF 50% or more, HR 2.36 (1.59 to 3.51)

A registry analysis followed 2,660 genotyped adults with dilated cardiomyopathy. Sixteen percent carried a pathogenic or likely pathogenic variant in a high-arrhythmic-risk gene (LMNA, DSP, FLNC, RBM20, PLN, SCN5A, DES or TMEM43), 17% had a variant in a lower-risk gene such as TTN, and 67% were gene-elusive.

Compared with gene-elusive patients, those with a high-risk gene variant had a hazard ratio of 3.25 (95% CI 2.63 to 4.01) for major ventricular arrhythmia, 2.42 for atrial fibrillation and 2.46 for heart failure events. These excesses held after adjustment for age, sex and ejection fraction. In patients with an ejection fraction of 50% or more, the arrhythmia hazard ratio was still 2.36 (1.59 to 3.51).

This supports sending patients with dilated cardiomyopathy for genetic testing and reading the result as a risk marker in its own right, not just as a diagnosis for relatives. The registry is observational and drawn from specialist centres, so it cannot say that an earlier device would improve survival.

• Offer genetic testing in dilated cardiomyopathy, with counselling and cascade testing of relatives
• Record which gene group the result falls in, since LMNA, DSP, FLNC, RBM20, PLN, SCN5A, DES and TMEM43 variants carried higher arrhythmic risk
• Do not use a preserved ejection fraction to reassure on its own when a high-risk variant is present
• Discuss device decisions with a specialist inherited cardiac conditions service
• A negative or gene-elusive result does not mean low risk; keep standard risk assessment

Why it matters

Ejection fraction alone has been the main trigger for device discussions, and this adds evidence that genotype carries risk beyond it.

Don't overread it

A registry shows risk, not benefit: it does not prove that implanting a defibrillator earlier in carriers improves survival.

The statistics, in plain English

A hazard ratio of 3.25 means that at any point in follow-up, major ventricular arrhythmia occurred at roughly three times the rate seen in gene-elusive patients. The narrow interval (2.63 to 4.01) reflects a large registry, but it cannot remove bias from who was referred and tested. A hazard ratio is relative, so the absolute risk depends on the baseline rate in each patient.

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