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Comment
. 2025 Jun 1;10(6):564-573.
doi: 10.1001/jamacardio.2025.0460.

Cardiomyopathy-Associated Gene Variants in Atrial Fibrillation

Leonoor F J M Wijdeveld  1   2 , Ezimamaka Ajufo  1 , Saketh P Challa  1 , Joel T Rämö  1   3   4 , Xin Wang  1 , Shinwan Kany  1   5   6 , Jennifer L Halford  1   7 , Lu-Chen Weng  1   8 , Seung Hoan Choi  1   9 , Krishna G Aragam  1   8 , J Peter van Tintelen  10 , Bianca J J M Brundel  2 , Sean J Jurgens  1   11 , Patrick T Ellinor  1   8   12
Affiliations
Comment

Cardiomyopathy-Associated Gene Variants in Atrial Fibrillation

Leonoor F J M Wijdeveld et al. JAMA Cardiol. .

Abstract

Importance: Patients with atrial fibrillation (AF), a common morbid arrhythmia, are more likely to carry rare genetic variants associated with inherited cardiomyopathies. Prior studies on rare pathogenic variants in AF relied on small, hospital referral populations, and knowledge on clinical outcomes remains limited.

Objective: To evaluate the prevalence and prognostic implications of cardiomyopathy-associated pathogenic or likely pathogenic (CMP-PLP) genetic variants in patients with AF.

Design, setting, and participants: In 2 prospective cohort studies, the prevalence of CMP-PLP variants was assessed in the population of patients with AF and early-onset AF. The association between carrying a CMP-PLP variant and the risk of incident cardiomyopathy or heart failure (CMP/HF) after AF diagnosis was evaluated. Finally, the joint contributions of CMP-PLP variants, clinical risk, and polygenic risk were assessed. Included in this study were 2 large longitudinal cohort studies, the UK Biobank (UKB) (data 2006-2023) and the All of Us Research Program (AllofUs) (2018-2022). The UKB and AllofUs cohorts, respectively, contained 393 768 and 193 232 unrelated genotyped participants.

Exposures: CMP-PLP variants.

Main outcomes and measures: Prevalence of CMP-PLP variants and risk of incident CMP/HF after AF diagnosis.

Results: In the UKB cohort, 32 281 participants (8%) had AF (mean [SD] age, 62 [6] years; 20 459 male [63.4%]). In the AllofUs cohort, 11 901 participants (6%) had AF (mean [SD] age, 67 [12] years; 6576 male [55.3%]). Compared with the biobank populations, CMP-PLP variants were twice as prevalent in patients with AF (UKB, 2.04%; 95% CI, 1.89%-2.20%; AllofUs, 2.52%; 95% CI, 2.25%-2.82%) and 5 times as prevalent in AF with onset before age 45 years (UKB, 4.99%; 95% CI, 3.07%-7.91%; AllofUs, 4.66%; 3.40%-6.32%). Cumulative incidence of CMP/HF was high in patients with AF (18%) compared with patients without AF (3%). Still, among patients with AF without prior CMP/HF (UKB, 20 226; AllofUs, 8330), carrying a CMP-PLP variant was associated with 1.6-fold risk of incident CMP/HF (meta-analysis, 95% CI, 1.32-1.90). Finally, CMP-PLP variants, a polygenic score, and clinical risk factors were independent estimators of CMP/HF.

Conclusions and relevance: Results of this cohort study suggest that the prevalence of CMP-PLP variants was substantial in patients with early-onset AF. Patients with AF carrying a CMP-PLP variant had an associated increased risk of future CMP/HF, independent of clinical and polygenic risk. These results indicate that genetic testing in patients with AF may identify individuals at higher risk for developing CMP/HF.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rämö reported receiving grants from Sigrid Jusélius Foundation during the conduct of the study. Dr van Tintelen reported receiving grants from ZonMW, the Netherlands Heart Foundation, and the Leducq Foundation and fees from Biomarin paid to department outside the submitted work. Dr Ellinor reported receiving grants from Bayer AG, Novo Nordisk, Pfizer, and Bristol Myers Squibb and personal fees from Bayer AG during the conduct of the study. No other disclosures were reported.

Comment on

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