Iswaree D Balakrishnan, Astrid B M Heymans, Brian Claggett, Garrick C Stewart, Christine E Seidman, Sophie L V M Stroeks, Nina J Beelen, Max F G H M Venner, Anjali T Owens, Sharlene M Day, Adam S Helms, Supriya Shore, Matthew T Wheeler, Alessandra Fornaro, Iacopo Olivotto, Luisa Mestroni, Sadiya S Khan, Gianfranco Sinagra, Marco Merlo, Joseph Rossano, Kimberly Y Lin, Lynne W Stevenson, Upasana Tayal, Matthew R G Taylor, Lisa D Wilsbacher, Sanjay K Prasad, Stephane R B Heymans, Carolyn Y Ho, Victoria N Parikh, Job A J Verdonschot, Neal K Lakdawala
In this large genotyped DCM cohort, AF burden and incident AF risk varied across genotypes. Only LMNA was associated with an increased risk of incident AF. AF onset was independently associated with adverse outcomes, supporting genotype-guided AF surveillance and management in DCM.
BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in dilated cardiomyopathy (DCM) and is associated with adverse outcomes. However, the genetic determinants of AF risk and its prognostic significance across genotyped DCM subtypes remain unknown.
METHODS: In this observational cohort study, we analyzed 3117 genotyped patients with DCM from the SHaRe (Sarcomeric Human Cardiomyopathy Registry). AF prevalence, incidence, and clinical characteristics were assessed by genotype. Patients were classified as genotype-positive [G(+)] if they had a pathogenic or likely pathogenic variant in a DCM-associated gene, and genotype-negative [G(-)] if genetic testing was negative. Factors associated with incident AF were evaluated using Cox regression. AF was modeled as a time-dependent variable to evaluate associations with clinical outcomes.
RESULTS: Among 3117 genotyped patients with DCM (mean age, 48±15 years; 39% were female; and 35% were G[+]), 12.3% (n=384) had prevalent AF. Of 2491 patients without prevalent AF and with follow-up, 312 (12.5%) developed AF during a median of 4.5 years (interquartile range, 1.6-9.0). Among 2851 patients with follow-up, cumulative AF prevalence was 23.6%. LMNA had the highest AF incidence (7.6/100 patient-years) and cumulative AF prevalence (56.7%) and was the only genotype independently associated with incident AF compared with that in G(-) patients (hazard ratio, 5.52 [95% CI, 3.84-7.95]; P<0.001). TTN had an AF incidence of 2.1 per 100 patient-years and cumulative AF prevalence of 24.4%, comparable to that in G(-) patients. Older age, male sex, and prior heart failure hospitalization were also independently associated with incident AF. AF was independently associated with a higher risk of the composite clinical outcome (hazard ratio, 1.58 [95% CI, 1.29-1.94]; P<0.001), including heart failure, ventricular arrhythmias, and all-cause mortality.
CONCLUSIONS: In this large genotyped DCM cohort, AF burden and incident AF risk varied across genotypes. Only LMNA was associated with an increased risk of incident AF. AF onset was independently associated with adverse outcomes, supporting genotype-guided AF surveillance and management in DCM.