Clinical trajectories and prognostic implications of incident heart failure versus atrial fibrillation in cardiomyopathy variant carriers

Background Cardiomyopathy (CMP) gene variant carriers are at increased risk for heart failure (HF) and atrial fibrillation (AF). However, due to the bidirectional relationship between both conditions, the temporal sequence of first clinical manifestations (AF vs. HF) and their subsequent prognostic implications are poorly defined. Purpose To define the incidence and trajectory of first clinical manifestations among CMP variant carriers and determine the impact of first-manifestation type on downstream ventricular tachycardia (VT) and cardiovascular mortality (CVM). Methods We defined CMP variant carriers in the UK Biobank (UKB, N=~500,000) and All of Us (AoU, N=~400,000) cohorts using genetic sequencing data. First-event definitions included incident AF-first, HF-first, or simultaneous diagnoses (occurring within 1 year). Cumulative incidence was assessed via Aalen-Johansen estimators. Sub-distribution hazard ratios (SHR) for initial presentation were derived using multivariable Fine-Gray regression models. The absolute risk of subsequent VT and CVM was evaluated based on the first manifestation. Results In UKB (N=4520 carriers, age 56.8±8.1, 55% female), AF-first was the predominant initial event (11.35%; incidence 9.80 per 1000 person-years), followed by HF-first (4.85%; 4.18 per 1000 person-years). Conversely, in AoU (N=3659 carriers, age 54 ±17, 40% female), HF-first was more common (10.22%; 1.92 per 1000 person-years) than AF-first (4.92%; 0.93 per 1000 person-years). Simultaneous diagnoses occurred in 2.54% of UKB and 4.59% of AoU carriers. By age 75, the cumulative incidence of HF-first reached 20.46% in AoU and 4.52% in UKB while AF-first reached 11.13% (AoU) and 12.18% (UKB), respectively. Hypertension was consistently associated with AF-first presentation in both UKB (SHR 1.49, 1.20-1.85, P<0.001) and AoU (SHR 2.23, 1.50-3.34, P<0.001). In AoU, chronic kidney disease (SHR 1.94, 1.51-2.50, P<0.001), hypertension (SHR 1.90, 1.44-2.51, P<0.001) and diabetes (SHR 1.69, 1.34-2.13, P<0.001) were significantly associated with HF-first presentation. Presenting with HF-first versus AF-first conferred a significantly higher risk for CVM (HR 3.29 [1.87-5.78], <0.001) in UKB and higher VT risk (HR 2.54 [1.55-4.15], P<0.001) in AoU. Conclusions Among CMP variant carriers, initial clinical presentation with heart failure confers a significantly higher risk of subsequent ventricular arrhythmias and cardiovascular mortality compared to atrial fibrillation. The type of first clinical manifestation allows for improved, targeted risk stratification in genetic cardiomyopathies.