Clinical Trajectories and Prognostic Implications of Incident Heart Failure Versus Atrial Fibrillation in Carriers of Cardiomyopathy-associated Genetic Variants

S. Kany (Hamburg)¹, V. Pilltula (Cambridge)², K. Biddinger (Cambridge)², L. Wijdeveld (Cambridge)³, A. Zheng (Cambridge)⁴, S. Challa (Cambridge)², J. Pirruccello (San Francisco)⁵, S. Kurshid (Cambridge)², S. Jurgens (Cambridge)², J. Huffman (Cambridge)², P. Ellinor (Boston)⁶, K. Aragam (Cleveland)^7
1Universitäres Herz- und Gefäßzentrum Klinik für Kardiologie Hamburg, Deutschland; ²Cambridge, USA; ³The Broad Institute of MIT and Harvard Cardiovascular Disease Initiative Cambridge, USA; ⁴The Broad Institute of MIT and Harvad Cardiovascular Disease Initiative Cambridge, USA; ⁵San Francisco, USA; ⁶Institute for Technology Assessment Massachusetts General Hospital, Harvard Medical School Boston, USA; ⁷Cleveland, USA

Background
Cardiomyopathy (CMP) gene variant carriers face an elevated risk of developing both heart failure (HF) and atrial fibrillation (AF). A well-documented bidirectional relationship exists between these two conditions. However, the temporal sequence of the initial clinical manifestation, specifically whether AF or HF occurs first, remains poorly defined. The subsequent prognostic implications of this sequence are similarly unclear.

Purpose
We sought to establish the incidence and trajectory of first clinical manifestations among CMP variant carriers. Furthermore, we aimed to determine how the type of first manifestation impacts the downstream risk of ventricular tachycardia (VT) and cardiovascular mortality (CVM).

Methods
We identified CMP variant carriers within the UK Biobank (UKB, N=~500,000) and All of Us (AoU, N=~400,000) cohorts using available genetic sequencing data. Initial clinical events were categorized as incident AF-first, HF-first, or simultaneous diagnoses, defined as occurring within one year of each other. We calculated cumulative incidence using Aalen-Johansen estimators. Multivariable Fine-Gray regression models generated sub-distribution hazard ratios (SHR) for the initial presentation. Finally, we evaluated the absolute risk of subsequent VT and CVM based on the initial clinical manifestation.

Results
In the UKB (N=4520 carriers, age 56.8±8.1, 55% female), AF-first was the predominant initial event, occurring in 11.35% of individuals with an incidence of 9.80 per 1000 person-years. HF-first followed at 4.85%, or 4.18 per 1000 person-years. Conversely, in the AoU cohort (N=3659 carriers, age 54±17, 40% female), an initial presentation of HF was more common (10.22%; 1.92 per 1000 person-years) than AF (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. By the same age, AF-first reached 11.13% in AoU and 12.18% in UKB. Hypertension was consistently associated with an AF-first presentation in both the 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, several factors were significantly associated with an HF-first presentation, including 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). Presenting with HF-first versus AF-first conferred a significantly higher risk for CVM in the UKB (HR 3.29 [1.87-5.78], P<0.001) and a higher VT risk in AoU (HR 2.54 [1.55-4.15], P<0.001).

Conclusions
Among CMP variant carriers, an initial clinical presentation of heart failure confers a significantly higher risk of subsequent ventricular arrhythmias and cardiovascular mortality compared to an initial presentation of atrial fibrillation. Identifying the type of first clinical manifestation allows for improved and targeted risk stratification in patients with genetic cardiomyopathies.

Figure 1: Risk of Events by First Presentation