Abstract 4114417: Polygenic Risk in Heart Failure – Evaluating the Ability of a Polygenic Risk Score to Identify Risk of Future Heart Failure Events in 60,000 Patients from 6 TIMI Randomized Trials

Background: The ability of polygenic risk scores (PRS) to predict heart failure (HF) beyond classic risk factors is unclear. Aims: To evaluate the risk of a HF PRS with incident hospitalization for HF (HHF) in patients with established cardiovascular disease. Methods: We analyzed a 59 SNP HF PRS (HERMES collaboration, Henry et al) in genotyped patients from six multinational TIMI randomized controlled trials (DECLARE, ENGAGE AF, FOURIER, PEGASUS, SAVOR, SOLID). Patients were stratified to low (quintile, Q1), intermediate (Q2-Q4), or high (Q5) genetic risk. We investigated the association of the HF PRS with incident HHF (median of 2.5 years) i) stratified by prior HF, and ii) across NTproBNP concentrations at baseline, using Cox-proportional hazard models. Results are reported as HR [95% CI], per 1-SD or with Q1 as a reference, and adjusted for ancestry (principal components 1-5), age, sex, trial, BMI, smoking, systolic BP, prior CAD, DM, AF, and eGFR. Results: In 59,906 pts (median age 66 years; 71% male; 26% prior HF), the HF PRS was associated with incident HHF (HR adj per 1-SD 1.08 [1.03, 1.13], p<0.001). Compared to low genetic risk pts, the HR adj for HHF was 1.12 [1.00, 1.26] in intermediate and 1.17 [1.02, 1.35] in high-risk pts. There were significant interactions between the HF PRS and prior HF (P int 0.001), and NTproBNP (P int 0.038), respectively. In pts without prior HF (Fig A), compared to low-risk pts, the risk was increased in high- (HR adj 1.56 [1.25, 1.94], p<0.001) and intermediate-risk pts (HR adj 1.27 [1.05, 1.54], p=0.013). In contrast, there was no significant association in pts with known HF at baseline ( Fig B ). Similarly, the HF PRS was significantly associated with HHF in pts with low but not elevated NTproBNP at baseline ( Fig C ). Conclusion: Our study confirms the role of polygenic risk for HF and demonstrates that a 59 SNP PRS can identify pts at increased risk of future HF events beyond traditional clinical factors, specifically in patients without established HF or elevated NTproBNP. These findings suggest a potential application of a HF PRS for screening and early identification of pts at increased risk for HF.