Association of PCSK9 Loss-of-Function Variants With Risk of Heart Failure

IMPORTANCE An animal (mouse) study indicated that deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) causes cardiac remodeling and heart failure (HF). Cardiac remodeling after PCSK9-inhibitor treatment is a concern for patients and for development of treatment directed against PCSK9. OBJECTIVE To determine whether genetic variants in the PCSK9 gene are associated with altered cardiac structure, cardiac function, and HF in humans. DESIGN, SETTING, PARTICIPANTS This was a nested case-control study within the UK Biobank. Between March 13, 2006, and October 1, 2010, the UK Biobank enrolled 502 480 individuals aged 40 to 69 years. This study focused on a subset of those individuals, who completed cardiac magnetic resonance (CMR) imaging and had available genetic data. Analyses were conducted between November 2, 2021, and October 28, 2022. EXPOSURES Carrier status of predicted loss-of-function (pLoF) PCSK9 variants, R46L missense variant, and a genetic risk score (GRS). MAIN OUTCOMES AND MEASURES A total of 11 CMR imaging measurements, generated using a machine learning algorithm, and HF diagnosis. RESULTS In up to 35135 individuals with CMR images, 18 252 (52%) were female individuals, and mean (SD) age was 55.0 (7.4) years. No significant association between PCSK9 carrier status and CMR indices were found for left ventricular mass (pLoF: beta = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: beta = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: beta = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: beta = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: beta = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: beta = -0.08; 95% CI, -0.35 to 0.20; P = .58) or HF (pLoF: odds ratio [OR], 1.14; 95% CI, 0.56-2.05; P = .69; R46L: OR, 0.99; 95% CI, 0.90-1.10; P = .91; GRS: OR, 1.04; 95% CI, 0.96-1.13; P = .32). CONCLUSIONS AND RELEVANCE Results of this case-control study suggest that there was no association between PCSK9 genetic variants and altered cardiac structure, cardiac function, or HF in humans.