Key result
PCSK9 loss-of-function variants show no association with altered LV mass or heart failure risk.
Why the study?
An animal study indicated that PCSK9 deficiency causes cardiac remodeling and heart failure, raising concerns for patients receiving PCSK9-inhibitor treatment.
Do genetic variants in the PCSK9 gene (proxies for PCSK9 inhibition) alter cardiac structure, cardiac function, or increase the risk of heart failure in humans?
Case-Control (n=35,135)
Yes
Do genetic variants in the PCSK9 gene (proxies for PCSK9 inhibition) alter cardiac structure, cardiac function, or increase the risk of heart failure in humans?
Effect estimate: β -1.01 (95% CI -2.99 to 0.98)
Absolute Event Rate: 45.69% vs 47.01%
p-value: p=.32
Genetic proxies for PCSK9 inhibition are not associated with adverse cardiac remodeling or increased risk of heart failure, providing reassuring safety data for PCSK9-targeted therapies.
Supports cardiac safety of PCSK9 inhibition; extends genetic data but leaves open randomized confirmation.
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 35 135 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: β = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: β = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: β = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: β = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: β = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: β = -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.
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Trudsø et al. (2022) conducted a case-control in Heart Failure (n=35,135). PCSK9 loss-of-function variants vs. Noncarriers was evaluated on Left ventricular mass (LVM) (β -1.01, 95% CI -2.99 to 0.98, p=.32). PCSK9 loss-of-function variants were not significantly associated with altered left ventricular mass (β -1.01) or increased risk of heart failure compared to noncarriers.
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