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Home All Specialties Cardiology

No known association between PCSK9 gene variants and risk of heart failure

byGursharan SohiandYuchen Dai
December 22, 2022
in Cardiology, Preclinical
Reading Time: 3 mins read
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1. There was no association detected between PCSK9 gene variants and alterations in cardiac morphology.

2. The odds of having heart failure were not significantly different in individuals with PCSK9 gene variants.

Level of Evidence Rating: 2 (Good)

Study Rundown: Modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression has drawn some interest in recent years as a treatment for hypercholesterolemia. However, recent animal studies have demonstrated potential adverse effects of this treatment in causing a degree of cardiac remodelling, which may potentiate the development of heart failure. These results were translated by a subsequent human study using a known PCSK9 variant found to be associated with echocardiographic morphology changes. The present study sought to determine whether loss-of-function mutations of the PCSK9 gene were associated with the development of heart failure.

In total, 35 135 individuals were included in this study, of which 333 (0.21%) carried a loss-of-function variant, 3.5% carried the R46L missense variant, and 4.91% had a genetic risk score above the 95th percentile. There was no significant association between loss-of-function carriers and risk of change in cardiac morphology (left ventricular size and ejection fraction). The odds of heart failure were also not significantly different in individuals with high genetic risk scores. Sensitivity analysis revealed that body composition and preexisting atherosclerotic disease did not significantly alter the reported results.

This nested case-control study demonstrated no significant effect of PCSK9 genetic variation on cardiac morphology and related change in risk of heart failure. Strengths of this work include the large sample size and thoroughness of the analysis in looking at imaging data rather than only clinical diagnoses of heart failure. A major limitation of this study is that only patients with European ancestry were included, thus significantly limiting the external validity of these findings. As well, there were no standardized means of classifying heart failure with preserved ejection fraction in this study. Therefore, the potential for misclassification bias is strong.

Click here to read this study in JAMA Cardiology

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Relevant reading: PSCK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages

In-Depth [case-control study]: A nested case-control study was conducted using data from the UK Biobank data set. Individuals who had undergone cardiac magnetic resonance imaging were included. Genetic data was obtained using exome-sequencing following a standardized methodology. Variants of the PCSK9 gene were associated with differential expression of low-density lipoprotein cholesterol. Several sensitivity analyses were planned a priori to assess the robustness of results, including stratifying participants by body mass index and waist-to-hip ratio and excluding patients with a history of atherosclerosis.

As established previously, the effect estimate for expression of low-density lipoprotein cholesterol correlated with PCSK9 genetic variants, with the largest effect estimate corresponding to the loss of function mutation (−27.81 mg/dL; 95% confidence interval [CI], −31.38 to −24.24; P = 1.61 × 10−52). There was no significant association between PCSK9 loss-of-function variant and change to left ventricular mass (β = −1.01; 95% CI, −2.99 to 0.98; P = .32) or ejection fraction (β = 0.43; 95% CI, −1.32 to 2.18; P = .63). There was also no significant association between missense R46L variant and change to left ventricular mass (β = −0.18; 95% CI, −0.55 to 0.19; P = .35) or ejection fraction (β = −0.19; 95% CI, −0.52 to 0.14; P = .26). Finally, the odds ratio for heart failure in individuals with high genetic risk scores was 0.87; (95% CI, 0.74-1.03). These findings were robust to sensitivity analysis.

Image: PD

©2022 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.

Tags: heart failurehypercholesterolemiapcsk9
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