Original Investigation
Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study

https://doi.org/10.1016/j.jacc.2022.02.018Get rights and content
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Abstract

Background

Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD.

Objectives

This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD.

Methods

Measured and genetically predicted Lp(a) levels were tested for association with 20,432 cases of incident AF in the UK Biobank (N = 435,579). Mendelian randomization analyses were performed by using summary-level data for AF from publicly available genome-wide association studies (N = 1,145,375).

Results

In the UK Biobank, each 50 nmol/L (23 mg/dL) increase in Lp(a) was associated with an increased risk of incident AF using measured Lp(a) (HR: 1.03; 95% CI: 1.02-1.04 ; P = 1.65 × 10–8) and genetically predicted Lp(a) (OR: 1.03; 95% CI: 1.02-1.05; P = 1.33 × 10–5). Mendelian randomization analyses using independent data replicated the effect (OR: 1.04 per 50 nmol/L Lp[a] increase; 95% CI: 1.03-1.05 per 50 nmol/L Lp[a] increase; P = 9.23 × 10–10). There was no evidence of risk-conferring effect from low-density lipoprotein cholesterol or triglycerides, and only 39% (95% CI: 27%-73%) of Lp(a) risk was mediated through ASCVD, suggesting that Lp(a) partly influences AF independent of its known effects on ASCVD.

Conclusions

Our findings implicate Lp(a) as a potential causal mediator in the development of AF which show that the effects of Lp(a) extend across myocardial tissues. Ongoing clinical trials for Lp(a)-lowering therapies should evaluate effects on AF prevention.

Key Words

atrial fibrillation
genetic risk score
lipoprotein(a)
Mendelian randomization
survival analysis
UK Biobank

Abbreviations and Acronyms

AF
atrial fibrillation
GWAS
genome-wide association study
LDL
low-density lipoprotein
Lp(a)
lipoprotein(a)
MR
Mendelian randomization

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Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on JACC.org.

Joshua W. Knowles, MD, served as Guest Associate Editor for this paper. Christie M. Ballantyne, MD, served as Guest Editor-in-Chief for this paper.

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