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

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 x 10(-8)) and genetically predicted Lp(a) (OR: 1.03; 95% CI: 1.02-1.05; P = 1.33 x 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 x 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. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Automated summary

This study revealed that lipoprotein(a) (Lp[a]) is associated with an increased risk of atrial fibrillation (AF) independent of atherosclerotic cardiovascular disease (ASCVD). The findings highlight the potential role of Lp(a) as a causal mediator in the development of AF and suggest that Lp(a)-lowering therapies should be evaluated for their effects on AF prevention.