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Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study
Pedrum Mohammadi-Shemirani1, Michael Chong2, Sukrit Narula3
1Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
Insights
Lipoprotein(a) (Lp[a]) is linked to increased atrial fibrillation (AF) risk, independent of atherosclerotic cardiovascular disease (ASCVD). Lp[a]-lowering therapies may help prevent AF.
Area of Science:
- Cardiology
- Genetics
- Biochemistry
Background:
- Atrial fibrillation (AF) increases stroke, heart failure, and mortality risks.
- Preventative therapies for AF with cardiovascular benefits are needed.
- Lipoprotein(a) (Lp[a]) is a risk factor for atherosclerotic cardiovascular disease (ASCVD), but its independent role in AF is unclear.
Purpose of the Study:
- To investigate the role of Lp(a) in the development of AF.
- To determine if Lp(a) is a causal mediator of AF independently of ASCVD.
Main Methods:
- Association analyses of measured and genetically predicted Lp(a) with incident AF in UK Biobank (N=435,579).
- Mendelian randomization analyses using summary-level data from genome-wide association studies (N=1,145,375).
Main Results:
- Increased Lp(a) levels were associated with higher incident AF risk (HR: 1.03; P=1.65×10⁻⁸).
- Mendelian randomization confirmed this association (OR: 1.04 per 50 nmol/L increase; P=9.23×10⁻¹⁰).
- Only 39% of Lp(a) risk was mediated through ASCVD, indicating an independent effect.
Conclusions:
- Lp(a) is implicated as a potential causal mediator in AF development, with effects extending to myocardial tissues.
- Ongoing Lp(a)-lowering therapy trials should assess AF prevention as an outcome.
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.
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