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

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.