Genetic data reveal link between Lp(a) level, atrial fibrillation risk
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Lipoprotein(a) may have a causal role in incident atrial fibrillation risk, independent of its effect on atherosclerotic CVD, according to an analysis of U.K. Biobank data.
“Lipoprotein(a) is associated with an increased risk for atrial fibrillation and this appears to be a causal relationship independent of coronary artery disease and aortic valve stenosis,” Guillaume Pare, MD, MSc, FRCPC, professor of pathology and molecular medicine and the Canada Research Chair in genetic and molecular epidemiology at McMaster University Population Health Research Institute and the David Braley Cardiac, Vascular and Stroke Institute, told Healio. “The main clinical implication is the exciting possibility that novel Lp(a) inhibitors, currently undergoing clinical evaluation, could reduce incident AF as a side benefit. Our findings also establish a new risk factor for AF and could be used to complement AF risk assessment.”
UK Biobank data analysis
Pare and colleagues measured and genetically predicted Lp(a) levels and assessed the association of Lp(a) with incident AF for 435,579 participants in the U.K. Biobank without prevalent AF at baseline. Researchers conducted Mendelian randomization analyses using summary-level data for AF from publicly available genome-wide association studies covering 1,145,375 individuals.
After a median 11 years of follow-up, the rate of incident AF was 4.37 events per 1,000 person-years.
The researchers found that each 23 mg/dL increase in Lp(a) was associated with a 3% increased risk for 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), with an OR of 1.03 (95% CI, 1.02-1.05; P = 1.33 x 10-5).
Mendelian randomization analyses using independent data replicated the effect, with an OR of 1.04 per 23 mg/dL increase (95% CI, 1.03-1.05; P = 9.23 x 10-10).
“In this group of at-risk participants, the prevalence of AF is 5.2% and, assuming an 80% decline in Lp(a), the prevalence of AF would fall to 4.9%, representing 0.4% and 8% absolute and relative reduction, respectively, comparable to 2 units reduction in body mass index or a 5 mm Hg reduction in blood pressure,” the researchers wrote. “In addition, subgroup analysis showed no evidence of effect modification or interaction according to common risk factors of AF.”
Researchers found no evidence of risk-conferring effect from LDL or triglycerides, whereas only 39% (95% CI, 27-73) of Lp(a) risk was mediated through ASCVD, suggesting Lp(a) partly influences AF independent of its known effects on ASCVD.
“We need to validate the predicted decrease in AF in randomized controlled trials of Lp(a) inhibitors,” Pare told Healio. “Beyond this, we also need to understand how Lp(a) affects risk for AF from a mechanistic point of view. In other words, what is the biology underlying this intriguing observation? This is a fascinating question, as no effect was seen on AF with any other lipids fraction other than Lp(a).”
AF as outcome in Lp(a) trials
In a related editorial, Daniel Seung Kim, MD, PHD, MPH, a fellow in cardiovascular medicine at Stanford University, and Abha Khandelwal, MD, MS, clinical associate professor of cardiovascular medicine at Stanford, wrote that the findings “strongly argue” for inclusion of AF as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
“As noted by Mohammadi-Shemirani et al, treatment of high Lp(a) levels with pelacarsen, which reduces Lp(a) levels by [about] 80%, would reduce AF risk by [about] 8%, equivalent to reduction in body mass index by 2 kg/m2,” Kim and Khandelwal wrote. “Moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and aortic stenosis risk. Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population.”
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For more information:
Guillaume Pare , MD, MSc, FRCPC, can be reached at pareg@mcmaster.ca.
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