Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study

Abstract

Aims Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. Methods and results Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22–1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80–1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92–2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. Conclusion Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention.

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

“…Main features of CAVD pathogenesis include lipid accumulation, inflammation, fibrosis and calcification. Low-density lipoprotein (LDL) and lipoprotein(a) levels have been shown to be causally associated with aortic stenosis 2,3 . Patients with familial hypercholesterolemia (FH) displayed a 7.9 -fold higher risk for CAVD 4 .…”

Mendelian randomization of plasma lipids and aortic valve stenosis: the importance of outlier variants and population stratification

“…We would like to thank the editors for the opportunity to respond to the letter by Jiang et al and to clarify aspects of our Mendelian randomization (MR) methodology. 1 We would also like to thank Jiang et al for their interest in our research and for raising issues in relation to methodology and statistical approaches. Jiang et al raised a question about the selection of a statistical method and concluded that based on the predefined algorithm, the best estimation for the univariate association between triglyceride and aortic stenosis should have been the weighted median.…”

Elevated Apolipoprotein B/A-1 Ratio is Associated With an Increased Risk of Aortic Stenosis: Experience From the AMORIS Cohort

“…Lipoprotein (a) contains an LDL-like particle containing an apoB-100 particle [9]. In the report by Nazarzadeh et al, increased LDL-C but not HDL-C or TG correlated to aortic stenosis in 1,961 cases [7].…”

“…If not treated, symptomatic and severe AS may cause heart failure and sudden death, with an estimated annual mortality of 50% [2,3]. Numerous underlying mechanisms of calcified non-rheumatic AS have been reported, including: congenital valve anomalies, mechanical stress, ageing process, high body mass index, stress, hypertension, elevated lipoprotein (a), high low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo) deposition, and genetic polymorphism with chronic inflammation [2][3][4][5][6][7][8][9]. In the prospective Malmö Diet and Cancer Study the highest quartile of LDL-C was associated with more than a doubled risk of incident AS during 16 years of follow-up [4].…”