Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: Mendelian randomization in the Copenhagen General Population Study

Abstract

Aims We tested the hypothesis that higher levels of plasma triglycerides and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis. Methods and results We included 108 559 individuals from the Copenhagen General Population Study. Plasma triglycerides, remnant cholesterol (total cholesterol minus low-density lipoprotein and high-density lipoprotein cholesterol), and 16 genetic variants causing such increased or decreased levels were determined. Incident aortic valve stenosis occurred in 1593 individuals. Observationally compared to individuals with triglycerides <1 mmol/L (<89 mg/dL), the multifactorially adjusted hazard ratio for aortic valve stenosis was 1.02 [95% confidence interval (CI) 0.87–1.19] for individuals with triglycerides of 1.0–1.9 mmol/L (89–176 mg/dL), 1.22 (1.02–1.46) for 2.0–2.9 mmol/L (177–265 mg/dL), 1.40 (1.11–1.77) for 3.0–3.9 mmol/L (266–353 mg/dL), 1.29 (0.88–1.90) for 4.0–4.9 mmol/L (354–442 mg/dL), and 1.52 (1.02–2.27) for individuals with triglycerides ≥5 mmol/L (≥443 mg/dL). By age 85, the cumulative incidence of aortic valve stenosis was 5.1% for individuals with plasma triglycerides <2.0 mmol/L (77 mg/dL), 6.5% at 2.0–4.9 mmol/L (177–442 mg/dL), and 8.2% for individuals with plasma triglycerides ≥5.0 mmol/L (443 mg/dL). The corresponding values for remnant cholesterol categories were 4.8% for <0.5 mmol/L (19 mg/dL), 5.6% for 0.5–1.4 mmol/L (19–57 mg/dL), and 7.4% for ≥1.5 mmol/L (58 mg/dL). Genetically, compared to individuals with allele score 13–16, odds ratios for aortic valve stenosis were 1.30 (95% CI 1.20–1.42; Δtriglycerides +12%; Δremnant cholesterol +11%) for allele score 17–18, 1.41 (1.31–1.52; +25%; +22%) for allele score 19–20, and 1.51 (1.22–1.86; +51%; +44%) for individuals with allele score 21–23. Conclusion Higher triglycerides and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.

Lipoprotein Proteomics and Aortic Valve Transcriptomics Identify Biological Pathways Linking Lipoprotein(a) Levels to Aortic Stenosis

“…β2GPI activates lipoprotein lipase and triglyceride-rich lipoprotein (TRL) catabolism [ 61 ]. High TRL levels have recently been linked with CAVS [ 62 ]. β2GPI was found to associate with ox-LDL [ 63 ] and, more interestingly, to Lp(a) particles [ 64 ].…”

Nonalcoholic fatty liver disease or metabolic dysfunction‐associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches

“…In the presence of steatosis, TG elevations are in particular associated with coronary plaques, both calcified and non‐calcified, as well as with non‐obstructive coronary stenoses 110 . Besides being correlated per se with calcified plaques independent of the presence of the metabolic syndrome in NAFLD patients, 111 higher TG and remnant cholesterol have been observationally and genetically associated with an increased risk of aortic valve stenosis 112 . Overall, the association between serum TG and hepatic steatosis is largely accounted for by a greater TG enrichment in VLDL particles 113 .…”

Triglyceride-Rich Lipoproteins and Their Remnants as Silent Promoters of Atherosclerotic Cardiovascular Disease and Other Metabolic Disorders: A Review

“…In the multifactorial adjusted analyses, higher concentrations of triglycerides and remnants were observationally and genetically linked to a higher rate of aortic valve stenosis. A novel etiopathogenic factor in aortic valve stenosis that warrants further research has been indicated by these findings [ 54 ].…”