Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification

Abstract

Aim Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression. Methods and results A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9–14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2–37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15–1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02–1.65), but not with AVC progression (β: −71 AU for each 50 mg/dL higher Lp(a); 95% CI −117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001). Conclusion In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.

Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity

“… 11 , 12 Global deletion of SORT1 reduces levels of very low-density lipoproteins from the liver 13 and in atherosclerotic mice, 14 , 15 which are associated with the onset of AV calcification. 16 Sortilin is also associated with calcified regions in patients’ atheroma with chronic renal disease, 17 and genetic deletion of Apoe/Sort1 reduces vascular calcification. 17 Moreover, mechanistic studies demonstrated that sortilin promotes vascular calcification by shuttling ALP into smooth muscle cell (SMC)-secreted extracellular vesicles, but its role in valvular calcification has not been characterized.…”

Atherosclerosis Calcification: Focus on Lipoproteins

“…Aortic valve calcification was already highly prevalent in younger individuals with Lp(a) above the 80th percentile, emphasizing the need for early identification of these subjects [ 70 ]. Moreover, very recently it has been reported, by analyzing the Rotterdam study on the apparently healthy general population, that Lp(a) levels were associated with aortic valve calcification onset, but not with its progression in subjects with an already established pathology on a 14-year follow-up [ 71 ]. This suggests that Lp(a) lowering strategies may be most effective in the early stage of calcification.…”

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in “Treating” Aortic Valve Calcification

“…However, in those with a preexisting AVC, disease progression was independent of Lp(a) levels. These results suggest that any emerging Lp(a) lowering treatment may be efficient only in the pre-sclerosis phase [ 32 ].…”