More evidence for association between higher Lp(a) levels and calcific aortic valve disease
Lipoprotein(a) and calcific aortic valve disease initiation and progression: a systematic review and meta-analysisLiterature - Pantelidis P, Oikonomou E, Lampsas S, et al. - Cardiovasc Res. 2023 Jul 6;119(8):1641-1655. doi: 10.1093/cvr/cvad062
Introduction and methods
Calcific aortic valve stenosis (AVS) is one of the most common age-related valvulopathies [1,2]. Recently, Lp(a) has emerged as a new risk factor for calcific aortic valve disease (CAVD), thereby mediating aortic valve calcification (AVC) and AVS [3,4]. Although there is evidence linking Lp(a) to CAVD , this association is still unclear, particularly with regard to demographic, genetic, and other interfering factors.
Aim of the study
The authors examined the existing evidence for the relationship between Lp(a) and the onset and progression of AVC and AVS.
In this systematic review and meta-analysis, a systematic search of 8 literature databases was performed (up to February 2023) to identify observational studies comparing high versus normal to low Lp(a) plasma levels with AVC or AVS as outcomes and studies exploring the association between relevant genetic risk factors and AVC or AVS.
A total of 44 studies (n=163,139) were included in the systematic review of the association between Lp(a) levels and CAVD. The overall quality was high for 33 studies (75%) and moderate for the remaining 11 (25%). After exclusion of outlying and influential studies, 11 studies (n=26,191) were included in the meta-analysis. In the systematic review of Lp(a)-related genetic risk and CAVD, 17 studies were included, 8 of which were eligible for meta-analysis.
Association between Lp(a) levels and aortic valve stenosis
- The qualitative synthesis of the systematic review indicated that despite considerable heterogeneity in the design and results of the included studies, there was an overall trend toward an increased risk of AVS in patients with high Lp(a) levels compared with those with normal/low levels (AVS risk ranging from adjusted HR of 1.70 (95%CI: 1.33–2.19; P<0.001) to adjusted OR of 3.4 (95%CI: 1.1–11.2)).
- The meta-analysis showed higher Lp(a) levels in patients with AVS compared with those with no AVS (standardized mean difference: 0.34; 95%CI: 0.19–0.48; P<0.001; statistical heterogeneity: I²=82%). Risk of publication bias was considered to be low.
- To correct for different measurement units and other variations, a sensitivity analysis was performed of the 5 studies reporting Lp(a) levels in nmol/L (n=5858), which confirmed the results of the meta-analysis (pooled mean difference: 22.63 nmol/L; 95%CI: 9.98–35.27; P=0.008; I²=53%).
- There was no significant difference in Lp(a) levels between patients with severe and mild/moderate AVS (standardized mean difference: 0.21; 95%CI: –0.12 to 0.54; P=0.130; I²=34%).
- In meta-regression analysis, smaller Lp(a) differences between AVS cases and controls were associated with older age (β: –0.02; 95%CI: –0.035 to –0.006; P=0.012) and a higher proportion of female subjects (β: –0.017; 95%CI: –0.03 to –0.004; P=0.017).
- Patients with high Lp(a) levels exhibited faster progression to AVS compared with those with low Lp(a) levels (mean difference in annualized peak aortic velocity change: 0.09 m/s per year; 95%CI: 0.09–0.09; P<0.001; I²=0%).
- The risk serious adverse outcomes, including death, was increased in patients with high Lp(a) levels compared with those with low Lp(a) levels (pooled HR: 1.39; 95%CI: 1.01–1.90; P=0.042; I²=63%), even after exclusion of influential studies (pooled HR: 1.56; 95%CI: 1.11–2.18; P=0.025).
//Association between Lp(a) levels and aortic valve calcification//
- In the qualitative synthesis, most studies showed an association between Lp(a) levels and AVC incidence (AVC risk ranging from adjusted relative risk of 1.05 (95%CI: 1.02–1.08) per 1-SD of Lp(a) increase to adjusted OR of 1.79 (95%CI: 1.32–2.43) for Lp(a) >50 mg/dL).
Association between genetic risk factors and aortic valve stenosis
- A higher risk of AVS was associated with the LPA gene single nucleotide polymorphisms (SNPs) rs10455872 (pooled OR: 1.42; 95%CI: 1.34–1.50; I²=29%) and rs3798220 (pooled OR: 1.27; 95%CI: 1.09–1.48; I²=0%).
- Age was inversely related to the effect size of rs10455872 (β: –0.013; 95%CI: –0.021 to –0.005; P=0.008) but not rs3798220 (P>0.05).
- There was no association between sex and either SNP (P>0.05).
This systematic review and meta-analysis showed higher Lp(a) levels were associated with the onset, progression, and serious adverse outcomes of CAVD. Both age and sex were significant predictors of the Lp(a) difference between AVS and non-AVS patients, with a stronger association seen in younger individuals and male-dominant populations. In addition, genetic variations in LPA loci were related to increased AVS risk. The authors believe their findings support the early onset of Lp(a)-related subclinical lesions before they become clinically evident.