High level of ApoCIII-Lp(a) complexes together with high Lp(a) or OxPL predicts rapid progression of aortic stenosis

ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis

Literature - Capoulade R, Torzewski M, Mayr M et al. - Heart 2020, doi:10.1136/heartjnl-2019-315840

Introduction and methods

Risk factors for aortic stenosis (AS) include age, hypertension, metabolic syndrome and elevated LDL-c levels [1]. Modest increases in LDL-c have, however, not shown difference in progression rate of AS of need for aortic valve replacement (AVR) in patients with AS [2].

Elevated lipoprotein(a) [Lp(a)] levels in individuals with SNPs in the LPA gene are associated with aortic valve calcification and AS [3-5]. Also, oxidized phospholipids (OxPL), which are associated with apoB-100 and Lp(a), are associated with AS, as potential causal mediators [6-8]. Autotaxin (ATX) mass and activity generates pro-calcifying lysophosphatidic acid from breakdown products of OxPL. ATX has also been suggested to be associated with AS [7,9,10]. High levels of ApoC-III are associated with high levels of triglycerides, and high triglycerides levels are observed in individuals with metabolic syndrome. Perhaps measures like Lp(a), OxPL, ATX and ApoC-III can predict the progression of AS, as others are suboptimal.

Assays to measure complexes of ApoC-III on Lp(a) [ApoCIII-Lp(a)] [11] were applied in samples of patients in the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial to examine the role of ApoCIII-Lp(a) in the progression of AS and need for AVR. In addition, ATX mass on Lp(a)[ATX-Lp(a)] and apoB [ATX-apoB] were measured by high-throughput ELISAs.

Outcomes in this study were assessed in 218 patients of the ASTRONOMER trial. Primary outcome of this study was progression rate of AS measured by echocardiography as annualized changes in peak aortic jet velocity (Vpeak). Secondary outcome was clinical events, a composite of AVR or cardiac death. Also, presence of ApoCIII was measured in surgically explanted aortic valves (of 68 patients). Median follow-up of this echocardiographic study was 3.5 years (2.9-4.5).

Main results

Staining of explanted valves showed that ApoC-III was detectable in every lesion, from grade 1-4, with more abundant deposition of ApoC-III in higher grades (3 and 4). ApoC-III colocalized with apo(a) in all grades of lesions, and colocalization with OxPL was observed in higher grades of lesions.
No difference was observed in annualized Vpeak between top tertile vs. middle and bottom tertiles of total ApoC-III and of ApoCIII-Lp(a). Also, no difference in annualized Vpeak between top tertile of ATX-apoB or ATX-Lp(a) vs. middle and bottom tertiles. Adjustment for multivariable did not change results. There was no effect of statin for all biomarkers.
There were significant interactions between ApoCIII-Lp(a) and Lp(a), OxPL-apoB or OxPL-apo(a) with regard to AS progression rate. After adjustment, tertile 3 of ApoCIII-Lp(a)-tertile 3 of Lp(a) remained significantly associated with annualized Vpeak (beta coeff: 0.28±0.07, P=0.001). Also, the top tertile of ApoCIII-Lp(a) and top tertile of OxPL-apoB (beta coeff: 0.29±0.07, P-0.001) and top tertile of ApoCIII-Lp(a) and top tertile of OxPL-apo(a) (P≤0.02) were associated with annualized Vpeak.
No significant interaction was observed between ApoC-III or ATX biomarkers and age, biscuspid aortic valve phenotype or presence of metabolic syndrome with regard to AS progression rate.
The tertile 3 of ApoCIII-Lp(a)-tertile 3 of Lp(a) was associated with a higher risk of rapid AS progression (defined as annualized Vpeak ≥0.20 m/s/year) (in multivariable analysis: OR 4.1, 95%CI:1.3-12.9, P=0.02). Also, tertile 3 of ApoCIII-Lp(a)-tertile 3 of OxPL-apoB and tertile 3 of ApoCIII-Lp(a)-tertile 3 of OxPL-apo(a) were associated with higher risk of rapid AS.
Tertile 3 of ApoCIII-Lp(a)-tertile 3 of Lp(a) was the only group associated with higher risk of AS-related clinical events (HR:2.56, 95%CI:1.12-5.86, P=0.03).
Proteomic analysis of isolated Lp(a) from 3 patients showed that proportion of ApoC-III on Lp(a) was 20.44%.

Conclusion

This study using samples from patients in the ASTRONOMER trial showed that ApoCIII is present on Lp(a) and in aortic valves. Highest levels of ApoCIII-Lp(a) complexes and highest levels of Lp(a) or highest levels of ApoCIIII-Lp(a) complexes and highest levels of OxPL are predictors of patients with rapid progression of AS. Highest levels of ApoCIII-Lp(a) complexes and highest levels of Lp(a) are a predictor of patients with highest risk of AS-related clinical events. These markers can be used to identify patients with fastest rate of AS progression and stratify risk in patients with AS.

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