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

ABSTRACT: Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.

SUBMITTER: Bourgeois R

PROVIDER: S-EPMC8307014 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.ObjectivesThis study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations.MethodsThis study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (Vmax >2.0 m/s), who underwent baseline 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells.ResultsOverall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL.ConclusionsIn patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.

Project description:IMPORTANCE:Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE:To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS:Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n?=?6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n?=?1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n?=?2527), Age Gene/Environment Study-Reykjavik (2000-2012; n?=?3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n?=?28,461). MAIN OUTCOMES AND MEASURES:Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS:The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n?=?2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n?=?473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n?=?205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P?=?.02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P?=?.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P?=?.02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P?=?.03) and aortic stenosis (P?=?.009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P?=?.02). CONCLUSIONS AND RELEVANCE:Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

Project description:BackgroundAortic valve stenosis is the most common type of valvular heart disease in the USA and Europe. Aortic valve stenosis is considered similar to atherosclerotic disease. Some studies have evaluated statins for aortic valve stenosis.ObjectivesTo evaluate the effectiveness and safety of statins in aortic valve stenosis.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS - IBECS, Web of Science and CINAHL Plus. These databases were searched from their inception to 24 November 2015. We also searched trials in registers for ongoing trials. We used no language restrictions.Selection criteriaRandomised controlled clinical trials (RCTs) comparing statins alone or in association with other systemic drugs to reduce cholesterol levels versus placebo or usual care.Data collection and analysisPrimary outcomes were severity of aortic valve stenosis (evaluated by echocardiographic criteria: mean pressure gradient, valve area and aortic jet velocity), freedom from valve replacement and death from cardiovascular cause. Secondary outcomes were hospitalisation for any reason, overall mortality, adverse events and patient quality of life.Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The GRADE methodology was employed to assess the quality of result findings and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 to create a 'Summary of findings' table.Main resultsWe included four RCTs with 2360 participants comparing statins (1185 participants) with placebo (1175 participants). We found low-quality evidence for our primary outcome of severity of aortic valve stenosis, evaluated by mean pressure gradient (mean difference (MD) -0.54, 95% confidence interval (CI) -1.88 to 0.80; participants = 1935; studies = 2), valve area (MD -0.07, 95% CI -0.28 to 0.14; participants = 127; studies = 2), and aortic jet velocity (MD -0.06, 95% CI -0.26 to 0.14; participants = 155; study = 1). Moderate-quality evidence showed no effect on freedom from valve replacement with statins (risk ratio (RR) 0.93, 95% CI 0.81 to 1.06; participants = 2360; studies = 4), and no effect on muscle pain as an adverse event (RR 0.91, 95% CI 0.75 to 1.09; participants = 2204; studies = 3; moderate-quality evidence). Low- and very low-quality evidence showed uncertainty around the effect of statins on death from cardiovascular cause (RR 0.80, 95% CI 0.56 to 1.15; participants = 2297; studies = 3; low-quality evidence) and hospitalisation for any reason (RR 0.84, 95% CI 0.39 to 1.84; participants = 155; study = 1; very low-quality evidence). None of the four included studies reported on overall mortality and patient quality of life.Authors' conclusionsResult findings showed uncertainty surrounding the effect of statins for aortic valve stenosis.The quality of evidence from the reported outcomes ranged from moderate to very low. These results give support to European and USA guidelines (2012 and 2014, respectively) that so far there is no clinical treatment option for aortic valve stenosis.

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

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