Abstract Background Elevated lipoprotein(a) (Lpa) is associated with aortic stenosis (AS). Oxidized phospholipids (OxPL) are key mediators of calcification in valvular cells and are carried by Lp(a). ...Objectives This study sought to determine whether Lp(a) and OxPL are associated with hemodynamic progression of AS and AS-related events. Methods OxPL on apolipoprotein B-100 (OxPL-apoB), which reflects the biological activity of Lp(a), and Lp(a) levels were measured in 220 patients with mild-to-moderate AS. The primary endpoint was the progression rate of AS, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography; the secondary endpoint was need for aortic valve replacement and cardiac death during 3.5 ± 1.2 years of follow-up. Results AS progression was faster in patients in the top tertiles of Lp(a) (peak aortic jet velocity: +0.26 ± 0.26 vs. +0.17 ± 0.21 m/s/year; p = 0.005) and OxPL-apoB (+0.26 ± 0.26 m/s/year vs. +0.17 ± 0.21 m/s/year; p = 0.01). After multivariable adjustment, elevated Lp(a) or OxPL-apoB levels remained independent predictors of faster AS progression. After adjustment for age, sex, and baseline AS severity, patients in the top tertile of Lp(a) or OxPL-apoB had increased risk of aortic valve replacement and cardiac death. Conclusions Elevated Lp(a) and OxPL-apoB levels are associated with faster AS progression and need for aortic valve replacement. These findings support the hypothesis that Lp(a) mediates AS progression through its associated OxPL and provide a rationale for randomized trials of Lp(a)-lowering and OxPL-apoB-lowering therapies in AS. (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin ASTRONOMER; NCT00800800 )
Abstract Background Routine apolipoprotein (apo) measurements for cardiovascular disease (CVD) are restricted to apoA-I and apoB. Here, the authors measured an unprecedented range of apolipoproteins ...in a prospective, population-based study and relate their plasma levels to risk of CVD. Objectives This study sought to measure apolipoproteins directly by mass spectrometry and compare their associations with incident CVD and to obtain a system-level understanding of the correlations of apolipoproteins with the plasma lipidome and proteome. Methods Associations of 13 apolipoproteins, 135 lipid species, and 211 other plasma proteins with incident CVD (91 events), defined as stroke, myocardial infarction, or sudden cardiac death, were assessed prospectively over a 10-year period in the Bruneck Study (N = 688) using multiple-reaction monitoring mass spectrometry. Changes in apolipoprotein and lipid levels following treatment with volanesorsen, a second-generation antisense drug targeting apoC-III, were determined in 2 human intervention trials, one of which was randomized. Results The apolipoproteins most significantly associated with incident CVD were apoC-II (hazard ratio per 1 SD HR/SD: 1.40; 95% confidence interval CI: 1.17 to 1.67), apoC-III (HR/SD: 1.38; 95% CI: 1.17 to 1.63), and apoE (HR/SD: 1.31; 95% CI: 1.13 to 1.52). Associations were independent of high-density lipoprotein (HDL) and non-HDL cholesterol, and extended to stroke and myocardial infarction. Lipidomic and proteomic profiles implicated these 3 very-low-density lipoprotein (VLDL)-associated apolipoproteins in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation. Notably, apoC-II/apoC-III/apoE correlated with a pattern of lipid species previously linked to CVD risk. ApoC-III inhibition by volanesorsen reduced plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II, and apoM (all p < 0.05 vs. placebo) without affecting apoB-100 (p = 0.73). Conclusions The strong associations of VLDL-associated apolipoproteins with incident CVD in the general community support the concept of targeting triacylglycerol-rich lipoproteins to reduce risk of CVD.
The Severe Hypercholesterolemia Phenotype Sniderman, Allan D., MD; Tsimikas, Sotirios, MD; Fazio, Sergio, MD, PhD
Journal of the American College of Cardiology,
05/2014, Letnik:
63, Številka:
19
Journal Article
Recenzirano
Odprti dostop
The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant ...hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor , apolipoprotein B ( APOB ), or proprotein convertase subtilisin kexin type 9 ( PCSK9 ) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Because the clinical consequences of extreme hypercholesterolemia are the same no matter the cause, the focus should be on the identification of subjects with severe hypercholesterolemia, followed by phenotypic screening of family members. Genetic screening is not necessary to diagnose or initiate treatment for the severe hypercholesterolemia phenotype. Management of severe hypercholesterolemia is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis is indicated for coronary artery disease (CAD) patients taking maximally tolerated therapy and with LDL-C levels >200 mg/dl (>300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against APOB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. PCSK9 inhibitors, currently in phase II and III trials, lower LDL-C up to an additional 70% in the setting of maximally tolerated medical therapy and have the potential to reduce LDL-C to <70 mg/dl in most patients. Early identification of affected individuals and aggressive treatment should significantly reduce the burden of cardiovascular disease in society.
A Test in Context: Lipoprotein(a) Tsimikas, Sotirios, MD
Journal of the American College of Cardiology,
02/2017, Letnik:
69, Številka:
6
Journal Article
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Odprti dostop
Abstract Evidence that elevated lipoprotein(a) (Lpa) levels contribute to cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS) is substantial. Development of isoform-independent ...assays, in concert with genetic, epidemiological, translational, and pathophysiological insights, have established Lp(a) as an independent, genetic, and likely causal risk factor for CVD and CAVS. These observations are consistent across a broad spectrum of patients, risk factors, and concomitant therapies, including patients with low-density lipoprotein cholesterol <70 mg/dl. Statins tend to increase Lp(a) levels, possibly contributing to the “residual risk” noted in outcomes trials and at the bedside. Recently approved proprotein convertase subtilisin/kexin-type 9 inhibitors and mipomersen lower Lp(a) 20% to 30%, and emerging RNA-targeted therapies lower Lp(a) >80%. These approaches will allow testing of the “Lp(a) hypothesis” in clinical trials. This review summarizes the current landscape of Lp(a), discusses controversies, and reviews emerging therapies to reduce plasma Lp(a) levels to decrease risk of CVD and CAVS.
Objectives This study sought to assess the long-term predictive value and net reclassification for risk of cardiovascular disease (CVD) of biomarkers reflecting oxidation-specific epitopes (OSEs). ...Background OSEs are immunogenic, proinflammatory, and proatherogenic. The long-term predictive value and net reclassification of OSEs for risk of CVD events are not known. Methods Oxidized phospholipids on apolipoprotein B-100 (OxPL/apoB) and immunoglobulin (Ig)-G (IgG) and IgM autoantibodies to malondialdehyde-modified, low-density lipoprotein (MDA-LDL) and copper-oxidized LDL (Cu-OxLDL) were measured in 765 subjects in 1995 and 656 subjects in 2000 in the Bruneck study, representing 45- to 84-year-old men and women from the general community. Results Over 15 years of follow-up, 138 subjects reached the primary endpoint of incident CVD (ischemic stroke, myocardial infarction, new-onset unstable angina, acute coronary interventions, and vascular death). In a multivariable Cox model, the highest tertile of OxPL/apoB was associated with higher risk of CVD (hazard ratio HR: 2.4; 95% confidence interval CI: 1.5 to 3.7) and stroke (HR: 3.6; 95% CI: 1.8 to 7.4) compared with the lowest tertile. IgG Cu-OxLDLs were associated with higher risk of CVD, whereas IgM MDA-LDLs were associated with lower risk. Using OxPL/apoB, IgG Cu-OxLDL, and IgM MDA-LDL variables, the area under the curve (AUC) for CVD risk prediction increased from 0.664 (95% CI: 0.629 to 0.697) to 0.705 (95% CI: 0.672 to 0.737) (p = 0.048). The net reclassification index (NRI) was 0.163 (p = 0.0044) and 0.332 (p < 0.0001) in all subjects (n = 765) and in subjects with intermediate risk (n = 305), respectively. Of 627 subjects who remained free of CVD, 108 were correctly reclassified to a lower risk category, and 83 were reclassified to a higher category (categories: 15-year risk <15%, 15% to 30%, >30%). Conclusions OSE biomarkers predict 15-year CVD and stroke outcomes and provide potential clinical utility by reclassifying a significant proportion of individuals into higher or lower risk categories after traditional risk assessment.
Objectives The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, ...and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a). Background OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators. Methods IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(−). Results Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio OR: 2.84; p = 0.001). This effect was accentuated in patients age ≤60 years (OR: 7.03; p < 0.001). In IL-1(−) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(−) group in patients age ≤60 years but not in those age >60 years. In IL-1(+) patients age ≤60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006). Conclusions Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events.
Objectives The purpose of this study was to assess the prognostic utility of lipoprotein(a) Lp(a) in individuals with coronary artery disease (CAD). Background Data regarding an association between ...Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. Methods Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. Results Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio OR: 1.03 per log-transformed SD, 95% confidence interval CI: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). Conclusions Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.
...complete data on high-sensitivity C-reactive protein, Lp(a), and other inflammatory biomarkers were not available; thus any mechanisms of TBR reduction beyond lowering of apoB-containing ...lipoproteins cannot be inferred. (8) should be congratulated on performing this unique translational study that takes advantage of a therapeutic technique coupled to an imaging technique to provide insights into acute plaque biology. Because apheresis has been shown to reduce cardiovascular events in patients who have both high LDL-C and high Lp(a), one could hypothesize that the FDG signal reduction noted here should reflect the clinical benefit in patients with appropriate responses.
Over the last decade, significant data has accumulated to suggest that biomarkers of oxidative stress accurately reflect the presence of cardiovascular risk factors, the extent of cardiovascular ...disease (CVD), and cardiovascular outcomes. This cumulative evidence has supported the approval of several of these biomarkers for clinical applications. For example, lipoprotein-associated phospholipase A2 (Lp-PLA2) and myeloperoxidase (MPO) mass assays are now available to assist clinicians in determining overall cardiovascular risk in asymptomatic patients thought to be at increased risk or in patients with cardiovascular symptoms. However, it is not yet firmly established whether and to what extent these oxidative biomarkers reflect changes in response to therapeutic interventions. This article reviews the latest data on MPO, isoprostanes, oxidized low-density lipoprotein, oxidized phospholipids, and Lp-PLA2 biomarker assays, and it assesses their role in reflecting therapeutic interventions to treat CVD.
Background Oxidized phospholipids (OxPL) on apolipoprotein B-100 (OxPL–apoB) reflect the biological activity of lipoprotein(a) (Lpa) and predict cardiovascular disease events. However, studies with ...statins and low-fat diets show increases in OxPL–apoB and Lp(a). Objective This study evaluated changes in OxPL–apoB and Lp(a) with extended-release niacin (N), ezetimibe/simvastatin (E/S) and combination E/S/N. A systematic literature review of previously published trials, measuring both OxPL–apoB and Lp(a) after therapeutic interventions, was also performed. Methods OxPL–apoB and Lp(a) were measured in 591 patients at baseline and 24 weeks after therapy with N, E/S, or E/S/N in a previously completed randomized trial of hypercholesterolemic patients. The literature review included 12 trials and 3896 patients evaluating statins, low-fat diets, antisense to apolipoprotein(a) and lipid apheresis. Results Niacin decreased OxPL–apoB levels (median interquartile range; 3.5 2.2–9.2 nM to 3.1 1.8–7.2 nM, P < .01) and Lp(a) (10.9 4.6–38.4 to 9.3 3.1–32.9 mg/dL, P < .01). In contrast, E/S and E/S/N significantly increased OxPL–apoB (3.5 2.1–7.8 to 4.9 3.0–11.1 nM, P < .01) and (3.3 1.9–9.3 to 4.3 2.6–11.2 nM, P < .01), respectively and Lp(a) (11.5 6.1–36.4 to 14.9 6.6–54.6 mg/dL, P < .01) and (11.3 5.4–43.8 to 11.6 5.9–52.8 mg/dL, P < .01), respectively. The systematic review of statins and diet demonstrated 23.8% and 21.3% mean increases in OxPL–apoB and 10.6% and 19.4% increases in Lp(a), respectively. However 44.1% and 52.0% decreases in OxPL–apoB and Lp(a), respectively, were present with Lp(a)–lowering therapies. Conclusions This study demonstrates differential changes in OxPL–apoB and Lp(a) with various lipid-lowering approaches. These changes in OxPL–apoB and Lp(a) may provide insights into the results and interpretation of recent cardiovascular disease outcomes trials.
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