The relationships between oxidation-specific epitopes (OSE) and lipoprotein (a) Lp(a) and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden ...death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools, and the necrotic core, and they were most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans.
Objectives This study sought to assess whether oxidized lipids are released downstream from obstructive plaques after percutaneous coronary and peripheral interventions using distal protection ...devices. Background Oxidation of lipoproteins generates multiple bioactive oxidized lipids that affect atherothrombosis and endothelial function. Direct evidence of their role during therapeutic procedures, which may result in no-reflow phenomenon, myocardial infarction, and stroke, is lacking. Methods The presence of specific oxidized lipids was assessed in embolized material captured by distal protection filter devices during uncomplicated saphenous vein graft, carotid, renal, and superficial femoral artery interventions. The presence of oxidized phospholipids (OxPL) and oxidized cholesteryl esters (OxCE) was evaluated in 24 filters using liquid chromatography, tandem mass spectrometry, enzyme-linked immunosorbent assays, and immunostaining. Results Phosphatidylcholine-containing OxPL, including (1-palmitoyl-2-9-oxo-nonanoyl PC), representing a major phosphatidylcholine-OxPL molecule quantitated within plaque material, 1-palmitoyl-2-(5-oxo-valeroyl)-sn-glycero-3-phosphocholine, and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine, were identified in the extracted lipid portion from all vascular beds. Several species of OxCE, such as keto, hydroperoxide, hydroxy, and epoxy cholesteryl ester derivatives from cholesteryl linoleate and cholesteryl arachidonate, were also present. The presence of OxPL was confirmed using enzyme-linked immunoassays and immunohistochemistry of captured material. Conclusions This study documents the direct release and capture of OxPL and OxCE during percutaneous interventions from multiple arterial beds in humans. Entrance of bioactive oxidized lipids into the microcirculation may mediate adverse clinical outcomes during therapeutic procedures.
Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of ...this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-C
). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31;
=0.005) but not for LDL-C
(1.07; 95% CI, 0.93-1.22;
=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-C
was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-C
was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions
LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.
Lp(a) lipoprotein is believed to be involved in the pathogenesis of coronary artery disease. This study provides evidence that its atherogenicity is related to proinflammatory oxidized phospholipids ...that are bound to it.
Lp(a) lipoprotein is believed to be involved in the pathogenesis of coronary artery disease. This study provides evidence that its atherogenicity is related to proinflammatory oxidized phospholipids that are bound to it.
Human coronary atherosclerosis is a chronic inflammatory disease that is superimposed on a background of lipid abnormalities. Proinflammatory oxidized low-density lipoprotein (LDL) may be a unifying link between lipid accumulation and inflammation in the vessel wall. In humans, oxidized LDL in plasma and within atherosclerotic lesions is strongly associated with coronary artery disease, acute coronary syndromes, and vulnerable plaques.
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Lp(a) lipoprotein is a lipoprotein of unknown physiologic function that is composed of apolipoprotein B-100 (apo B-100) to which apolipoprotein(a) is covalently bound. Increased plasma levels of Lp(a) lipoprotein are independent predictors of the presence of angiographically documented and clinical . . .
Effective therapies for reducing cardiovascular disease (CVD) risk in people with elevated lipoprotein(a) are lacking, especially for primary prevention. Because of the potential association of ...lipoprotein(a) with thrombosis, we evaluated the relationship between aspirin use and CVD events in people with elevated lipoprotein(a).
We used data from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of baseline cardiovascular disease. Due to potential confounding by indication, we matched aspirin users to nonusers using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, nonfatal myocardial infarction) stratified by baseline lipoprotein(a) level (threshold of 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. After propensity matching, the study cohort included 2183 participants, including 1234 (57%) with baseline aspirin use and 423 (19%) with lipoprotein(a) >50 mg/dL. Participants with lipoprotein(a) >50 mg/dL had a higher burden of CVD risk factors, more frequent aspirin use (61.7% versus 55.3%,
=0.02), and higher rate of incident CHD events (13.7% versus 8.9%,
<0.01). Aspirin was associated with a significant reduction in CHD events among those with elevated lipoprotein(a) (hazard ratio, 0.54 95% CI, 0.32-0.94;
=0.03). Those with lipoprotein(a) >50 mg/dL and aspirin use had similar CHD risk as those with lipoprotein(a) ≤50 mg/dL regardless of aspirin use.
Aspirin use was associated with a significantly lower risk for CHD events in participants with lipoprotein(a) >50 mg/dL without baseline CVD. The results of this observational propensity-matched study require confirmation in studies with randomization of aspirin use.
This article summarizes recent observations on the role of lipoprotein(a) Lp(a) as a risk factor mediating cardiovascular disease.
Lp(a) is a highly prevalent cardiovascular risk factor, with levels ...above 30 mg/dl affecting 20-30% of the global population. Up until now, no specific therapies have been developed to lower Lp(a) levels. Three major levels of evidence support the notion that elevated Lp(a) levels are a causal, independent, genetic risk factor for cardiovascular disease: epidemiologic studies and meta-analyses, genome-wide association studies and Mendelian randomization studies. Recent studies also have noted that individuals with low levels of Lp(a) are associated with a higher risk of incident type 2 diabetes mellitus, and conversely individuals with high levels have a lower risk, but this association does not appear to be causal. Novel therapies to lower Lp(a) include PCSK9 inhibitors and antisense oligonucleotides directly preventing translation of apolipoprotein(a) mRNA.
With this robust and expanding clinical database, a reawakening of interest in Lp(a) as clinical risk factor is taking place. Trials are underway with novel drugs that substantially lower Lp(a) and may reduce its contribution to cardiovascular disease.
Keloid formation following trauma or surgery is common among darkly pigmented individuals. Since lipoprotein(a) Lp(a) has been postulated to have a putative role in wound healing, and also mediates ...atherosclerotic cardiovascular disease, it was assessed whether Lp(a), its associated oxidized phospholipids and other oxidation-specific biomarkers were associated with keloid formation.
This case-control study included darkly pigmented individuals of African ancestry, 100 with keloid scarring and 100 non-keloid controls. The lipid panel, hsCRP, Lp(a), oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), IgG and IgM apoB-immune complexes and IgG and IgM autoantibodies to a malondialdehyde mimotope (MDA-mimotope) were measured. Immunohistochemistry of keloid specimens was performed for both Lp(a) and OxPL staining.
Cases and controls were well matched for age, sex and lipid profile. Mean Lp(a) (57.8 vs. 44.2 mg/dL; P = 0.01, OxPL-apoB 17.4 vs. 15.7 nmol/L; P = 0.009) and IgG and IgM apoB-immune complexes and IgG and IgM MDA-mimotope levels were significantly higher in keloid cases. Keloid tissue stained strongly for OxPL.
Darkly pigmented individuals of African ancestry with keloids have higher plasma levels of Lp(a), OxPL-apoB and oxidation-specific epitopes. The commonality of excessive wound healing in keloids and chronic complications from coronary revascularization suggests avenues of investigation to define a common mechanism driven by Lp(a) and the innate response to oxidized lipids.
Lipoprotein(a) Lp(a) is an independent, genetically determined, and causal risk factor for cardiovascular disease. Laboratory data have suggested an interaction of Lp(a) with platelet function, ...potentially caused by its interaction with platelet receptors. So far, the potential association of Lp(a) with platelet activation and reactivity has not been proven in larger clinical cohorts. This study analyzed intrinsic platelet reactivity before loading with clopidogrel 600 mg and on-treatment platelet reactivity tested 24 h following loading in patients undergoing elective coronary angiography. Platelet reactivity was tested by optical aggregometry following stimulation with collagen or adenosine diphosphate as well as by flow cytometry. Lp(a) levels were directly measured in all patients from fresh samples. The present analysis included 1912 patients. Lp(a) levels ranged between 0 and 332 mg/dl. There was a significant association of rising levels of Lp(a) with a higher prevalence of a history of ischemic heart disease (p < 0.001) and more extensive coronary artery disease (p = 0.001). Results for intrinsic (p = 0.80) and on-clopidogrel platelet reactivity (p = 0.81) did not differ between quartiles of Lp(a) levels. Flow cytometry analyses of expression of different platelet surface proteins (CD41, CD62P or PAC-1) confirmed these findings. Correlation analyses of levels of Lp(a) with any of the tested platelet activation markers did not show any correlation. The present data do not support the hypothesis of an interaction of Lp(a) with platelet reactivity.
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