Low‐fat diets have been shown to increase plasma concentrations of lipoprotein(a) Lp(a), a preferential carrier of oxidized phospholipids (OxPL) in plasma, as well as small, dense LDL particles. We ...sought to determine whether increases in plasma Lp(a) induced by a low‐fat, high‐carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high‐fat, low‐carbohydrate (HFLC) diet and a LFHC diet. Plasma lipids, lipoproteins, apolipoprotein (apo) B and A‐1, Lp(a) and OxPL content on apoB‐100 (OxPL/apoB) were measured at the end of each diet. Plasma concentrations of Lp(a) (P < 0.01) and OxPL/apoB (P < 0.005) were significantly higher on the LFHC diet compared to the HFLC diet, whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet‐induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were associated with diet‐induced decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). This study demonstrates that specific diets may influence circulating Lp(a) levels and their associated OxPL.
To test the hypothesis that the accumulation of oxidized phospholipids (OxPL) in the macula is toxic to the retina unless neutralized by a variety of mechanisms, including binding by lipoprotein(a) ...Lp(a), which is composed of apolipoprotein(a) apo(a) and apolipoprotein B-100 (apoB).
Human maculas and eyes from two Lp(a) transgenic murine models were subjected to morphologic, ultrastructural, and immunohistochemical analysis. "Wild-type Lp(a)" mice, which express human apoB-100 and apo(a) that contains oxidized phospholipid, and "mutant LBS(-) Lp(a)" mice with a defective apo(a) lysine binding site (LBS) for oxidized phospholipid binding, were fed a chow or high-fat diet for 2 to 12 months. Oxidized phospholipid-containing lipoproteins were detected by immunoreactivity to E06, a murine monoclonal antibody binding to the phosphocholine headgroup of oxidized, but not native, phospholipids.
Oxidized phospholipids, apo(a), and apoB accumulate in maculas, including drusen, of age-related macular degeneration (AMD) samples and age-matched controls. Lp(a) mice fed a high-fat diet developed age-related changes. However, mutant LBS(-) Lp(a) mice fed a high-fat diet developed retinal pigment epithelial cell degeneration and drusen. These changes were associated with increased OxPL, decreased antioxidant defenses, increased complement, and decreased complement regulators.
Human maculas accumulate Lp(a) and OxPL. Mutant LBS(-) Lp(a) mice, lacking the ability to bind E06-detectable oxidized phospholipid, develop AMD-like changes. The ability of Lp(a) to bind E06-detectable OxPL may play a protective role in AMD.
OBJECTIVE—Labeled oxidation-specific antibodies (Ox-AB) detect, quantify, and noninvasively image lipid-rich atherosclerotic lesions. However, it is unknown whether Ox-AB detect plaque stabilization.
...METHODS AND RESULTS—The aortic uptake of intravenously injected I-MDA2 (Ox-AB to malondialdehyde MDA–low-density lipoprotein LDL) was quantitated in(1) LDL receptor−/− mice with established atherosclerosis continued on Western diet (Progression) or switched to chow (Regression) or chow+vitamins E and C (Regression-VIT) for 6 months; and (2) Watanabe rabbits (3- to 57-months old) with naturally evolved atherosclerotic lesions. In mice, the Progression group had more extensive atherosclerosis, higher I-MDA2 uptake, high concordance of Sudan (lipid)-staining and I-MDA2 uptake, and stronger oxidized LDL (OxLDL) and macrophage immunostaining than both Regression groups. In contrast, the Regression groups showed Sudan-positive lesions with focally diminished I-MDA2 uptake, which coincided with reduced OxLDL and macrophages but more smooth muscle cells (SMCs) and collagen. In rabbits, areas of increased I-MDA2 uptake were associated with high Sudan concordance and strong immunostaining for OxLDL and macrophages. Interestingly, advanced lesions with focally diminished I-MDA2 uptake showed stronger immunostaining for SMCs and collagen, particularly at the fibrous cap.
CONCLUSION—Ox-AB uptake is focally diminished in plaques displaying accepted features of plaque stability. Imaging techniques to detect the presence and depletion of OxLDL may be useful in assessing plaque stabilization.
Oxidative stress, and in particular oxidation of lipoproteins, is a hallmark of atherosclerosis. Upon entry of lipoproteins into the vessel wall, a cascade of pro-atherogenic pathways is initiated ...whereby the reaction of reactive oxygen species with substrates amenable to oxidation, such as polyunsaturated fatty acids, generates a variety of oxidation-specific epitopes on lipoproteins, proteins in the vessel wall, and apoptotic macrophages. Several of these oxidation-specific epitopes have been well characterized and specific murine and fully human antibodies have been generated in our laboratory to detect them in the vessel wall. We have developed radionuclide, gadolinium and iron oxide based MRI techniques to noninvasively image oxidation-specific epitopes in atherosclerotic lesions. These approaches quantitate plaque burden and also allow detection of atherosclerosis regression and plaque stabilization. In particular, gadolinium micelles or lipid-coated ultrasmall superparamagnetic iron oxide particles containing oxidation-specific antibodies accumulate within macrophages in the artery wall, suggesting they may image the most unstable plaques. Translation of these approaches to humans may allow a sensitive technique to image and monitor high-risk atherosclerotic lesions and may guide optimal therapeutic interventions.
HIV-associated cardiovascular disease (CVD) risk in combination antiretroviral therapy (cART)-treated perinatally HIV-infected patients (PHIV+) remains unknown due to the young age of this ...population. Lipoprotein(a) (Lp(a)) has been established as an independent causal risk factor for CVD in the general population but has not been well established in the population of PHIV+.
We cross-sectionally compared lipid profiles, including nonfasting Lp(a), together with total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides between 35 cART-treated PHIV+ children aged 8-18 years and 37 controls who were matched for age, sex, ethnicity, and socioeconomic status. We explored associations between Lp(a) and disease- and treatment-related factors (inflammation, monocyte activation, and vascular), biomarkers, and neuroimaging outcomes using linear regression models.
PHIV+ children had significantly higher levels of Lp(a) compared with controls (median, 43.6 21.6-82.4 vs 21.8 16.8-46.6 mg/dL;
= .033). Other lipid levels were comparable between groups. Additional assessment of apolipoprotein B, apolipoprotein CIII, apolipoprotein E, and
genotype revealed no significant differences. Higher Lp(a) levels were associated with higher plasma apoB levels and with lower monocyte chemoattractant protein-1 and TG levels in PHIV+ children. Lp(a) was not associated with HIV- or cART-related variables or with neuroimaging outcomes.
cART-treated PHIV+ children appear to have higher levels of Lp(a) compared with ethnicity-matched controls, which may implicate higher CVD risk in this population. Future research should focus on the association between Lp(a) and (sub)clinical CVD measurements in cART-treated PHIV+ patients.
NRT4074.
BackgroundCurrent clinical methods for estimation or direct measurement of low-density lipoprotein cholesterol (LDL-C) include the content of cholesterol on lipoprotein (a) (Lp(a)-C), which may mask ...changes in true LDL (LDL-Ccorr) in therapeutic interventions.MethodsThe effect of alirocumab (75-150 mg every 2 weeks) or placebo in patients (alirocumab, n=1983; placebo, n=1011) on laboratory measured “LDL-C” and estimated LDL-Ccorr was analyzed in 5 ODYSSEY phase 3 studies using paired LDL-C and Lp(a) mass levels at baseline and at 24 weeks. LDL-C was estimated by the Friedewald formula or measured directly by beta-quantitation if triglycerides >400 mg/dL. Lp(a)-C was estimated as Lp(a) mass in mg/dL times 0.30. LDL-Ccorr was calculated as LDL-C minus Lp(a)-C. Additional analyses were carried out by categories of increasing Lp(a) levels (0-30, 30-50, 50-100, and >100 mg/dL).ResultsAt baseline, mean (SD) LDL-Ccorr levels were lower than LDL-C in both alirocumab and placebo groups and LDL-Ccorr declined progressively with higher Lp(a) levels (Table). In the entire group, alirocumab resulted in a greater reduction in LDL-Ccorr versus LDL-C (63.3% vs 58.8%, p<0.001). This was more evident as Lp(a) levels increasedLp(a)0-30 mg/dL (60.2% vs 59.5%, p<0.001), 30-50 mg/dL (63.1% vs 59.3%, p<0.001), 50-100 mg/dL (66.5% vs 58.4%, p<0.001), and >100 mg/dL (70.7% vs 55.7%, p<0.001).ConclusionAlirocumab results in a progressively greater reduction in estimated LDL-Ccorr versus LDL-C as Lp(a) increases. The true effect of alirocumab on LDL-Ccorr may be masked by methodological limitations in accurately measuring LDL-C versus Lp(a)-C.
The use of the pressure sensor coronary guidewire is expanding into the peripheral circulation as well as into the realm of valvular heart disease. Small mechanistic studies and case reports have ...described the use of pressure wire technology in the renal and femoral arteries as well as in mechanical aortic valves. The use of this technology to measure hemodynamically significant stenoses in noncoronary locations will be discussed and a review of basic and more advanced hemodynamics in relation to problems encountered in clinical practice will be provided.
Lipoprotein(a) Lp(a) plays an important role in atherosclerosis. The biological effects of Lp(a) have been attributed either to apolipoprotein(a) or to its low-density lipoprotein-like particle. ...Lp(a) contains platelet-activating factor acetylhydrolase, an enzyme that exhibits a Ca
2+
-independent phospholipase A
2
activity and is complexed to lipoproteins in plasma; thus, it is also referred to as lipoprotein-associated phospholipase A
2
. Substrates for lipoprotein-associated phospholipase A
2
include phospholipids containing oxidatively fragmented residues at the
sn-2
position (oxidized phospholipids; OxPLs). OxPLs may play important roles in vascular inflammation and atherosclerosis. Plasma levels of OxPLs present on apolipoprotein B-100 particles (OxPL/apolipoprotein B) are correlated with coronary artery, carotid, and peripheral arterial disease. Furthermore, OxPL/apolipoprotein B levels in plasma are strongly correlated with Lp(a) levels, are preferentially sequestered on Lp(a), and thus are potentially subjected to degradation by the Lp(a)-associated lipoprotein-associated phospholipase A
2
. The present review article focuses specifically on the characteristics of the lipoprotein-associated phospholipase A
2
associated with Lp(a) and discusses the possible role of this enzyme in view of emerging data showing that OxPLs in plasma are preferentially sequestered on Lp(a) and may significantly contribute to the increased atherogenicity of this lipoprotein.
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