Elevated Lipoprotein(a) in Perinatally HIV-Infected Children Compared With Healthy Ethnicity-Matched Controls.
ABSTRACT: Background: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+. Methods: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. Results: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; P = .033). Other lipid levels were comparable between groups. Additional assessment of apolipoprotein B, apolipoprotein CIII, apolipoprotein E, and APOE 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. Conclusions: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. Dutch Trial Register number:NRT4074.
Project description:The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ?3% 10-year risk of fatal CVD according to European guidelines, and/or ?10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ?50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a).We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.
Project description:Aims:Lipoprotein(a) (Lp(a)) elevation is a causal risk factor for cardiovascular disease (CVD). It has however been suggested that elevated Lp(a) causes CVD mainly in individuals with high low-density lipoprotein cholesterol (LDL-C) levels. We hypothesized that the risk associated with high Lp(a) levels would largely be attenuated at low LDL-C levels. Methods and results:In 16 654 individuals from the EPIC-Norfolk prospective population study, and in 9448 individuals from the Copenhagen City Heart Study (CCHS) parallel statistical analyses were performed. Individuals were categorized according to their Lp(a) and LDL-C levels. Cut-offs were set at the 80th cohort percentile for Lp(a). Low-density lipoprotein cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. Low-density lipoprotein cholesterol levels in the primary analyses were corrected for Lp(a)-derived LDL-C (LDL-Ccorr). Multivariable-adjusted hazard ratios were calculated for each category. The category with LDL-Ccorr <2.5 mmol/L and Lp(a) <80th cohort percentile was used as reference category. In the EPIC-Norfolk and CCHS cohorts, individuals with an Lp(a) ?80th percentile were at increased CVD risk compared with those with Lp(a) <80th percentile for any LDL-Ccorr levels ?2.5 mmol/L. In contrast, for LDL-Ccorr <2.5 mmol/L, the risk associated with elevated Lp(a) attenuated. However, there was no interaction between LDL-Ccorr and Lp(a) levels on CVD risk in either cohort. Conclusion:Lipoprotein(a) and LDL-C are independently associated with CVD risk. At LDL-C levels below <2.5 mmol/L, the risk associated with elevated Lp(a) attenuates in a primary prevention setting.
Project description:AIMS:Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a). METHODS AND RESULTS:Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P?<?0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C). CONCLUSION:Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).
Project description:Lipoprotein (a) [Lp(a)] is a low density lipoprotein (LDL) with one apolipoprotein (a) molecule bound to the apolipoprotein B-100 of LDL. Lp(a) is an independent risk factor for cardiovascular disease (CVD). However, the relationship of Lp(a) to diabetes and metabolic syndrome, both known for increased CVD risk, is controversial. In a population based study on type two diabetes mellitus (T2DM) development in women, Lp(a) plasma levels showed the well known skewed distribution without any relation to diabetes or impaired glucose tolerance. A modified clot lysis assay on a subset of 274 subjects showed significantly increased clot lysis times in T2DM subjects, despite inhibition of PAI-1 and TAFI. Lp(a) plasma levels significantly increased the maximal peak height of the clot lysis curve, indicating a change in clot structure. In this study Lp(a) is not related to the development of T2DM but may affect clot structure ex vivo without a prolongation of the clot lysis time.
Project description:Lipoprotein(a) [Lp(a)], aka "Lp little a", was discovered in the 1960s in the lab of the Norwegian physician Kåre Berg. Since then, we have greatly improved our knowledge of lipids and cardiovascular disease (CVD). Lp(a) is an enigmatic class of lipoprotein that is exclusively formed in the liver and comprises two main components, a single copy of apolipoprotein (apo) B-100 (apo-B100) tethered to a single copy of a protein denoted as apolipoprotein(a) apo(a). Plasma levels of Lp(a) increase soon after birth to a steady concentration within a few months of life. In adults, Lp(a) levels range widely from <2 to 2500?mg/L. Evidence that elevated Lp(a) levels >300?mg/L contribute to CVD is significant. The improvement of isoform-independent assays, together with the insight from epidemiologic studies, meta-analyses, genome-wide association studies, and Mendelian randomization studies, has established Lp(a) as the single most common independent genetically inherited causal risk factor for CVD. This breakthrough elevated Lp(a) from a biomarker of atherosclerotic risk to a target of therapy. With the emergence of promising second-generation antisense therapy, we hope that we can answer the question of whether Lp(a) is ready for prime-time clinic use. In this review, we present an update on the metabolism, pathophysiology, and current/future medical interventions for high levels of Lp(a).
Project description:Circulating concentrations of lipid biomarkers are associated with risk of cardiovascular diseases (CVD). The evidence for a relationship with cancer risk, however, is not entirely consistent. This study aims to assess the relationships of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein (a) (apo(a)), apoB-100, and lipoprotein(a) (Lp(a)) with risk of common cancer forms and total cancer mortality in comparison to incidence and mortality of CVD.We selected a case-cohort sample out of the prospective EPIC-Heidelberg study, including a random subcohort (n?=?2739), and cases of cancer (n?=?1632), cancer mortality (n?=?761), CVD (n?=?1070), and CVD mortality (n?=?381). Concentrations of lipid biomarkers were measured in pre-diagnostic blood samples. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Prentice-weighted Cox regression models.High levels of circulating apoB-100 and TG were inversely associated and high HDL-C levels were positively associated with breast cancer risk (highest vs. lowest quartile (Q4 vs. Q1), HRapoB 0.71, 95% CI 0.52-0.98; HRTG 0.65, 0.46-0.92; and HRHDL 1.39, 1.01-1.93). Higher levels of Lp(a) were associated with an increase in prostate cancer risk (Q4 vs. Q1, HRLp(a) 1.43, 1.02-2.03) and high levels of apo(a) were associated with a decrease in lung cancer risk (Q4 vs. Q1, HRapo(a) 0.52, 0.30-0.91). High TC, HDL-C, apo(a), and Lp(a) levels were associated with a reduction in total cancer mortality (Q4 vs. Q1, HRTC 0.71, 0.54-0.94; HRHDL 0.67, 0.50-0.91; HRapo(a) 0.71, 0.54-0.93; and HRLp(a) 0.74, 0.57-0.98). All lipid biomarkers were associated with risk of myocardial infarction, whereby TC, apoB-100, TG, and Lp(a) were positively and HLD-C and apo(a) inversely associated with risk. Only high levels of TG were associated with an increased risk of stroke. None of the lipids were associated with risk of colorectal cancer and with risk of CVD mortality after multivariable adjustments.This prospective study demonstrates inverse associations of lipid biomarkers with cancer incidence and mortality, with the exception of positive associations of HDL-C and Lp(a) with breast and prostate cancer risk, respectively. Thus, the observed cancer risk pattern clearly differs from the CVD risk pattern.
Project description:Plasma lipoproteins are important carriers of cholesterol and have been linked strongly to cardiovascular disease (CVD). Our study aimed to achieve fine-grained measurements of lipoprotein subpopulations such as low-density lipoprotein (LDL), lipoprotein(a) (Lp(a), or remnant lipoproteins (RLP) using electron microscopy combined with machine learning tools from microliter samples of human plasma. In the reported method, lipoproteins were absorbed onto electron microscopy (EM) support films from diluted plasma and embedded in thin films of methyl cellulose (MC) containing mixed metal stains, providing intense edge contrast. The results show that LPs have a continuous frequency distribution of sizes, extending from LDL (> 15 nm) to intermediate density lipoprotein (IDL) and very low-density lipoproteins (VLDL). Furthermore, mixed metal staining produces striking "positive" contrast of specific antibodies attached to lipoproteins providing quantitative data on apolipoprotein(a)-positive Lp(a) or apolipoprotein B (ApoB)-positive particles. To enable automatic particle characterization, we also demonstrated efficient segmentation of lipoprotein particles using deep learning software characterized by a Mask Region-based Convolutional Neural Networks (R-CNN) architecture with transfer learning. In future, EM and machine learning could be combined with microarray deposition and automated imaging for higher throughput quantitation of lipoproteins associated with CVD risk.
Project description:Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.
Project description:Despite the undisputed benefits of combination antiretroviral therapy (cART), perinatally acquired human immunodeficiency virus (PHIV) children on treatment often present with a spectrum of neurological deficits known as HIV-associated neurocognitive impairment. Even higher CD4 cell count does not seem to prevent the development of neurocognitive impairment in children with PHIV. While CD4 cell count has shown to have the greatest prognostic value, its association with neurocognitive abilities remains to be clarified. This study aimed at determining the correlation between plasma CD4+ lymphocyte and neurocognitive function in children with PHIV on cART. In total, 152 purposively recruited hospital-based sample of children with PHIV on cART, aged 3 years to 7 years 6 months (mean age, 63.13 months), underwent neurocognitive assessment using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition. Immunological status of each child was based on the plasma CD4+ lymphocyte levels. The mean CD4+ lymphocyte cell count at the time of neurocognitive assessment was 1,259.85 cells/mm3 (mean range, 139-2,717 cells/mm3), with significant age difference on CD4+ lymphocyte count levels [F (2, 149) = 13.58, p = 0.000]. CD4+ lymphocyte counts was significantly correlated with subdomains of neurocognitive function scores of task that measures working memory, processing speed, and perceptual reasoning. Global cognitive ability (Full Scale Intellectual Quotient) had no significant association with immunological status of the children. The findings support an association between immunological status of PHIV infection and executive function task. These neurocognitive faculties are critical for learning, school readiness and success in early childhood, and ultimately treatment adherence in adolescence. The need for early identification of neurodevelopment deficits in children, even when on cART, is crucial because early psychosocial and neurorehabilitative interventions can lead to better outcome for children with PHIV.
Project description:Lipoprotein(a), Lp(a), represents an apolipoprotein (apo) B-carrying lipoprotein, yet the relationship between Lp(a) and apoB levels has not been fully explored.We addressed the relationship between Lp(a) and apoB-containing lipoprotein levels in 336 Caucasians and 224 African-Americans. Our approach takes unique molecular properties of Lp(a) as well as contribution of Lp(a) to the levels of these lipoproteins into account.Levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apoB and apoB/apoA-1 did not differ across ethnicity. African-Americans had higher levels of Lp(a) and high-density lipoprotein cholesterol and lower triglyceride levels compared to Caucasians. Lp(a) levels were correlated with levels of TC (p < 0.005), LDL-C (p < 0.001), apoB (p < 0.05) or apoB/apoA-1 (p < 0.05) in both ethnic groups. These associations remained significant only in African-Americans after adjustments for the contribution of Lp(a)-cholesterol or Lp(a)-apoB. Furthermore, taking Lp(a)-apoB into account, allele-specific apo(a) levels were significantly associated with apoB levels and the apoB/apoA-1 ratio in African-Americans. The latter associations in African-Americans remained significant for allele-specific apo(a) levels for smaller apo(a) sizes (<26 K4 repeats), after controlling for the effects of age, sex, and BMI.Although TC, LDL-C, and apoB levels were comparable between African-Americans and Caucasians, the associations of these parameters with Lp(a) and allele specific apo(a) levels differed between these two ethnic groups. In African-Americans, apoB and apoB/apoA-1 remained consistently and positively associated with both Lp(a) and allele-specific apo(a) levels after adjustments for the contribution of Lp(a)-apoB. The findings suggest an interethnic difference with a closer relationship between Lp(a) and apoB among African-Americans.