Patients with HIV infection receiving highly active antiretroviral therapy (HAART) frequently develop a unique and complex metabolic syndrome characterized by dyslipidemia, lipodystrophy, central visceral obesity, and insulin resistance (10,13,27). These features are established, independent of risk factors for cardiovascular disease, and place patients with HIV/HAART-associated dyslipidemia or lipodystrophy at increased risk of atherosclerosis (4,7,18). Dyslipidemia in patients with HIV is frequently accompanied by abnormal plasma levels of several emerging and “nontraditional” cardiovascular risk factors, including plasma lipoprotein-associated factors such as lipoprotein-associated phospholipase A2 (Lp-PLA2) and inflammatory chemokines such as CCL5 or regulated on activation, normal T-cell expressed and secreted (RANTES) (19,21,25). The presence of these factors could accelerate atherosclerosis in patients with HIV due to their coexisting highly inflammatory state.
Lp-PLA2, also known as platelet-activating factor acetylhydrolase (PAF-AH), is a calcium-independent phospholipase that is secreted by macrophages and other inflammatory cells in the vessel wall (6,34,39). Circulating Lp-PLA2 is bound to apolipoprotein B-containing proteins and to a lesser extent by high-density lipoproteins (6,12,34,39). Lp-PLA2 hydrolyzes the sn-2-acyl bond of phospholipids in cell membranes and lipoproteins, yielding nonesterified fatty acids and lysophospholipids that are precursors of several proinflammatory mediators (17). In the Lp-PLA2 Studies Collaboration (36), Lp-PLA2 activity and mass were associated with risk for coronary heart disease that was similar in magnitude to that of non-HDL cholesterol (non-HDL-C) or systolic blood pressure. According to the Heart Protection Study (14), the associations of Lp-PLA2 mass and activity with vascular outcomes and events depend partly on plasma lipid levels. Furthermore, Lp-PLA2 activity is thought to be a significant mediator in the pathogenesis of several neurological, cardiovascular, and metabolic manifestations associated with HIV-1 infection and the acquired immunodeficiency syndrome (AIDS) (21,30). This is supported by the elevated Lp-PLA2 activity observed in the plasma of patients with AIDS compared with controls (21).
Chemokines and their G-protein-coupled receptors contribute significantly to the pathogenesis of both atherosclerosis and HIV infection (19). RANTES is a CC chemokine that is stored in the alpha granules of platelets. After platelet activation, it is released and deposited on inflamed or atherosclerotic endothelium mediating monocyte transmigration. The receptor for RANTES is CCR5, well known for its role as a coreceptor for HIV-1 infection (19). RANTES is elevated in patients with HIV infection or AIDS (25,31,41) compared with healthy controls, and it seems to be variably elevated in populations of patients with coronary artery disease (8,15).
Hypertriglyceridemia and low HDL-C are characteristic lipid defects in patients with HIV on HAART. Adverse drug interactions between HAART drugs and cytochrome P450 3A4-metabolized statins (9,16) and a high prevalence of hepatitis render standard lipid-lowering approaches inadequate in achieving recommended treatment goals in patients with HIV. Previous work by our group and others (summarized by Balasubramanyam et al. ) indicated that the key underlying defects are excessive lipolysis and inadequate oxidation of the released fatty acids. This prompted the choice of niacin (an antilipolytic drug) and fenofibrate (which promotes fatty acid oxidation) as the lipid-lowering agents in the Heart Positive Study.
Diets high in saturated fat and physical inactivity are associated with elevated levels of Lp-PLA2 and RANTES (1,40). There have been limited studies focused on the effects of dietary factors and physical activity or exercise on Lp-PLA2 and RANTES. The general consensus is that dietary and lifestyle factors that reduce LDL cholesterol (LDL-C) likely result in Lp-PLA2 reduction (40). In contrast, it remains unclear if similar diet and physical activity modifications would reduce RANTES levels; however, Garcia et al. (11), showed that a single session of moderate-intensity exercise (70% V˙O2max) for 1 h can decrease RANTES levels in sedentary women.
The aim of this study was to assess if an intensive diet and exercise (D/E) program, independently or combined with fenofibrate or niacin, could reduce elevated plasma levels of Lp-PLA2 mass and RANTES in a subset of patients enrolled in the Heart Positive Study, a randomized, double-blind, placebo-controlled trial to compare the effects of usual care to diet, exercise, fenofibrate, or niacin on lipid profiles of patients with HIV/HAART-associated dyslipidemia (3).
Subjects and design.
Details of the Heart Positive Study’s research design have been reported previously (3). All experimental protocols were approved by the institutional review board of Baylor College of Medicine, Legacy Community Health Center, and the Harris County Hospital District. Written informed consent was obtained from all participants (N = 107) before enrollment into the study.
Inclusion criteria were as follows: age, 21–65 yr; fasting triglycerides, >150 mg·dL−1 (1.70 mmol·L−1); body mass index (BMI), 18.5–35 kg·m−2; and stable HAART for 6 months with CD4+ T-cell count >100·mm−3 and viral load (VL) <5000 copies per cubic centimeter. Exclusion criteria were fasting triglycerides >1000 mg·dL−1 (11.3 mmol·L−1), history of coronary artery disease or diabetes, untreated hypogonadism or thyroid dysfunction, pregnancy, renal insufficiency, alcoholism, alanine aminotransferase, aspartate aminotransferase more than two times upper limit of normal, or use of nutritional supplements or lipid-lowering drugs for 6 wk before entry. Participants were randomized (Fig. 1) to five study groups: 1) usual care with two placebos; 2) intensive D/E with two placebos; 3) D/E with active fenofibrate and niacin placebo; 4) D/E with active niacin and fenofibrate placebo; and 5) D/E with active fenofibrate and active niacin. Details of randomization, stratification by classes of HAART, and interventions were as described previously (3). Briefly, participants in the usual care group received general advice on a heart-healthy diet and maintaining physical fitness. Participants in the other four groups (groups 2–5) were taught a weight-maintaining diet with 50% calories from carbohydrates, 30% calories from fat (<7% saturated, 15% monounsaturated, 8% polyunsaturated, and minimal trans), <200 mg·d−1 of cholesterol, and 20–30 g·d−1 of fiber. For the first 2 wk, all meals were packaged by the Baylor General Clinical Research Center kitchen and delivered to the subjects. During this stabilization period, subjects were instructed on food selection and preparation. Three days of food records were verified by a dietitian at 0, 8, 16, and 24 wk. Participants in groups 2–5 also participated in an exercise program at a study gymnasium. The sessions were supervised by certified trainers, three times weekly for 75–90 min, with aerobic and resistance exercise components. For subjects who could not attend the study gymnasium, membership was provided at a commercial fitness center. Study trainers provided exercise plans to subjects in this alternative program and reviewed their progress biweekly. Importantly, to avoid the confounding factor of weight loss in assessing the effect of the diet composition and exercise interventions on the outcome measures, caloric intake was adjusted by study dietitians to maintain a stable body weight throughout the study (3).
Participants in groups 4 and 5 took sustained-release niacin (Niaspan; Abbott Laboratories, Abbott Park, IL), starting with one 500-mg tablet plus three placebo pills at bedtime for 2 wk, increasing by one active tablet biweekly (with corresponding decrease in placebo) to four tablets from the seventh week. To minimize unblinding due to flushing, one placebo pill contained 50 mg niacin (3). Participants in groups 3 and 5 took 145 mg of fenofibrate (Tricor; Abbott Laboratories) at bedtime, while the other participants took placebos. Medication compliance was reviewed during monthly refills.
Baseline characteristics, lipid levels, and levels of LpPLA2 and RANTES were also compared with those of a cohort of 22 healthy adult control subjects (without chronic illnesses, medications, or HIV risk factors), matched to the HIV/HAART subjects for age and BMI.
Fasting (10 h) plasma samples were collected at baseline and after the 24-wk intervention and stored at −80°C until analysis. Every effort was made to collect plasma samples between 0700 and 1000 h. CD4+ T-cell counts were measured by LabCorp (Burlington, NC) using flow cytometry. HIV-1 VL was measured by LabCorp or Quest Diagnostics (Madison, NJ) using either of two quantitative real-time PCR assays (routine, with a lower limit of 400 copies per cubic centimeter, or ultrasensitive, with a lower limit of 50 copies per cubic centimeter). VL values measured as <400 copies per cubic centimeter by the first assay were assigned a value of 200 copies per cubic centimeter, and all the VL values were log-transformed before analysis.
Fasting plasma lipid levels were measured in the Atherosclerosis Clinical Laboratory of Baylor College of Medicine using an Olympus AU400e automated chemistry analyzer in which total cholesterol (TC) is measured using cholesterol dehydrogenase combined with the esterase and oxidase into a single enzymatic reagent. Triglycerides are measured by a procedure based on a series of coupled enzymatic reactions after hydrolysis by microbial lipases to release glycerol and fatty acids—glycerol is phosphorylated by glycerol kinase GK to produce glycerol-3-phosphate, which is oxidized by glycerol phosphate oxidase to produce H2O2 and dihydroxyacetone phosphate. The H2O2 oxidatively couples p-chlorophenol and 4-aminoantipyrine with catalysis by peroxidase to produce a red dye with an absorbance maximum at 500 nm; the increase in absorbance at 520/600 nm is proportional to the triglyceride content of the sample. HDL-C is measured in two steps—first, free cholesterol in non-HDL lipoproteins is solubilized and consumed by cholesterol oxidase, peroxidase, and DSBmT to generate a colorless end product; and second, a detergent selectively solubilizes HDL lipoproteins. The HDL-C is released for reaction with cholesterol esterase, cholesterol oxidase, and chromogen system to yield a blue-colored complex, which can be measured bichromatically at 600/700 nm. The resulting increase in absorbance is directly proportional to the HDL-C concentration. Plasma LDL-C concentrations were calculated according to the Friedewald equation.
Levels of Lp-PLA2 mass (diaDexus Inc., San Francisco, CA) and RANTES (R&D Systems, Minneapolis, MN) were measured using commercially available enzyme-linked immunosorbent assay kits. The sensitivity values of the Lp-PLA2 and RANTES assays were 15.6 pg·mL−1 and 0.34 ng·mL−1, respectively. The coefficient of variation was <5% for both Lp-PLA2 and RANTES assays.
On the basis of the assumption that the D/E program compared with usual care and fenofibrate plus niacin with D/E compared with D/E alone would reduce Lp-PLA2 mass by at least 10%, assuming alpha = 0.05, power = 0.80, and a two-tailed test, the necessary sample size was calculated to be 90 total subjects. Hence, 107 subjects were selected at random from a total of 127 who completed the 24-wk intervention in the Heart Positive Study. All descriptive data are presented as mean ± SEM. Independent sample t-tests were used to compare baseline age and BMI as well as levels of lipids and lipoproteins, Lp-PLA2, and RANTES. Separate general linear models (Statistical Package for the Social Sciences, version 18.0; SPSS Inc., Chicago, IL) were used to compare the five randomized groups with respect to Lp-PLA2, RANTES, and lipid and lipoprotein concentrations, while controlling for age, baseline BMI, baseline CD4+ T-cell count, baseline VL, duration of HIV, and duration of HAART as well as baseline outcome measures. When differences between groups were detected at P < 0.05, groups 2–5 were each compared with group 1 (simple contrast) using the sequential Sidak multiple comparison procedure. The mean of groups 2–5 (all receiving D/E) was also compared with group 1 (usual care) while controlling for the same covariates as previously mentioned. Simple Pearson product correlations were conducted to identify significant relationships between general descriptive characteristics (age, BMI, baseline CD4+ T-cell count, baseline VL, duration of HIV, and HAART), Lp-PLA2, RANTES, and lipid and lipoprotein concentrations. P < 0.05 was considered significant.
As previously reported (3), the weight-maintaining lifestyle intervention resulted in no significant changes or group differences in weight or BMI. Study dieticians advised subjects at monthly visits to reduce or increase calories as needed to maintain baseline weight. As in all exercise programs, there were minor fluctuations of weight despite the attempts at dietary correction—on average, weight change was approximately ±1.5 kg. Compliance with medications, diet, and gym visits have been reported (3) and were not different between the groups. A similar number of patients in each group participated in the alternative exercise program (9 patients in group 2, 8 patients in group 3, 11 patients in group 4, and 9 patients in group 5).
Demographic characteristics and baseline levels of HIV/HAART-related parameters and fasting plasma lipid, Lp-PLA2, and RANTES levels of the subjects are shown in Table 1. At baseline, there were no significant differences in these parameters between groups 1 and 5. When compared with healthy controls (Table 2) matched for age and BMI, the HIV group displayed significantly higher plasma concentrations of triglycerides (+169%), non-HDL-C (+22%), TC/HDL ratio (+66%), Lp-PLA2 (+38%), and RANTES (+95%) and significantly lower HDL-C concentration (−39%). Despite normal total plasma cholesterol concentrations, the HIV group had markedly elevated plasma Lp-PLA2 and RANTES levels.
Postintervention responses of D/E, fenofibrate, and niacin on concentrations of lipids, lipoproteins, Lp-PLA2, and RANTES are compared with usual care in Table 3. After the 24-wk intervention, Lp-PLA2 concentration was significantly lower in group 2 patients who participated in D/E only (323.0 ± 27.2 ng·mL−1), group 3 patients who received D/E plus fenofibrate (327.2 ± 25.9 ng·mL−1), and group 4 patients who received D/E plus niacin (311.1 ± 27.8 ng·mL−1) than among group 1 patients who received usual care (402.2 ± 25.3 ng·mL−1). There was no significant difference in Lp-PLA2 between patients who received D/E only, D/E plus fenofibrate, or D/E plus niacin. No significant differences were observed between groups for RANTES concentrations after the 24-wk intervention. Interestingly, group 5, who received D/E and both fenofibrate and niacin, did not have significant reductions in Lp-PLA2 and RANTES, although this was the only group to demonstrate significantly lower plasma concentrations of triglycerides (−47%), non-HDL-C (−19%), and TC/HDL ratio (−29%) and increase in HDL-C concentration (+30%) compared with usual care.
When all treatment groups (2–5) were combined and compared with the group receiving usual care (group 1), all patients in the intensive exercise and dietary program had significantly lower triglycerides (−33%), non-HDL-C (−12%), TC/HDL ratio (−16%), and Lp-PLA2 (−19%) and higher HDL-C (+16%) after the 24-wk intervention. Baseline Lp-PLA2 levels correlated with TC (r = 0.192), non-HDL-C (r = 0.205), and percent change in Lp-PLA2 (r = −0.416). These correlations are similar to those previously reported (for Lp-PLA2 with TC, r = 0.28, CI = 0.25–0.31; for Lp-PLA2 with non-HDL-C, r = 0.30, CI = 0.27–0.34) (15). Baseline levels of Lp-PLA2 and RANTES showed no significant correlation (r = 0.021, P = 0.83). No significant correlations were observed between RANTES and the patients’ demographic characteristics or lipid/lipoprotein levels.
The present data demonstrate that plasma Lp-PLA2 mass is markedly elevated in patients with HIV/HAART-associated dyslipidemia, and that it can be significantly reduced by 24 wk of intensive D/E. The addition of niacin (2 g·d−1) or fenofibrate (160 mg·d−1) to the lifestyle modification does not confer significant additional benefit about Lp-PLA2 mass reduction. Plasma levels of RANTES are highly variable but generally markedly elevated in these patients compared with those observed in many studies of populations with CAD, but none of the interventions used in this study resulted in significant reductions of this cytokine.
The Lp-PLA2 responses to fenofibrate (combined with D/E) contrast with those observed in other dyslipidemic populations receiving fenofibrate without intensive lifestyle modification. Rosenson (32) showed that treatment with fenofibrate (160 mg·d−1) for 3 months reduced concentrations of Lp-PLA2 by 13.2% in hypertriglyceridemic patients with metabolic syndrome and that this was associated with reductions in LDL-C, total LDL particles, and small LDL particles. Treatments that lower plasma LDL-C such as fibrates and statins might be expected to lower Lp-PLA2 mass and activity as well (26). An effect of fenofibrate on Lp-PLA2 was not observed in the present study, but fenofibrate alone was not tested and it is possible that the effect of the intensive lifestyle modification obscured a small direct effect of fenofibrate.
A few studies have examined the effects of niacin on Lp-PLA2 mass and activity. Kuvin et al. (22) reported 20% reduction in Lp-PLA2 mass after 3 months of niacin treatment (1 g·d−1) in patients with CAD, together with 7.5% increase in HDL-C and 15% reduction in triglycerides. In the present study, the HIV/HAART patients who received both the D/E program and niacin (2 g·d−1) experienced the largest mean reduction (−23%) in Lp-PLA2 mass, but this effect was not significantly greater than that of D/E with placebo. Paradoxically, the patients who received D/E with both niacin and fenofibrate did not achieve a significant reduction in Lp-PLA2 mass; but consistent with the overall results of the Heart Positive Study (3), they were the only group with significant improvements in triglyceride, TC, HDL-C, and non-HDL-C levels. In aggregate, these data suggest discordance between Lp-PLA2 mass and lipid and lipoprotein metabolism in HIV/HAART-associated dyslipidemia. Khovidhunkit et al. (21) also observed that the higher Lp-PLA2 activity in AIDS patients could not be explained by a relationship with plasma lipids because patients with AIDS had lower TC and LDL-C concentrations than healthy control subjects. Furthermore, there was no relationship between plasma Lp-PLA2 activity and plasma cholesterol, LDL-C, or apo B-100 concentrations. Factors such as macrophage activation, generation of platelet-activating factor and oxidized phospholipids, and elevated cytokines observed during HIV infection may stimulate Lp-PLA2 activity or synthesis (21). Alterations of specific HAART regimens have also been reported to reduce Lp-PLA2 activities in a dose-dependent manner (37), but this would not have affected the results of the present study because the subjects were on stable HAART regimens throughout and were stratified on three combinations of classes of HAART at randomization.
Dietary modifications with or without exercise training have demonstrated varied outcomes in lipid and lipoprotein–cholesterol concentrations among patients with HIV. In a group of patients with HIV/HAART with dyslipidemia and lipodystrophy, Terry et al. (35) reported no significant changes in plasma triglycerides, TC, or HDL-C after 12-wk of aerobic exercise training combined with a low-fat diet despite 25% increase in V˙O2max. Interestingly, the low-fat-diet-only group did not show improvements in blood lipids and lipoproteins, even with reductions in both body fat and waist-to-hip ratio. In contrast, a small group of patients with lipodystrophic HIV/HAART who completed a 10-wk aerobic and resistance exercise program experienced reductions in TC and triglyceride concentrations (20). The changes in blood lipids were matched by an increase in body mass and a reduction in body fat, indicating a positive adaptation in body composition. Interestingly, Lazzaretti et al. (24) showed that patients assigned a low-fat diet before initiating HAART maintained TC and LDL-C levels and reduced triglyceride concentrations by ∼25% at 12 months when compared with HAART-treated patients without the dietary intervention. During longer-term follow-up, 21% who received the low-fat diet displayed a dyslipidemic profile compared with 68% of the controls. Hence, diet alone could have a salutary effect on the lipid profile in patients with HIV/HAART. The design of our study does not permit us to distinguish the separate effects of D/E, but collectively, these data suggest that lifestyle changes (with attention to factors such as the type of exercise training, the amount and type of fat in the diet, and the timing of lifestyle modifications at the inception of HAART) should be considered part of an optimal treatment approach to dyslipidemia in patients with HIV.
The Lp-PLA2 Studies Collaboration, a meta-analysis of 32 prospective studies, reported that Lp-PLA2 mass and activity were associated with each other (r = 0.51, 95% CI = 0.47–0.56), with proatherogenic lipids and with risk for coronary heart disease and vascular death (36). With reference to epidemiologic data in which the 50th percentile Lp-PLA2 mass cut point of 235 ng·mL−1 is used to identify patients at increased CVD risk (23), the patients with HIV/HAART in the present study were clearly at elevated risk. Their baseline Lp-PLA2 mass was 388.5 ± 12.3 ng·mL−1 (mean ± SEM), and fewer than 7% had an Lp-PLA2 mass <235 ng·mL−1. These data underscore the clinical relevance of the ability of lifestyle modification to reduce Lp-PLA2 mass in patients with HIV/HAART with dyslipidemia.
The relevance of circulating RANTES levels to atherosclerosis and cardiovascular risk remains uncertain, in part because of wide ranges in its population levels, variability depending on whether the plasma samples are depleted of platelets, and ethnicity. Nomura et al. (28) found elevated levels of RANTES in patients with acute coronary syndromes, whereas Cavusoglu et al. (8) found that low levels of RANTES predicted adverse outcomes in patients with chronic CAD, and a recent large cross-sectional study of stored samples noted no association between CAD and RANTES levels (15). There may be a closer association between circulating RANTES levels and plaque characteristics. Virani et al. (38) noted positive associations between RANTES and carotid wall thickness and lipid-core volume, suggesting that higher RANTES levels may be associated with extensive carotid atherosclerosis and plaques at high risk of rupturing. As in the present study, RANTES levels have been noted previously to be elevated in HIV-infected patients; however, we found no relationship between RANTES levels and lipid/lipoprotein measures, and the treatments used in the present study did not reduce RANTES levels.
A limitation of the present study is that we measured only Lp-PLA2 mass but not Lp-PLA2 activity. However, Lp-PLA2 mass and activity are known to be strongly correlated with each other (r = 0.51; CI = 0.47–0.56) (36). In addition, we did not use platelet-free plasma for analyses of RANTES, which may pose a limitation in the comparison of RANTES levels with those in other studies. Given that we did not observe significant differences between study groups before or after treatment, this would not affect the outcomes of the study. It is also possible that the study was not adequately powered to observe an effect of the interventions on RANTES levels; the variance in mean RANTES level was wide in this cohort, and a larger sample size might be required to observe such an effect. Despite these limitations, the results of this randomized controlled trial in patients with well-characterized HIV with dyslipidemia provide strong evidence for the effectiveness of intensive lifestyle modification in reducing the levels of Lp-PLA2.
The metabolic abnormalities in patients with HIV on HAART are complex and heterogeneous, characterized by varying degrees of centripetal fat distribution, dyslipidemia, insulin resistance, and increased risk for CVD (2,29). The complexity of the condition is reflected in the discordant lipid-lowering effects of the combination of fenofibrate and niacin (with D/E), which did not decrease Lp-PLA2 mass while it achieved significant decrease in triglycerides (−47%), non-HDL-C (−19%), and TC/HDL ratio (−29%) and increase in HDL-C concentration (+30%) when compared with the usual care group. There is no simple explanation for these discordant effects, which may be due in part to interactions between the lipid-lowering drugs and HAART (5,9) and multiple pathogenic mechanisms acting in concert that are responsible for the marked and sustained postprandial hyperlipidemia observed in this population (33).
In summary, this randomized controlled study is the first to demonstrate that when compared with standard medical care, an intensive D/E program in patients with HIV/HAART-associated dyslipidemia can reduce plasma Lp-PLA2 mass. Further research is warranted to understand the discordance between Lp-PLA2 mass and lipid and lipoprotein metabolism in this condition.
This study was supported by the National Institutes of Health (NIH) (grant nos. RO1 HL73696 to A.B., RO1 HL30914 and HL56865 to H.J.P., and T32 HL07812 to J.S.W.), Baylor College of Medicine General Clinical Research Center (grant no. NIH R-0188), and the Diabetes and Endocrinology Research Center (grant no. P30DK079638) at Baylor College of Medicine. The ClinicalTrials.gov ID no. of the Heart Positive Study is NCT00246376. All study drugs, including matching placebos, were provided at no cost by Abbott Laboratories at the request of the investigators. Abbott had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
The authors thank Dinakar Iyer, Ph.D., and Joe Raya for technical assistance; Resa Labbe-Morris, R.N., and the nursing staff of the Baylor General Clinical Research Center; and Varsha Patel, R.Ph., and the staff of The Methodist Hospital Investigational Pharmacy.
C.M.B. has received the following from Abbott: grant/research support (significant, >$10,000), consultant fees (modest, <$10,000), and honoraria (modest, <$10,000). None of the other authors have a potential conflict of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
1. Anogeianaki A, Angelucci D, Cianchetti E, et al. Atherosclerosis: a classic inflammatory disease. Int J Immunopathol Pharmacol
. 2011; 24 (4): 817–25.
2. Badiou S, Merle De Boever C, Dupuy AM, Baillat V, Cristol JP, Reynes J. Decrease in LDL size in HIV-positive adults before and after lopinavir/ritonavir-containing regimen: an index of atherogenicity? Atherosclerosis
. 2003; 168 (1): 107–13.
3. Balasubramanyam A, Coraza I, Smith EO, et al. Combination of niacin
with lifestyle changes improves dyslipidemia
and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of “heart positive,” a randomized, controlled trial. J Clin Endocrinol Metab
. 2011; 96 (7): 2236–47.
4. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation
. 2001; 104 (25): 3046–51.
5. Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis
. 2000; 30 (2 Suppl): S135–42.
6. Caslake MJ, Packard CJ. Lipoprotein-associated phospholipase A2 as a biomarker for coronary disease and stroke. Nat Clin Pract Cardiovasc Med
. 2005; 2 (10): 529–35.
7. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA
. 1986; 256 (20): 2835–8.
8. Cavusoglu E, Eng C, Chopra V, Clark LT, Pinsky DJ, Marmur JD. Low plasma RANTES
levels are an independent predictor of cardiac mortality in patients referred for coronary angiography. Arterioscler Thromb Vasc Biol
. 2007; 27 (4): 929–35.
9. Dube MP, Stein JH, Aberg JA, et al.Adult ACTGCS, and America HIVMAotIDSo. Guidelines for the evaluation and management of dyslipidemia
in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis
. 2003; 37 (5): 613–27.
10. Galli M, Ridolfo AL, Gervasoni C. Cardiovascular disease risk factors in HIV-infected patients in the HAART era. Ann N Y Acad Sci
. 2001; 946: 200–13.
11. Garcia JJ, Bote E, Hinchado MD, Ortega E. A single session of intense exercise improves the inflammatory response in healthy sedentary women. J Physiol Biochem
. 2011; 67 (1): 87–94.
12. Gaubatz JW, Gillard BK, Massey JB, et al. Dynamics of dense electronegative low density lipoproteins and their preferential association with lipoprotein phospholipase A(2). J Lipid Res
. 2007; 48 (2): 348–57.
13. Grinspoon S. Insulin resistance in the HIV-lipodystrophy syndrome. Trends Endocrinol Metab
. 2001; 12 (9): 413–9.
14. Group HPSC. Lipoprotein-associated phospholipase A(2) activity and mass in relation to vascular disease and nonvascular mortality. J Intern Med
. 2010; 268 (4): 348–58.
15. Herder C, Peeters W, Illig T, et al. RANTES
/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PLoS One
. 2011; 6 (12): e25734.
16. Hulgan T, Sterling TR, Daugherty J, Arbogast PG, Raffanti S, Ray W. Prescribing of contraindicated protease inhibitor and statin combinations among HIV-infected persons. J Acquir Immune Defic Syndr
. 2005; 38 (3): 277–82.
17. Hurt-Camejo E, Camejo G, Peilot H, Oorni K, Kovanen P. Phospholipase A(2) in vascular disease. Circ Res
. 2001; 89 (4): 298–304.
18. James RW. Diabetes and other coronary heart disease risk equivalents. Curr Opin Lipidol
. 2001; 12 (4): 425–31.
19. Jones KL, Maguire JJ, Davenport AP. Chemokine receptor CCR5: from AIDS to atherosclerosis. Br J Pharmacol
. 2011; 162 (7): 1453–69.
20. Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M. Short-term exercise training improves body composition and hyperlipidaemia in HIV-positive individuals with lipodystrophy. AIDS
. 2001; 15 (15): 2049–51.
21. Khovidhunkit W, Memon RA, Shigenaga JK, et al. Plasma platelet-activating factor acetylhydrolase
activity in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Metabolism
. 1999; 48 (12): 1524–31.
22. Kuvin JT, Dave DM, Sliney KA, et al. Effects of extended-release niacin
on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol
. 2006; 98 (6): 743–5.
23. Lanman RB, Wolfert RL, Fleming JK, et al. Lipoprotein-associated phospholipase A2: review and recommendation of a clinical cut point for adults. Prev Cardiol
. 2006; 9 (3): 138–43.
24. Lazzaretti RK, Kuhmmer R, Sprinz E, Polanczyk CA, Ribeiro JP. Dietary intervention prevents dyslipidemia
associated with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected individuals: a randomized trial. J Am Coll Cardiol
. 2012; 59 (11): 979–88.
25. Lozano JM, Kindelan JM, Cabello A, Gonzalez R, Solana R, Pena J. IL-2 increased RANTES
production and CD25 expression in cultured PBMCs only from antiretroviral treated HIV-1+ patients with detectable viral loads. Int Immunopharmacol
. 2006; 6 (6): 1034–8.
26. Macphee CH, Nelson JJ, Zalewski A. Lipoprotein-associated phospholipase A2 as a target of therapy. Curr Opin Lipidol
. 2005; 16 (4): 442–6.
27. Mooser V, Carr A. Antiretroviral therapy-associated hyperlipidaemia in HIV disease. Curr Opin Lipidol
. 2001; 12 (3): 313–9.
28. Nomura S, Uehata S, Saito S, Osumi K, Ozeki Y, Kimura Y. Enzyme immunoassay detection of platelet-derived microparticles and RANTES
in acute coronary syndrome. Thromb Haemost
. 2003; 89 (3): 506–12.
29. Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery disease and human immunodeficiency virus infection. Clin Infect Dis
. 2000; 31 (3): 787–97.
30. Perry SW, Hamilton JA, Tjoelker LW, et al. Platelet-activating factor receptor activation. An initiator step in HIV-1 neuropathogenesis. J Biol Chem
. 1998; 273 (28): 17660–4.
31. Polo S, Veglia F, Malnati MS, et al. Longitudinal analysis of serum chemokine levels in the course of HIV-1 infection. AIDS
. 1999; 13 (4): 447–54.
32. Rosenson RS. Fenofibrate
reduces lipoprotein associated phospholipase A2 mass and oxidative lipids in hypertriglyceridemic subjects with the metabolic syndrome. Am Heart J
. 2008; 155 (3): 499.e9–16.
33. Sekhar RV, Jahoor F, Pownall HJ, et al. Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome. Am J Clin Nutr
. 2005; 81 (6): 1405–10.
34. Tellis CC, Tselepis AD. The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma. Biochim Biophys Acta
. 2009; 1791 (5): 327–38.
35. Terry L, Sprinz E, Stein R, Medeiros NB, Oliveira J, Ribeiro JP. Exercise training in HIV-1-infected individuals with dyslipidemia
and lipodystrophy. Med Sci Sports Exerc
. 2006; 38 (3): 411–7.
36. Thompson A, Gao P, Orfei L, et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet
. 2010; 375 (9725): 1536–44.
37. Tsoupras AB, Chini M, Tsogas N, et al. Anti-platelet-activating factor effects of highly active antiretroviral therapy (HAART): a new insight in the drug therapy of HIV infection? AIDS Res Hum Retroviruses
. 2008; 24 (8): 1079–86.
38. Virani SS, Nambi V, Hoogeveen R, et al. Relationship between circulating levels of RANTES
(regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. Eur Heart J
. 2011; 32 (4): 459–68.
39. Wilensky RL, Macphee CH. Lipoprotein-associated phospholipase A(2) and atherosclerosis. Curr Opin Lipidol
. 2009; 20 (5): 415–20.
40. Wong CK, White HD. Effects of dietary factors on lipoprotein-associated phospholipase A(2) (Lp-PLA (2)). Curr Atheroscler Rep
. 2011; 13 (6): 461–6.
41. Ye P, Kazanjian P, Kunkel SL, Kirschner DE. Lack of good correlation of serum CC-chemokine levels with human immunodeficiency virus-1 disease stage and response to treatment. J Lab Clin Med
. 2004; 143 (5): 310–9.