Hazard ratio (95% confidence interval) of ischemic stroke by FLI^*.

<p>Hazard ratio (95% confidence interval) of ischemic stroke by FLI^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194153#t002fn001" target="_blank">*</a>}.</p

Decreased Naive and Increased Memory CD4⁺ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis

<div><p>Background</p><p>Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4⁺ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.</p><p>Methods and Findings</p><p>We examined cross-sectional relationships of circulating CD4⁺ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4⁺ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and <i>H. Pylori</i> titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].</p><p>Conclusions</p><p>These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4⁺ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.</p></div

Hazard ratio of ischemic stroke by (A) AST, (B) ALT, and (C) GGT.

<p>Model 1: Cox proportional hazards model adjusted for age, race, and age*race</p> <p>Model 2: Additionally adjusted for the Framingham stroke risk factors</p> <p>Percentile cut-off values (U/L) for 20^th, 40^th, 60^th, 80^th for men: AST (15.4, 18.5, 21.3, 25.5), ALT (12.1, 15.1, 18.9, 24.2), GGT (17.0 21.6, 28.1, 41.8). For women: AST (14.1, 16.4, 19.4, 23.1), ALT (9.3, 12.5, 14.9, 19.2), GGT (12.8, 16.9, 22.6, 31.2).</p

Final regression model for coronary artery calcification.

<p>Backward elimination regression was used to develop multivariate models for coronary artery calcification (CAC) level. CAC was analyzed using the ln-agatston score in individuals with a score >0. Independent variables were divided by their standard deviations (shown in parentheses). The candidate starting variables were: age, gender, race/ethnicity, IL-6, BMI, systolic BP, use of BP lowering medication, smoking status, total-cholesterol, HDL-cholesterol, use of lipid lowering medication, type 2 diabetes status, CMV and <i>H. pylori</i> titers, and CD4⁺ memory cell proportions or, in separate analyses, CD4⁺ naive cell proportions. Only significant variables (p<0.05) were retained in the final model to obtain the model's R². ns: non-significant.</p

Regression models for CD4⁺ naive and memory cell subpopulations.

<p>Backward elimination regression was used to develop multivariate models for CD4⁺ T cell subpopulations. Independent variables were divided by their standard deviations (shown in parentheses). Age, gender, race/ethnicity, seasonality, BMI, IL-6, and CMV and <i>H. pylori</i> titers were included as the candidate starting variables. Only significant variables (p<0.05) were retained in the final models. BMI: Body mass index; CMV: Cytomegalovirus; IL-6: Interleukin-6; ns: non-significant.</p

Characteristics of the MESA sample population being studied.

<p>Data are from MESA exam 4 (2005–2007) unless otherwise noted. *: Data are from MESA baseline (exam 1; 2000–2002). **: Includes all participants with incident cardiovascular events (myocardial infarction, resuscitated cardiac arrest, definite or probable angina, and stroke) from baseline through the start of exam 4. AU: Agatston units; BMI: Body mass index; CAC: Coronary artery calcification; CMV: Cytomegalovirus; CRP: C-reactive protein; CVD: Cardiovascular disease; HSV: Herpes simplex virus; IL-6: Interleukin-6; IMT: Intimal media thickness.</p

Typical flow cytometric data for lymphocyte, CD4⁺ memory, and CD4⁺ naive cell populations.

<p>At least 30,000 lymphocytes were evaluated and were gated based on their forward (FCS; X-axis) and side (SCS; Y-axis) scatter (Panels A&B). Memory and naive cell subpopulations were gated by positive surface staining for CD4 (Y-axis, panels C–F); memory cells were gated by positive surface staining for CD45RO (X-axis, panels C&D); naive cells were gated by positive surface staining for CD45RA (X-axis, panels E&F). Typical data from respective isotype controls (Panels A, C, and E) and fluorescently labeled samples (Panels B, D, and F) are shown.</p

Angiotensin Converting Enzyme Inhibitor and HMG-CoA Reductase Inhibitor as Adjunct Treatment for Persons with HIV Infection: <em>A Feasibility Randomized Trial</em>

<div><h3>Background</h3><p>Treatments that reduce inflammation and cardiovascular disease (CVD) risk among individuals with HIV infection receiving effective antiretroviral therapy (ART) are needed.</p> <h3>Design and Methods</h3><p>We conducted a 2×2 factorial feasibility study of lisinopril (L) (10 mg daily) vs L-placebo in combination with pravastatin (P) (20 mg daily) vs P-placebo among participants receiving ART with undetectable HIV RNA levels, a Framingham 10 year risk score (FRS) ≥3%, and no indication for ACE-I or statin therapy. Tolerability and adherence were evaluated. Longitudinal mixed models assessed changes in blood pressure (BP), blood lipids, and inflammatory biomarkers from baseline through months 1 and 4.</p> <h3>Results</h3><p>Thirty-seven participants were randomized and 34 [lisinopril/pravastatin (n = 9), lisinopril/P-placebo (n = 8), L-placebo/pravastatin (n = 9), L-placebo/P-placebo (n = 8)] attended at least one follow-up visit. Participants were 97% male, 41% white, 67% were current smokers, and 65% were taking a protease inhibitor. Median age was 48 years, CD4 count 483 cells/mm³, FRS 7.79%, total cholesterol 184 mg/dL, and LDL-C 95 mg/dL. There was no treatment difference for pravastatin vs P-placebo in total cholesterol, LDL-C, or any of the inflammatory biomarkers. Participants randomized to lisinopril vs. L-placebo had significant declines in diastolic BP (−3.3 mmHg, p = 0.05), hsCRP (−0.61 µg/mL, p = 0.02) and TNF-α (−0.17 pg/mL, p = 0.04). Participants taking lisinopril vs L-placebo were more likely to report missed doses (88 vs 35%; p = 0.001) and have adherence <90% by pill count (42 vs. 0%; p = 0.02). Few participants from either group reported side effects (n = 3 vs. n = 1).</p> <h3>Conclusions</h3><p>The modest BP changes and decreased adherence with lisinopril and absence of lipid differences with pravastatin suggest future studies of these drug classes should consider a run-in period to assess adherence and use a different statin. Our results also indicate that ACE-I therapy may have anti-inflammatory benefits for ART-treated persons with HIV infection and this should be further evaluated.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00982189?term=NCT00982189&rank=1">NCT00982189</a></p> </div

Toxicity and Adherence During Follow-up.

1<p> <i>P-values from Fisher's exact tests; missed follow-up visit was assigned ‘declined to specify’ for adherence; n = 34 was used for analysis of self-reported side effects and missed doses; pill-count adherence was assessed for sample of n = 25 with data available as indicated.</i></p

Study Design Flow-Diagram.

<p>Study Design Flow-Diagram.</p