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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2012)

Children with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) are at risk for advanced atherosclerosis; however, they are often undiagnosed and undertreated. To examine the association among atherogenic lipids, inflammation, and endothelial dysfunction in children FH and FCH, a descriptive cross-sectional study was conducted. Dependent variables included endothelial function, as measured by brachial flow-mediated dilation, and inflammation, as measured by hsCRP. Independent variables included lipid profile and non-lipid variables. Lipid profile was measured by total cholesterol, triglycerides, LDL-C, HDL-C and nonHDL-C. Non-lipid predictors were measured by gender, age, BMI, blood pressure, and fasting blood glucose. Person Correlation Coefficients were calculated to evaluate the association between dependent variables and independent variables. Multiple linear regressions were modeled to identify predictors for endothelial function and inflammation.

Among 64 children with familial hyperlipidemia, the multiple regression models identified age as a significant independent variable for decreased brachial FMD. Increased fasting blood glucose and lower nonHDL-C were identified as significant independent variables for increased hsCRP. Age was a significant predictor, contributing 7% variance in brachial flow-mediated dilation (R² = 0.074, F = 4.978, p = 0.029). Beta coefficient indicated higher age was associated with higher brachial flow-mediated dilation. Individually, fasting blood glucose accounted for 14% variance and nonHDL-C accounted for 7% variance in hsCRP (R² = 0.232, F = 9.205, p = 0.000). Beta coefficients indicated lower fasting blood glucose and lower nonHDL-C were associated with higher LoghsCRP. Increased fasting blood sugar was associated with higher hsCRP and lower brachial flow-mediated dilation.

Although controversial to traditional findings, our data sheds a light on the complex impact of atherogenic lipids and inflammation on endothelial function in children. The important role of fasting sugar manifesting inflammation combined with the variability of total cholesterol, LDL-C and nonHDL-C in FH and FCH children aged 7 to 19 years old implicate a need for further investigation.

    Cover page: Endothelial Function in Familial Hyperlipidemia Children
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2021)
    Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie-2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross-sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow-mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (P<0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels (P<0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels (P<0.01) and 22% lower ANG2 levels (P<0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, P<0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (-12.35 cm/s, P=0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow-mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie-2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV-mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.
      Cover page: Effect of HIV‐1 Infection on Angiopoietin 1 and 2 Levels and Measures of Microvascular and Macrovascular Endothelial Dysfunction
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2014)

      Background

      Individuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B-cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B-cells, is an effective therapy for RA. The purpose of this study was to determine whether B-cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow-mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients.

      Methods and results

      RA patients received a single course of rituximab (1000 mg IV infusion at baseline and on day 15). FMD, reactive hyperemia, inflammatory markers, and clinical assessments were performed at baseline, week 12, and week 24. Twenty patients (95% female, median age 54 years) completed the study. Following treatment, FMD improved from a baseline of 4.5±0.4% to 6.4±0.6% at 12 weeks (mean±SE; P<0.0001), followed by a decline at week 24; a similar pattern was observed for hyperemic velocity. Significant decreases in RA disease scores, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, and circulating CD19+ B-cells were sustained through week 24. Cholesterol and triglycerides became significantly although modestly elevated during the study.

      Conclusions

      Depletion of B-cells with rituximab improved macrovascular and microvascular endothelial function and reduced systemic inflammation, despite modest elevation in lipids. Given these results, rituximab should be evaluated in the future for its possible role in reducing excess cardiovascular risk in RA.

      Clinical trial registration

      URL http://ClinicalTrials.gov. Unique identifier: NCT00844714.
        Cover page: Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2012)

        Objectives

        To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals.

        Design

        : Randomized, double-blinded, placebo-controlled study.

        Methods

        Fifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.

        Results

        At baseline, the median CD4 T-cell count was 498 cells/mm, nadir CD4 T-cell count was 191 cells/mm, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4 T-cell count and current abacavir use were associated with lower hyperemic velocity.

        Conclusions

        The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).
          Cover page: A Randomized Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection
          • Article
          • Peer Reviewed
          California HIV/AIDS Research Program Funded Publications (2014)

          The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts <350 cells/mm3 and plasma HIV RNA levels <40 copies/ml on antiretroviral therapy (ART) to add mesalamine vs. placebo to their existing regimen for 12 weeks followed by a 12 week crossover to the other arm. Compared to placebo-treated subjects, mesalamine-treated subjects did not experience any significant change in the percent CD38+HLA-DR+ peripheral blood CD4+ and CD8+ T cells at week 12 (P = 0.38 and P = 0.63, respectively), or in the CD4+ T cell count at week 12 (P = 0.83). The percent CD38+HLA-DR+ CD4+ and CD8+ T cells also did not change significantly in rectal tissue (P = 0.86, P = 0.84, respectively). During the period of mesalamine administration, plasma sCD14, IL-6, D-dimer, and kynurenine to tryptophan ratio were not changed significantly at week 12 and were similarly unchanged at week 24. This study suggests that, at least under the conditions studied, the persistent immune activation associated with HIV infection is not impacted by the anti-inflammatory effects of mesalamine.

          ClinicalTrials.gov NCT01090102.

            Cover page: The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial.
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