Conflicting effects of atazanavir therapy on atherosclerotic risk factors in stable HIV patients: A randomized trial of regimen switch to atazanavir.

Bilirubin acts as a potent endogenous antioxidant, with higher concentrations associated with lower rates of CVD; the antiretroviral drug atazanavir (ATV) increases bilirubin levels but may also increase von Willebrand factor levels. We tested the hypothesis that increasing endogenous bilirubin using ATV would improve cardiometabolic risk factors and vascular function in older patients with HIV. Ninety participants were enrolled in two study protocols. In protocol 1, we evaluated markers of inflammation, thrombosis, and conduit artery endothelial function in subjects on non-ATV containing regimens. Participants were randomly assigned to continue baseline treatment or switch to an ATV-based regimen. Measurements were made at baseline and 28 days. In the protocol 2, we enrolled 30 subjects who received atazanavir for more than one year and were compared to the aim 1 protocol subjects at baseline. 60 subjects were enrolled in the first protocol (mean age 53, +/- 6 years), with 31 randomized to ATV and 29 continuing baseline treatment. Atazanavir significantly increased serum total bilirubin levels (p<0.001) and acutely but not chronically plasma total antioxidant capacity (p<0.001). An increase in von Willebrand Factor (p<0.001) and reduction in hs-CRP (p = 0.034) were noted. No changes were seen in either flow-mediated endothelium-dependent or vasodilation. In cross-sectional analysis (second protocol), similar findings were seen in the baseline attributes of non-atazanavir-based and long-term atazanavir users. Increasing serum bilirubin levels with atazanavir in subjects with HIV reduces hs-CRP, temporarily reduces oxidative stress, but increases von Willebrand Factor. Atazanavir does not improve endothelial function of conduit arteries. TRIAL REGISTRATION: ClinicalTrials.gov NCT03019783.

Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity.

Quantification of stable isotope tracers has revealed the dynamic state of living tissues. A new form of imaging mass spectrometry quantifies isotope ratios in domains much smaller than a cubic micron, enabling measurement of cell turnover and metabolism with stable isotope tracers at the single-cell level with a methodology we refer to as multi-isotope imaging mass spectrometry. In a first-in-human study, we utilize stable isotope tracers of DNA synthesis and de novo lipogenesis to prospectively measure cell birth and adipocyte lipid turnover. In a study of healthy adults, we elucidate an age-dependent decline in new adipocyte generation and adipocyte lipid turnover. A linear regression model suggests that the aging effect could be mediated by a decline in insulin-like growth factor-1 (IGF-1). This study therefore establishes a method for measurement of cell turnover and metabolism in humans with subcellular resolution while implicating the growth hormone/IGF-1 axis in adipose tissue aging.

Androgen deprivation therapy reversibly increases endothelium-dependent vasodilation in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is a standard treatment for patients with aggressive prostate cancer. Although ADT improves survival, it increases the risk of diabetes. Emerging evidence suggests that ADT increases adverse cardiovascular events as early as 3 months after initiation in patients with cardiovascular disease, but the mechanism is unknown. We hypothesized that ADT may impair endothelium-dependent vasodilation due to increases in lipids and insulin resistance and may provide a link for heightened cardiovascular risk in this population. METHODS AND RESULTS: We prospectively evaluated conduit artery endothelium-dependent and -independent vasodilation, lipids, and insulin resistance in 16 consecutively treated men (mean age 66 ± 7 years; 25% with diabetes) with prostate cancer before and after 3 months of ADT. High-resolution B-mode ultrasound was used to assess flow-mediated (endothelium-dependent) and nitroglycerine-mediated (endothelium-independent) brachial artery vasodilation. ADT significantly increased insulin resistance, total cholesterol, HDL, and LDL. Endothelium-dependent vasodilation was greater at 3 months than at baseline (10.8% [interquartile range: 7.7% to 14.6%] versus 8.9% [interquartile range: 4.0% to 12.6%], respectively; P=0.046, allometric P=0.037). Nitroglycerine-mediated vasodilation did not change from baseline (P>0.2). The subset of participants on ADT for 6 months returned for reevaluation at 1 year. In this group, endothelium-dependent vasodilation increased from baseline to 3 months and returned to baseline 6 months after ADT withdrawal (9.4% [interquartile range: 6.9% to 10.9%], 11.6% [interquartile range: 7.9% to 15.2%], and 9.0% [interquartile range: 5.1% to 12.5%], respectively; P=0.05). CONCLUSIONS: In contrast to our expectation, ADT improved endothelium-dependent vasodilation and its cessation returned endothelium-dependent vasodilation to baseline. Determining the mechanism of this change requires further investigation.

Distinct effects of losartan and atenolol on vascular stiffness in Marfan syndrome.

We conducted a randomized, double-blind trial of losartan (100 mg QD) versus atenolol (50 mg QD) for 6 months in adults with Marfan syndrome. Carotid-femoral pulse wave velocity (PWV), central augmentation index (AIx), aortic diameter and left ventricular (LV) function were assessed with arterial tonometry and echocardiography. Thirty-four subjects (18 female; median age 35 years, IQR 27, 45) were randomized. Central systolic and diastolic blood pressure decreased comparably with atenolol and losartan (p = 0.64 and 0.31, respectively); heart rate decreased with atenolol (p = 0.02), but not with losartan. PWV decreased in patients treated with atenolol (-1.15 ± 1.68 m/s; p = 0.01), but not in those treated with losartan (-0.22 ± 0.59 m/s; p = 0.15; between-group difference p = 0.04). In contrast, AIx decreased in the losartan group (-9.6 ± 8.6%; p < 0.001) but not in the atenolol group (0.9 ± 6.2%, p = 0.57; between-group difference p < 0.001). There was no significant change in aortic diameters or LV ejection fraction in either treatment group. In adults with Marfan syndrome, 6 months of treatment with atenolol improves PWV, whereas losartan reduces the AIx. By improving vascular stiffness via distinct mechanisms of action, there is physiologic value to considering the use of both medications in individuals with Marfan syndrome.

Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus.

AIMS: Vascular disease is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). We previously demonstrated that patients with T1DM have impaired endothelial function, a forme fruste of atherosclerosis, as a result of increased oxidative stress. Bilirubin has emerged as a potent endogenous antioxidant with higher concentrations associated with lower rates of myocardial infarction and stroke. METHODS: We tested the hypothesis that increasing endogenous bilirubin using atazanavir would improve cardiometabolic risk factors and vascular function in patients with T1DM to determine whether targeting bilirubin may be a novel therapeutic approach to reduce cardiovascular disease risk in this population. In this single-arm, open-label study, we evaluated blood pressure, lipid profile, and conduit artery function in fifteen subjects (mean age 45 ± 9 years) with T1DM following a 4-day treatment with atazanavir. RESULTS: As anticipated, atazanavir significantly increased both serum total bilirubin levels (p < 0.0001) and plasma total antioxidant capacity (p < 0.0001). Reductions in total cholesterol (p = 0.04), LDL cholesterol (p = 0.04), and mean arterial pressure (p = 0.04) were also observed following atazanavir treatment. No changes were seen in either flow-mediated endothelium-dependent (p = 0.92) or nitroglycerine-mediated endothelium-independent (p = 0.68) vasodilation, measured by high-resolution B-mode ultrasonography at baseline and post-treatment. CONCLUSION: Increasing serum bilirubin levels with atazanavir in subjects with T1DM over 4 days favorably reduces LDL and blood pressure but is not associated with improvements in endothelial function of conduit arteries.