Increased risk of venous thromboembolism in patients with granulomatosis with polyangiitis: A population-based study.

We assessed the risk and time trends of venous thromboembolism (VTE) including pulmonary embolism (PE) and deep venous thrombosis (DVT) in new granulomatosis with polyangiitis (GPA) cases compared to the general population. Using a population-level database from the entire province of British Columbia, Canada, we conducted a matched cohort study of all patients with incident GPA with up to ten age-, sex-, and entry time-matched individuals randomly selected from the general population. We compared incidence rates of VTE, PE, and DVT between the two groups, and calculated hazard ratios (HR), adjusting for relevant confounders. Among 549 individuals with incident GPA (57.6% female, mean age 55.4 years), the incidence rates for VTE, PE, and DVT were 7.22, 2.73, and 6.32 per 1,000 person-years, respectively; the corresponding rates were 1.36, 0.74, and 0.81 per 1,000 person-years among the 5,490 non-GPA individuals. Compared with the non-GPA cohort, the fully adjusted HRs among GPA patients were 2.90 (95% CI, 1.10-7.64), 4.70 (95% CI, 1.74-12.69), and 1.66 (95% CI, 0.52-5.27) for VTE, PE, and DVT, respectively. The risks of VTE, PE, and DVT were highest during the first year after GPA diagnosis with HR (95% CI) of 11.04 (1.37-88.72), 26.94 (4.56-159.24), and 2.68 (0.23-31.21), respectively. GPA patients are at significantly increased risk of PE, but not DVT. Monitoring for these complications is particularly warranted in this patient population, especially early after diagnosis.

Premature Spinal Bone Loss in Women Living with HIV is Associated with Shorter Leukocyte Telomere Length.

With advances in combination antiretroviral therapy (cART), people living with HIV are now surviving to experience aging. Evidence suggests that individuals living with HIV are at greater risk for low bone mineral density (BMD), osteoporosis, and fractures. Better understanding of the pathophysiology of bone health in women living with HIV (WLWH) is important for treatment strategies. The goal of this study was to explore new biological factors linked to low BMD in WLWH. Standardized BMD measures of WLWH were compared to reference values from an unselected population of women from the same geographical region of the same age range. Linear regression analysis was used to assess relationships among health-related characteristics, cellular aging (measured by leukocyte telomere length; LTL), cART, and BMD of WLWH. WLWH (n = 73; mean age 43 ± 9 years) had lower BMD Z-scores at the lumbar spine (LS) (mean difference = -0.39, p < 0.001) and total hip (TH) (-0.29, p = 0.012) relative to controls (n = 290). WLWH between 50 and 60 years (n = 17) had lower Z-scores at the LS (p = 0.008) and TH (p = 0.027) compared to controls (n = 167). Among WLWH, LS BMD was significantly associated with LTL (R² = 0.09, p = 0.009) and BMI (R² = 0.06, p = 0.042). Spinal BMD was adversely affected in WLWH. Reduction of LTL was strongly associated with lower BMD and may relate to its pathophysiology and premature aging in WLWH.

Risk of Myocardial Infarction and Stroke in Patients With Granulomatosis With Polyangiitis (Wegener's): A Population-Based Study.

OBJECTIVE: To assess the relative risk of myocardial infarction (MI) and ischemic stroke in patients with newly diagnosed granulomatosis with polyangiitis (Wegener's) (GPA) compared with that in controls from the general population. METHODS: Using a population-based database from the province of British Columbia, Canada, we conducted a matched cohort study in which each patient with incident GPA was matched for age, sex, and entry time with up to 10 individuals from the general population. Patients in the GPA cohort were required to have received at least 1 prescription for oral glucocorticoids, methotrexate, cyclophosphamide, leflunomide, azathioprine, cyclosporine, mycophenolate mofetil, or rituximab within 1 month before or 6 months after the index date. We compared the incidence rates of MI and ischemic stroke between the 2 groups and calculated hazard ratios (HRs), adjusting for confounders. RESULTS: Among 504 patients with incident GPA (53.4% female, mean age 57.4 years), MI developed in 23 patients, and ischemic stroke developed in 18 patients (incidence rates of 11.7 per 1,000 person-years and 8.9 per 1,000 person-years, respectively). The incidence rates among 5,222 subjects without GPA were 5.2 per 1,000 person-years and 4.3 per 1,000 person-years, respectively. The multivariable HRs among GPA patients were 1.86 (95% confidence interval [95% CI] 1.05-3.31) for MI and 1.50 (95% CI 0.78-2.89) for ischemic stroke. The age-, sex-, and entry time-matched HR for cardiovascular disease (composite outcome of MI or stroke) was highest during the first year after GPA diagnosis (HR 2.88, 95% CI 1.37-6.08). CONCLUSION: Patients with GPA have a significantly increased risk of MI and a non-statistically significant trend toward an increased risk of ischemic stroke. Monitoring for this complication and vigilance in modifying risk factors are particularly warranted in this patient population, especially early after the diagnosis of GPA.

Endocrine abnormalities in HIV-infected women are associated with peak viral load - the Children and Women: AntiRetrovirals and Markers of Aging (CARMA) Cohort.

OBJECTIVES: To investigate the prevalence of endocrine disturbances in a group of HIV-positive (HIV+) women and to identify factors affecting presence of these disorders. To examine specifically whether cellular ageing, as measured by leukocyte telomere length (LTL), is correlated with the presence of endocrine disturbance. DESIGN: A cross-sectional retrospective substudy of an ongoing prospective cohort study. PATIENTS: Adult HIV+ (≥19 years) women enrolled in the CARMA (Children and Women: AntiRetrovirals and Markers of Aging) cohort study (N = 192). Prevalences of T2DM, glucose intolerance, dyslipidaemia, thyroid disorders, adrenal insufficiency, hypogonadism, primary ovarian insufficiency (POI), demographics, HIV and hepatitis C virus (HCV) infection status, baseline LTL, combined antiRetroviral therapy (cART) and substance exposures were collected. Statistical analysis included univariable followed by multivariable Poisson regression and step-wise reduction to refine the multivariable model. RESULTS: Prevalence of any endocrine abnormality was 58% (dyslipidaemia 43%, glucose intolerance/T2DM 13%, thyroid disorders 15%). In multivariable analysis, age was associated with number and type (any, glucose, lipid) of abnormality, while increasing body mass index (BMI) was associated with number of diagnoses and with glucose metabolism disorders. Interestingly, peak HIV pVL ≥100 000 copies/ml was associated with any abnormality, total number of disorders and presence of a thyroid disorder, while any disorder, glucose abnormalities and dyslipidaemia were negatively associated with alcohol use. LTL was not associated with number or type of endocrine abnormalities in this study. CONCLUSION: Further studies examining the relationship between duration and extent of exposure to HIV viraemia in relation to developing abnormal endocrine function are warranted.

Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition.

Vascular smooth muscle cells (VSMCs) undergo transcriptionally regulated reversible differentiation in growing and injured blood vessels. This dedifferentiation also contributes to VSMC hyperplasia after vascular injury, including that caused by angioplasty and stenting. Stents provide mechanical support and can contain and release rapamycin, an inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1). Rapamycin suppresses VSMC hyperplasia and promotes VSMC differentiation. We report that rapamycin-induced differentiation of VSMCs required the transcription factor GATA-6. Inhibition of mTORC1 stabilized GATA-6 and promoted the nuclear accumulation of GATA-6, its binding to DNA, its transactivation of promoters encoding contractile proteins, and its inhibition of proliferation. These effects were mediated by phosphorylation of GATA-6 at Ser(290), potentially by Akt2, a kinase that is activated in VSMCs when mTORC1 is inhibited. Rapamycin induced phosphorylation of GATA-6 in wild-type mice, but not in Akt2(-/-) mice. Intimal hyperplasia after arterial injury was greater in Akt2(-/-) mice than in wild-type mice, and the exacerbated response in Akt2(-/-) mice was rescued to a greater extent by local overexpression of the wild-type or phosphomimetic (S290D) mutant GATA-6 than by that of the phosphorylation-deficient (S290A) mutant. Our data indicated that GATA-6 and Akt2 are involved in the mTORC1-mediated regulation of VSMC proliferation and differentiation. Identifying the downstream transcriptional targets of mTORC1 may provide cell type-specific drug targets to combat cardiovascular diseases associated with excessive proliferation of VSMCs.