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1.  MEAN PLATELET VOLUME IS DECREASED IN HIV INFECTED WOMEN 
HIV medicine  2013;14(9):549-555.
Objectives
HIV infection is associated with higher than expected cardiovascular event rates and lowered platelet counts. These conditions are associated with an elevation of mean platelet volume (MPV). The present study compares MPV in HIV-infected and uninfected women and identifies factors influencing MPV values in HIV-infected women.
Methods
A total of 234 HIV-infected and 134 HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) had MPV values obtained. HIV-infected women were older, more likely to have diabetes, and have higher triglyceride levels than HIV-uninfected women.
Results
The mean platelet count was lower in HIV infected vs. uninfected women (249/µl 95% CI 238, 259 vs. 276/µl 95% CI 265, 287, p<0.01). Adjusted mean MPV values were lower in the HIV- infected than in the uninfected group (8.66 fl 95% CI 8.52, 8.79 vs. 9.05 fl 95% CI 8.87, 9.24). In multiple regression analysis after adjusting for other covariates, MPV was positively associated with platelet count, and negatively with HIV infection (model R2=0.20 p<0.01). In multiple regression analysis confined to HIV-infected women, a lower MPV was independently associated with history of AIDS defining illness (R2=0.28 p=0.03), but not with CD4 nadir count or HAART use.
Conclusions
HIV-infected women have lower MPV values than-uninfected women suggesting impaired production rather than increased destruction. Higher than expected cardiovascular event rates, cannot be attributed to greater platelet reactivity as measured by MPV.
doi:10.1111/hiv.12048
PMCID: PMC3775876  PMID: 23738819
HIV; mean platelet volume; WIHS
3.  Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV Study 
AIDS (London, England)  2013;27(9):1516-1519.
Summary
Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.
doi:10.1097/QAD.0b013e32835fd8a9
PMCID: PMC3909663  PMID: 23435295
lipids; HAART; HIV infection; inflammation
4.  Natural Progression of Low-Gradient Severe Aortic Stenosis with Preserved Ejection Fraction 
Texas Heart Institute Journal  2014;41(3):273-279.
Because the natural progression of low-gradient aortic stenosis (LGAS) has not been well defined, we performed a retrospective study of 116 consecutive patients with aortic stenosis who had undergone follow-up echocardiography at a median interval of 698 days (range, 371–1,020 d). All patients had preserved left ventricular ejection fraction (>0.50) during and after follow-up.
At baseline, patients were classified by aortic valve area (AVA) as having mild stenosis (≥1.5 cm2), moderate stenosis (≥1 to <1.5 cm2), or severe stenosis (<1 cm2). Severe aortic stenosis was further classified by mean gradient (LGAS, mean <40 mmHg; high-gradient aortic stenosis [HGAS], mean ≥40 mmHg). We compared baseline and follow-up values among 4 groups: patients with mild stenosis, moderate stenosis, LGAS, and HGAS.
At baseline, 30 patients had mild stenosis, 54 had moderate stenosis, 24 had LGAS, and 8 had HGAS. Compared with the moderate group, the LGAS group had lower AVA but similar mean gradient. Yet the actuarial curves for progressing to HGAS were significantly different: 25% of patients in LGAS reached HGAS status significantly earlier than did 25% of patients in the moderate-AS group (713 vs 881 d; P=0.035).
Because LGAS has a high propensity to progress to HGAS, we propose that low-gradient aortic stenosis patients be closely monitored as a distinct subgroup that warrants more frequent echocardiographic follow-up.
doi:10.14503/THIJ-13-3167
PMCID: PMC4060332  PMID: 24955041
Aortic valve stenosis; blood flow velocity; calcinosis/complications; disease progression; echocardiography; forecasting; prognosis; retrospective studies; risk assessment; stroke volume; time factors; ventricular function, left
5.  Biomarkers and Electrocardiographic Evidence of Myocardial Ischemia in Patients With Human Immunodeficiency Virus Infection 
The American journal of cardiology  2012;111(5):760-764.
We assessed the relation of inflammatory and coagulation biomarkers with electrocardiographic (ECG) evidence of myocardial ischemia. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at study entry for 3,085 human immunodeficiency virus-infected participants (mean age 44 years; 26.4% women; 24.6% black) in the Strategies for Management of Antiretroviral Therapy trial. Logistic regression models were used to examine the associations of these biomarkers with prevalent and incident myocardial ischemia. The latter analyses were performed for 1,411 participants who were randomly assigned to receive continuous antiretroviral therapy during follow-up to suppress the human immunodeficiency virus viral load and had ≥1 ECG reading during the follow-up period. The median hsCRP, IL-6, and D-dimer level was 1.65 µg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 µg/ml (interquartile range 0.11 to 0.32), respectively. At baseline, the prevalence of major or minor Q-QS or ST-T ECG abnormalities was 18.6%. The biomarker levels were associated with prevalent major or minor ischemic abnormalities on the univariate analyses; however, adjustment for traditional risk factors attenuated these associations. The adjusted odds ratio for major or minor ischemic abnormalities and 95% confidence intervals for the greatest versus lowest quartiles was 1.3 (95% confidence interval 0.9 to 1.7) for hsCRP, 1.0 (95% confidence interval 0.7 to 1.3) for IL-6, and 1.1 (95% confidence interval 0.9 to 1.5) for D-dimer. During a median follow-up of 2.3 years, new definite or probable ischemic ECG abnormalities developed in 11.7% of participants receiving continuous antiretroviral therapy. Biomarker levels were not associated with incident abnormalities on unadjusted or adjusted analyses. In conclusion, higher levels of hsCRP, IL-6, and D-dimer were not associated with ischemic ECG abnormalities. Elevated biomarker levels and ECG abnormalities indicating myocardial ischemia might reflect different risk pathways for cardiovascular disease.
doi:10.1016/j.amjcard.2012.11.032
PMCID: PMC3619189  PMID: 23276469
6.  Association of subclinical atherosclerosis with lipid levels amongst antiretroviral-treated and untreated HIV-infected women in the Women’s Interagency HIV Study 
Atherosclerosis  2012;225(2):408-411.
Objective
We examined serum lipids in association with carotid artery intima-media thickness (CIMT) in HIV-infected and HIV-uninfected women.
Methods
In 2003–4, among 1827 Women’s Interagency HIV Study participants, we measured CIMT and lipids (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], total cholesterol [TC], non-HDL-c). A subset of 520 treated HIV-infected women had pre-1997 lipid measures. We used multivariable linear regression to examine associations between lipids and CIMT.
Results
In HIV-uninfected women, higher TC, LDL-c and non-HDL-c were associated with increased CIMT. Among HIV-infected women, associations of lipids with CIMT were observed in treated but not untreated women. Among the HIV-infected women treated in 2003–4, CIMT was associated both with lipids measured a decade earlier in infection, and with late lipid measurements.
Conclusion
Among HIV-infected women, hyperlipidemia is most strongly associated with subclinical atherosclerosis in treated women. Among treated women, the association appeared strongest early in the disease course.
doi:10.1016/j.atherosclerosis.2012.09.035
PMCID: PMC3696584  PMID: 23089369
cardiovascular diseases; carotid arteries; HAART; HIV; lipids
7.  Dysregulation of ubiquitin-proteasome pathway and apolipoprotein A metabolism in sickle cell disease–related pulmonary arterial hypertension 
Pulmonary Circulation  2013;3(4):851-855.
Pulmonary arterial hypertension (PAH) is a major complication of sickle cell disease (SCD). Low levels of apolipoprotein A1 (Apo-A1) have been implicated in the development of PAH in SCD. We speculate that lower levels of Apo-A1 are related to dysregulation of the ubiquitin-proteasome pathway (UPP). Of 36 recruited patients with SCD, 14 were found to have PAH on the basis of right heart catheterization. Levels of Apo-A1 and Apo-B, polyubiquitin, total protease, and specific and normalized activity of chymotrypsin-like, trypsin-like, and caspase-like proteases in plasma were measured. Levels of Apo-A1 were found to be lower and polyubiquitin levels were found to be significantly higher in the PAH group () in SCD. Apo-A levels were inversely correlated with polyubiquitin levels (, ). These results indicate that lower levels of Apo-A1 in SCD patients with PAH are likely related to enhance degradation by UPP, potentially contributing to pulmonary vascular pathology. These findings may provide significant insight in identifying suitable therapeutic targets in these patients.
doi:10.1086/674763
PMCID: PMC4070832  PMID: 25006400
pulmonary arterial hypertension (PAH); sickle cell disease (SCD); ubiquitin-proteasome pathway (UPP); apolipoprotein A (Apo-A)
8.  Resolution of ischemia with β-blocker in a patient with anomalous right coronary artery 
BMJ Case Reports  2011;2011:bcr0420114164.
Anomalous origin of right coronary artery (RCA) has been associated with angina, myocardial infarction and sudden death. Often these patients are referred for surgery. However, long-term β-blocker therapy instead of surgery has been used in some cases with success. The authors report a case of anomalous RCA where resolution of ischemia with β-blocker was objectively demonstrated on serial stress testing.
doi:10.1136/bcr.04.2011.4164
PMCID: PMC3207731  PMID: 22675030
9.  Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment 
Background
Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly-active antiretroviral therapy (HAART).
Methods
In the Women's Interagency HIV Study (WIHS), 127 HIV-infected women studied pre- and post-HAART were matched to HIV-uninfected controls. Six semi-annual measurements of soluble CD14, tumor necrosis factor (TNF)-alpha, soluble interleukin (IL)-2 receptor, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness (CIMT) was measured by B-mode ultrasound.
Results
Relative to HIV-uninfected controls, HAART-naïve HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P<0.0001), TNF-alpha (6.3 vs 3.4 pg/mL, P<0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P<0.0001), IL-10 (3.3 vs 1.9 pg/mL, P<0.0001), MCP-1 (190 vs 163 pg/mL, P<0.0001) and D-dimer (0.43 vs 0.31 µg/mL, P<0.01). Elevated biomarker levels declined after HAART. While most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-alpha levels remained elevated compared to HIV-uninfected women (+0.8 pg/mL, P=0.0002). Higher post-HAART levels of soluble IL-2 receptor (P=0.02), IL-6 (P=0.05), and D-dimer (P=0.03) were associated with increased CIMT.
Conclusions
Untreated HIV infection is associated with abnormal hemostasis (e.g., D-dimer), and pro-atherogenic (e.g., TNF-alpha) and anti-atherogenic (e.g., IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.
doi:10.1097/QAI.0b013e31825b03be
PMCID: PMC3400505  PMID: 22592585
antiretroviral therapy; cardiovascular diseases; cytokines; hemostasis; HIV; inflammation
10.  CHRONIC DEPRESSIVE SYMPTOMS AND FRAMINGHAM CORONARY RISK IN HIV- INFECTED AND UNINFECTED WOMEN 
AIDS Care  2011;24(3):394-403.
Depression is common in people with cardiovascular diseases (CVD) and those with HIV, and is a risk factor for CVD-related mortality. However, little is known about whether HIV influences the relationship between depression and cardiovascular risk. 526 HIV-infected and 132 uninfected women from the Women’s Interagency HIV Study were included in an analysis of women who completed twice-yearly study visits over 9.5 years. CVD risk was calculated at baseline and approximately 9.5 years later using the Framingham Risk Score (FRS). Chronic depressive symptoms were defined as Center for Epidemiologic Studies Depression Scale scores of 16 or greater at ≥75% of study visits. Over the follow-up period, 22.8% of HIV-infected women and 15.9% of HIV-uninfected women had chronic depressive symptoms (p=0.08). Baseline FRS were similar between HIV infected and uninfected women (M=−5.70±SE=0.30 vs. M=−6.90± SE=0.60, p=0.07) as was follow-up FRS (M=0.82±SE=0.30 vs. M=−0.44± SE=0.73, p=0.11). Among HIV-infected and uninfected women, together, follow-up FRS were higher among women with chronic depressive symptoms as compared to those without (M=1.3± SE=0.6 vs. M=−0.3± SE=0.40, p<0.01), after adjusting for baseline FRS and other covariates. HIV status did not modify the relationship between chronic depressive symptoms and FRS. Chronic depressive symptoms accelerated CVD risk scores to a similar extent in both HIV infected and uninfected women. This implies that the diagnosis and treatment of depression may be an important consideration in CV risk reduction in the setting of HIV-infection. The determination of factors that mediate the depression/CVD relationship merits further study.
doi:10.1080/09540121.2011.608791
PMCID: PMC3243818  PMID: 21902560
11.  Effects of hepatitis C and HIV on cognition in women: Data from the Women’s Interagency HIV Study 
Objective
To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects.
Background
Some, but not all, studies have demonstrated that dual infection with HCV and HIV has worse effects on cognition than infection with HIV alone.
Design/Methods
The Women’s Interagency HIV Study (WIHS) is an ongoing prospective study of the natural history of HIV in women where participants are reevaluated every 6 months. In a cross-sectional analysis, we evaluated the effects of active HIV and HCV-infections on scores on symbol-digit test (SDMT), the Stroop interference test, and trails A and B after controlling for age, ethnicity, education, depression, liver disease, and current or past substance abuse.
Results
Data were available for 1338 women – 17.8 % had detectable hepatitis C virus and 67% were HIV-seropositive. In fully adjusted general linear models, HCV viremia was not associated with scores on any of the cognitive tests.
Conclusion
In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.
doi:10.1097/QAI.0b013e318240566b
PMCID: PMC3319079  PMID: 22107817
Hepatitis C; HIV; neurocognition; women
12.  A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African-American women 
Addiction biology  2010;17(1):181-191.
Previous studies of the association of the C17T polymorphism of the mu opiate receptor gene with substance dependence compared cases with substance dependence to controls and usually found no significant association. However, the studies were limited by small sample size - no study had more than 12 subjects with the TT genotype, a genotype that is rare in white and Asian subjects. Moreover, drug use is not dichotomous but follows a spectrum from non-use to modest, intermittent use, to use several times daily. We asked whether the Kreek-McHugh-Schluger-Kellogg (KMSK) scales for alcohol, cocaine, opiates, and tobacco that quantify substance use during the time of a subject's maximal use might be more sensitive measures than dichotomous outcomes. We administered the KMSK scales and completed C17T genotyping on 1009 HIV-infected and 469 HIV-uninfected women in The Women's Interagency HIV Study (WIHS), an ongoing study of HIV in women. Forty-two of 697 African-American, 1 of 182 Hispanic, and none of 161 white women had the TT genotype. KMSK cocaine, alcohol, and tobacco scores were significantly higher in African-American women with the TT genotype (p =0.008, 0.0001, and 0.006 respectively) but opiate scores were not. Ordinal regression models controlling for HIV-serostatus, age, education, and income had odds ratios for the TT genotype for predicting alcohol, tobacco, cocaine, and opiates scores of 2.1 (p = 0.02), 2.4 (p = 0.0004), 2.0 (p = 0.03), and 1.9 (p = 0.07). We conclude that the TT genotype of OPRM1 may increase the risk of substance use and abuse.
doi:10.1111/j.1369-1600.2010.00265.x
PMCID: PMC3117061  PMID: 21070507
C17T polymorphism; HIV; mu opioid receptor gene; quantitative measures; substance abuse; substance dependence
13.  Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women 
Journal of neurovirology  2011;17(5):469-476.
Despite use of HAART, cognitive impairment remains prevalent in HIV. Indeed, a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. Participants were members of the Women’s Interagency HIV Study (WIHS). In analysis of cross-sectional data using general linear models we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI: 3.5 to 17.5, p = 0.003, N = 1130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1130). Summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.
doi:10.1007/s13365-011-0052-3
PMCID: PMC3509940  PMID: 22006469
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
14.  Bone Mineral Density as a Predictor of Atherosclerosis and Arterial Wall Stiffness in Obese African-American Women 
Cardiorenal Medicine  2012;2(4):328-334.
Bone demineralization is associated with higher cardiovascular event rates, possibly due to vascular calcification and accelerated atherosclerosis. African-Americans have less bone loss and less calcium content within atherosclerotic plaques. However, whether loss of bone mass is related to atherosclerosis has not been examined in African-Americans. The objective of this study was to evaluate possible associations between bone mineral density (BMD), carotid intimal-medial thickness (CIMT), and arterial stiffness. We studied 100 obese African-American women (BMI: 26.6 ± 6.2; age: 63 ± 14 years) referred for BMD estimation by dual-energy X-ray absorptiometry scan. BMD (g/cm2) was obtained at the lumbar spine (L1–L4), femoral neck, and total hip. Arterial stiffness was evaluated by the heart rate-corrected augmentation index (AI@75) and pulse wave velocity (PWV) using applanation tonometry. CIMT was measured by vascular ultrasound. Mean CIMT, AI@75, and PWV were 0.72 ± 0.14 mm, 28.8 ± 9.0%, and 8.9 ± 1.6 m/s, respectively. Mean BMD values at the lumbar spine, femoral neck, and hip were 0.96 ± 0.19, 0.80 ± 0.16, and 0.91 ± 0.17 g/cm2. Older subjects had higher CIMT (r = 0.61, p < 0.001) and AI@75 (r = 0.42, p < 0.001). There was a significant correlation between AI@75 and CIMT (r = 0.45, p < 0.001). BMD was negatively correlated with AI@75 (lumbar: r = −0.22, p = 0.03; femoral neck: r = −0.24, p = 0.01; hip: r = −0.21, p = 0.03). BMD was unrelated to CIMT (lumbar: r = −0.09, p = 0.42; femoral neck: r = −0.15, p = 0.17; hip: r = −0.13, p = 0.23). On multivariate analysis, age (p < 0.001), hypertension (p = 0.02), and lumbar BMD (p = 0.01, R2 = 0.30) were independent predictors of increased AI@75 after adjusting for age, height, and cardiovascular risk factors. These findings were unchanged upon substitution of femoral neck BMD (p = 0.05, R2 = 0.28) into the model. There was a trend with hip BMD (p = 0.06, R2 = 0.28) in the regression model. Age-matched comparison between normal BMD (n = 25) and osteoporotic patients (n = 34) demonstrated a significant difference in AI@75 (26.6 ± 8.9 vs. 31.6 ± 9.1%, p = 0.04). In summary, women with lower BMD had increased arterial stiffness. There was no relationship between BMD and atherosclerosis. In conclusion, age, hypertension, and BMD are independent predictors of higher arterial stiffness. Vascular changes are related to bone mineral loss, suggesting lower BMD may increase cardiovascular risk in African-Americans.
doi:10.1159/000345461
PMCID: PMC3551407  PMID: 23381741
Bone mineral density; Osteoporosis; Atherosclerosis; Wave reflection; Aortic stiffness
15.  Narrowed Aortoseptal Angle Is Related to Increased Central Blood Pressure and Aortic Pressure Wave Reflection 
Cardiorenal Medicine  2012;2(3):177-183.
The left ventricular (LV) aortoseptal angle (ASA) decreases with age, and is associated with basal septal hypertrophy (septal bulge). Enhanced arterial pressure wave reflection is known to impact LV hypertrophy. We assessed whether ASA is related to central blood pressure (BP) and augmentation index (AI), a measure of the reflected pressure wave. We studied 75 subjects (age 62 ± 16 years; 66% female) who were referred for transthoracic echocardiography and had radial artery applanation tonometry within 24 h. Peripheral systolic BP (P-SBP), peripheral diastolic BP (P-DBP), and peripheral pulse pressure (P-PP) were obtained by sphygmomanometry. Central BPs (C-SBP, C-DBP, C-PP) and AI were derived from applanation tonometry. AI was corrected for heart rate (AI75). The basal septal wall thickness (SWT), mid SWT and ASA were measured using the parasternal long axis echocardiographic view. Mean ASA and AI75 were 117 ± 11° and 22 ± 11%, respectively. ASA correlated with AI75 (r = −0.31, p ≤ 0.01), C-SBP (r = −0.24, p = 0.04), C-PP (r = −0.29, p = 0.01), but only showed a trend towards significance with P-SBP (r = −0.2, p = 0.09) and P-PP (r = −0.21, p = 0.08). Interestingly, C-PP was correlated with basal SWT (r = 0.27, p = 0.02) but not with mid SWT (r = 0.19, p = 0.11). On multivariate linear regression analysis, adjusted for age, gender, weight, and mean arterial pressure, AI75 was an independent predictor of ASA (p = 0.02). Our results suggest that a narrowed ASA is related to increased pressure wave reflection and higher central BP. Further studies are needed to determine whether narrowed LV ASA is a cause or consequence of enhanced wave reflection and whether other factors are involved.
doi:10.1159/000338827
PMCID: PMC3433001  PMID: 22969773
Aortoseptal angle; Central blood pressure; Aortic wave reflection; Augmentation index
16.  PRE-EXISTING ALBUMINURIA PREDICTS AIDS AND NON-AIDS MORTALITY IN WOMEN INITIATING ANTIRETROVIRAL THERAPY 
Antiviral therapy  2011;16(4):591-596.
Background
We previously reported an increased risk of all-cause and AIDS mortality among HIV-infected women with albuminuria (proteinuria or microalbuminuria) enrolled in the Women’s Interagency HIV Study (WIHS) prior to the introduction of highly active antiretroviral therapy (HAART).
Methods
The current analysis includes 1,073 WIHS participants who subsequently initiated HAART. Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria from two consecutive study visits prior to HAART initiation were categorized as follows: confirmed proteinuria (both specimens positive for protein), confirmed microalbuminuria (both specimens positive with at least one microalbuminuria), unconfirmed albuminuria (one specimen positive for proteinuria or microalbuminuria), or negative (both specimens negative). Time from HAART initiation to death was modeled using proportional hazards analysis.
Results
Compared to the reference group of women with two negative specimens, the hazard ratio (HR) for all-cause mortality was significantly elevated for women with confirmed microalbuminuria (HR 1.9; 95% CI 1.2–2.9). Confirmed microalbuminuria was also independently associated with AIDS death (HR 2.3; 95% CI 1.3–4.3), while women with confirmed proteinuria were at increased risk for non-AIDS death (HR 2.4; 95% CI 1.2–4.6).
Conclusions
In women initiating HAART, pre-existing microalbuminuria independently predicted increased AIDS mortality, while pre-existing proteinuria predicted increased risk of non-AIDS death. Urine testing may identify HIV-infected individuals at increased risk for mortality even after the initiation of HAART. Future studies should consider whether these widely available tests can identify individuals who would benefit from more aggressive management of HIV infection and comorbid conditions associated with mortality in this population.
doi:10.3851/IMP1766
PMCID: PMC3119869  PMID: 21685547
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
17.  Characterization of altered patterns of endothelial progenitor cells in sickle cell disease related pulmonary arterial hypertension 
Pulmonary Circulation  2012;2(1):54-60.
Endothelial dysfunction plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH) in sickle cell disease (SCD). A variety of evidence suggests that circulating endothelial progenitor cells (EPCs) play an integral role in vascular repair. We hypothesized that SCD patients with PAH are deficient in EPCs, potentially contributing to endothelial dysfunction and disease progression. The number of circulating CD34+/CD14−/CD106+ EPCs was significantly lower in SCD patients with PAH than without PAH (P=0.025). CD34+/CD14−/CD106+ numbers significantly correlated with tricuspid regurgitation velocity (TRV, r=−0.44, P=0.033) 6-minute walk distance (6MWD, r= 0.72, P=0.001), mean pulmonary artery pressure (mPAP, r= −0.43, P=0.05), and pulmonary vascular resistance (PVR, r=−0.45, P=0.05). Other EPC subsets including CD31+/CD133+/CD146+ were similar between both groups. Numbers of EPCs did not correlate with age, sex, hemoglobin, WBC count, reticulocyte count, lactate dehydrogenase (LDH), iron/ferritin levels, and serum creatinine. These data indicate that subsets of EPC are lower in SCD patients with PAH than in those without PAH. Fewer EPCs in PAH patients may contribute to the pulmonary vascular pathology. Reduced number of EPCs in SCD patients with PAH might not only give potential insight into the pathophysiological mechanisms but also might be useful for identifying suitable therapeutic targets in these patients.
doi:10.4103/2045-8932.94834
PMCID: PMC3342749  PMID: 22558520
associated pulmonary arterial hypertension; sickle cell disease; stem cell; pathogenic mechanism
19.  Association between human immunodeficiency virus (HIV) infection and stiffness of the common carotid artery 
Background and purpose
Human immunodeficiency virus (HIV)-infected persons taking highly active antiretroviral therapy (HAART) may have an increased risk for cardiovascular-related events, although the underlying mechanism remains unclear. We tested the hypothesis that carotid arterial stiffness was higher among persons taking HAART compared to HAART-naïve and HIV-uninfected persons.
Methods
Between 2004 and 2006, we performed high resolution B-mode ultrasound on 2,789 HIV-infected and HIV-uninfected participants of the Women’s Interagency HIV Study (WIHS; 1865 women) and the Multicenter AIDS Cohort Study (MACS; 924 men) and determined carotid arterial distensibility, a direct measure of carotid arterial stiffness. We used generalized estimating equations to evaluate the association between distensibility and HIV infection, CD4+ cell count, and exposure to HAART adjusted for demographic, behavioral, and clinical characteristics.
Results
In multivariable analysis, distensibility was 4.3% lower (95% confidence interval (CI): -7.4% to -1.1%) among HIV-infected versus uninfected participants. Among HIV-infected participants with fewer than 200 CD4+ cells, distensibility was 10.5% lower (95% CI: -14.5% to -6.2%) than that among HIV-uninfected participants, and this effect did not differ significantly by cohort or race. Concurrent HAART use was independently associated with lower distensibility among MACS participants but not among WIHS participants.
Conclusions
Our finding that advanced HIV-related immunosuppression was associated with increased carotid arterial stiffness independent from the effects of traditional atherosclerosis risk factors suggests that the etiologic mechanism underlying reports of an increased cardiovascular disease risk among HIV-infected individuals might involve HIV-related immunosuppression leading to vascular dysfunction and arterial stiffening.
doi:10.1161/STROKEAHA.110.583856
PMCID: PMC2972735  PMID: 20798374
atherosclerosis; cardiovascular disease; carotid arteries; HIV; epidemiology
20.  MICROALBUMINURIA IS ASSOCIATED WITH ALL-CAUSE AND AIDS MORTALITY IN WOMEN WITH HIV INFECTION 
Prevalence of microalbuminuria is increased in patients with HIV. Microalbuminuria is associated with increased mortality in other populations, including diabetics, for whom microalbuminuria testing is standard of care. We investigated whether microalbuminuria is associated with mortality in HIV-infected women not receiving antiretroviral therapy.
Methods
Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria were performed in specimens from two consecutive visits in 1,547 HIV-infected women enrolled in the Women’s Interagency HIV Study in 1994–1995. Time to death was modeled using proportional hazards analysis.
Results
Compared to women without albuminuria, the hazard ratio (HR) for all-cause mortality was increased in women with one (HR 3.4; 95% CI 2.2–5.2) or two specimens positive for either proteinuria or microalbuminuria (HR 3.9; 95% CI 2.1–7.0). The highest risk was observed in women with both specimens positive for proteinuria (HR 5.8; 95% CI 3.4–9.8). The association between albuminuria and all-cause mortality risk remained significant after adjustment for demographics, HIV disease severity, and related comorbidities. Similar results were obtained for AIDS death.
Conclusions
We identified a graded relationship between albuminuria and the risk of all-cause and AIDS mortality.
doi:10.1097/QAI.0b013e3181cc1070
PMCID: PMC2888617  PMID: 20098331
HIV; microalbuminuria; proteinuria; mortality
21.  The Age-Dependent Contribution of Aortic Incident and Reflected Pressure Waves to Central Blood Pressure in African-Americans 
Aging is associated with increased central aortic systolic pressure (CSP) and pulse pressure which are predictive of cardiovascular events. Mechanisms implicated for higher central pressures include a higher forward incident pressure wave (P1), higher augmented pressure (AP), and shorter reflected wave round trip travel time (Tr). African-Americans (AA) have more frequent and deleterious blood pressure elevation. Using applanation tonometry, we studied the association of age and CSP with P1 and AP in 900 AA subjects. Data showed that in subjects ≤50 years old, CSP was mediated by AP but not P1 or Tr, whereas in those >50, CSP was mediated by both AP and P1 and to a lesser extent by Tr. Predictive models were significant (R2 = 0.97) for both age groups. In conclusion, wave reflection is the primary determinant of CSP in younger AA, while in older subjects, CSP is mediated by both the magnitude and timing of wave reflection as well as aortic impedance.
doi:10.4061/2011/585703
PMCID: PMC3163024  PMID: 21876787
22.  Prolongation of QRS duration and axis deviation in the right bundle branch block are not markers for left ventricular systolic dysfunction 
BACKGROUND:
Right bundle branch block (RBBB) is not commonly associated with structural heart disease and left ventricular (LV) systolic dysfunction. The purpose of the present study was to determine whether the QRS duration and degree of right axis deviation (RAD) or left axis deviation (LAD) in patients with RBBB predicted a subset of patients with significant LV systolic dysfunction.
METHODS:
In the present prospective study, 75 of 200 consecutive patients with RBBB had their ejection fraction (EF) evaluated by echocardiography. The relationship among QRS duration, axis and EF was derived.
RESULTS:
There were no significant differences in sex and EF among the patients with a normal axis, RAD or LAD. The EFs of patients with a normal axis (n=27), RAD (n=15) and LAD (n=33) were 52±15%, 49±14% and 46±17%, respectively (P=0.35). The mean EF (46±16%) of patients with a QRS duration of 150 ms or greater (n=53) was not significantly different from the mean EF (49±18%) of patients with a QRS duration of less than 150 ms (n=22) (P=0.54). For patients with a QRS of 120 ms or greater and less than 150 ms (n=22), QRS of 150 ms or greater and 180 ms or less (n=48), and QRS of greater than 180 ms (n=5), the mean EFs were 49±18%, 47±16% and 44±7%, respectively (P=0.78). There was no significant correlation between QRS duration and EF in all patients (r=0.03, P=0.83), EF and RAD (r=0.38, P=0.16) or EF and LAD (r=0.26, P=0.14).
CONCLUSIONS:
In patients with RBBB, the QRS duration and axis do not have a significant relationship with EF. Furthermore, prolongation of the QRS duration (150 ms or greater) in the presence of RBBB is not a marker of significant LV systolic dysfunction.
PMCID: PMC3005414  PMID: 22477595
Axis deviation; Ejection fraction; Left ventricular systolic function; QRS duration; Right bundle branch block
23.  Impact of sphingomyelin levels on coronary heart disease and left ventricular systolic function in humans 
Sphingomyelin (SM) is an abundant phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; therefore, higher levels of SM may promote atherogenesis. We investigated the relations between plasma SM levels and the presence of angiographic coronary heart disease (CHD) and left ventricular systolic dysfunction. We studied 732 patients referred for coronary angiography. Median SM levels were higher among patients with CHD and in those with LV systolic dysfunction (LVEF<50%) than in patients without CHD or LV dysfunction. SM levels were significantly correlated with fibrinogen levels, diabetes, apoB, and triglyceride levels. On multivariate analyses, higher median SM levels were associated with a higher risk of CHD and lower LV ejection fraction. The pro-atherogenic property of plasma SM might be related to 1) CHD; 2) LV systolic dysfunction; and 3) metabolism of apoB-containing or triglyceride-rich lipoproteins.
doi:10.1186/1743-7075-8-25
PMCID: PMC3111338  PMID: 21521522
sphingomyelin; left ventricular ejection fraction; coronary heart disease; lipids
24.  Elevated NT-pro-BNP Levels Are Associated with Comorbidities among HIV-Infected Women 
AIDS Research and Human Retroviruses  2009;25(10):997-1004.
Abstract
HIV infection is associated with left ventricular (LV) dysfunction and accelerated atherosclerosis. These conditions result in elevation of plasma natriuretic peptide (NP) levels. The present study compares N-terminal-pro-BNP (NT-pro-BNP) levels in HIV-infected and -uninfected women and identifies factors influencingNT-pro-BNP levels in HIV-infected women. A total of 454 HIV-infected and 200 HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) had NT-pro-BNP determination. Elevated NT-pro-BNP level was defined using previously determined age stratified cut-off values of >164 ng/liter (age <60 years) and >225 (age ≥ 60 years). HIV-infected women were older (41.6 ± 8.9 vs. 38.9 ± 10.5 years, p < 0.01) and were more likely to have anemia, hepatitis C virus (HCV) antibodies, and kidney dysfunction than HIV-uninfected women. HIV-infected women had significantly higher NT-pro-BNP levels (142.4 ± 524.8 vs. 73.6 ± 115.1 ng/liter, p = 0.01) and a higher prevalence of elevated NT-pro-BNP (12.1% vs. 7.5%; p = 0.08). In univariate analyses, elevated NT-pro-BNP was significantly associated with age, systolic BP, hypertension, anemia, triglyceride levels, kidney disease, and HCV seropositivity, but not HIV infection. In multivariate analysis, elevated NT-pro-BNP levels were significantly associated with anemia and kidney function, and had a borderline association with the presence of HCV antibodies. Among HIV-infected women, NT-pro-BNP levels were not independently associated with measures of severity of infection or with HAART use. Although HIV-infected women have higher NT-pro-BNP levels than HIV-uninfected women, the differences are due to non-HIV factors such as anemia, kidney disease, and HCV coinfection. These findings suggest that natriuretic peptide levels are a global marker of comorbidity in the setting of HIV infection.
doi:10.1089/aid.2009.0038
PMCID: PMC2791362  PMID: 19803714
25.  Arterial Wave Reflection in HIV-Infected and HIV-Uninfected Rwandan Women 
Abstract
To assess differences in arterial wave reflection, a marker of atherosclerosis, in HIV-positive and HIV-negative Rwandan women, applanation tonometry was performed on 276 HIV+ and 67 HIV− participants. Radial artery pressure waveforms were recorded and central aortic waveforms were derived by validated transfer function. Central augmentation index (C-AI), central pulse pressure (C-PP), and peripheral augmentation index (P-AI) were measured. HIV+ participants were younger and had lower diastolic blood pressure (BP) and 41% of the HIV+ women were taking antiretroviral therapy (ART). Mean C-AI and P-AI were significantly lower in HIV-infected than in uninfected participants (20.3 ± 12.0 vs. 25.5 ± 12.1, p = 0.002 and 74.6 ± 18.8 vs. 83.7 ± 20.0, p < 0.001). After age matching, C-AI, C-PP, and P-AI were similar among the groups. On multivariate analysis, age, heart rate, weight, and mean arterial pressure were independently associated with C-AI (R2 = 0.33, p < 0.0001). Among HIV-infected women, current CD4 count did not correlate with C-AI (Rho = −0.01, p = 0.84), C-PP (Rho = 0.09, p = 0.16), or P-AI (Rho = −0.01, p = 0.83). In conclusion, HIV infection was not associated with increased arterial wave reflection in women with little exposure to antiretroviral therapy and without CV risk factors. Whether long-term ART increases measures of arterial stiffness remains unknown.
doi:10.1089/aid.2008.0269
PMCID: PMC2858930  PMID: 19689195

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