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.
To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects.
Some, but not all, studies have demonstrated that dual infection with HCV and HIV has worse effects on cognition than infection with HIV alone.
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.
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.
In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.
Hepatitis C; HIV; neurocognition; women
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.
C17T polymorphism; HIV; mu opioid receptor gene; quantitative measures; substance abuse; substance dependence
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.
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
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.
Bone mineral density; Osteoporosis; Atherosclerosis; Wave reflection; Aortic stiffness
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.
Aortoseptal angle; Central blood pressure; Aortic wave reflection; Augmentation index
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).
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.
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).
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.
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
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.
associated pulmonary arterial hypertension; sickle cell disease; stem cell; pathogenic mechanism
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.
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.
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.
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.
atherosclerosis; cardiovascular disease; carotid arteries; HIV; epidemiology
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.
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.
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.
We identified a graded relationship between albuminuria and the risk of all-cause and AIDS mortality.
HIV; microalbuminuria; proteinuria; mortality
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.
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.
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.
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).
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.
Axis deviation; Ejection fraction; Left ventricular systolic function; QRS duration; Right bundle branch block
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.
sphingomyelin; left ventricular ejection fraction; coronary heart disease; lipids
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.
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.
Lipoprotein profiles in HIV-infected African women have not been well described. We assessed associations of lipoprotein levels and cardiovascular risk with HIV-infection and CD4 count in Rwandan women.
Cross-sectional study of 824 (218 HIV-negative, 606 HIV+) Rwandan women. Body composition by body impedance analysis, CD4 count, and fasting serum total cholesterol (total-C), triglycerides (TG) and high-density lipoprotein (HDL) levels were measured. Low-density lipoprotein (LDL) was calculated from Friedewald equation if TG < 400 and measured directly if TG ≥ 400 mg/dl.
BMI was similar in HIV+ and -negative women, < 1% were diabetic, and HIV+ women were younger. In multivariate models LDL was not associated with HIV-serostatus. HDL was lower in HIV+ women (44 vs. 54 mg/dL, p < 0.0001) with no significant difference by CD4 count (p = 0.13). HIV serostatus (p = 0.005) and among HIV+ women lower CD4 count (p = 0.04) were associated with higher TG. BMI was independently associated with higher LDL (p = 0.01), and higher total body fat was strongly associated with higher total-C and LDL. Framingham risk scores were < 2% in both groups.
In this cohort of non-obese African women HDL and TG, but not LDL, were adversely associated with HIV infection. As HDL is a strong predictor of cardiovascular (CV) events in women, this HIV-associated difference may confer increased risk for CV disease in HIV-infected women.
Whether hepatitis C virus coinfection might accelerate atherosclerosis in HIV-infected individuals is unclear. We examined the relationship of HIV and hepatitis C virus with carotid artery intima media thickness and the presence of carotid plaques in the Women’s Interagency HIV Study. Hepatitis C virus infection was not associated with greater carotid artery intima media thickness after adjustment for demographic and traditional cardiovascular risk factors. Further follow-up is needed to clarify whether HIV/hepatitis C virus coinfection may be associated with a greater risk of carotid plaque.
Emerging evidence illustrates the importance of the Positive Transcription Elongation Factor b (P-TEFb) in control of global RNA synthesis which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl terminal domain of RNA polymerase II (CTD RNA Pol II). We and others have shown that the activity of P-TEFb is inhibited by its association with CLP-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of CLP-1’s control of the P-TEFb activity in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by over-expression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC-cyclin T1/CLP-1+/−) by crossing MHC-cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy which is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of CTD and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced life span. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates de-repression of P-TEFb activity and emphasizes the importance of CLP-1’s role in the mechanism governing compensatory hypertrophy in cardiomyocytes.
myocardial hypertrophy; transcriptional elongation; CLP-1; HEXIM1
Left ventricular hypertrophy (LVH) is an independent predictor of major cardiovascular events. Cardiovascular risk is increased among human immunodeficiency virus (HIV)-infected patients. To assess LV mass/hypertrophy in HIV infection, 654 women enrolled in the Women's Interagency HIV Study underwent transthoracic echocardiography. There were 454 HIV-infected and 200 uninfected women, mean age 40.8 ± 9.3 years. LV mass/height2.7 was similar between the HIV-infected and the HIV-uninfected groups (41.4 ± 11.1 vs. 39.9 ± 10.3 g/h2.7; p = 0.37). The prevalence of LVH was similar between the two groups (LVH by LV mass/height2.7 criteria 15.0% vs. 13.0%, p = 0.29). Relative wall thickness (RWT), defined as the ratio of LV wall thickness to cavity diameter, was also similar between the HIV-infected and HIV-uninfected groups (0.36 ± 0.05 vs. 0.37 ± 0.06, p = 0.16). On multiple linear regression analysis adjusting for age, W/H ratio, triceps skinfold thickness, systolic/diastolic BP, diabetes, hypertension and dyslipidemia; HIV status (b = 2.08, p = 0.02, CI 0.27–3.88); weight (b per kg = 0.15, p<0.01, CI 0.08–0.22); and smoking duration (b per one-year increase = 0.08, p = 0.03, CI 0.01–0.16) were independent correlates of LV mass/height2.7 (Model R2 = 0.20, p<0.001). Weight (aOR = 1.04, CI 1.01–1.06) and smoking duration (aOR = 1.03, CI 1.01–1.06) were independent correlates of LVH. Being HIV negative, increased age, increased triceps skinfold thickness, and higher W/H ratio were independent correlates of higher RWT. Among HIV-infected women, higher LV mass was not associated with a history of AIDS-defining illness, nadir CD4+ count <200 cells/μl, or with the duration of highly active antiretroviral therapy (HAART). Women taking NRTIs had higher LV mass. Higher RWT was associated with current CD4+ count. In conclusion, HIV infection is associated with greater LV mass but not with a higher prevalence of LVH. Among HIV-infected women, RWT, but not LV mass, is associated with the degree of immunosuppression.
Left ventricular hypertrophy (LVH) is an independent predictor of major cardiovascular events. Cardiovascular risk is increased among human immunodeficiency virus (HIV)-infected patients. To assess LV mass/hypertrophy in HIV infection, 654 women enrolled in the Women's Interagency HIV Study underwent transthoracic echocardiography. There were 454 HIV-infected and 200 uninfected women, mean age 40.8 ± 9.3 years. LV mass/height2.7 was similar between the HIV-infected and the HIV-uninfected groups (41.4 ± 11.1 vs. 39.9 ± 10.3 g/h2.7; p = 0.37). The prevalence of LVH was similar between the two groups (LVH by LV mass/height2.7 criteria 15.0% vs. 13.0%, p = 0.29). Relative wall thickness (RWT), defined as the ratio of LV wall thickness to cavity diameter, was also similar between the HIV-infected and HIV-uninfected groups (0.36 ± 0.05 vs. 0.37 ± 0.06, p = 0.16). On multiple linear regression analysis adjusting for age, W/H ratio, triceps skinfold thickness, systolic/diastolic BP, diabetes, hypertension and dyslipidemia; HIV status (b = 2.08, p = 0.02, CI 0.27–3.88); weight (b per kg = 0.15, p < 0.01, CI 0.08–0.22); and smoking duration (b per one-year increase = 0.08, p = 0.03, CI 0.01–0.16) were independent correlates of LV mass/height2.7 (Model R2 = 0.20, p < 0.001). Weight (aOR = 1.04, CI 1.01–1.06) and smoking duration (aOR = 1.03, CI 1.01–1.06) were independent correlates of LVH. Being HIV negative, increased age, increased triceps skinfold thickness, and higher W/H ratio were independent correlates of higher RWT. Among HIV-infected women, higher LV mass was not associated with a history of AIDS-defining illness, nadir CD4+ count <200 cells/μl, or with the duration of highly active antiretroviral therapy (HAART). Women taking NRTIs had higher LV mass. Higher RWT was associated with current CD4+ count. In conclusion, HIV infection is associated with greater LV mass but not with a higher prevalence of LVH. Among HIV-infected women, RWT, but not LV mass, is associated with the degree of immunosuppression.
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 influencing NT-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.
Phospholipid transfer protein (PLTP) is an important modulator of lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. PLTP also plays an important role in inflammation and oxidative stress. Accordingly, PLTP has been implicated in the development of atherosclerosis. In this study, we evaluated the association between PLTP activity and lipoprotein metabolism in a Chinese patients cohort with or without coronary heart disease (CHD group n = 407, control group n = 215), the PLTP activity was measured and PLTP genotyping was screened for sequence anomalies by PCR. We found that human plasma PLTP activity was negatively associated with plasma HDL and apoA-I levels, and positively associated with plasma TG, apoB and apoE levels. We also found that PLTP rs2294213 polymorphism was tended to be associated with increased plasma PLTP activity.
To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical carotid artery atherosclerosis.
Cross-sectional study nested within a prospective cohort study
Among participants in the Women's Interagency HIV Study (1,331 HIV-infected women, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study (600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness (CIMT) using B-mode ultrasound. We estimated adjusted mean CIMT differences and prevalence ratios (PRs) for carotid lesions associated with HIV-related disease and treatments, with multivariate adjustment to control for possible confounding variables.
Among HIV-infected individuals, a low CD4+ T cell count was independently associated with an increased prevalence of carotid lesions. Compared to the reference group of HIV-uninfected individuals, the adjusted PR for lesions among HIV-infected individuals with CD4+ T-cell count <200 cells/mm3 was 2.00 (95% confidence interval 1.22, 3.28) in women and 1.74 (95% confidence interval 1.04, 2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis.
Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men.
Nonhuman primates are commonly used in cardiovascular research. Increased arterial stiffness is a
marker of subclinical atherosclerosis and higher CV risk. We determined the augmentation index (AI) using applanation tonometry
in 61 healthy monkeys (59% female, age 1–25 years). Technically adequate studies were obtained in all subjects and
required 1.5 ± 1.3 minutes. The brachial artery provided the highest yield (95%). AI was correlated with heart rate (HR) (r = −0.65, P < .001), crown rump length (CRL) (r = 0.42, P = .001), and left ventricular (LV) mass determined using
echocardiography (r = 0.52, P < .001). On multivariate analysis, HR (P < .001) and CRL (P = .005) were independent predictors of AI (R2 = 0.46, P < .001). Body Mass Index (BMI) and AI were independent predictors of higher LV mass on multivariate analysis (P < .001 and
P = .03). In conclusion, applanation tonometry is feasible for determining AI. Reference values are
provided for AI in bonnet macaques, in whom higher AI is related to HR and CRL, and in turn contributes to higher LV mass.