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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±10.3g/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 <200cells/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 a well-established independent predictor of major cardiovascular events. Increased LV mass is associated with increased risk for fatal and nonfatal myocardial infarction (MI), sudden cardiac death, serious ventricular arrhythmias, severe heart failure, and cerebrovascular events including stroke and transient ischemic attacks.1–3 A number of studies have shown LV mass to be strongly determined by blood pressure (BP) and to be related to body anthropometric measurements among healthy subjects and hypertensive patients.2,4
There is a growing recognition of increased cardiovascular risk among human immunodeficiency virus (HIV)-infected patients.5 HIV infection is associated with increased rates of MI,6 stroke,7 and cardiomyopathy,8 which in turn are associated with increased LV mass.1,2 The use of highly active retroviral therapy (HAART) and the resulting improved survival as well as the high prevalence of risk factors such as hypertension, diabetes, and smoking among these patients have further increased their cardiovascular risk.6,9 Few studies have examined LV mass/hypertrophy among patients with HIV infection. In addition, no study has specifically evaluated women.
The aims of the present study were to (1) compare LV mass in HIV-infected and high-risk uninfected women, (2) study the association between LV mass, BP, and other factors including clinical and demographic characteristics in this population, and (3) compare the prevalence of LVH between HIV-infected and -uninfected women.
The study was conducted in a sample of participants from the Women's Interagency HIV Study (WIHS), an ongoing multicenter study of natural history of HIV disease in women. Of the original cohort of 2054 HIV-infected and 569 high-risk HIV-uninfected women recruited at six centers across the United States (Brooklyn, Bronx, Chicago, Los Angeles, San Francisco, and Washington, DC), 654 women from the two New York sites (Brooklyn and Bronx) were included in this analysis. Data were collected in a cross-sectional manner between WIHS visits 21 (10/04–3/05) and 22 (4/05–9/05). The study was approved by the Institutional Review Boards of both study sites and all subjects provided written informed consent.
The WIHS semiannual follow-up visits include medical history and health behavior questionnaires, assessments of medication use, standardized clinical and laboratory measurements, and phlebotomy. Anthropometric measurements including height, weight, triceps skinfold thickness, and waist/hip (W/H) ratio were performed according to the Third National Health and Examination Survey (NHANES III) procedures.10 BP was measured in the right arm with a DINAMAP 1846 SX automated oscillometric device (Critikon, Inc., Tampa, FL). Three or more readings were taken after the subject sat for ≥5min and all readings per participant were averaged.
Subjects were instructed to fast for at least 8h prior to phlebotomy. Laboratory values including glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured at a central laboratory. Low-density lipoprotein cholesterol (LDL-C) was estimated from the Friedewald equation.11 For specimens that were nonfasting, and for fasting specimens with triglyceride levels over 400mg/dl, levels of LDL-C were measured directly. Diabetes was defined via either a self-reported diagnosis of diabetes, a fasting blood glucose of ≥126mg/dl,12 or treatment with medications. Dyslipidemia was defined as total cholesterol ≥240mg/dl, triglycerides ≥200mg/dl, HDL ≤35mg/dl or LDL ≥160mg/dl, or self-reported diagnosis.13 Hypertension was defined as either measured systolic BP ≥140mm Hg, diastolic BP >90mm Hg, or a self-reported diagnosis of hypertension with use of antihypertensive medications.
HIV status, RNA viral load and CD4+ lymphocyte counts were determined at the time of the WIHS visit. History of an AIDS-defining illness (ADI) was defined by a prior report of conditions consistent with the 1993 Centers for Disease Control and Prevention surveillance definition, but excluding the immunologic criterion of CD4+ cell count <200cells/ml. These events were ascertained through self-report or confirmed through cancer and tuberculosis registries. HAART was defined by the DHHS guidelines as reported use of (1) two or more nucleoside reverse transcriptase inhibitors (NRTIs) in combination with at least one protease inhibitor (PI) or one nonnucleoside RTI (NNRTI); (2) one NRTI in combination with at least one PI and at least one NNRTI; (3) a regimen containing ritonavir and saquinavir in combination with one NRTI and no NNRTIs; or (4) an abacavir or tenofovir containing regimen of three or more NRTIs in the absence of both PIs and NNRTIs, except for the three-NRTI regimens consisting of abacavir + tenofovir + lamivudine, or didanosine + tenofovir + lamivudine.14
Echocardiography was performed by a single experienced ultrasonographer using a Phillips (Phillips, Andover, MA) 500 machine with a 3.5–5.5MHz transducer. Two-dimensional and M-mode echocardiography was performed as per the standard protocol. Data were recorded on VHS tapes and analyzed by a single experienced echocardiographer. End-diastolic measurements of left ventricular chamber diameter (LVIDd), interventricular septum thickness (IVSTd), and posterior wall thickness (PWTd) were measured according to the guidelines of the American Society of Echocardiography.15 LV mass was calculated using the validated modified Devereux formula, .16
LV mass was analyzed as an unadjusted variable and after indexation to body surface area (BSA) and to height2.7. The prevalence of LVH was determined using partition values of ≥51g/m2.7 using height2.7 indexation and ≥110g/m2 using BSA indexation, as prognostically validated in the general population including women17,18 and used in minority populations.19
Relative LV wall thickness (RWT) was calculated as the ratio of PWTd+IVSTd/LVIDd. LVH was denoted as eccentric if the RWT was normal (<0.45) and concentric if RWT was increased (≥0.45).20 Fractional shortening (FS) was calculated as a measure of LV performance using LV end systolic and diastolic diameters.
Continuous variables were summarized via means±standard deviation (SD), and univariate ANOVA was used for statistical significance testing. Chi-square testing was used to assess statistical significance of differences between proportions for categorical variables. Multiple linear regressions models, using the forced entry method, were constructed to determine statistically significant independent variables that explain variation in LV mass indices. In addition to HIV status, other variables that were investigated included age, weight, triceps skinfold thickness, W/H ratio, systolic BP, diastolic BP, history of diabetes, dyslipidemia, hypertension, and duration of smoking. Weight was excluded from regression models used for predicting determinants of LV mass/BSA. To investigate the impact of HIV infection and other risk factors on the prevalence of LVH, logistic regression was performed using the same variables as in linear regression. To study the influence of AIDS, HIV RNA, nadir CD4+ cell count <200cells/μl, current CD4+ cell count, and prior HAART exposure, the HIV-infected group was analyzed separately with addition of these variables in a multivariate analysis. Statistical significance was defined as p<0.05. All analyses were conducted using SPSS version 15 (SPSS Inc., Chicago, IL).
Patient characteristics are shown in Table 1. There were 454 HIV-infected and 200 HIV-uninfected women; 63.% of the women were African-American, 25.4% were Hispanic, and 5.4% were white. As compared to the HIV-uninfected group, the HIV-infected group was older, had a lower BMI, lower triceps skinfold thickness, and a higher W/H ratio. Systolic BPs and pulse pressures were lower in the HIV-infected group compared to the HIV-uninfected group, while diastolic BPs were similar. The HIV-infected group had higher serum triglycerides, lower HDL cholesterol, and a higher total cholesterol/HDL cholesterol ratio compared to the HIV-uninfected group, whereas LDL cholesterol was similar between the two groups. The prevalence of dyslipidemia was higher in the HIV-infected group, whereas hypertension, diabetes, and smoking were similar among the two groups. The use of medications for treating hypertension, diabetes, and dyslipidemia was similar between the HIV-infected and -uninfected groups (hypertension treatment 22.6 vs. 23.0%, p=0.49; diabetes treatment 5.5 vs. 7.1%, p=0.28; dyslipidemia treatment 5.7 vs. 3.5%, p=0.16). Among the HIV-infected women, the mean duration since HIV diagnosis was 10.2 years, the mean HIV RNA viral load was 31.9±189.7copies/ml×103, and the mean duration of HAART use was 4.2±2.9 years.
As shown in Table 1, mean unadjusted LV mass, LV mass/height2.7, and FS were similar between the HIV-infected and HIV-uninfected groups. LV mass/BSA was significantly higher in the HIV-infected group (81.7±17.8 vs. 78.5±16.3g/m2; p=0.03). However, on adjusting for age, LV mass/BSA was also similar between the two groups. RWT was also similar between the two groups; however, after adjusting for age the HIV-infected group had significantly lower RWT (0.36±0.05 vs. 0.37±0.06, p=0.03). In univariate analyses, LV mass/height2.7 was significantly associated with age (b=0.21; CI 0.13–0.30), weight (b=0.17; CI 0.14–0.21), triceps skinfold thickness (b=0.21; CI 0.13–0.29), W/H ratio (b=22.9; CI 12.6–33.3), systolic BP (b=0.14; CI 0.10–0.18), diastolic BP (b=0.18; CI 0.10–0.25), hypertension (b=4.54; CI 2.69–6.39), and dyslipidemia (b=1.95; CI 0.14–3.76). As shown in Table 2, after adjusting for relevant covariates in multivariate analyses, HIV infection, increased weight, and increased duration of smoking were independent correlates of LV mass/height2.7 (Model R2=0.20; p<0.001). Independent correlates of RWT included HIV-negative serostatus, increased age, increased triceps skinfold thickness, and increased W/H ratio (Model R2=0.09; p<0.001).
The overall prevalence of LVH ranged from 5.2% to 14.4% depending on the indexation of LV mass to BSA or to height2.7. As shown in Table 1, the prevalence of LVH was similar between the HIV-infected and the HIV-uninfected groups (5.8% vs. 5.1%, p=0.44 using LV mass/BSA criteria and 15.0% vs. 13.0%, p=0.29 using LV mass/height2.7 criteria). Among patients with LVH, eccentric hypertrophy was the predominant pattern of LVH in both the groups (90.3% vs. 88%, p=0.74). As shown in Table 3, in univariate analyses, LVH was significantly correlated with age, weight, triceps skinfold thickness, W/H ratio, diastolic BP, and hypertension. On multivariate analysis, only weight (aOR=1.04, CI 1.02–1.06) and smoking duration (aOR=1.03, CI 1.01–1.06), but not HIV status, were independently associated with LVH.
As shown in Table 4, among the HIV-infected group, multivariate analysis with the addition of HIV infection-specific variables including history of ADI, viral RNA load, nadir CD4+ cell count <200cells/μl, current CD4+ cell count, and the duration of exposure to HAART revealed that LV mass/height2.7 was independently associated with weight only (Model R2=0.19; p<0.001). RWT was independently associated with current CD4+ count, age, W/H ratio, and triceps skinfold thickness (Model R2=0.13; p<0.001). Of the 454 HIV-infected participants in the study, 333 women reported using protease inhibitors for at least 6 months during the course of their treatment (PI group). When this group was compared to the remaining 121 patients who never reported taking protease inhibitors (non-PI group), there were no significant differences in LV mass/height2.7, in RWT, or in the prevalence of LVH between the two groups (LV mass/height2.7 151.3±40.4g/h2.7 vs. 149.4±37.9g/h2.7, p=0.67; RWT 0.36±0.05 vs. 0.36±0.05, p=0.96; LVH 14.9% vs. 15.0%, p=0.54). Among HIV-infected women, 288 were on one or more (maximum 4) NRTI drugs. The mean LV mass was significantly higher in subjects who were taking NRTIs compared to those who were not taking NRTIs (42.1±11.4 vs. 39.8±10.6g/h2.7, p=0.03). Similarly, 95 HIV-infected women were taking NNRTI drugs (maximum 1). However, LV mass was similar between women taking NNRTI compared to those not taking NNRTI drugs. (42.9±14.0 vs. 40.8±10.2g/h2.7, p=0.12).
The major finding of this study is the association between HIV infection and higher LV mass. Few prior studies have evaluated LV mass among HIV-infected patients and the results have been conflicting.21–24 None has determined the prevalence of LVH in this population group. Barbaro reported increased LV mass in asymptomatic HIV patients compared to healthy controls.21 Similarly, Lipshultz described a higher LV mass among children with HIV infection.22 Differences in LV mass between HIV infected and uninfected children waned with increasing age.22 In contrast, Martinez-Garcia found decreased LV mass in asymptomatic HIV-infected patients 23 and Samaan found decreased LV mass among patients with AIDS wasting syndrome, respectively.24 These studies, however, are limited by their lack of LV mass indexation or by indexation of LV mass to BSA. In the present study, higher LV mass/height2.7 was found among HIV-infected women, after controlling for age, anthropometric variables, BP variables, presence of diabetes, hypertension, and duration of smoking. These data suggest that multiple factors may be involved in increasing LV mass in the setting of HIV infection. Several autopsy and animal studies have shown that HIV virions directly affect myocardial cells and are associated with the local release of cytokines and other factors leading to inflammation, myocarditis, and dilated cardiomyopathy.8,21 Alternatively, increases or decreases in LV mass have been suggested to be associated with opportunistic infections25 and malnutrition.24 These factors were unlikely present in the population we studied as no patient had a current diagnosis of opportunistic infection and the mean BMI was 28.8±6.9kg/m2 in the HIV-infected group. Although Meng reported greater interventricular septal and posterior wall thicknesses among patients exposed to PIs compared to those who were not exposed, we did not find any difference.25,26 These disparate results may be related to fewer patients in the non-protease inhibitor group in our study and to differences in nutritional status of the population we studied. Similarly, NNRTIs were not associated with higher LV mass. In contrast, we found women taking NRTIs to have higher LV mass than those who were not. This finding confirms previous reports suggesting increased cardiac involvement in patients exposed to NRTIs compared to those not exposed to NRTIs.27 The mechanisms by which these adverse effects occur are not fully understood, but are thought to be related to mitochondrial toxicity.28 In the present study, we did not include specific drug classes in a multivariate analysis given variability in duration of treatments, specific drugs used, and concurrent use of multiple drug classes.
Although HIV infection was associated with a higher LV mass examined as a continuous variable, it was not associated with a higher prevalence of LVH. These findings suggest that though HIV infection influences LV mass, it does not appear to exceed the partition thresholds that are commonly used to define LVH. In the present study, LV mass was also found to be related to duration of cigarette smoking. Smoking has been previously linked to exercise-induced LV growth.29 Chronic smoking may increase LV mass possibly via increased circulating catecholamines with increased vascular tone and myocardial oxygen demand.30 In the present study, increased LV mass among HIV-infected women was not related to measures of severity of current or past immunosuppression, including a history of an ADI or nadir CD4+ cell count <200cells/μl nor with the use/duration of HAART. However, RWT was related to the level of immunosuppression as measured by current CD4+ cell count. Increased LV mass may result either due to dilatation of the LV cavity or due to increased wall thickness. Therefore, LV geometry becomes an important consideration in describing LV mass. In our study, HIV infection was negatively related to RWT, suggesting an eccentric pattern of LVH that is associated with an increase in LV cavity size rather than an increase in LV wall thickness. These findings confirm the increased incidence of LV dilatation among HIV-infected patients, as reported previously by Barbaro and other researchers.8,30–32
We are unaware of prior studies indexing LV mass to height2.7 in HIV-infected patients. Fat free mass has emerged as the preferred method of indexing LV mass to body size.33 Although BSA has been commonly used to index LV mass, in recent years it has been criticized for underestimating the prevalence of LVH due to obesity.34 The present study supports this notion as indexing LV mass to height2.7 increased the prevalence of LVH by approximately 3-fold over indexing to BSA. Other strengths of the study include the acquisition of images by a single experienced ultrasonographer and interpretation by a single echocardiography cardiologist, thus avoiding the effects of interobserver variability.
This study was subject to the limitations of a cross-sectional design. Moreover, the women were relatively young and predominantly African-American. Therefore, the results may not be generalizable to other HIV-infected or at-risk populations. In addition, data on specific hypertension and dyslipidemia medications were not available, so their effects could not be analyzed. Despite these limitations, we conclude that HIV infection is associated with greater LV mass but not with a higher prevalence of LVH. Among HIV-infected subjects, higher LV mass is not associated with a history of ADI. Future studies are needed to confirm the prognostic value of these findings in HIV-infected subjects.
Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group from centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos) and Brooklyn, NY (Howard Minkoff); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute and the National Institute on Drug Abuse (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590). Funding is also provided by the National Institute of Child Health and Human Development (Grant UO1-HD-23632) and the National Center for Research Resources (Grants MO1-RR-00071, MO1-RR-00079, and MO1-RR-00083).
No competing financial interests exist.