Premature atherosclerosis is more common in HIV-infected patients than in the age-matched noninfected population.1–8 This condition is caused not only by the high prevalence of traditional risk factors among these patients but also by a series of specific factors, including a direct effect of HIV infection, the HIV-related inflammation, and the use of antiretroviral drugs.1,8–14 Paradoxically, although long-term exposure to antiretroviral therapy, mainly protease inhibitors, is associated with an increased risk of cardiovascular events,10,11,13,14 interruption of antiretroviral therapy has also been associated with increased cardiovascular risk.15
Many diagnostic methods are currently available for detection of vascular damage. Noninvasive imaging methods can identify coronary artery calcium (computed tomography), detect vulnerable plaques (magnetic resonance), or measure carotid intimae media thickness (dimensional echocardiography). However, recent studies indicate that endothelial dysfunction is an early prognostic marker of coronary disease.16–21 This primary alteration of the vascular bed is the first stage of atherosclerosis and precedes the formation of atherosclerotic plaque. Several noninvasive functional tests to assess vascular endothelium have been created by medical research companies. One such test involves study of arterial stiffness by measuring pulse wave velocity (PWV). The results of this simple and reproducible technique to measure subclinical atherosclerosis are associated with all-cause and cardiovascular mortality,19,21–23 coronary artery disease,17,20 and stroke17,21 in non–HIV-infected individuals.
The first published studies on arterial stiffness in HIV-infected patients, all short case–control studies,4,7,9,14,24–26 reveal that HIV-infected individuals show greater arterial stiffness than age-matched and sex-matched noninfected controls. This finding is probably associated with premature aging of this population and other characteristics of HIV infection, including duration of antiretroviral therapy,10,25–27 concomitant impaired glucose tolerance,9,26 and time since diagnosis.25
Larger-scale studies are necessary to better define the effect of various factors on vascular elasticity in the HIV-infected patient. We used PWV to assess arterial elasticity, a marker of subclinical atherosclerosis, in a group of HIV-infected patients compared with healthy controls and identify factors associated with impaired elasticity.
Study Design and Participants
We performed a cross-sectional observational study to determine PWV using a noninvasive automated device (Complior, Artech-Medical, Pantin, France) in a cohort of HIV-infected patients compared with a group of non–HIV-infected subjects (control group). We included all HIV-infected patients consecutively attended in the outpatient clinic of our hospital (Germans Trias i Pujol University Hospital, Barcelona, Spain) between January 2010 and December 2011 who agreed to participate. Controls were healthy voluntary, older than 18 years, with a negative test for HIV in the previous 6 months, recruited from hospital staff and by a local advertisement who agreed to participate. One healthy subject was selected by each 2 HIV-infected patients matched by gender and age (±3 years); HIV-1 infection was ruled out in all of them by serologic testing. Written informed consent was obtained from all participating individuals before study entry, trial protocols were reviewed and approved by the appropriate institutional ethics committees and health authorities and were undertaken in accordance with the Declaration of Helsinki and Good Clinical Practice.
The primary objective was to compare the prevalence of arterial stiffness between HIV-infected patients and controls by measuring arterial elasticity in the carotid and femoral arteries using PWV. Arterial stiffness was considered to be present when PWV was >11 m/s in patients aged 20–40 years, >12 m/s in patients aged 41–59 years, and >13 m/s in patients aged >60 years according to establishes reference and normal values for PWV based on a large European population.28
The secondary objective was to identify factors associated with impaired elasticity, assessing HIV-related characteristics, antiretroviral therapy, and traditional cardiovascular risk factors.
Assessments and Definitions
Before the PWV study, a questionnaire was administered to record the following: sociodemographic features (age, gender, and race); personal or family history (first-degree relatives) of premature coronary heart disease, hypertension, diabetes mellitus, dyslipidemia, and other concomitant diseases (kidney disease, hepatitis coinfection); use of concomitant therapy (treatment for dyslipidemia, hypertension, and diabetes); the practice of regular exercise (at least 3 h/wk of cardiovascular exercise); and consumption of drugs, coffee, alcohol, and tobacco.
HIV-related data (time since HIV diagnosis, risk behavior, nadir CD4 T-cell count, time on antiretroviral therapy, current exposure to nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors) were recorded from the patient's records of the HIV-infected patients.
Laboratory data were recorded in both groups (HIV-infected patients and controls) and included: glucose level, lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), hepatic profile, and estimated glomerular filtration rate by the Modification of Diet in Renal Disease equation. In addition, plasma HIV-1 RNA and CD4 T-cell count were determined in HIV-1–infected patients.
Blood pressure (2 consecutive readings obtained on the right arm by manual sphygmomanometer), heart rate, weight, and height were recorded immediately before the determination of arterial elasticity by PWV.
The PWV measurements were performed by the same clinician, in the same room, at the same time of day (from 9 AM to 12 AM) according to user guidelines.29 Carotid–femoral PWV (CF-PWV) and carotid–radial PWV (CR-PWV) were determined using the Complior device (Artech-Medical, Pantin, France), which records PWV (calculated as the distance between recording sites measured over the surface of the body, divided by the time interval between the feet of the pressure waves, m/s) as an index of arterial elasticity. Participants were examined after resting at least 5 minutes in a supine position at a temperature-controlled room. No caffeine ingestion or cigarette smoking was allowed 2 hours before the examination.
High blood cholesterol in adults was defined according to the Third Report of the National Cholesterol Education Program Expert Panel of Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults,30 hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or the need for antihypertensive drugs and/or angiotensin-converting enzyme inhibitors. Patients were considered to have dyslipidemia when their total cholesterol level was >190 mg/dL and/or low-density lipoprotein cholesterol level was >130 mg/dL and/or triglycerides >150 mg/dL (according to our reference laboratory) or if they were taking lipid-lowering drugs.
To assess the difference in arterial stiffness between HIV-infected patients and non–HIV-infected patients (control group), the sample size was calculated to ensure a power of 80% and a confidence level of 95% to detect differences between the 2 groups. The required sample size was 78 patients in the Healthy controls and 156 in the HIV-infected patients. The match was done to reduce variability and make comparable both groups.
The data were analyzed in a nonpaired way but with the benefit of having groups of comparison comparable in gender and age values.
Mean (SD), median [interquartile range (IQR): 25th and 75th percentiles], and frequencies (%) had been used to describe patient's characteristic as appropriate. The differences between groups were assessed by t test procedure or Mann–Withney test, for the continuous variables, and χ2 or Fisher exact test for the categorical ones.
Univariate and multivariate logistic regression models were constructed to evaluate the impact of these factors on the risk of suffering arterial stiffness and for the comparison between HIV-infected patients and control group, respectively. Two sets of interest were considered separately: HIV-infected patients and controls.
All analyses had been performed using SPSS software version 15.0 (SPSS Inc, Chicago, IL). A P value <0.05 had been considered statistically significant.
Arterial elasticity was measured in 261 participants (174 HIV-infected patients and 87 controls). Because clinical and laboratory data were not available from 7 controls, these subjects were excluded, and, finally, data from 174 HIV-infected patients and 80 controls were analyzed.
Overall, 81.4% of subjects were male and the median age was 46.5 (IQR:41–52) years. As for cardiovascular risk factors, 15.3% of patients had a history of hypertension, 34.5% dyslipidaemia, and 10% diabetes mellitus; 38% were current smokers and 37% had a body mass index >25.
Regarding HIV-infected patients (Table 1), 84.1% were male and the median (IQR) age was 46.5 (42, 52) years. The median time from HIV diagnosis was 13 (IQR: 6–18) years and the median time on antiretroviral therapy was 11 (IQR: 5–15) years. Nearly, all patients (94.4%) were taking antiretroviral therapy and were virologically suppressed (89.7%). At the time of PWV measure, 12.6% of patients had a systolic blood pressure >140 mm Hg and 17.2% a diastolic blood pressure >90 mm Hg.
Regarding the controls (Table 1), 78.8% were male and the median (IQR) age was 46.3 (41–52) years. At the time PWV was measured, 8% of patients had a systolic blood pressure >140 mm Hg and 9% a diastolic blood pressure >90 mm Hg.
There were no differences in traditional cardiovascular risk factors between HIV-infected patients and controls except in the percentages of subjects with dyslipidemia (P = 0.013), current smoking habit (P = 0.002), and cumulative exposure to tobacco (P = 0.003), always higher in HIV-infected patients.
The characteristics of the study population are shown in Table 1.
Clinical and laboratory data at time of the study are shown in Table 2.
Arterial Elasticity and Factors Associated With Increased PWV
Arterial stiffness (increased CR-PWV and/or CF-PWV) in the global population was recorded in 52 patients (20.5%). Of these, 44 (84.6%) had increased CR-PWV and 13 (25%) CF-PWV.
There were no difference in the median (IQR) PWV values between HIV-infected patients and HIV-uninfected individuals, CR-PWV/CF-PWV median (IQR) values was 9.09 (7.08–11.02 m/s) and 8.07 (7.04–9.18 m/s) in HIV-infected patients and 9.5 (8.81–11.31)/7.14 (6.41–7.74) in control group.
In HIV-infected patients, CR-PWV and/or CF-PWV impairment was recorded in 33 patients (18.9%). According to age, increased CR-PWV and/or CF-PWV was observed in 7 of 33 (21.2%) subjects aged <40 years, 24 of 125 (19.2%) subjects aged 41–59 years, and 2 of 16 (12.5%) subjects aged >60.
No statistically significant associations were seen with impaired PWV when we stratified HIV-infected patients according to the viral load (suppressed viral load, defined as ≤50 copies/mL, or unsuppressed viral load defined as >50 copies/mL) (P = 0.477).
In controls, arterial stiffness was recorded in 19 patients (23.8%). Of these, 17 (89.5%) had increased CR-PWV and 5 (6.3%) had increased CF-PWV (Table 3). According to age, increased CR-PWV and/or CF-PWV was observed in 1 of 20 (5%) subjects aged <40 years, 2 of 54 (3.7%) subjects aged 41–59 years, and 2 of 6 (33.3%) subjects aged >60.
Despite descriptive analysis showed a higher rate of impaired PWV in the younger age subgroup when we considered the HIV group, and a higher rate in the older age subgroup in the controls, no statistical differences were seen in PWV for age using logistic regression (P= 0.405).
Logistic regression analysis including all population showed no association between the factors included in unadjusted analysis. Only among HIV-1–infected patients, analysis revealed an association between high diastolic blood pressure at the time of the study [odds ratio (OR): 3.211; 95% confidence interval (CI): 1.345–7.666; P = 0.009] and serum triglycerides levels (OR: 2.632; 95% CI: 1.144–6.050; P = 0.023) and increased PWV (Table 3). CD4+T-cell count and viral load at time of the study no showed any statistically significant association with PWV.
No models with combination of 2 or more variables with significant coefficients (P < 0.05) showed an OR different from 1. For this reason, it was not able to perform the multivariate logistic model.
Prevalence of arterial stiffness in our virologically suppressed HIV-infected patients, as assessed using PWV, was similar to that observed in control subjects, even considering the higher prevalence of some cardiovascular risk factors in infected subjects. Only high diastolic blood pressure and high levels of triglycerides at the time of the study were associated with loss of arterial elasticity in subjects with HIV infection. In contrast, other HIV-related or cardiovascular risk factors were not significantly associated with impaired elasticity.
Arterial stiffness is a complex process resulting from functional and structural changes in the arterial wall. The stability of the vascular wall depends on the balance between the 2 main scaffolding proteins: collagen and elastin. Dysregulation of this balance, mainly by stimulation of an inflammatory milieu, leads to overproduction of abnormal collagen and diminished quantities of normal elastin, which in turn leads to stiffness.31,32 Gross vascular specimens reveal these molecular changes as a doubling to tripling of intima-media thickness between ages 20 and 90 and a hypertrophied vascular smooth muscle layer.
Although these changes occur during normal aging, several conditions can speed up their development.26,31–33 In addition to the traditional cardiovascular risk factors that stimulate excessive collagen production, such as increased luminal pressure (hypertension),31,32,34,35 processes that induce chronic inflammation are also associated with arterial stiffness by inducing endothelial dysfunction,36 and promoting structural changes.31,33 In clinical terms, arterial stiffness means that greater pressure is necessary to expand the blood vessels leading to ventricular hypertrophy and left ventricular failure.37 Therefore, early diagnosis of arterial dysfunction is necessary to slow down the process, especially in those subjects with chronic inflammatory processes, such as HIV infection.
Some studies have already shown higher PWV levels in chronically HIV-infected patients than expected.1,3,4,6–9,24–27,38 Among our population, a significant proportion (almost 20%) showed impaired artery elasticity. Chronic inflammation resulting from HIV infection may explain the high prevalence of endothelial dysfunction in HIV-infected subjects as is the case for other chronic inflammatory diseases, such as rheumatoid arthritis.35,36 Most of our patients showed a prolonged exposure to HIV infection (mean time of 13 years). Additionally, the fact that most of the participants were less than 50 years old (only 9% were >60 years) could support premature aging described in this population. Nonetheless, this proportion was similar to that observed in non–HIV-infected subjects in accordance with other reported data,4,8,39 even when our patients showed a higher prevalence of cardiovascular risk factors (tobacco habit, dyslipidemia, and hypertension) than controls as expected. These data are contrary to that observed in other studies.3,6–9,26,27 Discrepancies between different studies could be explained by the different methodology used to assess arterial elasticity or differences in study populations. Almost all our patients were receiving antiretroviral therapy and showed a suppressed viral replication (almost 90%) at the time of PWV. The lack of viral replication at the time of the exploration could lead to a lower levels of systemic inflammation and explain the similar results between infected and noninfected subjects. Previous published data suggest that uncontrolled viral replication and its effect on biomarkers of inflammation are associated with endothelial dysfunction.7 Antiretroviral-naive HIV-infected patients showed more prevalence of arterial stiffness compared with treated patients, probably because HIV infection reduces carotid compliance.7 Although our group was not large enough to assess differences between antiretroviral drugs, some variations have been reported among the effect of different antiretroviral drugs in arterial elasticity.
On the other hand, our findings showed a lower rate of arterial stiffness among HIV-infected patients aged >60 years in comparison with younger participants. This was probably because cardiovascular risk factors such as current smoking, diastolic hypertension, and impaired lipid parameters at the time PWV were more prevalent in the younger age group.
The most described independent determinants of arterial stiffness in subjects with HIV infection are age, hypertension, high cholesterol levels, and a nadir CD4 T-cell count <350 cells per microliter.6,8,15,25,27,38–42 In accordance with these data, high diastolic blood pressure and high levels of serum triglycerides were associated with arterial stiffness among our patients, whereas other HIV-related characteristic and cardiovascular risk factors were not independent predictors of arterial stiffness similar to that observed in other recent study.38 The control of cardiovascular risk factors reduces the morbidity and mortality. However, strict diagnostic and therapeutic strategies are not always implemented to reduce morbidity and mortality of this population when a considerable rate of our patients has at least 1 cardiovascular risk factor.
The main limitations of the study were the absence of an adequate sample in extreme age groups (<40 years and >60 years) and the low proportion of women among our patients that prevent us from comparing differences in arterial stiffness between genders and ages, and no functional measurements have been analyzed to complete the study.
In conclusion, virologically suppressed HIV-infected patients showed similar arterial elasticity evaluated by PWV to non–HIV-infected patients. HIV-related conditions were not associated with arterial stiffness, probably because of the good immunologic and virological status of this group. However, high diastolic pressure at the time of PWV and high levels of triglycerides were risk factors. An optimal management of traditional risk factors, often present in HIV-infected population, is essential in these patients for reducing their cardiovascular risk. Additionally, measurement of carotid and femoral PWV is a simple noninvasive technique for identifying patients with subclinical atherosclerosis.
This manuscript was made possible through the collaboration of the staff AIDS care unit of Germans Trias i Pujol University Hospital, Barcelona, Spain.
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