CLINICAL RESEARCH: ATHEROSCLEROSIS
Functional and Structural Markers of Atherosclerosis in Human Immunodeficiency Virus-Infected Patients
Jeroen P.H. van Wijk, MD*,*,
Eelco J.P. de Koning, MD, PhD ,
Manuel Castro Cabezas, MD, PhD ,
Jorge Joven, MD, PhD ,
Jos op't Roodt, BSC,
Ton J. Rabelink, MD, PhD and
Andy M. Hoepelman, MD, PhD*
* Department of Internal Medicine and Infectious Disease, University Medical Center Utrecht, the Netherlands
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
Department of Internal Medicine, St. Franciscus Gasthuis, Rotterdam, the Netherlands
Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Reus, Spain
Manuscript received May 5, 2005;
revised manuscript received September 9, 2005,
accepted September 20, 2005.
* Reprint requests and correspondence: Dr. Jeroen P. H. van Wijk, Departments of Infectious Disease and Internal Medicine, University Medical Center Utrecht, G02.402, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. (Email: jwijk3{at}hotmail.com).
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Abstract
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OBJECTIVES: We investigated functional and structural markers of atherosclerosis in human immunodeficiency virus (HIV)-infected patients in relation to the presence of the metabolic syndrome (MS).
BACKGROUND: Antiretroviral combination therapy in HIV has been associated with cardiovascular risk factors that cluster in the MS.
METHODS: Thirty-seven HIV-infected patients underwent assessment of flow-mediated vasodilation (FMD), aortic pulse-wave velocity (PWV), and carotid intima-media thickness (IMT). Age-matched type 2 diabetic patients (n = 13) and healthy controls (n = 14) served as reference groups.
RESULTS: Fifteen HIV-infected patients (41%) fulfilled the National Cholesterol Education Program criteria of the MS. The FMD was similarly impaired in HIV-infected patients without the MS (MS– group) and the diabetic patients (5.1 ± 0.4% and 4.9 ± 0.6%, respectively) compared with controls (8.8 ± 0.7%). The HIV-infected patients with the MS (MS+ group) had even more impaired FMD (2.5 ± 0.3%). Carotid IMT was similarly increased in the MS+ group and the diabetic patients compared with the other groups. Aortic PWV was increased in the diabetic patients only. In HIV-infected patients, FMD was related to metabolic parameters, whereas aortic PWV and IMT were related to parameters of HIV infection, time on antiretroviral combination therapy, inflammatory (C-reactive protein and leukocytes) and metabolic parameters.
CONCLUSIONS: The data of the present study suggest an increased cardiovascular risk in HIV-infected patients, even in the absence of clustering of metabolic risk variables. The presence of the MS in HIV is associated with even more advanced atherosclerotic changes. Presumably, both HIV infection and antiretroviral therapy may promote atherosclerosis through mechanisms involving endothelial cells, either directly or indirectly via metabolic risk factors.
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Abbreviations and Acronyms
| | AIDS = acquired immunodeficiency syndrome | | CCA = common carotid artery | | CRP = C-reactive protein | | CVD = cardiovascular disease | | FMD = flow-mediated vasodilation | | HAART = highly active antiretroviral therapy | | HIV = human immunodeficiency virus | | IGT = impaired glucose tolerance | | IMT = intima-media thickness | | MS = metabolic syndrome | | NCEP-ATPIII = National Cholesterol Education Program-Adult Treatment Panel III | | PI = protease inhibitor | | PWV = pulse-wave velocity |
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The use of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) has been associated with insulin resistance, glucose intolerance, unfavorable fat distribution, and dyslipidemia (1–4). The clustering of these risk factors shows striking similarities with the metabolic syndrome (MS), as described in HIV-negative individuals (5). The increasing prevalence of the MS in HIV is cause for concern because the MS is associated with an increased risk for cardiovascular disease (CVD) (5). As survival of patients with HIV increases, CVD may become an important complication in the management of these patients. Despite the close relationship between HAART and metabolic risk factors, controversy surrounding HIV infection and CVD still exists. For example, in a large retrospective study, HAART was associated with a large benefit in terms of acquired immunodeficiency syndrome (AIDS)-related mortality that was not diminished by any increase in the rate of cardiovascular events or related mortality (6). However, in a multicenter prospective study, HAART was independently associated with a 26% relative increase in the rate of myocardial infarction per year of antiretroviral drug exposure during the first four to six years of use (7).
Endothelial dysfunction is an early marker of atherosclerosis and can be assessed clinically by ultrasound assessment of brachial artery flow-mediated vasodilation (FMD). Flow-mediated vasodilation is correlated with the severity and extent of coronary sclerosis (8), and predicts future cardiovascular events (9). Ultrasound measurement of carotid intima-media thickness (IMT) is a well-accepted, noninvasive method of assessing early changes in vascular structure, and is widely used as a surrogate marker for atherosclerotic disease (10). Aortic pulse-wave velocity (PWV) is a noninvasive measurement of arterial stiffness, and is associated with end-organ alterations, such as increased ventricular stress and arterial intima-media thickening (11). Aortic PWV is also an independent predictor of cardiovascular mortality (12). Assessment of all three preclinical atherosclerotic markers may provide important information on both functional and structural stages of atherosclerosis.
In a cross-sectional study of HIV-infected adults, it was shown that those on a protease inhibitor (PI)-containing regimen had markedly impaired FMD compared with those not taking PIs (13). However, in that study, FMD was not compared with an HIV-negative reference group, and the relative contributions of antiretroviral agents, chronic inflammation attributable to viral infection, and metabolic risk factors and their interactions were difficult to identify. Structural vascular abnormalities are also present in patients with HIV infection. Carotid IMT is higher in HIV patients than in age-matched control patients (14,15), and progresses much more rapidly than previously reported rates in non-HIV cohorts (16). Arterial stiffness has not been investigated in HIV-infected adults. Clearly, most studies using intermediate CVD end points suggest an increased risk for premature atherosclerosis in HIV-infected patients.
It is becoming increasingly important to identify those HIV-infected patients who have the highest risk for atherosclerosis. However, there is still a lack of studies on cardiovascular risk assessment using established intermediate end points in HIV-infected patients. In the present study, we investigated FMD, aortic PWV, and IMT in HIV-infected men on stable HAART and subdivided the group into those with and without the MS as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) guidelines (17). In addition, we related these well-established parameters of the vasculature to clinically easily obtainable anthropometric, hemodynamic, and laboratory parameters. The data were compared with data from age-matched type 2 diabetic patients, who are known to have a marked increased cardiovascular risk (18), and healthy men as controls.
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Patients and methods
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Patients.
Men between 18 and 70 years old with a documented HIV infection were recruited from the Department of Infectious Disease of the University Medical Center Utrecht. Inclusion criteria were HIV-RNA <10.000 copies/ml and HAART for at least 12 months. Exclusion criteria were the presence of opportunistic infectious disease and/or malignancies, renal and/or liver disease, diabetes mellitus, and the use of lipid-lowering and/or antihypertensive agents. The study protocol was approved by the local research ethics committee of the University Medical Center Utrecht. All participants gave written informed consent. The data on FMD and aortic PWV were compared with data from 15 age-matched type 2 diabetic and 15 healthy men. The diabetic patients were all treated with oral antihyperglycemic agents (four with sulfonylureum derivatives, four with metformin, and five with a combination of both) and had glycated hemoglobin <9%. None of the diabetic patients were taking statins and/or antihypertensive agents. Furthermore, the diabetic patients and the healthy controls met the same inclusion criteria as the HIV-infected patients. At inclusion, length, weight, blood pressure, and waist and hip circumference were measured.
Oral glucose tolerance test.
A standard oral glucose tolerance test was performed in the HIV-infected patients only. The patients visited our department after a 10-h fast. After placing a cannula for venous blood sampling, patients rested for 15 min before administration of the glucose load (75 g). Peripheral blood samples were obtained in sodium ethylenediaminetetraacetic acid (2 mg/ml) before and at regular 30-min intervals up to 2 h after glucose ingestion. All samples were kept on ice and centrifuged immediately for 15 min at 800 g at 4°C and stored at –80°C until assay.
Endothelial function.
Nitric oxide-dependent FMD, as percentage diameter change in the brachial artery after reactive hyperemia, was measured noninvasively by ultrasonography (19). Measurements were performed at the elbow of the right arm using a vessel wall movement system (Wall Track System, Pie Medical, Maastricht, the Netherlands), which consists of an ultrasound imager with a 10-MHz linear array transducer connected to a data acquisition system and a personal computer. Three measurements were averaged to calculate a baseline diameter of the brachial artery. By inflation of a blood pressure cuff for 5 min at a pressure of 200 mm Hg, ischemia was applied to the forearm distal to the location of the transducer. Ultrasonography continued for 5 min after cuff release, with measurements at 30-s intervals. The widest lumen diameter was taken as a measurement for maximal vasodilation. Nitroglycerin (400 µg) was used to determine endothelium-independent vasodilation. All measurements were performed by the same technician with patients supine in a quiet, temperature-controlled (20°C to 22°C) environment after at least 15 min of rest. All patients were requested to refrain from smoking on the morning of the vascular measurements.
PWV.
Arterial stiffness was assessed noninvasively by aortic PWV (20). Aortic PWV was calculated as distance/transit time (in centimeters per second) of the pulse wave from the base of the neck from the common carotid to the right femoral artery. The pulse waves at each of these sites were obtained sequentially with a tonometric sensor (Sphygmocor, Atcor Medical, Sydney, Australia). Pulse transit time was determined as the average of 10 consecutive beats. The distance traveled by the pulse waveform was measured over the participant's torso. The validation of this automatic method and its reproducibility have been published previously (20). The measurements were performed twice in each patient and then averaged to obtain the mean aortic PWV, which was used for the statistical analysis.
Carotid IMT.
To measure carotid IMT, ultrasonography of the left and right common carotid artery (CCA) was performed with a 10-MHz linear-array transducer (ATL UltraMark IV). In accordance with the Rotterdam Study ultrasound protocol (21), a careful search was performed for all interfaces of the anterior (near) and posterior (far) walls of the distal CCA. The optimal longitudinal image was frozen on the R wave of the electrocardiogram and stored on videotape. This procedure was repeated four times for both sides. From the videotape, the frozen images were digitized and displayed on the screen of a personal computer using additional dedicated software (22). With a cursor, the interfaces of the distal CCA were marked across a length of 10 mm. The beginning of the dilatation of the distal CCA served as a reference point for the start of the measurement. The average of the IMT of each of the four frozen images was calculated. For each individual, the IMT was determined as the average of near- and far-wall measurements of both the left and right arteries. The reproducibility of IMT measurements has been previously described (22). Measurement of IMT was performed in the HIV-infected patients only.
Analytical methods.
Total and high-density lipoprotein cholesterol, triglycerides, apolipoprotein B, glucose, and glycated hemoglobin were measured using standard laboratory procedures. Ultracentrifugation was used to isolate low-density lipoprotein. Insulin was measured by enzyme-linked immunosorbent assay (Mercodia, Uppsala, Sweden). Blood leukocyte counts were determined automatically using a Celldyn-3500 (Abbott, Abbott Park, Illinois). Plasma C-reactive protein (CRP) was measured using a high sensitivity method (Quantex hs-CRP kit, Biokit, S. A., Barcelona, Spain), with a lower limit of detection of 0.10 mg/l. The HIV viral load was determined by ultrasensitive assay (Roche Diagnostics Amplicor HIV-1 Monitor assay, Pleasanton, California), and CD4 cell counts were determined by flow cytometry.
Statistical analysis.
Data are expressed as mean (SEM) in the text, tables, and figures. The NCEP-ATPIII guidelines were used to identify patients with the MS (17). The MS was present when at least three of five risk determinants (increased waist circumference, increased blood pressure, elevated fasting triglyceride level, low high-density lipoprotein cholesterol, and elevated fasting glucose level) were present. Differences between two groups were tested with Mann-Whitney tests. Comparisons between three groups or more were performed with one-way analysis of variance, with the least significance difference test as post hoc analysis test. Bivariate correlations for the total group of HIV-infected patients were calculated using Spearman's correlation coefficients. All significantly correlated variables were used as independent variables in stepwise multiple regression analysis with FMD, aortic PWV and IMT as dependent variables. Calculations were performed using SPSS/PC + 11.5 (SPSS Inc., Chicago, Illinois). Statistical significance was taken as the 5% level.
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Results
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Characteristics of the study group.
Of the 37 HIV-infected patients included in the study, 15 (41%) fulfilled the NCEP-ATPIII criteria for having the MS. Elevated fasting plasma triglyceride level (68%), increased blood pressure (54%), and low high-density lipoprotein cholesterol (41%) were the most prevalent components of the MS, whereas high fasting glucose level (3%) and a high waist circumference (5%) were less prevalent. None of the healthy controls fulfilled the criteria for having the MS, whereas all type 2 diabetic patients had the MS. All HIV-infected patients were currently receiving HAART with nucleoside reverse transcriptase inhibitors and a PI and/or a nonnucleoside reverse transcriptase inhibitor (Table 1). Baseline characteristics and metabolic profile of the HIV-infected groups, the diabetic patients (n = 13), and the healthy men (n = 14) are shown in Table 2. Apolipoprotein B was similarly increased in the diabetic patients and the MS– group as compared with the healthy controls, and it was highest in the MS+ group. Nine HIV-infected patients (all in the MS+ group) had impaired glucose tolerance (IGT).
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Table 2. Characteristics of HIV-Infected Patients With (MS+ Group) and Without (MS– Group) the Metabolic Syndrome, Type 2 Diabetic Patients, and Healthy Control Patients
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Functional and structural vascular assessment.
Hemodynamic, inflammatory, and vascular parameters of the study group are shown in Table 3. Baseline brachial artery lumen diameter measurements were not different between the groups (Table 3). Flow-mediated vasodilation was similarly impaired in the MS– group and the diabetic patients compared with the control patients (Fig. 1A). The MS+ group had even more impaired FMD than the MS– group and the diabetic patients. Endothelium-independent vasodilation was higher in the control patients than in the other groups. The diabetic patients had increased aortic PWV compared with the other groups (Fig. 1B), but no difference in aortic PWV was observed between the MS+ group and the MS– group. The HIV-infected patients with IGT (n = 9) had increased aortic PWV compared with those with normal glucose tolerance (9.2 ± 0.7 cm/s vs. 7.7 ± 0.6 cm/s, p = 0.03). The patients on a PI-containing regimen (n = 25) had a tendency toward more impaired FMD compared with those not taking PIs (n = 12, 4.1 ± 0.4% vs. 5.3 ± 0.6%, respectively, p = 0.09), but similar aortic PWV (8.1 ± 1.1 cm/s vs. 7.9 ± 0.9 cm/s, respectively). Carotid IMT was increased in the MS+ group and the diabetic group compared with the other groups (Fig. 1C).
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Table 3. Hemodynamic, Inflammatory, and Vascular Parameters of HIV-Infected Patients With (MS+ Group) and Without (MS– Group) the Metabolic Syndrome, Type 2 Diabetic Patients, and Healthy Control Patients
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Determinants of vascular measurements in HIV-infected patients.
Correlations between the vascular measurements and anthropometric, hemodynamic, and laboratory parameters for the total group of HIV-infected patients (n = 37) are shown in Table 4. Using stepwise multiple regression analysis, FMD was best predicted by apolipoprotein B (standardized beta = 0.30, p = 0.01), explaining 40% of the variation. Aortic PWV was best predicted by the mean arterial pressure (standardized beta = 0.14, p = 0.03) and the two-hour glucose concentration (standardized beta = 0.24, p = 0.02), explaining 73% of the variation. Age (standardized beta = 0.54, p = 0.02), apolipoprotein B (standardized beta = 0.44, p = 0.03), and HIV viral load (standardized beta = 0.33, p = 0.04) were the best predictors of IMT, explaining 76% of the variation. In both the HIV-infected patients and the diabetic patients, glycated hemoglobin levels were not associated with the vascular measurements (data not shown).
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Table 4. Spearman Correlation Coefficients (r) Between Vascular Measurements and Other Parameters for the Total Group of HIV-Infected Patients (n = 37)
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Discussion
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As the survival of patients with HIV increases, it is becoming increasingly important to identify those patients who are at increased risk for accelerated atherosclerosis. In the present study, we determined the relationship between intermediate end points of CVD and clinically easily obtainable anthropometric, hemodynamic, and laboratory parameters in HIV-infected patients. Our main findings are that HIV-infected patients without the MS have endothelial dysfunction similar to that of type 2 diabetic patients. The presence of the MS in HIV was associated with even more advanced functional and structural vascular abnormalities.
In the present study, 41% of the patients fulfilled the definition of the MS according to the NCEP-ATPIII guidelines. In the U.S., approximately 24% of the general population fulfills this definition (23). Elevated triglyceride levels were the most prevalent component of the MS, whereas an increased waist circumference and high fasting plasma glucose level were less prevalent. Despite normal fasting glucose levels, 24% of the HIV-infected patients had IGT (24%). On average, both HIV-infected groups had a normal waist circumference (<102 cm) but a relatively high waist-to-hip ratio. Therefore, the presentation of the MS in HIV-infected patients may differ from that in the general population because of differences in body composition and direct effects of antiretroviral agents on glucose and lipid homeostasis. We have chosen to use the NCEP definition for the MS because these criteria do not include oral glucose tolerance test and urinary albumin level, making it more easily applicable for routine screening of HIV-infected patients than the World Health Organization definition (24).
Atherosclerosis is characterized by and preceded by endothelial dysfunction (8,9). In the present study, HIV-infected patients without the MS showed endothelial dysfunction comparable to that of age-matched type 2 diabetic patients, who are known to have a marked increased risk for CVD (18). These data suggest an increased CVD risk in HIV-infected patients, even in the absence of metabolic risk variable clustering. Several factors may explain this observation. First, in HIV-infected patients, the endothelium could be activated either directly by HIV or by a leukocyte-mediated inflammatory cascade triggered by HIV infection. Several studies have shown that HIV-associated proteins (gp120 and Tat) interact with chemokine receptors and induce endothelial cell apoptosis (25,26). Endothelial activation may also occur by cytokines secreted in response to leukocyte activation by HIV (27–29). We observed elevated blood leukocyte counts and elevated CRP levels in the HIV-infected patients, most likely because of chronic immune activation associated with HIV infection (27–29). However, in addition to chronic immune activation, CRP levels have also been related to body composition in HIV-infected patients (30). In HIV-negative patients, both leukocyte counts and CRP have been linked to endothelial dysfunction and future cardiovascular events (31–34). Second, it should be noted that the MS– group was characterized by high apolipoprotein B levels, despite the absence of other metabolic risk factors, and apolipoprotein B was also closely related to endothelial dysfunction in our study. This may be attributable to direct inhibitory effects of PI on proteosomal apolipoprotein B degradation in the liver (35). Third, antiretroviral agents may also directly induce endothelial dysfunction. For example, when healthy volunteers were given indinavir for four weeks, significant endothelial dysfunction was observed, independent of the lipid profile (36). Whether this effect also occurs in HIV-infected patients is not known. In our study, the patients on a PI-containing regimen showed a tendency toward more pronounced endothelial dysfunction compared with those on a non-nucleoside reverse transcriptase inhibitor-containing regimen, which may be significant if repeated in a larger group.
The nitroglycerin response was lower in both the HIV-infected and the diabetic patients compared with the control patients. Impaired smooth muscle responsiveness has been observed previously in patients with type 2 diabetes (37). No difference in nitroglycerin responsiveness was observed between both HIV-infected groups and the diabetic patients, allowing comparisons in endothelial function assessed by FMD between these groups.
In our study, we excluded patients with HIV-RNA >10,000 copies/ml and patients with AIDS-related diseases. Lymphocyte counts were normal in our group of HIV-infected patients, whereas these are generally low in untreated HIV-infected patients and in patients with AIDS-related diseases. Almost 80% of the patients had HIV-RNA <50 copies/ml. However, some patients had discordant responses in virologic and immunologic parameters. Virologic failure, immunologic failure, and clinical progression have distinct time courses and may occur independently or simultaneously. In patients with a history of extensive prior treatment and drug resistance, complete viral suppression is often difficult to achieve. Thus, the goal is to preserve immunologic function and prevent clinical progression, even with ongoing viremia. Even partial virologic suppression of HIV-RNA correlates with clinical benefits probably attributable to diminished viral fitness.
As expected, the presence of the MS was associated with more severe endothelial dysfunction, as well as a marked increased IMT, in our cohort of HIV-infected men, suggesting more advanced functional and structural atherosclerotic changes. Hence, the NCEP-ATPIII criteria of the MS may also be used in HIV-infected patients to identify patients at risk for accelerated atherosclerosis. Other observational studies have shown that IMT in HIV-infected patients is related to several traditional risk factors (14–16), but when a control group was added to the analysis, HIV infection was also an independent predictor of IMT (16). Furthermore, progression of IMT has been related to nadir CD4 counts ( 200) (16), which were unfortunately not available for most of our patients. We did not find a relationship between vascular parameters and the actual CD4 cell count, but the results of our study suggest that metabolic, virologic and inflammatory parameters, time since diagnosis of HIV infection, and time on HAART may contribute to structural atherosclerotic changes in HIV-infected patients. It must be noted that we only measured intermediate markers of CVD, and not CVD end points. Nevertheless, given the observed metabolic profile and vascular abnormalities, at least a number of HIV-infected patients in our study group would be eligible for lipid-lowering therapy.
The presence of the MS per se was not associated with increased arterial stiffness, despite impaired endothelial function and increased IMT in these patients. In contrast, the HIV-infected patients with IGT (n = 9) showed increased aortic PWV comparable to that of type 2 diabetic patients. This may suggest that increased arterial stiffness is confined to HIV-infected patients with deteriorating glucose tolerance status. Previous studies support a close relationship between IGT, type 2 diabetes, and arterial stiffness (38,39). The close associations between aortic PWV and the two-hour glucose concentration and insulin sensitivity support this concept. Aortic PWV was also associated with the time since diagnosis of HIV infection and the time on HAART.
In summary, endothelial function is disturbed in HIV-infected patients, even in the absence of metabolic risk variable clustering. The presence of the MS is associated with even more advanced atherosclerotic changes in HIV-infected patients. Presumably, both HIV infection and antiretroviral therapy may promote atherosclerosis through mechanisms involving endothelial cells, either directly or indirectly via metabolic risk factors. Future studies are necessary to investigate whether treatment of metabolic risk factors could lead to reduced cardiovascular risk in these patients.
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Footnotes
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Dr. van Wijk received educational grant support from the Dutch Organization for Scientific Research, and Dr. de Koning is recipient of a Career Development Grant from the Netherlands Diabetes Research Foundation.
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