Published online before print August 2, 2007, doi: 10.1161/STROKEAHA.106.479030
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(Stroke. 2007;38:2477.)
© 2007 American Heart Association, Inc.
Original Contributions |
The Role of Immunity and Inflammation in the Progression of Atherosclerosis in Patients With HIV Infection
From the Centre de Recerca Biomédica (B.C., G.A., J.C., J.J.), Servei de Medicina Interna (B.C., S.P., C.A.-V., L.M.), and Servei de Radiología (M.M.), Hospital Universitari Sant Joan, Reus, Spain.
Correspondence to Blai Coll, MD, Servei de Medicina Interna, Hospital Universitari Sant Joan, 43201 Reus, Spain. E-mail bcoll{at}grupsagessa.com
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Abstract |
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Background and Purpose— The initial steps of atherosclerosis and the entry of HIV into the cell share similar biological mechanisms. Therefore, our hypothesis is that the progression of atherosclerosis in patients with HIV infection can be influenced by variations in genes implicated in both processes.
Methods and Results— The progression of atherosclerosis over a 2-year follow-up period was measured as the combined carotid and femoral intima media thickness (IMT) in 141 patients with HIV infection. The 
IMT (IMTfollow-up–IMTbaseline) values were used to segregate patients as minimal progressors or regressors (lowest IMT tertile), slow progressors (mid IMT tertile), and rapid progressors (highest IMT tertile). Mutations CCR-532, CCR-2 64I, MCP-1-2518G, SDF1-3'A, and CX3CR-1 (T280 mol/L and V249I) in the host DNA were determined. Mean age of the patients was 38.96 (SEM: 0.61) and 68.8% were male. The mean IMT was 0.045 mm (0.01) per year, which represented a significant progression (P<0.001) with respect to baseline values. Patients with minimal progression or regression had a significantly (P=0.01) higher CD4 cell count than slow progressors and rapid progressors. Multivariate analyses indicated that age and total cholesterol were positively associated with IMT progression. In contrast, the CD4 cell count, the SDF1-3'A, and the CX3CR-1 249 I mutated alleles were associated with lesser IMT progression.
Conclusion— The course of atherosclerosis in patients with HIV infection is influenced by polymorphisms in the SDF1 and CX3CR1 genes by metabolic variables and by the CD4 cell count. These data would be of help in assessing therapeutic needs of these patients.
Key Words: atherosclerosis • chemokine polymorphisms • HIV • intima media thickness • nonconventional cardiovascular disease risk factors
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Introduction |
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Patients with HIV infection have higher rates of atherosclerosis1,2 and the progression is faster than in noninfected individuals.3 Chemokines play a significant role in atherosclerosis and HIV infection4,5 and chemokine-related genetic variants are implicated in the development of atherosclerosis as well as in the natural course of HIV infection.5–8
Circulating monocytes are attracted to the subendothelial space mainly mediated by monocyte chemoattractant protein-1 (MCP-1), where they become foam cells.7,9 A polymorphism in the promoter region of the MCP-1 gene (MCP-1-2518G) is associated with a higher MCP-1 expression.10 The bearers of this mutation are more prone to the development of AIDS-associated dementia11 or subclinical atherosclerosis.12 Its natural receptor, CCR-2, a minor coreceptor for the entry of HIV into the cell,13 has been implicated in the development of atherosclerosis14 as well as in disease progression in HIV-infected individuals.15 Similarly, the stromal derived factor-1 (SDF-1)16 activates platelets within the atheromatous plaque17 and promotes the migration of smooth muscle cells to the subendothelial space.18 A polymorphism in the untranslated region, SDF1-3'A, which is associated with a lower SDF-1 expression,19 influences the disease progression as well as the presence of subclinical atherosclerosis in patients with HIV infection.20,21
Another chemokine, fractalkine, is upregulated in inflamed tissues and it functions as a chemoattractant as well as an adhesion molecule. DNA polymorphisms in the gene for its specific receptor CX3CR1 (V249I and T280 mol/L) lead to a reduced number of fractalkine binding sites, to a reduced risk of coronary artery disease, and to a more rapid progression to AIDS.22,23
As a consequence, patients with HIV infection are prone to continuous inflammatory stimuli, which may trigger a cytokine imbalance that can influence the development of atherosclerosis.24 However, these patients also present with well-known, preexisting cardiovascular risk factors,25 and our aim was to evaluate these variables and to evaluate their relative contribution to the progression of atherosclerosis.
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Design and Methods |
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Participants and Design
We performed a prospective study aimed at evaluating atherosclerosis and its related factors in a cohort of patients with HIV infection (n=305) who were receiving regular attention in our outpatient HIV clinic. The results of the initial assessments have been published previously12,21 and the current article summarizes the follow-up data. In the first clinical consultation, a complete physical examination was performed, including the assessment of body weight, height, and blood pressure according to standard guidelines26; and a venous blood sample was drawn for blood chemistry and DNA analyses. At the same visit, the first ultrasound baseline scans of the carotid and femoral arteries were performed. The identical protocol was applied by the same investigators after 2 years of follow up. During this period, data on smoking habit, alcohol consumption, time since HIV diagnoses, nadir of the CD4 cell count (CD4 cell count before starting antiretroviral therapy), time on highly active antiretroviral therapy, and opportunistic infections were collated. Lipodystrophy and metabolic syndrome were diagnosed using accepted criteria.27,28 The laboratory measurements included plasma total cholesterol, high-density lipoprotein cholesterol, triglycerides, and glucose as well as serum HIV-1 RNA and blood lymphocyte T CD4+ cell count. Low-density lipoprotein cholesterol was calculated from the Friedewald formula. The study was approved by the Ethics Committee of Hospital Universitari Sant Joan.
Genotyping
DNA was obtained using the Pure Gene Kit (Gentra Systems, Inc). We determined MCP-1-2518G, CCR-2 V64I, SDF1-3'A, CCR-5 32, and CX3CR-1 (V249I and T280 mol/L) variants using previously published methods.11,16,20,24 For genotype comparisons, we used a general population-based control group of unrelated subjects (n=348) the details of which have been described previously.29 Briefly, they were healthy people (167 female, 181 male), mean age 42 years (range: 19 to 75 years), who were considered representative of the general population in our area.
Ultrasound Standardized Protocol
The carotid and femoral ultrasound measurements were performed under the identical protocol by the same investigators (M.M., B.C.) who were blinded with respect to the results of the other measured variables. We used a GE Logiq 700 with an ultrasound probe of 7 to 10 MHz. We identified and digitally recorded the far wall of the common carotid artery (1 cm proximal to the bifurcation), the carotid bulb (in the bifurcation), the internal carotid artery (1 cm distal to the bifurcation), and the common femoral artery. All the intima media thickness (IMT) measurements were performed at the predefined points using the image processing software AnaliSYS (Soft Imaging System, Münster, Germany). IMT measurements on each arterial segment were averaged and used in the statistical analyses as combined IMT, as previously described.13 The intraclass correlation coefficient between the 2 examiners in evaluating the images from 20 IMT measurements was 0.89 (P<0.001), and the absolute IMT difference was 0.01 mm (0.025). To assess reproducibility of measurements, the images of 20 randomly selected patients were remeasured applying the same protocol. The intraclass correlation coefficient between the 2 sets of measurements was 0.91, and the absolute difference in IMT was 0.007 mm (0.018). To assess the reproducibility of rescanning and remeasurement, 10 patients underwent a rescan within 1 month. The intraclass correlation coefficient for the measurement was 0.94.
Statistical Analyses
Results are expressed as the mean with SEM in parentheses or in percentages. Kolmogorov-Smirnov test was applied to test the distribution of variables. Paired Student’s t test was applied to evaluate differences in measurements of continuous variables at baseline and at follow up and the Wilcoxon test when the data were not normally distributed. The 
2 test was used to compare categorical variables. The difference in the combined IMT value between the 2 examinations was calculated as IMT=IMT follow up–IMT baseline. Univariate analyses were used to identify the variables having an impact on IMT. We defined as "rapid progressors" those individuals with a IMT value in the highest tertile (IMT 
0.18 mm), "slow progressors" as being those patients with IMT between 0.02 and 0.179 mm, and "minor progressors" or "regressors" as those in the lowest tertile (IMT 
0.019 mm). Differences among these groups were tested with analysis of variance and a post hoc analysis (Bonferroni test) was applied.
Stepwise regression analyses were performed to determine prognostic factors for baseline subclinical atherosclerosis (defined as the presence of an atherosclerotic plaque or as a combined IMT 0.8 mm) and for the change in the combined IMT at 2 years of follow up. The stepwise analysis method added variables one-by-one into the model with the variable with the smallest probability value significant at the 0.05 level.
For the identification of variables related to baseline subclinical atherosclerosis, we applied a logistic regression analyses and, for the IMT, a linear regression analyses in which the following were the independent variables: age, gender, body mass index, systolic and diastolic blood pressure, fasting plasma lipid concentrations, lipodystrophy, metabolic syndrome, and CD4 cell count. Also included were the duration of the patient’s antiretroviral treatment and the results of the genotype analyses. The multivariate linear regression analysis was adjusted for the baseline IMT values.
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Results |
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General Characteristics of HIV-Infected Participants
From the 183 participants who accepted to participate, 8 died from HIV-associated diseases, 27 were lost to follow up or declined to participate in the second evaluation, and in 7 patients, the recorded images were not of sufficient quality to perform the analyses.
The clinically relevant characteristics of the 141 patients included are summarized in Table 1. The mean time lapse to HIV seroprevalence (time from diagnoses) was 7.24 (0.36) years and 79 (56%) patients were coinfected with the hepatitis C virus. Most patients (56%) were current or past intravenous drug abusers and sexual intercourse-related factors were identified as the cause of the infection in the remaining patients. In the baseline examination, most patients were heavy smokers, relatively young, without significant obesity, and with normal blood pressure values. Mean plasma lipid and glucose concentrations were within the laboratory reference ranges. Mean CD4 cell count was significantly higher in the second evaluation and there was a trend toward more patients having undetectable HIV viral load (Table 1). Most patients (92.2%) were receiving highly active antiretroviral therapy treatment schemes and, during the follow up, there were no major changes in the prescriptions (Table 1).
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We found higher total plasma and low-density lipoprotein cholesterol concentrations in the baseline examination, but higher mean systolic blood pressure was observed in the second evaluation (Table 1). Similarly, we found more patients who fulfilled the criteria of lipodystrophy and metabolic syndromes in the second examination, although this difference did not reach statistical significance. During the follow up, 3 patients had cardiovascular disease events (2 patients with stroke and one patient with an acute coronary syndrome) and statins were prescribed to 10 patients.
Genotype Distribution
As shown in Table 2, there were no significant differences either in allele frequencies or genotype distributions between the group of patients with HIV infection (N=141) and the general population (N=348).
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For statistical purposes, those patients with at least one mutated allele for MCP-1, SDF-1, CCR-5, or CCR-2 were analyzed as a single group. From among the 9 possible CX3CR-1 haplotypes, we did not find any study participant with the VV/TM, VV/MM, and VI/MM genotypes. This indicated that the CX3CR-1 polymorphisms were in complete linkage disequilibrium. Because the 249I allele has been shown to be associated with less extensive development of atherosclerosis,24 we compared the V249V genotype against the other genotypes as a combined group (V249I or I249I).
There were no significant differences in the CD4 cell count and HIV viral load between those patients carrying the mutated alleles compared with those carrying the wild type and, as such, the HIV-related variables did not segregate with genotypes.
Factors Influencing Baseline and Follow-Up Values of Combined Intima Media Thickness
There was a significant (P<0.001) mean annual increase (0.045 mm) in the combined IMT between the baseline measurements [0.75 (0.01) mm] and the follow-up values [0.84 (0.01)] (Figure 1), and this tendency did not vary when carotid and femoral arteries were analyzed separately (data not shown). Males showed higher baseline IMT values than females, although patients of both genders had similar rates of increase (Figure 1). Baseline values were not significantly influenced by the lipid profile, the presence of metabolic syndrome, or the treatment with protease inhibitors.
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We used the IMT values to segregate the patients into regressors (N=45), slow progressors (N=48), and rapid progressors (N=48) so as to identify variables that may influence the course of atherosclerosis (Table 3). None of the classical cardiovascular disease risk factors were significantly associated with the course of IMT. The proportion of patients with metabolic syndrome was lower among the regressors, but the difference did not reach statistical significance (P=0.09). There were significant differences in the CD4 cell counts among groups. Regressors had a higher nadir and baseline CD4 cell counts than slow progressors and rapid progressors (Table 3; Figure 2), indicating that the better the immune status, the lower the likelihood of atherosclerosis progression.
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P=0.04 comparing the different rates of IMT progression segregated with respect to SDF-1 and CX3CR-1, respectively (analysis of variance).Genetic variables were distributed in a similar manner among groups, although the variant CX3CR-1 249I was more frequent among the regressors (P=0.08). Moreover, the simultaneous presence of the putatively atherosclerosis-protective alleles (ie, SDF1-3'A+CX3CR-1 249I+MCP-1- A2518) was significantly (P=0.008) higher in the group of regressors.
The differences in the rates of progression were not statistically significant with respect to the genetic variants in CCR-5, CCR-2, and MCP-1. However, those patients with either the SDF1-3'A or the CX3CR-1 249I alleles showed a significantly lower IMT increase than those with the corresponding wild-type alleles (Figure 3).
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Variables Related to Atherosclerosis Progression
We applied multivariate regression analyses to identify those variables that could influence baseline IMT values and atherosclerosis progression. The results of the analyses revealed that age, diastolic blood pressure, and the MCP-1 to 2518G mutated allele were positively, and significantly, associated with a higher likelihood of atherosclerosis in the baseline measurements (Table 4). The combined IMT in the baseline measurement was the strongest predictor of the course of IMT, ie, the higher the baseline values, the slower the rate of IMT increase. Age and total cholesterol were positively associated with a higher IMT increase (Table 4). The CD4 cell count was also an important determinant, ie, higher CD4 cell counts predicting slower IMT increase. Finally, the mutated SDF1-3'A allele and the presence of the I allele in position 249 of the CX3CR1 gene were also identified as protective factors in the increase of IMT (Table 4).
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The formula resulting from the application of the multivariate model predicts 60% of the variance of IMT, and the predicted values correlated closely (Pearson coefficient=0.74, P<0.001) with those observed (Figure 4).
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Discussion |
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Our data indicate that the IMT in patients with HIV infection increases at a faster rate (0.045 mm/year) than that considered as the threshold value (0.03 mm/year) beyond which the risk of experiencing cardiovascular disease events is significantly higher.30 Among the causes of such progression, only age and total cholesterol are among the classical cardiovascular risk factors that we observed to be significantly associated with a higher rate of IMT increase. Our data are similar to that of a previous study by Hsue et al,3 which had shown an IMT increase of 0.07 mm/year. The mean age of participants and different genetic background may explain the differences in the rates of atherosclerosis progression between studies. Furthermore, one relevant source of variability among studies is that we used different protocols to acquire and read the IMT images. However, their data reached similar conclusions and, as such, are highly informative.
Another variable that influences the rate of IMT increase is the baseline IMT. The use of a structural measure to assess atherosclerosis reflects the retrospective lifetime exposure to risk factors. Indeed, it may indicate that those patients with higher baseline IMT had been also exposed to a larger number of classical risk factors and which have been prospectively controlled. This may explain the negative association between baseline IMT and progression. However, a specifically designed controlled clinical trial would need to be performed to answer this question.
We observed, as well, that the CD4 cell count may play a relevant role in atherosclerosis progression; the higher the CD4 cell count, the lower the rate of atherosclerosis progression. It is plausible that patients with a better CD4 recovery were not under the deleterious influence of CD4 activation.31–33 Atherosclerotic plaques are constantly being remodeled, and this determines the rate of progression/regression of the disease. CD4+ cells can influence this dynamic process as has been described for monocytes in animal models of atherosclerosis regression.34
The detrimental influence of low CD4 cell counts in the IMT increase may be explained by a higher rate of antiretroviral prescriptions. However, in the multivariate analyses, none of the treatments analyzed were positively associated with atherosclerosis progression.
The progression of atherosclerosis in patients with HIV infection can be controlled through a reduction in cardiovascular risk factors, a reduction in the prescription of protease inhibitors, and an increase in concomitant treatments with lipid-lowering agents.35 These results warrant confirmatory large-scale multicentered trials should incorporate an assessment of the IMT within a standardized protocol. This is being recognized in clinical trials assessing the efficacy of lipid-lowering drugs.36
Chemokines and their natural receptors have received increasing attention in atherosclerosis research.5 This is especially relevant in patients with HIV infection because the chemokines have been implicated in both processes: the entry of HIV into the cell and the ability of the monocyte to enter the subendothelial space. MCP-1 is the more active molecule implicated in chemotaxis,7 a phenomenon in which other molecules such as fractalkine and its receptor CX3CR-1 participate. The fractalkine/CX3CR-1 axis is of particular interest because it can function as a chemoattractant and as a direct adhesion molecule.23 The presence of the 249I mutated allele has been associated with lower CX3CR-1 expression24 and, as such, the interaction between fractalkine and CX3CR-1 is less likely. Our results indicate that patients with HIV infection who bear the 249I allele have significant protection against atherosclerosis progression. Because heterozygous patients may have only a partial deficiency in CX3CR-1 function, and because alternative monocyte recruitment pathways can exist, our study addressing the role of MCP-1 and SDF-1 adds a different perspective to the atherosclerosis process. The SDF1-3'A mutation is associated with a lower SDF-1 expression. It appears not to have relevance in determining baseline subclinical atherosclerosis but seems, however, to have a beneficial influence on the progression of the disease. Moreover, the putative "atherosclerosis-protective" combination such as CX3CR-1 249I+SDF1-3'A+ MCP-1-2518A is associated with a lower rate of IMT increase.
Limitations of the Study
Previous reports in non-HIV-infected patients assessed the influence of genetics in the values of IMT. It was estimated that 35% to 45% of the variability in multivariable-adjusted carotid IMT is explained by genetic factors.37 One of the aims of our study was to investigate the relationship between selected genetic polymorphisms and the IMT course. Although the associations observed in univariate were not very robust, we included these variables in the multivariate model to determine, specifically, the influence of certain genetic variations in this clinical setting. However, to confirm such genetic associations, a larger patient population sample would be necessary. Furthermore, to preclude the effect of confounding variables associated with highly active antiretroviral therapy therapies, the study would need to be performed in treatment-naïve patients. There are lines of evidence suggesting a deleterious effect of protease inhibitors on the atherosclerosis process,38–40 but, to date, no studies have been specifically designed to prove such hypotheses and, as such, they have yet to be definitively demonstrated.
We expressed our data from carotid and femoral IMT as combined IMT mainly because the course of IMT in both territories was observed to be similar (significant progression was found in both carotid and femoral arteries). Also, atherosclerosis is a systemic disease in which disturbances in carotid and femoral arteries have been associated with a higher incidence of cardiovascular and peripheral vascular disease, respectively.41
Implications
Our multivariate analyses resulted in the configuration of a formula that predicts 60% of the variance in IMT. The only significant modifiable factors were total cholesterol and CD4 cell counts. For example, in a 40-year-old patient with a baseline IMT of 0.8 mm and wild type for the 2 critical genotypes (SDF1-3'A and CX3CR-1 249I), the reduction of 1 mmol/L of total cholesterol and the increase of 100 CD4 cells/mm3 would result in a 20% reduction in the predicted IMT. Our data also indicate that the putative deleterious effect of antiretroviral therapy is unlikely to occur if the patient’s plasma cholesterol concentration is properly managed.
In measuring IMT, we support the exploration and measurement of the degree of atherosclerosis and not just the assessment of risk factor status in the development of the disease. We propose that lipid-lowering agents should be used not only for the patient with high values of total plasma cholesterol and low-density lipoprotein cholesterol, but also for those patients with pathological baseline IMT as well as those with a higher rate of IMT increase.
Summary
The progression of atherosclerosis in patients with HIV infection is influenced by metabolic, inflammatory, and immunological variables. Our results indicate that, in the assessment of a patient population with HIV infection, the classical cardiovascular disease risk factors should be complemented with the study of the inflammatory response (especially those genetic factors that have an influence in HIV and in atherosclerosis). These include MCP-1, SDF-1, and CX3CR-1 and immune status (CD4 cell count at the moment of HIV diagnoses). This conclusion has been reached by another study in non-HIV-infected patients in which a combination of genetic polymorphisms and a proinflammatory score was strongly related with carotid and femoral IMT.42 Standardized protocols to measure IMT and the identification of the genetic susceptibility should be implemented for a better, and more individualized, cardiovascular disease risk assessment of the patient.
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Acknowledgments |
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Sources of Funding
Financial support was provided by grants from the Health Investigation Fund (Fondo de Investigación Sanitaria [FIS PI041752]) and Network of Centers for Metabolism and Nutrition (Red de Centros en Metabolismo y Nutrición [C03/08]). Blai Coll is the recipient of a career development award from the Carlos III Health Institute (Instituto de Salud Carlos III).
Disclosures
None.
Received December 1, 2006; revision received February 11, 2007; accepted March 6, 2007.
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