Influence of pravastatin on carotid artery structure and function in dyslipidemic HIV-infected patients receiving antiretroviral therapy
Boccara, Francka; Simon, Tabassomeb; Lacombe, Karinec; Cohen, Arield; Laloux, Brigittea; Bozec, Erwana; Durant, Stéphanieb; Girard, Pierre-Mariec; Laurent, Stéphanea; Boutouyrie, Pierrea
aDepartment of Pharmacology, Université Paris-Descartes, Faculté de Médecine, INSERM 652, Hôpital Européen Georges Pompidou, Paris, France
bDepartments of Pharmacology and URC-EST
dCardiology, Saint Antoine University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-VI, Paris, France.
Forty-two pravastatin-treated HIV-positive patients and 42 sex, age, and smoking status-matched hypercholesterolemic HIV-positive patients not under lipid-lowering treatment were compared for differences in intima-media thickness (IMT) of the common carotid artery (CCA) and aortic stiffness. Pravastatin had no influence on carotid artery structure and function, or aortic stiffness. Age and body mass index were independent determinants of IMT of the CCA. Mean arterial pressure, age, duration of HIV infection and protease inhibitor exposure determined aortic stiffness.
A linear association between increased intima-media thickness (IMT) of the common carotid artery (CCA), aortic stiffness (aortic pulse wave velocity; PWV) and the incidence of cardiovascular events has been reported in the general population [1–4]. The progression of IMT of the CCA has been shown to be predictive of cardiovascular events . Several case–control and longitudinal studies [6–12], with one exception , have suggested that increased IMT of the CCA in HIV-infected patients receiving HAART may be associated with an acceleration of atherosclerosis compared with non-HIV-infected patients and with HIV-infected patients not on antiretroviral treatment.
To the best of our knowledge, no study to date has evaluated the effects of statin therapy on the progression of carotid atherosclerosis in dyslipidemic HIV-infected patients. We hypothesized that long-term pravastatin therapy could decrease IMT of the CCA and reduce aortic stiffness in dyslipidemic HIV-infected patients.
Patients in the pravastatin group (cases) were consecutively enrolled if they fulfilled the following criteria: (i) HIV-infected treated with HAART for 12 months or more; (ii) dyslipidemia, defined as fasting serum LDL-cholesterol of 160 mg/dl or greater before the initiation of pravastatin plus one additional vascular risk factor; and (iii) treated with pravastatin for 12 months or longer. Controls were selected consecutively from: (i) HIV-infected patients treated with HAART for 12 months or more; (ii) those with fasting serum LDL-cholesterol of 160 mg/dl or greater plus one additional vascular risk factor; and (iii) those not under lipid-lowering drugs. Cases and controls were matched for age, sex and tobacco consumption. Written informed consent was obtained from each participant, and the study was approved by the Committee for the Protection of Human Subjects in Biomedical Research of Pitié-Salpétrière University hospital, Paris, and was sponsored by the French Society of Cardiology.
Two experienced technicians blinded to the patients' clinical features and treatments conducted all arterial measurements in a central core laboratory. Carotid internal diameter and IMT were measured on the right CCA at 2 cm beneath the carotid bifurcation, with a 7.5-MHz pulsed ultrasound echotracking system (Wall Track System; Pie Medical Imaging – Esaote SpA, Maastricht, the Netherlands) analysing the radiofrequency signal [7,14,15]. The elastic properties of the arterial wall material were estimated using Young's incremental elastic modulus calculated as previously described . Aortic (carotid-femoral) PWV was measured as previously described and validated .
Statistical analysis was performed using NCSS 2004 software (NCSS, Inc., Kaysville, Utah, USA). Between-group comparisons for quantitative variables were performed using Student's t-test or the Wilcoxon rank test according to distribution. The chi-square test was used for discrete variables. Multivariate robust regressions with stepwise selection of variables were performed to determine the relationship between arterial parameters and pravastatin therapy. Data are expressed as mean ± standard deviation. P < 0.05 was considered significant, and tests were two-sided.
Among cases, pravastatin was prescribed at a mean dose of 30 ± 10 mg/day with a mean duration of 23 ± 8 months. (see Table 1 for the baseline characteristics of the patients). Cardiovascular risk factors were well balanced in the two groups except for body mass index, which was significantly lower among pravastatin users (22.9 ± 2.3 versus 24.1 ± 2.7, P = 0.03). The duration of HIV infection and HIV treatments, the immunovirological status, and the presence of clinical lipodystrophy syndrome did not differ between the groups.
The geometrical and functional parameters of the carotid artery did not differ between the two groups and no difference in IMT in the CCA between HIV-infected patients under pravastatin and controls (689 ± 131 versus 717 ± 148 μm, P = 0.36) was observed. Aortic stiffness measured using the carotid-femoral PWV did not differ between the two groups (9.6 ± 1.7 versus 10.0 ± 1.8 m/s, P = 0.25).
After adjustment, age (each 10 years: increment R2 = 0.32, β = 82 ± 15, P = < 10−4) and body mass index (each 1 kg/m2: increment R2 = 0.07, β = 142 ± 73, P = 0.002) were predictors of IMT of the CCA. Duration of HIV infection and other HIV parameters [duration of antiretroviral therapy, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors (PI), AIDS classification, CD4 cell count] did not influence IMT of the CCA. However, the duration of HIV infection and the cumulative duration of PI exposure were predictors of arterial stiffness. Each 10 years of HIV infection was independently related to a 0.38 m/s increase in arterial stiffness (R2 = 0.03, β = 0.38 ± 0.15, P = 0.015) equivalent to ageing (each 10 years: increment R2 = 0.08, β = 0.38 ± 0.1, P = < 10−6) compared with each 10 years of PI exposure being independently related to a 0.7 m/s increase in arterial stiffness (R2 = 0.02, β = 0.7 ± 0.3, P = 0.037) equivalent to the impact of mean arterial pressure (R2 = 0.36, β = 0.59 ± 0.07, P = < 10−5).
Pravastatin has proved its efficacy in decreasing IMT in the CCA in randomized clinical trials in the general population . The effect of statins on IMT in the CCA regression is related to the degree of LDL-cholesterol reduction. This effect is dose-dependent. However, the reduction in LDL-cholesterol with pravastatin seems to be lower in HIV-infected patients compared with the general population. A 20% reduction in LDL-cholesterol was observed in HIV-infected patients treated with pravastatin 40 mg a day [17–19] compared with a 30% reduction in the general population at the same dose. HIV infection by itself could lower the efficacy of pravastatin in reducing carotid atherosclerosis, as was shown with Chlamydiae pneumoniae in the general population . The efficacy of more potent statins such as atorvastatin at a low dose or rosuvastatin (not metabolized by CYP 45O 3A4) on atherosclerosis may differ from that of pravastatin in dyslipidemic HIV-infected patients.
Aortic and arterial stiffness are independent predictors of cardiovascular events in the general population. We found that the influence of the duration of HIV infection on aortic stiffness was similar to that of ageing (independent of PI exposure). Like Schillaci and colleagues , we found that the duration of PI exposure influenced aortic stiffness similarly to mean arterial pressure. On the other hand, in a cross-sectional study of 49 HIV-infected children compared with 24 non-HIV-infected controls, Bonnet et al.  found that HIV infection affected arterial stiffness, whereas no additional detrimental effects were observed after a mean of 5 years of antiretroviral therapy. In the present study, the presence of clinical lipodystrophy was associated with greater, although non-significant, aortic stiffness (10.08 ± 1.95 versus 9.33 ± 1.07 m/s, P = 0.07). Further investigation of the vascular effects of adipocyte dysfunction and related adipocytokine disturbances in lipodystrophic HIV-infected patients is warranted .
The design of this study did not permit definitive conclusions to be drawn regarding the effects of pravastatin in either treated or non-treated HIV-infected patients. However, the evaluation of carotid atherosclerosis was performed using an echotracking system with confirmed high spatial resolution, reproducibility and accuracy [15,16]. A predefined number of patients were included to detect a clinically relevant difference in IMT in the CCA (6.5%). The two groups were appropriately matched, with similar cardiovascular risk factors including blood pressure and HIV infection parameters. The pertinent results revealed in this preliminary research merit additional investigation and confirmation by acknowledged study methods.
In this study, no impact of pravastatin therapy on carotid atherosclerosis and function in dyslipidemic HIV-infected patients receiving HAART was found. The duration of HIV infection and PI exposure were associated with increased aortic stiffness, with an impact similar to that of ageing. Randomized trials are essential to evaluate the efficacy of statins in reducing carotid atherosclerosis in HIV-infected patients.
The authors are extremely grateful to Professors Willy Rozenbaum and Gilles Pialoux, Infectious Disease Department, Tenon University Hospital, Paris, France; Professors Laurence Meyer and Michel Kazatchkine, Infectious Disease Department, Georges Pompidou University Hospital, Paris, France; Professor Christine Katlama, Infectious Disease Department, Pitie-Salpetriere University Hospital, Paris, France; and Professor Marie-Caroline Meyohas, Infectious Disease Department, Saint Antoine University Hospital, Paris, France, for their participation in the recruitment of patients to this study. The authors are also grateful for the editorial assistance of John Cochran in the review of this manuscript.
Sponsorship: This work was supported by grants from the Institut de Médecine et d'Epidémiologie Appliquée, Fondation Léon Mba, and Sanofi-Aventis Corporation, Paris, France.
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