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Endothelial Function in Patients with HIV Infection
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Clinical Infectious Diseases 2006;43:540-541
James H. Stein
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin
TO THE EDITOR-Although I agree with Solages et al. [1] that HIV-infected individuals have impaired endothelial function, our studies [2, 3] were not accurately described in their discussion. I disagree that their study "did not substantiate" [1, p. 1331] our observations. Their article actually confirmed our findings.
In contrast to Solages and colleagues' attribution, we did not show that lipids or insulin resistance predicted brachial artery flow-mediated vasodilation (FMD) [2]. We showed that, among HIV-infected individuals, receipt of a protease inhibitor, blood pressure, heart rate, and brachial artery diameter predicted FMD (R2 = 67.1%). In a separate model restricted to subjects receiving protease inhibitors, we again found that artery diameter and blood pressure predicted FMD, but the best models also included lipoprotein parameters (R2 = 70.6%). We then showed that most (but not all) of the protease-inhibitor effect on FMD was related to high-density lipoprotein (HDL) cholesterol, triglyceride-rich lipoproteins, and glucose [2], which suggests some degree of mediation of the protease-inhibitor effect by lipoproteins and possibly by insulin resistance. On the basis of our findings, impaired FMD would not be expected in a cohort with normal lipids and without lipodystrophy.
Subjects in our study who received protease inhibitors had a mean total cholesterol level of 219.8 mg/dL and a mean triglyceride level of 391.1 mg/dL [2]. Respectively, these values are 22% and 147% higher than those in the article by Solages et al. [1], in which essentially normal lipid values were reported and an unexpectedly low (6%) incidence of lipodystrophy was described. Without dyslipidemia or lipodystrophy, impaired FMD would not have been expected in patients in their study who received protease inhibitors, thereby confirming our findings. Indeed, Solages and colleagues' finding that -HDL triglycerides predicted FMD seems to support a relationship between lipoproteins and endothelial function [2].
Referring to another article of ours [3], Solages et al. [1] stated that use of pravastatin "did not lead to a significant improvement in FMD" [1, p. 1331]. Although this is correct from a statistical standpoint (the P value was .08), our finding of improved endothelial function recently was confirmed in a larger study in which pravastatin treatment led to a statistically significant increase in FMD (P = .03) [4]. Of note, changes in FMD in our study were predicted by lipoprotein and glucose levels [3].
Finally, I am concerned about the predictive model described on page 1328 of Solages et al. [1], which only accounts for 26% of the variability in FMD in patients with HIV infection. This is very low and suggests that unaccounted variables, such as blood pressure, heart rate, or brachial artery diameter (the denominator of the equation for calculating FMD), or measurement imprecision may be at play. The association with HIV load was of borderline statistical significance; however, linear associations with log parameters that have a finite lower bound (<50 copies/mL) are difficult to establish and interpret.
The perils of cross-study comparisons and the limitations of all cross-sectional studies, including ours, are well known. Prospective studies [5, 6] appear to suggest that viral control is an important short-term determinant of endothelial function, whereas classical risk factors are more important long-term determinants of atherosclerotic burden.
References
1. Solages A, Vita JA, Thornton DJ, et al. Endothelial function in HIV-infected persons. Clin Infect Dis 2006; 42:1325-32. First citation in article | Full Text | PubMed
2. Stein JH, Klein MA, Bellehumeur JL, Aeschlimann SE, McBride PE, Sosman JM. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001; 104:257-62. First citation in article | PubMed
3. Stein JH, Merwood MA, Bellehumeur JL, et al. The effects of pravastatin on atherogenic lipoproteins and endothelial function in patients with human immunodeficiency virus. Am Heart J 2004; 147:1-7. First citation in article | PubMed
4. Hurlimann D, Chenevard R, Ruschitzka F, et al. Effects of statins on endothelial function and lipid profile in HIV infected persons receiving protease inhibitor-containing anti-retroviral combination therapy: a randomized double-blind cross-over trial. Heart 2006; 92:110-2. First citation in article | PubMed | CrossRef
5. Stein JH, Cotter BR, Parker RA, et al. Antiretroviral therapy improves endothelial function in individuals with human immunodeficiency virus infection: a prospective, randomized multicenter trial (adult AIDS clinical trials group study A5152s) (abstract). Circulation 2005; 112:II-237. First citation in article
6. Currier J, Kendall M, Henry K, et al. 3-year Follow-up of carotid intima-media thickness in HIV-infected and uninfected adults: ACTG 5078. In: Program and abstracts of the 13th conference on retroviruses and opportunistic infections [abstract 145]. 2006. Available at http://www.retroconference.org/2006/Abstracts/27539.HTM. Accessed on 29 June 2006. First citation in article
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