Vascular endothelial dysfunction may contribute to the increase in cardiovascular events during HIV-1 infection and its treatment. Antiretroviral therapy (ART), metabolic factors, lipodystrophy, and HIV infection itself may be involved. Ninety-six HIV-infected subjects were evaluated for endothelial function by measurement of brachial artery flow-mediated dilation (FMD) by ultrasound, single-slice CT of the abdomen and mid-thigh, whole-body dual x-ray absorptiomety (DXA) scans, and metabolic evaluations in a cross-sectional study. The median age was 40 years; 28% were female, 38% black, 3% Hispanic, and 59% white. Forty-nine (51%) were receiving ART, which included a PI in 28 (57%) and was non-PI based in 21 (43%). FMD (±SD) in subjects not on ART was 5.5 ± 4.3%, PI-ART 5.3 ± 3.6%, and non-PI-ART 5.5 ± 4.1% (p = 0.9). Age, race, CD4 cell count, and HIV RNA did not correlate significantly with FMD. Among ART-treated subjects in the lowest tertile of thigh subcutaneous fat area (range 3–31 cm2), FMD was 4.4 ± 3.5% and in the highest tertile (range 67–237 cm2) FMD was 6.8 ± 3.6% (p = 0.07, t-test). However, in multivariate analyses, no body composition measure showed a significant association with FMD for either the group as a whole or in ART-treated subjects. ART use, PI use, CD4 cell count, and HIV RNA levels were not associated with endothelial dysfunction by brachial FMD. A definitive association with measures of adiposity was not detected in multivariate analysis, suggesting that lipoatrophy may not be an important contributor to endothelial dysfunction in HIV-infected individuals on ART.
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References
1.
D. A. D. Study Group. Friis-MollerN, ReissPet al.Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med, 2007; 356:1723–1735.
2.
Mary-KrauseM, CotteL, SimonA, PartisaniM, CostagliolaD. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS, 2003; 17:2479–2486.
3.
D. A. D. Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: A multi-cohort collaboration. Lancet, 2008; 371:1417–1426.
4.
Strategies for Management of Anti-Retroviral Therapy, Insight and D. A. D. Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS, 2008; 22:F17–F24.
5.
CelermajerDS. Endothelial dysfunction: Does it matter? Is it reversible?J Am Coll Cardiol, 1997; 30:325–333.
6.
KinlayS, GanzP. Role of endothelial dysfunction in coronary artery disease and implications for therapy. Am J Cardiol, 1997; 80:11I–16I.
7.
AndersonTJ. Prognostic significance of brachial flow-mediated vasodilation. Circulation, 2007; 115:2373–2375.
8.
SteinJH, KleinMA, BellehumeurJLet al.Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation, 2001; 104:257–262.
9.
TorrianiFJ, KomarowL, ParkerRAet al.Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am College Cardiol, 2008; 52:569–576.
10.
DubéMP, GorskiJC, ShenC. Severe impairment of endothelial function with the HIV-1 protease inhibitor indinavir is not mediated by insulin resistance in healthy subjects. Cardiovasc Toxicol, 2008; 8:15–22.
11.
ShankarSS, ConsidineRV, GorskiJC, SteinbergHO. Insulin sensitivity is preserved despite disrupted endothelial function. Am J Physiol Endocrinol Metab, 2006; 291:E691–E696.
12.
ShankarSS, DubéMP, GorskiJC, KlaunigJE, SteinbergHO. Indinavir impairs endothelial function in healthy HIV-negative men. Am Heart J, 2005; 150:933.
13.
DubéMP, ShenC, GreenwaldM, MatherKJ. No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: A placebo-controlled trial. Clin Infect Dis, 2008; 47:567–574.
14.
SolagesA, VitaJA, ThorntonDJet al.Endothelial function in HIV-infected persons. Clin Infect Dis, 2006; 42:1325–1332.
15.
MynarcikDC, McNurlanMA, SteigbigelRT, FuhrerJ, GelatoMC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr, 2000; 25:312–321.
16.
HadiganC, MeigsJB, CorcoranCet al.Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis, 2001; 32:130–139.
17.
GrinspoonS, CarrA. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med, 2005; 352:48–62.
18.
VigourouxC, MaachiM, NguyenTHet al.Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS, 2003; 17:1503–1511.
19.
MynarcikDC, CombsT, McNurlanMA, SchererPE, KomaroffE, GelatoMC. Adiponectin and leptin levels in HIV-infected subjects with insulin resistance and body fat redistribution. J Acquir Immune Defic Syndr, 2002; 31:514–520.
20.
TongQ, SankalAJ, HadiganCMet al.Regulation of adiponectin in human immunodeficiency virus-infected patients: Relationship to body composition and metabolic indices. J Clin Endocrinol Metab, 2003; 88:1559–1564.
21.
AddyCL, GavrilaA, TsiodrasS, BrodoviczK, KarchmerAW, MantzorosCS. Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. J Clin Endocrinol Metab, 2003; 88:627–636.
22.
SutinenJ, KorsheninnikovaE, FunahashiT, MatsuzawaY, NymanT, Yki-JarvinenH. Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy. J Clin Endocrinol Metab, 2003; 88:1907–1910.
23.
KosmiskiL, KuritzkesD, LichtensteinK, EckelR. Adipocyte-derived hormone levels in HIV lipodystrophy. Antiviral Ther, 2003; 8:9–15.
24.
TorrianiM, HadiganC, JensenME, GrinspoonS. Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with the HIV-lipodystrophy syndrome. J Appl Physiol, 2003; 95:1005–1010.
25.
CorrettiMC, AndersonTJ, BenjaminEJet al.Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol, 2002; 39:257–265. [Erratum appears in J Am Coll Cardiol 2002;39(6):1082.]
26.
FriedewaldWT, LevyRI, FredricksonDS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem, 1972; 18:499–502.
27.
RossAC, ArmentroutR, O'RiordanMAet al.Endothelial activation markers are linked to HIV status and are independent of antiretroviral therapy and lipoatrophy. J Acquir Immune Defic Syndr, 2008; 49,5:499–506.
28.
GuptaSK, JohnsonRM, SahaCet al.Improvement in HIV-related endothelial dysfunction using the anti-inflammatory agent salsalate: A pilot study. AIDS, 2008; 22:653–655.
29.
JiangB, HebertVY, ZaveczJH, DugasTR. Antiretrovirals induce direct endothelial dysfunction in vivo. J Acquir Immune Defic Syndr, 2006; 42:391–395.
30.
FuW, ChaiH, YaoQ, ChenC. Effects of HIV protease inhibitor ritonavir on vasomotor function and endothelial nitric oxide synthase expression. J Acquir Immune Defic Syndr, 2005; 39:152–158.
31.
ConklinBS, FuW, LinPH, LumsdenAB, YaoQ, ChenC. HIV protease inhibitor ritonavir decreases endothelium-dependent vasorelaxation and increases superoxide in porcine arteries. Cardiovasc Res, 2004; 63:168–175.
32.
MondalD, PradhanL, AliM, AgrawalKC. HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: Exacerbation by inflammatory cytokines and amelioration by antioxidants. Cardiovasc Toxicol, 2004; 4:287–302.
33.
ChenC, LuXH, YanS, ChaiH, YaoQ. HIV protease inhibitor ritonavir increases endothelial monolayer permeability. Biochem Biophys Res Commun, 2005; 335:874–882.
34.
GuptaSK, MatherKJ, AgarwalR, SahaCK, ConsidineRV, DubéMP. Proteinuria and endothelial dysfunction in stable HIV-infected patients. A pilot study. J Acquir Immune Defic Syndr, 2007; 45:596–598.
35.
GrubbJR, DejamA, VoellJet al.Lopinavir-ritonavir: Effects on endothelial cell function in healthy subjects. J Infect Dis, 2006; 193:1516–1519.
