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Risco cardiovascular em_pacientes_hiv_

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Risco cardiovascular em_pacientes_hiv_

  1. 1. Journal of the American College of Cardiology Vol. 47, No. 6, 2006© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00Published by Elsevier Inc. doi:10.1016/j.jacc.2005.12.018EDITORIAL COMMENT assessment of cardiovascular risk factors, a lack of medica- tion compliance data, and problems with ascertainment ofCardiovascular Risk case status (1,2). Despite these limitations, these studiesin Patients With Human (with one exception) have suggested that patients with HIV infection are at increased cardiovascular risk, and that use ofImmunodeficiency Virus Infection protease inhibitors may be especially disadvantageous from a cardiac standpoint. Although two prospective observa-Incomplete Data* tional studies also showed increased risk of myocardialJames H. Stein, MD infarction in patients receiving HAART, they also sufferedMadison, Wisconsin from low cardiovascular event rates, and concerns have been raised about problems with case ascertainment andSince the advent of highly active antiretroviral therapy between-group differences in the duration of HIV infection(HAART) in 1996, the death rate from acquired immune (2).deficiency syndrome (AIDS) in the U.S. has decreased Because of these limitations, many investigators havedramatically. Because of HAART, it is not uncommon to used surrogate imaging markers of atherosclerosis to evalu-meet patients who have lived with human immunodefi- ate cardiovascular risk. With one exception, these studiesciency virus (HIV) infection for well over two decades. have demonstrated that use of HAART is associated withShortly after its introduction, however, clinicians observed endothelial dysfunction, but each study was small andan increasing prevalence of a lipodystrophic syndrome cross-sectional, with attendant biases and limitations. Inamong patients taking HAART that included hyperlipid- these studies, atherogenic lipoproteins, markers of insulinemia, impaired glucose metabolism, and central adiposity resistance, and in some instances markers of virological(1,2). Although HAART-associated lipodystrophy shares control explained part of the differences in endothelialsimilarities with the more common insulin resistance syn- function (2). These observations have been corroborated bydrome that predisposes patients to coronary artery disease studies demonstrating that protease inhibitors damage en- dothelial cell mitochondrial deoxyribonucleic acid in cul- See page 1117 ture, impair vasomotor function, and reduce endothelial nitric oxide synthase expression by coronary artery rings (3,4). Several studies also have shown an increased preva-(“Metabolic Syndrome,” MetS), they clearly are different lence of carotid plaque or intima-media thickness (CIMT)disease processes. For example, an important component of among patients receiving protease inhibitors, but they alsoHAART-associated lipodystrophy is peripheral fat wasting were small and cross-sectional.(lipoatrophy), which is not seen in patients with coronary The study by van Wijk et al. (5) adds to the growingartery disease. It also is not clear if HAART-associated literature suggesting that individuals receiving HAARTlipodystrophy carries the same cardiovascular risk as MetS. have markers of vascular disease that are associated withTo complicate cardiovascular risk assessment further, un- increased cardiovascular risk. In this study, individuals ontreated HIV infection also has been associated with dysli- HAART had impaired flow-mediated vasodilation of thepoproteinemia and premature atherosclerosis (1). Thus, the brachial artery, a marker of endothelial dysfunction. Thisevaluation of cardiovascular risk in patients with HIV agrees with previous literature, but is not conclusive becausehinges upon a complex interplay of direct and indirect nitroglycerin-mediated vasodilation was impaired; makingvascular effects of HIV infection, antiretroviral therapy, it unclear if the differences between the groups were due toaging, and exposure to cardiovascular risk factors. endothelial dysfunction or a non-endothelium-mediated In the past five years, several cross-sectional and obser- process.vational studies have tried to provide clinical and patho- A very interesting and important aspect of this study wasphysiological insights into these interrelationships. Unfor- classifying patients according to the presence of MetS, usingtunately, the observational studies that have been published the National Cholesterol Education Adult Treatment Panelor reported at meetings have had significant limitations, III guidelines. Although this definition was not intended toincluding low rates of adverse cardiovascular events, a short be used for patients with lipodystrophy, HIV-infectedduration of exposure to HAART, and the usual limitations patients with MetS had increased levels of apolipoproteinassociated with retrospective studies such as nonsystematic B-100, C-reactive protein, insulin, and 2-h insulin com- pared with HIV-infected patients without MetS and HIV- *Editorials published in the Journal of the American College of Cardiology reflect theviews of the authors and do not necessarily represent the views of JACC or the negative controls. These findings suggest that HIV-infectedAmerican College of Cardiology. patients with MetS have markers of insulin resistance and From the Division of Cardiovascular Medicine, University of Wisconsin Medical increased cardiovascular risk (5). Indeed, the major strengthSchool, Madison, Wisconsin. Dr. Stein is the recipient of a research grant fromBristol-Myers Squibb. He has served as a consultant to Abbott Labs and is on the of this report is the completeness of imaging and metabolicSpeaker’s Bureau for Merck (not related to HIV treatment). data. A study with this complete a dataset regarding
  2. 2. JACC Vol. 47, No. 6, 2006 Stein 1125March 21, 2006:1124–5 Editorial CommentHAART, metabolic risk factors, and cardiovascular imaging carefully matched triads based on HIV serostatus, antiret-in patients with HIV and control subjects has not been roviral therapy, and cardiovascular risk factors. At baseline,reported previously, so it is unique in that regard. there were no differences in CIMT between the groups of The finding that CIMT was greater among HIV- HIV-infected patients (7). Three-year follow-up of changesinfected patients with MetS is consistent with the metabolic in CIMT, risk factors, and virological markers are expecteddata provided by the authors. This finding would have been in early 2006. These studies will help clarify the majormore powerful if it had been corroborated by the aortic contributors to cardiovascular risk in patients with HIVpulse wave velocity data; however, the sample size was infection.relatively small. Also, certain markers of MetS in HIV- Conclusions. In regard to cardiovascular risk in patientsinfected patients did predict increased pulse wave velocity, with HIV, we have incomplete data. Compared with thesuch as blood pressure, 2-h glucose, and fasting insulin, high death rate from AIDS in patients with inadequate viralsuggesting that insulin resistance may be involved in the suppression, cardiovascular event rates are low and controlpathophysiology of vascular dysfunction in patients on of viremia, regardless of the treatment strategy, is moreHAART. It is interesting that markers of inflammation and important for long-term survival than any increase inviral load were more associated with CIMT than flow- cardiovascular risk that may be related to metabolic changesmediated vasodilation or pulse wave velocity, but these associated with HAART. Uncontrolled viremia may beassociations are somewhat difficult to interpret in the more of a cardiovascular risk than controlled infection thatabsence of information about the specific antiretroviral results in hyperlipidemia and insulin resistance. The overallagents used by the subjects, because agents within classes message is that obtaining and maintaining virological con-have different effects on insulin-glucose metabolism and trol is the overriding concern in patients with HIV infec-lipoproteins (1). Although the imaging data in this study do tion. Metabolic and vascular effects secondary to HAART arenot conclusively demonstrate that MetS, as traditionally secondary considerations, but are worthy of rigorous investiga-defined, is useful for identifying increased cardiovascular tion, as suggested by the paper by van Wijk et al. (5).risk in HIV-infected patients, the metabolic abnormalitiesobserved in MetS patients suggest that insulin resistance Reprint requests and correspondence: Dr. James H. Stein,may be involved and that further studies are needed (5). University of Wisconsin Medical School, Cardiology, G7/341Future directions. To better understand cardiovascular CSC, MC 3248, 600 Highland Avenue, Madison, Wisconsin 53792. E-mail: jhs@medicine.wisc.edu.risk in patients on HAART, larger, prospective studies areneeded. The biases inherent in observational and cross- REFERENCESsectional studies are well known, and their results can bemisleading. In designing prospective studies, longitudinal 1. Dubé MP, Stein JH, Aberg JA, et al., for the Adult ACTG Cardio-data regarding changes in structural and functional markers vascular Disease Subcommittee. Guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiret-of vascular disease, risk factors, antiretroviral therapy, and roviral therapy: recommendations of the HIV Medical Association ofvirological control must be considered, as well as the effect the Infectious Disease Society of America and the Adult AIDS Clinicalof aging itself. Trials Group. Clin Infect Dis 2003;37:613–27. 2. Stein JH. Managing cardiovascular risk in patients with HIV infection. Two well-designed studies sponsored by the AIDS Clin- J Acquir Immune Defic Syndr 2005;38:115–23.ical Trial Group (ACTG) recently have been completed. 3. Fu W, Chai H, Yao Q, Chen C. Effects of HIV protease inhibitorACTG 5152s is a prospective study of 82 HIV-positive, ritonavir on vasomotor function and endothelial nitric oxide synthase expression. J Acquir Immune Defic Syndr 2005;39:152– 8.treatment-naïve patients randomized to receive one of three 4. Zhong DS, Lu XH, Conklin BS, et al. HIV protease inhibitor ritonavirHAART regimens that would be predicted to have very induces cytotoxicity of human endothelial cells. Arterioscler Thrombdifferent effects on lipids and insulin-glucose metabolism. Vasc Biol 2002;22:1560 – 6. 5. van Wijk JPH, de Koning EJP, Castro Cabezas M, et al. Functional andAs expected, flow-mediated dilation was impaired before structural markers of atherosclerosis in human immunodeficiency virus-starting treatment, but improved significantly and to a infected patients. J Am Coll Cardiol 2006;47:1117–23.similar degree in each arm after as few as four weeks of 6. Stein JH, Cotter BR, Parker RA, et al. Antiretroviral therapy improves endothelial function in individuals with human immunodeficiency virusHAART (6). Nitroglycerin-mediated vasodilation did not infection: a prospective, randomized multicenter trial (Adult AIDSchange, indicating that use of HAART rapidly improved Clinical Trials Group Study A5152s) (abstr). Circulation 2005;112:endothelial function and that cardiovascular risk may de- II237. 7. Currier JS, Kendall MA, Zackin R, et al. Carotid artery intima-mediacrease as HIV infection comes under control. ACTG 5078 thickness and HIV infection: traditional risk factors overshadow impactis a prospective cohort study of 134 subjects recruited into of protease inhibitor exposure. AIDS 2005;19:927–33.

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