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Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Infectious Diseases, Boston, Massachusetts 02215
BY DECREASING HIV
replication and its coincident deleterious effects on the immune
system, highly active antiretroviral therapy (HAART) has increased the
life expectancy of human immunodeficiency virus (HIV)-infected patients
(29). Consequently, the spectrum of HIV-related diseases
has shifted from opportunistic infections toward longer-term
complications of HIV such as malignancies, the consequences of
coinfection with other viruses such as hepatitis C, and the metabolic
effects of HAART therapy. Investigations are currently focusing on the
effects of HIV infection and HAART on primary cardiovascular
disorders, lipid metabolism, and atherosclerosis. The state of
available knowledge regarding these topics, as described below,
underscores the potential for HIV infection to lend insight into
the pathophysiologies underlying a host of cardiovascular diseases that
affect the general population.
HIV cardiomyopathy
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PRIMARY CARDIOVASCULAR ABNORMALITIES IN THE SETTING OF HIV
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Primary Pulmonary Hypertension
HIV-related primary pulmonary hypertension is increasingly being described in HIV-infected patients, and its presence decreases the probability of their survival by half (28). There is no correlation between the risk for pulmonary hypertension and the level of HIV-related immunosuppression, and histopathology is most commonly consistent with plexogenic pulmonary arteriopathy (26). There has been no definitive pathophysiological mechanism described in this disorder; however hypotheses include increased vascular endothelial growth factor-A or intrapulmonary platelet-derived growth factor (1), HIV-1 gp120-mediated stimulation of endothelin-1 and tumor necrosis factor-
(13), or HIV
tat-mediated stimulation of endothelial cells to produce
growth factors (18). There may be a mild beneficial effect
of HAART on this disorder (28).
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SECONDARY CARDIOVASCULAR CONSEQUENCES OF HIV INFECTION |
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Metabolic abnormalities are the most widely studied phenomena in patients with long-term HIV-1 infection and include impaired glucose tolerance, hyperlipidemia, fat redistribution with central obesity and peripheral fat wasting, and lactic acidosis, all of which may increase the risk for atherosclerosis.
Dyslipidemia and Atherosclerosis
Lipid abnormalities, particularly elevations in cholesterol and triglycerides and decreases in high-density lipoprotein (HDL) levels, are widely reported in the era of protease inhibitor (PI) therapy but have also been observed in the absence of PI therapy. Both viral- and drug-mediated mechanisms have been proposed to result in these observations. Recent reports suggest that HDL derangements are not a result of antiretroviral therapy per se, but due to HIV infection itself and may be a result of increased inflammatory cytokines such as interferon- and tumor necrosis factor (14), and that
increases in triglycerides and low-density lipoprotein (LDL)
cholesterol are largely related to antiretroviral therapy
(20). An increase in specifically atherogenic
lipoparticles apoE and apoC-III have also been observed in PI-treated
patients (5). Sequence homologies are described between
the HIV-1 protease and the human site-1 protease (S1P), which activates
the SREBP-1c and SREBP-2 pathways. A polymorphism in the S1P/SREBP-1c
gene confers a difference in risk for development of an increase in total cholesterol with PI therapy, suggesting the presence of a genetic
predisposition to developing hyperlipoproteinemia in PI-treated
patients (27).
Despite the concerning increase in prevalence of dyslipidemias
documented in HIV-infected patients, there have been contradicting reports of an increase in cardiac mortality risk in these patients. Recent studies of patients randomized to PI-based versus non-PI-based therapies showed myocardial infarction (MI) was not associated with PI
therapy but was independently associated with classic cardiovascular
risk factors (9). However, a recent retrospective study of
the French Hospital Database on HIV comparing data to the MONICA
project (a study of cardiac morbidity in the general population of 21 countries over 9 years) concluded that there was a correlation of MI
incidence to duration of PI therapy (25), with an
incidence rate of MI per 10,000 person-years of 34.7 ± 9.6 taking
30 mo of PI therapy compared with 8.9 ± 1.9 in subjects taking
18 mo of PI therapy (a rate similar to that of the general population). It is notable that these conclusions were based on 54 MI events in the HIV database of 19,795 subjects taking PI therapy,
and there was no comparison with patients taking non-PI-based therapy
so that there was no true matching of cases to controls. Another study
of first coronary events in 4,541 HIV-infected subjects matched by age
and sex to 41,000 HIV-negative subjects in the Kaiser Permanente
Northern California database concluded that there was no increase in
short-term risk for cardiac events during person-years of PI use versus
person-years of no PI use; however, the adjusted overall incidence rate
of cardiac events in the HIV-infected group was greater than twofold
that of the HIV-negative group (21).
Regarding risk for peripheral atherosclerosis, carotid atherosclerotic plaques were significantly more prevalent in a cohort of HIV-infected subjects taking PI-based HAART compared to PI-naïve subjects (24). Another study showed increases in cholesterol, triglycerides, intermediate density lipoprotein, and very LDL in subjects taking PI-based HAART compared with those not taking PIs, and the lipoprotein abnormalities in subjects taking PIs predicted impaired flow-mediated brachial artery vasodilation (32). Separate, but additional, factors that contribute to atherosclerosis in HIV-infected patients include the classic cardiovascular risk factors of age, male gender, LDL levels, smoking (11), hypertension (16), and HAART-related diabetes (8). Though the evidence suggests some degree of risk, it is possible that a relatively short period of HAART therapy precludes consistent findings of increased risk for symptomatic atherosclerosis. It is also unknown whether the natural history of atherosclerotic disease may be telescoped when the lipodystrophic effects of HAART are combined with other HAART-related complications such as insulin resistance and fat redistribution. At this point, standard guidelines are used to determine the appropriateness of lipid-lowering therapy in these patients, with specific recommendations to prevent interactions between the lipid-lowering agent and the patient's HAART therapy (12). However, the effects of lipid-lowering therapy on cardiovascular mortality in HIV-infected persons are unknown.
Lipodystrophy
Fat redistribution was first described with PIs but has also been described in patients naïve to PI therapies (23). Characteristic clinical findings include dorsocervical fat pad ("buffalo hump"), increased abdominal girth and breast size, lipoatrophy of subcutaneous fat of the face, buttocks, and limbs, and prominence of veins on the limbs ("pseudovenomegaly"). Despite the intensive investigations, a case definition for its general term ("lipodystrophy") still does not exist, and well-controlled studies and long-term followup data are lacking. An increased incidence of abdominal fat accumulation in HIV-positive women suggests that gender differences may be affecting the presentation of this syndrome (22). The mechanisms for this phenomenon are not well defined; however, several intriguing findings have suggested decreased lipolytic activity (4), stoichiometric similarity between the binding site of PIs with retinoic-acid binding protein type 1 (RBAP-1), and LDL-receptor-related protein (LRP) causing impaired adipocyte differentiation and apoptosis as well as chylomicron uptake and triglyceride clearance (7) and a decrease in mitochondrial DNA within the adipose cell (31). Unfortunately for the sufferers of these side effects, there are no consistent data showing reversal of fat redistribution after removal of the suspected offending antiretroviral(s) from the treatment regimen; however, lipid profiles tend to improve (6).Expanded study of the effects of HIV infection and its treatment on cardiovascular disease and metabolic abnormalities is warranted for several reasons. From an epidemiological standpoint, the data generated over the last few years attempt to address illnesses whose natural history is known to evolve over decades in the general population; therefore, well-designed longitudinal studies are warranted to properly assess the natural history of cardiovascular and metabolic abnormalities in the HIV-infected population. Additionally, studies specifically designed to assess the relative risk of metabolic and cardiovascular diseases in HIV-infected women are lacking, in light of the steadily increasing proportion of AIDS cases in women in the United States. From the perspective of basic science, the causes of many syndromes do not appear to be manifesting as single entities but rather a complex interaction among HIV-, drug-, and immune-related factors, especially in the study of metabolic complications of HIV. As such, proving the etiologies and defining successful management of specific cardiovascular syndromes in HIV infection may be infinitely more difficult.
There appears to be great opportunity at hand for further investigation into the pathophysiology of HIV-related metabolic and cardiac disorders in hopes of decreasing morbidity and cardiac mortality in all patients. Issues for special focus include: 1) the molecular and cellular mechanisms essential to the pathogenesis of dyslipidemias and/or atherosclerosis in this patient population, 2) genetic markers that may predispose patients taking long-term antiretroviral therapy to the development of lipid abnormalities and fat redistribution, 3) the relative impact of sex and the incremental impact of age on the risk for developing cardiovascular complications in HIV-infected patients taking long-term antiretroviral therapy, compared with HIV-negative patients, and 4) the effect of lipid-lowering therapy on cardiac morbidity and mortality in this population.
HIV infection has become a chronic disease with the potential for long-term survival with effective antiretroviral therapy. Metabolic complications aside, the risk for cardiovascular disease will increase as HIV-infected patients live longer. Current studies are investigating how the natural history of atherosclerosis and its treatments might differ under the stress of complicated antiretroviral regimens and HIV-induced immunosuppression.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. A. Panther, Beth Israel Deaconess Medical Center, 1 Autumn St., Kennedy 613, Boston, MA 02215 (E-mail: lpanther{at}caregroup.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00212.2002
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