According to data form the Joint United Nations Programme on HIV/AIDS, there are over 33 million people living with HIV/AIDS world-wide(19
) and over 1.1 million in the U.S.(20
) Recently, the number of individuals aged 50 years and older living with HIV/AIDS has increased dramatically: in 2005, persons aged 50 and over accounted for 15% of new HIV/AIDS diagnoses and 29% of persons living with AIDS. (21
) As this population continues to age, chronic health conditions such as cardiovascular disease will likely increase in importance. Higher rates of cardiovascular disease have already been reported in individuals with HIV infection(22
) along with higher rates of subclinical atherosclerosis.(23
) The widespread availability of combination antiretroviral therapy has resulted in dramatic reductions in the
risk of AIDS-defining complications among HIV-infected patients. The impact of HIV infection (and its treatment) on cardiac function has not been well described, even though this is a common source of morbidity and mortality in aging HIV-uninfected patients. Here, we show that significant structural abnormalities such as decreased ejection fraction, valvular heart disease, and LVH are not more common in a well characterized contemporary group of HIV patients (most of whom had been on long term antiretroviral therapy) compared to uninfected controls. At the same time, we do demonstrate that HIV disease is independently associated with both diastolic dysfunction, increased left atrial volumes, and increased LV mass index. All of these outcomes have been associated with higher mortality among uninfected patients.(1
) These observations support the growing concern that HIV infection may be linked with these diseases that have traditionally been associated with aging.(26
In our study, LV mass index was higher in HIV-infected individuals than the uninfected controls; this was true even after limiting our analysis to those without prior illicit drug use and to those without hypertension. The LV mass index, while elevated, did not exceed the gender-specific upper limit of normal in the majority of individuals and therefore did not imply clinical levels of left ventricular hypertrophy. Among our HIV-infected patients, a lower nadir CD4 count was associated with higher LV mass index. This finding was independent of risk factors that are traditionally associated with elevated LV mass including age, race, gender, diabetes mellitus, and hypertension. An association between LV mass index in HIV-infected women has been previously described, although this finding was no longer significant after adjusting for age.(27
) It is possible that HIV effect on LV mass may be secondary to subclinical atherosclerosis. We did not detect an association between prior coronary artery disease and LV mass index, although there were only 5% of HIV patients with a history of CAD in our study. Our group has previously demonstrated an association between nadir CD4 count and subclinical atherosclerosis as assessed by carotid artery intima-media thickness (IMT) in individuals with HIV infection(28
) and other groups have found an association between CD4 and cardiovascular events.(29
) Of note, the nadir CD4+ T-cell count has been strongly associated with the level of immune activation; in turn, even among antiretroviral treated patients, the levels of immune activation remain elevated.(30
) The higher levels of inflammation present in HIV patients may in theory contribute to increased LV mass, as has been suggested in studies of HIV-uninfected adults including individuals with systemic lupus erythematosus(31
) and rheumatoid arthritis.(32
The pathogenesis of HIV-associated diastolic dysfunction is likely multifactorial. First, although it remains controversial, several studies suggest that hypertension is associated with antiretroviral use, including prolonged duration of antiretroviral therapy(33
) and treatment with protease inhibitors.(34
) Hypertension was common in our HIV-infected study participants; however, this factor alone was unlikely to account for our findings as we still found an independent association between HIV infection and diastolic dysfunction both after adjustment for hypertension as well as after restricting the analysis to individuals without hypertension. Second, the increase in LVMI that we detected in our study may underlie the finding of mild diastolic dysfunction among HIV patients. Third, it is possible that HIV or other associated viral infection may directly affect the myocardium. HIV-1 has been detected in endomyocardial biopsy specimens in HIV patients with LV dysfunction(36
) while other autopsy studies have detected sequences of HIV-1 in myocytes of HIV patients at autopsy.(37
) Fourth, our group and others have shown that individuals with HIV infection have high rates of inflammation(23
) which may predispose HIV patients to diastolic dysfunction. In the uninfected population, higher levels of inflammatory markers such as hsCRP have been shown to be associated with diastolic dysfunction.(38
) Reversible and isolated diastolic dysfunction has been shown to occur in individuals with septic shock, a condition characterized by high levels of inflammation,(40
) as well as in the setting of chronic inflammatory states such as rheumatoid arthritis.(41
) Fifth, in unadjusted analysis lower CD4 count and longer duration of NRTI use were associated with diastolic dysfunction, suggesting that advanced immunodeficiency and/or side effects from medication may mediate the development of this abnormality. NRTI use has previously been associated with cardiomyopathy and mitochondrial damage.(42
) Finally, subclinical atherosclerosis as assessed by carotid artery intima-media thickness is common in HIV-infected individuals,(24
) and therefore another possible mechanism underlying diastolic dysfunction may be underlying ischemic heart disease as well as increased arterial stiffness which has been reported in HIV patients.(43
) In our study, diastolic dysfunction was not associated with a prior history of coronary artery disease, but only 5% of HIV-infected individuals studied had this diagnosis.
The results of our study demonstrate that the echocardiographic findings associated with HIV infection during the early years of the epidemic have shifted. Left ventricular systolic dysfunction, right ventricular enlargement, and pericardial effusions were common findings before the widespread usage of antiretroviral medications.(3
) Prior studies demonstrated that pericardial effusions were associated with reduced survival,(45
) and persistently low ejection fractions were associated with a high one year mortality rate.(46
) Our study suggests that LV and RV systolic dysfunction and pericardial effusions are now rare, while mild diastolic dysfunction is common. The low rate of LV systolic dysfunction that we detected in our study may bode well for the aging HIV population.
Our study was cross-sectional in nature and hence has several limitations commonly associated with this study design. Specifically, since our primary outcomes likely reflect a life-time of exposure to various risk factors, and since many of these factors are difficult to quantify retrospectively, a longitudinal study in which all such factors are measured is now needed. Still, we believe that our data are highly relevant, as they expand upon those of earlier studies(5
) by using advanced techniques to assess diastolic dysfunction, by being carefully restricted and adjusted for potential confounders, and by including an uninfected control group.
The long term clinical implications of our findings remain unclear. Among large population-based studies of asymptomatic middle aged adults, diastolic dysfunction was strongly associated with both all-cause and cardiac mortality.(47
) Although unstudied at this time, it is likely that diastolic dysfunction will be predictive of mortality in the HIV population as well. Our findings suggest that caregivers should maintain a high clinical suspicion for cardiovascular disease, aggressively treat all traditional cardiovascular risk factors, and consider the possibility of diastolic dysfunction in HIV-infected individuals. However, in the absence of symptoms, we believe it is premature to recommend routine screening echocardiograms for HIV-infected adults.
It is also unclear as to whether the HIV-infected patients require any unique therapeutic interventions to manage or prevent cardiac dysfunction. Reduction of HIV-related inflammation using antiretroviral therapy would appear to be a reasonable approach, although the benefit of treatment on cardiac function remains unproven. Several studies including the SMART study and ACTG 5142 suggest that using antiretroviral therapy prevents cardiovascular disease-associated outcomes (e.g., myocardial infarction), at least in the short term.(49
) These studies were not able to specifically address the impact of antiretroviral treatment on cardiac function, but given the strong association between atherosclerotic disease and cardiac function, it is reasonable to assume that effective antiretroviral treatment will be beneficial. Longer term studies along with further investigations into the pathogenesis of HIV-associated cardiovascular disease will be essential in guiding standards of clinical care in the future.