Our data suggest that HIV infection is associated with an increased risk of HF after adjusting for traditional CHD risk factors. This risk persisted even after restricting the sample to patients who did not have a diagnosis of CHD, HF, or angina at baseline or a diagnosis of CHD during the follow-up period prior to the diagnosis of HF, a diagnosis of alcohol abuse/dependence, or both. Ongoing viral replication (HIV-1 RNA level ≥500 copies/mL) was associated with a higher risk of developing HF. However, HIV-infected participants with baseline and recent HIV-1 RNA level less than 500 copies/mL did not have an increased risk of HF compared with HIV-uninfected participants.
To our knowledge, there are no definitive studies on the risk of HF that compared HIV-infected with HIV-uninfected people who are free of baseline CHD. Diastolic dysfunction has been reported in 48% to 50% of HIV-infected persons, but the proportion of this dysfunction attributable to preexisting CHD is not known.29-31
Myocarditis is present in up to half of patients with AIDS in autopsy studies,32,33
but overt antemortem HF or autopsy evidence of ventricular dysfunction is not present in all such cases. In addition, these smaller studies are from the pre-CART era and lack HIV-uninfected controls to determine a direct association with HIV infection. In contrast, one study5
of 91 HIV-infected participants did not find any significant evidence of right or left ventricular dysfunction as measured by radionuclide ventriculography. To our knowledge, our study is the largest to investigate the relationship between HF and HIV infection and the first to demonstrate such an association and provide evidence of HIV infection as an independent risk factor for HF.
Although the exact mechanism by which HIV infection is associated with HF is not well understood, several possible mechanisms exist, including direct effects of the HIV, comorbidities associated with HIV infection (eg, heavy alcohol consumption), antiretroviral therapy leading to an increased risk of CHD and subsequent HF, nutritional deficiencies, and immunologic damage to the myocardium. Our results suggest that HIV itself is playing an important and independent role. Even after excluding patients with a baseline history of CHD, HF, and angina, as well as a CHD event in the follow-up period prior to the diagnosis of HF and a history of alcohol abuse or dependence diagnosis, the risk of incident HF was still substantial among the HIV-infected cohort. Ongoing HIV replication appears to play an important role. Compared with HIV-uninfected participants, only participants with an HIV-1 RNA level greater than 500 copies/mL had a significantly increased risk of HF.
For participants who had baseline and recent HIV-1 RNA levels less than 500 copies/mL, there was no significantly increased risk of HF (). Antiretroviral therapy was associated with a slightly attenuated risk, although the difference between CART-naive and CART-experienced groups did not reach statistical significance. However, these results should be interpreted carefully given the small number of events in the stratified categories. Our findings that hypertension, obesity, alcohol abuse or dependence, and diabetes mellitus were associated with an increased risk of HF are consistent with reports34,35
from other established cohort studies of people without HIV infection and offer the possibility of interventions to reduce the risk of HF. In the current study, we were not able to assess the differential risk between controlled and uncontrolled hypertension or diabetes, but this is an attractive topic for further research.
Secondary infection of the myocardium in HIV-infected persons may also lead to myocarditis, myocardial dysfunction, and HF. Presence of cytomegalovirus, acid-fast bacilli, Toxoplasma gondii
species, Histoplasma capsulatum
, Cryptococcus neoformans
, and Staphylococcus aureus
in the myocardium of HIV-infected patients has been reported.11,33,36
A causal association is not clear in all instances, since in some cases, myocarditis is not associated with adjacent myocyte necrosis on histologic examination and evidence of disseminated disease is not present.
Other causes of heart muscle disease in HIV-infected persons include immunologic damage, nutritional deficiencies (eg, selenium, antioxidant vitamins, and carnitine), and antiretroviral therapy.11,13
Zidovudine has been associated with a specific dose-dependent skeletal myopathy attributed to mitochondrial toxicity and with cardiac dysfunction that resolves with discontinuation of the drug.11,12
However, in a study37
in HIV-infected children, zidovudine was not associated with worsening of cardiac function. We were unable to analyze the occurrence of HF associated with any specific antiretroviral drugs.
The role of traditional risk factors in the risk of HF needs to be emphasized. Increasing age, African American race, obesity, hypertension, diabetes, and alcohol use are established risk factors and were also significantly associated with a higher risk of HF in our study. Our data tend to suggest that these factors increase the risk of HF independent of their risk on clinically diagnosed CHD, evidenced by the fact that they remained significant even after people with prior CHD were excluded from the study. However, this finding should be interpreted with caution because we could not exclude subclinical CHD. Interventions to minimize the modifiable traditional risk factors, including glycemic and blood pressure control, weight reduction, and abstinence from alcohol, are prudent strategies that should be emphasized. The actual effect of such strategies on risk reduction among HIV-infected persons requires further study.
The strengths of our study include large numbers, participants drawn from validated and well-established cohorts, a national rather than geographically limited sample, and availability of HIV-uninfected controls. Certain limitations need to be understood as well. The diagnosis of HF was based on ICD-9
codes; however, codes for various cardiovascular end points have been extensively used in previous publications3,24,25
and are considered reasonable alternatives to adjudicated clinical outcomes. Moreover, since HF is a chronic condition, our ability to capture outpatient clinical diagnoses in the present study is advantageous; if the initial diagnosis of HF were made at an outside hospital, the diagnosis could be captured in our study via routine follow-up outpatient care within the VA health care system. We did not assess the effect of specific antiretroviral drugs owing to the small number of events for individual drugs, nor did we assess the role of adherence to medication therapy and control of blood pressure or blood glucose levels in the risk of HF. Our study was limited to men and so may not be generalized to women. Other than men being the predominant population, the HIV infection epidemic in veterans is largely similar to that in nonveterans.20
Since we used administrative data to identify incident HF events, this study was not able to distinguish between HF associated with systolic vs diastolic dysfunction. Finally, while we excluded diagnosed CHD as a preceding event to HF, we did not exclude subclinical atherosclerosis as a cause of HF.
There are major clinical implications of our findings. If HF is a major cardiovascular consequence of HIV infection rather than atherosclerotic heart disease, different approaches to manage such consequences are warranted. Cardiovascular risk factor reduction and antiplatelet agents (eg, aspirin) are the mainstay in the management of atherosclerotic heart disease; however, these strategies, plus aggressive blood pressure control and the treatment of the HIV infection, may also be required to prevent development of HF in this population. The exact approach would depend on the mechanism and mediators of this risk; therefore, further studies are needed. Several risk factors identified are modifiable, and intervention studies may be designed to look at the effect of strict blood pressure control, tight glycemic control, and weight loss on the risk of HF. Additional studies are also warranted to fully understand the mechanism of HF in HIV-infected persons, especially to understand the nature of HF, eg, systolic vs diastolic dysfunction.
In conclusion, HIV infection is associated with an increased risk of HF after adjusting for traditional risk factors for HF. This association persisted even after exclusion of patients with a baseline history of CHD, HF, and angina, as well as a CHD event in the follow-up period prior to the diagnosis of HF and a history of alcohol abuse or dependence diagnosis. Ongoing viral replication is associated with a higher risk of HF. Further studies to fully characterize this association and to understand the underlying mechanisms are warranted.