Cardiac Manifestations of HIV
Cardiac
Cardiac Manifestations of HIV
HIV InSite Knowledge Base Chapter
October 2005
Nina Rakhlin, MD, University of California San Francisco
Priscilla Hsue, MD, University of California San Francisco
Melvin D Cheitlin, MD, University of California San Francisco
Introduction
Cardiovascular Manifestations of HIV Infection
Pericarditis with and without Pericardial Effusion
Endocarditis
Myocardial Involvement
AIDS-Related Malignancy
Pulmonary Hypertension
HIV and Coronary Artery Disease
Cardiovascular Risk Factor Profiles of HIV Patients
Treatment of Coronary Risk Factors in HIV Patients
Summary
References
Introduction
At the end of 2002, the Joint United Nations Programme on HIV/AIDS estimated that more than 40 million adults and children were living with HIV/AIDS.( 1 ) From the beginning of the AIDS epidemic, it was recognized, first at autopsy and later by noninvasive techniques, that HIV infection can cause cardiac abnormalities. The prevalence of cardiac disease in HIV-infected individuals is not clear; the reported frequency of cardiac involvement depends on the population studied and the definition of cardiac abnormality. Before the advent of antiretroviral therapy (ART), clinically significant cardiac disease was unusual in the HIV-infected population and was detected in most cases only at autopsy. However, cardiac involvement in AIDS patients appears to be more common than previously thought. In fact, when HIV-infected patients were examined by echocardiography in the late 1980s, cardiac abnormalities were detected more often than would be expected from clinical symptoms and physical examination. Although most conditions are clinically quiescent, some may have devastating and fatal outcomes. Pericardial effusion and myocarditis are among the most commonly reported abnormalities, though cardiomyopathy, endocarditis, and coronary vasculopathy also have been reported. At San Francisco General Hospital and elsewhere, over the past 10 years, an increasing number of HIV-infected patients have been hospitalized with acute coronary syndromes. However, the incidence of clinical cardiac involvement remains low and, with the widespread use of ART in the United States and other resource-rich countries, overall HIV-associated morbidity and mortality in these countries have decreased dramatically.
As patients with HIV infection are living longer, they are at risk of developing chronic diseases, including coronary atherosclerosis. Clinicians should be vigilant in addressing known risk factors for coronary disease in their patients with HIV infection and also should be aware of the various cardiovascular manifestations of HIV infection.
Cardiovascular Manifestations of HIV Infection
Pericarditis with and without Pericardial Effusion
Since HIV infection first appeared in 1981, pericarditis has been recognized as a possible complication. Pericarditis in HIV-infected patients may present with large effusions or cardiac tamponade.( 2-4 ) The incidence of pericardial effusion in patients with asymptomatic AIDS (defined as patients with CD4 count <200 cells/µL) was 11% per year before the introduction of effective ART.( 4 ) The survival of AIDS patients with effusion was significantly shorter (36% at 6 months) than the survival of AIDS patients without effusions (93% at 6 months). This shortened survival remained statistically significant after adjustment for lead-time bias and was independent of CD4 count and albumin level.( 4 )
The etiology of pericardial effusion in HIV-infected patients is often difficult to identify. Culture of pericardial fluid is often unrevealing, and effusion may be part of a generalized serous effusive process also involving pleural and peritoneal surfaces, possibly related to enhanced expression of cytokines in the later stage of HIV infection, although this has not been well studied. There are isolated case reports of pathogens such as Mycobacterium tuberculosis ,( 5-7 ) Staphylococcus aureus ,( 8,9 ) Cryptococcus neoformans ,( 10 ) and herpes simplex ( 11 ) as causes of pericarditis. One evaluation of pericardial fluid cultures and pericardial biopsies in 29 patients established etiology in only 7 of those patients. The causes included S aureus (1 patient), M tuberculosis (1 patient), and cardiac neoplasms (5 patients).( 12 ) Another study evaluated 14 of 17 HIV-infected patients with pericardial effusions. Bacteriologic and cytologic findings were diagnostic in 5 patients (36%): 2 of these were found to have lymphoma and 1 each had S aureus , Mycobacterium avium , and hyphae characteristic of a fungal infection.( 13 )
Endocarditis
Case reports describe both nonbacterial thrombotic endocarditis ( 14 ) and infective endocarditis in patients with HIV infection, with infections at times caused by unusual organisms such as Candida or Aspergillus .( 15 ) Among HIV-infected patients, infective endocarditis is seen almost exclusively in intravenous drug users, where its prevalence varies from 6.3% to 34% of HIV patients and is rare otherwise.( 16 ) Right-sided valves are predominantly affected, and the most frequent pathogens include S aureus (>75% of cases), Streptococcus pneumoniae , Haemophilus influenzae , Candida albicans , Aspergillus fumigatus , and C neoformans .( 17 ) The presentation of and survival from infective endocarditis generally are similar in HIV-infected and HIV-uninfected patients (survival rate of 85% in HIV-positive patients compared with 93% in HIV-negative patients).( 18 ) However, patients with late-stage HIV infection have a 30% higher mortality with endocarditis than asymptomatic HIV-infected patients; this may be related to the degree of immunodeficiency.( 18 )
Before the advent of ART, marantic endocarditis was reported with a prevalence of 4-10% of autopsied cases of HIV patients. At present, it is much less commonly encountered, suggesting that its prevalence was overestimated in the past. It is seen mostly in patients with HIV wasting syndrome and is characterized by friable endocardial vegetations, affecting predominantly the left-sided valves and consisting of platelets and inflammatory cells within a fibrin mesh. Systemic embolization from marantic endocarditis is a rare cause of death in HIV-infected patients treated with ART.
Myocardial Involvement
The HIV virus has been recognized as an important cause of dilated cardiomyopathy (DCM). The diagnosis of HIV-related DCM carries a very poor prognosis, with mortality hazard ratio of 4.0 when compared with uninfected controls with idiopathic DCM.( 19 ) Myocarditis and HIV infection are the most studied causes of DCM in HIV disease.( 20 )
In one study conducted before the advent of ART, global left ventricular dysfunction was detected by echocardiography in 15% of randomly selected HIV-infected patients.( 21 ) In almost all cases, myocardial biopsy revealed myocarditis with cardiotropic viral infection.( 22 ) In autopsy studies of patients with HIV infection, myocarditis was identified in more than half of the 71 patients evaluated, and biventricular dilatation was present in 10% of cases.( 23 ) In children with HIV infection, increased left ventricular wall thickness and depressed left ventricular function were independent predictors of mortality.( 24 )
Zidovudine (ZDV) has been demonstrated to cause mitochondrial myopathy in skeletal muscles, and may cause similar dysfunction in myocardial muscle.( 25 ) Studies performed on transgenic mice suggest that ZDV is associated with diffuse destruction of cardiac mitochondrial ultrastructures and with inhibition of cardiac mitochondrial DNA replication.( 26 ) A study of 6 patients with cardiac dysfunction reported clinical association between cardiac disease and therapy with ZDV and dideoxyinosine (didanosine).( 27 ) Three patients improved after ZDV was discontinued. However, another study evaluated left ventricular dysfunction by echocardiography in 60 HIV-infected patients with left ventricular dysfunction who were receiving ZDV and in 38 HIV-infected patients not on ZDV. It found that patients receiving ZDV did not have worse left ventricular function or more frequent evidence of diastolic dysfunction than did patients who were not on ZDV.( 28 ) These findings are consistent with those of a previous study by the same investigators showing that ZDV does not affect left ventricular function during short-term use.( 29 )
Many organisms, such as herpes simplex virus,( 11 ) cytomegalovirus, M tuberculosis , M avium ,( 30 ) C neoformans ,( 10,31 ) Toxoplasma gondii ,( 32-34 ) and Histoplasma capsulatum , may cause pericarditis and myocarditis in HIV-infected individuals. In one autopsy series, cardiac toxoplasmosis was diagnosed at autopsy in 21 of 182 (12%) HIV-infected patients.( 34 ) In another autopsy series performed before the introduction of potent combination ART, myocarditis was documented in 40-52% of patients who died of AIDS. In more than 80% of these patients, no specific etiologic factor was found, whereas the remaining cases were attributable to above-mentioned infectious agents.( 17 )
The introduction of potent ART regimens seems to influence the course of HIV-associated DCM, and a lower rate of mortality for congestive heart failure has been observed. The incidence and prevalence of DCM in HIV patients in countries with access to effective ART remains unknown. In a study performed in 1999 in the Netherlands involving 105 ambulatory HIV patients, the prevalence of myocardial systolic dysfunction was low (3%) and none of the patients developed end-stage DCM. The authors suggest a myocardial protective effect of ART to explain this low prevalence of cardiac dysfunction compared with the findings of previous studies.( 35 ) A retrospective study conducted in Italy among HIV-positive patients treated with antiretroviral medications showed a lower incidence of cardiac involvement in patients treated with combination ART from 1996 to 1998 in comparison with those treated with nucleoside reverse transcriptase inhibitors (NRTIs) in earlier years.( 36 )
AIDS-Related Malignancy
Reports describe Kaposi sarcoma (KS) ( 37-39 ) and non-Hodgkin lymphoma ( 40-46 ) involving the heart and pericardium. Cardiac KS most often involves the visceral and parietal pericardium, though involvement of the myocardium, coronary artery adventitia, great vessels, epicardium, and epicardial fat also has been described.( 30 ) Cardiac KS is not usually associated with obstruction or with clinical cardiac dysfunction, morbidity, or mortality. Thus, cardiac KS remains occult and is rarely diagnosed during life. Pericardial involvement usually does not affect underlying myocardial function, but may rarely cause tamponade or constriction.
Lymphoma involving the heart occurs infrequently in patients with AIDS. Lymphomatous infiltration may represent metastatic disease from extranodal sites of lymphoma or contiguous spread from a mediastinal mass through the pericardium. These infiltrations may be diffuse or may be represented by isolated lesions, which usually are derived from Burkitt or immunoblastic-type B cells.( 30 ) The introduction of potent ART led to a reduction in the overall incidence of cardiac involvement by KS and non-Hodgkin lymphoma. This change may be attributed to the improved immunologic state of the patients and to the prevention of the pathogens (human herpes virus-8 and Epstein-Barr virus) known to play an etiologic role in these neoplasms.( 47 )
Pulmonary Hypertension
Severe pulmonary disease occurs frequently in patients who have advanced HIV disease and cardiac abnormalities; right ventricular dilatation and failure are not unusual. In the 1980s, at San Francisco General Hospital, 6 patients with advanced HIV disease were found to have pulmonary hypertension (proven by cardiac catheterization) and right ventricular hypertrophy.( 48 ) Other sites have since reported similar patients with pulmonary hypertension.( 49-51 )
Pulmonary hypertension has been reported in HIV-infected patients who have no history of thromboembolic disease, intravenous drug use, or pulmonary infection.( 52 ) Primary pulmonary hypertension has been described in a disproportionate number of HIV-infected individuals and in the 1980s was estimated to occur in 0.5% of hospitalized AIDS patients.( 48 ) One review of the literature concluded that only one third of the HIV-positive patients with pulmonary hypertension had AIDS, and that neither AIDS, pulmonary infection, low CD4 cell counts, nor hypoxemia was needed for the development of pulmonary hypertension.( 50 ) Before the advent of ART, HIV-associated pulmonary hypertension was associated with a poor prognosis. For example, in 131 cases, half of the patients died during a median follow-up period of 8 months; about half of these patients died within 6 months of their diagnosis of pulmonary hypertension.( 53 )
The effect of antiretroviral infection on pulmonary hypertension is not known; however, a recent report from the Swiss Cohort Study, showed that pulmonary artery pressure increased in untreated patients but decreased in patients treated with ART.( 54 ) The oral endothelin receptor antagonist, bosentan, improved exercise tolerance and hemodynamic measurements in a small study of HIV patients.( 55 )
HIV and Coronary Artery Disease
Recent reports of myocardial infarction (MI) in young HIV-infected patients receiving protease inhibitors (PIs) have focused interest on the association between HIV infection and antiretroviral medications. Although it is not yet entirely clear whether there is a direct or indirect association between HIV infection or its treatment and acute coronary syndrome, data on the incidence of coronary heart disease among HIV-infected patients continue to accumulate. The retrospective data are somewhat contradictory, and controlled prospective data will be required to establish whether there is an association between HIV infection or its treatment and ischemic cardiac disease.
In a small French study, patients treated with PIs had almost a 3-fold increase in the risk of MI compared with untreated HIV-infected patients, suggesting that rapidly forming drug-induced plaques are unstable and prone to rupture.( 56 ) A retrospective analysis of 2 large cohorts of patients with HIV infection over the course of an 8-year period showed that MI rates in patients receiving PI therapy were 5 times greater than MI rates in those not on such therapy.( 57 ) However, a larger retrospective study reported no relationship between cardiovascular events and the use of PIs or other classes of antiretroviral drugs.( 58 ) This study evaluated records of more than 36,000 HIV patients in the U.S. Veterans Administration database. It found a decrease in hospital admissions for cardiovascular events after the dates at which combination ART began to be used widely.
This study's findings are in contrast to those of the DAD study, a prospective study of 23,000 patients with HIV infection. During the initial study period, 126 patients had an MI. During the first 4 to 6 years of combination therapy, there was a 26% relative increase in the rate of MI per year of exposure to antiretroviral medication. There was not sufficient power to permit comparisons among patients receiving different types of antiretroviral regimens.( 59 ) Further follow-up of the DAD cohort showed that longer exposure to combined ART was associated with increased overall absolute risk of MI. This relative increase in risk was explained partly but not completely by dyslipidemia.( 60 ) Analysis of risk factors for cardiovascular disease showed that the risk profile of patients in the DAD study had worsened from 1999 to 2004, with an increase in the proportion of patients at high risk for cardiovascular disease.( 61 )
A retrospective study at San Francisco General Hospital compared HIV patients discharged with the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis of MI or unstable angina with an uninfected control group. HIV-infected patients with acute coronary syndrome were more than a decade younger than controls and were more likely to be cigarette smokers and to have a lower HDL cholesterol level. These HIV-infected patients had lower TIMI (thrombolysis in myocardial infarction) risk assessment scores and were more likely to have single-vessel disease. Interestingly, HIV-infected patients who had undergone coronary angioplasty had a significantly higher rate of restenosis than did their HIV-negative counterparts.( 62 )
Cardiovascular Risk Factor Profiles of HIV Patients
(See " Managing Medical Conditions Associated with Cardiac Risk in Patients with HIV ," HIV InSite Knowledge Base .)
Many studies have demonstrated high rates of traditional cardiovascular risk factors in patients with HIV infection. Some of these, such as dyslipidemia, diabetes mellitus, and the metabolic syndrome, may be related to HIV infection or to HIV therapies. Others, such as smoking, are independent of HIV infection.
Studies conducted internationally and in the United States have examined the coronary risk factor profiles in cohorts of HIV-infected patients.( 63-65 ) In a Norwegian cross-sectional study, a 10-year coronary heart disease risk of >20% was twice as common among patients receiving combination ART as in a matched control group without HIV infection, 11.9% vs 5.3%, respectively.( 63 ) A high level of risk was also documented in HIV-infected patients in the United Kingdom ( 64 ) and in the United States.( 65 ) High smoking rates, low HDL cholesterol levels, and the other components of the metabolic syndrome are the main contributors to calculated cardiovascular risk in these patients. It should be noted that, in these studies, coronary risk assessment was based upon the Framingham risk calculator. However, this system has not been studied in patients with HIV infection and does not take into consideration any HIV-specific factors such as chronic inflammation or altered immune system function.
Dyslipidemia has been seen in patients with HIV infection, and has been linked both to HIV infection and to ART. In untreated HIV-infected patients, lower CD4 counts are associated with lower total blood cholesterol, lower HDL cholesterol, and higher triglyceride levels.( 66 ) A study of lipid levels in 50 HIV-infected patients from the Multicenter AIDS Cohort Study ( 67 ) examined blood samples taken before infection with HIV, samples taken before initiation of ART (a mean of 7.8 years later), and samples obtained during treatment with antiretroviral medications. ART included at least 1 PI in 48 of 50 cases. Total and LDL cholesterol decreased after the onset of HIV disease, but rose to preinfection levels or higher with ART, while HDL cholesterol levels decreased markedly after the onset of HIV and did not recover. Triglycerides were measured only once, during treatment, and were elevated at 225 mg/dL.
Several PIs may induce or worsen dyslipidemia and insulin resistance in HIV patients, independent of body composition abnormalities.( 68 ) PIs appear to have drug-specific effects on lipid and glucose metabolism. Some PIs, such as atazanavir, do not appear to perturb lipid or glucose levels. However, in studies of HIV-uninfected subjects, ritonavir increased triglycerides and lowered HDL cholesterol slightly, with no increase in LDL cholesterol,( 69,70 ) whereas indinavir did not affect lipoproteins but caused insulin resistance.( 71 ) Lopinavir/ritonavir increased triglycerides without affecting LDL or HDL cholesterol or insulin resistance;( 72 ) amprenavir had no effect on lipoproteins.( 70 ) In HIV-infected patients, clinical studies of the effects of PIs on lipid levels have shown that PIs increased total cholesterol by 66%, LDL cholesterol by 37%, and triglycerides by 80% at 48 weeks.( 73 ) In the DAD cohort of HIV-infected patients, total cholesterol exceeded 240 mg/dL in 27% of those receiving a PI, 23% of those receiving an NNRTI, 44% of those receiving a PI and an NNRTI, and 10% of those receiving only an NRTI, compared with 8% of patients not receiving ART.( 74 ) Triglyceride levels above 200 mg/dL were present in 40% of PI-treated patients, 32% of those treated with NNRTIs, 54% of those receiving both PIs and NNRTIs, 23% of NRTI-treated patients, and 15% of the untreated.
Insulin resistance and hyperglycemia appear to be more common in persons with HIV infection than in uninfected individuals. Patients receiving ART may have even higher rates of insulin resistance and diabetes, and certain ARV medications, such as indinavir,( 71 ) may confer greater risk than others.( 75 )
Hypertension occurs in up to one third of patients with HIV infection.( 76,77 ) NNRTIs or PIs have been linked to hypertension in some studies ( 78,79 ) but not in others.( 76 ) The hypertension associated with HIV appears to be linked to insulin resistance and the metabolic syndrome.( 77 )
Treatment of Coronary Risk Factors in HIV Patients
(See " Managing Medical Conditions Associated with Cardiac Risk in Patients with HIV ," HIV InSite Knowledge Base .)
There are no definitive studies at present showing that treatment of traditional coronary risk factors improves outcomes in patients with HIV infection. However, while studies are ongoing, it appears reasonable to extrapolate from the treatment of coronary risk factors in non-HIV patients.
The Adult AIDS Clinical Trials group recommends that dyslipidemia be managed according to the guidelines of the National Cholesterol Education Program Adult Treatment Panel III.( 80 ) Certain considerations should guide the selection of lipid-lowering agents in HIV-infected individuals who are taking PIs. Both PIs and statins (with the exception of pravastatin) are metabolized by the cytochrome P450 system. In non-HIV-infected individuals, the combination of ritonavir/saquinavir has been shown to increase the area under the curve (AUC) by 30-fold for simvastatin and by 79% for atorvastatin, whereas the AUC decreased by 50% for pravastatin.( 81 ) Simvastatin and lovastatin are contraindicated in patients taking PIs, whereas atorvastatin should be used cautiously, and, if used, should be initiated at low dosage.( 80 ) Pravastatin is safe, but has lower potency with respect to LDL cholesterol lowering. The cholesterol absorption inhibitor ezetimibe has not been studied in HIV-infected patients, but represents an attractive approach to LDL cholesterol lowering because of its lack of drug-drug interactions. A newer PI, atazanavir, does not appear to be associated with lipid abnormalities;( 82 ) thus, switching patients with hyperlipidemia who are on other PIs to atazanavir represents an alternate approach to lipid management.
Many HIV-infected patients also have elevated triglyceride levels. Fibrates (bezafibrate, fenofibrate, and gemfibrozil) appear to reduce triglycerides effectively in HIV-infected patients receiving ART.( 83,84 ) Fibrates should be used cautiously in combination with statins because of the increased risk of myopathy. Niacin is an alternate option for triglyceride reduction, but may be a poor choice for many HIV patients because of its propensity to worsen blood glucose levels.
Hypertriglyceridemia is often accompanied by the other components of the metabolic syndrome: low HDL cholesterol, increased remnant lipoproteins, small LDL particle size, abdominal obesity, hypertension, insulin resistance and glucose intolerance, a proinflammatory state, and a prothrombotic state.( 85 ) Even in the absence of HIV disease, the metabolic syndrome is associated with increased cardiovascular risk.( 85 ) The primary treatment target for the metabolic syndrome is obesity, and the recommended measures include diet and exercise.( 86 ) Even modest reductions in body weight may improve dyslipidemia, hypertension, and glucose intolerance, as well as levels of inflammatory and thrombotic markers.( 86 )
There have been a limited number of studies investigating cigarette smoking in HIV-infected patients. The prevalence of cigarette smoking in HIV patients has been reported to be as high as 70-80% in some areas,( 87 ) and HIV-infected persons appear less likely to have contemplated tobacco cessation compared with other smokers.( 87 ) Pilot studies of cessation interventions in HIV-infected smokers include a nurse-managed, peer-led intervention ( 88 ) and the provision of cellular telephones to low-income, HIV-infected smokers to facilitate counseling.( 89 ) Smoking cessation should be a major focus of attention in the clinical care of HIV-infected smokers.
Summary
Studies published before the introduction of potent combination ART have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults. The role of infection and inflammation in non-HIV-related cardiovascular disease is beginning to be recognized, and discovering the molecular mechanisms of HIV-related heart disease may provide the basis for rational therapeutic strategies and improved care. The effects of ART on cardiovascular disease are undergoing investigation and require long-term follow-up. Clinicians should be aware of the various cardiovascular complications of HIV infection, especially coronary artery disease, and should aggressively treat all risk factors in their patients with HIV infection.
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