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Cardiovascular manifestations of HIV infection have been observed for more than 15 years and finally prospective data substantiates this association.1 Studies published over the past 2–3 years have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults (table 1). These recent studies show that subclinical echocardiographic abnormalities independently predict adverse outcomes and identify high risk groups to target for early intervention and treatment.
The introduction of highly active antiretroviral therapy (HAART) regimens has significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV infected subjects expected. However, early data raised concerns about HAART being associated with an increase in both peripheral and coronary arterial diseases.
Importantly, the studies listed in table 1 were performed in the era before HAART. Understanding the effects of HAART on the cardiovascular system is only possible by understanding the effects of HIV co-infections first. HAART is only available to a minority of HIV infected individuals worldwide and studies before HAART remain globally applicable. UNAIDS estimates that 36.1 million people were living with HIV infection at the end of the year 2000. If 8–10% of patients develop symptomatic heart failure over a 2–5 year period, then three million cases of HIV related heart failure will have presented in that time period.2 Dilated cardiomyopathy, coronary artery disease, endocarditis, and pericardial effusion related to HIV infection will be reviewed here.
HIV disease is recognised as an important cause of dilated cardiomyopathy (fig 1), with a prevalence reported at 3.6% among cardiomyopathy patients, increasing as patients with HIV infection live longer.1 Compared to patients with idiopathic dilated cardiomyopathy, those with HIV infection and dilated cardiomyopathy have greatly reduced survival and a hazard ratio of death of 4.0.3 The importance of cardiac dysfunction is demonstrated by a reported median survival to AIDS related death which is 101 days in patients with left ventricular dysfunction and 472 days in patients with a normal heart by echocardiography at similar infection stage.2
Myocarditis still represents the best studied cause of dilated cardiomyopathy in HIV disease.4 HIV virions appear to infect myocardial cells in patchy distributions4 without a clear direct association between HIV and cardiac myocyte dysfunction.4 5 It is unclear how virus enters CD4 receptor negative cells such as myocytes. Reservoir cells (for example, dendritic cells) may play a pathogenic role in the interaction between HIV and the myocyte and in the activation of multifunctional cytokines that contribute to progressive and late tissue damage.3Asymptomatic left ventricular dysfunction and increased left ventricular mass independently predict accelerated mortality in both adults and children infected with HIV.6 Treatment for dilated cardiomyopathy associated with HIV infection is generally similar to treatment for non-ischaemic cardiomyopathy. Angiotensin converting enzyme inhibitors are recommended based on general heart failure studies, but may be poorly tolerated because of low systemic vascular resistance from diarrhoeal disease, infection, or dehydration. No studies have investigated the efficacy of specific therapeutic regimens, including HAART, other than intravenous immunoglobulin.7 The apparent efficacy of immunoglobulin treatment may be the result of immunoglobulins inhibiting cardiac autoantibodies by competing for Fc receptors or dampening the secretion or effects of cytokines and cellular growth factors.8
Encephalopathy influences negatively the clinical course of dilated cardiomyopathy in HIV disease. Several studies reported that patients with encephalopathy were more likely to die of congestive heart failure than were patients without encephalopathy with a hazard ratio after multivariate analysis of 3.4.9 HIV may persist in reservoir cells in the myocardium and the cerebral cortex even after antiretroviral treatment.9 The reservoir cells may hold HIV-1 on their surfaces for extended time periods and may chronically release cytotoxic cytokines (tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), endothelin-1 (ET-1)) contributing to progressive and late tissue damage in both systems independently of HAART.9
Coronary artery disease
Accelerated coronary artery disease in HIV infected patients may result from atherogenesis stimulated by virus infected monocyte–macrophages, possibly caused by altered leucocyte adhesion or arteritis.10 Coronary artery disease is observed with increasing frequency among HIV patients receiving protease inhibitors in the ambit of HAART.1 Despite the clinical benefits of protease inhibitors, complications such as lipodystrophy, insulin resistance, and high concentrations of low density lipoprotein and triglycerides have been described in up to 60% of patients treated with HAART regimens.2 11 In 10–20% of patients, these alterations of metabolism have severe manifestations.2 11Effects of pre-existing cardiovascular risk factors combined with atherogenic effects of current drug treatments for HIV infection appear to result in an increase in acute coronary syndromes, even in young HIV infected individuals.
It may be important to consider traditional coronary risk profiles and to alter those that can be modified in the evaluation and continued treatment of patients for HAART. Diet and exercise should not be overlooked, because both can be effective in managing these complications without causing further side effects.11Fibric acid derivatives and statins can lower HIV associated cholesterol and triglyceride concentrations, although further data are needed on interactions between statins and protease inhibitors.11 12 Lovastatin should be avoided in patients receiving concomitant drugs that may potentiate skeletal muscle toxicity with this agent.13 Hypoglycaemic agents may have some role in managing glucose abnormalities, although troglitazone cannot be recommended for fat abnormalities alone and metformin may cause lactic acidosis.12 Perhaps a better understanding of protease inhibitors' effects on lipid and metabolic pathways will lead to a new generation of drug treatments without metabolic alterations. This understanding may also lead to new treatments for dyslipidaemias and alterations of metabolism unrelated to HIV infection.
HIV associated pulmonary hypertension and right ventricular dysfunction
The incidence of HIV associated pulmonary hypertension is estimated to be 1/200, much higher than the 1/200 000 found in the general population.1 Primary pulmonary hypertension is estimated to occur in about 0.5% of hospitalised AIDS patients and is a cause of severe cardiac impairment with associated cor pulmonale and death.1 The pathogenesis is multifactorial and poorly understood. HIV may cause endothelial damage and mediator related vasoconstriction through stimulation by the envelope glycoprotein 120, including direct release and pulmonary vasoconstrictor effects of ET-1, IL-6 and TNF-α. HIV is frequently identified in alveolar macrophages on histology.1 14 These macrophages release TNF-α, oxide anions, and proteolytic enzymes in response to infection. Effects of HAART on pulmonary artery endothelial cells are unknown.
The prevalence of infective endocarditis in HIV infected patients is similar to that of patients of similar behaviour risk—that is, intravenous drug use.1 Estimates of endocarditis occurrence vary from 6.3–34% of HIV infected patients who use intravenous drugs.1 5 Right sided valves are predominantly affected5 (fig 2).1 Patients with and without HIV generally have similar presentation and survival rates from infective endocarditis. However, patients with late stage HIV disease have higher mortality from infective endocarditis than do asymptomatic HIV infected patients.1 As the autoimmune response to bacterial endocarditis is often largely responsible for associated valvar destruction, HIV infected patients may have an altered course. For example, HIV infected patients have a higher risk of developing salmonella endocarditis than immunocompetent patients because they are more likely to develop salmonella bacteraemia during salmonella infection. However, they respond better to antibiotic treatment and may be less likely to sustain valvar damage because of impaired immune function.1
The prevalence of pericardial effusion in asymptomatic HIV infected patients is estimated at 22%.15 Pericardial effusion in HIV disease may be related to opportunistic infections (fig3) or to malignacy, but most often a clear aetiology is not found.15 The effusion may be part of a generalised serous effusive process also involving pleural and peritoneal surfaces. This “capillary leak” syndrome is likely related to enhanced cytokine expression in the later stages of HIV disease.1 15Pericardial effusion spontaneously resolves in up to 42% of patients.1 Mortality remains increased in HIV infected patients who develop an effusion, even if the effusion resolves over time.1 Pericardiocentesis is currently recommended only in large or poorly tolerated effusions, for diagnostic evaluation of systemic illness, or in the presence of cardiac tamponade.1 15 The effects of HAART on pericardial effusion are largely unexplored.
Cardiovascular complications of HIV infection are generally late disease manifestations. Often symptoms of congestive heart failure or pericardial effusion in HIV infected patients are non-specific and may be attributed to generalised illness or co-infection. Echocardiographic screening non-invasively and accurately aids diagnosis during any change in clinical status and directs treatment. Patients will usually respond to early treatment for left ventricular dysfunction and increased left ventricular mass. Treatment based on these findings may prolong the quality and duration of life, and direct further patient evaluation. The role of the cardiologist in the evaluation and treatment of patients with HIV infection should therefore be expanded to include patients who are being evaluated for or who are receiving HAART regimens, especially those with underlying cardiovascular risk. HIV associated heart disease may be an important model for aetiologic mechanisms of dilated cardiomyopathy with important implications in non-HIV related cardiovascular diseases. The role of infection and inflammation in many other cardiovascular diseases is beginning to be recognised, and discovering the molecular mechanisms of HIV related heart disease may provide the basis for rational therapeutic strategies and improved care.
The authors wish to thank Giulia D'Amati, MD, Department of Experimental Medicine and Pathology, University “La Sapienza”, Rome, Italy, for kindly providing the pathological materials reproduced in this editorial.
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