HIV infection, highly active antiretroviral therapy and the cardiovascular system

Cardiovascular complications in the course of human immunodeficiency virus (HIV) infection are multifactorial and may be caused by the virus itself or by the related opportunistic infections and neoplasms. Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy/lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in peripheral artery and coronary artery diseases. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients candidate to antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk with the available guidelines.     

Cardiovascular effects of HAART in infants and children of HIV-infected mothers

Over the past decade, the course of human immunodeficiency virus (HIV) infection has been markedly altered by highly active antiretroviral therapy (HAART). As advances in early diagnosis and aggressive therapy, as well as better supportive care, become available to more HIV-infected patients, survival is being prolonged and more patients are experiencing cardiac abnormalities. Cardiovascular manifestations of pediatric HIV infection have especially proven to be an ongoing challenge to practicing physicians, who face cardiac abnormalities ranging from asymptomatic cardiomyopathy to severe heart failure. Antiretroviral therapy has substantially decreased vertical transmission of HIV; however, studies of adults receiving HAART have found increased peripheral and coronary artery disease. Children exposed to this therapy in utero are thus at an increased risk for toxicity and cardiac abnormalities, regardless of their HIV status. Preliminary studies have reported complications including lactic acidosis and mitochondrial toxicity, as well as cardiomyopathy. Further studies are needed to explore the long-term effects and possible toxicities of prophylactic antiretroviral therapy on infants born to HIV-infected mothers.     

Cardiovascular disease in HIV infection

The survival of patients with HIV infection who have access to highly active antiretroviral therapy has dramatically increased. In HIV-infected persons, cardiovascular disease can be associated with HIV infection, opportunistic infections or neoplasias, use of antiretroviral drugs or treatment of opportunistic complications, mode of HIV acquisition (such as intravenous drug use), or with the classic non-HIV-related cardiovascular risk factors (such as smoking or age). Diseases of the heart associated with HIV infection or its opportunistic complications include pericarditis and myocarditis. Pericarditis may lead to pericardial effusion rarely causing tamponade. Cardiomyopathy is often clinically silent with asymptomatic left ventricular systolic dysfunction. Endocarditis is mainly the consequence of intravenous drug abuse, possibly leading to life-threatening valvular insufficiency with the need for cardiac surgery. A further serious condition associated with HIV infection is pulmonary hypertension potentially leading to right heart failure. The cardiovascular complications of HIV infection such as cardiomyopathy and pericarditis have been reduced by highly active antiretroviral therapy, but premature coronary atherosclerosis is now a growing problem because antiretroviral drugs can lead to serious metabolic disturbances resembling those in the metabolic syndrome. Lipodystrophy, a clinical syndrome of peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance, is most prevalent among patients treated with protease inhibitors. These patients should thus be screened for hyperlipidemia, hyperglycemia, and hypertension, and they may be candidates for lipid-lowering therapies. When initiating lipid-lowering therapy, interactions between statins and HIV protease inhibitors affecting cytochrome P450 function must be considered. Restenosis rate after percutaneous coronary intervention may be unexpectedly high.     

Left ventricular dysfunction in human immunodeficiency virus infection

The relationship between human immunodeficiency virus (HIV) infection and cardiovascular disease is still under debate, but it appears that the risk of myocardial infarction in those with HIV infection who are receiving highly active antiretroviral therapy (HAART) is increased. There has been less focus, however, on the effect of HIV and HAART on left ventricular function. Evidence from the past 20 years in both Westernized and developing countries has indicated that subclinical left ventricular dysfunction in HIV-infected individuals with and without well-controlled HIV infection is prevalent and may represent emerging cardiac disease. The specific roles of HIV infection and HAART are unclear, but they may exert independent direct and indirect effects on the myocardium. These effects may include chronic inflammation, metabolic complications (ie, insulin resistance, lipotoxicity, dyslipidemia), and mitochondrial toxicity. The objective of this article is to review the evidence for HIV- and HAART-related left ventricular dysfunction in persons infected with HIV.     

Clinical impact of HIV-related lipodystrophy and metabolic abnormalities on cardiovascular disease

Metabolic complications and altered fat distribution associated with HIV infection and antiretroviral therapy may lead to accelerated coronary artery disease (CAD). The high prevalence of multiple cardiovascular risk factors in a significant number of HIV patients is a cause for concern in both patients and physicians. Non-invasive strategies to measure subclinical CAD have been inconclusive. Long-term studies are underway to determine cardiac event rates, intervention strategies and consequences for the clinical management of HIV disease. In the present paper, we summarize the most prevalent risk factors in individuals with HIV infection receiving highly active antiretroviral therapy by focusing on the clinical implications of metabolic abnormalities and HIV-related lipodystrophy on CAD.     

CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

The prognosis for patients with human immunodeficiency virus (HIV) infection has improved remarkably as a result of effective antiretroviral therapy. This has resulted in an increased awareness of cardiac complications from HIV infection, including cardiomyopathy and overt heart failure. Mechanisms responsible for HIV cardiomyopathy and heart failure are unknown, but may include direct effects of HIV proteins on the heart. We have previously reported that the HIV envelope glycoprotein, gp120, has a p38 MAP kinase-dependent negative inotropic effect on adult rat ventricular myocytes (ARVM). This signaling pathway presumably results from the binding of gp120 to a specific receptor on the surface of cardiac myocytes. HIV gp120 has been shown to bind to CD4, CXCR4, and CCR5 receptors on lymphocytes and macrophages. Accordingly, we sought to determine if HIV gp120 regulated its negative inotropic effect through activation of one of these binding sites on cardiac myocytes. AMD3100, a highly selective CXCR4 receptor antagonist, reversed HIV gp120-induced negative inotropic effect on ARVM. AMD3100 also blocked HIV gp120 phosphorylation of both p38 MAP kinase and Troponin I. The binding of gp120 to the CXCR4 receptor on ARVM was confirmed by co-immunoprecipitation. We conclude that the negative inotropic effect of HIV gp120 is mediated by a novel signaling pathway that begins with binding to a cardiac myocyte CXCR4 receptor, followed by phosphorylation of both p38 MAP kinase and Troponin I.     

Diagnostik kardialer Manifestationen bei HIV-positiven Patienten mittels nichtinvasiver Bildgebung

HIV infection is frequently associated with cardiovascular involvement. Particularly new treatment concepts, including the highly active antiretroviral therapy, are suspected to increase the rate of cardiac and cardiovascular complications in this patient population. Hence, noninvasive techniques such as transthoracic echocardiography and magnetic resonance imaging will become more important in the routine screening as well as in specific diagnostics of cardiovascular involvement of HIV infection. The present article describes the options of these noninvasive techniques for the detection of HIV-associated cardiac manifestations.     

HIV,highly active antiretroviral therapy and the heart: a cellular to epidemiological review

The advent of potent highly active antiretroviral therapy (HAART) for persons infected with HIV‐1 has led to a “new” chronic disease with complications including cardiovascular disease (CVD). CVD is a significant cause of morbidity and mortality in persons with HIV infection. In addition to traditional risk factors such as smoking, hypertension, insulin resistance and dyslipidaemia, infection with HIV is an independent risk factor for CVD. This review summarizes: (1) the vascular and nonvascular cardiac manifestations of HIV infection; (2) cardiometabolic effects of HAART; (3) atherosclerotic cardiovascular disease (ASCVD) risk assessment, prevention and treatment in persons with HIV‐1 infection.     

Diabetes, insulin resistance, and HIV

The transformation of HIV infection into a chronically managed illness through the widespread use of highly active antiretroviral therapy has brought with it comorbid conditions such as increased risk of cardiovascular disease. Diabetes and insulin resistance have emerged as important comorbidities associated with HIV infection and the use of antiretroviral therapy. Significant inroads have been made towards understanding the etiology of insulin resistance and diabetes in association with HIV and highly active antiretroviral therapy, and there are also emerging data on the prevalence and incidence of this problem. The recognition and management of diabetes mellitus, insulin resistance, and related complications will be an important part of long-term health maintenance for HIV-infected patients.     

Long QT and torsade de pointes in a patient with acquired human immunodeficiency virus infection in multitherapy with drugs affecting cytochrome P450]

In acquired human immunodeficiency virus (HIV) infection, a long depolarization period at ECG may be the consequence of cardiac complications due to viral myocarditis or cardiomyopathy or indirectly due to autonomic neuropathy, or sometimes resulting from pharmacological treatments. Several drugs administered for direct treatment of HIV disease or its complications, such as antiretrovirus, fluconazole, and antibiotics, may induce ventricular arrhythmias due to long QT prolonged depolarization period. Also methadone, frequently associated with HIV therapy to treat patients with opiate addiction, is described in the literature to have cardiac inotropic effects. It has also the potential to increase the QT period and to develop ventricular torsade de pointes, primarily through interference with the rapid component of the delayed rectifier potassium ion current. Moreover, the use of methadone associated with other inhibitors of cytochrome P450 might increase plasma concentrations and contribute to methadone cardiac toxicity. We report the case of an HIV patient receiving antiretroviral treatment, fluconazole and high-dose methadone, who suddenly complained of vertigo, dizziness, pre-syncope and syncope due to severe ventricular arrhythmias that disappeared after discontinuation of all treatments.     

Getting to the Heart of the Matter: A Review of Drug Interactions Between HIV Antiretrovirals and Cardiology Medications

The past 20 years have seen remarkable advances in the treatment of HIV such that most people diagnosed with HIV today can live long, healthy lives by taking antiretrovirals which are usually life-long. Advancements in antiretroviral therapy include the availability of well tolerated, single tablet regimens that are associated with a lower risk of drug-drug interactions. Despite this, many people living with HIV infection might be taking antiretroviral agents that are associated with significant drug-drug interactions. Because HIV infection itself is associated with cardiovascular complications and this population is living longer, concomitant use of antiretrovirals and medications to treat cardiovascular-related diseases is often required. For this reason, it is imperative that clinicians are aware of the potential for clinically significant drug-drug interactions between antiretroviral agents and cardiac medications as well as the useful HIV drug interaction resources that might provide guidance. Available data on significant interactions are summarized and suggested guidance regarding management is discussed.     

Osteoporosis in HIV-infected patients

Bone disorders have emerged in the last 5 yr as additional long-term complications of human immunodeficiency virus (HIV) infection and its treatment. In particular, multiple studies suggest that HIV-infected patients receiving potent antiretroviral therapy have an increased prevalence of both osteopenia and osteoporosis. Studies prior to the era of potent antiretroviral therapy suggest that HIV infection has a modest effect on bone turnover. Treatment of HIV increases bone turnover with a greater effect on bone resorption. The mechanisms for increased bone demineralization in HIV-infected patients are unclear, although there is some evidence that specific drugs may inhibit bone formation in vitro. Small studies suggest that, in general, bone loss is not progressive over a short period of follow-up, and that the bisphosphonates may be useful in management; however, larger studies are needed to confirm these findings and assess the long-term implications of bone loss in HIV-infected persons.     

HIV and chronic obstructive pulmonary disease: is it worse and why?

Smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are of particular concern in the HIV-infected population. Smoking rates are high in this population, and long-term exposure to cigarette smoke in the setting of HIV infection may increase the number of complications seen. Before the era of combination antiretroviral therapy, HIV-infected persons were noted to have an accelerated form of COPD, with significant emphysematous disease seen in individuals less than 40 years old. Unlike many of the AIDS-defining opportunistic infections, HIV-associated COPD may be more common in the current era of HIV because it is frequently reported in patients without a history of AIDS-related pulmonary complications and because many aging HIV-infected individuals have had a longer exposure to smoking and HIV. In this review, we document the epidemiology of HIV-associated COPD before and after the institution of combination antiretroviral therapy, review data suggesting that COPD is accelerated in those with HIV, and discuss possible mechanisms of HIV-associated COPD, including an increased susceptibility to chronic, latent infections; an aberrant inflammatory response; altered oxidant-antioxidant balance; increased apoptosis associated with HIV; and the effects of antiretroviral therapy.     

Relation of subepicardial adipose tissue to carotid intima-media thickness in patients with human immunodeficiency virus

Patients infected with human immunodeficiency virus (HIV) are at increased risk for subclinical atherosclerosis. Whether increased cardiac adiposity may be related to HIV subclinical atherosclerosis is still unexplored. The objective of this study was to evaluate whether echocardiographically determined subepicardial adipose tissue, an index of cardiac adiposity, is related to carotid intima-media thickness (IMT), an index of subclinical atherosclerosis, in HIV-infected patients receiving highly active antiretroviral therapy. Echocardiographic epicardial fat thickness and ultrasonographic IMT were measured in 103 consecutive HIV-infected Caucasian subjects receiving highly active antiretroviral therapy. Echocardiographic subepicardial adipose tissue showed an excellent correlation with IMT (r = 0.92, p <0.01). Multiple regression analysis showed that IMT was best predicted by epicardial fat thickness (r(2) = 0.81, p <0.01). In conclusion, this study suggests, for the first time, that epicardial adipose tissue, an index of cardiac adiposity, may be significantly related to subclinical atherosclerosis in HIV-infected patients.     

Pathogenesis of HIV-associated cardiovascular complications

Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults. The introduction of HAART regimens has significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV-infected people expected. However, early data raised concerns about HAART being associated with an increase in both peripheral and coronary arterial diseases. In this review we discuss HIV-associated cardiovascular complications focusing on pathogenetic mechanisms that could have a role in diagnosis, management, and therapy of these complications in the HAART era.     

Complications of HIV disease and antiretroviral therapy. Highlights of the 11th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2004, San Francisco, California, USA

This year's conference provided newer insights on the complications of antiretroviral therapy, as well as into the complications that arise from HIV infection itself. Many presentations at the conference centered around metabolic complications of therapy, including lipid abnormalities, diabetes, body composition changes, bone disorders, and cardiovascular disease. New data on complications of HIV infection itself were presented, including those on coinfections with hepatitis B, C, and herpes simplex viruses, malaria, and tuberculosis, as well as complications that are important during pregnancy. This article summarizes these presentations.     

Presentation, diagnosis, and management of renal failure in patients with HIV infection

HIV infected patients are at increased risk of developing renal failure when compared to the general population. Renal disease occurs both as a primary manifestation of HIV infection and secondary to complications such as intercurrent illness or drug therapy. Examples of primary HIV renal disease, including HIV associated nephropathy (HIV AN) and immune complex glomerulonephronephritis, and secondary causes of renal failure are reviewed with full discussion about investigation and treatment methods.     

Cardiac manifestations of acquired immune deficiency syndrome: a 1991 update

Cardiac involvement is being identified more often clinically and at autopsy in patients with AIDS. Recent estimates suggest that in the United States as many as 5000 patients per year may have cardiac complications resulting from HIV infection. Patients with AIDS may have pericardial, myocardial, and/or endocardial disease. Pericardial tamponade and/or constriction may be related to neoplasms, infections, or nonspecific effusions. Myocardial dysfunction may result from specific neoplastic infiltration or myocarditis. Particularly intriguing is the role of HIV-1 in the nonspecific myocarditis and dilated cardiomyopathy that occurs in patients with AIDS. As in other debilitating conditions patients with AIDS can have nonbacterial thrombotic endocarditis. Infective endocarditis may be a complication, especially in AIDS associated with intravenous drug abuse. Most patients with AIDS have no overt clinical evidence of cardiac disease. When cardiac dysfunction does develop, the signs and symptoms are often misinterpreted to be the result of noncardiac causes (pulmonary failure or infection) which can mimic heart failure. This review is intended to alert the reader to the cardiac manifestations of AIDS, which present a number of diagnostic and therapeutic challenges.     

Mechanisms of Arrhythmia and Sudden Cardiac Death in Patients With HIV Infection

Long-term survival of HIV-infected patients has significantly improved with the use of antiretroviral therapy (ART). As a consequence, cardiovascular diseases are now emerging as an important clinical problem in this population. Sudden cardiac death is the third leading cause of mortality in HIV patients. Twenty percent of patients with HIV who died of sudden cardiac death had previous cardiac arrhythmias including ventricular tachycardia, atrial fibrillation, and other unspecified rhythm disorders. This review presents a summary of HIV-related arrhythmias, associated risk factors specific to the HIV population, and underlying mechanisms. Compared with the general population, patients with HIV have several cardiac conditions and electrophysiological abnormalities. As a result, they have an increased risk of developing severe arrhythmias, that can lead to sudden cardiac death. Possible explanations may be related to non-ART polypharmacy, electrolyte imbalances, and use of substances observed in HIV-infected patients; many of these conditions are associated with alterations in cardiac electrical activity, increasing the risk of arrhythmia and sudden cardiac death. However, clinical and experimental evidence has also revealed that cardiac arrhythmias occur in HIV-infected patients, even in the absence of drugs. This indicates that HIV itself can change the electrophysiological properties of the heart profoundly and cause cardiac arrhythmias and related sudden cardiac death. The current knowledge of the underlying mechanisms, as well as the emerging role of inflammation in these arrhythmias, are discussed here.     

Cardiovascular disease in human immunodeficiency virus

With widespread access to high‐quality medical care as in Australia, human immunodeficiency virus (HIV) is now considered a chronic, treatable condition, with a good life expectancy. The use of combined highly active antiretroviral therapy has enabled effective suppression of the virus, but has also been associated with increased cardiac morbidity and mortality. Over representation of traditional cardiac risk factors, such as hyperlipidaemia and diabetes, as well as an increased incidence of ischaemic and non‐ischaemic heart disease is now considered a major concern of treatment with antiretroviral therapy. Therefore, a contemporary management strategy for patients with HIV must include active prevention and treatment of cardiovascular risk. This review will outline the complex interplay between HIV infection, antiretroviral drug regimens and accelerated cardiovascular disease, with a particular focus on screening, prevention and treatment options in a contemporary Australian HIV population.