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Pathogenesis of HIV-associated cardiovascular complications
HIV-associated cardiovascular complications
Review
Pathogenesis of HIV-associated cardiovascular complications Giuseppe Barbaro, Stacy D Fisher, and Steven E Lipshultz
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 HIVassociated cardiovascular complications focusing on pathogenetic mechanisms that could have a role in diagnosis, management, and therapy of these complications in the HAART era. Lancet Infectious Diseases 2001; 1: 115–124
Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) regimens have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults.1-3 HAART regimens have 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. 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 small number of HIV-infected individuals worldwide and studies before HAART therapy remain globally applicable. UNAIDS estimates that 36·1 million people are living with HIV infection at the end of the year 2000.4 If 8–10% of patients develop symptomatic heart failure over a 2–5 year period,5 then 3 million cases of HIV-related heart failure will present in that period.6 Various possible causes have been postulated in HIV-related heart disease (table 1), including myocardial infection with HIV, opportunistic infections, viral infections, autoimmune response to viral infection, drug related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression.
Dilated cardiomyopathy HIV disease is recognised as an important cause of dilated cardiomyopathy (figure 1) with a rate reported in previous reviews as 3·6% among cardiomyopathy patients, increasing as patients with HIV infection live longer.2 The importance of cardiac dysfunction is shown by a reported median THE LANCET Infectious Diseases Vol 1 September 2001
survival to AIDS-related death that is 101 days in patients with left-ventricular dysfunction and 472 days in patients with a normal heart by echocardiography at similar infection stage.6 HIV-related cardiomyopathy compared with idiopathic cardiomyopathy has an unadjusted hazard ratio of 4·0 and, after multivariate analysis, of 5·86 for death.7 In the multicentre Pulmonary and Cardiac Complications of HIV study (P2C2 HIV), children with vertically transmitted HIV infection (median age 2·1 years) had a 5-year cumulative survival of 64%.8 Deaths were higher in children with baseline-depressed left-ventricular fractional shortening or increased left-ventricular dimension, thickness, mass, wall stress, heart rate, or blood pressure. Decreased left-ventricular fractional shortening and increased wall thickness were also predictive of survival after multivariate adjustment.8 Rapid-onset congestive heart failure has a grim prognosis in HIV-infected adults and children, with over half of patients dying from primary cardiac failure within 6–12 months of presentation.5,8 Chronic-onset heart failure could respond better to medical therapy in this population. There is no evidence from published prospective studies about HAART benefit on HIV-associated cardiomyopathy. However, improvement in the immunologic state of the patients and better control of opportunistic infections could be examples of the beneficial effects of HAART in the incidence and clinical course of HIV-associated heart disease as reported by some preliminary retrospective studies.9 Animal models
Simian immunodeficiency virus (SIV) infection in rhesus macaques is a valuable model in understanding the pathogenesis of cardiac injury associated with retroviral infection.10 Chronic SIV infection resulted in depressed leftventricular systolic function and an extensive coronary arteriopathy suggestive of injury due to cell-mediated immune response.10 Two-thirds of chronically infected macaques that died of SIV had related myocardial effects. Lymphocytic myocarditis was seen in nine of 15 macaques and coronary arteriopathy in nine of 15 (six alone and three GB is cardiologist and a medical researcher at the Department of Emergency Medicine, University La Sapienza, Rome, Italy; SDF is a senior instructor in medicine (cardiology) at the University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; and SEL is professor of paediatrics and of oncology at the University of Rochester. Correspondence: Dr G Barbaro, Viale Anicio Gallo 63, 00174 Rome, Italy. Tel/fax +39 06 710 2889; email [email protected]
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association between HIV-1 and cardiac myocyte dysfunction.5,11 It is unclear how HIV-1 could enter CD4receptor-negative cells such as myocytes. Reservoir cells (eg, dendritic cells) could have a pathogenic role in the interaction between HIV-1 and the myocyte, and in the activation of multifunctional cytokines (eg, tumor necrosis factor-alpha [TNFα], interleukin-1 [IL-1], interleukin-6 [IL-6], interleukin-10 [IL-10]) that contribute to progressive and late tissue damage.7,12 Coinfection with other viruses (usually, coxsackievirus B3 and cytomegalovirus) also seems to have an important pathogenetic role, as reported both in necropsy and clinical studies.5,11 Autoimmunity
in combination with myocarditis) upon necropsy. In infected macaques, coronary arteriopathy was extensive, with evidence of vessel occlusion and recanalisation, and related regions of myocardial necrosis in four macaques. On necropsy, two animals had marantic endocarditis and one had a left-ventricular mural thrombus. Macaques with cardiac pathology were emaciated to a greater extent than macaques with SIV and similar periods of infection who did not experience cardiac pathology10.
Compared with patients with idiopathic dilated cardiomyopathy, who had predominantly CD4 and B lymphocytes, the inflammatory-cell infiltrates in HIVinfected patients who had an echocardiographic diagnosis of dilated cardiomyopathy and a histological diagnosis of myocarditis were predominantly CD3 and CD8 lymphocytes, possibly indicating the number of circulating lymphocytes in these patients.7 In roughly 70% of both HIVassociated and idiopathic-dilated cardiomyopathy patients, increased staining was limited to MHC class-I molecules.7 The combination of viral hybridisation and increased myocardial expression of MHC class-I strongly suggests an active immune process in the myocardium. Increased frequency of cardiac-specific autoantibodies (anti-alpha myosin autoantibodies) has been reported by Currie et al.13 They reported that HIV-infected patients were more likely to have cardiac-specific autoantibodies than were controls (15% vs 3·5%). Those with echocardiographic evidence of left-ventricular dysfunction were especially likely to have cardiac autoantibodies (43%), supporting the theory that cardiac autoimmunity has a role in the pathogenesis of HIV-related heart disease and suggesting that cardiac autoantibodies could be markers of leftventricular dysfunction in HIV-positive patients with previously normal echocardiographic findings.13 Monthly immunoglobulin infusions in HIV-infected paediatric patients have been associated with minimum left-ventricular dysfunction, an increase in left-ventricular-wall thickness, and a reduction in peak left-ventricular-wall stress, suggesting that both impaired myocardial growth and leftventricular dysfunction may be immunologically mediated.3,8 The apparent efficacy of immunoglobulin therapy could 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 as also reported in HIV-negative subjects with chronic heart failure.14 Immunomodulatory therapy could be helpful in adults and children with declining leftventricular function, but further study is needed to assess the efficacy of this therapy.3,8
Myocarditis and viral myocardial infection
Myocardial cytokine expression
Myocarditis and HIV-1 myocardial infection still represent the best-studied cause of dilated cardiomyopathy in HIV disease5. HIV-1 virions seem to infect myocardial cells in patchy distributions5 (figure 2) without a clear direct
Tinkle et al15 reported that transgenic mice with a portion of the genome of a proviral, non-infectious HIV developed ventricular dysfunction and, in some cases, myocarditis, arteritis, and vasculitis. PCR detected no HIV, suggesting
Figure 1. Dilated cardiomyopathy in a patient who died of AIDS. The heart has a globular shape with rounded apex due to ventricular dilatation. On cut surface, the left-ventricular cavity is enlarged, with mild myocardial hypertrophy. There is also a diffuse endocardial fibrous thickening (a). Histology showed mild myocardial hypertrophy and vacuolisation. Interstitial collagen was increased (haematoxylin-eosin, x20) (b).
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HIV-associated cardiovascular complications
Review
Table 1. Principal HIV-associated cardiovascular abnormalities Type Dilated cardiomyopathy
Possible causes and associations Infectious: HIV, Toxoplasma gondii, coxsackievirus group B, Epstein-Barr virus, cytomegalovirus, adenovirus. Autoimmune response to infection. Drug-related: cocaine, possibly nucleoside analogues, IL-2, doxorubicin, interferon. Metabolic/endocrine: nutritional deficiency/ wasting, selenium, B12, carnitine, thyroid hormone, growth hormone, adrenal insufficiency, hyperinsulinaemia. Cytokines: TNF, nitric oxide, TGF, endothelin-1. Hypothermia. Hyperthermia. Autonomic insufficiency, encephalopathy. Acquired immunodeficiency: HIV viral load, length of immunosuppression. Coronary heart disease and hypertension Protease-inhibitors-induced metabolic and coagulative disorders. HIV-induced endothelial dysfunction. Erythropoietin-induced increase of haematocrit and blood viscosity. Vasculitis. Pericardial effusion Bacteria: staphylococcus, streptococcus, proteus, nocardia, pseudomonas, klebsiella, enterococcus, listeria, mycobacteria (Mycobacterium tuberculosis, M avium intracellulare, M kansaii). Viral pathogens: HIV, herpes simplex virus, herpes simplex virus type-2, cytomegalovirus. Other pathogens: cryptococcus, toxoplasma, histoplasma. Malignancy: Kaposi’s sarcoma, malignant lymphoma. Capillary leak/wasting/malnutrition. Hypothyroidism. Prolonged acquired immunodeficiency. Primary pulmonary hypertension Plexogenic pulmonary arteriopathy. Mediator release from endothelium.
that the cardiac abnormalities were due to circulating factors or cytokines.15 HIV-associated myocarditis and dilated cardiomyopathy are associated with local cytokine production that may be markedly higher than to circulating concentrations, making peripheral cytokine rates uninformative.7 Viral infection in the context of a nonspecific stimulator of monokines such as IL-1 or TNF is much more likely to lead to myocarditis and myocyte damage than viral infection alone.16 TNF produces a negative inotropic effect by altering intracellular calcium homeostasis, and possibly by inducing nitric oxide synthesis, which also reduces myocyte contractility.7,17 Compared with patients with idiopathic dilated cardiomyopathy, a greater intensity of both TNF and inducible nitric oxide synthase (iNOS) staining has been reported in myocardial biopsy samples from patients with HIV-associated cardiomyopathy, specifically in those with a myocardial viral infection independently of antiretroviral treatment.7 Patients with HIV-associated cardiomyopathy who were co-infected with coxsackievirus B3, cytomegalovirus, or other viruses had samples that stained more intensely for both TNFa and iNOS. Moreover, patients co-infected with HIV-1 and coxsackievirus B3 had samples that stained more intensely for iNOS than did patients with idiopathic dilated cardiomyopathy and myocardial infection with coxackievirus B3 or who had adenovirus infection alone .18 HIV-associated encephalopathy
Several studies reported that patients with encephalopathy were more likely to die of congestive heart failure than were THE LANCET Infectious Diseases Vol 1 September 2001
Incidence Estimated 15·9 patients/1000 symptom-free HIV-infected people5
Largely limited to case reports
11%/year55–58 Spontaneous resolution in up to 42% of affected patients55–58
0·5% incidence24
patients without encephalopathy with a hazard ratio after multivariate analysis of 3·4.8,17,19 HIV-1 could persist in reservoir cells in the myocardium and the cerebral cortex even after antiretroviral treatment.17 The reservoir cells could hold HIV-1 on their surfaces for extended time periods and could chronically release cytotoxic cytokines (TNF, IL-6, endothelin-1) contributing to progressive and late tissue damage in both systems independently of HAART.17 Figure 3 shows the possible mechanisms involved in the development of HIV-associated cardiomyopathy and encephalopathy. These mechanisms are speculative but could warrant further controlled clinical and experimental investigations.
Figure 2. Endomyocardial biopsy from an HIV-1 positive patient with dilated cardiomyopathy. In situ hybridisation with an HIV-1 specific probe, labelled with S35 reveals a positive myocyte not surrounded by inflammatory cells (haematoxylin-eosin, x40).
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CD4-receptor
HIV/other viruses (CVB3, CMV, EBV, ADV)
HIV
Lymphocyte/ monocyte CD4-receptor
O2-
Dendritic cell/ macrophage
CD4-receptor
TNF IL-1 IL-6 IL-10
ROS Dendritic cell/ macrophage
TNF IL-1 IL-6 IL-10
iNOS
iNOS NO CD4-receptor
Fas/fas-ligand
NO
MHC-I/II Fas/fas-ligand
cGMP Ca++ turnover
Bid
autoantigens MHC-II
B lymphocyte/ plasma cell
MHC-I
Nerve cell
cGMP Ca++ turnover
Bid
Mitochondrial damage
Myocardial cell
Mitochondrial damage
Caspases Apoptosis Cyto C AIF
Caspases Apoptosis Cyto C AIF
Impairment of the autonomic system Increased adrenergic activity Increased consumption of oxygen by myocardial tissue Down regulation of beta-adrenergic receptors and reduced contarctility of myocardial cells
autoantibodies (anti-myosin antibodies)
Figure 3. The possible pathogenic mechanisms involved in the development of HIV-associated cardiomyopathy and encephalopathy and in their relationship. The infection of dendritic cells, of CD4 lymphocytes, and of myocardial or neuronal cell by HIV-1 or by other viruses could be responsible for release of specific cytokines (TNF, IL-1, IL-6, IL-10) which activate the inducible form of nitric oxide synhase (iNOS). The interaction between cytotoxic T lymphocytes and the receptoral complex fas/fas ligand located on the surface of the target cell could cause mitochondrial damage with release of mitochondrial pro-apoptosis factors (cytochome c, apoptosis inducing factor [AIF]). Similar mitochondrial damage may be caused by reactive oxygen species (ROS) released by activated lympho-monocytes. The interaction between autoantigens and MHC molecules on the surface of dendritic cells/macrophages, of myocardial cells (MHC-I), and of B lymphocytes (MHC-II) determine the production of autoantibodies (eg, alpha-antimyosin) which are responsible for direct cellular damage. The neuronal damage, specifically the impairment of the autonomic system, could increase the functional damage to myocardial cells because of increased adrenergic activity and down-regulation of beta-adrenergic receptors. ADV=adenovirus; Bid=a protein of the bcl2 family involved in apoptosis; CMV=cytomegalovirus; CVB3= coxsackievirus B3; EBV=Epstein-Barr virus.
Nutritional deficiencies
Drug cardiotoxicity
Nutritional deficiencies are common in HIV infection, particularly in late-stage disease, and could contribute in inducing ventricular dysfunction independently of HAART regimens. Poor absorption and diarrhoea both lead to electrolyte imbalances and deficiencies in elemental nutrients. Deficiencies of trace elements have been associated directly or indirectly with cardiomyopathy.20 Selenium replacement reverses cardiomyopathy and restores left-ventricular function in nutritionally deplete patients.20 Concentrations of vitamin B12, carnitine, and growth and thyroid hormone could also be altered in HIV disease; all have been associated with left-ventricular dysfunction.20 Electrolyte imbalances (eg, hypokalaemia, hypocalcaemia, hypomagnesaemia), related to malnutrition and/or to chronic diarrhoea, could contribute in inducing ventricular arrhythmias (torsade de pointes and ventricular fibrillation) by prolongation of the electrocardiographic QTc interval.
Previous reviews have noted an association between zidovudine and dilated cardiomyopathy in both adults and children.1,2 Studies done on transgenic mice suggest that zidovudine is associated with diffuse destruction of cardiac mitochondrial ultrastructures and inhibition of mitochondrial DNA replication.21 Lactic acidosis related to mitochondrial dysfunction could further contribute in myocardial cell dysfunction.22 In a P2C2 HIV Study Group trial infants born to HIV-positive mothers were followed from birth to age 5 years with serial echocardiographic studies every 4–6 months. No association with acute or chronic abnormalities in left-ventricular structure or function was found with perinatal exposure to zidovudine.23 Other nucleoside reverse transcriptase inhibitors such as didanosine and zalcitabine do not seem either to promote or to prevent dilated cardiomyopathy.5 As reported in previous reviews, in AIDS patients with Kaposi’s sarcoma, reversible cardiac dysfunction was
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HIV-associated cardiovascular complications
associated with prolonged, high-dose therapy with interferon alpha.2 Doxorubicin (Adriamycin), which is used to treat AIDS-related Kaposi’s sarcoma and non-Hodgkin lymphoma, has a dose-related effect on dilated cardiomyopathy, as does foscarnet sodium when used to treat cytomegalovirus oesophagitis.2 The principal cardiovascular actions/ interactions of common HIV therapies with related cardiac effects are reported in table 2.
HIV
Macrophage Platelets Lymphocyte
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.24 Pulmonary hypertension is often explained in HIV-infected patients by lung infections, venous thromboembolism, or left-ventricular dysfunction. Pulmonary hypertension found on screening echocardiography or right-heart catheterisation warrants an aggressive investigation for treatable pulmonary infections.24 Primary pulmonary hypertension has been reported in HIV-infected patients without a history of thromboembolic disease, intravenous drug use, or pulmonary infections associated with HIV. One necropsy and one biopsy specimen revealed precapillary muscular pulmonary artery and arteriole medial hypertrophy, fibroelastosis, and eccentric intimal fibrosis without direct viral infection of pulmonary artery cells.24,25 This finding suggests mediator release from infected cells elsewhere and possibly cytokine mediated injury. The pathogenesis of primary pulmonary hypertension has many factors and is poorly understood. Primary pulmonary hypertension has been found in haemophiliacs receiving lyophilised factor VIII, intravenous drug users, and patients with left-ventricular dysfunction, obscuring any relationship with HIV-1.24,25 It could be that HIV-1 causes endothelial damage and mediator-related vasoconstriction through stimulation by the envelope glycoprotein 120, including direct release and effects of endothelin-1 (vasoconstrictor), IL-6, and TNF, in the pulmonary arteries (figure 4).24,25 HIV-1 is frequently identified in alveolar macrophages on histology.24,25 These macrophages release TNF, oxide anions, and proteolytic enzymes in response to infection. Lymphokines could also contribute to endothelial proliferation seen in pulmonary hypertension by promoting leucocyte adhesion to the endothelium.26 Clinical symptoms and outcome of patients with right-ventricular dysfunction is related to the degree of pulmonary hypertension, varying from a mild symptomless condition to severe cardiac impairment with corpulmonale and death.24 Activation of α1receptors and genetic factors (increased frequency of HLA DR6 and DR52) have been also suggested in the pathogenesis of HIV-associated pulmonary hypertension.26 The effects of HAART regimens on the clinical course of HIV-associated pulmonary hypertension are unknown.
ET-1 PDGF IL6 IL1 TNF
Endothelial cell
•Reduction of NO synthesis
Endothelial cell
Smooth-muscle cells
•Proliferation •Proliferation •Vasoconstriction •Migration of smooth muscle cells
Figure 4. The possible pathogenetic mechanisms involved in the development of HIV-associated pulmonary hypertension. HIV-infected macrophages, platelets and lymphocytes could release multifunctional cytokines (endothelin-1 [ET-1], platelet derived growth factor [PGDF], IL6, IL-1, TNF), which could affect the endothelial cells of the pulmonary vessels, inducing their proliferation and vasoconstriction by a reduction of nitric oxide (NO) production. Moreover, ET-1 produced by endothelial cells could affect the smooth muscle cells of the pulmonary vessels inducing their migration and proliferation.
abnormalities and exposure to various xenoantigens such as HIV-1 itself, other infectious agents (eg, cytomegalovirus), and drugs.27 Endothelial dysfunction and/or injury, which is pivotal to the development of cardiovascular and inflammatory pathology, has been described in HIV infection.28 Elaboration of circulating markers of endothelial activation such as soluble adhesion molecules and procoagulant proteins arises in HIV infection.28 Virus entry into endothelial cells could happen via CD4 antigen or galactosyl-ceramide receptors. Other mechanisms of entry including chemokine receptors have been proposed. Nonetheless, endothelial activation could also happen in HIV infection, either caused by cytokines secreted in response to mononuclear or adventitial cell activation by virus, or by the effects of the secreted HIV-associated proteins gp 120 and tat on endothelium.28 Enhanced adhesiveness of endothelial cells, endothelial cell proliferation, and apoptosis as well as activation of cytokine secretion have all been shown. A synergy between inflammatory cytokines and viral proteins in inducing endothelial injury has been shown.28 In HIV infection, dysfunctional or injured endothelial cells can cause tissue injury, inflammation and remodelling, and accelerate the development of cardiovascular disease.28
Endothelial dysfunction A wide range of inflammatory vascular diseases (eg, polyarteritis nodosa, Henoch-Schonlein purpura, druginduced hypersensitivity vasculitis) could arise in HIVinfected people.27 Vascular inflammation seems to have many factors and could result from HIV-induced immunological THE LANCET Infectious Diseases Vol 1 September 2001
Coronary heart disease Accelerated coronary artery disease in HIV-infected patients could result from atherogenesis stimulated by virus-infected monocyte-macrophages, possibly owing to altered leukocyte adhesion or arteritis.29 Coronary artery disease is observed 119
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HIV-associated cardiovascular complications
Fat acids Glycerol Adipocyte PI Lipodystropy/ lipoatrophy
RA CRABP-1 LRP PI LPL
PI
P-450 3A Cis-9 RA
PI PI
Hyperlipidaemia Circulating triglycerides
Triglyceride storing
PI
RXR Lipid release Apoptosis Reduced differentiation
LRP Liver
Insulinresistance
Figure 5. Pathogenetic mechanisms involved in the development of PI-induced lipodystrophy/lipoatrophy, hyperlipidaemia, and insulin-resistance.The marked black lines show the metabolic blocks made by PI. LPL=lipoproteinlipase, RA=retinoic acid, RXR= retinoic acid receptor.
with increasing frequency among HIV patients receiving HAART regimens that contain protease inhibitors (PIs). Despite the clinical and immunological benefits, complications such as lipodystrophy, hyperlipidaemia, hyperglycaemia, and insulin-restistance could develop in up to 60% of patients treated with PIs,30-34 with an increased risk for acute coronary syndromes and stroke.35-40 However, data on the incidence of coronary heart disease among HIVinfected subjects receiving PIs are largely limited to case reports.41 According to Carr et al,30 the metabolic and somatic alterations in PIs-treated patients could be ascribed to the homology of the catalytic region of HIV protease, the molecular target of PIs, to regions of two human proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein 1 (CRABP-1) and LDL-receptor-related protein (LRP). The hypothesis is that PIs inhibit CRABP-1-modified and CYP3A-mediated synthesis of cis-9-retinoic acid and peroxisome proliferator-activated receptor-type-gamma (PPAR-gamma) heterodimer. This results in an increased apoptosis of adipocytes and in reduced differentiation from pre-adipocytes to adypocytes, with the final effect of reduced triglyceride storage and increased lipid release. PIs binding to LRP would impair hepatic chylomicron uptake and endothelial triglyceride clearance, resulting in hyperlipidemia and insulin resistance30 (figure 5). Recent data indicate that dyslipidaemia could be accounted for, at least in part, by PI-mediated inhibition of the proteasome activity and accumulation of the active portion of sterol regulatory element-binding protein-1c in 120
liver cells and adipocytes.42 There is also evidence that PIs directly inhibit the uptake of glucose by insulin-sensitive tissues, such as fat and skeletal muscle, and by selective inhibition of the glucose transporter Glut4.43 Similarities between HIV-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis suggest the pathophysiological involvement of nuclear factors such as lamin A/C and druginduced mitochondrial dysfunction.44 However,there is a continuing discussion about the case definition, diagnostic procedure, and treatment options for PI-induced body-shape changes and metabolic disturbances.44 It could be important to consider traditional coronary risk profiles and to alter those that can be modified in the assessment and continued therapy of patients for HAART.45 Fibric acid derivatives and statins can lower HIV-associated cholesterol and triglyceride rates, although further data are needed on interactions between statins and PIs.46,47 Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of people.48 Lovastatin should be avoided in patients receiving other drugs that could cause skeletal muscle toxicity with this agent.49 Hypoglycaemic agents could have some role in managing glucose abnormalities, although troglitazone cannot be recommended for fat abnormalities alone and metformin could cause lactic acidosis.47
Hypertension and coagulative disorders HIV patients are at higher risk of developing hypertension at a younger age than the general population.50 Predisposing THE LANCET Infectious Diseases Vol 1 September 2001
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HIV-associated cardiovascular complications
Review
factors for developing hypertension include vasculitis in small, medium, and large vessels in the form of leucocytoclastic vasculitis, atherosclerosis secondary to HAART regimens, aneurysms of the large vessels with impairment of flow to the renal arteries, and PI-induced insulin resistance with increased sympathetic activity and sodium retention.50,51 A syndrome of acquired glucocorticoid resistance has been described in HIV-infected patients with hypercortisolism and a lower affinity of the glucocorticoid receptors.50 The syndrome is characterised clinically by weakness, hypertension or hypotension, and skin pigmentation changes. Acute and chronic renal failure is often associated with HIV infection.50 The prevalence of hypertension associated with erythropoietin therapy is 47%; the effect could be related to the increase in haematocrit and blood viscosity.50 Various coagulation abnormalities (eg, increased levels of D-Dimer, plasminogen activator inhibitor-1 and tissue-type plasminogen-activator antigen) have been reported in HIVinfected patients, especially in those with fat redistribution.52,53 These abnormalities have been associated with documented thromboses of veins and arteries.51,52 The routine assessment of coagulative parameters is probably not advisable until a benefit of widespread screening is assessed in prospective studies. A heightened awareness of the possiblity of coagulative disorders, together with controlled trials and basic research, are needed.
Endocardial involvement The frequency of infective endocarditis in HIV-infected patients is similar to that of patients of closely similar behaviour risk—ie, intravenous drug use (IDUs), independently of HAART regimens.2 Estimates of endocarditis incidence vary from 6·3% to 34% of HIVinfected IDUs.11 Right-sided valves are usually involved in HIV-infected IDUs. Vegetations could form on the tricuspid or pulmonic valves resulting in pulmonary embolism and septic pulmonary infarcts, which appear as multiple opacities on chest radiograms.11 Systemic emboli often involve coronary arteries, spleen, bowel, extremities, and central nervous system. Cardiac rhythm alterations (ie, atrioventricular block) could suggest the presence of an abscess near the atrioventricular node.11 Peripheral pulses must be examined for signs of embolic occlusion or pulsating mass suggesting mycotic aneurysm. Mycotic aneurysms could arise in the intracranial arteries, potentially leading to intracranial haemorrhage.11 The most frequent bacterial agents are Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae.11 The HACEK group of organisms, which includes Haemophilus spp, Actinobacillus actinomycetem-comitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, are fastidious bacteria and can be difficult to culture. Cryptococcus and candida fungal endocarditis can also be seen in AIDS patients, especially in IDUs.11 Candidiasis of the oropharynx and oesophagus is most often the primary focus, which then progresses to systemic infection. In HIV-infected patients with fungaemia, signs of systemic or cerebral embolism could indicate the presence of endocarditis.11 THE LANCET Infectious Diseases Vol 1 September 2001
Figure 6. Lymphomatous lesions involving the atrial septum in a patient who died of AIDS (a). On histology, the lesions were characterised by myocardial infiltration by large B-cell lymphoma, associated with diffuse myocardial damage (haematoxylin-eosin, x40) (b).
Patients with and without HIV generally have much the same presentation and survival rates from infective endocarditis. However, patients with late-stage HIV disease have a mortality about 30% higher from infective endocarditis than do symptom-free HIV-infected patients.11 The diagnosis is based on clinical, echocardiographic, and bacterial culture data. HIV-infected patients usually present with fever, sweats, weight loss, co-existing pneumonia, and/or meningitis. Echocardiographic findings in endocarditis include mobile echodensemasses attached to the inflow side of valvular leaflets or mural endocardium. Transthoracic echocardiography (TTE) is useful for detecting relatively large valvular masses but perivalvular abscess, leaflet perforation, or rupture of valvular chordae are better assessed by transoesophageal echocardiography (TEE). Both TTE and TEE are useful to guide the duration of antibiotic therapy and assess timing for surgery when necessary. Surgical management is indicated in selected patients, especially when valvular dysfunction resulting in acute heart failure becomes intractable to medical therapy.54 Hospital morbidity and mortality rates are higher than usual in this group of patients.54 Non-bacterial thrombotic endocarditis, also known as marantic endocarditis, is most common in patients with HIV wasting syndrome.11 It is characterised by friable endocardial vegetations, consisting of platelets within a fibrin mesh with few inflammatory cells. The lesions may involve any of the four valves, but are more common on the mitral and aortic valves. Marantic endocarditis has not been reported in 121
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HIV-associated cardiovascular complications
Table 2. Cardiovascular actions and interactions of common HIV therapies Class Anti-retroviral Nucleoside reverse transcriptase inhibitors
Drugs
Cardiac drug interactions
i) Abacavir ii) Zidovudine
ii) Dipyridamole
Non-nucleoside reverse transcriptase inhibitors
i) Delavirdine ii) Efavirenz iii) Nevirapine i) Amprenavir ii) Indinavir iii) Nelfinavir iv) Ritonavir v) Saquinavir
Warfarin (class interaction) i) Calcium channel blockers iii) Beta blockers, nifedipine, quinidine, steroids, theophylline. All are metabolised by cytochrome p-450 and interact with: Implicated in premature sildenafil, amiodarone, lidocaine, quinadine, warfarin, “statins” atherosclerosis, dyslipidaemia, insulin resistance, fativ) Calcium channel blockers, prednisone, quinine, increases wasting and redistribution beta blocker levels 1·5–3x (lipodystrophy)
i) Erythromycin ii) Trimethoprim/sulfamethoxazole
i) Cytochrome p-450 metabolism and drug interactions ii) Increases warfarin effects
Protease inhibitors
Anti-infective Antibiotics
Antifungal agents
i) Amphotericin B ii) Ketoconazole iii) Itraconazole
Antiviral agents
i) Foscarnet ii) Ganciclovir
Anti-parasitic
i) Pentamidine (IV)
Chemotherapy agents i) Vincristine ii) Interferon-
iii) IL-2
iv) Doxorubicin
Rare: Lactic acidosis i) hypotension ii) skeletal muscle myopathy, (mitochondrial dysfunction hypothesised, but not seen clinically)
Orthostatic hypotension, ventricular tachycardia, bradycardia, torsades (drug interactions) Orthostatic hypotension, anaphylaxis, QT prolongation Digoxin toxicity i) Hypertension, arrhythmia, ii) & iii) Cytochrome p-450 metabolism and drug interactions- renal failure, hypokalaemia, increases levels of sildenafil, warfarin, "statins", nifedipine, thrombophlebitis, digoxin bradycardia, angioedaema, dilated cardiomyopathy i) Reversible cardiac failure, electrolyte abnormalities ii) Zidovudine ii) Ventricular tachycardia, hypotension i) Hypotension, arrhythmias (torsade de pointes, VT), hyperglycaemia, hypoglycaemia, sudden death. Note: contraindicated if baseline QTc>0·48 i) Decreases digoxin level i) Arrhythmia, myocardial infarction, cardiomyopathy ii) Orthostatic hypotension, myocardial infarction, cardiomyopathy, ventricular and supraventricular arrhythmias, sudden death, atrioventricular block iii) Hypotension, arrhythmia, sudden death, myocardial infarction, cardiac failure, capillary leak, thyroid alterations iv) Decreases digoxin level iv) Myocarditis, cardiomyopathy, cardiac failure
published work in the era of improved antiretroviral therapy. The incidence of marantic endocarditis and systemic embolisation from marantic endocarditis is low in AIDS patients receiving HAART regimens.
Pericardial involvement The incidence of pericardial effusion among those patients meeting criteria for AIDS is 11% per year and 22% per year in symptomless AIDS patients.55-58 HIV infection should be included in the differential diagnosis of unexplained pericardial effusion or tamponade. AIDS patients with pericardial effusion survive a median of 6 months, significantly shorter than do AIDS patients without effusion. Survival is independent of CD4 count and albumin concentrations.55-58 122
Cardiac side effects
Pericarditis and pericardial effusion in HIV disease are generally related to opportunistic infections (Mycobacterium tuberculosis, M avium intracellulare, S aureus, Nocardia asteroides, Rhodococcus equi, Listeria monocytogenes, Chlamydia trachomatis, coxsackievirus, Epstein-Barr virus, cytomegalovirus, adenovirus, herpes virus, Histoplasma capsulatum, Cryptococcus neoformans, and Toxoplasma gondii), or to malignancy (Kaposi’s sarcoma, non-Hodgkin lymphoma), but most often a clear cause is not found.11 Fever, chest pain, and pericardial friction rub should suggest acute pericarditis, which can be confirmed by echocardiography.11 Pericardial effusion spontaneously resolves in up to 42% of patients.55-58 Mortality remains increased in HIV-infected patients who develop a pericardial effusion, even if the effusion resolves over time. THE LANCET Infectious Diseases Vol 1 September 2001
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Pericardiocentesis is currently recommended only in large or poorly tolerated effusions, for diagnostic evaluation of systemic illness, or in the presence of cardiac tamponade.54 The effects of HAART therapy on pericardial effusion are largely unexplored.
Cardiac involvement in AIDS-related tumours Cardiac Kaposi’s sarcoma in AIDS could cause visceral and parietal pericardial lesions and, less frequently, myocardial lesions. The prevalence has ranged from 12% to 28% in retrospective necropsy studies done in pre-HAART period.11 Cardiac Kaposi’s sarcoma is not usually obstructive or associated with clinical cardiac dysfunction, morbidity, or mortality.11 Lymphomas have a predilection to invade the heart in immunocompromised conditions, as has been observed in some animal models of AIDS (SCID mice).59 However, malignant lymphoma involving the heart is infrequent in human AIDS.11 Lymphomatous infiltration can be diffuse or can result in discrete isolated lesions, which are usually derived from the Burkitt or immunoblastic type B cells60,61 (figure 6). The lesions are usually nodular or polypoid masses, and predominantly involve the pericardium, with variable myocardial infiltration.11,60,61 The prognosis of patients with HIV-associated cardiac lymphoma is generally poor, although clinical remission has been observed with combination chemotherapy.62 The improvement of the immunologic state of the patients and the better control in the incidence of some opportunistic infections (eg, human herpes virus-8 and Epstein-Barr virus, which could cause these tumours), could result in reduction of overall incidence of cardiac involvement by both Kaposi’s sarcoma and non-Hodgkin lymphomas after the introduction of the HAART regimens.62
Conclusions Cardiac and pulmonary complications of HIV disease are generally late manifestations and could be related to prolonged effects of immunosuppression and a complex interplay of mediator effects from opportunistic infections, viral infections, autoimmune response to viral infection, drug related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression.22 We hope that HAART regimens, by improving the clinical course of HIV disease, might bring an important reduction in the incidence of both pericardial effusions and myocardial involvement of HIVassociated malignacies and co-infections. However, infectious diseases specialists should be included in the evaluation of patients who are being considered for or who are receiving HAART regimens, especially those with underlying cardiovascular risk factor, because the atherogenic effects of PIs could increase the risk of death for coronary heart disease and stroke. HIV-associated heart disease could be an important model for the mechanisms behind dilated cardiomyopathy. Virus-induced activation of specific proinflammatory cytokines induces iNOS, reduces myocyte contractility, and decreases responsiveness to beta-adrenergic agonists.17,18 Further research in this field should help to direct therapies and to allow preventive measures in the care of patients with HIV-associated cardiac illness. Since the role of infection THE LANCET Infectious Diseases Vol 1 September 2001
Review
Search strategy and selection criteria 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. Data for this review were identified by searches of Medline and AIDSline, and references from articles from 1996 to 2001. We reviewed English language articles about the pathogenetic mechanisms involved in the development of HIV-associated cardiovascular complications, related or not to HAART regimens. and inflammation in many other cardiovascular diseases is beginning to be recognised, discovering the molecular mechanisms of HIV-related heart disease could provide the basis for rational therapeutic strategies and improved care for a broader range of patients.6,63 Moreover, a better understanding of PIs’ effects on lipid and metabolic pathways will lead to a new generation of drug therapies without metabolic alterations and could also lead to new therapies for dyslipidaemias and alterations of metabolism unrelated to HIV infection. Acknowledgments
We thank Giulia D’Amati, Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy, and Adriano M Pellicelli, National Institute for Infectious Diseases, Rome, Italy, for kindly providing the pathological materials and the pathogenetic schemes reproduced in this review. References
1 Yunis NA, Stone VE. Cardiac manifestations of HIV/AIDS: a review of disease spectrum and clinical management. J Acquir Immune Defic Syndr 1998; 18: 145–54. 2 Rerkpattanapipat P, Wongpraparut N, Jacobs LE, Kotler MN. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 2000; 160: 602–8. 3 Lipshultz SE, Easley KA, Orav EJ, et al. Cardiac dysfunction and mortality in HIV-infected children. The Prospective P2C2 HIV Multicenter Study. Circulation 2000; 102: 1542–48. 4 Temesgen Z. Overview of HIV infection. Ann Allergy Asthma Immunol 1999; 83: 1–5. 5 Barbaro G, Di Lorenzo G, Grisorio B, et al, for the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS investigators. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV positive patients. N Engl J Med 1998; 339: 1093–99. 6 Lipshultz SE. Dilated cardiomyopathy in HIV-infected patients. N Engl J Med 1998; 339: 1153–55. 7 Barbaro G, Di Lorenzo G, Soldini M, et al, for the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS investigators. The intensity of myocardial expression of inducible nitric oxide synthase influences the clinical course of human immunodeficiency virusassociated cardiomyopathy. Circulation 1999; 100: 633–39. 8 Lipshultz SE, Easley KA, Orav EJ, et al. Left ventricular structure and function in children infected with human immunodeficiency virus. The prospective P2C2 HIV multicenter study. Circulation 1998; 97: 1246–56. 9 Pugliese A, Isnardi D, Saini A, Scarabelli T, Raddino R, Torre D. Impact of higly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect 2000; 40: 282–84. 10 Shannon RP, Simon MA, Mathier MA, Geng YJ, Mankad S, Lackner AA. Dilated cardiomyopathy associated with simian AIDS in nonhuman primates. Circulation 2000; 101: 185–93. 11 Barbaro G, Di Lorenzo G, Grisorio B, et al, for the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS investigators. Cardiac involvement in the acquired immunodeficiency syndrome. A multicenter clinical-pathological study. AIDS Res Hum Retroviruses 1998; 14: 1071–77. 12 Kasten-Sportes C, Weinstein C. Molecular mechanisms of HIV cardiovascular disease. In: Lipshultz SE, editor. Cardiology in AIDS. New York: Chapman & Hall, 1998. p. 265–82.
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13 Currie PF, Goldman JH, Caforio AL, et al. Cardiac autoimmunity in HIV related heart muscle disease. Heart 1998; 79: 599-604. 14 Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 2001; 103: 220–25. 15 Tinkle BT, Ngo L, Luciw PA, Maciag T, Jay G. Human immunodeficiency virus-associated vasculopathy in transgenic mice. J Virol 1997; 71: 4809–14. 16 Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol 1998; 274: 577–95. 17 Barbaro G, Di Lorenzo G, Soldini M, et al, for the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS investigators. Clinical course of cardiomyopathy in HIV-infected patients with or without encephalopathy related to the myocardial expression of TNFα and iNOS. AIDS 2000; 14: 827–38. 18 Barbaro G, Di Lorenzo G, Soldini M, et al, for the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS. The intensity of myocardial expression of inducible nitric oxide synthase influences the clinical course of HIV-associated cardiomyopathy. Internal Med 1999; 7: S90. 19 Cooper ER, Hanson C, Diaz C, et al. Encephalopathy and progression of human immunodeficiency virus disease in a cohort of children with perinatally acquired human immunodeficiency virus infection. J Pediatr 1998; 132: 808–12. 20 Miller TL, Orav EJ, Colan SD, Lipshultz SE. Nutritional status and cardiac mass and function in children infected with the human immunodeficiency virus. Am J Clin Nutr 1997; 66: 660–64. 21 Lewis W, Grupp IL, Grupp G, et al. Cardiac dysfunction in the HIV-1 transgenic mouse treated with zidovudine. Lab Invest 2000; 80: 187–97. 22 Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective. Prog Cardiovasc Dis 2000; 43: 151–70. 23 Lipshultz SE, Easley KA, Orav EJ, et al, for the Pediatric Pulmonary Cardiac Complications of Vertically Transmitted HIV Infection Study Group. Absence of cardiac toxicity of zidovudine in infants. N Engl J Med 2000; 343: 759–66. 24 Pellicelli A, Barbaro G, Palmieri F, et al. Primary pulmonary hypertension in HIV disease: a systematic review. Angiology 2001; 52: 31–41. 25 Pellicelli AM, Palmieri F, D’Ambrosio C, et al. Role of human immunodeficiency virus in primary pulmonary hypertension:case reports. Angiology 1998; 49: 1005–11. 26 Mesa RA, Edell ES, Dunn WF, Edwards WD. Human immunodeficiency virus infection and pulmonary hypertension. Mayo Clin Proc 1998; 73: 37–44. 27 Gisselbrecht M. [Vasculitis during human acquired immunodeficiency virus infection]. Pathol Biol (Paris) 1999; 47: 245–47. 28 Chi D, Henry J, Kelley J, Thorpe R, Smith JK, Krishnaswamy G. The effects of HIV infection on endothelial function. Endothelium 2000; 7: 223–42. 29 Barbaro G, Barbarini G, Pellicelli AM. HIV-associated coronary arteritis in a patient with fatal myocardial infarction. N Engl J Med 2001; 344: 1799–800. 30 Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–83. 31 Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor- associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353: 2093–99. 32 Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIVinfected individuals treated with protease inhibitors: the Swiss HIV Cohort Study. Circulation 1999; 100: 700–05. 33 Koppel K, Bratt G, Eriksson M, Sandstrom E. Serum lipid levels associated with increased risk for cardiovascular disease is associated with highly active antiretroviral therapy (HAART) in HIV-1 infection. Int J STD AIDS 2000; 11(7): 451–55. 34 Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32: 130–39. 35 Sullivan AK, Nelson MR, Moyle GJ, Newell AM, Feher MD, Gazzard BG. Coronary artery disease occuring with protease inhibitor therapy. Int J STD AIDS 1998; 9: 711–12. 36 Henry K, Melrow H, Huebsch J, et al. Severe coronary heart disease with protease inhibitors. Lancet 1998; 351: 1328 (letter). 37 Behrens G, Schmidt H, Meyer D, Stoll M, Schmidt RE. Vascular complications associated with use of HIV protease inhibitors. Lancet
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1998; 351: 1958 (letter). 38 Jutte A, Schwenk A, Franzen C, et al. Increasing morbidity from myocardial infarction during HIV protease inhibitor treatment? AIDS 1999; 13: 1796–7 (letter). 39 Flynn TE, Bricker LA. Myocardial infarction in HIV-infected men receiving protease inhibitors. Ann Intern Med 1999; 131: 548 (letter). 40 Rickerts V, Brodt H, Staszewski S, Stile W. Incidence of myocardial infarction in HIV-infected patients between 1983 and 1998: the Frankfurt HIV-cohort study. Eur J Med Res 2000; 5: 329–33. 41 Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery disease and human immunodeficiency virus infection. Clin Infect Dis 2000; 31: 787–97. 42 Mooser V, Carr A. Antiretroviral therapy-associated hyperlipidemia in HIV disease. Curr Opin Lipidol 2001; 12: 313–19. 43 Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000; 275: 20251-4. 44 Behrens GM, Stoll M, Schmidt RE. Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed? Drug Saf 2000; 23: 57–76. 45 Depairon M, Chessex S, Sudre P, et al. Premature atherosclerosis in HIV-infected individuals: focus on protease inhibitor therapy. AIDS 2001; 15: 329–34. 46 Dube MP, Sprecher D, Henry WK, et al. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis 2000; 31: 1216–24. 47 Currier JS. How to manage metabolic complications of HIV therapy: what to do while we wait for answers. AIDS Read 2000; 10: 162–69. 48 Distler O, Cooper DA, Deckelbaum RJ, Sturley SL. Hyperlipidemia and inhibitors of HIV protease. Curr Opin Clin Nutr Metab Care 2001; 4: 99–103. 49 Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacotherapy 2000; 20: 1066–71. 50 Aoun S, Ramos E. Hypertension in the HIV-infected patient. Curr Hypertens Rep 2000; 2: 478–81. 51 Nair R, Robbs JV, Chetty R, Naidoo NG, Woolgar J. Occlusive arterial disease in HIV-infected patients: a preliminary report. Eur J Vasc Endovasc Surg 2000; 20: 353–57. 52 Witz M, Lehmann J, Korzets Z. Acute brachial artery thrombosis as the initial manifestation of human immunodeficiency virus infection. Am J Hematol 2000; 64: 137–39. 53 Hadigan C, Meigs JB, Rabe J, et al. Increased PAI-1 and tPA antigen levels are Reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2001; 86: 939–43. 54 Abad C, Cardenes MA, Jimenez PC, Armas MV, Betancor P. Cardiac surgery in patients infected with human immunodeficiency virus. Tex Heart Inst J 2000; 27: 356–60. 55 Estok L, Wallach F. Cardiac tamponade in a patient with AIDS: a review of pericardial disease in patients with HIV infection. Mt Sinai J Med 1998; 65: 33–39. 56 Chen Y, Brennessel D, Walters J, Johnson M, Rosner F, Raza M. Human immunodeficiency virus-associated pericardial effusion: report of 40 cases and review of the literature. Am Heart J 1999; 137: 516–21. 57 Silva-Cardoso J, Moura B, Martins L, Mota-Miranda A, Rocha-Goncalves F, Lecour H. Pericardial involvement in human immunodeficiency virus infection. Chest 1999; 115: 418–22. 58 Miller RF, Howling SJ, Reid AJ, Shaw PJ. Pleural effusions in patients with AIDS. Sex Transm Infect 2000; 76: 122–25. 59 Aftabuddin M, Islam N, Alimuzzaman M, Koiralla TR, Hori Y. Cardiac malignant lymphoma in severe combine immunodeficient mice. Indian Heart J 1996; 48: 368–70. 60 Sanna P, Bertoni F, Zucca E, et al. Cardiac involvement in HIVrelated non-Hodgkin’s lymphoma: a case report and short review of the literature. Ann Hematol 1998; 77: 75–78. 61 Duong M, Dubois C, Buisson M, et al. Non-Hodgkin’s lymphoma of the heart in patients infected with human immunodeficiency virus. Clin Cardiol 1997; 20: 497–502. 62 Dal Maso L, Serraino D, Franceschi S. Epidemiology of HIVassociated malignancies. Cancer Treat Res 2001; 104: 1–18. 63 Barbaro G. Dilated cardiomyopathy in the acquired immunodeficiency syndrome. Eur Heart J 1999; 20: 629–30. THE LANCET Infectious Diseases Vol 1 September 2001
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Review
Pathogenesis of HIV-associated cardiovascular complications Giuseppe Barbaro, Stacy D Fisher, and Steven E Lipshultz
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 HIVassociated cardiovascular complications focusing on pathogenetic mechanisms that could have a role in diagnosis, management, and therapy of these complications in the HAART era. Lancet Infectious Diseases 2001; 1: 115–124
Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) regimens have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults.1-3 HAART regimens have 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. 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 small number of HIV-infected individuals worldwide and studies before HAART therapy remain globally applicable. UNAIDS estimates that 36·1 million people are living with HIV infection at the end of the year 2000.4 If 8–10% of patients develop symptomatic heart failure over a 2–5 year period,5 then 3 million cases of HIV-related heart failure will present in that period.6 Various possible causes have been postulated in HIV-related heart disease (table 1), including myocardial infection with HIV, opportunistic infections, viral infections, autoimmune response to viral infection, drug related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression.
Dilated cardiomyopathy HIV disease is recognised as an important cause of dilated cardiomyopathy (figure 1) with a rate reported in previous reviews as 3·6% among cardiomyopathy patients, increasing as patients with HIV infection live longer.2 The importance of cardiac dysfunction is shown by a reported median THE LANCET Infectious Diseases Vol 1 September 2001
survival to AIDS-related death that is 101 days in patients with left-ventricular dysfunction and 472 days in patients with a normal heart by echocardiography at similar infection stage.6 HIV-related cardiomyopathy compared with idiopathic cardiomyopathy has an unadjusted hazard ratio of 4·0 and, after multivariate analysis, of 5·86 for death.7 In the multicentre Pulmonary and Cardiac Complications of HIV study (P2C2 HIV), children with vertically transmitted HIV infection (median age 2·1 years) had a 5-year cumulative survival of 64%.8 Deaths were higher in children with baseline-depressed left-ventricular fractional shortening or increased left-ventricular dimension, thickness, mass, wall stress, heart rate, or blood pressure. Decreased left-ventricular fractional shortening and increased wall thickness were also predictive of survival after multivariate adjustment.8 Rapid-onset congestive heart failure has a grim prognosis in HIV-infected adults and children, with over half of patients dying from primary cardiac failure within 6–12 months of presentation.5,8 Chronic-onset heart failure could respond better to medical therapy in this population. There is no evidence from published prospective studies about HAART benefit on HIV-associated cardiomyopathy. However, improvement in the immunologic state of the patients and better control of opportunistic infections could be examples of the beneficial effects of HAART in the incidence and clinical course of HIV-associated heart disease as reported by some preliminary retrospective studies.9 Animal models
Simian immunodeficiency virus (SIV) infection in rhesus macaques is a valuable model in understanding the pathogenesis of cardiac injury associated with retroviral infection.10 Chronic SIV infection resulted in depressed leftventricular systolic function and an extensive coronary arteriopathy suggestive of injury due to cell-mediated immune response.10 Two-thirds of chronically infected macaques that died of SIV had related myocardial effects. Lymphocytic myocarditis was seen in nine of 15 macaques and coronary arteriopathy in nine of 15 (six alone and three GB is cardiologist and a medical researcher at the Department of Emergency Medicine, University La Sapienza, Rome, Italy; SDF is a senior instructor in medicine (cardiology) at the University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; and SEL is professor of paediatrics and of oncology at the University of Rochester. Correspondence: Dr G Barbaro, Viale Anicio Gallo 63, 00174 Rome, Italy. Tel/fax +39 06 710 2889; email [email protected]
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association between HIV-1 and cardiac myocyte dysfunction.5,11 It is unclear how HIV-1 could enter CD4receptor-negative cells such as myocytes. Reservoir cells (eg, dendritic cells) could have a pathogenic role in the interaction between HIV-1 and the myocyte, and in the activation of multifunctional cytokines (eg, tumor necrosis factor-alpha [TNFα], interleukin-1 [IL-1], interleukin-6 [IL-6], interleukin-10 [IL-10]) that contribute to progressive and late tissue damage.7,12 Coinfection with other viruses (usually, coxsackievirus B3 and cytomegalovirus) also seems to have an important pathogenetic role, as reported both in necropsy and clinical studies.5,11 Autoimmunity
in combination with myocarditis) upon necropsy. In infected macaques, coronary arteriopathy was extensive, with evidence of vessel occlusion and recanalisation, and related regions of myocardial necrosis in four macaques. On necropsy, two animals had marantic endocarditis and one had a left-ventricular mural thrombus. Macaques with cardiac pathology were emaciated to a greater extent than macaques with SIV and similar periods of infection who did not experience cardiac pathology10.
Compared with patients with idiopathic dilated cardiomyopathy, who had predominantly CD4 and B lymphocytes, the inflammatory-cell infiltrates in HIVinfected patients who had an echocardiographic diagnosis of dilated cardiomyopathy and a histological diagnosis of myocarditis were predominantly CD3 and CD8 lymphocytes, possibly indicating the number of circulating lymphocytes in these patients.7 In roughly 70% of both HIVassociated and idiopathic-dilated cardiomyopathy patients, increased staining was limited to MHC class-I molecules.7 The combination of viral hybridisation and increased myocardial expression of MHC class-I strongly suggests an active immune process in the myocardium. Increased frequency of cardiac-specific autoantibodies (anti-alpha myosin autoantibodies) has been reported by Currie et al.13 They reported that HIV-infected patients were more likely to have cardiac-specific autoantibodies than were controls (15% vs 3·5%). Those with echocardiographic evidence of left-ventricular dysfunction were especially likely to have cardiac autoantibodies (43%), supporting the theory that cardiac autoimmunity has a role in the pathogenesis of HIV-related heart disease and suggesting that cardiac autoantibodies could be markers of leftventricular dysfunction in HIV-positive patients with previously normal echocardiographic findings.13 Monthly immunoglobulin infusions in HIV-infected paediatric patients have been associated with minimum left-ventricular dysfunction, an increase in left-ventricular-wall thickness, and a reduction in peak left-ventricular-wall stress, suggesting that both impaired myocardial growth and leftventricular dysfunction may be immunologically mediated.3,8 The apparent efficacy of immunoglobulin therapy could 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 as also reported in HIV-negative subjects with chronic heart failure.14 Immunomodulatory therapy could be helpful in adults and children with declining leftventricular function, but further study is needed to assess the efficacy of this therapy.3,8
Myocarditis and viral myocardial infection
Myocardial cytokine expression
Myocarditis and HIV-1 myocardial infection still represent the best-studied cause of dilated cardiomyopathy in HIV disease5. HIV-1 virions seem to infect myocardial cells in patchy distributions5 (figure 2) without a clear direct
Tinkle et al15 reported that transgenic mice with a portion of the genome of a proviral, non-infectious HIV developed ventricular dysfunction and, in some cases, myocarditis, arteritis, and vasculitis. PCR detected no HIV, suggesting
Figure 1. Dilated cardiomyopathy in a patient who died of AIDS. The heart has a globular shape with rounded apex due to ventricular dilatation. On cut surface, the left-ventricular cavity is enlarged, with mild myocardial hypertrophy. There is also a diffuse endocardial fibrous thickening (a). Histology showed mild myocardial hypertrophy and vacuolisation. Interstitial collagen was increased (haematoxylin-eosin, x20) (b).
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Review
Table 1. Principal HIV-associated cardiovascular abnormalities Type Dilated cardiomyopathy
Possible causes and associations Infectious: HIV, Toxoplasma gondii, coxsackievirus group B, Epstein-Barr virus, cytomegalovirus, adenovirus. Autoimmune response to infection. Drug-related: cocaine, possibly nucleoside analogues, IL-2, doxorubicin, interferon. Metabolic/endocrine: nutritional deficiency/ wasting, selenium, B12, carnitine, thyroid hormone, growth hormone, adrenal insufficiency, hyperinsulinaemia. Cytokines: TNF, nitric oxide, TGF, endothelin-1. Hypothermia. Hyperthermia. Autonomic insufficiency, encephalopathy. Acquired immunodeficiency: HIV viral load, length of immunosuppression. Coronary heart disease and hypertension Protease-inhibitors-induced metabolic and coagulative disorders. HIV-induced endothelial dysfunction. Erythropoietin-induced increase of haematocrit and blood viscosity. Vasculitis. Pericardial effusion Bacteria: staphylococcus, streptococcus, proteus, nocardia, pseudomonas, klebsiella, enterococcus, listeria, mycobacteria (Mycobacterium tuberculosis, M avium intracellulare, M kansaii). Viral pathogens: HIV, herpes simplex virus, herpes simplex virus type-2, cytomegalovirus. Other pathogens: cryptococcus, toxoplasma, histoplasma. Malignancy: Kaposi’s sarcoma, malignant lymphoma. Capillary leak/wasting/malnutrition. Hypothyroidism. Prolonged acquired immunodeficiency. Primary pulmonary hypertension Plexogenic pulmonary arteriopathy. Mediator release from endothelium.
that the cardiac abnormalities were due to circulating factors or cytokines.15 HIV-associated myocarditis and dilated cardiomyopathy are associated with local cytokine production that may be markedly higher than to circulating concentrations, making peripheral cytokine rates uninformative.7 Viral infection in the context of a nonspecific stimulator of monokines such as IL-1 or TNF is much more likely to lead to myocarditis and myocyte damage than viral infection alone.16 TNF produces a negative inotropic effect by altering intracellular calcium homeostasis, and possibly by inducing nitric oxide synthesis, which also reduces myocyte contractility.7,17 Compared with patients with idiopathic dilated cardiomyopathy, a greater intensity of both TNF and inducible nitric oxide synthase (iNOS) staining has been reported in myocardial biopsy samples from patients with HIV-associated cardiomyopathy, specifically in those with a myocardial viral infection independently of antiretroviral treatment.7 Patients with HIV-associated cardiomyopathy who were co-infected with coxsackievirus B3, cytomegalovirus, or other viruses had samples that stained more intensely for both TNFa and iNOS. Moreover, patients co-infected with HIV-1 and coxsackievirus B3 had samples that stained more intensely for iNOS than did patients with idiopathic dilated cardiomyopathy and myocardial infection with coxackievirus B3 or who had adenovirus infection alone .18 HIV-associated encephalopathy
Several studies reported that patients with encephalopathy were more likely to die of congestive heart failure than were THE LANCET Infectious Diseases Vol 1 September 2001
Incidence Estimated 15·9 patients/1000 symptom-free HIV-infected people5
Largely limited to case reports
11%/year55–58 Spontaneous resolution in up to 42% of affected patients55–58
0·5% incidence24
patients without encephalopathy with a hazard ratio after multivariate analysis of 3·4.8,17,19 HIV-1 could persist in reservoir cells in the myocardium and the cerebral cortex even after antiretroviral treatment.17 The reservoir cells could hold HIV-1 on their surfaces for extended time periods and could chronically release cytotoxic cytokines (TNF, IL-6, endothelin-1) contributing to progressive and late tissue damage in both systems independently of HAART.17 Figure 3 shows the possible mechanisms involved in the development of HIV-associated cardiomyopathy and encephalopathy. These mechanisms are speculative but could warrant further controlled clinical and experimental investigations.
Figure 2. Endomyocardial biopsy from an HIV-1 positive patient with dilated cardiomyopathy. In situ hybridisation with an HIV-1 specific probe, labelled with S35 reveals a positive myocyte not surrounded by inflammatory cells (haematoxylin-eosin, x40).
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CD4-receptor
HIV/other viruses (CVB3, CMV, EBV, ADV)
HIV
Lymphocyte/ monocyte CD4-receptor
O2-
Dendritic cell/ macrophage
CD4-receptor
TNF IL-1 IL-6 IL-10
ROS Dendritic cell/ macrophage
TNF IL-1 IL-6 IL-10
iNOS
iNOS NO CD4-receptor
Fas/fas-ligand
NO
MHC-I/II Fas/fas-ligand
cGMP Ca++ turnover
Bid
autoantigens MHC-II
B lymphocyte/ plasma cell
MHC-I
Nerve cell
cGMP Ca++ turnover
Bid
Mitochondrial damage
Myocardial cell
Mitochondrial damage
Caspases Apoptosis Cyto C AIF
Caspases Apoptosis Cyto C AIF
Impairment of the autonomic system Increased adrenergic activity Increased consumption of oxygen by myocardial tissue Down regulation of beta-adrenergic receptors and reduced contarctility of myocardial cells
autoantibodies (anti-myosin antibodies)
Figure 3. The possible pathogenic mechanisms involved in the development of HIV-associated cardiomyopathy and encephalopathy and in their relationship. The infection of dendritic cells, of CD4 lymphocytes, and of myocardial or neuronal cell by HIV-1 or by other viruses could be responsible for release of specific cytokines (TNF, IL-1, IL-6, IL-10) which activate the inducible form of nitric oxide synhase (iNOS). The interaction between cytotoxic T lymphocytes and the receptoral complex fas/fas ligand located on the surface of the target cell could cause mitochondrial damage with release of mitochondrial pro-apoptosis factors (cytochome c, apoptosis inducing factor [AIF]). Similar mitochondrial damage may be caused by reactive oxygen species (ROS) released by activated lympho-monocytes. The interaction between autoantigens and MHC molecules on the surface of dendritic cells/macrophages, of myocardial cells (MHC-I), and of B lymphocytes (MHC-II) determine the production of autoantibodies (eg, alpha-antimyosin) which are responsible for direct cellular damage. The neuronal damage, specifically the impairment of the autonomic system, could increase the functional damage to myocardial cells because of increased adrenergic activity and down-regulation of beta-adrenergic receptors. ADV=adenovirus; Bid=a protein of the bcl2 family involved in apoptosis; CMV=cytomegalovirus; CVB3= coxsackievirus B3; EBV=Epstein-Barr virus.
Nutritional deficiencies
Drug cardiotoxicity
Nutritional deficiencies are common in HIV infection, particularly in late-stage disease, and could contribute in inducing ventricular dysfunction independently of HAART regimens. Poor absorption and diarrhoea both lead to electrolyte imbalances and deficiencies in elemental nutrients. Deficiencies of trace elements have been associated directly or indirectly with cardiomyopathy.20 Selenium replacement reverses cardiomyopathy and restores left-ventricular function in nutritionally deplete patients.20 Concentrations of vitamin B12, carnitine, and growth and thyroid hormone could also be altered in HIV disease; all have been associated with left-ventricular dysfunction.20 Electrolyte imbalances (eg, hypokalaemia, hypocalcaemia, hypomagnesaemia), related to malnutrition and/or to chronic diarrhoea, could contribute in inducing ventricular arrhythmias (torsade de pointes and ventricular fibrillation) by prolongation of the electrocardiographic QTc interval.
Previous reviews have noted an association between zidovudine and dilated cardiomyopathy in both adults and children.1,2 Studies done on transgenic mice suggest that zidovudine is associated with diffuse destruction of cardiac mitochondrial ultrastructures and inhibition of mitochondrial DNA replication.21 Lactic acidosis related to mitochondrial dysfunction could further contribute in myocardial cell dysfunction.22 In a P2C2 HIV Study Group trial infants born to HIV-positive mothers were followed from birth to age 5 years with serial echocardiographic studies every 4–6 months. No association with acute or chronic abnormalities in left-ventricular structure or function was found with perinatal exposure to zidovudine.23 Other nucleoside reverse transcriptase inhibitors such as didanosine and zalcitabine do not seem either to promote or to prevent dilated cardiomyopathy.5 As reported in previous reviews, in AIDS patients with Kaposi’s sarcoma, reversible cardiac dysfunction was
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associated with prolonged, high-dose therapy with interferon alpha.2 Doxorubicin (Adriamycin), which is used to treat AIDS-related Kaposi’s sarcoma and non-Hodgkin lymphoma, has a dose-related effect on dilated cardiomyopathy, as does foscarnet sodium when used to treat cytomegalovirus oesophagitis.2 The principal cardiovascular actions/ interactions of common HIV therapies with related cardiac effects are reported in table 2.
HIV
Macrophage Platelets Lymphocyte
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.24 Pulmonary hypertension is often explained in HIV-infected patients by lung infections, venous thromboembolism, or left-ventricular dysfunction. Pulmonary hypertension found on screening echocardiography or right-heart catheterisation warrants an aggressive investigation for treatable pulmonary infections.24 Primary pulmonary hypertension has been reported in HIV-infected patients without a history of thromboembolic disease, intravenous drug use, or pulmonary infections associated with HIV. One necropsy and one biopsy specimen revealed precapillary muscular pulmonary artery and arteriole medial hypertrophy, fibroelastosis, and eccentric intimal fibrosis without direct viral infection of pulmonary artery cells.24,25 This finding suggests mediator release from infected cells elsewhere and possibly cytokine mediated injury. The pathogenesis of primary pulmonary hypertension has many factors and is poorly understood. Primary pulmonary hypertension has been found in haemophiliacs receiving lyophilised factor VIII, intravenous drug users, and patients with left-ventricular dysfunction, obscuring any relationship with HIV-1.24,25 It could be that HIV-1 causes endothelial damage and mediator-related vasoconstriction through stimulation by the envelope glycoprotein 120, including direct release and effects of endothelin-1 (vasoconstrictor), IL-6, and TNF, in the pulmonary arteries (figure 4).24,25 HIV-1 is frequently identified in alveolar macrophages on histology.24,25 These macrophages release TNF, oxide anions, and proteolytic enzymes in response to infection. Lymphokines could also contribute to endothelial proliferation seen in pulmonary hypertension by promoting leucocyte adhesion to the endothelium.26 Clinical symptoms and outcome of patients with right-ventricular dysfunction is related to the degree of pulmonary hypertension, varying from a mild symptomless condition to severe cardiac impairment with corpulmonale and death.24 Activation of α1receptors and genetic factors (increased frequency of HLA DR6 and DR52) have been also suggested in the pathogenesis of HIV-associated pulmonary hypertension.26 The effects of HAART regimens on the clinical course of HIV-associated pulmonary hypertension are unknown.
ET-1 PDGF IL6 IL1 TNF
Endothelial cell
•Reduction of NO synthesis
Endothelial cell
Smooth-muscle cells
•Proliferation •Proliferation •Vasoconstriction •Migration of smooth muscle cells
Figure 4. The possible pathogenetic mechanisms involved in the development of HIV-associated pulmonary hypertension. HIV-infected macrophages, platelets and lymphocytes could release multifunctional cytokines (endothelin-1 [ET-1], platelet derived growth factor [PGDF], IL6, IL-1, TNF), which could affect the endothelial cells of the pulmonary vessels, inducing their proliferation and vasoconstriction by a reduction of nitric oxide (NO) production. Moreover, ET-1 produced by endothelial cells could affect the smooth muscle cells of the pulmonary vessels inducing their migration and proliferation.
abnormalities and exposure to various xenoantigens such as HIV-1 itself, other infectious agents (eg, cytomegalovirus), and drugs.27 Endothelial dysfunction and/or injury, which is pivotal to the development of cardiovascular and inflammatory pathology, has been described in HIV infection.28 Elaboration of circulating markers of endothelial activation such as soluble adhesion molecules and procoagulant proteins arises in HIV infection.28 Virus entry into endothelial cells could happen via CD4 antigen or galactosyl-ceramide receptors. Other mechanisms of entry including chemokine receptors have been proposed. Nonetheless, endothelial activation could also happen in HIV infection, either caused by cytokines secreted in response to mononuclear or adventitial cell activation by virus, or by the effects of the secreted HIV-associated proteins gp 120 and tat on endothelium.28 Enhanced adhesiveness of endothelial cells, endothelial cell proliferation, and apoptosis as well as activation of cytokine secretion have all been shown. A synergy between inflammatory cytokines and viral proteins in inducing endothelial injury has been shown.28 In HIV infection, dysfunctional or injured endothelial cells can cause tissue injury, inflammation and remodelling, and accelerate the development of cardiovascular disease.28
Endothelial dysfunction A wide range of inflammatory vascular diseases (eg, polyarteritis nodosa, Henoch-Schonlein purpura, druginduced hypersensitivity vasculitis) could arise in HIVinfected people.27 Vascular inflammation seems to have many factors and could result from HIV-induced immunological THE LANCET Infectious Diseases Vol 1 September 2001
Coronary heart disease Accelerated coronary artery disease in HIV-infected patients could result from atherogenesis stimulated by virus-infected monocyte-macrophages, possibly owing to altered leukocyte adhesion or arteritis.29 Coronary artery disease is observed 119
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HIV-associated cardiovascular complications
Fat acids Glycerol Adipocyte PI Lipodystropy/ lipoatrophy
RA CRABP-1 LRP PI LPL
PI
P-450 3A Cis-9 RA
PI PI
Hyperlipidaemia Circulating triglycerides
Triglyceride storing
PI
RXR Lipid release Apoptosis Reduced differentiation
LRP Liver
Insulinresistance
Figure 5. Pathogenetic mechanisms involved in the development of PI-induced lipodystrophy/lipoatrophy, hyperlipidaemia, and insulin-resistance.The marked black lines show the metabolic blocks made by PI. LPL=lipoproteinlipase, RA=retinoic acid, RXR= retinoic acid receptor.
with increasing frequency among HIV patients receiving HAART regimens that contain protease inhibitors (PIs). Despite the clinical and immunological benefits, complications such as lipodystrophy, hyperlipidaemia, hyperglycaemia, and insulin-restistance could develop in up to 60% of patients treated with PIs,30-34 with an increased risk for acute coronary syndromes and stroke.35-40 However, data on the incidence of coronary heart disease among HIVinfected subjects receiving PIs are largely limited to case reports.41 According to Carr et al,30 the metabolic and somatic alterations in PIs-treated patients could be ascribed to the homology of the catalytic region of HIV protease, the molecular target of PIs, to regions of two human proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein 1 (CRABP-1) and LDL-receptor-related protein (LRP). The hypothesis is that PIs inhibit CRABP-1-modified and CYP3A-mediated synthesis of cis-9-retinoic acid and peroxisome proliferator-activated receptor-type-gamma (PPAR-gamma) heterodimer. This results in an increased apoptosis of adipocytes and in reduced differentiation from pre-adipocytes to adypocytes, with the final effect of reduced triglyceride storage and increased lipid release. PIs binding to LRP would impair hepatic chylomicron uptake and endothelial triglyceride clearance, resulting in hyperlipidemia and insulin resistance30 (figure 5). Recent data indicate that dyslipidaemia could be accounted for, at least in part, by PI-mediated inhibition of the proteasome activity and accumulation of the active portion of sterol regulatory element-binding protein-1c in 120
liver cells and adipocytes.42 There is also evidence that PIs directly inhibit the uptake of glucose by insulin-sensitive tissues, such as fat and skeletal muscle, and by selective inhibition of the glucose transporter Glut4.43 Similarities between HIV-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis suggest the pathophysiological involvement of nuclear factors such as lamin A/C and druginduced mitochondrial dysfunction.44 However,there is a continuing discussion about the case definition, diagnostic procedure, and treatment options for PI-induced body-shape changes and metabolic disturbances.44 It could be important to consider traditional coronary risk profiles and to alter those that can be modified in the assessment and continued therapy of patients for HAART.45 Fibric acid derivatives and statins can lower HIV-associated cholesterol and triglyceride rates, although further data are needed on interactions between statins and PIs.46,47 Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of people.48 Lovastatin should be avoided in patients receiving other drugs that could cause skeletal muscle toxicity with this agent.49 Hypoglycaemic agents could have some role in managing glucose abnormalities, although troglitazone cannot be recommended for fat abnormalities alone and metformin could cause lactic acidosis.47
Hypertension and coagulative disorders HIV patients are at higher risk of developing hypertension at a younger age than the general population.50 Predisposing THE LANCET Infectious Diseases Vol 1 September 2001
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HIV-associated cardiovascular complications
Review
factors for developing hypertension include vasculitis in small, medium, and large vessels in the form of leucocytoclastic vasculitis, atherosclerosis secondary to HAART regimens, aneurysms of the large vessels with impairment of flow to the renal arteries, and PI-induced insulin resistance with increased sympathetic activity and sodium retention.50,51 A syndrome of acquired glucocorticoid resistance has been described in HIV-infected patients with hypercortisolism and a lower affinity of the glucocorticoid receptors.50 The syndrome is characterised clinically by weakness, hypertension or hypotension, and skin pigmentation changes. Acute and chronic renal failure is often associated with HIV infection.50 The prevalence of hypertension associated with erythropoietin therapy is 47%; the effect could be related to the increase in haematocrit and blood viscosity.50 Various coagulation abnormalities (eg, increased levels of D-Dimer, plasminogen activator inhibitor-1 and tissue-type plasminogen-activator antigen) have been reported in HIVinfected patients, especially in those with fat redistribution.52,53 These abnormalities have been associated with documented thromboses of veins and arteries.51,52 The routine assessment of coagulative parameters is probably not advisable until a benefit of widespread screening is assessed in prospective studies. A heightened awareness of the possiblity of coagulative disorders, together with controlled trials and basic research, are needed.
Endocardial involvement The frequency of infective endocarditis in HIV-infected patients is similar to that of patients of closely similar behaviour risk—ie, intravenous drug use (IDUs), independently of HAART regimens.2 Estimates of endocarditis incidence vary from 6·3% to 34% of HIVinfected IDUs.11 Right-sided valves are usually involved in HIV-infected IDUs. Vegetations could form on the tricuspid or pulmonic valves resulting in pulmonary embolism and septic pulmonary infarcts, which appear as multiple opacities on chest radiograms.11 Systemic emboli often involve coronary arteries, spleen, bowel, extremities, and central nervous system. Cardiac rhythm alterations (ie, atrioventricular block) could suggest the presence of an abscess near the atrioventricular node.11 Peripheral pulses must be examined for signs of embolic occlusion or pulsating mass suggesting mycotic aneurysm. Mycotic aneurysms could arise in the intracranial arteries, potentially leading to intracranial haemorrhage.11 The most frequent bacterial agents are Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae.11 The HACEK group of organisms, which includes Haemophilus spp, Actinobacillus actinomycetem-comitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, are fastidious bacteria and can be difficult to culture. Cryptococcus and candida fungal endocarditis can also be seen in AIDS patients, especially in IDUs.11 Candidiasis of the oropharynx and oesophagus is most often the primary focus, which then progresses to systemic infection. In HIV-infected patients with fungaemia, signs of systemic or cerebral embolism could indicate the presence of endocarditis.11 THE LANCET Infectious Diseases Vol 1 September 2001
Figure 6. Lymphomatous lesions involving the atrial septum in a patient who died of AIDS (a). On histology, the lesions were characterised by myocardial infiltration by large B-cell lymphoma, associated with diffuse myocardial damage (haematoxylin-eosin, x40) (b).
Patients with and without HIV generally have much the same presentation and survival rates from infective endocarditis. However, patients with late-stage HIV disease have a mortality about 30% higher from infective endocarditis than do symptom-free HIV-infected patients.11 The diagnosis is based on clinical, echocardiographic, and bacterial culture data. HIV-infected patients usually present with fever, sweats, weight loss, co-existing pneumonia, and/or meningitis. Echocardiographic findings in endocarditis include mobile echodensemasses attached to the inflow side of valvular leaflets or mural endocardium. Transthoracic echocardiography (TTE) is useful for detecting relatively large valvular masses but perivalvular abscess, leaflet perforation, or rupture of valvular chordae are better assessed by transoesophageal echocardiography (TEE). Both TTE and TEE are useful to guide the duration of antibiotic therapy and assess timing for surgery when necessary. Surgical management is indicated in selected patients, especially when valvular dysfunction resulting in acute heart failure becomes intractable to medical therapy.54 Hospital morbidity and mortality rates are higher than usual in this group of patients.54 Non-bacterial thrombotic endocarditis, also known as marantic endocarditis, is most common in patients with HIV wasting syndrome.11 It is characterised by friable endocardial vegetations, consisting of platelets within a fibrin mesh with few inflammatory cells. The lesions may involve any of the four valves, but are more common on the mitral and aortic valves. Marantic endocarditis has not been reported in 121
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HIV-associated cardiovascular complications
Table 2. Cardiovascular actions and interactions of common HIV therapies Class Anti-retroviral Nucleoside reverse transcriptase inhibitors
Drugs
Cardiac drug interactions
i) Abacavir ii) Zidovudine
ii) Dipyridamole
Non-nucleoside reverse transcriptase inhibitors
i) Delavirdine ii) Efavirenz iii) Nevirapine i) Amprenavir ii) Indinavir iii) Nelfinavir iv) Ritonavir v) Saquinavir
Warfarin (class interaction) i) Calcium channel blockers iii) Beta blockers, nifedipine, quinidine, steroids, theophylline. All are metabolised by cytochrome p-450 and interact with: Implicated in premature sildenafil, amiodarone, lidocaine, quinadine, warfarin, “statins” atherosclerosis, dyslipidaemia, insulin resistance, fativ) Calcium channel blockers, prednisone, quinine, increases wasting and redistribution beta blocker levels 1·5–3x (lipodystrophy)
i) Erythromycin ii) Trimethoprim/sulfamethoxazole
i) Cytochrome p-450 metabolism and drug interactions ii) Increases warfarin effects
Protease inhibitors
Anti-infective Antibiotics
Antifungal agents
i) Amphotericin B ii) Ketoconazole iii) Itraconazole
Antiviral agents
i) Foscarnet ii) Ganciclovir
Anti-parasitic
i) Pentamidine (IV)
Chemotherapy agents i) Vincristine ii) Interferon-
iii) IL-2
iv) Doxorubicin
Rare: Lactic acidosis i) hypotension ii) skeletal muscle myopathy, (mitochondrial dysfunction hypothesised, but not seen clinically)
Orthostatic hypotension, ventricular tachycardia, bradycardia, torsades (drug interactions) Orthostatic hypotension, anaphylaxis, QT prolongation Digoxin toxicity i) Hypertension, arrhythmia, ii) & iii) Cytochrome p-450 metabolism and drug interactions- renal failure, hypokalaemia, increases levels of sildenafil, warfarin, "statins", nifedipine, thrombophlebitis, digoxin bradycardia, angioedaema, dilated cardiomyopathy i) Reversible cardiac failure, electrolyte abnormalities ii) Zidovudine ii) Ventricular tachycardia, hypotension i) Hypotension, arrhythmias (torsade de pointes, VT), hyperglycaemia, hypoglycaemia, sudden death. Note: contraindicated if baseline QTc>0·48 i) Decreases digoxin level i) Arrhythmia, myocardial infarction, cardiomyopathy ii) Orthostatic hypotension, myocardial infarction, cardiomyopathy, ventricular and supraventricular arrhythmias, sudden death, atrioventricular block iii) Hypotension, arrhythmia, sudden death, myocardial infarction, cardiac failure, capillary leak, thyroid alterations iv) Decreases digoxin level iv) Myocarditis, cardiomyopathy, cardiac failure
published work in the era of improved antiretroviral therapy. The incidence of marantic endocarditis and systemic embolisation from marantic endocarditis is low in AIDS patients receiving HAART regimens.
Pericardial involvement The incidence of pericardial effusion among those patients meeting criteria for AIDS is 11% per year and 22% per year in symptomless AIDS patients.55-58 HIV infection should be included in the differential diagnosis of unexplained pericardial effusion or tamponade. AIDS patients with pericardial effusion survive a median of 6 months, significantly shorter than do AIDS patients without effusion. Survival is independent of CD4 count and albumin concentrations.55-58 122
Cardiac side effects
Pericarditis and pericardial effusion in HIV disease are generally related to opportunistic infections (Mycobacterium tuberculosis, M avium intracellulare, S aureus, Nocardia asteroides, Rhodococcus equi, Listeria monocytogenes, Chlamydia trachomatis, coxsackievirus, Epstein-Barr virus, cytomegalovirus, adenovirus, herpes virus, Histoplasma capsulatum, Cryptococcus neoformans, and Toxoplasma gondii), or to malignancy (Kaposi’s sarcoma, non-Hodgkin lymphoma), but most often a clear cause is not found.11 Fever, chest pain, and pericardial friction rub should suggest acute pericarditis, which can be confirmed by echocardiography.11 Pericardial effusion spontaneously resolves in up to 42% of patients.55-58 Mortality remains increased in HIV-infected patients who develop a pericardial effusion, even if the effusion resolves over time. THE LANCET Infectious Diseases Vol 1 September 2001
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HIV-associated cardiovascular complications
Pericardiocentesis is currently recommended only in large or poorly tolerated effusions, for diagnostic evaluation of systemic illness, or in the presence of cardiac tamponade.54 The effects of HAART therapy on pericardial effusion are largely unexplored.
Cardiac involvement in AIDS-related tumours Cardiac Kaposi’s sarcoma in AIDS could cause visceral and parietal pericardial lesions and, less frequently, myocardial lesions. The prevalence has ranged from 12% to 28% in retrospective necropsy studies done in pre-HAART period.11 Cardiac Kaposi’s sarcoma is not usually obstructive or associated with clinical cardiac dysfunction, morbidity, or mortality.11 Lymphomas have a predilection to invade the heart in immunocompromised conditions, as has been observed in some animal models of AIDS (SCID mice).59 However, malignant lymphoma involving the heart is infrequent in human AIDS.11 Lymphomatous infiltration can be diffuse or can result in discrete isolated lesions, which are usually derived from the Burkitt or immunoblastic type B cells60,61 (figure 6). The lesions are usually nodular or polypoid masses, and predominantly involve the pericardium, with variable myocardial infiltration.11,60,61 The prognosis of patients with HIV-associated cardiac lymphoma is generally poor, although clinical remission has been observed with combination chemotherapy.62 The improvement of the immunologic state of the patients and the better control in the incidence of some opportunistic infections (eg, human herpes virus-8 and Epstein-Barr virus, which could cause these tumours), could result in reduction of overall incidence of cardiac involvement by both Kaposi’s sarcoma and non-Hodgkin lymphomas after the introduction of the HAART regimens.62
Conclusions Cardiac and pulmonary complications of HIV disease are generally late manifestations and could be related to prolonged effects of immunosuppression and a complex interplay of mediator effects from opportunistic infections, viral infections, autoimmune response to viral infection, drug related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression.22 We hope that HAART regimens, by improving the clinical course of HIV disease, might bring an important reduction in the incidence of both pericardial effusions and myocardial involvement of HIVassociated malignacies and co-infections. However, infectious diseases specialists should be included in the evaluation of patients who are being considered for or who are receiving HAART regimens, especially those with underlying cardiovascular risk factor, because the atherogenic effects of PIs could increase the risk of death for coronary heart disease and stroke. HIV-associated heart disease could be an important model for the mechanisms behind dilated cardiomyopathy. Virus-induced activation of specific proinflammatory cytokines induces iNOS, reduces myocyte contractility, and decreases responsiveness to beta-adrenergic agonists.17,18 Further research in this field should help to direct therapies and to allow preventive measures in the care of patients with HIV-associated cardiac illness. Since the role of infection THE LANCET Infectious Diseases Vol 1 September 2001
Review
Search strategy and selection criteria 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. Data for this review were identified by searches of Medline and AIDSline, and references from articles from 1996 to 2001. We reviewed English language articles about the pathogenetic mechanisms involved in the development of HIV-associated cardiovascular complications, related or not to HAART regimens. and inflammation in many other cardiovascular diseases is beginning to be recognised, discovering the molecular mechanisms of HIV-related heart disease could provide the basis for rational therapeutic strategies and improved care for a broader range of patients.6,63 Moreover, a better understanding of PIs’ effects on lipid and metabolic pathways will lead to a new generation of drug therapies without metabolic alterations and could also lead to new therapies for dyslipidaemias and alterations of metabolism unrelated to HIV infection. Acknowledgments
We thank Giulia D’Amati, Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy, and Adriano M Pellicelli, National Institute for Infectious Diseases, Rome, Italy, for kindly providing the pathological materials and the pathogenetic schemes reproduced in this review. References
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