Cardiac Manifestations of Acquired Immunodeficiency Syndrome

REVIEW ARTICLE Cardiac Manifestations of Acquired Immunodeficiency Syndrome

Pairoj Rerkpattanapipat, MD; Nattawut Wongpraparut, MD; Larry E. Jacobs; Morris N. Kotler, MD

cquired immunodeficiency syndrome is a serious problem worldwide. Recent advances in the knowledge about human immunodeficiency virus (HIV) replication and the treatment of HIV infection have improved survival in HIV patients. Because of the longer survival in HIV patients, the more manifestations of late-stage HIV infection Awill be seen, including HIV-related cardiac diseases. The common cardiac manifestations in patients with the acquired immunodeficiency virus are pericardial effusion, myocarditis, dilated cardiomyopathy, endocarditis, pulmonary hypertension, malignant neoplasms, and drug-related cardiotoxicity. This review focuses on these cardiac manifestations in patients with the acquired immunodeficiency syndrome. Arch Intern Med. 2000;160:602-608 Acquired immunodeficiency syndrome cal manifestations, which include asymp- (AIDS) is characterized by an acquired, tomatic pericardial effusion, pericarditis, profound, irreversible immunosuppres- cardiac tamponade, and constrictive peri- sion that predisposes the patient to mul- carditis. Approximately one fifth of AIDS tiple opportunistic infections, malignant patients have pericardial effusion.6-11 The neoplasms, and a progressive dysfunc- pericardial effusion is often small and with- tion of multiple organ systems. Cardiac in- out hemodynamic consequence; how- volvement in AIDS patients was first de- ever, large effusion can occur and may cause scribed in 1983 by Autran et al,1 who cardiac tamponade.12-14 reported myocardial Kaposi sarcoma at au- The clinical manifestations of pericar- topsy. The prevalence of cardiac involve- ditis are similar between patients with and ment in AIDS patients has been reported without HIV infection.15 Moreno et al16 re- to range between 28% and 73%.2 Recent viewed echocardiographic studies in 141 advances in the knowledge about human HIV-infected patients, and 55 (39.0%) of immunodeficiency virus (HIV) replica- them had pericardial effusion. Most (34 of tion and the treatment of HIV infection the 55) were small. The clinical presenta- have improved survival in HIV pa- tion of pericarditis was compared be- tients.3-5 Because of the longer survival in tween patients with small pericardial effu- HIV patients, the more manifestations of sion and those with moderate to large late-stage HIV infection will be seen, in- pericardial effusion. They found that the cluding HIV-related cardiac diseases. These presence of a pericardial friction rub and cardiac diseases include pericardial effu- electrocardiographic repolarization abnor- sion, myocarditis, dilated cardiomyop- malities consistent with pericarditis were athy, endocarditis, pulmonary hyperten- more often seen in patients with moderate sion, malignant neoplasms, coronary artery to large pericardial effusions. The reason for disease, and drug-related cardiotoxicity. these findings is unclear. Specific identifi- able causes of pericardial effusion in AIDS PERICARDIAL EFFUSION patients are not always possible.17,18 The causative factors involved in the develop- Pericardial effusion is one of the most com- ment of pericardial effusion have been demon forms of cardiovascular involvement scribed. Flum et al18 performed pericar- in HIV infection. There are varieties of clini- dial fluid cultures and pericardial biopsies in 29 AIDS patients with pericardial effu- From the Division of Cardiovascular Diseases, Department of Medicine, Albert Einstein sion who underwent a pericardial win- Medical Center, Philadelphia, Pa. dow procedure. The causes were identi-

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 fied in 7 (24%) of the 29 patients. The than in those without effusion (0.059 cleic acid hybridization, and by causes included Staphylococcus au- vs 0.146 ϫ 109/L).14 Pericardial effu- Southern blot tests.38-40 reus (1 patient), Mycobacterium tu- sion in HIV patients may be a marker Superantigen plays an impor- berculosis (1 patient), adenocarci- of end-stage HIV infection because it tant role in the pathogenesis of many noma (2 patients), and lymphoma (3 is associated with low CD4 cell count diseases by forming a trimolecular patients). Staphylococcus aureus peri- and is often caused by opportunistic complex with major histocompat- carditis is a serious condition, and infections and malignant neoplasms ibility complex class II molecule on cardiac tamponade may develop rap- seen in the advanced state of AIDS. the antigen-presenting cells and the idly.19 Karve et al20 reported pneu- Although pericardial effusion is seen V␤-specific region on the T- mococcal pericarditis in 2 HIV pa- in patients with the advanced stage of lymphocyte receptor. The binding tients, and both of them developed HIV infection, it rarely causes death results in a massive stimulation of cardiac tamponade. Sunderam et al21 in these patients. the T lymphocyte. The role of su- studied a select group of 29 AIDS pa- perantigen in the pathogenesis of tients who had M tuberculosis.Of MYOCARDITIS AIDS has been described.41 After the these 29 patients, 21 (72%) had ex- binding of HIV regulatory protein trapulmonary tuberculosis. Tuber- Anderson et al37 suggested that myo- (Nef) with major histocompatibil- culous pericarditis was found in 1 carditis in HIV patients may play a ity complex class II on antigen- (5%) of these 21 patients with extra- role in the development of ventricu- presenting cells, the T lympho- pulmonary tuberculosis. Zuger et al22 lar dysfunction. The autopsy inci- cytes become activated. The reported that 1 (4%) of 26 AIDS pa- dence of myocarditis was approxi- activation of T lymphocytes stimu- tients with cryptococcal infection had mately one third of all AIDS patients. lates the proliferation and release of pericarditis. Eisenberg et al23 could A specific cause was found in less cytokines such as interferon ␥ and identify the cause of pericardial ef- than 20% of these patients. Com- interleukin 2. Therefore, the viral fusion in 4 (29%) of 14 AIDS pa- mon pathogens in AIDS myocar- load in the heart will increase from tients with pericardial effusion. The ditis include Toxoplasma gondii, creating a cellular reservoir for HIV. causes included lymphoma (1 pa- M tuberculosis, and Cryptococcus T-lymphocyte depletion may be tient), myocardial infarction (1 pa- neoformans. Other infectious organ- caused by apoptosis, anergy, or both. tient), and endocarditis (2 patients). isms have been reported to include Proliferation of the B cell may re- Kaposi sarcoma has been reported to Myocobacterium avium-intracellu- sult in hypergammaglobulinemia. cause pericardial effusion and car- lare complex, Aspergillus fumigatus, Autoimmune response may occur as diac tamponade.24 Numerous case re- Candida albicans, Histoplasma cap- a result of B-cell differentiation into ports have shown multiple unusual sulatum, Coccidioides immitis, cyto- immunoglobulin-secreting cells and organisms associated with peri- megalovirus, and herpes simplex.2 activation of the T lymphocyte.41 cardial effusion in HIV patients Recent data suggested that HIV alone Lymphocytic myocarditis was (Table 1). can cause myocarditis. Either HIV or found in 37 (52%) of 71 patients Heidenreich et al14 studied the its proteins (p17, p24, and gp120/ who died of AIDS.37 There were 3 incidence of pericardial effusion and 160) have been found in the heart types of histological features: lym- its relation to mortality in HIV pa- specimens of patients with AIDS phocytic infiltrate with necrosis of tients. Two hundred thirty-one pa- with or without cardiac diseases by the myocardial fibers, lymphocytic tients were recruited during a 5-year culture, by in situ deoxyribonu- infiltrate without necrosis of the period, and 74 had AIDS. Fifteen patients with HIV infection had peri- Table 1. Causative Factors Associated With Pericardial Effusion in Patients cardial effusion, and 12 (80%) of these With the Human Immunodeficiency Virus pericardial effusions were small. Only 2 patients (1 with a moderate and 1 Source, y Factor with a large pericardial effusion) de- Flum et al,18 1995 and Decker and Tuazon,19 1994 Staphylococcus aureus veloped symptoms and signs of car- Karve et al,20 1992 Streptococcus pneumoniae diac tamponade, which required Holtz et al,25 1985 Nocardia asteroides drainage. Patients with AIDS who Ferguson et al,26 1993 Listeria monocytogenes have pericardial effusion have a 9% Lee-Chiong et al,27 1995 and Legras et al,28 1994 Rhodococcus equi annual incidence of cardiac tampon- Kroon et al,29 1989 Chlamydia trachomatis ade, and 1% of all AIDS patients de- Sunderam et al,21 1986 Mycobacterium tuberculosis Woods and Goldsmith,30 1989 and Choo and Mycobacterium avium veloped cardiac tamponade annu- McCormack,31 1995 14 ally. The size of pericardial effusion Moreno et al,32 1994 Mycobacterium kansasii did not correlate with the shortened Zuger et al,22 1986 Cryptococcus neoformans survival, but the presence of pericar- Zakowski and Ianuale-Shanerman,33 1993 Histoplasma capsulatum dial effusion did. The mean ± SD Guerot et al,34 1995 Toxoplasma gondii Nathan et al,35 1991 Cytomegalovirus 6-month survival was 36% ± 11% 36 compared with 93% ± 3% in AIDS pa- Freedberg et al, 1987 Herpes simplex Stotka et al,24 1989 Kaposi sarcoma tients without effusion. The CD4 (T- Flum et al,18 1995 Lymphoma and adenocarcinoma helper lymphocyte) cell count was Eisenberg et al,23 1992 Postmyocardial infarction lower in AIDS patients with effusion

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 myocardial fibers,42 and focal and ever, there was no association out an inflammatory reaction. It is mild myocarditis with a mono- between the progression of left ven- estimated that this condition occurs nuclear infiltrate.37 Reilly et al7 stud- tricular dysfunction and the rate of in 3% to 5% of AIDS patients.58 It ied the relation between clinical and CD4 cell count decline.52 usually occurs in patients older than histopathological cardiac findings in The pathogenesis of cardiomy- 50 years. Marantic endocarditis is patients with AIDS. Interestingly, opathy remains unclear. Several known to be associated with malig- myocarditis was found in all pa- studies35,44,53 have supported the di- nant neoplasms, hypercoagulable tients with congestive heart failure, rect role for HIV-1–mediated car- states, and chronic wasting dis- left ventricle dysfunction, and ven- diac injury, but the mechanism re- ease.59-61 Mitral and aortic valves are tricular tachycardia. Baroldi et al43 mains unclear. One hypothesis commonly involved in HIV- evaluated the relation between car- focuses on the role of an alteration negative patients,60 but the tricus- diac dysfunction and myocarditis. Of of T-helper cell function inducing pid valve is usually involved in AIDS 26 patients with AIDS, 8 under- myocardial inflammation by uncon- patients.62 Systemic embolism can went premortem echocardiogra- trolled hypergammaglobulinemia.42 occur in up to 42% of patients, but phy. Of these 8 patients, 6 had ab- The HIV gene may provoke cell sur- most of these events are clinically si- normal cardiac function (abnormal face cardiac muscle protein, result- lent. Embolization can involve the fractional shortening, globular ing in the induction of circulated car- brain, lung, spleen, kidney, and shape, hypokinesis, or mild ven- diac autoantibodies, which can coronary arteries.63 Systemic embo- tricular dilation). All patients with trigger a progressively destructive lization from marantic endocardi- abnormal echocardiographic find- autoimmune reaction.54 tis is a rare cause of death in AIDS ings had lymphocytic myocarditis Selenium deficiency and its as- patients.12 with or without myocardial necro- sociation with cardiomyopathy have Infective endocarditis in pa- sis post mortem. been described. Case reports55,56 of tients with AIDS usually occurs in pediatric AIDS patients have shown parenteral drug users. Human im- DILATED CARDIOMYOPATHY an improvement of cardiac func- munodeficiency virus infection may tion after selenium supplementa- increase the risk of infective endo- In 1986, Cohen et al44 described the tion. Barbaro et al57 performed a pro- carditis among intravenous drug us- first case of rapidly fatal, dilated car- spective, long-term clinical and ers.64 Nahass et al65 studied the diomyopathy in a patient with AIDS. echocardiographic follow-up study causes of infective endocarditis in 34 The prevalence of dilated cardiomy- of 952 asymptomatic HIV-positive HIV patients, and they found that S opathy ranges from 10% to 30% by patients. An echocardiographic di- aureus (75%) and Streptococcus viri- echocardiographic and autopsy stud- agnosis of dilated cardiomyopathy dans (20%) were the major respon- ies.37,45,46 Several prospective clini- was made in 76 patients (8.0%), with sible organisms. Other unusual or- cal and echocardiographic studies a mean annual incidence of 15.9 per ganisms described as case reports have suggested that a subgroup of 1000 patients during a mean ± SD were Salmonella,66 A fumigatus,67,68 HIV-infected patients may be pre- follow-up period of 60.0 ± 5.3 and Pseudallescheria boydii.69 The tri- disposed to the development of clini- months. All patients with an echo- cuspid valve is the most commonly cally significant and progressive cardiographic diagnosis of dilated affected valve. The affected pa- heart disease. Herskowitz et al47 cardiomyopathy underwent endo- tients usually present with fever, found that patients with severe myocardial biopsy within 1 month. sweats, weight loss, and coexisting symptomatic heart failure usually They found myocarditis in 63 (83%) pneumonia and/or meningitis.70 The had a low CD4 cell count, myocar- of the patients with dilated cardio- presentation and survival of infec- ditis, and a persistent elevation of an- myopathy on histological examina- tive endocarditis in patients with and tiheart antibodies. The postmor- tion, and 36 (57%) of the patients without HIV infection are gener- tem gross findings of dilated with myocarditis had a positive hy- ally not different; however, in the late cardiomyopathy in patients with bridization signal for HIV nucleic stage of HIV-infected patients, sig- AIDS have included increased heart acid sequences. Among these 36 pa- nificant increased mortality from in- weight, with either biventricular or tients who had myocarditis and a fective endocarditis has been re- 4-chamber dilation, and a pale- positive hybridization signal for HIV ported compared with asymptomatic appearing myocardium.48 Echocar- nucleic acid sequences, 6 (17%) were HIV patients.65 diographic findings included infected with Coxsackievirus group 4-chamber enlargement, diffuse left B, 2 (6%) were infected with cytome- PULMONARY HYPERTENSION ventricular hypokinesis, and de- galovirus, and 1 (3%) was infected creased fractional shortening.45 Cou- with Epstein-Barr virus. Human immunodeficiency virus– dray and colleagues49 demon- associated pulmonary hyperten- strated that left ventricular diastolic ENDOCARDITIS sion was first described by Kim and impairment could occur in the early Factor in 1987.71 By 1998, 88 pa- stage of HIV infection. Dilated car- Marantic endocarditis or nonbacte- tients with HIV infection were de- diomyopathy occurs late in the rial thrombotic endocarditis is char- scribed with this entity. The inci- course of HIV infection and is usu- acterized by friable, fibrinous clumps dence of HIV-associated pulmonary ally associated with a significantly re- of platelets and red blood cells ad- hypertension is 1 in 200 compared duced CD4 cell count47,50,51; how- herent to the cardiac valves with- with 1 in 200 000 in the general

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 population.72 It is more common in pertension. Morse et al78 found that posi sarcoma of the visceral layer of male and young patients (mean age, the incidence of HLA-DR6 and HLA- serous pericardium or pericardium 32 years). The common risk fac- DR52 was increased in 10 HIV pa- causing fatal tamponade in the pa- tors are intravenous drug use, ho- tients with primary pulmonary hy- tients with AIDS. Pericardicentesis mosexual contacts, and hemo- pertension compared with matched was performed, resulting in a tran- philia. The major symptom of this control subjects. Human immuno- sient improvement in vital signs but condition is dyspnea.72 There was no deficiency virus–associated pulmo- with subsequent deterioration and correlation between either a his- nary hypertension is a diagnosis death within a variable period rang- tory of opportunistic infections or of exclusion. Other causes of pul- ing from 5 hours to a few days. The CD4 cell count and the develop- monary hypertension include talc diagnosis of pericardial Kaposi sar- ment of pulmonary hyperten- granuloma, especially in intrave- coma was delayed until autopsy. All sion.73 The mean pulmonary artery nous drug abusers, portal hyperten- were noted to have a tense pericar- systolic pressure was 68 mm Hg. The sion, thromboembolism, and an air- dial sac with dark bloody fluid, pre- major causes of death were right- way disease.72 sumably as a result of the pericardi- sided heart failure and respiratory centesis needle penetrating the failure. Half of the patients died in CARDIAC NEOPLASM AND HIV Kaposi sarcoma lesions. Pericardi- 1 year.72 Petitpretz et al74 performed centesis not only has no diagnostic a prospective study of 20 patients Two types of malignant neoplams af- role but it is also a high-risk proce- with HIV infection and pulmonary fecting the heart have been de- dure in this group of patients. In pa- hypertension and compared them scribed in patients with HIV infec- tients with AIDS in whom the cli- with a group of 93 patients with pri- tion: Kaposi sarcoma and malignant nician has a high index of suspicion mary pulmonary hypertension who lymphoma. of Kaposi sarcoma pericardial effu- were HIV negative. They found that sion, a pericardial window should be patients with HIV infection were Kaposi Sarcoma the procedure of choice for provid- younger and had a lesser degree of ing decompression and establish- disabilities. Interestingly, mortality In 1983, Autran et al1 first de- ing the pathologic diagnosis. between these 2 groups was not dif- scribed Kaposi sarcoma of the heart ferent. Plexogenic pulmonary arte- in an HIV patient. The incidence of Malignant Lymphoma riopathy was the most frequent Kaposi sarcoma involving the heart pathologic finding.74 ranged from 12% to 28% in retro- In 1985, the Centers for Disease The pathogenesis of pulmo- spective autopsy findings.17,79 Most Control and Prevention recognized nary hypertension associated with (90%) of the autopsies were per- the linkage between intermediate- HIV infection is unclear. Mette et al75 formed on homosexual or bisexual and high-grade lymphoma and HIV were unable to demonstrate the pres- patients.17 Cardiac involvement with seropositivity and included this in ence of HIV in pulmonary endothe- Kaposi sarcoma in an HIV-infected the diagnostic criteria for AIDS. lial cells by electron microscopy, patient usually occurs as a part of Lymphoma is the second most com- immunochemistry, DNA in situ hy- disseminated Kaposi sarcoma. Ac- mon tumor that involves the heart. bridization, and the polymerase quired immunodeficiency syn- Cardiac involvement with non- chain reaction technique. This find- drome–related metastatic Kaposi sar- Hodgkin lymphoma, usually de- ing supports an indirect mecha- coma involves either the visceral rived from B cells, is typically high nism for HIV-associated pulmo- layer of serous pericardium or the grade and is often disseminated early nary hypertension. Ehrenreich et al76 subepicardial fat. There is a predi- in patients with AIDS. Dissemi- demonstrated that HIV-1 envelope lection of Kaposi sarcoma to in- nated cardiac lymphoma is more glycoprotein (GP-120) stimulated volve the subepicardial adipose tis- common than primary cardiac lym- the production of the secretion of en- sue adjacent to a major coronary phoma. It has been reported to ac- dothelin 1 (a potent vasoconstric- artery with or without involvement count for 15% of all cardiac and peri- tor) and tumor necrosis factor ␣ of the adventitia of the ascending cardial metastases in non-AIDS from macrophage. Human immu- aorta or pulmonary trunk.79 Peri- series.83 Primary cardiac lymphoma nodeficiency virus–infected alveo- cardial and myocardial involve- is extremely rare.84 Patients may pre- lar macrophage released tumor ne- ment have also been reported.59 sent with intractable congestive heart crosis factor ␣ and proteolytic Chyu et al80 demonstrated premor- failure, pericardial effusion, car- enzymes. Lymphokine can en- tem detection of cardiac Kaposi sar- diac arrhythmia,85-87 or cardiac tam- hance the adherence of the leuko- coma by transthoracic echocardiog- ponade.88 Patients usually have non- cyte to the endothelium and pro- raphy, which revealed pericardial specific symptoms, but rapid mote endothelial proliferation.72 tamponade and a mobile multilobu- progression of cardiac dysfunction Platelet-derived growth factor can lar mass at the apex protruding into can occur after these symptoms. The stimulate smooth muscle cell and fi- the pericardial space. Clinical car- most common gross appearance is broblast proliferation and migra- diac findings are obscure; most of the nodular or polypoid masses pre- tion. Humbert et al77 showed that cases are found at autopsy. Fatal car- dominantly involving the pericar- platelet-derived growth factor ex- diac tamponade24,81 and pericardial dium, with variable myocardial in- pression was increased in patients constriction have been reported.2 Vi- filtration. Histologically, these are with HIV-associated pulmonary hy- jay et al82 reported 5 cases of Ka- diffuse, aggressive lymphomas, usu-

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 ally of small noncleaved or immu- tions. Some of these medications may patients), AV block (2 patients), and noblastic types.85 Patients with me- have cardiovascular toxicities. Di- congestive heart failure (1 patient). chanical obstruction may benefit lated cardiomyopathy has been re- Cardiac adverse effects from inter- from surgical resection.89 The prog- ported in a young male patient treated feron were not associated with the nosis of patients with HIV-associ- with amphotericin B.97 In this pa- dosage or the duration of treatment ated cardiac lymphoma is generally tient, cardiac function returned to and were reversible in most pa- poor, although clinical remission normal after the medication had been tients.104 QT prolongation has been has been observed with combination discontinued for 6 months.97 Brady- reported in patients treated with pen- chemotherapy.90 cardia was described in children tamidine,105,106 pyrimethamine,107 and treated with amphotericin B. The in- the combination drug trimethoprim CORONARY ARTERY DISEASE cidence was 6.7% in the patients who and sulfamethoxazole.108 Cardiac dys- received amphotericin B and usu- function has been found in adults or Coronary artery disease has been re- ally occurred between day 3 and day children treated with zidovudine. ported in a patient with HIV infec- 7 after the start of therapy.98 Hyper- Zidovudine inhibits retroviral repli- tion91,92 at autopsy. Eccentric ath- tension was found in 2 patients cation and interferes with the action erosclerosis or fibrosis of the tunica treated with amphotericin B, and the of reverse transcriptase of HIV.109,110 media of the coronary artery was mechanism of this adverse effect was Diffuse destruction of cardiac mito- found at autopsy.91 Sclerohyalino- unclear.99 Doxorubicin cardiomyop- chondrial ultrastructures and inhi- sis of the smaller arteries and myo- athy has been well described and oc- bition of mitochondrial DNA repli- cardial interstitial fibrosis lesions curred with a total dose of 400 mg/m2 cation may be responsible for were also found.91 The cause of these or more.100 The prevalence of hyper- zidovudine-induced cardiomyop- lesions is uncertain. Coronary ar- tension associated with erythropoi- athy (Table 2).111 tery disease in HIV-positive pa- etin therapy is 47%, and the mecha- tients may be due to atherogenesis nism of this adverse effect may be CONCLUSIONS as a result of virus-infected mono- related to an increase in hematocrit cytes-macrophages, possibly through and blood viscosity.101 Reversible car- Cardiac involvement is commonly altered adhesion93 or due to angi- diomyopathy has been described in seen in AIDS patients, and the peri- itis.42,94 Atherosclerosis and athero- HIV patients treated with foscarnet cardium, myocardium, and/or en- thrombosis from dyslipoprote sodium for cytomegalovirus esopha- docardium may be involved in these inemia caused by highly active gitis.102 Cohen et al103 described 2 pa- patients. Pericardial effusion is one antiretroviral therapy, especially tients who developed ventricular of the most common types of car- protease inhibitors, have been re- tachycardia during an intravenous in- diac involvement in HIV patients, ported.95,96 fusion of ganciclovir. Sonnenblick and its mechanism is unclear but it and Rosin104 reviewed 44 cases of in- may be related to infections or neo- DRUG-INDUCED terferon-induced cardiotoxicity. Ar- plasms. Myocarditis, the cause of CARDIOTOXICITY rhythmia was the most common which is usually difficult to iden- manifestation of cardiotoxicity (25 tify, may be responsible for myocar- Patients with HIV are exposed to patients). Other cardiotoxicities in- dial dysfunction. Opportunistic in- many medications to treat condi- cluded myocardial infarction or is- fections have been reported to be a tions related to HIV diseases, such as chemia (9 patients), cardiomyop- cause of myocarditis, including the cancer and opportunistic infec- athy (5 patients), sudden death (2 HIV itself. Dilated cardiomyopathy is usually found in the late stage of HIV infection, and myocarditis may Table 2. Cardiotoxicity of Medications Used in HIV Patients* be the triggering causative factor. Nonbacterial thrombotic endocar- Medications Treatment Cardiovascular Adverse Effects ditis and infective endocarditis have been described in AIDS patients, Amphotericin B Antifungal Dilated cardiomyopathy, hypertension, and bradycardia both of which can cause significant Doxorubicin Kaposi sarcoma Cardiomyopathy morbidity in these patients. Hu- Epoetin alfa Anemia Hypertension man immunodeficiency virus– Foscarnet sodium CMV Cardiomyopathy related pulmonary hypertension is Ganciclovir CMV Ventricular tachycardia a diagnosis of exclusion, and symp- Interferon alfa Antineoplastic, antiviral, and Arrhythmia, myocardial infarction or immunomodulator ischemia, cardiomyopathy, sudden toms and signs may mimic other pul- death, AV block, and congestive heart monary conditions in AIDS pa- failure tients. Cardiac Kaposi sarcoma and Pentamidine Pneumocystis carinii QT prolongation and Torsades de cardiac lymphoma are the fre- pointes quently encountered malignant neo- Pyrimethamine Toxoplasmosis QT prolongation plasms in AIDS patients, and the Trimethoprim- P carinii QT prolongation and Torsades de sulfamethoxazole pointes prognosis is grave in patients with Zidovudine Antiretroviral Myocarditis and dilated cardiomyopathy these conditions. Coronary artery disease has previously been docu- *HIV indicates human immunodeficiency virus; CMV, cytomegalovirus. mented and may be related to highly

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 active antiretroviral therapy. Many 13. Thuesen L, Moller A. Heart involvement in HIV lateral facial palsy in a patient with AIDS. N Y State infection. Nord Med. 1994;109:298-299. J Med. 1987;87:304-306. cardiovascular adverse effects from 14. Heidenreich PA, Eisenberg MJ, Kee LL, et al. Peri- 37. Anderson DW, Virmani R, Reilly JM, et al. Preva- medications used in HIV patients cardial effusions in AIDS: incidence and sur- lent myocarditis at necropsy in acquired immu- have been described. As the survival. Circulation. 1995;92:3229-3234. nodeficiency syndrome. J Am Coll Cardiol. 1988; 15. Malu K, Longo-Mbenza B, Lurhuma Z, Odio W. 11:792-799. vival of HIV patients has improved Pericarditis and acquired immunodeficiency syn- 38. Calabrese LH, Proffitt MR, Yen-Lieberman B, mainly because of aggressive anti- drome [in French]. Arch Mal Coeur Vaiss. 1988; Hobbs RE, Ratliff NB. Congestive cardiomyop- 81:207-211. athy and illness related to the acquired immu- retroviral therapy, it is anticipated 16. Moreno R, Villacastin JP, Bueno H, et al. Clini- nodeficiency syndrome (AIDS) associated with that more late complications from cal and echocardiographic findings in HIV pa- isolation of retrovirus from myocardium. Ann In- this fatal viral infection, including tients with pericardial effusion. Cardiology. 1997; tern Med. 1987;107:691-692. 88:397-400. 39. Cotton P. AIDS giving rising to cardiac prob- cardiac involvement, will be encoun- 17. Lewis W. AIDS: cardiac findings from 115 au- lems [letter]. JAMA. 1990;263:2149. tered. Early recognition and prompt topsies. Prog Cardiovasc Dis. 1989;32:207- 40. Grody WW, Cheng L, Lewis W. Infection of the treatment are important to prevent 215. heart by the human immunodeficiency virus. Am 18. Flum DR, McGinn JT Jr, Tyras DH. The role of J Cardiol. 1990;66:203-206. significant morbidity from cardiac the “pericardial window” in AIDS. Chest. 1995; 41. Johnson HM, Torres BA, Soos JM. Superanti- involvement. Whether this ap- 107:1522-1525. gens: structure and relevance to human 19. Decker CF, Tuazon CU. Staphylococcus aureus disease. Proc Soc Exp Biol Med. 1996;212:99- proach will prolong survival in AIDS pericarditis in HIV-infected patients. Chest. 1994; 109. patients remains to be seen. 105:615-616. 42. Acierno LJ. Cardiac complications in acquired im- 20. Karve MM, Murali MR, Shah HM, Phelps KR. munodeficiency syndrome (AIDS): a review. Rapid evolution of cardiac tamponade due to bac- J Am Coll Cardiol. 1989;13:1144-1154. Accepted for publication May 27, terial pericarditis in two patients with HIV-1 in- 43. Baroldi G, Corallo S, Moroni M, et al. Focal lym- 1999. fection. Chest. 1992;101:1461-1463. phocytic myocarditis in acquired immunodefi- Reprints: Morris N. Kotler, MD, 21. Sunderam G, McDonald RJ, Maniatis T, Oleske ciency syndrome (AIDS): a correlative morpho- J, Kapila R, Reichman LB. Tuberculosis as a logic and clinical study in 26 consecutive fatal Division of Cardiovascular Diseases, manifestation of the acquired immunodefi- cases. J Am Coll Cardiol. 1988;12:463-469. Department of Medicine, Albert Ein- ciency syndrome (AIDS). JAMA. 1986;256:362- 44. Cohen IS, Anderson DW, Vermani R, et al. Con- 366. gestive cardiomyopathy in association with the stein Medical Center, 5501 Old York 22. Zuger A, Louie E, Holzman RS, Simberkoff MS, acquired immunodeficiency syndrome. N Engl Rd, Philadelphia, PA 19141 (e-mail: Rahal JJ. Cryptococcal disease in patients with J Med. 1986;315:628-630. [email protected]). the acquired immunodeficiency syndrome: di- 45. Himelman RB, Chung WS, Chernoff DN, Schiller agnostic features and outcome of treatment. Ann NB, Hollander H. Cardiac manifestations of hu- Intern Med. 1986;104:234-240. man immunodeficiency virus infection: a two- REFERENCES 23. Eisenberg MJ, Gordon AS, Schiller NB. HIV- dimensional echocardiographic study. J Am Coll associated pericardial effusions. Chest. 1992; Cardiol. 1989;13:1030-1036. 102:956-958. 46. Levy WS, Simon GL, Rios JC, Ross AM. Preva- 1. Autran B, Gorin I, Leibowitch M, et al. AIDS in a 24. Stotka JL, Good CB, Downer WR, Kapoor WN. lence of cardiac abnormalities in human immu- Haitian woman with cardiac Kaposi’s sarcoma and Pericardial effusion and tamponade due to Ka- nodeficiency virus infection. Am J Cardiol. 1989; Whipple’s disease. Lancet. 1983;1:767-768. posi’s sarcoma in acquired immunodeficiency 63:86-89. 2. Kaul S, Fishbein MC, Siegel RJ. Cardiac mani- syndrome. Chest. 1989;95:1359-1361. 47. Herskowitz A, Willoughby SB, Vlahov K, Baugh- festations of acquired immune deficiency syn- 25. Holtz HA, Lavery DP, Kapila R. Actinomycetales man KL, Ansari AA. Dilated heart muscle dis- drome. Am Heart J. 1991;122:535-544. infection in the acquired immunodeficiency syn- ease associated with HIV infection. Eur Heart J. 3. Enger C, Graham N, Peng Y, et al. Survival from drome. Ann Intern Med. 1985;102:203-205. 1995;16(suppl O):50-55. early, intermediate, and late stages of HIV infec- 26. Ferguson R, Yee S, Finkle H, Rose T, Schneider 48. Roldan EO, Moskowitz L, Hensley GT. Pathol- tion. JAMA. 1996;275:1329-1334. V, Gee G. Listeria-associated pericarditis in an ogy of the heart in acquired immunodeficiency 4. Monsuez JJ, Vittecoq D, Kinney EL. Increased AIDS patient. J Natl Med Assoc. 1993;85:225- syndrome. Arch Pathol Lab Med. 1987;111:943- survival of AIDS patients with heart disease within 228. 946. 10 years? Circulation. 1996;94:2312-2313. 27. Lee-Chiong T, Sadigh M, Simms M, Buller G. 49. Coudray N, de Zuttere D, Force D, et al. Left ven- 5. Mocroft A, Youle M, Morcinek J, et al. Survival Case reports: pericarditis and lymphadenitis due tricular diastolic function in asymptomatic and after diagnosis of AIDS: a prospective observa- to Rhodococcus equi. Am J Med Sci. 1995;310: symptomatic human immunodeficiency virus car- tional study of 2625 patients. BMJ. 1997;314: 31-33. riers: an echocardiographic study. Eur Heart J. 409-413. 28. Legras A, Lemmens B, Dequin PF, Cattier B, Be- 1995;16:61-67. 6. Fink L, Reichek N, Sutton MG. Cardiac abnor- snier JM. Tamponade due to Rhodococcus equi 50. Currie PF, Jacob AJ, Foreman AR, Elton RA, malities in acquired immune deficiency in acquired immunodeficiency syndrome. Chest. Brettle RP, Boon NA. Heart muscle disease re- syndrome. Am J Cardiol. 1984;54:1161-1163. 1994;106:1278-1279. lated to HIV infection: prognostic implications. 7. Reilly JM, Cunnion RE, Anderson DW. Fre- 29. Kroon F, van’t Wout JW, Weiland HT, van Furth BMJ. 1994;309:1605-1607. quency of myocarditis, left ventricular dysfunc- R. Chlamydia trachomatis pneumonia in an HIV- 51. Jacob AJ, Sutherland GR, Bird AG, et al. Myo- tion and ventricular tachycardia in the acquired seropositive patient. N Engl J Med. 1989;320: cardial dysfunction in patients infected with HIV: immunodeficiency syndrome. Am J Cardiol. 806-807. prevalence and risk factors. Br Heart J. 1992; 1988;62:789-793. 30. Woods GL, Goldsmith JC. Fatal pericarditis due 68:549-553. 8. Hecht SR, Berger M, VanTosh A, Croxson S. to Mycobacterium avium intracellulare in ac- 52. Lipshultz SE, Easley KA, Orav EJ, et al. Left ven- Unsuspected cardiac abnormalities in the quired immunodeficiency syndrome. Chest. tricular structure and function in children in- acquired immune deficiency syndrome: an 1989;95:1355-1357. fected with human immunodeficiency virus: the echocardiographic study. Chest. 1989;96:805- 31. Choo PS, McCormack JG. Mycobacterium avium: prospective P2C2 HIV Multicenter Study. Circu- 808. a potentially treatable cause of pericardial effu- lation. 1998;97:1246-1256. 9. Corallo S, Mutinelli M, Moroni M, et al. Echo- sions. J Infect. 1995;30:55-58. 53. Ho DD, Pomerantz RJ, Kaplan JC. Pathogen- cardiography detects myocardial damage in AIDS: 32. Moreno F, Sharkey-Mathis PK, Mokulis E, Smith esis of infection with human immunodeficiency prospective study in 102 patients. Eur Heart J. JA. Mycobacterium kansasii pericarditis in pa- virus. N Engl J Med. 1987;317:278-286. 1988;9:887-892. tients with AIDS. Clin Infect Dis. 1994;19:967- 54. Herskowitz A, Neumann DA, Ansari AA. Con- 10. Monsuez JJ, Kinney EL, Vittecoq D, et al. Com- 969. cepts of autoimmunity applied to idiopathic di- parison among acquired immune deficiency syn- 33. Zakowski MF, Ianuale-Shanerman A. Cytology of lated cardiomyopathy. J Am Coll Cardiol. 1993; drome patients with and without clinical evi- pericardial effusions: AIDS patients. Diagn Cy- 22:1385-1388. dence of cardiac disease. Am J Cardiol. 1988; topathol. 1993;9:266-269. 55. Dworkin BM, Antonecchia PP, Smith F, et al. Re- 62:1311-1313. 34. Guerot E, Aissa F, Kayal S, et al. Toxoplasma peri- duced cardiac selenium content in AIDS. JPEN 11. Strang JI, Kakaza HH, Gibson DG, Girling DJ, carditis in acquired immunodeficiency syn- J Parenter Enteral Nutr. 1989;13:644-647. Nunn AJ, Fox W. Controlled trial of predniso- drome. Intensive Care Med. 1995;21:229-230. 56. Kavanaugh-McHugh AL, Ruff AL, Perlman E, Hut- lone as adjuvant in treatment of tuberculous con- 35. Nathan PE, Arsura EL, Zappi M. Pericarditis with lon N, Modlin J, Rowe S. Selenium deficiency and strictive pericarditis in Transkei. Lancet. 1987; tamponade due to cytomegalovirus in the ac- cardiomyopathy in acquired immunodeficiency 2:1418-1422. quired immunodeficiency syndrome. Chest. syndrome. JPEN J Parenter Enteral Nutr. 1991; 12. Anderson DW, Virmani R. Emerging patterns of 1991;99:765-766. 15:347-349. heart disease in human immunodeficiency vi- 36. Freedberg RS, Gindea AJ, Dieterich DT, Greene 57. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. rus infection. Hum Pathol. 1990;21:253-259. JB. Herpes simplex type 2 pericarditis and bi- Incidence of dilated cardiomyopathy and detec-

ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM 607

Downloaded From: https://jamanetwork.com/ on 10/02/2021 tion of HIV in myocardial cells of HIV-positive pa- sible viral etiology for some forms of hyperten- in children with AIDS-related complex. Am J Oph- tients. N Engl J Med. 1998;339:1093-1099. sive pulmonary arteriopathy. Am Rev Respir Dis. thalmol. 1985;100:614-615. 58. Currie PF, Sutherland GR, Jacob AJ, Bell JE, 1992;145:1196-1200. 95. Henry K, Melroe H, Huebsch J, et al. Severe pre- Brettle RP, Boon NA. A review of endocarditis 76. Ehrenreich H, Rieckmann P, Sinowatz F, et al. mature coronary artery disease with protease in- in acquired immunodeficiency syndrome and hu- Potent stimulation of monocytic endothelin-1 pro- hibitors [letter]. Lancet. 1998;351:1328. man immunodeficiency virus infection. Eur Heart duction by HIV-1 glycoprotein 120. J Immunol. 96. Behrens G, Schmidt H, Meyer D, Stoll M, Schmidt J. 1995;16(suppl B):15-18. 1993;150:4601-4609. RE. Vascular complications associated with use 59. Cammarosano C, Lewis W. Cardiac lesion in ac- 77. Humbert M, Monti G, Fartoukh M, et al. Platelet- of HIV protease inhibitors [letter]. Lancet. 1998; quired immune deficiency syndrome (AIDS). derived growth factor expression in primary pul- 351:1958. J Am Coll Cardiol. 1985;5:703-706. monary hypertension: comparison of HIV sero- 97. Arsura EL, Ismail Y, Freeman S, Karunakav AR. 60. Lopez JA, Ross RS, Fishbein MC, Seigel RJ. Non- positive and HIV seronegative patients. Eur Respir Amphotericin B–induced dilated cardiomyop- bacterial thrombotic endocarditis. Am Heart J. J. 1998;11:554-559. athy. Am J Med. 1994;97:560-562. 1987;113:773-784. 78. Morse JH, Barst RJ, Itescu S, et al. Primary pul- 98. Levy M, Domaratzki J, Koren G. Amphotericin- 61. Rosen P, Armstrong O. Nonbacterial throm- monary hypertension in HIV infection: an out- induced heart rate decrease in children. Clin Pe- botic endocarditis in patients with malignant neo- come determined by particular HLA class II al- diatr (Phila). 1995;34:358-364. plastic disease. Am J Med. 1973;54:23-29. leles. Am J Respir Crit Care Med. 1996;153: 99. Le Y, Rana KZ, Dudley MN. Amphotericin B–as- 62. Anderson DW, Virmani R. Cardiac pathology of 1299-1301. sociated hypertension. Ann Pharmacother. 1996; HIV disease. In: Joshi VV, ed. Pathology of AIDS 79. Silver MA, Macher AM, Reichert CM, et al. Car- 30:765-767. and Other Manifestations of HIV Infection. New diac involvement by Kaposi’s sarcoma in 100. Bristow MR, Mason JW, Billingham ME, Daniels York, NY: Igaku-Shoin Medical Publishers; 1992: acquired immune deficiency syndrome. Am J JR. Doxorubicin cardiomyopathy: evaluation by 165-185. Cardiol. 1984;53:983-985. phonocardiography, endomyocardial biopsy, and 63. Patel RC, Frishman WH. Cardiac involvement in 80. Chyu KY, Birnbaum Y, Naqvi T, Fishbeim MC, cardiac catheterization. Ann Intern Med. 1978; HIV infection. Med Clin North Am. 1996;80:1493- Seigal RJ. Echocardiographic detection of Ka- 88:168-175. 1512. posi’s sarcoma causing cardiac tamponade in a 101. Raine AE. Hypertension, blood viscosity and car- 64. Manoff SB, Vlahov D, Herskowitz A, et al. Hu- patient with acquired immunodeficiency syn- diovascular morbidity in renal failure: implica- man immunodeficiency virus infection and drome. Clin Cardiol. 1998;21:131-133. tions of erythropoietin therapy. Lancet. 1988;1: infective endocarditis among injecting drug us- 81. Steigman CK, Anderson DW, Maher AM, Sen- 97-100. ers. Epidemiology. 1996;7:566-570. nesh JD, Virmani R. Fatal cardiac tamponade in 102. Brown DL, Sather S, Cheitlin MD. Reversible car- 65. Nahass RG, Weinstein MP, Bartels J, Gocke DJ. AIDS with epicardial Kaposi’s sarcoma. Am Heart diac dysfunction associated with foscarnet Infective endocarditis in intravenous drug us- J. 1989;116:1105-1107. therapy for cytomegalovirus esophagitis in an ers: a comparison of human immunodeficiency 82. Vijay V, Aloor RK, Yalla SM, et al. Pericardial tam- AIDS patient. Am Heart J. 1993;125:1439- virus type 1–negative and –positive patients. ponade from Kaposi’s sarcoma: role of early peri- 1441. J Infect Dis. 1990;162:967-970. cardial window. Am Heart J. 1996;132:897-899. 103. Cohen AJ, Weiser B, Afzal Q, Fuhrer J. Ventricu- 66. Bestetti RB, Figueiredo JF, Da Costa JC. Salmo- 83. Peterson CD, Robinson QA, Kurnich JE. Involve- lar tachycardia in two patients with AIDS receiv- nella tricuspid endocarditis in an intravenous drug ment of the heart and pericardium in the malig- ing ganciclovir (DHPG). AIDS. 1990;4:807- abuser with human immunodeficiency virus in- nant lymphoma [letter]. Am J Med Sci. 1976; 809. fection. Int J Cardiol. 1991;30:361-362. 272:161. 104. Sonnenblick M, Rosin A. Cardiotoxicity of inter- 67. Henochowicz S, Mustafa M, Lawrinson WE, 84. Roberts WC. Primary and secondary neo- feron: a review of 44 cases. Chest. 1991;99:557- Pistole M, Lindsay J Jr. Cardiac aspergillosis in plasms of the heart. Am J Cardiol. 1997;80:671- 561. acquired immune deficiency syndrome. Am J 682. 105. Girgis I, Gualberti J, Langan L, et al. A prospec- Cardiol. 1985;55:1239-1240. 85. Holladay AO, Siegel RJ, Schwartz DA. Cardiac tive study of the effect of I.V. pentamidine therapy 68. Cox JN, di Dio F, Pizzolato GP, Lerch R, Pochon malignant lymphoma in acquired immune defi- on ventricular arrhythmias and QTc prolonga- N. Aspergillus endocarditis and myocarditis in ciency syndrome. Cancer. 1992;70:2203-2207. tion in HIV-infected patients. Chest. 1997;112: a patient with the acquired immunodeficiency 86. Goldfarb A, King CL, Rosenzweig BP, et al. Car- 646-653. syndrome (AIDS): a review of the literature. Vir- diac lymphoma in the acquired immunodefi- chows Arch. 1990;417:255-259. ciency syndrome. Am Heart J. 1989;118:1340- 106. Stein KM, Haronian H, Mensah GA, Acosta A, Ja- 69. Raffanti SP, Fyfe B, Carreiro S, Sharp SE, Hyma 1344. cobs J, Kligfield P. Ventricular tachycardia and BA, Ratzan KR. Native valve endocarditis due to 87. Constantino A, West TE, Gupta M, Loghmanee torsades de pointes complicating pentamidine Pseudallescheria boydii in a patient with AIDS: F. Primary cardiac lymphoma in a patient with therapy of Pneumocystis carinii pneumonia in case report and review. Rev Infect Dis. 1990;12: acquired immune deficiency syndrome. Can- the acquired immunodeficiency syndrome. Am 993-996. cer. 1987;60:2801-2805. J Cardiol. 1990;66:888-889. 70. Rivera Del Rio JR, Flores R, Melendez J, Gomez 88. Aboulafia DM, Bush R, Picozzi VJ. Cardiac tam- 107. von Seidlein L, Jaffar S, Greenwood B. Prolon- MA, Vila S, Hunter R. Profile of HIV patients with ponade due to primary pericardial lymphoma in gation of QTc interval in African children treated and without bacterial endocarditis. Cell Mol Biol a patient with AIDS. Chest. 1994;106:1295- for falciparum malaria. Am J Trop Med Hyg. 1997; (Noisy-le-grand). 1997;43:1153-1160. 1299. 56:494-497. 71. Kim KK, Factor SM. Membranoproliferative glo- 89. Horowitz MD, Cox MM, Neibart RM, Blaker AM, 108. Lopez JA, Harold JG, Rosenthal MC, Oseran DS, merulonephritis and plexogenic pulmonary ar- Interian A Jr. Resection of right atrial lym- Schapira JN, Peter T. QT prolongation and tor- teriopathy in a homosexual man with acquired phoma in a patient with AIDS. Int J Cardiol. 1992; sades de pointes after administration of trimeth- immunodeficiency syndrome. Hum Pathol. 1987; 34:139-142. oprim-sulfamethoxazole. Am J Cardiol. 1987; 18:1293-1296. 90. Duong M, Dubois C, Buisson M, et al. Non- 59:376-377. 72. Mesa RA, Edell ES, Dunn WF, Edwards WD. Hu- Hodgkin’s lymphoma of the heart in patients in- 109. Domanski MJ, Sloas MM, Follmann DA, et al. Ef- man immunodeficiency virus infection and pul- fected with human immunodeficiency virus. Clin fect of zidovudine and didanosine treatment on monary hypertension. Mayo Clin Proc. 1998;73: Cardiol. 1997;20:497-502. heart function in children infected with human 37-44. 91. Paton P, Tabib A, Loire R, Tete R. Coronary ar- immunodeficiency virus. J Pediatr. 1995;127: 73. Aarons EJ, Nye FJ. Primary pulmonary hyper- tery lesions and human immunodeficiency vi- 137-146. tension and HIV infection [letter]. AIDS. 1991; rus infection. Res Virol. 1993;144:225-231. 110. Herskowitz A, Willoughby SB, Baughman KL, 5:1276-1277. 92. Tabib A, Greenland T, Mercier I, Loire R, Mornex Schlman SP, Bartlett JD. Cardiomyopathy as- 74. Petitpretz P, Brenot F, Azarian R, et al. Pulmo- JF. Coronary lesions in young HIV-positive sub- sociated with anti-retroviral therapy in patients nary hypertension in patients with human im- jects at necropsy [letter]. Lancet. 1992;340: with human immunodeficiency virus infection: munodeficiency virus infection: comparison with 730. a report of six cases. Ann Intern Med. 1992;116: primary pulmonary hypertension. Circulation. 93. Meltzer MS, Skillman DR, Hoover DL, et al. Mac- 311-313. 1994;89:2722-2727. rophages and the human immunodeficiency vi- 111. Lewis W, Simpson JF, Meyer RR. Cardiac mito- 75. Mette SA, Palevsky HI, Pietra GG, et al. Primary rus. Immunol Today. 1990;11:217-223. chondrial DNA polymerase-gamma is inhibited pulmonary hypertension in association with hu- 94. Kestelyn P, Lepage P, Van de Perre P, et al. Peri- competitively and noncompetitively by phosphory- man immunodeficiency virus infection: a pos- vasculitis of retinal vessels as an important sign lated zidovudine. Circ Res. 1994;74:344-348.

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