Cardiac involvement in aids

Charles K. Francis, M.D., is Professor of Clinical Medicine at the College of Physicians and Surgeons of Columbia University and Chairman of the Department of Medicine at the Harlem Hospital Center in New York City. He graduated from Dartmouth College and received his medical degree from Jeflerson Medical College in Philadelphia. Followmg internship at Philadelphia General Hospital, Dr. Francis served for three years as a General Medical OfJicer in the U.S. Air Force. He received his training in internal medicine and cardiology at the Boston City Hospital and the Massachusetts General Hospital and has held posts as clinical instructor and clinical fellow in medicine at the Tufts University School of Medicine, clinical and research fellow in cardiology and senior medical resident at the Massachusetts General Hospital and the Harvard Medical School. Prior to his present position in New York City, he was Associate Professor of Medicine at the Yale University School of Medicine and Director of the Cardiac Catheterization Laboratory at the Yale-New Haven Hospital. Dr. Francis is a Fellow of the American College of Cardiology, a member of the Institute of Medicine of the National Academy of Sciences, the national Board of Directors of the American Heart Association, the national Board of Directors of the Association of Black Cardiologists and numerous scienti$c and professional organizations. In addition to his interest in cardiovascular disease associated with HIV infection and AIDS, he has contributed to the literature in the areas of hypertension and the heart, thrombolysis in myocardial infarction, valvular heart disease, and health care in minorities. Cum

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CARDIAC

INVOLVEMENT

IN AIDS

The recognition of the syndrome now known as acquired immunodeficiency syndrome (AIDS) began with reports of previously rare infections with the opportunistic pathogen, Pneumocystis carinii, and increased incidence of Kaposi’s sarcoma in previously healthy homosexual men. Initial reports described P. carinii pneumonia1 and Kaposi’s sarcoma’ in male homosexuals, but as new cases accumulated in the literature, it became evident that AIDS affected intravenous drug abusers (IVDAS),~ hemophiliacs,4 other recipients of blood products,5 some groups of immigrants from countries where heterosexual transmission was predominant,6 the sexual partners of the previously mentioned risk group~,~ and children of women with AIDS.’ Since these early reports, understanding of the epidemiology, etiology, pathogenesis, clinical manifestations, and management of the syndrome has increased dramatically. DEFINITION

OF AIDS

A diverse array of epidemiologic, immunologic, and clinical features of AIDS have now been recognized. The Centers for Disease Control (CDC) developed a surveillance case definition for the syndrome, which was revised in 1985’ and 1987” to assist in reporting and tracking the syndrome. The definition requires documentation of the occurrence of diseases that are pathogenetically linked to immune suppression in persons with no known conditions that would produce such a defect. Thus, in persons without prior conditions associated with immunocompromise, AIDS may be diagnosed without confirmation of human immunodeficiency virus (HIV) infection if a definitive diagnosis of any of a variety of opportunistic infections, Kaposi’s sarcoma, or primary lymphoma of the central nervous system (in patients <60 years old) is present. If HIV infection is confirmed, AIDS may be diagnosed with identification of opportunistic infection resulting from disseminated histoplasmosis, coccidioidomycosis, or mycobacteriosis, isosporiasis (>l month’s duration), extrapulmonary tuberculosis, or recurrent SaZmoneZZa septicemia. The occurrence at any age of Kaposi’s sarcoma, primary central nervous Curr

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system lymphoma, or non-Hodgkin’s lymphoma also satisfies the condition. In addition, with confirmed HIV infection, the diagnosis of AIDS can be made with the presumptive diagnosis of specified opportunistic infections, malignancies, and HIV-related conditions.

EPIDEMIOLOGY The occurrence of AIDS in IVDAs, as well as in homosexual men, suggested that the disease may be transmitted through a bloodborne infectious agent. Transmission of the disease to hemophiliacs and other blood product recipients confirmed the notion of spread through blood or blood products. The risk of infection with HIV-infected blood is now negligible because of careful antibody screening of blood products and potential donorsl’ Although health care workers often are exposed to HIV-contaminated blood through inadvertent needle sticks and small breaks in the skin, the risk of contracting AIDS is very low, although cases of AIDS attributed to needle stick in health care workers have been reported.” The use of “universal precautions” by all health care workers is generally recommended.13 Risk of HIV transmission through sexual contact has also been modified by adoption of safer sexual practices among some risk groups. Evidence of the effect of alterations in behaviors associated with increased HIV risk may be seen in the incidence of AIDS in San Francisco.14 In New York City, the number of newly reported cases of AIDS in IVDAs has now exceeded the number of new cases among male homosexuals.15 Although this change in the rate of new cases among IVDAs and male homosexuals has not been noted universally, it is an indication of the changing epidemiology of AIDS. As the second most common risk group for AIDS, IVDAs have been studied extensively to determine the factors associated with their increased HIV infection. The practice of sharing unsterile injection equipment has been identified as one of the major contributors to the spread of HIV infection among IVDA.*’ Included in the drug culture are gathering places for group drug use called “shooting galleries,” where needle sharing has evolved as an answer to limited availability of injection paraphernalia. Perhaps partially related to this practice, it is estimated that 40% to 50% of IVDAs in New York, New Jersey, and Puerto Rico are infected with the H1V.l’ Intravenous drug abusers comprise a major reservoir for heterosexual and maternal transmission of HIV infection, with a large proportion of the cases of resulting from transmission from HIV-infected AIDS in children” mothers who are either IVDAs or the sexual partners of IVDAs.” The risk of heterosexual and maternal transmission of HIV infection is also increased among minorities.” The dramatic increase in the use of cocaine by IVDAs has also affected the epidemiology of HIV infec576

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tion.‘l Several reports have now documented an increased risk of HIV infection in IVDAs who also use cocaine as well as heroin. Because cocaine addicts are frequent users of the drug, often in “shooting galleries,” the number of opportunities for exposure to HIV-contaminated injection equipment is probably increased. The risk for endocarditis may also be increased in cocaine usersz2 The risk of heterosexual transmission of HIV infection may be increased in those addicted to “crack cocaine” because of the practice of trading sexual favors for drugs in the drug subculture. The prevalence of AIDS and HIV infection is also increased in blacks and Hispanics, perhaps because these ethnic groups are often the targets of drug dealers.‘” ETIOLOGY

AND PATHOGENESIS

Perhaps the most important factor in understanding AIDS was the detection of antibodies to the AIDS virus and precise identification of the etiologic agent responsible for the disease. In 198324 and 1984,25 the retrovirus that eventually was proved to cause AIDS was isolated from patients with AIDS. The virus was initially termed HTLV-III, and then, by international consensus, the name was changed to (HIV). The virus has an affinity for the helper T lymphocyte CD4 surface antigen and invades these cells, eventually causing severe depletion as the infection progresses. The clinical stages of HIV infection reflect the extent and severity of the consequent defect in cellular immunity. DIAGNOSIS

OF HIV INFECTION

Human immunodeficiency virus infection may be detected reliably by immunologic techniques, including detection of specific antibodies against the virus, detection of the viral antigen, and by culture of the virus from infected tissue. The enzyme-linked immunosorbent assay (ELISA) is commonly used and is extremely accurate, with a specificity of 95% to 99% and sensitivity of >99%. Positive ELISA tests should be confirmed with more sensitive tests, such as an immunofluorescence assay or Western blot test. Both DNA probes and in situ hybridization techniques may also be used for more precise cytoimmunologic identification of HIV infection.‘” CLASSIFICATION

OF HIV INFECTION

With the development of serologic techniques to detect HIV infection, screening of populations at risk for HIV infection has documented a clinical continuum from primary HIV infection to AIDS. Curr

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The recognition of a clinical syndrome characterized by persistent generalized lymphadenopathy was one of the important early clinical observations that led to appreciation of AIDS as a clinical entithat the spectrum of HIV infection exw”” 2g It is now recognized tends from an asymptomatic state, through series of progressive clinical stages, culminating in the syndrome now known as AIDS. The term AIDS-related complex (ARC) was proposed as a diagnostic category encompassing persons who do not yet satisfy strict criteria for AIDS, but nevertheless have clinical manifestations of immunocompromise, ranging from dermatologic findings, thrush, and hairy leukoplakia to neurologic and hematologic abnormalities?g Several staging or classification systems of HIV infection have been developed.30 The CDC has developed a four-stage system based on clinical manifestations: Group I, acute infection; Group II, asymptomatic seropositive; Group III, persistent generalized adenopathy, and Group IV, symptomatic. In the system developed by Redfield and colleagues at the Walter Reed Army Hospital, patients are categorized from Walter Reed stage 0 WRO) to WR6, depending on the presence or absence of six clinical and immunologic factors: HIV antibody or antigen; lymphadenopathy, CD4+ lymphocyte level (5400/mm3); skin tests; thrush; and opportunistic infection. The AIDS diagnosis is made in stage WR6 when HIV antibody/antigen is positive, lymphadenopathy is or is not present, CD4+ lymphocytes are <400/mm3, anergy is complete, thrush is present, and opportunistic infections are definitively diagnosed.31 These systems have not been used in patients with cardiac abnormalities associated with HIV infection or AIDS, however. NATURAL

HISTORY

OF AIDS

In many patients with HIV infection, the initial clinical manifestations include an acute viral illness similar to influenza that is characterized by fever, intermittent diaphoresis, muscle and joint aches, diarrhea, sore throat, and other nonspecific symptoms.32 Some patients may experience a maculopapular rash or desquamation of the palms or soles. Lymphadenopathy may also be present. Signs and symptoms of cardiac disease associated with primary HIV infection have not been reported. This initial stage may progress to a syndrome of persistent generalized lymphadenopathy. Enlarged extrainguinal lymph nodes are the characteristic feature of this stage of HIV disease. Mycobacterial infection, lymphoma, and Kaposi’s sarcoma, as well as other causes for lymphadenopathy, should be excluded. Histologically, the lymph nodes usually show follicular hyperplasia. Patients may be classified as having ARC after the initial acute viral illness but before the development of opportunistic infec578

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tions. During this stage the manifestations of AIDS develop to a variable degree. Fever, fatigue, diarrhea, night sweats, and weight loss may accompany the lymphadenopathy. Hematologic abnormalities, such as leukopenia or thrombocytopenia, may also be noted. Skin tests for delayed hypersensitivity may also become abnormal during this stage. Laboratory abnormalities, without clinical evidence of immune compromise, are not sufficient to label a patient as having ARC. Development of esophageal candidiasis or Pneumocystis often serves as a marker for conversion from ARC to AIDS. The development of AIDS-associated cardiac disease may occur at various stages of AIDS, including ARC, but significant cardiac abnormalities are most common in the terminal phases of AIDS. b D. MCCALL: In this introductotv section Dr. Francis provides the reader with an excellent ovetview of the clinical features of, and diagnostic criteria for, AIDS. He traces the natural history of the disease from HIV infection through ARC and frank clinical AIDS. For the cardiologist, who perhaps sees HIV related diseases less frequently than other medical specialists, this synopsis is particularly helpful in drawing attention to the salient clinical features of AIDS. It also serves to alert the cardiologist, when faced with one of the protean cardiac manifestations of the disease, to consider this possibility by paying careful attention to these important clinical features.

PATHOLOGIC

STUDIES

OF CARDIAC

INVOLVEMENT

IN AIDS

The appreciation of the protean manifestations of AIDS and the widespread visceral involvement that characterizes HIV infection emanates from pathologic and clinical evidence that chronicles early experience with the syndrome. Initial descriptions of pathologic findings in AIDS focused primarily on abnormalities associated with opportunistic infection or neoplasm. It is unclear whether fewer cardiac abnormalities were present or that cardiac abnormalities related to AIDS were not generally appreciated, but cardiac pathology was not prominently described in early studies of AIDS. In early mports, it appeared that HIV disease manifested typically by opportunistic infections or neoplasm, most commonly leading to signs and symptoms of pulmonary, central nervous system, or gastrointestinal disease. Reichert and co-workers,33 in one of the earliest pathologic studies of AIDS, reviewed autopsies of 10 patients with AIDS. The common

opportunistic

infections

in AIDS

were

described

in

this

study. Two groups of pathogens were described: those without specific effective therapy, such as Mycobacterium avium-intracellulare and cytomegalovirus and those that are very difficult to treat, such as P. carinii, Candida albicans, Cryptococcus neoformans, and Togoplasma gondii. Even though therapy for P. carinii was relatively effective in this study, 6 of 9 patients who responded to treatment of P. Curr

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carinii pneumonia

succumbed instead to cytomegalovirus infection with respiratory failure. Pathologically, cytomegalovirus was the most common infectious agent and cytomegalovirus pneumonia was the most common cause of death. Neoplasms, particularly Kaposi’s sarcoma and non-Hodgkin’s lymphoma were common, but often clinically silent. In two patients, Kaposi’s sarcoma was a factor in the cause of death. Cardiac involvement was described in one patient in whom Kaposi’s sarcoma was noted adjacent to the right coronary artery in the absence of coronary ischemia. In another, bioassay for T. gondii was positive but not confirmed histologically postmortem. Welch and associates34 reviewed autopsies in 36 patients (most were homosexual) with AIDS. Cytomegalovirus was the most common pathogen detected postmortem but was diagnosed antemortem in only 9 (25%) patients. The lung was most commonly involved with cytomegalovirus infection. Pneumocystis carinii was the next most common infection of the lung, often appearing concurrently with cytomegalovirus. Kaposi’s sarcoma was diagnosed in 18 of 36 (50%) patients. While the heart was normal in 25 of 36 cases (69% 1, 6 had myocardial focal interstitial cellular infiltrates and 2 had acute focal necrosis. Kaposi’s sarcoma involving the epicardium and epicardial adipose tissue was present in 3 cases. The myocardium was extensively involved by Kaposi’s sarcoma in 1 case where no clinical cardiac manifestations were noted antemortem. An intramyocardial cytomegalovirus inclusion body was noted in one patient, although this finding had rarely been encountered in the heart previously. No other opportunistic infection of the heart was noted. Cytomegalovirus was widespread, involving the lungs, gastrointestinal tract, liver, central nervous system, and lymphoid system, with marked involvement of the adrenals. In another necropsy study comparing the antemortem and postmortem diagnoses in 12 homosexual males with AIDS, Hui and coworkers3’ noted the frequent occurrence of unrecognized episodes of disease. In 10 of 12 (83%) patients, disease noted at autopsy had not been detected clinically. Of 15 unrecognized episodes of disease, cytomegalovirus of the lung was the one most commonly missed during autopsy. Cardiac involvement at autopsy was not commented upon, suggesting that the clinical and pathologic cardiac manifestations were not prominent. Disseminated cytomegalovirus and Kaposi’s sarcoma were also the most commonly diagnosed infections at autopsy in 13 homosexuals reported by Guarda. Pulmonary involvement, often in association with P. carinii pneumonia, was also common. Pathologic evidence of cytomegalovirus involvement of the heart was observed in one patient. Nonbacterial thrombotic endocarditis, or marantic endocarditis, in which large friable sterile vegetations form on the cardiac valves, was noted in several patients. These lesions were associated with disseminated intravas580

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cular coagulation and systemic embolization to the brain, lungs, and spleen. Niedt and co-workers37 reviewed autopsy data in 56 patients, 47 male homosexuals, 4 IVDAs, 1 Haitian, and 2 homosexual drug abusers. Cytomegalovirus was the most common histologic diagnosis, occurring in 43 (77%) cases. The myocardium demonstrated cytomegalovirus inclusions in four cases, in whom congestive heart failure, arrhythmia, or electrocardiographic (ECG) changes were also noted. Pneumocystis carinii pneumonia was the most common infection noted. Fourteen of 33 cases (42%) of P. carinii pneumonia treated antemortem persisted despite appropriate therapy. In this study, pyogenie bacterial and mycobacterial infections were more commonly underdiagnosed, in contrast to earlier studies where occult cytomegalovirus was common. Bacterial infections were present in 52% of patients, but infective endocarditis was not described. Disseminated Kaposi’s sarcoma was found in 29 (52%) cases and lymphoma in 5 (9%) patients. The heart was not involved with any neoplastic process. Cough and dyspnea were the presenting complaints in 14 (56%) patients and were associated with P. carinii pneumonia in 12, cytomegalovirus in 1 and Kaposi’s sarcoma in 1. Respiratory failure was the immediate cause of death in 30 (53%) patients and was because of cytomegalovirus, P. carinii pneumonia, or both in all cases. Congestive heart failure, arrhythmias, and ECG changes were noted in four cases with cytomegalovirus but were not considered as direct causes of death. The specific etiology of these symptoms was not addressed. The relationship of pathologic findings of the heart to clinical manifestations of cardiac disease has been the subject of several studies. In a retrospective review of 41 cases of AIDS, Cammarosano and Lewis38 described 10 cases with cardiovascular involvement at autopsy: 8 homosexuals, 1 bisexual, and 1 Haitian heterosexual. Three patients had cardiovascular symptoms or signs. No IVDAs were studied. Several different cardiac lesions were noted, including 4 cases of Kaposi’s sarcoma metastatic to either the epicardium or myocardium, nonbacterial thrombotic endocarditis with systemic embolism in 3 cases, fibrinous pericarditis in two cases, and myocardial infection by C. neojbrmans in 1 case. Even though 13 patients had disseminated M. avium-intracellulare with sepsis, intramyocardial acid-fast organisms were not observed in any heart. In contrast with other earlier pathologic studies, evidence of cytomegalovirus, at either extracardiac or cardiac sites, is not described. Roldan and coinvestigators3’ reviewed cardiac pathologic findings in 54 AIDS patients. Pathologic lesions were observed in 30 patients, including 19 Haitian men and 7 Haitian women, 19 homosexual men, 4 male IVDAs, 1 female IVDA, and 1 hemophiliac (some patients had two risk factors). Pathologic changes were most frequent in the myocarCum

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581

dium, occurring in 10 Haitian men, 4 Haitian women, 9 homosexual men, and 2 IVDAs. Myocarditis was the most common histologic finding, occurring in 17 patients. Per&u&al involvement was evident in 5 cases. Four patients had endocardial disease. Even though histopathologic lesions of the heart were common, the only cardiovascular death occurred in a patient with overwhelming To,xoplasma myocarditis. Pulmonary infection or central nervous system disease was the cause of death in all other patients with cardiac lesions. b D. MCCALL: From this review it is obvious that cardiac involvement in AIDS is relatively common, from a pathologic standpoint. It is seldom clinically important because the AIDS sufferer frequently dies of overwhelming infection before these cardiac manifestations assume a place of clinical relevance. With the advent of newer therapeutic modalities for treating Infections such as pneumocystis carinii it is likely that patients with AIDS will survive longer and that cardiac involvement will become a more prominent part of the clinical picture.

The relationship of pathologic findings to clinical characteristics and cause of death has been the subject of several reports. Anderson and colleagues,40 in a study of 71 consecutive necropsy patients with AIDS, 53 homosexuals, 5 IVDAs, and 13 with unspecified risk, found myocarditis in 37 cases (52% 1. In 30 cases, no evidence of viral, protozoan, bacterial, fungal, or mycobacterial etiology was found. Biventricular dilatation was present in 7 cases, all had myocarditis, and 3 died of sepsis. Congestive heart failure was the immediate cause of death in 4 of these patients and in another without myocarditis. One patient with myocarditis died from ventricular arrhythmia and another had sudden unexpected death. No relationship was established between biventricular dilatation and the duration of disease or opportunistic infection. In one of the few studies that included a significant proportion of IVDAs, Baroldi and associates41 correlated morphologic and clinical findings in 26 AIDS cases: 4 homosexuals (1 IVDA), 20 IVDAs, and 2 of unspecified risk. Opportunistic infection was present in all cases. Lymphocytic infiltrates were present in 20 patients, 9 with myocyte necrosis (myocarditis by Dallas criteria). No patient had clinical evidence or history of heart disease, even though cardiac abnormalities were noted in 6 of 8 patients

who

were

studied

echocardiographically.

Globular

shape

and

diffuse hypokinesis were demonstrated in 5 patients and left ventricular dilatation in 3. Despite the well-known association of infective endocarditis with IVDA, no valvular vegetations are described and the cardiac valves were pathologically normal. Moskowitz and associates4’ studied the immediate causes of death in 54 patients examined post mortem in Miami. The study group contained 25 Haitians, 19 men and 6 women, 5 IVDAs, 2 male hemophiliacs, and 3 with no known risk. The only death attributed to cardiac disease occurred in Haitian men with cardiac toxoplasmosis. Deaths in Haitians were 582

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most often related to opportunistic infections, 72% in Haitians vs. 21% in homosexuals, while homosexuals died most often of P. carinii pneumonia or Kaposi’s sarcoma, 63% of homosexuals vs. 20% of Haitians. Even though pathologic studies suggest that histopathologic evidence of cardiac involvement may occur in up to 50% of patients in necropsy studies, clinical manifestations of cardiac disease have been observed in a relatively small proportion of patients with cardiac abnormalities at postmortem. The clinical expression of the pathologic lesions of the heart in AIDS encompass the entire range of cardiac involvement, from disease of the pericardium, epicardium, and myocardium to the endocardium. Fink and co-workers43 retrospectively reviewed clinical and echocardiographic data in 15 patients with AIDS. Of 13 patients in whom M-mode or two-dimensional echocardiography was performed, 10 demonstrated one or more abnormalities, even though no patient had evidence of cardiac disease on clinical examination. Echocardiographic abnormalities included pericardial effusion, left ventricular hypokinesis, and mitral valve prolapse. This study was one of the first to use clinical and echocardiographic data rather than pathologic findings to demonstrate the high prevalence and clinically “unobtrusive” nature of cardiac involvement in hospitalized patients with AIDS. Cohen and associates‘@’ reported clinical echocardiographic and morphologic findings in three patients with congestive cardiomyopathy associated with AIDS. In each case multiple organ failure and cardiac decompensation occurred after weeks of recurrent AIDS-related complications. Four-chamber enlargement, diffuse left ventricular hypokinesis, and reduced ejection fraction was demonstrated echocardiographically in two cases. Pericardial effusion was present in two cases and pericardial fluid cultures were positive for ~4. avium-intracelldare in one case. Two patients were examined postmortem. Focal lymphocytic myocardial infiltrates, in the absence of bacterial, mycobacterial, protozoal, or fungal infection, were observed at histopathologic examination. Because of these findings, a myocarditis of viral etiology was postulated as an explanation of myocardial damage and the clinical findings consistent with dilated cardiomyopathy. Corboy and colleagues45 have also reported congestive cardiomyopathy in 3 homosexual males with AIDS. Even though the clinical course in these patients included episodes of Pneumocystis carinii pneumonia and cytomegalovirus infection, no focal lymphocytic infiltrates were noted at autopsy. Webb and co-workers46 reported 5 homosexual males with cardiac dysfunction and pericardial effusion confirmed by echocardiography and radionuclide ventriculogram. Left ventricular dilatation, diffuse hypokinesis, and reduced left ventricular ejection fraction were demonstrated with radionuclide venCurr

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triculography in all patients. A clinical history of multiple opportunistic infections was common to all 5 patients. Using echocardiography and radionuclide ventriculogram, Raffanti and co-workers47 have also assessed cardiac function in 12 patients with AIDS. Eight study patients were IVDAs, 3 were homosexual males, and 1 was the spouse of an IVDA. Radionuclide ventriculography revealed abnormal left ventricular ejection fraction in 2 patients. Decreased ejection fraction, however, did not correlate with the stage of HIV disease, risk group, clinical course, or survival, In a prospective echocardiographic study of 102 patients with AIDS, Corallo and co-investigatorsM studied 72 (70%) IVDAs, 27 (26%) homosexuals and 3 (3%) hemophiliacs. Seventy-four (72%) patients had opportunistic infection and 6 (5.8%) had Kaposi’s sarcoma. All study patients were free of heart failure or cardiac tamponade. Clinical clues to cardiac involvement were persistent tachycardia in 55 (54%) and a third heart sound in 48 (47%) patients. Abnormal echocardiographic indices in those patients with tachycardia included increased left ventricular diastolic dimension, increased left ventricular wall thickness, and decreased left ventricular fractional shortening. Echocardiography revealed a globular, dilated, ditfusely hypocontractile left ventricle in 42 (41%) patients and pericardial effusion in 39 (38%) patients. Cardiac chamber dilation and left ventricular wall thinning were confirmed at autopsy in all patients. Valvular vegetations were noted in 4 patients who were IVDAs. A mass on the cardiac surface was noted in two patients and an intracavitary mass in another, which at autopsy proved to be the result of Kaposi’s sarcoma. Interstitial myocardial fibrosis and lymphocytic infiltrates were observed in all patients with left ventricular dilatation.

CARDIAC INVOLVEMENT OF HIV INFECTION

IN THE

EARLY

STAGES

As more has been learned regarding the pathogenesis and natural history of HIV infection, it has become evident that AIDS is the final stage of a continuum of clinical features reflective of progressive compromise of cell-mediated immunity related to HIV infection. While the diverse clinical features of neurologic, pulmonary, gastroenterologic, and hematologic involvement in AIDS have been well-documented, less is known of the evolution of cardiac involvement. Although ARC and the earlier stages of HIV infection are characterized by typical clinical manifestations, the relationship of clinical cardiac symptoms and signs, congestive heart failure, and abnormalities on noninvasive testing to the stages of HIV infection remains incompletely elucidated. The prevalence and severity of cardiac abnormalities related to AIDS may vary according to the stage of HIV infection. 584

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The majority of reports of cardiac involvement in HIV disease has described findings in patients meeting the CDC criteria for AIDS, although the features of cardiac disease in the earlier stages of HIV infection have been considered in several studies. In a study of patients with AIDS from Miami and France, Monsuez and colleagues4’ compared the clinical characteristics of patients with cardiac symptoms to those of patients without clinical evidence of cardiac disease. In the group with cardiac symptoms, there was a higher proportion of patients with AIDS than with ARC. The symptomatic group also contained more women and more patients with prior opportunistic infections. Among patients without clinical evidence of heart disease, the number of patients with ARC and AIDS was comparable. Although left ventricular dyssynergy and dilatation were comparable in patients-with cardiac symptoms and in those without, mortality was significantly increased in patients with clinical cardiac manifestations. Other studies have found that patients with ARC had similar proportions of echocardiographic abnormalities compared to patients with AIDS. Kinney and colleagues” compared the echocardiographic findings and demographic features of 15 patients with AIDS and 24 patients with ARC (93% IVDAs and 9% homosexuals) to determine the relationship to clinical features of heart disease to the stage of HIV infection. The prevalence of echocardiographic abnormalities was similar in ARC and AIDS patients, although pericardial effusions were more common in AIDS patients. All effusions were small to moderate in size. Echocardiographic left ventricular dysfunction was found only in 4 patients with AIDS. Two patients developed left ventricular hypokinesis during the study period, one during Staphylococcus aureus sepsis and one following apparent viral pericarditis. Kinny and colleagues concluded that the echocardiographic findings are of limited prognostic value and advise against screening of AIDS patients without symptoms. The prevalence of clinical and laboratory cardiac abnormalities has been compared by Levy and associates51 in three groups of HIV seropositive patients: pre-AIDS; AIDS with active opportunistic infection; and AIDS without opportunistic infection. Cardiac abnormalities were more common in patients with AIDS than in pre-AIDS, but unrelated to opportunistic infection. There was no significant difference in the prevalence of echocardiographic abnormalities, left ventricular dilatation, or hypokinesis between groups. The magnitude of left ventricular dilatation and hypokinesis was strikingly greater in AIDS patients with opportunistic infections, however. Patients with CD4 counts 1100/mm3 also had more echocardiographic abnormalities. The prevalence of echocardiographic abnormalities may also differ between ambulatory and hospitalized HIV patients. Himelman and co-worken? found echocardiographic abnormalities to be rare in ambulatory patients with AIDS but demonstrated findings consisCur-r

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585

tent with dilated cardiomyopathy only in hospitalized patients. The low proportion of ARC patients with cardiac abnormalities on echocardiography and, conversely, the increased prevalence of echocardiographic abnormalities or cardiomyopathy in hospitalized patients, those with low CD4 lymphocyte counts, those with active opportunistic infections, and those with overt AIDS suggests that involvement of the heart in AIDS is a late phenomenon, related to the duration and severity of immune compromise and the sequelae of opportunistic infection. However, the demonstration of clinical and laboratory clinical abnormalities in some patients in the early stages of HIV infection suggests a multifactorial etiology of cardiac dysfunction in AIDS. (Table 1) SPECIFIC ETIOLOGIC DISEASE IN AIDS PROTOZOAN

AGENTS AND CARDIAC

INFECTIONS

Pneumocystis carinii.-Among patients with HIV infection, P. carinii pneumonia is the initial opportunistic infection in up to 60% of patients. Eighty percent of patients will experience infection with P. carinii at some point during their illness. The organism is widely disseminated, with organisms commonly residing in the alveoli of asymptomatic individuals. In AIDS, P. carinii pneumonia is often the initial clinical disease in AIDS, usually presenting as fever, nonproductive cough, shortness of breath, and dyspnea on exertion. Onset of the disease may be subtle and progression slow, but it may also accelerate quickly, producing severe pulmonary involvement and acute respiratory decompensation. Chest radiography may show a diffuse reticular pattern, typically sparing the peripheral lung fields. Pleural effusion is unusual. The degree of hypoxemia may be out of proportion to the amount of involvement indicated on the radiograph. Diagnosis of P. carinii pneumonia may be made by identification of the organism in sputum, bronchial washings obtained at bronchoscopy, or lung biopsy. Treatment with a combination of trimethoprim and sulfamethoxazole (cotrimoxazolel or pentamidine may be successful, but relapses are common. Aerosolized pentamidine or. cotrimoxazole may be used prophylactically in asymptomatic patients with HIV infection. Although the heart has not been shown to be directly involved in P. carinii infection, the development of P. carinii pneumonia is usually an indication of marked immunodeficiency. Cardiac abnormalities have been noted in the final phases of HIV disease, often after the patient has been treated for P. carinii pneumonia. Cardiac abnormalities seen during echocardiography have been found to be

586

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more common in hospitalized patients, and because P. carinii pneumonia is the most common cause of hospital admission, it is likely that many hospitalized patients have a history of active or prior P. carinii pneumonia. Pericardial &fusions have also been detected more commonly in patients with P. carinii pneumonia, although not related specifically to P. carinii.52 The pulmonary decompensation associated with P. carinii pneumonia may be a factor in the pathogenesis of cardiac abnormalities in AIDS. While biventricular dilatation has not been shown to be related to most opportunistic infections in AIDS, isolated right ventricular dilatation has been noted in association with P. carinii pneumonia and cytomegalovirus infection of the 1ung.52

ToFoplasma gondii. -To,xopZasma gondii is one of the most important protozoan infections in AIDS. Cerebral toxoplasmosis is the most common cause of focal encephalitis and intracerebral mass lesions in patients with AIDS.53 In AIDS, infection is usually the result of reactivation of prior chronic latent infection. Because of the high endemic rates of infection in Haiti, toxoplasmosis is one of the most commonly reported opportunistic infections. In patients with HIV infection, the disease occurs most often in the late stages, when the diagnosis of AIDS is established. Clinical manifestations usually involve the central nervous system, with mild mental changes or neurologic deficits, headache, lethargy, confusion, and visual abnormalities succeeded by seizures, stroke-like symptoms, and coma as the disease progresses. Definitive diagnosis using immunologic techniques is not specific, since antibodies to the organism are not uniformly detected. When possible affected tissue can be obtained, the T. gondii trophozoites invading cells and toxoplasma cysts may be detected. Computed tomography (CT) is most useful in diagnosis of central nervous system disease. Demonstration of the typical ringenhancing lesions in the brain by CT may provide a presumptive diagnosis, but is not pathognomonic, because other mass lesions may occasionally present a similar picture. Use of a double dose of contrast and delayed scanning has improved diagnostic sensitivity. Magnetic resonance imaging may also provide additional diagnostic sensitivity in patients in whom central nervous system disease is suspected in the face of negative CT results. Definitive diagnosis requires brain biopsy. Some would resort to empiric therapy in patients with strong clinical evidence for ToFoplasma infection of the central nervous system, rather than perform. brain biopsy. Pyrimethamine therapy, sustained for an undefined but significant period, may provide effective resolution of central nervous system lesions. Sulfadiazine has also proved effective. Side effects, such as neutropenia and thrombocytopenia, may be problematic. Megaloblastic anemias related to therapy require administration of folinic Curr

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587

acid during suppressive, as well as acute therapy. Extended suppressive therapy may be necessary since relapses are common.54’ 55 Although T. go&ii infection is most commonly confined to the central nervous system, clinical cardiac disease resulting from To&oplasma infection is an important clinical consideration. Guarda and associates36 observed toxoplasma cysts within the myocardium, as well as in the central nervous system, in 1 of 13 necropsies in male homosexuals with AIDS. Toxoplasmosis may be found more frequently in populations with high background rates of infection. In an autopsy study of 54 AIDS patients in Miami, including 25 Haitians, To)toplasma encephalitis was found at autopsy in 11 cases and was diagnosed antemortem in 3 subjects. Tachyzoites of T. gondii were observed within myocardial foci of lymphocytic infiltration in 6 of 17 (35%) cases of myocarditis. One patient, who had isolated cardiac involvement that was not confirmed until autopsy, died of severe cardiac decompensation secondary to To,xopZasma myocarditis. In 5 patients, myocardial involvement was associated with central nervous system disease. The difficulty in establishing a definitive etiologic diagnosis of To)copZasma infection in AIDS is exemplified by a case described by Mullins and associates.56 In this case, serologic tests for cytomegalovirus and toxoplasmosis were positive early in the course of illness, but did not rise chronically. Six months later, clinical congestive heart failure developed. A dilated, diffusely hypocontractile left ventricle and a small pericardial effusion were detected by echocardiography. Can&da albicans was also cultured from the right middle lobe bronchus. Cardiac symptoms improved with diuretics and digoxin and the fungal infection was treated with amphotericin B. Computed tomography revealed intracerebral lesions consistent with toxoplasmosis; treatment with sulfadiazine and pyrimethamine was begun but did not control the infection, and the patient expired. At postmortem, myocarditis and intramyocardial toxoplasma cysts were found. Even though the cardiac manifestations in this case may be attributed to To)toplasma because of the identification of cysts within the myocardium, the relationship of the congestive heart failure and ventricular dilation to To)toplasma cysts, cytomegalovirus, or viral myocarditis is uncertain. Tschirhart and Klatt,” in a study of 164 patients with AIDS, identified toxoplasmosis at autopsy in 14 patients (9% 1. In 4 cases in which death was associated toxoplasmosis, ToFoplasma myocarditis was confirmed in 1 case. Death was directly related to central nervous system involvement in the other three cases. A relationship between toxoplasmic infection and cardiac disease in immunocompetent patients was suggested in an early report by Leak and Meghji.58 Because of chronically increased titers of toxoplasmic antibody, higher than in the community and in a control series of patients, I8 patients with arrhythmias, atypical chest pain, pericarditis, and car588

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1990

disc failure were diagnosed as To)topZasma myocarditis. The diverse cardiac complaints were attributed to toxoplasmic infection. Nine patients received pyrimethamine and sulfadiazine. This report points out the difficulty in relating immunologic data, even in immunocompetent patients, to clinical cardiac disease, without a tissue or culture diagnosis. In AIDS, where multiple infections often occur, specific definitive diagnostic criteria have been proposed to assure accurate diagnosis. Adherence to established criteria is critical. Prompt evaluation using reliable diagnostic procedures is important so that appropriate therapy can be commenced as early as possible. In some instances, where diagnostic procedures may be of unusual risk or complexity, empirical therapy may be considered. FUNGAL INFECTIONS In the general population, fungal infections occur infrequently, but have been commonly reported in association with iatrogenic factors, such as prolonged broad spectrum antibiotic use following cardiac surgery and in association with long-term intravenous catheters. Prior to the AIDS epidemic, cardiac surgery was the most common predisposing factor, followed by hematopoietic or lymphoid neoplasms. Antibiotic or corticosteroid therapy was also associated with fungal myocarditis. Fungal infections have increased in certain groups, such as IVDAs and immunocompromised individuals, particularly with the advent of AIDS, where infection is usually endogenous. As AIDS has grown in significance, fungal infections have also assumed increased prominence, since defective immunity and intravenous drug abuse are both characteristic of the syndrome and are prerequisites of fungal infection. Although a variety of fungal infections may occur, infection with Candida species and C. neojbrmans have attracted the most clinical discussion.5s Candida aZbicans.-This infection has been recognized as one of the hallmarks of AIDS. In the immunocompetent individual Candida may normally be found on the skin, in the vagina, and in the gastrointestinal tract, and has been associated with diabetes mellitus. In AIDS, mucosal involvement of the oropharynx or esophagus is the most common site of opportunistic infection. The typical white, cottage cheese-like patches on the tongue and oral mucosa are now recognized as indicative of AIDS, even among lay populations in which the syndrome is common6’ In addition to oral and esophageal candidiasis in AIDS, the organism may also be associated with significant disease of the gastrointestinal tract, lung, and urinary tract, and often produces systemic infection. Candida endocarditis has been widely appreciated as one of the most serious complications in IVDAs. Since IVDAs comprise the second most common risk Cum

Probl

Cardiol,

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1990

589

group for AIDS, Candida infection of the heart is a particular concern in this group. While endocarditis is the most common cardiac lesion, myocarditis and pericarditis may also occur. Because Candida infection is a frequent opportunistic pathogen in AIDS, a similar high prevalence of systemic candidiasis with cardiac involvement might be expected. The prevalence of Candida endocarditis, as well as systemic candidiasis, however, is much less than oral or esophageal infection in patients with AIDS. With disseminated candidiasis, Candida myocarditis may occur in the absence of valvular involvement.61’ 62 AspergilloskInfection with the mold Aspergihs fimigatus may also occur commonly in AIDS. Even though the organism is present in most environments, including hospitals, disease in immunocompetent hosts is uncommon. Although relatively unusual in AIDS patients, aspergillosis may involve cardiac structures. Cardiac disease associated with aspergillosis in AIDS is usually the result of endocarditis, although intramyocardial abscesses and purulent pericarditis may also occur.63 In a report by Henochowicz and colleagues,64 cardiac aspergillosis was described in a 32-year-old IVDA with pulmonary aspergillosis. A large mitral valvular vegetation was detected on two-dimensional echocardiography. At autopsy A. $.Imigatus was cultured from the heart. In the pathologic study by Niedt and Schinella,37 pulmonary aspergillosis was found postmortem, but not antemortem, in 5 of 56 (9%) patients with AIDS. None of these patients had cardiac involvement. These studies suggest that cardiac disease may follow the development of pulmonary aspergillosis and spread via the bloodstream to multiple organs. The diagnosis of aspergillosis is difficult because the organism rarely can be cultured from blood. In studies prior to the AIDS epidemic, Aspergillus endocarditis was encountered commonly, although Candida infection caused endocarditis more commonly following cardiac surgery in some report~.~~ Immune compromised patients, even without an antecedent cardiac lesion, were at greater risk of aspergillosis.66 With the general increase in Candida infections, Candida endocarditis is now the most common cause of fungal endocarditis.67 Aspergillus may be an invasive infection and erode through adjacent myocardial structures, with the production of myocardial abscesses or thrombotic embolization. Systemic embolism to the cerebrovascular vessels may produce central nervous system damage. Coronary embolization with myocardial infarction may also occur.68 Cryptococcosis.-This is an infrequent but life-threatening fungal infection in AIDS patients. It is commonly found in pigeon droppings and may cause human disease from inhalation of airborne organisms6’ Although uncommon, cryptococcal infection is a major 590

Cum

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1990

cause of death in AIDS patients, exceeded in lethality only by P. carinii pneumonia, cytomegalovirus, and mycobacterial infections. Cryptococcal infection is more common in lVDAs and minorities.70 In a pathologic study, Ambrose and colleagues’l found cryptococcus to be more common in IVDAs than in those at risk for AIDS through sexual practices. In studies of AIDS patients in Miami,3s’4z no cases of crytptococcosis at autopsy were reported, suggesting regional differences in the prevalence of cryptococcal infection in AIDS. The central nervous system is most commonly affected in cryptococcal infection in AIDS patients, most commonly as meningoencephalitis. After toxoplasmosis of the central nervous system, cryptococcal infection is the second most common cause of neurologic infection, occurring in up to 80% of patients with symptomatic cryptococcal infection. Disseminated candidiasis and cryptococcosis are the most common systemic infections in AIDS.72 Cryptococcal meningitis patients may present with fever, malaise, and headache. Focal neurologic complaints are unusual, but cranial nerve involvement, hemiparesis, and seizure may occur. Although involvement of the central nervous system is most often observed pathologically, extracerebral sites of infection are common and may include the lung, bone, lymph nodes, and kidney. With disseminated infection, diagnosis may be made by detection of cryptococcal antigen in the cerebrospinal fluid. In the presence of active cryptococcal infection, 95% of patients will be positive for antigen. India ink stain of affected tissue is less reliable, with positive stains ranging from 50% to 90% with active disease. In cryptococcal meningitis, intracranial pressure may rise significantly. With papilledema or other signs of increased intracranial pressure, CT should be performed before lumbar puncture.73 Culture of the organism from blood or tissue may be difficult. In reviews of the clinical manifestations and the management of cryptococcosis in AIDS, cardiac lesions have been observed infrequently.74 In a retrospective review by Zuger and colleagues of 26 patients with AIDS and cryptococcosis, 1 patient with pericardial disease and cardiac tamponade was noted.” Even though cryptococcal meningoencephalitis often is of primary clinical concern in patients with AIDS, cryptococcal infection of the heart often accompanies central nervous system infection and may also evolve spontaneously, particularly on previously damaged valves, as in IVDAs. Although endocarditis occurs most commonly, cryptococcosis may involve the pericardium, as well as the myocardium. Lafont and coworkers75 reported a case of a 20-year-old AIDS patient with clinical congestive heart failure. On echocardiography, the left ventricle was markedly akinetic without dilatation. Serologic evidence of cryptococcal infection was strongly positive and blood and sputum cultures were positive for Cryptococcus neoformans. At postmortem the Cur-r Probl

Cardiol,

October

1990

591

myocardium revealed multiple inflammatory cell infiltrates containing cryptococcal organisms. The lungs demonstrated P. carinii cysts and there was evidence of disseminated M. avium-intracellulare in multiple viscera. The case was notable in that no central nervous system signs or symptoms were described, since cardiac involvement usually accompanies central nervous system involvement. In an autopsy study by Lewis and associates,76 in which 11 of 44 (25%) patients had cardiac lesions, 2 patients were found to have cryptococcal involvement of the heart, 1 as part of a disseminated disease. Foci of necrotic myocardial cells and fungi were noted histopathologically. Interestingly, acute inflammation was minimal and no granulomas or chronic inflammation was noted. Clinical evidence of heart disease was absent in both cases; at microscopic examination, no inflammation was present, although organisms filled the involved myocytes. Tuberculosis .-Epidemiologic and clinical evidence has confirmed the association of tuberculosis and AIDS. Prior to the AIDS epidemic, tuberculosis had begun to wane in most communities, except for the notable exception of low income and minority populations. With the advent of HIV disease, the incidence of tuberculosis has increased. It is now one of the common initial manifestations of AIDS in many previously infected HIV seropositive individuals. In patients with AIDS, tuberculosis is often the result of reactivation of prior infection in patients with AIDS. The risk of tuberculosis is particularly high in blacks and IVDAs. The prevalence and incidence of tuberculous infection has been shown to be comparable in HIV seropositive and HIV seronegative patients; however, HIV seropositive individuals are at greater risk of active tuberculosis.77 In reviewing autopsy data in Haitian patients with AIDS, even though tuberculosis is common in this population, the myocardium was uncommonly involved with mycobacterial infection.3s’42 Pericardial disease, however, was common in this patient population. Similarly, in the study by Monsuez and associates4’ in which AIDS patients with and without clinical evidence of heart disease were compared, in 10 of 18 (55% 1 symptomatic patients that had pericardiotomy, Mycobacterium tuberculosis was found in 5, M. avium-intracehlare in 1, lymphoma in 1, and nonspecific pericarditis in 3 patients. An increase in the incidence of pericardial disease has also been noted in Tanzania and may be associated with the increased incidence of tuberculosis linked to the epidemic of HIV disease.78 Tuberculosis involvement of the heart has primarily manifested as pericardial disease. Extrapulmonary tuberculosis is relatively common in AIDS patients and may occasionally be associated with cardiac sequelae. Tuberculosis is often widespread, with involvement of multiple organ systems. Involvement of the heart may develop 592

Curr

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1990

through contiguous spread from adjacent tuberculous lymph nodes or pulmonary disease, although hematogenous spread is common. reported a 2.5year-old male homosexual D’Cruz and colleagues7’ with fever and pulmonary infiltrate with necrotizing granulomatous lesions on endobronchial biopsy (and cytomegalovirus on culture of bronchial washings) who abruptly developed pericardial effusion and died. M. tuberculosis was cultured from multiple organs at autopsy. At postmortem, the heart was dilated and flabby. On histopathologic examination, the pericardium showed multiple granulomas and the myocardium demonstrated nonspecific neutrophilic and lymphocytic infiltrates, but no granulomas. In a study of 136 patients with AIDS, Sunderam and associatess4 found M. tubercuZosis in 29 and M. avium-intracellular-e in 19 patients. Extrapulmonary disease was present in 21 patients (72%). Cardiac involvement, limited to the pericardium, caused acute cardiac tamponade in 1 patient. b D. MCCALL: The development of a pericardial effusion in an HIV positive individual, as in all other individuals, mandates that the physician make a diligent attempt to establish an etiologic agent. it is particularly important to establish whether or not this is due to tuberculosis since tuberculous infection of the pericardium is most amenable to therapy even in the immunocompromised individual. In establishing the diagnosis it is important to remember that needle aspiration of the pericardial fluid may yield negative results in more than 50Y0 of cases of tuberculous pericarditis. A much greater diagnostic yield is obtained from open pericardiotomy, with biopsy of any nodules found on examination of the pericardial sac. Until the latter has been obtained it is frequently impossible to exclude the possibility rium tuberculosis.

that the pericardial

effusion

is related

to mycobacte-

Mycobacterium avium-intraceZZulare is a common opportunistic infection in AIDS and may involve multiple organs, including the gastrointestinal tract, liver, spleen, and lymph nodes. Because the organism is not very virulent, M. avium-intracelhlare is noted most often in the later stages of HIV disease. Woods and Goldsmith” found pericarditis resulting from M. avium-intracellulare in a homosexual man in whom per&u-dial effusion was documented antemortern. Clinical assessment revealed left ventricular dilation and diffusely an abnormal function. At autopsy, the pericardium showed chronic inflammation. At postmortem, M. avium-intracellulare was cultured from the pericardium, and other viral cultures were negative. The myocardium was histologically normal, with no inflammatory infiltrates or myocyte necrosis. Cardiac disease has also been associated with rarer infections, such as Actinomycetales and Nocardia. Holtz and co-worke# described four IVDAs with AIDS and nonmycobacterial Actinomycetales infection. Pericardial effusion was present in two cases. Cultures of pericardial fluid grew Nocardia asteroides in both. One case demonstrated chronic fibrinous pericarditis on histologic examinaCum

Probl

Cardiol,

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593

tion. Two patients expired. Two patients had concurrent mycobacterial infection and the authors postulate a common susceptibility in immunosuppressed patients to Actinomycetdes infection and mycobacteria. Table 1 lists common opportunistic infections in AIDS. NEOPZa4SMS Kaposi’s Sarcoma.-Kaposi’s sarcoma is one of the main malignancies to which AIDS patients are susceptible. Prior to the AIDS era, Kaposi’s sarcoma was a rare malignancy in Europe and the United States. In the classic form, which affects primarily males of Jewish or Mediterranean ethnicity, the disease is slowly progressive, with only 15% mortality in 10 years. Visceral or systemic involvement is rare and skin lesions are usually limited to the lower legs and arms. In Africa, where Kaposi’s sarcoma accounts for 10% of all malignant tumors, a more aggressive form has been recognized in young black males. The African disease also progresses slowly and the mortality rates are also low. Visceral and mucosal involvement is uncommon and lesions are limited to the extremities. Skin lesions are typically nodular or exophytic. Another more virulent form has also been described in patients receiving corticosteroids or other immunosuppressive therapy in a variety of clinical contexts, including systemic lupus erythematosus, renal transplantation, and temporal arteritis. In patients taking immunosuppressive drugs, the disease incidence is 400% greater than the general population. Red to purple papular or nodular lesions are widespread, occurring on the neck and trunk, as well as extremities, but may disappear when immunosuppressive drugs are discontinued.” Kaposi’s sarcoma is the most common neoplasm associated with TABLE

1.

Common

Opportunistic

Infections

in AIDS

Protozoa Pneumocystis carinii To,xoplasma gondii’ Cwtosporidium species Entamoeba histolytica Giardia lamblia Bacteria Mycobacterium tuberculosis* Mycobacterium avium complex’ Nocardia asteroides’ Streptococcus pneumoniae* Staphylococcus aureus’ ‘May directly 694

involve

Fungi Aspergillus* Candida species Cryptococcus neoformans* Histoplasma capsulatum’ Coccidioides immitis* Viruses Cytomegalovirus’ Herpes simplex virus* Epstein-Barr virus* Coxsackievirus* HIV*

the heart in AIDS Curr

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1990

AIDS, occurring in approximately 25% to 35% of patients. In contrast to the classic variety of the disease, the clinical characteristics of Kaposi’s sarcoma in AIDS patients range from a primarily dermatologic disease to a virulent disease involving multiple viscera and producing severe and sometimes lethal disease. Male homosexuals with HIV infection are more commonly affected than other AIDS risk groups. Kaposi’s sarcoma is rarely found in populations of patients with AIDS containing large proportions of IVDAS.~‘, ” Kaposi’s sarcoma is often diagnosed by the typical skin lesions, which usually occur prior to visceral involvement. In AIDS, as in the other forms, the skin lesions are usually purple, hemorrhagic, and plaque-like, but occur more diffusely, in the intertriginous areas, and on the face and neck. In contrast to other forms of Kaposi’s sarcoma, lymph node, mucosal, and-visceral involvement are also frequent. Although the primary manifestations of Kaposi’s sarcoma involve the skin, visceral involvement has been noted postmortem in the absence of skin lesions in AIDS patients. Niedt and Schinella3’ found disseminated Kaposi’s sarcoma in 28 of 56 autopsies of AIDS patients. Two patients had no evidence of involvement of the skin and were not diagnosed antemortem. Guarda and colleagues36 found Kaposi’s sarcoma postmortem in 10 of 13 homosexual patients with AIDS and visceral involvement without skin lesions in 2 of 8 cases. Kaposi’s sarcoma did not contribute to death except in 1 case with massive multiorgan involvement. Cardiac involvement with Kaposi’s sarcoma in patients with AIDS most commonly is associated with metastatic or disseminated disease. Even though cardiac lesions resulting from Kaposi’s sarcoma have been commonly found at autopsy, clinical symptoms have been rarely associated with Kaposi’s sarcoma. Although cardiac involvement is usually part of disseminated Kaposi’s sarcoma, Kaposi’s sarcoma limited to the heart has also been reported in AIDS. When Kaposi’s sarcoma does involve the heart, the epicardial surface is a common site of involvement. In a study of 10 AIDS patients autopsied at the National Institutes of Health (NIH), Kaposi’s sarcoma was an immediate cause of death in 1 patient and contributed directly to death in another, in which Kaposi’s sarcoma of the lung led to massive pulmonary hemorrhage.33 Kaposi’s sarcoma was found in lymph nodes but was not clinically significant. Kaposi’s sarcoma was the most common neoplasm at necropsy and the immediate cause of death in 6 of 54 autopsies reported by Moskowitz and colleagues.” The mode of demise was not specified. Kaposi’s sarcoma infiltrated the myocardium in 2 cases, entered a small branch of the left anterior descending artery (LAD) in one case, and involved only the epicardium in 2 cases. Cardiac involvement with Kaposi’s sarcoma was not clinically significant. Cammarosano and Lewis,38 in a study of cardiac lesions in 41 AIDS autopsies, found that Kaposi’s Curr

Probl

Cardiol,

October

1990

595

sarcoma involved the heart in 4 patients (10%). Welch and associates34 found Kaposi’s sarcoma in 18 of 36 (50%) AIDS autopsies, but Kaposi’s sarcoma contributed to morbidity and mortality in 10 cases. Kaposi’s sarcoma involved the epicardium and epicardial adipose tissue in 3 cases. Extensive myocardial involvement was present in 1 of these cases and was associated with heart failure and contributed directly to death. In an autopsy study of 54 patients with AIDS, Roldan and co-workers3’ found Kaposi’s sarcoma in 2 cases, 1 involving the myocardium and 1 with pericardial lesions. In a patient with widespread Kaposi’s sarcoma, the epicardial coronary arteries revealed intimal proliferation, the significance of which is unknown. Kaposi’s sarcoma has been assessed in clinical studies of cardiac involvement with AIDS. Fink and associates43 found clinical evidence of Kaposi’s sarcoma in 7 of 15 patients (47%) with AIDS, 4 of whom also had pericardial effusion. In a prospective echocardiographic study of 102 AIDS patients (70% IVDAs) by Corallo and co-workers,4s Kaposi’s sarcoma occurred in 6 (5.8%) cases, with cardiac involvement in 2 patients. Cardiac findings in these 2 patients included focal metastatic Kaposi’s sarcoma lesions and a paracardiac mass. In Monsuez and colleagues’4s comparison of 86 AIDS patients with and without clinical evidence of cardiac disease, 1 patient died of pleural and pericardial hemorrhage associated with Kaposi’s sarcoma and 1 had infiltration of the left ventricle with Kaposi’s sarcoma. Autran and colleagues,s3 in one of the earliest reports of Kaposi’s sarcoma of the heart in AIDS, described a 24-year-old Haitian woman with hematologic and serologic findings of immunocompromise who presented with multiple complications of AIDS, including esophageal candidiasis, vulvar and perianal ulcers resulting from herpes virus, staphylococcal sepsis, cytomegalovirus, and P. carinii pneumonia infections. At postmortem, Kaposi’s sarcoma involved the entire anterior cardiac wall. There was no pericardial effusion, other organ involvement, or cutaneous lesions. Kaposi’s sarcoma unassociated with immune compromise has also been reported. Levison and Semples4 described a case of primary cardiac Kaposi’s sarcoma in a 14year-old boy with a presumptive diagnosis of tuberculosis pericardial effusion in whom a liter of bloodstained pericardial fluid was removed at pericardiocentesis. At postmortem a Kaposi’s sarcoma tumor filling the right atrium was found and assumed to be responsible for the large effusion. The difficulty in distinguishing Kaposi’s sarcoma from other forms of angiosarcoma is illustrated by this case. Steigman and co-workers85 reported a fatal case of Kaposi’s sarcoma with cardiac and pulmonic involvement with hemorrhagic pericardial effusion and tamponade. Nodular coalescent dark red lesions consistent with Kaposi’s sarcoma were found in the epicardial fat. Silver and colleaguess6 reviewed the autopsies of 18 patients with 596

Curr

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1990

AIDS and widely disseminated visceral, lymphatic, and mucocutaneous Kaposi’s sarcoma. Cardiac involvement by Kaposi’s sarcoma was found in 5 (28%) cases. None of these cases had symptoms antemortern. Cardiac lesions included small focal hemorrhagic lesions in the subepicardial adipose tissue adjacent to a major coronary artery, with or without involvement of the adventitia of the aorta or pulmonary artery. Stotka and colleaguess7 described a patient with massive pericardial effusion and tamponade associated with Kaposi’s sarcoma. The patient developed an episode of P. carinii pneumonia and cryptococcal meningitis, as well as evidence of oral Kaposi’s sarcoma. Despite removal via pericardiocentesis of 1,600 ml of serosanguinous fluid, the patient died. Postmortem examination revealed pulmonary and esophageal Kaposi’s sarcoma. The pericardium demonstrated purple nodules on the surface of the epicardium, which was studded with violaceous plaques and nodules. In a study of the frequency of myocarditis in AIDS in 58 autopsied AIDS patients, Reilly and associates,88 found Kaposi’s sarcoma in 33 patients (57% 1. Congestive heart failure or left ventricular dilatation was not related to concurrent disease, including Kaposi’s sarcoma, P. carinii pneumonia, or cytomegalovirus. In a study of 26 AIDS patients at necropsy, Baroldi and co-workers41 found 1 case of Kaposi’s sarcoma of the anterior surface of the heart, and 1 case in which the only evidence of Kaposi’s sarcoma were small; subepicardial nodules around the LAD. In autopsies of 71 patients with AIDS, Anderson and colleagues4o found epicardial Kaposi’s sarcoma in 7 cases. Myocarditis was found in 37 cases (52% 1 but was not associated with Kaposi’s sarcoma. LYMPHOXD

NEOPLASM

AND

AIDS

The increased risk of the development of malignant lymphoma in immunocompromised individuals is well known. The B lymphocyte lymphomas have been described in association with congenital disorders of immunodeficiency, such as the Wiskott-Aldrich syndrome, as well as in patients with organ transplantation. Because lymphadenopathy was one of the earliest features noted in AIDS, an early link between HIV infection and lymphoma was established by pathologic and clinical studies. Lymph node biopsies revealed that lymphoma was common in AIDS patients. Non-Hodgkin’s lymphoma is now a diagnostic criterion for AIDS and the increased prevalence of Hodgkin’s disease in HIV infection is well recognized. Generalized lymphadenopathy is common in AIDS as well as pie-AIDS syndromes, and presents a complex differential diagnostic challenge. In IVDAs, lymphadenopathy may be the result of repeated unsterile injections, but, because generalized lymphadenopathy is also common with tuberculosis in HIV infection, mycobacterial disease must Curr

Probl

Cardiol,

October

1990

597

also be considered.” With lymphoma, follicular hyperplasia is usually demonstrated on lymph node biopsy. Histopathologically, the non-Hodgkin’s lymphomas in AIDS are most often aggressive large cell, intermediate, or high grade cell types. With development of fullblown disease, the central nervous system is often involved, producing typical mass lesions visualized on CT of the brain. The gastrointestinal tract, liver, bone marrow, and other extranodal sites are also commonly involved.so Hodgkin’s disease in AIDS is usually more virulent than in immunocompetent individuals, often with extranodal involvement. Therapy for lymphoid malignancies is less successful in AIDS than in other clinical contexts.‘l Cardiac involvement with malignant lymphoma in AIDS has been noted postmortem, but clinical manifestations appearing antemortern are unusual. As with Kaposi’s sarcoma, the heart may be the target of metastases, contiguous extension, or lymphatic or bloodborne spread. Symptoms usually relate to pericardial effusion or tamponade. Tables 2 and 3 describe the clinical assessment of heart disease in AIDS and guidelines for management. PERICARDIAL PREVALENCE

DISEASE

RELATED

OF PERZCAZ3DL4L.

TO AIDS

DZSEASE

With the recognition of the broad clinical and pathologic spectrum of cardiac disease associated with AIDS, the important role of pericardial disease in AIDS-related cardiac symptoms has also been appreciated (Table 4). It has become evident that the pericardium is commonly involved in a variety of pathologic states associated with TABLE Clinical

2. Assessment

of Cardiac

Disease

in AIDS

History and physical examination Routine complete blood cell count, urinalysis, and Skin testing for tuberculosis, mumps, and fungi Toxicology screen Liver function tests Immunoglobulins UgG, IgA, IgM) Beta micmglobulin T-cell subset analysis Antibodies to the.following pathogens: Hepatitis Toxoplasmosis Cytomegalotirus Epstein-Barr virus Herpes virus Coxsackie B virus Echovirus 598

blood

chemistries

Cum

Probl

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1990

TABLE Heart

3. Disease

Related

to AIDS:

Guidelines

for Management

I. Understand that the frequency of specific infections depends on the prevalence of infection with these pathogens in the locale and population. 2. Recognize that the majority of HIV-associated opportunistic infections result from the endogenous reactivation of a previously acquired organism and do not represent a threat to other persons. 3. Correct associated factors that might contribute to cardiac symptoms (e.g., anemia, dehydration, malnutrition, and electrolytes). 4. Identity and treat traditional cardiopulmonary diseases known to be common in the locale, population, and specific risk group. 5. Initiate empiric antimicrobial therapy promptly, while awaiting culture results in life-thmatening situations. 6. Reassess accuracy of diagnosis and efficacy of therapy frequently, since polymicmbial infections and relapses are common.

AIDS. Although cardiac involvement is frequently asymptomatic in AIDS patients, pericardial disease is the most common cause of clinical cardiovascular symptoms and signs. Early recognition of pericardial effusion and tamponade may have critical clinical ramifications, since early therapeutic intervention may be life-saving. Several studies have confirmed the high prevalence of pericardial disease in AIDS patients. In a study of 15 patients with AIDS, Fink and coworkers44 noted pericardial effusion in 6 of 13 (46%) patients studied with echocardiography. In 2 of 3 patients with tamponade, cardiovascular collapse occurred after long periods of hospitalization characterized by opportunistic infections, fevers for which no bacteriologic etiology could be determined, and sudden cardiac arTABLE Pericardial

4. Disease

Related

to AIDS

Prevalence Acute vs. chronic pericarditis Pericardial effusion vs. tamponade Effusive, constrictive, or restrictive? Pericardial effusion common clinically Etiology Opportunistic infection or malignancy Idiopathic effusions vs. infectious causes Features Usually associated with similar systemic infection Acute pericarditis: fever, chest pain, rub Chronic pericarditis: recurrent effusion Low pressure cardiac tamponade common Physical findings as in non-AIDS Routine laboratory examination: chest x-ray shows Electmcardiogram: low voltage, ST-T changes, etc. Curr

Probl

Cardiol,

October

1990

enlarged

cardiac

silhouette

699

rest. At pericardiocentesis, only a small amount of fluid was obtained from 2 patients. In the third patient with tamponade, open pericardiocentesis obtained 400 cc of fluid. In a patient who died of respiratory failure, echocardiography results indicated right ventricular overload. The pericardium contained 100 cc of fluid postmortem but the pulmonic and tricuspid valve revealed marantic endocarditis. In the 4 patients who had pericardial biopsy or pericardial examination at autopsy, no culture evidence of involvement by opportunistic infection or histologic evidence of tumor was found. Pericardial effusion was present in 1 of 3 patients with left ventricular hypokinesis on echocardiography. No patients had clinical cardiac symptoms prior to the terminal illness. Fink and co-workers suggest that prospective evaluation with echocardiography might be helpful in uncovering cardiac tamponade, valvular disease, and abnormal cardiac function in patients with AIDS. In a report of congestive cardiomyopathy in association with AIDS by Cohen and co-workers,‘s,44 pericardial effusion was present in two of three patients described. In a 28-year-old woman studied, echocardiography demonstrated normal chamber size but markedly reduced performance with a small to moderate posterior pericardial effusion. In the other patient, a 33-year-old homosexual man, pericardial effusion as well as pleural effusion were noted at postmortem examination. In another report of congestive cardiomyopathy related to AIDS by Corboy and associates,45 pericardial effusions, ranging from 20 to 200 ml and identified in the pericardium during autopsy, were present in each of the 3 patients described. In a review of autopsy findings in 41 patients with AIDS, Cammarosano and Lewis38 noted fibrinous pericarditis in 3 of 10 (30%) patients with major pathologic findings in the heart. In Webb and associates’ study,46 pericardial effusion was present in each of the five AIDS patients, with mild to moderate cardiac dysfunction on radionuclide ventriculography or echocardiography. Raffanti and coworkers4T found pericardial effusion with fibrinous strands in 1 of 12 patients with AIDS studied echocardiographically. There was no evidence of abnormal left ventricular or right ventricular function in this patient. Comparable prevalence of pericardial effusion was found in 39 of 102 (38%) patients with AIDS in a prospective echocardiographic study by Corallo and associates.48 Monsuez and co11eagues4’ found tamponade or moderate to severe pericardial effusion in 13 of 18 (72%) patients with clinical cardiac disease and 5 of 68 (7%) without cardiac disease. Since tamponade and echocardiographic pericardial effusion were part of the definition of “cardiac disease,” interpretation of the difference in groups is problematic. However, when the two groups are combined, 18 of 88 (20%) had pericardial disease. Significant pericardial disease was associated with the severity and duration of complications of AIDS, 666

Cur-r

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1960

as well as clinical and laboratory manifestations of cardiac involvement. Other studies, however,50-52 have not found that the frequency of pericarditis, pericardial effusion, and pericardial tamponade was related to the clinical stage of HIV infection. In an echocardiographic study, the prevalence of pericardial effusion was comparable in 15 patients with AIDS and 24 patients with ARC by Levy and associates,51 and no difference was noted in the prevalence of pericardial effusion between HIV seropositive patients without AIDS and patients with AIDS. Pericardial effusion was also comparable in AIDS patients with or without active opportunistic infection. In a study comparing HIV patients with a group of acute leukemia patients, no difference was noted between groups in the prevalence of pericardial effusion.52 Of 70 Hy seropositive patients, 7 (10%) had pericardial effusion. In 6, the effusion was small. In 1 patient, with echocardiographic findings consistent with a large effusion and impending tamponade, the size of the effusion decreased with nonsteroidal anti-inflammatory drug therapy, obviating the need for pericardiocentesis. Three of these patients had “dilated cardiomyopathy.” ETIOLOGY

OF PERICARDIAL

DISEASE

IN AIDS

Pericardial disease related to AIDS may be caused by a wide array of opportunistic infections (see Table 51. Since multiple opportunistic infections are common in AIDS, isolation of a particular pathogen from an organ has been the primary method of ascribing a causal relationship for infection of a given anatomic site. Fungal infections are the second most common infections in AIDS, exceeded only by P. carinii infections. Fungal infections with C. albicans, the most common fungal infection, most often involve the mucosa of the oropharynx and esophagus. Although not as common as one might expect, systemic candidiasis is not infrequent and may prove particularly lethal. Cryptococcal infection is the most common systemic fungal infection in AIDS. Cryptococcal meningitis is common, usually in conjunction with disseminated infection, which may also involve the heart. Disseminated cryptococcosis involves the pericardium infrequently. Zuger and colleagues,” in a review of 396 patients with AIDS, analyzed cryptococcal infection in 34 (9%) patients. Cryptococcal pericarditis was found in only 1 patient who presented with signs and symptoms of tamponade but no signs of central nervous system disease. A case of cryptococcal pericarditis has been reported by Schuster and associates,gz who described a 40year-old woman who was also an IVDA with a history of treated S. aureus bacteremia and disseminated acid fast bacterial infection who presented with signs and symptoms of cardiac tamponade. Fluid obtained during pericardiotomy was negative upon Gram Curr

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1990

601

stain, acid fast stain, and India ink preparation, but budding yeast was identified in the fluid upon further examination. The pericardial fluid subsequently grew C. neoformans. Cryptococcal antigen titer in the fluid was 1: 400 and 1: 64 in the serum. The patient responded to therapy with amphotericin B and serum cryptococcal antigen decreased and a presumptive diagnosis of AIDS was made. Brivet et aLg3 described long-standing cryptococcal disease in an African man with AIDS. After 3 months of antifungal therapy with amphotericin and fluorocytosine, the patient was readmitted with clinical and hemodynamic evidence for cardiac tamponade. A diagnosis of cryptococcal pericardial effusion was made on the basis of positive cultures for C. neoformans on bronchoalveolar lavage and high cerebrospinal fluid cryptococcal antigen. Fungal infections of the heart may readily spread to contiguous cardiac structures in the immunocompromised patient. Although pericardial infection with other fungi is more common, AspergiZZus pancarditis has been reported to occur following bone marrow transplantation.68 Pathologic examination of this patient revealed extensive myocardial fungal abscesses, epicardial and pericardial mycotic plaques. Vegetations containing Aspergillus were demonstrated on the endocardium, in papillary muscles and chordae tendineae, but not on the valve leaflets. The heart revealed biventricular dilatation. THE MYCOBACTERlA Mycobacterium tuberculosis and M. avium-intracellulare have become major opportunistic infections in AIDS, especially in populations with high rates of endemic mycobacterial infection, such as IVDAs and low-income, minority populations. Involvement of the pericardium with clinical symptoms of constrictive pericarditis has long been recognized as a classic manifestation of M. tuberculosis infection. With the recrudescence of tuberculosis in many locales in which AIDS is also endemic, pericardial disease resulting from infection with M. tuberculosis has once again become an important clinical consideration. While findings typical of reactivation of an earlier primary tuberculous infection are still common in patients with AIDS, tuberculosis in AIDS is often atypical, with a high prevalence of extrapulmonary manifestations, atypical chest radiograph features, and high rates of disseminated disease. In contrast to the pie-AIDS era when tuberculous involvement of the heart, causing constrictive pericarditis, was often the first clinical clue to cardiac disease, more acute problems, such as recurring pericardial effusion, pericardial abscess, and pericarditis, are currently encountered. D’Cruz et aL7’ described a 25year-old homosexual male with moderate pericardial effusion on echocardiography. The patient subsequently died; at autopsy dis602

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IWO

seminated tuberculosis was found, with multiple necrotizing granulomas in the lung and other viscera. There were multiple tuberculous granulomas on the visceral and parietal pericardium. Sunderam et alg4 and Lin and colleaguesg5 described a patient with AIDS and acute tuberculous pericardial effusion with cardiac tamponade who subsequently developed a tuberculous pericardial-cutaneous fistula following open pericardiotomy, despite sustained antituberculous therapy. M. avium-intracellulare infection has become common in patients with AIDS. This usually noninvasive organism has now been isolated from multiple sites in patients with AIDS, most commonly the lungs and lymph nodes. Involvement of the gastrointestinal tract is also common. While M. avium-intracelfulare is frequently cultured from the sputum, blood, and viscera, its relationship to the natural history of AIDS is unclear.g6 M. Cum-intracellulare has also been isolated in patients with cardiac disease related to AIDS, often from pericardial tissue or fluid. In one of three patients with AIDS-associated cardiomyopathy described by Cohen et aI.,44 M. avium-intracellulare was cultured from the pericardial fluid obtained at emergency pericardiocentesis in one case. This patient also had severe global hypokinesis and four-chamber enlargement. The relationship of the pericardial effusion and M. avium-intracellulare to the clinical findings of congestive cardiomyopathy and to the ultimate demise of this patient is unclear. In contrast with two of the cases previously described,44 .m which the myocardium revealed lymphocytic inflammatory infiltrates, Woods and Goldsmith” described a case with fatal pericardial disease and disseminated M. avium-intracellulare infection involving the pericardium, in whom histologic examination of the myocardium was normal. The pericardium may also be involved by nonmycobacterial infections, as shown by Holtz et al.,81 who reported nonmycobacterial, ActinomycetaZes infection, in the AIDS. These unusual infections were noted in four IVDAs, three with infection by Nocardia species, and one with Streptomyces lymphadenitis. Two patients had concurrent infection with Nocardia or Streptomyces species and M. tubercuZosis. In one case, M. tuberculosis was cultured 8 months prior to echocardiographic demonstration of a pericardial effusion. Pericardiotomy yielded 400 ml of fluid, which grew N. asteroides. In another case, pericardial effusion developed abruptly and pericardiocentesis was performed. Cultures of 1,100 ml of greenish fluid yielded N. asteroides and pericardial biopsy demonstrated yeast-like organisms. Cohen and colleagues suggested that investigation of pericardial disease in AIDS should include consideration of nocardiosis, as well as tuberculous infection. In contrast to tuberculosis, infection with nontuberculous mycobacteria occurs more commonly in homosexuals and younger patients.g7 Burr

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1990

603

VIRAL PERICARDIAL

DISEASE

The role of viruses in diseases of the pericardium has been well established prior to the AIDS epidemic. Pericardial disease in the immunocompetent host may be associated with a variety of viruses, most commonly coxsackievirus. It is likely that pericardial involvement in AIDS is also related to infection with other common viral pathogens, but there are few reports documenting this association. Even though herpes viruses are uncommon cardiac pathogens, pericardial disease in AIDS related to herpes simplex virus has been reported. Freedberg et al.” described a &t-year-old cachectic homosexual patient with multiple complications of AIDS, including possible cytomegalovirus or herpes esophagitis, respiratory failure resulting from presumed refractory P. carinii pneumonia and ventricular arrhythmias. Pericardial effusion was demonstrated by echocardiography and at open pericardial biopsy, 200 ml of fluid was removed. Microscopic examination revealed fibrosis. Culture of pericardial fluid yielded herpes simplex type 1, suggesting pericardial effusion resulting from herpes simplex virus serositis. We speculate that the pericardial effusions found in immunocompromised patients may be caused by reactivation of viral infections that are usually self-limited in immunocompetent individuals. Pericarditis and pericardial effusion resulting from herpes simplex virus type 2 has been reported in a 32-year-old homosexual with AIDS and echocardiographic evidence of significant pericardial effusion.gg At pericardiocentesis, 1,070 ml of pericardial fluid was removed. All cultures were negative, except for herpes simplex virus type 2, suggesting that the pericardial disease was caused by that pathogen. In both of these reports, however, cultures and serologic tests for other pathogens were also variably positive. Even though herpes virus was the only pathogen cultured from pericardial fluid, cytomegalovirus was also cultured from the lung in both cases. Disseminated cytomegalovirus infection is common in AIDS and may involve the heart. Pericardial disease may occur even though it is not a prominent clinical or pathologic finding in cytomegalovirus infection. MALIGNANCY

AND

PERZCARDZAL

DISEASE

Kaposi’s sarcoma, the most common malignancy found in AIDS, may cause significant pericardial disease. Cardiac involvement with Kaposi’s sarcoma most commonly affects the pericardium, but involvement of the myocardium and endocardium has been reported. Even though evidence of involvement of the heart is frequently observed postmortem in AIDS patients, clinical cardiac symptoms related to Kaposi’s sarcoma of the pericardium are uncommon. In an early report of Kaposi’s sarcoma in AIDS, Silver et als6 found cardiac 604

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1990

abnormalities in 5 of 18 patients 128%). The abnormalities consisted of subepicardial focal deposits of Kaposi’s sarcoma in each case. Epicardial involvement with Kaposi’s sarcoma may lead to signs and symptoms related to involvement of the adjacent pericardium. In AIDS, Kaposi’s sarcoma usually involves the heart as part of disseminated Kaposi’s sarcoma. Steigman et a1.85 reported a case of Kaposi’s sarcoma, primarily involving the lung, where hemorrhagic pericardial effusion and fatal tamponade developed. Nodular coalescent dark-red lesions characteristic of Kaposi’s sarcoma were found in the epicardial fat postmortem. Focal myocarditis was also noted. Stotka and associatess7 reported pericardial tamponade resulting from Kaposi’s sarcoma in a 29-year-old homosexual man with oral Kaposi’s sarcoma and cryptococcal meningitis who was found to have a large pericardial effusion by echocardiography. Pericardiocentesis removed 1,600 cc of fluid, but the patient died after 8 weeks’ hospitalization. Violaceous plaques and nodules typical of Kaposi’s sarcoma were found on the pericardium and in the epicardial fat. The endocardium and myocardium were free of tumor. Two patients with disseminated Kaposi’s sarcoma and massive pericardial effusion with tamponade have been described by Langer and colleagues.1o0 Multiple pericardiocentesis removed large amounts of fluid but no malignant cells or other pathogens were found. At autopsy, cytomegalovirus and cryptococcus septicemia were present, along with generalized Kaposi’s sarcoma with infiltration of the heart extending along the great vessels and the coronary vessels. The pericardium contained a large sanguinous effusion. Interestingly, histopathologic studies did not reveal cytomegalic inclusion bodies or fungal granulomas in the heart. This case demonstrates the typical pathogenesis of cardiac involvement with Kaposi’s sarcoma. Kaposi’s sarcoma commonly infiltrates the subepicardial adipose tissue and adjacent pericardium. Occasionally the myocardium may also be involved. Typically, Kaposi’s sarcoma then extends along coronary vessels, with spread of tumor through the lymph channels along the vasa vasorum. Kaposi’s sarcoma limited to the heart without cutaneous or other visceral involvement may also occur in AIDS. Autran et a1.83 described a case in which Kaposi’s sarcoma involving the entire anterior cardiac surface was found postmortem in a 24-year-old Haitian woman with AIDS who had initially presented with severe vulvoperineal herpetic ulceration and S. aureus septicemia. Cytomegalovirus was cultured from blood and urine. Despite appropriate antibiotic therapy, the patient died of febrile cardiogenic collapse. There were no cutaneous or other visceral evidence of Kaposi’s sarcoma and no pericardial effusion. Levison and Semple,84 in a report of Kaposi’s sarcoma of the heart in an immunocompetent patient, described a I4-year-old with cardiac tamponade in whom over a liter of pericarCur-r

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1990

606

dial fluid was aspirated. At autopsy only a large right atria1 tumor, consistent with Kaposi’s sarcoma, was found. With Kaposi’s sarcoma involving the heart or pericardium in the absence of cutaneous or other visceral involvement, it may be difficult to distinguish Kaposi’s sarcoma from angiosarcoma. LYMPHOh4A AND PERZCARDIAL DISEASE Clinical manifestations of pericardial involvement are most common with malignant lymphoma associated with AIDS. The association of non-Hodgkin’s lymphoma and AIDS has been well documented. Extranodal involvement is common in non-Hodgkin’s lymphoma, as well as in Hodgkin’s disease in AIDS. Metastatic involvement of the heart with malignant lymphoma may occur in 20% of patientslo Gill et allo reported 9 patients with malignant lymphoma who presented with cardiac involvement. Lymphoma was widespread in 4 of 9 cases, with chest pain in four and extensive involvement of the GI tract clinically in 3 patients. Four of the 9 patients had AIDS-related lymphoma. Pericardial effusion was demonstrated in 6 cases by echocardiography. A mass lesion of the heart was demonstrated in 3 patients. In one patient the mass prolapsed across the tricuspid valve, and in another the inferior portions of the right and left ventricle were involved. Cardiac tamponade occurred in 2 patients. Lymphoma involved multiple organs at postmortem. Ioachim and colleagues,‘o3 in reviewing lymphomas in 21 men at high risk for AIDS, found massive involvement of the pericardium and myocardium at autopsy in 2 cases at autopsy. The cardiac lesions were not clinically significant. Primary non-Hodgkin’s lymphoma of the heart has also been described,lo4 but pericardial effusion was absent.lo5 Balasubramanyam et allo described 2 patients with malignant lymphoma of the heart in which signs and symptoms of cardiac dysfunction occurred clinically and were a harbinger of death related to the tumors. Intractable congestive heart failure and pericardial effusion occurred in 1 patient and fibrinous pericarditis and first degree heart block in another. In contrast to other lymphomas in patients without AIDS,lo7 in which the lymphoma was epicardial or pericardial in location, in AIDS the tumor is intramyocardial or subendocardial, which may account for the congestive failure reported. Congestive heart failure or arrhythmias in patients with AIDS may suggest cardiac involvement with metastatic or primary lymphoma or Kaposi’s sarcoma. CLINICAL FEATURES OF PERZCARDZAL DISEASE IN AIDS In the immunocompromised patient, the classic clinical features of pericarditis, pericardial effusion, and cardiac tamponade are com606

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1990

mon, but may be overshadowed by concurrent signs and symptoms of other opportunistic infection. Often pericardial involvement is clinically silent, although characteristic signs and symptoms may occur. Acute pericarditis, although not common in AIDS, may be accompanied by the classic sharp chest pain that changes with position or respiration. With pericardial effusion, typical pain may not be present, although with development of very large effusions a feeling of fullness or pressure may ensue. Occasionally, with very large effusion, visceral compression may produce symptoms such as cough from tracheal or bronchial compression, dysphagia from compression of the esophagus, or dyspnea from lung compression or atelectasis. Hiccups may occur with phrenic nerve involvement and hoarseness with compression of the recurrent laryngeal nerve. Low cardiac output, decreased blood pressure, paradoxical pulse, and elevated jugular venous pressure occur with tamponade. With increased intrapericardial pressure, diminished diastolic filling, decreased stroke volume, and diminished tissue perfusion ensue. Dyspnea may become a prominent symptom with tamponade. Even though pericardial effusion has been observed commonly at postmortem in patients with AIDS, clinical symptoms are not often reported. This may be because of severe inanition and dehydration, common in patients with AIDS who have cardiac abnormalities.108 In this clinical context, so called “low pressure tamponade” may occur. In this clinical syndrome, usually occurring early in the development of pericardial tamponade, physical signs of tamponade, such as increased jugular venous pressure or pulsus paradoxus, are absent. Because of extremely low right ventricular filling pressures, the increased intrapericardial pressure induced by the accumulation of pericardial fluid reaches hemodynamic equilibrium at a low pressure, minimizing peripheral stigmata of tamponade.lOs This phenomenon may occur with tumors involving the pericardium, in the presence of tuberculous pericardial disease, and with severe volume depletion. Diagnosis Defining the basic underlying cause of signs and symptoms is fundamental to establishing an effective therapeutic strategy in AIDS (Table 6). Because of the large number of potential pathogens in AIDS, exclusion of nonAIDS-related cardiac disease, such as coronary artery disease, hypertensive heart disease, alcoholic cardiomyopathy, and rheumatic heart disease, is essential. The appearance of the heart on chest radiographs with pericardial effusion will vary depending on the volume of the effusion and the rapidity with which the efli.rsion is formed. With very slow accumulation of fluid, the pericardium may stretch and accommodate very large volumes while with rapid accumulation, evidence of increasing Curr

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1990

607

TABLE

5.

Management

of Per&u-dial

Disease

Related

to AIDS

Diagnosis Effisions small with normal intrapericardiac pressure; no symptoms Dysphagia, cough, and dyspnea may occur Clues to tamponade: Fall in blood pressure, pulsus paradoxus, small quiet heart, elevated venous pressure Routine laboratory examination: Chest x-ray is nondiagnostic, ECG shows typical evolutionary changes of pericarditis Electrical alternans with tamponade Tests Echocardiography: Most reliable in evaluating effusion Differentiate constriction, cardiomyopathy, tumor, pericardial tamponade Tamponade primarily a clinical diagnosis. Echo may show right ventricular or right atrial diastolic collapse Computed tomography, magnetic resonance imaging may be helpful Therapy Antimicrobial therapy for opportunistic infection Pericardiocentesis is a therapeutic rather than a diagnostic tool Consider pericardiotomy vs. pericardiectomy

cardiac compression may occur with very small amounts of fluid. Diagnosis of the underlying cause of pericardial disease in AIDS may involve a series of skin tests, serologic studies, and immunologic investigations. Noninvasive cardiac diagnostic tests should be considered early, and may be particularly useful in establishing baseline levels of function (see Table 5). For patients with a high likelihood of cardiac disease associated with AIDS, such as IVDAs, blacks, Hispanics, and persons with positive tuberculin skin test, echocardiography should be considered early in the course of disease. Demonstration on twodimensional echocardiography of right atrial compression and right ventricular diastolic collapse are specific diagnostic signs of pericardial tamponade. In the presence of hemodynamic compromise and classic echocardiographic findings of tamponade, pericardiocentesis is indicated. Serial echocardiography is an effective means of assessing the potential for tamponade and detecting early cardiac decompensation or structural alterations. With subacute pericardial disease in patients with AIDS, the timing of invasive procedures, such as endoscopy, bronchoscopy, lymph node biopsy, or endocardial biopsy, will depend on the relative severity and multiplicity of AIDS complications.

Therapy Treatment of pericardial disease in AIDS, in the absence of evidence for tamponade, is largely supportive and nonspecific (see Table 6). Patients with active pericarditis should avoid physical exer608

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1990

TABLE Myocardial

6. Disease

Related

to AIDS

Prevalence Cardiomyopathy vs. myocarditis Lymphocytic myocarditis and AIDS Etiology Primary or secondary cardiomyopathy Role of opportunistic infection (pyogenic bacteria, Malignancies: Non-Hodgkin’s lymphoma HIV infection of the heart Malnutrition, anemia, catechols Features Symptoms occur late in the course of disease Pericardial disease may be qymptomatic Other cardiac symptoms less common Usually associated with disseminated infection Cardiac findings often unrecognized or overlooked

protozoa,

viruses)

tion. Chest pain may be treated symptomatically, usually with nonsteroidal agents, such as aspirin. Steroid therapy remains controversial, and probably should be avoided in AIDS patients because of the high likelihood of concurrent infection (such as tuberculosis), which may be exacerbated by steroid therapy. Oral anticoagulants are also not advised in patients with AIDS-related pericardial disease, because of the risk, not only of intrapericardial hemorrhage, but of central nervous system bleeding and mycotic aneurysm. In the presence of echocardiographic or other evidence of cardiac compression or tamponade, pericardiocentesis is the major therapy, and will provide prompt hemodynamic improvement in this circumstance. Pericardiocentesis should be considered a therapeutic procedure and is best performed after the diagnosis has been clearly established, except in life-threatening circumstances. The prognosis of pericardial disease in AIDS depends on the underlying etiology. In patients in the final stages of disease with multiple and repeated opportunistic infection, it is unlikely that treatment for one pathogen will alter the natural history of the disease. On the other hand, in patients with early disease, particularly tuberculous pericardial disease, effective acute therapy and prophylactic antibiotics may be helpful. As newer and more effective therapies for HIV infection are developed, cardiac disease may assume greater clinical significance. Therefore, it is important to recognize pericardial involvement early, to institute treatment for those pathogens for which effective treatment exists, to monitor patients closely for evolving hemodynamic compromise, and to drain the pericardium if indicated by echocardiographic and clinical parameters. Reaccumulation of pericardial effusion, reinfection by the same or new pathoCur-r

/‘rob/

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October

1666

606

gens, and detection of previously factors that must be considered. MYOCARDIAL PREVALENCE

DISEASE

RELATED

OF MYOCARDIAL

unrecognized

complications

are

TO AIDS

DISZ3ASE

IN AIDS

Because the relatively high prevalence of cardiac abnormalities associated with AIDS has been appreciated only recently, it is difficult to be precise in assessing the overall frequency of myocardial disease (Table 6). In a report of cardiomyopathy associated with AIDS in 1983, Cohen et ala stated that only 3 of 24 (12.5%) patients with AIDS studied had severe cardiac dysfunction antemortem. In 1989, however, Levy et alsl reported that 32 of 60 (53%) had a cardiac abnormality, either on echocardiogram, electrocardiogram, or with ambulatory electrocardiograph monitoring. ETIOLOGY

OF MYOCARDZAL

DZSZI?ASE IN AIDS

Despite the high prevalence of opportunistic infections, particularly of the lung and central nervous system, opportunistic infectious pathogens have been infrequently identified within myocardial cells (see Table 7).3s-41 Indirect evidence of myocardial involvement has been noted more commonly. Myocarditis, suggested by lymphocytic cellular infiltrates and myocyte necrosis, has been described in several studies.3sP 40844 A causal relationship between lymphocytic cellular infiltration of the myocardium and the structural or functional abnormalities of the heart has not been firmly established, although a direct or indirect etiologic role of HIV in the development of myocarditis has been suggested.l” In populations where toxoplasmosis is common, myocarditis resulting from this agent may be prevalent, with Haitian patients having increased toxoplasma infections postmortem. While M. tuberculosis and M. avium-intracellulare infections are common, particularly in IVDAs and minorities, these pathogens do not preferentially damage the heart muscle. Cytomegalovirus and the cardiotropic viruses, such as coxsackievirus, are common pathogens and may be associated with dilated cardiomyopathy. However, in patients with AIDS, coxsackievirus has been infrequently identified as a cause of postmyocarditic cardiomyopathy?’ AIDS

CARDIOMYOPATHY

The severe cardiac dysfunction reported in patients with AIDS has frequently been termed “cardiomyopathy.” This term, however, has various definitions with varied pathogenetic and clinical ramifica610

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1990

tions. Cardiomyopathies may be “primary,” in which myocardial (heart muscle) dysfunction, the cause of which is not established, is the paramount pathologic process and not associated with other pathologic states affecting other organ systems, or “secondary,” in which heart abnormalites am but one aspect of an established and recognized disease process involving multiple organ systems (see Table 7). Functional and structural descriptors have also been used in classifying cardiomyopathies. A generally accepted categorization scheme includes (1) dilated cardiomyopathy, in which left ventricular dilatation, signs and symptoms of left (and sometimes right) ventricular failure and significant systolic dysfunction are typical; (2) hypertrophic cardiomyopathy typified by hypertrophy of the left ventricle, often in characteristic patterns; and (3) restrictive cardiomyopathy, in which disordered diastolic ventricular function is characteristic, usually without significantly increased ventricular volume. ‘I2 The cardiac abnormalities described in association with AIDS have most often had features typical of dilated cardiomyopathy. However, because of the ubiquity of opportunistic infection, the cardiomyopathy related to AIDS may eventually prove to be of the secondary variety. In several case reports in which clinical manifestations were attributed to specific microorganisms, it was not always readily obvious whether the microorganism identified was an “innocent bystander”l13 or was directly related to the signs, symptoms, or laboratory findings observed.110’ 1X1 DIFFERENTIAL

DIAGNOSIS

In evaluating the diagnostic possibilities in congestive cardiomyopathy, it is important to consider other common causes of left ventricular dilatation. In the United States, where coronary disease is the most common cause of clinical disease, ischemic cardiomyopathy must be excluded. While clinical findings consistent with dilated cardiomyopathy have been observed primarily in AIDS patients, concurrent end-stage hypertensive heart disease and ischemic cardiomyopathy may also produce similar signs and symptoms. In populations with a high prevalence of hypertension and diabetes (such as blacks and Hispanics), the interaction of hypertension, coronary ischemia, and HIV infection may lead to marked systolic as well as diastolic left ventricular dysfunction.1’4 In IVDAs, hypersensitivity reactions to foreign substances contaminating illicit intravenous drugs may also be a factor in the pathogenesis of cardiac abnormalities. In addition, cocaine, a drug commonly used alone and in combination with “street heroin” may produce cardiac disease, most likely through coronary spasm and ischemia.115’“6 Cocaine use has also been shown to be strongly associated with endocarditis in IVDAs. Other possible etiologies of AIDS-related cardiac disease include curr

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611

TABLE Management

7. of Myocardiai

Disease

Related

to AIDS

Diagnosis Consider pathogens common to population and locate ? Cardiac etiology or cardiopulmonary complaints Physical examination: Classic findings absent? Routine laboratory examination: ? Cardiac etiology of abnormal chest x-ray Consider Holter with dysrhythmia or chest x-ray abnormal electrocardiogram Tests Echocardiography: ? four chamber enlargement, hypokinesis. Serial ethos detect deterioration Radionuclide: Gallium scanning for myocarditis Biopsy: Endocardial biopsy for etiology of myocarditis or cardiomyopathy? Genomic probes for human immunodeficiency virus, other viruses Antimyosin antibodies, autoantibodies Therapy Correction of anemia, malnutrition, electrolytes Consider therapeutic trial (toxoplasmosis, tuberculosis) Consider risks of digoxin, diuretics, vasodilators Consider steroids or immunosuppressive therapy?

late

severe anemia,l17’ *I8 selenium deficiency,“’ excess catechol stimulation,l” autoimmune phenomena,l’l and malnutrition.122 Precise delineation of the etiology of the cardiac failure observed in AIDS patients may be aided by wider application of sophisticated diagnostic tools, such as immunocytochemistry, DNA probes, and in situ hybridization techniques. MYOCARDITIS

Because of the wide range of cardiac abnormalities occurring in AIDS patients, the relationship of histopathologic abnormalities that might indicate myocarditis and abnormalities related to clinical cardiac dysfunction are of interest. An AIDS-related postmyocarditic cardiomyopathy has been postulated, because histologic evidence of myocarditis has been found commonly in AIDS patients with diffuse left ventricular dysfunction (Table 7). However, congruity between the clinical or gross anatomical cardiac findings and histopathologic observations has been lacking. Several studies have documented the increased prevalence of myocarditis associated with AIDS, but when the small proportion of cases in which an opportunistic pathogen has been identified in the myocardium are considered, an idiopathic or viral etiology of the myocarditis, rather than a secondary process, is most likely. Perhaps because the cardiac abnormalities associated with AIDS are often obscured by the clinical manifestations of opportunistic in-

612

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1!390

fection or neoplasm, early reviews of the pathologic findings in AIDS did not show signiIicant myocardial involvement. The Dallas criteria for histologic diagnosis of myocarditis include an inflammatory infiltrate and myocyte necrosis or damage not related to ischemic disease.lZ3 In addition to myocarditis in which intramyocardial microorganisms have been identified, three histopathologic patterns have been described in patients with AIDS: lymphocytic infiltration with necrosis of myocytes (meeting the Dallas criteria), lymphocytic infiltration without inflammatory infiltrates, and myocyte damage in the absence of cellular inflammatory inIiltrates.s The pathogenetic significance of these histologic patterns and their relationship to other structural and morphologic findings in the heart, as well as to the natural history of AIDS, remain a topic for further investigation. In an autopsy study, Baroldi et a141 found lymphocytic infiltrates in the hearts of 20 of 26 (77%) patients with AIDS. Cardiac symptoms were absent in all cases. In 34% (9 of 26 patients) the lymphocytic infiltrate surrounded or was within necrotic myocytes, meeting the Dallas criteria for myocarditis. In 7 cases the lymphocytic infiltrates were found in myocardium without myocyte damage and in 4 patients epicardial lymphocytic infiltrates alone were found. In 8 patients who had echocardiographic evaluation, abnormal left ventricular fractional shortening was noted in 6, left ventricular dilatation in 3, globular shape and diffuse hypokinesis in 5. In the 2 cases with normal echocardiograms, no lymphocytic infiltrates were found. But, upon histologic examination of the myocardium in the 6 with abnormal echocardiograms, Dallas criteria for myocarditis were met in 4, lymphocytic infiltration without myocyte necrosis was seen in 1 and lymphocytic infiltration confined to the epicardium found in another. Baroldi and associates concluded that the myocardial dysfunction noted in AIDS patients could not be attributed solely to lymphocytic myocarditis. In contrast, Anderson and associates,40 in a review of 71 necropsy patients, found myocarditis in 52% (37 of 71 cases), and suggests that biventricular dilatation in AIDS may be related to this pathologic finding. In 7 cases an infectious pathogen was present, but in 30 cases (42%) no evidence of viral, protozoan, bacterial, fungal, or mycobacterial etiology was found. Inflammatory cell infiltrates without myocyte necrosis were found in 10 patients who were not diagnosed with myocarditis. These changes were no more common in AIDS patients than in a control group of patients with sudden traumatic death. In 2 cases without myocarditis, intramyocardial opportunistic pathogens were found. Biventricular dilatation was present in 7 cases; in 4 of these the cause of death was congestive heart failure. All cases with biventricular dilatation had myocarditis, but myocarditis was not associated with isolated right ventricular dilatation or pericardial effusion.

Curr

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1990

613

Biventricular dilatation was present in 3 patients without clinical congestive heart failure who died of septic shock. Reilly et al.lz4 studied the relationship between clinical and histopathologic findings in 26 of 58 AIDS patients satisfying the Dallas criteria for myocarditis. Fifteen of 26 (58%) patients with myocarditis had one or more clinical cardiac abnormalities compared with 6 of 32 (19%) patients without histopathologic myocarditis. Symptoms of congestive heart failure or echocardiographic evidence of left ventricular dysfunction were found in 6 cases with myocarditis. Major cardiac abnormalities, including congestive heart failure, left ventricular dysfunction or ventricular tachycardia, occurred only in patients with myocarditis. Biventricular failure was only noted in 3 patients with myocarditis. Lymphocytic myocarditis was also the most common histopathologic abnormality found by Roldan et a13’ in an autopsy study of 54 patients with AIDS. Lymphocytic infiltration with myocyte necrosis was the predominant histopathologic pattern observed, occurring in 31% (17 of 54) of cases. In 6 of these cases, toxoplasmic myocarditis was present. Cardiac involvement was asymptomatic in all patients except 1, who had toxoplasmic myocarditis. In a report of 3 cases of possible dilated cardiomyopathy associated with AIDS, Cohen et a1.44 found focal lymphocytic myocarditis in 2 cases examined postmortem. This finding, in the absence of evidence of other opportunistic infection, suggested a viral etiologv for the cardiac dysfunction noted antemortem. Myocarditis and Opportunistic Infections Even though a wide variety of opportunistic infections have been documented in patients with AIDS, relatively few have been definitely linked to myocarditis through identification of the infectious agents in the myocardium. Myocardial disease resulting from opportunistic infection is usually part of the disseminating process, with major extracardiac involvement and multiple foci of infection systemically. Because patients with AIDS often have multiple and sequential opportunistic infections, even when an organism is found in the myocardium at histologic exam, a definite relationship to other pathologic abnormalities or clinical manifestations may not always be certain. In the study by Anderson and associates,40 a diverse array of opportunistic pathogens were identified histologically within the myocardium in 19% (7 of 37) of AIDS patients. In 2 patients, organisms were identified within a locus of inflammatory cell infiltration, acidfast organisms in 1 patient and gram-positive cocci in another. In 5 patients evidence of opportunistic pathogens, including T. gondii cysts, Histoplasma capsulatum yeast cells, and cytomegalovirus inclusion bodies, were unaccompanied by myocarditis, although myo614

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1990

carditis was found elsewhere in the tissue sections. In the study by Baroldi et al.,41 myocardial microorganisms (7’. gondii, sarcosporidium, and C. neoformans) without associated inflammatory reaction, were documented in 3 patients. In another study of myocarditis in AIDS by Reilly et al.,lz4 only 2 cases demonstrated intramyocardial organisms. Both cases involved cytomegalovirus, one with associated myocarditis and one without an inflammatory infiltrate.

Viral Myocardial

Disease

The clinical sequelae of cytomegalovirus in myocardial disease related to AIDS are difficult to assess. Although cytomegalovirus is one of the most frequently identified opportunistic pathogens at postmortem in patients with AIDS, the infrequent finding of inclusion bodies in the heart prior- to the advent of AIDS has cast doubt on the significance of cytomegalovirus in most patients with myocarditis. In the AIDS era, cytomegalovirus has also been rarely demonstrated in the myocardium.“’ Neidt and Schinella,37 in a pathologic study of 56 patients with AIDS, found cytomegalovirus in 43 cases (77%), 4 of whom had congestive heart failure, arrhythmia, or electrocardiographic changes and demonstrated inclusion bodies and myocarditis. Welch et al.34 found only cytomegalovirus inclusion bodies in the epicardium of 1 AIDS patient. However, cytomegalovirus may be present in tissue without detection of the characteristic inclusion bodies. Myerson and colleague? studied cytomegalovirus infection in patients following bone marrow transplantation using a biotinylated DNA probe. With this more sensitive technique, cytomegalovirus infection was detected in many viscera, often in the absence of typical inclusions. The DNA probe also revealed cytomegalovirus infection of cardiac myocytes, without evidence of inclusion bodies. Compared with other viscera, the extent and quantity of cytomegalovirus infection in myocytes detected by the DNA probe was minimal. Myocarditis resulting from cytomegalovirus was reported uncommonly prior to the growth in clinical importance of AIDS. Wink and Schmitz127 described a 31-year-old man who presented with shortness of breath, dyspnea on exertion, ankle and leg swelling, and nocturia with diffuse left ventricular enlargement on chest x-ray. On echocardiography, four-chamber enlargement and decreased left ventricular posterior wall motion, but no pericardial effusion, were seen. Serologic and immunologic studies were consistent with cytomegalovirus infection. After 3 weeks of bed rest, clinical and laboratory evidence of heart failure diminished and the echocardiogram showed no abnormal findings. Wilson et a1.l” also reported a case of cytomegalovirus myocarditis in a 60-year-old woman who presented with a history of “a head cold” 3 weeks prior to the development of Curr

Probl

Cardiol,

October

1990

615

dyspnea and paroxysmal nocturnal dyspnea. Serologic cultures and immunologic tests were negative for bacterial and viral pathogens except for a marked rise in cytomegalovirus antigen. Digitalis and diuretic therapy provided transient improvement, but because of continued signs and symptoms of cardiac dysfunction, a diagnosis of viral myocarditis was made. The authors concluded that the signs and symptoms of congestive heart failure and concurrent rise in cytomegalovirus titers were consistent with cytomegalovirus myocarditis. Histologic findings are not described in either of these earlier studies. In AIDS, cytomegalovirus may be associated with a wide variety of clinical manifestations. Cytomegalovirus infection most commonly causes a pneumonitis, often associated with P. carinii infection. Although cytomegalovirus was rarely associated with clinically significant cardiac findings before the AIDS epidemic, the increased incidence of disseminated cytomegalovirus infection in AIDS may be associated with more cardiac involvement. Although up to 90% of patients with AIDS will develop cytomegalovirus infection, including chorioretinitis, pneumonia, adrenalitis, or gastrointestinal disease, only 25% of these disorders will seriously jeopardize vision or become life-threatening.*2s Male homosexuals may have a higher rate of cytomegalovirus seropositivity and more clinical disease, although other studies have reported conflicting data.3s Appreciation of the role of cytomegalovirus in myocardial disease in AIDS is limited because cytomegalovirus infection may not always be related to clinical disease, even though the organism is cultured from the heart or pericardium. With the demonstration in several studies of the inconsistent relationship of inflammatory cellular infiltrates and myocyte necrosis to intramyocardial opportunistic microorganisms, the possibility that the myocardial lymphocytic infiltrates described in a substantial proportion of AIDS patients may represent occult viral infection of the heart cannot be easily dismissed. The failure to detect cytomegalovirus inclusion bodies no longer precludes consideration of cytomegalovirus as an explanation for the cardiac histopathology findings in AIDS. Evidence from pathologic studies of patients with AIDS suggests that, even though some patients with lymphocytic myocarditis may present with cardiac signs and symptoms, many will remain asymptomatic, with myocarditis incidentally detected at autopsy or with endocardial biopsy. Roberts and co11eagues,13o in a study of 67 IVDAs, 4.2 with AIDS and 25 without AIDS, compared the prevalence of lymphocytic infiltrates with myocyte degeneration in the two groups. The prevalence of myocarditis was similar in both groups, 57% with AIDS and 44% without AIDS. Ventricular dilatation was also comparable in both groups. Pyogenic infection, as evidenced by infiltration of the endocardium with neutrophils, was more common 616

Cur-r

Pmbl

Cardiol,

October

1666

in IVDAs without AIDS. Since approximately 50% of IVDA in New York City harbor the HIV virus, it is conceivable that the similar frequency of lymphocytic infiltrates in both groups reflect early occult HIV myocarditis or the cardiac effects of other HIV-related immune processes active early in the course of HIV infection. Histopathologic changes related to viral myocarditis occurring prior to the development of an AIDS-defining clinical event may persist and would be detected in the course of evaluation of pyogenic or other opportunistic infection or at autopsy. In IVDAs, in whom other life-threatening disease may supercede AIDS, depending on the degree of immune suppression and virulence of other opportunistic microorganisms in the population, the histopathologic changes in the heart may be equally prevalent in those with and without AIDS-defining disease. Conversely, the -cardiac histopathologic changes in IVDAs may be unrelated to HIV infection, resulting from unrecognized myocardial involvement in the course of other systemic disease, subclinical opportunistic infection, or non-HIV virus infections. In addition to pathologic studies of patients with HIV infection, the frequent occurrence of unrecognized lymphocytic myocarditis at postmortem examinations has been demonstrated in several studies of patients without AIDS. Histologic evidence of myocarditis may occur at autopsy in up to 10% of routine postmortem examinations131 and in 17% to 21% of autopsies of young persons who experienced sudden death.13’ Myofibrillar degeneration and cellular infiltrates have also been found in association with severe psychologic stress133 and with excessive catechol stimu1ation.l” Lymphocytic infiltrates have also been noted in patients with ventricular arrhythmias and no structural heart disease.134 Tazelaar and Billingham found inflammatory cell infiltrates in 87% of endocardial biopsies of 108 excised hearts of cardiac transplant recipients with a diagnosis of idiopathic congestive dilated cardiomyopathy. Roberts and Ferrans, 136 however, found no myocardial inflammatory infiltrates in an autopsy study of 64 patients with congestive cardiomyopathy. The wide range of incidence of myocarditis reported in idiopathic dilated cardiomyopathy, as well as in the general autopsy population, reflects disagreement over the histologic definitions of myocarditis and the high level of confusion regarding the significance of lymphocytic myocardial infiltrates in various clinical contexts. Tazelaar and BillinghamlW suggest that inflammatory cell infiltrates in the myocardium (possibly even in the presence of myocyte necrosis) does not justify the diagnosis of myocarditis, and consider the inflammatory cells as part of the “background” of dilated cardiomyopathy. Even though investigators have conflicting opinions regarding the pathogenesis and significance of lymphocytic infiltrates in the myocardium of patients with dilated cardiomyopathy, the diagnosis of lymphocytic myocarditis still has important clinical and prognostic Curr

Bob/

Cardiol,

October

1990

617

implications. Because of several reports of successful treatment of postmyocarditic dilated cardiomyopathy with steroid and immunosuppressive therapy, a continuing interest in the use of these therapies in any patient in whom congestive heart failure is not obviously related to hypertension or coronary disease has persisted. The efficacy of these drugs in the treatment of postmyocarditic dilated cardiomyopathy, as well as idiopathic cardiomyopathy, remains moot. Even though steroids and immunosuppressive drugs have not been recommended in patients with AIDS, the advent of anti-HIV agents may provide a new approach to cardiomyopathy in AIDS, provided the cardiac disease in AIDS is HIV-related. Levy et al.137 have reported two cases of AIDS with significant cardiac dysfunction in whom endocardial biopsy demonstrated lymphocytic myocarditis. Interestingly, one patient responded to high-dose intravenous corticosteroids and zidovudine. Viral cultures of biopsy tissue were negative. As part of the diagnostic investigation of a 32-year-old homosexual man with a 4-year history of AIDS and clinical and laboratory evidence of congestive heart failure, Calabrese and co-workers7’ performed a “subendocardial biopsy.” Light and electron microscopic analysis revealed myocyte degeneration but no inflammatory infiltrate or viral particles. However, co-culture of myocytes was positive for HIV antigen. Although neither direct visualization of virus nor in situ hybridization or immunohistochemical techniques were utilized in this case, the authors acknowledge that the cardiac abnormalities in AIDS may be the result of direct or indirect effects of the HIV virus. Dittrich et all” reported a similar case of a 28-yearold homosexual man with congestive cardiomyopathy in whom coculture of tissue obtained at endocardial biopsy was also positive for HIV. No inflammatory response or viral particles were identified. In contrast to the previously reported case, immunocytochemistry and in situ cytohybridization with full length probe were performed, but failed to detect HIV. Acute and convalescent phase titer for coxsackie B2 virus, however, were consistent with recent infection with this well-known cardiotropic virus. Dittrich and colleagues point out the limits of endocardial biopsy in establishing the etiology of myocarditis because of spurious results arising from analysis of contaminated blood obtained with the biopsy. The inconsistent demonstration of myocarditis on endocardial biopsy contrasts with pathologic studies of AIDS, which have shown up to a 50% prevalence of myocarditis. This may be explained by the nonuniform and focal distribution of the inflammatory infiltrates of myocarditis and the difficulties with sampling inherent in the biopsy technique. To,xoplasmic Myocarditis in AIDS Despite the diverse and unusual opportunistic infections that occur with AIDS, toxoplasmosis continues to be the most common 618

Cum

Probl

Cardid,

October

ISIO

documented infectious cause of myocarditis in AIDS, and occurs most often in populations with high rates of AIDS infection. In studies of non-Haitian AIDS patients, T. gondii is an uncommon cause of myocarditis. For definitive diagnosis of T. gondii infection, identification of the typical To)toplasma cysts is necessary. In the autopsy study by Roldan et aL3’ 17 of 54 (31%) patients had histologic evidence of myocarditis. Of those patients with myocarditis, tachyzoites were noted in 6 patients, 5 of whom were Haitian. To)coplasma cysts were found in only 1 patient. In an autopsy study of 26 AIDS patients, Baroldi and associates4* found intramyocardial toxoplasma organisms in 3 patients. To&opZasma organisms were identified in 2 myocells but no inflammatory reaction was noted. Klatt and Meyer,13’ in a letter describing their findings in 187 cardiac lesions in patients with AIDS, found nonspecific myocarditis in 12 patients with To)toplasma infection elsewhere. Toyoplasma cysts or tachyzoites were identified in only 1 patient. Toxoplasma infection of the central nervous system was present in 5. In yet another case, isolated toxoplasmic myocarditis led to overwhelming cardiac decompensation and death. b D. MCCALL: From the review provided by Dr. Francis it is apparent that myocardial involvement with myocarditis and dilated cardiomyopathy may occur from a wide variety of infectious agents in the HIV positive individual. Until recent years these did not assume a role of clinical prominence since the majority of patients succumbed to other intercurrent infections earlier in the course of their disease. With improved therapy of these other infections, the mean survival time for patients with AIDS is increasing, and it is probable that the myocat&tides will be seen more frequently with both myocarditis and frank congestive heart failure playing a mom prominent role as a terminal illness in AIDS.

Fungai Infection

and Myocardial

Disease in AIDS

Evidence for myocardial disease related to fungal, mycobacterial, and pyogenic infection in AIDS occurs almost exclusively with disseminated disease with intramyocardial colonization. Widespread organ involvement is typical, probably because of immunocompromise. In the pie-AIDS era, the nature of fungal infection varied. Walsh et al.,66 in a study of 51 autopsies of patients with fungal infections prior to the AIDS era, found that cryptococcus accounted for 6% of cases of myocarditis, and 71% of cases of myocarditis were caused by Candida. Aspergillus caused 50% of cases of endocarditis. Atkinson et al.,65 m . an autopsy study of 60 patients, also found Candida to be the most common etiologic organism; with Aspergilhs second. Phycomycetes infection was found in 7 patients, 6 of whom had myocarditis; cryptococcosis was found in 2 patients (3%), 1 with myocarditis and endocarditis, and another with pericarditis. Walsh and colleagues66 do not mention intravenous drug abuse as a contributing factor, and only 2 of the patients reported by Atkinson et a1.65 were IVDAs. Curr

Probl

Cardiol,

October

1990

619

The prevalence of various pathogens in myocarditis diagnosed at necropsy in patients with AIDS is indicated in Table 8, and the incidence of several pathologic findings in these patients is included in Table 9. DIAGNOSTIC

TESTS

The CDC criteria for the diagnosis of AIDS have incorporated guidelines for the diagnosis of AIDS-defining opportunistic infections and neoplasms. Standard procedures for the evaluations of patients with possible AIDS have been generally accepted. The extensive array of serologic, immunologic, and bacteriologic studies that comprise the diagnostic armamentarium for AIDS is beyond the scope of this monograph. The electrocardiogram, while invaluable in assessing arrhythmias in the patient with AIDS, may also reveal concurrent ventricular hypertrophy or ischemic heart disease. The conduction system may be involved with microabscess formation in some opportunistic infections. With diffuse left ventricular dilatation, as in cardiomyopathy, the electrocardiogram may demonstrate nonspecific ST and T wave changes, which indicate the need for further evaluation. Because AIDS often afflicts individuals earlier in life than coronary artery and hypertensive heart disease, electrocardiograph changes that might be dismissed as normal variants in a young population without HIV infection may warrant further investigation in patients at risk for AIDS. The chest radiograph may provide an early clue to cardiac inTABLE

8.

Prevalent

Myocarditis

Clinical

at Necmpsy

Features

No. of Patients Age (years) Men Women Risk factors Sexual Intravenous drug abuse Other Opportunistic pathogens Bacterial Fungal Mycobacterial Protozoan Virus Kaposi’s sarcoma Lymphoma 6243

in AIDS Anderson“”

Bamldi“l

71 38 67 4

26 31 25 1

53 (75%) 5(7%) 13 (1SWl

4 (15%) 20 (77%) 2(8%)

0 41 (58%) 30 (42%) 57 k3owr 0 (O%J 35 (49%) l(l%)

3 (1lWl 24 (92%) 1(4%) 7(27%) 11 (42%) 1(4X) 0 (0%)

Curr

Probl

Cardioi,

October

1990

TABLE

9.

Prevalent

Myocarditis

Necrupsy

Findings

at Necropsy

in AIDS* Andersonw

Baroldf’l

No. of Patients

71

26

Cachectic habitus Heart weight RV dilation BV dilation

37 (52%) 326 2 69 gm 12 (17%) 7 (10%) 15 (21%)

10

37 (52%) 9 (13%)

9 (35%) 3 (lZ%b)

Per&u-dial

effusion

Myocarditis 01 in myocardium *RV = right ventricular;

BV = biventricular;

01 = opportunistic

352

(38%) + 67~

? ? ?

infection.

volvement, since evidence of cardiomegaly, incipient congestive heart failure, or pericardial effusion may be revealed. Even in the absence of distinct cardiomegaly, the chest x-ray may help distinguish between respiratory symptoms of pulmonary or cardiac origin. The echocardiogram remains the single most useful noninvasive cardiac diagnostic test in assessing possible cardiac involvement in AIDS. With myocardial disease, it is particularly important to determine the level of functional performance of the left ventricle, as well as the structural characteristics of the valves, cardiac chambers, and myocardium. Reduced systolic function may be present without chamber enlargement in some patients. Detection of diastolic dysfunction may also be an indication of significant cardiac involvement. Since there is usually paucity of signs and symptoms of cardiac disease in many patients with AIDS, the echocardiogram may uncover unsuspected valvular vegetations in a febrile patient with cryptococcal meningitis, or pericardial effusion in a patient with milky tuberculosis. Endocardial biopsy may prove to be a valuable tool in diagnosis of cardiac disease in AIDS patients because it provides an opportunity to obtain tissue antemortem for culture and further study using DNA probes, in situ hybridization, and other techniques. Because of the multiplicity of possible infectious processes in AIDS patients, thorough cardiac evaluation should be considered very early in the course of disease, since abrupt and often clandestine clinical deterioration is not uncommon.

THERAPY

Discussion of the specific antimicrobial choices for management of the array of opportunistic infections that might involve the myocardium in patients with AIDS is beyond the scope of this review. Whenever possible, tissue diagnosis, isolation, and identification of Curr

Probl

Cardiol,

October

1990

621

specific etiologic agents should be aggressively pursued, particularly if there is evidence of cardiac decompensation. Appropriate antimicrobial therapy, based on culture and sensitivity studies, is critical. The role of systemic corticosteroid and immunosuppressive therapy remains a topic of debate. Steroids as well as immunosuppression are best avoided in the treatment of AIDS-related cardiac disease, unless administered as part of an investigation of the efficacy of new and alternative therapies for cardiac involvement in AIDS. In some instances, such as in the presence of toxoplasmosis, a therapeutic trial of specific antimicrobial therapy may be considered, especially when definitive diagnosis involves a procedure with significant risk, such as brain biopsy. In populations at increased risk for tuberculosis, prophylactic antituberculous therapy may be considered in patients with positive skin tests. ENDOCARDIAL

DISEASE

IN AIDS

Involvement of the pericardium, with associated effusion or tamponade, or of the myocardium, with associated cardiomyopathy or arrhythmia, have been reported with increasing frequency as the AIDS epidemic has gained momentum. Paradoxically, reports of infective endocarditis in AIDS, either because of pyogenic or opportunistic pathogens, have been relatively less common (Table 10). This is particularly surprising, since IVDAs comprise the second largest risk group for AIDS and, in some locales, approximately half of this population is infected with HIV. When IVDAs with AIDS have been TABLE

10.

Endocardial

Disease

Related

to AIDS*

Prevalence Increased pyogenic infections in IVDAs Infective endocarditis common in IVDAs Nonbacterial thrombotic endocarditis common Etiology Pyogenic bacteria (such as S. aureusl Opportunistic pathogens (such as fungi) Often associated with disseminated infection Neoplastic involvement may occur Features Acute rather than insidious onset, fever, murmur Tricuspid valve infection common, with embolic pneumonia, chest pain, Polymicmbial and culture negative varieties Systemic embolization, peripheral stigmata Destruction of valve leaflets and pancarditis Extracardiac involvement common (such as stroke, osteomyelitis, mycotic ‘MIAs 622

= intravenous

cough

aneurysm)

drug abusers. Cum

Probl

Cardid,

October

1990

compared to a group of IVDAs without AIDS, pyogenic infections were significantly greater in IVDAs without AIDS. Since IVDAs remain at increased risk for pyogenic infections, even after developing HIV infection, it is likely that many succumb to pyogenic infections before clinical evidence of immunosuppression is noted. Abuse of multiple drugs has increased among IVDAs. Cocaine, used intravenously in combination with heroin, has become increasingly popular. The risk of endocarditis increases in IVDAs who also use cocaine. In addition, alcohol abuse, which is common among IVDAs, as well as heroin abuse, may also lead to bacterial infection through adverse effects on host defenses.13” X4’ Abnormal immunologic function may also be directly associated with intravenous opiate abuse. Because infections commonly occurring in IVDAs in the past were not related to immunocompromise, it-is likely that, even though cellular immunity is depressed in AIDS, the spectrum of infection with pyogenic organisms in IVDA will not be changed significantly as the epidemic of AIDS continues. NONBACTERZAL

THROMBOTIC

ENDOCARDITZS

Nonbacterial thrombotic endocarditis or marantic endocarditis, a process commonly associated with severe wasting diseases, particularly malignancy or severe inanition, has been found at postmortem in patients with AIDS.141 In non-HIV-infected patients, the process has also been linked to much-i-secreting tumors. It may also occur in systemic lupus erythematosus. Characterized by large, friable vegetations on the cardiac valves along coaptation points, the lesions are sterile and not associated with inflammatory response.14’ Systemic embolization is frequent, and focal neurologic deficits or other signs of peripheral embolization are often encountered clinically.143 Garcia et al.144 described a case of nonbacterial thrombotic endocarditis with Kaposi’s sarcoma in a 36-year-old homosexual man with multiple infectious complications, typical of immune deficiency. After treatment for Pneumocystis pneumonia, Kaposi’s sarcoma, fungal infection, and StaphyZococcus epidermidis bacteremia, the patient expired. Postmortem examination revealed nonbacterial thrombotic endocarditis of the mitral and aortic valves with infarctions of the brain and multiple viscera. Nonbacterial or marantic endocarditis has been reported in several studies of cardiac abnormalities in AIDS. Right-sided marantic endocarditis was detected in 1 of 15 AIDS patients reported by Fink in 3 of 30 AIDS et al.43 Roldan et aL3’ found marantic endocarditis patients with cardiac lesions at autopsy. In another autopsy study, Guarda and colleagues36 noted nonbacterial thrombotic endocarditis involving the aortic or atrioventricular valves in 2 of 13 patients with AIDS. The cardiac lesions were accompanied by systemic emCur-r

Probl

Cardiol,

October

1999

623

bolization to the brain and other viscera or disseminated intravascular coagulation. The combination of nonbacterial thrombotic endocarditis and disseminated intravascular coagulation has been reported by previous investigators,‘45 but the mechanism for this association is poorly understood. Systemic embolization with cerebral infarcts from vegetations caused by nonbacterial thrombotic endocarditis has also been noted antemortem. Cammarosano and Lewis3’ found nonbacterial thrombotic endocarditis in 3 of 10 AIDS patients with major pathologic findings of the heart. In 2 cases, 1 with vegetations on all cardiac valves and 1 with only mitral valve involvement, cerebral infarcts were noted antemortem. In these 2 patients, embolization to the brain was considered the cause of death. In the third case, vegetations were confined to the tricuspid and pulmonic valves. Nonbacterial thrombotic endocarditis may play a role in the pathogenesis of some cases of pyogenic or fungal infective endocarditis, when, in the course of transient bacteremia, the lesions of nonbacterial thrombotic endocarditis become infected with pyogenic organisms and typical infective endocarditis ensues. FUNGAL ENDOCAZ-IDZAL DZSZXASE While the incidence of infective endocarditis resulting from pyogenie endocarditis has remained relatively stable in IVDAs with AIDS, the incidence of fungal endocarditis has grown with the increasing prevalence of AIDS, particularly among IVDAs. Like nonbacterial thrombotic endocarditis, infective endocarditis resulting from fungal infection is characterized by systemic embolization. Prior to the AIDS epidemic, fungal endocarditis was noted most commonly in postsurgical patients, particularly those subjected to prolonged broad spectrum antimicrobial therapy, IVDAs, and patients with immunologic deficits. In AIDS, fungal infections of the heart are often related to systemic spread of fungal infection from extracardiac foci. Fungal endocarditis, especially that from cryptococcus or Candida, is common in AIDS, particularly in IVDAs. Candidiasis of the oropharynx and esophagus is most often the primary focus, often progressing to systemic infection. Surprisingly, infective endocarditis resulting from Candida has not occurred more frequently in patients with AIDS, but remains a serious complication of oral and esophageal candidiasis. In a study of the pathologic findings in AIDS, Neidt and Schinella37 found that Candida was the most common fungal infection, with 44 of 56 (82%) patients diagnosed either postmortem or antemortem. In twelve cases with disseminated candidiasis, the organism was found in the heart, spleen, testes, and kidney. Fungal endocarditis was not described in any patients. Guarda et al.36 reported systemic Candida infection in 4 of 13 (31%) patients with AIDS. Welch and associates34 also found that oral candidiasis was 624

Cur-r

Probl

Car&d,

October

1990

the most common infection among 36 AIDS patients studied at necropsy. Even though the organism could be cultured from numerous sites, clinical cardiac disease was not related to the infection. Cryptococcus neoformans is one of the most common serious infections in AIDS patients. Although cryptococcosis may affect many viscera, meningitis and encephalitis are the most frequent manifestations. Involvement of the heart, particularly with pericardial effusion, is common in AIDS. Fungal myocarditis with significant heart failure may also occur with valve destruction or with intramyocardial abscesses. Because cryptococcal meningitis is often the focus of clinical attention, cardiac involvement with disseminated disease may be overlooked. Conversely, neurologic complications secondary to cerebral embolization from primary cardiac infection may be the initial presenting complaint. Fungal endocarditis associated with disseminated aspergillosis may also occur in AIDS. Henochowicz et al.64 described a 3&year-old IVDA with AIDS and pulmonary aspergillosis in whom the first evidence of fungal endocarditis was the development of focal neurologic signs. With aspergillosis, as well as other fungi, signs of systemic or cerebral embolism may indicate the presence of endocarditis because of the absence of positive blood cultures and unobtrusive clinical evidence of heart disease. PYOGENIC

BACTERIAL

ENDOCABDITIS

The clinical features of infective endocarditis in patients with AIDS is very similar clinically to that of the non-AIDS population. However, because of the deficit in cellular immunity, the infection may be more virulent, leading to more significant cardiac structural damage and functional deterioration. Although the ditferential diagnosis of febrile illness is dramatically expanded in AIDS, especially in IVDAs,14’ the spectrum of pyogenic bacteria causing infective endocarditis has not been significantly altered. Although transient bacteremia may occur commonly in the course of daily living, IVDAs are more likely to develop infective endocarditis because of increased exposures to blood-borne pathogens because of unsterile injection techniques.148 Infections of the skin, sinuses, and lungs are particularly common. The most common pathogens are encapsulated bacteria, including S. aureus, S. pneumoniae, and Haemophilus injhenzae. As in the past, streptococci or staphylococci most commonly cause infective endocarditis. S. aureus endocarditis remains the most common cause of acute endocarditis in IVDAs, with or without AIDS. Methicillin-resistant staphylococci are common and require appropriate adjustment of antibiotic therapy. Because of repeated hospitalizations inherent in the prolonged care patients with AIDS require, acquisition of resistant organisms may be a special problem. Infection with unCurr

Probl

Cardiol,

October

19Yo

625

common bacteria is also frequent.‘48’14s The HACEK group of organisms, which include Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominus, Eikenella corrodens, and Kingella kingae, are very fastidious organisms that are difficult to culture .150 These organisms are often part of the endogenous flora of the mouth, and because endocarditis may be related to periodontal disease, these organisms may be an important consideration in endocarditis in some risk groups. Sepsis, most often originating because of S. epidermidis or S. aureus, is also increased in patients with AIDS. Intravenous drug abusers infected with HIV are more likely to develop bacterial pneumonia because of the marked debilitation common in AIDS patients. Austrian’s syndrome, which is characterized by acute S. pneumoniae endocarditis, pneumococcal pneumonia, and meningitis, has been noted more commonly in AIDS (personal communication, Francis CK, 19881, although this syndrome was originally described in alcoholics.

CLINICAL FEATURES Because endocarditis in patients with AIDS is often part of widespread systemic opportunistic infection, it is important to distinguish the clinical characteristics of endocarditis from the signs and symptoms of the complications of opportunistic infections (see Tables 10 and 111. In IVDAs, this may be especially difficult because of the overlap of clinical syndromes related to AIDS with those unassociated with HIV infection. Symptoms suggestive of endocarditis common to non-AIDS and AIDS-related disease include weight loss, weakness, lethargy, fever, and chills. Depending on the extent of cardiac and pulmonary involvement, patients may complain of dyspnea, chest pain, cough, or fatigue. In addition to fever and cardiac murmur, peripheral stigmata of endocarditis may be noted. The presence of petechiae of the skin or conjunctivae, Osler’s nodes (tender erythematous nodules on the fingertips), Janeway lesions (nontender, flat, red spots on the palms and soles), and Roth’s spots (white or yellow lesions surrounded by an irregular red halo in the retina), and digital clubbing may help in the diagnosis, but are nonspecific and inconsistent findings. Even though the physical examination findings classically associated with endocarditis have been observed less commonly in the general population with infective endocarditis, they continue to be seen commonly in IVDAs with AIDS. With staphylococcal endocarditis, peripheral stigmata are common. Petechiae are unusual in nonbacterial thrombotic endocarditis, however. Endocarditis may be associated with immunologic stimulation, which may involve the kidney, producing focal, diffuse, or immune complex glomerulonephritis. Renal involvement rarely 626

Curr

Probl

Car&id,

October

1666

TABLE

11.

Management

of Endocarditis

Related

to AIDS*

Diagnosis Fever, positive blood cultures Physical signs (heart murmur may be absent) Routine lab, chest x-ray (? pneumonia, empyema), electrocardiogram Tests Echocardiography: Vegetation, thrumbus, valve integrity Distinguish between bacteremia and endocarditis? Consider nonbacterial thmmbotic endocarditis Consider immunopathologic complications Radionuclide: Gallium scanning may be helpful Functional, hemodynamic, and angiographic tests? Therapy Urgent therapy with acute left-sided endocarditis Aminoglycoside may be added, pending cultures Intravenous drug abuse, assume resistant staph, start vancomycin Treat for 4-6 weeks, frequently check for congestive heart failure Role of cephalosporins and quinolones is uncertain Surgery Indications may be the same as in non-AIDS In MJAs discontinuation of drug abuse is critical ‘MJA

=

intravenous

(?I

drug abusers.

progresses to renal failure. Immunologic phenomena may also be responsible for musculoskeletal complaints and pericardial involvement. Congestive heart failure is the most common complication of infective endocarditis, but is infrequently reported. Because endocarditis in AIDS is often accompanied by intense bacteremia with seeding of multiple organs, the initial clinical manifestations of endocarditis in AIDS are often extracardiac. Since P. carinii pneumonia is the most common pulmonary infection in AIDS, the major@ of patients with AIDS receive medical attention because of pulmonary complaints, and a presumptive diagnosis of P. carinii pneumonia is often made. Cardiac disease is often suspected in patients at risk for HIV infection who present with respiratory complaints. With tricuspid valve involvement, septic pulmonary embolism is a major consideration. Septic pulmonary embolism may lead to pulmonary cavitation, lung abscess, and empyema, and should be distinguished from other pulmonary infections, particularly tuberculosis and P. carinii pneumonia. With the increased awareness that tuberculosis in AIDS may present with atypical chest radiographs, it is important to distinguish pulmonary involvement associated with endocarditis from other pulmonary complications of AIDS.

Curr

Pmbl

Cardiol,

October

1990

627

Acute endocarditis may evolve to a marked fulminant course, with rapid onset of congestive failure, often resulting from perforation of valve leaflets, acute mitral regurgitation arising from rupture of chordae tendineae or papillary muscle or myocardial invasion with ventricular septal perforation or fistula formation. Conduction disturbances may occur with myocardial abscess formation or myocardial necrosis and infarction. Extension of infection into the pericardium, with purulent pericarditis, may also occur. Gram-negative infective endocarditis, especially with Pseudomonas species, have become more common in AIDS patients, perhaps because frequent hospitalizations lead to increased exposures to these organisms. LABORATORY

DIAGNOSIS

Infective endocarditis should be suspected in any patient with HIV infection, fever, and a cardiac murmur. Routine laboratory investigations will often reveal anemia or leukocytosis, although these findings are variable (see Table 12). Urinary sediment is often abnormal, demonstrating hematuria or proteinuria of varying degrees. The appropriate number of blood cultures required to make the diagnosis of infective endocarditis has been the subject of prolonged debate. Because bacteremia is common and intense in patients with AIDS, blood cultures are usually positive in patients with significant infection. Three blood cultures drawn at the time of initial diagnostic evaluation is usually sufficient, although some have recommended a larger number. Culture-negative endocarditis, although commonly proposed, is unusual. Failure to obtain positive blood cultures in the patient with AIDS with strong clinical evidence for infective endocarditis should suggest prior antibiotic therapy or fungal endocarditis. The HACEK organisms and other fastidious organisms may also cause culture-negative infections. Candida species are cultured in less than 50% of patients and AspergiZlus can rarely be cultured from blood. Because IVDAs often medicate themselves with antibiotics obtained “on the street,““’ it is prudent to obtain additional cultures several days later to detect recurrent infection. Since relapses and polymicmbial infections are common in AIDS, it is also important to obtain blood cultures during the latter phases of therapy so that recrudescence of partially treated infection or infection with a previously unsuspected pathogen may be unmasked. The chest x-ray in the HIV-infected patient may present a wide array of diagnostic possibilities. The differential diagnosis of pulmonary infiltrates in AIDS is extensive, with P. carinii pneumonia and tuberculosis the most prominent conditions considered. The chest x-ray is fundamental to the assessment of congestive heart failure. Pulmonary venous congestion and vascular redistribution may precede overt clinical pulmonary edema and be an early clue to cardiac 626

Curr

Probl

Cardiol,

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1996

decompensation. Pneumonia resulting from septic emboli may appear as multiple, diffuse, small, patchy infiltrates that may cavitate. Echocardiography is perhaps the most important tool in the diagnosis of infective endocarditis, but should not be relied upon exclusively (see Table 12). When vegetations are demonstrated, the diagnosis of endocarditis is usually established, since false positive studies are unusual. The sensitivity of echocardiography in detecting endocarditis may range from 40% to 90% .15’ The failure to demonstrate vegetations, however, does not exclude endocarditis. The large vegetations of fungal endocarditis and nonbacterial thrombotic endocarditis are usually readily detected by echocardiography. Demonstration of vegetations has been associated with subsequent embolization and invasive infection. Echocardiography may also provide important information regarding the functional status of the heart. Deterioration of echocardiographic indices of ventricular function followed sequentially may be helpful in early detection of myocardial involvement and congestive failure. In addition to serial clinical evaluation, including repeated auscultation, echocardiographic data is important for decision-making regarding surgical therapy and prognostication. In the patient with cardiac disease associated with AIDS, CT may be especially valuable. Because cardiac involvement may be the source of disseminated infection and may involve the central nervous system, detection of neurologic lesions, such as brain abscess, mycotic aneurysm, or septic emboli should prompt cardiac evaluation. Cardiac catheterization and angiography are usually considered in patients who have not responded to antibiotic therapy or in whom congestive failure has ensued, usually when cardiac surgery is being contemplated. In the patient with AIDS, as in the patient with known malignancy, the decision to proceed to invasive diagnostic studies will depend on individual patient considerations. As the newer therapies for HIV infection evolve and the prognosis of AIDS changes, decisions for surgical intervention will become more complex. In most series, cardiac decompensation and evidence of severe left ventricular dysfunction have occurred predominantly in patients in the terminal phases of HIV disease. In these instances, the decision to perform surgery will be based on factors very different from those considered in a patient in the earlier stages of HIV infection. Presently, surgery would not be a strong consideration in patients in the latter stages of disease and cardiac catheterization would not be indicated, although changing attitudes are likely with time. In patients with active endocarditis, Welton and co-workers153 found that the information obtained at cardiac catheterization provided important clinical and prognostic information, and could be performed safely. Radionuclide techniques may also be useful in the serial asCurr

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sessment of ventricular function tural and anatomical information DRUG-RELATED

but do not provide the added strucof echocardiography.

CARDJAC DISEASE IN AIDS

The patient with AIDS may encounter a diverse selection of pharmaceuticals during the course of therapy for opportunistic infections or neoplasm. Since most patients with AIDS will experience P. carinii pneumonia during the course of illness, the potential for adverse reactions to antimicrobial agents used in the treatment of this opportunistic infection is substantial. Sulfamethoxazole-trimethoprim and pentamidine isethionate have proved effective in patients with AIDS. Adverse reactions to sulfamethoxazole-trimethoprim include nausea and vomiting, skin rashes, nephritis, elevations in transaminase levels, and granulocytopenia. Direct cardiac toxicity has not been reported with this agent. Pentamidine, which has been effective in patients with AIDS, may be associated with significant cardiovascular side effects, as well as abnormal liver function tests, defective glucose metabolism, and neurologic deficits. Significant hypotension has been reported with intravenous and intramuscular pentamidine administration. Navin and Fontaine154 reported 12% hypotension with intramuscular administration and no effect with intravenous therapy. In another study by Helmick and Green,‘55 hypotension was common with either intravenous or intramuscular administration, 78% and 67% respectively. Mallory et al. 16’ monitored hemodynamics during intravenous and intramuscular pentamidine administration in 11 patients. Blood pressure was monitored by intra-arterial catheters. A small but comparable decrease in mean arterial blood pressure was noted in both groups. Pulse rate also decreased slightly in both groups, but there was no difference in cardiac output, pulmonary capillary occlusion pressure, or systemic vascular resistance. Severe ventricular arrhythmias have been observed with administration of pentamidine. Loescher et al. reported severe ventricular arrhythmias during pentamidine administration in an AIDS patient.156 Pujol and coworkersls7 reported a case of nonsustained ventricular tachycardia and marked QT prolongation in a patient treated with intramuscular pentamidine isethionate. Torsades de pointes, a polymorphic has been reported in association with ventricular tachycardia, pentamidine therapy in 2 male homosexual patients with P. carinii In 1 patient, prolonged QT interval and bursts of pneumonia.158 nonsustained polymorphic ventricular tachycardia developed after intramuscular pentamidine was administered for a total of 20 days. All medications were discontinued and the dysrhythmia was successfully managed medically. No further cardiac symptoms were 630

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experienced. In another patient, lightheadedness and syncope developed after 12 days of intravenous pentamidine isethionate. An electrocardiogram subsequently showed sinus bradycardia (55 beats/min), ventricular bigeminy, bizarre biphasic T wave changes, and a markedly prolonged QT interval. Several episodes of nonsustamed polymorphic ventricular tachycardia were also noted. Serum potassium and magnesium were abnormally low. Pentamidine was discontinued and electrolytes corrected. The QT interval remained prolonged, however. No further syncope or lightheadedness occurred. Since intramuscular administration of pentamidine is associated with significant local discomfort, intravenous administration may be preferable and less likely to be associated with hypotension or dysrhythmia. Interferon alpha is a naturally occurring protein produced by leukocytes in response to viral infection and has produced clinical responses in hairy cell leukemia, non-Hodgkin’s lymphoma, and AIDSassociated Kaposi’s sarcoma.15s Deyton and associates16o reported congestive cardiomyopathy after prolonged high-dose interferon therapy in three patients with AIDS and Kaposi’s sarcoma. Chest tightness and dyspnea were the presenting complaints in two patients; one patient had fatigue and edema of the lower extremities. All patients demonstrated evidence of cardiac failure on noninvasive cardiac laboratory testing and with right heart catheterization. Cardiac symptoms resolved in all patients after discontinuation of interferon therapy; in two patients symptoms abated only after the addition of diuretic therapy and afterload reduction or digoxin. Fourteen to 2.5 months after decreasing or stopping interferon and discontinuing all cardiac medications, there were no cardiac symptoms. Since cardiac dysfunction has not been noted when higher doses of interferon were used in the treatment of other diseases, Deyton et al.160 postulate a synergism between HIV infection and interferon in the pathogenesis of the cardiomyopathy seen in patients receiving interferon therapy. b D. MCCALL: Dr. Francis has provided the reader with an extensive and carefully cataloged review of cardiac involvement in patients with AIDS. As such, the review provides a very clear description of the extensive nature of potential cardiac involvement in AIDS patients, and the extensive bibliography provides an invaluable reference source. It is clear from Dr. Francis’ review that cardiac involvement, through a variety of etiologic agents, both infectious and neoplastic, in patients with AIDS is extensive and common. With the escalation of the AIDS epidemic it is likely that, with increasing frequency, cardiologists are going to be confronted with the management of these diverse manifestations of cardiac involvement in AIDS patients. This scholarly work provides us not only with a description of these multiple entities but with guidelines for the management of pericardial, myocardial and endocardial involvement in the AIDS syndrome.

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Cardiac involvement in AIDS may occur at any stage of HIV disease and may manifest as congestive cardiomyopathy, potentially lethal arrhythmia, or pericardial effusion and tamponade. The heart may be a@ected by nearly all of the opportunistic infections and many of the malignancies associated with the syndrome. Although often clinically unobtrusive, cardiac lesions may be important in the pathogenesis of significant clinical symptoms and play an often unrecognized role in the prognosis and natural history of AIDS. b R. C. SCHMNT: Dr. Francis has provided a thorough and scholarly review of the current literature on the involvement of the cardiovascular system in AIDS. It should be very useful to all physicians and nurses dealing with HIV infection or AIDS.

ACKNOWLEDGMENTS

The author wishes to thank Ms. Ruth Currey for her invaluable secretarial assistance, Mr. Jake Pena for his wordprocessing technical support, and Waffa El-Sadr, M.D., Chief of the Infectious Disease Division at Harlem Hospital Center, for her informative and expert discussions of AIDS-related infectious disease. REFERENCES

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