**2. Myocarditis in HIV positive patients**

HIV infection and AIDS have a well-recognized association with myocarditis and dilated cardiomyopathy [Azis F et al., 2010]. This increased predisposition is multifactorial and may include the direct effects of HIV itself, co-infection by opportunistic organisms, toxic effects of commonly used medications or illicit drugs, and nutritional deficiencies [Azis F et al., 2010]. Further, autoimmunity can be an important contributor to the pathogenesis of cardiomyopathy in these patients as many studies demonstrated the presence of cardiac-

Myocarditis in HIV Positive Patients 153

Pericardial tuberculosis has been reported in association with AIDS, typically in the setting of widespread disease. However, myocardial tuberculosis appears rare [Miller-Catchpole et

Fungal myocarditis is an unusual complication of disseminated infection that is identified most often at autopsy [Olson 2003]. Various fungal organisms identified in the myocardium at autopsy with associated myocarditis have included *Aspergillus fumigatus*, *Candida albicans*, *Histoplasma capsulatum*, *Coccidioides immitis*, and *Cryptococcus neoformans*. Cardiac cryptococcus has been diagnosed in association with congestive heart failure and shown to resolve after therapy with amphotericin B and flucytosine [Kinney et al., 1989, Lewis et al.,

Several viruses have been implicated in myocarditis associated with AIDS. Cytomegalovirus (CMV) is a common opportunistic pathogen in AIDS, but it is associated less frequently with myocarditis [Michaels et al., 1997]. When inclusion bodies are the criterion for the detection and diagnosis of solid organ involvement by CMV, the rate of infection is underestimated compared to in situ DNA hybridization techniques [Wu et al., 1992, Myerson et al., 1984]. Other viruses identified by culture or polymerase chain reaction (PCR) within the myocardium of HIV-infected or AIDS patients, either at antemortem endomyocardial biopsy or from autopsy material, have included Epstein-Barr and coxsackie B virus in adults [Barbaro et al., 1988a] and adenovirus in children [Bowles et al., 1999]. These viruses may be present as either primary infection or as coinfection and can occur with or without

The first clinical report to suggest a relationship between nonspecific myocarditis and dilated cardiomyopathy in AIDS patients appeared in 1986 [Cohen et al., 1986]; 3 patients had clinical, echocardiographic, and pathologic findings of dilated cardiomyopathy and 2 of the patients had focal lymphocytic infiltration associated with myocyte necrosis. Subsequent reports suggested an association between focal nonspecific myocarditis at autopsy and clinical cardiomyopathy [Barbaro et al., 1998a, Reilly et al., 1988]. Numerous hypotheses have been suggested to account for the etiology of nonspecific myocarditis and cardiomyopathy observed in HIV-infected patients, including direct HIV-1 infection of myocardial cells or coinfection with other cardiotropic viruses, [Olson 2003] cytokine cardiotoxicity [Suffredini et al., 1989, Lahdevirta et al., 1988, Levine et al., 1990], postviral cardiac autoimmunity [Herskowitz et al., 1989, 1993], nutritional deficiencies [Olson 2003], and cardiotoxicity due to illicit drugs [Olson 2003] or pharmacologic agents [Herskowitz et

The histologic findings of a monoclonal or oligoclonal inflammatory cellular infiltrate suggest a viral or autoimmune cause for the myocarditis associated with HIV infection. Myocarditis is more likely in individuals with more profound immunosuppression because CD4 < 400 cells/µL is more frequently observed in patients with dilated cardiomyopathy [Barbaro et al., 1998b]. In this same series, inflammatory myocardial cellular infiltrates were predominantly CD3 lymphocytes in 12 patients and CD8 lymphocytes in 64 patients. A separate report [Herskowitz et al., 1992b] described 35 HIV-infected patients with global LV dysfunction who underwent endomyocardial biopsy in which active or borderline myocarditis was observed in 55% of patients. For those patients with biopsy-proven myocarditis, mean LV ejection fraction was 28% whereas for patients without myocarditis it

was 48%. The cellular infiltrate was primarily composed of CD8 T lymphocytes.

associated myocarditis and with or without associated LV dysfunction.

al., 1989, Kinney et al., 1989].

1985, Lafont et al., 1987].

**2.2 Pathogenesis** 

al., 1992a, Olson 2003].

specific antibodies in HIV positive patients when compared with HIV negative controls [Currie & Boon 2003, Currie et al., 1998]. Thus, although the precise mechanisms are poorly understood, alterations in the immune system likely play an important role in the pathogenesis of heart muscle disease in HIV-infected patients. The prevalence of myocarditis in HIV infected patients has been difficult to establish with estimates ranging from 6% [Barbaro et al., 1998b] to 52% [Levy et al., 1989]. In other studies about 10 percent of people with HIV develop myocarditis, either because HIV directly invades the heart muscle or because the patient's weakened immune system makes the heart muscle more susceptible to attack by other infectious agents, especially toxoplasmosis [Grange et al., 1990, Matturi et al., 1990].

HIV deserves special mention because it seems to function differently than other viruses. HIV-1 glycoprotein 120 can directly disrupt cardiac contractility without any inflammatory response [Currie & Boon, 2003]. This may explain why HIV genomes can be amplified from patients without histologic signs of inflammation. Myocarditis is the most commonly cardiac abnormality found on biopsy tissue, present in some degree, in more than 50% of HIV patients [Howes et al., 2010]. In addition, in patients who are infected with HIV, T-cell – mediated immune suppression increases the risk of contracting myocarditis due to other infectious causes [Howes et al., 2010].

#### **2.1 Etiology**

The actual pathogenesis of cardiac injury in HIV infection is not clear. It is however generally agreed that several factors come into play either singly or in combination to produce cardiac pathology [Aziz 2010]. There is a wide range of hypotheses regarding the pathogenesis of HIV associated heart muscle disease. These include myocardial invasion with HIV itself, opportunistic infections, viral infections, and autoimmune response to viral infection, drug-related cardiac toxicity, nutritional deficiencies, endothelial dysfunction, autonomic dysfunction, and prolonged immunosuppression. Zidovudine (AZT), an antiretroviral drug used in treatment of HIV, has also been associated with myocarditis [Herskowitz et al., 1992a].

Opportunistic infections are common complications of AIDS and the most frequent cause of morbidity and mortality. However, relatively few pathogens have been isolated from the myocardium of AIDS patients [Olson 2003]. Myocardial involvement is usually associated with disseminated disease and multiple foci of infection. Typically, infectious organisms are identified in patients dying of noncardiac causes, and the findings of myocardial abnormalities are regarded as incidental. Opportunistic pathogens represent diverse causes of infectious disease, including bacteria, fungi, protozoa, and viruses [Olson 2003].

*Toxoplasma gondii* (T gondii) is the most frequently documented infectious cause of myocarditis associated with AIDS, and the heart is the second most common site of infection after the brain. Autopsy series have described T gondii myocarditis (myocardial toxoplasmosis) in 1% to 16% of patients dying of AIDS [Baroldi et al., 1988, Anderson et al., 1988, Matturi et al., 1990]. Evidence of myocardial toxoplasmosis includes trophozoites or pseudocysts in myocardial fibers. A minority of cases has associated myocarditis with focal areas of necrosis and lymphocytic infiltrates [Jautzke 1993]. Antemortem diagnosis of toxoplasma myocarditis associated with left ventricular (LV) dysfunction has been described, including its successful treatment [Grange et al., 1990, Albrecht et al., 1994].

specific antibodies in HIV positive patients when compared with HIV negative controls [Currie & Boon 2003, Currie et al., 1998]. Thus, although the precise mechanisms are poorly understood, alterations in the immune system likely play an important role in the pathogenesis of heart muscle disease in HIV-infected patients. The prevalence of myocarditis in HIV infected patients has been difficult to establish with estimates ranging from 6% [Barbaro et al., 1998b] to 52% [Levy et al., 1989]. In other studies about 10 percent of people with HIV develop myocarditis, either because HIV directly invades the heart muscle or because the patient's weakened immune system makes the heart muscle more susceptible to attack by other infectious agents, especially toxoplasmosis [Grange et al., 1990, Matturi et

HIV deserves special mention because it seems to function differently than other viruses. HIV-1 glycoprotein 120 can directly disrupt cardiac contractility without any inflammatory response [Currie & Boon, 2003]. This may explain why HIV genomes can be amplified from patients without histologic signs of inflammation. Myocarditis is the most commonly cardiac abnormality found on biopsy tissue, present in some degree, in more than 50% of HIV patients [Howes et al., 2010]. In addition, in patients who are infected with HIV, T-cell – mediated immune suppression increases the risk of contracting myocarditis due to other

The actual pathogenesis of cardiac injury in HIV infection is not clear. It is however generally agreed that several factors come into play either singly or in combination to produce cardiac pathology [Aziz 2010]. There is a wide range of hypotheses regarding the pathogenesis of HIV associated heart muscle disease. These include myocardial invasion with HIV itself, opportunistic infections, viral infections, and autoimmune response to viral infection, drug-related cardiac toxicity, nutritional deficiencies, endothelial dysfunction, autonomic dysfunction, and prolonged immunosuppression. Zidovudine (AZT), an antiretroviral drug used in treatment of HIV, has also been associated with myocarditis

Opportunistic infections are common complications of AIDS and the most frequent cause of morbidity and mortality. However, relatively few pathogens have been isolated from the myocardium of AIDS patients [Olson 2003]. Myocardial involvement is usually associated with disseminated disease and multiple foci of infection. Typically, infectious organisms are identified in patients dying of noncardiac causes, and the findings of myocardial abnormalities are regarded as incidental. Opportunistic pathogens represent diverse causes of infectious disease, including bacteria, fungi,

*Toxoplasma gondii* (T gondii) is the most frequently documented infectious cause of myocarditis associated with AIDS, and the heart is the second most common site of infection after the brain. Autopsy series have described T gondii myocarditis (myocardial toxoplasmosis) in 1% to 16% of patients dying of AIDS [Baroldi et al., 1988, Anderson et al., 1988, Matturi et al., 1990]. Evidence of myocardial toxoplasmosis includes trophozoites or pseudocysts in myocardial fibers. A minority of cases has associated myocarditis with focal areas of necrosis and lymphocytic infiltrates [Jautzke 1993]. Antemortem diagnosis of toxoplasma myocarditis associated with left ventricular (LV) dysfunction has been described, including its successful treatment [Grange et al., 1990, Albrecht et al., 1994].

al., 1990].

**2.1 Etiology** 

[Herskowitz et al., 1992a].

protozoa, and viruses [Olson 2003].

infectious causes [Howes et al., 2010].

Pericardial tuberculosis has been reported in association with AIDS, typically in the setting of widespread disease. However, myocardial tuberculosis appears rare [Miller-Catchpole et al., 1989, Kinney et al., 1989].

Fungal myocarditis is an unusual complication of disseminated infection that is identified most often at autopsy [Olson 2003]. Various fungal organisms identified in the myocardium at autopsy with associated myocarditis have included *Aspergillus fumigatus*, *Candida albicans*, *Histoplasma capsulatum*, *Coccidioides immitis*, and *Cryptococcus neoformans*. Cardiac cryptococcus has been diagnosed in association with congestive heart failure and shown to resolve after therapy with amphotericin B and flucytosine [Kinney et al., 1989, Lewis et al., 1985, Lafont et al., 1987].

Several viruses have been implicated in myocarditis associated with AIDS. Cytomegalovirus (CMV) is a common opportunistic pathogen in AIDS, but it is associated less frequently with myocarditis [Michaels et al., 1997]. When inclusion bodies are the criterion for the detection and diagnosis of solid organ involvement by CMV, the rate of infection is underestimated compared to in situ DNA hybridization techniques [Wu et al., 1992, Myerson et al., 1984].

Other viruses identified by culture or polymerase chain reaction (PCR) within the myocardium of HIV-infected or AIDS patients, either at antemortem endomyocardial biopsy or from autopsy material, have included Epstein-Barr and coxsackie B virus in adults [Barbaro et al., 1988a] and adenovirus in children [Bowles et al., 1999]. These viruses may be present as either primary infection or as coinfection and can occur with or without associated myocarditis and with or without associated LV dysfunction.
