Cardiomyopathy in AIDS: A pathophysiological perspective

Cardiomyopathy in AIDS: APathophysiological Perspective

William Lewis

This report addresses issues of pathogenesis, patho-physiology, and epidemiology of an increasinglyprevalent cardiomyopathy in acquired immunodefi-ciency syndrome (AIDS). As patient survival in-creases with more effective antiretroviral therapy,cardiomyopathy in AIDS will become more appar-ent. The interactions of cellular and organism factorsin AIDS and their relationships to the development ofcardiomyopathy are reviewed herein. Amongst thefactors addressed in this review are: (1) comorbidconditions found with AIDS, (2) the role of inflamma-tory heart disease and cytokines in the developmentof AIDS cardiomyopathy, (3) the pathogenetic role ofvascular cells and myocardial cells in the develop-ment of cardiomyopathy, (4) the role of myocardialretroviral infection in AIDS, and (5) the impact oftoxicity from antiretroviral therapy on the develop-ment of cardiomyopathy. Because it is possible thatmore than 1 of these factors is present in a givenpatient inflicted with AIDS, a multifactorial pathogen-esis in AIDS cardiomyopathy must be considered.Copyright r 2000 by W.B. Saunders Company

Acquired immunodeficiency syndrome (AIDS)is a health crisis with approximately 30

million people affected worldwide.1 Tragically,younger patients are disproportionately repre-sented in these statistics. AIDS still remains anurban epidemic, but numbers of nonurban pa-tients are increasing. In New York City, New York,the number of years of potential life lost wasincreased 15-fold between 1983 and 1994 andhuman immunodeficiency virus (HIV)-1/AIDShas become a principal cause of death in youngadults.2 Similarly, AIDS became the leading causeof death of homeless young adults in Boston (ages25 to 44).3 In Europe, AIDS became the leadingcause of premature death among Italian men andwomen.4 Morbidity caused by HIV-1/AIDS in-creased 6-fold in Zimbabwe where HIV-1 infec-tion has highest prevalence in the world.5

In parallel to adult data mentioned earlier,numbers of pediatric patients with AIDS dramati-cally increased in some areas. As of 1996, in theUnited States more than 7,400 children under theage of 13 were believed to be infected withHIV-1.6

As the AIDS epidemic spreads, it is increasinglyclear to clinicians and basic scientists alike thatcardiovascular problems resulting from AIDS maybecome more prominent.7 This may stem fromboth increased numbers of newly diagnosed pa-tients with AIDS and enhanced patient survivalrates resulting from combined antiretroviraltherapy.8 Heart muscle diseases (including cardio-myopathy [CM] and myocarditis) now appear tobe the most important cardiac complications ofAIDS in the Western world,9,10 but pathophysi-ological mechanisms are unclear. Congestive heartfailure (CHF) has become the leading noninfec-tious cause of death in pediatric patients withAIDS.6 Myocardial dysfunction in AIDS may havebeen overlooked earlier in the epidemic becauseof the urgency of other life-threatening AIDS-related problems.11 One estimate of the preva-lence of cardiac involvement in patients withHIV-1 (asymptomatic and symptomatic) is from28% to 73%.12 Other investigators suggest thatmore than 6% of patients infected with HIV-1 mayhave symptomatic heart disease.13

Although HIV-1 is causally linked to AIDS,14,15

controversy persists regarding the prevalence,

From the Department of Pathology, Emory UniversitySchool of Medicine, Atlanta, GA.

Supported in part by HL 59798 and HL 65167.Address reprint requests to William Lewis, MD, Depart-

ment of Pathology, Emory University School of Medicine,7117 Woodruff Memorial Building, 1639 Pierce Drive,Atlanta, GA 30322; e-mail: [email protected].

Copyright r 2000 by W.B. Saunders Company0033-0620/00/4302-0001$10.00/0doi:10.1053/pcad.2000.9031

Progress in Cardiovascular Diseases, Vol. 43, No. 2 (September/October), 2000: pp 151-170 151

clinical impact, and the pathogenetic role ofHIV-1 infection of the myocardium in the develop-ment of pathological and clinical heart disease inpatients with AIDS.

AIDS CM was described in 198616 and othercases were reported subsequently.17 The pathogen-esis of AIDS CM remains obscure. A 1-yearconsecutive enrollment study of patients admit-ted to the intensive care unit in an urban centerrevealed that 6% of admissions with either HIV-1infection or AIDS had echocardiographically-documented CM. The mortality rate was 25%.18

Persistent echocardiographic abnormalities inAIDS were considered ominous, but other changeswere reversible and, thus, considered less seri-ous.19

In Britain, 13 of 173 patients with AIDS hadCM as a correlate of advanced HIV-1 disease. Dataindicated no correlation between AIDS CM andother potential causes of CM or myocarditisincluding zidovudine (AZT) treatment, or infec-tion with cytomegalovirus or Toxoplasma gondii.20

In patients with hemophilia, 2 of 27 patients withHIV-1 infection had echocardiographically docu-mented CM.21 Despite these intriguing clinicaldata, it is reasonable to suggest that unrelatedillnesses or comorbid conditions also impact onthe cardiovascular health of patients with AIDS.The impact of and role of these conditions mustbe ascertained before unambiguously associatingAIDS as the solitary factor in CM development.22

Recent clinical studies from Italy suggest thatAIDS CM has a prevalence of approximately 8%and that decreased immune function related to anincreased incidence of CM.23 Myocarditis waspresent histologically in over 80% of patients withCM in that study. Inflammatory infiltrates werecomposed predominantly of CD3 and CD8 lym-phocytes. Cardiac myocytes were infected withHIV-1 in 58 patients and nearly two thirds ofthose samples showed myocarditis. The investiga-tors concluded that the observed CM was relatedto direct action of HIV-1 or to autoimmuneprocesses. The presence of CM at autopsy wasapproximately 3%.23 Other investigators ques-tioned patient selection for inclusion becausefactors such as nutritional status,24 coronary ar-tery status,25 or duration of HIV-1 infection26

were not addressed clearly.This article focuses on aspects of the cause,

pathogenesis, clinical impact, and epidemiologyof CM in AIDS. It addresses aspects of therelationship of myocarditis in patients with AIDSto CM and some features of CM that are beingactively investigated. It addresses the effects ofcomorbid conditions and drug toxicity on thedevelopment of CM in patients with AIDS. Thefollowing sections deal with pathological, clini-cal, and experimental aspects of CM in patientswith AIDS, and point to some areas in whichfurther experimental work may serve to help. Aconceptual overview of the interactions of variousfactors involved in heart disease in patients withAIDS is presented in Fig 1.

Causes and PathogeneticRelationships in AIDS CM

A review of patients who received a diagnosticendomyocardial biopsy for CHF showed that 5%carried a diagnosis of AIDS heart disease.27 Thisconclusion was based on serological and other-wise undefined pathological criteria for the diag-nosis of AIDS. Proposed causes of CM in patientswith AIDS include direct infection of the heart byHIV-1 (with or without myocarditis; see later),toxic CM resulting from AIDS therapeutics, ef-fects of circulating or systemic toxins, infection ofthe heart by opportunistic pathogens, toxicity ofillicit or self-prescribed pharmaceuticals or homeremedies, and nutritional disorders. Additionally,more than 1 factor may be operative (or present)in a single patient, opening the possibility ofcombined effects or comorbidity.28-30

Comorbidity in AIDS CM

Ethanol Abuse, CM, and AIDS

Ethanol consumption per se leads to alteredcardiac contractile function, is a leading cause ofCM in the United States, and may be the majorknown cause of CM in Western society.31 Alco-holic CM in some patients with AIDS may beconsidered a comorbid condition with AIDS CMor may be a contributor to CM development inthat subset (Fig 1). Pathological features of alco-holic CM are not pathognomonic, but they reflectcontractile changes. Alcoholic CM hearts areenlarged with endocardial thickening, remodel-

WILLIAM LEWIS152

ing, interstitial fibrosis, myocyte hypertrophy andatrophy, and focal necrotic myocytes.32 Dilation ofthe intercalated discs was found by transmissionelectron microscopy33,34 and mitochondrial disar-ray was observed. It should be emphasized thatsome of these pathological changes are nonspe-cific for alcoholic CM and may be found in otherCMs.

Compared with AIDS CM, alcoholic CM hasbeen extensively studied in human and animalmodels. This background information may berelevant in defining some pathophysiologicalevents in AIDS CM. Decreased capacity for oxida-tive metabolism with reduced state 3 respiration(adenosine diphosphate [ADP]-stimulated) wasfound in mitochondria from the hearts of ethanol-fed animals.35-39 Mitochondria exhibited a de-creased respiratory control ratio (suggesting areduction in the efficiency with which the respira-tory chain is coupled to adenosine triphosphate[ATP] synthesis), reduced fatty acid oxidation,

and increased triglyceride deposition.33,38 In thesetting of CM with AIDS and alcohol, these mayalso relate to mitochondrial defects caused byantiretroviral therapy (see later).

In contrast to AIDS CM in which models arebeing developed at present and clinical informa-tion may be limited, cardiac function with etha-nol consumption has been examined in the rat,mouse, dog, turkey, rhesus monkey, and ba-boon.40-43 Chronic ethanol feeding is associatedwith increased left ventricle (LV) mass.44-47 Onestudy46 described cardiac remodeling, increasedLV volume, and decreased LV wall thickness.Prolonged ethanol feeding of rats led to a reducednumber of LV myocytes48 with multiple foci ofdamaged myocytes near replacement fibrosis.46,48

LVs of dogs fed ethanol for 18 months or longerdisplayed increased collagen and reduced ventricu-lar compliance.34 Ultrastructural features of alco-holic CM include distension of the mitochondrialmatrix, cristae disorganization, sarcoplasmic retic-

Fig 1. Proposed diagram forthe development of AIDS.The complex nature of pa-tients with AIDS suggests thepossibility of multifactorialCM.

CARDIOMYOPATHY IN AIDS 153

ulum and T-tubule swelling, dehiscence of interca-lated discs, disruption of the myofibrils, and lipiddroplet accumulation.32,34,36

Decreased diastolic function (ie, prolongationof relaxation time) and decreased rate of contrac-tion (maximum dP/dt) occur in alcoholic CM. LVbiopsies from dogs with alcoholic CM showedaccumulation of interstitial glycoprotein. In-creased LV mass (2° to wall thickening) is ob-served in asymptomatic alcoholics49-51 and cardio-megaly was found by other techniques.52,53

Increased cardiac mass before overt CM is associ-ated with small increases in end-diastolic measure-ments. Structural changes can precede functionalloss.49,50 Impaired cardiac function develops incre-mentally with ethanol consumption. The cellularmechanisms underlying chronic alcohol-inducedalterations in systolic and diastolic function re-main unclear, but may relate to alterations in[Ca21]i handling, altered myofilament sensitivityto [Ca21]i, or specific reductions in the concentra-tions of contractile proteins and their assemblyinto sarcomeres.54,55

Cocaine Abuse, CM, and AIDS

Cocaine use also may contribute to the develop-ment of CM in patients with AIDS both as acardiotoxin to myocardial cells or through indi-rect mechanisms based on cocaine’s vasculareffects and resultant, secondary myocardialchanges. Accordingly, CM from cocaine may be acomorbid condition in AIDS CM and its patho-physiological events may impact on AIDS CM andvice versa.

Cocaine is an alkaloid derived from Erythroxy-lum coca that grows naturally in South America.56

Snorting and intravenous administration of co-caine are common in the United States. Thesocietal impact of cocaine is alarming with esti-mates of death (<4,000 reported) and disability(134,000 emergency visits) that may fall short ofthe true census of affected individuals.56

Cocaine is rapidly cleared and distributed tothe heart, brain, spinal cord, and other tis-sues.57-59 Tomographic scans show high cardiacuptake of cocaine.56 The 2 most abundant cocainemetabolites (in humans and rodents) are benzylec-gonine (comprising <40% of the breakdownproducts) and ecgonine methyl ester (comprising<40% of the breakdown products).56 Neither

metabolite is believed to be pharmacologicallyactive. However, in vitro studies suggest thatbenzylecgonine is cytotoxic and may cause spasmof coronary and cerebral vessels by altering cal-cium flux and regulation of calcium channels.60-63

In vivo effects of cocaine metabolites on cardiacfunction have not been examined in the setting ofAIDS or HIV-1 infection.

Myocardial effects of cocaine administrationinclude cardiomegaly and left ventricular hyper-trophy (LVH). In humans, some echocardio-graphic studies of asymptomatic cocaine usersfound increases in LV mass and posterior LV wallthickness.64,65 Other investigators did not supportthe findings.66,67 Inherent difficulties in examin-ing cocaine administration in humans include theinsensitivity of echocardiography as a tool todetect small differences in LV mass. Autopsystudies revealed minimally increased heart size(<10%).68-70 Cardiomegaly was confirmed bydirect measurements made at autopsy.68,71

Some clinical reports noted an associationbetween cardiac dysfunction and cocaine admin-istration. However, many reports were incom-plete and described the occurrence of CHF inpolydrug abusers without angiographic or biopsyevidence of CM.72-77 Based on the relative paucityof pathological confirmations, cocaine CM isbelieved to be related to long-term effects ofcatecholamines (see later). This suggests that CMfrom cocaine is morphologically similar to otherforms of CM in which catecholamine excess mayserve as a principal pathophysiological fea-ture.78-80

The myocardial response to chronic catechol-amine exposure is similar in humans and inanimals.81 Histologically, this type of myocardialcell death is indistinguishable from that resultingfrom pheochromocytoma.82 Contraction band ne-crosis is the earliest recognizable lesion. This is aprominent feature of cocaine cardiotoxicity, pheo-chromocytoma, and resembles the pressor-relatedchanges that are frequently found in transplantdonor hearts.83 Nonetheless, some controversyexists concerning the importance of this pathologi-cal change in cocaine toxicity.84,85

Focality is the pathological hallmark of boththe acute and healed catecholamine lesion. Cat-echolamine-induced necrosis and ischemic necro-sis are distinguished by their anatomic distribu-tion. Ischemic injury affects the cardiac myocytes

WILLIAM LEWIS154

supplied by an artery. In contrast, catecholamineexcess is characterized by individual necroticmyocytes interspersed between normal cells. Ifthe insult is ischemic, the myofilaments remain inregister. In catecholamine excess, filaments aredisrupted. There is no zone of injury with cat-echolamine necrosis and no anatomic relation-ship to blood supply. Necrotic myocytes arereplaced by fibrous tissue. With repetitive necro-sis, fibrosis increases until altered function andabnormal impulse propagation occur.78,83,86

Morphological features in hearts from chroniccocaine abusers differed from those in nonco-caine abusers. Fewer nuclear abnormalities andless myocyte hypertrophy were found. Fibrosiswas focal. Small lymphocytic infiltrates werepresent.83 Endomyocardial biopsy findings (7patients with recent onset of CHF) showed simi-lar features. There was myocyte necrosis in 5 ofthe 7 patients. Again, the pattern of distributionresembled that of contraction band necrosis (cat-echolamine toxicity). Necrotic cells were adjacentto normal cells. Interstitial fibrosis was noted.Although contraction band necrosis may be afeature of myocardial biopsies, it may be difficultto ascribe a cause or pathogenesis to it.78

Cytokines, CM, and AIDS

Cytokines play key roles in AIDS, cardiac dysfunc-tion, and CHF. Thus, it is reasonable to considerthat circulating or locally acting cytokines may beinvolved in CM in patients with AIDS. Candidatecytokines include endothelin (ET; particularlyET-1) and tumor necrosis factor a (TNFa).87,88 LVexpression of atrial natriuretic factor (ANF), amarker of LVH and cardiac dysfunction andremodeling,89 also may be important diagnosti-cally and prognostically.90

One approach to understanding the effects ofcytokines on the cardiomyocyte comes fromMuller-Werdan et al91 who proposed that thesesubstances exert negative inotropic effects. Impor-tantly, some of the deleterious effects of cytokinesoccur in noninfectious, non-AIDS–related CMand CHF, suggesting a common subcellular mech-anism for the dysfunction.

Increased expression of both inducible nitricoxide syntheses (iNOS), messenger ribonucleicacid (mRNA), and polypeptide was shown invitro in cardiac myocytes treated with TNFa,

interleukin (IL)-1b, and interferon (IFN)-g.92

Myocyte death in culture paralleled increasednitric oxide (NO) synthesis. Myocyte death couldoccur as a result of NO produced by macrophagesor within the myocyte. The latter mechanism isimplicated in cytotoxicity induced by infusions ofa variety of agents (TNFa, IFNg, IL-2) and mayrelate directly to immune dysfunction in AIDS.

It is understood that cytokines do not causemyocyte dysfunction or necrosis directly butindirectly may alter myocyte function, possiblythrough the b1-adrenoceptor-G protein-adenylylcyclase axis.93-95 Long-term treatment of cardio-myocytes with immune cell supernatants (contain-ing IL-1 and TNFa) reduced contractility andcyclic adenosine monophosphate (cAMP) accu-mulation by inhibition of adrenergic responsive-ness.96 Myocardial depressant effects of TNFaoccurred with TNFa infusion in dogs and re-sulted in LV dysfunction.97 Conversely, anti-TNFa antibodies reduced cardiac dysfunctionduring sepsis.98 TNFa is elevated in patients withCHF and in patients with non-AIDS CM. Its rolein CM in AIDS is not yet elucidated.

Remodeling encompasses a complex of molecu-lar and cellular events that lead to changes in thestructure, function, and phenotype of the myocar-dium.99 These include hypertrophy and death ofmyocytes, reversion to a molecular phenotypecharacterized by the expression of fetal genes andproteins, and alterations in the quantity andcomposition of the extracellular matrix.100 Fac-tors that may play a role in AIDS and that have thepotential to cause or contribute to myocardialremodeling include ETs (ET-1) and their recep-tors, cytokines (mentioned earlier), NO, andreactive oxygen species.99

ET-1 is a potent vasoconstrictor peptide thathas long-term effects on cellular growth andphenotype.99,101 It is synthesized in the vascula-ture and myocardium by various cell types, includ-ing vascular endothelial cells, ventricular myo-cytes, and fibroblasts. Its cardiovascular actionsare mediated by ET-A and ET-B receptors. In thevasculature, stimulation of ET-A receptors onvascular smooth-muscle cells (SMCs) causes vaso-constriction, whereas stimulation of ET-B recep-tors on endothelial cells generally causes vasodila-tion. In humans, the vasoconstrictor effectspredominate. ET receptors are located on severalcell types in the myocardium, including myo-


cytes, fibroblasts, and endothelial cells. In vitro,ET stimulates myocyte hypertrophy and expres-sion of a fetal phenotype.90,99 It also has importanteffects on the synthesis and degradation of theextracellular matrix.100 Plasma ET-1 levels areraised in patients with heart failure102,103 andcorrelate with worsening functional class, ejec-tion fraction, and exercise capacity.104 At present,plasma ET-1 values are not available for patientswith AIDS CM or cocaine CM.

The cytokine IL-1 has a suppressive effect onadrenergic agonist-mediated increases in cAMP inneonatal rat cardiomyocytes.94,96,105 Reversiblemyocardial depressant effects occurred with infu-sions of IL-2 and IL-6 in vivo.97,106 These effectsappear to be mediated by NO.105 Kawamura etal107 identified IL-6 as a mediator of myocardialinjury and Finkel et al106 reported that IL-6 was amediator of stunned myocardium in humans.

When neonatal rat cardiac myocytes were ex-posed to IL-1b, aside from expected changesinvolving fetal gene programming related to theinduction of cardiac myocyte hypertrophy, expres-sion of 3 central calcium regulatory genes wasfound to be decreased. These included sarcoplas-mic reticulum Ca21 adenosine triphosphatase(ATPase) (SERCA2), calcium release channel(CRC), and voltage-dependent L-type Ca21 chan-nel. The addition of N-monomethyl-L-arginine(L-NMMA), a NO antagonist, had no effect onthis reduction in mRNA suggesting that the IL-1beffect is independent of NO.90,92,93,96,99,101

A subsequent study from Italy108 suggested thatiNOS and TNFa influence the clinical course ofCM in patients with AIDS. Endomyocardial biop-sies from 82 patients with AIDS CM and 80control patients without AIDS with idiopathicCM were examined immunohistochemically forTNFa and iNOS immunoreactivity. Staining inten-sity for these markers was quantitated and wasgreater in patients with AIDS CM than in patientswith non-AIDS CM. This correlated inverselywith the CD4 count. Data suggest that cytokine-mediated cell signaling is involved in AIDS CM.

Vascular Changes and AIDS CM

Vascular cells (particularly endothelial cells[ECs]), SMCs, and myocardial interstitial cellsmay impact on the development of CM in patientswith AIDS. EC changes in patients with AIDS may

be linked causally to infection of the EC by HIV-1,to EC effects of HIV-1 polypeptides, or to toxicityof AIDS therapeutics to vascular cell elements.Combined effects may occur (Fig 1).

One potential mechanism for CM in patientswith AIDS may relate to vascular changes fromHIV-1, cytokines, and immune responses. Dys-functions of vascular and endocardial ECs areassociated with the development of CM. It is longestablished that altered function of vascular ECsis associated with hyperactivity of the microcircu-lation and with coronary vasospasm, resemblingthe changes seen in cocaine abuse.109 Coronaryartery vasospasm may lead to focal myocellularnecrosis and scarring that causes normal cardio-myocytes to undergo hypertrophy110 and for theheart to remodel (as described earlier). Endocar-dial ECs modulate the performance of the heartthrough the release of cardioactive substances orinteractions with inflammatory cells.111 Endocar-dial EC dysfunction can disturb cardiac perfor-mance and ultimately may influence the develop-ment of CM.

On this basis, the pathogenesis of AIDS CM(and possibly other types of CM including co-caine CM) may be attributable to vascular se-quellae of AIDS. Many studies on the relationshipbetween EC and HIV-1 infection focus on theimportant pathogenetic relationship of EC toKaposi’s Sarcoma (KS) or EC/HIV-1/immunocyteinteractions. EC changes per se have been studiedless thoroughly, but with increasing survival ratesof patients with HIV-1 infection, the possibility ofand relationship to EC dysfunction in patientswith AIDS becomes more important. The role ofcardiovascular disease resulting from AIDS prote-ase-inhibitor therapy may become more impor-tant as these agents are more widely used.

Aortic samples from patients infected withHIV-1 showed a disturbed intima, increased leu-kocyte adherence, and up-regulation of the vascu-lar cell adhesion molecule (VCAM-1) and E-selectin (ELAM).112 This indicated profound andrepeated activation of aortic ECs in patients withAIDS. HIV-1 infection of retinal vessel ECs wasdocumented immunohistochemically with anti-body staining of gp120 and p24 antigens in thecytoplasm of capillary endothelium.113 Infectionof human umbilical vein EC with HIV-1 has beenaccomplished in vitro114 and contact of U1 pro-monocytic cells with human umbilical vein ECs

WILLIAM LEWIS156

induced significant biosynthesis of HIV-1 p24.115

ECs constitutively synthesized enhancing factorsIL-6, IL-1b, and granulocyte-macrophage colonystimulating factor. Productive HIV-1 infection ofECs required EC proliferation and was stimulatedwith IL-1b and TNFa.116

Based on the earlier points, it is possible thatstructural proteins, such as tat, may play anintegral role in EC dysfunction in AIDS. Thefollowing supports such a hypothesis. The HIV-1tat protein serves as a transactivator for HIV-1replication. Tat is secreted by infected cells andcontributes to the activation of ECs and expres-sion of EC adhesion molecules (ELAMs; ELAM-1,VCAM-1, and ICAM-1).117-119 Extracellular HIV-1tat protein promotes the growth of spindle cellsderived from KS and normal vascular cells.120

Basic fibroblast growth factor and HIV-1 tat actedsynergistically to induce KS-like lesions in nudemice.121 HIV-1 tat protein transactivates HIV-1,viral, and some host genes.122 HIV-1–infectedcells release tat.123 Tat acts extracellularly andregulates the functions of immunocompetent andmesenchymal cells.124

Tat induces functional programs for angiogen-esis and inflammation (including migration, pro-liferation, expression of plasminogen activatorinhibitor-1, and E selectin).125,126 Angiogenic prop-erties of tat may relate to arginine- and lysine-richsequences shared with other potent angiogenicfactors. Angiogenesis induced by HIV-1 tat ismediated by the Flk-1/KDR receptor on vascularECs. Together, these in vitro observations supportthe suggestion that HIV-1–infected inflammatorycells may release mitogenic tat to initiate alocalized cascade of molecular events. The cas-cade could result in the production of growthfactors and cytokines relevant to the initiationand perpetuation of vascular cells. Such effectsmay impact on the development of vascularchanges in the heart of patients with AIDS andpoint to alternative mechanisms involved in thepathogenesis of AIDS CM.

Antiretroviral Therapy and AIDS CM

The DNA pol-g hypothesis is useful to explainsome events in models of toxic CM in patientswith AIDS127 and fits into the schema for CMdevelopment in patients with AIDS (Fig 1). Phar-macologically induced CM occurs with AZT treat-

ment of rats and mice,128-131 and may have clinicalimpact in patients with AIDS when AZT isadministered for relatively long durations. ‘‘Aphenocopy of mtDNA [mitochondrial deoxyribo-nucleic acid] depletion syndrome has been ob-served in AIDS patients treated with Zidovu-dine.’’132 With the development of AZT CM in ratand mouse models, investigators could define therole of anti–HIV-1 chemotherapy in the pathogen-esis and pathophysiology of AIDS CM in a con-trolled setting without some confounding influ-ences inherent in clinically based AIDSstudies.29,127,129,131,133-137 Altered mtDNA replica-tion, arguably a hallmark of AZT CM, is linked tomitochondrial toxicity of nucleoside agents usedin treatment of viral illnesses including HIV-1 andhepatitis B.138-140 Accordingly, AZT (for HIV-1)and fialuridine (initially evaluated for treatment ofhepatitis B, 1-2-deoxy-2-fluoro-b-D-arabinofuranosyl-5-iodouracil [FIAU]) serve as tools in AIDS CMmodels because they inhibit DNA pol-g, theenzyme responsible for mtDNA replication.

In these pharmacologically induced CMs,changes in mtDNA replication reflect combinedeffects of the antiviral agent on the mitochondri-on’s ability to replicate DNA and result in down-stream effects on mtRNA and synthesis of mito-chondrial polypeptides. Factors that influence thetoxicity of these agents include subcellular avail-ability and abundance of the nucleoside analog inthe tissue target, the ability of the nucleosideanalog to become phosphorylated intracellularly,the ability of the triphosphate to inhibit DNApol-g (possibly reflected in its Ki in vitro), tissuerequirement for oxidative phosphorylation, andpossibly other pharmacological and cell biologi-cal factors. Using FIAU as a model compound,members of this class possess 38-hydroxyl groupsand compete with native nucleotide (eg, FIAUTPcompetes with deoxythymidine triphosphate[dTTP]). The nucleoside analog monophosphateincorporates into mtDNA and extends the na-scent mtDNA chain. In essence, it serves as analternative substrate for dTTP. With agents thatresemble AZT structurally, the 58-triphosphatesalso are used as substrates for mtDNA synthesisby DNA pol-g and compete with the naturaldNTP. However, these compounds also terminatenascent mtDNA chains because they lack 38-hydroxyl groups for mtDNA extension. Theirinhibition is mixed: competitive with the natural


substrate dTTP and noncompetitive by serving asa mtDNA chain terminator.

Alternative explanations for AZT myopathyhave been proposed. In experiments with maleSprague Dawley rats, short-term treatment proto-cols, and low-dose AZT,141 studies of muscleperformance were undertaken. Mitochondrialstructural changes were apparent. The mtDNAabundance was unchanged. Decreased muscleperformance and blood pressure were found alongwith decreased cytochrome c oxidase activity inheart and oxidative muscle. Parallel studies withdidanosine revealed no effects on these tissues.However, in the didanosine studies, it was unclearif the drug was administered in buffered water.Previous studies included examination of heartsamples ultrastructurally. Treatment with didano-sine resulted in no changes in cardiac mitochon-drial ultrastructure (#500 mg/kg/d didanosine;35 days; female Sprague Dawley rats; 200 g initialweight).128 Another group of investigators sug-gested that significant increases in peroxynitriteand reactive oxygen species in heart tissues oc-curred and may not be directly related to alter-ations in mtDNA replication.142 Data from thatstudy suggested that oxidative damages may playbasic roles in CM in the neonatal and developingrat.

On a clinical basis, it seems reasonable tosuggest that AZT induces CM in patients withAIDS by depleting mtDNA,138 but the mechanismhas not been proven. Herskowitz et al143 de-scribed cases of CM in patients with AIDS whoreceived various antiviral nucleoside agents. Re-moval of the toxic agent resulted in reduction inLV hypokinesis leading the investigators to sug-gest regimens in which AZT was alternated withother therapies.

In pathological studies, a single case was foundof a 45-year-old, HIV-1–seropositive, homosexualman who was treated with high-dose AZT (1,200mg/d) for 2 years. He manifested symptoms ofCHF with LV dilatation and a 20% ejectionfraction. The endomyocardial biopsy showed noactive myocarditis, and the presence of numerousintramyocytic cytoplasmic vacuoles. Transmis-sion electron microscopy revealed mitochondrialcristae with distortion and myofibrillar loss butno paracrystals. At autopsy, a 100-mL pericardialeffusion, cardiomegaly, and biventricular dilata-tion were present.144

Subsequently, 3 additional cases of CM associ-ated with AZT treatment were referred. All pa-tients shared documented HIV-1 infection, long-term AZT therapy, and clinical features of CM.Pathological and ultrastructural changes on endo-myocardial biopsy were nonspecific, correlatedwith clinical features, and resembled changes ofCM of various causes. Myocarditis was absent.Ultrastructurally, mitochondrial degeneration,swelling, enlargement, vacuolization, fragmenta-tion, and loss of cristae occurred. Paracrystalswere absent. In 1 case, reversal of cardiac dysfunc-tion followed up the clinical trial of discontinua-tion of AZT therapy.145 This resembled previouslyreported findings by Herskowitz et al.143

Recent evidence has suggested that AZT maybe incorporated into DNA of children exposed toAZT,146 and this resembles the findings in AZT-treated mice and Erythrocebus patas primates.147

In vertically infected children with AIDS, subclini-cal problems are common, persistent, and oftenlead to the development of CM.148 Immune dys-function correlated early with cardiac dysfunc-tion but not long term.

Other therapeutic agents have been related toCM in patients with AIDS, but the association hasnot been tested experimentally. Foscarnet therapycaused reversible cardiac dysfunction.149 Inter-feron-b administration was associated with revers-ible cardiac dysfunction leading to CM.150 Tors-ades de pointes was a rare complication ofpentamidine therapy.151,152 The class of proteaseinhibitors is now associated with syndromes oflipodystrophy, diabetes mellitus, hyperlipidemia,and coronary syndromes.153 This new toxicitymay impact on cardiac pump function on anischemic basis in patients with AIDS and bring tolight a new and complex series of side effects ofAIDS therapy.

Global Left Ventricular Dysfunctionin Patients With AIDS

In a prospective evaluation, global left ventriculardysfunction (GLVD) in individuals infected withHIV-1 is not rare in the clinical course of AIDS, isoften fatal, and may be associated with activemyocarditis.154,155 A subgroup of patients withGLVD with AIDS progressed to overt CHF. Thestructural changes in the heart were not clearbecause pathological findings were not fully de-

WILLIAM LEWIS158

scribed. Based on behavioral risks, 4 of 7 patientsused intravenous drugs, another critical cause ofGLVD. In a study of 101 unselected patientsinfected with HIV-1 (71 with AIDS), a higherprevalence of echocardiographic abnormalitieswas found compared with controls.156

Nutritional Deficiency and AIDS CM

Deficiencies of specific micronutrients (eg, sele-nium and L-carnitine) have been implicated in thepathophysiology of heart failure in patients withAIDS and in the pathogenesis of AIDS CM.Experimentally, carnitine administration reversedmyopathic changes induced by AZT in vitro,157,158

but clinical trials have yet to be completed tosupport these in vitro data. Heart function did notcorrelate with any nutritional marker in 1 study,but heart rate and mass were correlated withskeletal muscle mass.159 Selenium deficiency hasbeen suggested as a cause of CM in patients withAIDS.160 This was based on showing decreasedselenium content in AIDS hearts.161 In 1 pediatricpatient, reversal of CM occurred after seleniumsupplementation.162 Overall, few studies of nutri-tional deficiencies as a cause for AIDS CM havebeen performed.

Myocarditis and AIDS CM

Inflammatory heart disease (myocarditis) in pa-tients with AIDS163 may be an antecedent to CMin AIDS. Variability in the reported prevalence ofmyocarditis in patients with AIDS was found.Some AIDS-associated risk behaviors (particu-larly intravenous drug abuse) have associatedcardiovascular pathological changes that couldconfound the interpretation of AIDS CM ormyocarditis on a pathological basis. The multifac-torial nature of myocarditis in AIDS was stated byAnderson and Virmani.13 It may be related toinnocent bystander destruction of cardiac myo-cytes, microvascular spasm with subsequent ne-crosis, or humorally mediated immune (or auto-immune) mechanisms of myocyte destruction(with or without associated inflammation).

As mentioned, the prevalence of myocarditis inpatients with AIDS is variable. In a Scandinavianstudy of 60 consecutive autopsies of patients withAIDS, myocarditis was present in 42%, diffusemyocardial fibrosis in 67%, and dilatation and/or

hypertrophy of the right ventricle in 38%. Al-though the relevance of the latter finding isunclear, it was concluded that the prevalence ofheart failure will increase in patients with AIDS.164

Asymptomatic patients infected with HIV-1showed cardiac abnormalities less commonly.165

Investigators in southern California found a74% prevalence of lymphocytic infiltrates of themyocardium.166 In that study, intravenous drugabuse was a prominent behavioral risk factor.More recently, of 100 autopsies of patients withAIDS from Puerto Rico, almost all had a history ofintravenous drug abuse. Pathological changes inthe heart occurred in 32% of patients. Histopatho-logically, mononuclear interstitial inflammationand myocyte necrosis were prominent. Opportu-nistic infections with Histoplasma capsulatum, Tgondii, Mycobacterium tuberculosis, cytomegalovi-rus, and Cryptococcus also were prominent comor-bid conditions.167 Importantly, there is no re-ported study that delineates the effects of HIV-1infection or AIDS, and intravenous drug abuse,cocaine abuse, or any other substance abuse–related injury on the development of CM.

Overall, the prevalence of interstitial mono-nuclear inflammation in patients with AIDS washigh; however, the clinical impact of that patho-logical diagnosis was less clear. Reilly et al168

reviewed cardiac samples from 26 of 58 patientswith AIDS that satisfied the Dallas criteria formyocarditis. Clinical correlations with myocardi-tis included CHF and cardiac rhythm distur-bances. In a study that more closely resembled theauthor’s previous experience in Los Angeles,169 a34% prevalence of lymphocytic infiltrates wasfound.170 In other autopsy series, the prevalenceof myocardial inflammation was 52%.171 Roldanet al172 found lymphocytic infiltrates and necrosisin 17 of 54 autopsies. Benign, small, interstitialmononuclear infiltrates have been reported inCM of many causes,173 and their pathologicalsignificance may be questioned.

The apparent difference in the prevalence ofmyocarditis found in different studies may relateto a variety of clinical factors. The author’s initialstudies came from a population that was heavilyweighted with gay men with AIDS who died ofPneumocystis carinii pneumonia, Mycobacteriumavium-intracellulare, or KS, but who were other-wise healthy. In the past, the author suggestedthat different risk behaviors for the development


of AIDS (such as intravenous drug abuse) mayinfluence some of the pathological changes foundin the heart at autopsy,169,174,175 and in essencemay be a secondary contributor to the develop-ment of myocarditis or CM in patients with AIDS.

Intravenous drug abuse is the second mostcommon risk behavior associated with AIDS andaccounts for 27% of reported AIDS cases through1989. It may be prudent to suggest that therelative contribution of AIDS and its inherent riskfactors (such as intravenous drug abuse) must beaddressed in studies that discriminate betweenmultiple factors in the pathogenesis of AIDSmyocarditis.176 Other important elements (suchas coronary artery disease, hypertension, or sub-stance abuse with cardiotoxins like cocaine oralcohol) can contribute to the development ofheart failure in patients with AIDS. In support ofthese general concepts, the prevalence of idio-pathic myocarditis and CM was higher in patientswhose risk behavior was intravenous drugabuse.22,177,178

In another retrospective study, more than 500histological sections of myocardium were re-viewed. Focal microscopic interstitial mono-nuclear infiltrates occurred in 16% of samples.169

Generous sampling was required for detection ofthe tiny lesions and their clinical impact is notclear from the study.

Cardiac Retroviral Infection andAIDS CM

The pathogenesis of AIDS has been elucidated byidentification of HIV-1 as the causative agent.179

HIV-1 is capable of infecting various cell types,including monocytes/macrophages,180 peripheralblood cells,181 corneal epithelial cells,182 glialcells,183 esophageal mucosal cells,184 peripheralnerve cells,185 Sertoli and germ cells of the tes-tes,186 Kupffer cells of the liver,187 and glomerularcells of the kidney.188

The direct effect of HIV-1 on the developmentof heart disease was evaluated in 1 clinical reportfrom Scandinavia in a population of patientsinfected with HIV-1 without opportunistic infec-tions. According to echocardiography, no patienthad significant pericardial effusions, cardiac tu-mors, endocarditis, or CM. In a subgroup ofpatients whose infection progressed to AIDS andwho died, no evidence supported HIV-1 as a

myocardial pathogen. Other studies suggestedthat myocardial filling and relaxation abnormali-ties are important in HIV-1 infection.189 Althoughcardiac abnormalities are prevalent, they may beof little significance clinically.156 However, pri-mates infected with chronic Simian immundefi-ciency virus (SIV) showed evidence of CM.190

HIV-1 is not universally accepted as a causativeagent of myocarditis or CM in patients withAIDS,191 but its role in the development of CM inpatients with AIDS may be important based onclinical and experimental data. Efforts in theauthor’s laboratory have been directed towarddefining the individual contribution of HIV-1 andother factors in patients with AIDS in the develop-ment of AIDS CM. In situ hybridization (ISH) wasused and revealed HIV-1 infection of the heart inapproximately 25% of the samples, albeit at a lowsignal level.192 ISH does not require extraction oftarget sequences and allowed for preservation ofhistological architecture and more precise localiza-tion of HIV-1 sequences within particular celltypes. Recent evidence from studies of SIV-infected primates supports retroviral infection ofnonmyocytes as being an integral cell type ininflammatory heart disease in that model system(see later).193,194

Other investigators confirmed the presence ofan ISH signal for HIV-1 in human myocardium.Our findings were independently confirmed orsupported by other groups, using both ISH andother methods.195-198 In one study of autopsies, insitu hybridization failed to show an HIV-1 signalin the myocardium of patients with AIDS.199

Other evidence of cardiac HIV-1 infection wasbased on isolation and cultivation of HIV-1 froman endomyocardial biopsy from a patient withAIDS and CM,197 by detection of nucleic acidsequences of extracted DNA by using the polymer-ase chain reaction and by Southern blottinganalysis,198 or by individually isolating cardiacmyocytes by microdissection and polymerasechain reaction amplification of HIV-1 sequencesand Southern blotting.196 In their study, Calabreseet al197 correctly raised the possibility that thepositive culture results were caused by contamina-tion of the heart biopsy specimen with HIV-1,possibly from the patients’ infected blood. Simi-larly, polymerase chain reaction amplification of asample contaminated with as little as 1 HIV-1

WILLIAM LEWIS160

sequence (hypothetically) can yield artifacts thatrender interpretation of the data difficult.

On a pathogenetic basis, the profoundly unbal-anced immune function in patients with AIDS200

may give rise to a clinical (or subclinical) myocar-ditis (see earlier). A viral cardiac infection inpatients with AIDS could account for the develop-ment of myocarditis and ultimately lead to thedevelopment of AIDS CM. If HIV-1 were theinfectious agent in the development of myocardi-tis in patients with AIDS, different strains ofHIV-1 could exhibit different propensities of myo-cardial infectivity and to morbidity, but this hasyet to be proven from clinical data or by usingmodel systems. Different infectivities of HIV-1strains have been reported in studies on othertissues.201

In recent experimental studies with SIV-infected macaques, in situ hybridization indicatedSIV-infected monocytes more frequently than myo-cytes.193 A report of giant cell myocarditis wasmade by the same group. Experimentally gener-ated myocarditis in SIV-infected macaques doesnot resemble the pathological features of myocar-ditis in human AIDS in which classical mono-nuclear infiltrates of varying intensity are found.Giant cell myocarditis is rarely (if ever) seen inhuman AIDS myocarditis.

Shannon et al194 further studied a cohort of 15rhesus macaques infected with SIVmac251 (.18months) that died of simian AIDS. Transmuralhistological sections of the LV were stained withantibodies for a T-cell marker (CD3 and colla-gen), and underwent terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling(TUNEL) to identify apoptotic cells. A markedincrease in TUNEL-positive cells was found in themyocardium of macaques with myocarditis com-pared with those with fibrosis or normal myocar-dium. Most TUNEL-positive cells were cardiomyo-cytes. This suggested that acute myocarditis inSIV CM is associated with apoptotic myocytedeath.

In Vivo Models of AIDS CM

Clinical scientists often attempt to create in vivomodels of disease to explore pathogenetic mecha-nisms. Because of the unique nature of HIV-1infection, its limited host range, and relationshipsto human retrovirus that are exclusive to HIV-1,

many models have been proposed, but authentic-ity is a persistent problem. Although some mayoffer insights into immune mechanisms, dysfunc-tion, or myocarditis, they are less illuminating ofmechanisms of altered myocardial function inAIDS CM. The models described later are in-cluded as a group of potentially useful models toexplore mechanisms of heart and vascular diseasein patients with AIDS.

Transgenic Mice

Transgenic mice (TG) are useful to study viralgene function and pathogenesis in AIDS andother viral illnesses.202-207 Aside from the obviousadvantages of small size, easy maintenance, lowcost, and well characterized genetics, a uniqueadvantage of TGs is the targeted cellular incorpo-ration of viral sequences into selected (or nonse-lected) cells. Problems associated with viral admin-istration are obviated. Viral sequences arecontained within every target cell. Another advan-tage of the TG system is the permanent incorpora-tion of the transgene into the genetic material (ofthe mouse). These features enable evaluation ofeffects (from the TG) and allows monitoring ofdisease progression from preclinical developmentthroughout the natural history.

The hemizygous NL4-3D gag/pol TG mouse is amodel of generalized HIV-1 infection and of AIDSand is used for experiments on AIDS131,136,208;it shows important phenotypic features of CM.NL4-3D gag/pol show AIDS nephropathy, wasting,and skin diseases. This TG model contains anHIV-1 construct with an internal deletion thateliminated much of the gag/pol coding sequence.

TG models can also be used to determine thecontribution of AIDS therapy to AIDS CM.131,208

TGs and FVB/n mice received water ad libitumwith and without AZT (0.7 mg/mL) for 21 or 35days. Echocardiographic studies were performed,and an abundance of mRNAs for cardiac sarcoplas-mic reticulum calcium ATPase (SERCA2), so-dium calcium exchanger (NCX1), and ANF weredetermined individually by using Northern analy-sis of extracts of LVs. Contractile function andrelaxation were analyzed in isolated work perform-ing hearts. Depressed SERCA2 and increasedANF mRNA abundance were found in LVs fromAZT-treated TGs. NCX1 abundance was un-changed. Eccentric LV hypertrophy was deter-


mined echocardiographically. Cardiac dysfunc-tion was worst in AZT-treated and -untreatedTGs. Decreases in the first derivative of themaximal change in LV systolic pressure withrespect to time (1dP/dt) occurred at baseline inTGs with and without AZT treatment. Increasedhalf-time of relaxation and ventricular relaxation(2dP/dt) occurred in AZT-treated and -untreatedTGs. Increased time to peak pressure was foundonly in AZT-treated TGs. In AZT-treated wildtypes (WTs), 2dP/dt was decreased. Ultrastructur-ally, mitochondrial destruction was most pro-nounced in AZT-treated TGs, but also was foundin AZT-treated WTs. Transgenic mice that expressHIV-1 show cardiac dysfunction. AZT treatmentof WTs causes mitochondrial ultrastructural alter-ations and alterations in 2dP/dt. In TGs, AZTtreatment worsens CM. Data suggest that HIV-1and AZT each contribute to cardiac dysfunctionin this transgenic model of AIDS CM.131

Available clinical and pathological data aboutAIDS CM may suggest that a preferable approachuses a targeted gene construct to create a TG witha replication defective HIV-1 (with deletion of orinclusion of 1 or more of the structural genes).Targeted expression of defective HIV-1 may bedriven by the tissue-specific promoters. However,because most of the genome is complete, amurine retrovirus may still be capable of pseudo-typing the subgenomic HIV-1 RNA molecule. Asmentioned previously, pseudotypes may allowinfection of other cells but must be maintained bya subsequent pseudotyping event. In this case, thedefective virus could not reproduce to yieldvirions and is safe to use as a model.

A variation on such an approach determinesthe pathological consequences from expression ofan individual viral gene product by creatingsingle-gene TGs with tissue-specific expressiondriven by a specific promoter. However, severalviral proteins may be required to interact witheach other to induce pathological or physiological(phenotypic) changes.

Nonhuman Primates

SIVs are lentiviruses related to HIV-1. Someisolates (eg, SIVsmm and SIVmac) are closelyrelated to HIV-2.209 These viruses are morphologi-cally identical to HIV-1 by electron microscopy,serologically related to HIV-1, and are cytopathic

for CD41 cells. With respect to the developmentof an authentic animal model, some SIV strainsinduce a disease syndrome in experimentallyinfected macaques that bears remarkable resem-blance to human AIDS. Their use in modelingAIDS CM and myocarditis may be limited by thedifficulty in handling primates and other logisticfactors.210

Based on genetic, biological, and antigeniccharacteristics, the SIVs are the closest knownrelatives of HIV. These characteristics, in additionto the clinical, hematologic, immunologic, andpathological changes induced in experimentallyinfected macaques, make the SIV model the bestcurrently available model system for study ofhuman AIDS, but the nature of SIV-induced CMhas only begun to be explored in meaningfulways.193,194

Experimentally, macaques exposed to SIVsmmor SIVmac develop persistent virus infection. Thisresults in severe immunosuppression character-ized by a marked, progressive decrease in CD41

cells and markedly decreased CD41/CD81 cellratio. The AIDS-like state associated with SIVinfection and progressively worsening immuno-suppression is characterized by chronic diarrhea,weight loss, hematologic abnormalities includinganemia and thrombocytopenia, central nervoussystem involvement (comparable with AIDS en-cephalopathy), and opportunistic infections withorganisms including Candida species, Mycobacte-ria, Cryptosporidium, P carinii, cytomegalovirus,and adenovirus. The natural history of the AIDS-like disease in rhesus macaques experimentallyinfected with SIV is 3 months to 5 years frominfection to death with a median of 7 months.This depends on the infecting SIV isolate. Despitethese important similarities, other limitationsmake studies that examine SIV heart disease anuncommon but powerful experimental system.

Feline AIDS and CM

Feline immunodeficiency virus (FIV), as a natu-rally occurring lentiviral infection of cats, hasemerged as an important cause of feline disease.FIV may serve as a useful model of AIDS CM.Originally isolated from feline leukemia virus-negative cats with chronic opportunistic infec-tions and neurological changes,211 FIV has be-come a bonafide AIDS model. Naturally acquired

WILLIAM LEWIS162

FIV infection is associated with severe immunode-ficiency manifested by infections, diarrhea, wast-ing, neurological, ocular, and myeloproliferativedisorders.211 Accordingly, some FIV-associated dis-eases are very similar to HIV-1–associated dis-eases.

Like HIV-1, FIV is primarily cell associated andlymphocytomonocytotropic leading to immuno-suppression, usually in the face of a strongantibody response.212 In the clinic, FIV infectionis diagnosed by the presence of a serum antibodyto FIV as detected by indirect immunofluores-cence or enzyme-linked immunosorbent as-says.211 However, cases exist in which cats are FIVnucleic-acid positive in the absence of seroconver-sion.213

In vivo, experimental FIV infection leads towell-documented acute plasma viremia that, likeHIV-1, is rapidly cleared to almost undetectablelevels until frank disease is apparent.214-216 Chroniclymphopenia and neutropenia are other impor-tant features of experimental FIV infection.217,218

Experimental transmission studies with FIV haverevealed wide variation in the pathogenesis ofdifferent isolates.214,216 Disease induction variesbased on the isolate used, route of virus chal-lenge, and the presence or absence of cofac-tors.218,219 Despite these important features, limi-tations of size and upkeep have made the FIVmodel uncommonly used for studies of cardiovas-cular disease in AIDS.

Because naturally occurring FIV infections aretypically present in older cats ($6 years of age), itis thought that the time period from infection tofrank disease may be lengthy.216 In naturallyinfected cats, wasting is common. However, thisdisease is less common in specific-pathogen freecats that have been experimentally infected andhoused under barrier conditions.220 Nonspecific-pathogen free cats experimentally infected withFIV develop an AIDS-like disease after about a2-year incubation period.

Morphology, reverse transcriptase biochemis-try, and genomic sequence homology have allconfirmed FIV as a lentivirus that has similaritiesto HIV-1.221-225 Reverse transcriptase of FIV isMg11 dependent,224,225 is as sensitive to nucleo-side analogs as HIV-1 in vitro, and readily ac-quires antiviral drug resistance.226 At present, fewstudies of cardiac dysfunction or AIDS CM haveused the FIV cat model.

Summary

Significant advances have been made in thediagnosis and treatment of HIV-1 infection andAIDS. Accordingly, the numbers of patients withAIDS CM, myocarditis, and cardiac dysfunctionhave increased. The impact of HIV-1, its corre-sponding immunologic events, its therapies, andrelated conditions on the development of CM inpatients with AIDS are now becoming clearer.Future experimental and clinical work will focusmore on subcellular mechanisms of CM in pa-tients with AIDS and help define the extent andnature of contributing pathogenetic factors inAIDS CM.

AcknowledgmentsThe author thanks his colleagues and coinvestigators whohave contributed to the data presented herein. Kelly Sjogren isthanked for word processing.

References

1. Karon JM, Rosenberg PS, McQuillan G, et al: Preva-lence of HIV infection in the United States, 1984 to1992. JAMA 276:126-131, 1996

2. Obiri GU, Fordyce EJ, Singh TP, et al: Effect ofHIV/AIDS versus other causes of death on prematuremortality in New York City, 1983-1994. Am J Epide-miol 147:840-845, 1998

3. Hwang SW, Orav EJ, O’Connell JJ, et al: Causes ofdeath in homeless adults in Boston. Ann Intern Med126:625-628, 1997

4. Conti S, Masocco M, Farchi G, et al: Prematuremortality in Italy during the first decade of the AIDSepidemic: 1984-1993. Int J Epidemiol 26:873-879,1997

5. Mudiayi TK, Onyanga-Omara A, Gelman ML: Trendsof morbidity in general medicine at United BulawayoHospitals, Bulawayo, Zimbabwe. Cent Afr J Med43:213-219, 1997

6. Johann-Liang R, Cervia JS, Noel GJ: Characteristicsof human immunodeficiency virus-infected childrenat the time of death: An experience in the 1990s.Pediatr Infect Dis J 16:1145-1150, 1997

7. Cotton P: AIDS giving rise to cardiac problems[news]. JAMA 263:2149, 1990

8. Fischl MA: Antiretroviral therapy in 1999 for antiretro-viral-naive individuals with HIV infection [In ProcessCitation]. Aids 13:S49-S59, 1999 (suppl 1)

9. Currie PF, Boon NA: Cardiac involvement in humanimmunodeficiency virus infection. QJM 86:751-753,1993 (editorial)

10. Hsia JA, McQuinn LB: AIDS cardiomyopathy. Resi-dent Staff Physician 39:21-24, 1993


11. Jacob AJ, Boon NA: HIV cardiomyopathy: A darkcloud with a silver lining? Br Heart J 66:1-2, 1991(editorial)

12. Akhras F, Dubrey S, Gazzard B, et al: Emergingpatterns of heart disease in HIV infected homosexualsubjects with and without opportunistic infections: Aprospective colour flow Doppler echocardiographicstudy. Eur Heart J 15:68-75, 1994

13. Anderson DW, Virmani R: Emerging patterns of heartdisease in human immunodeficiency virus infection.Hum Pathol 21:253-259, 1990

14. Barre-Sinoussi F, Chermann JC, Rey F, et al: Isola-tion of a T-lymphotropic retrovirus from a patient atrisk for acquired immune deficiency syndrome (AIDS).Science 220:868-871, 1983

15. Popovic M, Sarngadharan MG, Read E, et al: Detec-tion, isolation, and continuous production of cyto-pathic retroviruses (HTLV-III) from patients with AIDSand pre-AIDS. Science 224:497-500, 1984

16. Cohen IS, Anderson DW, Virmani R, et al: Conges-tive cardiomyopathy in association with the acquiredimmunodeficiency syndrome. N Engl J Med 315:628-630, 1986

17. Corboy JR, Fink L, Miller WT: Congestive cardiomy-opathy in association with AIDS. Radiology 165:139-141, 1987

18. De Palo VA, Millstein BH, Mayo PH, et al: Outcome ofintensive care in patients with HIV infection. Chest107:506-510, 1995

19. Blanchard DG, Hagenhoff C, Chow LC, et al: Revers-ibility of cardiac abnormalities in human immunodefi-ciency virus (HIV)-infected individuals: A serial echo-cardiographic study. J Am Coll Cardiol 17:1270-1276, 1991

20. Jacob AJ, Sutherland GR, Bird AG, et al: Myocardialdysfunction in patients infected with HIV: Prevalenceand risk factors. Br Heart J 68:549-553, 1992

21. Jacob AJ, Sutherland GR, Boon NA, et al: Dilatedcardiomyopathy in haemophiliacs infected with thehuman immunodeficiency virus. Scott Med J 38:112-113, 1993

22. van Hoeven KH, Segal B, Factor SM: AIDS cardiomy-opathy: First rule out other myocardial risk factors. IntJ Cardiol 29:35-37, 1990

23. Barbaro G, Di Lorenzo G, Grisorio B, et al: Incidenceof dilated cardiomyopathy and detection of HIV inmyocardial cells of HIV-positive patients. GruppoItaliano per lo Studio Cardiologico dei Pazienti Affettida AIDS [see comments]. N Engl J Med 339:1093-1099, 1998

24. Chariot P, Perchet H, Monnet I: Dilated cardiomyopa-thy in HIV-infected patients [letter; comment]. N EnglJ Med 340:732, 1999

25. Malnick S, Goland S: Dilated cardiomyopathy inHIV-infected patients [letter; comment]. N Engl J Med340:732-733, 1999

26. Flotats A, Domingo P, Carrio I: Dilated cardiomyopa-thy in HIV-infected patients [letter; comment]. N EnglJ Med 340:733-734, 1999

27. Kasper EK, Agema WR, Hutchins GM, et al: Thecauses of dilated cardiomyopathy: A clinicopatho-

logic review of 673 consecutive patients [see com-ments]. J Am Coll Cardiol 23:586-590, 1994

28. Kaminski HJ, Katzman M, Wiest PM, et al: Cardiomy-opathy associated with the acquired immune defi-ciency syndrome. J Acquir Immune Defic Syndr HumRetrovirol 1:105-110, 1988

29. Leidig GAJr: Clinical, echocardiographic, and electro-cardiographic resolution of HIV-related cardiomyopa-thy. Mil Med 156:260-261, 1991

30. Hecht SR, Berger M, Van Tosh A, et al: Unsuspectedcardiac abnormalities in the acquired immune defi-ciency syndrome. An echocardiographic study [seecomments]. Chest 96:805-808, 1989

31. Burch GE, Giles TD: Alcoholic cardiomyopathy. Con-cept of the disease and its treatment. Am J Med50:141-145, 1971

32. Hibbs RG, Ferrans VJ, Walsh JJ, et al: Electronmicroscopic observations on lysosomes and relatedcytoplasmic components of normal and pathologicalcardiac muscle. Anat Rec 153:173-185, 1965

33. Regan TJ, Khan MI, Ettinger PO, et al: Myocardialfunction and lipid metabolism in the chronic alcoholicanimal. J Clin Invest 54:740-752, 1974

34. Thomas G, Haider B, Oldewurtel HA, et al: Progres-sion of myocardial abnormalities in experimentalalcoholism. Am J Cardiol 46:233-241, 1980

35. Weishaar R, Sarma JS, Maruyama Y, et al: Reversibil-ity of mitochondrial and contractile changes in themyocardium after cessation of prolonged ethanolintake. Am J Cardiol 40:556-562, 1977

36. Segel LD, Rendig SV, Choquet Y, et al: Effects ofchronic graded ethanol consumption on the metabo-lism, ultrastructure, and mechanical function of therat heart. Cardiovasc Res 9:649-663, 1975

37. Sarma JS, Ikeda S, Fischer R, et al: Biochemical andcontractile properties of heart muscle after prolongedalcohol administration. J Mol Cell Cardiol 8:951-972,1976

38. Bing RJ: Effect of alcohol on the heart and cardiacmetabolism. Fed Proc 41:2443-2446, 1982

39. Segel LD, Klausner SC, Gnadt JT, et al: Alcohol andthe heart. Med Clin North Am 68:147-161, 1984

40. Rubin E: Alcoholic myopathy in heart and skeletalmuscle. N Engl J Med 301:28-33, 1979

41. Regan TJ: Alcoholic cardiomyopathy. Prog Cardio-vasc Dis 27:141-152, 1984

42. McCall D, Ryan K: The effect of ethanol and acetalde-hyde on Na pump function in cultured rat heart cells.J Mol Cell Cardiol 19:453-463, 1987

43. Regan TJ, Morvai V: Experimental models for study-ing the effects of ethanol on the myocardium. ActaMed Scand Suppl 717:107-113, 1987

44. Segel LD, Rendig SV, Mason DT: Alcohol-inducedcardiac hemodynamic and Ca21 flux dysfunctionsare reversible. J Mol Cell Cardiol 13:443-455, 1981

45. Chan TC, Sutter MC: The effects of chronic ethanolconsumption on cardiac function in rats. Can JPhysiol Pharmacol 60:777-782, 1982

46. Capasso JM, Li P, Guideri G, et al: Left ventriculardysfunction induced by chronic alcohol ingestion inrats. Am J Physiol 261:H212-H219, 1991

WILLIAM LEWIS164

47. King DC, Hirst M: Suppression of ethanol-inducedcardiac hypertrophy by beta-adrenoceptor blockade.J Mol Cell Cardiol 22:523-531, 1990

48. Capasso JM, Bruno S, Cheng W, et al: Ventricularloading is coupled with DNA synthesis in adultcardiac myocytes after acute and chronic myocardialinfarction in rats. Circ Res 71:1379-1389, 1992

49. Askanas A, Udoshi M, Sadjadi SA: The heart inchronic alcoholism: A noninvasive study. Am Heart J99:9-16, 1980

50. Mathews EC Jr, Gardin JM, Henry WL, et al: Echocar-diographic abnormalities in chronic alcoholics withand without overt congestive heart failure. Am JCardiol 47:570-578, 1981

51. Urbano-Marquez A, Estruch R, Navarro-Lopez F, etal: The effects of alcoholism on skeletal and cardiacmuscle [see comments]. N Engl J Med 320:409-415,1989

52. Regan TJ, Levinson GE, Oldewurtel HA, et al:Ventricular function in noncardiacs with alcoholicfatty liver: Role of ethanol in the production ofcardiomyopathy. J Clin Invest 48:397-407, 1969

53. Steinberg JD, Hayden MT: Prevalence of clinicallyoccult cardiomyopathy in chronic alcoholism. AmHeart J 101:461-464, 1981

54. Thomas AP, Rozanski DJ, Renard DC, et al: Effectsof ethanol on the contractile function of the heart: Areview. Alcohol Clin Exp Res 18:121-131, 1994

55. Figueredo VM, Chang KC, Baker AJ, et al: Chronicalcohol-induced changes in cardiac contractility arenot due to changes in the cytosolic Ca21 transient.Am J Physiol 275:H122-H130, 1998

56. Karch SB: The Pathology of Drug Abuse. BocaRaton, FL, CRC Press, 1996

57. Som P, Oster ZH, Wang GJ, et al: Spatial andtemporal distribution of cocaine and effects of phar-macological interventions: Wholebody autoradio-graphic microimaging studies. Life Sci 55:1375-1382, 1994

58. Volkow ND, Fowler JS, Wolf AP, et al: Distributionand kinetics of carbon-11-cocaine in the human bodymeasured with PET. J Nucl Med 33:521-525, 1992

59. Inaba T, Stewart DJ, Kalow W: Metabolism of co-caine in man. Clin Pharmacol Ther 23:547-552, 1978

60. Madden JA, Powers RH: Effect of cocaine andcocaine metabolites on cerebral arteries in vitro. LifeSci 47:1109-1114, 1990

61. Erzouki HK, Baum I, Goldberg SR, et al: Comparisonof the effects of cocaine and its metabolites oncardiovascular function in anesthetized rats. J Cardio-vasc Pharmacol 22:557-563, 1993

62. Covert RF, Schreiber MD, Tebbett IR, et al: Hemody-namic and cerebral blood flow effects of cocaine,cocaethylene and benzoylecgonine in conscious andanesthetized fetal lambs. J Pharmacol Exp Ther270:118-126, 1994

63. Schreiber MD, Madden JA, Covert RF, et al: Effectsof cocaine, benzoylecgonine, and cocaine metabo-lites in cannulated pressurized fetal sheep cerebralarteries. J Appl Physiol 77:834-839, 1994

64. Brickner ME, Willard JE, Eichhorn EJ, et al: Leftventricular hypertrophy associated with chronic co-caine abuse. Circulation 84:1130-1135, 1991

65. Om A, Ellahham S, Vetrovec GW, et al: Left ventricu-lar hypertrophy in normotensive cocaine users. AmHeart J 125:1441-1443, 1993

66. Hoegerman GS, Lewis CE, Flack J, et al: Lack ofassociation of recreational cocaine and alcohol usewith left ventricular mass in young adults. The Coro-nary Artery Risk Development in Young Adults (CAR-DIA) study. J Am Coll Cardiol 25:895-900, 1995

67. Eisenberg MJ, Jue J, Mendelson J, et al: Leftventricular morphologic features and function in non-hospitalized cocaine users: A quantitative two-dimensional echocardiographic study. Am Heart J129:941-946, 1995

68. Karch SB, Green GS, Young S: Myocardial hypertro-phy and coronary artery disease in male cocaineusers. J Forensic Sci 40:591-595, 1995

69. Chakko S, Sepulveda S, Kessler KM, et al: Fre-quency and type of electrocardiographic abnormali-ties in cocaine abusers (electrocardiogram in co-caine abuse). Am J Cardiol 74:710-713, 1994

70. Nademanee K: Cardiovascular effects and toxicitiesof cocaine. J Addict Dis 11:71-82, 1992

71. Escobedo L, Ruttenbar A, Anda R: Coronary arterydisease, left ventricular hypertrophy, and the risk ofcocaine overdose death. Coron Artery Dis 3:853-857, 1992

72. Seballos RJ, Mendel SG, Mirmiran-Yazdy A, et al:Sarcoid cardiomyopathy precipitated by pregnancywith cocaine complications. Chest 105:303-305, 1994

73. Wiener RS, Lockhart JT, Schwartz RG: Dilated cardio-myopathy and cocaine abuse. Report of two cases.Am J Med 81:699-701, 1986

74. Chokshi SK, Moore R, Pandian NG, et al: Reversiblecardiomyopathy associated with cocaine intoxica-tion. Ann Intern Med 111:1039-1040, 1989

75. Duell PB: Chronic cocaine abuse and dilated cardio-myopathy [letter]. Am J Med 83:601, 1987

76. Wolfson H, Hogya P, Wolfson A: Chronic cocaineabuse associated with dilated cardiomyopathy. Am JEmerg Med 8:203-204, 1990

77. Mendelson MA, Chandler J: Postpartum cardiomy-opathy associated with maternal cocaine abuse. AmJ Cardiol 70:1092-1094, 1992

78. Karch SB, Billingham ME: Myocardial contractionbands revisited. Hum Pathol 17:9-13, 1986

79. Peng SK, French WJ, Pelikan PC: Direct cocainecardiotoxicity demonstrated by endomyocardial bi-opsy. Arch Pathol Lab Med 113:842-845, 1989

80. Henzlova MJ, Smith SH, Prchal VM, et al: Apparentreversibility of cocaine-induced congestive cardiomy-opathy. Am Heart J 122:577-579, 1991

81. Szakaacs J, Cannon A: L-norepinephrine myocardi-tis. Am J Clin Pathol 30:425-434, 1958

82. Rosenbaum JS, Ginsburg R, Billingham ME, et al:Effects of adrenergic receptor antagonists on cardiacmorphological and functional alterations in rats har-boring pheochromocytoma. J Pharmacol Exp Ther241:354-360, 1987


83. Karch SB, Billingham ME: The pathology and etiol-ogy of cocaine-induced heart disease. Arch PatholLab Med 112:225-230, 1988

84. Isner JM, Estes NAD, Thompson PD, et al: Acutecardiac events temporally related to cocaine abuse.N Engl J Med 315:1438-1443, 1986

85. Virmani R, Robinowitz M, Smialek JE, et al: Cardio-vascular effects of cocaine: An autopsy study of 40patients [see comments]. Am Heart J 115:1068-1076, 1988

86. Weber KT, Sun Y, Guarda E: Structural remodeling inhypertensive heart disease and the role of hor-mones. Hypertension 23:869-877, 1994

87. Bristow MR: Tumor necrosis factor-alpha and cardio-myopathy [comment]. Circulation 97:1340-1341, 1998(editorial)

88. Wilbert-Lampen U, Seliger C, Zilker T, et al: Cocaineincreases the endothelial release of immunoreactiveendothelin and its concentrations in human plasmaand urine: Reversal by coincubation with sigma-receptor antagonists. Circulation 98:385-390, 1998

89. Rosenzweig A, Seidman CE: Atrial natriuretic factorand related peptide hormones. Annu Rev Biochem60:229-255, 1991

90. Hunter JJ, Chien KR: Review articles: Mechanismsof disease: Signaling pathways for cardiac hypertro-phy and failure. N Engl J Med 341:1276-1283, 1999

91. Muller-Werdan U, Koidl B, Autenrieth A, et al: Pre-formed natural antibodies: Their impact on contrac-tile activity of cardiomyocytes. Transplant Proc 27:2109-2111, 1995

92. Pinsky DJ, Cai B, Yang X, et al: The lethal effects ofcytokine-induced nitric oxide on cardiac myocytesare blocked by nitric oxide synthase antagonism ortransforming growth factor beta. J Clin Invest 95:677-685, 1995

93. Werdan K, Muller U, Reithman C: Negative inotropiccascades in cardiomyocytes triggered by substancesrelevant to sepsis, in Schlag G, Redl H (eds):Pathophysiology of Shock, Sepsis, and Organ Fail-ure. Berlin, Germany, Springer-Verlag, 1995, pp787-834

94. Barry WH: Mechanisms of immune-mediated myo-cyte injury. Circulation 89:2421-2432, 1994

95. Kasten-Sportes CWC: Molecular mechanisms of HIVcardiovascular disease. New York, NY, Chapmanand Hall, 1998

96. Gulick T, Chung MK, Pieper SJ, et al: Interleukin 1and tumor necrosis factor inhibit cardiac myocytebeta-adrenergic responsiveness. Proc Natl Acad SciU S A 86:6753-6757, 1989

97. Pagani FD, Baker LS, Hsi C, et al: Left ventricularsystolic and diastolic dysfunction after infusion oftumor necrosis factor-alpha in conscious dogs. J ClinInvest 90:389-398, 1992

98. Vincent JL, Bakker J, Marecaux G, et al: Administra-tion of anti-TNF antibody improves left ventricularfunction in septic shock patients. Results of a pilotstudy. Chest 101:810-815, 1992

99. Colucci WS: Molecular and cellular mechanisms ofmyocardial failure. Am J Cardiol 80:15L-25L, 1997

100. Weber KT: Extracellular matrix remodeling in heartfailure. A role for de novo angiotensin II generation.Circulation 96:4065-4082, 1997

101. Shubeita HE, McDonough PM, Harris AN, et al:Endothelin induction of inositol phospholipid hydroly-sis, sarcomere assembly, and cardiac gene expres-sion in ventricular myocytes. A paracrine mechanismfor myocardial cell hypertrophy. J Biol Chem 265:20555-20562, 1990

102. Cody RJ, Haas GJ, Binkley PF, et al: Plasma endo-thelin correlates with the extent of pulmonary hyper-tension in patients with chronic congestive heartfailure [published erratum appears in Circulation87:1064, 1993]. Circulation 85:504-509, 1992

103. Wei CM, Lerman A, Rodeheffer RJ, et al: Endothelinin human congestive heart failure. Circulation 89:1580-1586, 1994

104. Krum H, Goldsmith R, Wilshire-Clement M, et al:Role of endothelin in the exercise intolerance ofchronic heart failure. Am J Cardiol 75:1282-1283,1995

105. Finkel MS, Oddis CV, Jacob TD, et al: Negativeinotropic effects of cytokines on the heart mediatedby nitric oxide. Science 257:387-389, 1992

106. Finkel MS, Hoffman RA, Shen L, et al: Interleukin-6(IL-6) as a mediator of stunned myocardium. Am JCardiol 71:1231-1232, 1993

107. Kawamura T, Inada K, Okada H, et al: Methylpredniso-lone inhibits increase of interleukin 8 and 6 duringopen heart surgery. Can J Anaesth 42:399-403, 1995

108. Barbaro G, Di Lorenzo G, Soldini M, et al: Intensity ofmyocardial expression of inducible nitric oxide syn-thase influences the clinical course of human immu-nodeficiency virus-associated cardiomyopathy.Gruppo Italiano per lo Studio Cardiologico dei pazi-enti affetti da AIDS (GISCA). Circulation 100:933-939, 1999

109. Sonnenblick EH, Fein F, Capasso JM, et al: Microvas-cular spasm as a cause of cardiomyopathies and thecalcium-blocking agent verapamil as potential pri-mary therapy. Am J Cardiol 55:179B-184B, 1985

110. Mohan P, Sys SU, Brutsaert DL: Mechanisms ofendocardial endothelium modulation of myocardialperformance. Adv Exp Med Biol 382:249-260, 1995

111. Andries LJ, Kaluza G, De Keulenaer GW, et al:Endocardial endothelial dysfunction and heart failure.J Card Fail 2:S195-S202, 1996 (suppl)

112. Zietz C, Hotz B, Sturzl M, et al: Aortic endothelium inHIV-1 infection: Chronic injury, activation, and in-creased leukocyte adherence.Am J Pathol 149:1887-1898, 1996

113. Pomerantz RJ, Kuritzkes DR, de la Monte SM, et al:Infection of the retina by human immunodeficiencyvirus type I. N Engl J Med 317:1643-1647, 1987

114. Corbeil J, Evans LA, McQueen PW, et al: Productivein vitro infection of human umbilical vein endothelialcells and three colon carcinoma cell lines with HIV-1.Immunol Cell Biol 73:140-145, 1995

115. Fan ST, Hsia K, Edgington TS: Upregulation ofhuman immunodeficiency virus-1 in chronically in-

WILLIAM LEWIS166

fected monocytic cell line by both contact with endo-thelial cells and cytokines. Blood 84:1567-1572, 1994

116. Conaldi PG, Serra C, Dolei A, et al: Productive HIV-1infection of human vascular endothelial cells requirescell proliferation and is stimulated by combined treat-ment with interleukin-1 beta plus tumor necrosisfactor-alpha. J Med Virol 47:355-363, 1995

117. Frankel AD, Young JA: HIV-1: Fifteen proteins and anRNA. Annu Rev Biochem 67:1-25, 1998

118. Dhawan S, Puri RK, Kumar A, et al: Human immuno-deficiency virus-1-tat protein induces the cell surfaceexpression of endothelial leukocyte adhesion mol-ecule-1, vascular cell adhesion molecule-1, and inter-cellular adhesion molecule-1 in human endothelialcells. Blood 90:1535-1544, 1997

119. Ensoli B, Barillari G, Salahuddin SZ, et al: Tat proteinof HIV-1 stimulates growth of cells derived fromKaposi’s sarcoma lesions of AIDS patients. Nature345:84-86, 1990

120. Albini A, Barillari G, Benelli R, et al: Angiogenicproperties of human immunodeficiency virus type 1Tat protein. Proc Natl Acad Sci U S A 92:4838-4842,1995

121. Ensoli B, Markham P, Kao V, et al: Block of AIDS-Kaposi’s sarcoma (KS) cell growth, angiogenesis,and lesion formation in nude mice by antisenseoligonucleotide targeting basic fibroblast growth fac-tor. A novel strategy for the therapy of KS. J ClinInvest 94:1736-1746, 1994

122. Vaishnav YN, Wong-Staal F: The biochemistry ofAIDS. Annu Rev Biochem 60:577-630, 1991

123. Ensoli B, Buonaguro L, Barillari G, et al: Release,uptake, and effects of extracellular human immunode-ficiency virus type 1 Tat protein on cell growth andviral transactivation. J Virol 67:277-287, 1993

124. Lotz M, Clark-Lewis I, Ganu V: HIV-1 transactivatorprotein Tat induces proliferation and TGF beta expres-sion in human articular chondrocytes. J Cell Biol124:365-371, 1994

125. Barillari G, Buonaguro L, Fiorelli V, et al: Effects ofcytokines from activated immune cells on vascularcell growth and HIV-1 gene expression. Implicationsfor AIDS-Kaposi’s sarcoma pathogenesis. J Immunol149:3727-3734, 1992

126. Albini A, Soldi R, Giunciuglio D, et al: The angiogen-esis induced by HIV-1 tat protein is mediated by theFlk-1/KDR receptor on vascular endothelial cells. NatMed 2:1371-1375, 1996

127. Lewis W, Dalakas MC: Mitochondrial toxicity of antivi-ral drugs. Nat Med 1:417-422, 1995

128. Lewis W, Papoian T, Gonzalez B, et al: Mitochondrialultrastructural and molecular changes induced byzidovudine in rat hearts. Lab Invest 65:228-236,1991

129. Lewis W, Gonzalez B, Chomyn A, et al: Zidovudineinduces molecular, biochemical, and ultrastructuralchanges in rat skeletal muscle mitochondria. J ClinInvest 89:1354-1360, 1992

130. Lamperth L, Dalakas MC, Dagani F, et al: Abnormalskeletal and cardiac muscle mitochondria induced by

zidovudine (AZT) in human muscle in vitro and in ananimal model. Lab Invest 65:742-751, 1991

131. Lewis W, Grupp IL, Grupp G, et al: Cardiac dysfunc-tion occurs in the HIV-1 transgenic mouse treatedwith Zidovudine. Lab Invest 80:187-197, 2000

132. Wallace DC: Diseases of the mitochondrial DNA.Annu Rev Biochem 61:1175-1212, 1992

133. Lewis W, Simpson JF, Meyer RR: Cardiac mitochon-drial DNA polymerase-gamma is inhibited competi-tively and noncompetitively by phosphorylated zidov-udine. Circ Res 74:344-348, 1994

134. Lewis W, Meyer RR, Simpson JF, et al: MammalianDNA polymerases alpha, beta, gamma, delta, andepsilon incorporate fialuridine (FIAU) monophos-phate into DNA and are inhibited competitively byFIAU Triphosphate. Biochemistry 33:14620-14624,1994

135. Lewis W, Levine ES, Griniuviene B, et al: Fialuridineand its metabolites inhibit DNA polymerase gammaat sites of multiple adjacent analog incorporation,decrease mtDNA abundance, and cause mitochon-drial structural defects in cultured hepatoblasts. ProcNatl Acad Sci U S A 93:3592-3597, 1996

136. Lewis W, Griniuviene B, Tankersley KO, et al: Deple-tion of mitochondrial DNA, destruction of mitochon-dria, and accumulation of lipid droplets result fromfialuridine treatment in woodchucks (Marmotamonax). Lab Invest 76:77-87, 1997

137. d’Amati G, Lewis W: Zidovudine causes early in-creases in mitochondrial ribonucleic acid abundanceand induces ultrastructural changes in cultured mousemuscle cells. Lab Invest 71:879-884, 1994

138. Swartz MN: Mitochondrial toxicity—new adverse drugeffects [comment]. N Engl J Med 333:1099-1105,1995 (editorial)

139. Morris AA, Carr A: HIV nucleoside analogues: Newadverse effects on mitochondria? [In Process Cita-tion]. Lancet 354:1046-1047, 1999

140. Brinkman K, ter Hofstede HJ, Burger DM, et al:Adverse effects of reverse transcriptase inhibitors:Mitochondrial toxicity as common pathway. AIDS12:1735-1744, 1998 (editorial)

141. Freyssenet D, DiCarlo M, Escobar P, et al: Zidovu-dine (AZT) induced alterations in mitochondrial bio-genesis in rat striated muscles [In Process Citation].Can J Physiol Pharmacol 77:29-35, 1999

142. Szabados E, Fischer GM, Toth K, et al: Role ofreactive oxygen species and poly-ADP-ribose poly-merase in the development ofAZT-induced cardiomy-opathy in rat. Free Radic Biol Med 26:309-317, 1999

143. Herskowitz A, Willoughby SB, Baughman KL, et al:Cardiomyopathy associated with antiretroviral therapyin patients with HIV infection: A report of six cases.Ann Intern Med 116:311-313, 1992

144. D’Amati G, Kahn HJ, Butany J, et al: Altered distribu-tion of desmin filaments in hypertrophic cardiomyopa-thy: An immunohistochemical study. Mod Pathol5:165-168, 1992

145. Koehler A, Lewis W: Mitochondrial cardiomyopathyin HIV-1 patients with zidovudine. Lab Invest 72:33A,1995


146. Olivero OA, Shearer GM, Chougnet CA, et al: Incor-poration of zidovudine into leukocyte DNA fromHIV-1-positive adults and pregnant women, and cordblood from infants exposed in utero. AIDS 13:919-925, 1999

147. Olivero OA, Anderson LM, Diwan BA, et al: Transpla-cental effects of 38-azido-28,38-dideoxythymidine(AZT): Tumorigenicity in mice and genotoxicity inmice and monkeys [see comments]. J Natl CancerInst 89:1602-1608, 1997

148. Lipshultz SE, Easley KA, Orav EJ, et al: Left ventricu-lar structure and function in children infected withhuman immunodeficiency virus: The prospectiveP2C2 HIV Multicenter Study. Pediatric Pulmonaryand Cardiac Complications of Vertically TransmittedHIV Infection (P2C2 HIV) Study Group. Circulation97:1246-1256, 1998

149. Brown DL, Sather S, Cheitlin MD: Reversible cardiacdysfunction associated with foscarnet therapy forcytomegalovirus esophagitis in an AIDS patient. AmHeart J 125:1439-1441, 1993

150. Deyton LR, Walker RE, Kovacs JA, et al: Reversiblecardiac dysfunction associated with interferon alfatherapy in AIDS patients with Kaposi’s sarcoma [seecomments]. N Engl J Med 321:1246-1249, 1989

151. Stein KM, Haronian H, Mensah GA, et al: Ventriculartachycardia and torsades de pointes complicatingpentamidine therapy of Pneumocystis carinii pneumo-nia in the acquired immunodeficiency syndrome. AmJ Cardiol 66:888-889, 1990

152. Wharton JM, Demopulos PA, Goldschlager N: Tors-ade de pointes during administration of pentamidineisethionate. Am J Med 83:571-576, 1987

153. Flexner C: HIV-protease inhibitors [see comments].N Engl J Med 338:1281-1292, 1998

154. De Castro S, d’Amati G, Gallo P, et al: Frequency ofdevelopment of acute global left ventricular dysfunc-tion in human immunodeficiency virus infection. J AmColl Cardiol 24:1018-1024, 1994

155. Herskowitz A, Vlahov D, Willoughby S, et al: Preva-lence and incidence of left ventricular dysfunction inpatients with human immunodeficiency virus infec-tion. Am J Cardiol 71:955-958, 1993

156. Fong IW, Howard R, Elzawi A, et al: Cardiac involve-ment in human immunodeficiency virus-infected pa-tients. J Acquir Immune Defic Syndr Hum Retrovirol6:380-385, 1993

157. De Simone C, Tzantzoglou S, Jirillo E, et al: L-carnitine deficiency in AIDS patients. AIDS 6:203-205, 1992

158. Semino-Mora MC, Leon-Monzon ME, Dalakas MC:The effect of L-carnitine on the AZT-induced destruc-tion of human myotubes. Part II: Treatment withL-carnitine improves the AZT-induced changes andprevents further destruction. Lab Invest 71:773-781,1994

159. Miller TL, Orav EJ, Colan SD, et al: Nutritional statusand cardiac mass and function in children infectedwith the human immunodeficiency virus. Am J ClinNutr 66:660-664, 1997

160. Dworkin BM: Selenium deficiency in HIV infectionand the acquired immunodeficiency syndrome(AIDS). Chem Biol Interact 91:181-186, 1994

161. Dworkin BM, Antonecchia PP, Smith F, et al: Re-duced cardiac selenium content in the acquiredimmunodeficiency syndrome [see comments]. JParenter Enteral Nutr 13:644-647, 1989

162. Kavanaugh-McHugh AL, Ruff A, Perlman E, et al:Selenium deficiency and cardiomyopathy in acquiredimmunodeficiency syndrome. J Parenter Enteral Nutr15:347-349, 1991

163. Levy WS, Varghese PJ, Anderson DW, et al: Myocar-ditis diagnosed by endomyocardial biopsy in humanimmunodeficiency virus infection with cardiac dys-function. Am J Cardiol 62:658-659, 1988

164. Hansen BF: Pathology of the heart in AIDS. A studyof 60 consecutive autopsies. APMIS 100:273-279,1992

165. Thuesen L, Moller A, Kristensen BO, et al: Cardiacfunction in patients with human immunodeficiencyvirus infection and with no other active infections.Dan Med Bull 41:107-109, 1994

166. Klatt EC, Meyer PR: Pathology of the heart inacquired immunodeficiency syndrome (AIDS) [let-ter]. Arch Pathol Lab Med 112:114, 1988

167. Altieri PI, Climent C, Lazala G, et al: Opportunisticinvasion of the heart in Hispanic patients with ac-quired immunodeficiency syndrome. Am J Trop MedHyg 51:56-59, 1994

168. Reilly JM, Cunnion RE, Anderson DW, et al: Fre-quency of myocarditis, left ventricular dysfunctionand ventricular tachycardia in the acquired immunedeficiency syndrome. Am J Cardiol 62:789-793, 1988

169. Lewis W, Grody WW: AIDS and the heart: Reviewand consideration of pathogenetic mechanisms. Car-diovasc Pathol 1:53-64, 1992

170. Baroldi G, Corallo S, Moroni M, et al: Focal lympho-cytic myocarditis in acquired immunodeficiency syn-drome (AIDS): A correlative morphologic and clinicalstudy in 26 consecutive fatal cases. J Am Coll Cardiol12:463-469, 1988

171. Anderson DW, Virmani R, Reilly JM, et al: Prevalentmyocarditis at necropsy in the acquired immunodefi-ciency syndrome. J Am Coll Cardiol 11:792-799,1988

172. Roldan EO, Moskowitz L, Hensley GT: Pathology ofthe heart in acquired immunodeficiency syndrome.Arch Pathol Lab Med 111:943-946, 1987

173. Tazelaar HD, Billingham ME: Leukocytic infiltrates inidiopathic dilated cardiomyopathy. A source of confu-sion with active myocarditis. Am J Surg Pathol10:405-412, 1986

174. Cammarosano C, Lewis W: Cardiac lesions in ac-quired immune deficiency syndrome (AIDS). J AmColl Cardiol 5:703-706, 1985

175. Lewis W: AIDS: Cardiac findings from 115 autopsies.Prog Cardiovasc Dis 32:207-215, 1989

176. Turnicky RP, Goodin J, Smialek JE, et al: Incidentalmyocarditis with intravenous drug abuse: The pathol-ogy, immunopathology, and potential implications for

WILLIAM LEWIS168

human immunodeficiency virus-associated myocardi-tis. Hum Pathol 23:138-143, 1992

177. Factor SM: Acquired immune deficiency syndrome:The heart of the matter. J Am Coll Cardiol 13:1037-1038, 1989

178. Segal BH, Factor SM: Myocardial risk factors otherthan human immunodeficiency virus infection maycontribute to histologic cardiomyopathic changes inacquired immune deficiency syndrome. Mod Pathol6:560-564, 1993

179. Levy JA: HIV and the Pathogenesis of AIDS. Wash-ington, DC, ASM Press, 1998

180. Koenig S, Gendelman HE, Orenstein JM, et al:Detection of AIDS virus in macrophages in braintissue from AIDS patients with encephalopathy. Sci-ence 233:1089-1093, 1986

181. Feremans WW, Huygen K, Menu R, et al: Fifty casesof human immunodeficiency virus (HIV) infection:Immunoultrastructural study of circulating lympho-cytes. J Clin Pathol 41:62-71, 1988

182. Salahuddin SZ, Palestine AG, Heck E, et al: Isolationof the human T-cell leukemia/lymphotropic virus typeIII from the cornea. Am J Ophthalmol 101:149-152,1986

183. Wiley CA, Schrier RD, Nelson JA, et al: Cellularlocalization of human immunodeficiency virus infec-tion within the brains of acquired immune deficiencysyndrome patients. Proc NatlAcad Sci U SA83:7089-7093, 1986

184. Rabeneck L, Popovic M, Gartner S, et al: Acute HIVinfection presenting with painful swallowing andesophageal ulcers. JAMA 263:2318-2322, 1990

185. Bailey RO, Baltch AL, Venkatesh R, et al: Sensorymotor neuropathy associated with AIDS. Neurology38:886-891, 1988

186. da Silva M, Shevchuk MM, Cronin WJ, et al: Detec-tion of HIV-related protein in testes and prostates ofpatients with AIDS [see comments]. Am J Clin Pathol93:196-201, 1990

187. Hoda SA, Gerber MA: The value of the autopsy forthe 1990s [letter]. Hum Pathol 21:980-981, 1990

188. Karlsson-Parra A, Dimeny E, Fellstrom B, et al: HIVreceptors (CD4 antigen) in normal human glomerularcells [letter]. N Engl J Med 320:741, 1989

189. Coudray N, de Zuttere D, Force G, et al: Leftventricular diastolic function in asymptomatic andsymptomatic human immunodeficiency virus carri-ers: An echocardiographic study. Eur Heart J 16:61-67, 1995

190. Hsi D, Manders WT, Shannon RP: SIV in non-humanprimates causes myocardial injury and cardiomyopa-thy following chronic but not acute infection. Circula-tion 92:1471, 1995

191. Dittrich H, Chow L, Denaro F, et al: Human immuno-deficiency virus, coxsackievirus, and cardiomyopa-thy [letter]. Ann Intern Med 108:308-309, 1988

192. Grody WW, Cheng L, Lewis W: Infection of the heartby the human immunodeficiency virus. Am J Cardiol66:203-206, 1990

193. Shannon RP, Mathier MA, Mankod S, et al: Macro-phages not cardiac myocytes are the reservoir for

lentivirus in SIV cardiomyopathy. Circulation 100:I-382, 1999 (suppl I)

194. Shannon RP, Simon MA, Mathier MA, et al: Dilatedcardiomyopathy associated with Simian AIDs in non-human primates. Circulation 101: 185-193, 2000

195. Lipshultz SE, Fox CH, Perez-Atayde AR, et al:Identification of human immunodeficiency virus-1RNA and DNA in the heart of a child with cardiovascu-lar abnormalities and congenital acquired immunedeficiency syndrome. Am J Cardiol 66:246-250, 1990

196. Wu AY, Forouhar F, Cartun RW, et al: Identification ofhuman immunodeficiency virus in the heart of apatient with acquired immunodeficiency syndrome.Mod Pathol 3:625-630, 1990

197. Calabrese LH, Proffitt MR, Yen-Lieberman B, et al:Congestive cardiomyopathy and illness related to theacquired immunodeficiency syndrome (AIDS) associ-ated with isolation of retrovirus from myocardium.Ann Intern Med 107:691-692, 1987

198. Flomenbaum M, Soeiro R, Udem SA, et al: Prolifera-tive membranopathy and human immunodeficiencyvirus in AIDS hearts. J Acquir Immune Defic Syndr2:129-135, 1989

199. Beschorner WE, Baughman K, Turnicky RP, et al:HIV-associated myocarditis. Pathology and immuno-pathology. Am J Pathol 137:1365-1371, 1990

200. Pantaleo G, Graziosi C, Fauci AS: New concepts inthe immunopathogenesis of human immunodefi-ciency virus infection. N Engl J Med 328:327-335,1993

201. Cheng-Mayer C, Seto D, Tateno M, et al: Biologicfeatures of HIV-1 that correlate with virulence in thehost. Science 240:80-82, 1988

202. Small JA, Scangos GA, Cork L, et al: The earlyregion of human papovavirus JC induces dysmyelin-ation in transgenic mice. Cell 46:13-18, 1986

203. Hinrichs SH, Nerenberg M, Reynolds RK, et al: Atransgenic mouse model for human neurofibromato-sis. Science 237:1340-1343, 1987

204. Green JE, Hinrichs SH, Vogel J, et al: Exocrinopathyresembling Sjogren’s syndrome in HTLV-1 tax trans-genic mice. Nature 341:72-74, 1986

205. Kim CM, Koike K, Saito I, et al: HBx gene of hepatitisB virus induces liver cancer in transgenic mice.Nature 351:317-320, 1991

206. Klotman PE, Notkins AL: Transgenic models of hu-man immunodeficiency virus type-1. Curr Top Micro-biol Immunol 206:197-222, 1996

207. Tinkle BT, Ueda H, Ngo L, et al: Transgenic dissec-tion of HIV genes involved in lymphoid depletion. JClin Invest 100:32-39, 1997

208. Lewis W, Samarel A: Molecular and ultrastructuralfeatures of cardiomyopathy occur in AIDS transgenic(TG) mice treated with zidovudine. Circulation 100:I-269, 1999 (suppl I)

209. Norley S, Kurth R: Simian immunodeficiency virus asa model of HIV pathogenesis. Springer Semin Immu-nopathol 18:391-405, 1997

210. Nathanson N, Auerbach JD: Confronting the HIVpandemic. Science 284:1619, 1999


211. Pedersen NC, Ho EW, Brown ML, et al: Isolation of aT-lymphotropic virus from domestic cats with animmunodeficiency-like syndrome. Science 235:790-793, 1987

212. Ackley CD, Yamamoto JK, Levy N, et al: Immuno-logic abnormalities in pathogen-free cats experimen-tally infected with feline immunodeficiency virus. JVirol 64:5652-5655, 1990

213. Hopper CD, Sparkes AH, Gruffydd-Jones TJ, et al:Clinical and laboratory findings in cats infected withfeline immunodeficiency virus. Vet Rec 125:341-346,1989

214. Hayes KA, Lafrado LJ, Erickson JG, et al: Prophylac-tic ZDV therapy prevents early viremia and lympho-cyte decline but not primary infection in feline immu-nodeficiency virus-inoculated cats. J Acquir ImmuneDefic Syndr Hum Retrovirol 6:127-134, 1993

215. Hayes KA, Wilkinson JG, Frick R, et al: Early suppres-sion of viremia by ZDV does not alter the spread offeline immunodeficiency virus infection in cats. JAcquir Immune Defic Syndr Hum Retrovirol 9:114-122, 1995

216. Tompkins MB, Nelson PD, English RV, et al: Earlyevents in the immunopathogenesis of feline retrovi-rus infections. J Am Vet Med Assoc 199:1311-1315,1991

217. Harbour DA, Williams PD, Gruffydd-Jones TJ, et al:Isolation of a T-lymphotropic lentivirus from a persis-tently leucopenic domestic cat. Vet Rec 122:84-86,1988

218. Shelton GH, McKim KD, Cooley PL, et al: Felineleukemia virus and feline immunodeficiency virusinfections in a cat with lymphoma. J Am Vet MedAssoc 194:249-252, 1989

219. Beebe AM, Faith TG, Sparger EE, et al: Evaluation ofin vivo and in vitro interactions of feline immunodefi-ciency virus and feline leukemia virus. AIDS 8:873-878, 1994

220. English RV, Nelson P, Johnson CM, et al: Develop-ment of clinical disease in cats experimentally in-fected with feline immunodeficiency virus. J InfectDis 170:543-552, 1994

221. Olmsted RA, Hirsch VM, Purcell RH, et al: Nucleotidesequence analysis of feline immunodeficiency virus:Genome organization and relationship to other lenti-viruses. Proc Natl Acad Sci U S A 86:8088-8092,1989

222. Olmsted RA, BarnesAK, Yamamoto JK, et al: Molecu-lar cloning of feline immunodeficiency virus. ProcNatl Acad Sci U S A 86:2448-2452, 1989

223. Talbott RL, Sparger EE, Lovelace KM, et al: Nucleo-tide sequence and genomic organization of felineimmunodeficiency virus. Proc Natl Acad Sci U S A86:5743-5747, 1989

224. North TW, North GL, Pedersen NC: Feline immuno-deficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune defi-ciency syndrome. Antimicrob Agents Chemother 33:915-919, 1989

225. North TW, Cronn RC, Remington KM, et al: Directcomparisons of inhibitor sensitivities of reverse tran-scriptases from feline and human immunodeficiencyviruses. Antimicrob Agents Chemother 34:1505-1507, 1990

226. Remington KM, Zhu YQ, Phillips TR, et al: Rapidphenotypic reversion of zidovudine-resistant felineimmunodeficiency virus without loss of drug-resistantreverse transcriptase. J Virol 68:632-637, 1994

WILLIAM LEWIS170

Date post:	21-Sep-2016
Category:	Documents
Upload:	william-lewis
View:	216 times
Download:	1 times

Cardiomyopathy in AIDS: A pathophysiological perspective

Documents