cardiomyopathy and encephalopathy in aids

121

Cardiomyopathy and Encephalopathy in AIDS

ANDREA ANTINORI, MARIA LETIZIA GIANCOLA, LUCIA ALBA, FABIO SOLDANI, AND SUSANNA GRISETTI

National Institute for Infectious Diseases “Lazzaro Spallanzani”—IRCCS, 00149 Rome, Italy

A

BSTRACT

: HIV encephalopathy has been in the past years the most typicalCNS disorder in patients with AIDS. Histologic abnormalities consist in astro-cytosis, myelin pallor, infiltration by infected macrophages, resident microgliaand multinucleated giant cells, generally in absence of direct infection of neu-rons. Mononuclear phagocytes in the brain are the main target of HIV-1 infec-tion and the site of productive viral replication, and viral stimulation leads tothe release of neurotoxic products causing neurologic damage. Subclinical car-diac abnormalities are common in HIV

+

patients and several studies suggesteda role for cytokines and other inflammatory products as mediators of cardiacabnormalities. The common pathway for neurologic and cardiac manifesta-tions supports the relationship between neurologic disease and cardiac dys-function in HIV infection. Clinical observations suggest that cardiomyopathycould be associated with encephalopathy in HIV

+

patients and that it mayaffect survival. Antiretroviral therapy may reduce impact of neurologic andcardiac abnormalities by suppressing plasma HIV-1 viral load.

K

EYWORDS

: HIV; cardiomyopathy; HIV-dementia; TNF-

�

; inducible nitricoxide synthase; antiretroviral therapy

INTRODUCTION

During the last two decades, before the introduction of the new antiretroviral thera-pies, approximately one-third of the adults and one-half of the children with acquiredimmunodeficiency syndrome (AIDS) eventually showed neurologic symptoms directlydue to HIV-1 infection of the central nervous system (CNS).

1

The CNS is exposed toHIV-1 early in the natural history of infection, and evidence exists that direct infectionis the base for various neurologic dysfunctions at different stages of disease. However,the most relevant determinant of pathogenetic susceptibility for CNS involvement byHIV-1 remains the degree of immunosuppression resulting from chronic infection andprogressive depletion of cellular immunity. HIV-encephalopathy—alternatively knownas AIDS dementia complex or HIV-dementia (HIVD)—was in past years the mainand most typical CNS disorder in patients with AIDS.

2

Histologic abnormalities indemented patients, such as astrocytosis, myelin pallor, infiltration by infected macroph-ages, resident microglia, and multinucleated giant cells, occur despite the absence ofdirect infection of neurons. Mononuclear phagocytes in the brain are the main target of

Address for correspondence: Andrea Antinori, M.D., Instituto Nazionale per le MalattieInfettive Diseases, “Lazzaro Spallanzani”—IRCCS, Via Portuense, 292, 00149 Rome, Italy.Voice: +39-06-55170477-300; fax: +39-06-55170477.

[email protected]

122 ANNALS NEW YORK ACADEMY OF SCIENCES

HIV-1 infection and the site of productive viral replication.

3

The abnormal response ofinfected macrophages to viral stimulation leads to the release of large amounts of neu-rotoxic substances, which are the cause of neurologic damage.

Subclinical cardiac abnormalities are common in HIV

+

patients.

4

Several studieshave focused on the role of cytokines and other inflammatory products as mediatorsof cardiac abnormalities in HIV

+

patients. The common pathway for neurologic andcardiac manifestations supports the relationship between advanced neurologic dis-ease and cardiac dysfunction in HIV infection. Clinical observations suggest that car-diomyopathy may be associated with encephalopathy and that it may affect survival.

5

Highly active antiretroviral therapy (HAART) is highly effective in suppressingplasma HIV-1 viral load, thereby preserving or restoring immune function and con-sequently reducing neurologic complications of disease. The global impact ofHAART on the natural history of neurologic disorders is still largely unknown. Com-plex effects of antiretroviral therapy on the pathogenetic network that contributes toneurologic damage may be translated to cardiac manifestations of HIV disease.

CARDIAC INVOLVEMENT IN HIV-1 INFECTION

Pathogenetic Implications

Little is known about the etiology and pathogenetic mechanisms of dilated cardi-omyopathy in the general population, even though genetic mutations, viral myo-carditis, and autoimmune disease have been implicated. Nitric oxide (NO) is abiological mediator with multiple actions. Two NO-synthases invariably present inneuronal and endothelial cells were found, and a third form is inducible in many cellsby cytokines such as interferon-

γ

, interleukin-1 and tumor necrosis factor alpha(TNF-

α

). High levels of TNF-

α

and increased production of NO have been associ-ated with dilated cardiomyopathy (DCM). In particular, has been demonstrated thatinduced NO production has a negative inotropic effect on cardiac myocytes and thathigh levels of NO produced by inducible NO synthase (iNOS) are cytotoxic.

6

More-over, iNOS gene expression has been associated with heart failure, and iNOS proteinhas been detected in ventricular myocytes from patients with end-stage heart failurediseases.

7

A relationship between TNF-

α

and iNOS is also suggested by the corre-lation between plasma concentration of acid-labile nitroso compound, end-productsof NO methabolism, and TNF-

α.

8

Giving these findings, a pathway has been hypothesized with local NO produc-tion stimulated by TNF-

α

in the cardiac tissue leading to dilated cardiomyopathy viaa chronic negative inotropic effect. Moreover, TNF-

α

has been found locallyexpressed predominantly in blood vessels but also in the cardiac myocytes ofpatients with DCM but not in patients with ischemic heart disease.

6

The increasedlevels of iNOS in DCM could depend on local availability of TNF-

α

resulting froman inflammatory response to causal agents, even though a role of other cytokinesmay be hypothesized. Moreover, it has been suggested that TNF-

α

production bycardiac myocytes

in vivo

may play a relevant pathophysiologic role not only in thepathogenesis of DCM but also in its progression in terms of progressive left ventric-ular dysfunction and enlargement of ventricular volume.

9

123ANTINORI

et al.

: CARDIOMYOPATHY AND ENCEPHALOPATHY IN AIDS

In AIDS patients, prevalence of myocardial diseases is influenced by definitionand diagnostic approach. Microscopic signs of focal myocarditis range from 15

%

to50

%

in serial autopsies. Clinical cardiomyopathy defined as myocardial diseasecausing signs and symptoms of heart failure is relatively unusual (1–3

%

of AIDSpatients). In prospective observations with serial echocardiography among HIV

+

patients a prevalence of 4–8

%

with an annual incidence rate of 11–15.9 cases per1000 patients was documented.

4,10

If only AIDS patients were included, the inci-dence would be more than 3

%

per year.The pathogenesis of these disorders has not yet been definitively explained, even

though current hypotheses include direct infection of myocardiocytes with HIV-1,coinfection with other viruses, postviral cardiac autoimmunity, cardiotoxicity relatedto psychotropic substances and pharmacologic agents (zidovudine, foscarnet, penta-midine, cytotoxic agents, etc.). HIV nucleic acid sequences were detected in a vari-able proportion of cardiac tissue sections (15–76

%

). In most patients histologic andimmunohistologic examination found myocarditis. The extent of immunodeficiency,as assessed by a CD4 cell count less than 400 cells per cubic millimeter in HIV

+

asymptomatic patients, has been demonstrated to be correlated with a higher inci-dence of DCM in adults. Furthermore, the role of myocarditis in the development ofDCM has not been conclusively ascertained, and lymphocytic myocarditis has beenfound in 46–83

%

of patients with AIDS. The advanced stage of immunodeficiencymay enhance the pathogenic role of HIV-1 and several other viruses such as coxsack-ievirus group B, cytomegalovirus, and Epstein-Barr virus, and the increased expres-sion of MHC class I molecules suggests an active immune process in themyocardium.

4,11

Studies investigating the characteristics and pathogenesis of HIV-associated car-diomyopathy in infected children identified progressive left ventricular dilatationwith compensatory hypertrophy as the main cause of decreasing ventricular perfor-mance. Moreover, the abnormalities of left ventricular size occurred independentlyof zidovudine use.

12

Subclinical cardiac abnormalities are common and progressivein HIV

+

children and correlated with immunodeficiency at baseline, even thoughCD4 count could not be a useful surrogate marker of progression of cardiac diseases.

5

HIV-ENCEPHALOPATHY

Pathogenetic Implications

Neurologic disorders during natural history of HIV infection may occur either inpresence of opportunistic infections or cancers, or may be directly attributable toinfection of the brain by the HIV-1 itself. From a pathologic point of view, the char-acteristics of HIV-1 infection of the brain (HIV-encephalopathy) consist of reactiveastrocytosis, infiltration by circulating macrophages, resident microglia and multi-nucleated giant cells, and myelin pallor. At the clinical level, these abnormalitiesdetermine the onset of the syndrome characterized by cognitive and motor deficitsdefined as AIDS dementia.

2

Nevertheless, the clinical progression of HIV-dementiaseems to be due not to the direct infection of neurons by HIV-1 or to an autoimmuneprocess induced by the virus, but there is a good evidence that the infection of the


brain follows two steps mediated by macrophages. First, the viral coat glycoproteingp120 binds a receptor on the macrophage surface such as CD4 and the virus is inter-nalized by the macrophage. This process can stimulate macrophages to release lowlevels of neurotoxins, and similarly gp120, tat and nef could stimulate uninfectedcells to release neurotoxins as well.

13,14

In the second step, the HIV-1 genome isintegrated into the macrophage genome and active replication of the virus occurs.During this step the macrophage is induced to release a large amount of neurotoxicsubstances—eicosanoids and free radicals—which can contribute to neuronal dam-age by increasing the release of glutamate or decreasing its re-uptake.

15

TNF-

α

andIL-1

β

stimulate astrocytosis,

16

whereas platelet-activating factor from macrophagesmay cause neuronal death

in vitro

by increasing calcium ions and the release ofglutamate.

17

One of the substances released from macrophages in response to replication ofHIV-1 is arachidonic acid and its metabolites. Arachidonic acid acts synergisticallywith endogenous glutamate to activate neuronal N-methyl-

D

-aspartate (NMDA)receptors, which mediate excitatory neurotransmission in the brain acting on chan-nels permeable to calcium ions. Calcium ions may enter neurons that contain theconstitutive form of nitric oxide synthase stimulating the formation of nitric oxide,which contributes to the cascade of neurotoxic events. In particular, NO is generatedfollowing activation of NO synthase (NOS), of which there are three isoforms, neu-ronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). nNOSregulates neuronal signals by overt glutamate excitoxicity. In this way, NO reactswith superoxid anion to form peroxynitrite that damages DNA, RNA, proteins, andlipids with mitochondrial impairment, loss of energy and cell death. The neuronaldeath following iNOS activation occurs slowly over time with the morphologic fea-tures of apoptosis.

18

A role for iNOS in HIV dementia comes from both human post mortem studiesand experimental models. A correlation between gp41 levels, iNOS expression andseverity, and rate of progression of HIV dementia has been demonstrated, and theexpression of gp41 and iNOS is predominantly localized to macrophage/microgliaof the frontal lobe and basal ganglia.

19

Moreover, perivascular macrophage/micro-glia are the predominant source of iNOS in the HIV

+

brain and its expression corre-lates with productive infection. This correlation, combined with the observation thatiNOS is not induced in all stages of macrophage activation, suggests that immuneactivation may be not a sufficient condition for NO production in HIV

+

brain, andthis is also in agreement with

in vitro

observations that HIV

+

monocytes,lipopolysaccharide- and TNF-

α

activated, produce more NO than either activated orinfected monocytes alone.

20

Tat has also been demonstrated to induce iNOS causingneurotoxicity in culture, an effect that may be mediated by TNF-

α.

21

Using theseobservations one may assume that the interaction between HIV proteins and varioushost signals forms a complex network that underlies the development of cerebralinjury in response to HIV infection. Moreover, it has been recently demonstrated thatthere is a similar distribution of staining within the basal ganglia for TNF-

α

and acti-vated NF-

κ

B-

α

, a host transcriptional factor that upregulates the expression ofHIV-1 and host proinflammatory factors, including cytokines, and which itself canbe activated by TNF-

α

.

19

Putative NF-

κΒ

binding sites have been identified within

125ANTINORI

et al.


the promoter region of the iNOS gene, suggesting a potential mechanism linkingiNOS regulation to TNF-

α

expression in the HIV

+

brain. The complex network ofactivated cytokines is completed by the lack of IL-4 downregulation leading touncontrolled activation of macrophages and production of neurotoxic mediators

22

(see F

IGURE

1).Moreover, it has been observed that cell death by apoptosis can occur in some oli-

godendrocytes in the presence of TNF-

α

, and this could imply a role of TNF-

α

indemyelinating processes. In particular, myelin-forming cells may be exposed chroni-cally to TNF-

α

bound to or derived from activated microglia

in vivo

. This could resultin the striking demyelination that can be observed in HIV-1 vacuolar myelopathy.

23

FIGURE 1. Uncontrolled macrophage activation and dementia pathogenesis duringHIV infection. (From Griffin, D.E. 1997. J. Clin. Invest.22)


CARDIOMYOPATHY AND ENCEPHALOPATHY IN HIV-INFECTED PATIENTS

Several observations among children and adults with HIV infection suggested astrong clinical relationship between cardiomyopathy and encephalopathy. In HIV

+

children, the development of encephalopathy was associated with a deterioration ofleft ventricular function, and this association has been confirmed in subsequent stud-ies on HIV

+

children and adults.

5

In particular, children who presented encephalopa-thy had depressed initial fractional shortening and this continued to decline during thefollow-up period influencing survival. This defect, as well as the associated encepha-lopathy, did not correlate with CD4 count.

In another study, a diagnosis of cardiomyopathy was significantly more frequentin HIV

+

children with encephalopathy (30

%

prevalence) than in those withoutencephalopathy (2

%

). No markers associated with time of onset of encephalopathyand cardiomyopathy were identified, even though high HIV-1 viral load in the firstyear of life may be associated with diagnosis of encephalopathy.

24

In HIV

+

adultswith dilated cardiomyopathy, those who also had encephalopathy had more abnormalechocardiographic functional parameters independent of the duration of documentedcardiomyopathy, and these parameters tended to worsen progressively for patientswith concomitant encephalopathy, who had a higher mortality rate (73

%

) for conges-tive heart failure.

25

These parameters were inversely correlated with HIV-1 RNA andCD4 cell count. There may be several causes for this strong association between car-diomyipathy and encephalopathy. Neuronal loss may occur as a result of highly pro-ductive infection with strong macrophage activation; moreover, mediators of theinflammation and HIV-1 viral proteins may act as neurotoxins, causing apoptosis ofthe neuronal cells. Furthermore, the involvement of the nervous system during HIVinfection is associated with an alteration of the cardiac parasympathetic nervous sys-tem, which may cause a release of catecholamine, increased consumption of oxygenby myocardial tissue, downregulation of the myocardial

β

-adrenoceptors and subse-quent progressive reduction of the contractile function of the myocytes. The HIV-1virus itself could be responsible for some manifestations of cardiomyopathy andencephalopathy, as suggested by the positive signals for HIV-1 nucleic acid sequenc-es found within the multinucleated giant cells of the cerebral cortex at autopsy in79

%

of patients with encephalopathy who died of dilated cardiomyopathy. Moreover,in the same case series, a significantly higher proportion of patients with encephal-opathy were positive for nucleic sequences of HIV-1 within myocardial cells thanpatients without encephalopathy.

25

Other manifestations could however be due to immunological factors and cytok-ines: in particular the interaction between dendritic cells, responsible for the primaryimmunological response to HIV-1 and for the presentation of the antigen to T lym-phocytes, and CD8 cells could induce a release of cytokines such as TNF-

α

, inter-leukin-1, interleukin-6, interleukin-10, producing neurocardiotoxic activities. Astrong immunoreactivity for TNF-

α

and iNOS within cardiomyocytes was found inHIV

+

patients with cardiomyopathy. The intensity of immunostaining was increasedby the coexistence of HIV-encephalopathy and inversely related to absolute CD4 cellcount. Moreover, a marked immunoreactivity for TNF-

α

and iNOS was found withinglial cells and astrocytes of patients with encephalopathy who died of congestive

127ANTINORI

et al.


heart failure. This specific pathway may be responsible for inducing apoptotic sig-naling in both myocardial and neuronal cells, especially in the presence of markedimmunodeficiency.

25

IMPACT OF HAART AND PERSPECTIVES

The introduction of potent combined antiretroviral therapy has strongly modifiedthe clinical course and survival time of HIV

+

persons. The probabilty of survivalafter 24 months in HIV

+

patients with opportunistic infections increased from 49

%

of those diagnosed in 1993 to 80

%

in those diagnosed in 1997.

26

HAART has alsohad an impact on the main HIV-related neurologic diseases. Incidence rates of HIVdementia, cryptococcal meningitis, and CNS lymphoma have dramaticallydecreased since the introduction of HAART.

27,28

However, estimates on temporaltrends and changes in the natural history of HIV-associated neurologic diseases suchas HIV-dementia should be completely defined. Reduction trends were observedmostly in homosexual men with high treatment adherence and good virologicalresponse, but no definitive data were observed from other groups such as IV drugusers or in patients with increasing resistance and virological failure. Studies onsurvival of HAART-treated neurologic cases documented a benefit of therapy alsoindependent from virological effect, but in nonresponder populations a relevant rolemay be played by HIV-dementia and emerging disorders as PML or leukoencephal-opathy of unknown origin

29

(see F

IGURE

2). Cerebrospinal fluid (CSF) and plasmaHIV-1 dynamics become increasingly independent in advanced HIV disease, and the

FIGURE 2. Specific neurologic diseases as proportion of CNS disorders by HAARTexposure. Data from Italian Register Investigative Neuro AIDS (IRINA) Study. TE, toxo-plasma encephalitis; PML, progressive multifocal leukoencephalopathy; Crypto, cryptococ-cal meningitis; PCL, primary cerebral lymphoma; TB, tubercular meningitis; NHL,nonHodgkin’s lymphoma with secondary CNS involvement; CMV, cytomegalovirusencephalitis; NDL, not determined leukoencephalopathy; Other, other CNS disorders.


compartmental discrepancy was largest in HIVD.

30,31

Divergent evolution of HIV-1in the two different compartments has been observed with different mutations con-ferring resistance.

32

Pharmacokinetic studies of antiretrovirals showed variable pro-files of drugs in CSF, and in some cases the efficacy of therapy may be differentbetween compartments. A divergent, independent replicative process in CNS coulddetermine a unforeseeable scenario in neurologic expression of HIV disease in com-ing years. How these conditions may affect the parallel occurrence of cardiac dys-function related to common pathways remains to be established.

ACKNOWLEDGMENTS

This work was supported by the Ricerca Finalizzata e Corrente degli IRCCS,Ministero della Sanità and by the Programma Nazionale di Ricerca sull’AIDS, Isti-tuto Superiore di Sanità, Italy.

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cardiomyopathy and encephalopathy in aids

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