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Craiova Medicală
Vol 9, Nr 4, 2007
Referat general
Patogeneza complicaţiilor cardiace determinate
de HIV
ALINA GIUCĂ (1), D. BULUCEA (2), I. DONOIU(3)
(1)
Centrul de Cardiologie Craiova,(2)Facultatea de Medicină, UMF Craiova, disciplina Pediatrie,
Spitalul Municipal de Pediatrie Craiova,(3)Facultatea de Medicină, UMF Craiova, disciplina Cardiologie
Pathogenesis of HIV-related cardiac complications
REZUMAT Afectarea cardiacă în relaţie cu infecţia
HIV şi SIDA apare relativ târziu în evoluţia bolii, şi de
aceea incidenţa sa creşte odata cu supravieţuirea,
respectiv cu progresul terapeutic şi îmbunătăţirea
supravieţuirii. Afectarea cardiovasculară poate creşte
morbiditatea şi mortalitatea la pacienţii infectaţi HIV,
ducând în acelaşi timp şi la scăderea calităţii vieţii. Nu
de puţine ori, anomaliile cardiace trec nerecunoscute şi
implicit netratate. Marea majoritate a complicaţiilor
cardiovasculare pot fi decelate în stadiul subclinic, cu
condiţia cunoaşterii lor şi a unei monitorizari corecte. Au
fost menţionaţi o multitudine de factori potenţial implicaţi
în etiologia afectării cardiace în infecţia HIV, cum ar fi:
infecţia miocardică cu însuşi virusul HIV, răspunsul
autoimun la infecţia virală, infecţii oportuniste, deficienţe
nutriţionale, imunosupresia prelungită, cardiotoxicitatea
unor medicamente antiretrovirale. Patogeneza afectării
Preamble
The cardiac complications of HIV infection
occur late in the disease; the longer HIV infected
patients live and the more advanced their disease,
the higher the risk of cardiac complications.
Before the HAART (highly active antiretroviral
therapy) was discovered, the retrospective studies
and anatomopathological data indicated that 2575% of HIV infected patients had cardiac
complications (Barbaro, 2001).
It is clear that HAART increased the quality of
life and survival of the HIV patient, but the
concern about the association between this type of
therapy and the development of peripheral and
coronary vascular complications remains.
Taking into account the improvement of life
expectancy and the number of patients recently
diagnosed (5.3 million only in 2000) we consider
that the incidence of HIV-related heart failure will
be higher in the near future.
Cardiac complications in AIDS were noticed
17 years ago, and were demonstrated through
histopathological data and prospective clinical
studies.
The prospective studies succeeded to point out
that
asymptomatic
changes
on
the
echocardiography have a negative independent
predictive value; at the same time, these anomalies
Dr. Alina Giucă, Centrul de Cardiologie Craiova
cardiace nu este încă pe deplin cunoscută, existând mai
multe ipoteze de lucru privind mecanismul declanşator.
Unele ipoteze susţin afectarea miocitară indusă direct
de virusul HIV, dar nu au reuşit sa precizeze exact
mecanismul. Pe de altă parte, există şi posibilitatea
apariţiei de autoanticorpi cardiaci în circulatie, rezultaţi
din sinteza HIV-indusă de proteine asemănătoare celor
din membrana miocitară, proteinele membranare fiind
recunoscute ca antigene, ceea ce duce la declanşarea
unui proces autoimun urmat de distrucţie miocitară. S-a
emis ipoteza că şi unele deficienţe nutriţionale ar fi
incriminate în apariţia disfuncţiei contractile
CUVINTE CHEIE HIV, patogeneză, miocardită,
cardiomiopatie
KEY WORDS HIV, pathogenesis, myocarditis,
cardiomyopathy
identified a high-risk population, which required
early therapy.
A wide variety of possible etiological agents
were postulated in HIV related cardiac
complications like: myocardial infection with HIV
itself, autoimmune response to viral infection,
opportunistic infections, other viral infections,
nutritional
deficiencies,
prolonged
immunosupression, cardiotoxicity of antiretroviral
therapy.
Pathogenesis of myocardial disability in
HIV infection/AIDS
AIDS is characterized by the severe acquired
immunosupression, which leads to a great number
of infections or malignancy; it also leads to
irreversible
and
progressive
multiorgan
dysfunction.
The prevalence of cardiac disability is 28-73%
in HIV infected individuals (Kaul et al., 1991).
Pathogenesis of cardiac complications is not yet
fully known; there are many theories concerning
triggering mechanism. Some theories suggest the
direct action of HIV on the myocardial tissue,
without specifying the mechanism of this action.
Some authors suggest the autoimmune
disability due to T-helper lymphocytes, followed
by hypergammaglobulinaemia; that leads to
systemic inflammatory response, which affects the
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myocytes, followed by a negative inotropic effect
(Acierno, 1989; Herskowitz et al., 1993).
On the other hand, cardiac autoantibodies were
detected in patients’ blood, as a result of HIVinduced synthesis of proteins similar to those in
the myocytes membrane. The membrane proteins
are identified as antigens causing an autoimmune
process followed by structural disability of the
myocytes.
HIV may persist in receiver cells of the
myocardium and cortex, even after antiretroviral
therapy. Receiver cells can maintain HIV-1 for
long periods and they may chronically release the
cytotoxic cytokines (tumor necrosis factor α, IL-6,
endothelin-1), leading to the appearance and
development of cells injuries, despite the specific
therapy (HAART).
The speculative pathogenesis mechanism,
which might be possible and could inspire new
clinical studies in order to prove its veracity, is the
following: the HIV-1 or other virus infection of
dendrites, CD4 lymphocytes, myocytes or
neurons, may be responsible for the release of the
cytotoxic cytokines (TNFα, IL-1, IL-6) and these
cytokines will activate the induced NO-synthase.
It was proved that HIV-related GP120 increases
the synthesis of NO activating nuclear
transcription factor (NF-kappa β) into mice cells;
this process is activated by MAP kinase p38.
Other studies are necessary to confirm this
possible mechanism of cardiac injury.
The increase of TNFα levels and induced NOsynthase levels was also found in HIV-negative
patients with dilated cardiomyopathy.
The increase of IL-6 levels, a multifunctional
cytokine, was reported for a limited number of
patients with evidence of myocarditis or
borderline myocarditis. Although the role of IL-6
in murine myocarditis is still unclear, it is known
that IL-6 plays an important part in triggering
immune response and viral replication.
Levels of TNFα and induced NO-synthase
were higher in myocytes from the HIV-infected
patients with dilated cardiomiopathy in
comparison with the levels from HIV-negative
patients with idiopatic dilated cardiomyopathy.
Levels of both markers varied inversely with CD4
count; particularly, the level of induced NOsynthase is correlated with mortality and it was
increased in patients with viral co-infections
(cytomegalovirus and Coxsackie virus group B).
The interaction between cytotoxic T
lymphocytes and the complex Fas/Fas (receptorligand) in target cells, may cause mitochondrial
injuries followed by pro-apoptotic mitochondrial
factors release (cytocrome C, apopthosis induction
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factor - AIF). The same mitochondrial injuries
may be caused by the reactive species of oxygen
released through lymphocytes and monocytes
activation.
Hipergammaglobulinaemia, high levels of
circulating immune complex and different type of
autoantibodies were identified in HIV-infected
patients blood; that usually has a negative
prognosis.
Although
the
importance
of
some
autoantibodies is not clear (antineutrophil,
anticytoplasma, antiphospholipid), it is possible
that unidentified autoimmune processes may
appear. The reaction between autoantigens and
major histocompatibility complex in dendrites,
phagocytes, myocytes (MHC I) and B
lymphocytes (MHC II), leads to the synthesis of
autoantibodies
(anti
α myosine);
these
autoantibodies are responsible for the direct cell
injury.
Central nervous system injuries, especially of
the autonomic nervous system, may amplify
functional and structural disability of myocytes,
by increasing sympathetic tonus and by the
releasing of the cathecolamines, followed by the
down regulation of β adrenoreceptors.
From histopathological point of view,
myocarditis is the most studied of the possible
causes of dilated cardiomyopathy in AIDS.
HIV virions seem to infect myocardiocytes in
patchy distribution and no clear association was
made between the infection and functional
disability.
We do not know exactly how the viruses reach
cells without receptors for CD4, like
myocardiocytes. Receiver cells (for examples
dendrites) may play an important part in
pathogenesis; they may interfere in the interaction
between the virus and myocardiocytes, and also in
the multifunctional cytokines activation.
Some authors suggested that nutritional
deficiencies have a negative inotropic effect; for
example, it was mentioned that extra selenium
intake improves the myocardium contractility.
Autoimmunity and myocardial
complications in AIDS
Some authors suggested that different types of
autoimmune process might appear in AIDS, in
patients predisposed to autoimmune diseases
through the presence of Human Leukocyte
Antigens or the non-HLA genes.
Some common viruses induce or only facilitate
cardiac autoimmune process in HIV-infected
patient. For example, viruses with cardiac affinity
can modify the myocytes antigens or only hidden
epitopes placed on the cell membrane, leading to
Craiova Medicală
an aberrant autoimmune response against
autoantigenic endogenous peptides associated
with MHC. The expression of myocytes antigens
may be responsible for the chronic inflammation
and for the microscopic injuries in some cases of
myocarditis, although the mechanism is not yet
fully known. Nevertheless, this hypothesis was
demonstrated through experimental studies on
animals in case of myocarditis with
cytomegalovirus and coxsackie virus group B
(Herskowitz et al., 1992; Herskowitz et al., 1994).
The antigens of MHC I are not represented in
the
normal
myocytes
or
in
dilated
cardiomyopathy, but the antigen impregnation of
sarcolema in HIV-negative patients with
myocarditis and dilated cardiomyopathy has been
demonstrated by the use of immunoperoxydase
method. Moreover, a significant number of CD8
and CD4 lymphocytes in association with the
increase of MHC I antigens expression was found
in apparently normal histological tissue through
endomyocardial biopsy from HIV-infected
patients with heart failure (Herskowitz et al.,
1994).
These immunohistochemical results were
identical with the results from HIV-infected
patients with heart failure and histological
evidence of myocarditis, showing that histological
methods are not sufficiently to exclude the
presence of myocarditis in AIDS patients.
Cardiac autoantibodies were detected through
immunofluorescent methods in 30% of HIVinfected individuals with cardiomyopathy and in
20% of their asymptomatic relatives. Anti α
myosine
autoantibodies
are
the
most
cardiospecific antibodies and their presence in
dilated cardiomyopathy was demonstrated through
ELISA (
Goldman et al., 1995).
Experimental models have also demonstrated
the association between α myosine and
autoimmune cardiac complications: some mice
may develop dilated cardiomyopathy with anti- α
myosine antibodies after immunization with α
myosine or Coxsackie virus group B infection
(Neu et al., 1987).
Not only α myosine is involved in the
pathogenesis of dilated cardiomyopathy. β
myosine involvement was shown through a minor
study, by Herskowitz and his colleagues; they
identified by the immunofluorescent method the
presence of cardiac β myosine autoantibodies in
patients with dilated cardiomyopathy and evidence
of active myocarditis, and the absence of these
autoantibodies in HIV-infected individuals
without cardiac complications. For the first group
of patients, it was found by ELISA that anti β
Vol 9, Nr4 , 2007
myosine antibodies are cross interacting with
scheletal muscle and mytocondrial adenosinenucleotid translocator (Herskowitz et al., 1989).
The incidence and clinical importance of
specific cardiac autoantibodies were studied on 74
HIV-infected patients (Currie et al., 1998). 28 of
these patients had echocardiographic evidence of
myocarditis, 16 of them left ventricular
dysfunction and 12 of them suffered from dilated
cardiomyopathy. The second group, HIV-negative
control group, included 52 patients with low risk
of infection and 14 i.v. drug users, all of them with
no echocardiographic evidence of cardiac
dysfunction. Specific cardiac autoantibodies
detected by immunofluorescent methods were
frequently found in patients with myocardial
complications, especially in HIV-infected patients.
High levels of cardiac autoantibodies (anti α
myosine) were detected trough ELISA in HIVinfected individuals with myocardial dysfunction
as compared to those without myocardial
dysfunction or those from the control group.
Besides that, the medium level of anti α
myosine autoantibodies was higher in HIVinfected individuals as compared to HIV-negative
individuals; the highest level of these antibodies
was in HIV-infected patients with cardiac
complications. So, once again, the involvement of
autoimmunity
in
HIV-related
cardiac
complications is documented. More than that,
these autoantibodies were not found in the blood
of the HIV-negative i.v. drug users, demonstrating
that the autoantibodies are not consequence of
certain type of lifestyle, but the consequence of
HIV infection itself.
Therefore, it is possible that in the future, these
autoantibodies will be used as biological markers
for active cardiac injury in HIV infected patients.
At present, we certainly know that interstitial
cells of the myocardium structure may be infected
with HIV, but there are few data regarding the
presence of HIV in the myocardial cells (Wu et
al., 1992).
The contamination with own infected plasma
cells leads to a difficult interpretation of the PCR
and a difficult examination of cell cultures. The
immunohistochemical studies did not bring any
evidence about the cardiac expression of GP120 or
p24 antigens (Rodriguez et al., 1991).
The presence of a least one gene part of HIV-1
was proved through PCR in endomyocardial
samples from 15 HIV-infected patients, 5 of them
suffering from cardiac disease.
Although these results are not correlated with
clinical and histological evidences of cardiac
dysfunction, the increased number of interstitial
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Giucă Alina şi colab: Patogeneza complicaţiilor cardiace determinate de HIV
dendrite cells was demonstrated in HIV-infected
individuals with heart failure.
Although in vitro studies showed that HIV
cannot penetrate scheletal muscle cells (Clapham
et al., 1989), there is recent data about the
development of new fetal myocardial cells; this
fact suggests that despite the absence of CD4
receptors on the myocardial cells, HIV-1 could be
introduced in cells by means of specific receptor
Fc. Therefore, the opinion that HIV plays an
important direct part in pathogenesis of
myocardial complications is still plausible.
HIV could injure myocardial cells by means of
some innocent markers of destruction; this
hypothesis suggests that proteolytic enzymes
released in the interstice after viral replication
attack some cells; this attack is important
especially in myocardium, where a great number
of interstitial infected cells were described in HIVinfected individuals with evidence of myocarditis
(Ho et al., 1987).
Some authors suggest that HIV infection may
increase the production of abnormal interferon;
this interferon stimulates the production of TNFα
or IL, which induce an autoimmune destructive
process (Skurkovich et al., 1994).
In conclusion, the mechanisms involved in the
appearance of cardiac complications in AIDS or
HIV-infection are not fully known. The
participation of own abnormal immune system
and the interaction with other possible induced
factors is important in this process (for example
co-infections). There is evidence that demonstrate
the participation of myocardial tissue to its own
destruction after triggering immune and
autoimmune response which lead to cytotoxic
cytokines release. Probably, the next research will
discover unknown parts of this process
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Adresa pentru corespondenţă Dr. Giucă Alina, Centrul de Cardiologie Craiova, str. Tabaci nr.1, email:
[email protected]
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