Cardiomyopathy protection in Chagas Disease

doi:10.4236/wjcd.2013.37069

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World Journal of Cardiovascular Diseases, 2013, 3, 442-447 WJCD

http://dx.doi.org/10.4236/wjcd.2013.37069 Published Online October 2013 (http://www.scirp.org/journal/wjcd/)

Cardiomyopathy protection in Chagas Disease

Jorge E. Mitelman1,2,3, Luisa Gimenez4,5,6,7

1Instituto Centenario, Buenos Aires, Argentine

2Chagas Disease of the Inter-American Society of Cardiology, Buenos Aires, Argentine

3Department of Chagas, the University Institute of Health Science Foundation H A Barcelo, Buenos Aires, Argentine

4Teodoro Alvarez Hospital, Buenos Aires, Argentine

5Cardiology in Northern Province of Buenos Aires, Buenos Aires, Argentine

6Chagas in the City of Buenos Aires, Buenos Aires, Argentine

7University Institute of Health Science Foundation H A Barcelo, Buenos Aires, Argentine

Email: [email protected]

Received 28 July 2013; revised 29 August 2013; accepted 15 September 2013

bution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

cited.

ABSTRACT

There is some published evidence suggesting micro

vascular endothelial dysfunction and dysautonomia

involvement in Chagas disease in association with

cardiomyocyte changes favoring disease progression.

The combined treatment between angiotensin con-

verting enzyme (ACE) inhibitor drugs; Simvastatin,

muscarinic antibody immunoadsorbent together with

fungicidal drugs would open therapeutic possibilities

in this disease.

Keywords: Chagas Disease; Chronic Period without

Demonstrable Pat hology; Ex Indeterminate Phase;

Endothelial Dysfunction; Cardiac Dysautonomia;

Simvastatin; ACE (Angiotensin Converting Enzyme)

Inhibitor; Muscarinic Antibody

1. INTRODUCTION

Chagas Disease, American trypanosomiasis, is a parasitic

disease coming from rural environments and caused by

the flagellated protozoan, Trypanosoma cruzi. Chagas

disease is endemic throughout much of Mexico, Central

America, and South America where the estimated 8 mil-

lion people are infected, but in the last few years, it has

been observed in the United States of America, Canada,

Europe and including Japan. This is the product of inter-

nal and external migrations of people between Latin

America and the rest of the world [1-4]. The Trypano-

soma cruzi parasites are transmitted by the infected fae-

ces of blood-sucking triatomine bugs. These bugs live in

adobe houses and thatched roofs in rural and suburban

areas. Generally they become active at night when they

feed on human b lood. They usually bite an exposed area

of skin such as the face, and the bug defecates close to

the bite. The parasites enter the body when the person

instinctively smears the bug faeces into the bite. Other

forms of transmission are through blood transfusions,

congenital transmission (passing from mother to baby),

organ donations and recently by oral transmission of

contaminated juices. Chagas disease is recognized as one

of the most unattended tropical diseases as a disease of

negligence and poverty and continues to be a relevant

social and economic concern in the majority of the coun-

tries of Latin America. The medical and social impact of

Chagas disease is high. For instance, it is estimated that

about 752,000 of working years per year are lost due

premature deaths caused by disease in the American

countries [5].

Chagas disease goes through two stages, one is acute

and the other chronic. During the acute stage, a large

number of parasites circulate in the blood stream and

symptoms can include fever, lymphaldenopathy, the

enlargement of the liver and spleen and occasionally,

myocarditis or meningoencephalitis with a serious prog-

nosis. In some cases, the Romana’s sign (palpebral

edema) is present. During this period, treatment with

parasiticides, like benznidazole or nifurtimox, is suc-

cessful. In the chronic stage, the parasites are present;

however, they are not easy to find. Of all the chagasic

patients that arrive and are attended: between 30 to 40

per cent tend to have serious cardiomyopathy (arrhyth-

mias and heart failure) or pathologic dilation (megavis-

cera) of the esophagus and colon. The importance of

trypanosomiasis is particularly given because of its high

prevalence, th e large economic losses due to the inability

to work and sudden death as well as the impact on public

health due to high costs for prolonged hospitalization,

OPEN ACCESS

J. E. Mitelman, L. Gimenez / World Journal of Cardiovascular Diseases 3 (2013) 442-447 443

medicine, heart transplants, and the implant of electronic

devices like pacemakers, cardiac defibrillators and re-

synchronization devic es .

Unfortunately, in spite of the time that has passed

since Carlos Chagas discovered this nosology, up until

now and even today, there are still doubts regarding the

mechanisms that determine the unfavorable evolution in

some of the sick. Hypotheses have been postulated that

link the infected strains whether these are myotropic or

pantropic, with neurological, immunological or vascular

interpretations, etc.

2. PATHOPHYSIOLOGY

Intervening factors in the development of cardiomyopa-

thy [6-10].

1) Intrensic myocardial damage during the acute and

chronic phase because of:

a) Direct parasitic action.

b) Immunological disturbances.

c) Neurol o g i c al dama ge .

2) Induced disorders due to the host immune response.

3) Alterations in the automatic nervous system.

4) Microvascular lesions with alterations in the

microcirculation and subsequent myocytolysis.

Based on these findings, we can confirm that signifi-

cant efforts have been made to prevent the infection;

however, initiatives have not been developed to prevent

the manifestations of cardiomyopathy. During the chro-

nic period, the lack of resources for antiparasitic and

therapeutic drugs has been confused with the impossibil-

ity to act with broader medical and therapeutic criteria

than those that are exclusively antiparasitic.

In the evolutionary characterization of the so called

Chagas disease, a wide range of chronic affected patients

has been found without evidence of demonstrable pa-

thology with the current diagnostic methods. This would

not allow them to be considered sick. It is important to

highlight the evidence that denies the fact that during this

chronic period (without evidence) nothing happens. On

the contrary, dysautonomy has been detected early, al-

terations in the microvasculature, in the diastolic func-

tion as well as the presence of antibodies against recap-

tors to neurotransmitters in a significant percentage and

sudden death. Therefore, today the idea that the simple

presence of reactive serology must be considered as a

risk factor for the development of cardiomyopathy and

sudden death and that this could occur in a later period,

forces us to consider that this risk must be prevented by

configuring protocols that are inclined to avoid the re-

modeling, to improve the dysfunction and to homogenize

the refractory periods (O. Mordini) [11,12].

3. DIAGNOSIS OF CHAGAS DISEASE

The diagnosis is based on three fundamental parameters:

1) epidemiological history (having been born or having

lived in an endemic area), 2) laboratory (reactions from

specific laboratories) and 3) clinic.

The laboratory techniques used in acute Chagas are

the direct search for the parasite in the blood. The first-

line test to confirm the diagnosis of acute-phase disease

is direct examination of blood, by microscopy of fresh

preparations of anticoagulated blood, in the chronic

phase it can be confirmed by blood; xenodiagnosis; and

PCR. Positive PCR results can occu r in chronic infection

in the absenc e of reactivation, and also it can be detected

through immunoglobulins in an indirect form. Today

they are: Indirect immunoflurescence (IFA); Enzyme-

Linked Immunosorbant Assay (ELISA); Indirect He-

mogglutination test (IHA); the Particle Agglutination test

(PA), requiring the positivization of two techniques.

Therefore, if one is positive and the other is negative

then a third study must be carried out.

Every patient with positive serology for Chagas dis-

ease must be incorporated in the secondary prevention.

On March 20, 2010, in th e Fou r Seasons Ho tel of Buen os

Aires, it was agreed that the State would guarantee the

access to the following diagnostic exams for every pa-

tient with Chagas disease. Routine laboratory tests of: the

complete blood count (hemogram), glycemia, urea, crea-

tinemia, electrolytes, cholesterol, aminotransferase, liver,

urinalysis and a chest X-ray.

Electrocardiogram with twelve derivations.

Gradual cardiac stress test according to th e Bruce pro-

tocol.

Two-dimensional echocardiography, doppler echocar-

diogram and tissue doppler imag ing.

Holter for 24 hours.

Measurement of antibodies against muscarinic recap-

tors.

Rest/stress gated 99 m Tc-sestamibi myocardial perfu-

sion SPECT to evaluate simultaneously the perfusion and

function. Radioisotope ventriculography to evalutate the

systolic function and gadolinium enhanced Cardiac Mag-

netic Resonance to evaluate the presence or not of myo-

carditis.

Radiologic studies contrasted with the gastrointestinal

transit [11,12].

Diverse clinical studies would suggest an initial exten-

sive vasculoendothelial compromise, detected in some

patients in the chronic phase without proven ex indeter-

minate pathology and more frequent in the chronic phase

with cardiopathy, causing profound changes in the myo-

cardial cells. The parasite could harm the endothelium

but it is not truly known how this is done [13,14].

Some authors have postulated that the action of the

nueraminidase (of the parasite) would act by removing

the electronegative groups of sialic acid of the phos-

phosphingolipids from the membrane (which normally

J. E. Mitelman, L. Gimenez / World Journal of Cardiovascular Diseases 3 (2013) 442-447

444

facilitate the blood flow by electrostatic rejection) in-

creasing the resistance to the flow and altering the nor-

mal state of the microcirculation [9]. This damage or

disturbance of the endothelium, secondary to the loss of

sialic acid not only would complicate the microcircula-

tion but would also predispose to thrombosis, by in-

creasing vi s co sity and platelet aggregation.

With regard to the last position, Jorge and his collabo-

rators in 1974 and more recently with views from

Tanowitz focused their attention on the microvascular

endothelial lesion.

Other authors have reported that the endothelium

would respond to the action of the inflammatory cyto-

kines, altering the production of nitric oxide (NO), which

could have a connection with the chagasic pathogenesis.

Whatever the original mechanism may be, provoked

alterations in the endothelial function would elevate the

platelet reactivity and the platelet-endothelial cell inter-

action producing modifications in the structured proteins,

biochemical disturbances in the signal transduction with

changes in the proliferation, cell function and inflamma-

tory responses. Once the lesion is established in the mi-

crocirculation, the ischemia would produce myocytoly-

sis replacing the cardiac tissue with fibrosis. The platelet

aggregation, the microthrombosis and the contact be-

tween lymphocytes and endothelial cells would con-

tribute to the progression of the illness. The von Wille-

brand factor is a protein produced by the endothelial cell

and the megakaryocytes. It is present in the plasma,

platelets and vascular endothelium forming unions be-

tween the collagen of the subendothelium and the glycol-

proteins of the platelets. The endothelium, in presence of

functional alterations like those described beforehand,

puts in risk the mechanisms of the thrombus resistance,

intervening among other factors that of Von Willebrand,

resulting in a marker of endothelial disturbance that al-

lows for its increase and the early detection of this phe-

nomenon [15- 17].

The abnormalities of the coronary microvascular and

epicardial vasomotion due to the dysfunction of the vas-

cular endothelium was described among other areas by

our group with a brachial echo Doppler and the von

Willebrand factor; from Dr. Harry Aquatella through the

realization of the acetylcholine test given to chagasic

patients in different stages and from Dr. Perez Baliño

with gamma camera [14].

All this evidence would suggest that the myocardial

alterations occur because of an additive and progressive

cellular necrosis initiated and perpetuated by alterations

in the myocardial microcirculation.

At the same time, there could be a consistent auto-

nomic imbalance in the sympathetic and parasympathetic

dysfunction in chagasic patients that would predispose

their coronary arteries to a constrictor stimulus. The

clinical importance of these finding s would lie in linking

them with the symptoms of angina suffered by chagasic

patients and their contribution towards the advance of

chronic chagasic cardiomyopathy, and with the patients

that have this abnormality of vasomotion in the chronic

phase without evidence of ex indeterminate pathology.

Celermajer and team used the test for ischemia by

means of brachial ultrasound as a diagnostic method of

the endothelial lesion in diverse illnesses like athero-

sclerosis, in factors of cardiovascular risk ad in other

processes in which the endothelial function was dis-

turbed, with excellent sensitivity, specificity and predic-

tive value. Immune alterations are produced in Chagas

disease that could play a role in its beginning and evolu-

tion. The antibodies could alter the ionic flow of the car-

diac cell membranes with irreversible lesions [15,16,

18-21].

The management of Chagas disease today in both the

diagnosis and treatment is extrapolated from the man-

agement of the cardiac pathologies of non-chagasic ori-

gins.

Many concerns have arisen concerning the function of

new diagnostic tools to evaluate cardiac problems.

4. RISK SCORE

Recently our group of investigators established a com-

prehensive risk score for chronic patients without de-

monstrable ex indeterminate pathology to develop com-

plications (Mitelman-Gimenez) (Table 1).

The present score (of clinical outcome) was not used

Table 1. Risk score.

Exploration of the autonomic nervous system:

Antimuscarinic receptor antibodies 3

Ergometry 3

Variability of cardiac frequency 2

QT dispersion analysis 2

Exploration of the endothelium:

Soluble thrombomodulin or the von Willebrand factor 3

Brachial echo Doppler 3

Evaluation of the autonomic myocardial substrate:

Two-dimensional echocardiogram-tissue Doppler Imaging4

Signal averaged electrocardiogram 3

Mild

1 - 9

Moderate

10 - 18

Risk score

Severe

19 - 23

J. E. Mitelman, L. Gimenez / World Journal of Cardiovascular Diseases 3 (2013) 442-447 445

to determine sudden death but to evaluate a set of risk

factors of activity and associated progression with new

tools that would permit the detection of critical patients

that could develop in their evolution cardiomyopathy,

thus, enabling the utilization of new therapeutic strate-

gies. There is a growing consensus that the presence of

Trypanosoma cruzi is a necessary condition and suffi-

cient for the development of lesions characterized in

chronic Chagas disease, both in animals and humans; and

that the eradication of the parasite is a prerequisite in

order to avoid the evolution of terminal forms of the dis-

ease [22-29].

5. TREATMENT

The drugs available today for the etiological treatment of

Chagas disease have serious deficiencies particularly due

to their very low efficacy in the treatment of chronic in-

fections and their frequent side effects.

The physiopathological mechanisms that trigger the

progression of the disease after parasitic aggression

could be used in the future to guide the therapeutic proc-

ess of those patients towards the use of ß-receptor an-

tagonists for the modulation of the coronary vasomotor

tone, the angiotensin-converting-enzyme inhibitors to

inhibit the vasoconstrictor effect of the angiotensin and

the calcium channel blockers to prevent tissue hypoxia

because of their vasodilatory and antiplatelet effects.

The use of angiotensin-converting-enzyme (ACE) in-

hibitors and statins in chronic patients without evidence

of ex indetermin ate pathology is based on what was pre-

sented earlier and will surely open the doors to the ap-

plication of new therapeutic treatments combined with

antiparasitic and those that would act temporarily on the

consequences triggered by the action of the Trypanosoma

cruzi avoiding the development of cardiomyopathy and

its effects.

Recent studies have shown that the statins would im-

prove the endothelial lesion by means of antioxidant and

anti-inflammatory actions to increase the activity and

expression of the endothelial sintetase nitric oxide that

would mean an improvement in the vascular function.

Possibly, its beneficial effect in this pathology should be

sought in the effects of the immunomodulators. The an-

giotensin-converting-enzyme inhibitors have also shown

in diverse studies the attenuation of the endothelial lesion

[30].

Once the lesion is established in the microcirculation,

the ischemia would produce myocytolysis, replacing the

cardiac tissue for fibrosis.

Chronic chagasic myocarditis may have a process of

fibrosis and necrosis as a histologic substrate (dissemi-

nated multifocal panmyocarditis characterized by Rosen-

baum) that would have a place in an infinite number of

microscopic focal points that are at times confluent.

These abnormalities that could compromise the spe-

cialized conduction tissue, the common myocardium and

the autonomic nervous system could lead to the multiple

electrophysiological anomalies. The prevalence and com-

plexity of ventricular arrhythmias are directly related

with the extension of the damage. The ventricular extra-

systoles and interventricular conduction disturbances

would be the earliest ventricular compromise [31].

A close relationship could exist between the severity

of the ventricular dysfunction, the ventricular arrhyth-

mias and the probability of sudden death. The angio-

tensin II receptor antagonist, Losartan inhibits the growth

and proliferation of the cardiac muscular cells and the

smooth vascular and endothelial cells, inducing the fi-

broblast apoptosis and activating diverse collagenases.

These antiproliferative effects that are associated with

the inhibition of the kinase pathway activated by mito-

gens diminish the cardiovascular fibrosis and the cardiac

remodeling as well as the neointima formation in re-

sponse to the vascular lesion.

Different authors have reported the presence in ap-

proximately 30% of population with serological positive

muscarinic antibodies that in many occasions are corre-

lated with the presence of alterations in the variability of

frequency and the QT dispersion. This would permit the

diagnosing of cardiac dysautonomy and in addition,

other authors point out the evolutionary aggravation in

those where it is detected. These results would gain im-

portance in the search for therapeutic neutralizers or

blockers as well as the removal by means of an immu-

nosorbent, which is done in idiopathic dilated cardio-

myopathy [19-22].

6. CONCLUSION

We believe that the persistence of the parasite in the in-

fected organism would not be the only mechanism that

would have a determinate role in the development of the

pathogenesis of the illness and consequently even a suc-

cessful etiological treatment would not be able to avoid

the development of the terminal lesions characterized by

the disease. Therefore, the treatment should include the

objective to protect the myocardium the statins, angio-

tensin-converting-enzyme inhibitors and losartan in ac-

cordance with the stage of the disease. Chagasic cardio-

myopathy would constitute a model of nonischemic vas-

cular cardiomyopathy of parasitic origin that would re-

quire the combined action of, immunomodulators, anti-

inflammatory and parasitic drugs attenuating the endo-

thelial and antifibrotic lesion depending upon the stage

of the disease.

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