Clin. Cardiol.
23, 883-889 (2000)
Review
Chagas’ Heart Disease
h s RAssr, R, M.D., ANISRASSI,M.D., WUIAM C. L m , M.D.*
Section of Cardiology,Anis Rassi Hospital, Goihia, Goik, Brazil; *CardiologySection,Wake Forest University School of Medicine,
Wmston-Salem,North Carolina, USA
Summary: Chagas’ disease is caused by a protozoan
parasite, Trypunosom cruzi,that is transmitted to humans
through the feces of infectedbloodsuckinginsects in endemic
areas of Latin America, or occasionally by nonvectorial
mechanisms, such as blood transfusion.Cardiac involvement,
which typically appears decades after the initial infection,
may result in cardiac arrhyhmas, ventricularaneurysm,con-
gestive heart failure, thromboembolism, and sudden cardiac
death. Between 16 and 18 million persons are infected in
Latin America. The migrationof infectedLatin Americansto
the United States or other countries where the disease is un-
common poses two problems: the misdiagnosis or undiagno-
sis of Chagas’heart diseasein these immigrantsand the possi-
bility of transmissionof Chagas’ disease through blood trans-
fusions. Diagnosisis based on positive serologictests and the
clinical features. The antiparasiticdrug, benznidazole, is ef-
fective when given for the initial infection and may also be
beneficial for the chronic phase. The use of amiodarone, an-
giotensin-convertingenzyme inhibitors,and pacemaker im-
plantation may contribute to a better survival in selected pa-
tients with cardiac involvement of chronic Chagas’ disease.
Key words: Chagas’ heart disease, Chagas’ disease, chronic
chagasiccardiopathy, review
Introduction
Chagas’ disease results from infection with the protozoan,
Trypunosom cruzi. It was first described in 1909 by the
Brazilian physician Carlos Chagas.’ He discoveredthe para-
site, described the vector and the cycle of infection,and subse-
quently reported the signs and symptoms present in each phase
Address for reprints:
Anis Rassi, Jr., M.D.
Anis Rassi Hospital
Section of Cardiology
Av. A, 453 - Setor Oeste
Goilnia (GO),Brazil 74.1 10-020
Received: September 30, 1999
Accepted with revision: November 11, 1999
of the disease. This parasitic infection is usually transmitted
through the feces of an infected bloodsuckinginsect (the redu-
viid bug), although the infection can also occur by nonvectori-
al mechanisms,such as bloodtransfusion.The major manifes-
tations are cardiac, including heart failure, arrhythmias, and
thromboembolism.The disease is endemic in Latin America,
most frequently in Argentina,Bolivia, Brazil, Chile, Uruguay,
and Venezuela. It is estimated that 100million individualsare
at risk for infection and 16to 18million are infected?
Although transmissionof Chagas’ diseaseby its insect vec-
tor is exceedingly rare in the United States, migration of in-
fected individuals from Latin America poses two problems.
First, a potentially treatable disease may escape recognition
and diagnosis;second, there is a risk of transmissionof the dis-
ease through blood or organ donation.
Zkypanosoma cruzi Life Cycleand Mode of
’lkansmission
The life cycle of I: cruzi involvesfour distinctforms in in-
sect vectors and mammalian hosts: (1) the epimastigote, pre-
sent in the intestinal tract of the insect, that replicates; (2) the
infective metacyclic trypomastigote in the vector’s hindgut;
(3) a blood stage form (trypomastigote)that penetrates mam-
malian cells; and (4) an intracellularform (amastigote)that
replicates. Infection occurs when an infected bloodsucking
bug bites and it defecateson the skin of a susceptiblehost. The
metacyclic trypomastigotesin the feces produce a local infec-
tion when it is rubbed into the site of the bite (chagoma)or by
penetrating the intact mucous membrane of the eye (Romaiia’s
sign). Once inside the local reticuloendotelialand connective
cells, the infective ?: cruzi differentiatesinto amastigotesthat
begin replicating. When the cell is full of amastigotes, they
transform once more and become trypomastigotes by growing
flagellae. The trypomastigotes lyse the cells, infect adjacent
tissue, and enter the bloodstream.Circulatingtrypomastigotes
disseminatethe infectionby penetratingmuscle cells (cardiac,
smooth, and skeletal),neurons,lymph nodes, liver, and spleen.
The cycle is completedwhen areduviid bug becomes infected
by ingestingthe blood from an infected human or animal.
Most I: cruzi infections in humans are acquired from the
insect vector, but may occur by transfusion of blood from an
infected donor, even in nonendemic countrie~.~ Congenital
transmission, accidental contamination, and transmission by
organ transplantationare other possible routes of infection.
884 Clin. Cardiol. Vol. 23, December 2000
Acute and Chronic Infection
Trypanosoma cruzi produces disease during the initial in-
fection (acutephase) and again decades later! Acute Chagas’
diseaseusually affects children or young adults in endemic ar-
eas. It produces local inflammation at the parasiteentry site, as
well as malaise; fever; enlargement of the liver, spleen, and
lymph nodes; and subcutaneous edema. Mortality in the acute
phase occasionallyoccurs (< 5% of cases) due to acute myo-
carditisandor meningoencephalitis. In most infected persons,
the illness is not diagnosedbecause of the nonspecificnature
of the signs and symptoms and the lack of access of poor pa-
tients to medical care. In this phase,treatmentwith an antipar-
asitic drug, such as benznidazole,will usually cure the infec-
tied and prevent the chronic manifestations.If untreated,the
manifestations of the acute disease resolve spontaneously
within 4 to 8 weeks in approximately 90%of infected individ-
uals. About half of these patients will never develop chronicle-
sions. They can be recognized by positive serologicaltests, but
do not have electrocardiographic(ECG) and radiologicalevi-
dences of involvement of the heart, esophagus, or colon. The
other half of patients will develop megaesophagus,megacol-
on, andor cardiac disease 10to 30 years after the acute infec-
tion.6A direct progression from the acute phase to a clinical
form of Chagas’ diseaseoccurs in a few patients (5 to 10%).
Cardiac involvement is the most frequentand seriousman-
ifestation of chronic Chagas’ disease and typicallyleads to ar-
rhythmias,cardiac failure, thromboembolicphenomena, and
sudden death.
Pathogenesis of Cardiac Lesions
The pathogenesisof the cardiac lesions appearingdecades
after the initial infection is incompletely understood. The fail-
ure of conventional histological methods to find parasites
in the myocardium led to the hypothesisthat autoimmunere-
sponses are involved in the late clinical manifestation^.^ Stud-
ies in animals suggest involvement of cellular mechanisms,
particularly CD4+T lymphocytes, along with macrophage ac-
tivation and inflammatory cytokine mediators.*. It appears
that self-reactivecytotoxicT lymphocytesdevelop following
the initial infection and are able to lyse nonparasitized myo-
cardial cells.I0Humoral immunity, expressed by a variety of
antibodies against endothelium,vascular structures,and inter-
stitium,have been implicatedin the pathogenesis of Chagas’
myocarditis,” although not confirmed by other studies.I2
Using very sensitive immunohistochemicaltechniques13
and the in situ polymerasechain reaction amplificationmeth-
o d ~ ,parasitic
’~ antigenshave been found recently in the hearts
of patientswith chronic Chagas’disease. In addition,an asso-
ciation between the presence of T cruzi antigens and the in-
tensity of the inflammatoryprocess was observed,suggesting
a direct participation of the parasite in the genesis of chronic
Chagas’ myocarditis.l5 It is possible that even low-grade
persistent parasitisms serve as a continuous antigenic stimu-
lus, and that both I: cruzi inflammation and an autoimmune
response may play important roles in the pathogenesis of
Chagas’ heart disease.
Another hypothesis, based on the focal nature of the my-
ocytolyticnecrosisand experimentalevidenceof dynamic ab-
normalitiesof the coronary microvasculatureassociated with
formation of platelet aggregates and thrombi, proposes that
the microcirculationcould participatein the disease process.16
Autonomic denervation is another typical finding and ex-
plains the digestive alterations (megaesophagus and mega-
colon).l7 The specific cardiac parasympathetic impairment
does not seem to produce myocyte damage,I8but could pre-
dispose patients to arrhythrmasand sudden cardiac death.
PathophysiologicCharacteristics
The chronic cardiac form of Chagas’ disease is character-
ized by a focal inflammatory process composed of lympho-
mononuclear cells that produce progressive destruction of
cardiac fibers and marked reactive and reparative fibrosis af-
fecting multiple areas of the myocardium4~l9 (Fig. 1). The
parasympathetic cardiac nerves and the conduction system
are preferentially producing intraventricular and
atrioventricular (AV) blocks, sinus node dysfunction, and
ventriculararrhythmias (Fig. 2). The right bundle and the left
anteriorfascicleare most frequently affected.
The focal myocardial fibrosis provides the anatomic sub-
strate for ventricular and/or atrial arrhythmias,predisposesto
cardiacdilation and failure,and leads to formationof narrow-
necked left ventricular apical aneurysms, a halhark of
Chagas’ heart disease.21Thrombi are often present in the left
ventricular aneurysm and in the right atrial appendage. This
may explain the common occurrence of thromboembolic phe-
nomena in the systemicand pulmonary circulation.22
Clinical Features
Chagas’ heart disease is the most common cause of car-
diomyopathyin South and Central America and, in endemic
areas,it is the leadingcauseof cardiovasculardeath among pa-
tients between the ages of 30 and 50 years.
Arrhythmias
Chagas’ heart disease is an arrhythmogeniccardiomyopa-
thy. Frequent, complexventricularprematurebeats, including
runs of ventricular tachycardia, are a common finding on
Holter monitoring or stress te~ting.2~. 24 They correlate with
the severity of ventricular dysfunction, but can also occur in
patients with preserved ventricular function.Episodesof non-
sustainedventricular tachycardiaare presentin approximately
40% of patients with mild wall motion abnormalities and in
90%of those with heart failure, an incidencethat is higher than
that observedin other cardiornyopathie~?~
Sustained ventricular tachycardia is anotherimportantfind-
ing.25-26 It can be reproducedduring programmed ventricular
stimulationin approximately85% of patients and seems to re-
sult from an intramyocardial or subepicardial macroreentry
circuit usually located at the inferolaterowall of the left ventri-
 A. Rassi, Jr., et al. : Chagas’ heart disease 885

FIG.1 Photomicrographs of ventricular myocardium in different

stages of chronic Chagas’ heart disease. (A) Intact muscle cell con-
taining amastigote forms of I: cruzi forming a pseudocyst; no inflam-
matory response (hematoxylin and eosin stain).(B) Rupture of the
pseudocyst with an intense lymphomononuclearinflammatoryreac-
tion (hematoxylin and eosin stain). (C) Marked interstitial fibrosis (in
blue) replacing necrotic myocytes or separating muscle fibers (in ma-
roon, Gomori trichrome stain).Courtesy of Prof. Edison Reis Lopes.

cle” and not at the apex where the wall motion abnormalities
are more predominant.28
Bradyarrhythmias are also prevalent in Chagas’ heart dis-
ease and among them, sick sinus syndrome and second and
third degree AV blocks are the most common. Not infrequent-
ly, ventriculartachyarrhythmaand AV conduction abnormal-
ities coexist in the same patient.
Another typical feature of Chagas’ heart disease is sudden
which is caused by ventricular fibrillation in the vast
majority of cases (Fig. 2). It can occur as the initial clinical
manifestation of the disease. Bradyarrhythmia, thromboem-
bolic phenomena, and, in exceptional cases, the rupture of
the apical aneurysm, are other possible causes of sudden
death.

FIG.2 Diagram of the pathophysiologyof Chagas’ heart disease. AV = atrioventricular, IV = intraventricular,S S S = sick sinus syndrome.
886 Clin. Cardiol. Vol. 23, December 2000
Congdve Heart Failure
Congestiveheart failure usually evolves slowly, presenting
in patients 20 years or more after the acute infection. Isolated
left heart failure may be present in the early stages of cardiac
decompensation,but by the time of presentation, biventricu-
lar failure is frequently present with peripheral edema, hep-
atomegaly, and limited cardiac output more prominent than
pulmonary congestion.
Thmmboembolism
Thromboembolic manifestations arisingfrom mural throm-
bi in the cardiac chambers are relatively frequentF2Although
brain embolism is by far the most common clinically recog-
nizedfeature(followed by limbs and lungs),at necropsy emboli
are found more frequently in the lungs, kidneys, and spleen.
Noncardiac Features
Gastrointestinal dysfunction (megaesophagus and/or
megacolon) is the second most common manifestation of
chronic Chagas’ disease and is found in 5 to 20%of patients
with cardiomyopathy. The megaesophagusproduces dyspha-
gia with odynophagia, as well as epigastricpain, regurgitation,
ptyalism, and malnutrition in severe cases. Megacolon pro-
duces obstipation.
DiagnosticEvaluation
The diagnosis of Chagas’ heart disease is based on the
demonstrationof antibodies directed against T cruzi antigens
by at least two different serologicaltests (indirect immunoflu-
orescence, indrect hemagglutination, complement fixation,
and immunoenzymaticand radioimmuneassays), and a clini-
cal syndromecompatible with the disease (Table I).
FIG.3 ’Isrpicalclinical features of Chagas’ disease in a 42-year-old man from rural Brazil who presented with palpitations. (A) Electro-
cardiogramshowing right bundle-branch block, left anterior hemiblock, anterior Q waves, and frequent prematuxe ventricular contractions.(B)
Two-dimensionalechocardiogramshowing an apical left ventricular aneurysm.
TABLE1 Clinical suspicion of chnic Chagas’ heart disease
Typicalfeatures:
Malegender, age 30-50 yean
Childhood resident of endemic area of LatinAmerica
Symptomsof palpitations, syncope,chest pain, andor heart failure
ECGchanges: RBBB + LAH;PVCs; ST-Tchanges;abnormal Q
waves; AV blocks; SSS
Occurrence of both brady- and tachyarrhythmias
Complex and fresuentventriculararrhythmiason HoIterEIT
(usuallyasymptomatic)
H a failure (predominanceof right-sidedfailure in advanced stages)
Apical left ventricular aneurysmthat may contain thrombus
Thromboembolicphenomena
Associated megaesophagusand/or megacolon
Abbreviations:ECG = electrocardiogram,AV = atrioventricular,Em
=exercisetreadmill testing, LAH = left anterior hemiblock, PVCs =
premature ventricular contractions, RBBB = right bundle-branch
block, SSS =sick sinus syndrome.
The most frequent ECG abnormalitiesare ventricularpre-
mature beats, bundle-branch block, left anterior fascicular
block, T-wave inversion, abnormal Q waves, variable AV
block, low voltage of QRS, and manifestations of sick sinus
syndrome. The combination of right bundle-branch block and
left anterior fascicular block is very typical in Chagas’ heart
disease (Fig. 3).
Echocardiography is useful in the diagnosis of myocardial
involvement.28The most typical finding is an apical left ven-
tricular aneurysm (Fig. 3) with or without thrombi, and/or pos-
terior basal akinesia or hypokinesiawith preserved septalcon-
traction. In cases of advanced cardiomyopathy with cardiac
failure, biventricular dilatation occurs without hypertrophy.
Studies employing Doppler techniques indicate that abnor-
malities in left ventriculardiastolic function may precede the
developmentof systolic
 A. Rassi, Jr., et al.: Chagas’ heart disease
The presence of complex ventriculararrh-as on Holter
monitoring31or the development of ventricular tachycardia
during treadmill exercise32identify patients with an increased
risk of sudden cardiacdeath.Also, the relatively frequentpres-
ence of asymptomatictransitoryarrhythmiasand the associa-
tion of ventriculartachyarrhythmiawith sinus node dysfunc-
tion and/or AV conduction abnormalities in the same patient
reinforcethe usefulnessof both tests.%
Patients with Chagas’ heart disease frequently experience
chest pain without evidence of coronary artery disease. Be-
cause Chagas’ disease produces chest pain, left ventricular
aneurysms,ECG abnormalities,and ventriculararrhythmias,
it can mimic coronary artery disease. In nonendemic coun-
tries, the presence of normal coronary angiograms in such a
patient should raise the suspicion of Chagas’disease.
Natural History and Prognosis
Since Carlos Chagas’ initial description, it is apparent that
many patients remain asymptomatic throughout life; some
have conduction defects and mild segmental wall motion ab-
normalities; some develop severe symptoms of heart failure,
thromboembolic phenomena, and multiple disturbances of
rhythm; and others die suddenly and unexpectedly in the ab-
sence of previous cardiac symptoms. In general, sudden car-
diac death (usually due to ventricularfibrillation)is the princi-
pal cause of death, occurringin 55 to 65% of patients, follow-
ed by congestive heart failure in 25 to 30%, and cerebral or
pulmonary embolism in 10to 15%.29 Sudden death predomi-
nates in patients with less extensive myocardial involvement
(without heart failure)and with significantventriculararrhyth-
mias, whereas pump failure is the principal mechanism of
death in patientswith congestiveheart failure.
’hatment
Antimicrobials
Antiparasitic therapy is indicated in the infectious acute
phase of the disease and for the prophylaxis of reactivationof
the infection in immunosuppressedpatients? The recent find-
ings suggesting that I: cruzi may play a role in maintenance
of myocardial inflammation in the chronic phase of Chagas’
disease,13-15 and the experimentalobservation of regression
of hystopathologic lesions in mice chronically infected with
I: cruzi treated with antiparasiticagents,33suggest that anti-
trypanosornal drugs should also be administered to chronic
patients. Furthermore, it has now been reported by some au-
t h o r that ~ ~chronically
~ ~ ~ infected patients treated with an-
tiparasitic agents and followed for up to 16 years were much
less likely to developcardiac abnormalitiessubsequentlythan
do untreated patients.
The two effective antitrypanosomal agents for clinical use
are benznidazole and nifurtimox, which was recently with-
drawn from the market. Benznidazoleis given in an adult dose
of 5 rngn<g/day(5-1 0 mg/kg/dayfor children) administered ev-
ery 12 h for 60days. Both drugs may cause side effects includ-
887
ing dermatitis, polyneuritis, leukopenia, and gastrointestinal
intolerance, sometimes requiringdiscontinuation of treatment.
lkeatment of Cardiac Manifestations
Management of the clinical manifestationsof Chagas’heart
diseaseis based on the treatment of similarcardiac abnormali-
ties produced by other cardiomyopathies.
Rhythm Disturbance
Severe bradyarrhyhuas are treated with pacemaker im-
plantation,but the electrode should be placed in the subtricus-
pid area, not in the right ventricular apex. Apical fibrosis is
common in Chagas’ disease and may result in failure of a
pacemaker placed in the apex to capture. Ventricular pacing in
patients with Chagas’ heart disease and advanced conduction
abnormalitiesappearsto improve survival comparedwith his-
toric controlsin whom this treatment was not possible.29
Although there is no evidence from randomized controlled
trials that antiarrhythrmcdrugs prolong life or prevent sudden
cardiac death in Chagas’ heart disease, we recommend the
use of empiric amiodarone for patients with sustained and
nonsustainedventriculartachycardia,particularly in the pres-
ence of significant myocardial dysfunction.Amiodarone is a
potent antiarrhythmicdrug that markedly reduces the severi-
ty and complexity of ventricular arrhythmias in patients with
Chagas’ disease,37does not have negative inotropic proper-
ties, is well tolerated (when administered at low doses), has
fewer proarrhythmic effects than class I agents, and may re-
duce total mortality and sudden cardiac death in patients with
heart failure of other etiologie~.~~
For example, Rassi et al. compared the survival of 34 pa-
tients with Chagas’diseaseand sustained ventriculartachycar-
dia, treated with amiodarone, with an earlier matched cohort
of 42 patients not treated or receiving class I agents. Survival
rate at 1 year (87 vs. 57%), 4 years (65 vs. 22%), and 8 years
(59 vs. 7%) was significantlygreater in the treated
In patients failing empiric amiodarone therapy, electro-
physiologicguided antiarrhythmictherapy has been advocat-
ed by some authors.26Implantation of a cardioverter-defibril-
lator should be considered for patients with refractory and
hemodynamicallyunstable sustained ventricular tachycardia
or for survivors of suddencardiac death.24However, to reduce
frequent shocks, antiarrhythmicdrug therapy is required in
most patients because of the high prevalenceof nonsustained
ventriculartachycardia.
Aneury~mectorny,3~surgical ablation,40 transcoronary
chemical ablation$I and catheter ablation42.43 have been at-
tempted in some patients,but efficacyand/or long term effects
on survival and arrhythmiarecurrence are not established.
Congestive Heart Failure
Congestiveheart failure responds to routine management,
including sodium restriction, diuretics, digitalis, and angio-
tensin-converting enzyme (ACE) inhibitors.For patients with
888 Clin. Cardiol. Vol. 23, December 2000
severe cardiac failure, higher doses of diureticsare usually nec-
essary. Although no long-termcontrolledtrial demonstrating
benefits of ACE inhibitors in Chagas’ heart disease has been
reported,we recommend their use, even in asymptomaticpa-
tients with reduced left ventricular ejection fraction, based on
their efficacy in left ventricular systolic dysfunction of other
etiologies.44Although beta b l o ~ k e r sand ~ ~spir~nolactone~~
,~~
improve survival in heart failure due to other etiologies, they
have not been studied in Chagas’ disease. Beta blockers have
been avoided in patients with Chagas’ disease because of brad-
yarrhyhmas and AV conduction defects, but spironolactoneis
a theoretically attractive therapy because of the major role that
cardiacfibrosis plays in the disease.
For selected patients with end-stage heart failure, cardiac
transplantationremains an 49 It has been per-
formed in some patients with promising results. However, pa-
tients must be treated with antitrypanosomalagents, because
of the possibility of T. cruzi infection reactivation with the con-
comitant use of immunosuppressive drugs.5O
Dynamic cardiomyoplasty, another surgical option, was
performed in a few patients with disappointingresults.5l More
recently, the Brazilian cardiac surgeon Randas Batista intro-
duced a left ventriculectomy?* applying it first to some pa-
tients with Chagas’ disease with end-stage cardiomyopathy.
However, other in a small series of patients, found
no satisfactory results in patients with Chagas’ disease.
Thromboembolism
Because of the high incidence of thromboembolic phenom-
ena in Chagas’ heart disease, anticoagulants are recommended
in patients with atrial fibrillation,previous embolic episodes,
and apical aneurysm with thrombus, even in the absence of
controlled clinical trials demonstrating their efficacy.
Chagas’ Disease in Nonendemic Countries
Chagas’ diseaseis widespread in South and Central Ameri-
ca. Although T. cruzi-infected insects are present in many parts
of the southern and western United States, only a few cases of
acuteChagas’ disease resulting from vector transmission have
been described in North America.54 This probably results
from the better living conditionsthat discouragethe establish-
ment of domiciliaryinsect population,the lack of contact be-
tween people and infected vectors, and variations in the behav-
ior of the North American species of the reduviidbug.
With migration from endemic areas, Chagas’ disease is
becoming a more frequent problem in the United States,
where it is estimatedthat 500,000to 675,000 Latin American
immigrants may be chronically infected with T. c r u ~ iBe- .~~
cause the manifestationsof Chagas’ heart disease are diverse
and the disease is perceived to be extremely rare, it may be
unrecognized in nonendemic To diagnose and
treat Chagas’heart disease correctly,cliniciansin nonendem-
ic areas must become more familiar with its characteristics.
Transmission of the disease is possible by contaminated
blood transfusion or by organ transplantationfrom an infected
donor and may become a serious problem.57Since screening
tests are not performed in blood banks of nonendemic coun-
tries, the best policy for the time being is not to accept organ
transplantation and blood transfusion from Latin American in-
dividuals with a positive epidemiologichistory.
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