The long way to defeating Chagas cardiomyopathy
The long way to defeating Chagas cardiomyopathy
Mario Petretta 0 2
Alberto Cuocolo 0
0 Reprint requests: Alberto Cuocolo, MD, Department of Advanced Biomedical Sciences, University Federico II , Naples , Italy; J Nucl Cardiol 1071-3581/$34.00 Copyright 2018 American Society of Nuclear Cardiology
1 Department of Advanced Biomedical Sciences, University Federico II , Naples , Italy
2 Department of Translational Medical Sciences, University Federico II , Naples , Italy
Chagas disease was named after the Brazilian
hygienist, scientist, and bacteriologist Carlos Chagas,
who in 1909 identified Trypanosoma cruzi as the
pathogen agent in a 2-year-old girl named Berenice who
was feverish with enlarged spleen and liver and swollen
lymph nodes. Chagas also discovered that triatoma bugs
are vectors of the parasite and that various animals (first,
the armadillo) are wild reservoirs for the parasite.
Chagas named the parasite in honor of his mentor, the
Brazilian physician and bacteriologist Oswaldo
Gonc¸alves Cruz (1872 to 1917), founder of the Oswaldo
Cruz Institute.1 The disease is, of course, much older
than Chagas’ discovery and has been associated with
humans shortly after they arrived in the Americas some
15,000 years ago. T. cruzi has been found in mummies
from northern Chile and southern Peru that are nearly
9000 years old. Chagas disease is becoming a worldwide
health and economic burden due to multiple
bioecological, sociocultural, and political factors, including
migration. The World Health Organization estimates
that 8 to 10 million people are infected worldwide,
mostly in Latin America where the disease remains
endemic.2 A recent study estimates global costs of $7.19
billion/year for Chagas disease and, noteworthy, more
than 10% of these costs emanate from the United States
and Canada, where Chagas disease is not recognized as a
significant health problem.3
Chagas disease is characterized by an acute and a
chronic phase of infection. In the acute phase most
patients are asymptomatic, while the remaining infected
individuals usually show a non-specific febrile disease.
Severe acute disease is rare, occurring in \ 1% of
patients, and the clinical manifestations include acute
myocarditis, pericardial effusion, and/or
meningoencephalitis.4 In the chronic phase two well-defined forms
of disease are distinguished: indeterminate (latent
preclinical) and determinate (clinical), the latter subdivided
into cardiac, digestive, and cardiodigestive forms.
Although megaesophagus and megacolon produce
typical clinical conditions in about 10% of patients, cardiac
involvement is the most serious and frequent
manifestation (about 30% of patients) of chronic Chagas
As Chagas disease is perceived as restricted to
Mexico and Latin America, in the United States and
Europe the condition is usually ignored in the
differential diagnosis of cardiomyopathies. Thus, Chagas
disease may be misdiagnosed as idiopathic
cardiomyopathy. As a consequence, patients with Chagas disease
are not informed about their infection and can
potentially transmit the parasite through blood or organ
The clinical presentation of cardiac Chagas disease
varies widely according to the extent of myocardial
damage. It manifests as three major syndromes that may
coexist in the same patient: arrhythmic, heart failure,
and thromboembolism (systemic and pulmonary).
Several pathogenetic mechanisms have been called into
question to explain the development of Chagas heart
disease: cardiac dysautonomia, microvascular
disturbances, parasite-dependent myocardial damage, and
immune-mediated myocardial injury. There is ample
experimental and clinical evidence that functional and
structural microvascular abnormalities occur in patients
with Chagas cardiomyopathy, possibly due to the
inflammatory process and/or autonomic disturbances
caused by T. cruzi infection.6
Symptoms suggestive of myocardial ischemia such
as atypical angina pectoris are frequent in patients with
Chagas heart disease. Most of these patients have
concomitant transient or definite ST-T changes on a 12-lead
electrocardiogram and abnormal Q waves compatible
with electrically inactive left ventricular (LV) areas.7
Similar to coronary heart disease, segmental LV wall
motion abnormalities are common in patients with
chronic Chagas disease and are even occasionally
detected when the LV chamber is already globally
dilated. Despite the occurrence of these manifestations,
suggesting the presence of myocardial ischemia,
invasive coronary angiography in Chagas’ cardiomyopathy
nearly invariably demonstrates the absence of significant
obstructive coronary disease at the epicardial level.8 On
the other hand, several studies demonstrated myocardial
perfusion abnormalities in patients with Chagas disease
and angiographically normal coronary arteries,
supporting the concept of abnormal myocardial flow
regulation at the microvascular level.6 Accordingly,
impairment of endothelium-dependent (acetylcholine)
and endothelium-independent (hyperventilation,
nitrates, and adenosine) coronary vasodilatation has
been described, also if with mixed results, in patients
with Chagas heart disease.9
Kuschnir et al.10,11 first reported a reduction in
global myocardial flow measured with 86Rb at rest and
in response to physical exercise in patients with Chagas
disease compared to control subjects. After these
pioneristic reports, myocardial perfusion abnormalities
have been described in patients with Chagas disease and
angiographically normal coronary arteries using 201Tl
stress-redistribution planar scintigraphy12 and
singlephoton emission computed tomography (SPECT),13 or
99mTc-sestamibi SPECT.14 Interestingly, the progression
of LV systolic dysfunction may be associated with
reversible perfusion defects at first examination and an
increase in perfusion defects at rest at the second
examination performed after * 5.6 years of
followup.15 Wall motion abnormalities may be induced during
stress echocardiography in Chagas disease patients
despite angiographically normal coronary arteries, even
in those without overt heart disease and with normal LV
wall motion at baseline,16 further supporting the role of
abnormalities in coronary circulation in these patients.
However, the ultrastructural alterations in myocardium
observed even in Chagasic asymptomatic subjects17 and
myocardial sympathetic denervation might contribute to
contractile dysfunction and blunted chronotropic
response during dobutamine infusion.13
Several animal models, including mice, rats,
rabbits, hamster, guinea pig, chicken, dogs, and monkeys,
have been employed for Chagas disease. All of these
models have some drawback, and the most appropriate
animal model for translation into humans is still unclear.
The requisites of a good experimental model to study
Chagas disease have been established.18 In this issue of
the Journal, Tanaka et al.19 investigated whether
myocardial perfusion disturbance precedes LV systolic
dysfunction and tested the hypothesis that prolonged use
of dipyridamole could reduce myocardial perfusion
defect in an experimental model of chronic Chagas
cardiomyopathy in hamsters. For the purpose of the
study, Tanaka et al.19 properly used the Syrian hamster
Mesocricetus auratus that when infected with the
Ystrain develops a cardiomyopathy resembling human
Chagas’ disease. The results show that myocardial
perfusion disturbance is frequent in experimental chronic
Chagas cardiomyopathy and precedes the development
of myocardium systolic dysfunction. Noteworthy, the
prolonged administration of dipyridamole was
associated with a significant reversion of resting myocardial
perfusion defects confirming the occurrence of
reversible microvascular dysfunction in experimental chronic
Chagas cardiomyopathy. Surprisingly, dipyridamole
slight increased interstitial fibrosis in controls so that no
difference was detectable in the comparison with the
infected groups (see Fig. 3 of Tanaka et al.).
Furthermore, from Table 1 of Tanaka et al.19 it appears that the
reduction in LV ejection fraction after dipyridamole is
comparable to placebo treatment. This finding seems in
agreement with the paradigm shift in favor of
antiparasitic treatment for all adult chronic Chagas patients.20
Nevertheless, the findings of Tanaka et al.19 give
support for future prospective studies testing the impact
of drugs targeting the myocardial perfusion derangement
over the myocardial systolic dysfunction progression in
chronic Chagas cardiomyopathy.
Recently, it has been demonstrated for the first time
that dipyridamole has a trypanocidal effect in vitro on T.
cruzi proliferation and decreases parasitaemia in infected
mice.21 Interestingly, in vivo the trypanocidal drug
nifurtimox at a dosage of 40 mg/kg with or without
dipyridamole had a therapeutic effect, with 84% to 92%
survival rate and elimination of parasitaemia and heart
tissue amastigotes, the common intracellular lifecycle
stage of T. cruzi. Nifurtimox 10 mg/kg, the
recommended dose for treating Chagas disease in humans, had
only subtherapeutic effect with no survival and
persistence of amastigotes, inflammation, and fibrosis in heart
tissue; adding dipyridamole the survival rate increased to
85%, and all tested parameters were significantly
improved.21 Of note, dipyridamole alone, despite the
trypanocidal effect in vitro, did not change the amastigote
density in cardiac tissue, thus other mechanisms are
probably involved in the beneficial effects of the drug.
Theoretically, the beneficial effect of dipyridamole
could be associated with mechanisms at least in part
independent from its effect on coronary vasodilatation
and inhibitions of platelet aggregation. Kuschnir et al.22
reported that dipyridamole improves cardiac
contractility of hypokinetic areas and ejection fraction in patients
with Chagas cardiomyopathy. Dipyridamole may also
act as an immunomodulator agent, an effect mainly
mediated by adenosine A2A receptors, reducing
interleukin-6 and tumor-necrosis factor-a, while increasing
interleukin-10 levels, so counteracting necrosis, fibrosis,
and cardiac remodeling associated with severe
inflammation.23 Finally, the production of free radicals
increases during Chagasic cardiomyopathy
development, due to mitochondrial damage and inefficient
antioxidant defense, and dipyridamole may act as a free
radical scavenger, whose capacity is even greater than
atocopherol and vitamin C.24 However, in the study of
Tanaka et al.19 quantitative histopathology findings
showed comparable degrees of myocardial inflammation
and fibrosis in both infected groups treated with placebo
or dipyridamole, indicating that the effect of prolonged
dipyridamole in reducing myocardial perfusion defects
was not due to a reduction of myocardial inflammation,
eventually associated to the drug effect.
An important aspect that deserves to be investigated
is whether cardiac sympathetic denervation, assessed by
single-photon emission computed tomography or
positron emission tomography, ameliorates after
dipyridamole treatment. Cardiac sympathetic
denervation has been clearly demonstrated in chronic Chagas
cardiomyopathy and a correlation between sympathetic
denervation and the occurrence of severe ventricular
arrhythmia has been reported in patients with normal or
mildly reduced LV ejection fraction.25 The severity of
ventricular arrhythmias correlates with the extent of
myocardial sympathetic denervation, but not with
myocardial fibrosis extent in chronic Chagas
cardiomyopathy.26 Despite the shortage of systematic
studies in Chagas disease investigating the prevalence of
sudden death, its mechanisms, risk factors, and
prevention it is generally admitted that sudden death is the
major cause of death in this disease.27 From the studies
carried out in Chagas’ patients receiving
implantable cardioverter defibrillator therapy, it has
become clear that sustained ventricular tachycardia is
the most frequently observed life-threatening ventricular
arrhythmia, that about 30% of patients develop
ventricular fibrillation without having sustained ventricular
tachycardia as a precursor of the index event, and that
sustained ventricular tachycardia or ventricular
fibrillation may affect about 10% of Chagas’ disease patients
with no LV systolic dysfunction.28 It should be also
considered that the destruction of the parasympathetic
innervation could induce an increased sympathetic tone
with either a direct effect in arrhythmogenesis via
altering the electrophysiologic properties of the heart or
an indirect effect via other mechanisms, such as
increased oxygen demand by catecholamine, increased
coronary vasomotor tone, and augmented platelet
adhesiveness.29 However, currently, there are no
realistic techniques for imaging the cardiac parasympathetic
It should be also considered that Tanaka et al.19
used an adaptation of a pinhole collimator to a gamma
camera designed for clinical use. This may have caused
an underestimation of the myocardial perfusion
disturbance that could be more accurately evaluated by other
quantitative dedicated imaging techniques, and advances
in animal preparation, anesthesia, radiotracers, and
images post-processing.30 Future researches, mainly
focused on positron emission tomography and magnetic
resonance imaging techniques, have the potential to
contribute to a better understanding of chronic Chagas
cardiomyopathy and eventually of the role, if any, of
dipyridamole in helping to prevent or treat this
M Petretta and A. Cuocolo declare that they have no
conflict of interest.
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