Chagas Disease:
Chagas disease (Trypanosomiasis Americana) is caused by the protozoan parasite
Trypanosoma cruzi, which is transmitted to humans through the feces of a hematophagous
insect (family Triatominae) in most cases. The infection usually occurs in childhood, and
the acute phase has an incubation period of 1 to 2 weeks and can last up to 3 months.
Then follows the chronic phase, in which for a long time - 2-4 decades most of the time -
patients have only positive serology for Chagas disease (CD), without symptoms or other
signs of clinically apparent disease.
Therefore, such patients present the so-called indeterminate form of Chagas disease,
whose prognosis is essentially benign.
While due to pathogenic mechanisms still incompletely understood, many patients remain
with this form of the disease for life around 30 to 50% of infected individuals evolve to
certain forms like cardiac, digestive, or mixed. Chronic Chagas cardiomyopathy (CCC) has
a hemodynamic pattern like dilated idiopathic cardiomyopathy but has marked
pathophysiological peculiarities. The most common and most serious clinical form of CD is
responsible for significant morbidity and mortality in many Latin countries -Americans
(and with epidemiological relevance also contemporarily recognized in countries with
immigration by individuals from those countries).
It is estimated that 8-10 million people are infected with Trypanosoma cruzi in Latin
America and other countries. Considering the worst-case scenario, we can deduce that 3-5
million infected individuals will manifest clinical forms of the disease in its chronic
phase.
The disease severity:
In addition to the criteria used in the risk stratification shown in Tables 1 and 2,
several markers of worse prognosis have been identified by several authors, especially
concerning sudden cardiac death in different clinical contexts.
Characteristics such: as presyncope and syncope; left ventricular dysfunction; heart
failure; sustained ventricular tachycardia (VT) or non-sustained ventricular tachycardia;
severe bradyarrhythmia (sinus node disease and advanced atrioventricular block); and
previous cardiac arrest were identified as markers of risk of sudden cardiac death (SCD).
On the other hand, isolated ventricular extrasystoles on Holter monitoring and right
bundle-branch block do not significantly interfere with the prognosis of CCC. SCD is
often associated with manifestations of heart failure (HF), but it can also occur in
patients with asymptomatic left ventricular dysfunction. It accounts for approximately 55
to 65% of all causes of death, whereas refractory HF is a cause of death in about 25 to
30% of patients and systemic or pulmonary thromboembolism in about 10 to 15%. Indicador
não definido. Very rarely, aneurysm rupture can be the mechanism of sudden death in CCC.
Recently, the correlation between CCC stages and causes of mortality has been
schematically described. SCD usually affects patients from stage II of the disease
onwards, being more relevant in stage III and a little less in stage IV, in which
refractory heart failure as a cause of death becomes quite frequent.
Therapeutic Options for Heart Failure. As in other heart diseases, the treatment of HF in
CCC is based on the routine use of a combination of three types of drugs: diuretics,
angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARB)
and adrenergic beta-blockers (BB). However, despite CD representing an important cause of
HF in Latin America, patients with CD and HF were not included in the large studies that
validated those drugs to treat HF. Therefore, the real efficacy and tolerability of these
drugs in patients with CCC have not been scientifically established, and their use is
empirically extrapolated from the support obtained in HF of other etiologies.
In the same sense, the scientific evidence regarding the role of CRT in CCC is not
supported by randomized studies. Furthermore, the low prevalence of left bundle block, an
independent marker of CRT response, in CCC is a limiting factor for its indication of
this therapeutic option. Some observational studies have been carried out to recognize
other candidates for CRT in CCC, but the evidence is still poor.
Heart transplantation is a good option for severe cases, but its application is very
limited by the low availability of donors.
Recently, an excellent adjunctive option was introduced, and tested in several heart
diseases but not in patients with CCC. It is an implantable device capable of modulating
myocardial contractility: Cardiac Contractility Modulation (CCM).
Cardiac Contractility Modulation:
CCM consists of high-tension stimulation of the right ventricular septum during the
absolute refractory period, 30-40ms after cardiomyocyte activation. This stimulation acts
on calcium currents and increases ventricular contractility and, as a consequence,
improves functional capacity.
In a 2019 meta-analytic study, Mando R et al. evaluated four randomized studies that
immigration by individuals from those countries).

It is estimated that 8-10 million people are infected with Trypanosoma cruzi in Latin
America and other countries. Considering the worst-case scenario, we can deduce that 3-5
million infected individuals will manifest clinical forms of the disease in its chronic
phase.

The disease severity:

In addition to the criteria used in the risk stratification shown in Tables 1 and 2,
several markers of worse prognosis have been identified by several authors, especially
concerning sudden cardiac death in different clinical contexts.

Characteristics such: as presyncope and syncope; left ventricular dysfunction; heart
failure; sustained ventricular tachycardia (VT) or non-sustained ventricular tachycardia;
severe bradyarrhythmia (sinus node disease and advanced atrioventricular block); and
previous cardiac arrest were identified as markers of risk of sudden cardiac death (SCD).
On the other hand, isolated ventricular extrasystoles on Holter monitoring and right
bundle-branch block do not significantly interfere with the prognosis of CCC. SCD is
often associated with manifestations of heart failure (HF), but it can also occur in
patients with asymptomatic left ventricular dysfunction. It accounts for approximately 55
to 65% of all causes of death, whereas refractory HF is a cause of death in about 25 to
30% of patients and systemic or pulmonary thromboembolism in about 10 to 15%. Indicador
não definido. Very rarely, aneurysm rupture can be the mechanism of sudden death in CCC.

Recently, the correlation between CCC stages and causes of mortality has been
schematically described. SCD usually affects patients from stage II of the disease
onwards, being more relevant in stage III and a little less in stage IV, in which
refractory heart failure as a cause of death becomes quite frequent.

Therapeutic Options for Heart Failure. As in other heart diseases, the treatment of HF in
CCC is based on the routine use of a combination of three types of drugs: diuretics,
angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARB)
and adrenergic beta-blockers (BB). However, despite CD representing an important cause of
HF in Latin America, patients with CD and HF were not included in the large studies that
validated those drugs to treat HF. Therefore, the real efficacy and tolerability of these
drugs in patients with CCC have not been scientifically established, and their use is
empirically extrapolated from the support obtained in HF of other etiologies.

In the same sense, the scientific evidence regarding the role of CRT in CCC is not
supported by randomized studies. Furthermore, the low prevalence of left bundle block, an
independent marker of CRT response, in CCC is a limiting factor for its indication of
this therapeutic option. Some observational studies have been carried out to recognize
other candidates for CRT in CCC, but the evidence is still poor.

Heart transplantation is a good option for severe cases, but its application is very
limited by the low availability of donors.

Recently, an excellent adjunctive option was introduced, and tested in several heart
diseases but not in patients with CCC. It is an implantable device capable of modulating
myocardial contractility: Cardiac Contractility Modulation (CCM).

Cardiac Contractility Modulation:

CCM consists of high-tension stimulation of the right ventricular septum during the
absolute refractory period, 30-40ms after cardiomyocyte activation. This stimulation acts
on calcium currents and increases ventricular contractility and, as a consequence,
improves functional capacity.

In a 2019 meta-analytic study, Mando R et al. evaluated four randomized studies that
applied the CCM technique compared to optimized drug therapy. The authors concluded that,
in short-term follow-up, there is health-related quality of life gains (as measured by
the Minnesota questionnaire) and that these were significantly greater in patients
treated with CCM. However, they did not observe significantly better results in the
functional test evaluated by the 6-minute walk test, nor regarding mortality and
hospitalization from any causes.
Abraham WT et al. performed an open-label randomized trial to evaluate the adjunctive
effect of CCM therapy to optimized therapy in 160 patients with symptoms of HF functional
class III or IV by NYHA classification, sinus rhythm, QRS duration <130ms, and LVEF ≥25%,
and ≤45%. Of these, 74 patients underwent CCM therapy for 24 weeks. The results indicated
that CCM therapy is safe and improves exercise tolerance and quality of life. The
composite endpoint of cardiovascular death and HF hospitalizations was also reduced and
clinical effects were observed for the entire LVEF range studied. More specifically,
superior clinical efficacy was observed in patients with LVEF between 35% and 45%. These
data point in the direction that CCM may be an interesting adjuvant option in HF therapy.
Hypothesis:
The hypothesis of this study is that patients with CCC, advanced heart failure, severe
systolic dysfunction, and non-LBB have better clinical and functional responses when
undergoing implantation of a CCM device than when undergoing cardiac resynchronization
therapy.
Objectives:
Primary objective - To assess the short-term impact on quality of life and myocardial
contractility of an implantable electronic cardiac device for cardiac contractility
modulation compared to CRT in patients with CCC, non-LBBB, and advanced HF.
Secondary objectives - To record the clinical evolution, including the need for
hospitalization, the functional class according to the New York Heart Association, and
the functional capacity of an implantable electronic cardiac device for cardiac
contractility modulation compared to CRT, in patients with CCC, non-LBBB, and advanced
HF.