Mortality prediction in Chagas heart disease

Review

THEMED ARTICLE y Inflammation & Infection For reprint orders, please contact [email protected]

Mortality prediction in Chagas heart disease Expert Rev. Cardiovasc. Ther. 10(9), 1173–1184 (2012)

Maria Carmo Pereira Nunes*, Andre Assis Lopes do Carmo, Manoel Otávio Costa Rocha and Antonio Luiz Ribeiro Faculdade de Medicina e Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil *Author for correspondence: Tel.: +55 313 409 9746 Fax: +55 313 409 9437 [email protected]

Chagas disease continues to be an important cause of cardiac disease in many countries of Latin America. Dilated cardiomyopathy constitutes the more severe manifestation and main cause of death in the disease. Typical clinical presentations include three basic syndromes: heart failure, cardiac arrhythmia and thromboembolism. The identification of markers related to the progression of Chagas heart disease is relevant for appropriate patient management. The most important predictors of death are New York Heart Association functional class, left ventricular systolic dysfunction and nonsustained ventricular tachycardia, which reflect the severity of myocardial damage. Several other potential prognostic factors have recently been reported. Scores for mortality prediction using a combination of prognostic variables have contributed to overall improvement in risk stratification in the setting of Chagas disease. Keywords: cardiomyopathy • Chagas disease • heart failure • mortality • sudden death

Chagas heart disease

Chagas disease, caused by the parasite Trypanosoma cruzi, is an important cause of cardiac disease in many countries of Latin America [1] . Although a marked decrease in incidence has been observed in the last decade, new patterns of immigration have made this disease a worldwide problem [2] . It is estimated that 8–10 million people are currently infected, and 20–40% of them will develop chronic myocardial disease decades after the initial infection [1,3,4] . Dilated cardiomyopathy constitutes the main cause of death [5–7] . Most patients are seen in the chronic phase of the disease, which includes an indeterminate form, in which there are no clinical, ECG or radiological manifestations, and chronic definite forms, including mild to severe heart disease [8] . Chagas cardiomyopathy is characterized by a chronic myocarditis with a progressive fibrotic process of the myocardium and damage to the conduction system [9,10] . The pathogenesis of myocardial lesions in the chronic form of Chagas heart disease is hypothesized to involve parasite persistence in cardiac tissue and immunemediated myocardial injury [9] . However, the contributions of parasite and immune system for disease pathogenesis remain unresolved and controversial [10,11] . Early manifestations of Chagas heart disease are usually conduction system abnormalities, www.expert-reviews.com

10.1586/ERC.12.111

most frequently right bundle branch block or left anterior fascicular block [12] , and segmental left ventricular wall motion abnormalities [13,14] . Subsequently, complex ventricular arrhythmias, sinus node dysfunction and more advanced conduction abnormalities are observed [6,7] . In the later stages of the disease, there is a progressive enlargement of the left ventricle and deterioration in overall systolic function with heart failure. Clinical manifestation of Chagas heart disease varies widely according to the degree of myocardial damage [5] . In general, symptoms appear years or decades after the acute infection. Typical clinical presentations include three basic syndromes: heart failure, cardiac arrhythmia and t hromboembolism [7,15,16] . The cardinal manifestation of Chagas heart failure is dyspnea due to an impairment of left ventricular myocardial function [7] . Initially, patients have exercise intolerance without evidence of fluid retention. Although clinical manifestation of right ventricular dysfunction was formerly reported as the classical feature of the disease, usually pulmonary congestion and peripheral edema dominate the clinical picture at the same time [16] . In the later stages of the disease, patients may complain primarily of edema and report few symptoms of dyspnea, with low cardiac output more prominent than pulmonary congestion [17] .

© 2012 Expert Reviews Ltd

ISSN 1477-9072

1173

Review

Nunes, Carmo, Rocha & Ribeiro

Thromboembolic manifestations are relatively frequent and may also be a cause of death [18–25] . Apical aneurysm, mural thrombus, congestive heart failure and cardiac arrhythmias seem to be important risk factors in the genesis of ischemic stroke related to Chagas cardiomyopathy [19,21,26,27] . Stroke may also be the first manifestation of Chagas disease in patients with mild or undetected systolic dysfunction [19,20,26] . Chagas heart disease is typically characterized by a wide variety of arrhythmias, which are the main triggering factors of sudden death [28] . Frequent, complex ventricular premature beats, including runs of ventricular tachycardia, are a common finding on Holter monitoring. Ventricular arrhythmias correlate with the severity of left ventricular dysfunction, but can also occur in patients with preserved ventricular function [28] . Predictors of progression of the disease

The clinical course of Chagas disease is variable with a wide range of mortality rates. The prognosis depends on the clinical form and the complications during its evolution. In indeterminate chronic clinical form, infected individuals remain totally asymptomatic, a parasite–host state of equilibrium, and with an excellent prognosis [5,29] . In chronic Chagas cardiomyopathy, there is myocarditis, extensive myocardial fibrosis, destruction of the conduction system, and a large reduction in the numbers of cardiac neurons with progressive deterioration of heart function, and the appearance of lethal ventricular arrhythmias with a poor prognosis [30] . To date, however, no determinants of progression from the indeterminate into the cardiac form have been identified. Several variables have been described as predictors of mortality in Chagas disease. However, the populations enrolled in the prognostic studies are heterogeneous, and include patients without apparent cardiac involvement and, also, patients at different stages of heart disease. A systematic review on prognostic factors in Chagas disease has emphasized the wide range of reported annual mortality rates across the studies (varying from 0.2 to 19.2%), which are related to the specific characteristics of selected patient population [31] . The most consistent independent predictors of death identified in the majority of the studies are left ventricular dysfunction, New York Heart Association (NYHA) functional class and nonsustained ventricular tachycardia (NSVT), which reflect a more advanced degree of myocardial damage [31] . The majority of studies, however, have mainly focused on mortality, and few data are available on progression of heart disease enrolling patients in the early stages of the disease. The myocardial damage begins early in the course of chronic T. cruzi infection and is progressive in a subpopulation of those infected [12] . The evolution of Chagas heart disease is poorly understood. Several longitudinal studies demonstrate that many factors can be associated with the progression of cardiopathy in Chagas disease, including male sex, exposure to reinfection, parasite strain, genetic background, black color, age, severity of acute infection, nutritional status, alcoholism and other concomitant diseases [5] . A study using PCR demonstrated an association between the presence of parasitic DNA in the blood and progression of cardiac 1174

damage [32] . Therefore, the prognosis varies considerably based on individual characteristics of patients. In the chronic phase, Chagas infection may present as an indeterminate form, in which it remains totally asymptomatic, with anatomically and physiologically normal x-ray results for the heart, esophagus and colon and no changes seen on ECG [29,33] . Epidemiological studies carried out in endemic areas have shown that approximately 2–5% of patients with the indeterminate phase develop cardiac disorders every year [29,34] . Patients with discrete and nonspecific ECG changes, such as primary ST–T changes, right bundle branch block of nonadvanced degree, first-degree atrioventricular block and premature ventricular beats (PVB) tend to remain stable and most of them survive for long periods [8] . Heart disease worsens in some of them, with severe underlying cardiac involvement and a poor prognosis. At this stage of the disease, patients may present with a high frequency of complex arrhythmias, including periods of ventricular tachycardia and bradycardia secondary to sinus node disease and atrioventricular block. In a longitudinal case–control follow-up study carried out in endemic areas over a period of 10 years, more than a third of patients with chronic Chagas disease experienced clinical or ECG deterioration [35] . The risk of progressive ECG changes and of mortality is greatest for seropositive individuals who had ventricular conduction defects on the initial ECG [12] . Patients with ECG abnormalities that reflect some degree of cardiomyopathy are those at risk of progression of the disease. In the early stages of cardiac involvement, segmental cardiac lesions on echocardiography may be detected [13] . The presence of regional contractility abnormality identifies individuals at risk of evolving with progressive worsening of left ventricular systolic function [36] . Complex ventricular arrhythmias observed during stress testing also have a prognostic value for the progression of early chronic Chagas heart disease [37] . The enlargement of the left ventricle and the deterioration in overall systolic function, which appears in the final stages of the disease, is a common pathway to all dilated cardiomyopathies. The host immune response is critical for Chagas disease evolution. Despite many uncertainties and the complexity of the immune response generated during T. cruzi infection, the host immune response is an important determinant of outcome [38] . Circulating activated T cells obtained from patients with chronic disease express both inflammatory and anti-inflammatory cytokines, consistent with an active immunoregulation; those with cardiac lesions have a preferential expression of inflammatory cytokines, especially TNF-α and IFN-γ [38] . Several auto antibodies have been detected in Chagas disease, which could be a useful tool for risk stratification. A previous study with asymptomatic Chagas patients showed that specific autoantibody patterns correlate with the development of clinical manifestation [39] . The severity of heart disease is associated with the maturation and migratory properties of the memory CD8+ T-cell compartment, as a result of continuous antigenic stimulation by persistent parasites. Considering that inflammation is an important hallmark of Chagas’ heart disease, and it is modulated by genes of the Expert Rev. Cardiovasc. Ther. 10(9), (2012)

Mortality prediction in Chagas heart disease

immune response and the genetic background of the infected individuals, there are some studies that support that particular polymorphisms in TNF-α [40] and CCR5 [41,42] may influence the risk of developing severe cardiomyopathy. Predictors of mortality: risk factors

There are several potential prognostic factors in Chagas cardiomyopathy assessed in different populations. However, the optimal strategy to combine prognostic determinants to better stratify risk of death is still a matter of debate. The majority of studies have evaluated patients with Chagas cardiomyopathy only, and some of them also included patients without cardiac involvement (Table 1) .

Review

Demographic factors

Although some demographic characteristics, such as male sex and advanced age, can be associated with an adverse prognosis in Chagas disease, they remain a controversial issue due to different results in several studies. It is well known that male patients are more commonly affected with Chagas cardiomyopathy [43,44] and male sex was associated with increased mortality in some prospective studies [32,45] , but in other studies this association has not been demonstrated [46,47] . The same scenario is described for advanced age. RodriguezSalas et al. described an association between age >56 years and increased mortality [46] . Similarly, Salles et al. found that every

Table 1. Prognostic factors in Chagas disease. Study (year)

Follow-up

Prognostic factors

Espinosa et al. (1991) 66

With and without All-cause mortality cardiomyopathy

Up to 10 years

SBP, AF, cardiothoracic index and LVEDV

[55]

Salles et al. (2003)

738

With and without All-cause mortality cardiomyopathy

58 ± 39 months

Age, HR, Q waves, QTd, cardiomegaly and LVSD

[47]

Viotti et al. (2004)

849

With and without New ECG abnormalities, 9.9 years cardiomyopathy change in clinical group or death

Change in clinical group, LVSD and LVEF

[13]

Viotti et al. (2005)

856

With and without Progression of the cardiomyopathy disease or death

8 years

Age, LVSD, ICD, SVT and benznidazole treatment

[85]

Rassi Jr et al. (2006)

424

With cardiomyopathy

7.9 ± 3.2 years

NYHA class, cardiomegaly on x-ray, LV systolic dysfunction, NSVT, QRS voltage and male sex

[45]

Benchimol-Barbosa (2007)

50

With and without Cardiac death or cardiomyopathy documented ventricular tachycardia

84.2 ± 39 months Apical aneurysm, isolated PVC count and LVEF

[91]

Ribeiro et al. (2008)

184

With and without Cardiovascular death cardiomyopathy

74 ± 17 months

LVEF, NSVT, prolonged filtered QRS duration >133 ms (SAECG)

[60]

Theodoropoulos et al. (2008)

127

With systolic heart failure

All-cause mortality

25 ± 19 months

Lack of BB use, digoxine use, Na, LVEF, NYHA class

[53]

Nunes et al. (2009)

192

With cardiomyopathy

Death or cardiac transplantation

34 months

NYHA class, LVEF, RV function, LAV and E/e’ ratio

[75]

Lima-Costa et al. (2010)

524

With and without Death cardiomyopathy

8.9 years

BNP, ECG (Minnesota code) major abnormalities

[68]

Pedrosa et al. (2011)

130

With cardiomyopathy

9.9 years

Exercise-induced ventricular arrhythmia and cardiomegaly on chest x-ray

[65]

Ribeiro et al. (2011)

113

With and without Cardiovascular death cardiomyopathy

106 ± 28 months

T-wave variability, LVEF, NSVT, QRS >130 ms

[62]

Bestetti et al. (2011)

231

With and without Death or cardiac cardiomyopathy transplantation

19 months

Lack of BB, inotropic support and LVSD

[52]

Nunes et al. (2012)

232

With cardiomyopathy

3.4 years

NYHA class, LVEF, RV function, LAV, E/e’ ratio

[77]

n

Population

End points

All-cause mortality

Cardiovascular death

Death or cardiac transplantation

Ref.

AF: Atrial fibrillation; BB: β-blocker; BNP: β-type natriuretic peptide; HR: Heart rate; ICD: Intraventricular conduction disorders; LAV: Left atrial volume; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; LVSD: Left ventricular systolic dimension; Na: Serum sodium level; NSVT: Nonsustained ventricular tachycardia; NYHA: New York Heart Association; PVC: Premature ventricular contraction; QTd: QT dispersion; RV: Right ventricle; SAECG: Signal-averaged ECG; SBP: Systolic blood pressure; SVT: Sustained ventricular tachycardia.

www.expert-reviews.com

1175

Review


10 years of increase was linked to a worst prognosis [47] . In other studies, age was not an independent predictor of survival [48,49] . Clinical factors

Functional capacity as evaluated by NYHA functional class is the most consistent marker of poor prognosis. Among the clinical factors evaluated as predictors of increased mortality in patients with Chagas cardiomyopathy, NYHA functional class III and IV provide independent and additional prognostic information to the left ventricular ejection fraction [31,45,46,48] . Conversely, syncope has a more complex interaction with prognosis in Chagas disease. The rationale for considering syncope as a marker of increased mortality is the assumption that the underlying cause of syncope is malignant ventricular tachycardia. Nevertheless, there are many other causes for syncope [50] , and it does not appear to be an independent predictor of death [47,48] . Paroxysmal atrioventricular block may be associated with a favorable prognosis [47,48,51] . Recently, other clinical factors related to therapy for heart failure, such as lack of use of β-blocker [52,53] , inotropic support [52] , use of digoxine [53] and number of shocks after 30 days of cardioverter–defibrillator implant (Figure 1) [54] , have been identified as unconfirmed as predictors of increased mortality in prospective studies.

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

Resting ECG

Resting ECG is an important medical tool in the management of patients with Chagas disease. ECG evaluation is essential not only to assess the risk of adverse outcomes but also to determine the presence of cardiac involvement. The physiopathology of heart injury in Chagas disease, including extensive fibrosis in different portions of ventricular wall and autonomic dysfunction, leads to numerous ECG abnormalities, ranging from different types of impulse block (Figure 2) to repolarization abnormalities and malignant ventricular arrhythmias. Epidemiologic studies have shown that patients with a normal ECG have an excellent medium-term survival [12,29] . Abnormal ECG has been associated with increased mortality in Chagas disease. Right bundle branch block [46] , ST-segment elevation [46] , atrial fibrillation [55] , increased heart rate [47] , PVB on resting ECGs [47] , pathological Q waves [47] and low QRS voltage [45] have all been independently associated with worse prognosis. Salles et al. [47] evaluated parameters of repolarization as predictors of increased mortality in patients with and without cardiac involvement. This study showed that QT dispersion or maximal-corrected QT interval were predictors of mortality. Another parameter evaluated in this study was Tpeak–Tend interval (measured from the peak to the end of the T wave), a marker that

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

* R

297 305 297 305 305 305 301 301 309 316 309 316 309 309 313 320 309 316 309 316 316 316 297 348 320 324 R R R R R R R R R R R R R R R R R R R R R R R R R R 16 17 18 19 20 21 22 23 24 VVI VVI

* R

* R

R

R

316 320 316 324 R R R R 24 25

H V

X S

830V 26

598 R

27

699 R

B 750 R 28

B 750 V 29

S 551 V

B 750 R 30

S

RS 563 V 31

0 R

B 32

Figure 1. Ventricular tachycardia successfully reverted by implantable cardioverter–defibrillator shock in a Chagas disease patient.

1176

Expert Rev. Cardiovasc. Ther. 10(9), (2012)


Review

Figure 2. An ECG showing the typical findings of Chagas cardiomyopathy: right bundle branch block and left anterior hemiblock.

provides a measure of spacial dispersion of repolarization and has been associated with increased risk of mortality in patients with long-QT syndrome [56] , hypertrophic cardiomyopathy [57] , in patients undergoing primary percutaneous coronary intervention [58] and even in the general population [59] . However, in this study Tpeak–Tend was not associated, in multivariate analysis, with the risk of death in patients with Chagas disease.

Signal-averaged ECG

A filtered signal-averaged ECG, a technique that predicts arrhythmic events and death in several conditions, was also an independent predictor of death in Chagas cardiomyopathy. It may be related to larger myocardial scarring in patients with longer filtered QRS [60] . Blood biomarkers

Holter monitoring

NSVT on ambulatory ECG monitoring has been demonstrated as a prognostic factor in Chagas cardiomyopathy [31,45,60] . In addition, the combination of NSVT and left ventricular dysfunction was associated with a 15-fold increased risk of death compared with patients without both risk markers [31] . Recently, Sarabanda and Marin-Neto have shown that patients with Chagas cardiomyopathy presenting with either NSVT or sustained ventricular tachycardia and not treated with an implantable cardioverter–defibrillator were at high risk for death when they had concomitant severe or even moderate left ventricular systolic dysfunction [61] . A cut-off value for left ventricular ejection fraction of 40% had the best accuracy for predicting both all-cause m ortality and sudden death in patients with Chagas cardiomyopathy. Another prognostic marker evaluated T-wave amplitude variability during a 10-min rest period while on Holter monitoring and this noninvasive technology was independently related to the risk of death [62] . Exercise test

The maximal oxygen consumption during cardiopulmonary test is also a strong predictor of survival in patients with heart failure due to Chagas disease, even in patients with mild dysfunction [63] . Moreover, exercise-induced ventricular tachycardia (sustained and NSVT) has been significantly associated to sudden cardiac death in short- [64] and long-term follow-up [60] . More recently, Salles et al. showed that exercise-induced ventricular arrhythmia (PVB and NSVT) in clinically stable Chagas disease subjects with cardiomegaly is a significant marker of cardiovascular mortality [65] . www.expert-reviews.com

Natriuretic peptides have been shown as a sensitive marker capable of detecting gradual impairments in cardiac function and poor survival in patients with Chagasic cardiomyopathy [66,67] . β-type natriuretic peptide (BNP), a peptide released from cardiomyocytes in response to ventricular wall stretch, has predicted all-cause mortality in community-dwelling older adults infected with T. cruzi, independently of ECG abnormalities [68] . A strategy including ECG and BNP performed better than the classical approach with ECG and chest x-ray in the recognition of patients with left ventricular systolic dysfunction. Moreover, higher levels of BNP have prognostic value for stroke mortality in older adults [24] . Other biomarkers, such as troponin T [69] , brainderived neurotrophic factor [70] and TNF-α [71] correlate with severity of cardiac disease and can eventually be incorporated into clinical practice. Chest radiography

Many studies have shown that a cardiothoracic ratio of more than 0.5–0.55 is a consistent marker of increased mortality in Chagas cardiomyopathy [13,45–48] , probably representing an advanced stage of heart failure. Pulmonary congestion on chest x-ray seems to be less marked in patients with Chagas cardiomyopathy than in patients with dilated cardiomyopathy of other etiologies. Echocardiogram

Echocardiography is considered a useful complementary method for initial approach and follow-ups of patients with chronic Chagas disease. Several prognostic echocardiographic parameters have been described, most of them related to left ventricular function. 1177

Review


Viotti et al. carried out a prospective study evaluating ten echocardiographic factors as markers of adverse prognosis and found that both left ventricular systolic dimension and ejection fraction were independent prognostic markers of mortality [13] . However, it is important to note that sustained ventricular tachycardia, the main cause of sudden death in Chagasic patients, may occur in patients with preserved left ventricular function [72] . Although less well studied, right ventricular dysfunction is associated with increased mortality in Chagas cardiomyopathy (Figure 3) [73] . Nunes et al. found that right ventricular dysfunction was a powerful predictor of death, adding incremental prognostic value to NYHA functional class and left ventricular ejection fraction [30,74] . Parameters of abnormal diastolic function have also been studied in Chagas cardiomyopathy. Left atrial volume normalized for body surface area [75] and left atrial dimension [76] correlated with increased mortality in Chagas disease. Recently, a study has demonstrated the value of the ratio of early transmitral velocity to tissue Doppler mitral annular early diastolic velocity (E/e’) in predicting mortality in Chagas cardiomyopathy. The E/e’ ratio had a stronger prognostic value in patients with mild and moderate left ventricular dysfunction and was inversely associated with mortality in patients with advanced systolic heart failure due to Chagas cardiomyopathy [77] . Invasive ventriculography

Some studies assessed different ventriculographic factors as predictors of mortality in Chagas disease [49,55] . Reduced left ventricular ejection fraction, increased end-systolic stress, increased end-diastolic volume and left ventricular aneurysm or dysfunction were all associated with worse outcomes. These factors have not been evaluated in other studies and their role in independently

predicting adverse outcomes in comparison to the several other markers of left ventricular dysfunction is unknown. Electrophysiology study

There are limited data on electrophysiologic study as a predictor of increased mortality in Chagas cardiomyopathy. Leite et al. [48] assessed eletrophysiologic testing in patients presenting with spontaneous sustained ventricular tachycardia after oral loading with class III antiarrhythmic drugs. In patients with inducible nontolerated VT, the prognosis was significantly worse than in patients with inducible tolerated or noninducible VT. In other clinical scenarios, the role of electrophysiology study is inferred from studies in different cardiomyopathies. Other factors

Other factors have been described to be associated with surrogates for death, such as progression to heart failure or sustained VT, and are probably associated with increased mortality. Rochitte et al. [78] showed that myocardial delayed enhancement by MRI enables quantification of myocardial fibrosis and parallels left ventricular dysfunction. In addition, myocardial delayed enhancement was present in all patients with ventricular tachycardia, supporting the role of re-entry as the electrophysiologic substrate of this arrhythmia. Previous studies have shown that patients with Chagas cardio myopathy may have fixed or reversible perfusion defects on myocardial perfusion scintigraphy, even in patients with normal coronary arteries [79,80] . The increase in perfusion defects correlated with progression of left ventricular systolic dysfunction [81] . Furthermore, the amount of sympathetically denervated viable myocardium, assessed by 123I-metaiodobenzylguanidine scintigraphy, is associated with the occurrence of sustained ventricular tachycardia [82] . Scores for risk stratification

LV

LV

RV

RV

RA

LA

RA

LA

Figure 3. Two-dimensional echocardiogram apical four-chamber views of Chagas cardiomyopathy patients. Both patients have dilated and a diffusely hypokinetic left ventricle but with different degree of right ventricular involvement. The right ventricle is normal (on the left) and severely impaired (on the right). LA: Left atrium; LV: Left ventricle; RA: Right atrium; RV: Right ventricle.

1178

The identification of markers of poor prognosis in Chagas disease is essential for clinical decision making. However, the risk stratification continues to be a great challenge [83,84] . Several demographic, clinical and noninvasive variables have been tested. A few studies have used these variables to build a risk score. Viotti et al. demonstrated that age, left ventricular systolic diameter, intraventricular conduction abnormalities, sustained ventricular tachycardia and treatment with benznidazole were predictors of heart disease progression. These variables were used to construct clinical risk scores [85] . The scores assigned to each variable are shown in Table 2 . The derived clinical risk score can be used to predict the progression of chronic myocarditis in patients with Chagas disease without heart failure. Expert Rev. Cardiovasc. Ther. 10(9), (2012)


Review

Table 2. Scores for risk stratification in Chagas disease. Study (year)

Risk factors for progression of cardiac disease

Points

Viotti et al. (2005) [85]

Age older than 50 years

2

Systolic diameter more than 40 mm

3

Intraventricular conduction disorders

2

Sustained ventricular tachycardia

3

Benznidazole treatment

-2

Total points:

Risk of progression:

0

3.6%

1–3

6.9%

4–6

16.0%

7–10

52.5%

New York Heart Association class III or IV

5

Cardiomegaly (chest x-ray)

5

Segmental or global wall motion abnormality (echo)

3

Nonsustained ventricular tachycardia (24-h Holter)

3

Low QRS voltage (ECG)

2

Male sex

2

Total points:

5-year mortality:

10-year mortality:

0–6

2%

10%

7–11

18%

44%

12–20

63%

84%

Left ventricular ejection fraction 150 ms at SAECG (or QRS >133 ms at ECG)

1

Number of risk factors:

5-year mortality:

0–1

1%

2

20%

3

50%

Rassi Jr et al. (2006) [46]

Ribeiro et al. (2008) [60]

SAECG: Signal-averaged ECG.

Rassi et al. [45] developed a score to predict mortality in patients with Chagas heart disease that combines prognostic factors related to the main pathophysiologic features of the disease. The independent prognostic factors were identified, and each was assigned a number of points. Symptoms of heart failure, expressed as the NYHA class III or IV (five points), evidence of cardiomegaly on chest x-ray (five points), segmental or global wall motion abnormality on echocardiography (three points), NSVT on 24-h Holter monitoring or stress testing (three points), low QRS voltage on ECG (two points) and male sex (two points). A risk score derived by the combination of points attributed to each of these features accurately classified patients into a low-, medium- or high-risk group, with 10-year mortality rates of 10, 44 and 84%, respectively (Table 2) . This score was validated in two external cohorts [45,86] . However, among these variables, male sex and low QRS voltage were of borderline significance for the prediction of death www.expert-reviews.com

and their importance was not confirmed in other studies [46,47] . Moreover, to be calculated, this score needs data from several different diagnostic methods, including clinical examination, ECG, chest x-ray, echocardiogram and Holter monitoring or stress testing. Subsequently Ribeiro et al. [60] developed another risk score testing the value of a wide QRS complex in predicting risk of death in patients with Chagas disease. Three independent prognostic factors were identified: left ventricular ejection fraction 150 ms) filtered QRS complex (Table 2) . However, important and established risk factors for Chagas disease, such as NYHA class, were not selected in the final model because of the limited number of deaths [30,31,45] . In addition, the use of signal-averaged ECG is not used in many centers, which limits the routine use of this score. Considering this limitation, the 1179

Review


authors showed that if the prolonged filtered signal-averaged ECG QRS duration was substituted by standard ECG QRS d uration >133 ms, the model maintained its excellent performance. An important limitation of both risk-prediction models is that they were developed considering all-cause mortality as an end point. Sudden cardiac death, however, is the most common mode of death (55–65% of patients) in Chagas disease [28,61,87] . In general, sudden death predominates in patients with less extensive myocardial involvement, whereas death from pump failure is slightly more common in those with severe left ventricular systolic dysfunction [28,61] . Sudden death, but not death from progressive heart failure, is preventable by the implantation of cardiodefibrillators (Figure 1) and the development of a risk score specifically designed to recognize the risk of sudden death would be of great clinical value. Recently, studies assessing the long-term prognostic value of echocardiographic parameters in Chagas cardiomyopathy have identified other variables that can predict unfavorable outcome. A risk prediction model, taking into account a combination of four echocardiographic variables (left ventricular ejection fraction, left atrial volume, right ventricular function and E/e’ ratio) was able to identify four risk groups of patients according to the number of risk factors [75] . At 1-year follow-up, the event-free survival rate was 96% for patients with no echocardiographic risk factors versus 43% for those with three or more risk factors, with intermediate groups showing results between these figures. Although the risk stratification can improve by assessing these echocardiographic variables, this score gives the same weight for each parameter. In addition, as the echocardiographic assessment of right ventricle has limitations, the importance of right ventricular dysfunction may be underestimated. A mathematical model to describe time course of myocardial damage was also developed and validated [88] . This model introduces the concept that there is a direct proportionality between the extension of the initial insult and the progression rate of the disease. In this way, the progression of cardiac remodeling in Chagas disease is well explained by a modified logistic model. Nevertheless, this model may not be appropriate to describe possible oscillations in cardiac function during the course of the disease, taking into account that the treatment has impact on cardiac remodeling and survival. A main limitation of this mathematical model is the selection of patients with Chagas heart disease; it did not focus on the progression from the indeterminate to cardiac form of the disease. The prognosis of Chagas cardiomyopathy seems to be worse than idiopathic cardiomyopathy, independent of well-established markers of poor survival in heart failure [89] . Recently, a study has assessed the correlation between the Heart Failure Survival Score (HFSS) and classic prognostic tests for heart failure in a population with Chagas disease [90] . The HFSS combines data from different prognostic parameters to better assess risk in the heart failure population. In heart failure patients with Chagas disease, the HFSS correlated well with the cardiopulmonary test variables, 6-min walking test, left ventricle ejection fraction and left atrium diameter. The authors highlighted that the HFSS 1180

might be an useful tool for prognostic assessment in heart failure due to Chagas disease. However, the HFSS score included patients with end-stage heart failure to select candidates for cardiac transplant. Conversely, the score to predict death in Chagas disease encompasses a wide spectrum of cardiac disease [45] . As Chagas cardiomyopathy has some peculiarities, specific scores enable b etter risk stratification. Several relevant prognostic tools have been developed to predict mortality in diverse clinical settings. In Chagas disease, risk assessment is an integral part of clinical decision making, especially for increasing the rational use of pharmaceutical-, procedure- or device-based therapies. Some proposed risk scores using a combination of prognostic factors have contributed to overall improvement in risk prediction. Expert commentary

Chagas disease is still an important cause of cardiac disease in many countries of Latin America and in several North America and European nations, due to the presence of infected immigrants from endemic regions. Chagas heart disease is the most important clinical form of the disease, since it is related both to morbidity and mortality. While most individuals do not develop clinically patent disease, a large percentage may develop severe cardiac forms that eventually lead to death. Although it is clear that immune mechanisms may have a role in determining whose patients will develop overt Chagas heart disease, these processes are not completely deciphered and more research is needed to fully elucidate these mechanisms. The discovery of host genetic elements that influence the development of different clinical forms of the disease and understanding environmental factors that may influence the host–parasite interactions are some of the key questions remaining to be answered. Moreover, very few follow-up studies of molecular biomarkers addressed their prognostic value in detecting early cardiac commitment in patients with Chagas disease without apparent cardiac disease. Indeed, early markers of higher risk of development of cardiopathy would be welcome. Concerning the recognition of markers of higher risk of death, several longitudinal studies helped to define a large number of variables of potential clinical usefulness. However, the hetero geneity of the studied populations and the paucity of confirmation of the prognostic value of some of these variables limit their utility in the clinical setting. Although a few prediction scores of the risk of death were developed, only one (which requires information from several diagnostic methods) was fully validated and is ready to use. The development of a simple risk score that could recognize the risk of sudden death is desirable, since it could help in the recognition of candidates for primary prevention of sudden death by the implantation of cardiodefibrillators. Five-year view

The following years will probably show us some important improvements in the knowledge of risk prediction in Chagas disease. More data will be available on the mechanisms involved in the evolution from the indeterminate form to clinical Expert Rev. Cardiovasc. Ther. 10(9), (2012)


syndromes, helping the recognition of the underlying parasito logical, immunological and genetic mechanisms. The value of markers of early cardiac involvement, such as regional contractility abnormalities on echocardiographic studies or complex ventricular arrhythmia in Holter monitoring or stress testing, should be confirmed and validated. New approaches in the research of molecular markers of disease progression during Chagas cardiomyopathy are required. These studies will guarantee the accurate assessment of disease progression using molecular markers that have been of importance in basic and translational studies. One of these approaches might be the study of parasite load by quantitative PCR in infected individuals and its possible correlation with cardiac damage. Further studies could help to define the value of classical risk factors for mortality in Chagas disease in specific populations, such as in the older and infected immigrants living outside endemic regions. Moreover, the value of blood biomarkers could be confirmed, especially those related to immunological

Review

and inflammatory processes. The expected publication of the results of a multicenter clinical trial on the effectiveness of specific trypanocidal therapy in Chagas disease could also define the value of the specific treatment – and the persistence of the parasitism – in the evolution of the disease. Finally, improvement is expected in the recognition of patients at high risk of sudden death and candidates to receive an implantable cardiac defibrillator. ‍Financial & competing interests disclosure

This study was partly supported by grants from Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq), Brasília, Brazil; and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Belo Horizonte, Brazil. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Chagas heart disease is the most severe manifestation of chronic Chagas disease, which affects 8–10 million persons mainly in Latin America. Typical clinical presentations include heart failure, cardiac arrhythmia and thromboembolism. • The determinants of progression to the cardiac form are largely unknown, but it is clear that the host’s immune response is decisive in this process. • Markers of early cardiac lesion – as regional contractility abnormalities on echocardiographic studies or complex ventricular arrhythmia in stress testing – are predictive of progression of early chronic Chagas heart disease. • There are several potential prognostic factors in Chagas cardiomyopathy assessed in different populations. The most important predictors of death are New York Heart Association functional class, left ventricular systolic dysfunction and nonsustained ventricular tachycardia, which reflect the severity of myocardial damage. • Some proposed risk scores using a combination of prognostic factors have contributed to overall improvement in risk prediction. A sixitem risk score that combines variables obtained by different methods was validated and may be useful in the clinical setting. Trypanosoma cruzi and routes of transmission of the disease.

References Papers of special interest have been highlighted as: • of interest •• of considerable interest 1

2

Biolo A, Ribeiro AL, Clausell N. Chagas cardiomyopathy – where do we stand after a hundred years? Prog. Cardiovasc. Dis. 52(4), 300–316 (2010). Schmunis GA, Yadon ZE. Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop. 115(1–2), 14–21 (2010).

3

Coura JR, Viñas PA. Chagas disease: a new worldwide challenge. Nature 465(7301), S6–S7 (2010).

4

Bern C, Kjos S, Yabsley MJ, Montgomery SP. Trypanosoma cruzi and Chagas’ disease in the USA. Clin. Microbiol. Rev. 24(4), 655–681 (2011).

•• Review of the epidemiology of Chagas disease in the USA, with special focus on the life cycle of


5

Prata A. Clinical and epidemiological aspects of Chagas disease. Lancet Infect. Dis. 1(2), 92–100 (2001).

•• An overview of epidemiology, clinical manifestation and management of Chagas disease. 6

Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet 375(9723), 1388–1402 (2010).

•

An overview of Chagas disease, with comments about antitrypanosomal treatment, cardiac and gastrointestinal management of symptoms.

7

Rocha MO, Teixeira MM, Ribeiro AL. An update on the management of Chagas cardiomyopathy. Expert Rev. Anti. Infect. Ther. 5(4), 727–743 (2007).

•

Comprehensive overview of management of Chagas cardiomyopathy, discussing specific treatment and management of the

main cardiac complications: heart failure, arrhythmias and embolic phenomena. 8

Coura JR. Chagas disease: what is known and what is needed – a background article. Mem. Inst. Oswaldo Cruz 102(Suppl. 1), 113–122 (2007).

9

Marin-Neto JA, Cunha-Neto E, Maciel BC, Simões MV. Pathogenesis of chronic Chagas heart disease. Circulation 115(9), 1109–1123 (2007).

10

Machado FS, Tyler KM, Brant F, Esper L, Teixeira MM, Tanowitz HB. Pathogenesis of Chagas disease: time to move on. Front. Biosci. (Elite Ed.) 4, 1743–1758 (2012).

11

Talvani A, Teixeira MM. Inflammation and Chagas disease some mechanisms and relevance. Adv. Parasitol. 76, 171–194 (2011).

12

Maguire JH, Hoff R, Sherlock I et al. Cardiac morbidity and mortality due to Chagas’ disease: prospective electrocardiographic study of a Brazilian

1181

Review


community. Circulation 75(6), 1140–1145 (1987). 13

14

15

16

28

Acquatella H. Echocardiography in Chagas heart disease. Circulation 115(9), 1124–1131 (2007).

Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas’ disease. Arq. Bras. Cardiol. 76(1), 75–96 (2001).

29

Ribeiro AL, Rocha MO. [Indeterminate form of Chagas disease: considerations about diagnosis and prognosis]. Rev. Soc. Bras. Med. Trop. 31(3), 301–314 (1998).

Coura JR, Borges-Pereira J. Chagas disease: 100 years after its discovery. A systemic review. Acta Trop. 115(1–2), 5–13 (2010). Rocha MO, Ribeiro AL, Teixeira MM. Clinical management of chronic Chagas cardiomyopathy. Front. Biosci. 8, e44–e54 (2003). Rassi A Jr, Rassi A, Little WC. Chagas’ heart disease. Clin. Cardiol. 23(12), 883–889 (2000).

18

Bestetti R. Stroke in a hospital-derived cohort of patients with chronic Chagas’ disease. Acta Cardiol. 55(1), 33–38 (2000).

20

30

Carod-Artal FJ, Ribeiro Lda S, Vargas AP. Awareness of stroke risk in Chagasic stroke patients. J. Neurol. Sci. 263(1–2), 35–39 (2007). Carod-Artal FJ, Gascon J. Chagas disease and stroke. Lancet Neurol. 9(5), 533–542 (2010).

22

Carod-Artal FJ. Stroke: a neglected complication of American trypanosomiasis (Chagas’ disease). Trans. R. Soc. Trop. Med. Hyg. 101(11), 1075–1080 (2007).

23

Carod-Artal FJ. Trypanosomiasis, cardiomyopathy and the risk of ischemic stroke. Expert Rev. Cardiovasc. Ther. 8(5), 717–728 (2010).

Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation 115(9), 1101–1108 (2007).

•

Systematic review of some observational studies evaluating predictors of mortality in Chagas disease. Impaired left ventricular function, New York Heart Association functional class III/ IV, cardiomegaly and nonsustained ventricular tachycardia were the most important predictors.

32

Paixão LC, Ribeiro AL, Valacio RA, Teixeira AL. Chagas disease: independent risk factor for stroke. Stroke 40(12), 3691–3694 (2009).

26

Nunes Mdo C, Barbosa MM, Rocha MO. Peculiar aspects of cardiogenic embolism in patients with Chagas’ cardiomyopathy: a transthoracic and transesophageal echocardiographic study. J. Am. Soc. Echocardiogr. 18(7), 761–767 (2005).

1182

Basquiera AL, Sembaj A, Aguerri AM et al. Risk progression to chronic Chagas cardiomyopathy: influence of male sex and of parasitaemia detected by polymerase chain reaction. Heart 89(10), 1186–1190 (2003).

33

Marin-Neto JA, Almeida Filho OC, Pazin-Filho A, Maciel BC. [Indeterminate form of Chagas’ disease. Proposal of new diagnostic criteria and perspectives for early treatment of cardiomyopathy]. Arq. Bras. Cardiol. 79(6), 623–627 (2002).

34

Ianni BM, Arteaga E, Frimm CC, Pereira Barretto AC, Mady C. Chagas’ heart disease: evolutive evaluation of electrocardiographic and echocardiographic parameters in patients with the indeterminate form. Arq. Bras. Cardiol. 77(1), 59–62 (2001).

Lima-Costa MF, Matos DL, Ribeiro AL. Chagas disease predicts 10-year stroke mortality in community-dwelling elderly: the Bambui cohort study of aging. Stroke 41(11), 2477–2482 (2010).

25

Rocha MO, Nunes MC, Ribeiro AL. Morbidity and prognostic factors in chronic Chagasic cardiopathy. Mem. Inst. Oswaldo Cruz 104(Suppl. 1), 159–166 (2009).

31

Carod-Artal FJ, Vargas AP, Horan TA, Nunes LG. Chagasic cardiomyopathy is independently associated with ischemic stroke in Chagas disease. Stroke 36(5), 965–970 (2005).

21

24

Nunes MC, Barbosa MM, Ribeiro AL, Barbosa FB, Rocha MO. Ischemic cerebrovascular events in patients with Chagas cardiomyopathy: a prospective follow-up study. J. Neurol. Sci. 278(1–2), 96–101 (2009).

Viotti RJ, Vigliano C, Laucella S et al. Value of echocardiography for diagnosis and prognosis of chronic Chagas disease cardiomyopathy without heart failure. Heart 90(6), 655–660 (2004).

17

19

27

35

36

Coura JR, de Abreu LL, Pereira JB, Willcox HP. [Morbidity in Chagas’ disease. IV. Longitudinal study of 10 years in Pains and Iguatama, Minas Gerais, Brazil]. Mem. Inst. Oswaldo Cruz 80(1), 73–80 (1985). Pazin-Filho A, Romano MM, Almeida-Filho OC et al. Minor segmental wall motion abnormalities detected in patients with Chagas’ disease have adverse

prognostic implications. Braz. J. Med. Biol. Res. 39(4), 483–487 (2006). 37

Viotti R, Vigliano C, Lococo B et al. Exercise stress testing as a predictor of progression of early chronic Chagas heart disease. Heart 92(3), 403–404 (2006).

•

Longitudinal study showing that complex ventricular arrhythmia observed during stress testing has prognostic value for the progression of early chronic Chagas heart disease.

38

Dutra WO, Gollob KJ. Current concepts in immunoregulation and pathology of human Chagas disease. Curr. Opin. Infect. Dis. 21(3), 287–292 (2008).

39

Wallukat G, Muñoz Saravia SG, Haberland A et al. Distinct patterns of autoantibodies against G-protein-coupled receptors in Chagas’ cardiomyopathy and megacolon. Their potential impact for early risk assessment in asymptomatic Chagas’ patients. J. Am. Coll. Cardiol. 55(5), 463–468 (2010).

40

Campelo V, Dantas RO, Simões RT et al. TNF microsatellite alleles in Brazilian Chagasic patients. Dig. Dis. Sci. 52(12), 3334–3339 (2007).

41

Fernández-Mestre MT, Montagnani S, Layrisse Z. Is the CCR5-59029-G/G genotype a protective factor for cardiomyopathy in Chagas disease? Hum. Immunol. 65(7), 725–728 (2004).

42

Calzada JE, Nieto A, Beraún Y, Martín J. Chemokine receptor CCR5 polymorphisms and Chagas’ disease cardiomyopathy. Tissue Antigens 58(3), 154–158 (2001).

•• A database derived and external validated score for predicting risk of death in Chagas cardiomyopathy. The risk factors were New York Heart Association class III or IV, cardiomegaly (chest x-ray), segmental or global wall motion abnormality (echocardiography), nonsustained ventricular tachycardia (24 h Holter), low QRS voltage (ECG) and male sex. 43

Barretto AC, Arteaga E, Mady C, Ianni BM, Bellotti G, Pileggi F. [Male sex. Prognostic factor in Chagas’ disease]. Arq. Bras. Cardiol. 60(4), 225–227 (1993).

44

Espinosa R, Carrasco HA, Belandria F et al. Life expectancy analysis in patients with Chagas’ disease: prognosis after one decade (1973-1983). Int. J. Cardiol. 8(1), 45–56 (1985).

45

Rassi A Jr, Rassi A, Little WC et al. Development and validation of a risk score



therapy. J. Cardiovasc. Electrophysiol. 18(12), 1236–1240 (2007).

for predicting death in Chagas’ heart disease. N. Engl. J. Med. 355(8), 799–808 (2006).

55

46

Rodriguez-Salas LA, Klein E, Acquatella H et al. Echocardiographic and clinical predictors of mortality in chronic Chagas’ disease. Echocardiography 15(3), 271–278 (1998).

Espinosa RA, Pericchi LR, Carrasco HA, Escalante A, Martínez O, González R. Prognostic indicators of chronic Chagasic cardiopathy. Int. J. Cardiol. 30(2), 195–202 (1991).

56

47

Salles G, Xavier S, Sousa A, HasslocherMoreno A, Cardoso C. Prognostic value of QT interval parameters for mortality risk stratification in Chagas’ disease: results of a long-term follow-up study. Circulation 108(3), 305–312 (2003).

Topilski I, Rogowski O, Rosso R et al. The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias. J. Am. Coll. Cardiol. 49(3), 320–328 (2007).

57

Shimizu M, Ino H, Okeie K et al. T-peak to T-end interval may be a better predictor of high-risk patients with hypertrophic cardiomyopathy associated with a cardiac troponin I mutation than QT dispersion. Clin. Cardiol. 25(7), 335–339 (2002).

•

Prospective study demonstrating that ventricular conduction defects during the early stages of infection were predictors of progressive ECG changes and mortality.

58

Haarmark C, Hansen PR, Vedel-Larsen E et al. The prognostic value of the Tpeak-Tend interval in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. J. Electrocardiol. 42(6), 555–560 (2009).

48

49

50

51

52

53

54

Leite LR, Fenelon G, Simoes A Jr, Silva GG, Friedman PA, de Paola AA. Clinical usefulness of electrophysiologic testing in patients with ventricular tachycardia and chronic Chagasic cardiomyopathy treated with amiodarone or sotalol. J. Cardiovasc. Electrophysiol. 14(6), 567–573 (2003). Carrasco HA, Parada H, Guerrero L, Duque M, Durán D, Molina C. Prognostic implications of clinical, electrocardiographic and hemodynamic findings in chronic Chagas’ disease. Int. J. Cardiol. 43(1), 27–38 (1994). Moya A, Sutton R, Ammirati F et al.; Task Force for the Diagnosis and Management of Syncope; European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA); Heart Failure Association (HFA); Heart Rhythm Society (HRS). Guidelines for the diagnosis and management of syncope (version 2009). Eur. Heart J. 30(21), 2631–2671 (2009). Martinelli Filho M, Sosa E, Nishioka S, Scanavacca M, Bellotti G, Pileggi F. Clinical and electrophysiologic features of syncope in chronic Chagasic heart disease. J. Cardiovasc. Electrophysiol. 5(7), 563–570 (1994). Bestetti RB, Otaviano AP, Cardinalli-Neto A, da Rocha BF, Theodoropoulos TA, Cordeiro JA. Effects of β-blockers on outcome of patients with Chagas’ cardiomyopathy with chronic heart failure. Int. J. Cardiol. 151(2), 205–208 (2011). Theodoropoulos TA, Bestetti RB, Otaviano AP, Cordeiro JA, Rodrigues VC, Silva AC. Predictors of all-cause mortality in chronic Chagas’ heart disease in the current era of heart failure therapy. Int. J. Cardiol. 128(1), 22–29 (2008). Cardinalli-Neto A, Bestetti RB, Cordeiro JA, Rodrigues VC. Predictors of all-cause mortality for patients with chronic Chagas’ heart disease receiving implantable cardioverter defibrillator


59

60

61

62

63

Review

64

de Paola AA, Gomes JA, Terzian AB, Miyamoto MH, Martinez Fo EE. Ventricular tachycardia during exercise testing as a predictor of sudden death in patients with chronic Chagasic cardiomyopathy and ventricular arrhythmias. Br. Heart J. 74(3), 293–295 (1995).

65

Pedrosa RC, Salles JH, Magnanini MM, Bezerra DC, Bloch KV. Prognostic value of exercise-induced ventricular arrhythmia in Chagas’ heart disease. Pacing Clin. Electrophysiol. 34(11), 1492–1497 (2011).

66

Moreira Mda C, Wang Y, HeringerWalther S, Wessel N, Walther T. Prognostic value of natriuretic peptides in Chagas’ disease: a head-to-head comparison of the 3 natriuretic peptides. Congest. Heart Fail. 15(2), 75–81 (2009).

67

Barbosa MM, Nunes Mdo C, Ribeiro AL, Barral MM, Rocha MO. N-terminal proBNP levels in patients with Chagas disease: a marker of systolic and diastolic dysfunction of the left ventricle. Eur. J. Echocardiogr. 8(3), 204–212 (2007).

68

Panikkath R, Reinier K, Uy-Evanado A et al. Prolonged Tpeak-to-Tend interval on the resting ECG is associated with increased risk of sudden cardiac death. Circ. Arrhythm. Electrophysiol. 4(4), 441–447 (2011).

Lima-Costa MF, Cesar CC, Peixoto SV, Ribeiro AL. Plasma B-type natriuretic peptide as a predictor of mortality in community-dwelling older adults with Chagas disease: 10-year follow-up of the Bambui Cohort Study of Aging. Am. J. Epidemiol. 172(2), 190–196 (2010).

69

Ribeiro AL, Cavalvanti PS, Lombardi F, Nunes Mdo C, Barros MV, Rocha MO. Prognostic value of signal-averaged electrocardiogram in Chagas disease. J. Cardiovasc. Electrophysiol. 19(5), 502–509 (2008).

Saravia SG, Haberland A, Bartel S et al. Cardiac troponin T measured with a highly sensitive assay for diagnosis and monitoring of heart injury in chronic Chagas disease. Arch. Pathol. Lab. Med. 135(2), 243–248 (2011).

70

Sarabanda AV, Marin-Neto JA. Predictors of mortality in patients with Chagas’ cardiomyopathy and ventricular tachycardia not treated with implantable cardioverter–defibrillators. Pacing Clin. Electrophysiol. 34(1), 54–62 (2011).

Martinelli PM, da Costa Rocha MO, Teixeira AL, do Carmo Pereira Nunes M, da Silva Camargos ER. Brain-derived neurotrophic factor is up regulated in chronic Chagas disease. Int. J. Cardiol. 149(2), 277–278 (2011).

71

Cunha-Neto E, Nogueira LG, Teixeira PC et al. Immunological and nonimmunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy. Mem. Inst. Oswaldo Cruz 104(Suppl. 1), 252–258 (2009).

72

Sternick EB, Martinelli M, Sampaio R et al. Sudden cardiac death in patients with chagas heart disease and preserved left ventricular function. J. Cardiovasc. Electrophysiol. 17(1), 113–116 (2006).

73

Nunes Mdo C, Barbosa Mde M, Brum VA, Rocha MO. Morphofunctional characteristics of the right ventricle in

Ribeiro AL, Rocha MO, Terranova P, Cesarano M, Nunes MD, Lombardi F. T-wave amplitude variability and the risk of death in chagas disease. J. Cardiovasc. Electrophysiol. 22(7), 799–805 (2011). Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas’ cardiomyopathy. Circulation 90(6), 3098–3102 (1994).

1183

Review


Chagas’ dilated cardiomyopathy. Int J Cardiol. 94, 79–85 (2004). 74

75

Nunes Mdo C, Rocha MO, Ribeiro AL et al. Right ventricular dysfunction is an independent predictor of survival in patients with dilated chronic Chagas’ cardiomyopathy. Int. J. Cardiol. 127(3), 372–379 (2008). Nunes MC, Barbosa MM, Ribeiro AL, Colosimo EA, Rocha MO. Left atrial volume provides independent prognostic value in patients with Chagas cardiomyopathy. J. Am. Soc. Echocardiogr. 22(1), 82–88 (2009).

76

Bestetti RB, Dalbo CM, Arruda CA, Correia Filho D, Freitas OC. Predictors of sudden cardiac death for patients with Chagas’ disease: a hospital-derived cohort study. Cardiology 87(6), 481–487 (1996).

77

Nunes MP, Colosimo EA, Reis RC et al. Different prognostic impact of the tissue Doppler-derived E/e’ ratio on mortality in Chagas cardiomyopathy patients with heart failure. J. Heart Lung Transplant. 31(6), 634–641 (2012).

78

Rochitte CE, Oliveira PF, Andrade JM et al. Myocardial delayed enhancement by magnetic resonance imaging in patients with Chagas’ disease: a marker of disease severity. J. Am. Coll. Cardiol. 46(8), 1553–1558 (2005).

79

Marin-Neto JA, Marzullo P, Marcassa C et al. Myocardial perfusion abnormalities in chronic Chagas’ disease as detected by thallium-201 scintigraphy. Am. J. Cardiol. 69(8), 780–784 (1992).

1184

80

81

Simões MV, Pintya AO, Bromberg-Marin G et al. Relation of regional sympathetic denervation and myocardial perfusion disturbance to wall motion impairment in Chagas’ cardiomyopathy. Am. J. Cardiol. 86(9), 975–981 (2000). Hiss FC, Lascala TF, Maciel BC, Marin-Neto JA, Simões MV. Changes in myocardial perfusion correlate with deterioration of left ventricular systolic function in chronic Chagas’ cardiomyopathy. JACC. Cardiovasc. Imaging 2(2), 164–172 (2009).

•

A cross-sectional study assessing right ventricular function in patients with Chagas cardiomyopathy. Right ventricular dysfunction was evident when there was associated and significant involvement of the left ventricle and pulmonary hypertension.

82

Miranda CH, Figueiredo AB, Maciel BC, Marin-Neto JA, Simões MV. Sustained ventricular tachycardia is associated with regional myocardial sympathetic denervation assessed with 123I-metaiodobenzylguanidine in chronic Chagas cardiomyopathy. J. Nucl. Med. 52(4), 504–510 (2011).

83

84

Rassi Jr A, Rassi A, Marin-Neto JA. Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Mem. Inst. Oswaldo Cruz 104(Suppl. 1), 152–158 (2009). Nunes MC, Reis RC, Colosimo EA et al. Risk estimation approach in Chagas disease is still needed. Int. J. Cardiol. 147(2), 294–296 (2011).

85

Viotti R, Vigliano C, Lococo B et al. [Clinical predictors of chronic Chagasic myocarditis progression]. Rev. Esp. Cardiol. 58(9), 1037–1044 (2005).

86

Rocha MO, Ribeiro AL. A risk score for predicting death in Chagas’ heart disease. N. Engl. J. Med. 355(23), 2488–2489; author reply 2490 (2006).

87

Bestetti RB, Cardinalli-Neto A. Sudden cardiac death in Chagas’ heart disease in the contemporary era. Int. J. Cardiol. 131(1), 9–17 (2008).

88

Benchimol-Barbosa PR. Nonlinear mathematical model for predicting long-term cardiac remodeling in Chagas’ heart disease: introducing the concepts of ‘limiting cardiac function’ and ‘cardiac function deterioration period’. Int. J. Cardiol. 145(2), 219–221 (2010).

89

Pereira Nunes Mdo C, Barbosa MM, Ribeiro AL, Amorim Fenelon LM, Rocha MO. Predictors of mortality in patients with dilated cardiomyopathy: relevance of chagas disease as an etiological factor. Rev. Esp. Cardiol. 63(7), 788–797 (2010).

90

Ritt LE, Carvalho AC, Feitosa GS et al. Heart failure survival score in patients with Chagas disease: correlation with functional variables. Rev. Esp. Cardiol. 65(6), 538–543 (2012).

91

Benchimol-Barbosa PR. Noninvasive prognostic markers for cardiac death and ventricular arrhythmia in long-term follow-up of subjects with chronic Chagas’ disease. Braz. J. Med. Biol. Res. 40(2), 167–178 (2007).
