Inspiratory muscle endurance is similarly reduced in the early and late stages of chronic Chagas heart disease.

OBJECTIVE: Inspiratory muscle strength (IMS) appears to be reduced in subjects with chronic Chagas heart disease (CHD), especially in the presence of heart failure (HF). However, only one study about IMS and inspiratory muscle endurance (IME) in those with CHD without heart failure is available. This study aimed to compare IMS and IME in subjects with CHD in the presence and absence of HF. METHODS: This is a cross-sectional study in which 30 CHD adult patients were divided into CHD-CC group (initial phase of CHD, without HF; n = 15) and CHD-HF group (advanced phase of CHD, with HF; n = 15). We assessed IMS by maximum inspiratory pressure (MIP) and IME by incremental (Pthmax) and constant load (TLim) tests. Reduced IMS and IME were considered by predicted MIP values <70% and Pthmax/MIP <75%, respectively. RESULTS: Inspiratory muscle weakness (IMW) was more frequent in CHD-HF than in CHD-CC (46.7% vs. 13.3%; p = 0.05), and both groups had high frequencies of reduced IME (93.3% CHD-CC vs. 100.0% CHD-HF; p = 0.95). Age-adjusted logistic regression analysis using HF as a dependent variable showed that HF was associated with an increased chance of IMW compared with the CHD-CC group (OR = 7.47; p = 0.03; 95% CI 1.20-46.19). CONCLUSION: This study suggests that, in patients with CHD, HF is associated with IMW, and that reduction of IME is already present in the initial phase, similar to the advanced phase with HF.

Chagas Cardiomyopathy and Myocardial Sympathetic Denervation.

PURPOSE OF REVIEW: More than a century since its discovery, the pathogenesis of Chagas heart disease (CHD) remains incompletely understood. The role of derangements in the autonomic control of the heart in triggering malignant arrhythmia before the appearance of contractile ventricular impairment was reviewed. RECENT FINDINGS: Although previous investigations had demonstrated the anatomical and functional consequences of parasympathetic dysautonomia upon the heart rate control, only recently, coronary microvascular disturbances and sympathetic denervation at the ventricular level have been reported in patients and experimental models of CHD, exploring with nuclear medicine methods their impact on the progression of myocardial dysfunction and cardiac arrhythmias. More important than parasympathetic impaired sinus node regulation, recent evidence indicates that myocardial sympathetic denervation associated with coronary microvascular derangements is causally related to myocardial injury and arrhythmia in CHD. Additionally, 123I-MIBG imaging is a promising tool for risk stratification of progression of ventricular dysfunction and sudden death.

Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease.

Chagas Disease (CD) is one of the leading causes of heart failure and sudden death in Latin America. Treatments with antioxidants have provided promising alternatives to ameliorate CD. However, the specific roles of major reactive oxygen species (ROS) sources, including NADPH-oxidase 2 (NOX2), mitochondrial-derived ROS and nitric oxide (NO) in the progression or resolution of CD are yet to be elucidated. We used C57BL/6 (WT) and a gp91PHOX knockout mice (PHOX-/-), lacking functional NOX2, to investigate the effects of ablation of NOX2-derived ROS production on the outcome of acute chagasic cardiomyopathy. Infected PHOX-/- cardiomyocytes displayed an overall pro-arrhythmic phenotype, notably with higher arrhythmia incidence on ECG that was followed by higher number of early afterdepolarizations (EAD) and 2.5-fold increase in action potential (AP) duration alternans, compared to AP from infected WT mice. Furthermore, infected PHOX-/- cardiomyocytes display increased diastolic [Ca2+], aberrant Ca2+ transient and reduced Ca2+ transient amplitude. Cardiomyocyte contraction is reduced in infected WT and PHOX-/- mice, to a similar extent. Nevertheless, only infected PHOX-/- isolated cardiomyocytes displayed significant increase in non-triggered extra contractions (appearing in ~75% of cells). Electro-mechanical remodeling of infected PHOX-/-cardiomyocytes is associated with increase in NO and mitochondria-derived ROS production. Notably, EADs, AP duration alternans and in vivo arrhythmias were reverted by pre-incubation with nitric oxide synthase inhibitor L-NAME. Overall our data show for the first time that lack of NOX2-derived ROS promoted a pro-arrhythmic phenotype in the heart, in which the crosstalk between ROS and NO could play an important role in regulating cardiomyocyte electro-mechanical function during acute CD. Future studies designed to evaluate the potential role of NOX2-derived ROS in the chronic phase of CD could open new and more specific therapeutic strategies to treat CD and prevent deaths due to heart complications.

Exercise training improves microvascular function in patients with Chagas heart disease: Data from the PEACH study.

BACKGROUND: Chagas heart disease (CHD) impairs the systemic microvascular function. We investigated the effects of exercise training on cutaneous microvascular function among patients with CHD. METHODS: Patients from the PEACH study were randomly assigned to a supervised exercise training 3 times/week for 6 months (Trained; n = 10) or a control group (Untrained; n = 8). Both groups underwent evaluation of microvascular function before, and at 3- and 6-months of follow-up. Cutaneous vascular conductance (CVC) was assessed in the skin of the forearm using laser speckle contrast imaging coupled with iontophoresis of acetylcholine (ACh), sodium nitroprusside (SNP) and during post-occlusive reactive hyperemia (PORH). RESULTS: At 3-months of follow-up, no difference was detected between groups in CVC responses to ACh (p = 0.50), SNP (p = 0.26) and HRPO (p = 0.65). However, at 6-months of follow-up, trained vs. untrained patients improved CVC induced by SNP-iontophoresis (0.19 ± 0.10 vs. 0.14 ± 0.15 APU.mmHg-1; p = 0.05) and PORH (0.63 ± 0.15 vs. 0.48 ± 0.18 APU.mmHg-1; p = 0.05). CVC response to ACh-iontophoresis was similar between groups (0.19 ± 0.11 vs. 0.22 ± 0.17 APU.mmHg-1; p = 0.38). CONCLUSION: Exercise training performed during 6 months improved the cutaneous microvascular function of CHD patients. Further studies evaluating the mechanism involved in this response are warranted.

Accuracy of health-related quality of life in identifying systolic dysfunction in patients with Chagas cardiomyopathy.

OBJECTIVE: Systolic dysfunction is a well-established marker of mortality in patients with Chagas cardiomyopathy (CC). However, its diagnosis is expensive and useful tools for screening these patients are required. The evaluation of the health-related quality of life (HRQoL) detects the patient's perception of the disease's impact. However, its accuracy in identifying patients with CC and systolic dysfunction is unknown. The study aimed to verify the sensitivity, specificity and predictive values of the physical and mental components related to HRQoL in identifying patients with CC and systolic dysfunction. METHODS: 75 patients with CC, aged 49 (95% confidence interval: 47-51) years, were evaluated by echocardiography and Short-Form of Health Survey (SF-36) questionnaire. Systolic dysfunction was defined by left ventricular ejection fraction <52% for men and <54% for women and left ventricular diastolic diameter >55 mm. RESULTS: Most patients (73%) had systolic dysfunction, with lower HRQoL values in the physical functioning, physical role functioning and general health perceptions domains and in the physical component summary. The accuracy of identifying patients with systolic dysfunction by the scores of physical components was 73% and 62% of mental components. The optimal cut-off point was 46 for physical and 54 for mental components, with respective positive predictive values of 91% and 80%. CONCLUSION: The evaluation of the HRQoL by the SF-36, a low-cost instrument, can be useful in identifying patients with systolic dysfunction, assisting in the screening and risk stratification of patients.

PARP1 depletion improves mitochondrial and heart function in Chagas disease: Effects on POLG dependent mtDNA maintenance.

Chagasic cardiomyopathy is caused by Trypanosoma cruzi infection. Poly(ADP-ribose) polymerase 1 (PARP1) is known for its function in nuclear DNA repair. In this study, we have employed genetic deletion and chemical inhibition approaches to determine the role of PARP1 in maintaining mtDNA dependent mitochondrial function in Chagas disease. Our data show that expression of PARP1 and protein PARylation were increased by >2-fold and >16-fold, respectively, in the cytosolic, nuclear, and mitochondrial fractions of the human cardiac myocytes and the myocardium of wildtype (WT) mice chronically infected with T. cruzi. The nuclear and cytosolic PARP1/PAR did not interfere with the transcription and translation of the components of the mtDNA replisome machinery in infected cardiomyocytes and chagasic murine myocardium. However, PARP1 binding to Polymerase γ and mtDNA in mitochondria were increased, and associated with a loss in mtDNA content, mtDNA-encoded gene expression, and oxidative phosphorylation (OXPHOS) capacity, and an increase in mitochondrial ROS production in cells and heart of WT mice infected with T. cruzi. Subsequently, an increase in oxidative stress, and cardiac collagen deposition, and a decline in LV function was noted in chagasic mice. Genetic deletion of PARP1 or treatment with selective inhibitor of PARP1 (PJ34) improved the mtDNA content, mitochondrial function, and oxidant/antioxidant balance in human cardiomyocytes and chronically infected mice. Further, PARP1 inhibition was beneficial in preserving the cardiac structure and left ventricular function in chagasic mice. We conclude that PARP1 overexpression is associated with a decline in Pol γ-dependent maintenance of mtDNA content, mtDNA-encoded gene expression, and mitochondrial respiratory function, and subsequently contributes to an increase in mtROS and oxidative stress in chagasic myocardium. Inhibition of mitochondrial PARP1/PAR offers a novel therapy in preserving the mitochondrial and LV function in chronic Chagas disease.

Ventricular arrhythmias in the Chagas disease are not random phenomena: Long-term monitoring in Chagas arrhythmias.

BACKGROUND: Variability of ventricular arrhythmias among days in patients with Chagas disease is not detected by 24 hours of Holter monitoring. OBJECTIVE: To analyze whether ventricular arrhythmias are a random phenomenon or have a reproducible behavior in patients with Chagas cardiomyopathy. METHOD: Holter monitoring was recorded in 16 subjects with a mean age of 52 ± 8 years. They were clinically stable and had ventricular couplets, isolated premature ventricular contractions (PVCs), and nonsustained ventricular tachycardia (NSVT). The recordings occurred for 7 days. Hurst exponent (HE) evaluated randomness and predictability index (PI) and repeated analysis of variance (ANOVA) assessed reproducibility. RESULTS: The HE was significantly greater than 0.5 in all 16 patients, which confirms the nonrandomness of arrhythmias in this Chagas sample. The PI for ventricular couplets and isolated PVCs was, on average, 38% and 54%, respectively. ANOVA with repeated measurement showed significant differences in the daily frequency of ventricular couplets (n = 15, P ≤ .05), isolated PVC (n = 12, P ≤ .05), and NSVT (n = 7, P ≤ .05). CONCLUSION: Ventricular arrhythmias in Chagas cardiomyopathy are not random. Dissimilarities in arrhythmias frequency make unlikely that 24 hours of Holter recording can capture this variability.

Chagas disease is associated with a worse prognosis at 1-year follow-up after implantable cardioverter-defibrillator for secondary prevention in heart failure patients.

INTRODUCTION: There are conflicting data regarding the efficacy of implantable cardioverter-defibrillator (ICD) in Chagas disease (CD) patients. This study aims to evaluate the short-term outcome after ICD for secondary prevention, in a population where CD is a prevalent cause of heart failure (HF). METHODS AND RESULTS: Consecutive patients with HF and reduced left ventricular ejection fraction (LVEF), who underwent ICD implantation for secondary prevention of SCD. Clinical and demographic data were collected to investigate mortality predictors at 1 year. During the study period, 117 patients underwent ICD implantation, of which 108 were included. The most frequent causes of HF was CD: 52 (48.1%) and ischemic cardiomyopathy: 20 (18.5%). Chagas and non-Chagas patients were well balanced-male: 32 (61.5%) vs 38 (67.9%), P = .548; age: 59.2 (±10.9) vs 56.8 (±13.4), P = .681; and LVEF: 34.1 (±0.2) vs 31.3 (±8.7), P = .064, respectively. At the mean follow-up of 15.7 months, overall mortality occurred in 14 (12.9%) patients, with a higher incidence in patients with CD cardiomyopathy, 11 (21.2%) vs 3 (5.4%), P = .021 (log-rank). In the multivariate analysis, CD remained as an independent predictor for death (hazard ratio: 4.62, confidence interval [95% CI]: 1.27-16.81, P = .021). CONCLUSION: CD was associated with a poor short-term outcome in patients with HF submitted to ICD implantation for secondary prevention when compared with other HF etiologies. In this specific HF population, ICD indication should be individualized, considering the worst prognosis of these patients.

Comparison of the amount and patterns of late enhancement in Chagas disease according to the presence and type of ventricular tachycardia.

BACKGROUND: Ventricular tachycardia (VT) is one of the main predictors of mortality in Chagas cardiomyopathy (CC). Although the substrate of sustained and nonsustained-VT (NS-VT) seems to be the same, little is known about the distribution of late enhancement (LE). Our aim was to compare the clinical findings and the amount and patterns of LE in Chagas disease according to the presence and type of VT. METHODS AND RESULTS: Magnetic resonance imaging was performed in 54 Chagas seropositive patients: 8 indeterminate and 46 with CC of whom 15 were without VT, 13 with NS-VT, and 18 with sustained-VT (S-VT). There were 31 males (57%), mean age was 55.9 ± 12.2 years. LE was found in 87% of all patients and in 50%, 80%, and 100% of the indeterminate, without VT and VT groups, respectively. The percentage of LE increased progressively in the indeterminate, CC without VT, and CC with VT groups; without a significant difference between NS-VT and S-VT (0.93%, 15.2%, 23.2%, and 21.4%, respectively). The amount of LE increased with the functional class. LE in the basal and mid lateral wall was more frequent in VT, without difference between S-VT and NS-VT. The only predictor of VT was the percentage of LE, odds ratio (OR), 6.2; (95% confidence interval [CI], 3.7-28.4; P = .01) with a cutoff of Odds Ratio 17.1%. CONCLUSIONS: The amount of LE increases in relation to the clinical stage of the disease and its functional class in Chagas seropositive patients. The amount of LE was the main predictor of VT, without difference between S-VT and NS-VT.

Renal denervation in patients with heart failure secondary to Chagas' disease: A pilot randomized controlled trial.

INTRODUCTION: Chagas disease is one of the most relevant endemic parasitic diseases in Latin America, affecting approximately 6 million people. Overt Chagas heart disease is an ominous condition, occurring in 20-30% of infected individuals, which has besides the persistent myocarditis a peculiar intracardiac ganglionic neuronal depletion and dysautonomy. This study aims to evaluate the safety and feasibility of renal denervation for patients with advanced symptomatic Chagas cardiomyopathy. METHODS: Open-label prospective pilot study that randomized patients with Chagas heart disease to either renal denervation or conservative treatment (2:1 ratio). The primary endpoint was the incidence of major adverse events at 9 months, defined as a composite of all-cause death, myocardial infarction, stroke, need for renal artery invasive treatment, or worsening renal function. RESULTS: A total of 17 patients were allocated for renal denervation (n = 11) or conservative treatment (n = 6). Included patients had severe symptomatic heart disease, with markedly depressed left ventricular function (average ejection fraction 26.7 ± 4.9%). For patients randomized to renal denervation, the procedure was performed successfully and uneventfully. After 9 months, the primary endpoint occurred in 36.4% of patients in the renal denervation group and 50.0% in the control arm (p = .6). After 9 months, clinical, laboratory, functional, echocardiographic, and quality of life parameters were similar between groups. CONCLUSIONS: This pilot study suggests that renal denervation is safe and feasible in patients with Chagas cardiomyopathy, warranting future studies to better evaluate the clinical efficacy of the interventional strategy in improving the prognosis of this high-risk population.

Myocardial fibrosis in chagas disease and molecules related to fibrosis.

Chronic Chagas cardiomyopathy (CCC) is responsible for the disease's greater morbidity and poor prognosis. Although understanding the pathophysiology of CCC and the fundamentals of its clinical management derives from research related to other cardiomyopathies, there are peculiarities that distinguish CCC from the others. CCC is the most fibrous heart disease, and its myocardial involvement is important as it disorganizes or disrupts the extracellular matrix, creating an environment conducive to the formation of arrhythmogenic foci. It is also considered the most arrhythmogenic of the known heart diseases, giving rise to complex arrhythmias, usually associated with varying degrees of stimulus conduction disorders. The central proposal of this review is to describe a possible association between the distribution and degree of myocardial fibrosis and cardiac arrhythmogenicity in patients with Chagas cardiomyopathy, drawing attention to the importance of noninvasive biomarkers for the quantification of myocardial fibrosis.

Dysregulation of insulin levels in Chagas heart disease is associated with altered adipocytokine levels.

Metabolic, inflammatory, and autonomic nervous system (ANS) dysfunction are present in patients with heart failure. However, whether these changes are due to left ventricular dysfunction or heart failure etiology is unknown. We evaluated metabolism and inflammatory activity in patients with idiopathic dilated cardiomyopathy (IDC) and Chagas cardiomyopathy (CHG) and their correlation with the ANS. Forty-six patients were divided into 3 groups: IDC, CHG, and control. We evaluated adiponectin, leptin, insulin, interleukin-6, and tumor necrosis factor-alpha. ANS were analyzed by heart rate variability in time and frequency domains on a 24-hour Holter monitor. Levels of glucose, cholesterol, leptin, and adiponectin did not show differences between groups. Insulin levels were lower in CHG group (5.4 ± 3.3 µU/mL) when compared with control (8.0 ± 4.9 µU/mL) and IDC (9.9 ± 5.0 µU/mL) groups (p = 0.007). Insulin was positively associated with LFr/HFr ratio (r = 0.562; p = 0.029) and with the LFr component (r = 0.562; p = 0.029) and negatively associated with adiponectin (r = -0.603; p = 0.017) in CHG group. The addition of an adiponectin unit reduced average insulin by 0.332 µg/mL. Insulin levels were decreased in the CHG group when compared with the IDC group and were associated with ANS indexes and adiponectin levels.

Physiological and unappreciated roles of CaMKII in the heart.

In the cardiomyocyte, CaMKII has been identified as a nodal influencer of excitation-contraction and also excitation-transcription coupling. Its activity can be regulated in response to changes in intracellular calcium content as well as after several post-translational modifications. Some of the effects mediated by CaMKII may be considered adaptive, while effects of sustained CaMKII activity may turn into the opposite and are detrimental to cardiac integrity and function. As such, CaMKII has long been noted as a promising target for pharmacological inhibition, but the ubiquitous nature of CaMKII has made it difficult to target CaMKII specifically where it is detrimental. In this review, we provide a brief overview of the physiological and pathophysiological properties of CaMKII signaling, but we focus on the physiological and adaptive functions of CaMKII. Furthermore, special consideration is given to the emerging role of CaMKII as a mediator of inflammatory processes in the heart.

Dysregulated Network of Immune, Endocrine and Metabolic Markers is Associated to More Severe Human Chronic Chagas Cardiomyopathy.

Individuals who are infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC), which is a complication involving a series of immune pathogenetic mechanisms, although an association between immune and metabolic alterations was more recently proposed. Accordingly, we investigated the immuno-metabolic response in chagasic patients and their possible influence on CCC pathogenesis. To this end, T. cruzi-seropositive (asymptomatic or with CCC) and sero-negative individuals were studied. Serum tumour necrosis factor (TNF)-α, interleukin (IL)-6, adipocytokines and the expression of their receptors in peripheral blood mononuclear cell (PBMC) were evaluated, together with other factors influencing the immune response. CCC patients showed major metabolic and hormonal abnormalities, in parallel with increased IL-6 and leptin serum levels. TNF-α receptor s, leptin and adiponectin receptors (ObR and Adipo-Rs respectively), as well as PPAR-γ expression in PBMCs from CCC patients were compatible with a counteracting response leading to an unfavourable immune-metabolic profile. These results suggest that persistently increased levels of immune-metabolic pro-inflammatory mediators along with the adverse endocrine anti-inflammatory response of CCC individuals, may contribute to the underlying mechanisms dealing with myocardial tissue damage.

A cohort study of cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy.

Aims: Cardiac resynchronization therapy (CRT) is an established procedure for patients with heart failure. However, trials evaluating its efficacy did not include patients with chronic Chagas cardiomyopathy (CCC). We aimed to assess the role of CRT in a cohort of patients with CCC. Methods and results: This retrospective study compared the outcomes of CCC patients who underwent CRT with those of dilated (DCM) and ischaemic cardiomyopathies (ICM). The primary endpoint was all-cause mortality and the secondary endpoints were the rate of non-advanced New York Heart Association (NYHA) class 12 months after CRT and echocardiographic changes evaluated at least 6 months after CRT. There were 115 patients in the CCC group, 177 with DCM, and 134 with ICM. The annual mortality rates were 25.4%, 10.4%, and 11.3%, respectively (P < 0.001). Multivariate analysis adjusted for potential confounders showed that the CCC group had a two-fold [hazard ratio 2.34 (1.47-3.71), P < 0.001] higher risk of death compared to the DCM group. The rate of non-advanced NYHA class 12 months after CRT was significantly higher in non-CCC groups than in the CCC group (DCM 74.0% vs. ICM 73.9% vs. 56.5%, P < 0.001). Chronic Chagas cardiomyopathy and ICM patients had no improvement in the echocardiographic evaluation, but patients in the DCM group had an increase in left ventricular ejection fraction and a decrease in left ventricular end-diastolic diameter. Conclusion: This study showed that CCC patients submitted to CRT have worse prognosis compared to patients with DCM and ICM who undergo CRT. Studies comparing CCC patients with and without CRT are warranted.

Dysautonomy in different death risk groups (Rassi score) in patients with Chagas heart disease.

BACKGROUND: It has been difficult to prove that "catecholamine-induced cardiomyopathy" contributes to the mechanism of sudden cardiac death in Chagas heart disease. Also, it is almost impossible to rule out the possibility that it is not involved in the process. More importantly, the vagal-cholinergic pathway in the ventricle plays a direct role in the prevention of the initiation of complex ventricular arrhythmias, including nonsustained ventricular tachycardia, ventricular fibrillation responsible for sudden death. OBJECTIVE: To determine frequency of parasympathetic autonomic indices among the different groups of risk of cardiovascular death when stratified by Rassi score. METHODS: Patients with Chagas heart disease were selected and divided into three risk groups by Rassi score. A fourth group, non-Chagas group, was of similar age and gender. All were subjected to analysis of heart rate variability during controlled breathing (RSA) and tilt table passive test (tilt test). High frequency and low frequency/high frequency ratio were calculated and presented by box-plot. Also, t-test was used to compare the two groups. RESULTS: It was observed that the parasympathetic and sympathetic component were affected, when the risk group increased the response was worsened to the stimulus (RSA or Tilt). Also, the low-risk group was jeopardized, when compared to the non-Chagas group. CONCLUSION: The loss of parasympathetic modulation was present in all Rassi risk groups, including the low risk, indicating that a morphological change of the myocardium represents a detectable neurofunctional change.

Cardiac autonomic modulation and long-term use of amiodarone in patients with chronic Chagasic cardiopathy.

BACKGROUND: Patients with chronic Chagas cardiopathy (CCC), which may be associated with cardiac arrhythmias, frequently use amiodarone, an antiarrhythmic drug that, experimentally, appears to modulate the cardiac autonomic function. OBJECTIVE: The present cross-sectional observational study aimed to evaluate autonomic cardiac modulation in patients with CCC undergoing chronic amiodarone therapy. METHODS: Three groups were investigated: Group 1 included patients with CCC not treated with amiodarone (n = 27); Group 2 included patients with CCC with prolonged use (at least 6 months) of amiodarone (n = 16); and Group 3 included non-Chagasic control patients (n = 23). All patients underwent a complete clinical and laboratory assessment, followed by autonomic function tests, consisting of a basal continuous electrocardiogram in the resting supine position for 10 minutes, followed by a change the orthostatic posture for a further 5 minutes. Heart rate variability (HRV) parameters (median and interquartile interval) were quantified using linear methods in the time- and frequency-domains (autoregressive spectral analysis) and nonlinear methods, including symbolic analysis. RESULTS: Patients with CCC using amiodarone had changes in HRV suggestive of an offset in the sympatho-vagal balance with a vagal modulation predominance (normalized HF, 49.7[27.4] vs 31.1[22.8] [P < 0.05]; and percentage 2V, 40.1 [14.6] vs 21.5 [13.4] [P < 0.05] vs untreated CCC group). These changes were further accompanied by increases in parameters indicative of greater complexity of HRV. CONCLUSIONS: The deviation in the sympatho-vagal balance and the increase in the complexity of HRV strongly suggest that amiodarone may have a cardioprotective effect, in addition to its antiarrhythmic effects, which could increase the survival of these patients.

Prognostic value of serum brain-derived neurotrophic factor levels in patients with Chagas cardiomyopathy.

BACKGROUND: Serum brain-derived neurotrophic factor (BDNF) levels have been shown to be lower in patients with Chagas cardiomyopathy (ChC) than in patients with non-dilated chagasic cardiomyopathy. However, its prognostic value was not established in patients with ChC. METHODS: Forty-nine patients with ChC (50 ± 7 years, New York Heart Association "NYHA" I-III); were evaluated by echocardiography, exercise testing, and blood analysis. Serum BDNF levels were determined using enzyme-linked immunosorbent assay sandwich. Patients were followed-up, and cardiac death was considered the end-point. The survival analyses were performed using Kaplan-Meier and Cox regression. RESULTS: After 39 ± 14 months of follow-up, 12 patients (25%) died. The concentration of 2.5 ng/mL was the optimal cut-off value to predict survival with significant difference between the groups with low (≤ 2.5 ng/mL) and high (> 2.5 ng/mL) BDNF levels (p = 0.006). Lower serum BDNF levels (hazards ratio (HR) 1.1, 95% confidence interval (CI) 1.1-1.4; p = 0.001), peak oxygen uptake (HR 1.2, 95% CI 1.0-1.3; p = 0.009), and left ventricular ejection fraction (HR 0.8, 95% CI 0.7-0.9; p = 0.001) were the independent predictors of survival. The combination of low serum BDNF levels and reduced left ventricular ejection fraction were highly predictive of death (HR 5.6, 95% CI: 1.2-9.7; p = 0.026). CONCLUSION: In patients with ChC, reduced serum BDNF levels, especially if associated with systolic function, may provide useful prognostic information.

Association between typical electrocardiographic abnormalities and NT-proBNP elevation in a large cohort of patients with Chagas disease from endemic area.

Chagas cardiomyopathy is the most harmful complication of Chagas disease. The electrocardiogram is a well-studied exam and has been considered an important tool for detection and evaluation of Chagas cardiomyopathy since the first years of its description. Many of its abnormalities have been described as associated with a worse prognosis. Serum BNP levels were described as inversely related to the left ventricular ejection fraction and as an independent predictor of death. It was not reported how electrocardiographic alterations correlate to NT-proBNP and its analog. The present study aims to describe the baseline electrocardiograms of a large cohort of patients with Chagas disease from endemic area and to establish an association between the number of electrocardiogram alterations and high levels of NT-ProBNP in Chagas disease patients. This study selected 1959 Chagas disease patients in 21 municipalities within a limited region in the northern part of the State of Minas Gerais (Brazil), 1084 of them had Chagas cardiomyopathy. NT-proBNP levels were suggestive of heart failure in 11.7% of this population. One or more electrocardiographic alterations have an Odds Ratio of 9.12 (CI 95% 5.62-14.80) to have NT-proBNP elevation. Considering the association between the number of 1, 2, and 3 or more alterations in electrocardiogram and NT-proBNP elevation, the ORs were 7.11 (CI 95% 4.33-11.67); 16.04 (CI 95% 9.27-27.77) and 47.82 (CI 95% 17.98-127.20), respectively. The presence and the number of typical electrocardiographic alterations of Chagas disease are independently associated with the severity of the cardiomyopathy.

Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole-blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8+ T-cell cytotoxicity, separated the 2 groups. NK/CD8+ T-cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression.