Prevalence and factors associated with impaired left ventricular global longitudinal strain in patients with Chagas disease: SaMi-Trop cohort study.

Cardiomyopathy is a major cause of death in Chagas disease and early detection of cardiac involvement is essential. Myocardial strain is a reliable technique for assessment of subtle left ventricular (LV) contractility alterations. This study assessed LV global longitudinal strain (GLS) in a large Chagas disease population living in remote areas. Between 2015 and 2016, Chagas disease patients were selected in the northern of the Minas Gerais state. All patients underwent T. cruzi antibodies tests and those who had positive tests were included. A resting 12-lead ECG was recorded and classified using the Minnesota Code criteria. Echocardiography was performed at public health primary care units and speckle-tracking strain was analyzed offline. LV dysfunction was defined as ejection fraction (LVEF < 50%) and reduced GLS was defined as < 16% (absolute value). A total of 1387 patients were included, mean age of 60.0 ± 12.5 years, 68% were women, and 14% had LV dysfunction. Among patients with normal LVEF, 59% had impaired LV GLS. Overall, patients with impaired GLS were older, had more comorbidities and ECG abnormalities than those with normal GLS. The independent factors associated with reduced GLS were ST-T abnormalities (OR 1.954; 95% CI 1.027-3.718), QRS duration (OR 1.009; 95% CI 1.002-1.016), LVEF (OR 0.947; 95% CI 0.923-0.972), and E/e' ratio (OR 1.059; 95% CI 1.009-1.112). In a cohort of Chagas disease from endemic areas, impaired LV GLS was detected in a significant proportion of patients, despite normal ECG and preserved LVEF. The main determinants of reduced LV GLS were ST-T abnormalities, QRS duration, LVEF and E/e' ratio, adjusting for demographical and clinical data.

Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease.

Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. METHODS: We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. RESULTS: We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction. CONCLUSION: Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

Speckle tracking echocardiographic deformation indices in Chagas and idiopathic dilated cardiomyopathy: Incremental prognostic value of longitudinal strain.

BACKGROUND: Chagas cardiomyopathy (CDC) is associated with a poor prognosis compared to other cardiomyopathies. Speckle tracking echocardiography (STE), which provides direct assessment of myocardial fiber deformation, may be useful in predicting prognosis. OBJECTIVE: This study assessed STE in CDC and compared with idiopathic cardiomyopathy (IDC), and also examined the incremental prognostic information of STE over left ventricular ejection fraction (LVEF) in these patients. METHODS: We enrolled 112 patients, age of 56.7 ± 11.8 years, 81 with CDC and 31 with IDC. STE indices were obtained at baseline in all patients. The endpoint was a composite of death, hospitalization for heart failure, or need for heart transplantation. RESULTS: Patients with IDC had worse LV systolic function compared to CDC, with LVEF of 34.5% vs 41.3%, p = 0.004, respectively. After adjustment for LVEF, there were no differences in STE values between CDC and IDC. During a median follow-up of 18.2 months (range, 11 to 22), 26 patients met the composite end point (24%). LV longitudinal strain was a strong predictor of adverse events, incremental to LVEF and E/e' ratio (HR 1.463, 95% CI 1.130-1.894; p = 0.004). The risk of cardiac events increased significantly in patients with GLS > - 12% (log-rank p = 0.035). CONCLUSIONS: STE indices were abnormal in patients with dilated cardiomyopathy, without differences between CDC and IDC. LV longitudinal strain was a powerful predictor of outcome, adding prognostic information beyond that provided by LVEF and E/e' ratio.