Cardiac magnetic resonance imaging in Chagas' disease: a parallel with electrophysiologic studies.

Chagas' disease (CD), caused by the parasite Trypanosoma cruzi, is the leading cause of cardiac disability from infectious diseases in Central and South America. The disease progresses through an extended, asymptomatic form characterized by latency without clinical manifestations into a symptomatic form with cardiac and gastro-intestinal manifestations. In the terminal phase, chronic Chagas' myocarditis results in extensive myocardial fibrosis, chamber enlargement with aneurysms and ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) has proven useful in characterizing myocardial fibrosis (MF). Sub-epicardial and mid-wall fibrosis are less common patterns of MF in CHD than transmural scar, which resembles myocardial infarction. Commonly involved areas of MF include the left ventricular apex and basal infero-lateral wall, suggesting a role for watershed ischemia in the pathophysiology of MF. Electrophysiology studies have helped refine the relationship between MF and VT in this setting. This article reviews the patterns of MF in CHD and correlate these patterns with electrogram patterns to predict risk of ventricular arrhythmias and sudden death.

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-ß.

Chagas disease is caused by the trypanosomatid Trypanosoma cruzi, which chronically causes heart problems in up to 30% of infected patients. Chagas disease was initially restricted to Latin America. However, due to migratory events, this disease may become a serious worldwide health problem. During Chagas disease, many patients die of cardiac arrhythmia despite the apparent benefits of anti-arrhythmic therapy (e.g., amiodarone). Here, we assimilate the cardiac form of Chagas disease to an inflammatory cardiac disease. Evidence from the literature, mostly provided using experimental models, supports this view and argues in favor of new strategies for treating cardiac arrhythmias in Chagas disease by modulating cytokine production and/or action. But the complex nature of myocardial inflammation underlies the need to better understand the molecular mechanisms of the inflammatory response during Chagas disease. Here, particular attention has been paid to tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGF-ß) although other cytokines may be involved in the chagasic cardiomyopathy.

Use of Noninvasive Parameters to Evaluate Swiss Webster Mice During Trypanosoma cruzi Experimental Acute Infection.

Until now, there has been neither an agreed-upon experimental model nor descriptors of the clinical symptoms that occur over the course of acute murine infection. The aim of this work is to use noninvasive methods to evaluate clinical signs in Swiss Webster mice that were experimentally infected with the Y strain of Trypanosoma cruzi during acute phase (Inf group). Infected mice showed evident clinical changes beginning in the second week of infection (wpi) when compared to the noninfected group (NI): (1) animals in hunched postures, closed eyes, lowered ears, peeling skin, increased piloerection, prostration, and social isolation; (2) significant decrease in body weight (Inf: 26.2 ± 2.6 g vs. NI: 34.2 ± 2.5 g) and in chow (1.5 ± 0.3 vs. 6.3 ± 0.5 mg) and water (2.4 ± 0.5 vs. 5.8 ± 0.7 ml) intake; (3) significant decrease of spontaneous activity as locomotor parameters: distance (0.64 ± 0.06 vs. 1.8 ± 0.13 m), velocity (1.9 ± 0.3 vs. 6.7 ± 1.5 cm/sec), and exploratory behavior by frequency (1.0 ± 0.5 vs. 5.7 ± 1.0 events) and duration (1.4 ± 0.3 vs. 5.1 ± 0.5 sec in central arena region); (4) significant increase in the PR (41.7 ± 8.7 vs. 27.6 ± 1.9 msec) and QT intervals (39.7 ± 2.0 vs. 27.5 ± 4.0 msec), and a decreased cardiac frequency (505 ± 52.8 vs. 774 ± 17.8 msec), showing a marked sinus bradycardia and an atrioventricular block. At 3 and 4 wpi, the surviving animals showed a tendency of recovery in body weight, food intake, locomotor activity, and exploratory interest. Through the use of noninvasive parameters, we were able to monitor the severity of the infection in individuals prior to death. Our perspective is the application of noninvasive methods to describe clinical signs over the course of acute infection complementing the preclinical evaluation of new agents, alone or in combination with benznidazole.

The TGF-ß pathway as an emerging target for Chagas disease therapy.

Transforming growth factor-ß (TGF-ß) influences the development of myocardiopathy in Chagas disease through regulation of (i) parasite invasion of heart cells, (ii) an intracellular parasite cycle, (iii) inflammation and immune response, (iv) heart fibrosis and remodeling, and (v) gap junction modulation and heart conduction. In this review, we discuss the rationale for developing TGF-ß signaling-interfering therapies as adjuvant approaches for the management of the cardiac alterations of Chagas disease-affected patients.

Transfection by eukaryotic expression vector pcDNA3-HERG inhibits the cultured neonatal rabbit ventricular myocyte hypertrophy induced by phenylephrine.

OBJECTIVE: Prolonged action potential and decreased outward K(+) currents are consistent findings in hypertrophic myocardium. The relation between action potential prolongation and myocyte hypertrophy has remained unclear. The present study investigated the temporal relation between action potential prolongation and myocyte hypertrophy, and the effect of enhancing repolarization on myocyte hypertrophy induced by phenylephrine. METHODS: Neonatal rabbit ventricular myocytes were cultured and treated with 10 µmol/l phenylephrine. At 6 and 48 h after phenylephrine stimulation, myocyte hypertrophic parameters (including myocyte volume, total protein content, and membrane capacitance), action potential duration (APD), and calcineurin activity were measured; meanwhile, the effect of human-ether-a-go-go-related gene (HERG; encoding the αsubunit of rapidly activating delayed rectifier potassium channel) transfection on the above parameters at 48 h of phenylephrine stimulation was also measured. RESULTS: At 6 h after phenylephrine treatment, APD at 90% repolarization of neonatal rabbit ventricular myocytes was prolonged by 14.3% (P<.05), but myocyte hypertrophy was not found. At 48 h after phenylephrine stimulation, APD at 90% repolarization of neonatal rabbit ventricular myocytes was furthermore prolonged by 18.8% (P<.05); at the same time, myocyte volume, total protein content, membrane capacitance, and calcineurin activity were increased by 40.0%, 41.8%, 36.4%, and 124.1%, respectively (P<.01). Neonatal rabbit ventricular myocytes transfected by pcDNA3-HERG overexpressed I(HERG,tail) current, which was about fourfold higher than I(Kr) (rapidly activating delayed rectifier K(+) current) of neonatal rabbit ventricular myocytes without transfection of HERG. HERG overexpression could accelerate repolarization and shorten APD at 90% repolarization prolonged by phenylephrine and partially inhibit myocyte hypertrophy and calcineurin activation. CONCLUSIONS: During the myocyte hypertrophy induced by phenylephrine, prolongation of APD at 90% repolarization is not secondary to but precedes myocyte hypertrophy. HERG overexpression could enhance the repolarization and inhibit the calcineurin activation and myocyte hypertrophy induced by phenylephrine.

A rare form of trifascicular block with intermittent complete atrioventricular block in a patient with Chagas disease.

Trifascicular block, which consists of impaired conduction in the three main fascicles of the ventricular conduction system, may progress to high-grade or complete atrioventricular block. Exceptionally, it is possible to register in the same patient paroxysmal alternating atrioventricular block and bilateral bundle branch block. This is the electrocardiogram of a male, 60 year-old patient coming from an endemic area, with positive serology for Chagas disease, with the exclusively dromotropic form (there are no signs of cardiac muscle involvement), manifest by repetitive pre-syncope and syncope episodes.

[Cardiac neuronal depopulation in hamsters (Mesocricetus auratus) chronically infected with Trypanosoma cruzi]. / Despopulação neuronal cardíaca em hamsters (Mesocricetus auratus) cronicamente infectados com o Trypanosoma cruzi.

The aim of this study was to obtain an experimental animal model of destruction of cardiac neurons in order to investigate the behavior of the cardiac nervous system of hamsters chronically infected with Trypanosoma cruzi. We counted the neuronal cells of the cardiac autonomic nervous plexus in hamsters inoculated with 35,000 blood forms of three different T. cruzi strains and killed 5, 8 and 10 months after infection. We showed for the first time severe neuronal destruction in an experimental animal model with characteristics similar to those observed in human Chagas'disease.

Contribuiçäo ao conhecimento da cardiopatia chagásica aguda: estudo sistematizado dos sistemas excito-condutor e nervoso autônomo intracardíaco em caso autóctone do Acre / A contribution to the knowledge of acute chagasic cardiopathy: a systematized study of the conducting system and the autonomic intracardiac nervous system in an autochthonous case in Acre

The histopathology of the heart is described in an acute case of Chagas' disease (DC). Lesions involving the conducting system (SC) and the autonomic intracardiac nervous system (SNAIC) are emphasized. Light microscopy showed acute pan-carditis with plenty of Trypanosoma cruzi amastigotes within heart muscle cells. Multiple inflammatory foci were found in the SC with parasitic nests within the atrioventricular node and left his bundle. There were also severe atrial periganglionitis and perineuritis with or without peripheral involvement of those structures. Apparently there was no cardiac neuronal depopulation. The epidemiological study suggested transmission through Rhodnius pictipes. To the best of our knowledge, this is the first reported case of acute DC from the Amazonian basin with systematized microscopy study of the SC and SNAIC.

[Acute Chagas cardiopathy. A systematic study of the intracardiac excitatory-conduction and autonomic nervous systems in an autochthonous case in Acre]. / Contribuição ao conhecimento da cardiopatia chagásica aguda. Estudo sistematizado dos sistemas excito-condutor e nervoso autônomo intracardíaco em caso autóctone do Acre.

The histopathology of the heart is described in an acute case of Chagas' disease (DC). Lesions involving the conducting system (SC) and the autonomic intracardiac nervous system (SNAIC) are emphasized. Light microscopy showed acute pan-carditis with plenty of Trypanosoma cruzi amastigotes within heart muscle cells. Multiple inflammatory foci were found in the SC with parasitic nests within the atrioventricular node and left his bundle. There were also severe atrial periganglionitis and perineuritis with or without peripheral involvement of those structures. Apparently there was no cardiac neuronal depopulation. The epidemiological study suggested transmission through Rhodnius pictipes. To the best of our knowledge, this is the first reported case of acute DC from the Amazonian basin with systematized microscopy study of the SC and SNAIC.

Histopathology of the heart conducting system in experimental Chagas disease in mice.

Although mice infected with Trypanosoma cruzi develop a wide variety of electrocardiographic (ECG) alterations, the typical isolated right bundle branch block or its association with the left anterior hemiblock patterns are not found in this model. This has been explained as related to topographic differences in the anatomy of the murine conducting system. However, there is no conclusive evidence that the murine conducting system differs from the human system. In this study, the anatomy of the murine conducting system is described, as well as its involvement in the chronic stages of experimental infection. 24 three-month-old C3H mice were infected with 50 bloodstream forms of T. cruzi, Tulahuén strain. Animals were killed after 3, 8 and 12 months. Whole frontal sections of the heart, including the conducting system, were serially studied. The sinoatrial node was located in the right atrial appendage, or in the junction between the superior vena cava and the right atrium, or "riding" on the interatrial septum. The atrioventricular (A-V) node and the His bundle showed a similar anatomic course to that in man. Therefore, there was no important anatomical difference that might have explained the lack of the ECG patterns observed in human chagasic myocardiopathy. The inflammatory involvement and the lesions of the conducting system were diverse and rarely severe. No significant difference was observed in animals killed at different times. The lesions in the working myocardium were similar to those observed in humans (chronic inflammatory infiltrates). Nevertheless, the topography of lesions was different: there was a selective involvement in the neighbourhood of the A-V groove.(ABSTRACT TRUNCATED AT 250 WORDS)