Galectin-1 Prevents Infection and Damage Induced by Trypanosoma cruzi on Cardiac Cells.

BACKGROUND: Chronic Chagas cardiomyopathy caused by Trypanosoma cruzi is the result of a pathologic process starting during the acute phase of parasite infection. Among different factors, the specific recognition of glycan structures by glycan-binding proteins from the parasite or from the mammalian host cells may play a critical role in the evolution of the infection. METHODOLOGY AND PRINCIPAL FINDINGS: Here we investigated the contribution of galectin-1 (Gal-1), an endogenous glycan-binding protein abundantly expressed in human and mouse heart, to the pathophysiology of T. cruzi infection, particularly in the context of cardiac pathology. We found that exposure of HL-1 cardiac cells to Gal-1 reduced the percentage of infection by two different T. cruzi strains, Tulahuén (TcVI) and Brazil (TcI). In addition, Gal-1 prevented exposure of phosphatidylserine and early events in the apoptotic program by parasite infection on HL-1 cells. These effects were not mediated by direct interaction with the parasite surface, suggesting that Gal-1 may act through binding to host cells. Moreover, we also observed that T. cruzi infection altered the glycophenotype of cardiac cells, reducing binding of exogenous Gal-1 to the cell surface. Consistent with these data, Gal-1 deficient (Lgals1-/-) mice showed increased parasitemia, reduced signs of inflammation in heart and skeletal muscle tissues, and lower survival rates as compared to wild-type (WT) mice in response to intraperitoneal infection with T. cruzi Tulahuén strain. CONCLUSION/SIGNIFICANCE: Our results indicate that Gal-1 modulates T. cruzi infection of cardiac cells, highlighting the relevance of galectins and their ligands as regulators of host-parasite interactions.

Biophysical and molecular characterization of a novel de novo KCNJ2 mutation associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry.

BACKGROUND: Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1 or IKir2.1), have been identified in Andersen-Tawil syndrome. Andersen-Tawil syndrome is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia. METHODS AND RESULTS: Our proband displayed dysmorphic features including micrognathia, clinodactyly, and syndactyly and exhibited multiform extrasystoles and bidirectional ventricular tachycardia both at rest and during exercise testing. The patient's symptoms continued after administration of nadolol but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p.R260P) in KCNJ2. Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild-type human KCNJ2 cDNA (WT-KCNJ2) yielded robust IKir2.1 but no measurable current in cells expressing the R260P mutant. Coexpression of WT and R260P-KCNJ2 (heterozygous expression) yielded a markedly reduced inward IKir2.1 compared with WT alone (-36.5±9.8 pA/pF versus -143.5±11.4 pA/pF, n=8 for both, P<0.001, respectively, at -90 mV), indicating a strong dominant negative effect of the mutant. The outward component of IKir2.1 measured at -50 mV was also markedly reduced with the heterozygous expression versus WT (0.52±5.5 pA/pF versus 23.4±6.7 pA/pF, n=8 for both, P<0.001, respectively). Immunocytochemical analysis indicates that impaired trafficking of R260P-KCNJ2 channels. CONCLUSIONS: We report a novel de novo KCNJ2 mutation associated with classic phenotypic features of Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. The R260P mutation produces a strong dominant negative effect leading to marked suppression of IK1 secondary to a trafficking defect.

Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle.

The neuregulin receptor tyrosine kinase Erb-b4, initially linked to early cardiac development, is shown here to play a critical role in adult cardiac function. In wild-type mice, Erb-b4 protein localized to Z lines and to intercalated disks, suggesting a role in subcellular and intercellular communications of cardiomyocytes. Conditional inactivation of erb-b4 in ventricular muscle cells led to a severe dilated cardiomyopathy, characterized by thinned ventricular walls with eccentric hypertrophy, reduced contractility, and delayed conduction. This cardiac dysfunction may account for premature death in adult erb-b4-knockout mice. This study establishes a critical role for Erb-b4 in the maintenance of normal postnatal cardiac structure and function.

Natriuretic peptides as prognostic and diagnostic markers in Chagas' disease.

Atrial natriuretic factor (ANF) is a hormone secreted predominantly from atrial myocardium in response to changes in wall tension. Chagas' disease is caused by the parasite Trypanosom cruzi (T. cruzi), the heart being one of the most affected organs, resulting in myocarditis and chronic cardiomyopathy. The inflammatory response of the myocardium may be the result of factors such as ischemia, direct parasite invasion, and autoimmune mechanisms. In this review, we discuss the current knowledge about ANF in Chagas' disease and describe our findings in studying: (1) the development of chagasic cardiomyophathy in T. cruzi-infected rats and its relationship with plasma ANF levels; (2) the evolution of plasma ANF in chagasic patients in different stages (asymptomatic, with conduction defects and with chronic heart failure [CHF]); and (3) the possible usefulness of plasma ANF as a prognostic factor of development of myocardial compromise and survival. In rats, the elevated ANF levels found could mirror the inflammatory response of myocardial cells to acute T. cruzi infection and of progressive failure of cardiac function in the chronic infection. In patients, plasma ANF could be a sensitive marker capable of detecting gradual impairments in cardiac function and poor survival in CHF patients and of myocardiopathy development in the asymptomatic state.

Síncope en pediatría (Parte 2): etiología, diagnóstico y tratamiento del lactante al adolescente / Pediatric syncope (Part 2): ethiology, diagnostic and treatment from infancy to adolescence

El síncope es una entidad clínica de características abruptas, generalmente estresante y muchas veces causa incapacidad física y emocional, con graves restricciones sociales y ocupacionales. Una detallada anamnesis y el minucioso examen físico constituyen la clave del diagnóstico. El empleo excesivo, repetido y asistemático de exámenes de laboratorio y métodos complementarios generalmente es decepcionante, oneroso y la mayoría de las veces no mejora el índice de certeza diagnóstica. El tratamiento varía desde cambios en el estilo de vida hasta cirugía cardíaca a cielo abierto. El gran desafío en el abordaje de estos pacientes es implementar una terapéutica segura, efectiva y con una relación costo-beneficio adecuada , desde el estudio de los pacientes con un curso benigno hasta aquellos en los que el episodio sincopal pone en riesgo su vida.

Síncope en pediatría (Parte 1): etiología, diagnóstico y tratamiento del lactante al adolescente / Pediatric syncope: etiology, diagnosis and theraphy from infancy to adolescence

El síncope es una entidad clínica relativamente frecuente en niños y adolescentes. La palabra deriva del griego syncoptein (cortar), y consiste en la pérdida transitoria de la conciencia y del tono postural, con recuperación espontánea. Conjuntamente síndrome y síntoma, se calcula que uno de cada cinco niños que alcanzan la adultez han padecido por lo menos un episodio sincopal, que despierta una tremenda carga de ansiedad en padres, maestros y educadores físicos, y genera un impacto negativo que no pocas veces interfiere con la calidad de vida del paciente. Discutimos a continuación su epidemiología, clasificación, causas y presentación clínica

Inappropriate single chamber ICD discharges due to supraventricular tachycardia with high degree atrioventricular block.

Supraventricular tachycardia with rapid ventricular response is well recognized as the more frequent cause of single chamber ICD inappropriate therapies. We report here a 18-year-old-woman with surgically corrected transposition of the great arteries who received repetitive inappropriate discharges from an ICD implanted for ventricular tachycardia. Rapid atrial activity during episodes of supraventricular tachycardia with high degree atrioventricular block was oversensed as ventricular fibrillation by a single chamber ICD causing repetitive painful discharges. Pharmacological treatment of the supraventricular tachycardia solved the problem.

Atrial natriuretic factor as marker of myocardial compromise in Chagas' disease.

This study investigated the evolution of plasma atrial natriuretic factor (ANF) in patients in different stages of Chagas' disease and analyzed its usefulness as prognostic factor of the development of myocardial compromise in asymptomatic chagasic patients. Chagas' disease, a determinant of heart failure, is caused by the parasite Trypanosoma cruzi. A total of 21 chagasic patients were studied: 9 in the asymptomatic stage, 6 with conduction defects (CD), and 6 with chronic heart failure (CHF); and 31 controls: 16 healthy, 6 with CD, and 9 with CHF. Plasma ANF radioimmunoassay (RIA) and complementary studies were performed twice for each patient, with an interval period of 12 months. First sample: chagasic patients showed higher ANF levels in the CHF group than in CD and asymptomatic subjects; second sample: the peptide levels were higher in CHF patients than in the asymptomatic group. In non-chagasic CHF patients, ANF levels were higher than in CD patients and controls in both samples. ANF levels were not able to differentiate chagasic asymptomatic and CD patients from healthy subjects and CD controls; meanwhile, chagasic CHF patients showed lower plasma ANF than their controls. Furthermore, ANF is a sensitive marker capable of detecting gradual impairments in cardiac function in all patients studied.

Presentacion de un niño con síndrome de QT largo / Long-QT syndrome: a case report

El síndrome de QT largo es una enfermedad caracterizada por cambios a nivel electrocardiográficos en la repolarización,prolongación del intervalo QT( corregido para la frecuencia cardíaca)síncope y muerte súbita.En su forma congénita,múltiples mutaciones han sido descriptas en 5 diferentes genes,responsables delas alteraciones en la expresión de los canales iónicos de sodio y potasio.Debido a la creciente aparición de la forma adquirida,asociada a un importante número de fármacos utilizados en la práctica pediátrica habitual,este síndrome ha despertado recientemente considerable atención en las publicaciones internacionales.Tanto en la forma congénita como en la adquirida el síndrome se asocia a una arritmia ventricular rápida polimorfa,denominada torsión de punta(torsades des pointes) que en no pocos casos degenera en fibrilación ventricular.EL diagnósticos permite instituir un tratamiento adecuado y con el seguimiento,disminuir la frecuencia de muerte súbita cardíaca,de alta incidencia en esta población pediátrica particular