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.

Sera from patients with chronic Chagas heart disease recognize the carboxyl-terminal regions of the Trypanosoma cruzi ribosomal P proteins defined by B cell epitopes P013 (EDDDDDFGMGALF) and R13 (EEEDDDMGFGLFD) corresponding to the T. cruzi ribosomal P0 (TcP0) and P2beta (TcP2beta) proteins, respectively. It has been hypothesized that both epitopes may induce antibodies that cross-react and stimulate the beta1-adrenoreceptor. However, no proof as to their pathogenicity has been obtained. We investigated the consequences of immunizing mice with either TcP0 or TcP2beta proteins. Of 24 immunized animals, 16 generated antibodies against the carboxyl-terminal end of the corresponding protein, 13 of which showed an altered ECG (P<0.001, 81%). Immunization with TcP0 induced anti-P013 antibodies that bind to and stimulate cardiac G-protein-coupled receptors and are linked to the induction of supraventricular arrhythmia, repolarization, and conduction abnormalities as monitored by serial electrocardiographic analysis. In contrast, immunization with TcP2beta generated anti-R13 antibodies with an exclusive beta1-adrenergic-stimulating activity whose appearance strictly correlated with the recording of supraventricular tachycardia and death. These findings demonstrate that anti-P antibodies are arrhythmogenic in the setting of a normal heart, since no inflammatory lesions or fibrosis were evident to light microscopic examination.

BackgroundChronic 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 FindingsHere 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/SignificanceOur 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.

This study demonstrates the presence of circulating autoantibodies against myosin heavy chain in a significant percentage of patients with idiopathic paroxysmal atrial fibrillation and raises the possibility of an autoimmune process in some patients with paroxysmal atrial fibrillation.

Summary: As the head-up tilt test (HUT) is employed to verify the efficacy of undertalung a treatment, we prospectively evaluated the reproducibility of positive and negative results, as well as that of the response type in 64 consecutive patients (mean age 34.6 & 22.9 years) with syncope of unknown cause. Two HUTS (60 min, 75"), separated by an interval of 9.77 k 8.21 days, were performed on each patient. Positive responses were reproduced in the second HUT in 54.5% of the patients. A greater reproducibility (84.3%) was observed for negative responses. Of the 3 1 patients with a negative first test, 5 had a positive response during the second HUT. Using a multivariate analysis, no clinical variable correlated with the reproducibility of positive or negative results. Likewise, neither arterial pressure nor heart rate observed during the test were correlated with reproducibility. Of 18 patients who reproduced positive responses, 12 (66.6%) did so with the same response modality. In three patients with documented monomorphic sustained ventricular tachycardia, which was hemodynamically well tolerated, and in one patient with temporal spike wave activity in the electroencephalogram, HUT was also positive. It was concluded that the low reproducibility of HUT limits its usefulness as a tool for evaluating treatment efficacy. The variability of the type of response suggests a common mechanism leading to cardioinhibitory and vasodepressor reactions. A positive result in only the second study shows the rationale of performing two tests when the first one is negative.