One-year follow-up of heart failure patients after their first admission.

BACKGROUND: Outcomes related to heart failure remain relatively poor. AIM: To examine the clinical course of patients for one year after their first admission because of heart failure, including prognosis, mortality, and rehospitalization. DESIGN: Prospective observational study. METHODS: Of 121 patients hospitalized over 6 months for decompensation of previously unknown heart failure, we excluded those with a possible previous diagnosis of heart failure (n = 5), who suffered from another serious disease with a poor prognosis (n = 6), died during the index hospitalization (n = 5), refused to participate (n = 4) or were lost to follow-up (n = 6). Mortality and readmissions were identified by prospective follow-up of all patients. RESULTS: Of the 98 patients evaluated, half (49) were women. Mean +/- SD age was 75.2 +/- 12 years. The 1-year case-fatality rate after the first admission was 24%; 19% of the deaths were heart failure-related, with progressive pump failure the predominant cause (14% of the total). Age was the only factor associated with increased mortality (p < 0.007). Of the 74 survivors, 32% experienced at least one hospital readmission during follow-up. DISCUSSION: The prognosis of unselected new cases of heart failure after their first hospitalization remains relatively poor, despite recent advances in pharmacological therapy and medical care.

Regulation of beta-catenin structure and activity by tyrosine phosphorylation.

beta-Catenin plays a dual role as a key effector in the regulation of adherens junctions and as a transcriptional coactivator. Phosphorylation of Tyr-654, a residue placed in the last armadillo repeat of beta-catenin, decreases its binding to E-cadherin. We show here that phosphorylation of Tyr-654 also stimulates the association of beta-catenin to the basal transcription factor TATA-binding protein. The structural bases of these different affinities were investigated. Our results indicate that the beta-catenin C-terminal tail interacts with the armadillo repeat domain, hindering the association of the armadillo region to the TATA-binding protein or to E-cadherin. Phosphorylation of beta-catenin Tyr-654 decreases armadillo-C-terminal tail association, uncovering the last armadillo repeats. In a C-terminal-depleted beta-catenin, the presence of a negative charge at Tyr-654 does not affect the interaction of the TATA-binding protein to the armadillo domain. However, in the case of E-cadherin, the establishment of ion pairs dominates its association with beta-catenin, and its binding is greatly dependent on the absence of a negative charge at Tyr-654. Thus, phosphorylation of Tyr-654 blocks the Ecadherin-beta-catenin interaction, even though the steric hindrance of the C-tail is no longer present. These results explain how phosphorylation of beta-catenin in Tyr-654 modifies the tertiary structure of this protein and the interaction with its different partners.

Regulation of E-cadherin/Catenin association by tyrosine phosphorylation.

Alteration of cadherin-mediated cell-cell adhesion is frequently associated to tyrosine phosphorylation of p120- and beta-catenins. We have examined the role of this modification in these proteins in the control of beta-catenin/E-cadherin binding using in vitro assays with recombinant proteins. Recombinant pp60(c-src) efficiently phosphorylated both catenins in vitro, with stoichiometries of 1.5 and 2.0 mol of phosphate/mol of protein for beta-catenin and p120-catenin, respectively. pp60(c-src) phosphorylation had opposing effects on the affinities of beta-catenin and p120 for the cytosolic domain of E-cadherin; it decreased (in the case of beta-catenin) or increased (for p120) catenin/E-cadherin binding. However, a role for p120-catenin in the modulation of beta-catenin/E-cadherin binding was not observed, since addition of phosphorylated p120-catenin did not modify the affinity of phosphorylated (or unphosphorylated) beta-catenin for E-cadherin. The phosphorylated Tyr residues were identified as Tyr-86 and Tyr-654. Experiments using point mutants in these two residues indicated that, although Tyr-86 was a better substrate for pp60(c-src), only modification of Tyr-654 was relevant for the interaction with E-cadherin. Transient transfections of different mutants demonstrated that Tyr-654 is phosphorylated in conditions in which adherens junctions are disrupted and evidenced that binding of beta-catenin to E-cadherin in vivo is controlled by phosphorylation of beta-catenin Tyr-654.