A-kinase anchoring protein-Lbc promotes pro-fibrotic signaling in cardiac fibroblasts

In response to stress or injury the heart undergoes an adverse remodeling process associated with cardiomyocyte hypertrophy and fibrosis. Transformation of cardiac fibroblasts to myofibroblasts is a crucial event initiating the fibrotic process. Cardiac myofibroblasts invade the myocardium and secrete excess amounts of extracellular matrix proteins, which cause myocardial stiffening, cardiac dysfunctions and progression to heart failure. While several studies indicate that the small GTPase RhoA can promote profibrotic responses, the exchange factors that modulate its activity in cardiac fibroblasts are yet to be identified. In the present study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor (GEF) activity, is critical for activating RhoA and transducing profibrotic signals downstream of type I angiotensin II receptors (AT1Rs) in cardiac fibroblasts. In particular, our results indicate that suppression of AKAP-Lbc expression by infecting adult rat ventricular fibroblasts with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly reduces the ability of angiotensin II to promote RhoA activation, differentiation of cardiac fibroblasts to myofibroblasts, collagen deposition as well as myofibroblast migration. Interestingly, AT1Rs promote AKAP-Lbc activation via a pathway that requires the α subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as a key Rho-guanine nucleotide exchange factor modulating profibrotic responses in cardiac fibroblasts.

Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass.

Postoperative delirium after cardiac surgery is associated with increased morbidity and mortality as well as prolonged stay in both the intensive care unit and the hospital. The authors sought to identify modifiable risk factors associated with the development of postoperative delirium in elderly patients after elective cardiac surgery in order to be able to design follow-up studies aimed at the prevention of delirium by optimizing perioperative management. A post hoc analysis of data from patients enrolled in a randomized controlled trial was performed. A single university hospital. One hundred thirteen patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. None. MEASUREMENTS AND MAINS RESULTS: Screening for delirium was performed using the Confusion Assessment Method (CAM) on the first 6 postoperative days. A multivariable logistic regression model was developed to identify significant risk factors and to control for confounders. Delirium developed in 35 of 113 patients (30%). The multivariable model showed the maximum value of C-reactive protein measured postoperatively, the dose of fentanyl per kilogram of body weight administered intraoperatively, and the duration of mechanical ventilation to be independently associated with delirium. In this post hoc analysis, larger doses of fentanyl administered intraoperatively and longer duration of mechanical ventilation were associated with postoperative delirium in the elderly after cardiac surgery. Prospective randomized trials should be performed to test the hypotheses that a reduced dose of fentanyl administered intraoperatively, the use of a different opioid, or weaning protocols aimed at early extubation prevent delirium in these patients.

A-kinase anchoring proteins: Molecular regulators of the cardiac stress response

In response to stress or injury the heart undergoes a pathological remodeling process, associated with hypertrophy, cardiomyocyte death and fibrosis, that ultimately causes cardiac dysfunction and heart failure. It has become increasingly clear that signaling events associated with these pathological cardiac remodeling events are regulated by scaffolding and anchoring proteins, which allow coordination of pathological signals in space and time. A-kinase anchoring proteins (AKAPs) constitute a family of functionally related proteins that organize multiprotein signaling complexes that tether the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to ensure integration and processing of multiple signaling pathways. This review will discuss the role of AKAPs in the cardiac response to stress. Particular emphasis will be given to the adaptative process associated with cardiac hypoxia as well as the remodeling events linked to cardiac hypertrophy and heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007.

To evaluate the in-hospital outcome of STEMI (ST elevation myocardial infarction) patients admitted to Swiss hospitals between 2000 and December 2007, and to identify the predictors of in-hospital mortality and major cardiac events. Data from the Swiss national registry AMIS Plus (Acute Myocardial Infarction and Unstable Angina in Switzerland) were used. All patients admitted between January 2000 and December 2007 with STEMI or a new LBBB (left bundle branch block) were included in the registry. We studied 12 026 STEMI patients admitted to 68 hospitals. The mean age was 64 +/- 13 years and 73% of the patients were male. Incidence of in-hospital death was 7.6% in 2000 and 6% in 2007. Reinfarction fell from 3.7% in 2000 to 0.9% in 2007. Thrombolysis decreased from 40.2% in 2000 to 2% in 2007. Clinical predictors of mortality were: age >65 years, Killips class III or IV, diabetes, Q wave myocardial infarction (at presentation). Patients undergoing percutaneous coronary intervention (PCI) had lower mortality and reinfarction rates (3.9% versus 11.2% and 1.1% versus 3.1% respectively, p <0.001) over time, although their numbers increased from 43% in 2000 to 85% in 2007. Patients admitted to hospitals with PCI facilities had lower mortality than patients hospitalised in hospitals without it, but the demographic characteristics differ widely between the two groups. Both in-hospital mortality and reinfarction decreased significantly over the time, parallel to an increased number of PCI. PCI was also the strongest predictor of survival. In-hospital mortality and reinfarction rate have decreased significantly in Swiss STEMI patients in the last seven years, parallel to a significant increase in the number of percutaneous coronary interventions in addition to medical therapy. Outcome is not related to the site of admission but to PCI access.

Cost evaluation and comparison of three decision strategies for cardiac revascularization : results of the suspected CAD protocol of the European CMR registry

Background: The public health burden of coronary artery disease (CAD) is important. Perfusion cardiac magnetic resonance (CMR) is generally accepted to detect and monitor CAD. Few studies have so far addressed its costs and costeffectiveness. Objectives: To compare in a large CMR registry the costs of a CMR-guided strategy vs two hypothetical invasive strategies for the diagnosis and the treatment of patients with suspected CAD. Methods: In 3'647 patients with suspected CAD included prospectively in the EuroCMR Registry (59 centers; 18 countries) costs were calculated for diagnostic examinations, revascularizations as well as for complication management over a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive X-ray coronary angiography (CXA) and revascularization at the discretion of the treating physician (=CMR+CXA strategy). Ischemia was found in 20.9% of patients and 17.4% of them were revascularized. In ischemia-negative patients by CMR, cardiac death and non-fatal myocardial infarctions occurred in 0.38%/y. In a hypothetical invasive arm the costs were calculated for an initial CXA followed by FFR testing in vessels with ≥50% diameter stenoses (=CXA+FFR strategy). To model this hypothetical arm, the same proportion of ischemic patients and outcome was assumed as for the CMR+CXA strategy. The coronary stenosis - FFR relationship reported in the literature was used to derive the proportion of patients with ≥50% diameter stenoses (Psten) in the study cohort. The costs of a CXA-only strategy were also calculated. Calculations were performed from a third payer perspective for the German, UK, Swiss, and US healthcare systems.

Arrest du Conseil d'Etat du roi et lettres patentes portant règlement pour l'administration des revenus du collège de Navarre [1738]

[Acte royal. 1738]

Le terme de Pasques sans trébuchet, en vers burlesque. Suivant l'arrest du 14. d'avril mil six quarante-neuf. [sic]

[Mazarinade. 1649]

Arrest du conseil d'Estat du Roy, qui supprime, en faveur du public, les droits des offices de controlleurs des greffiers gardes-minutes des chancelleries . Et ordonne que le remboursement en sera fait sur le caissier de la Compagnie des Indes. Du 19 decembre 1719. Extrait des registres du Conseil d'Estat.

[Acte. 1719-12-19. Paris]

Departemens de messieurs les regisseurs generaux de la Caisse des remboursemens des dettes de l'Estat , & des droits rétablis. Par arrest des vingt & vingt-deux mars 1722.

[Acte. 1722-05-03]

Instruction des devoirs et fonctions des commis par ville, pour la régie des droits rétablis par arrest du Conseil du 22 mars 1722 et déclaration de S. M. du 15 may suivant, sur les ports, quays, halles, places et marchez de... Paris...

[Acte. 1723-07-00. Paris]

Instruction [de l'Assemblée générale de la régie des droits rétablis] pour la régie de la caisse de crédit établie pour le commerce des vins à Paris, en conformité de l'arrest du conseil du 27 Septembre 1723, vu les trois modèles de soumission, de certificat de remboursement et de congé d'enlèvement...

[Acte. 1723-11-10. Paris]

« Ce qui s'est passé au Parlement sur le subject des thèses touchant l'infaillibilité du pape, et de son pouvoir au-dessus des conciles, où sont aussi des harangues de messrs Talon, advocat général, et de Harlay,... tant en ladicte cour qu'en Sorbonne, depuis le XIXe janvier 1663 jusques au 30e may ensuivant, comme aussi l'enregistrement de l'arrest de la cour par toutes les Universitez ».

Contient : « Receuil de ce qui c'est passé au Parlement touchant les thèzes de Mr Gabriel de Villeneufve, bachelier en théologie, et frère Laurens Desplantes, Bernardin, en l'année 1663 »