Restoration of myocardial β-adrenergic receptor signaling after left ventricular assist device support

ObjectiveLeft ventricular assist device support for patients with chronic heart failure can significantly improve β-adrenergic receptor signaling, which is likely critical to myocardial recovery. The mechanism underlying the restoration of β-adrenergic receptor signaling is unclear. This study investigates our hypothesis that restoration of cardiac β-adrenergic receptor signaling by left ventricular assist devices results from inhibition of the G protein–coupled receptor kinase-2, a G protein–coupled receptor kinase that specifically phosphorylates and desensitizes agonist-occupied β-adrenergic receptors.MethodsLeft ventricular β-adrenergic receptor signaling was assessed in biopsy specimens taken from patients with chronic heart failure (n = 12) at the time of left ventricular assist device implantation (heart failure group) and again at the time of heart transplantation (left ventricular assist device group). Signaling was also studied in left ventricular biopsy specimens from nonfailing control (n = 8) hearts (nonfailing control group). Signaling was assessed by measuring sarcolemmal membrane β-adrenergic receptor density, adenylyl cyclase activity, G protein expression, and G protein–coupled receptor kinase-2 expression and activity.ResultsLeft ventricular β-adrenergic receptor signaling was severely decreased in the heart failure group versus that seen in the nonfailing control group, as demonstrated by adenylyl cyclase activity. G protein–coupled receptor kinase-2 expression and activity was increased 3-fold in the heart failure group versus that seen in the nonfailing control group. After left ventricular assist device support, β-adrenergic receptor signaling was restored to levels similar to those seen in the nonfailing control group. G protein–coupled receptor kinase-2 expression and activity were markedly diminished after left ventricular assist device support compared with that seen in the heart failure group and were not different from that seen in the nonfailing control group.ConclusionIn chronic heart failure left ventricular assist device support leads to restoration of cardiac β-adrenergic receptor signaling. The primary mechanism appears to be diminished myocardial G protein–coupled receptor kinase-2 activity. This demonstrates the potentially beneficial effects of G protein–coupled receptor kinase-2 inhibition on β-adrenergic receptor signaling in heart failure and might represent a novel therapeutic strategy for this disease process

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism

Spontaneous left main coronary artery dissection complicated by pseudoaneurysm formation in pregnancy: role of CT coronary angiography

We report a case of a 26-year-old female, who presented at 34 weeks of an uncomplicated pregnancy with an acute ST elevation anterior wall myocardial infarction. Cardiac catheterization suggested a left main coronary artery dissection with pseudoaneurysm formation. The patient's course was complicated by congestive heart failure. She was initially managed conservatively by a multidisciplinary team including heart failure specialists, obstetricians, and cardiovascular surgeons. 4 days after admission, her LMC was imaged by dual-source 64 slice Cardiac computed tomography, coronary dissection was identified extending to the lumen, and the presence of pseudoaneurysm was confirmed. She underwent subsequently a staged procedure, which included placement of an intra-aortic balloon pump, cesarean section, and coronary artery bypass grafting. This case illustrates the utility of coronary artery CT imaging to assess the complexity and stability of coronary artery dissections, thereby helping to determine the need for, and timing of revascularization procedures

Simulation in coronary artery anastomosis early in cardiothoracic surgical residency training: The Boot Camp experience

We evaluated focused training in coronary artery anastomosis with a porcine heart model and portable task station

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

Reduction of microglial activity in a model of multiple sclerosis by dipyridamole

BACKGROUND: Despite extensive and persistent activation of microglia in multiple sclerosis (MS), microglia inhibitors have not yet been identified for treatment of the disorder. We sought to identify medications already in clinical use that could inhibit the activation of microglia. On the basis of the reported inhibitory effects of dipyridamole on phosphodiesterase activity that result in the production of various anti-inflammatory outcomes, we selected it for study. Dipyridamole is used clinically for secondary prevention in stroke. In this study, dipyridamole was examined using microglia in culture and in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). RESULTS: We found that dipyridamole attenuated the elevation of several cytokines and chemokines in human microglia caused by Toll-like receptor stimulation. Morphological characteristics of activated microglia in culture were also normalized by dipyridamole. In mice, dipyridamole decreased the clinical severity of EAE and reduced microglial activity and other histological indices of EAE in the spinal cord. CONCLUSIONS: Dipyridamole is an inhibitor of microglia activation and may have a role in MS and other neurological conditions to attenuate microglial activity

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació