Atrial activation sequence during atrial flutter in the canine pericarditis model and its effects on the polarity of the flutter wave in the electrocardiogram

Stable atrial flutter induced in both conscious and open chest states was studied in 30 mongrel dogs after production of sterile pericarditis. During the conscious state studies, induced atrial flutter (mean cycle length 128 +/- 15 ms) was always sustained greater than 15 min and was stable. Three types of flutter wave polarity were noted in electrocardiogram (ECG) lead II: positive in 16 dogs, negative in 3 and flat or slightly positive in 11. Sequential site atrial mapping during atrial flutter (mean cycle length 133 +/- 18 ms) in the open chest state showed either clockwise (18 dogs) or counterclockwise (12 dogs) circus movement in the right atrium. In 19 of 30 dogs, the circus movement clearly did not require any naturally existing anatomic obstacle; in 11, the orifice of the superior vena cava probably was also involved. Double potentials were recorded from the center of the reentrant circuit during atrial flutter, and fractionated electrograms were recorded from a pivot point of the reentrant wave front. A positive flutter wave in ECG lead II (12 dogs with counterclockwise circus movement) was associated with early activation of the Bachmann's bundle region compared with the posteroinferior left atrium and activation of the left atrium mainly in a superoinferior direction. A negative flutter was associated with the early activation of the posteroinferior left atrium compared with Bachmann's bundle and activation of a considerable portion of the left atrium in an inferosuperior direction. A flat or slightly positive flutter wave (14 of 18 with clockwise circus movement) was associated with activation of the left atrium almost simultaneously by two wave fronts coming from both these sites. In conclusion, atrial flutter in this dog model is due to circus movement in the right atrium, the center of which does not necessarily require an anatomic obstacle. Although atrial flutter is generated by circus movement in the right atrium, the flutter wave polarity in the ECG is determined primarily by the activation sequence of the left atrium.     

RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development.Wnt ligands are highly conserved secreted glycoproteins responsible for important developmental and homeostatic processes throughout the animal kingdom (1, 2). They play a key role in morphogenesis, patterning, and lineage decision during central and peripheral nervous system development (3). Wnt ligands control gene expression (4), and their dysregulation has been implicated in cancer and major neuropathologies (5–9).The sustained expression of Wnt ligands and Wnt signaling components in the mature mammalian CNS and their involvement in neuropathologies suggest that these signaling cascades might also play a part in synaptic maintenance and function beyond embryonic development (10, 11). However, because of the pleiotropy and complexity of Wnt signaling, it has been difficult to dissect the components of Wnt signaling present in mature neurons and their role, if any, in the regulation of established synaptic connections and synaptic transmission.Although most excitatory glutamatergic neurotransmission in the brain is mediated by AMPA-type glutamate receptors [i.e., AMPA receptors (AMPARs)], unique properties allow the NMDA-type glutamate receptors [i.e., NMDA receptors (NMDARs)] to play a critical role in synaptic plasticity, learning and memory, and the establishment and maturation of functional neural circuits (12–14). Despite their importance, it is not known what controls the number and subunit composition of synaptic NMDARs. Dysfunction of NMDARs has been implicated in numerous diseases, including Huntington disease, Parkinson disease, depression, bipolar disorder, and schizophrenia (14, 15), in which a deficit in NMDAR mediated neurotransmission may be central (16). Interestingly, NMDAR-mediated currents can be acutely and specifically up-regulated by Wnt5a, a noncanonical Wnt ligand (17), but little is known regarding the signaling pathway and mechanisms involved in such regulation.The receptor tyrosine kinase-like orphan receptor 2 (RoR2) is part of a conserved family of tyrosine kinase-like receptors that have been proposed to serve as a receptor for noncanonical Wnt ligands, participating in developmental processes like cell movement and cell polarity (18, 19). Although RoR2 protein has been detected in mammalian neurons (20), its function and signaling pathways are not known. Here we show that RoR2 acts as a receptor for noncanonical Wnt ligands capable of regulating synaptic NMDARs. In hippocampal neurons, activation of RoR2 by noncanonical Wnt ligand Wnt5a activates PKC and JNK, two kinases involved in the regulation of NMDAR currents. In addition, we show that signaling through RoR2 is necessary for the maintenance of basal NMDAR-mediated synaptic transmission and the acute regulation of NMDAR synaptic responses by Wnt5a.Identification of RoR2 as a Wnt receptor that regulates synaptic NMDARs provides a mechanism for Wnt signaling to control synaptic transmission and synaptic plasticity acutely, and is a critical first step toward understanding the role played by Wnt signaling in the regulation of glutamatergic synaptic function under normal or pathological conditions.     

An approach to therapy of supraventricular tachyarrhythmias: An algorithm versus individualized therapy

Approaches to the treatment of supraventricular arrhythmias, including atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular (AV) reentrant tachycardia, and AV nodal reentrant tachycardia, continue to evolve. Within the past two decades, many new and effective treatments have become available. These include several new antiarrhythmic agents, ablative therapies, pacing and surgical modalities, and cardioversion/defibrillation techniques. This paper provides an algorithm for the treatment of these supraventricular arrhythmias which includes therapy for the acute episode as well as the prevention of subsequent episodes of the tachyarrhythmia.     

Antithrombotic therapy practices in US hospitals in an era of practice guidelines

BACKGROUND: Antithrombotic therapy is efficacious for the prevention of thromboembolic disease, but it necessitates careful risk-benefit assessment. METHODS: Antithrombotic therapy data were retrospectively collected from inpatient medical records at 38 US hospitals. Patients treated for atrial fibrillation, acute myocardial infarction, deep vein thrombosis, or pulmonary embolism and patients given prophylaxis for total knee replacement, total hip replacement, or hip fracture surgery between July 1, 2000, and June 30, 2003, were randomly selected. RESULTS: The medical records of 3778 patients (53.3% men) were included. The mean patient age was 66.1 years. Of patients with atrial fibrillation at high risk for stroke, only 54.7% received warfarin sodium, and 20.6% received neither aspirin nor warfarin. Of patients with acute myocardial infarction, only 75.5% received aspirin on hospital arrival. After orthopedic surgery procedures, only 85.6% of patients received prophylaxis with a parenteral anticoagulant agent or warfarin. In 49.4% of patients with deep vein thrombosis, pulmonary embolism, or both, unfractionated or low-molecular-weight heparin use was discontinued before an international normalized ratio of 2.0 or greater was achieved for 2 consecutive days. Patients with deep vein thrombosis or pulmonary embolism were rarely discharged from the hospital with bridge therapy (an injectable anticoagulant agent plus warfarin), although the length of hospitalization was significantly shorter than if discharged taking warfarin alone (4.0 vs 8.1 days; P < .001). CONCLUSIONS: A significant percentage of hospitalized patients do not receive adequate antithrombotic therapy for the primary and secondary prevention of thromboembolic disease.     

Predictors and Outcomes of Staged Versus One-Time Multivessel Revascularization in Multivessel Coronary Artery Disease: Insights From the VA CART Program

Objectives

The aim of this study was to determine predictors and outcomes associated with staged percutaneous coronary intervention (PCI) versus one-time multivessel revascularization (OTMVR) in patients with multivessel coronary artery disease.