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Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I , in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K current, I , in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.
The beta isoform of Neuregulin-1 (NRG-1β), along with its receptors (ErbB2-4), is required for cardiac development. NRG-1β, as well as the ErbB2 and ErbB4 receptors, is also essential for maintenance of adult heart function. These observations have led to its evaluation as a therapeutic for heart failure. Animal studies and ongoing clinical trials have demonstrated beneficial effects of two forms of recombinant NRG-1β on cardiac function. In addition to the possible role for recombinant NRG-1βs as heart failure therapies, endogenous NRG-1β/ErbB signaling appears to play a role in restoring cardiac function after injury. The potential mechanisms by which NRG-1β may act as both a therapy and a mediator of reverse remodeling remain incompletely understood. In addition to direct effects on cardiac myocytes NRG-1β acts on the vasculature, interstitium, cardiac fibroblasts, and hematopoietic and immune cells, which, collectively, may contribute to NRG-1β's role in maintaining cardiac structure and function, as well as mediating reverse remodeling.
Cardiovascular drugs are the most commonly prescribed medications. Some prior assays successfully detect cardiovascular drugs among multiple classes using a single sample. Here, we develop an assay to detect a broad range of cardiovascular drug classes to include commonly used cardiovascular drugs and evaluate the assay's analytical and statistical properties in a clinical setting. We describe a protocol for drug detection that encompasses 34 commonly prescribed cardiovascular drugs or drug metabolites with a single LC-MS/MS method using 100μL of serum or plasma. Drug classes monitored by this assay include: anticoagulants, angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta blockers, calcium channel blockers, diuretics, statins, and vasodilators, as well as digoxin, fenofibrate, and niacin. Analytical accuracy and precision for each drug were evaluated by repeating the assay on spiked samples at low, medium, and high concentrations. In 294 clinical samples obtained from hospitalized patients for whom medication administration was recorded, we evaluated the assay's statistical sensitivity, specificity, and accuracy. For the 34 drugs or drug metabolites, the assay was statistically sensitive (>0.90) for all drugs except captopril (0.25), isosorbide (0.81), and niacin (0.89). The assay was statistically specific for all drugs, with a minimum specificity of 0.94 (aspirin). To our knowledge, this method is the first method of simultaneous analysis of 34 cardiovascular drugs or drug metabolites from nine drug classes evaluated using clinical samples from hospitalized patients.
Copyright © 2013 Elsevier B.V. All rights reserved.
Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established critical pathways and specific loci modulating therapeutic responses to commonly used drugs such as clopidogrel, warfarin, and statins. In addition, genomic approaches have defined mechanisms and genetic variants underlying important toxicities with these and other drugs. These findings have not only resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described to date might be deployed in clinical decision making.
The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.
Copyright © 2012 Mosby, Inc. All rights reserved.
Patients vary in their responses to drug therapy, and some of that variability is genetically determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented, such as cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and antiplatelet agents. A brief view of potential pathways to implementation is presented.
Aortic valvular stenosis remains the most common debilitating valvular heart lesion. Despite the benefit of aortic valve (AV) replacement, many high-risk patients cannot tolerate surgery. AV implantation treats aortic stenosis without subjecting patients to sternotomy, cardiopulmonary bypass (CPB), and aorta cross-clamping. This transcatheter procedure is performed via puncture of the left ventricular (LV) apex or percutaneously, via the femoral artery or vein. Patients undergo general anesthesia, intense hemodynamic manipulation, and transesophageal echocardiography (TEE). To elucidate the role of the anesthesiologist in the management of transcatheter AV implantation, we review the literature and provide our experience, focusing on anesthetic care, intraoperative events, TEE, and perioperative complications. Two approaches to the aortic annulus are performed today: transfemoral retrograde and transapical antegrade. Iliac artery size and tortuosity, aortic arch atheroma, and pathology in the area of the (LV) apex help determine the preferred approach in each patient. A general anesthetic is tailored to achieve extubation after procedure completion, whereas IV access and pharmacological support allow for emergent sternotomy and initiation of CPB. Rapid ventricular pacing and cessation of mechanical ventilation interrupts cardiac ejection and minimizes heart translocation during valvuloplasty and prosthesis implantation. Although these maneuvers facilitate exact prosthesis positioning within the native annulus, they promote hypotension and arrhythmia. Vasopressor administration before pacing and cardioversion may restore adequate hemodynamics. TEE determines annulus size, aortic pathology, ventricular function, and mitral regurgitation. TEE and fluoroscopy are used for positioning the introducer catheter within the aortic annulus. The prosthesis, crimped on a valvuloplasty balloon catheter, is implanted by inflation. TEE immediately measures aortic regurgitation and assesses for aortic dissection. After repair of femoral vessels or LV apex, patients are allowed to emerge and assessed for extubation. Observed and published complications include aortic regurgitation, prosthesis embolization, mitral valve disruption, hemorrhage, aortic dissection, CPB, stroke, and death. Transcatheter AV implantation relies on intraoperative hemodynamic manipulation for success. Transfemoral and transapical approaches pose unique management challenges, but both require rapid ventricular pacing, the management of hypotension and arrhythmias during beating-heart valve implantation, and TEE. Anesthesiologists will care for debilitated patients with aortic stenosis receiving transcatheter AV implantation.