This proposal describes a 5-year training program for the development of an academic career in the clinical pharmacology of arrhythmias. This program is designed to expand the laboratory-based skills of a clinical scientist that will result in a translational research program focused on arrhythmogenesis. Heart failure can be broadly characterized by a sympathetic hyperactivity and is associated with an increased risk for the development of atrial fibrillation. The slow component of the delayed rectifier current, IKs, is regulated by acute adrenergic receptor-mediated phosphorylation but its functional status and regulation during heart failure are unknown. Alterations of IKs function during heart failure could have therapeutic implications since the enhanced function of this current has been associated with the generation of atrial fibrillation. The central hypothesis for this application is that;sustained adrenergic-receptor activation contributes to an atrial arrhythmogenic substrate via lasting alterations in the regulation of the phosphorylation status, and hence function of IKs. We propose a systematic series of investigations to assess pathological alterations in the regulation of IKs and mechanisms of atrial arrhythmias in an experimental model of sustained adrenergic receptor activation.
Specific Aim 1 will test the functionality, regulation, and phosphorylation status of the proteins underlying IKs following sustained adrenergic receptor stimulation.
Specific Aim 2 will test electrophysiological mechanisms for atrial arrhythmogenesis during left ventricular dysfunction by assessing the interplay of focal triggers and reentrant mechanisms. Overall, this research sequence corresponds directly to the proposed training program that has been designed to impact a clinical problem while setting the foundation for a career in translational research. This will lead to a translational research program combining mechanistic studies with clinical research to rationally develop effective preventative strategies for atrial fibrillation in patients at the highest risk to develop the arrhythmia.
Patients with heart failure are at an increased risk to develop atrial fibrillation which substantially contributes to their morbidity and mortality. This proposal is designed to positively impact public health by identifying therapeutic targets to prevent arrhythmias in the early stages of heart failure.
|Shugg, Tyler; Johnson, Derrick E; Shao, Minghai et al. (2018) Calcium/calmodulin-dependent protein kinase II regulation of IKs during sustained ?-adrenergic receptor stimulation. Heart Rhythm 15:895-904|
|Tisdale, James E; Jaynes, Heather A; Overholser, Brian R et al. (2016) Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study. JACC Clin Electrophysiol 2:765-774|
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|Abdelhady, Ahmed M; Shugg, Tyler; Thong, Nancy et al. (2016) Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers. J Cardiovasc Electrophysiol 27:1206-1213|
|Tisdale, James E; Allen, Matthew R; Overholser, Brian R et al. (2015) Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements. J Cardiovasc Electrophysiol 26:671-7|
|Tisdale, James E; Jaynes, Heather A; Kingery, Joanna R et al. (2014) Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 7:381-90|
|Abdelhady, A M; Desta, Z; Jiang, F et al. (2014) Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz. J Clin Pharmacol 54:87-96|
|Tisdale, James E; Jaynes, Heather A; Kingery, Joanna R et al. (2013) Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 6:479-87|
|Mohamed, Ahmed N; Abdelhady, Ahmed M; Spencer, Dustin et al. (2013) Pharmacokinetic modeling and simulation of procainamide and N-acetylprocainamide in a patient receiving continuous renal replacement therapy: a novel approach to guide renal dose adjustments. Am J Kidney Dis 61:1046-8|
|Tisdale, James E; Overholser, Brian R; Wroblewski, Heather A et al. (2012) Enhanced sensitivity to drug-induced QT interval lengthening in patients with heart failure due to left ventricular systolic dysfunction. J Clin Pharmacol 52:1296-305|
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