title: β-Adrenergic stimulation and rapid pacing mutually promote heterogeneous electrical failure and ventricular fibrillation in the globally ischemic heart.
abstract: Global ischemia, catecholamine surge, and rapid heart rhythm (RHR) due to ventricular tachycardia or ventricular fibrillation (VF) are the three major factors of sudden cardiac arrest (SCA). Loss of excitability culminating in global electrical failure (asystole) is the major adverse outcome of SCA with increasing prevalence worldwide. The roles of catecholamines and RHR in the electrical failure during SCA remain unclear. We hypothesized that both β-adrenergic stimulation (βAS) and RHR accelerate electrical failure in the globally ischemic heart. We performed optical mapping of the action potential (OAP) in the right ventricular (RV) and left (LV) ventricular epicardium of isolated rabbit hearts subjected to 30-min global ischemia. Hearts were paced at a cycle length of either 300 or 200 ms, and either in the presence or in the absence of β-agonist isoproterenol (30 nM). 2,3-Butanedione monoxime (20 mM) was used to reduce motion artifact. We found that RHR and βAS synergistically accelerated the decline of the OAP upstroke velocity and the progressive expansion of inexcitable regions. Under all conditions, inexcitability developed faster in the LV than in the RV. At the same time, both RHR and βAS shortened the time to VF (TVF) during ischemia. Moreover, the time at which 10% of the mapped LV area became inexcitable strongly correlated with TVF (R(2) = 0 .72, P < 0.0001). We conclude that both βAS and RHR are major factors of electrical depression and failure in the globally ischemic heart and may contribute to adverse outcomes of SCA such as asystole and recurrent/persistent VF.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah;
authors.forename: Vivek
authors.initials: V
authors.lastname: Garg
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; Department of Bioengineering, University of Utah, Salt Lake City, Utah; and.
authors.forename: Tyson
authors.initials: T
authors.lastname: Taylor
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; Department of Bioengineering, University of Utah, Salt Lake City, Utah; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Warren
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; Department of Bioengineering, University of Utah, Salt Lake City, Utah; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Venable
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; Department of Bioengineering, University of Utah, Salt Lake City, Utah; and.
authors.forename: Katie
authors.initials: K
authors.lastname: Sciuto
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah.
authors.forename: Junko
authors.initials: J
authors.lastname: Shibayama
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; Department of Bioengineering, University of Utah, Salt Lake City, Utah; and zaitsev@cvrti.utah.edu.
authors.forename: Alexey
authors.initials: A
authors.lastname: Zaitsev
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists; D000818:Animals; D002304:Cardiac Pacing, Artificial; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D010477:Perfusion; D011817:Rabbits; D012307:Risk Factors; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D016277:Ventricular Function, Left; D016278:Ventricular Function, Right; D017725:Ventricular Pressure; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D000318:Adrenergic beta-Agonists; D007545:Isoproterenol
keywords: inexcitability; myocardial ischemia; optical mapping; ventricular fibrillation; β-adrenergic stimulation