title: Blockade of CaMKII depresses conduction preferentially in the right ventricular outflow tract and promotes ischemic ventricular fibrillation in the rabbit heart.
abstract: Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates the principle ion channels mediating cardiac excitability and conduction, but how this regulation translates to the normal and ischemic heart remains unknown. Diverging results on CaMKII regulation of Na+channels further prevent predicting how CaMKII activity regulates excitability and conduction in the intact heart. To address this deficiency, we tested the effects of the CaMKII blocker KN93 (1 and 2.75 μM) and its inactive analog KN92 (2.75 μM) on conduction and excitability in the left (LV) and right (RV) ventricles of rabbit hearts during normal perfusion and global ischemia. We used optical mapping to determine local conduction delays and the optical action potential (OAP) upstroke velocity (dV/dtmax). At baseline, local conduction delays were similar between RV and LV, whereas the OAP dV/dtmaxwas lower in RV than in LV. At 2.75 μM, KN93 heterogeneously slowed conduction and reduced dV/dtmax, with the largest effect in the RV outflow tract (RVOT). This effect was further exacerbated by ischemia, leading to recurrent conduction block in the RVOT and early ventricular fibrillation (at 6.7 ± 0.9 vs. 18.2 ± 0.8 min of ischemia in control,P< 0.0001). Neither KN92 nor 1 μM KN93 depressed OAP dV/dtmaxor conduction. Rabbit cardiomyocytes isolated from RVOT exhibited a significantly lower dV/dtmaxthan those isolated from the LV. KN93 (2.75 μM) significantly reduced dV/dtmaxin cells from both locations. This led to frequency-dependent intermittent activation failure occurring predominantly in RVOT cells. Thus CaMKII blockade exacerbates intrinsically lower excitability in the RVOT, which is proarrhythmic during ischemia.NEW & NOTEWORTHYWe show that calcium/calmodulin-dependent protein kinase II (CaMKII) blockade exacerbates intrinsically lower excitability in the right ventricular outflow tract, which causes highly nonuniform chamber-specific slowing of conduction and facilitates ventricular fibrillation during ischemia. Constitutive CaMKII activity is necessary for uniform and safe ventricular conduction, and CaMKII block is potentially proarrhythmic.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah Mark.Warren@utah.edu.
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.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Sciuto
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Tyson G
authors.initials: TG
authors.lastname: Taylor
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.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Torres
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, 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.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Spitzer
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Zaitsev
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001596:Benzylamines / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D003326:Coronary Circulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D017202:Myocardial Ischemia / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000503:physiopathology*; D014694:Ventricular Outflow Obstruction / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology*; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: calcium/calmodulin-dependent protein kinase II; cardiac conduction; ischemia; right ventricular outflow tract; ventricular fibrillation