title: Optical mapping of propagation changes induced by elevated extracellular potassium ion concentration in genetically altered mouse hearts.
abstract: Diabetes is associated with high rates of cardiovascular disease and sudden death. Therefore, dissecting specific mechanisms, such as the effects of impaired insulin signaling on cardiac electrophysiology may lead to better diagnosis and treatment. Lack of insulin receptors in mouse myocytes has been shown to reduce repolarizing potassium currents and prolong action potential duration. We hypothesized that these changes would manifest as rate-related effects on electrical propagation in the intact heart. This study employed optical mapping to characterize propagation changes in intact mouse hearts with cardiomyocyte-restricted knock out of insulin receptors (CIRKO).
  
  
  METHODS
  Fluorescent signals emitted from excited Di-4-ANEPPS in isolated Langendorff perfused mouse hearts were recorded from the left ventricular epicardium using an 8 by 8 photo diode array. The study included hearts from 8 CIRKO mice and 8 wild type (WT) littermate controls. Hearts were stimulated from the right atrium or the left ventricle at basic cycle lengths ranging from 160 to 280 ms under normal conditions and then after 5 minutes of perfusion with elevated potassium ion concentration (9.4 mM).
  
  
  RESULTS
  None of the 8 CIRKO hearts maintained regular responses to atrial stimulation at the 160 ms cycle length under normal conditions; however, all of the WT hearts were captured at this rate. Total activation time for a 4 mm by 4 mm area was longer for CIRKO hearts when compared with WT. Average epicardial conduction velocity was slower for the CIRKO when compared to WT. Propagation delay due to the presence of high [K+]e was significant in both CIRKO and WT mice, but significantly longer for the CIRKO hearts.
  
  
  CONCLUSIONS
  These results show that in addition to reducing repolarization currents, impaired myocardial insulin signaling leads to impaired electrical impulse propagation particularly at increased heart rates. These data suggest a link between impaired myocardial insulin signaling and the increased risk of arrhythmia and sudden death in patients with diabetes.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112-5000, USA. punske@cvrti.utah.edu
authors.forename: Bonnie B
authors.initials: BB
authors.lastname: Punske
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossi
authors.forename: Philip
authors.initials: P
authors.lastname: Ershler
authors.forename: Isaac
authors.initials: I
authors.lastname: Rasmussen
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002304:Cardiac Pacing, Artificial / Q000379:methods; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects*; D005456:Fluorescent Dyes; D006339:Heart Rate / Q000187:drug effects*; D007328:Insulin / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D009924:Organ Culture Techniques; D010496:Pericardium / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology*; D011726:Pyridinium Compounds; D011972:Receptor, Insulin / Q000032:analysis / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005456:Fluorescent Dyes; D007328:Insulin; D011726:Pyridinium Compounds; C050019:1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium betaine; D011972:Receptor, Insulin; D011188:Potassium