In the previous 11 years of the grant, our laboratory uncovered and characterized the electrical heterogeneity intrinsic to canine ventricular myocardium. Epicardium, endocardium and a unique population of cells termed M cells were shown to differ with respect to electrophysiological function and responsiveness to drugs. These distinctions were then shown to underlie the various waveforms of the ECG and when amplified to create the substrate for the development of life-threatening ventricular arrhythmias, including the polymorphic ventricular arrhythmias associated with the congenital long QT, short QT, and Brugada syndromes as well as catecholaminergic ventricular tachycardia (VT). Recently, we and others have linked the long QT, short QT and Brugada syndromes to sudden death in children and infants and provided evidence that these mechanisms may contribute in small part to sudden infant death syndrome (SIDS). In the last period of the grant, we defined the developmental stages at which these electrical and pharmacologic heterogeneities arise in the canine heart so as to better understand how ion channel dysfunction may contribute to manifestation of these hereditary syndromes in early stages of life. In the next period of the grant we propose to 1) examine the characteristics of the experimental models of long QT, short QT and Brugada syndromes previously developed in adult canine ventricular wedge preparations, in wedge preparations from neonatal hearts; 2) extend our findings to mechanical aspects of transmural heterogeneity, defining distinctions in cell shortening and calcium transients among the three cell types and their change with development; and 3) examine to what extent electrical and pharmacologic heterogeneity uncovered in the ventricle apply to the atria at each stage of development. The principal goals of our competitive renewal are to probe the extent to which mechanical heterogeneity complements transmural electrical heterogeneity within the ventricles of the heart at each stage of development and how accentuation of these transmural distinctions contributes to the development of life-threatening ventricular and atrial arrhythmias. Our long-range goal is to generate information that will contribute meaningfully to our understanding of arrhythmic death in infants and young children. ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL047678-13
Application #
6987649
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
1993-05-01
Project End
2009-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
13
Fiscal Year
2005
Total Cost
$437,500
Indirect Cost
Name
Masonic Medical Research Laboratory, Inc
Department
Type
DUNS #
077307437
City
Utica
State
NY
Country
United States
Zip Code
13501
Burashnikov, Alexander; Antzelevitch, Charles (2018) Is extensive atrial fibrosis in the setting of heart failure associated with a reduced atrial fibrillation burden? Pacing Clin Electrophysiol 41:1289-1297
Hasdemir, Can; Juang, Jimmy Jyh-Ming; Kose, Sedat et al. (2018) Coexistence of atrioventricular accessory pathways and drug-induced type 1 Brugada pattern. Pacing Clin Electrophysiol 41:1078-1092
Savio-Galimberti, Eleonora; Argenziano, Mariana; Antzelevitch, Charles (2018) Cardiac Arrhythmias Related to Sodium Channel Dysfunction. Handb Exp Pharmacol 246:331-354
Di Diego, José M; Antzelevitch, Charles (2018) J wave syndromes as a cause of malignant cardiac arrhythmias. Pacing Clin Electrophysiol :
Krych, Michalina; Biernacka, El?bieta Katarzyna; Poni?ska, Joanna et al. (2017) Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias - Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene. J Cardiol 70:504-510
Patocskai, Bence; Yoon, Namsik; Antzelevitch, Charles (2017) Mechanisms Underlying Epicardial Radiofrequency Ablation to Suppress Arrhythmogenesis in Experimental Models of Brugada Syndrome. JACC Clin Electrophysiol 3:353-363
Antzelevitch, Charles; Patocskai, Bence (2017) Ajmaline-Induced Slowing of Conduction in the Right Ventricular Outflow Tract Cannot Account for ST Elevation in Patients With Type I Brugada ECG. Circ Arrhythm Electrophysiol 10:
Mizusawa, Yuka; Morita, Hiroshi; Adler, Arnon et al. (2016) Prognostic significance of fever-induced Brugada syndrome. Heart Rhythm 13:1515-20
Patocskai, Bence; Barajas-Martinez, Hector; Hu, Dan et al. (2016) Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome. Heart Rhythm 13:1326-34
Antzelevitch, Charles; Patocskai, Bence (2016) Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects. Curr Probl Cardiol 41:7-57

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