(Verbatim from the application): Accurate prediction and prevention of ventricular tachyarrhythmias would have a major impact on the survival of approximately 300,000 persons/year in the US. Yet, the current status of the field is such that further efforts at identification, comprehension and application of novel approaches are warranted. Therefore, the goal of the proposed studies is to seek new directions for understanding the fundamental plasticity of myocardium such that we can deliberately induce therapeutically beneficial remodeling. Our general hypothesis is that we can remodel ion channels and gap junctions to prevent the occurrence of potentially lethal arrhythmias. Our approach focuses on the modulation of cardiac memory, a non-pathological form of remodeling that can be induced by ventricular pacing or arrhythmias and that is associated with altered repolarization, refractoriness and gap junctional density and distribution. Our protocols focus on integration of basic mechanism and clinical expression in pursuing three aims: to determine (1) the mechanisms underlying cardiac memory-induced regional ventricular alterations in repolarization and refractoriness in normal and arrhythmic infarcted hearts and the interaction with antiarrhythmic drugs; (2) the electrophysiological significance of the remodeling of gap junctions associated with cardiac memory in normal and infarcted, arrhythmic hearts; and (3) the ionic and molecular determinants of the electrophysiologic changes that characterize cardiac memory. The model is the chronically instrumented canine with or without infarction which undergoes 3 weeks of cardiac pacing to induce memory, and is studied in a clinical surrogate (the conscious dog) using electrocardiographic and vectorcardiographic techniques. We use cardiac mapping to determine ventricular activation and repolarization characteristics in the setting of memory with and without infarction, microelectrode techniques to determine the cellular mechanisms responsible for the changes seen in the intact animal studies, and biophysical and molecular techniques to understand accompanying sarcolemmal ion channel and gap junctional changes with the intent of identifying the subcellular mechanisms responsible for memory and its interaction with arrhythmias. Incorporated in the proposal as well are experiments aimed at understanding the mechanisms responsible for the unpredictability of antiarrhythmic drug actions, which may be a consequence of drug-memory interactions. The overall approach is both reductionist (asking questions about mechanism at the subcellular level) and integrative. We believe it will permit us to understand and to modulate memory and arrhythmias predictably and reproducibly in a clinical setting based on the mechanistic information derived.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067101-03
Application #
6638748
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lathrop, David A
Project Start
2001-07-05
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$649,449
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Haugaa, Håkon; Gómez, Hernando; Maberry, Donald R et al. (2015) Effects of inhalation of low-dose nitrite or carbon monoxide on post-reperfusion mitochondrial function and tissue injury in hemorrhagic shock swine. Crit Care 19:184
Harleton, Erin; Besana, Alessandra; Chandra, Parag et al. (2015) TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation. Am J Physiol Heart Circ Physiol 308:H126-34
Costet, Alexandre; Provost, Jean; Gambhir, Alok et al. (2014) Electromechanical wave imaging of biologically and electrically paced canine hearts in vivo. Ultrasound Med Biol 40:177-87
Harleton, Erin; Besana, Alessandra; Comas, George M et al. (2013) Ability to induce atrial fibrillation in the peri-operative period is associated with phosphorylation-dependent inhibition of TWIK protein-related acid-sensitive potassium channel 1 (TASK-1). J Biol Chem 288:2829-38
Lu, Zhongju; Jiang, Ya-Ping; Wu, Chia-Yen C et al. (2013) Increased persistent sodium current due to decreased PI3K signaling contributes to QT prolongation in the diabetic heart. Diabetes 62:4257-65
Sosunov, Eugene A; Anyukhovsky, Evgeny P (2012) Differential effects of ivabradine and ryanodine on pacemaker activity in canine sinus node and purkinje fibers. J Cardiovasc Electrophysiol 23:650-5
Özgen, Nazira; Lu, Zhongju; Boink, Gerard J J et al. (2012) Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing. Heart Rhythm 9:1865-72
Lu, Zhongju; Wu, Chia-Yen C; Jiang, Ya-Ping et al. (2012) Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome. Sci Transl Med 4:131ra50
Janse, Michiel J; Coronel, Ruben; Opthof, Tobias et al. (2012) Repolarization gradients in the intact heart: transmural or apico-basal? Prog Biophys Mol Biol 109:6-15
Lu, Zhongju; Ballou, Lisa M; Jiang, Ya-Ping et al. (2011) Restoration of defective L-type Ca2+ current in cardiac myocytes of type 2 diabetic db/db mice by Akt and PKC-ýý. J Cardiovasc Pharmacol 58:439-45

Showing the most recent 10 out of 75 publications