verbatim): This is a competitive renewal application to the National Heart, Lung, and Blood Institute, where it has been administered in the past, for a continuing ROl grant on """"""""Microscopic Discontinuities as a Basis for Arrhythinias."""""""" This renewal application is also designated in relation to Program Announcement 99-035 entitled """"""""Impact of Aging on Atrial Fibrillation Development"""""""" because the proposed research is intended to link the initiation of atrial reentrant arrhythmias to changes in atrial microstructure that occur during aging in association with the escalating incidence of atrial fibrifiation. The research is focused on determining the mechanisms that lead to reentrant arrhythmias when changes in cardiac microstructure occur secondary to aging and disease. Implicit in this objective, the long-term goal is to understand the interrelationships between cell-to-cell current flow, ionic current flow through cell membranes, current flow in interstitial space, and propagation phenomena. The hypothesis of the project is that changes in cardiac microstructure due to aging and disease produce loading mechanisms that create conduction disturbances which induce and maintain reentrant arrhythmias.
The specific aims are to: 1) determine how variations in the specific components of cardiac microstructure (e.g., distribution of gap junctions, cell morphology, variations of interstitial space) affect propagation at a cellular level; 2) develop a quantitative representation (model) of microscopic multidimensional propagation based on natural cell geometry, gap junction distribution, and interstitial space variations; and, 3) explore the sensitivity of conduction disturbances that occur with premature action potentials to variations in the different components of cardiac microstructure. Toward this end, we have established procedures to investigate these mechanisms by combining experimental measurements of intracellular, interstitial, and extracellular potentials with computer simulations that are based on multidimensional cellular models developed from documented microscopic substrates at different ages. Such computer models are essential since they provide a way to evaluate the role of the specific components of myocardial architecture at a microscopic level. Elucidation of the role of microscopic discontinuities has significant implications for new therapeutic approaches to arrhythmias associated with aging and structural heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050537-07
Application #
6476953
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Spooner, Peter
Project Start
1993-08-01
Project End
2005-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
7
Fiscal Year
2002
Total Cost
$231,000
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Johnson, Chad R; Barr, Roger C; Klein, Stephen M (2007) A computer model of electrical stimulation of peripheral nerves in regional anesthesia. Anesthesiology 106:323-30
Karagueuzian, Hrayr S (2007) Re: mechanism of origin of conduction disturbances in aging human atrial bundles: experimental and model study. Heart Rhythm 4:989;author reply 989-90
Spach, Madison S; Heidlage, J Francis; Dolber, Paul C et al. (2007) Mechanism of origin of conduction disturbances in aging human atrial bundles: experimental and model study. Heart Rhythm 4:175-85
Pollard, Andrew E; Barr, Roger C (2006) Cardiac microimpedance measurement in two-dimensional models using multisite interstitial stimulation. Am J Physiol Heart Circ Physiol 290:H1976-87
Adamson, Philip B; Barr, Roger C; Callans, David J et al. (2005) The perplexing complexity of cardiac arrhythmias: beyond electrical remodeling. Heart Rhythm 2:650-9
Wiley, J James; Ideker, Raymond E; Smith, William M et al. (2005) Measuring surface potential components necessary for transmembrane current computation using microfabricated arrays. Am J Physiol Heart Circ Physiol 289:H2468-77
Spach, Madison S; Heidlage, J Francis; Barr, Roger C et al. (2004) Cell size and communication: role in structural and electrical development and remodeling of the heart. Heart Rhythm 1:500-15
Pollard, Andrew E; Smith, William M; Barr, Roger C (2004) Feasibility of cardiac microimpedance measurement using multisite interstitial stimulation. Am J Physiol Heart Circ Physiol 287:H2402-11
Barr, Roger C; Plonsey, Robert (2004) Field stimulation of 2-D sheets of excitable tissue. IEEE Trans Biomed Eng 51:539-40
Spach, Madison S (2003) Transition from a continuous to discontinuous understanding of cardiac conduction. Circ Res 92:125-6

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