Serious ventricular arrhythmias often occur in man immediately after a coronary occlusion, as well as for weeks to years after the infarction. Ventricular ectopy also occurs after the onset of experimentally produced myocardial infarction in the dog heart. Transmembrane action potentials from subendocardial Purkinje fibers that survive infarction (24hr) resulting from coronary artery occlusion in the dog have reduced resting potentials, slow rates of depolarizations, enhanced diastolic depolarization and prolonged durations. It has been suggested that one or more of these electrophysiologic abnormalities and structural changes that occur may lead to ventricular arrhythmias. Therefore, the mechanisms for these electrophysiologic changes may be important to understand in terms of developing therapeutic interventions. It is our aim to identify and quantify the ionic mechanisms of these abnormalities using disaggregated single cells, standard microelectrode and voltage clamp techniques. Specifically, we will disaggregate single Purkinje cells from the subendocardium of the noninfarcted heart, and Purkinje cells from the subendocardium of the infarcted heart (24hr). Electrophysiological and ultrastructural studies will be done on these cells the results of which will be compared to the results of our studies on Purkinje cells disaggregated from free running fiber bundles. We will determine the basis for a difference in resting potential between groups by determining PNa/Pk ratios, by measuring intracellular K+ and Na+ concentrations, and by determining steady state Na-K pump contribution to membrane potential. In addition, we will characterize Na-K pump function in both cell groups and compare the results. Interventions will be used to both inhibit and stimulate the Na-K pump and the effects on membrane potential and net membrane currents determined. We will combine voltage clamp techniques and microelectrode techniques to determine what alterations in ionic permeabilities underlie the differences in rates of depolarization, action potential amplitude and action potential duration of the cells in the different groups. Furthermore, we will determine the ionic mechanism underlying phase 4 depolarization if it is found in the isolated control cell, and compare it to phase 4 depolarization that is seen in Purkinje cell from the endocardium of the infarcted myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL034477-01
Application #
3347401
Study Section
Cardiovascular Study Section (CVA)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Pinto, J M; Boyden, P A (1998) Reduced inward rectifying and increased E-4031-sensitive K+ current density in arrhythmogenic subendocardial purkinje myocytes from the infarcted heart. J Cardiovasc Electrophysiol 9:299-311
Aggarwal, R; Boyden, P A (1996) Altered pharmacologic responsiveness of reduced L-type calcium currents in myocytes surviving in the infarcted heart. J Cardiovasc Electrophysiol 7:20-35
Boyden, P A (1996) Cellular electrophysiologic basis of cardiac arrhythmias. Am J Cardiol 78:4-11
Jeck, C; Pinto, J; Boyden, P (1995) Transient outward currents in subendocardial Purkinje myocytes surviving in the infarcted heart. Circulation 92:465-73
Boyden, P A (1995) Animal models of atrial flutter. J Interv Cardiol 8:687-96
Boyden, P A (1995) Models of atrial reentry. J Cardiovasc Electrophysiol 6:313-24
Steinberg, S F; Zhang, H; Pak, E et al. (1995) Characteristics of the beta-adrenergic receptor complex in the epicardial border zone of the 5-day infarcted canine heart. Circulation 91:2824-33
Aggarwal, R; Boyden, P A (1995) Diminished Ca2+ and Ba2+ currents in myocytes surviving in the epicardial border zone of the 5-day infarcted canine heart. Circ Res 77:1180-91
Boyden, P A; Pinto, J M (1994) Reduced calcium currents in subendocardial Purkinje myocytes that survive in the 24- and 48-hour infarcted heart. Circulation 89:2747-59
Tseng, G N; Boyden, P A (1991) Different effects of intracellular Ca and protein kinase C on cardiac T and L Ca currents. Am J Physiol 261:H364-79

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