Ventricualr tachucardias which may occur during chronic ischemic heart disease are often resistant to drug therapy, as many times anriarrhythmic drug therapy fails to correct these thythm disorders.
The aims of the pressent proposal, which are an integral part of the long term objectives of our laboratory are first to determine the mechanism of such resistance to these potentially lethal rhythm disorders. Specifically we will test two hypotheses. First, resistance of ventricular tachycardia to drugs occurs because of inadequate and deficient delivery of drugs to the site of the arrhythmia. This hypothesis stems from the observations that the site of origin of the arrhythmia reside in the territory of the occluded vessel, where blood flow and drug delivery are limited. Second, resistance of the arrhythmia to drugs is caused because of inadequate antiarrhythmic efficacy of the drug itself. These two hypotheses, which are not mutually exclusive, will be tested on canine models of ischemic arrhythmias caused by coronary artery occlusion that we have developed. The site of origin if ventricular tachycardia will be determined by computer-assisted mapping techniques. Regional myocardial drug distribution and binding will be determined by new immunohistochemical techniques that we are developing and regional myocardial drug concentration will be measured by established biochemical assay techniques. Interventions designed to enhance drug delivery to the site of origin of the arrhythmia will consist if administering the drug through 1) intracoronary route, administered at a point just distal to the site of occlusion, 2) coronary venous retroperfusions systems and, 3) coronary artery reperfusion by release of the occlusive device. The influence of these interventions on regional myocardial electrophysiologic properties (conduction, excitability, refractoriness) and on ventricular tachycardia in the intact dog will then be evaluated. The results of the present study could have important clinical significance, since it has been demonstrated that ventricular arrhythmias in patients with myocardial infarction constitute independent predictors of sudden death and that their effective control with drugs, if possible, could significantly reduce mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001293-02
Application #
3073730
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1984-04-01
Project End
1989-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Meesmann, M; Karagueuzian, H S; Ino, T et al. (1991) The role of enhanced vagal activity on ischemic ventricular tachycardia: pharmacologic basis of inefficiency. Am Heart J 121:1703-13
Ino, T; Karagueuzian, H S; Hong, K et al. (1988) Relation of monophasic action potential recorded with contact electrode to underlying transmembrane action potential properties in isolated cardiac tissues: a systematic microelectrode validation study. Cardiovasc Res 22:255-64
Sugi, K; Karagueuzian, H S; Fishbein, M C et al. (1987) Cellular electrophysiologic characteristics of surviving subendocardial fibers in chronically infarcted right ventricular myocardium susceptible to inducible sustained ventricular tachycardia. Am Heart J 114:559-69
Katoh, T; Karagueuzian, H S; Sugi, K et al. (1987) Effects of propafenone on sinus nodal and ventricular automaticity: in vitro and in vivo correlation. Am Heart J 113:941-52
Ohta, M; Karagueuzian, H S; Mandel, W J et al. (1987) Acute and chronic effects of amiodarone on delayed afterdepolarization and triggered automaticity in rabbit ventricular myocardium. Am Heart J 113:289-96
Meesmann, M; Karagueuzian, H S; Ino, T et al. (1987) Selective perfusion of ischemic myocardium during coronary venous retroinjection: a study of the causative role of venoarterial and venoventricular pressure gradients. J Am Coll Cardiol 10:887-97
Karagueuzian, H S; Ohta, M; Drury, J K et al. (1986) Coronary venous retroinfusion of procainamide: a new approach for the management of spontaneous and inducible sustained ventricular tachycardia during myocardial infarction. J Am Coll Cardiol 7:551-63
Karagueuzian, H S; Sugi, K; Ohta, M et al. (1986) The efficacy of lidocaine and verapamil alone and in combination on spontaneously occurring automatic ventricular tachycardia in conscious dogs one day after right coronary artery occlusion. Am Heart J 111:438-46
Karagueuzian, H S; Sugi, K; Ohta, M et al. (1986) The efficacy of cibenzoline and propafenone against inducible sustained and nonsustained ventricular tachycardias in conscious dogs with isolated chronic right ventricular infarction: a comparative study with procainamide. Am Heart J 112:1173-83
Sugi, K; Karagueuzian, H S; Fishbein, M C et al. (1985) Spontaneous ventricular tachycardia associated with isolated right ventricular infarction, one day after right coronary artery occlusion in the dog: studies on the site of origin and mechanism. Am Heart J 109:232-44

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