The long-term objective of this research is to provide information needed to develop pharmacologic and electrical therapies for the cardiac arrhythmias which arise after myocardial infarction. To do this we will employ optical recording to make the first ever maps of membrane action potentials in the healing infarct of the canine. In the healing phase following infarction produced by LAD ligation it is possible to induce ventricular tachycardia and fibrillation using programmed stimulation. These arrhythmias are due to or arise from reentrant excitation in the epicardial border zone, the thin layer of muscle which survives over the infarcted ventricular wall.
The specific aims of this proposal are to determine the precise mechanisms responsible for the initiation, perpetuation and stability of this reentrant activity. To do this we will employ optical recording, a technique which exploits the ability of a voltage sensitive dye to transduce the cardiac action potential into a fluorescence signal. The myocardium will be stained with this dye so that an optical recording system can monitor electrical activity at 256 adjacent sites within small areas of the surviving muscle. Although optical mapping can not cover as large an area as electrographic mapping, it has the advantage of providing the time courses of the cardiac action potentials within its field of view. We have demonstrated that the anisotropic fiber structure of the myocardium surviving over the infarct determines the properties of this reentrant excitation. The precise means by which this occurs is not yet known. Through the use of optical recordings we will be able to assess the electrophysiological and structural substrates for anisotropic reentry. To investigate the initiation of reentry we will determine the spatial distribution of excitability, refractoriness and the uniformity of anisotropy since steep gradients in these parameters, individually or in combination, can cause an initial arc of block which leads to reentry. The perceptuation of reentry is dependent on the formation of a central obstacle to impulse propagation. We will measure the spatial distribution of the electrical events in the area forming the obstacle in order to understand its mechanism. We will look at central obstacles caused by wavefront collision (leading circle), wavefront curvature (spiral wave), or refractoriness (anisotropic reentry). The stability of reentry and its response to pharmacologic and electrical perturbations is in part determined by the excitable gap. We will determine the mechanisms giving rise to the excitable gap, membrane properties vs. anisotropy, and measure its spatial and temporal extent at various points on the circuit. In order to develop a rational paradigm for arrhythmia therapy we must first have accurate knowledge of the mechanisms of clinically relevant arrhythmias as they occur in vivo. This proposal's use of optical mapping of reentrant tachycardia in the canine will provide such data.
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