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Repolarization Distribution in LQT3. Introduction: The occurrence of significant spatial dispersion of repolarization in vivo as it relates to the mechanism of arrhythmia formation in the long QT syndrome (LQTS) continues to be questioned. Methods and Results: We investigated a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution of rate-dependent spatial dispersion of repolarization in the intact heart to the arrhythmogenicity of LQTS. Optical action potentials were measured using potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action potential duration (APD) gradient, resulting in rate-dependent increased APD dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced functional conduction block along boundaries where large nonuniform APD gradient occurred setting the stage for circulating wavefronts and ventricular tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but nonuniform epicardial APD gradient persisted and could be challenged by a stimulated premature stimulus to induce VT. Conclusion: The study shows that in LQT3, spatial variations in steady-state properties result in zones of nonuniform APD gradients. These provide a substrate for functional conduction block and reentrant excitation when challenged by subendocardial “early afterdepolarization-triggered” premature beats. The study emphasizes the key importance of spatial dispersion of repolarization, whether located in epicardial or intramyocardial layers, in arrhythmia formation in LQTS. (J Cardiovasc Electrophysiol, Vol. 15, pp. 323-331, March 2004) [ABSTRACT FROM AUTHOR]