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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.

Risk Stratification and Management of SCD. Management of SCD is undergoing radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiologic processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large.

Introduction: Compared to concordant T wave alternans (CA), discordant T wave alternans (DA) may be associated with an increased dispersion of repolarization (DR) and a greater propensity to develop reentrant ventricular tachyarrhythmias. The electrophysiologic mechanisms of DA in the in vivo heart are not well understood., Methods and Results: The mechanisms of DA were investigated in the canine anthopleurin-A surrogate model of long QT3 syndrome using tridimensional analysis of activation and repolarization patterns from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. Two mechanisms for the development of DA were observed. (1) Stepwise shortening of cycle length (CL) superimposed on preexisting DR resulted in different diastolic intervals (DI) at midmyocardial sites compared to epicardial and endocardial sites. The dispersion of DI coupled with different restitution kinetics at those sites induced DA. (2) The dependence of conduction velocity on DI as the CL is abruptly shortened could result in differential conduction delays at mid sites. This enhanced the dispersion of DI between sites and, coupled with the different restitution kinetics, induced DA. The critical step for the development of DA in both mechanisms was the occurrence of short ARI in two consecutive beats either at epicardial sites in the first mechanism or at mid sites in the second mechanism. Sites with DA had significantly more DR compared to sites with concordant T wave alternans, and ventricular tachyarrhythmias developed mainly in the presence of DA., Conclusion: In the in vivo heart, DA developed due to critical interaction between dispersion of DI and differences in restitution kinetics at different myocardial sites. The dispersion of DI could result from preexisting DR or differential conduction delay at a critical short CL. DA is critically linked to the development of malignant tachyarrhythmias.

Introduction: Microvolt T wave alternans (TWA) has been proposed as a strong independent predictor of malignant ventricular tachyarrhythmias and sudden cardiac death. TWA reproducibility during bicycle stress test has not been previously investigated. We sought to assess the short-term reproducibility of TWA, as well as heart rate (HR) threshold for TWA, and its spatial distribution and magnitude., Methods and Results: The study enrolled 42 patients who were able to complete two bicycle stress tests with HR at peak exercise >110 beats/min within 4 hours of each other and who had technically adequate recordings for TWA analysis during both tests. Concordant results for TWA determination were obtained in 39 (93%) of 42 cases. TWA was present during both tests in 23 patients and was absent during both tests in 16 patients. In the 23 patients with two positive tests, HR at the onset of TWA was not significantly different during the two tests. Further, the number of leads showing TWA and the magnitude of TWA were not significantly different between the two tests., Conclusion: TWA is characterized by satisfactory short-term reproducibility and, when present, by high temporal and spatial stability.