SUMMARYTo obtain information conceming the time course and instantaneous distribution of the excitatory process of the normal human healt, studies were made on isolated human hearts from seven individuals who died from various cerebral conditions, but who had no history of cardiac disease. Measurements were made from as many as 870 intramural terminals.In the isolated human hearts three endocardial areas were synchronously excited o to 5 msec after the start of the left ventricular activity potential. These areas increased rapidly in si ze dUl'ing the next 5 to 10 msec and became confluent in 15 to 20 msec. The left ventricular areas Rrst excited were (1) high on the anterior paraseptal wall just below the attachment of the mitral valve; (2) central on the left surface of the interventricular septum and (3) posterior paraseptal about one third of the distance from apex to base. The last part of the left ventricle to be activated usually was the posterobasal area. Endocardial activation of the right ventricle was found to start ne ar the insertion of the anterior papillary muscle 5 to 10 msec af ter onset of the left ventricular cavity potential. Septal activation started in the micldle third of the left side of the interventricular septurn, somewhat anteriorly, and at the lower third at the junction of the septum and posterior wall. The epicardial excitation pattem reflected the movements of the intramural excitation wave. Conduction velo city was determined in one heart by an appropriate stimulation technic. Atrial excitation, explored in two hearts, spread more or less according to concentric isochronic lines. Control studies, carried out on Rve canine hearts, disclosed that the pattem of ventricular excitation did not change af ter isolation and perfusion. However, total excitation was completed earlier in the isolated heart, and conduction velo city increased.Careful mapping illustrations are presented.Additional Indexing W ords:Ventricular excitation Intramural conduction velo city Epicardial excitation Atrial excitation K NOWLEDGE of the time course and instantaneous distribution of the excitatory pro ce ss of the normal human heart would be of value for an understanding of the QRS complex.Studies of this process during surgical intervention for heart disease or pulmonary

Slow conduction perpendicular to the fiber direction in infarcted myocardial tissue is caused by a "zigzag" course of activation at high speed. Activation proceeds along pathways lengthened by branching and merging bundles of surviving myocytes ensheathed by collagenous septa.

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The Lambeth Conventions are guidelines intended to be of practical value in the investigation of arrhythmias induced by ischaemia, infarction, and reperfusion. They cover the design and execution of experiments and the definition, classification, quantification, and analysis of arrhythmias. Investigators are encouraged to adopt the conventions in the hope that this will improve uniformity and interlaboratory comparisons.

The scientific and clinical basis of drug-induced QT prolongation and proarrhythmia was summarized by formal presentations. The speakers were chosen for their particular competence in the relevant field. Furthermore, selected topics were discussed in detail in separate workshops. This document represents the executive summary of the Conference. It is based on written reports composed by the speakers and the chairs of the workshops. Before preparation of the final version of the document, a draft was circulated to all participants of the Conference for suggestions and comments. The opinions expressed in this document are those of the participants and do not necessarily reflect the official position of their organisations or agencies. The meeting was made possible by unrestricted educational grants to the Committee for Scientific and Clinical Initiatives of the ESC from several companies listed in the Appendix. The problemQT interval prolongation, and possibly increased QT dispersion, are risk factors in a number of cardiovascular as well as non-cardiovascular diseases. A variety of drugs prolong the QT interval, although the major examples are the so-called class III antiarrhythmics. These drugs generally exert their therapeutic effect by affecting potassium ion channels, thereby reducing outward, repolarizing current, and prolonging action potential duration and the QT interval. Many of these drugs have been developed for conversion of atrial fibrillation and/or maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Such patients are at low risk of potentially fatal arrhythmias, at least in the absence of antiarrhythmic drug therapy.However, antiarrhythmic drugs which prolong cardiac repolarization are not harmless, as they may induce

Background-Progressive activation delay starting at long coupling intervals of premature stimuli has been shown to correlate with sudden cardiac death in patients with hypertrophic cardiomyopathy. The purpose of this study was to elucidate the mechanism of increased activation delay in chronically diseased myocardium. Methods and Results-High-resolution unipolar mapping (105, 208, or 247 recording sites with interelectrode distances of 0.8, 0.5, or 0.3 mm, respectively) of epicardial electrical activity was carried out during premature stimulation in 11 explanted human hearts. The hearts came from patients who underwent heart transplantation and were in the end stage of heart failure (coronary artery disease, 4; hypertrophic cardiomyopathy, 1; and dilated cardiomyopathy, 6). Eight hearts were Langendorff-perfused. Epicardial sheets were taken from the remaining hearts and studied in a tissue bath. Activation maps and conduction curves were constructed and correlated with histology. Conduction curves revealing prominent increase of activation delay were associated with zones of dense, patchy fibrosis with long fibrotic strands. Dense, diffuse fibrosis with short fibrotic strands only marginally affected conduction curves. The course of conduction curves in patchy fibrotic areas greatly depended on the direction of propagation relative to fiber direction. Conclusions-The study demonstrates that in chronically diseased human myocardium, nonuniform anisotropic characteristics imposed by long fibrotic strands cause a progressive increase of activation delay, starting at long coupling intervals of premature stimuli. The increase strongly depends on the direction of the wave front with respect to fiber direction and the architecture of fibrosis.

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This review focuses mainly on studies in non-ischemic animal models of heart failure. These animals develop ventricular arrhythmias, mostly non-sustained ventricular tachycardia, and often die suddenly. Clinical studies suggest that sudden death is due to ventricular tachycardia or fibrillation in about 50% of cases, the other half to bradyarrhythmias or electromechanical dissociation. Electrophysiologic changes in heart failure are not confined to the ventricles: the intrinsic sinus rate is reduced due to a downregulation of If and sensitivity to acetylcholine is enhanced by upregulation of the muscarinic receptor. Reduction of heart rate may be a protective mechanism since at rapid rates contractility is reduced and the likelihood for triggered activity due to delayed afterdepolarizations is enhanced. The beneficial effect of beta-adrenergic blockade in patients may be partly due to the reduction in sinus rate. Although the results of different studies often vary, the most consistent electrophysiological changes in the ventricles are prolongation of the action potential, especially at slow rates, a reduction in the transient outward current Ito, the rapid and slow components of the delayed rectifier Ikr and Iks, and the inward rectifier Ik1. Abnormalities in intracellular calcium handling play a major role in the genesis of delayed afterdepolarizations. Triggered activity based on delayed afterdepolarizations has been demonstrated in failing myocardium and are caused by spontaneous release of calcium from the sarcoplasmic reticulum (SR), especially in the presence of noradrenaline. Three factors combine to the enhanced propensity for the occurrence of delayed afterdepolarizations: (1) increased activity of the Na/Ca exchanger, (2) a reduced inward rectifier, (3) residual beta-adrenergic responsiveness required to raise the reduced sarcoplasmic calcium content to a level where spontaneous calcium release occurs. Early afterdepolarizations have also been demonstrated, especially in human myocytes from failing hearts in the presence of noradrenaline. Mapping experiments have shown that the ventricular arrhythmias are mainly due to non-reentrant mechanisms, most likely triggered activity based on delayed afterdepolarizations.