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Alterations in cardiac electrophysiology that accompany myocardial infarction were studied in dogs subjected to a two-stage ligation of the anterior descending coronary artery. A multipolar transmural needle electrode was used to record electrical activity from the in situ infarcted heart 24 hours after coronary occlusion. Bipolar electrograms recorded from subendocardial regions of infarcted myocardium demonstrated the persistence of early, rapid deflections suggesting Purkinje fiber activity; evidence of ventricular muscle activity in the infarct was absent in both subendocardial and intramural electrograms. The infarcted myocardium and the adjacent non-infarcted tissue were then excised and studied with intracellular microelectrodes in vitro. Transmembrane action potentials could be recorded from one or two cell layers of subendocardial Purkinje fibers at all sites within the infarcted region, but no ventricular muscle action potentials were found. Subendocardial Purkinje fibers which survived in the infarct had reduced maximum diastolic potentials, action potential amplitudes, and maximum depolarization velocities compared with normal subendocardial Purkinje fibers; also, action potential durations in these surviving fibers were extraordinarily prolonged. Spontaneous diastolic depolarization was evident in some surviving fibers. Since subendocardial Purkinje fibers that generate abnormal action potentials survive in an infarct, these fibers may participate in the genesis of ventricular arrhythmias that accompany infarction.

The various effects of digitalis upon the electrocardiogram are reviewed and grouped with regard to their clinical significance. Therapeutic or toxic actions of digitalis seem to depend on as yet poorly understood relationships to potassium metabolism. An insight into this relationship might be gained in the future in view of recent developments in the field of cardiac electrophysiology.

In the application of antiarrhythmic drugs in patients, a thorough knowledge of their pharmacological effects greatly aids the clinician in the more rational selection of the drug or combination of drugs in terms of expected benefits, favourable additive actions, and contra-indications. Each of the agents depresses disorders of rapid impulse formation (repetitive ectopic pacemaker activity) by reducing diastolic depolarisation and thereby diminishing automaticity, and inhibits disorders of impulse conduction (re-entry tachyarrhythmias) by altering conduction velocity and refractory period and thereby interrupting reciprocal excitation pathways.

The catheter technique of His bundle (HBE) recordings proved to be useful in the analysis of retrograde conduction in the human heart. Retrograde activation of the His bundle was more easily detected in bipolar HBE leads with interelectrode distances of 1 mm (or less) than in leads with an interelectrode distance of 10 mm. A high bipolar atrial electrogram (BAE) simultaneously recorded with the HBE was essential to differentiate between superoinferior (sinoventricular) or inferosuperior (retrograde) activation of the atria. V-A delays occurred both above (nodal region) and below (Purkinjebundle branch specialized tissues) the His bundle. The greatest area of delay was seen in the A-H (nodal) region. Ventricular echoes were observed during continuous and intermittent paired ventricular pacing. The atria appeared to be a necessary link in the production of echoes. The echoes, which passed through the His bundle during their forward and retrograde propagation, were best explained by a functional (longitudinal) intranodal dissociation. The reciprocating circuit was represented as follows: V → H → FCP → α → A → β → FCP → H → V. The study of His bundle recordings has enhanced our knowledge of cardiac electrophysiology.

His bundle electrocardiography has enhanced our knowledge of cardiac electrophysiology. The catheter technique for recording potentials from the specialized conducting tissues is most useful in determining the site (or sites) of atrioventricular and ventriculoatrial delays and blocks. Various types of ventricular preexcitation resulting from conduction through Kent, Mahaim and James bundles are adequately identified with this method. In some cases it provides the only means of differentiation between supraventricular and ventricular arrhythmias. A secondary gain obtained from His bundle recordings is the evaluation of the electrophysiologic effects of various drugs. Information thus obtained is not only academically important but also clinically useful, since it is a significant factor in establishing the proper therapy.

T he use of transvenous pacing catheters is not without potential complications and problems. One of these, associated with a high incidence of failure to pace, is inadvertent passage of the catheter through the coronary sinus into a coronary veL1x2 The use of a routine posteroanterior chest x-ray film to diagnose this complication is often unreliable.2 A superior location of the catheter tip between the left atrium and the posterobasal (or lateral) aspect of the left ventricle suggests passage into the great cardiac vein or beyond.3 However, passage into the middle cardiac vein is more difficult to diagnose with a posteroanterior film, although a lateral view will demonstrate the posterior location of the tip.2 Electrocardiographic diagnosis of malposition may be of some help. For instance, the mean QRS vector of paced ventricular beats when the catheter tip is in the great cardiac vein is inferiorly directed and associated with a right bundle branch block (RBBB) pattern due to delayed activation of the right ventricle,4 while a middle cardiac vein location is indicated by left axis duration (due to inferior site of stimulation) and a RBBB pattern (due to the posterior location of the electrodes) .2 Despite the fact that great cardiac vein catheterization is a troublesome complication for purposes of pacing, the intentional use of this technique for studies of human cardiac electrophysiology may prove to be quite useful. We are currently evaluating the use of coronary sinus and His bundle electrograms in analyzing the activation process of the human heart.

The sequence of conduction through the intraventricular conducting system and endocardial muscle was studied by microelectrode mapping of large areas of isolated canine ventricular tissue. We found that most of the endocardium of the right ventricular free wall is activated simultaneously whereas the left endocardial muscle is activated in an apex-to-base sequence. Right septal activation is from apex to base, and the left septum is activated first at the junction of the middle and lower thirds of the septum and then as a bidirectional wave front toward the apex and the base. These right-left differences occur because the sites of impulse input into muscle on the right encompass the entire free wall, base of the papillary muscle, and the lowermost septum, and on the left are primarily limited to the lower ventricular cavity, lower septum, and bases of the papillary muscles. These patterns of left ventricular excitation relate to the presence of a functionally continuous ring of conducting tissue formed by a merger of the major divisions of the left bundle branch on the upper left ventricular free wall. The "ring" itself is electrophysiologically isolated from muscle, but connects to a network of subendocardial conducting tissue extending to the apex and having input to muscle only in its lower portions.

Electrocardiograms recorded during movement of the patient may be distorted by gradual and abrupt shifts in the base line. Both forms of artifact can be visually excluded by interpreting only those complexes that appear in superimposable pairs. Base-line horizontality is not essential for the accurate measurement of waves. The overlap in time and consequent voltage summations of T, U, and P waves in tachycardia may cause misinterpretations of cardiac electrophysiology by obscuring the onsets and terminations of waves, by altering the position of wave apexes, and by producing distortions of amplitude. Wave summations alone may in some cases explain apparent P-wave enlargement and T a -wave visualization. P-R segment extrapolation techniques for S-T segment evaluation can be safely employed only with a knowledge of the undistorted P amplitude and duration and the components of the sloping P-R segment.

In the atrioventricular (AV) nodal Wenckebach phenomenon, there is a progressive increase in the P-R interval and a concomitant reduction in the R-P interval. Two series of experiments were conducted on anesthetized dogs to ascertain whether the changes in the P-R interval depended on the associated changes in the R-P interval. In one series of experiments, the atrium was paced at various basic cycle lengths, and a single test cycle was interposed about every 100 beats. When the test cycle was very short, the increase in the P-R interval sometimes exceeded the associated reduction in the R-P interval. During the subsequent basic cycle, although the P-P interval was much greater than it was during the test cycle, there was a further reduction in the R-P interval. When this change in the R-P interval was appreciable, AV conduction failed despite the increase in cycle length. In the second series of experiments, the AV nodal Wenckebach phenomenon was induced by rapid atrial pacing. When the stimulation mode was suddenly altered to maintain a constant R-P interval, the Wenckebach rhythm immediately ceased, although the mean heart rate had not changed significantly. Therefore, it appears that above a critical heart rate a positive feedback loop is established in which an increase in the P-R interval evokes a corresponding decrease in the R-P interval. In turn, the curtailed R-P interval that reflects a less complete recovery of AV nodal excitability elicits a still greater increase in the P-R interval. This cycle continues until an impulse is ultimately blocked. Clamping the R-P interval opens the feedback loop and terminates the arrhythmia.

Experiments were performed on open-chest anesthetized dogs to determine the quantitative effects of autonomic nerve stimulation on pacemaker activity and conduction. The lead II electrocardiogram together with bipolar electrograms were recorded from the atria, the His bundles, and the ventricles. The vagi or the stellate ganglia were stimulated in dogs which exhibited either sinus rhythm, ectopic atrial rhythm, junctional rhythm, or ectopic ventricular rhythm. The time courses of the change in heart rate in response to vagal or stellate stimulation were characteristic for each type of rhythm. The characteristic responses of different cardiac pacemaker sites to autonomic influence were demonstrated to be important factors in the production of wandering pacemakers and in the emergence of ectopic beats. Sinus pacemaker activity was more sensitive to modification by autonomic stimulation than was atrioventricular (AV) conduction. However, subliminal autonomic effects on AV transmission were brought out during conduction of premature atrial beats, thereby demonstrating a coupling interval dependency of autonomic influences on AV conduction. The present experiments also showed how fluctuations in autonomic activity could result in Mobitz type II second-degree heart block, pseudosupernormal conduction, and the concertina effect observed in the preexcitation syndrome.

In this review, we are concerned with the most recent advances in single cell cardiac electrophysiology and pharmacology. We have restricted ourselves to research papers that appeared in the 2 years since our last review [1] and additionally certain articles of special interest. The reader is referred to the comprehensive review by SZEKERES and PAPP published in this journal [2] and to the monograph by the same authors for more extensive surveys of the many actions of numerous antiarrhythmic drugs [3]. There also are several recently published reviews and symposia dealing with various aspects of cardiac arrhythmias and therapy [4–12]. We agree with SZEKERES and PAPP [3] that it is almost impossible to completely review the ever increasing number of publications on this subject. One reason for the voluminous literature is the multiple experimental approaches used to attack the problems of arrhythmia formation and the modes of action of antiarrhythmic drugs. Our own approach is based to a great extent on studies utilizing intracellular microelectrode recording techniques [13–15]. This method permits the direct characterization of the electrophysiological properties of single cells in the heart. We will consider and evaluate recent publications concerned with cardiac arrhythmias and antiarrhythmic drugs with particular emphasis on new experimental methods which expand the physiological significance of data obtained through the use of microelectrode recording techniques.

Current concepts of the mechanisms responsible for the cardiac action potential are reviewed, as are the relations between the electrical activity and cardiac contraction. The development of techniques allowing direct control of the membrane voltage of cardiac cells has led to a rapid increase in our understanding of the cellular basis of cardiac electrophysiology. There appear to be 8 separately identifiable ionic channels that interact to produce the distinctive cardiac action potential. These “voltage clamp” methods also provide a new approach to the study of excitation-contraction coupling in heart muscle. The application of these methods has led to several new ideas about the relation between membrane voltage and contraction. In addition to triggering contraction, the cardiac action potential plays an important role in the control of contraction, and the nature of this electrical control is examined.

The potential distribution at the atrial surface during depolarization and repolarization was studied in intact dogs. A preparation was developed by implanting 30 to 40 miniature electrodes permanently on each atrium to record unipolar electrograms in the intact animal. Heart block was created to dissociate atrial and ventricular activity. The electrograms were recorded on magnetic tape and atrial isopotential heart maps produced with the use of a digital computer. The changing potential distribution during excitation indicated the early presence of multiple wave fronts which were related primarily to the crista terminalis, Bachmann's bundle, and a special bundle to the base of the right appendage. The interatrial septum provided a conducting bridge which had an important influence of global atrial excitation, depending on the site of impulse formation. Colliding excitation wave fronts were quite prominent. During terminal atrial excitation, repolarization maxima were present simultaneously with depolarization maxima. Repolarization was characterized by a changing potential distribution which followed the same general pattern as excitation spread; and, furthermore, the earliest areas of excitation were associated with a repolarization maximum and terminal areas of excitation were associated with repolarization minima.

Action potentials studied in 36 human atrial strips at 27°C were found to be separated into two components. Simultaneous recordings with two microelectrodes demonstrated an independent conduction of the second component through selective and variable pathways. Increased separation of the two components was elicited by higher rate and lower intensity of stimulation, high K + , low Ca 2+ hypertonic solutions as well as by low temperature. Opposite procedures resulted in a more homogeneous and less variable excitation. Consequently, low rate and high intensity of stimulation allowed the study of the membrane permeabilities related to the two successive depolarizations. The first was suppressed by tetrodotoxin, the second by MnCl 2 and both by low Na + solutions. Hence, it was concluded that the separation was related to a nonhomogeneous excitation of the preparation and that the two components are triggered by two relatively independent depolarizations using different channels. Furthermore, the small amplitude of the first depolarization, without overshoot, and its modifications with stimulation intensity suggest that it might be due to an electrotonic spread or to a junctional mechanism.

Microelectrode studies of transmembrane potentials of canine Purkinje fibers show that phase-4 depolarization causes voltage-dependent changes in conduction and responsiveness similar to those occurring during repolarization at comparable levels of potential. Abnormalities ranged from simple slowing of conduction to decrement, unidirectional and bidirectional block, and unexcitability. Reentrant excitation also developed. Significant conduction disturbances usually appeared at -75 to -70 mv; decrement and advanced block at -65 to -60 mv, or below. Because the threshold potential of normal Purkinje cells is approximately -70 mv, depolarization to lower levels implies shifts in this variable toward 0. Determinations of threshold potential confirm such shifts. It may be further inferred that significant abnormalities would most likely occur in fibers in which threshold potential is shifted toward 0 or membrane responsiveness impaired. Alterations in conduction due to phase-4 depolarization provide a reasonable explanation for various peculiarities of cardiac rhythm, including occurrence of conduction disturbances and reentrant rhythms at low heart rates, exit and entry block about parasystolic foci, instability of peripheral Purkinje pacemaakers, and supernormal conduction. Circumstances that enhance phase-4 depolarization are common in diseased hearts, indicating that this mechanism may be a significant factor in human arrhythmias.

Pacemakers have special value in the primary treatment of major arrhythmias. With the availability of cardiac pacemakers and cardioversion with direct-current countershock, indications for medical therapy of both bradycardias and tachycardias have been revised.

Lidocaine has been found to be effective in the control of mechanically induced arrhythmias as may occur during the course of cardiac surgery.