Myron Prinzmetal

Angina pectoris. IV. Clinical and experimental difference between ischemia with S-T elevation and ischemia with S-T depression.

Abstract 1. 1. Two types of primary S-T deviation, primary S-T depression and primary S-T elevation, have been observed clinically and demonstrated in experiments on animals. 2. 2. Experiments in dogs demonstrated that S-T segment elevation is associated with more severe ischemia than S-T segment depression, confirming clinical impressions in patients with myocardial infarction and/or angina pectoris. 3. 3. Release of the tie on a large coronary artery resulted in reduced severity of ischemia; S-T elevation was diminished and in most instances replaced by transient S-T depression. This parallels clinical observations in patients during a severe attack of the variant form of angina pectoris. 4. 4. Hemorrhagic hypotension following ligation of a large coronary artery resulted in further increase in S-T segment elevation over the cyanotic area and widely scattered “islands” of S-T depression appeared over both ventricles. S-T elevation over the cyanotic area decreased and the “islands” of S-T depression disappeared upon restoration of normal blood pressure. This illustrates the deleterious effect of shock in acute coronary occlusion and underlines the importance of maintaining adequate systemic blood pressure. 5. 5. Primary S-T depression, as demonstrated in different experiments, occurs with ischemia and under nonischemic conditions due to chemical alterations. Primary S-T depression is in no way at variance with the principle of reciprocity or other fundamental laws of electrocardiography. 6. 6. S-T segment depression and S-T segment elevation are due to two different types of cellular response. 7. 7. The experimental findings suggest that development of ischemia and recovery from ischemia may occur along different metabolic pathways. 8. 8. The effect of collateral circulation was studied by means of two artificial coronary artery circuits providing independent control of the blood supply to the central part of the ischemic area and its periphery. It was demonstrated that collateral circulation diminishes the extent and degree of ischemia simultaneously with the appearance of primary S-T depression from the periphery of the ischemic area.

Myocardial Ischemia Nature of Ischemic Electrocardiographic Patterns in the Mammalian Ventricles as Determined by Intracellular Electrographic and Metabolic Changes

Abstract Severe ischemia results in serious damage to myocardial cells and their membranes. As a consequence, K+ is lost from these cells and intracellular Na+ concentration probably rises. These changes produce a decrease in the transmembrane ionic gradient for these substances and probably hypopolarization of the cell membranes. This is manifested in the intracellular electrogram by a decrease in negativity of the membrane resting potential of the individual subepicardial ischemic cells. In direct electrograms from the epicardium over these cells the T-Q segment becomes depressed. This T-Q depression is indicated in the clinical electrocardiogram as S-T elevation. Perfusion of nonischemic myocardium with solutions of high K+ or low Na+ concentration produces intracellular and surface electrographic changes similar to those of severe ischemia. This supports the theory that metabolic changes such as those just described are at least part of the fundamental cause of the electrocardiographic changes of severe ischemia. In all probability, other chemical and metabolic factors also play a role in their production. Mild ischemia produces an increased uptake of K+ and probably glucose by the myocardial cells. As a result, the transmembrane ionic gradient for K+ increases and a state of hyperpolarization may occur. This causes an increase in membrane resting potential of the individual cells, manifested in the overlying surface electrogram by elevation of the T-Q segment. In the clinical electrocardiogram this appears as S-T depression. Perfusion of nonischemic myocardium with solutions of low K+ or high Na+ ion concentration produces intracellular and surface electrocardiographic changes similar to those of mild ischemia. This again provides support for the belief that such metabolic changes may be in part responsible for the electrocardiographic phenomena of mild ischemia. The increase in amplitude of the R wave often observed early in severe ischemia appears to be the result of delayed conduction in the ischemic muscle. The tall R wave is also widened because of this delay. The S wave is buried in the wide R wave and thus becomes smaller or entirely invisible. The increase in intracellular K+ and glucose in mild ischemia may represent a homeostatic mechanism by which the cells prepare themselves for injury by severe ischemia. The fact that the electrographic and electrocardiographic phenomena of the two kinds of ischemia are almost opposite in nature then becomes understandable as a manifestation of such a mechanism.

Angina pectoris. V. Giant R and receding S wave in myocardial ischemia and certain nonischemic conditions.

Abstract 1. 1. Increase in the R wave and decrease in the S wave have been clinically observed with myocardial infarction and during episodes of the variant form of angina pectoris. 2. 2. The same changes have been reproduced in experiments with animals by acute ischemia. 3. 3. The electrocardiographic changes were most marked from the center of the ischemic area, where ischemia is most severe, and became progressively smaller as recorded toward the periphery. 4. 4. The term “giant R” wave has been used to describe this marked increase in amplitude of the R wave. 5. 5. The giant R wave has been demonstrated during severe attacks of the variant form of angina pectoris. As pain subsided, the R wave gradually returned to the preattack level. These findings are similar to those observed in experiments on animals after ligation of a large coronary artery and release of the ligation. 6. 6. Hemorrhagic hypotension following coronary occlusion resulted in increased severity of ischemia. There was an additional increase in the R wave and the S wave receded or disappeared. These changes were reversed with return to normal systemic pressure by transfusion. 7. 7. In ischemia with S-T depression due to hemorrhagic hypotension, a decrease in the R wave and an increase in the S wave sometimes occur. This is similar to findings in severe classic angina pectoris. R and S wave changes in ischemia with S-T depression are opposite to those seen in ischemia with S-T elevation. 8. 8. Injection of potassium and sodium in various concentrations directly into a coronary artery produced characteristic R and S changes under nonischemic conditions. High concentration potassium or low concentration sodium resulted in increased amplitude of R waves and decreased amplitude of S waves. Low concentration potassium or high concentration sodium resulted in reduced amplitude of R waves and increased amplitude of S waves. Five per cent glucose in water injected directly into the coronary artery produced a large increase in the amplitude of the R wave and a marked receding or disappearance of the S wave, together with the appearance of S-T depression. 9. 9. Among the explanations for these changes in the R and S waves, the possible role of the membrane action potential, of electrical conductivity of the extracellular medium and of the propagation process have been discussed. 10. 10. Increases in the R wave and decreases in the S wave are noted in severe acute ischemia and may have great clinical significance. When decrease in the R wave and increase in the S wave occur, ischemia probably is less severe in that particular part of the heart. 11. 11. Similar changes in the R and S waves can occur with electrolyte alterations without ischemia.

Intramural Depolarization Potentials in Myocardial Infarction A Preliminary Report

By means of small intramural electrodes, potentials at multiple depths within the ventricular wall were recorded in myocardial infarction and in normal hearts. In 41 animals with coronary artery occlusion, electrocardiographic and histologic correlations indicated that coronary QS waves may represent negative potentials transmitted from viable intramural muscle as well as from the cavity. Coronary QR waves were obtained over transmural infarcts containing a mixture of viable and dead tissue, but not over purely subendocardial lesions. In the normal ventricle, positive depolarization potentials greatly predominated over negative potentials. Clinical applications are discussed.

Angina pectoris: III. Demonstration of a chemical origin of ST deviation in classic angina pectoris, its variant form, early myocardial infarction, and some noncardiac conditions∗☆

Abstract The experimental data here reported indicate that ST deviation is related largely to a change in the balance between intra- and extracellular electrolytes. This change in intra- and extracellular electrolyte balance occurs in ischemic heart disease as well as in a wide variety of noncardiac conditions.

ANOMALOUS ATRIOVENTRICULAR EXCITATION: PANEL DISCUSSION

H. H. HECHT (University of Utah, Salt Lake City, Utah) : Although we are not primarily concerned with the clinical and physiological aspects of abnormal ventricular excitation, it would seem beneficial to follow the searching analysis of the normal propagation of depolarization presented on the preceding pages with an account of a peculiar syndrome that may occur in otherwise normal individuals-a syndrome characterized by an unusual deformation of the early portion of the QRS complex. Detailed electrocardiographic analyses have led to certain inevitable conclusions that presented the anatomist and the histologist with pointed questions. FIGURE 1 illustrates the general configuration of the entity, a short PR interval with a wide QRS complex in a subject who a t other times displayed an entirely normal atrioventricular (AV) and intraventricular conduction, and who, in the sequence from which the illustration was taken, alternated between normal and abnormal complexes. When the two types of complexes are superimposed (FIGURE 2) it is clear that a relationship exists between the normal and the abnormal complex: the QRS deformation involves only the early portion of QRS, and ventricular depolarization obviously begins earlier in the abnormal complex, encroaching upon the normal PR interval. PR is, therefore, short, while PS and the interval from the beginning of P to the summit of R are identical with those of the normal complexes. Because of its shape, the abnormal early portion of QRS has been termed the “delta wave.”’ If the disorder is due to some unusual spread of excitation over ventricular musculature, the spread of recovery will be altered correspondingly and, therefore, T will change in size and direction (FIGURES 1 and 2). The basic myocardial function will remain unchanged and the total area of QRS and T, the ventricular gradient, will therefore remain unaltered. Some frontal plane measurements for normal and abnormal complexes are listed in TABLE 1. I t is generally referred to as the Wolff-Parkinson-White (WPW) syndrome according to the authors of the first definite account: although isolated cases were reported before, the first by Wilson in 1915.3 The more descriptive term “anomalous atrioventricular excitation,” coined in 194S14 implies no more than the existence of an unusual excitatory sequence, the presence of which cannot be denied. We have made this term the title for the panel. Prinzmetal has demonstrated that experimental procedures involving the atrioventricular junction may result in similar electrocardiographic complexes, and he has proposed the concept of “accelerated conduction.llS Others have demonstrated that complexes of this type may occur as a consequence of damage to certain portions of the ventricular musculature, including the septum.6

Mechanism of the Auricular Arrhythmias

The four auricular arrhythmias, premature systoles, paroxysmal tachycardia, flutter, and fibrillation, have been investigated in over 200 dogs by three methods: (1) high speed cinematography, (2) cathode-ray oscillography, and (3) multiple-channel electrocardiography. The hitherto unexplored body of the left auricle has been surgically exposed and thoroughly studied. Results indicate that all four arrhythmias are of unitary origin and may occur from one ectopic focus. The resulting arrhythmia depends largely upon the rate of discharge from that focus. There is no circus movement. Corroborative observations have been made on the arrhythmias in man. This conception of the auricular arrhythmias simplifies the understanding of their mechanism.

Angina pectoris. II. Observations on the classic form of angina pectoris (preliminary report)

1. 1. Surgical procedures for the treatment of arteriosclerotic heart disease has made the recording of direct epicardial electrocardiograms possible in 15 patients with severe classic angina pectoris. Numerous “islands” of S-T segment depression widely scattered over all epicardial surfaces of both ventricles have been demonstrated. Areas other than these “islands” showed isoelectric S-T segments. “Islands” with epicardial S-T depression were not found in control patients. 2. 2. The “islands” with S-T segment depression could not be distinguished by virtue of pallor or cyanosis from the areas with isoelectric S-T segments. 3. 3. The occurrence of S-T segment depression in standard leads in classic angina is explained by the diffuse distribution of these “islands” of S-T segment depression. Standard leads face the “islands” of depression. 4. 4. The absence of reciprocal S-T segment elevation in other standard leads in classic angina is also explained. Reciprocal S-T elevation in standard leads is not manifest since the primary areas of S-T depression are located all over the ventricles. The occurrence of primary S-T segment elevation in the variant form of angina is noted, together with its restriction to a large discrete area supplied by a large coronary artery. In the variant form of angina the S-T segment depression is reciprocal in nature, in contrast to classic angina pectoris, in which reciprocal S-T segment changes are not noted in standard leads. 5. 5. Diffuse “islands” of epicardial S-T segment depression were produced experimentally in dogs by bleeding to markedly hypotensive levels. These “islands” of S-T segment depression in dogs could not be distinguished visually from areas with isoelectric S-T segments. Similar findings were noted in human beings with angina pectoris. 6. 6. Ligation of a large branch of the anterior descending coronary artery in dogs produced a large discrete area in which only epicardial S-T segment elevation was recorded. This area with S-T elevation was distinctly cyanotic, in contrast to the previously described “islands” with S-T depression which were not visually distinguishable. These findings were similar to those in patients with the variant form of angina pectoris. 7. 7. The similarity of local hypotension at the distal end of partially constricted coronary arteries, to generalized hypotension in the presence of normal coronary arteries is noted. 8. 8. The frequent persistence of classic angina following a myocardial infarction is explained by the diffuse location of the “islands” with S-T depression. Following infarction, many such “islands” remain. The disappearance of the variant form of angina following a myocardial infarction also is explained as being due to the localization of the changes to the single area which has been infarcted. 9. 9. The occurrence of S-T elevation in the variant form of angina makes prediction of the site of future infarction possible. The occurrence of S-T depression in classic angina does not permit prediction of the site of future infarction. 10. 10. The appearance of epicardial cyanosis in areas with S-T segment elevation on temporary ligation of a coronary artery suggests that coronary artery hypertonus may precipitate the variant form of angina with its S-T segment elevation. The absence of epicardial cyanosis in patients with classic angina, and in dogs with hypotension, suggests that coronary artery hypertonus is not the usual cause of classic angina. 11. 11. Ventricular arrhythmias are noted frequently in the clinical and simulated variant form of angina. They occur after the pain has been present awhile and has risen to a certain intensity. Arrhythmias are rare in the simulated form of classic angina, except for terminal ventricular fibrillation. Sudden deaths in classic angina probably occur as a result of ventricular fibrillation developing suddenly. 12. 12. Several clinical conditions are presented in which S-T segment depression is found in the absence of changes limited to the subendocardium. A number of experiments are presented indicating that the subendocardium does not contribute in significant degree to S-T segment deviations. These experiments indicate that S-T segment depressions are due to disturbances in the outer myocardial layers. 13. 13. The marked difference between S-T changes in classic angina pectoris (with S-T depression) and those in the variant form of angina or early myocardial infarction (with S-T elevation) suggests different chemical changes within the myocardium.7

Studies on the Mechanism of Ventricular Activity

Controlled studies of ventricular excitation were performed in dogs exhibiting various Degreess of right and left bundle-branch block. Increases in the intraventricular conduction time during complete bundle-branch block are attributed to free wall as well as septal factors. Incomplete bundle-branch block may be either segmental or diffuse. In the segmental type, delayed excitation is present in only a portion of the involved ventricle. In the diffuse type, delayed excitation of the entire homolateral ventricle occurs, but some portions of the ventricle tend to be delayed to a greater extent than others. Certain segements of the ventricular myocardium appear to be supplied by fixed portions of the conducting system, without cross connections operating physiologically. The clinical implications of these observations are briefly discussed.

Studies on the mechanism of ventricular activity. V. Intramural depolarization potentials in the normal heart with a consideration of currents of injury in coronary artery disease.

Abstract 1. 1. By means of a specially designed plunge electrode, intraventricular leads were recorded from multiple sites throughout the walls, papillary muscle, septum and cavities of thirty-two dogs during normal sinus rhythm. A series of experiments was performed which established (a) that the presence of the plunge electrode in the myocardium did not alter the normal course of depolarization, and (b) that the depolarization complexes registered by the plunge electrode represented essentially local potentials. 2. 2. Pure QS or rS waves were recorded throughout at least the innermost two-thirds of the intramural myocardium in both ventricles as well as from all levels of the left papillary muscle. Intraseptal leads also exhibited essentially negative deflections, although considerable positivity was noted in the center and right side of the septum. Only the epicardial surface and a thin subjacent layer of the walls yielded predominantly positive depolarization complexes. In general, negative potentials were found to predominate in roughly 80 per cent of the musculature during ventricular depolarization while about 20 per cent of the myocardium was predominantly positive. This observation indicates that the ventricular wall does not depolarize in the same manner as the auricles. 3. 3. Pure QS waves consistently were obtained throughout the left ventricular cavity as well as from all portions of the right ventricular cavity except in the immediate vicinity of the septum. Cavity leads recorded near the right septal surface occasionally displayed a small R wave derived from the initial positivity of the right septal surface. 4. 4. The velocity of the depolarization wave was measured in twenty animals by timing the onset of the downstrokes in intramural leads from multiple depths of the left ventricular wall. As determined by this method, the rate of depolarization appears to be considerably more rapid in the innermost two-thirds of the wall than in the superficial layers. 5. 5. Currents of injury, manifested by RS-T segment elevation, always occurred for a brief period following the introduction of the plunge electrode into the myocardium. The RS-T segment deviation was markedly less in subendocardial leads than in subepicardial leads, indicating that subepicardial muscle characteristically is capable of producing more intense injury currents than are the deeper layers of the myocardium. 6. 6. The observed weakness of subendocardial injury currents in experimental animals suggests that the downward RS-T segment deviation, which is seen clinically in angina pectoris, is not attributable to subendocardial anoxia as is generally believed. On the basis of the same experimental observation, a new theory concerning the cause of RS-T segment elevation following coronary occlusion is proposed which appears to reconcile apparent discrepancies among the electrocardiographic, anatomic, and pathologic findings.