The genesis of cardiac arrhythmias

The Genesis of Cardiac Arrhythmias By BRIAN F. HOFFMAN HIS PAPER will be concerned with several general mechanisms which are thought to be causes of disturbances of cardiac rhythm. Possible mechanisms operative in the genesis of specific arrhythmias encountered in the clinic will not be considered. The reasons for this approach are several. The information derived from experiment, which forms the basis for our ideas concerning the genesis of cardiac arrhythmias, 1 is known to be valid only for isolated preparations of cardiac tissue or, in some instances, for the normal in situ canine heart. The applicability of these ideas to the diseased or disordered human heart has not been tested sufficiently. Also, although there is some information on the specific causes of certain experimental arrhythmias, appropriate studies of the disorders of rhythm observed in man are generally lacking. It is hoped that the general mechanisms to be described may provide a framework on which studies of clinical arrhythmias can be based and that such studies ultimately will provide the desired understanding of specific mechanisms. An understanding of the genesis of arrhythmias must be based on an understanding of the normal manner in which excitation of the heart is brought about. For this reason a brief consideration of the origin and spread of the cardiac impulse is in order; a more extensive description may be found elsewhere. 2 Excitation of a cardiac fiber may occur either spontaneously or as a result of the action of some external stimulus. The former property is described by the term automaticity. Automatic cells are those which are capable of self-excitation. 1 The latter type of excitation, i.e., that due to an external stimulus, normally is the result of propagation of the impulse. In this case excitation is a result of the electrical currents caused by the action potential, and is in many ways analogous to excitation by an artificial electrical impulse provided by a stimulator. These considerations permit one to classify cardiac fibers as automatic or nonautomatic. Normally the distribution of automatic fibers is that shown in Table 1. In general, the specialized cardiac fibers are likely to be automatic, while the ordinary muscle fibers of the atria and ventricles, except under most unusual conditions, are not automatic/ More will be said below both about the manner in which automatic cells operate and the way in which nonautomatic cells are excited. However, the considerations presented so far provide the main basis for our classification of arrhythmias. If excitation of cardiac fibers can result either from automatic activity or conduction of the impulse,

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From the Department of Phermacologv, College of Physicians and Surgeons, Columbia University, New York, New York. Original studies were supported in part by grants from the New York Heart Association, the American Heart Association and the United States Public Health Service Research Grant No. HE 08508-02 from the National Heart Institute.

319 PROGlt.ESSIN CARDIOVASCULARDISEASES,VOL.8, No. 4 (JANUARY),1966

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Table 1

A. Specialized Cardiac Tissues I. Sino-atrial node 1. Other automatic atrial cells II. Atrial Conduction paths 1. Internodal 2. Interatrial* III. Atrioventricular Node 1. A-N region* 2. N region* 3. N-H region IV. His-Purkinjesystem 1. Commonbundle 2. Bundle branches 3. Subendocardial Purkinje fibers 4. Intramyocardial Purkinje fibers B. Non-specializedCardiac Tissues I. Atrial muscle fibers II. Ventricu|ar muscle fibers *These cell groups, although showing other evidence of specialization, have not yet been shown conclusively to possess automaticity. one can think of arrhythmias in terms of alterations in automatieity, alterations in conductivity or both (Table 2). An understanding of the development of the excitatory process in cardiac tissues has resulted largely from use of intracellular microelectrodes to record the potential difference which exists across the membrane of cardiac fibers (the transmembrane potential) and to apply depolarizing currents of known strength (Fig. 1). If measurement is made on a quiescent atrial or ventricular muscle fiber, a steady potential difference of about - 9 0 mV, the resting potential, is recorded. When brief pulses of depolarizing current are passed across the membrane it is found that excitation, i.e., the development of the action potential, results when the transmembrane potential is reduced from its resting value to a critical level, at about - 7 0 to - 6 5 mV, which is called the threshold potential (Fig. 2). Propagation of the impulse is caused by electrotonic currents engendered by the action potential. These currents cross the membrane of ceils not yet excited, lower the transmembrane potential to the threshold potential and thus trigger the development of the action potential upstroke in these ceils. In normally automatic ceils the cause of excitation is different. A steady resting potential is not recorded from these cells. Instead, as soon as repolarization from prior activity is complete, a slow spontaneous depolarization commences. If this slow diastolic depolarization lowers the transmembrane potential to the threshold potential, excitation results and an action potential begins to propagate through adjacent fibers. The records of transmembrane potential typically obtained from automatic and nonautomatic fibers are shown in Figures 1, 2 and 3. The mechanism for automaticity shown in Figure 3 and described above

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Table 2.--Mechanlsms for Cardiac Arrhythmias I. Disturbances of Automaticity A. Normal Mechanism (slow diastolic depolarization) 1. Changes in Rate a. slope of phase 4 b. level of threshold potential c. magnitude of maximum diastolic potential d. combinations of a, b, and c 2. Location a. sinus node b. single ectopic site c. normal plus ectopic sites d. multiple ectopie sites B. Abnormal Mechanisms 1. Afterpotentials 2. Delayed repolarization 3. Persistent depolarization 4. Other II. Disturbances of Conductivity A. Failure of Propagation 1. Intermittent 2. Permanent B. Slowed Conduction with Unidirectional Block 1. Decremental conduction 2. Re-entry III. Disturbances of Automaticity and Conductivity A. Parasystolic Rhythms B. Echos or Return Extrasystoles is referred to as normal automaticity, in contrast to other mechanisms to be described subsequently. Since a large number of specialized cardiac cells possess normal automaticity, while only one or a limited number can initiate a given beat, it has been necessary to speak of pacemaker cells and latent or potential pacemaker cells. The term pacemaker is restricted to the cell or cell group which initiates a propagated impulse that excites all or some part of the nonautomatic fibers of the heart. 1 Arrhythmias due to altered automaticity may result from changes in the normal mechanism or to some other mechanism. Before considering the abnormal mechanisms, it seems appropriate to include a brief summary of the ways in which the firing frequency of a normally automatic cell can be varied. 8 In general, the frequency at which a normally automatic cell fires depends on the rate of change of m e m b r a n e potential during diastole, the value of the threshold potential and the maximum level of membrane potential attained at the end of repolarization (Fig. ,3). Changes in rate can be shown to result from changes in any one of these variables or from simultaneous changes in more than one. Any factor which significantly changes the firing rate of normally automatic cells can cause arrhythmia. Sinus tachyeardia or bradycardia will result from acceleration or slowing of automatic cells in or around the normal pacemaker. A decrease

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Fig. 1.--A, diagrammatic representation of the tip of a glass capillary microelectrode showing the approximate tip diameter, the filling solution, (3 molar potassium chloride) and the silver-silver chloride wire which makes contact with the electrolyte solution. B, diagrammatic representation of a tissue bath containing a preparation os cardiac muscle. At (a) the microelectrode is extraeellular in position; at (b) it is intracellular. The connection of the indifferent electrode to ground also is indicated. C, diagrammatic representation of the transmembrane action potential and unipolar electrogram recorded from an isolated preparation of cardiac muscle: The zero or reference line, (a) is recorded when microelectrode tip is extracellular in position. The transmembrane resting potential (b) is recorded when the electrode tip penetrates the quiescent fiber. At (c) an action potential is initiated. Depolarization and the various phases of repolarization are designated by the symbols 0, 1, 2, and 3; symbol 4 is used to designate the diastolic period. See text for discussion. The bottom trace shows a unipolar electrogram recorded from the immediate vicinity of the microelectrode tip. Note that the intrinsic deflection of the R wave is synchronous with phase 0 of the transmembrane action potential and that the T wave of the electrogram is inscribed during phase 3. (From Hoffman and Singer, 7) in the automaticity os the normal pacemaker may permit the escape of a latent pacemaker, similarly, an increase in the automaticity os the latent pacemaker may permit it to assume the role of pacemaker. Changes of this kind are responsible for most escape rhythms, whether the ectopie pacemaker is located in the atrium or in the His-Purkinje system. Since there are many normally automatic cells in the heart, some arrhythmias will result from competition between the sinus pacemaker and one or more ectopic pacemakers or between multiple ectopic pacemakers. Many agents which influence the rate and rhythm of the heart do so by specific effects on one or more of the variables which control the rate of automatic cells. 4 Acetylcholine slows the rate of the sinus node in part by decreasing the slope of diastolic depolarization and in part by causing some hyperpolarization3

323

GENESIS OF CARDIAC ARILFIYTI-I1V~IAS

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juA Fig. 2.--Diagrammatic representation of the changes in transmembrane potential which are produced by subthreshold and threshold stimuli. Records of transmembrane potential are shown above; records of stimulus current below. In response to subthreshold currents 1 and 2 there is a graded, local change in the transmembrane potential. With stimulus current 3, the local response reaches the threshold potential (TP) and merges with the upstroke of the transmembrane action potential. (See text for discussion.) Catecholamines increase rate primarily by increasing the slope of diastolic depolarization. Changes in extraceUular calcium concentration, if moderate, act mainly on the absolute magnitude of the threshold potential. An increase in ionized Ca ++ concentration displaces the threshold potential to lower values (i.e., closer to zero potential) while a decrease in [Ca ++] has the opposite effect.~ An extreme decrease in [Ca++], however, also increases the slope of depolarization during diastole, Changes in extracellular potassium concentration alter the maximum diastolic potential as well as the slope of diastolic depolarization. A description of many other agents which influence these variables can be found elsewhere. 1,2,4 Some of the arrhythmias due to agents such as digitalis 7 and quinidine and procaine amide s are due to alterations in normal automaticity. Since the sensitivity of various automatic cells to a given agent differs considerably under normal conditions, and since such differences in sensitivity may be enhanced by disease, the production of a variety of arrhythmias it is possible. Automaticity due to the normal mechanism also is influenced by hypoxia, 9 ischernia, stretch I~ and other factors. 11 Such changes, if local, are particularly prone to cause arrhythmia. Finally, it has been shown that weak constant electric currents will increase the slope of diastolic depolarization of normally automatic Purkinje fibers and thus initiate eetopic pacemaker activity3 2 It may be that some of the arrhythmias associated with myocardial infarction are initiated in this manner by the current of injury that flows between the damaged and normal cells. However, there are at least several other mechanisms for impulse initiation which may involve all types of cardiac fibers (Table 2). In a strict sense, these probably should not be classified under the heading of "automaticity" since one or more propagated initiating impulses may be required to start selfsustaining aetivity of the eetopie focus. They are mechanisms for impule initia-

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Fig. 3.~A, transmembrane potentials simultaneously recorded from a single fiber in the sinoatrial node, P, and atrial muscle, A, of the rabbit heart. (See text for discussion.) B, transmembrane potentials from a pacemaker fiber showing rate change due to a change in the slope of slow diastolic depolarization h'om a to b. C, transmembrane potentials from a pacemaker fiber showing changes in rate due to a shift in the threshold potential from TP-1 to TP-2 and in the level of the resting potential from a to d. Letters b, c, and e indicate respective times of firing of the pacemaker. D, transmembrane potentials recorded h'om a true pacemaker fiber and a latent pacemaker, a. (From Hoffman.Zg) tion, however, and differ conceptually from the arrhythmias due to disorders of conduction. The first mechanism listed in Table 2, afterpotentials, is one which has been invoked for many years to explain a variety of arrhythmias. 13,14 In recent years by use of mieroelectrodes definite evidence has been .obtained which shows that cardiac arrhythmias may result from afterpotentials which initiate new propagated impulses. Such afterpotentials may cause a single ectopic beat to follow each normally propagated beat or may initiate a sustained train of impulses which dominates the cardiac rhythm. Veratrine 15 and aconitine, 16 employed by Matsuda in studies of ventricular muscle fibers, cause repetitive ectopic firing by somewhat different mechanisms. The former agent changes the time course of repolarization so that new impulses originate during a greatly prolonged phase 2 and 3. Aconitine, on the other hand, causes an oscillatory afterpotential which follows the end of phase 3; if this oscillatory depolarization reaches the threshold potential, a new impulse is initiated. A different form of afterpotential and arrhythmia has been recorded by Sleator from isolated human atrial preparations studied at reduced temperature) 7 Some afterpotentials, such as those due to veratrine, are in reality a delay in repolarization. However, a major change in the voltage-time course of

GENESIS O F C A R D I A C A R R H Y T H M I A S

325

phases 2 and 3 usually accompanies this delay. The separate category for delayed repolalSzation in Table 2 is employed to suggest that, in the absence of any change in the configuration of the action potential, a sufficient delay in repolarization of a group of cells might permit them to cause re-excitation of adjacent cells which had repolarized sooner and thus had regained a sufficient degree of excitability. Although the duration of action potentials recorded from various parts of the heart shows major variations, normally the transition from one duration to another is gradual, as a function of distance. However, under abnormal conditions, adjacent fiber groups may repolarize at different times. 18 The apposition of fully repolarized and not yet repolarized fibers may be expected to result in the flow of excitatory current, just as in the case of the normally propagating impulse. This condition differs only in terms of its periodicity from that in which there is persistent depolarizaton of a group of fibers. In either case an "injury current" or demarcation current may be expected and this current will change the membrane potential of normal cells in its path. It has not yet been shown by experiment that the current of injury is sufficient to excite nonautomatic cells; however, if injury enhances the excitability of such cells the proposed mechanism might be operative. In addition to the arrhythmias caused by alterations in normal automaticity or by abnormal mechanisms for automatic firing, we are convinced that a number of disturbances of rhythm are the result of changes in conduction. The disturbances of rhythm which result from impaired conduction in the atrioventricular node are well-known1~ and need not be described at this time. However, the mechanism responsible for such changes in A-V transmission, decremental conduction, 2~ has been shown by recent experiments to be operative in other types of cardiac fibers and t o be the cause of re-entrant arrhythmias. In the His-Purkinje system, decremental conduction results from a decrease in the magnitude of the transrnembrane potential prior to excitation. Such loss of membrane potential may be the result of incomplete repolarization ~3 or the slow depolarization which is present in normally automatic fibers.24,25 In either case the effects on excitability and impulse propagation are s.imilar. As a result of the decrease in membrane potential there is a decrease in the rate of rise and amplitude of the action potential and a decrease in the speed of propagation. Furthermore, as the impulse propagates with decrement, these changes progress. Complete failure of conduction may be the result. Finally, in regions of decremental conduction unidirectional block can occur. This was shown many years ago for atrial and ventricular muscle2G,27 and more recently for fibers of the atrioventricular node? ,2s These properties of cardiac fibers are sufficient to permit local re-entry of the impulse to occur in almost any part of the heart which has an appropriate anatomic arrangement. A diagram of unidirectional block with reentry involving a peripheral branch of the Purkinje system is shown in Figure 4. It is assumed that there is a region of decremental conduction with unidirectional block in one peripheral branch. The decremental conduction may be thought to result from partial depolarization due to local ischemia. Because of the great reduction in the speed of propagation in this area, there

3e26

BRIANF. HOFFIVfAN

is no need for the path length to be greater than a few millimeters. The impulse spreading into this region from the Purkinje system undergoes complete decrement and thus is blocked before reaching the ventricular muscle. However, activity entering the same region in a retrograde direction from the ventricle is not blocked but spreads very slowly back to the point of bifurcation. If there is a proper balance between the time required for retrograde spread and the time required for repolarization of the Purkinje fibers proximal to the region of decrement, re-entry and re-excitation will occur. As suggested by the diagram in Figure 4, the re-entrant path may cause either coupled extrasystoles or a self-sustaining ectopic rhythm. Our most recent studies have been concerned with conditions in which there is a disturbance of both automaticity and conduction. One example of such a disturbance is found in the parasystolic focus. It would appear that the mechanisms responsible for entry and exit block around such a focus can be understood if one considers the effect of the loss of membrane potential during diastole on excitability and conductivity. Under conditions which lower the threshold potential sufficiently, diastolic depolarization in an ectopic focus may not only initiate an ectopic beat but at the same time cause the spread of this impulse to be decremental. The ectopic focus thus surrounds itself with a region in which conduction is impaired. The production of entry block thus requires no special explanation. Exit block, which may vary, most likely is quite similar to partial block at the A-V node, i.e., due to decremental conduction. The fact that block is not dependent on refractoriness of ventricular muscle or Purkinje fibers thus is no longer a puzzle. In studies of isolated canine Purkinje fibers it has been possible to demonstrate that this relationship between changes in automaticity and conduction does exist both when automaticity is altered by excessive concentrations of digitalis r or by other means. 25 In this instance the impairment of conduction is a direct result of the loss of membrane potential due to diastolic depolarization of the automatic fiber. Altered automaticity can cause impaired conduction by another mechanism. However, in this case a premature beat, caused by the escape of an automatic focus, encounters fibers which, because of the prematurity, have not yet fully repolarized. The reduction of membrane potential associated with incomplete repolarization has the expected effect on responsiveness and slowed or decremental conduction results3 ~ Finally, altered automaticity and impaired conduction may be related in quite a different manner. It can be concluded from experiments on isolated cardiac tissues that failure of conduction may isolate a group of normally automatic cells from the repetitive depolarization which would occur with the dominant cardiac rhythm. The automatic cells then may escape in the sense that they initiate an impulse which propagates through a region of unidirectional block and excites some or all of the heart. Although the basic mechanism for the arrhythmia is the same--decremental conduction with unidirectional block-the cause-effect relationship is reversed from that described previously. It is obvious that much experimentation is needed to determine whether

327

GENESIS OF GARDIAG ARRHXTH1VIIAS

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Fig. 4.--Diagrammatic representation of arrhythmias due to delayed conduction and unidirectional block. The upper drawing represents a peripheral part of the Purkinje system (P) and attached ventrieular muscle (V). In the branch A, conduction proceeds at normal velocity and the action potential is shown by trace A. In branch B, conduction velocity is reduced and unidirectional block is present in the hatched area. The locally recorded action potential is shown by trace B. The aetion potential in branch A elicits the ventricular action potential number 1; the slowly propagating action potential in B initiates the second ventrieular action potential, number 2. The lower drawing shows, by the direction of the arrows, a possible meehanism for production of a self-sustaining arrhythmia. Here the direction of unidirectional block is opposite to that in the upper drawing. (From Hoffman. s) or not these postulated mechanisms are operative in the variety of arrhythmias encountered in man. As indicated in the introduction, the classification which we have proposed 1 appears to be satisfactory when tested by a limited number of arrhythmias produced in the experimental animal. Also, as has been indicated elsewhere s this classification may be tested selectively by use of

328

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c e r t a i n a n t i a r r h y t h m i c agents. H o w e v e r , e v e n if t h e s c h e m e p r o v e s i n a d e q u a t e to a c c o u n t for m a n y of t h e d i s t u r b a n c e s of r h y t h m of t h e h u m a n h e a r t , it m a y at l e a s t h e l p i n d i c a t e t h e e x t e n t to w h i c h o u r u n d e r s t a n d i n g of t h e electrop h y s i o l o g y of m a m m a l i a n c a r d i a c tissue is a p p l i c a b l e t o m a n .

REFERENCES 1. Hoffman, B. F., and Cranefield, P. F.: The physiological basis of cardiac arrhythmias. Amer. J. Med. 37:670, 1964. 2 . - - , and - - : The Electrophysiology of the Heart. New York, McGraw-Hill, 1960. 3. Carmeliet, E. E.: Pacemaker potentials in left auricular tissue of the guinea pig. Arch. Intern. Physiol. Biochim. 73:171, 1965. 4. Trautwein, W.: Generation and conduction of impulses in the heart as affected by drugs. Pharmacol. Rev. 15: 277, 1963. 5. Hutter, O. F., and Trautwein, W.: Vagal and sympathetic effects on the pacemaker fibers of the sinus venosus of the heart. J. gen. Physiol. 39:715, 1956. 6. Weidmann, S.: Effects of calcium ions and local anaesthetics on electrical properties of Purkinje fibers. J. Physiol. 129:568, 1955b. 7. Hoffman, B. F., and Singer, D. H.: Effects of digitalis on electrical activity of cardiac fibers. Progr. Cardiov. Dis. 7:670, 1964. 8. - - : The possible mode of action of antiarrhythmic agents. In Conn, H. L., Jr., and Briller, S. A. (Eds.): The Myocardial Cell. New York, Harper & Row, in press. 9. Trautwein, W., and Dudel, J.: Aktionspotential und Kontraktion des Herzmuskels im Sauerstoffmangel. Pfliigers Arch. ges. Physiol. 266:324, 1958. 10. Dudel, J., and Trautwein, W . : Das Aktionspotential und Mechanogram des Herzmuskels unter dem Einfluss der Dehnung. Cardiologia 25:344, 1954. 11. Coraboeuf, E., and Boistel, J.: L'action des taux 6lev6s de gaz carbonique sur le tissu cardiaque, 6tudi6e a raide de micro61ectrodes intraeellulaires. Compt. rend. Soe. Biol. 147:654,

1953. 12. Trautwein, W., and Kassebaum, D. G.: On the mechanism of spontaneous impulse generation in the pacemaker of the heart. J. gen. Physiol. 45:317, 1961, 13, Katz, L. N., and Pick, A.: Clinical Electrocardiography. I. The Arrhythmias. Philadelphia, Lea & Febiger, 1956. 14. Scherf, D., and Schott, A.: Extrasystoles and Allied Arrhythmias. London, Wm. Heinemann Ltd., 1953. 15. Brooks, C. McC., Hoffman, B. F., Suckling, E. E., and Orias, O.: The Excitability of the Heart. New York, Grune & Stratton, Inc., 1955. 16. Matsuda, K., Takeshi, H., and Shigenori, K.: Effects of aconitine on the cardiac membrane potential of the dog. Jap. J. Physiol. 9:419, 1959. 17. Sleator, W., and de Gubareff, T.: Transmembrane action potentials and contractions of human atrial muscle. Amer. J. Physiol. 206:1000, 1964. 18. Matsumura, M., and Takaori, S.: The effect of drugs on the cardiac membrane potentials in the rabbit. II. Auricular muscle fibers and the sinoatrial node. Jap. J. Pharmacol. 8: 143, 1959. 19. Cranefield, P. F., Hoffman, B. F., and Paes de Carvalho, A.: Effects of acetylcholine on single fibers of the atrioventricular node. Circulation Res. 7:19, 1959. 20. Hoffman, B. F.: Electrical activity of the atrioventrieular node. In: Specialized Tissues of the Heart. Amsterdam, The Netherlands, Elsevier Publishing Company, 1961, p. 143. 2 1 , - - , Cranefield, P. F., and Stuckey, J. H.: Concealed conduction. Circulation Res. 9:194, 1961. 22. Hoffman, B. F., Paes de Carvalho, A., de Mello, W. C., and Cranefield, P. F.: Electrical activity of single fibers of the atrioventricular node. Circula-

GENESIS OF CARDIACARRHYTI-IMIAS tion Res. 7:11, 1959. 23. - - , Moore, E. N., Stuckey, J. H., and Cranefield, P. F.: Functional properties of the atrioventricular conduction system. Circulation Res. 13:308, 1963. 24. Weidmann, S.: The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J. Physiol. 127:213, 1955a. 25. Singer, D. H., Lazzara, R., and Hoffman, B. F.: Membrane potential and conduction in Purkinje fibers. Circulation Res. Submitted ~or publication. 26. Drury, A. N.: Further observations on interauricular block produced by pres-

329 sure or cooling. Heart 12:143, 1925. 27. Schmitt, F. O., and Erlanger, J.: Directional differences in the conduction of the impulse through heart muscle and their possible relation to extrasystolic and fibrillary contractions. Amer. J. Physiol. 87:326, 1928-9. 28. Paes de Carvalho, A., and de Almeida, D. F.: Spread of activity through the atrioventricular node. Circulation Res. 8:801, 1960. 29. Hoffman, B. F.: The origin of the heart beat. In Luisada, A. (Ed.): Cardiology. Vol. 1, Chap. 4. New York, Blakiston, 1959,