7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Enhanced cardiac automaticity : Philip J Podrid, MD, FACC : Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 02, 2021. INTRODUCTION Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). The discharge rate of normal or abnormal pacemakers may be accelerated by drugs, various forms of cardiac disease, reduction in extracellular potassium, or alterations of autonomic nervous system tone. Enhanced normal automaticity accounts for the occurrence of sinus tachycardia, while abnormal automaticity may result in various atrial or ventricular arrhythmias, for example, an accelerated idioventricular rhythm or an ectopic atrial tachycardia. This topic will review the physiologic principles underlying both enhanced normal automaticity and automatic automaticity. The diagnosis and treatment of arrhythmias resulting from enhanced cardiac automaticity are discussed separately. (See "Sinus tachycardia: Evaluation and management" and "Focal atrial tachycardia".) ENHANCED NORMAL AUTOMATICITY Enhanced normal automaticity is best understood by beginning with a brief review of the physiology and hierarchy of stimulation of normal cardiac automaticity. This will be followed by a discussion of the electrophysiologic principles underlying the normal and enhanced automaticity of the sinoatrial (SA) node, the subsidiary atrial pacemakers, the atrioventricular (AV) node, and the ventricles. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 1/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Normal automaticity Normal automaticity involves the slow, progressive depolarization of the membrane potential (spontaneous diastolic depolarization or phase four depolarization) until a threshold potential is reached, at which point an action potential ( figure 1 and figure 2) is initiated. Although automaticity is an intrinsic property of all myocardial cells, the occurrence of spontaneous activity is prevented by the natural hierarchy of pacemaker function. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) The spontaneous discharge rate of the SA nodal complex exceeds that of all other subsidiary or latent pacemakers. As a result, the impulse initiated by the SA node depresses the activity of subsidiary pacemaker sites before they can spontaneously depolarize to threshold. However, slowly depolarizing and previously suppressed pacemakers in the atrium, AV node, or ventricle can become active and assume pacemaker control of the cardiac rhythm if the SA node pacemaker becomes slow or unable to generate an impulse or if impulses generated by the SA node are unable to activate the surrounding atrial myocardium. The emergence of subsidiary or latent pacemakers under such circumstances is an appropriate fail-safe mechanism which assures that ventricular activation is maintained. A subsidiary pacemaker may also become activated if there is sympathetic stimulation or increased catecholamines, resulting in a pacemaker discharge rate that is faster than the rate of sinus node discharge. This represents an accelerated rhythm. SA node The ionic mechanisms responsible for normal pacemaker activity in the SA node have not been conclusively defined, but are likely the result of a hyperpolarization-activated inward current and decay of outward potassium currents [1]. This progressive net gain of positive charge underlies the spontaneous diastolic depolarization of SA node cells which results from the following sequence of events ( figure 2) [2,3]: During the first third of diastolic depolarization, the inward leak of sodium ions is coupled with a time-dependent decrease in the outward potassium current. During the latter two thirds of depolarization, a slow inward movement of calcium ions occurs. This process moves the membrane potential to the threshold potential, at which time there is a more rapid inward calcium current, generating a slow action potential. Effects of drugs and autonomic tone on the SA node Drugs and autonomic neurotransmitters perturb these currents, thereby altering the SA node discharge rate. As an example, agents and neurotransmitters that accelerate the sinus node discharge rate bind to the beta adrenergic receptor, leading to an increase in the inward movement of calcium due to the phosphorylation of a protein that modulates the opening of calcium https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 2/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate channels ( figure 3) [4,5]. The ensuing influx of calcium accelerates the rate of diastolic depolarization [2]. Parasympathetic tone, on the other hand, reduces the spontaneous discharge rate of the SA node, while its withdrawal accelerates SA node automaticity. Acetylcholine, the principle neurotransmitter of the parasympathetic nervous system, inhibits spontaneous impulse generation in the SA node by increasing potassium conductance [3]. The resulting hyperpolarization of the membrane potential lengthens the time required for the membrane potential to depolarize to threshold, thereby decreasing the automaticity of the SA node. In addition to altering ionic conductance, changes in autonomic tone can also produce changes in the rate of the SA node by shifting the primary pacemaker region within the pacemaker complex, which is described as a cylindrical crescent [6]. Intrinsic discharge frequencies vary within different regions of the SA node; the discharge rate is faster in the cranial portion of the node, while it is slower in the caudal region. As a result, autonomically-mediated shifts of pacemaker regions may be accompanied by changes in the sinus rate [7,8]. Vagal fibers are more dense in the cranial portion of the SA node and stimulation of the parasympathetic nervous system shifts the pacemaker center to a more caudal region of the SA nodal complex, resulting in slowing of the heart rate, whereas stimulation of the sympathetic nervous system or withdrawal of vagal stimulation shifts the pacemaker center cranially, resulting in an increase in heart rate ( figure 4). The following are examples of stimuli which can alter the automaticity of the SA node: Exercise, which augments sympathetic tone, enhances normal automaticity in the SA node and can produce sinus tachycardia (heart rates exceeding 100 beats/minute). (See "Sinus tachycardia: Evaluation and management".) Respiratory sinus arrhythmia (respirophasic arrhythmia that is irregularly irregular) is primarily caused by withdrawal of vagal tone during inspiration (and hence a faster heart rate) and by reinstitution of vagal tone during expiration (and hence a slower heart rate). These alterations in vagal tone are mediated by peripheral sensors linked to arterial chemoreceptors and baroreceptors, intracardiac reflexes, and pulmonary stretch receptors [9-11]. (See "Normal sinus rhythm and sinus arrhythmia".) Digitalis has a well-known negative chronotropic effect on the SA node, caused by enhancement of vagal (parasympathetic) tone [9,12]. Digoxin does not appear to have any direct depressant effects on the intrinsic functions of the sinus node [13]. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 3/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Beta blockers, which block the effect of sympathetic stimulation and circulating catecholamines on the SA node, result in a reduction in its normal automaticity. However, their effect at rest is less marked, as normal resting SA nodal function is not dependent upon sympathetic stimulation but is mediated more by vagal tone. However, during times of sympathetic stimulation, these agents will blunt the acceleration in heart rate. Calcium channel blockers, especially verapamil and diltiazem, reduce the influx of calcium ions, and therefore will reduce the rate of diastolic depolarization and hence the rate of SA nodal discharge. Ivabradine, which has a direct effect on SA automaticity and impulse discharge. Its action is unlike beta blockers, digoxin, or calcium channel blockers. It works by modulating the "f- current" (I ). Ivabradine slows the sinus rate by prolonging the slow depolarization phase. f Subsidiary atrial pacemakers Latent atrial pacemakers have been identified in the atrial myocardium (especially the crista terminalis), coronary sinus, and AV valves [14-18], while ectopic atrial pacemakers have been identified in the region around the pulmonary veins [19]. They may responsible for precipitating atrial fibrillation and their elimination or isolation with radiofrequency catheter ablation has been found to be effective for the prevention of paroxysmal atrial fibrillation [20]. (See "Atrial fibrillation: Catheter ablation".) Latent atrial pacemakers (located in the atrial myocardium) may be expected to contribute to impulse initiation in the atrium if the discharge rate of the SA node is reduced temporarily or permanently. In contrast to the normal pacemaker tissue, these latent or ectopic pacemakers usually generate a fast action potential, mediated by sodium ion fluxes. However, when severely damaged, the atrial tissue may not be able to generate a fast action potential (which is energy- dependent) but rather generates a slow, calcium ion-mediated action potential (which is energy- independent). Automaticity of subsidiary atrial pacemakers may also be enhanced by coronary disease and ischemia, chronic pulmonary disease, or drugs such as digitalis and alcohol, possibly overriding normal SA node activity [9,21,22]. AV node or junction It is uncertain if the AV node itself has pacemaker cells, but it is clear that the AV junction, which is an area that includes atrial tissue, the AV node and His-Purkinje tissue, does have pacemaker cells and is capable of exhibiting automaticity. Automaticity of the AV junction appears to arise via a mechanism similar to that which occurs in the SA node [23-25]. Diastolic depolarization is caused by a gradual decrease in the outward potassium current and an increase in the inward movement of calcium ions. Acceleration of AV nodal automaticity by https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 4/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate beta-adrenergic agonists is believed to result from activation of the calcium channel, resulting in an increased inward calcium current, similar to that induced in the SA node. Ectopic AV nodal tachycardias due to enhanced automaticity have the following clinical features: Marked sinus bradycardia or SA node exit block can result in an escape ectopic AV nodal or junctional rhythm. The emergence of an ectopic AV junctional rhythm is usually characterized by a gradual increase in spontaneous discharge rate (a warm-up phenomenon) until a reasonably regular rate of 35 to 60 beats per minute is attained [25]. Acceleration of the AV junctional rate to 70 to 130 beats per minute (ectopic junctional tachycardia) can occur with an inferior myocardial infarction, open heart surgery, myocarditis, digitalis intoxication (which is associated with an increase in outputs from the central sympathetic nervous system), or sympathetic activation. The onset and termination of accelerated junctional tachycardias are usually gradual (ie, nonparoxysmal). The tachycardia rate is slowed by enhanced vagal tone and is accelerated by vagolytic or sympathomimetic agents. Ventricle Isolated cells of the His-Purkinje system discharge spontaneously at rates of 15 to 60 beats per minute, whereas ventricular myocardial cells usually do not exhibit spontaneous diastolic depolarization or automaticity [26,27]. The relatively slow spontaneous discharge rate of Purkinje fibers ensures that pacemaker activity in the His-Purkinje system will be suppressed on a beat-to-beat basis by the more rapid discharge rate of the SA node [28,29]. Under normal conditions, the Purkinje fibers do not exhibit spontaneous automaticity because of "overdrive suppression" by more proximal pacemakers (ie, sinus and AV node) that have a faster discharge rate ( figure 5). However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as a myocardial infarction. In this setting, some Purkinje fibers which survive the infarction have moderately reduced maximum diastolic membrane potentials and therefore accelerated spontaneous discharge rates [30-36]. In the presence of ischemia or myocardial infarction, myocardial cells may demonstrate spontaneous automaticity. ABNORMAL AUTOMATICITY https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 5/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Enhanced automaticity of the SA node, subsidiary atrial pacemakers, or the AV node due to a mechanism other than acceleration of normal automaticity has not been demonstrated clinically. However, abnormal automaticity of Purkinje fibers and atrial and ventricular tissue can occur. As noted above, isolated cardiac Purkinje fibers usually have relatively slow spontaneous discharge rates, whereas atrial and ventricular muscles are quiescent. However, depolarization of these tissues by a disease process, in particular acute myocardial ischemia, can induce spontaneous activity. With an acute myocardial infarction, there is loss of the normal energy- dependent fast sodium-mediated action potential (due to inactivation of the normal sodium- potassium ATPase pump, which requires energy and O to synthesize ATP). As a result, resting 2 membrane potential (which is normally -90 mV) becomes less negative and reaches the threshold potential of -60 mV. The normal rapid influx of sodium, which accounts for the fast action potential, is lost, and the fast action potential is no longer generated. However, the slow influx of calcium currents, which is energy independent and normally occurs during phase 2 of the action potential, still occurs. Hence, as a result of the loss of the fast inward sodium influx but maintenance of the slow influx of calcium ions, the fast action potential is converted to a slow action potential which has spontaneous automaticity. Thus, latent energy-independent slow action potential (mediated by calcium currents) is therefore exposed. This automaticity is not suppressed by overdrive pacing, is more easily suppressed by calcium channel blockade than by sodium channel blockade, and is accelerated by beta-adrenergic agonists [35-40]. Thus, abnormal automaticity in these tissues resembles normal automaticity in the sinus and AV nodes (ie, results from a time-dependent decay of outward potassium currents and progressive activation of inward calcium currents) [41,42]. Acceleration of Purkinje fiber automaticity can also be augmented by the elevated levels of catecholamines and increased sympathetic tone which occurs during ischemia [43]. Purkinje fibers surviving myocardial infarction appear to be more sensitive to the positive chronotropic effects of catecholamines than normal Purkinje fibers, perhaps because of denervation supersensitivity [44,45]. There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of myocardial infarction, for example, an accelerated idioventricular rhythm. However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. Isolated myocytes obtained from hypertrophied and failing hearts have been shown to manifest spontaneous diastolic depolarization and enhanced pacemaker currents, suggesting that https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 6/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate abnormal automaticity may contribute to the occurrence of some arrhythmias in heart failure and left ventricular hypertrophy [46,47]. It has been shown that stretch of the myocardium can increase its automaticity (ie, electromechanical feedback). This may account for arrhythmias that are seen with heart failure and acute dilation of the atrial or ventricular myocardium. (See "Left ventricular hypertrophy and arrhythmia".) Some of the arrhythmias that occur with digoxin toxicity may be related to suppression of sinus node activity by increased vagal tone as well as enhanced automaticity (resulting from an increase in central sympathetic neural outputs occurring with elevated digoxin levels), although this is not firmly established since delayed potentials (delayed after depolarizations [DADs]) and triggered automaticity are other potential mechanisms. It is likely that both mechanisms play a role as triggered automaticity may be enhanced by sympathetic stimulation. (See "Cardiac arrhythmias due to digoxin toxicity".) The role of abnormal automaticity in the genesis of other clinical arrhythmias has generally not been established. Although automaticity is not responsible for most clinical tachyarrhythmias, which are usually due to a reentry, it may certainly precipitate or trigger any reentrant arrhythmia. SUMMARY Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). (See 'Introduction' above.) The spontaneous discharge rate of the sinoatrial (SA) nodal complex exceeds that of all other subsidiary or latent pacemakers, thereby depressing the activity of subsidiary pacemaker sites before they can spontaneously depolarize to threshold. However, previously suppressed pacemakers in the atrium, atrioventricular (AV) node, or ventricle can assume pacemaker control of the cardiac rhythm if the SA node pacemaker becomes slow or unable to generate an impulse or if impulses generated by the SA node are unable to activate the surrounding atrial myocardium. (See 'Normal automaticity' above.) Drugs and autonomic neurotransmitters alter the SA node discharge rate (see 'Effects of drugs and autonomic tone on the SA node' above): Increased sympathetic input or withdrawal of parasympathetic input (eg, exercise, beta agonist medications) results in higher sinus rates. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 7/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Decreased sympathetic input or increased parasympathetic input (eg, beta blockers, digoxin) leads to lower sinus rates. The AV junction, an area that includes atrial tissue, the AV node, and His-Purkinje tissue, contains pacemaker cells and is capable of exhibiting automaticity, which may result in ectopic AV nodal tachycardias. (See 'AV node or junction' above.) Isolated cells of the His-Purkinje system discharge spontaneously at rates of 15 to 60 beats per minute, whereas ventricular myocardial cells usually do not exhibit spontaneous diastolic depolarization or automaticity. Under normal conditions, the Purkinje fibers do not exhibit spontaneous automaticity because of suppression by more proximal pacemakers that have a faster discharge rate. However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as a myocardial infarction. (See 'Ventricle' above.) There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of myocardial infarction, for example, an accelerated idioventricular rhythm. However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. (See 'Abnormal automaticity' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. DiFrancesco D. The pacemaker current (I(f)) plays an important role in regulating SA node pacemaker activity. Cardiovasc Res 1995; 30:307. 2. Irisawa, H, Hagiwara, N . Ionic current in sinoatrial node cells. J Cardiovasc Electrophysiol 1991; 2:531. 3. Brown HF. Electrophysiology of the sinoatrial node. Physiol Rev 1982; 62:505. 4. Reuter H. Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 1983; 301:569. 5. Kameyama M, Hofmann F, Trautwein W. On the mechanism of beta-adrenergic regulation of the Ca channel in the guinea-pig heart. Pflugers Arch 1985; 405:285. 6. Boineau JP, Canavan TE, Schuessler RB, et al. Demonstration of a widely distributed atrial pacemaker complex in the human heart. Circulation 1988; 77:1221. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 8/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate 7. Bouman LN, Gerlings ED, Biersteker PA, Bonke FI. Pacemaker shift in the sino-atrial node during vagal stimulation. Pflugers Arch 1968; 302:255. 8. Goldberg JM. Intra-SA-nodal pacemaker shifts induced by autonomic nerve stimulation in the dog. Am J Physiol 1975; 229:1116. 9. Zipes DP. Specific arrhythmias: diagnosis and treatment. In: Heart Disease: A Textbook of Ca rdiovascular Medicine, Braunwald E (Ed), Saunders, Philadelphia 1992. p.667. 10. Eckberg DL. Human sinus arrhythmia as an index of vagal cardiac outflow. J Appl Physiol Respir Environ Exerc Physiol 1983; 54:961. 11. Grossman P, Kollai M. Respiratory sinus arrhythmia, cardiac vagal tone, and respiration: within- and between-individual relations. Psychophysiology 1993; 30:486. 12. Steinbeck G, Bonke FI, Allessie MA, Lammers WJ. The effect of ouabain on the isolated sinus node preparation of the rabbit studied with microelectrodes. Circ Res 1980; 46:406. 13. Alboni P, Shantha N, Filippi L, et al. Clinical effects of digoxin on sinus node and atrioventricular node function after pharmacologic autonomic blockade. Am Heart J 1984; 108:1255. 14. Wit AL, Cranefield PF. Triggered and automatic activity in the canine coronary sinus. Circ Res 1977; 41:434. 15. Jones SB, Euler DE, Randall WC, et al. Atrial ectopic foci in the canine heart: hierarchy of pacemaker automaticity. Am J Physiol 1980; 238:H788. 16. Wit AL, Fenoglio JJ Jr, Wagner BM, Bassett AL. Electrophysiological properties of cardiac muscle in the anterior mitral valve leaflet and the adjacent atrium in the dog. Possible implications for the genesis of atrial dysrhythmias. Circ Res 1973; 32:731. 17. Hogan PM, Davis LD. Evidence for specialized fibers in the canine right atrium. Circ Res 1968; 23:387. 18. James TN, Sherf L, Fine G, Morales AR. Comparative ultrastructure of the sinus node in man and dog. Circulation 1966; 34:139. 19. Ha ssaguerre M, Ja s P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659. 20. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999; 100:1879. 21. Swerdlow CD, Liem LB. Atrial and junctional tachycardias: clinical presentation, course and t herapy. In: Cardiac Electrophysiology. From Cell to Bedside, Zipes,DP, Jalife J (Eds), Saunders, Philadelphia 1990. p.742. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 9/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate 22. Goldreyer BN, Gallagher JJ, Damato AN. The electrophysiologic demonstration of atrial ectopic tachycardia in man. Am Heart J 1973; 85:205. 23. Kokubun S, Nishimura M, Noma A, Irisawa H. The spontaneous action potential of rabbit atrioventricular node cells. Jpn J Physiol 1980; 30:529. 24. Noma A, Irisawa H, Kokobun S, et al. Slow current systems in the A-V node of the rabbit heart. Nature 1980; 285:228. 25. Watanabe Y, Nishimura M, Noda T, et al. Atrioventricular junctional tachycardias. In: Cardiac Electrophysiology. From Cell to Bedside, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 1990. p.564. 26. DiFrancesco D. A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol 1981; 314:359. 27. Hirano Y, Hiraoka M. Barium-induced automatic activity in isolated ventricular myocytes from guinea-pig hearts. J Physiol 1988; 395:455. 28. Vassalle M. The relationship among cardiac pacemakers. Overdrive suppression. Circ Res 1977; 41:269. 29. Vassalle M. Electrogenic suppression of automaticity in sheep and dog purkinje fibers. Circ Res 1970; 27:361. 30. Allen JD, Brennan FJ, Wit AL. Actions of lidocaine on transmembrane potentials of subendocardial Purkinje fibers surviving in infarcted canine hearts. Circ Res 1978; 43:470. 31. Friedman PL, Stewart JR, Wit AL. Spontaneous and induced cardiac arrhythmias in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 1973; 33:612. 32. Lazzara R, el-Sherif N, Scherlag BJ. Electrophysiological properties of canine Purkinje cells in one-day-old myocardial infarction. Circ Res 1973; 33:722. 33. Dangman KH, Danilo P Jr, Hordof AJ, et al. Electrophysiologic characteristics of human ventricular and Purkinje fibers. Circulation 1982; 65:362. 34. Horowitz LN, Spear JF, Moore EN. Subendocardial origin of ventricular arrhythmias in 24- hour-old experimental myocardial infarction. Circulation 1976; 53:56. 35. Imanishi S. Calcium-sensitive discharges in canine Purkinje fibers. Jpn J Physiol 1971; 21:443. 36. Imanishi S, Surawicz B. Automatic activity in depolarized guinea pig ventricular myocardium. Characteristics and mechanisms. Circ Res 1976; 39:751. 37. Grant AO, Katzung BG. The effects of quinidine and verapamil on electrically induced automaticity in the ventricular myocardium of guinea pig. J Pharmacol Exp Ther 1976; 196:407. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 10/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate 38. Elharrar V, Zipes DP. Voltage modulation of automaticity in cardiac Purkinje fibers. In: The sl ow inward current and cardiac arrhythmias, Zipes DP, Bailey JC, Elharrar V (Eds), Martinus Nij hoff, The Hague 1980. p.357. 39. Katzung BG. Effects of extracellular calcium and sodium on depolarization-induced automaticity in guinea pig papillary muscle. Circ Res 1975; 37:118. 40. Pappano AJ, Carmeliet EE. Epinephrine and the pacemaking mechanism at plateau potentials in sheep cardiac Purkinje fibers. Pflugers Arch 1979; 382:17. 41. Hauswirth O, Noble D, Tsien RW. The mechanism of oscillatory activity at low membrane potentials in cardiac Purkinje fibres. J Physiol 1969; 200:255. 42. Katzung BG, Morgenstern JA. Effects of extracellular potassium on ventricular automaticity and evidence for a pacemaker current in mammalian ventricular myocardium. Circ Res 1977; 40:105. 43. Ceremuzy ski L, Staszewska-Barczak J, Herbaczynska-Cedro K. Cardiac rhythm disturbances and the release of catecholamines after acute coronary occlusion in dogs. Cardiovasc Res 1969; 3:190. 44. Cameron JS, Han J. Effects of epinephrine on automaticity and the incidence of arrhythmias in Purkinje fibers surviving myocardial infarction. J Pharmacol Exp Ther 1982; 223:573. 45. Barber MJ, Mueller TM, Henry DP, et al. Transmural myocardial infarction in the dog produces sympathectomy in noninfarcted myocardium. Circulation 1983; 67:787. 46. Nuss HB, K b S, Kass DA, et al. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am J Physiol 1999; 277:H80. 47. Hoppe UC, Jansen E, S dkamp M, Beuckelmann DJ. Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation 1998; 97:55. Topic 952 Version 19.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 11/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate GRAPHICS Relationship between fast sodium-mediated myocardial action potential and surface electrocardiogram Each phase of the myocardial action potential (numbers, upper panel) corresponds to a deflection or interval on the surface ECG (lower panel). Phase 4, the resting membrane potential, is responsible for the TQ segment; this segment has a prominent role in the ECG manifestations of ischemia during exercise testing. ECG: electrocardiogram. Graphic 64133 Version 4.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 12/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Spontaneous slow or calcium-mediated action potential generated by pacemaker structures - sinoatrial and atrioventricular nodes The normal sinoatrial node generates a spontaneous slow action potential (panel A), mediated primarily by calcium currents (panel B). The resting membrane potential is -65 mV and manifests spontaneous diastolic depolarization (phase 4), due to an inward leak of sodium ions via a hyperpolarization- dependent pacemaker current (If) and a gradual decline in the delayed rectifier current (Ik), resulting in a decline in the outward flow of potassium ions; these changes are superimposed upon a background current (Ib). The net result is an increase in intracellular positivity with the potential gradually reaching -40 mV, at which point a spontaneous action potential is generated, resulting from a marked increase in the influx of calcium (ICa), followed by a slow inward calcium current (Isi), and activation of Ik and the outward movement of potassium ions. Graphic 70961 Version 2.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 13/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Interaction between sympathetic activation and the calcium channel Acceleration of sinus node automaticity by sympathetic stimulation results from an increase in the influx of sodium (If) during diastolic depolarization and an increase in calcium (Ca++) influx during phase 0; both are due to a direct stimulatory effect of the alpha subunit of the guanosine nucleotide binding protein (G protein) on the respective channels. In the resting nonstimulated state (panel A) guanosine diphosphate is bound to the alpha subunit of the G protein. With beta receptor activation (panel B), guanosine triphosphate (GTP) displaces GDP, stimulating adenyl cyclase; this generates cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) (panel C). Generation of cAMP activates protein kinase A and phosphorylation of the regulatory component of the CA++ channel; the opening of the Ca++ channel in response to membrane depolarization is increased. Activation of the alpha subunit of the G protein may also activate the Ca++ channel. With deactivation of the beta receptor, an intrinsinc GTPase hydrolyzes GTP to GDP (panel D). Graphic 68194 Version 1.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 14/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Location of pacemaker sites in the human sinus node Filled circles represent the location of sites under autonomic control, while the open circles are "escape" sites that are not under the control of the autonomic nervous system and are capable of generating ectopic impulses. There is a predominant clustering of all sites along the sulcus terminalis and superior vena caval (SVC)-right atrial (RA) junction in the upper posterior right atrium; a few escape sites are also located in the left atrium, below the pulmonary vein (PV). Stimulation of the parasympathetic nervous system shifts the dominant pacemaker site to a more caudal region of the sinus complex, while sympathetic stimulation shifts the site to a more cranial location. LAA: left atrial appendage; RAA: right atrial appendage. From Boineau, JP, Canavan, TE, Schuessler, RB, et al Circulation 1988; 77:1221. Graphic 55214 Version 1.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 15/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Effect of overdrive pacing on spontaneous automaticity of Purkinje fiber The more rapid discharge from the sinus node produces overdrive suppression of Purkinje fiber automaticity. Microelectrode recording from a Purkinje fiber at baseline shows a maximum diastolic potential of -77 mV. During overdrive pacing, the membrane becomes hyperpolarized and maximum diastolic potential increases to -85 mV, resulting in part from the accumulation of sodium ions, activation of the sodium-potassium pump, and an increased influx of potassium as sodium is extruded. After the cessation of overdrive pacing, the onset of the next spontaneous action potential is delayed since the slow of phase 4 diastolic depolarization is reduced and the more negative diastolic potential increases in the time required to reach threshold. Graphic 61185 Version 2.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 16/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC Consultant/Advisory Boards: Bain Institute [CRO for trials involving Edwards percutaneous valve devices]; Cardiovascular Research Foundation [Data safety monitoring board (RELIEVE-HF Trial)]; Caristo Diagnostics Limited [Imaging and inflammation/atherosclerosis]; Philips Image Guided Therapy Corporation [Imaging]; Sirtex Med Limited [General consulting]; Thrombosis Research Institute [Data safety monitoring board (GARFIELD study)]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 17/17