Ventricular arrhythmias in ischemic heart disease.

UCLA

CONFERENCE

Ventricular Arrhythmias in Ischemic Heart Disease Moderator: James N . Weiss, MD; Discussants: Koonlawee Nademanee, MD; William G. Stevenson, MD; and Bramah Singh, MD, PhD

Ventricular arrhythmias remain the leading cause of death from coronary artery disease. This review summarizes current thinking in several areas relating to the pathophysiology, prognosis, and therapy of ventricular arrhythmias associated with acute and chronic coronary artery disease syndromes. The experimental basis of arrhythmias in the setting of acute myocardial ischemia and chronic myocardial infarction is described, stressing the important pathophysiologic differences between these two conditions. The effects of the autonomic nervous system as a key modulator of ischemic arrhythmogenesis are discussed. Insights, derived from endocardial mapping studies, into the nature of ventricular tachycardia in humans with chronic myocardial infarction are described, including implications for risk stratification and therapy to prevent arrhythmia recurrence. Current therapeutic principles are discussed in the management of ventricular arrhythmias associated with coronary artery disease, including pharmacologic approaches, surgical and catheter ablation, and automatic implantable cardioverting and defibrillating devices.

Annals of Internal Medicine. 1991;114:784-797.

Dr James N. Weiss (Department of Medicine, Division of Cardiology, UCLA School of Medicine): Despite its declining incidence since the 1960s, coronary artery disease remains the leading cause of death in the United States. Annually, approximately 1.5 million Americans suffer an acute myocardial infarction, with a total 1-year mortality approaching 500 000 (1). Most deaths are caused by ventricular arrhythmias associated with an acute ischemic episode (1, 2) and a smaller number are associated with lethal ventricular arrhythmias arising from chronically infarcted myocardium (3). In this conference, we discuss aspects of the pathophysiology and clinical management of ventricular arrhythmias in these two settings.

Pathophysiology of Ischemic Ventricular Arrhythmias Mechanisms of Cardiac Arrhythmias Cardiac arrhythmia mechanisms fall into two major categories: automaticity and reentry. Automaticity, or spontaneous electrical activity arising from a specific focus, is a normal property of sinus nodal, atrioventricular (AV) junctional, and His-Purkinje tissue. Under pathologic conditions, however, it can occur at accelerated rates in specialized fibers and working myocardium (Figure 1) (4). Automaticity may also be caused by triggered activity. Triggered activity needs an impulse from another site to first excite the focus, which then triggers repetitive action potentials by generating "afterdepolarizations," classified as either ''early" or " l a t e " depending on their timing relative to the repolarization phase of the action potential. Whereas pathologic automaticity is a disorder of impulse formation, reentry is a disorder of impulse conduction in which continuous electrical activity, once initiated, proceeds in a circuit (Figure 2) (4). Two conditions are essential for reentry: slow conduction and unidirectional conduction block. Slow conduction can result from alterations in either active membrane properties or passive membrane properties. Membrane depolarization and depression of the action potential are examples of the former, whereas uncoupling of lowelectrical-resistance electrical pathways (gap junctions) connecting adjacent myocytes is an example of the latter. In addition to intrinsic electrophysiologic properties of the diseased tissue comprising the anatomic substrate of the arrhythmia, the propensity for an arrhythmia to develop can be greatly influenced by extrinsic modulating factors, such as autonomic tone. In addition, reentry (or triggered activity) cannot occur de novo in the absence of the appropriate triggering factors, such as premature ventricular complexes (PVCs). All of these factors play key roles in the development of ischemic ventricular arrhythmias, and each represents a valid point of attack in developing effective antiarrhythmic strategies. Arrhythmias during Acute Myocardial Ischemia

An edited summary of an Interdepartmental Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles, California. William M. Pardridge, MD, Professor of Medicine, is Director of Conferences. Authors who wish to cite a section of the conference and specifically indicate its author can use this example as the form of the reference: Singh BN. Principles of pharmacologic and nonpharmacologic therapy, pp. 792-795. In: Weiss JN, moderator. Ventricular arrhythmias in ischemic heart disease. Ann Intern Med. 1991;114:784-797. 784

The time course of ventricular arrhythmias after coronary occlusion in the dog was first characterized by Harris and Rojas (6). They found a high incidence of PVCs in the first 20 to 30 minutes after coronary occlusion, which frequently triggered ventricular tachycardia and fibrillation. After this early phase, ventricular arrhythmias decreased for 6 to 8 hours and then recurred in a late phase lasting up to 72 hours. Subsequent studies have shown that the initial phase of ar-

© 1991 American College of Physicians

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rhythmias is usually due to reentry arising from the ischemic zone (7-10) (Figure 2). Conduction through the ischemic tissue worsens progressively, eventually making the bulk of the ischemic zone inexcitable, at which point the early phase reentrant arrhythmias disappear. After 6 to 8 hours, however, surviving subendocardial Purkinje fibers underlying the infarcted myocardium,

which are partially nourished by intracavitary blood, develop abnormal automaticity (8). Premature ventricular complexes arising from these fibers may trigger reentry (or triggered automaticity) in the border zone of the infarct, where depressed excitability and slow conduction remain. The early-phase ventricular arrhythmias after coronary occlusion are the most likely cause of the

Figure 1. Activation mapping of ventricular tachycardia due to automaticity. An isolated arterially perfused rabbit ventricle loaded with the membrane potential-sensitive dye WW781 (5) was exposed to acetylstrophanthidin (ACS). Membrane potential was optically sampled every 4 ms at 128 sites (indicated by dots) over the surface of the ventricle using a laser scanning system (4). Top. Representative, optically recorded, action potentials at several sites in the left ventricular free wall (LVFW), interventricular septum (RVS), and near the border zone (BZ) during ACS-induced ventricular tachycardia. Bottom. Maps of the spread of excitation during two successive beats of tachycardia, reconstructed from the timing of the action potential upstroke at each of the 128 sites. The asterisk indicates the earliest site of activation and the isochrome lines show the position of the action potential upstroke every 10 ms. Each beat originated from the same area and rapidly activated the remaining tissue within 60 ms, with about a 250-ms period of electrical silence between successive beats. (The experiments shown in Figures 1 and 2 were done in collaboration with S. Dillon and M. Morad at the University of Pennsylvania.) From Weiss (4): reproduced with permission of Futura Publishing Company. 1 May 1991 • Annals of Internal Medicine • Volume 114 • Number 9


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300 000 sudden deaths annually in patients with acute myocardial infarction who die before reaching the hospital. The late-phase ventricular arrhythmias provide the rationale for cardiac monitoring for at least 72 hours in patients hospitalized with acute myocardial infarction. The heterogeneity of electrophysiologic properties between adjacent regions of perfused and nonperfused tissue is particularly important for the development of reentrant arrhythmias during acute ischemia, and several factors contribute to the underlying electrophysiologic abnormalities. A key factor causing membrane depolarization is the rapid loss of cellular K + , which begins within 30 seconds of the onset of ischemia and accumulates extracellularly due to the lack of washout by blood flow, reaching levels as high as 18 mmol/L within the central ischemic region after 10 minutes (11). It has been shown that K + influx via the Na + -K + pump remains intact during this period and that the net K + loss is due to a marked increase in K + efflux (12-14). Increased intracellular free Ca +2 levels may also be an important factor contributing to membrane depolarization and other electrophysiologic abnormalities. It has recently been shown that intracellular free [Ca+2] rises substantially earlier during ischemia than was previously appreciated (15-17). Elevated intracellular free Ca +2 may result in activation of depolarizing inward currents through nonspecific Ca+2-activated cation channels or electrogenic Na + -Ca +2 exchange (18), resulting in afterdepolarizations and triggered activity (10). The arrhythmogenic effects of catecholamines and cyclic AMP during ischemia are well known (19) and will be discussed in more detail later. Elevation of intracellular free [Ca+2] may also be important in the activation of intracellular proteases and phospholipases, which degrade cellular phospholipids, producing lysophosphoglycerides. These compounds have been shown to have marked electrophysiologic toxicity, causing membrane depolarization, changes in action-potential configuration, and automaticity (20). Intracellular acidosis, another important component of the ischemic environment, has been shown to potentiate the toxicity of lysophosphoglycerides (20). Acidosis, as well as lactate, has direct electrophysiologic effects (21, 22). Inhibition of oxidative phosphorylation leads to intracellular accumulation of byproducts of fatty acid metabolism including free fatty acids, long-chain acylcarnitines, and long-chain acylcoenzyme A, which have prominent electrophysiologic toxicity (20). Oxygen-derived free radicals have also been shown to cause electrophysiologic abnormalities and may contribute particularly to reperfusion arrhythmias (23). Although the alterations in active membrane properties are the most striking and probably the dominant arrhythmogenic factors in acute ischemia, alterations in passive membrane properties are also important. Both intracellular acidosis and elevated intracellular free [Ca+2] uncouple the low-resistance electrical pathways (gap junctions) connecting the individual myocytes (24), contributing to slowing of conduction during acute ischemia (25). Many of the factors that predispose the heart to ventricular arrhythmias during acute ischemia may also 786

contribute to the susceptibility of the heart to reperfusion arrhythmias (26). The contribution of lethal reperfusion arrhythmias to sudden cardiac death is difficult to estimate, but could be important in view of the significant incidence of spontaneous reperfusion during acute myocardial infarction and unstable coronary insufficiency syndromes. Arrhythmias in Chronic Myocardial Infarction Unlike ventricular arrhythmias during acute ischemia, the arrhythmogenic substrate in a chronic completed myocardial infarction is generally stable. Reentry is the predominant mechanism, originating in areas of slow conduction in the border zone between normal and infarcted tissue. In contrast to acute ischemia, changes in passive membrane properties rather than active membrane properties seem to be the major cause of slow conduction (27). The border zone region is characterized histologically by bundles of viable myofilaments interspersed with bands of collagen and connective tissue (28). The scar tissue disrupts the normal low electrical-resistance pathways between bands of myofilaments, impeding the flow of current necessary to activate adjacent myofilament bundles. Even in normal myocardium, conduction velocity is anisotropic, that is, not equal in all directions with respect to the myofilament orientation (29). In normal myocardium, anisotropy is uniform, whereas in the border zone of an infarct, the haphazard disruption of the normal architecture by scar tissue can markedly accentuate anisotropic conduction in a nonuniform manner, leading to extremely slow conduction and predisposing the region to unidirectional conduction block and development of reentry (30). Figure 3 (28) shows how the presence of slow conduction in infarcted regions can be detected by extracellular catheter recordings, which provides the basis for using intracardiac catheter techniques to detect areas of slow conduction clinically in human ventricle. Human catheter mapping studies have provided important evidence supporting the reentrant nature of most ventricular tachycardia in the setting of chronic myocardial infarction, which will be discussed in greater detail later. Autonomic Influences and Ischemic Ventricular Arrhythmias Dr. Koonlawee Nademanee (Division of Cardiology, Denver General Hospital, and the Department of Medicine, University of Colorado School of Medicine): During the last 20 years, extensive research has led to considerable progress in our understanding of how the sympathetic and parasympathetic nervous systems contribute to the development of malignant ventricular arrhythmias in patients with ischemic heart disease (3243). Both animal and clinical studies strongly support the role of increased sympathetic activity as a key arrhythmogenic factor during ischemia (32-43). The role of beta-blockade in reducing ventricular fibrillation during ischemia is well established (44, 45), although the

1 May 1991 • Annals of Internal Medicine • Volume 114 • Number 9


Figure 2. Activation mapping of reentrant ventricular tachycardia. Top. Optically recorded action potentials at several of 128 scanned sites during ventricular tachycardia caused by regional ischemia in an isolated rabbit ventricle. The dashed line indicates the border zone (BZ) between the perfused interventricular septum (RVS) and the ischemic left ventricular free wall (LVFW). Bottom. The spread of excitation during the three beats of tachycardia was reconstructed from the timing of the action potential upstroke at the 128 sites. Isochrome lines are 10 ms apart. The first beat originated from the perfused RVS and conducted rapidly (widely spaced isochrome lines) to the BZ. Conduction block (heavy black line) occurred just across the BZ at the base, but the impulse propagated slowly (closely spaced isochrome lines) around the apex in the direction of the arrows. The slow conduction allowed recovery of excitability at the initial area of conduction block, and the impulse conducted through this zone from the opposite direction, reentering the normally perfused myocardium and proceeding in a similar circuit to cause the second and third beats of the tachycardia. The tachycardia terminated spontaneously when the third beat was unable to penetrate the ischemic tissue at the apex. From Weiss (4): reproduced with permission of Futura Publishing Company.



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role of a-stimulation and blockade remains controversial (35, 39, 46). Autonomic Interactions in Normal and Ischemic Heart The net autonomic state of the heart is determined by a complex interaction between the sympathetic and parasympathetic systems, which modulates the susceptibility of the heart to ventricular arrhythmias. Sympathetic stimulation lowers the ventricular fibrillation threshold, whereas vagal stimulation alone has little effect (33, 34). However, vagal stimulation substantially attenuates the decrease in ventricularfibrillationthreshold evoked by sympathetic stimulation (33). Within 30 minutes of the onset of a myocardial infarction, most patients develop signs of autonomic disturbance (41). Parasympathetic hyperactivity and sinus bradycardia are more prevalent among patients with acute inferior wall infarction, due to stimulation of vagal sensory nerve endings in the posterior inferior wall region of the left ventricle, eliciting the Bezold-Jarisch reflex (47). Conversely, sympathetic hyperactivity and sinus tachycardia are more common in acute anterior wall infarction due to stimulation of afferent sympathetic mechanosensitive, chemosensitive, and barosensitive nerve endings prevalent in the anterior left ventricular wall. Vagal hyperactivity during myocardial ischemia may exert a beneficial effect, decreasing the incidence of ventricular fibrillation, although this remains controversial (48, 49). However, the adverse effect of sympathetic hyperactivity on the incidence of ventricular fibrillation is clear (32-36). Lombardi and coworkers (40) showed that after 2 minutes of left coronary artery occlusion, preganglionic sympathetic impulse activity increased coincident with a fall in the ventricularfibrillationthreshold. With maintained coronary occlusion, sympathetic activity and the ventricular fibrillation threshold gradually returned to baseline. When the occlusion was released, however, the ventricularfibrillationthreshold again fell without a change in sympathetic activity. Stellate ganglionectomy or betablockade prevented the increase in sympathetic activity and fall in the ventricular fibrillation threshold during coronary occlusion, but did not affect the ventricular fibrillation threshold during reperfusion. This suggests that the ventricular electrical instability is closely related to increased sympathetic activity during acute ischemia but not during reperfusion. The major arrhythmogenic electrophysiologic effects of increased sympathetic activity during myocardial ischemia seem to be mediated through ^-adrenergic receptors (33, 35, 40, 46, 50). This finding agrees with the results of clinical trials showing the effectiveness of beta-blockade in reducing the incidence of sudden death in survivors of acute myocardial infarction (45), as discussed later. In cardiac muscle, sympathetic fibers run subepicardial^ from the base to the apex before penetrating transmurally to the endocardium. In contrast, subepicardial vagal fibers cross to the subendocardium at the atrioventricular groove and run subendocardially from the base to the apex before penetrating transmurally to the epicardium. Differential ischemia or injury to the subendocardium and subepicardium may therefore 788

cause an imbalance between sympathetic and parasympathetic activity between ischemic and normal myocardial tissue, which may promote ventricular fibrillation (33, 51-60). With a transmural infarct, the surviving myocardium apical to the infarct may be denervated (58) and may exhibit denervation-supersensitivity (57). Using 123I-metaiodobenzylguanidine sulfate (MIBG) radionuclide imaging, Minardo and colleagues (59) recently showed that regional sympathetic denervation and reinnervation occurred after transmural infarction and supersensitivity persisted even after reinnervation. Autonomic Disturbances in Survivors of Myocardial Infarction Although the incidence of ventricular fibrillation declines dramatically 24 hours or more after the onset of acute myocardial infarction, survivors continue to face a high risk of lethal ventricular arrhythmias and sudden cardiac death. Regions of myocardial scar from a previous infarction may provide the substrate for ventricular tachyarrhythmias, and residual coronary artery disease may result in transient myocardial ischemia triggering autonomic disturbance. Schwartz and associates (36, 42, 61) have examined the interaction among previous myocardial infarction, superimposed acute ischemia, and autonomic disturbance that leads to sudden cardiac death in a canine model. In dogs with healed anterior wall infarct subjected to transient coronary artery occlusion during exercise, those with a strong vagal reflex, as assessed by baroreceptor reflex testing, did not develop ventricularfibrillation,whereas those with a weak vagal reflex did. There is growing evidence that noninvasive techniques to assess autonomic function after myocardial infarction may provide useful prognostic information for identifying patients at a high risk for sudden cardiac death. Measurements of heart rate variability (62), the baroreflex slope (62), and 123 I-MIBG scanning (59, 60) have been shown in preliminary studies to successfully identify patients at a high risk for sudden cardiac death after myocardial infarction (59, 60). If the initial promise of these studies is substantiated, these techniques will permit clinicians to tailor, with even greater precision, sympathetic blockade therapy to these patients. Epidemiologic evidence has shown that behavioral stress may play an important role in the susceptibility to ventricular arrhythmias after myocardial infarction. Ruberman and coworkers (63) found that male survivors of acute myocardial infarction who were socially isolated and had high stress levels were four times more likely to die suddenly over a 3-year period than less socially isolated and stressed patients. Several studies have found an association between central neural influences and arrhythmogenesis (32, 37, 43, 46, 64, 65). Case examples also support a relation between psychologic and environmental strain and episodes of ventricular fibrillation and sudden death (38, 64). In summary, animal and clinical studies have unequivocally shown that the autonomic nervous system is one of the most important factors modulating the susceptibility to ventricular fibrillation in patients who have ischemic heart disease. Many aspects of the inter-



play between sympathetic and vagal tone in ischemic heart disease have been elucidated, and through future research our clinical knowledge about how best to identify and treat patients at the highest risk will improve.

grammed electrical stimulation permits study under controlled conditions. These investigations suggest that reentry is the most common mechanism of sustained ventricular tachycardia in humans (27, 68, 71-74).

Studies of Human Ventricular Tachycardia in Healed Myocardial Infarction

Evidence for Slow Conduction in Myocardial Scars

Dr. William G. Stevenson (Division of Cardiology, UCLA School of Medicine): Sustained ventricular tachycardia that occurs late after myocardial infarction can usually be initiated and terminated by critically timed ventricular pacing stimuli in the catheterization laboratory (66). Coronary artery bypass surgery alone does not prevent recurrences of arrhythmia (67). Thus, in some survivors of myocardial infarction, the electrophysiologic substrate for ventricular tachycardia persists late after the infarction, causing arrhythmias that are not due to acute ischemia. These arrhythmias could theoretically be due to reentry or triggered automaticity, because either can be provoked by programmed electrical stimulation (68). Slow conduction and heterogeneous refractoriness—the substrates for reentry—and triggered activity have been found in surgically resected human ventricular tissue (27, 69, 70). In patients, the electrophysiology of the infarct scar can be investigated by recording electrical activity with transvascular electrode catheters maneuvered about the ventricles or from a hand-held probe or network of electrodes applied to the heart during cardiac surgery. The ability to initiate and terminate ventricular tachycardia by pro-

Compared with electrograms recorded from normal myocardium, those recorded from myocardial scar are often low amplitude, long duration, and have a fractionated appearance caused by multiple high-frequency components (Figure 4) (74-77). Fractionated electrograms can be caused by slow conduction, as discussed previously, or by recording artifact (76, 77). Additional evidence of slow conduction can often be shown by ventricular pacing during endocardial catheter mapping (Figure 5) (78). During pacing at normal left ventricular sites, the paced stimulus artifact is immediately followed by the QRS complex because the stimulated depolarization wavefronts propagate rapidly away from the pacing site. However, at approximately half the sites with fractionated electrograms, there is a delay between the stimulus artifact and the QRS onset, consistent with slow conduction between the pacing site and myocardium outside the infarct scar. The low-amplitude electrical activity generated by slow conduction is not detectable in the surface electrocardiogram, resulting in an isoelectric segment between the stimulus and QRS onset. Surgical resection of areas with fractionated electrograms often frees the patient from inducible ventricular tachycardia (75).

Figure 3. Fractionated extracellular electrograms indicate slow conduction. In two different experiments (A-C [left] and D-E [right]), extracellular electrograms recorded with a standard bipolar pacing catheter from the border zones of chronic canine myocardial infarcts were abnormally fractionated with multiple deflections, unlike the rapid monophasic electrogram from normal tissue (not shown). The positions of the bipolar catheter leads (O) are shown relative to the histology of the underlying myocardium in both cases, with the cross-hatched areas representing viable myocardium and the speckled areas, scar. The action potential upstrokes (AP0) in bundles A-C or D-E each coincided with one of the major deflections (EG1, EG2, or EG3) in the extracellular electrogram, reflecting slow conduction between the adjacent bundles. From Gardner et al. (28); reproduced with permission of Circulation. 1 May 1991 • Annals of Internal Medicine • Volume 114 • Number 9


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Figure 4. Fractionated intracardiac electrograms in a patient with inducible sustained ventricular tachycardia. From the top of panels A and B are 50-ms time lines (T)\ surface electrocardiogram leads I, AVF, and VI; and endocardial bipolar recordings from two left ventricular sites (LV8 and LV7) and the right ventricular apex (RVA). During sinus rhythm (panel A) the electrograms at the LV8 and LV7 are low amplitude (less than 1 mV) and fractionated, and extend beyond the QRS complex at site LV8. During sustained monomorphic ventricular tachycardia (SMVT; panel B) electrograms at the LV8 and LV9 remain fractionated and now precede the QRS complex. When intracardiac electrograms are recorded simultaneously with the surface electrocardiogram, fractionated electrograms often extend beyond the end of the QRS complex (Figure 4). This low-amplitude electrical activity can be detected from the body surface electrocardiogram by signal averaging the surface electrocardiogram to reduce random noise. A high-frequency, low-amplitude "tail" at the end of the QRS complex, designated a "late potential," is detectable in 60% to 100% of patients after infarction who suffer from sustained ventricular tachycardia (79, 80). Evidence that areas of slow conduction participate in ventricular tachycardia circuits has been provided by detailed intraoperative activation mapping and programmed electrical stimulation (27, 71-74). In some cases, activation mapping has delineated an apparent reentry circuit in its entirety (27, 71, 72). More often, an area through which conduction is slowed is identified. Some portions of, if not the entire, reentry circuit are usually within subendocardial areas of scar, and resection of these subendocardial areas is usually successful in abolishing inducible ventricular tachycardia. The resected scar contains viable myocytes encased in fibrous tissue, many of which have relatively normal action potentials (27, 81, 82). Estimated conduction velocity through segments of the scar ranges from 0.06 m/s to 0.7 m/s (27). Programmed electrical stimulation during ventricular tachycardia induced in the electrophysiology laboratory has provided further evidence of slow conduction in the tachycardia circuit. Okumura and coworkers (73, 83) showed that pacing at a rate faster than the tachycardia (but which did not terminate the tachycardia) could accelerate the reentry circuit to the pacing rate and designated this phenomenon "entrainment." Entrainment occurred because each paced excitation wavefront entered the reentry circuit and propagated through the circuit. Further, when the pacing site was proximal to an area of slow conduction in the circuit, relatively long conduction times were found between the last pacing stimulus and the final tachycardia beat, which was accelerated to the pacing rate. The ability to entrain a tachycardia is strong evidence that reentry is the mechanism. The ability to show entrainment depends, how790

ever, on the locations of the pacing site and the recording site relative to areas of slow conduction in the reentry circuit. Entrainment may not always be detected even though it is occurring (concealed entrainment) (73, 83). However, by pacing at several sites and recording from sites in or near the reentry circuit, entrainment can be shown for most ventricular tachycardias that occur late after myocardial infarction. Programmed electrical stimulation at sites in the scar can be used to locate areas of slow conduction in the reentry circuit during catheter mapping procedures (74, 84-86). Stimuli at reentry circuit sites produce specific effects on tachycardia depending on the conduction characteristics of the circuit, the location of the pacing site relative to areas of slow conduction in the circuit, and the stimulus timing (Figure 6) (84). During pacing at areas of slow conduction within the reentry circuit, the tachycardia can be entrained or reset without altering the QRS morphology during pacing and with a long delay between the stimulus and advanced tachycardia beat as shown in Figure 6. In preliminary studies, catheter ablation at such sites has been successful in preventing ventricular tachycardia (74, 85, 86). Implications for Identifying the High-Risk Patient Denniss and associates (87) did programmed electrical stimulation 7 to 28 days after acute myocardial infarction in 403 patients. Ventricular tachycardia was inducible in 20% of patients. The 2-year actuarial risk of sudden death or spontaneous sustained ventricular tachycardia was 22% for patients who had inducible ventricular tachycardia compared with 5% for patients who did not (P < 0.001). In smaller studies sustained ventricular tachycardia has been inducible in up to 44% of survivors of infarction (88-90). Signal-averaged electrocardiograms were obtained in 306 (76%) of patients after infarction studied by Denniss and associates (87); late potentials were identified in 26% of patients. The 2-year actuarial risk of sudden death or spontaneous ventricular tachycardia was 21% in the group with late potentials compared with 4% in the group without late potentials (P < 0.01). Late potentials were found in 41% of 315 patients after myo-



cardial infarction in two additional studies (91, 92). During mean follow-ups of 14 months, 19% of patients with late potentials, but only 3% without, suffered sudden death or spontaneous ventricular tachycardia. Interestingly, 80% of patients with inducible tachycardia or late potentials after myocardial infarction remain free of life-threatening arrhythmias, at least for the next 1 to 2 years. A reentry circuit is present but does not become clinically manifest. In some patients, the arrhythmia substrate may change or disappear with time (87, 93). In others, the degree of slow conduction may be an important determinant of spontaneous arrhythmias. Denniss and associates (87) noted that patients who had inducible tachycardias that were slower than 260 beats/min were at higher risk for spontaneous sustained arrhythmias than patients whose inducible tachycardias were faster. Similarly, Brugada and colleagues (94) noted that inducible ventricular tachycardias in patients who had not suffered spontaneous sustained ventricular tachycardia were faster than in patients with spontaneous ventricular tachycardia. Faster tachycardias generally need aggressive programmed electrical stimulation for induction, with multiple premature stimuli (74, 94). The rate of a reentrant tachycardia depends on the revolution time through the circuit and therefore on the length of the reentry path and the conduction velocity in the circuit. Faster circuits, having relatively rapid conduction or a small area of slow conduction,

may be more difficult to engage with premature beats, changes in heart rate, and other spontaneous tachycardia-initiating mechanisms. Hence, inducible rapid arrhythmias are more likely to be "false positive" findings, unrelated to spontaneous ventricular tachycardia, than are relatively slower inducible tachycardia. Preventing Slow Conduction in the Infarct Scar Ventricular arrhythmias are more likely to develop in patients who have a large infarction. The size of the myocardial infarction, as reflected by residual left ventricular function, is the best predictor of risk for sudden death in survivors of myocardial infarction (91, 92). Most patients who suffer from sustained ventricular tachycardia after the acute phase of the infarction have left ventricular ejection fractions below 0.4 (89, 95). Late potentials, detected by signal-averaged electrocardiograms, are most common in patients who have a left ventricular ejection fraction less than 0.4 and are uncommon in patients with normal or near-normal ventricular function (91, 92). Therapy that reduces infarct size will probably reduce the likelihood of slow conduction areas in the residual myocardial scar. In preliminary studies successful coronary reperfusion has been associated with a lower incidence of late potentials and inducible ventricular tachycardia (88, 96). In summary, slow conduction in the infarct scar pro-

Figure 5. Pacing at left ventricular sites mimics sustained ventricular tachycardia and unmasks slow conduction. Surface electrocardiogram leads I, VI, and V3 during sustained monomorphic ventricular tachycardia (SMVT 1) and during endocardial pacing at three left ventricular sites (7, 8, and 11-12) at the locations indicated in the schematic (top right). During pacing at site 7 and site 8 there is about an 80-ms interval between the stimulus artifact and the QRS onset (large and small arrows, respectively, in lead I), consistent with slow propagation of the stimulated wavefront away from the pacing site. The paced QRS is also morphologically similar to the tachycardia QRS, suggesting proximity to the tachycardia reentry circuit. In contrast, during pacing at site 11-12 outside the scar, the stimulus to QRS interval is much shorter, consistent with rapid propagation away from the pacing site. 1 May 1991 • Annals of Internal Medicine • Volume 114 • Number 9


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vides the substrate for ventricular tachycardia late after myocardial infarction. Evolving methods to localize slow conduction areas hold promise for improving surgical and catheter ablation techniques for controlling ventricular tachycardia. Detection of this arrhythmogenic substrate with programmed electrical stimulation, or noninvasively with signal-averaged electrocardiograms, is theoretically attractive for risk stratification of the patient after myocardial infarction. The clinical use of these methods is limited, however, because many patients who have slow conduction in the infarct scar remain free of spontaneous arrhythmias. Reducing infarct size may diminish the likelihood that the ventricular tachycardia substrate will develop. Principles of Pharmacologic and Nonpharmacologic Therapy Dr. Bramah N. Singh (Division of Cardiology, Department of Veterans Affairs Medical Center of West Los Angeles and the Department of Medicine, UCLA School of Medicine): Current therapy of ventricular arrhythmias is at a crossroads. With recent advances (97, 98) in the synthesis of newer drugs, refinements of surgical techniques, electrode catheter or chemical ablation, and implantable defibrillating and cardioverting devices, there is a need to integrate the newer modalities into the appropriate therapeutic option for specific ventricular arrhythmias. A rational approach must consider the nature of the arrhythmia, the underlying substrate, the intrinsic and extrinsic trigger mechanisms, hemodynamic disturbances due to the arrhythmia, and the prognostic significance.

laying conduction (class IC agents, for example, flecainide) or prolonging refractoriness (class III agents, for example, amiodarone) have been the focus (102). Class IC agents cause a striking depression of conduction with potent PVC suppression, which formed the rationale for including them in a controlled study, the Cardiac Arrhythmia Suppression Trial (CAST) (103), to test the PVC hypothesis in patients surviving myocardial infarction. This trial tested the effects of flecainide, encainide, and ethmozine compared with placebo in survivors of myocardial infarction who had PVCs. Of the 730 patients on encainide or flecainide for an average of 10 months, 56 died or had cardiac arrest, whereas of the 725 given placebo, 23 died or had cardiac arrest, a 3.64-fold increase in cardiac death in patients on encainide or flecainide compared with placebo (Figure 7) (103). CAST is continuing, in a modified form, with ethmozine and placebo. Whether the CAST data can be extrapolated to other class I agents remains uncertain but it is likely that other class IC agents (propafenone, indecainide) will exert similar proarrhythmic effects. A meta-analysis of various class I antiarrhythmic agents (104) indicated either an unfavorable trend with slight increase in mortality or no effect in survivors of infarction. Taken in conjunction with CAST, these data suggest a need for skepticism about the use of class I agents in general in any (including acute myocardial infarction) patient with PVCs (105) and about the use of PVC suppression as an end point in arrhythmia mortality trials. The alternative, that sudden death may be prevented by an antifibrillatory mechanism without an effect on PVCs, must be considered.

Which Ventricular Arrhythmias Should Be Treated? In deciding whether to treat a ventricular arrhythmia, the overriding concerns are the patient's symptoms and their effect on the quality of life, the prognostic implications of the arrhythmia, and the efficacy and safety of treatment. Three categories of ventricular arrhythmias should be considered: premature ventricular complexes (PVCs) in patients with minimal or no structural heart disease; PVCs in patients with significant heart disease including myocardial infarction; and symptomatic sustained ventricular tachycardia with a propensity to degenerate to ventricular fibrillation or arrhythmias in survivors of cardiac arrest. The prognosis in the first group is normal (99), and PVC suppression is only necessary for troublesome symptoms. In the second category, PVCs are considered an independent marker of sudden death (100, 101) in patients after infarction, hypertrophic or dilated cardiomyopathy, or valvular disease. It has been traditionally hypothesized that sudden death may be prevented by the elimination of PVCs by antiarrhythmic agents (the PVC hypothesis). In the third category, antiarrhythmic agents may prevent ventricular fibrillation by preventing or slowing the rate of ventricular tachycardia (an antifibrillatory action). Mortality Reduction by Pharmacologic Suppression of Potentially Lethal Ventricular Arrhythmias In the recent development of antiarrhythmics, newer agents exhibiting either the property of selectively de792

Mortality Reduction in Survivors of Infarction by Other Electrophysiologic Classes of Antiarrhythmic Drugs Emerging data indicate that a beneficial effect may be attained by other classes of agents, such as beta-blockers (class II agents), which also have anti-ischemic and bradycardie actions. When started between 4 and 28 days after acute infarction and continued for 90 days or longer, these drugs produce a significant reduction in sudden cardiac death (18% to 39%) and in reinfarction rate (35% and 40%) in the first year after infarction (106). Unlike CAST, these trials have not been PVCsuppression trials. When the drugs were given early in the course of infarction and in the coronary care unit, the occurrence of ventricular fibrillation was also significantly reduced (106). Currently, beta-blockers remain the only class of drugs shown in blinded studies to reduce sudden death in survivors of myocardial infarction. In contrast, in these patients, calcium antagonists (class IV agents) seem not to affect—or to increase slightly (5% to 10%)—mortality (107). Class III agents, however, hold greater promise. A recent study (108) randomized 312 patients after infarction who had complex PVCs into three treatment groups. The first group in = 114) was not given antiarrhythmic treatment; the second group (n = 100) was given conventional antiarrhythmic treatment to produce a defined degree of PVC suppression; and the third group (n = 98) was treated with amiodarone. Over 12



months there were 15 sudden deaths in the untreated group, 12 in the group with individualized antiarrhythmic therapy, and 5 in the amiodarone group (P < 0.01 compared with the first group). Several larger placebocontrolled trials to determine whether the results of this pilot study can be confirmed are in progress.

Pharmacologic Approaches to Life-Threatening Ventricular Tachyarrhythmias It remains uncertain whether pharmacologic therapy, the most widely used modality for controlling ventricular tachycardia-ventricular fibrillation (VT-VF), prolongs survival. Antiarrhythmic agents do not eradicate the anatomic substrate responsible for an arrhythmia

but alter the substrate by influencing conduction, by prolonging refractoriness, or by removing the arrhythmia trigger mechanisms (109, 110). Of importance is the nature and frequency of their pro-arrhythmic effects, particularly incessant VT-VF or torsade de pointes, which may confound the evaluation of their effectiveness in controlling VT-VF (111). Despite these limitations, a reasonably uniform approach has evolved in the pharmacologic treatment of patients presenting with sustained symptomatic VT-VF and of survivors of cardiac arrest (97). In this approach, it is critical not only to exclude reversible causes of VT-VF, but also to quantify ventricular function and to determine the role of ischemia. However, only in a few patients is myocardial revascularization alone effective in controlling VT-VF.

Figure 6. Resetting of ventricular tachycardia by a single stimulus delivered in an area of slow conduction within the reentry circuit. From the top are surface electrocardiogram leads AVF and Vl and intracardiac recordings from the right ventricle (RV)> left ventricular stimulus marker (LVSt), and left ventricular pacing catheter (pLV^). During sustained monomorphic ventricular tachycardia, a stimulus (S) delivered at site LV1-2 10 ms after the QRS onset does not alter the portion of the QRS following the stimulus, but the subsequent QRS complex is early (390 ms after the preceding beat as compared with the tachycardia cycle length of 440 ms). The substantial delay of 400 ms between the stimulus and the advanced QRS complex is consistent with slow conduction between the pacing site and the exit to normal myocardium. Further, the QRS morphology of the advanced tachycardia beat is unchanged, suggesting that the paced excitation wavefront exited from the scar at the same site as the tachycardia wavefront (illustrated schematically in thefigure-eighttype circuit at the bottom). During ventricular tachycardia, two circulating wavefronts ( - • ) propagate rapidly around two arcs of conduction block ( ), sharing a common central pathway in an area of scar (thin irregular line) through which conduction is slow (—— , panel 1). A single stimulus at site S in the common central pathway (panel 2) produces orthodromic (upward) and antidromic (downward) wavefronts. The antidromic wavefronts collide with returning tachycardia wavefronts and do not penetrate normal tissue sufficiently to alter the portion of the QRS immediately after the stimulus. The orthodromic wavefront propagates slowly through the scar, eventually exiting after 400 ms to produce the advanced QRS {panel 3). From Stevenson et al (74), reproduced with permission of The American Heart Journal. 1 May 1991 • Annals of Internal Medicine • Volume 114 • Number 9


793

Figure 7. Mortality in the Cardiac Arrhythmia Suppression Trial (CAST). Survival curves are shown for 1455 patients randomly assigned to receive encainide or flecainide or matching placebo. The cause of death was arrhythmia or cardiac arrest. The nominal P value was based on a traditional two-sided log-rank test adjusted for multiple groups. From the CAST Investigators (103); reproduced with the permission of The New England Journal of Medicine. The response to programmed electrical stimulation shows inducible VT-VF in 70% to 90% of patients with clinical VT-VF and suggests a reentrant mechanism. Less frequently, ambulatory electrocardiogram monitoring shows the frequent occurrence of complex PVCs and nonsustained ventricular tachycardia. Both programmed electrical stimulation and ambulatory electrocardiogram monitoring have been advocated as methods to gauge the effectiveness of antiarrhythmic drug therapy. Combination therapy (for example, class IA plus class IB agents) is often used but has not been critically evaluated. The programmed electrical stimulation approach appears superior in its predictive accuracy, but controlled studies are few (111). The results of a controlled multicenter study, the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) Trial (112), are likely to be of value in providing future guidelines. The overall efficacy of the various classes of antiarrhythmic drugs with programmed electrical stimulation compared with the ambulatory electrocardiogram monitoring is summarized in Table 1. The major drug classes that appear effective in recurrent VT-VF are those that act fundamentally by depressing conduction and those that predominantly prolong refractoriness. The role of class I agents is likely to diminish because of proarrhythmia, and that of class III agents, especially with associated anti-adrenergic effects, to grow. This is suggested by increasing experience with sotalol (113) and amiodarone. Amiodarone seems to be effective in over two thirds of refractory cases of recurrent VT-VF; this unusual potency needs to be balanced against its well-known complex, potentially lethal side effects. The role of newer class III agents is being investigated (102). Beta-blockers and calcium-channel blockers are generally of limited use for patients with manifest VT-VF or aborted cardiac arrest. Nonpharmacologic Approaches to Life-Threatening Ventricular Arrhythmias An increasing number of invasive modalities of treatment are at various stages of development and, in se794

lected groups of patients, their effectiveness has been documented (97). The salient features of these modalities of treatment, compared with the pharmacologic approach, are listed in Table 2. By eradicating, isolating, or interrupting the arrhythmia substrate, map-guided surgery cures 60% to 80% of selected patients, although the surgical mortality is 10% to 20% or higher (114). The most widely used technique is map-guided subendocardial resection; in appropriate patients other techniques, including cardiac transplantation in truly refractory VT-VF in patients with low ejection fractions, are occasionally used. Electrode catheter ablation may cure approximately 25% of selected patients (115). Chemical ablation remains investigational. Perhaps the most promising recent advance in the control of VT-VF is the use of implantable defibrillating and cardioverting devices. The value of these implantable devices in selected patients is now well documented (97, 116). Patients currently considered for implantation include those surviving cardiac arrest, those with recurrent VT-VF, despite therapy or intolerant of it, and those felt to be a high risk for sudden death in which other modalities of treatment are inappropriate. Experience with these devices indicates a potential for a

Table 1. Antiarrhythmic Agents and Their Effects on Inducibility of Ventricular Tachycardia and Fibrillation and on Premature Ventricular Complexes* Suppression Suppression Suppression of Drug by Electrophysiologic of VT-VF of PVCs Ventricular Class by PES (by > 75%) Tachycardia (by > 90%) - % of Patient s

< Class IA Quinidine Procainamide Disopyramide IB Mexiletine Tocainide Ethmozine IC Encainide Flecainide Propafenone Indecainide II Beta-blockers III Amiodarone Sotalol IV Verapamil Diltiazem

>

15-20 15-25 ?

60 60 60

?70 ?70 ?70

15 10-15 15-20

60 60 60

>70 ?>70 ?>70

10-15 10-15 10-20 10-15

80 80 70 70

90-100 90-100 90-100 90-100

?l-2

50

?70-80

8-40 40-45

80 50-60

90-100 80

1-2 ?

< 10 < 10

< 10 < 10

* The data included are crude estimates from reports of controlled and uncontrolled studies. About 80% of all patients mentioned had ischemic heart disease. However, they provide a reasonable approximation of the overall effects of various antiarrhythmic agents in effecting two major end points used in determining the efficacy of pharmacologic therapy of ventricular arrhythmias. In the case of amiodarone the exact percentage might vary with duration of therapy. Note that class IC drugs are the most powerful PVC suppressants. They exert only a modest effect on inducible VT-VF and increase mortality while markedly decreasing PVCs (see text). PES = programmed electrical stimulation; PVC = premature ventricular complex; VT-VF = ventricular tachycardia-ventricular fibrillation.



Table 2. Current Modes of Treating Arrhythmias in Relation to Effect on Arrhythmia Substrate, Costs, Required Expertise, Long-Term Efficacy, and Side Effects* Variable

Arrhythmia substrate removed Costs Specialized center Long-term efficacy Side effects

Drugs

Surgery

Electrical Ablation

Chemical Ablation

Defibrillating and Cardioverting Devices

No Low ? Yes Yes

Yes High Required Yes 10% to 15% mortality in ventricular tachycardia

Yes Moderate Required ? Myocardial damage

Yes Moderate Required ? Myocardial damage

No High Required ? Psychologic disturbance

* From reference 97.

reduction of mortality from arrhythmia, in some series to less than 5% (compared with an expected mortality of 20% to 30% per year) when they are used alone or in combination with antiarrhythmic drugs (97, 116). Their use also permits safer testing of antiarrhythmic agents in patients with life-threatening arrhythmias. With continued technologic improvement, the use of these devices is likely to grow exponentially, resulting in major inroads into the mortality from ventricular arrhythmias. Acknowledgments: The authors thank Annette V. Terzian for editorial assistance. Grant Support: Dr. Weiss is the recipient of Research Career Development Award 1K04 HLO1890 from the National Institutes of Health. Requests for Reprints: James N. Weiss, MD, Department of Medicine, Division of Cardiology, UCLA School of Medicine, Los Angeles, CA 90024. Current Author Addresses: Drs. Weiss and Stevenson: Division of Cardiology, 47-123 CHS, UCLA School of Medicine, Los Angeles, CA 90024. Dr. Nademanee: Division of Cardiology, Denver General Hospital, 77 Van Nock Street, Mail Code 0940, Denver, CO 80204. Dr. Singh: Division of Cardiology, Wadsworth Veterans Affairs Medical Center, Mailcode 691-1 HE, Sawtelle Avenue and Wilshire Boulevard, Los Angeles, CA 90073-1691. References 1. 1987 Heart Facts. Dallas: American Heart Association; 1986;2. 2. Goldman L, Cook F, Hashimoto B, Stone P, Midler J, Loscalzo A. Evidence that inhospital care for acute myocardial infarction has not contributed to the decline in coronary mortality between 1973-4 and 1978-9. Circulation. 1982;65:936-42. 3. Stevenson WG, Linssen GC, Havenith MG, Brugada P, Wellens HJ. Late death after myocardial infarction: mechanisms, etiologies and implications for sudden death. In: Brugada P, Wellens, HJJ, eds. Cardiac Arrhythmias: Where To Go from Here? New York: Future Publishing Company, Inc; 1987:367-76. 4. Weiss J. Metabolic effects of ischemia: what as the implications for arrhythmogenesis and the treatment of arrhythmias? In: Brugada P, Wellens HJJ, eds. Cardiac Arrhythmias; Where to Go From Here? New York: Futura Publishing Co; 1987:83-104. 5. Morad M, Dillon S, Weiss J. An acousto-optical steered laser scanning system for measurement of action potential spread over the surface of the heart. In: Deweer P, Salzburg BM, eds. Optical Methods in Cellular Physiology. New York: John Wiley & Sons; 1986:211-26. 6. Harris AS, Rojas AG. The initiation of ventricular fibrillation due to coronary occlusion. Experimental Med Surg. 1943;1:105-22. 7. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989;69:1049-168. 8. El-Sherif N, Scherlag BJ, Lazzara R. Electrode catheter recordings during malignant ventricular arrhythmia following experimental acute myocardial ischemia. Circulation. 1975;51:1003-14. 9. Janse MJ, Van Capelle FJ, Morsink H, et al. Flow of "injury" current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Circ Res. 1980;47:151-65.

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1 May 1991 • Annals

of Internal

Medicine

• V o l u m e 114 • N u m b e r 9


797

Ventricular arrhythmias in ischemic heart disease: mechanism, prevalence, significance, and management.

Ventricular tachycardia in ischemic heart disease substrates.

Ventricular arrhythmias in heart failure.

Management of ventricular arrhythmias in structural heart disease.

Cellular mechanism for ischemic ventricular arrhythmias.

Relationship between fibrosis and ventricular arrhythmias in Chagas heart disease without ventricular dysfunction.

Arrhythmias in structural heart disease.

Ventricular arrhythmias during spontaneous ischemic ST-segment depression.

Effect of milrinone on ventricular arrhythmias in congestive heart failure.

Arrhythmias in Complex Congenital Heart Disease.

[Usefulness of cardiac magnetic resonance in patients with ventricular arrhythmias without previous heart disease].

Prognostic implications of asymptomatic ventricular arrhythmias: the Framingham Heart Study.

Echocardiography in ischemic heart disease.

Aspirin in ischemic heart disease.

Left ventricular markers of mortality and ventricular arrhythmias in heart failure patients with cardiac resynchronization therapy.

Ventricular arrhythmias in arrhythmogenic right ventricular dysplasia.

[Risk stratification for sudden cardiac death in ischemic heart disease. Programmed ventricular stimulation].

Response to "Effects of Ivabradine on left ventricular function in patients with ischemic heart disease".

Obesity and ischemic heart disease.

Elements of ischemic heart disease.

Irradiation-related ischemic heart disease.

Taxol stabilizes gap junctions and reduces ischemic ventricular arrhythmias in rats in vivo.

Identification of ischemic heart disease.

Continuous concealed ventricular arrhythmias.