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(Circulation. 1997;96:3215-3223.)
© 1997 American Heart Association, Inc.

Articles

Sudden Death in Coronary Artery Disease

Acute Ischemia Versus Myocardial Substrate

Davendra Mehta, MD, PhD; Jay Curwin, MD; J. Anthony Gomes, MD; ; Valentin Fuster, MD, PhD

From the Cardiovascular Institute, Mount Sinai Hospital and School of Medicine, New York, NY.

Correspondence to Valentin Fuster, MD, PhD, Cardiovascular Institute, The Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029. E-mail Valentin-Fuster{at}SMTPLINK.MSSM.EDU


Key Words: arrhythmia • reperfusion • myocardial infarction • ischemia


*    Introduction
up arrowTop
 *Introduction
down arrowPathophysiological Mechanisms
 down arrowPathological Findings in Victims...
 down arrowClinical Observations
 down arrowReferences
 
Sudden cardiac death accounts for {approx}50% of the estimated 500 000 cardiovascular deaths that occur annually in the United States, and a vast majority are the result of coronary artery disease.1-4 Although in some subjects there is a history of angina pectoris, myocardial infarction, or previous cardiac arrest, a significant proportion of events occur in subjects without any history of cardiac disease.1,5 Advanced therapies such as thrombolytic agents and implantable cardioverter/defibrillators are of no value to the thousands of victims who do not survive to receive medical attention. Because so many instances of sudden cardiac death cannot be predicted, any intervention directed toward the general community would have to be applied to an estimated 1000 persons for every 1 person in whom sudden death might be prevented.6

Ventricular tachyarrhythmias are responsible for most cases of sudden cardiac death, although there is more than one mechanism for these arrhythmias. Some victims die from ventricular fibrillation, which can result from acute coronary ischemic thrombosis in an otherwise normal heart,7-9 whereas others die from tachyarrhythmias arising from chronic scar.9 The relative incidence of the two mechanisms is uncertain due to (1) the lack of a consistent definition of sudden cardiac death, especially in terms of the timing between the onset of symptoms and death, and (2) the frequent overlap of the two mechanisms.

Most authors define sudden death as that which occurs within 1 hour of the onset or abrupt change of symptoms.1 Some earlier series used more liberal criteria and included subjects who died up to 24 hours after symptom onset.10 However, there are important pathophysiological differences between deaths that occur instantaneously and those that occur hours after the onset of symptoms, as noted by Friedman et al11 more than 2 decades ago. Most instantaneous deaths appeared to be caused by primary arrhythmic events, whereas deaths that occurred several hours after the onset of symptoms were more often related to arrhythmias that arose in the setting of acute myocardial ischemia or infarction. The hearts of subjects who died instantaneously had fewer acute coronary lesions but more extensive myocardial scarring and old coronary artery occlusions than did the hearts of those whose death was not instantaneous.11,12

Acute ischemia is often responsible for sudden death in patients without a prior history of heart disease, in whom a fatal ventricular arrhythmia may be the first manifestation of coronary atherosclerosis. Although in this setting ventricular fibrillation is the most common terminal rhythm, it is at times preceded by polymorphic ventricular tachycardia.13,14 On the other hand, what is frequently termed substrate-related or nonischemic sudden death occurs more frequently in patients with impaired left ventricular function, in whom acute ischemia is usually less important than is the presence of a myocardial scar from a previous infarction. A low left ventricular ejection fraction has been consistently shown to be one of the better predictors of future arrhythmic events in these patients.15,16 Scar tissue may provide the anatomic substrate for reentrant ventricular arrhythmias, manifested most commonly by monomorphic ventricular tachycardia with or without degeneration into ventricular fibrillation. Complex interactions between structural and functional abnormalities probably trigger a tachyarrhythmia in the setting of chronic substrate.1 Neurohormonal, electrolyte and acid-base changes, hypoxemia, proarrhythmic effects of medications, and superimposition of acute ischemia on prior infarction contribute to arrhythmia development.

The goal of this article was to provide a review of the topic of sudden cardiac death from coronary artery disease by contrasting events that occur chiefly as a result of acute ischemia with those that occur in the setting of abnormal myocardial substrate. Of course, there is considerable overlap between these two broad categories; in a large proportion of patients, the combination of ischemia and scar is probably responsible for the genesis of lethal arrhythmias. Still, numerous studies that concentrate on pathological findings, pathophysiological mechanisms, or clinical observations have revealed that sudden cardiac death often is primarily ischemic and at other times is primarily related to scar with or without concomitant ischemia. Approaching the problem of sudden cardiac death from these perspectives has implications for both understanding its causes and directing future prevention and treatment.


*    Pathophysiological Mechanisms
up arrowTop
 up arrowIntroduction
 *Pathophysiological Mechanisms
down arrowPathological Findings in Victims...
 down arrowClinical Observations
 down arrowReferences
 
Acute Myocardial Ischemia and Cardiac Arrhythmias
The mechanisms by which myocardial ischemia leads to derangements in cellular electrophysiology and to the generation of clinical arrhythmias have been extensively explored.17-20 Animal models of abrupt coronary artery occlusion provide an opportunity to understand the biochemical and electrical changes in a controlled manner. Within seconds of coronary occlusion, high-energy phosphates are hydrolyzed, intracellular and extracellular Ph falls, and extracellular potassium level rises.18,21 The rise in extracellular potassium lasts for {approx}10 minutes. During this time period, the resting membrane potential falls, resulting in voltage difference between the resting membrane potential and the threshold potential with speeding of conduction.22-24 This is followed by inhomogeneous and rate-dependent conduction slowing and block. These changes are inhomogeneous and are present across the lateral margin of the ischemic zone; at the endocardial surface21,25; between the subendocardium, midendocardium, and subepicardium; and between closely spaced sites within the same layer.21,22,26 The inhomogeneities in ionic changes after ischemia result in conduction block.22 With these changes, there is an initial shortening of refractory period followed by a lengthening of the period.27-29 Because the metabolic and ionic changes occurring during ischemia are inhomogeneous, likewise changes in refractoriness across and within the ischemia zone are inhomogeneous, resulting in dispersion of recovery of exitability.30,31 Dispersion of conduction and refractoriness favor reentrant ventricular arrhythmias.18,31 Despite these advances in the understanding of the biochemistry and electrophysiology of acute ischemia, no correlation has been found between the occurrence of ventricular tachyarrhythmias and the magnitude of extracellular potassium or pH change, the inhomogeneities in conduction and refractories, or characteristics of the border zone.

Monitoring of cardiac rhythm during coronary artery occlusion in animals has revealed a time-dependent occurrence of three arrhythmogenic phases.32,33 The first phase of arrhythmia induction occurs within 30 minutes of ischemia and corresponds with a rise in extracellular potassium and a fall in pH. This phase causes high mortality in several animal species. At this stage, no structural damage occurs, and on reperfusion, ischemic cells survive and generally recover function. The second phase last from 30 to 90 minutes and is relatively arrhythmia free; this phase corresponds to the plateau phase of the rise in potassium ions as a result of the decrease in inhomogeneity. The third phase is associated with most arrhythmias and occurs with the onset of irreversible cell damage; reperfusion at this stage does not reduce the amount of cell damage. Inhomogenicity of conduction and refractoriness at the interface of dead and still-viable myocardium probably leads to arrhythmias from these sites. The final disappearance of arrhythmias remains to be explained, although in the dog model, it corresponds to the regaining of normal electrical function by the surviving Purkinje fibers.34 Other abnormalities that may contribute to the occurrence of arrhythmias in acute ischemia by increased automaticity and triggered activity include increases in intracellular calcium ions, the production of free fatty acids and oxygen free radicals, acidosis, and an increased catecholamine level.18,35

Despite a substantial understanding of the biochemical aspects of acute myocardial ischemia, our knowledge of which patients with acute myocardial ischemia will develop sustained ventricular tachyarrhythmias remains unclear. Factors such as the size of the infarct, the presence of collaterals, reperfusion or the lack of it, and the microvasculature could play an important role.

Arrhythmias Related to Myocardial Scar
Electrophysiological studies, including high-density mapping in an animal model of myocardial infarction and intraoperative mapping in patients, have lead to a better understanding of the pathophysiology. Most evidence suggests that ventricular arrhythmias that occur in the absence of acute ischemia are related to reentry.36-40 This is based on observations that include conduction defects in sinus rhythm, reproducible initiation and termination by programmed stimulation techniques, requirement of conduction delay for initiation, entrainment, activation mapping with areas of slow conduction, termination of tachycardia by damage to area of slow conduction, and response to antiarrhythmic agents. In infarcted tissue, there frequently are islands of surviving myocytes with altered orientations interspersed among fibrotic tissue.39 Although even normal myocardium conducts impulses at different velocities depending on muscle fiber orientation (a property known as anisotropy), this property becomes disrupted in infarcted myocardium. The resultant nonuniform anisotropy can predispose to areas of slow conduction and unidirectional conduction block and may establish a classic reentry circuit, especially in the setting of functional abnormalities mentioned earlier.38,41 Typically, the clinical event is manifest as monomorphic ventricular tachycardia, with features of reentry.38 Polymorphic ventricular tachycardia may also occur in some patients with chronic coronary disease in the absence of ischemia, although its frequency in this setting remains uncertain.14

Arrhythmias Related to Acute Ischemia/Scar Interaction
An interaction between acute ischemia and chronic substrate in the evolution of ventricular arrhythmias has been demonstrated in numerous experimental studies. Kimura et al,42 for example, observed significant differences in transmembrane action potential properties between cells in normal versus previously infarcted zones of cat ventricle during the superimposition of acute ischemia. In this study, spontaneous rapid ventricular activity was noted after 30 minutes of ischemia in four of eight cat ventricles with healed myocardial infarction but in none of six preparations with acute ischemia alone in the absence of prior infarction. Garan et al43 noted a marked increase in the incidence of spontaneous ventricular fibrillation during 10-minute circumflex marginal branch coronary artery occlusion in dogs with prior myocardial infarction but not in sham-operated dogs without prior infarction who were exposed to the same degree of acute ischemia. Similarly, Furukawa et al44 demonstrated that even moderate reductions in coronary blood flow increased the likelihood of inducible sustained ventricular tachycardia in dogs with 3-week-old experimental myocardial infarctions but not in sham-operated control animals.31 Again, although similar mechanisms are difficult to document in humans, it is probable that at least some cases of sudden cardiac death result from acute ischemia superimposed on myocardial scar, the arrhythmia originating from the rim of tissue around the scar.

Other Pathophysiological Factors Related to Sudden Cardiac Death
Autonomic Influences
In both acute ischemia and substrate-related sudden death, there is ample evidence that autonomic nervous system imbalances contribute to the development of malignant ventricular arrhythmias.45-51 Diminished vagal tone is especially detrimental after myocardial infarction. For instance, the incidence of ventricular fibrillation resulting from acute coronary occlusion is significantly lower in dogs with 1-month-old infarctions when the vagus nerve is stimulated just before coronary occlusion.46 In humans, decreased heart rate variability, which probably reflects increased sympathetic or decreased vagal tone, is associated with an increased risk of mortality after myocardial infarction.48-51 Furthermore, elevated epinephrine levels may facilitate reentry or contribute to the development of triggered and automatic rhythms.51

The precise mechanisms by which autonomic changes result in ventricular arrhythmias have not been fully defined; it has been well established in experimental models that sympathetic stimulation decreases the threshold for ventricular fibrillation.52 During acute myocardial ischemia or infarction, there are alterations in sympathetic and parasympathetic flow to the heart caused by neuronal damage as well as by metabolic derangements.53 Denervation may begin within minutes of the onset of ischemia, creating electrophysiological heterogeneity between ischemic and normal myocardium. Furthermore, autonomic activity can affect infarct size, coronary blood flow, platelet aggregation, and free radical formation.53

Mechanoelectric Feedback
There is some evidence to suggest that mechanically induced changes play a role in arrhythmogenesis, especially in the dysfunctional ventricle.54-56 Increased preload and afterload shorten action potential duration and can lead to spontaneous depolarizations via a process that has been termed mechanoelectric feedback.56 Changes in ventricular wall stress may contribute to a nonuniform dispersion of repolarization and thereby increase the propensity to reentrant arrhythmias. Stimulation of ventricular stretch receptors can lead to an increase in spontaneous Purkinje fiber activity.17 Although the cellular mechanisms responsible for mechanically induced arrhythmias are unclear, they may be related to a rise in intracellular calcium or to increased membrane permeability to potassium.56

Circadian Variation
There are substantial epidemiological data that reveal that circadian factors play a role in the development of sudden cardiac death, with an increased incidence of events in the early morning hours.56-61 Recent observations regarding the time of occurrence of ventricular arrhythmias and, subsequently, appropriate defibrillator discharges in patients with implantable defibrillators have further confirmed earlier observation.62,63 Many biological phenomena exhibit similar circadian rhythms,64 including systemic blood pressure and heart rate,65 blood viscosity,66 plasma catecholamine levels,61 platelet aggregability,67 and function,68 and basal vascular tone.64 Interactions between some or all of these factors may predispose to myocardial infarction, cerebrovascular accidents, and sudden cardiac death, all of which follow a similar circadian pattern. Although some authors have argued that the apparent circadian variation is merely an artifact related to diverse factors such as the time of day when events are reported or increased platelet activity with upright posture, the evidence in support of circadian variation is noteworthy, especially recent data regarding the timing of defibrillator shocks in patients with coronary artery disease and recurrent ventricular tachyarrhythmias in whom arrhythmias are related to myocardial scar and caused by reentry.62,63

Significance of the `Open Artery'
Several angiographic studies have demonstrated that both short-term69 and long-term70 survival after myocardial infarction is improved in the presence of a patent "infarct-related" artery, regardless of whether the artery is rendered patent by a thrombolytic agent, an angioplasty procedure, or spontaneous recanalization. In the Western Washington trial of intracoronary streptokinase, only 2 of 80 patients (2.5%) in whom complete reperfusion was reestablished had died by 1 year compared with 6 of 41 patients (14.6%) in whom no reperfusion was seen.69 This significant difference was found after an adjustment was made for a minor imbalance in left ventricular ejection fraction. A survival advantage with a decreased incidence of sudden death in patients with early reperfusion of the infarct-related artery was also seen in the angiographic substudy of the GUSTO trial.71 Furthermore, Sager et al72 observed a decreased incidence of ventricular tachycardia induction via programmed electrical stimulation in patients with patent as opposed to occluded infarct-related arteries, despite comparable ventricular function between the two groups. The incidence of late potentials seen on the signal-averaged ECG is also lower in patients treated with thrombolytic agents,73-75 even as early as the first week after myocardial infarction.74 One hypothesis to explain the benefit of prompt reperfusion is that it results in salvage of cells in the infarct border zone and thereby prevents the formation of the substrate for a reentrant arrhythmia.75 Reperfusion may also have an impact on ventricular remodeling after myocardial infarction, even in the absence of myocardial cell salvage.70 The mechanisms to explain this phenomenon are not defined but may relate to accelerated healing in reperfused hearts. It has been suggested that increased cell swelling, hemorrhage, and contraction band necrosis in reperfused hearts can lead to increased stiffness and therefore decreased systolic ventricular expansion76,77 and subsequently less incidence of stretch-related arrhythmias.


*    Pathological Findings in Victims of Sudden Cardiac Death
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 up arrowIntroduction
 up arrowPathophysiological Mechanisms
 *Pathological Findings in Victims...
down arrowClinical Observations
 down arrowReferences
 
Thrombosis Versus Myocardial Scar
Pathologists attempting to determine the relative importance of acute coronary thrombosis in the evolution of sudden cardiac death may face difficulties in distinguishing antemortem lesions from postmortem artifacts and in detecting acute ischemic myocardial injury through the use of conventional techniques.78 Still, there is evidence to suggest that acute coronary thrombosis is present in a substantial proportion of cases of sudden death. In an often-cited study, Davies and Thomas79 performed autopsies on subjects with coronary artery disease who had died within 6 hours of the onset of cardiac symptoms and found coronary thrombi in 74 of 100 subjects, with no intraluminal thrombi found in age-matched control patients who died suddenly from noncardiac causes. Of interest, many thrombi in the "sudden" death victims occurred at sites at which there was a <50% luminal stenosis caused by the plaque underlying the thrombus. The observation that an occlusive thrombus can form at a location that did not appear to have a significant underlying stenosis has been borne out by several angiographic studies.79-81 Fissuring of lipid-rich atheromatous plaques is believed to be a frequent inciting event in a series of complex interactions that lead to thrombus formation in acute coronary syndromes such as myocardial infarction and sudden death.82,83

Although intriguing, the data from Davies and Thomas79 must be interpreted cautiously. The proportion of subjects with acute coronary lesions was no doubt increased by inclusion of many patients with evolving myocardial infarctions, some of whom died as late as 6 hours after symptom onset.13 However, in a follow-up study, Davies et al12,84 concluded that sudden death in fact represents two distinct entities, caused in some patients by acute ischemia from a new coronary occlusion and in others by an arrhythmia arising from myocardial scar. In this study, acute coronary thrombosis was more prevalent in subjects who had one-vessel coronary artery disease and acute infarction at autopsy, and it is likely that most of these patients died from acute myocardial ischemia. On the other hand, the presence of an old myocardial infarction, three-vessel disease, or a known clinical history of coronary artery disease was associated with the absence of acute thrombosis, and in these patients, a primary arrhythmia arising from a myocardial scar was the presumptive mechanism of death.84 The findings in this and similar studies demonstrate the importance of patient selection criteria and helps to explain why some pathologists have reported acute coronary lesions in as few as 20% of their subjects who died suddenly, whereas others have reported figures of >90%.10,75-87 Furthermore, there appears to be a discrepancy between a low incidence of myocardial infarction in survivors of sudden cardiac death and a high incidence of coronary thrombosis in victims of sudden cardiac death at pathological examination. If the substrate were identical, it is likely that the thrombosis resolves more often in survivors than in the victims, thereby influencing survival.

Microthromboembolism
Controversy exists regarding the significance not only of acute epicardial coronary lesions but also of platelet microthrombi and emboli seen in the intramyocardial vessels of sudden death victims. Twenty years ago, Haerem88,89 suggested that occlusive platelet aggregates may predispose to ischemia and subsequent sudden death when he observed mural platelet microthrombi in a greater number in the hearts of patients who died suddenly from coronary disease than in those dying from noncardiac causes. One proposed mechanism for the formation of platelet microthrombi is the downstream embolization from platelet aggregates formed on atherosclerotic plaques, a process that might exacerbate ischemia via the release of vasoconstrictor substances such as serotonin and thromboxane A2.7,90-92 It is also possible that in situ thrombus formation can result from ischemia, with subsequent endothelial damage and platelet adhesion and aggregation. Enhanced platelet reactivity may also contribute to the formation of microthrombi.93 Some authors have expressed caution in assigning significance to the presence of platelet aggregates in the microcirculation, suggesting that increased platelet reactivity is a nonspecific terminal "stress" response that has been observed in a variety of acute illnesses.94 Others have noted that platelet and fibrin microthrombi are common in various types of heart disease, including ischemic heart disease, and endocarditis, and after cardiac surgery.93 Nevertheless, in examining hearts from sudden death victims, Falk94 saw platelet aggregates almost exclusively at sites distal to epicardial artery thrombi, a finding that he considered to be evidence against an underlying systemic cause of these aggregates. Similarly, Davies et al90 noted that microscopic necrosis with involvement of the full thickness of the ventricular wall was more common in patients who had evidence of platelet emboli; again, these emboli were seen almost exclusively in myocardial regions that were distal to a fissured plaque or mural thrombus. That platelet microthrombi may play an important role in the evolution of sudden cardiac death has been supported by experimental work as well. Jorgensen et al,95 for example, noted the early formation of platelet aggregates in pigs that died suddenly from arrhythmias after receiving intracoronary ADP, with many fewer platelet aggregates seen in the animals that survived longer.


*    Clinical Observations
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 up arrowPathophysiological Mechanisms
 up arrowPathological Findings in Victims...
 *Clinical Observations
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Ambulatory ECG (Holter) Monitoring
In a review of the published reports that include >=10 patients who died suddenly while wearing Holter monitors, Bayes de Luna et al96 noted that the vast majority of sudden deaths recorded (83.4%) were caused by tachyarrhythmias, with bradyarrhythmias and electromechanical dissociation leading to sudden death in a smaller percentage of patients with coronary disease.96,97 Ventricular tachycardia (usually degenerating to ventricular fibrillation) was seen in 62.4%, torsades de pointes was seen in 12.7%, and primary ventricular fibrillation was seen in 8.3%. Interestingly, it has been observed that the duration of ventricular tachycardia before its degeneration into ventricular fibrillation may be dependent on the morphology of the tachycardia.98,99 In a study by Leclercq et al,99 for example, monomorphic ventricular tachycardia had a mean duration of 167 seconds, whereas polymorphic ventricular tachycardia lasted for only a mean period of 34 seconds before degenerating into ventricular fibrillation. Almost identical figures were reported by Olshausen et al,98 who found that resuscitation attempts were successful in 50% of their patients with monomorphic ventricular tachycardia but only 30% of their patients with polymorphic ventricular tachycardia; this was probably related to maintenance of at least some cardiac output in the former group. The role of acute ischemia in the initiation of terminal arrhythmias has been examined in numerous studies that have focused on changes in the ST segment on Holter monitors. Bayes de Luna et al96 reported that the incidence of ischemic ST changes before fatal arrhythmia was only 12.6%; however, these authors acknowledged that ischemia may be underdiagnosed with Holter recordings, which frequently incorporate only one or two ECG leads. Pepine et al100 found ischemic ST changes before cardiac arrest in 52% of 35 cases, and Savage et al101 reported marked ischemic changes in 9 of 14 patients who died suddenly while monitored. Other investigators have noted increased ventricular ectopic activity during periods of ischemia.102-104 Whether ischemia itself or the increased ectopy leads to sustained ventricular tachyarrhythmia is debated. Gomes et al105 studied the role of silent ischemia in patients with previous myocardial infarction; they found that silent ischemia was not a major determinant of ventricular tachycardia. Although silent ischemia was quite common in survivors of ventricular tachycardia or fibrillation, its incidence was not different from that in patients with angina pectoris and no sustained ventricular tachyarrhythmias. They concluded that in the absence of an acute myocardial infarction, sudden death is frequently triggered by a ventricular premature beat with a preceding short-long cycle that probably leads to dispersion of refractoriness in the arrhythmic substrate.

Despite these reports, the true percentage of patients who have sudden cardiac death as a result of acute ischemia has not been determined. A large proportion of patients who wear Holter monitors do so because of known arrhythmias or syncope, and they are frequently taking digitalis, diuretics, or antiarrhythmic agents, all of which may contribute to the onset of arrhythmia in the absence of ischemia.96-98 For example, although Kempf and Josephson106 found ventricular tachycardia in 20 of 27 patients who died suddenly while wearing Holter monitors, >=13 of their patients were taking digitalis, and 13 were taking other antiarrhythmic agents. Also, the majority of these Holter examinations were ordered for indications such as a history of syncope or cardiac arrest or for antiarrhythmic drug evaluation. In such patients, the frequent recording of monomorphic ventricular tachycardia is not surprising.

Programmed Electrical Stimulation
The belief that acute ischemia plays a role in some cases of sudden cardiac death has been supported by several studies in which the results of programmed electrical stimulation in sudden death survivors were analyzed.107,108 Kehoe et al108 performed programmed electrical stimulation in 38 patients who had been found by paramedics in ventricular fibrillation and who were subsequently ruled out for myocardial infarction; patients with previous episodes of sustained ventricular tachycardia were excluded from this study. Twenty-two patients (58%) had inducible ventricular tachycardia, whereas 16 (42%) had no inducible arrhythmias. Those with inducible arrhythmias were much more likely to have had myocardial infarctions, congestive heart failure, or cardiac arrest, and they had significantly worse left ventricular function than patients without inducible arrhythmias.

On the other hand, as a group, the patients without inducible arrhythmias had significantly more critical proximal coronary artery lesions. Furthermore, 13 of 16 patients (81%) without inducible ventricular tachycardia had historical factors (eg, the onset of arrhythmia during physical exertion) suggestive of ischemia just before their arrests compared with 1 of 22 patients (5%) who did have inducible ventricular tachycardia. Patients in the noninducible group were treated exclusively with anti-ischemic measures, including coronary artery bypass graft surgery, ß-blockade, and angioplasty. At 38±9 months, there were no recurrences of arrhythmia in this group. In contrast, all 4 of the patients who had inducible sustained ventricular tachycardia that persisted despite serial antiarrhythmic drug testing had clinical recurrences. This study suggests that in patients with out-of-hospital cardiac arrests who have clinical and angiographic features suggestive of a reversible ischemic cause of the arrest, as well as preserved left ventricular function, anti-ischemic therapy alone can confer a good prognosis.

Kelly et al109 examined retrospectively the results of surgical revascularization in a selected subgroup of 50 survivors of cardiac arrest who underwent both preoperative and postoperative electrophysiological studies. None of the patients who had ventricular fibrillation (in general, a nonspecific finding) induced during a preoperative electrophysiological examination had inducible arrhythmias after revascularization. However, in the patients with inducible monomorphic ventricular tachycardia at the preoperative study, this arrhythmia persisted in 80%, despite surgery. Although acute ischemia may have been responsible for the development of ventricular fibrillation in the former group of cardiac arrest victims, the persistence of inducible ventricular tachycardia in the latter is consistent with the concept that scarred myocardium can serve as a fixed arrhythmogenic substrate. One must be cautious in extending the results of this study to the overall population of cardiac arrest survivors, however, because all of these selected patients had operable coronary artery disease and reasonably intact ventricular function, and none had a discrete left ventricular aneurysm. Furthermore, it is possible that programmed stimulation was performed too early to show a benefit from surgery; there may have been a reduction in inducibility in the months after surgery. Still, the findings in this and other studies110-112 suggest that some cardiac arrests are caused by acute ischemia, often resulting from acute thrombus formation on complex atherosclerotic plaques. Cardiac arrest survivors without inducible sustained ventricular tachycardia who have evidence of myocardial ischemia and well-preserved left ventricular function can often be managed effectively with revascularization and anti-ischemic therapy alone. On the other hand, if ventricular function is significantly impaired in the cardiac arrest survivor, the risk of recurrence is high even in the setting of a negative electrophysiological study.15,16

Although acute ischemia may be the cause of sudden cardiac death in a significant proportion of victims, in those who survive to undergo evaluation with programmed electrical stimulation, rapid sustained ventricular arrhythmias can be induced in a majority of patients. The induction of sustained monomorphic ventricular tachycardia is a highly reproducible finding and therefore provides an objective measure of therapeutic efficacy, at least in the short term.113-115 Wilber et al15 reported their experience with programmed electrical stimulation in 166 survivors of out-of-hospital cardiac arrest, the majority of whom had coronary artery disease. Sustained ventricular arrhythmias were induced in 79% of patients at baseline, and these arrhythmias were suppressed by drug therapy or surgery in 72%. After a median follow-up period of 21 months, cardiac arrest recurred in 12% of patients in whom inducible arrhythmias had been suppressed, 33% of patients in whom inducible arrhythmias persisted despite therapy, and 17% of patients in whom no arrhythmia was induced during the baseline study. Another interesting finding (in a small group of patients) was that those without inducible arrhythmias but with severely impaired left ventricular function were at highest risk for recurrent cardiac arrest, again supporting the role of left ventricular dysfunction as a predictor of a poor prognosis.

Monomorphic Versus Polymorphic Ventricular Tachycardia
Some investigators have questioned whether there are differences in anatomic substrate and electrophysiological responses between patients presenting with monomorphic ventricular tachycardia and those with polymorphic ventricular tachycardia or primary ventricular fibrillation.13,116-119 Vaitkus et al117 performed signal-averaged ECG and endocardial mapping in patients with coronary artery disease to compare those with hemodynamically well-tolerated ventricular tachycardia with those who had survived a cardiac arrest. Patients with spontaneous ventricular tachycardia were more likely to have had a prior myocardial infarction and inducible arrhythmias (usually monomorphic ventricular tachycardia). Also, more of these patients had findings on signal-averaged ECGs and on endocardial mapping studies suggestive of the presence of an arrhythmogenic substrate. Likewise, Adhar et al118 observed that sustained ventricular tachycardia was inducible in only 30% of their patients who had survived a cardiac arrest compared with 69% in patients who presented with well-tolerated ventricular tachycardia. The induction of a polymorphic ventricular tachycardia was noted to be the most significant independent variable that differentiated the cardiac arrest survivors from the patients who presented with sustained ventricular tachycardia. It is quite possible that the polymorphic rhythm reflects a more poorly organized tachycardia mechanism with a greater propensity to progress to ventricular fibrillation. Despite these studies, the suggestion that patients with aborted sudden cardiac death differ in their electrophysiological characteristics from patients with well-tolerated ventricular tachycardia remains controversial. The difference between the two groups is probably related to tachycardia cycle length, with faster tachycardias occurring more commonly in patients who present with cardiac arrest.120,121

Conclusions
Sudden cardiac death will remain a major public health problem in the Western world for years to come and usually results from complex pathophysiological interactions in patients with coronary artery disease. Although most published clinical series include survivors of cardiac arrest and other patients with suspected or known ventricular arrhythmias, the problem of sudden death as it affects the population-at-large has been less well studied; although in some series a majority of survivors of out-of-hospital sudden death had inducible sustained monomorphic ventricular tachycardia during electrophysiological testing, it cannot be concluded that victims who never reach the hospital die from this arrhythmia. Postmortem examinations suggest that there are at least two major subsets into that sudden death survivors fall, with many patients dying from acute coronary thrombosis that leads to ventricular fibrillation, and others dying from monomorphic ventricular tachycardia arising from scarred myocardium, not necessarily with coexisting ischemia. On clinical evaluation, in a proportion of patients with sudden cardiac death, it might be possible to differentiate these two groups (TableDown). Regardless of whether ischemic or substrate-related mechanisms predominate, there are numerous other factors that contribute to the development of terminal arrhythmias, including neurohormonal and autonomic nervous system influences, drug effects, electrolyte imbalances, circadian rhythms, and interactions between acute ischemia and myocardial scar, to name just a few. Unfortunately, because in many patients sudden death is the initial manifestation of coronary artery disease, therapy that prolongs survival in those with documented ventricular arrhythmias or previous cardiac arrests solves only part of the problem. Continued efforts must be directed toward primary prevention and modification of coronary artery disease risk factors, as well as toward improvement in resuscitation services, before any significant impact on the problem of sudden cardiac death can be realized.


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  		Table 1. Features Suggestive of Etiology of Sudden Cardiac Death in Patients With Coronary Artery Disease


*    Footnotes
 


*    References
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 up arrowIntroduction
 up arrowPathophysiological Mechanisms
 up arrowPathological Findings in Victims...
 up arrowClinical Observations
 *References
 

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