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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

Top Introduction Pathophysiological Mechanisms Pathological Findings in Victims... Clinical Observations References

 
Sudden cardiac death accounts for 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

Top Introduction Pathophysiological Mechanisms Pathological Findings in Victims... Clinical Observations References

 
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 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 surface^21,25; 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 expansion^76,77 and subsequently less incidence of stretch-related arrhythmias.

	Pathological Findings in Victims of Sudden Cardiac Death

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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 al^12,84 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, Haerem^88,89 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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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 studies^110-112 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 (Table). 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.

View this table: [in this window] [in a new window]   Table 1. Features Suggestive of Etiology of Sudden Cardiac Death in Patients With Coronary Artery Disease

	Footnotes

 

	References

Top Introduction Pathophysiological Mechanisms Pathological Findings in Victims... Clinical Observations References

 
1. Myerburg RJ, Castellanos A. Cardiac arrest and sudden cardiac death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Pa: WB Saunders; 1992:756-789.

2. Gillum RF. Sudden coronary death in the United States, 1980-1985. Circulation. 1989;79:756-765.[Abstract/Free Full Text]

3. Goldstein S, Landis JR, Leighton R, Ritter G, Vasu CM, Lantis A, Serokman R. Characteristics of the resuscitated out-of-hospital cardiac arrest victim with coronary heart disease. Circulation. 1981;64:977-984.[Abstract/Free Full Text]

4. Goldstein S, Medendorp SV, Landis JR, Wolfe RA, Leighton R, Ritter G, Vasu CM, Acheson A. Analysis of cardiac symptoms preceding cardiac arrest. Am J Cardiol. 1986;58:1195-1198.[Medline] [Order article via Infotrieve]

5. Epstein SE, Quyyumi AA, Bonow RO. Sudden cardiac death without warning. N Engl J Med. 1989;321:320-323.[Medline] [Order article via Infotrieve]

6. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: structure, function, and time-dependence of risk. Circulation. 1992;85(suppl I):I-2-I-10.

7. Verheugt FWA, Brugada P. Sudden death after acute myocardial infarction: the forgotten thrombotic view. Am J Cardiol. 1991;67:1130-1134.[Medline] [Order article via Infotrieve]

8. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242-250, 310-318.[Medline] [Order article via Infotrieve]

9. Hurwitz JL, Josephson ME. Sudden cardiac death in patients with chronic coronary heart disease. Circulation. 1992;85(suppl I):I-43-I-49.

10. El Fawal MA, Berg GA, Wheatley DJ, Harland WA. Sudden cardiac death in Glasgow: nature and frequency of acute coronary lesions. Br Heart J. 1987;57:329-335.[Abstract/Free Full Text]

11. Friedman M, Manwaring JH, Rosenman RH, Donlon G, Ortega P, Grube SM. Instantaneous and sudden deaths: clinical and pathological differentiation in coronary artery disease. JAMA. 1973;225:1319-1328.[Abstract/Free Full Text]

12. Davies MJ, Bland JM, Hangartner JRW, Angelini A, Thomas AC. Factors influencing the presence or absence of acute coronary artery thrombi in sudden ischaemic death. Eur Heart J. 1989;10:203-208.[Abstract/Free Full Text]

13. Meissner MD, Akhtar M, Lehmann MH. Nonischemic sudden tachyarrhythmic death in atherosclerotic heart disease. Circulation. 1991;84:905-912.[Free Full Text]

14. Akhtar M. Clinical spectrum of ventricular tachycardia. Circulation. 1990;82:1563-1573.

15. Wilber DJ, Garan H, Finkelstein D, Kelly E, Newell J, McGovern B, Ruskin JN. Out-of-hospital cardiac arrest: use of electrophysiologic testing in the prediction of long-term outcome. N Engl J Med. 1988;318:19-24.[Abstract]

16. Roy D, Waxman HL, Kienzle MG, Buxton AE, Marchlinski FE, Josephson ME. Clinical characteristics and long-term follow-up in 119 survivors of cardiac arrest: relation to inducibility at electrophysiologic testing. Am J Cardiol. 1983;52:969-974.[Medline] [Order article via Infotrieve]

17. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989;69:1049-1169.[Free Full Text]

18. Opitz CF, Mitchell GF, Pfeffer MA, Pfeffer JM. Arrhythmias and death after coronary occlusion in the rat: continuous telemetric ECG monitoring in conscious, untethered rats. Circulation. 1995;92:253-261.[Abstract/Free Full Text]

19. El-Sherif N, Scherlag BJ, Lazzara R. Electrode catheter recordings during malignant ventricular arrhythmia following experimental acute myocardial ischemia. Circulation. 1975;51:1003-1014.[Abstract/Free Full Text]

20. Wiggers CJ, Wegria R, Pinera B. The effects of myocardial ischemia on the fibrillation threshold: the mechanism of spontaneous fibrillation following coronary occlusion. Am J Physiol. 1940;131:309-316.

21. Hill JL, Gettes LS. Effects of acute coronary occlusion on local myocardial extracellular potassium activity in swine. Circulation. 1980;61:768-778.[Abstract/Free Full Text]

22. Coronel R, Fiolet JWT, Wilms-Schopman FJG, Schaapherder AFM, Johnson TA, Gettes LS, Janse MJ. Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart. Circulation. 1988;77:1125-1138.[Abstract/Free Full Text]

23. Harris AS, Bisteni A, Russel RA, Brigham JC, Firestone JE, Excitatory factors in ventricular tachycardia resulting from myocardial ischemia: potassium-a major excitant. Science. 954;199:200-203.

24. Ansdorf MF, Schreiner E, Gambella M, Friedlander I, Childers RW. Electrophysiological change in the canine atrium and ventricle during progressive hyperkalemia: electrocardiographical correlates and the in vivo validation of in vitro predictors. Cardiovasc Res. 1977;11:409-418.[Medline] [Order article via Infotrieve]

25. Wilenky RL, Tranum-Jensen J, Coronel R, Wilde AAM, Frolet JWT, Jansen MJ. The subendocardial border zone during acute ischemia of the rabbit heart: an electrophysiologic, metabolic, and morphologic correlative study. Circulation. 1986;74:1137-1146.[Abstract/Free Full Text]

26. Johnson TA, Engle CL, Jenkins MG, Getts LS. Magnitude of potassium inhomogenicity during acute ischemia in the pig. Circulation. 1988;78(suppl. II):II-638. Abstract.

27. Brooks CM, Gilbert JL, Greenspan ME, Lange G, Mazella HM. Excitability and electrical response of ischemic heart muscle. Am J Physiol. 1960;198:1143-1147.

28. Elharrar Y, Zipes DP. Cardiac electrophysiologic alterations during myocardial ischemia. Am J Physiol. 1977;233:H329-H345.[Free Full Text]

29. Downar E, Janse MJ, Durrer D. The effects of acute coronary artery occlusion on subepicardial transmembrane potentials in the intact porcine heart. Circulation. 1977;56:217-224.[Abstract/Free Full Text]

30. Antall BS, Naimi AH, Brilla AH, Levine HJ. A computerized system for measuring dispersion of repolarization in the intact heart. J Appl Physiol. 1974;37:456-458.[Free Full Text]

31. Horacek T, Neumann M, Mutius S, Budden M, Meesmann W. Nonhomogeneous epicardial changes and the bimodal distribution of early ventricular arrhythmias during acute coronary artery occlusion. Basic Res Cardiol. 1984;79:649-667.[Medline] [Order article via Infotrieve]

32. Harris AS. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation. 1950;1:1318-1325.[Medline] [Order article via Infotrieve]

33. Kaplinsky E, Ogawa S, Balke CW, Dreifus LS. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation. 1979;60:397-403.[Abstract/Free Full Text]

34. Friedman PL, Fenoglio JJ, Wit AL. Time course for reversal of electrophysiologic and ultrasound abnormalities in the subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res. 1975;36:127-144.[Abstract/Free Full Text]

35. Challoner DR, Steinberg D. Effect of free fatty acids on the oxygen consumption of perfused rat heart. Am J Physiol. 1966;210:280-286.

36. Akhtar M, Garan H, Lehmann MH, Troup PJ. Sudden cardiac death: management of high-risk patients. Ann Intern Med. 1991;114:499-512.

37. Breithardt G, Borggrefe M, Martinez-Rubio A, Budde T. Pathophysiological mechanisms of ventricular tachyarrhythmias. Eur Heart J. 1989;10(suppl):E9-E18.

38. DeBakker JMT, Van Capelle FJL, Janse MJ, Wilde AAM, Coronel R, Becker AE, Dingemans KP, van Hemel NM, Hauer RNW. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation. Circulation. 1988;77:589-606.[Abstract/Free Full Text]

39. Denniss AR, Richards DA, Waywood JA, Yung T, Kam CA, Ross DL, Uther JB. Electrophysiological and anatomic differences between canine hearts with inducible ventricular tachycardia and fibrillation associated with chronic myocardial infarction. Circ Res. 1989;64:155-166.[Abstract/Free Full Text]

40. Gardner PI, Ursell PC, Fenoglio JJ, Wit AL. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation. 1985;72:596-611.[Abstract/Free Full Text]

41. Dillon S, Allessie MA, Ursell PC, Wit AL. Influence of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res. 1988;63:182-206.[Abstract/Free Full Text]

42. Kimura S, Bassett AL, Cameron JS, Huikuri H, Kozlovskis PL, Myerburg RJ. Cellular electrophysiological changes during ischemia in isolated, coronary-perfused cat ventricle with healed myocardial infarction. Circulation. 1988;78:401-406.[Abstract/Free Full Text]

43. Garan H, McComb JM, Ruskin JN. Spontaneous and electrically induced ventricular arrhythmias during acute ischemia superimposed on 2 week old canine myocardial infarction. J Am Coll Cardiol. 1988;11:603-611.[Abstract]

44. Furukawa T, Moroe K, Mayrovitz HN, Sampsell R, Furukawa N, Myerburg RJ. Arrhythmogenic effects of graded coronary blood flow reductions superimposed on prior myocardial infarction in dogs. Circulation. 1991;84:368-377.[Abstract/Free Full Text]

45. Rea RF, Martins JB, Mark AL. Baroreflex impairment and sudden death after myocardial infarction. Circulation. 1988;78:1072-1074.[Free Full Text]

46. Vanoli E, DeFerrari GM, Stramba-Badiale M, Hull SS, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res. 1991;68:1471-1481.[Abstract/Free Full Text]

47. Cerati D, Schwartz PJ. Single cardiac vagal fiber activity, acute myocardial ischemia, and risk for sudden death. Circ Res. 1991;69:1389-1401.[Abstract/Free Full Text]

48. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with decreased mortality after acute myocardial infarction. Am J Cardiol.. 1987;59:256-260.[Medline] [Order article via Infotrieve]

49. Martin GJ, Magid NM, Myers G, Barnett PS, Schaad JW, Weiss JS, Lesch M, Singer DH. Heart rate variability and sudden death secondary to coronary artery disease during ambulatory electrocardiographic monitoring. Am J Cardiol. 1987;60:86-89.[Medline] [Order article via Infotrieve]

50. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Correlations among time and frequency domain measures of heart period variability two weeks after acute myocardial infarction. Am J Cardiol. 1992;69:891-898.[Medline] [Order article via Infotrieve]

51. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death: experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85:(suppl I):I-77-I-91.

52. Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol. 1975;36:45-49.[Medline] [Order article via Infotrieve]

53. Zipes DP. Sympathetic stimulation and arrhythmias. N Engl J Med. 1991;325:656-657.[Medline] [Order article via Infotrieve]

54. Dean JW, Lab MJ. Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology. Lancet. 1989;1:1309-1311.[Medline] [Order article via Infotrieve]

55. Lab MJ. Mechanically dependent changes in action potentials recorded from the intact frog heart. Circ Res. 1978;42:519-528.[Abstract/Free Full Text]

56. Lerman BB, Burkhoff D, Yue DT, Sagawa K. Mechanoelectrical feedback: independent role of preload and contractility in modulation of canine ventricular excitability. J Clin Invest. 1985;76:1843-1850.

57. Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G, Klangus I, Stone PH. Circadian variation in the frequency of sudden cardiac death. Circulation. 1987;75:131-138.[Abstract/Free Full Text]

58. Willich SN, Levy D, Rocco MB, Tofler GH, Stone PH, Muller JE. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol. 1987;60:801-806.[Medline] [Order article via Infotrieve]

59. Muller JE, Tofler GH, Stone PH. Clinical Progress Series: Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733-743.[Abstract/Free Full Text]

60. Smolensky M, Halberg F, Sargent F. Chronobiology of the life sequence. In: Itoh S, Ogata K, Yoshimura H, eds. Advances in Climatic Physiology. New York, NY: Springer-Verlag; 1972:281-318.

61. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sorbel BE, Willerson JT, Braunwald E, and the MILIS Study Group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313:1315-1322.[Abstract]

62. Mallavarapu C, Pancholy S, Schwartzman D, Callans DJ, Heo J, Gottlieb CD, Marchlinski FE. Circadian variation of ventricular arrhythmia recurrence after cardioverter-defibrillator implantation in patients with healed myocardial infarcts. Am J Cardiol. 1995;75:1140-1144.[Medline] [Order article via Infotrieve]

63. d'Avila A, Wellens F, Andries E, Brugada P. At what time are implantable defibrillator shocks delivered? evidence for individual circadian variance in sudden cardiac death. Eur Heart J. 1995;16:1231-1233.[Abstract/Free Full Text]

64. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha sympathetic vasoconstrictor activity. N Engl J Med. 1991;325:986-990.[Abstract]

65. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood pressure. Lancet. 1978;1:795-797.[Medline] [Order article via Infotrieve]

66. Ehrly AM, Jung G. Circadian rhythm of human blood viscosity. Biorheology. 1973;10:577-583.[Medline] [Order article via Infotrieve]

67. Tofler GH, Brezinski DA, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden death. N Engl J Med. 1987;316:1514-1518.[Abstract]

68. Jafri SM, Van Rollins M, Ozawa T, Mammen EF, Goldberg AD, Goldstein S. Circadian variation in platelet function in healthy volunteers. Am J Cardiol. 1992;69:951-954.[Medline] [Order article via Infotrieve]

69. Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, Fritz JK. The Western Washington Randomized Trial of Intracoronary Streptokinase in Acute Myocardial Infarction: a 12-month follow-up report. N Engl J Med. 1985;312:1073-1078.[Abstract]

70. Cigarroa RG, Lange RA, Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J Cardiol. 1989;64:155-160.[Medline] [Order article via Infotrieve]

71. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329:1615-1622.[Abstract/Free Full Text]

72. Sager PT, Perlmutter RA, Rosenfeld LE, McPherson CA, Wackers FJTh, Batsford WP. Electrophysiologic effects of thrombolytic therapy in patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation. J Am Coll Cardiol. 1988;12:19-24.[Abstract]

73. Bourke JP, Young AA, Richards DAB, Uther JB. Reduction in incidence of inducible ventricular tachycardia after myocardial infarction by treatment with streptokinase during infarct evolution. J Am Coll Cardiol. 1990;16:1703-1710.[Abstract]

74. Gang ES, Lew AS, Hong M, Wang FZ, Siebert CA, Peter T. Decreased incidence of ventricular late potentials after successful thrombolytic therapy for acute myocardial infarction. N Engl J Med. 1989;321:712-716.[Abstract]

75. Pedretti R, Laporta A, Etro MD, Gementi A, Bonelli R, Anza C, Colombo E, Maslowsky F, Santoro F, Caru B. Influence of thrombolysis on signal-averaged electrocardiogram and late arrhythmic events after acute myocardial infarction. Am J Cardiol. 1992;69:866-872.[Medline] [Order article via Infotrieve]

76. Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation. 1987;75:299-306.[Abstract/Free Full Text]

77. Althaus U, Baur H, Gurtner HP, Hamburger S, Roos B. Consequences of myocardial reperfusion following temporary coronary occlusion in pigs: effects of morphologic, biochemical and haemodynamic findings. Eur J Clin Invest. 1977;7:437-443.[Medline] [Order article via Infotrieve]

78. Lie JT, Titus JL. Pathology of the myocardium and the conduction system in sudden coronary death. Circulation. 1975;52(suppl III):III-41-III-52.

79. Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310:1137-1140.[Abstract]

80. Ambrose JA, Winters SL, Arora RR, Haft JI, Goldstein J, Rentrop KP, Gorlin R, Fuster V. Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction. J Am Coll Cardiol. 1985;6:1233-1238.[Abstract]

81. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:1157-1166.[Abstract/Free Full Text]

82. Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1-17.

83. Fuster V, Steele PM, Chesebro JH. Role of platelets and thrombosis in coronary atherosclerotic disease and sudden death. J Am Coll Cardiol. 1985;5:175B-84B.

84. Davies MJ. Anatomic features in victims of sudden coronary death: coronary artery pathology. Circulation. 1992;85(suppl I):I-19-I-24.

85. Lo Y-SA, Cutler JE, Blake K, Wright AM, Kron J, Swerdlow CD. Angiographic coronary morphology in survivors of cardiac arrest. Am Heart J. 1988;115:781-785.[Medline] [Order article via Infotrieve]

86. Warnes CA, Roberts WC. Sudden cardiac death: comparison of patients with to those without coronary thrombosis at necropsy. Am J Cardiol. 1984;54:1206-1211.[Medline] [Order article via Infotrieve]

87. Vanantiz JM, Becker AE. Sudden cardiac death and acute pathology of coronary arteries. Eur Heart J. 1986;7:987-991.[Abstract/Free Full Text]

88. Haerem JW. Mural platelet microthrombi and major acute lesions of main epicardial arteries in sudden coronary death. Atherosclerosis. 1974;19:529-541.[Medline] [Order article via Infotrieve]

89. Haerem JW. Platelet aggregates in intramyocardial vessels of patients dying suddenly and unexpectedly of coronary artery disease. Atherosclerosis. 1972;15:199-213.[Medline] [Order article via Infotrieve]

90. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation. 1986;73:418-427.[Abstract/Free Full Text]

91. Gelman JS, Mehta J. Platelets and prostaglandins in sudden death: therapeutic implications. In: Josephson ME, Brest AN, eds. Sudden Cardiac Death: Cardiovascular Clinics. Philadelphia, Pa: FA Davis; 1985:65-80.

92. Hirsh PD, Hillis LD, Campbell WB, Firth BG, Willerson JT. Release of prostaglandins and thromboxane into the coronary circulation in patients with chronic ischemic heart disease. N Engl J Med. 1981;304:685-691.[Abstract]

93. El-Maraghi N, Genton E. The relevance of platelet and fibrin thromboembolism of the coronary microcirculation, with special reference to sudden cardiac death. Circulation. 1980;62:936-943.[Abstract/Free Full Text]

94. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation. 1985;71:699-708.[Abstract/Free Full Text]

95. Jorgensen L, Rowsell HC, Hovig T, Glynn MF, Mustard JF. Adenosine diphosphate-induced platelet aggregation and myocardial infarction in swine. Lab Invest. 1967;17:616-644.[Medline] [Order article via Infotrieve]

96. Bayes de Luna AB, Coumel P, Leclercq JF. Curriculum in Cardiology: Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J. 1989;117:151-159.[Medline] [Order article via Infotrieve]

97. Luu M, Stevenson WG, Stevenson LW, Baron K, Walden J. Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation. 1989;80:1675-1680.[Abstract/Free Full Text]

98. Olshausen KV, Witt T, Pop T, Treese N, Bethge K-P, Meyer J. Sudden cardiac death while wearing a Holter monitor. Am J Cardiol. 1991;67:381-386.[Medline] [Order article via Infotrieve]

99. Leclercq JF, Coumel P, Maison-Blanche P, Cauchemez B, Zimmermann M, Chouty F, Slama R. Mise en evidence des mechanismes determinants de la mort subite. Arch Mal Coeur. 1986;79:1024-1033.

100. Pepine CJ, Morganroth J, McDonald JT, Gottlieb SO. Sudden death during ambulatory electrocardiographic monitoring. Am J Cardiol. 1991;68:785-788.[Medline] [Order article via Infotrieve]

101. Savage HR, Kissane JQ, Becher EL, Maddocks WQ, Murtaugh JT, Dizadji H. Analysis of electrocardiograms in 14 patients who experienced sudden cardiac death during monitoring. Clin Cardiol. 1987;10:621-632.[Medline] [Order article via Infotrieve]

102. Stern S, Banai S, Keren A, Tzivoni D. Ventricular ectopic activity during myocardial ischemic episodes in ambulatory patients. Am J Cardiol. 1990;65:412-416.[Medline] [Order article via Infotrieve]

103. Turitto G, Zanchi E, Maddaluna A, Pellegrini A, Risa AL, Prati PL. Prevalence, time course and malignancy of ventricular arrhythmia during spontaneous ischemic ST-segment depression. Am J Cardiol. 1989;64:900-904.[Medline] [Order article via Infotrieve]

104. Hoberg E, Schuler G, Kunze B, Obermoser AL, Hauer K, Mautner HP, Schlierf G, Kubler W. Silent myocardial ischemia as a potential link between lack of premonitoring symptoms and increased risk of cardiac arrest during physical stress. Am J Cardiol. 1990;65:583-589.[Medline] [Order article via Infotrieve]

105. Gomes JAC, Alexopoulous D, Winters SL, Deshmukh P, Fuster V, Suh K. The role of silent ischemia, the arrhythmic substrate and the short-long sequence in the genesis of sudden death. J Am Coll Cardiol. 1989;14:1618-1625.[Abstract]

106. Kempf FC, Josephson ME. Cardiac arrest recorded on ambulatory electrocardiograms. Am J Cardiol. 1984;53:1577-1582.[Medline] [Order article via Infotrieve]

107. Zheutlin TA, Steinman RT, Mattioni TA, Kehoe RF. Long-term arrhythmic outcome in survivors of ventricular fibrillation with absence of inducible ventricular tachycardia. Am J Cardiol. 1988;62:1213-1217.[Medline] [Order article via Infotrieve]

108. Kehoe R, Tommaso C, Zheutlin T, Meyers S, Mattioni T, Dunnington C, Lesch M. Factors determining programmed stimulation responses and long-term arrhythmic outcome in survivors of ventricular fibrillation with ischemic heart disease. Am Heart J. 1988;116:355-363.[Medline] [Order article via Infotrieve]

109. Kelly P, Ruskin JN, Vlahakes GJ, Buckley MJ, Freeman CS, Garan H. Surgical coronary revascularization in survivors of prehospital cardiac arrest: its effect on inducible ventricular arrhythmias and long-term survival. J Am Coll Cardiol. 1990;15:267-273.[Abstract]

110. Stevenson WG, Wiener I, Yeatman L, Wohlgelernter D, Weiss JN. Complicated atherosclerotic lesions: a potential cause of ischemic ventricular arrhythmias in cardiac arrest survivors who do not have inducible ventricular tachycardia? Am Heart J. 1988;116:1-6.[Medline] [Order article via Infotrieve]

111. Morady F, DiCarlo L, Winston S, Davis JC, Scheinman MM. Clinical features and prognosis of patients with out of hospital cardiac arrest and a normal electrophysiologic study. J Am Coll Cardiol. 1984;4:39-44.[Abstract]

112. Fogoros RN, Elson JJ, Bonnet CA, Fiedler SB, Chenarides JG. Long-term outcome of survivors of cardiac arrest whose therapy is guided by electrophysiologic testing. J Am Coll Cardiol. 1992;19:780-788.[Abstract]

113. Schoenfeld MH, McGovern B, Garan H, Kelly E, Grant G, Ruskin JN. Determinants of the outcome of electrophysiologic study in patients with ventricular tachyarrhythmias. J Am Coll Cardiol. 1985;6:298-306.[Abstract]

114. Rosenbaum MS, Wilber DJ, Finkelstein D, Ruskin JN, Garan H. Immediate reproducibility of electrically induced sustained monomorphic ventricular tachycardia before and during antiarrhythmic therapy. J Am Coll Cardiol. 1991;17:133-138.[Abstract]

115. Schoenfeld MH, McGovern B, Garan H, Ruskin JN. Long-term reproducibility of responses to programmed cardiac stimulation in spontaneous ventricular tachyarrhythmias. Am J Cardiol. 1984;54:564-568.[Medline] [Order article via Infotrieve]

116. Poole JE, Mathisen TL, Kudenchuk PJ, McAnulty JH, Swerdlow CD, Bardy GH, Greene HL. Long-term outcome in patients who survive out of hospital ventricular fibrillation and undergo electrophysiologic studies: evaluation by electrophysiologic subgroups. J Am Coll Cardiol. 1990;16:657-665.[Abstract]

117. Vaitkus PT, Kindwall E, Marchlinski FE, Miller JM, Buxton AE, Josephson ME. Differences in electrophysiologic substrate in patients with coronary artery disease and cardiac arrest or ventricular tachycardia. Circulation. 1991;84:672-678.[Abstract/Free Full Text]

118. Adhar GC, Larson LW, Bardy GH, Greene HL. Sustained ventricular arrhythmias: differences between survivors of cardiac arrest and patients with recurrent sustained ventricular tachycardia. J Am Coll Cardiol. 1988;12:159-165.[Abstract]

119. Denniss AR, Ross DL, Richards DA, Holley LK, Cooper MJ, Johnson DC, Uther JB. Differences between patients with ventricular tachycardia and ventricular fibrillation as assessed by signal-averaged electrocardiogram, radionuclide ventriculography and cardiac mapping. J Am Coll Cardiol. 1988;11:276-283.[Abstract]

120. Buxton AE, Waxman HL, Marchlinski FE, Untereker WJ, Waspe LE, Josephson ME. Role of triple extrastimuli during electrophysiologic study of patients with documented sustained ventricular tachyarrhythmias. Circulation. 1984;69:532-540.[Abstract/Free Full Text]

121. Sager PT, Perlmutter RA, Rosenfeld LE, Batsford WP. Determinants of the hemodynamic consequence to sustained ventricular arrhythmias after a single myocardial infarction. Am Heart J. 1992;124:1484-1490.[Medline] [Order article via Infotrieve]

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				J. Mikkelsson, M. Perola, P. Laippala, A. Penttila, and P. J. Karhunen Glycoprotein IIIa PlA1/A2 polymorphism and sudden cardiac death J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1317 - 1323. [Abstract] [Full Text] [PDF]

				S. H. Hohnloser Prevention of recurrent life-threatening arrhythmias: will lipid-lowering therapy make a difference? J. Am. Coll. Cardiol., September 1, 2000; 36(3): 773 - 775. [Full Text] [PDF]

				H. V. Huikuri, T. H. Makikallio, C.-K. Peng, A. L. Goldberger, U. Hintze, and M. Moller Fractal Correlation Properties of R-R Interval Dynamics and Mortality in Patients With Depressed Left Ventricular Function After an Acute Myocardial Infarction Circulation, January 4, 2000; 101(1): 47 - 53. [Abstract] [Full Text] [PDF]

				J. Mikkelsson, M. Perola, P. Laippala, V. Savolainen, J. Pajarinen, K. Lalu, A. Penttila, and P. J. Karhunen Glycoprotein IIIa PlA Polymorphism Associates With Progression of Coronary Artery Disease and With Myocardial Infarction in an Autopsy Series of Middle-Aged Men Who Died Suddenly Arterioscler. Thromb. Vasc. Biol., October 1, 1999; 19(10): 2573 - 2578. [Abstract] [Full Text] [PDF]

				P. Theroux and V. Fuster Acute Coronary Syndromes : Unstable Angina and Non–Q-Wave Myocardial Infarction Circulation, March 31, 1998; 97(12): 1195 - 1206. [Full Text] [PDF]

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