James K Gilman, MD., graduated from Indiana University School of Medicine. He completed his residency and cardiologv fellowship at the Brooke Army Medical Center in San Antonio, Te&as. He also completed a fellowship in cardiac electrophysiology at the University of Te,xas Medical School at Houston. His current position is Assistant Chief of Cardiology and Cardiac Electrophysiologist at the Brooke Army Medical Center in San Antonio. His major clinical and research interests are in the hemodynamics of cardiac arrhythmias and in the evaluation and therapy of patients with syncope.
Gerald V. Naccarelli, M.D., graduated from the Pennsylvania State University School of Medicine in Hershey, Pennsylvania. He completed his residency in internal medicine at the North Carolina Baptist Hospital in Winston-Salem, North Carolina. He received his cardiology fellowship training at the Pennsylvania State University College of Medicine and his training in cardiac electrophysiolosy at the Indiana University School of Medicine in Indianapolis, Indiana. Since 1981 he has been the Director of Clinical Electrophysiologv at the University of Texas Medical School at Houston, where he is currently Professor of Medicine and Vice-Chairman of the Division of Cardiology. His research interests include antiarrhythmic drug development, autonomic aspects of arrhythmogenesis, implantable devices, and radiofrequency catheter ablation. 888
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SUDDEN CARDIAC DEATH
INTRODUCTION
Few clinical entities are more difficult to study than the syndrome of sudden cardiac death. A number of inherent problems hinder understanding of this syndrome. Most significant of these problems is the lack of a consistent definition. Definition is seldom a problem for the clinician confronted with an individual patient. Sudden cardiac death is the “. . . unexpected cessation of breathing and circulation caused by an underlying heart disease.“’ However, the clinician and the epidemiologist define this syndrome differently. Epidemiologic studies typically define sudden cardiac death in terms of the time of death relative to the onset of symptoms or the physical location of the patient relative to hospital admission at the time of demise. Such definitions allow the gathering of data on large numbers of patients with a minimum of effort. However, these epidemiologic definitions contain no obligatory link to the pathologic cardiac states that form the substrate of sudden cardiac death. Definitions used in clinical studies have a more solid basis in pathophysiology but also are somewhat arbitrary. There may be no uniformly suitable definition. A second diiliculty is the diversity of cardiac conditions in which sudden cardiac death occurs. Although an estimated 80% of adult patients with sudden death have underlying obstructive coronary artery disease, sudden cardiac death is also a feature of the cardiomyopathies, hypertensive heart disease, and a variety of primary electrical disorders of the heart. Although sudden cardiac death may be the final common pathway in these varied states, the pathophysiology of sudden death may not be the same in all. Conclusions and generalizations based on a homogeneous population of patients with coronary artery disease may not be applicable to more heterogeneous populations. Indeed, among patients with coronary artery disease, the pathophysiology of sudden death in acute coronary syndromes may be quite different than in patients with chronic ischemic cardiomyopathy. A third problem is the dynamic nature of the factors that are postulated to precipitate sudden cardiac death in susceptible individuals. These factors include ischemia, abnormalities of potassium and Curr
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magnesium, variations in autonomic tone, and the effects of a number of medications. Some of these factors can be measured directly-like the serum levels of potassium and magnesium or the level of a medication in the blood. Ischemia can be assessed semiquantitatively in an indirect fashion by a variety of means. However, techniques to assess autonomic tone in vivo are only now being developed. Even when these tools are available, the ability to assess the relationship of these dynamic factors to the genesis of sudden cardiac death will be hindered by their transience and the brevity of the sudden death syndrome. Despite our understanding of the pathophysiology of sudden cardiac death being far from complete, the incidence of cardiac death has declined significantly in recent years. This decline extends to all racial and sexual divisions of the population and parallels a decline in the incidence of coronary artery disease.” 3 Nevertheless, sudden cardiac death afflicts 350,000 patients in the United States annually and is the leading cause of death in most Western societies. The health care costs attributable to sudden cardiac death are enormous. Thus every physician who cares for patients with heart disease and every primary care provider who professes to practice preventive medicine has a mandate to understand this essential clinical syndrome. Many reviews of the subject of sudden cardiac death focus primarily on the evaluation of the sudden death smvivor to the exclusion of the patient who is at high risk for, but has yet to experience, an episode of sudden death. This latter group is often dealt with as an entirely separate topic. Because division is artificial, we will discuss both groups since they represent different points on the clinical continuum of sudden cardiac death. This combination also acknowledges the fact that only about 20% of patients survive to hospital discharge after an episode of sudden death and that future treatment strategies will evolve toward prevention of the first episode.4’ 5 The terms sudden death and sudden cardiac death will be used interchangeably throughout this monograph for the sake of convenience and to imply sudden death caused by a ventricular tachyarrhythmia, ventricular tachycardia (VT), or ventricular fibrillation (VF). However, it is understood that sudden death is not always cardiac in origin. Neurologic and vascular catastrophes and massive pulmonary emboli can produce a rapid demise and are easily confused with sudden cardiac death. It is also understood that sudden cardiac death is not always due to an arrhythmia. Hemodynamic emergencies like myocardial rupture or acute valvular insufficiency can be easily confused with dysrhythmic death, and these conditions must be considered in the differential diagnosis of patients resuscitated from sudden death. Finally, it is also understood that arrhyth700
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mic sudden death is not always due to a tachyarrhythmia. Ambulatory electrocardiographic recordings in patients experiencing out-ofhospital sudden death indicate that approximately 20% to 25% of events are precipitated by bradycardia, asystole, or electromechanical dissociation.6’ ’ Of the remaining number, approximately half (40%) are precipitated by monomorphic VT and the remaining 40% by polymorphic VT or VF.7
PATHOPHYSIOLOGY
The basic mechanism of the genesis of malignant ventricular arrhythmias remains unknown. This fact plus the diversity of clinical situations in which these arrhythmias occur have thwarted most simple theories concerning the pathophysiology of sudden cardiac death. Contemporary theories emphasize interactions among multiof these theories is useful for ple factors (Fig 1): ’ An understanding providing a framework for understanding the clinical evaluation and, to a more limited extent, the treatment of the sudden death survivor or the patient at risk for a first episode of sudden death. The first set of factors is intrinsic to the cardiac substrate. A variety of clinical tools, most of them using some form of cardiac imaging, are available for assessment of the structural and functional aspects of the cardiac substrate. Abnormalities can be regional (as in coronary artery disease or hypertrophic cardiomyopathy) or global (as in dilated cardiomyopathy). Additional means- principally signal-averaged
Electrolyte Abnormal&s
lschemia
Circulating Catecholamines
4 Ventricular Arrhythmias
4 SUDDEN CARDIAC DEATH
FIG 1. Schematic representation Cut-r Probl
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of sudden cardiac death 701
electrocardiographic and electrophysiologic study-are used to assess the electrical features of the cardiac substrate. Ant&rhythmic surgery is aimed at modification of the substrate structure, whereas antiarrhythmic drug therapy targets the functional aspects of the electrical characteristics of the substrate. The second set of factors, often referred to as trigger factors, is sometimes transient and its relationship to arrhythmogenesis is more difficult to assess. The best studied and most widely implicated of the trigger factors are myocardial ischemia and the array of interactions between the heart and the autonomic nervous system. Other factors implicated are abnormalities of electrolytes, principally potassium and magnesium, and the proarrhythmic effects of antiarrhythmic drugs. The assessment of myocardial ischemia through provocative testing with exercise or pharmacologic maneuvers is an example of testing used to assess the importance of dynamic ischemia on arrhythmogenesis. Exercise invokes catecholamine responses that may be important triggers as well. Although exercise testing has been a mainstay of clinical practice for some time, only now are clinical means being developed to assess autonomic influences on the heart through methods like the analysis of heart rate variability. Treatment aimed at these trigger factors includes revascularization, use of /3-blocking medications, and electrolyte supplementation. Multiple lines of evidence implicate the importance of coronary artery disease as the cardiac substrate for sudden cardiac death. Clinical observations include the association of sudden death with the occurrence of acute myocardial infarction, the presence of significant obstructive coronary disease in 79% to 91% of patients surviving sudden death,loT1’ and the autopsy studies of patients who observations providing further supdo not survive.13 Experimental port include the ventricular arrhythmias that occur in animal models of coronary occlusion. l4 The evidence that acute ischemia is the trigger that precipitates the fatal arrhythmia in many patients with coronary disease is also substantial. Clinical evidence for ischemia as the responsible precipitant includes the occasional occurrence of sudden death during exercise testing accompanied by subjective and objective evidence of ischemia. Symptoms or signs of ischemia are reported to occur in 30% to 50% of patients with coronary disease experiencing sudden death.l’ Other evidence includes the association of sudden death during exercise and coronary disease in athletes 35 years of age and older.16 Pathologic studies demonstrate thrombi, plaque fissuring, or platelet aggregates in a high percentage In experimental preparations, the combinaof sudden deaths.“-” tion of remote infarction and scar formation with ischemia is more arrhythmogenic than scar or ischemia alone.20-22 Nevertheless, many patients with coronary disease who experience sudden death 702
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do not exhibit symptoms or signs of ischemia or go on to evolve evidence of acute infarction. Many episodes of sudden death in patients with coronary disease are not related to exercise or strenuous physical activity. Although it is possible that non-demand-related ischemia caused by platelet aggregation, thrombus formation, or alterations in vasomotor tone could be responsible for some of these episodes, it is more likely that acute ischemia is not the precipitant in a signiticant percentage of cases.23 Physicians have been aware of the interactions between the heart and the central nervous system for many years. Biorck et al’” demonstrated that denervation of the dog heart prevented most of the deaths after ligation of the left anterior descending coronary artery in the conscious animal. The occurrence of syncope and sudden death during extremes of emotion in patients with the congenital ‘long QT syndromes has also been known for sometime. Schwartz et al? have demonstrated in a feline model the occurrence of QT prolongation and life-threatening ventricular arrhythmias after ablation of the right stellate ganglion. Increased sympathetic nervous activity may also be important in the pathogenesis of ventricular arrhythmias in patients with left ventricular dysfunction. The occurrence of increased circulating levels of norepine hrine in patients with heart failure has been known for some time. F6 Recently, Meredith et al?’ have demonstrated a marked increase in cardiac norepinephrine spillover in patients with coronary artery disease and sustained arrhythmias. Although total norepinephrine spillover was 80% higher than in patients without heart disease or in patients with coronary artery disease without arrhythmias, the coronary norepinephrine spillover rate in patients with arrhythmias was over four times that of patients in the control groups?’ This strongly suggests that intracardiac sympathetic activity is significantly increased in patients with coronary artery disease and sustained arrhythmias. Stimulation of cardiac sympathetics reduces ventricular fibrillation threshold in canine models?’ Evidence of the importance of sympathetic nervous activity in ventricular arrhythmias in patients with the congenital long QT syndromes and patients with congestive heart failure have led to therapeutic trials with (3-adrenergic blocking agents in these disorders. b R.C. SCHLANT: The importance syndrome is further emphasized ganglionectomy, which helps to some patients it is necessary to P-blocker therapy.
of the central nervous system in the long QT by the value of left cervicothoracic sympathetic prevent syncope and sudden cardiac death. In combine stellate sympathectomy with chronic
The effects of electrolytes (principally potassium, calcium, and magnesium) on the genesis of arrhythmias have been extensively studied in vitro. Perturbations of electrolyte levels have important efCut-r Probl
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fects on normal action potential formation and propagation, as well as on the development of abnormal forms of electrical activity. Gross perturbations of electrolytes may result in life-threatening arrhythmias in patients without overt heart disease but are particularly arrhythmogenic in patients with heart disease and those receiving antiarrhythmic agents and digitalis.zs Potassium supplementation ameliorates many of the arrhythmias of digitalis excess, whereas magnesium infusion has been reported to be an effective treatment for torsades de pointes caused by an antiarrhythmic drug.30’ 31 However, the relevance of these observations to most clinical ventricular arrhythmias in humans is questionable. Evaluation of sudden death survivors seldom discloses evidence of electrolyte abnormalities sufficient to induce life-threatening arrhythmias. In vivo study is hampered because blood or serum levels of electrolp may have a poor correlation to total body or myocardial levels.’ ’ 33 Although electrolyte abnormalities should be treated or, preferably, avoided, little evidence shows that this step alone will have significant impact on the clinical problem of sudden cardiac death. Thus, although much is known about potential mechanisms of arrhythmogenesis in patients with malignant ventricular arrhythmias, much remains unknown. The mechanisms of interaction of substrate-specific factors and the so-called trigger factors remain to be explained.
RELATI’W
RISK AND INDMDUAL
DISEASE
STATES
Because sudden cardiac death has been reported to occur even in patients with ostensibly normal hearts,” no one has absolute immunity. Risk is best represented in relative terms (Table 1). Patients without evident cardiac disease form the low-risk end of the spectrum. Patients who have been successfully resuscitated from an episode of sudden death not associated with acute myocardial infarction form the hi est risk group with a recurrence rate of 10% to 30% annually.35’ P6 Most patients with chronic cardiac pathologic conditions fall between the two extremes. In general, more diffuse cardiac disease and more severe impairment of ventricular function signify greater risk for sudden death. However, exceptions to this general rule exist. Patients with hypertrophic cardiomyopathy have normal or above normal left ventricular ejection fractions but are at high risk for sudden death?’ Patients with primary electrical problems often have, by definition, anatomically normal hearts and normal ventricular function. Although patients with dilated cardiomyopathy generally are at very high risk for sudden cardiac death,38 relatively low-risk subgroups exist within this diagnostic category.3s An individual patient’s risk may change with time. Risk may increase 70.4
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TABLE 1. Sudden Clinical
Cardiac
Death
Gruup
Sudden death sutivors Dilated cardiomyopathy First year post-myocardial infarction Hypertmphic cardiomyopathy Long QT syndrome U.S. Adult population Mitral valve prolapse without regurgitation
Relative
Risk Average Annual Risk (96) 10-30 10 5 l-3 1-3
0.22 0.019
with progression of disease. Likewise, risk may be reduced by an intervention or medical treatment of the underlying cardiac pathologic condition. Thus risk assessment is a complex, dynamic process requiring thorough clinical evaluation of the patient, a correct diagnosis, and further substratification of risk categories within groups of patients with the same basic disease process. General clinical and epidemiologic data connecting sudden death with a number of cardiologic syndromes are presented in this section. The use of a wide variety of tools to aid risk stratification and management of individual patients is presented in a subsequent section.
DILATED
CARDIOMYOPATHY
Dilated cardiomyopathy (DCM) is the primary diagnosis in 7% to 23% of patients undergoing electrophysiologically guided therapy after surviving out-of-hospital sudden cardiac death not in association with an acute myocardial infarction (Table 2).40-44 In contrast to coronary disease the incidence of idiopathic (presumably viral) cardiomyopathy is increasing.38 Approximately 10,000 deaths in the United States each year are attributable to this disease. The annual mortality rate is estimated at 20% per year.= Approximately one half of these deaths are due to congestive heart failure, whereas the remaining half are sudden and presumably caused by ventricular arrhythmias ?-‘l Vasodilators, hydralazine in combination with nitrates, and angiotensin-converting enzyme inhibitors have altered the natural history of dilated cardiomyopathy by preventing or at least postponing deaths caused by myocardialgump failure when added to chronic digoxin and diuretic therapy. ’ 53 Of interest, use of these agents has had no appreciable effect on sudden death morCurr
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706
e 0w
2 ii
N
of Survivors
Coronary Disease N (WI
Disease in Series Studies
9 4 5 5 17 13 48
Death
(8) (9) (1.51 (1.5) (27) (8) (11)
Cardiomyopathy N I%)
of Sudden
119 85 (71) Morady=” 45 35 (78) Benditt4’ 34 20 (58) Bendip 34 20 (58) Sale* 62 35 (57) Wilbe? 166 125 (75) Total 426 300 (70) *Includes both dilated and hypertmphic cardiomyopathy. tExcludes Mvp without mitral regurgitation. *includes WPW and long QT syndrome patients. Mvp = mitral valve prolapse; WFW = Wolff-Parkinson-White
B@’
Author
Underlying Heart Electmphysiologic
TABLE 2. with
7 3 2 2 2 10 24
16) (7) (61 (6) (3) (6) (6)
VaIve and Hypertensive Diiease* N (W)
Unassociated
Acute
7 2 0 0 2 6 17
MVPt
Myocardial
(3) (4) (4)
(6) (4)
N (W)
Infarction
on the
10 1 7 7 6 8 32
IS) (2) (211 (21) (10) (5) (8)
Primary Electrical Disorder& N (%I
Treated
Basis
of
1 I11 0 0 0 0 4 (2) 5 (1)
Other N (96)
30-
.E % 20. 9 E nE P=O.o045 0
6
12
16
24
30
36
42
0
6
12
16
24
30
36
4246
46
Months FIG 2. Mortality caused by progressive heart failure (A) (P = 0.0045) and presumed to be caused by an arrhythmia but not preceded by worsening congestive heart failure (B) (Pvalue not significant). (Reprinted with permission from the New England Journal of Medicine [325;297, 19911.)
tality (Fig 2).54 Patients with compensated heart failure are still at cardiomyoparisk for sudden death.55 In contrast to hypertrophic thy, sudden death as the initial disease manifestation in dilated cardiomyopathy is uncommon. HYPERTROPHIC
CARDIOMYOPATHY
Hypertrophic cardiomyopathy (HCM) occurs in both familial and sporadic forms.37 Recent work by Hejtmancik et alF6 using the techniques of molecular genetics and linkage analysis, have identified Cum
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the genetic locus for the familial form in the United States on the fourteenth chromosome confirming previous studies of Jarcho et a15’ and Solomon et al?’ Like patients with DCM, patients with HCM die from heart failure or sudden death. In marked contrast to almost all other forms of heart disease, risk for sudden death in HCM appears to decline with age:5g sudden death in HCM is uncommon after the age of 40. 37 In view of the association of HCM with sudden death in young athletes,16’ 60,” this apparent anomaly may represent the effect of a decrease in physical or athletic activity with age. Another potential explanation, however, is that patients with HCM at risk for sudden death do not reach middle age. Spirit0 and Man&” have correlated the risk of sudden death in HCM with the severity of left ventricular hypertrophy (LVI-I). Sudden death has also been reported in a patient without LVH who at autopsy had the disorder of septal myocytes that characterizes HCM histologically.63 Patients with HCM comprise 0% to 5% of patients in series of survivors of sudden cardiac death undergoing electrophysiologic evaluation.40-44 The occurrence of sudden death as the initial manifestation of heart disease is also reflected by the frequency with which this disease is implicated in the sudden death of young athletes?” 6o861 The familial occurrence of this disease commands accurate diagnosiseven if diagnosis is established at postmortem examination. Family screening of patients with HCM should be performed and genetic counseling provided in appropriate cases.
MITRAL
VALVE PROLAPSE
The establishment of a causal link between isolated mitral valve prolapse (MVP) and sudden death has been difficult, Mitral valve thickening and leaflet redundancy have been reported in sudden death victims in the absence of any other heart disease.“4-66 Reported series of sudden death survivors also contain 3% to 7% op-atients with MVP as the only identifiable cardiac abnormality. 44 Given the ubiquity of mitral valve prolapse and that cardiac electrical problems occur in the absence of structural abnormalities, however, the occasional association of MVP and sudden death is insufficient to establish a cause-and-effect relationship. In a recent review, only 106 cases of sudden death in association with MVP could be identified!’ This is far fewer than the number expected if a true causal relationship exists. In a series of 237 minimally symptomatic or asymptomatic patients with echocardiographically documented MvP, Nishimura et a16’ described only six episodes of sudden death in an average follow-up of 6.2 years. The smvivaI of the patients in the MVP group did not differ signitlcantly from that of an agematched and sex-matched control group. In a second large series, 708
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reported by Duren et al.,“’ 300 patients with MVP were followed up for an average of 6.1 years. These authors found only three episodes of sudden death. Kligfield et al.,“’ extrapolating from autopsy data reported by Davies et a.l.,‘l calculated an estimated annual risk of sudden death attributable to MVP of 1.9 per 10,000 patients with MVP without mitral regurgitation. This figure is only one tenth as high as the annual risk of sudden death by all causes in the adult population of the United States. Using similar autopsy data in patients with MW and mitral regurgitation, these same authors calculated a risk for sudden death that was 50 to 100 times greater than the risk in patients with h4VP alone.” These lines of reasoning cannot exclude a pathophysiologic role of h4W in an isolated case of sudden death. However, they do suggest that the risk of sudden cardiac death in MVP is low. b R.C. SCHLANT: Further support for the conclusion that the risk of sudden death in h&T is very low is found in autopsy studies performed in older patients. In general, the occurrence of evidence of MVP is about the same in older patients as in younger patients, a finding that would not be expected if hNP were associated with a significant incidence of sudden death in younger years.
HYPERTENSION
AND LVH
A resurgence of interest has occurred in the role of LVH in the pathophysiology of sudden death. Hypertension, as the most common cause of LVH, has also received a second look in regard to its relation to sudden death. This resurgence is due to several factors. Among the most important of these factors has been the development and validation of echocardiographic techniques for the quantification of left ventricular mass.72-74 Echocardiographic techniques are far more sensitive in the detection of LVH than electrocardiographic techniques formerly usedT5 Echocardiographically determined left ventricular mass has been shown to be a powerful predictor of cardiovascular morbidity and mortality, including sudden death, in several studies.76-7s The degree to which risk is elevated correlates with the severity of LVH.” A second factor contributing to the renewed interest in the importance of hypertension and LVH has been the demonstration that LVH contributes to the development of malignant arrhythmias in animal models involving acute coronary occlusion.7s~80 These studies suggest that the contribution of hypertension to sudden death is twofold. The more well-known effect is indirect as a risk factor for coronary artery disease. A second more direct effect is the apparent electrical instability of the hypertrophied heart under conditions of acute ischemia. Finally, the demonstration that LV mass can be modified in Cut-r
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hypertensive patients by some antihypertensive therapies has also contributed to the renewal of interest in the heart in hypertension. Central sympatholytic agents and angiotensinconverting enzyme inhibitors have consistently been shown to reduce LV mass in animal models and patients.81-83 Some other classes of medications, equally efficacious in lowering blood pressure, do not produce regression of LVH.83’ 84 What impact reduction in LV mass by antihypertensive therapy will have on sudden death in these patients is a subject of considerable controversy. For all of the recent interest, the mechanism of arrhythmias in hypertrophied ventricles is still not known. The same mechanisms that facilitate sudden death in hypertension-induced LVH may be operant in other hypertrophy states (e.g., valvular heart disease). It is our opinion that the importance of LVH in the pathophysiology of sudden death is underrepresented in reported series of sudden death survivors. This is probably due to the tendency to classify patients with coronary disease and LVH on the basis of their coronary disease. It is also due to the absence of quantitative echocardiographic techniques for determination of LV mass when many of the series were collected. A more ominous possibility is that patients with significant LVH are less likely to be resuscitated from an episode of sudden death than patients without LVH.
ISCHEMIC
HEART
DISEASE
Coronary artery disease is the predominant substrate in all autopsy series of sudden death patients and in reported series of sudden death suIvivors.40-44 In part, this relates to the relative ease with which coronary disease can be characterized clinically and pathologically. However, the fact that sudden cardiac death usually means sudden coronary death is inescapable (Table 2). According to data from the Framingham study, 50% of sudden deaths in men and 64% in women occur without prior clinically manifest coronary disease.85 Thus sudden death is all too frequently the first and only manifestation of coronary artery disease. The risk for sudden death in patients with known coronary artery disease is increased in patients with multivessel disease especially when accompanied by LV dysfunction.86 Sudden death in coronary artery disease usually is seen as one of two syndromes. The first, often occurring in patients without known disease, is characterized by acute ischemia caused by abrupt occlusion of a major coronary artery. The severity of the underlying stenosis is variable. Abrupt occlusion usually occurs at the site of a preexistent atherosclerotic plaque, although the severity of vessel narrowing before the event may be mild.87 Plaque rupture or fissuring may 710
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establish a nidus for latelet aggregation and, ultimately, occlusive thrombus formati0n.l B’ 8888g Vasospasm may play a role in this cascade of events.go Endothelial and platelet-derived factors are believed to mediate many of these processes?l The dynamic nature of these processes may account for the fact that many patients experiencing sudden death in the setting of acute ischemia do not evolve acute infarctions.g2-g4 Animal studies suggest that reentry within the acutely ischemic myocardium is the probable mechanism of arThis syndrome is responsible for most sudden rhythmogenesis.g5 deaths. Patients who survive an episode of sudden death and evolve a myocardial infarction with new Q waves are at no greater risk than the patient who has an infarction uncomplicated by sudden death,35 whereas patients with sudden death who do not evolve infarctions are at high risk for recurrence.12J 35,g2, g6 An aggressive approach to evaluation and treatment of the underlying heart disease and the arrhythmia is indicated. The second presentation is that of sudden death in patients with known coronary artery disease often accompanied by focal wall motion abnormalities from prior infarction and depressed global ventricular function. These arrhythmias are almost certainly reentrant in origin with reentry occurring within the areas of viable myocardium at the borders of myocardial scar?’ Programmed stimulation techniques and electrophysiologically guided therapy have been most effectively applied in this subgroup of patients. These patients also are at high risk of recurrence if effective treatment is not used. Full characterization of the anatomic substrate and dynamic factors contributing to arrhythmias in this subgroup of patients is also warranted. The risk of sudden death in patients with coronary artery disease, which can change drastically over time, is probably highest soon after abrupt vessel closure. For those patients who survive the early stages of an abrupt occlusion, however, risk declines exponentially withii a few hours, perhaps even within a few minutes. The risk of sudden death declines to 4% to 5% by the time the patient is disFor those patients surviving the first charged from the hospital.” year after infarction, risk is further reduced?’ Risk rapidly escalates with abrupt occlusion of an additional major artery. This process can continue until a chronic ischemic myopathy develops.
PRIMARY
ELECTRICAL
ABNORMALITIES
This category includes patients experiencing sudden cardiac death in the absence of any structural abnormalities of the heart. Incorporated in this group are patients with primary ventricular arrhythmias, patients with the long QT syndromes, and the unusual Curr
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711
patients with the more malignant forms of the Wolif-ParkinsonWhite &VPWl syndrome. Combined, these patients form 2% to 12% of patients in reported series of survivors of out-of-hospital sudden death (Table 2).4 -44 Although combined for the purposes of classification and discussion, the pathogenesis of sudden death in these different syndromes is very different. Schwartz et al.” have presented data indicating the importance of the adrenergic nervous system in the genesis of arrhythmias and sudden death in the long QT syndrome (LQTS). The natural history of this fascinating disorder is still under active study. In a cohort of 196 patients with LQTS followed prospectively, the incidence of sudden death was 1.3% per year.” This figure is remarkable considering the average age of the patients in the cohort was only 24 years. The disease occurs in both inherited and sporadic forms. As with HCM, family screening and genetic counseling are in order when an affected patient is identified. The arrhythmias occurring in patients with LQTS are very similar to those occurring in patients experiencing the proarrhythmic effects of QT prolonging medications.1oo Thus insights into arrhythmogenesis derived from LQTS may have much wider applicability. Somewhat in contrast to LQTS, sudden death in the WPW syndrome is unusual. In a rare population-based study, Guize et al.*” followed up 151 patients with manifest WPW for a mean of 4.6 years. Only one episode of sudden death occurred. Atrial fibrillation with rapid antegrade in an accessory pathway is the most accepted explanation for the occurrence of sudden death in WPW. The resulting extreme ventricular rate may produce hemodynamic deterioration directly or result in a ventricular arrhythmia.l”
SUDDEN
DEATH
IN CHILDREN
AND YOUNG ADULTS
Sudden nontraumatic death accounts for 2% to 20% of deaths between the ages of 1 and 20 years.‘o3’ lo4 In contrast to reported series of adult patients where coronary disease is the dominant underlying disease, the underlying cardiac pathologic condition in pediatric series is more varied (Fig 31. For those series drawn from the general population, myocarditis, HCM, and congenital coronary anomalies are mentioned most often.‘oz-1o7 For series drawn from children and young adults with known heart disease, aortic stenosis, pulmonary hypertension (primary or secondary), and tetralogy of Fallot appear most often.108-11’ Primary electrical problems (long QT patients and WPW patients) also sometimes have sudden death in this young age group. A population of increasing concern to pediatric cardiologists and adult cardiologists alike is the group of patients with surgically re712
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118%) < 35YEARS
OLD
2 35 YEARS OLD
FIG 3. Causes of sudden death in athletes less than 35 years old and 35 years and older. (Reprinted with permission from the American College of Cardiology [Journal of the American College of Cardiology, 1986;7:204-2141.)
paired complex congenital heart disease. Patients with surgically corrected tetralogy of Fallot are at greatest risk for ventricular arrhythmias.‘l’ b R.C. common
In small infants the crib sudden and its cause is still an enigma.
SCHLANT:
UNCOMMON
SUDDEN
death
syndrome
is still too
DEATH
In addition to the major categories of heart disease discussed above, a number of uncommon causes of sudden arrhythmic death exist (Table 3). The unique features of each condition require recognition for proper diagnosis. The mechanism of sudden cardiac death (bradyarrhythmia or tachyarrhythmia) is not know-n in some cases. The tachyarrhythmias associated with these conditions often are particularly difficult to treat. ‘IXwo of the more common of these unusual causes of sudden death will be discussed briefly. Arrhythmogenic right ventricular dysplasia usually is seen with hemodynamically tolerated arrhythmias, although sudden death does occur. Afflicted patients are otherwise healthy and arrhythmias may be exercise related.l13 Diagnosis requires a high index of suspicion and demonstration of functional and structural abnormalities of the myocardium of the right ventricle. Replacement of right ventricular muscle by adipose or fibrous tissue is the characteristic histologic finding.‘14 The occurrence of nocturnal unexplained sudden death has been recognized in Far Eastern countries for some time. The Filipino version of the condition is known as Bangungut. In Japan, the disorder is called Pokkuri disease.ll’ This condition, occurring almost excluCut-r Probl
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TABLE 3. Unusual Causes of Arhythmic Sudden Death Myocarditis Arrhythmogenic right ventricular dysplasia Sleep-death in Southeast Asians -‘W”W POkkuri Tumors mary Metastatic InfWative cardiomyopathies Sarcoid Amyloid Hemochrumatosis Chagas’ disease Neurumuscular diseases Muscular dystrophy Friedreich’s ataxia Myotonic dystrophy
sively in men, was recognized in the United States after the influx of Southeast Asian refugees that followed the end of the Vietnam War:= Death occurs during sleep in apparently healthy individuals. Careful histologic study has revealed minor abnormalities of the conduction system, though a causal relationship between these findings and the clinical syndrome remains speculative?”
EVALUATION
The comprehensive evaluation of a patient’s risk for sudden cardiac death is a complex process. For conceptual purposes, this evaluation can be divided into three separate steps. The first step involves the full characterization of all underlying cardiac disease and any comorbid noncardiac conditions that are present. The nature of the underlying pathologic condition provides a first approximation of the magnitude of risk for sudden cardiac death. The nature and severity of the cardiac disease also are important determinants of the methods used to evaluate and treat the associated cardiac arrhythmias. Concomitant systemic disease can likewise be an itnportant consideration in the choice of treatment options. The second phase of patient assessment involves patient-specific risk stratification within the context of a general diagnostic category. This sub&ratification step is most important in disease states associated with intermediate risk of sudden death (e.g., HCM or long QT 714
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November
1992
syndromes). The annual risk of sudden death among all patients with these syndromes is relatively low at 1% to 3% .37,” Intervention to prevent sudden death in all affected patients is probably unnecessary and, considering the toxicity of antiarrhythmic agents, potentially harmful. On the other hand, the identification of subgroups at high risk for sudden death within diagnostic groups allows the more selective application of interventions. Risk substratification plays a less important role in high-risk disease states. In this context, patient-specific factors can identify low-risk groups of patients less likely to benefit from medical or surgical therapies. For a group of patients with instance, Stewart et a13’ have identified DCM that have a much better prognosis than the 20% per year mortality of the group as a whole. Risk substratification is least important in the evaluation of those patients who have already experienced sudden cardiac death unassociated with acute infarction. However, even in this group at high risk, some patients have a low probability of recurrence. The third objective in the evaluation of patients in the context of sudden cardiac death is the identification of markers that can be .used to assess the efficacy ‘of therapy. Although controversy continues to exist regarding the best means to assess the safety and efficacy of therapy, objective means must be used whenever possible. Except for the use of P-adrenergic receptor blocking agents in the patient who has had a myocardial infarction (MI), empiric therapy has been of little efficacy in the prevention of sudden death. Patient assessment begins with a thorough general history and examination. Because few patients who experience sudden death have premonitory symptoms, the history focuses on general signs of cardiovascular disease. Because coronary artery disease is the most common substrate, particular attention must be paid to any history of chest discomfort or exertional intolerance. Because many patients at high risk have LV dysfunction, potential heart failure symptoms must be carefully evaluated as well. In several subgroups of patients, syncope has been advocated as a harbinger or risk factor for sudden death. This includes patients with HCM and the long QT syndromes.“’ ‘I7 Auricchio et a1118 have recently reported on the absence of prognostic value of syncope in patients with WPW. In their study, the occurrence of syncope did not correlate with any measure of electrical abnormality caused by the presence of an accessory pathway.l18 Evaluation of syncope in the general population must be made with an awareness of the fact that this symptom occurs in up to 37% of healthy young adults.11s Some authors have suggested that the circumstances of syncope and, in particular, the association of syncope with exercise is a more specific sign of heart disease and increased risk for sudden death.“’ This postulate has Curr
Probl
Cat-did,
November
1992
716
not been tested in a prospective or controlled fashion. Family history is of obvious importance in cases where HCM or long QT syndrome is suspected. Historical information is also of importance in the evaluation of the patient who has survived an episode of sudden death. In this setting the most important information often comes from those who have witnessed the event rather than from the patient. Seizures and fainting episodes can easily be confused with episodes of sudden death even by experienced observers. Because the treatment of bradyasystolic arrest and sudden death caused by tachyarrhythmias differs dramatically, documentation of all rhythms recorded during the episode is paramount.121 In our experience no substitute has been found for direct conversation with as many witnesses to the event as possible. No amount of subsequent evaluation can nullify a mistake in the diagnosis of aborted sudden death. Physical examination may also provide insight into the presence and nature of cardiac disease. Funduscopic examination can indicate the presence of long-standing hypertension. Carotid pulse examination may indicate evidence of HCM. Palpation of the cardiac apex may also suggest HCM or the presence of an apical aneurysm. Cardiac auscultation may disclose the presence of valvular heart disease. In young patients systolic murmurs must be evaluated thoroften using a series of dynamic maneuvers-so as not to oughlymiss the patient with HCM. All signs of heart failure should be sought diligently. The traditional cardiac noninvasive screening modalities (electrocardiography and chest radiography) are important adjuncts to the history and physical examination. The electrocardiogram (ECG) is helpful in the diagnosis of coronary disease, as well as the preexcitation syndromes. The ECG is a specific, but insensitive, indicator of LVH. Conduction abnormalities characteristic of cardiomyopathy may also be seen. Electrocardiographic abnormalities are required for the diagnosis of the long QT syndromes although the changes may be present only intermittently. The chest radiogram in this setting is most useful in the assessment or diagnosis of LV dysfunction with congestive heart failure.
SPECIAL
TESTS
The physician evaluating a sudden death survivor or patient suspected to be at risk for sudden death has an array of noninvasive and invasive tests that may be useful in the diagnosis of such patients. Some tests are useful prognostically whereas others can be used to guide therapy. Certainly not all tests are necessary or even desirable in all patients. However, some basic knowledge of all these 716
Curr
Prwbl
Cardiol,
November
1992
modalities disease.
is necessary
for physicians
caring for patients
with heart
AU patients with complex ventricular arrhythmias, as well as those patients suspected to be at risk for these arrhythmias, should have some form of noninvasive assessment of cardiac function. Echocardiography has become a favored means to accomplish this goal because of its ease of applicability in the intensive care setting and the wide spectrum of information available by the application of echocardiographic and Doppler techniques. M-mode and twodimensional echocardiographic abnormalities that may be documented in patients with arrhythmias include segmental LV wall motion abnormalities consistent with coronary disease; significant valvular dysfunction; evidence of HCM, MVP, chamber dilatation, and ventricular dysfunction characteristic of DCM; pericardial disease; intracardiac tumors; arrhythmogenic right ventricular dysplasia; and congenital heart abnonnalities.122-128 Echocardiography is much more sensitive than electrocardiography in the diagnosis of techniques provide the ability to noninvasively LVHT5 Doppler quantitate valvular stenoses and regurgitation and also to identify intracardiac shunts. Echocardiography is useful in the assessment of regional as well as global LV function. Aneurysms can frequently be diagnosed with echo assessment of regional wall motion.‘2s Patients with discrete aneurysms may be considered for surgical therapy of their atrhythmias. The presence of LV dysfunction within any arrhythmia subclass may increase that patient’s risk for sudden death and influence the decision to undertake therapy?30-132 Documentation of serious LV dysfunction by echocardiography may preclude the use of antiarrhythmic agents that produce significant negative inotropy. b R.C. SCHLANT: Evaluation of ventricular function by transthoracic or transesophaged echocardiography can sometime8 by enhanced by the simultaneous application of stress by cardiac pacing or pharmacologic agents such as dobutamine.
RADIONUCLIDE
ANGI -oGwHY
Radionuclide angiocardiography is another noninvasive test used for the quantitative assessment of LV function and regional LV performance. LV ejection fraction can be measured using the first-pass technique or the gated cardiac blood pool imaging technique.133 Right ventricular function can also be assessed. Radionuclide angioCurr
Probl
Cardiol,
November
Xi%?
717
cardiography is particularly useful in obese patients or patients with chronic lung disease in whom a technically satisfactory echocardiogram cannot be obtained. In patients who have frequent ventricular ectopy or atrial fibrillation, gating is difficult and the results of radionuclide angiocardiography are often less accurate.‘= This technique also does not supply direct data regarding valvular disease, wall thicknesses, and chamber dimensions as echocardiography does. Ejection fraction measurements by nuclear techniques have been found to be accurate, to be reproducible (+6% 1, and to correlate well with measurements made at cardiac catheterization. Regional or segmental wall motion can be assessed well by gated studies. Regional LV hypokinesis, akinesis, or dyskinesis can be determined.‘35 As an inherently quantitative technique, radionuclide angiocardiography has been very useful in studies designed to determine optimal risk stratification strategies in the post-MI patient. A depressed ejection fraction in this group of patients is associated with enhanced mortality. The presence of LV dysfunction may be useful in determining which patients in this population need prophylactic treatment. As with echocardiography, radionuclide angiocardiography may be useful in directing antiarrhythmic therapy. Agents with negative inotropic effects can be avoided in patients with poor ventricular function. The combination of rest and stress radionuclide angiocardiograms is a useful noninvasive screening test in the diagnosis of coronary artery disease.136 The use of exercise gated studies is more sensitive and specific than electrocardiographic stress tests in the diagnosis of coronary artery disease and approaches stress thallium testing in predictive accuracy.
EXERCISE
STREBS TJBTING
Exercise testing serves several purposes in patients with complex ventricular arrhythmias. Despite well-recognized limitations of sensitivity and specificity, the graded exercise test remains the most commonly used noninvasive test for the diagnosis of coronary disease in patients with chest pain. Augmentation of routine stress testing by the use of nuclear medicine techniques improves the sensitivalso ity and specificity figure~.*~‘~ 13’ Nuclear medicine techniques extend the use of exercise testing to many patients with electrocardiographic abnormalities that preclude the reliable interpretation of the electrocardiographic response to exercise. Nuclear techniques may also be useful in efforts to localize regions of ischemia and determine the amount of myocardium in jeopardy. Positron emission tomography may be even better at many of these applications but is 718
Curr
Probl
Cardioi,
November
1%~
not yet readily available in many areas. Clinical decisions based on positive and negative results for any of these tests must take into account the pretest probability of coronary disease as dictated by Bayes’ theorem.137,139,149 When one considers that over half the victims of sudden death, most of whom have coronary disease, have no antecedent symptoms, the desirability of a noninvasive means of latent coronary disease detection is obvious. Exercise testing has been used for this purpose although its performance in this regard has been somewhat disappointing. Detection of coronary disease during exercise testing depends on the production of myocardial ischemia by supply-demand imbalance resulting from the metabolic demands of exercise in the presence of a flow-limiting coronary stenosis. Epthat the patient at risk for sudden stein et al.87 have hypothesized death without antecedent symptoms is the coronary patient without severe stenoses. These patients suffer abrupt vessel closure caused by endothelial injury, platelet aggregation, and finally thrombosis. The abruptness of closure precludes the development of collateral vessels that would minimize the amount of myocardial injury. Thus treadmill testing and other tests that depend on the presence of severe stenoses for the detection of coronary disease may not be the best means for identifying presymptomatic patients at risk for sudden death.87 Exercise stress testing is useful in the identification of patients with exercise-induced or exercise-aggravated ventricular tachycadia.'41-143 Frequently these patients are young and have no evidence of serious organic heart disease. These patients may not have inducible ventricular tachycardia in the electrophysiologic laboratory. Therefore stress testing may be the only method available to guide drug therapy. Stress testing has been found to be useful for risk stratification of post-MI patients?37’13s,144-146 Several studies have shown that the occurrence of exercise-induced angina, exercise-induced ventricular arrhythmia, or exercise-induced diagnostic ST segment changes I to 2 weeks after myocardial infarction is predictive of future events including sudden death.‘&’ 145 Patients found to have exerciseinduced ischemia appear to be in a high-risk category, These patients should be strongly considered for prophylactic P-blocker protection or early cardiac catheterization with appropriate treatment in an effort to alter this natural history.13’ Finally, exercise testing may be a useful adjunct in guiding antiarrhythmic drug therapy. Catecholamines, which increase during exercise, have been shown to reverse beneficial effects of antiarrhythmic drugs .147,14a Presumed adequate suppression of arrhythmia on ambulatory ECG (Halter) monitoring may be noted during drug therapy yet stress testing may reveal persistent repetitive activity. The Curr
Probl
Cardiol,
November
1992
719
proarrhythmia of intracardiac agents may be manifest as the development of incessant tachycardia during exercise.14s’ 150
LONG-TERM
ELECTROCAIUB
IOGRAPHIC
RECORDINGS
Since the original description in the 195Os, Holter monitoring, or continuous ambulatory electrocardiographic monitoring IAECG), has been a useful technique in the evaluation of patients with arrhythmias.151’ 152 With respect to sudden death, AECG recordings are used to screen selected patients who have clinical syndromes in which the presence of an arrhythmia may increase the patient’s risk for sudden death. These situations include the post-MI period,153-155 congestive heart failure, and DCM,13” 13’, 156-160 HCM,“’ and the congenital prolonged QT syndrome.162 On the contrary, even frequent and complex ectopy, when asymptomatic, has little prognostic significance in patients without heart disease.163’ 164 In riskstratification of post-MI patients, late in-hospital arrhythmias have prognostic significance and are used in conjunction with ejection fraction determination and other noninvasive tests. Patients with benign profiles (all factors negative1 have a 3% l-year mortality compared with a 15% l-year mortality when all factors are positive. Serial AECG monitoring has been used to guide antiarrhythmic drug therapy. Patients have a first AECG monitoring period in the drug-free state. The patients are then placed on antiarrhythmic therapy and after the drug reaches steady state conditions for the prescribed dosage AECG monitoring is repeated. Comparison of the frequency and complexity of background arrhythmia is made in an effort to determine whether the prescribed medication has had an effect. Graboys et al?65 used this method in conjunction with exercise testing before and after drug therapy to assess the efficacy of antiarrhythmic therapy in 123 patients with a history of sustained VI or VF. The AECG monitoring periods before and after drug therapy were 48 hours. Drug efficacy in this study was defined as a 50% or greater reduction in total premature ventricular contractions (WCs), 90% or greater reduction in the number of paired ventricular responses, and a total suppression of nonsustained ventricular tachycardia and R-on-T WCs. Ninety-eight of 123 patients (80%) left the hospital on effective therapy as assessed by the methods used in the study. Freedom from sudden death at 3 years of follow-up was 90% in the effective therapy group versus 15% in the group that could not be effectively suppressed. A second study bg6the same group also supported the role of AECG-guided therapy. In this study of 118 patients 3-year freedom from sudden death was determined to be 84% in the group on effective therapy but only 48% in the group of patients that could not be effectively suppressed.‘66 720
Curr
Probl
Cardiol,
November
1992
Studies like those of Graboys et al.‘65 and Lampert et al?66 that indicated the benefit of AECG-guided therapy gave rise to the “PVC hypothesis.” The basic premise of this hypothesis is that ventricular ectopy and nonsustained ventricular arrhythmias are linked pathophysiologically to more malignant arrhythmias. If one accepts this premise, the next logical conclusion is that suppression of WCs and nonsustained ventricular tachycardia can be used as a marker of suppression of the less frequent, but clinically more significant, sustained ventricular arrhythmias. The attraction of the theory is that it would preclude the need for invasive electrophysiologic (EP) studies in many patients. However, the results of the Cardiac Arrhythmia Suppression Trial (CAST) have seriously undermined the premise on which the PVC hypothesis is based.‘67 This multicenter study was designed to test the hypothesis that suppression of ventricular arrhythmias in patients with LV dysfunction after MI would reduce arrhythmic death. Flecainide, encainide, and moricizine were the antiarrhflhmic agents used in the trial. Patients were only entered in this randomized, double-blind, placebo-controlled trial if they achieved 80% suppression of WCs on drug therapy during a period of open-label drug titration that preceded randomization. The encainide and flecainide arms of the study were terminated when a 2.5-fold increase in sudden death was found for patients in these two arms as compared with patients receiving placebo.167 Although one should not extrapolate the results of CAST to other patient populations or other antiarrhythmic agents, it is impossible to escape the conclusion that PVC suppression with intracardiac agents in this group of patients with coronary disease was associated with an increased risk of sudden death. This is directly opposite to the result expected if the PVC hypothesis were valid. Despite its limitations, serial AECG monitoring to guide therapy is still used in those patients who do not have inducible arrhythmias at EP testing and who are not candidates for device therapy. Understanding the concept of spontaneous variability of arrhythmias is key to use of this modality. Figure 4 shows the variability in PVC frequency in a cardiac arrest patient who underwent 2 consecutive days of monitoring. Although the patient had frequent ectopic activity during the first 24 hours, a marked decrease in arrhythmia occurred spontaneously on the second day. Spontaneous variability can mimic drug effect. The capability of repeated monitoring to demonstrate a true drug effect is a function of two factorsthe frequency of the arrhythmia and the duration of the monitoring period. Patients with a low frequency of WCs and/or nonsustained arrhythmias who have a history of life-threatening arrhythmias are not good candidates for AECG-guided therapy. This occurs in up to two thirds of sudden death surviv~rs.~~ In patients with more frequent arrhythmias, pooled data suggest that a reduction of 83% in the number of CUJT Probl
Cardiol,
November
1992
721
FIG 4. Variability in PVC frequency noted in a patient with a history of sustained VT. Note marked variability over 2 consecutive days of recording off antiarrhythmic therapy. (From Naccarelli et al: Patient assessment: Laboratory studies, in Andreoli KG, Zipes DP, Wallace A, et al (eds): Comprehensive Cardiac Care. St Louis, CV Mosby, 1987, pp 58-81. Used with permission.)
WCs is indicative of drug effect based on 24-hour monitoring.168’ 16’ Unfortunately, this finding is indicative only of a short-term drug effect. Variability changes with the passage of time, presumably as the underlying cardiac substrate changes.17’ Thus to be certain that drug effect persists, it is necessary to discontinue the drug and redetermine the frequency of arrhythmia in the drug-free state. More variability has been noted in coronary disease patients than in patients without coronary disease.171 SIGNAL-AVERAGED
ELECTFtOCARDIOGRAM
In experimental models of acute MI, low amplitude, fragmented, and delayed electrical activity can be recorded from areas bordering the infarction but not from areas more remote from the zone of inThese areas are thought to be the substrate for reentrant farcti0n.l” ventricular arrhythmias seen in these experimental preparations and may underly many lethal clinical arrhythmias as well. The 7zz
Curr
Prvbl
Cardiol,
November
ICEIZ
signal-averaged ECG, sometimes referred to as a high-resolution ECG, uses a number of signal-conditioning steps in an effort to record the delayed fractionated activity from the body surface (Fig 5). The frrst step, amplification, is necessary because of the extremely low amplitude of the delayed electrical activity, often referred to as late potentials. The next step, high-pass filtering, takes advantage of the fact that the late potentials are made up predominantly of highfrequency signals whereas the surface QRS and ST segments, which obscure the late potentials on the surface ECG, are composed of lower frequencies. An industry standard has not been established for the cutoff frequency of the filtering step. Values between 25 and 100 Hz have been advocated by different investigators. Bidirectional flltering of the signal is used to avoid artifact caused by ringing in the offset of the QRS complex that would obscure late potentials as well.173 Finally, the amplified, filtered signal is averaged over a period of time or specified number of beats. The theory of signal averaging in this application is simply that noise is random and positive voltage noise will be counterbalanced by negative noise as the averaging process proceeds. Late potentials are not random and will not cancel during the averaging process. Thus averaging reduces the
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Cardid,
November
1992
723
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noise level to a degree sufficient to allow detection of the late potentials. The signal-averaged ECG is usually recorded with three bipolar, orthogonal (Frank - X,Y,Z) leads. For purposes of display and analysis, the leads are usually combined into a single vector, the magnitude of which is calculated by taking the square root of the average of the squared amplitudes of the three individual lead voltages. The presence of late potentials is represented by an increase in the total QRS duration, a reduction in amplitude of vectoral QRS voltage in the last portion (typically 40 ms) of the QRS, and/or an increase in the duration of low-amplitude signals at the end of the QRS (Fig 6). The requirement of multiple positive criteria for an abnormal test increases the specificity of the test but at the expense: of sensitivity. Likewise, choice of cutoff values for QRS duration, terminal root mean square voltage, and duration of low-amplitude signals involves a similar trade-off. The presence of late potentials is a predictor of inducible sustained VT at EP study in patients with nonsustained VT.174’ 175 In this population the signal-averaged electrocardiogram may be useful in screening patients for EP study. In a report by Hall et al.,174 two thirds of patients with late potentials and a history of nonsustained VT had sustained VT induced by programmed electrical stimulation,. The signal-averaged ECG may also be of value for risk stratification after MI. The use of signal averaging in this application usually implies performance of the test a minimum of a few weeks after the completed infarction. The presence of late potentials in the early post-MI period has not been shown to be useful in predicting subsequent arrhythmias. Late potentials are often transiently present during this time. Kuchar et al?76 performed signal-averaged ECGs an average of 11 days after MI, as well as radionuclide ventriculography and AECG monitoring in 210 patients. An abnormal signal-averaged electrocardiogram was defined as the presence of a low-voltage signal (less than 20 V) in the terminal 40 ms of the QRS or a filtered QRS duration greater than 120 ms. Low-amplitude signal criteria were not used in the study. Patients were followed up for a median of 14 months for arrhythmic events- sudden death or sustained VT. The results of each of the three tests studied were independently predictive of arrhythmia events. Ejection fraction (EF) by radionuclide venFIG 6. (A) Presence of late potentials in a patient with a history of sustained VT. (8) Normal signal-averaged ECG in a syncopal patient. DUR = duration; RMS = root mean square; IN = integral; LAS = low amplitude signals. (From Naccarelli et al: Noninvasive cardiac evaluation of patients with arrhythmias, in Naccarelli GV (ed): Cardiac Arrhythmias: A Practical Approach. Mt. Kisco, NY, Futura Publishing, 1991, p 54. Used with permission.) Curr
Probl
Cardiol,
November
1992
726
triculography was the most powerful predictor but the combination of an EF less than 40% and a signal-averaged ECG indicating the presence of late potentials suggested a higher risk than any single abnormal variable alone. Patients with this combination had a 34% probability of an arrhythmic event. The risk of a low EF alone was only 4%. Thus the presence of late potentials in a patient with LV dysfunction after an MI portends a poor prognosis.176 The location of infarction influences the ability of the signalaveraged ECG to detect late potentials: the test is most predictive of arrhythmic events in patients with inferior infarctions and less useful in anterior infarcts. This difference is probably due to discrepancies in the time course of the activation of the per&infarct zone for the two infarct locations. Per&infarct tissue in anterior infarctions is activated relatively early in the sequence of ventricular activation. Thus late potentials occur during the body of the QRS complex where they are hardest to detect in spite of the signalconditioning steps used to augment their presence. Activation of per&infarct zones late in the course of ventricular depolarization, as occurs with inferior infarctions, produces late potentials in the terminal portion of the QRS where they are more easily detected. Although most studied in the coronary disease patient, the signalaveraged ECG has been found to be of prognostic value in other diseases as well. Cripps et all” obtained signal-averaged studies on 64 patients with HCM and found abnormalities in 13 (20% ). Abnormalities were signiiicantly more common than in control subjects. Of more clinical significance is the fact that the signal-averaged ECG was abnormal in patients with HCM who had a history of sudden death or nonsustained ventricular tachycardia on 4S-hour AECG more often than in patients with HCM who had no history of sudden death or VT. The sensitivity of the signal-averaged ECG as a marker of electrical instability in this study was only 50%. Thus the presence of an abnormal signal-averaged ECG in this patient group implies increased risk, but the absence of an abnormal signalaveraged ECG cannot be construed to indicate particularly low risk. Late potentials are also associated with sustained ventricular arrhythmias in patients with DCM.178 Although incompletely studied in patients with LVH, the signal-averaged ECG may be less useful in this patient gro~p.‘~~ Standard time-domain analysis of the signal-averaged ECG cannot be performed in patients with bundle branch block or severe intraventricular conduction abnormalities. This precludes the use of this technique in a group of patients in whom the test could be potentially very useful. Frequency domain or spectral analysis of the terminal QRS and ST segment of the amplified QRS is unaffected bz bundle branch block and may be useful in this group of patients.’ ’ Although time-domain analysis is more predictive of inducible VT 7243
Curr
Fmbl
Cardid,
November
1992
during programmed stimulation in patients with VT, it is less predictive in patients with VF. In one recent study, frequency-domain analysis indicated abnormalities in patients with VF and VT.“* The signal-averaged ECG is of no value in following up patients on antiarrhythmic drug therapy. However, patients who undergo successful surgery for elimination of the arrhythmic focus will often have disappearance of their late potentials as welll”
HEART
RATE VAFUABILITY
A relatively recent addition to the arsenal of noninvasive tests used in the assessment of risk for sudden cardiac death is the analysis of heart rate variability. Schneider and CostiloelB3 first reported the relationship between sinus arrhythmia and prognosis after myocardial infarction more than 25 years ago. These investigators made three important observations: (1) sinus arrhythmia decreases in normal patients with age, (2) sinus arrhythmia is less evident after MI, and (9) those patients with the least evidence of sinus arrhythmia had the worst prognosis during follow-up after discharge.lB3 The use of heart rate variability, any of a variety of quantitative expressions of sinus arrhythmia, received little additional attention for more than 20 years. In 1987, Kleiger et al.,la in a report from the Multicenter Post Infarction Group, demonstrated that decreased heart rate variability is an important indicator of prognosis in patients after MI (Fig 7). As a determinant of prognosis, heart rate variability was indepenclent of other traditional risk factorsincluding LV function, ventricular ectopic beats, and drug treatment. In this study of 808 patients after MI, signal-averaged ECGs were not performed.‘84 In a recent study Farrell et al.lB5 found decreased heart rate variability also to be a powerful independent predictor of arrhythmic events in 487 patients less than 70 years of age after MI. In fact, reduced heart rate variability was more predictive of arrhythmic events (sustained VT or sudden death) than late potentials, frequency and complexity of ventricular arrhythmias on AECG, treadmill results, and EF. In the analysis of combinations of risk factors, the combination of late potentials on signal-averaged electrocardiogram and impaired heart rate variability on AFCG was more predictive of arrhythmic events than any other combination. Surprisingly, the addition of EF to the combination of late potentials and heart rate variability did not improve the predictive accuracy for arrhythmic events.185 If these results are confirmed by other investigators, the way patients are risk stratified after MI could undergo significant changes. Interest in heart rate variability as a clinical tool is a product of better understanding of the importance of the autonomic nervous Curr
Probl
Car&o!,
November
1992
727
‘-\
O.S{
0
Above IO0
Below 50
1.0 2.0 3.0 4.0 TIME AFTERMI(Yeors)
FIG 7. Cumulative survival over total follow-up period as a function of heart rate variability. Survival curves were calculated by method of Kaplan and Meier. Heart rate variability is expressed as the standard deviation of the RR interval. (From Kleiger et al: Decreased heart rate variability and its association with increased mortality after acute myocardial infarction Am J Cardiol 1987;59:256-262.)
system in heart failure and sudden death. It is increasingly apparent that the heart depends on a balance between sympathetic and parasympathetic inputs. Increased arrhythmogenicity results from increased sympathetic activity or a reduction in parasympathetic activity.=” Reduced heart rate variability is simply a reflection of the reduction, relative or absolute, in parasympathetic influence. As with the signal-averaged ECG, heart rate variability can be analyzed in the time domain or the frequency domain. Also as in the case of signal averaging, no standard convention for expression of heart rate variability exists among investigators. Mathematically, the simplest time-domain analysis is the determination of the standard deviation of the RR intewal about the mean RR for a specified number of beats or period of time. The resulting single value includes the effects of both sympathetic and parasympathetic activity.184J la7 Spec72.9
Cum
Probl
Cardiol,
November
1~~2
tral analysis (frequency-domain analysis) offers the advantage of separating the sympathetic and parasympathetic influences so that each can be studied separately. Higher frequency variations in RR interval reflect parasympathetic influence almost exclusively whereas lower frequency components are influenced by both sympathetic and parasympathetic activity.lss-lsO CARDIAC
CATHETERlZATION
We perform cardiac catheterization and coronary angiography in nearly every sudden death survivor. In the patient with coronary disease the need for concomitant surgical revascularization will have a bearing on management of the patient’s arrhythmia. The risk of defibrillator implantation or map-guided surgical resection is more readily assumed if the patient requires bypass surgery as well. On the other hand, patients who do not need concomitant revascularization or who cannot be adequately revascularized may be evaluated more intensively for medical therapy. We perform angiography in the younger sudden death survivors to exclude the presence of congenital coronary artery anomalies associated with sudden death in this age group. Although performed principally for the determination of coronary anatomy, a large amount of additional information may be obtained at catheterization that is of value in the comprehensive management of the patient. In some instances the catheterization merely confirms the results of noninvasive studies. Thus LV function, wall motion abnormalities, and the presence and severity of valvular disease can be assessed. Although not of direct benefit in arrhythmia management, determination of left and right ventricular filling pressures may be useful in the titration of therapy for heart failure, which many of these patients experience. ELECTROPHYSIOLOGIC
TESTING
Just as catheterization and angiography are necessary to define treatment options in the patient with coronary disease, invasive EP testing is essential in the determination of potential therapeutic alternatives in patients with malignant arrhythmias. Patients with inducible arrhythmias at baseline EP study can be considered for EPguided serial drug testing. Clinically relevant arrhythmias at EP study in this patient group include sustained (>3O set) monomorphic VT or the induction of polymorphic or monomorphic VT or VF with hemodynamic collapse manifested by hypotension with loss of consciousness (Fig 8). Considerable controversy still exists regarding the optimal EP protocol to use in the evaluation of sudden death survivors. The tradeCurr
Probl
Cardiol,
November
1992
729
AG
FIG 8. Surface leads I, Ii, III and V, and intracardiac ECGs from the high right atrium (HRA) and right ventricular apex (WA) with intraarterial blood pressure (BP) recording from a patient with a history of recurrent syncope, right bundle branch block and left anterior hemiblock. After a ventricular paced drive run (S, S, of 500 ms-120 beats per min), two ventricular extrastimuli (S, S,) are introduced that induce a right bundle branch morphologic ventricular tachycardia at a cycle length of 270 ms (220 beats per min) with AV dissociation. Also note the marked decrease in BP during the tachycardia. (From Naccarelli GV, Med C/in N Am, 1984;68:1211- 1230. Used with permission.)
off involved in selection of stimulation protocol is the desire to achieve a high rate of inducibility on the one hand while minimizing the induction of poorly reproducible, nonclinical responses on the other. The issues involved in this controversy were more relevant before strategies using implantable defibrillators were developed for noninducible patients. The protocol we use is outlined in Table 4. From 60% to 90% of patients surviving sudden death unassociated with acute MI are inducible at baseline EP study (Table 5).40-44,1s1 Differences among the various reported series in this regard probably reflect the different stimulation protocols used and the inclusion of nonsustained ventricular tachycardia as an endpoint by some investigators but not by others. In general, the likelihood of arrhythmia induction is higher in patients with coronary disease than in patients with other disease processes (Table 5). Unfortunately, few disease-specific series of sudden death survivors using EP testing 730
Curr
Probl
Cardiol,
Nowmber
1992
TABLE 4. Electrophysiology
Protocol
horn
University
of Texas
(Houston)
1. Recording of spontaneous intervals 2. Assessment of sinus node function: sinus node recovery assessed at multiple pacing cycle lengths (600 ms, 500 ms, 400 ms) 3. Assessment of AV nodal function: incremental atrial pacing and atrial extrastimulus techniques 4. Assessment of VA conduction: incremental ventricular pacing and ventricular extrastimulus techniques 5. Assessment of ventricular function: ventricular extrastimuli at multiple pacing cycle lengths (600 ms, 500 ms, 400 ms) 6. Tachycardia induction: double and then triple extrastimuli at two right ventricular pacing sites and at three paced cycle lengths 7. In selected patients: left ventricular pacing or pacing during isoprotemnol infusion AV = atrioventricular;
VA = ventriculoatrial.
have been reported. One exception is a recent report by Fananapazir and Epstein”’ of 30 sudden death survivors with HCM. Seventy percent of these patients had inducible sustained arrhythmias, principally polymorphic VT, using a protocol that used LV and right ventricular stimulation. In other experiences, including our own, the induction of sustained VT or VF in this group of patients is much less.lg3 Patients with idiopathic VF also have sustained arrhythmias induced in 70% of cases.lW From 47% to 68% of patients with DCM and symptoms related to arrhythmia have sustained arrhythmias induced at EP study.1g5-1g7 These series are not limited to sudden death survivors but include patients who have sustained VT without hemodynamic collapse, syncope, and sometimes even patients with symptomatic nonsustained tachycardia. Patients with the long QT syndrome represent the one group in which invasive EP testing may not be as usefuL1” These patients seldom have inducible arrhythmias. This may relate to the relatively unique mechanisms of arrhythmia operant in this disease an&or the inability to reproduce the autonomic milieu necessary for arrhythmogenesis in these patients in the EP laboratory. The use of intracardiac monophasic action potential recordings with provocative adrenergic challenge may be useful in these patients.l”’ ‘O” Localization and functional characterization of the accessory pathway(s) are the goals of EP study in the unusual patient with WPW who presents with rapid atrial and/or ventricular fibrillation and survives cardiac arrest. The response to programmed stimulation of sudden death sun+ vors in the drug-free state has important prognostic implications. Patients with inducible VT or VF at baseline study have more arrhythmia recurrences and fatal arrhythmia recurrences than patients who are noninducible. Freedman et aLzol found a 41% rate of arrhythmia recurrence at 1 year in inducible patients, whereas only Curr
Probl
Car&of,
November
1992
731
Wilbera Total
1
.-
Moradf Benditt4’
166 242
45 31
119 58 117
Roy40 Sale& Total
zii
2
N
Rs in Study
of Ventricular
Author
Inducibility
TABLE 5.
180 125
35 20 (67) (751
(78) 164)
Both
(76)
B. Studies
Using
Coronary Disease
(71) (571 (67)
n
in Series
A. Studies
85 33 118
Arrhythmias
62 41
10 11
and
(26) (25)
(22) (36)
Symptomatic
(29) (43) (33)
(WI
by Serial
72 37 109
N
Total Inducible
Arrhythmias
192 131
34 27
Nonsustained
Treated
Sustained
Survivors
Inducible
Death
Other Heart Disease
34 25 59
n
Only
Sustained
Using
of Sudden
(79) (791
176) (87)
Arrhythmias
(61) 641 (62)
(961
pts
as Endpoints
Electruphysiologic
147 102
27 18
as Endpoints
56 25 81
n
Coronary Disease Inducible
Study
182) (82)
177) (90)
(66) (76) (69)
1%)
45 29
7 9
16 12 28
n
Other Disease Inducible
(72) (71)
(70) (82)
(34) (481 (47)
(76)
14% of noninducible patients suffered recurrent arrhythmias in the same time frame. Kron et alzo2 found a similarly low probability of recurrence in noninducible patients. However, Sager et alzo3 reported an actuarial rate of recurrent sudden death in noninducible patients of 30% at 1 year. Patients without LV dysfunction (EF < 40%), frequent ventricular ectopy (>lO PVCs/hour), or the diagnosis of DCM had a much better prognosis than patients with these characteristics (Fig 9) .‘03 Baseline EP study is performed in the drug-free state whenever feasible. Patients with frequent arrhythmias are monitored carefully in the coronary care unit as therapy is withdrawn at least five halflives before study. Occasional patients (less than 5%) have so frequent or incessant tachyarrhythmias that drug-free study becomes impossible. These patients are studied on active therapy, but the results must be evaluated cautiously. A noninducible patient in this setting does not have the same prognosis as an inducible patient rendered noninducible by an appropriate therapeutic agent because they may not have had arrhythmia induced at baseline study. Although we perform invasive EP testing in nearly every survivor of sudden death unassociated with acute MI, EP testing of patients in
I
1
p - 0.002
LVEF < 0.40 and PVC’S > 1 O/hr (n = 6)
LVEF > 0.40 PVC?s”Z Whr (n=.20
FIG 9. Effect of ejection fraction and frequent PVCs on the probability of recurrent cardiac arrest in “noninducible” patients. (From Sager PT, Choudhary R, Leon C, et al: The long-term prognosis of patients with out-of-hospital cardiac arrest but no inducible ventricular tachycardia. Am Heart J 1990;120:1334-1342.) Curr
Probl
Cardiol,
November
1992
733
high-risk groups who have yet to experience an episode of sudden death remains controversial. Several reports have described the results of EP testing in the post-MI population.2”-21z Most have found the results of EP testing in the patient without coml$ications after MI to be poorly predictive of late sudden death?05j 06,‘OS8‘Og Most studies that have indicated a prognostic role for EP testing after MI have limited testing to higher risk groups (e.g., patients with congestive heart failure or bundle branch block).’ 6, ‘1X Even in these groups, routine clinical use of EP study depends on the development of strategies that can be demonstrated to reduce risk and prolong survival. Patients with nonsustained VI on AECG monitoring after MI represent a particular1 high-risk group that has been subjected to study. Buxton et al. Kl3 found that 45% of patients in this group had inducible sustained arrhythmias. A larger retrospective study, reported by the Philadelphia Arrhythmia Gro~p,‘~~ found sustained arrhythmias inducible in 35%. In a study reported by Wilber et al.‘15 that included only post-MI patients with EFs circulatory arrest with cardioplegic solutions may hinder the reinduction of tachycardia intraoperatively. The results of direct arrhythmia surgery for VT are excellent considering that these procedures are generally reserved for patients refractory to medical therapy. Operative mortality has ranged from 0% to 21% with an average of 12.4% .‘a The need for emergency surgery for intractable arrhythmias and presence of New York Heart Association (NYHA) Class III or lV heart failure symptoms are the major clinical variables associated with operative mortality.z88 Intraoperative factors that are associated with perioperative death include the inability to perform aneurysmectomy and the use of the encircling endocardial ventriculotomy.283’287 The efficacy of surgery as assessed by the inability to induce sustained arrhythmias at postoperative EP study averages 70% to 80%. COXES’has recently reported a reinducibility rate of only 2% in a series of 65 patients. Tachycardia associated with an inferoposterior infarction and multiple VT structures are associated with a higher probability of surgical failure.28s-2s1 Comparison of map-guided and visually guided procedures within the same institution indicates the benefit of intraoperative mapping.284 A trend toward higher cure rates is present in patients treated with wider endocardial resection as opposed to more localized proceduresW 746
Curr
Pmbl
Cardiol,
November
1992
Five-year survival for patients undergoing VT surgery ranges from series?&? In one series persistent inducibility at postoperative EP study was the only factor predictive of clinical recurrence of VT or sudden cardiac death.= Many patients who remain inducible postoperatively can be controlled medically by using regimens that were ineffective before surgery. The numbers of patients in this category are small, even when data are pooled. Medical suppression after surgical failure is associated with a favorable prognosis.288 Of the three major avenues of therapy for patients with ventricular arrhythmias-drugs, devices, and surgery-only surgery offers the opportunity for cure in the conventional sense. Many patients with ventricular arrhythmias require revascularization. The opportunity to address the arrhythmia directly at the time of revascularization is another appealing feature of the surgical approach. Surgery also offers the greatest opportunity for freedom from the pitfalls and sequelae of long-term use of antiarrhwic medications. In one recent comparison, 33% of patients required ant&rhythmic medication after map-guided surgery compared with 61% of patients who underwent implantation of automatic cardioverter defibrillators in the same institutions in the same time f&une.zs2 If success rates of 98% reported by Coti” and 96% reported by Krafchek et al?= can be reproduced in other institutions, the number of patients requiring medical therapy after surgery can be expected to be even lower. However, VT surgery has its own set of problems. Like serial drug testing, map-guided surgery is an option only in patients with inducible VT. Patients who have inducible VF or who are noninducible are not candidates for this approach. Patients inducible preoperatively in the EP laboratory may not be inducible intraoperatively. This occurs in up to 37% of patients undergoing VT surgery. This necessitates reliance on the preoperative map or changing to a visually guided surgical approach. The use of computerized multipoint mapping systems has shortened the time needed to perform intraoperative mapping. This facilitates mapping multiple morphologically different tachycardias and nonsustained arrhythmias; however, a finite period of monomorphic tachycardia is still required to map successfully. The surgical experience and technical expertise needed to use map-guided surgery have generally been concentrated at a few select referral centers. The significant perioperative mortality and surgical failure rate are the other major drawbacks to the surgical approach. Most reported series of patients treated surgically for ventricular arrhythmias contain a paucity of sudden death survivors. Surgical results for this subgroup are seldom presented or analyzed separately. One exception is the series reported by Moran et alzs2 The surgical approach used in this study was map-guided extended sub33% to 70% in reported
Curr
Probl
Cardiol,
November
1992
747
endocardial resection. Results for 17 patients whose presenting arrhythmia was VF were analyzed separately. The surgical mortality and postoperative inducibility of this=nmp were similar to that of the group of 20 patients who had VT. Yee et alFg3 reported the results of various surgical procedures-revascularization alone, endocardial resection alone, revascularization plus endocardial resection, defibrillator implantation, defibrillator implantation plus revascularization, and endocardial resection plus defibrillator implantation-in 62 sudden death survivors. In this nonrandomized study, endocardial resection with revascularization had a statistically increased perioperative mortality (22%) compared with the other surgical groups. However, late deaths were uncommon in the patients treated by endocardial resectionzg3 Thus, although surgical data on the treatment of sudden death survivors is far from conclusive, survivors with inducible VT are potential candidates for endocardial resection. Factors that augur for the surgical approach include the need for concomitant mvascularization or other open heart procedure, failure of medical therapy in patients with frequent episodes of arrhythmia, presence of a resectable discrete aneurysm, and preservation of function of the nonaneurysmal wall. In patients without discrete aneurysms, global LV function must be well preserved if endocardial resection is to be performed. Multiple morphologically different tachycardias and poor LV function remain the most significant relative contraindications.
ReVASCtJLARWATION
ALONE IN SUDDEN
DEATH
SURVIVORS
The effect of revascularization alone on the risk of recurrent arrhythmias in sudden death survivors is a subject of considerable controversy. In experimental preparations, the combination of acute ischemia and scar from previous infarction is more arrhythmogenic than ischemia or scar alone?“-22 Thus revascularization without concomitant direct arrhythmia surgery may be expected to have an impact on arrhythmia recurrence and subsequent sudden death. In a study reported by Tresch et al.,‘= 6 of 49 (12%) sudden death survivors treated with revascultiation alone had fatal arrhythmias during a mean follow-up of 55 months. The annual rate of recurrence of sudden death is well below the 10% to 20% per year risk reported in a series of sudden death survivors. However, 35% of the patients in this study experienced sudden death preoperatively in the setting of acute infarction and would be expected to have a relatively low probability of recurrence.294 Of 11 sudden death survivors treated with revascularization alone in the report by Yee et al.,2g3 2 (18%) had arrhythmia recurrences during an unspecified length of follow-up. 748
Curr
Pmbl
Car&of,
November
1992
Garan et alzs5 performed EP studies before and after coronary artery bypass procedures in 17 patients with a history of sudden death or VT resulting in syncope. Preoperatively, 15 of 17 (88%) patients had inducible arrhythmias. Postoperatively, only six patients remained inducible while one additional patient experienced spontaneous occurrence of VI’. The authors concluded that revascularization did have an impact on the arrhythmia substrate but that a significant number of patients had inducible arrhythmias despite bypass surgery.2g5 Interpretation of the results of this study is complicated by the fact that nonsustained VT was regarded as a positive response to programmed stimulation. Most of the patients who remained inducible after surgery were in the nonsustained group. Only one patient studied had a clinical recurrence of arrhythmia. All four patients with inducible VP preoperatively were noninducible postoperatively. These initial observations on the effect of revascularization alone on the results of EP study and recurrence of arrhythmia were recently expanded bz6the report of a larger group of 50 patients from the same center. Thirty-three of 41 patients (80%) studied preoperatively without medication had inducible arrhythmias. Only 19 of 42 (45% 1 patients studied postoperatively were inducible. In this study, only sustained VT and VF were considered to be positive responses. Again noted patients with inducible VP preoperatively were rendered noninducible by revascularization alone. In contrast, 80% of patients with VT induced preoperatively remained inducible after surgery. During a mean follow-up of 39 months, four arrhythmic events occurred, three unassociated with acute infarction. Two of the three events occurred in patients who remained inducible postoperatively, and the third occurred in a patient who was noninducible postoperatively.2v6 In contrast to the results of Garan et al. and Kelly et al. is the finding of inducibility of VP in two of seven sudden death survivors after bypass surgery reported by Kron et al?07 Three patients, including the two with inducible VP postoperatively, had recurrences of VF in the perioperative period. These authors concluded that the results of revascularization in patients with VF are much less predictable than previously thought and recommended full postoperative EP evaluation before hospital discharge.‘07 The following conclusions regarding the effects of revascularization on risk of recurrence of sudden death appear reasonable based on the available data: (1) revascularization alone probably reduces the likelihood of a recurrence of sudden death, (2) the magnitude of the reduction in risk is impossible to determine based on available data, and (3) revascularization alone is ineffective in preventing recurrences of arrhythmia in sudden death survivors with inducible VT. Indirect surgical procedures have a role in the treatment of sudCurr
Probl
Cardiol,
November
1992
749
den death survivors other than patients with coronary disease. High thoracic left sympathectomy is the treatment recommended for patients with the congenital long QT syndromes who remain symptomatic after treatment with ~-blockers.2s8 Aortic valve replacement in symptomatic patients with severe aortic stenosis makes a favorable impact on total mortality. Presumably part of the reduction in total mortality is due to a reduction in sudden death mortality. The impact of myectomy/myotomy procedures on sudden death mortality in patients with HCM has not been assessed. In patients with refractory arrhythmias and severe ventricular dysfunction, heart transplantation may be the only therapy that offers the possibility of longterm survival. AUTOMATIC IMPLANTABLFJ CARDIOVl3RTER-DEFIBRILLATORS
Since the implantation of the first automatic implantable defibrillator in 1980, the number of devices implanted each year has increased. Since Food and Drug Administration (FDA) approval and commercial availability of automatic implantable defibrillators with synchronized cardioversion capability (AICD) in 1985, the increase has reached geometric proportions (Fig 13).“’ The rapid rise in popularity of this mode of therapy is, in part, due to a measure of frustration with the conventional medical and surgical approaches to the treatment of patients with malignant arrhythmias. The increase in popularity of device-related therapy is also a tribute to the ease with which this therapy can be applied and to the rapid pace of technical advancement in the areas of automatic arrhythmia detection and termination made possible by microprocessor technologv. Device-based therapy, however, has its own set of pitfalls and is not appropriate for all patients. Full knowledge of the risks and benefits of AICD therapy is requisite for successful application of this modality. AICDs are implanted through one of three surgical approaches. Electrode placement using a spring electrode in the superior vena cava and a patch electrode applied to the heart has been supplanted by patch-patch systems because of superior defibrillation thresholds is used for pa(DFI’) with the latter approach.300 A left thoracotomy tients who have had prior surgery through median sternotomy. This approach avoids the need to perform extensive dissection of adhesions resulting from the prior operation. Patients who have not had prior surgery and who do not require concomitant cardiac surgery are usually implanted through a subxiphoid incision. Patients implanted through this approach have shorter recovery times than patients implanted by sternotomy or thoracotomy.301’ 302 Median sternotomy is reserved for patients requiring concomitant revasculariza760
Cum
Probi
Cardiol,
November
1992
1980198119821983198419851986198719881989 NnOOOO+ FIG 13. Growth in AICD implants over a IO-year period. AID = automatic implantable defibrillator; AICD = automatic implantable defibrillator with synchronized cardioversion capability. (From Nisam et al: ICD Clinical update: First decade, initial 10,000 patients. PACE 1991 ;14:256. Used with permission.)
tion and/or valve replacement. Median sternotomy is also used in those cases in which intraoperative testing indicates that satisfactory positioning of the rate-sensing electrodes or morphology-sensing defibrillator patches cannot be achieved from the subxiphoid approach. The patches are typically positioned over the anterior portion of the right ventricle and posterior left ventricle. The goal in establishing the patch positions is to avoid severely scarred myocardium and also to have as much viable myocardium as possible between the two patches. Positioning one patch over the right atrium through a mini-thoracotomy has been reported to be a successful alternative to median sternotomy when difficulty is encountered from the subxiphoid approach?03 Patches may be placed within the pericardium or extrapericardially. The rate-sensing electrodes are positioned over the diaphragmatic portion of the right ventricle or the lateral wall of the left ventricle, depending on the surgical approach. In contrast to the patches, the object of positioning the rate-sensing leads is to place them as close together as possible to minimize sensing interference from extraneous signals. Once positioned, the adequacy of placement of patches and leads is checked by both Curr
Probl
Cardiol,
November
ICI%?
761
pacemaker system analyzer and intracardiac electrogram recording. The importance of intraoperative testing using an external cardioverter defibrillator before device implantation has been demonstrated by Winkle et a1304 and Marchlinski et a1305 Cooperation and communication among the implanting surgeon, anesthesiologist, and electrophysiologist are requisite to a successful result. The goal is a safety factor of two or greater between the DFT and the maximum output of the implanted device. On occasion, we are forced to settle for a safety margin of only 10 joules (DFI of 20 joules in a 30joule device). This appears to be adequate for long-term device efficacy. 305 We use alternating current applied to the heart by means of temporary pacing wires to induce VF. Induction of VF is requisite in our opinion because the amount of energy necessary to terminate monomorphic VT is substantially less than the amount required to defibrillate the heart. Lead the patch placement in sudden death survivors should be tested under a worst case scenario. Measures that may be taken when DFTs are unacceptably high include reversing the polarity of the patches, moving one or both patches in an effort to encompass more of the viable myocardium, using larger patches, an&or resorting to a higher output device. Only after satisfactory DFIs have been demonstrated is the device implanted. Most devices are placed in the abdominal wall. Recently, a technique for incorporation of the device in the bony thorax has been described?06 After the device is connected to the rate-sensing leads and morphology-sensing defibrillator patches, the device is activated and programmed to the test mode. This blinds the device so that ventricular arrhythmia can be induced again. The device is then unblinded and successful tachycardia detection and termination by the implanted device is verified. The value of routine postoperative testing is a subject of ongoing controversy, although more uniform agreement exists regarding postoperative testing in patients placed on antiarrhflhmic medications between implantation and hospital discharge. Medication-related change in tachycardia cycle length often necessitates reprogramming the rate at which the device is triggered. The latest generation of devices commercially available has several programmable features. Programmable features include tachycardia detection criteria, tachycardia detection rate cutoff, first-shock energy, and first-shock delay. Tachycardia detection criteria include rate and probability density function (PDF). PDF takes advantage of the fact that the ECG signal during VF fluctuates minimally about the isoelectric level. Patients in supraventricular rhythms have larger amplitude fluctuations, and the amplitude of the signal at any moment in time is less likely (probable) to be at or near the isoelectric level. Although PDF successfully discriminates between most supraventricular rhythms and VF in most instances, it is less success762
Cur-r Probl
Cadiol,
November
1992
ful in differentiating VI from less dangerous rhythms. In some instances VT must degenerate to fibrillation before PDF criteria are satisfied. Because VT is more easily terminated than fibrillation, this delay may prevent successful arrhythmia termination. As a result, we routinely leave PDF programmed to the off position and rely on ratedetection criteria alone. Although this prevents delay in therapy for ventricular arrhythmias, it enhances the probability for shocks during supraventricular arrhythmias. The purposes of a programmable first-shock energy are to minimize patient discomfort and prolong generator longevity in patients whose clinical arrhythmia is VT. Many tachycardias can be terminated with energies of 1 joule or less. Subsequent shocks at full energy will rescue the patient if the initial low-energy shock is not successful. However, in our experience low-energy shocks are still perceived by patients as quite painful, Since the likelihood of successful arrhythmia termination depends on the duration of the arrhythmia, unsuccessful shocks are to be avoided. A several-fold safety margin for VT should be assured before the first-shock energy is programmed to a lower value. First-shock delay can be prolonged to allow the patient to lose consciousness before shock delivery. Again, because of concern of making the arrhythmia more difficult to terminate by delaying the initial shock, we seldom reprogram delay above the minimum value. Current technology mandates a period of 6.5 to 9 seconds for charging capacitors. This, coupled with a detection time that varies depending on the cycle length of the tachycardia (more rapid rhythms satisfy the detection algorithm more quickly), brief synchronization period, and the first-shock delay lead to a minimum time from the onset of arrhythmia to delivery of the first shock of 10-15 seconds. Subsequent shocks are governed by the detection algorithm and time required to recharge the capacitors: there is no additional delay. With current devices, five shocks can be delivered for a single episode of arrhythmia. The AICD is spectacularly successful from the standpoint of prevention of sudden death. In the largest single series reported to date, Winkle et a1307 reported an actuarial sudden death mortality rate of 4.4% in 5 years (Table 7). Data on 9,807 patients recently compiled by Cardiac Pacemakers, Inc. (St. Paul, Minnesota) also indicate an actuarial sudden death rate of 4.5% at 5 yearszgg Smaller series, however, report 5-year sudden death mortality in the 20% to 25% range.308, 3og Furthermore, sudden death rates may overstate the benefits of AICD therapy because operative deaths and nonsudden arrhythmiarelated deaths are not included in the sudden death calculation. The importance of arrhythmia-related nonsudden death was tirst stated by Guarnieri et al1 The term ‘total arrhythmic death” has been coined by Kim et aI?*’ to refer to the sum of perioperative deaths, arrhythmia-related nonsudden death, and sudden deaths. Curr
Probl
Cardid,
November
1992
763
TABLE 7. Kaplan-Meier
Actuarial
Mortality
Rate in 270 Patients
1 Year (n = 188) Sudden death Cardiac (nonsudden) death All cardiac deaths Total Reprinted ofcardiology,
with permission
2 Years In = 113)
3 Years In = 69)
4 Years In = 51)
5 Years fn = 12)
0.9% 6.2%
3.1% 13.0%
4.4% 13.9%
4.4% 15.3%
4.4% 20.3%
7.0% 7.7%
15.6% 16.3%
17.8% 18.4%
19.1% 19.7%
23.8% 26.2%
fmm the American
College of Cardiology
~Jour’nal
of rhe American
College
1989;13:1354-13611.
Actuarially determined freedom from sudden death in their series was 92% at 3 years. Freedom from total at-rhythmic death was only 85% at 3 years. At the b-year mark, actuarial survival was 76% for sudden death and 70% for total arrhythmic death.31o Operative mortality is a major determinant of the difference between sudden death rates and the rate of total arrhythmic death. This varies from 1% to 1.5% in some reports to 5% or more in others.307~310-312 The need for concomitant surgery is probably the factor that most consistently makes an impact on perioperative mortality.2gg Thus inclusion of all perioperative deaths in the total arrhythmic death category would appear to overstate the risk of AICD implantation. The true indication of the benefits of the AICD would appear to be somewhere between the actuarial survival free from sudden death and survival free from total arrhythmic death. There are no prospective randomized data comparing the results of AICD therapy with those of serial drug testing or direct arrhythmia surgery. Direct-comparison studies are difficult to perform because patients without inducible arrhythmias are not candidates for either serial drug testing or arrhythmia surgery. On the other hand, the results of EP study have little bearing on the use or benefits of AICD-based treatment.311 In the retrospective studies by Yee et alFg3 and Elefteriades et aLzg2 long-term survival in patients treated by endocardial resection with or without revascularization was equivalent to survival in patients having AICD implantation with or without revascularization. In a study by Fogoros et aL312 use of an early-generation defibrillator in conjunction with amiodarone was superior to amiodarone alone in patients with sustained ventricular arrhythmias seen with loss of consciousness, The technical requirements and surgical expertise for AICD implantation are less than those for map-guided arrhythmia surgery. The operative mortality for AICD implantation with revascularization is less than the average figure for endocardial resection. However, antiarrhythmic drug therapy is required in up to 70% of patients re754
Curr
Probl
Cardiol,
November
1992
ceiving defibrillators versus 20% to 30% of patients who have resection. Although drugs are often necessary, the intensity of drug therapy is often lower than in patients undergoing EP-guided therapy because the goal of therapy is a reduction in the frequency of discharges and not total suppression of the arrhythmia. Multidrug regimens and more toxic agents can usually be avoided. Device-based therapy is not without peril. Surgical complications are rare but quite serious when they do occur. The effects of antiarrhythmic drugs on defibrillation thresholds must be considered before the prescription of an antiarrhythmic agent. The Ic agents reportedly have the most marked effect on DFTs, but the effects of many drugs are incompletely characterized.313-315 The interactions between pacemakers and AICDs are even more complex (Table 8)?16 Because 10% of patients receiving defibrillators require permanent pacemakers as well, these interactions represent a common clinical problem. Unnecessary shocks are a painful nuisance. Device-based therapy is expensive. Some of the problems of AICD therapy will be overcome as further improvements in device design occur. The incorporation of antitachycardic pacing, bradycardiac pacing, and cardioversion-defibrillation capabilities in the same device will address several of the problems. Pacemaker interactions should be minimized because all functions would be controlled by the same logic circuitry. Antitachycardic pacing should reduce the need for concomitant medical therapy in selected patients. Improved telemetry and storage of diagnostic data should enable the number of spurious discharges to be reduced. However, the need for antiarrhythmic drug therapy may increase in some patients in an attempt to slow rapid VTNF to a hemodynamically stable VT so that pacing reversion can be attempted. Development of new patch and electrode designs is important to eventual reduction in the size of the implanted device. A device that can be implanted routinely without a thoracotTABLE 8. Adverse
Device
Interactions
in Patients
With
Pacemakers
Interaction
Result
Pacemaker dysfunction: failure to sense after AICD discharge Double counting: pacemaker artifact and wave counted separately by AICD AICD sensing pacemaker artifact during VIorVF Pacemaker repmgrammlng by AICD discharge
Post-shock
*Adapted from Calkins et al?16 AICD = automatic implantable defibrillator with ular tachycardia; VF = ventricular fibrillation.
Cur-r Pmbl
Cardiol,
November
1992
It
and AICDs”
bradycardia
or asystole
Inappropriate
discharges
Inappropriate
failure
Pacemaker
synchronized
reversion
cardioversion
by AICD of AICD
to backup
capabiiity;
to discharge mode
VI = ventric-
756
omy would have a major impact on patient acceptance and the total cost of device-based therapy. The effects of the AICD on total mortality are more modest than the effects on sudden death mortality. Five-year actuarial sutvival in patients after implantation is only 73.8% in the Winkle series (Table 7).307 Survival is worse in those patients who receive discharges than in those who do not.317 Most late deaths in reported series are due to progressive myocardial dysfunction. Luceri et a1318 have reported that a significant number of the late follow-up sudden deaths are due to electromechanical dissociation and not intractable ventricular arrhythmias. This reflects progressive myocardial disease after implantation. Progressive myocardial dysfunction makes care of the AICD patient complex and time-consuming. These patients require frequent medication adjustments and close monitoring. They often have special psychological needs that also must be met. THE ECONOMICS
OF SUDDEN
CARDIAC
DEATH
The current climate in medicine is marked by the prevalence of new technologies in many areas of practice and by appropriate concern for the escalation of health care costs that are inherent in the use of many of these technologies. In few areas are these issues brought more sharply into focus than in the care of the sudden death survivor. Empiric antiarrhythmic therapy is relatively inexpensive but also ineffective. Device-based therapy, antiarrhythmic surgery, and pharmacologic therapy guided by EP study are all expensive. Even very expensive therapies for uncommon conditions contribute little to the overall cost of health care delivery. Unfortunately, sudden cardiac death afflicts hundreds of thousands of patients each year. Allowing for those events occurring during an episode of infarction and the fact that only 15% to 25% of patients who experience sudden death will be successfully resuscitated and survive to hospital discharge, still many thousands survive sudden death experiences annually and are candidates for the expensive therapies described in the previous section. Because of the large number of patients affected, relative differences in the costs of different therapies are important. O’Donoghue et a131s have published data comparing the initial hospitalization cost of serial drug testing and defibrillator implantation as initial therapy after baseline EP testing (Table 9). Cost of hospitalization was calculated from the date of baseline EP study to the date of discharge and included costs of implanted devices. The authors concluded that early defibrillator implantation was no more costly than serial drug testing. Patients inducible at baseline EP study rendered noninducible by medical therapy had 756
Curr
Probl
Cardiol,
November
1992
TABLE 9. Hospital
Stay
and Costs
in the Patient Group I (direct AICD)
No. of patients No. of drugs No. of EP studies Hospital stay (days) cost (X $1,000) *Reprinted
Groups’ Group II (EP-guided therapy)
7 1.4 -+ 1.2 1 12.6 k 6.2 40.4 k 8.3
with permission
ti-om the American
3.3 3.0 202 48.9
32 2 * + f
1.2* 1.0* 9.3 31.6
Group IIA Idrug) 3.0 2.6 12.0 17.2
12 k 1.4t +- 0.90 2 6.25 + 9.598
Group IIB (late AICD) 3.5 3.3 26.3 73.4
College of Cardiology
~Journal of the American
with
cardiovenion
20 2 f 2 k
1.1* 1.04 5.8* 17.01 College
ofcardiology199o;16:1258~.
tP < 0.05 compared with group I. *P < 0.001 compared with group 1. §P < 0.001 compared with group IIB. AICD = automatic implantable defibrillator electmphysiologic
synchronized
capability;
EP =
substantially lower total costs than patients who received defibrillators.31s Total costs were highest in patients inducible at baseline EP study who failed serial drug testing and subsequently underwent device implantation. Thus a treatment allocation strategy restricting serial drug testing to those patients with greater likelihood of responding to pharmacologic therapy could be the most cost-effective. Although the cost of the initial hospitalization is but one aspect of the total cost of the ongoing care of the sudden death survivor, the importance of being able to predict with reasonable accuracy who will respond to antiarrhythmic drugs and who will not is evident. This would appear to remain a fruitful area for future investigation. Kuppermann et aL3” have published an elegant analysis of the cost-effectiveness of therapy with the implantable defibrillator. Using data from a variety of sources supplemented by the opinions and estimates of a panel of experts, these investigators calculated the incremental benefit of defibrillator therapy in comparison to medical therapy under a variety of different scenarios. The total life expectancy of a defibrillator patient was determined to be 5.1 years, whereas the life expectancy of a patient treated medically was 3.2 years (incremental benefit of 1.9 years). The incremental cost incurred to accrue this benefit was estimated to be between $15,000 and $25,000 per life-year saved. Cost of initial hospitalization for patients with defibrillators was determined to be $49,830 (1986 dollars) and total expected cost for the lifetime of the defibrillator patient, including generator replacement and concomitant medical therapy, was estimated to be $121,540 (average of $23,800 per annum). The cost per life-year saved for implantable defibrillator therapy was compared with a number of health care interventions and costeffectiveness of defibrillator therapy compared favorably with therapies like heart transplantation or chronic dialysis (Table 10)?” This Curr
Probl
Cardiol,
November
1992
767
TABLE 10. Cost per Year
of Life Saved
for Some
Health
Investments”” Cost
Investment Neonatal intensive care (weight l,OOO-1,499 g) Coronary artery bypass surgery (three-vessel disease) Thyroxine (T,) thyroid screening Treatment of seven? hypertension (diastolic 105 mmHg) in men aged 40 years Implantable defibrillator Treatment of mild hypertension (diastolic 95-104 mmHg1 in men aged 40 years Heart transplantation Estrogen therapy for postmenopausal symptoms in women without a prior hysterectomy Neonatal intensive can? (weight 500-999 g) Coronary artery bypass surgery for one-vessel disease with moderately severe angina School tuberculin testing pmgram Continuous ambulatory peritoneal dialysis Hospital hemodialysis Data reproduced 8191-100.
with
Copyright
permission 1990 American
fmm
Kupperman
Heart
M, Lute
BR, McCovem
per Life-Year Saved I%) 5,500 7,200 7,700 11,000
17,400 23,200 26,900 32,900 38,800 44,200 53,100 57,300 59,500 8, et al. Circulation
1990;
Association.
study has been criticized for perhaps overestimating the incremental benefit of defibrillator therapy.321 However, the importance of this type of analysis can not be overstated. A major question facing medicine and society at this juncture is not only whether a therapy or technologic advance is effective in prolonging life but also how many of these life-saving therapies we can afford. Despite the enormous sums of money involved, care of the sudden death sutivor is a money-losing venture for many hospitals. In patients receiving defibrillators, reimbursement by Medicare for the entire hospitalization is little more than the cost of the device alone in some instances. Clearly a need exists to establish equitable reimbursement guidelines if effective therapy for sudden death survivors is to remain within the reach of most Americans. Concomitantly, ways to reduce the cost of the care of these patients must be sought. Few breakthroughs are on the horizon that will make an impact on the cost of serial drug testing or antiarrhythmic surgery. On the other hand, costs of device-based therapy will be reduced by greater device longevity and by the development of devices that can routinely be implanted without the need for a thoracotomy. Availability of multiple devices from competing manufacturers also may make an impact on those aspects of care directly related to the device. Responsibility for reducing the cost of care without sacrificing the quality of care must rest with a partnership among physicians, hos768
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November
1992
pitals, governmental agencies, commercial insurers, and manufacturers and suppliers of health-related products. If the economic consequences of caring for the sudden death survivor are substantial, the financial implications of prophylactic therapy for patients at high risk are even more so. The low survival rates of patients experiencing initial episodes of sudden death indicate that prophylactic therapy is requisite to make a major impact on the overall cardiac sudden death problem. Considerable resources are already expended in risk-stratification procedures and treatment of the post-MI patient. Prospective studies are underway to identity patients who may benefit from device therapy or EP-guided therapy. If these studies demonstrate efficacy of these approaches in selected subgroups of patients, the expense of caring for the patient at risk for sudden death will rise accordingly. b R.C. domized
A need exists for a prospective carefully designed, study of the cost-effectiveness of implanted AICD devices.
SCHLANT:
large,
ran-
CONCLUSION
Significant changes have occurred since the first issue of Current Problems in Cardiology dealing with sudden cardiac death, which was published in 1980 by Lown and colleagues.322 At that juncture, EP-guided therapy was in its infancy, limited experience with mapguided arrhythmia surgery had been published, and the first human implant of an automatic defibrillator had not been performed. The past 12 years have produced a revolution in technology that has been brought to bear on the problem of sudden cardiac death. Not all steps have been in the forward direction. Empiric use of antiarrhythmic agents to treat patients at risk for sudden death or the sudden death survivor (the norm of medical practice for a number of years) clearly was ineffective and potentially harmful. Although the arsenal of antiarrhythmic drug therapy is better stocked than it was in 1980, the toxicities and low efficacy rates of many of these agents in patients with life-threatening ventricular arrhythmias have been clearly demonstrated. Nevertheless, three effective treatment modalities- EP-guided pharmacologic therapy, antiarrhythmic surgery, and AICD therapyhave evolved in a relatively brief time for treatment of the sudden death survivor. The availability of more than one form of therapy is key. Many patients are candidates for one approach and not others. Many patients prefer one approach over others. Many patients require combined modalities. What of the next 12 years? Certainly the rate of progress in this area of clinical medicine makes long-range forecasting ill-advised. On the other hand, short-range projections are probably acceptable. Evolution of the current therapeutic modalities will continue. The Curr
Pmbl
Cardiol,
November
1992
759
techniques of primary arrhythmia surgery are constantly being refined, but no major breakthroughs in this field are on the horizon. Surgical experience and technical expertise will remain the major factors responsible for the success of surgical techniques in carefully selected patients. Catheter ablation techniques, which have revolutionized the care of patients with supraventricular arrhythmias, have found a much more limited role in patients with ventricular arrhythmias.323-325 The area to be mapped is large, and simultaneous mapping of multiple points is not possible. Chemical, or ercoronary, ablation has not received widespread application.326J 3P’ The entire field of antiarrhythmic pharmacologSr is in a state of turmoil in the aftermath of the CAST study. Although the CAST trial is commendable for subjecting an important clinical question to a rigorous test, one of the unfortunate outcomes is that development of new antiarrhythmic agents has been curtailed significantly. One drug, encainide, has been withdrawn from the commercial marketplace altogether. Plans for further testing and market release of other agents have been abandoned. Although the efficacy of individual agents in patients with life-threatening arrhythmias is low, clinical usefulness is present in having a wide choice of agents for the patient with a life-threatening arrhythmia. Although the development of some new agents has been discontinued, other avenues for progress in the application of pharmacotherapy to the problem of sudden death have been opened. Ongoing investigations include the delivery of drug directly to the myocardium by implantable iontophoretic systems. These systems can potentially achieve myocardial levels of drugs unattainable with systemic therapy but with less systemic toxicity.32S Chemical defibrillation using a bolus of antiarrhythmic drug retroperfused into the coronary sinus at the onset of arrhythmia is another new application that is under investigation for both new and conventional antiarrhythmic agents.32g Device therapy is certainly still in an evolutionary phase. The expected release by the FDA of devices with bradycardiac pacing, antitachycardic pacing, and defibrillation capabilities is an important step. The importance of the development of devices that can be implanted without the need for major surgery has already been stated. Clinical trials with a number of nonthoracotomy devices are ongoing. Although observing the growth and maturation of existing therapeutic modalities is exciting, one still has a sense that all the current treatment modalities are somewhat lacking. All are expensive. All are invasive. Antiarrhythmic drug toxicity and surgical morbidity and mortality and economic considerations preclude the application of current techniques to many patients at increased risk for sudden death but who have not experienced an episode. The 760
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1992
need still exists for more creative thought. Clearly the need exists for more knowledge of the cellular and subcellular mechanisms of life-threatening arrhythmias. In our opinion the application of this knowledge will produce the next quantum advances in the clinical approach to sudden cardiac death. b R.C. SCHLANT: Dr. Gilman and Dr. Naccarelli have given us a splendid, detailed review of the current (and future) status of sudden-cardiac death, including its pathophysiology, its occurrence in many disease states, its clinical evaluation and current management, and economic considerations of the management of patients with the syndrome. Their review should be of great value to all cardiologists and to all other physicians who see patients who have experienced sudden cardiac death or who have a condition In which it is more likely to occur. Their superb review is well Illustrated and extensively referenced.
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gical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979,60:1430-1439. 281. Horowitz LN, Harken AH, Kastor JA, Josephson ME: Ventricular resection guided by epicardial and endocardial mapping for treatment of recurrent ventricular tachycardia. N Engl J Med 1980;302589-593. 282. Moran JM, Kehoe RF, Loeb JM, et al: Extended endocardial resection for the treatment of ventricular tachycardia and ventricular fibrillation. Ann Thorac Surg 1982;34:538-552. 283. Ostermeyer J, Borggrefe M, Breithardt G, et al: Direct operations for the management of life-threatening ischemic ventricular tachycardia. J Thorac
CardiovascSurg1987,%~8-865. 284. Swerdlow CD, Mason JW, Stinson EB, et al: Results of operations for ventricular tachycardia in 105 patients. J Thorac Cardiovasc Surg 1986,92:
105-113. 285. Kron IL, Lerman BB, Nolan SP, et al: Sequential endocardial resection for the surgical treatment of refractory ventricular tachycardia. J Thorac Cardiovaac Surg 1987;94:843- 847. 286. Krafchek J, Lawrie GM, Roberts R, et al: Surgical ablation of ventricular tachycardia: Improved results with a map-guided regional approach. Circulation 1986,73:1239- 1247. 287. Cox JL, Gallagher JJ, Ungerleider RM: Encircling endocardial ventriculotomy (EEV) for refractory ischemic ventricular tachycardia. IV. Clinical indications, surgical technique, mechanism of action, and results. J Thorac Cardiovasc Surg 1982;83%65-872. 288. Cox JL: Patient selection criteria and results of surgery for refractory ischemit ventricular tachycardia. Circulation 1989;793163-1177. 289. hey TD, Brady GH, Misbach GA, Greene HL: Surgical management of refractory ventricular arrhythmias in patients with prior inferior myocardial infarction. J Thorac Cardiovasc Surg 1985;89:369-377. 290. Hammon JW, Primm KR, Smith RF, et al: Indications for different modes of surgical therapy in medically refractory ventricular arrhythmias. Ann Surg 1986203679-684. 291. Kron IL, Lerman B, DiMarco JP: Surgical management of sustained ventricular arrhythmias presenting within eight months of acute myocardial infarction. Ann Thorac Surg 1986;42:13-16. 292. Elefteriades JA, Biblo LA, Batsord WP, et al: Evolving patterns in the surgical treatment of malignant ventricular tachyarrhythmias. Ann Thorac Surg 1990;49:94-100. 293. Yee ES, Scheinman MM, Grit& JC, Ebert PA: Surgical options for treating ventricular tachyarrhythmia and sudden death. J Thorac Cardiovasc Surg 1987;94:866-873, 294. Tresch DD, Wetherbee JN, Siegel R, et al: Long-term follow-up of survivors of prehospital sudden cardiac death treated with coronary bypass surgery. Am HeartJ 1985;110:1139-1145. 295. Garan H, Ruskin JN, DiMarco JP, et al: Electrophysiologic studies before and after myocardial revascularization in patients with life-threatening ventricular arrhythmias. Am J Caro!iol1983;51519-524. 296. Kelly P, Ruskin JN, Vlahakes GJ, et al: Surgical coronary revascularization in survivors of prehospital cardiac arrest: Its effect on inducible ventri-cular arrhythmias and long-term survival. J Am Co11 Cardiol 1990;15: 267-273. 297. Kron IL, Lerman BB, Haines DE, et al: Coronary artery bypass grafting in patients with ventricular fibrillation. Ann Thorac Surg 1989;4865-89. 77e
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Schwartz PJ: Long Q-T syndrome, in Horowitz LN ted): Current ManagePhiladelphia, B.C. Decker, 1991, pp 194-198. 299. Nisam S, Mower M, Moser S: ICD clinical update: First decade, initial 10,000 patients. PACE 1991;14255-262. 300. Troup P, Chapman P, Olinger G, et al: The implanted defibrillator: Relation of defibrillating lead configuration and clinical variables to defibrillation threshold. .I Am Co11Cardiol 1985;6:1315- 1321. 301. Watkins L, Mirowski M, Mower M, et al: Implantation of the automatic defibrillator: The subxiphoid approach. Ann Thorac Surg 1982;34515-520. 302. Lawrie GM, GrifIin J, Wyndham C: Epicardial implantation of the automatic defibrillator by left subcostal thoracotomy. PACE 1984;7:1370-1374, 303. Lawrie GM, Kaushik RR, Pacific0 A: Right mini-thoracotomy: An adjunct to left subcostal automatic implantable cardioverter-defibrillator implantation. Ann Thorac Surg 1989;47:780- 781. 304. Winkle R, Stinson E, Bach S, et al: Cardioversion defibrillation thresholds using a truncated exponential waveform and an apical patch-SVC spring electrode configuration. Circulation 1984; 69:766-771. 305. Marchlinski F, Flores B, Miller J, et al: Relation of the intraoperative defibrillator threshold to successful postoperative defibrillation with an automatic implantable cardioverter defibrillator. Am J Cardiol 1988,$2:393-398. 306. Hartz R8, Kehoe R, Frederiksen JW, et al: New approach to defibrillator insertion. J Thorac Cardiovasc Surg 1989,97:920-922. 307. Winkle RA, Mead RH, Ruder MA, et al: Long-term outcome with the automatic implantable cardioverter-defibrillator. J Am Co11 Cardiol 1989;13: 1353-1361. 308. Lehmann MH, Steinman RT, Schuger CD, Jackson K: The automatic implantable cardioverter defibrillator as antiarrhythmic treatment modality of choice for survivors of cardiac arrest unrelated to acute myocardial infarction. Am J Cardiol 1988;62:803-805. 309. Gross J, Zilo P, Ferrick K, et al: Sudden death mortality in implantable cardioverter defibrillator patients. PACE 1991;14250-254. 310. Kim SG,Fisher JD, Furman S,et al: Benefits of implantable defibrillators are overestimated by sudden death rates and better represented by the total arrhythmic death rate. J Am Co11 Cardiol 1991;17:587-1592. 311. Veltri EP, Mower MM, Mirowski M, et al: Follow-up of patients with ventricular tachyarrhythmia treated with the automatic implantable cardioverterdefibrillator: Programmed electrical stimulation results do not predict clinical outcome. J Electrophys 1989;3:467-476. 312. Fogoros RN, Fiedler SB, Elson JJ: The automatic implantable cardioverterdefibrillator in drug refractory ventricular arrhythmias. Ann Intern Med 1987;107:635- 641. 313. Mead RH, Ruder M, Schmidt P, et al: Improved defibrillation efficacy with chronically implanted defibrillation leads. Circulation 1986;74:11-110.Abstract. 314. Kadri N, Niazi I, Caceres J, et al: Electrical stability of chronically implanted lead systems in patients with automatic cardioverter defibrillators. Circulation 1987;9:%461. Abstract. 315. Chapman PD, Troup PJ, Wetherbee JN, et al: The implanted defibrillator: Defibrillation threshold stability over time. J Am Co11 Cardiol 1987;9:186A. Abstract. 316. Calkins H, Brinker .I, Veltri EP, et al: Clinical Interaction between pacemakers and automatic implantable cardioverter-defibrillators, J Am Co11 Cardiol
298.
ment of Arrhythmias.
1990; Curr
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16:666-673. Cardid,
Nwember
1992
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317. Zilo P, Gross JN, Benedek M, et al: Occurrence of ICD shocks and patient survivaLPACE 1991;14273-279. 318. Luceri RM, Habal SM, Castellanos A, et al: Mechanism of death in patients with the automatic implantable cardioverter defibrillator. PACE 1988;112015-2022. 319. O’Donoghue S, Platia EV, Brooks-Robinson S, Mispireta L: Automatic implantable cardiovertor-defibrillator: Is early implantation cost-effective? J Am Co11 Cardiol 1990;16:1258-1263. 320. Kupperman M, Lute BR, McGovern B, et al: An analysis of the cost effectiveness of the implantable defibrillator. Circulation 1990;81:91-100. 321. Bigger JT: Prophylactic use of implantable cardioverter defibrillator: Medical, technical, economic considerations. PACE 1991;14(2 part 2):376-380. 322. Lown B, Podrld PJ, De Silva RA, Graboys TB: Sudden cardiac death: Management of the patient at risk, in Harvey WP ted): Current Problems in Cardiology. St Louis, MO, Year Book Medical Publishers, 1980, IV(121, pp l-62. 323. Scheinman MM, Evans GT: Catheter electrical ablation of cardiac arrhythmias: A summary report of the percutaneous cardiac mapping and ablation registry in Brugada P, Wellens HJJ feds): Cardiac Arrhythmias: Where To Go From Here. Mount Kisco, NY, Futura Publishing, 1987, pp 529-538. 324. Stevenson WG, Weiss J, Wiener I, et al: Localization of slow conduction in a ventricular tachycardia circuit: Implications for catheter ablation. Am Heart J 1987;114:1253-1258. 325. Hartzler GO: Electrode catheter ablation of refractory focal ventricular tachycardia. J Am Co11 Cardiol 1983;2:1107- 1113. 326. Chilson DA, Peigh PS, Mahomed Y, et al: Chemical ablation of ventricular tachycardia in the dog. Am Heart J 1986;111:1113-1118. 327. Brugada P, de Swart H, Smeets JLRM, Wellens HJJ: Transcoronary chemical ablation of ventricular tachycardia. Circulation 1989;79:475-482. 328. Avltall B, Hare J, Lessila C, et al: Implantable epicardial iontophomtic drug delivery system. Circulation 1991;84:II-125. Abstract. 329. Cammilli L, Mugelli A, Grassi G, et al: Implantable pharmacological defibrillator (AIPhD): Preliminary investigation in animals. PACE 1991;14(2 part 2):381-386.
778
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Gerald V. Naccarelli, M.D., graduated from the Pennsylvania State University School of Medicine in Hershey, Pennsylvania. He completed his residency in internal medicine at the North Carolina Baptist Hospital in Winston-Salem, North Carolina. He received his cardiology fellowship training at the Pennsylvania State University College of Medicine and his training in cardiac electrophysiolosy at the Indiana University School of Medicine in Indianapolis, Indiana. Since 1981 he has been the Director of Clinical Electrophysiologv at the University of Texas Medical School at Houston, where he is currently Professor of Medicine and Vice-Chairman of the Division of Cardiology. His research interests include antiarrhythmic drug development, autonomic aspects of arrhythmogenesis, implantable devices, and radiofrequency catheter ablation. 888
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SUDDEN CARDIAC DEATH
INTRODUCTION
Few clinical entities are more difficult to study than the syndrome of sudden cardiac death. A number of inherent problems hinder understanding of this syndrome. Most significant of these problems is the lack of a consistent definition. Definition is seldom a problem for the clinician confronted with an individual patient. Sudden cardiac death is the “. . . unexpected cessation of breathing and circulation caused by an underlying heart disease.“’ However, the clinician and the epidemiologist define this syndrome differently. Epidemiologic studies typically define sudden cardiac death in terms of the time of death relative to the onset of symptoms or the physical location of the patient relative to hospital admission at the time of demise. Such definitions allow the gathering of data on large numbers of patients with a minimum of effort. However, these epidemiologic definitions contain no obligatory link to the pathologic cardiac states that form the substrate of sudden cardiac death. Definitions used in clinical studies have a more solid basis in pathophysiology but also are somewhat arbitrary. There may be no uniformly suitable definition. A second diiliculty is the diversity of cardiac conditions in which sudden cardiac death occurs. Although an estimated 80% of adult patients with sudden death have underlying obstructive coronary artery disease, sudden cardiac death is also a feature of the cardiomyopathies, hypertensive heart disease, and a variety of primary electrical disorders of the heart. Although sudden cardiac death may be the final common pathway in these varied states, the pathophysiology of sudden death may not be the same in all. Conclusions and generalizations based on a homogeneous population of patients with coronary artery disease may not be applicable to more heterogeneous populations. Indeed, among patients with coronary artery disease, the pathophysiology of sudden death in acute coronary syndromes may be quite different than in patients with chronic ischemic cardiomyopathy. A third problem is the dynamic nature of the factors that are postulated to precipitate sudden cardiac death in susceptible individuals. These factors include ischemia, abnormalities of potassium and Curr
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1992
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magnesium, variations in autonomic tone, and the effects of a number of medications. Some of these factors can be measured directly-like the serum levels of potassium and magnesium or the level of a medication in the blood. Ischemia can be assessed semiquantitatively in an indirect fashion by a variety of means. However, techniques to assess autonomic tone in vivo are only now being developed. Even when these tools are available, the ability to assess the relationship of these dynamic factors to the genesis of sudden cardiac death will be hindered by their transience and the brevity of the sudden death syndrome. Despite our understanding of the pathophysiology of sudden cardiac death being far from complete, the incidence of cardiac death has declined significantly in recent years. This decline extends to all racial and sexual divisions of the population and parallels a decline in the incidence of coronary artery disease.” 3 Nevertheless, sudden cardiac death afflicts 350,000 patients in the United States annually and is the leading cause of death in most Western societies. The health care costs attributable to sudden cardiac death are enormous. Thus every physician who cares for patients with heart disease and every primary care provider who professes to practice preventive medicine has a mandate to understand this essential clinical syndrome. Many reviews of the subject of sudden cardiac death focus primarily on the evaluation of the sudden death smvivor to the exclusion of the patient who is at high risk for, but has yet to experience, an episode of sudden death. This latter group is often dealt with as an entirely separate topic. Because division is artificial, we will discuss both groups since they represent different points on the clinical continuum of sudden cardiac death. This combination also acknowledges the fact that only about 20% of patients survive to hospital discharge after an episode of sudden death and that future treatment strategies will evolve toward prevention of the first episode.4’ 5 The terms sudden death and sudden cardiac death will be used interchangeably throughout this monograph for the sake of convenience and to imply sudden death caused by a ventricular tachyarrhythmia, ventricular tachycardia (VT), or ventricular fibrillation (VF). However, it is understood that sudden death is not always cardiac in origin. Neurologic and vascular catastrophes and massive pulmonary emboli can produce a rapid demise and are easily confused with sudden cardiac death. It is also understood that sudden cardiac death is not always due to an arrhythmia. Hemodynamic emergencies like myocardial rupture or acute valvular insufficiency can be easily confused with dysrhythmic death, and these conditions must be considered in the differential diagnosis of patients resuscitated from sudden death. Finally, it is also understood that arrhyth700
Curr
f’robl
Cardioi,
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1992
mic sudden death is not always due to a tachyarrhythmia. Ambulatory electrocardiographic recordings in patients experiencing out-ofhospital sudden death indicate that approximately 20% to 25% of events are precipitated by bradycardia, asystole, or electromechanical dissociation.6’ ’ Of the remaining number, approximately half (40%) are precipitated by monomorphic VT and the remaining 40% by polymorphic VT or VF.7
PATHOPHYSIOLOGY
The basic mechanism of the genesis of malignant ventricular arrhythmias remains unknown. This fact plus the diversity of clinical situations in which these arrhythmias occur have thwarted most simple theories concerning the pathophysiology of sudden cardiac death. Contemporary theories emphasize interactions among multiof these theories is useful for ple factors (Fig 1): ’ An understanding providing a framework for understanding the clinical evaluation and, to a more limited extent, the treatment of the sudden death survivor or the patient at risk for a first episode of sudden death. The first set of factors is intrinsic to the cardiac substrate. A variety of clinical tools, most of them using some form of cardiac imaging, are available for assessment of the structural and functional aspects of the cardiac substrate. Abnormalities can be regional (as in coronary artery disease or hypertrophic cardiomyopathy) or global (as in dilated cardiomyopathy). Additional means- principally signal-averaged
Electrolyte Abnormal&s
lschemia
Circulating Catecholamines
4 Ventricular Arrhythmias
4 SUDDEN CARDIAC DEATH
FIG 1. Schematic representation Cut-r Probl
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1992
of sudden cardiac death 701
electrocardiographic and electrophysiologic study-are used to assess the electrical features of the cardiac substrate. Ant&rhythmic surgery is aimed at modification of the substrate structure, whereas antiarrhythmic drug therapy targets the functional aspects of the electrical characteristics of the substrate. The second set of factors, often referred to as trigger factors, is sometimes transient and its relationship to arrhythmogenesis is more difficult to assess. The best studied and most widely implicated of the trigger factors are myocardial ischemia and the array of interactions between the heart and the autonomic nervous system. Other factors implicated are abnormalities of electrolytes, principally potassium and magnesium, and the proarrhythmic effects of antiarrhythmic drugs. The assessment of myocardial ischemia through provocative testing with exercise or pharmacologic maneuvers is an example of testing used to assess the importance of dynamic ischemia on arrhythmogenesis. Exercise invokes catecholamine responses that may be important triggers as well. Although exercise testing has been a mainstay of clinical practice for some time, only now are clinical means being developed to assess autonomic influences on the heart through methods like the analysis of heart rate variability. Treatment aimed at these trigger factors includes revascularization, use of /3-blocking medications, and electrolyte supplementation. Multiple lines of evidence implicate the importance of coronary artery disease as the cardiac substrate for sudden cardiac death. Clinical observations include the association of sudden death with the occurrence of acute myocardial infarction, the presence of significant obstructive coronary disease in 79% to 91% of patients surviving sudden death,loT1’ and the autopsy studies of patients who observations providing further supdo not survive.13 Experimental port include the ventricular arrhythmias that occur in animal models of coronary occlusion. l4 The evidence that acute ischemia is the trigger that precipitates the fatal arrhythmia in many patients with coronary disease is also substantial. Clinical evidence for ischemia as the responsible precipitant includes the occasional occurrence of sudden death during exercise testing accompanied by subjective and objective evidence of ischemia. Symptoms or signs of ischemia are reported to occur in 30% to 50% of patients with coronary disease experiencing sudden death.l’ Other evidence includes the association of sudden death during exercise and coronary disease in athletes 35 years of age and older.16 Pathologic studies demonstrate thrombi, plaque fissuring, or platelet aggregates in a high percentage In experimental preparations, the combinaof sudden deaths.“-” tion of remote infarction and scar formation with ischemia is more arrhythmogenic than scar or ischemia alone.20-22 Nevertheless, many patients with coronary disease who experience sudden death 702
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do not exhibit symptoms or signs of ischemia or go on to evolve evidence of acute infarction. Many episodes of sudden death in patients with coronary disease are not related to exercise or strenuous physical activity. Although it is possible that non-demand-related ischemia caused by platelet aggregation, thrombus formation, or alterations in vasomotor tone could be responsible for some of these episodes, it is more likely that acute ischemia is not the precipitant in a signiticant percentage of cases.23 Physicians have been aware of the interactions between the heart and the central nervous system for many years. Biorck et al’” demonstrated that denervation of the dog heart prevented most of the deaths after ligation of the left anterior descending coronary artery in the conscious animal. The occurrence of syncope and sudden death during extremes of emotion in patients with the congenital ‘long QT syndromes has also been known for sometime. Schwartz et al? have demonstrated in a feline model the occurrence of QT prolongation and life-threatening ventricular arrhythmias after ablation of the right stellate ganglion. Increased sympathetic nervous activity may also be important in the pathogenesis of ventricular arrhythmias in patients with left ventricular dysfunction. The occurrence of increased circulating levels of norepine hrine in patients with heart failure has been known for some time. F6 Recently, Meredith et al?’ have demonstrated a marked increase in cardiac norepinephrine spillover in patients with coronary artery disease and sustained arrhythmias. Although total norepinephrine spillover was 80% higher than in patients without heart disease or in patients with coronary artery disease without arrhythmias, the coronary norepinephrine spillover rate in patients with arrhythmias was over four times that of patients in the control groups?’ This strongly suggests that intracardiac sympathetic activity is significantly increased in patients with coronary artery disease and sustained arrhythmias. Stimulation of cardiac sympathetics reduces ventricular fibrillation threshold in canine models?’ Evidence of the importance of sympathetic nervous activity in ventricular arrhythmias in patients with the congenital long QT syndromes and patients with congestive heart failure have led to therapeutic trials with (3-adrenergic blocking agents in these disorders. b R.C. SCHLANT: The importance syndrome is further emphasized ganglionectomy, which helps to some patients it is necessary to P-blocker therapy.
of the central nervous system in the long QT by the value of left cervicothoracic sympathetic prevent syncope and sudden cardiac death. In combine stellate sympathectomy with chronic
The effects of electrolytes (principally potassium, calcium, and magnesium) on the genesis of arrhythmias have been extensively studied in vitro. Perturbations of electrolyte levels have important efCut-r Probl
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703
fects on normal action potential formation and propagation, as well as on the development of abnormal forms of electrical activity. Gross perturbations of electrolytes may result in life-threatening arrhythmias in patients without overt heart disease but are particularly arrhythmogenic in patients with heart disease and those receiving antiarrhythmic agents and digitalis.zs Potassium supplementation ameliorates many of the arrhythmias of digitalis excess, whereas magnesium infusion has been reported to be an effective treatment for torsades de pointes caused by an antiarrhythmic drug.30’ 31 However, the relevance of these observations to most clinical ventricular arrhythmias in humans is questionable. Evaluation of sudden death survivors seldom discloses evidence of electrolyte abnormalities sufficient to induce life-threatening arrhythmias. In vivo study is hampered because blood or serum levels of electrolp may have a poor correlation to total body or myocardial levels.’ ’ 33 Although electrolyte abnormalities should be treated or, preferably, avoided, little evidence shows that this step alone will have significant impact on the clinical problem of sudden cardiac death. Thus, although much is known about potential mechanisms of arrhythmogenesis in patients with malignant ventricular arrhythmias, much remains unknown. The mechanisms of interaction of substrate-specific factors and the so-called trigger factors remain to be explained.
RELATI’W
RISK AND INDMDUAL
DISEASE
STATES
Because sudden cardiac death has been reported to occur even in patients with ostensibly normal hearts,” no one has absolute immunity. Risk is best represented in relative terms (Table 1). Patients without evident cardiac disease form the low-risk end of the spectrum. Patients who have been successfully resuscitated from an episode of sudden death not associated with acute myocardial infarction form the hi est risk group with a recurrence rate of 10% to 30% annually.35’ P6 Most patients with chronic cardiac pathologic conditions fall between the two extremes. In general, more diffuse cardiac disease and more severe impairment of ventricular function signify greater risk for sudden death. However, exceptions to this general rule exist. Patients with hypertrophic cardiomyopathy have normal or above normal left ventricular ejection fractions but are at high risk for sudden death?’ Patients with primary electrical problems often have, by definition, anatomically normal hearts and normal ventricular function. Although patients with dilated cardiomyopathy generally are at very high risk for sudden cardiac death,38 relatively low-risk subgroups exist within this diagnostic category.3s An individual patient’s risk may change with time. Risk may increase 70.4
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TABLE 1. Sudden Clinical
Cardiac
Death
Gruup
Sudden death sutivors Dilated cardiomyopathy First year post-myocardial infarction Hypertmphic cardiomyopathy Long QT syndrome U.S. Adult population Mitral valve prolapse without regurgitation
Relative
Risk Average Annual Risk (96) 10-30 10 5 l-3 1-3
0.22 0.019
with progression of disease. Likewise, risk may be reduced by an intervention or medical treatment of the underlying cardiac pathologic condition. Thus risk assessment is a complex, dynamic process requiring thorough clinical evaluation of the patient, a correct diagnosis, and further substratification of risk categories within groups of patients with the same basic disease process. General clinical and epidemiologic data connecting sudden death with a number of cardiologic syndromes are presented in this section. The use of a wide variety of tools to aid risk stratification and management of individual patients is presented in a subsequent section.
DILATED
CARDIOMYOPATHY
Dilated cardiomyopathy (DCM) is the primary diagnosis in 7% to 23% of patients undergoing electrophysiologically guided therapy after surviving out-of-hospital sudden cardiac death not in association with an acute myocardial infarction (Table 2).40-44 In contrast to coronary disease the incidence of idiopathic (presumably viral) cardiomyopathy is increasing.38 Approximately 10,000 deaths in the United States each year are attributable to this disease. The annual mortality rate is estimated at 20% per year.= Approximately one half of these deaths are due to congestive heart failure, whereas the remaining half are sudden and presumably caused by ventricular arrhythmias ?-‘l Vasodilators, hydralazine in combination with nitrates, and angiotensin-converting enzyme inhibitors have altered the natural history of dilated cardiomyopathy by preventing or at least postponing deaths caused by myocardialgump failure when added to chronic digoxin and diuretic therapy. ’ 53 Of interest, use of these agents has had no appreciable effect on sudden death morCurr
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1992
706
e 0w
2 ii
N
of Survivors
Coronary Disease N (WI
Disease in Series Studies
9 4 5 5 17 13 48
Death
(8) (9) (1.51 (1.5) (27) (8) (11)
Cardiomyopathy N I%)
of Sudden
119 85 (71) Morady=” 45 35 (78) Benditt4’ 34 20 (58) Bendip 34 20 (58) Sale* 62 35 (57) Wilbe? 166 125 (75) Total 426 300 (70) *Includes both dilated and hypertmphic cardiomyopathy. tExcludes Mvp without mitral regurgitation. *includes WPW and long QT syndrome patients. Mvp = mitral valve prolapse; WFW = Wolff-Parkinson-White
B@’
Author
Underlying Heart Electmphysiologic
TABLE 2. with
7 3 2 2 2 10 24
16) (7) (61 (6) (3) (6) (6)
VaIve and Hypertensive Diiease* N (W)
Unassociated
Acute
7 2 0 0 2 6 17
MVPt
Myocardial
(3) (4) (4)
(6) (4)
N (W)
Infarction
on the
10 1 7 7 6 8 32
IS) (2) (211 (21) (10) (5) (8)
Primary Electrical Disorder& N (%I
Treated
Basis
of
1 I11 0 0 0 0 4 (2) 5 (1)
Other N (96)
30-
.E % 20. 9 E nE P=O.o045 0
6
12
16
24
30
36
42
0
6
12
16
24
30
36
4246
46
Months FIG 2. Mortality caused by progressive heart failure (A) (P = 0.0045) and presumed to be caused by an arrhythmia but not preceded by worsening congestive heart failure (B) (Pvalue not significant). (Reprinted with permission from the New England Journal of Medicine [325;297, 19911.)
tality (Fig 2).54 Patients with compensated heart failure are still at cardiomyoparisk for sudden death.55 In contrast to hypertrophic thy, sudden death as the initial disease manifestation in dilated cardiomyopathy is uncommon. HYPERTROPHIC
CARDIOMYOPATHY
Hypertrophic cardiomyopathy (HCM) occurs in both familial and sporadic forms.37 Recent work by Hejtmancik et alF6 using the techniques of molecular genetics and linkage analysis, have identified Cum
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1992
707
the genetic locus for the familial form in the United States on the fourteenth chromosome confirming previous studies of Jarcho et a15’ and Solomon et al?’ Like patients with DCM, patients with HCM die from heart failure or sudden death. In marked contrast to almost all other forms of heart disease, risk for sudden death in HCM appears to decline with age:5g sudden death in HCM is uncommon after the age of 40. 37 In view of the association of HCM with sudden death in young athletes,16’ 60,” this apparent anomaly may represent the effect of a decrease in physical or athletic activity with age. Another potential explanation, however, is that patients with HCM at risk for sudden death do not reach middle age. Spirit0 and Man&” have correlated the risk of sudden death in HCM with the severity of left ventricular hypertrophy (LVI-I). Sudden death has also been reported in a patient without LVH who at autopsy had the disorder of septal myocytes that characterizes HCM histologically.63 Patients with HCM comprise 0% to 5% of patients in series of survivors of sudden cardiac death undergoing electrophysiologic evaluation.40-44 The occurrence of sudden death as the initial manifestation of heart disease is also reflected by the frequency with which this disease is implicated in the sudden death of young athletes?” 6o861 The familial occurrence of this disease commands accurate diagnosiseven if diagnosis is established at postmortem examination. Family screening of patients with HCM should be performed and genetic counseling provided in appropriate cases.
MITRAL
VALVE PROLAPSE
The establishment of a causal link between isolated mitral valve prolapse (MVP) and sudden death has been difficult, Mitral valve thickening and leaflet redundancy have been reported in sudden death victims in the absence of any other heart disease.“4-66 Reported series of sudden death survivors also contain 3% to 7% op-atients with MVP as the only identifiable cardiac abnormality. 44 Given the ubiquity of mitral valve prolapse and that cardiac electrical problems occur in the absence of structural abnormalities, however, the occasional association of MVP and sudden death is insufficient to establish a cause-and-effect relationship. In a recent review, only 106 cases of sudden death in association with MVP could be identified!’ This is far fewer than the number expected if a true causal relationship exists. In a series of 237 minimally symptomatic or asymptomatic patients with echocardiographically documented MvP, Nishimura et a16’ described only six episodes of sudden death in an average follow-up of 6.2 years. The smvivaI of the patients in the MVP group did not differ signitlcantly from that of an agematched and sex-matched control group. In a second large series, 708
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reported by Duren et al.,“’ 300 patients with MVP were followed up for an average of 6.1 years. These authors found only three episodes of sudden death. Kligfield et al.,“’ extrapolating from autopsy data reported by Davies et a.l.,‘l calculated an estimated annual risk of sudden death attributable to MVP of 1.9 per 10,000 patients with MVP without mitral regurgitation. This figure is only one tenth as high as the annual risk of sudden death by all causes in the adult population of the United States. Using similar autopsy data in patients with MW and mitral regurgitation, these same authors calculated a risk for sudden death that was 50 to 100 times greater than the risk in patients with h4VP alone.” These lines of reasoning cannot exclude a pathophysiologic role of h4W in an isolated case of sudden death. However, they do suggest that the risk of sudden cardiac death in MVP is low. b R.C. SCHLANT: Further support for the conclusion that the risk of sudden death in h&T is very low is found in autopsy studies performed in older patients. In general, the occurrence of evidence of MVP is about the same in older patients as in younger patients, a finding that would not be expected if hNP were associated with a significant incidence of sudden death in younger years.
HYPERTENSION
AND LVH
A resurgence of interest has occurred in the role of LVH in the pathophysiology of sudden death. Hypertension, as the most common cause of LVH, has also received a second look in regard to its relation to sudden death. This resurgence is due to several factors. Among the most important of these factors has been the development and validation of echocardiographic techniques for the quantification of left ventricular mass.72-74 Echocardiographic techniques are far more sensitive in the detection of LVH than electrocardiographic techniques formerly usedT5 Echocardiographically determined left ventricular mass has been shown to be a powerful predictor of cardiovascular morbidity and mortality, including sudden death, in several studies.76-7s The degree to which risk is elevated correlates with the severity of LVH.” A second factor contributing to the renewed interest in the importance of hypertension and LVH has been the demonstration that LVH contributes to the development of malignant arrhythmias in animal models involving acute coronary occlusion.7s~80 These studies suggest that the contribution of hypertension to sudden death is twofold. The more well-known effect is indirect as a risk factor for coronary artery disease. A second more direct effect is the apparent electrical instability of the hypertrophied heart under conditions of acute ischemia. Finally, the demonstration that LV mass can be modified in Cut-r
Probl
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1992
709
hypertensive patients by some antihypertensive therapies has also contributed to the renewal of interest in the heart in hypertension. Central sympatholytic agents and angiotensinconverting enzyme inhibitors have consistently been shown to reduce LV mass in animal models and patients.81-83 Some other classes of medications, equally efficacious in lowering blood pressure, do not produce regression of LVH.83’ 84 What impact reduction in LV mass by antihypertensive therapy will have on sudden death in these patients is a subject of considerable controversy. For all of the recent interest, the mechanism of arrhythmias in hypertrophied ventricles is still not known. The same mechanisms that facilitate sudden death in hypertension-induced LVH may be operant in other hypertrophy states (e.g., valvular heart disease). It is our opinion that the importance of LVH in the pathophysiology of sudden death is underrepresented in reported series of sudden death survivors. This is probably due to the tendency to classify patients with coronary disease and LVH on the basis of their coronary disease. It is also due to the absence of quantitative echocardiographic techniques for determination of LV mass when many of the series were collected. A more ominous possibility is that patients with significant LVH are less likely to be resuscitated from an episode of sudden death than patients without LVH.
ISCHEMIC
HEART
DISEASE
Coronary artery disease is the predominant substrate in all autopsy series of sudden death patients and in reported series of sudden death suIvivors.40-44 In part, this relates to the relative ease with which coronary disease can be characterized clinically and pathologically. However, the fact that sudden cardiac death usually means sudden coronary death is inescapable (Table 2). According to data from the Framingham study, 50% of sudden deaths in men and 64% in women occur without prior clinically manifest coronary disease.85 Thus sudden death is all too frequently the first and only manifestation of coronary artery disease. The risk for sudden death in patients with known coronary artery disease is increased in patients with multivessel disease especially when accompanied by LV dysfunction.86 Sudden death in coronary artery disease usually is seen as one of two syndromes. The first, often occurring in patients without known disease, is characterized by acute ischemia caused by abrupt occlusion of a major coronary artery. The severity of the underlying stenosis is variable. Abrupt occlusion usually occurs at the site of a preexistent atherosclerotic plaque, although the severity of vessel narrowing before the event may be mild.87 Plaque rupture or fissuring may 710
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1992
establish a nidus for latelet aggregation and, ultimately, occlusive thrombus formati0n.l B’ 8888g Vasospasm may play a role in this cascade of events.go Endothelial and platelet-derived factors are believed to mediate many of these processes?l The dynamic nature of these processes may account for the fact that many patients experiencing sudden death in the setting of acute ischemia do not evolve acute infarctions.g2-g4 Animal studies suggest that reentry within the acutely ischemic myocardium is the probable mechanism of arThis syndrome is responsible for most sudden rhythmogenesis.g5 deaths. Patients who survive an episode of sudden death and evolve a myocardial infarction with new Q waves are at no greater risk than the patient who has an infarction uncomplicated by sudden death,35 whereas patients with sudden death who do not evolve infarctions are at high risk for recurrence.12J 35,g2, g6 An aggressive approach to evaluation and treatment of the underlying heart disease and the arrhythmia is indicated. The second presentation is that of sudden death in patients with known coronary artery disease often accompanied by focal wall motion abnormalities from prior infarction and depressed global ventricular function. These arrhythmias are almost certainly reentrant in origin with reentry occurring within the areas of viable myocardium at the borders of myocardial scar?’ Programmed stimulation techniques and electrophysiologically guided therapy have been most effectively applied in this subgroup of patients. These patients also are at high risk of recurrence if effective treatment is not used. Full characterization of the anatomic substrate and dynamic factors contributing to arrhythmias in this subgroup of patients is also warranted. The risk of sudden death in patients with coronary artery disease, which can change drastically over time, is probably highest soon after abrupt vessel closure. For those patients who survive the early stages of an abrupt occlusion, however, risk declines exponentially withii a few hours, perhaps even within a few minutes. The risk of sudden death declines to 4% to 5% by the time the patient is disFor those patients surviving the first charged from the hospital.” year after infarction, risk is further reduced?’ Risk rapidly escalates with abrupt occlusion of an additional major artery. This process can continue until a chronic ischemic myopathy develops.
PRIMARY
ELECTRICAL
ABNORMALITIES
This category includes patients experiencing sudden cardiac death in the absence of any structural abnormalities of the heart. Incorporated in this group are patients with primary ventricular arrhythmias, patients with the long QT syndromes, and the unusual Curr
Probl
Cat-did
November
1992
711
patients with the more malignant forms of the Wolif-ParkinsonWhite &VPWl syndrome. Combined, these patients form 2% to 12% of patients in reported series of survivors of out-of-hospital sudden death (Table 2).4 -44 Although combined for the purposes of classification and discussion, the pathogenesis of sudden death in these different syndromes is very different. Schwartz et al.” have presented data indicating the importance of the adrenergic nervous system in the genesis of arrhythmias and sudden death in the long QT syndrome (LQTS). The natural history of this fascinating disorder is still under active study. In a cohort of 196 patients with LQTS followed prospectively, the incidence of sudden death was 1.3% per year.” This figure is remarkable considering the average age of the patients in the cohort was only 24 years. The disease occurs in both inherited and sporadic forms. As with HCM, family screening and genetic counseling are in order when an affected patient is identified. The arrhythmias occurring in patients with LQTS are very similar to those occurring in patients experiencing the proarrhythmic effects of QT prolonging medications.1oo Thus insights into arrhythmogenesis derived from LQTS may have much wider applicability. Somewhat in contrast to LQTS, sudden death in the WPW syndrome is unusual. In a rare population-based study, Guize et al.*” followed up 151 patients with manifest WPW for a mean of 4.6 years. Only one episode of sudden death occurred. Atrial fibrillation with rapid antegrade in an accessory pathway is the most accepted explanation for the occurrence of sudden death in WPW. The resulting extreme ventricular rate may produce hemodynamic deterioration directly or result in a ventricular arrhythmia.l”
SUDDEN
DEATH
IN CHILDREN
AND YOUNG ADULTS
Sudden nontraumatic death accounts for 2% to 20% of deaths between the ages of 1 and 20 years.‘o3’ lo4 In contrast to reported series of adult patients where coronary disease is the dominant underlying disease, the underlying cardiac pathologic condition in pediatric series is more varied (Fig 31. For those series drawn from the general population, myocarditis, HCM, and congenital coronary anomalies are mentioned most often.‘oz-1o7 For series drawn from children and young adults with known heart disease, aortic stenosis, pulmonary hypertension (primary or secondary), and tetralogy of Fallot appear most often.108-11’ Primary electrical problems (long QT patients and WPW patients) also sometimes have sudden death in this young age group. A population of increasing concern to pediatric cardiologists and adult cardiologists alike is the group of patients with surgically re712
Cur-r Probl
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1992
118%) < 35YEARS
OLD
2 35 YEARS OLD
FIG 3. Causes of sudden death in athletes less than 35 years old and 35 years and older. (Reprinted with permission from the American College of Cardiology [Journal of the American College of Cardiology, 1986;7:204-2141.)
paired complex congenital heart disease. Patients with surgically corrected tetralogy of Fallot are at greatest risk for ventricular arrhythmias.‘l’ b R.C. common
In small infants the crib sudden and its cause is still an enigma.
SCHLANT:
UNCOMMON
SUDDEN
death
syndrome
is still too
DEATH
In addition to the major categories of heart disease discussed above, a number of uncommon causes of sudden arrhythmic death exist (Table 3). The unique features of each condition require recognition for proper diagnosis. The mechanism of sudden cardiac death (bradyarrhythmia or tachyarrhythmia) is not know-n in some cases. The tachyarrhythmias associated with these conditions often are particularly difficult to treat. ‘IXwo of the more common of these unusual causes of sudden death will be discussed briefly. Arrhythmogenic right ventricular dysplasia usually is seen with hemodynamically tolerated arrhythmias, although sudden death does occur. Afflicted patients are otherwise healthy and arrhythmias may be exercise related.l13 Diagnosis requires a high index of suspicion and demonstration of functional and structural abnormalities of the myocardium of the right ventricle. Replacement of right ventricular muscle by adipose or fibrous tissue is the characteristic histologic finding.‘14 The occurrence of nocturnal unexplained sudden death has been recognized in Far Eastern countries for some time. The Filipino version of the condition is known as Bangungut. In Japan, the disorder is called Pokkuri disease.ll’ This condition, occurring almost excluCut-r Probl
Cardiol,
November 1992
713
TABLE 3. Unusual Causes of Arhythmic Sudden Death Myocarditis Arrhythmogenic right ventricular dysplasia Sleep-death in Southeast Asians -‘W”W POkkuri Tumors mary Metastatic InfWative cardiomyopathies Sarcoid Amyloid Hemochrumatosis Chagas’ disease Neurumuscular diseases Muscular dystrophy Friedreich’s ataxia Myotonic dystrophy
sively in men, was recognized in the United States after the influx of Southeast Asian refugees that followed the end of the Vietnam War:= Death occurs during sleep in apparently healthy individuals. Careful histologic study has revealed minor abnormalities of the conduction system, though a causal relationship between these findings and the clinical syndrome remains speculative?”
EVALUATION
The comprehensive evaluation of a patient’s risk for sudden cardiac death is a complex process. For conceptual purposes, this evaluation can be divided into three separate steps. The first step involves the full characterization of all underlying cardiac disease and any comorbid noncardiac conditions that are present. The nature of the underlying pathologic condition provides a first approximation of the magnitude of risk for sudden cardiac death. The nature and severity of the cardiac disease also are important determinants of the methods used to evaluate and treat the associated cardiac arrhythmias. Concomitant systemic disease can likewise be an itnportant consideration in the choice of treatment options. The second phase of patient assessment involves patient-specific risk stratification within the context of a general diagnostic category. This sub&ratification step is most important in disease states associated with intermediate risk of sudden death (e.g., HCM or long QT 714
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1992
syndromes). The annual risk of sudden death among all patients with these syndromes is relatively low at 1% to 3% .37,” Intervention to prevent sudden death in all affected patients is probably unnecessary and, considering the toxicity of antiarrhythmic agents, potentially harmful. On the other hand, the identification of subgroups at high risk for sudden death within diagnostic groups allows the more selective application of interventions. Risk substratification plays a less important role in high-risk disease states. In this context, patient-specific factors can identify low-risk groups of patients less likely to benefit from medical or surgical therapies. For a group of patients with instance, Stewart et a13’ have identified DCM that have a much better prognosis than the 20% per year mortality of the group as a whole. Risk substratification is least important in the evaluation of those patients who have already experienced sudden cardiac death unassociated with acute infarction. However, even in this group at high risk, some patients have a low probability of recurrence. The third objective in the evaluation of patients in the context of sudden cardiac death is the identification of markers that can be .used to assess the efficacy ‘of therapy. Although controversy continues to exist regarding the best means to assess the safety and efficacy of therapy, objective means must be used whenever possible. Except for the use of P-adrenergic receptor blocking agents in the patient who has had a myocardial infarction (MI), empiric therapy has been of little efficacy in the prevention of sudden death. Patient assessment begins with a thorough general history and examination. Because few patients who experience sudden death have premonitory symptoms, the history focuses on general signs of cardiovascular disease. Because coronary artery disease is the most common substrate, particular attention must be paid to any history of chest discomfort or exertional intolerance. Because many patients at high risk have LV dysfunction, potential heart failure symptoms must be carefully evaluated as well. In several subgroups of patients, syncope has been advocated as a harbinger or risk factor for sudden death. This includes patients with HCM and the long QT syndromes.“’ ‘I7 Auricchio et a1118 have recently reported on the absence of prognostic value of syncope in patients with WPW. In their study, the occurrence of syncope did not correlate with any measure of electrical abnormality caused by the presence of an accessory pathway.l18 Evaluation of syncope in the general population must be made with an awareness of the fact that this symptom occurs in up to 37% of healthy young adults.11s Some authors have suggested that the circumstances of syncope and, in particular, the association of syncope with exercise is a more specific sign of heart disease and increased risk for sudden death.“’ This postulate has Curr
Probl
Cat-did,
November
1992
716
not been tested in a prospective or controlled fashion. Family history is of obvious importance in cases where HCM or long QT syndrome is suspected. Historical information is also of importance in the evaluation of the patient who has survived an episode of sudden death. In this setting the most important information often comes from those who have witnessed the event rather than from the patient. Seizures and fainting episodes can easily be confused with episodes of sudden death even by experienced observers. Because the treatment of bradyasystolic arrest and sudden death caused by tachyarrhythmias differs dramatically, documentation of all rhythms recorded during the episode is paramount.121 In our experience no substitute has been found for direct conversation with as many witnesses to the event as possible. No amount of subsequent evaluation can nullify a mistake in the diagnosis of aborted sudden death. Physical examination may also provide insight into the presence and nature of cardiac disease. Funduscopic examination can indicate the presence of long-standing hypertension. Carotid pulse examination may indicate evidence of HCM. Palpation of the cardiac apex may also suggest HCM or the presence of an apical aneurysm. Cardiac auscultation may disclose the presence of valvular heart disease. In young patients systolic murmurs must be evaluated thoroften using a series of dynamic maneuvers-so as not to oughlymiss the patient with HCM. All signs of heart failure should be sought diligently. The traditional cardiac noninvasive screening modalities (electrocardiography and chest radiography) are important adjuncts to the history and physical examination. The electrocardiogram (ECG) is helpful in the diagnosis of coronary disease, as well as the preexcitation syndromes. The ECG is a specific, but insensitive, indicator of LVH. Conduction abnormalities characteristic of cardiomyopathy may also be seen. Electrocardiographic abnormalities are required for the diagnosis of the long QT syndromes although the changes may be present only intermittently. The chest radiogram in this setting is most useful in the assessment or diagnosis of LV dysfunction with congestive heart failure.
SPECIAL
TESTS
The physician evaluating a sudden death survivor or patient suspected to be at risk for sudden death has an array of noninvasive and invasive tests that may be useful in the diagnosis of such patients. Some tests are useful prognostically whereas others can be used to guide therapy. Certainly not all tests are necessary or even desirable in all patients. However, some basic knowledge of all these 716
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1992
modalities disease.
is necessary
for physicians
caring for patients
with heart
AU patients with complex ventricular arrhythmias, as well as those patients suspected to be at risk for these arrhythmias, should have some form of noninvasive assessment of cardiac function. Echocardiography has become a favored means to accomplish this goal because of its ease of applicability in the intensive care setting and the wide spectrum of information available by the application of echocardiographic and Doppler techniques. M-mode and twodimensional echocardiographic abnormalities that may be documented in patients with arrhythmias include segmental LV wall motion abnormalities consistent with coronary disease; significant valvular dysfunction; evidence of HCM, MVP, chamber dilatation, and ventricular dysfunction characteristic of DCM; pericardial disease; intracardiac tumors; arrhythmogenic right ventricular dysplasia; and congenital heart abnonnalities.122-128 Echocardiography is much more sensitive than electrocardiography in the diagnosis of techniques provide the ability to noninvasively LVHT5 Doppler quantitate valvular stenoses and regurgitation and also to identify intracardiac shunts. Echocardiography is useful in the assessment of regional as well as global LV function. Aneurysms can frequently be diagnosed with echo assessment of regional wall motion.‘2s Patients with discrete aneurysms may be considered for surgical therapy of their atrhythmias. The presence of LV dysfunction within any arrhythmia subclass may increase that patient’s risk for sudden death and influence the decision to undertake therapy?30-132 Documentation of serious LV dysfunction by echocardiography may preclude the use of antiarrhythmic agents that produce significant negative inotropy. b R.C. SCHLANT: Evaluation of ventricular function by transthoracic or transesophaged echocardiography can sometime8 by enhanced by the simultaneous application of stress by cardiac pacing or pharmacologic agents such as dobutamine.
RADIONUCLIDE
ANGI -oGwHY
Radionuclide angiocardiography is another noninvasive test used for the quantitative assessment of LV function and regional LV performance. LV ejection fraction can be measured using the first-pass technique or the gated cardiac blood pool imaging technique.133 Right ventricular function can also be assessed. Radionuclide angioCurr
Probl
Cardiol,
November
Xi%?
717
cardiography is particularly useful in obese patients or patients with chronic lung disease in whom a technically satisfactory echocardiogram cannot be obtained. In patients who have frequent ventricular ectopy or atrial fibrillation, gating is difficult and the results of radionuclide angiocardiography are often less accurate.‘= This technique also does not supply direct data regarding valvular disease, wall thicknesses, and chamber dimensions as echocardiography does. Ejection fraction measurements by nuclear techniques have been found to be accurate, to be reproducible (+6% 1, and to correlate well with measurements made at cardiac catheterization. Regional or segmental wall motion can be assessed well by gated studies. Regional LV hypokinesis, akinesis, or dyskinesis can be determined.‘35 As an inherently quantitative technique, radionuclide angiocardiography has been very useful in studies designed to determine optimal risk stratification strategies in the post-MI patient. A depressed ejection fraction in this group of patients is associated with enhanced mortality. The presence of LV dysfunction may be useful in determining which patients in this population need prophylactic treatment. As with echocardiography, radionuclide angiocardiography may be useful in directing antiarrhythmic therapy. Agents with negative inotropic effects can be avoided in patients with poor ventricular function. The combination of rest and stress radionuclide angiocardiograms is a useful noninvasive screening test in the diagnosis of coronary artery disease.136 The use of exercise gated studies is more sensitive and specific than electrocardiographic stress tests in the diagnosis of coronary artery disease and approaches stress thallium testing in predictive accuracy.
EXERCISE
STREBS TJBTING
Exercise testing serves several purposes in patients with complex ventricular arrhythmias. Despite well-recognized limitations of sensitivity and specificity, the graded exercise test remains the most commonly used noninvasive test for the diagnosis of coronary disease in patients with chest pain. Augmentation of routine stress testing by the use of nuclear medicine techniques improves the sensitivalso ity and specificity figure~.*~‘~ 13’ Nuclear medicine techniques extend the use of exercise testing to many patients with electrocardiographic abnormalities that preclude the reliable interpretation of the electrocardiographic response to exercise. Nuclear techniques may also be useful in efforts to localize regions of ischemia and determine the amount of myocardium in jeopardy. Positron emission tomography may be even better at many of these applications but is 718
Curr
Probl
Cardioi,
November
1%~
not yet readily available in many areas. Clinical decisions based on positive and negative results for any of these tests must take into account the pretest probability of coronary disease as dictated by Bayes’ theorem.137,139,149 When one considers that over half the victims of sudden death, most of whom have coronary disease, have no antecedent symptoms, the desirability of a noninvasive means of latent coronary disease detection is obvious. Exercise testing has been used for this purpose although its performance in this regard has been somewhat disappointing. Detection of coronary disease during exercise testing depends on the production of myocardial ischemia by supply-demand imbalance resulting from the metabolic demands of exercise in the presence of a flow-limiting coronary stenosis. Epthat the patient at risk for sudden stein et al.87 have hypothesized death without antecedent symptoms is the coronary patient without severe stenoses. These patients suffer abrupt vessel closure caused by endothelial injury, platelet aggregation, and finally thrombosis. The abruptness of closure precludes the development of collateral vessels that would minimize the amount of myocardial injury. Thus treadmill testing and other tests that depend on the presence of severe stenoses for the detection of coronary disease may not be the best means for identifying presymptomatic patients at risk for sudden death.87 Exercise stress testing is useful in the identification of patients with exercise-induced or exercise-aggravated ventricular tachycadia.'41-143 Frequently these patients are young and have no evidence of serious organic heart disease. These patients may not have inducible ventricular tachycardia in the electrophysiologic laboratory. Therefore stress testing may be the only method available to guide drug therapy. Stress testing has been found to be useful for risk stratification of post-MI patients?37’13s,144-146 Several studies have shown that the occurrence of exercise-induced angina, exercise-induced ventricular arrhythmia, or exercise-induced diagnostic ST segment changes I to 2 weeks after myocardial infarction is predictive of future events including sudden death.‘&’ 145 Patients found to have exerciseinduced ischemia appear to be in a high-risk category, These patients should be strongly considered for prophylactic P-blocker protection or early cardiac catheterization with appropriate treatment in an effort to alter this natural history.13’ Finally, exercise testing may be a useful adjunct in guiding antiarrhythmic drug therapy. Catecholamines, which increase during exercise, have been shown to reverse beneficial effects of antiarrhythmic drugs .147,14a Presumed adequate suppression of arrhythmia on ambulatory ECG (Halter) monitoring may be noted during drug therapy yet stress testing may reveal persistent repetitive activity. The Curr
Probl
Cardiol,
November
1992
719
proarrhythmia of intracardiac agents may be manifest as the development of incessant tachycardia during exercise.14s’ 150
LONG-TERM
ELECTROCAIUB
IOGRAPHIC
RECORDINGS
Since the original description in the 195Os, Holter monitoring, or continuous ambulatory electrocardiographic monitoring IAECG), has been a useful technique in the evaluation of patients with arrhythmias.151’ 152 With respect to sudden death, AECG recordings are used to screen selected patients who have clinical syndromes in which the presence of an arrhythmia may increase the patient’s risk for sudden death. These situations include the post-MI period,153-155 congestive heart failure, and DCM,13” 13’, 156-160 HCM,“’ and the congenital prolonged QT syndrome.162 On the contrary, even frequent and complex ectopy, when asymptomatic, has little prognostic significance in patients without heart disease.163’ 164 In riskstratification of post-MI patients, late in-hospital arrhythmias have prognostic significance and are used in conjunction with ejection fraction determination and other noninvasive tests. Patients with benign profiles (all factors negative1 have a 3% l-year mortality compared with a 15% l-year mortality when all factors are positive. Serial AECG monitoring has been used to guide antiarrhythmic drug therapy. Patients have a first AECG monitoring period in the drug-free state. The patients are then placed on antiarrhythmic therapy and after the drug reaches steady state conditions for the prescribed dosage AECG monitoring is repeated. Comparison of the frequency and complexity of background arrhythmia is made in an effort to determine whether the prescribed medication has had an effect. Graboys et al?65 used this method in conjunction with exercise testing before and after drug therapy to assess the efficacy of antiarrhythmic therapy in 123 patients with a history of sustained VI or VF. The AECG monitoring periods before and after drug therapy were 48 hours. Drug efficacy in this study was defined as a 50% or greater reduction in total premature ventricular contractions (WCs), 90% or greater reduction in the number of paired ventricular responses, and a total suppression of nonsustained ventricular tachycardia and R-on-T WCs. Ninety-eight of 123 patients (80%) left the hospital on effective therapy as assessed by the methods used in the study. Freedom from sudden death at 3 years of follow-up was 90% in the effective therapy group versus 15% in the group that could not be effectively suppressed. A second study bg6the same group also supported the role of AECG-guided therapy. In this study of 118 patients 3-year freedom from sudden death was determined to be 84% in the group on effective therapy but only 48% in the group of patients that could not be effectively suppressed.‘66 720
Curr
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1992
Studies like those of Graboys et al.‘65 and Lampert et al?66 that indicated the benefit of AECG-guided therapy gave rise to the “PVC hypothesis.” The basic premise of this hypothesis is that ventricular ectopy and nonsustained ventricular arrhythmias are linked pathophysiologically to more malignant arrhythmias. If one accepts this premise, the next logical conclusion is that suppression of WCs and nonsustained ventricular tachycardia can be used as a marker of suppression of the less frequent, but clinically more significant, sustained ventricular arrhythmias. The attraction of the theory is that it would preclude the need for invasive electrophysiologic (EP) studies in many patients. However, the results of the Cardiac Arrhythmia Suppression Trial (CAST) have seriously undermined the premise on which the PVC hypothesis is based.‘67 This multicenter study was designed to test the hypothesis that suppression of ventricular arrhythmias in patients with LV dysfunction after MI would reduce arrhythmic death. Flecainide, encainide, and moricizine were the antiarrhflhmic agents used in the trial. Patients were only entered in this randomized, double-blind, placebo-controlled trial if they achieved 80% suppression of WCs on drug therapy during a period of open-label drug titration that preceded randomization. The encainide and flecainide arms of the study were terminated when a 2.5-fold increase in sudden death was found for patients in these two arms as compared with patients receiving placebo.167 Although one should not extrapolate the results of CAST to other patient populations or other antiarrhythmic agents, it is impossible to escape the conclusion that PVC suppression with intracardiac agents in this group of patients with coronary disease was associated with an increased risk of sudden death. This is directly opposite to the result expected if the PVC hypothesis were valid. Despite its limitations, serial AECG monitoring to guide therapy is still used in those patients who do not have inducible arrhythmias at EP testing and who are not candidates for device therapy. Understanding the concept of spontaneous variability of arrhythmias is key to use of this modality. Figure 4 shows the variability in PVC frequency in a cardiac arrest patient who underwent 2 consecutive days of monitoring. Although the patient had frequent ectopic activity during the first 24 hours, a marked decrease in arrhythmia occurred spontaneously on the second day. Spontaneous variability can mimic drug effect. The capability of repeated monitoring to demonstrate a true drug effect is a function of two factorsthe frequency of the arrhythmia and the duration of the monitoring period. Patients with a low frequency of WCs and/or nonsustained arrhythmias who have a history of life-threatening arrhythmias are not good candidates for AECG-guided therapy. This occurs in up to two thirds of sudden death surviv~rs.~~ In patients with more frequent arrhythmias, pooled data suggest that a reduction of 83% in the number of CUJT Probl
Cardiol,
November
1992
721
FIG 4. Variability in PVC frequency noted in a patient with a history of sustained VT. Note marked variability over 2 consecutive days of recording off antiarrhythmic therapy. (From Naccarelli et al: Patient assessment: Laboratory studies, in Andreoli KG, Zipes DP, Wallace A, et al (eds): Comprehensive Cardiac Care. St Louis, CV Mosby, 1987, pp 58-81. Used with permission.)
WCs is indicative of drug effect based on 24-hour monitoring.168’ 16’ Unfortunately, this finding is indicative only of a short-term drug effect. Variability changes with the passage of time, presumably as the underlying cardiac substrate changes.17’ Thus to be certain that drug effect persists, it is necessary to discontinue the drug and redetermine the frequency of arrhythmia in the drug-free state. More variability has been noted in coronary disease patients than in patients without coronary disease.171 SIGNAL-AVERAGED
ELECTFtOCARDIOGRAM
In experimental models of acute MI, low amplitude, fragmented, and delayed electrical activity can be recorded from areas bordering the infarction but not from areas more remote from the zone of inThese areas are thought to be the substrate for reentrant farcti0n.l” ventricular arrhythmias seen in these experimental preparations and may underly many lethal clinical arrhythmias as well. The 7zz
Curr
Prvbl
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ICEIZ
signal-averaged ECG, sometimes referred to as a high-resolution ECG, uses a number of signal-conditioning steps in an effort to record the delayed fractionated activity from the body surface (Fig 5). The frrst step, amplification, is necessary because of the extremely low amplitude of the delayed electrical activity, often referred to as late potentials. The next step, high-pass filtering, takes advantage of the fact that the late potentials are made up predominantly of highfrequency signals whereas the surface QRS and ST segments, which obscure the late potentials on the surface ECG, are composed of lower frequencies. An industry standard has not been established for the cutoff frequency of the filtering step. Values between 25 and 100 Hz have been advocated by different investigators. Bidirectional flltering of the signal is used to avoid artifact caused by ringing in the offset of the QRS complex that would obscure late potentials as well.173 Finally, the amplified, filtered signal is averaged over a period of time or specified number of beats. The theory of signal averaging in this application is simply that noise is random and positive voltage noise will be counterbalanced by negative noise as the averaging process proceeds. Late potentials are not random and will not cancel during the averaging process. Thus averaging reduces the
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1992
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300
Cardiol,
noise level to a degree sufficient to allow detection of the late potentials. The signal-averaged ECG is usually recorded with three bipolar, orthogonal (Frank - X,Y,Z) leads. For purposes of display and analysis, the leads are usually combined into a single vector, the magnitude of which is calculated by taking the square root of the average of the squared amplitudes of the three individual lead voltages. The presence of late potentials is represented by an increase in the total QRS duration, a reduction in amplitude of vectoral QRS voltage in the last portion (typically 40 ms) of the QRS, and/or an increase in the duration of low-amplitude signals at the end of the QRS (Fig 6). The requirement of multiple positive criteria for an abnormal test increases the specificity of the test but at the expense: of sensitivity. Likewise, choice of cutoff values for QRS duration, terminal root mean square voltage, and duration of low-amplitude signals involves a similar trade-off. The presence of late potentials is a predictor of inducible sustained VT at EP study in patients with nonsustained VT.174’ 175 In this population the signal-averaged electrocardiogram may be useful in screening patients for EP study. In a report by Hall et al.,174 two thirds of patients with late potentials and a history of nonsustained VT had sustained VT induced by programmed electrical stimulation,. The signal-averaged ECG may also be of value for risk stratification after MI. The use of signal averaging in this application usually implies performance of the test a minimum of a few weeks after the completed infarction. The presence of late potentials in the early post-MI period has not been shown to be useful in predicting subsequent arrhythmias. Late potentials are often transiently present during this time. Kuchar et al?76 performed signal-averaged ECGs an average of 11 days after MI, as well as radionuclide ventriculography and AECG monitoring in 210 patients. An abnormal signal-averaged electrocardiogram was defined as the presence of a low-voltage signal (less than 20 V) in the terminal 40 ms of the QRS or a filtered QRS duration greater than 120 ms. Low-amplitude signal criteria were not used in the study. Patients were followed up for a median of 14 months for arrhythmic events- sudden death or sustained VT. The results of each of the three tests studied were independently predictive of arrhythmia events. Ejection fraction (EF) by radionuclide venFIG 6. (A) Presence of late potentials in a patient with a history of sustained VT. (8) Normal signal-averaged ECG in a syncopal patient. DUR = duration; RMS = root mean square; IN = integral; LAS = low amplitude signals. (From Naccarelli et al: Noninvasive cardiac evaluation of patients with arrhythmias, in Naccarelli GV (ed): Cardiac Arrhythmias: A Practical Approach. Mt. Kisco, NY, Futura Publishing, 1991, p 54. Used with permission.) Curr
Probl
Cardiol,
November
1992
726
triculography was the most powerful predictor but the combination of an EF less than 40% and a signal-averaged ECG indicating the presence of late potentials suggested a higher risk than any single abnormal variable alone. Patients with this combination had a 34% probability of an arrhythmic event. The risk of a low EF alone was only 4%. Thus the presence of late potentials in a patient with LV dysfunction after an MI portends a poor prognosis.176 The location of infarction influences the ability of the signalaveraged ECG to detect late potentials: the test is most predictive of arrhythmic events in patients with inferior infarctions and less useful in anterior infarcts. This difference is probably due to discrepancies in the time course of the activation of the per&infarct zone for the two infarct locations. Per&infarct tissue in anterior infarctions is activated relatively early in the sequence of ventricular activation. Thus late potentials occur during the body of the QRS complex where they are hardest to detect in spite of the signalconditioning steps used to augment their presence. Activation of per&infarct zones late in the course of ventricular depolarization, as occurs with inferior infarctions, produces late potentials in the terminal portion of the QRS where they are more easily detected. Although most studied in the coronary disease patient, the signalaveraged ECG has been found to be of prognostic value in other diseases as well. Cripps et all” obtained signal-averaged studies on 64 patients with HCM and found abnormalities in 13 (20% ). Abnormalities were signiiicantly more common than in control subjects. Of more clinical significance is the fact that the signal-averaged ECG was abnormal in patients with HCM who had a history of sudden death or nonsustained ventricular tachycardia on 4S-hour AECG more often than in patients with HCM who had no history of sudden death or VT. The sensitivity of the signal-averaged ECG as a marker of electrical instability in this study was only 50%. Thus the presence of an abnormal signal-averaged ECG in this patient group implies increased risk, but the absence of an abnormal signalaveraged ECG cannot be construed to indicate particularly low risk. Late potentials are also associated with sustained ventricular arrhythmias in patients with DCM.178 Although incompletely studied in patients with LVH, the signal-averaged ECG may be less useful in this patient gro~p.‘~~ Standard time-domain analysis of the signal-averaged ECG cannot be performed in patients with bundle branch block or severe intraventricular conduction abnormalities. This precludes the use of this technique in a group of patients in whom the test could be potentially very useful. Frequency domain or spectral analysis of the terminal QRS and ST segment of the amplified QRS is unaffected bz bundle branch block and may be useful in this group of patients.’ ’ Although time-domain analysis is more predictive of inducible VT 7243
Curr
Fmbl
Cardid,
November
1992
during programmed stimulation in patients with VT, it is less predictive in patients with VF. In one recent study, frequency-domain analysis indicated abnormalities in patients with VF and VT.“* The signal-averaged ECG is of no value in following up patients on antiarrhythmic drug therapy. However, patients who undergo successful surgery for elimination of the arrhythmic focus will often have disappearance of their late potentials as welll”
HEART
RATE VAFUABILITY
A relatively recent addition to the arsenal of noninvasive tests used in the assessment of risk for sudden cardiac death is the analysis of heart rate variability. Schneider and CostiloelB3 first reported the relationship between sinus arrhythmia and prognosis after myocardial infarction more than 25 years ago. These investigators made three important observations: (1) sinus arrhythmia decreases in normal patients with age, (2) sinus arrhythmia is less evident after MI, and (9) those patients with the least evidence of sinus arrhythmia had the worst prognosis during follow-up after discharge.lB3 The use of heart rate variability, any of a variety of quantitative expressions of sinus arrhythmia, received little additional attention for more than 20 years. In 1987, Kleiger et al.,la in a report from the Multicenter Post Infarction Group, demonstrated that decreased heart rate variability is an important indicator of prognosis in patients after MI (Fig 7). As a determinant of prognosis, heart rate variability was indepenclent of other traditional risk factorsincluding LV function, ventricular ectopic beats, and drug treatment. In this study of 808 patients after MI, signal-averaged ECGs were not performed.‘84 In a recent study Farrell et al.lB5 found decreased heart rate variability also to be a powerful independent predictor of arrhythmic events in 487 patients less than 70 years of age after MI. In fact, reduced heart rate variability was more predictive of arrhythmic events (sustained VT or sudden death) than late potentials, frequency and complexity of ventricular arrhythmias on AECG, treadmill results, and EF. In the analysis of combinations of risk factors, the combination of late potentials on signal-averaged electrocardiogram and impaired heart rate variability on AFCG was more predictive of arrhythmic events than any other combination. Surprisingly, the addition of EF to the combination of late potentials and heart rate variability did not improve the predictive accuracy for arrhythmic events.185 If these results are confirmed by other investigators, the way patients are risk stratified after MI could undergo significant changes. Interest in heart rate variability as a clinical tool is a product of better understanding of the importance of the autonomic nervous Curr
Probl
Car&o!,
November
1992
727
‘-\
O.S{
0
Above IO0
Below 50
1.0 2.0 3.0 4.0 TIME AFTERMI(Yeors)
FIG 7. Cumulative survival over total follow-up period as a function of heart rate variability. Survival curves were calculated by method of Kaplan and Meier. Heart rate variability is expressed as the standard deviation of the RR interval. (From Kleiger et al: Decreased heart rate variability and its association with increased mortality after acute myocardial infarction Am J Cardiol 1987;59:256-262.)
system in heart failure and sudden death. It is increasingly apparent that the heart depends on a balance between sympathetic and parasympathetic inputs. Increased arrhythmogenicity results from increased sympathetic activity or a reduction in parasympathetic activity.=” Reduced heart rate variability is simply a reflection of the reduction, relative or absolute, in parasympathetic influence. As with the signal-averaged ECG, heart rate variability can be analyzed in the time domain or the frequency domain. Also as in the case of signal averaging, no standard convention for expression of heart rate variability exists among investigators. Mathematically, the simplest time-domain analysis is the determination of the standard deviation of the RR intewal about the mean RR for a specified number of beats or period of time. The resulting single value includes the effects of both sympathetic and parasympathetic activity.184J la7 Spec72.9
Cum
Probl
Cardiol,
November
1~~2
tral analysis (frequency-domain analysis) offers the advantage of separating the sympathetic and parasympathetic influences so that each can be studied separately. Higher frequency variations in RR interval reflect parasympathetic influence almost exclusively whereas lower frequency components are influenced by both sympathetic and parasympathetic activity.lss-lsO CARDIAC
CATHETERlZATION
We perform cardiac catheterization and coronary angiography in nearly every sudden death survivor. In the patient with coronary disease the need for concomitant surgical revascularization will have a bearing on management of the patient’s arrhythmia. The risk of defibrillator implantation or map-guided surgical resection is more readily assumed if the patient requires bypass surgery as well. On the other hand, patients who do not need concomitant revascularization or who cannot be adequately revascularized may be evaluated more intensively for medical therapy. We perform angiography in the younger sudden death survivors to exclude the presence of congenital coronary artery anomalies associated with sudden death in this age group. Although performed principally for the determination of coronary anatomy, a large amount of additional information may be obtained at catheterization that is of value in the comprehensive management of the patient. In some instances the catheterization merely confirms the results of noninvasive studies. Thus LV function, wall motion abnormalities, and the presence and severity of valvular disease can be assessed. Although not of direct benefit in arrhythmia management, determination of left and right ventricular filling pressures may be useful in the titration of therapy for heart failure, which many of these patients experience. ELECTROPHYSIOLOGIC
TESTING
Just as catheterization and angiography are necessary to define treatment options in the patient with coronary disease, invasive EP testing is essential in the determination of potential therapeutic alternatives in patients with malignant arrhythmias. Patients with inducible arrhythmias at baseline EP study can be considered for EPguided serial drug testing. Clinically relevant arrhythmias at EP study in this patient group include sustained (>3O set) monomorphic VT or the induction of polymorphic or monomorphic VT or VF with hemodynamic collapse manifested by hypotension with loss of consciousness (Fig 8). Considerable controversy still exists regarding the optimal EP protocol to use in the evaluation of sudden death survivors. The tradeCurr
Probl
Cardiol,
November
1992
729
AG
FIG 8. Surface leads I, Ii, III and V, and intracardiac ECGs from the high right atrium (HRA) and right ventricular apex (WA) with intraarterial blood pressure (BP) recording from a patient with a history of recurrent syncope, right bundle branch block and left anterior hemiblock. After a ventricular paced drive run (S, S, of 500 ms-120 beats per min), two ventricular extrastimuli (S, S,) are introduced that induce a right bundle branch morphologic ventricular tachycardia at a cycle length of 270 ms (220 beats per min) with AV dissociation. Also note the marked decrease in BP during the tachycardia. (From Naccarelli GV, Med C/in N Am, 1984;68:1211- 1230. Used with permission.)
off involved in selection of stimulation protocol is the desire to achieve a high rate of inducibility on the one hand while minimizing the induction of poorly reproducible, nonclinical responses on the other. The issues involved in this controversy were more relevant before strategies using implantable defibrillators were developed for noninducible patients. The protocol we use is outlined in Table 4. From 60% to 90% of patients surviving sudden death unassociated with acute MI are inducible at baseline EP study (Table 5).40-44,1s1 Differences among the various reported series in this regard probably reflect the different stimulation protocols used and the inclusion of nonsustained ventricular tachycardia as an endpoint by some investigators but not by others. In general, the likelihood of arrhythmia induction is higher in patients with coronary disease than in patients with other disease processes (Table 5). Unfortunately, few disease-specific series of sudden death survivors using EP testing 730
Curr
Probl
Cardiol,
Nowmber
1992
TABLE 4. Electrophysiology
Protocol
horn
University
of Texas
(Houston)
1. Recording of spontaneous intervals 2. Assessment of sinus node function: sinus node recovery assessed at multiple pacing cycle lengths (600 ms, 500 ms, 400 ms) 3. Assessment of AV nodal function: incremental atrial pacing and atrial extrastimulus techniques 4. Assessment of VA conduction: incremental ventricular pacing and ventricular extrastimulus techniques 5. Assessment of ventricular function: ventricular extrastimuli at multiple pacing cycle lengths (600 ms, 500 ms, 400 ms) 6. Tachycardia induction: double and then triple extrastimuli at two right ventricular pacing sites and at three paced cycle lengths 7. In selected patients: left ventricular pacing or pacing during isoprotemnol infusion AV = atrioventricular;
VA = ventriculoatrial.
have been reported. One exception is a recent report by Fananapazir and Epstein”’ of 30 sudden death survivors with HCM. Seventy percent of these patients had inducible sustained arrhythmias, principally polymorphic VT, using a protocol that used LV and right ventricular stimulation. In other experiences, including our own, the induction of sustained VT or VF in this group of patients is much less.lg3 Patients with idiopathic VF also have sustained arrhythmias induced in 70% of cases.lW From 47% to 68% of patients with DCM and symptoms related to arrhythmia have sustained arrhythmias induced at EP study.1g5-1g7 These series are not limited to sudden death survivors but include patients who have sustained VT without hemodynamic collapse, syncope, and sometimes even patients with symptomatic nonsustained tachycardia. Patients with the long QT syndrome represent the one group in which invasive EP testing may not be as usefuL1” These patients seldom have inducible arrhythmias. This may relate to the relatively unique mechanisms of arrhythmia operant in this disease an&or the inability to reproduce the autonomic milieu necessary for arrhythmogenesis in these patients in the EP laboratory. The use of intracardiac monophasic action potential recordings with provocative adrenergic challenge may be useful in these patients.l”’ ‘O” Localization and functional characterization of the accessory pathway(s) are the goals of EP study in the unusual patient with WPW who presents with rapid atrial and/or ventricular fibrillation and survives cardiac arrest. The response to programmed stimulation of sudden death sun+ vors in the drug-free state has important prognostic implications. Patients with inducible VT or VF at baseline study have more arrhythmia recurrences and fatal arrhythmia recurrences than patients who are noninducible. Freedman et aLzol found a 41% rate of arrhythmia recurrence at 1 year in inducible patients, whereas only Curr
Probl
Car&of,
November
1992
731
Wilbera Total
1
.-
Moradf Benditt4’
166 242
45 31
119 58 117
Roy40 Sale& Total
zii
2
N
Rs in Study
of Ventricular
Author
Inducibility
TABLE 5.
180 125
35 20 (67) (751
(78) 164)
Both
(76)
B. Studies
Using
Coronary Disease
(71) (571 (67)
n
in Series
A. Studies
85 33 118
Arrhythmias
62 41
10 11
and
(26) (25)
(22) (36)
Symptomatic
(29) (43) (33)
(WI
by Serial
72 37 109
N
Total Inducible
Arrhythmias
192 131
34 27
Nonsustained
Treated
Sustained
Survivors
Inducible
Death
Other Heart Disease
34 25 59
n
Only
Sustained
Using
of Sudden
(79) (791
176) (87)
Arrhythmias
(61) 641 (62)
(961
pts
as Endpoints
Electruphysiologic
147 102
27 18
as Endpoints
56 25 81
n
Coronary Disease Inducible
Study
182) (82)
177) (90)
(66) (76) (69)
1%)
45 29
7 9
16 12 28
n
Other Disease Inducible
(72) (71)
(70) (82)
(34) (481 (47)
(76)
14% of noninducible patients suffered recurrent arrhythmias in the same time frame. Kron et alzo2 found a similarly low probability of recurrence in noninducible patients. However, Sager et alzo3 reported an actuarial rate of recurrent sudden death in noninducible patients of 30% at 1 year. Patients without LV dysfunction (EF < 40%), frequent ventricular ectopy (>lO PVCs/hour), or the diagnosis of DCM had a much better prognosis than patients with these characteristics (Fig 9) .‘03 Baseline EP study is performed in the drug-free state whenever feasible. Patients with frequent arrhythmias are monitored carefully in the coronary care unit as therapy is withdrawn at least five halflives before study. Occasional patients (less than 5%) have so frequent or incessant tachyarrhythmias that drug-free study becomes impossible. These patients are studied on active therapy, but the results must be evaluated cautiously. A noninducible patient in this setting does not have the same prognosis as an inducible patient rendered noninducible by an appropriate therapeutic agent because they may not have had arrhythmia induced at baseline study. Although we perform invasive EP testing in nearly every survivor of sudden death unassociated with acute MI, EP testing of patients in
I
1
p - 0.002
LVEF < 0.40 and PVC’S > 1 O/hr (n = 6)
LVEF > 0.40 PVC?s”Z Whr (n=.20
FIG 9. Effect of ejection fraction and frequent PVCs on the probability of recurrent cardiac arrest in “noninducible” patients. (From Sager PT, Choudhary R, Leon C, et al: The long-term prognosis of patients with out-of-hospital cardiac arrest but no inducible ventricular tachycardia. Am Heart J 1990;120:1334-1342.) Curr
Probl
Cardiol,
November
1992
733
high-risk groups who have yet to experience an episode of sudden death remains controversial. Several reports have described the results of EP testing in the post-MI population.2”-21z Most have found the results of EP testing in the patient without coml$ications after MI to be poorly predictive of late sudden death?05j 06,‘OS8‘Og Most studies that have indicated a prognostic role for EP testing after MI have limited testing to higher risk groups (e.g., patients with congestive heart failure or bundle branch block).’ 6, ‘1X Even in these groups, routine clinical use of EP study depends on the development of strategies that can be demonstrated to reduce risk and prolong survival. Patients with nonsustained VI on AECG monitoring after MI represent a particular1 high-risk group that has been subjected to study. Buxton et al. Kl3 found that 45% of patients in this group had inducible sustained arrhythmias. A larger retrospective study, reported by the Philadelphia Arrhythmia Gro~p,‘~~ found sustained arrhythmias inducible in 35%. In a study reported by Wilber et al.‘15 that included only post-MI patients with EFs circulatory arrest with cardioplegic solutions may hinder the reinduction of tachycardia intraoperatively. The results of direct arrhythmia surgery for VT are excellent considering that these procedures are generally reserved for patients refractory to medical therapy. Operative mortality has ranged from 0% to 21% with an average of 12.4% .‘a The need for emergency surgery for intractable arrhythmias and presence of New York Heart Association (NYHA) Class III or lV heart failure symptoms are the major clinical variables associated with operative mortality.z88 Intraoperative factors that are associated with perioperative death include the inability to perform aneurysmectomy and the use of the encircling endocardial ventriculotomy.283’287 The efficacy of surgery as assessed by the inability to induce sustained arrhythmias at postoperative EP study averages 70% to 80%. COXES’has recently reported a reinducibility rate of only 2% in a series of 65 patients. Tachycardia associated with an inferoposterior infarction and multiple VT structures are associated with a higher probability of surgical failure.28s-2s1 Comparison of map-guided and visually guided procedures within the same institution indicates the benefit of intraoperative mapping.284 A trend toward higher cure rates is present in patients treated with wider endocardial resection as opposed to more localized proceduresW 746
Curr
Pmbl
Cardiol,
November
1992
Five-year survival for patients undergoing VT surgery ranges from series?&? In one series persistent inducibility at postoperative EP study was the only factor predictive of clinical recurrence of VT or sudden cardiac death.= Many patients who remain inducible postoperatively can be controlled medically by using regimens that were ineffective before surgery. The numbers of patients in this category are small, even when data are pooled. Medical suppression after surgical failure is associated with a favorable prognosis.288 Of the three major avenues of therapy for patients with ventricular arrhythmias-drugs, devices, and surgery-only surgery offers the opportunity for cure in the conventional sense. Many patients with ventricular arrhythmias require revascularization. The opportunity to address the arrhythmia directly at the time of revascularization is another appealing feature of the surgical approach. Surgery also offers the greatest opportunity for freedom from the pitfalls and sequelae of long-term use of antiarrhwic medications. In one recent comparison, 33% of patients required ant&rhythmic medication after map-guided surgery compared with 61% of patients who underwent implantation of automatic cardioverter defibrillators in the same institutions in the same time f&une.zs2 If success rates of 98% reported by Coti” and 96% reported by Krafchek et al?= can be reproduced in other institutions, the number of patients requiring medical therapy after surgery can be expected to be even lower. However, VT surgery has its own set of problems. Like serial drug testing, map-guided surgery is an option only in patients with inducible VT. Patients who have inducible VF or who are noninducible are not candidates for this approach. Patients inducible preoperatively in the EP laboratory may not be inducible intraoperatively. This occurs in up to 37% of patients undergoing VT surgery. This necessitates reliance on the preoperative map or changing to a visually guided surgical approach. The use of computerized multipoint mapping systems has shortened the time needed to perform intraoperative mapping. This facilitates mapping multiple morphologically different tachycardias and nonsustained arrhythmias; however, a finite period of monomorphic tachycardia is still required to map successfully. The surgical experience and technical expertise needed to use map-guided surgery have generally been concentrated at a few select referral centers. The significant perioperative mortality and surgical failure rate are the other major drawbacks to the surgical approach. Most reported series of patients treated surgically for ventricular arrhythmias contain a paucity of sudden death survivors. Surgical results for this subgroup are seldom presented or analyzed separately. One exception is the series reported by Moran et alzs2 The surgical approach used in this study was map-guided extended sub33% to 70% in reported
Curr
Probl
Cardiol,
November
1992
747
endocardial resection. Results for 17 patients whose presenting arrhythmia was VF were analyzed separately. The surgical mortality and postoperative inducibility of this=nmp were similar to that of the group of 20 patients who had VT. Yee et alFg3 reported the results of various surgical procedures-revascularization alone, endocardial resection alone, revascularization plus endocardial resection, defibrillator implantation, defibrillator implantation plus revascularization, and endocardial resection plus defibrillator implantation-in 62 sudden death survivors. In this nonrandomized study, endocardial resection with revascularization had a statistically increased perioperative mortality (22%) compared with the other surgical groups. However, late deaths were uncommon in the patients treated by endocardial resectionzg3 Thus, although surgical data on the treatment of sudden death survivors is far from conclusive, survivors with inducible VT are potential candidates for endocardial resection. Factors that augur for the surgical approach include the need for concomitant mvascularization or other open heart procedure, failure of medical therapy in patients with frequent episodes of arrhythmia, presence of a resectable discrete aneurysm, and preservation of function of the nonaneurysmal wall. In patients without discrete aneurysms, global LV function must be well preserved if endocardial resection is to be performed. Multiple morphologically different tachycardias and poor LV function remain the most significant relative contraindications.
ReVASCtJLARWATION
ALONE IN SUDDEN
DEATH
SURVIVORS
The effect of revascularization alone on the risk of recurrent arrhythmias in sudden death survivors is a subject of considerable controversy. In experimental preparations, the combination of acute ischemia and scar from previous infarction is more arrhythmogenic than ischemia or scar alone?“-22 Thus revascularization without concomitant direct arrhythmia surgery may be expected to have an impact on arrhythmia recurrence and subsequent sudden death. In a study reported by Tresch et al.,‘= 6 of 49 (12%) sudden death survivors treated with revascultiation alone had fatal arrhythmias during a mean follow-up of 55 months. The annual rate of recurrence of sudden death is well below the 10% to 20% per year risk reported in a series of sudden death survivors. However, 35% of the patients in this study experienced sudden death preoperatively in the setting of acute infarction and would be expected to have a relatively low probability of recurrence.294 Of 11 sudden death survivors treated with revascularization alone in the report by Yee et al.,2g3 2 (18%) had arrhythmia recurrences during an unspecified length of follow-up. 748
Curr
Pmbl
Car&of,
November
1992
Garan et alzs5 performed EP studies before and after coronary artery bypass procedures in 17 patients with a history of sudden death or VT resulting in syncope. Preoperatively, 15 of 17 (88%) patients had inducible arrhythmias. Postoperatively, only six patients remained inducible while one additional patient experienced spontaneous occurrence of VI’. The authors concluded that revascularization did have an impact on the arrhythmia substrate but that a significant number of patients had inducible arrhythmias despite bypass surgery.2g5 Interpretation of the results of this study is complicated by the fact that nonsustained VT was regarded as a positive response to programmed stimulation. Most of the patients who remained inducible after surgery were in the nonsustained group. Only one patient studied had a clinical recurrence of arrhythmia. All four patients with inducible VP preoperatively were noninducible postoperatively. These initial observations on the effect of revascularization alone on the results of EP study and recurrence of arrhythmia were recently expanded bz6the report of a larger group of 50 patients from the same center. Thirty-three of 41 patients (80%) studied preoperatively without medication had inducible arrhythmias. Only 19 of 42 (45% 1 patients studied postoperatively were inducible. In this study, only sustained VT and VF were considered to be positive responses. Again noted patients with inducible VP preoperatively were rendered noninducible by revascularization alone. In contrast, 80% of patients with VT induced preoperatively remained inducible after surgery. During a mean follow-up of 39 months, four arrhythmic events occurred, three unassociated with acute infarction. Two of the three events occurred in patients who remained inducible postoperatively, and the third occurred in a patient who was noninducible postoperatively.2v6 In contrast to the results of Garan et al. and Kelly et al. is the finding of inducibility of VP in two of seven sudden death survivors after bypass surgery reported by Kron et al?07 Three patients, including the two with inducible VP postoperatively, had recurrences of VF in the perioperative period. These authors concluded that the results of revascularization in patients with VF are much less predictable than previously thought and recommended full postoperative EP evaluation before hospital discharge.‘07 The following conclusions regarding the effects of revascularization on risk of recurrence of sudden death appear reasonable based on the available data: (1) revascularization alone probably reduces the likelihood of a recurrence of sudden death, (2) the magnitude of the reduction in risk is impossible to determine based on available data, and (3) revascularization alone is ineffective in preventing recurrences of arrhythmia in sudden death survivors with inducible VT. Indirect surgical procedures have a role in the treatment of sudCurr
Probl
Cardiol,
November
1992
749
den death survivors other than patients with coronary disease. High thoracic left sympathectomy is the treatment recommended for patients with the congenital long QT syndromes who remain symptomatic after treatment with ~-blockers.2s8 Aortic valve replacement in symptomatic patients with severe aortic stenosis makes a favorable impact on total mortality. Presumably part of the reduction in total mortality is due to a reduction in sudden death mortality. The impact of myectomy/myotomy procedures on sudden death mortality in patients with HCM has not been assessed. In patients with refractory arrhythmias and severe ventricular dysfunction, heart transplantation may be the only therapy that offers the possibility of longterm survival. AUTOMATIC IMPLANTABLFJ CARDIOVl3RTER-DEFIBRILLATORS
Since the implantation of the first automatic implantable defibrillator in 1980, the number of devices implanted each year has increased. Since Food and Drug Administration (FDA) approval and commercial availability of automatic implantable defibrillators with synchronized cardioversion capability (AICD) in 1985, the increase has reached geometric proportions (Fig 13).“’ The rapid rise in popularity of this mode of therapy is, in part, due to a measure of frustration with the conventional medical and surgical approaches to the treatment of patients with malignant arrhythmias. The increase in popularity of device-related therapy is also a tribute to the ease with which this therapy can be applied and to the rapid pace of technical advancement in the areas of automatic arrhythmia detection and termination made possible by microprocessor technologv. Device-based therapy, however, has its own set of pitfalls and is not appropriate for all patients. Full knowledge of the risks and benefits of AICD therapy is requisite for successful application of this modality. AICDs are implanted through one of three surgical approaches. Electrode placement using a spring electrode in the superior vena cava and a patch electrode applied to the heart has been supplanted by patch-patch systems because of superior defibrillation thresholds is used for pa(DFI’) with the latter approach.300 A left thoracotomy tients who have had prior surgery through median sternotomy. This approach avoids the need to perform extensive dissection of adhesions resulting from the prior operation. Patients who have not had prior surgery and who do not require concomitant cardiac surgery are usually implanted through a subxiphoid incision. Patients implanted through this approach have shorter recovery times than patients implanted by sternotomy or thoracotomy.301’ 302 Median sternotomy is reserved for patients requiring concomitant revasculariza760
Cum
Probi
Cardiol,
November
1992
1980198119821983198419851986198719881989 NnOOOO+ FIG 13. Growth in AICD implants over a IO-year period. AID = automatic implantable defibrillator; AICD = automatic implantable defibrillator with synchronized cardioversion capability. (From Nisam et al: ICD Clinical update: First decade, initial 10,000 patients. PACE 1991 ;14:256. Used with permission.)
tion and/or valve replacement. Median sternotomy is also used in those cases in which intraoperative testing indicates that satisfactory positioning of the rate-sensing electrodes or morphology-sensing defibrillator patches cannot be achieved from the subxiphoid approach. The patches are typically positioned over the anterior portion of the right ventricle and posterior left ventricle. The goal in establishing the patch positions is to avoid severely scarred myocardium and also to have as much viable myocardium as possible between the two patches. Positioning one patch over the right atrium through a mini-thoracotomy has been reported to be a successful alternative to median sternotomy when difficulty is encountered from the subxiphoid approach?03 Patches may be placed within the pericardium or extrapericardially. The rate-sensing electrodes are positioned over the diaphragmatic portion of the right ventricle or the lateral wall of the left ventricle, depending on the surgical approach. In contrast to the patches, the object of positioning the rate-sensing leads is to place them as close together as possible to minimize sensing interference from extraneous signals. Once positioned, the adequacy of placement of patches and leads is checked by both Curr
Probl
Cardiol,
November
ICI%?
761
pacemaker system analyzer and intracardiac electrogram recording. The importance of intraoperative testing using an external cardioverter defibrillator before device implantation has been demonstrated by Winkle et a1304 and Marchlinski et a1305 Cooperation and communication among the implanting surgeon, anesthesiologist, and electrophysiologist are requisite to a successful result. The goal is a safety factor of two or greater between the DFT and the maximum output of the implanted device. On occasion, we are forced to settle for a safety margin of only 10 joules (DFI of 20 joules in a 30joule device). This appears to be adequate for long-term device efficacy. 305 We use alternating current applied to the heart by means of temporary pacing wires to induce VF. Induction of VF is requisite in our opinion because the amount of energy necessary to terminate monomorphic VT is substantially less than the amount required to defibrillate the heart. Lead the patch placement in sudden death survivors should be tested under a worst case scenario. Measures that may be taken when DFTs are unacceptably high include reversing the polarity of the patches, moving one or both patches in an effort to encompass more of the viable myocardium, using larger patches, an&or resorting to a higher output device. Only after satisfactory DFIs have been demonstrated is the device implanted. Most devices are placed in the abdominal wall. Recently, a technique for incorporation of the device in the bony thorax has been described?06 After the device is connected to the rate-sensing leads and morphology-sensing defibrillator patches, the device is activated and programmed to the test mode. This blinds the device so that ventricular arrhythmia can be induced again. The device is then unblinded and successful tachycardia detection and termination by the implanted device is verified. The value of routine postoperative testing is a subject of ongoing controversy, although more uniform agreement exists regarding postoperative testing in patients placed on antiarrhflhmic medications between implantation and hospital discharge. Medication-related change in tachycardia cycle length often necessitates reprogramming the rate at which the device is triggered. The latest generation of devices commercially available has several programmable features. Programmable features include tachycardia detection criteria, tachycardia detection rate cutoff, first-shock energy, and first-shock delay. Tachycardia detection criteria include rate and probability density function (PDF). PDF takes advantage of the fact that the ECG signal during VF fluctuates minimally about the isoelectric level. Patients in supraventricular rhythms have larger amplitude fluctuations, and the amplitude of the signal at any moment in time is less likely (probable) to be at or near the isoelectric level. Although PDF successfully discriminates between most supraventricular rhythms and VF in most instances, it is less success762
Cur-r Probl
Cadiol,
November
1992
ful in differentiating VI from less dangerous rhythms. In some instances VT must degenerate to fibrillation before PDF criteria are satisfied. Because VT is more easily terminated than fibrillation, this delay may prevent successful arrhythmia termination. As a result, we routinely leave PDF programmed to the off position and rely on ratedetection criteria alone. Although this prevents delay in therapy for ventricular arrhythmias, it enhances the probability for shocks during supraventricular arrhythmias. The purposes of a programmable first-shock energy are to minimize patient discomfort and prolong generator longevity in patients whose clinical arrhythmia is VT. Many tachycardias can be terminated with energies of 1 joule or less. Subsequent shocks at full energy will rescue the patient if the initial low-energy shock is not successful. However, in our experience low-energy shocks are still perceived by patients as quite painful, Since the likelihood of successful arrhythmia termination depends on the duration of the arrhythmia, unsuccessful shocks are to be avoided. A several-fold safety margin for VT should be assured before the first-shock energy is programmed to a lower value. First-shock delay can be prolonged to allow the patient to lose consciousness before shock delivery. Again, because of concern of making the arrhythmia more difficult to terminate by delaying the initial shock, we seldom reprogram delay above the minimum value. Current technology mandates a period of 6.5 to 9 seconds for charging capacitors. This, coupled with a detection time that varies depending on the cycle length of the tachycardia (more rapid rhythms satisfy the detection algorithm more quickly), brief synchronization period, and the first-shock delay lead to a minimum time from the onset of arrhythmia to delivery of the first shock of 10-15 seconds. Subsequent shocks are governed by the detection algorithm and time required to recharge the capacitors: there is no additional delay. With current devices, five shocks can be delivered for a single episode of arrhythmia. The AICD is spectacularly successful from the standpoint of prevention of sudden death. In the largest single series reported to date, Winkle et a1307 reported an actuarial sudden death mortality rate of 4.4% in 5 years (Table 7). Data on 9,807 patients recently compiled by Cardiac Pacemakers, Inc. (St. Paul, Minnesota) also indicate an actuarial sudden death rate of 4.5% at 5 yearszgg Smaller series, however, report 5-year sudden death mortality in the 20% to 25% range.308, 3og Furthermore, sudden death rates may overstate the benefits of AICD therapy because operative deaths and nonsudden arrhythmiarelated deaths are not included in the sudden death calculation. The importance of arrhythmia-related nonsudden death was tirst stated by Guarnieri et al1 The term ‘total arrhythmic death” has been coined by Kim et aI?*’ to refer to the sum of perioperative deaths, arrhythmia-related nonsudden death, and sudden deaths. Curr
Probl
Cardid,
November
1992
763
TABLE 7. Kaplan-Meier
Actuarial
Mortality
Rate in 270 Patients
1 Year (n = 188) Sudden death Cardiac (nonsudden) death All cardiac deaths Total Reprinted ofcardiology,
with permission
2 Years In = 113)
3 Years In = 69)
4 Years In = 51)
5 Years fn = 12)
0.9% 6.2%
3.1% 13.0%
4.4% 13.9%
4.4% 15.3%
4.4% 20.3%
7.0% 7.7%
15.6% 16.3%
17.8% 18.4%
19.1% 19.7%
23.8% 26.2%
fmm the American
College of Cardiology
~Jour’nal
of rhe American
College
1989;13:1354-13611.
Actuarially determined freedom from sudden death in their series was 92% at 3 years. Freedom from total at-rhythmic death was only 85% at 3 years. At the b-year mark, actuarial survival was 76% for sudden death and 70% for total arrhythmic death.31o Operative mortality is a major determinant of the difference between sudden death rates and the rate of total arrhythmic death. This varies from 1% to 1.5% in some reports to 5% or more in others.307~310-312 The need for concomitant surgery is probably the factor that most consistently makes an impact on perioperative mortality.2gg Thus inclusion of all perioperative deaths in the total arrhythmic death category would appear to overstate the risk of AICD implantation. The true indication of the benefits of the AICD would appear to be somewhere between the actuarial survival free from sudden death and survival free from total arrhythmic death. There are no prospective randomized data comparing the results of AICD therapy with those of serial drug testing or direct arrhythmia surgery. Direct-comparison studies are difficult to perform because patients without inducible arrhythmias are not candidates for either serial drug testing or arrhythmia surgery. On the other hand, the results of EP study have little bearing on the use or benefits of AICD-based treatment.311 In the retrospective studies by Yee et alFg3 and Elefteriades et aLzg2 long-term survival in patients treated by endocardial resection with or without revascularization was equivalent to survival in patients having AICD implantation with or without revascularization. In a study by Fogoros et aL312 use of an early-generation defibrillator in conjunction with amiodarone was superior to amiodarone alone in patients with sustained ventricular arrhythmias seen with loss of consciousness, The technical requirements and surgical expertise for AICD implantation are less than those for map-guided arrhythmia surgery. The operative mortality for AICD implantation with revascularization is less than the average figure for endocardial resection. However, antiarrhythmic drug therapy is required in up to 70% of patients re754
Curr
Probl
Cardiol,
November
1992
ceiving defibrillators versus 20% to 30% of patients who have resection. Although drugs are often necessary, the intensity of drug therapy is often lower than in patients undergoing EP-guided therapy because the goal of therapy is a reduction in the frequency of discharges and not total suppression of the arrhythmia. Multidrug regimens and more toxic agents can usually be avoided. Device-based therapy is not without peril. Surgical complications are rare but quite serious when they do occur. The effects of antiarrhythmic drugs on defibrillation thresholds must be considered before the prescription of an antiarrhythmic agent. The Ic agents reportedly have the most marked effect on DFTs, but the effects of many drugs are incompletely characterized.313-315 The interactions between pacemakers and AICDs are even more complex (Table 8)?16 Because 10% of patients receiving defibrillators require permanent pacemakers as well, these interactions represent a common clinical problem. Unnecessary shocks are a painful nuisance. Device-based therapy is expensive. Some of the problems of AICD therapy will be overcome as further improvements in device design occur. The incorporation of antitachycardic pacing, bradycardiac pacing, and cardioversion-defibrillation capabilities in the same device will address several of the problems. Pacemaker interactions should be minimized because all functions would be controlled by the same logic circuitry. Antitachycardic pacing should reduce the need for concomitant medical therapy in selected patients. Improved telemetry and storage of diagnostic data should enable the number of spurious discharges to be reduced. However, the need for antiarrhythmic drug therapy may increase in some patients in an attempt to slow rapid VTNF to a hemodynamically stable VT so that pacing reversion can be attempted. Development of new patch and electrode designs is important to eventual reduction in the size of the implanted device. A device that can be implanted routinely without a thoracotTABLE 8. Adverse
Device
Interactions
in Patients
With
Pacemakers
Interaction
Result
Pacemaker dysfunction: failure to sense after AICD discharge Double counting: pacemaker artifact and wave counted separately by AICD AICD sensing pacemaker artifact during VIorVF Pacemaker repmgrammlng by AICD discharge
Post-shock
*Adapted from Calkins et al?16 AICD = automatic implantable defibrillator with ular tachycardia; VF = ventricular fibrillation.
Cur-r Pmbl
Cardiol,
November
1992
It
and AICDs”
bradycardia
or asystole
Inappropriate
discharges
Inappropriate
failure
Pacemaker
synchronized
reversion
cardioversion
by AICD of AICD
to backup
capabiiity;
to discharge mode
VI = ventric-
756
omy would have a major impact on patient acceptance and the total cost of device-based therapy. The effects of the AICD on total mortality are more modest than the effects on sudden death mortality. Five-year actuarial sutvival in patients after implantation is only 73.8% in the Winkle series (Table 7).307 Survival is worse in those patients who receive discharges than in those who do not.317 Most late deaths in reported series are due to progressive myocardial dysfunction. Luceri et a1318 have reported that a significant number of the late follow-up sudden deaths are due to electromechanical dissociation and not intractable ventricular arrhythmias. This reflects progressive myocardial disease after implantation. Progressive myocardial dysfunction makes care of the AICD patient complex and time-consuming. These patients require frequent medication adjustments and close monitoring. They often have special psychological needs that also must be met. THE ECONOMICS
OF SUDDEN
CARDIAC
DEATH
The current climate in medicine is marked by the prevalence of new technologies in many areas of practice and by appropriate concern for the escalation of health care costs that are inherent in the use of many of these technologies. In few areas are these issues brought more sharply into focus than in the care of the sudden death survivor. Empiric antiarrhythmic therapy is relatively inexpensive but also ineffective. Device-based therapy, antiarrhythmic surgery, and pharmacologic therapy guided by EP study are all expensive. Even very expensive therapies for uncommon conditions contribute little to the overall cost of health care delivery. Unfortunately, sudden cardiac death afflicts hundreds of thousands of patients each year. Allowing for those events occurring during an episode of infarction and the fact that only 15% to 25% of patients who experience sudden death will be successfully resuscitated and survive to hospital discharge, still many thousands survive sudden death experiences annually and are candidates for the expensive therapies described in the previous section. Because of the large number of patients affected, relative differences in the costs of different therapies are important. O’Donoghue et a131s have published data comparing the initial hospitalization cost of serial drug testing and defibrillator implantation as initial therapy after baseline EP testing (Table 9). Cost of hospitalization was calculated from the date of baseline EP study to the date of discharge and included costs of implanted devices. The authors concluded that early defibrillator implantation was no more costly than serial drug testing. Patients inducible at baseline EP study rendered noninducible by medical therapy had 756
Curr
Probl
Cardiol,
November
1992
TABLE 9. Hospital
Stay
and Costs
in the Patient Group I (direct AICD)
No. of patients No. of drugs No. of EP studies Hospital stay (days) cost (X $1,000) *Reprinted
Groups’ Group II (EP-guided therapy)
7 1.4 -+ 1.2 1 12.6 k 6.2 40.4 k 8.3
with permission
ti-om the American
3.3 3.0 202 48.9
32 2 * + f
1.2* 1.0* 9.3 31.6
Group IIA Idrug) 3.0 2.6 12.0 17.2
12 k 1.4t +- 0.90 2 6.25 + 9.598
Group IIB (late AICD) 3.5 3.3 26.3 73.4
College of Cardiology
~Journal of the American
with
cardiovenion
20 2 f 2 k
1.1* 1.04 5.8* 17.01 College
ofcardiology199o;16:1258~.
tP < 0.05 compared with group I. *P < 0.001 compared with group 1. §P < 0.001 compared with group IIB. AICD = automatic implantable defibrillator electmphysiologic
synchronized
capability;
EP =
substantially lower total costs than patients who received defibrillators.31s Total costs were highest in patients inducible at baseline EP study who failed serial drug testing and subsequently underwent device implantation. Thus a treatment allocation strategy restricting serial drug testing to those patients with greater likelihood of responding to pharmacologic therapy could be the most cost-effective. Although the cost of the initial hospitalization is but one aspect of the total cost of the ongoing care of the sudden death survivor, the importance of being able to predict with reasonable accuracy who will respond to antiarrhythmic drugs and who will not is evident. This would appear to remain a fruitful area for future investigation. Kuppermann et aL3” have published an elegant analysis of the cost-effectiveness of therapy with the implantable defibrillator. Using data from a variety of sources supplemented by the opinions and estimates of a panel of experts, these investigators calculated the incremental benefit of defibrillator therapy in comparison to medical therapy under a variety of different scenarios. The total life expectancy of a defibrillator patient was determined to be 5.1 years, whereas the life expectancy of a patient treated medically was 3.2 years (incremental benefit of 1.9 years). The incremental cost incurred to accrue this benefit was estimated to be between $15,000 and $25,000 per life-year saved. Cost of initial hospitalization for patients with defibrillators was determined to be $49,830 (1986 dollars) and total expected cost for the lifetime of the defibrillator patient, including generator replacement and concomitant medical therapy, was estimated to be $121,540 (average of $23,800 per annum). The cost per life-year saved for implantable defibrillator therapy was compared with a number of health care interventions and costeffectiveness of defibrillator therapy compared favorably with therapies like heart transplantation or chronic dialysis (Table 10)?” This Curr
Probl
Cardiol,
November
1992
767
TABLE 10. Cost per Year
of Life Saved
for Some
Health
Investments”” Cost
Investment Neonatal intensive care (weight l,OOO-1,499 g) Coronary artery bypass surgery (three-vessel disease) Thyroxine (T,) thyroid screening Treatment of seven? hypertension (diastolic 105 mmHg) in men aged 40 years Implantable defibrillator Treatment of mild hypertension (diastolic 95-104 mmHg1 in men aged 40 years Heart transplantation Estrogen therapy for postmenopausal symptoms in women without a prior hysterectomy Neonatal intensive can? (weight 500-999 g) Coronary artery bypass surgery for one-vessel disease with moderately severe angina School tuberculin testing pmgram Continuous ambulatory peritoneal dialysis Hospital hemodialysis Data reproduced 8191-100.
with
Copyright
permission 1990 American
fmm
Kupperman
Heart
M, Lute
BR, McCovem
per Life-Year Saved I%) 5,500 7,200 7,700 11,000
17,400 23,200 26,900 32,900 38,800 44,200 53,100 57,300 59,500 8, et al. Circulation
1990;
Association.
study has been criticized for perhaps overestimating the incremental benefit of defibrillator therapy.321 However, the importance of this type of analysis can not be overstated. A major question facing medicine and society at this juncture is not only whether a therapy or technologic advance is effective in prolonging life but also how many of these life-saving therapies we can afford. Despite the enormous sums of money involved, care of the sudden death sutivor is a money-losing venture for many hospitals. In patients receiving defibrillators, reimbursement by Medicare for the entire hospitalization is little more than the cost of the device alone in some instances. Clearly a need exists to establish equitable reimbursement guidelines if effective therapy for sudden death survivors is to remain within the reach of most Americans. Concomitantly, ways to reduce the cost of the care of these patients must be sought. Few breakthroughs are on the horizon that will make an impact on the cost of serial drug testing or antiarrhythmic surgery. On the other hand, costs of device-based therapy will be reduced by greater device longevity and by the development of devices that can routinely be implanted without the need for a thoracotomy. Availability of multiple devices from competing manufacturers also may make an impact on those aspects of care directly related to the device. Responsibility for reducing the cost of care without sacrificing the quality of care must rest with a partnership among physicians, hos768
Curr
Probl
Cardiol,
November
1992
pitals, governmental agencies, commercial insurers, and manufacturers and suppliers of health-related products. If the economic consequences of caring for the sudden death survivor are substantial, the financial implications of prophylactic therapy for patients at high risk are even more so. The low survival rates of patients experiencing initial episodes of sudden death indicate that prophylactic therapy is requisite to make a major impact on the overall cardiac sudden death problem. Considerable resources are already expended in risk-stratification procedures and treatment of the post-MI patient. Prospective studies are underway to identity patients who may benefit from device therapy or EP-guided therapy. If these studies demonstrate efficacy of these approaches in selected subgroups of patients, the expense of caring for the patient at risk for sudden death will rise accordingly. b R.C. domized
A need exists for a prospective carefully designed, study of the cost-effectiveness of implanted AICD devices.
SCHLANT:
large,
ran-
CONCLUSION
Significant changes have occurred since the first issue of Current Problems in Cardiology dealing with sudden cardiac death, which was published in 1980 by Lown and colleagues.322 At that juncture, EP-guided therapy was in its infancy, limited experience with mapguided arrhythmia surgery had been published, and the first human implant of an automatic defibrillator had not been performed. The past 12 years have produced a revolution in technology that has been brought to bear on the problem of sudden cardiac death. Not all steps have been in the forward direction. Empiric use of antiarrhythmic agents to treat patients at risk for sudden death or the sudden death survivor (the norm of medical practice for a number of years) clearly was ineffective and potentially harmful. Although the arsenal of antiarrhythmic drug therapy is better stocked than it was in 1980, the toxicities and low efficacy rates of many of these agents in patients with life-threatening ventricular arrhythmias have been clearly demonstrated. Nevertheless, three effective treatment modalities- EP-guided pharmacologic therapy, antiarrhythmic surgery, and AICD therapyhave evolved in a relatively brief time for treatment of the sudden death survivor. The availability of more than one form of therapy is key. Many patients are candidates for one approach and not others. Many patients prefer one approach over others. Many patients require combined modalities. What of the next 12 years? Certainly the rate of progress in this area of clinical medicine makes long-range forecasting ill-advised. On the other hand, short-range projections are probably acceptable. Evolution of the current therapeutic modalities will continue. The Curr
Pmbl
Cardiol,
November
1992
759
techniques of primary arrhythmia surgery are constantly being refined, but no major breakthroughs in this field are on the horizon. Surgical experience and technical expertise will remain the major factors responsible for the success of surgical techniques in carefully selected patients. Catheter ablation techniques, which have revolutionized the care of patients with supraventricular arrhythmias, have found a much more limited role in patients with ventricular arrhythmias.323-325 The area to be mapped is large, and simultaneous mapping of multiple points is not possible. Chemical, or ercoronary, ablation has not received widespread application.326J 3P’ The entire field of antiarrhythmic pharmacologSr is in a state of turmoil in the aftermath of the CAST study. Although the CAST trial is commendable for subjecting an important clinical question to a rigorous test, one of the unfortunate outcomes is that development of new antiarrhythmic agents has been curtailed significantly. One drug, encainide, has been withdrawn from the commercial marketplace altogether. Plans for further testing and market release of other agents have been abandoned. Although the efficacy of individual agents in patients with life-threatening arrhythmias is low, clinical usefulness is present in having a wide choice of agents for the patient with a life-threatening arrhythmia. Although the development of some new agents has been discontinued, other avenues for progress in the application of pharmacotherapy to the problem of sudden death have been opened. Ongoing investigations include the delivery of drug directly to the myocardium by implantable iontophoretic systems. These systems can potentially achieve myocardial levels of drugs unattainable with systemic therapy but with less systemic toxicity.32S Chemical defibrillation using a bolus of antiarrhythmic drug retroperfused into the coronary sinus at the onset of arrhythmia is another new application that is under investigation for both new and conventional antiarrhythmic agents.32g Device therapy is certainly still in an evolutionary phase. The expected release by the FDA of devices with bradycardiac pacing, antitachycardic pacing, and defibrillation capabilities is an important step. The importance of the development of devices that can be implanted without the need for major surgery has already been stated. Clinical trials with a number of nonthoracotomy devices are ongoing. Although observing the growth and maturation of existing therapeutic modalities is exciting, one still has a sense that all the current treatment modalities are somewhat lacking. All are expensive. All are invasive. Antiarrhythmic drug toxicity and surgical morbidity and mortality and economic considerations preclude the application of current techniques to many patients at increased risk for sudden death but who have not experienced an episode. The 760
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Probl
Cardiol,
November
1992
need still exists for more creative thought. Clearly the need exists for more knowledge of the cellular and subcellular mechanisms of life-threatening arrhythmias. In our opinion the application of this knowledge will produce the next quantum advances in the clinical approach to sudden cardiac death. b R.C. SCHLANT: Dr. Gilman and Dr. Naccarelli have given us a splendid, detailed review of the current (and future) status of sudden-cardiac death, including its pathophysiology, its occurrence in many disease states, its clinical evaluation and current management, and economic considerations of the management of patients with the syndrome. Their review should be of great value to all cardiologists and to all other physicians who see patients who have experienced sudden cardiac death or who have a condition In which it is more likely to occur. Their superb review is well Illustrated and extensively referenced.
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