(Circulation. 1998;98:2334-2351.)
© 1998 American Heart Association, Inc.
Clinical Cardiology: New Frontiers |
Sudden Cardiac Death
From the Krannert Institute of Cardiology, Indiana University School of Medicine and the Roudebush Veterans Administration Medical Center, Indianapolis (D.P.Z.), and the Department of Cardiology, Academic Hospital Maastricht and the Interuniversity Cardiology Institute of the Netherlands, Utrecht (H.J.J.W.).
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46202-4800.
Key Words: death, sudden • mortality • coronary disease
Sudden cardiac death describes the unexpected natural
death from a cardiac cause within a short time period, generally 
1
hour from the onset of symptoms, in a person without any prior
condition that would appear fatal.1 2 Such a
rapid death is often attributed to a cardiac arrhythmia, but
with the advent of monitoring capabilities from implantable
cardioverter-defibrillators (ICDs), it is now well recognized that
classifications based on clinical circumstances can be misleading and
often impossible, because 40% of sudden deaths can be
unwitnessed.3 Only an ECG or a
ventricular electrogram recorded from an implanted
device at the time of death can provide definitive information about an
arrhythmia. Prodromal symptoms are often nonspecific, and even
those taken to indicate ischemia (chest pain), a
tachyarrhythmia (palpitations), or congestive heart
failure symptoms (dyspnea) can only be considered suggestive. For these
reasons, total mortality, rather than classifications of cardiac and
arrhythmic mortality, should be used as primary objectives for many
outcome studies.
Magnitude of the Problem
Sudden cardiac death accounts for 300 000 to 400 000 deaths
annually in the United States, depending on the definition
used.1 2 When restricted to death <2 hours from
the onset of symptoms, 12% of all natural deaths were classified as
sudden in one study, and 88% of those were due to cardiac
disease.1 Sudden cardiac death is the most common
and often the first manifestation of coronary heart disease and
is responsible for 
50% of the mortality from
cardiovascular disease in the United States and other
developed countries. In less-developed countries, sudden cardiac death
rates parallel the rates of ischemic heart disease as a whole
and therefore are lower. Several population-based studies have
documented a 15% to 19% decline in the incidence of sudden cardiac
deaths caused by coronary heart disease since the early 1980s.
However, the increasing incidence of congestive heart failure may halt
this decline in the future.4
Figure 1
places the problem into
perspective by expressing the incidence of sudden cardiac death in
different subgroups at varying risk while indicating the overall number
of events per year for each. Thus, if one considers an overall
incidence in the adult population of only 0.1% to 0.2% per year, when
applied to the entire US population, that accounts for more than
300 000 events per year. In contrast, although 33% of patients in
the convalescent phase after a large myocardial infarction experience
sudden cardiac death in the year thereafter, overall they account for a
small number of the total sudden cardiac deaths per year. The use of
interventions that limit infarct size, such as
thrombolytic agents, has reduced this number still
further. These factors have an impact on the effects of therapeutic
interventions because, although it is relatively easy to identify
patients in the small high-risk subgroups and then to possibly prevent
or reverse a ventricular tachyarrhythmia,
the overall impact on the total number of sudden cardiac deaths will be
small. It becomes obvious that, to significantly reduce the incidence
of sudden cardiac death, more specific markers are needed for the
general population to identify large numbers in subgroups that account
for a bigger percentage of the more than 300 000 who die suddenly. The
present risk factors (see below) generally identify the risk of
developing the structural heart disease underlying sudden cardiac death
rather than the proximate precipitator of the event. Because the risk
of sudden cardiac death does not necessarily equate with the risk of
developing structural heart disease, these risk factors have limited
ability in identifying specific individuals at risk for sudden cardiac
death. Nevertheless, their control, with concomitant reduction in death
from coronary artery disease, is probably at least in part
responsible for the reduction in overall sudden cardiac death. Figure 1B shows idealized curves of survival from sudden cardiac death for a
population free of major cardiovascular events versus a
population that has survived a major cardiovascular
event. After an initial high attrition rate for the high-risk group in
the first 6 to 18 months, the curves then become parallel, illustrating
the modulating effects of time on the incidence of sudden cardiac
death. Ultimately, risk stratification will be important only if it can
be coupled with a therapeutic intervention that reduces the risk of
dying.
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Risk Factors of Sudden Cardiac Death
Influence of Age, Race, and Sex
Because up to 80% of individuals who suffer sudden cardiac death
have coronary heart disease, the
epidemiology of sudden cardiac death to a great
extent parallels that of coronary heart disease. As such, the
incidence of sudden cardiac death increases with age in both men and
women, whites and nonwhites, because the prevalence of ischemic
heart disease increases with age (Figure 2). However, among patients with
coronary heart disease, the proportion of coronary
deaths that are sudden decreases with age. Sudden cardiac death has a
much higher incidence in men than women, reflecting sex differences in
the incidence of coronary heart disease as well. Thus, 75%
of sudden cardiac deaths occur in men, with an annual incidence 3 to 4
times higher than in women. The peaks in incidence of sudden cardiac
death occur between birth and 6 months of age because of the sudden
infant death syndrome, and then again between 45 and 75 years of age as
a result of coronary artery disease. Sudden cardiac death
accounts for 19% of sudden deaths in children between 1 and 13 years
of age and 30% between 14 and 21 years of
age.5
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Activity
The impact of physical activity on sudden cardiac death is
somewhat controversial. Although vigorous exercise can trigger sudden
cardiac death and acute myocardial infarction,6
in part possibly by increasing platelet adhesiveness and
aggregability, moderate physical activity may be beneficial by
decreasing platelet adhesiveness and
aggregability.7 In cardiac rehabilitation
programs, cardiac arrests occur at a rate of 1 in 12 000 to 15 000,
and during stress testing, cardiac arrest occurs at a rate of 1 per
2000, at least 6 times greater than the general incidence of sudden
cardiac death for patients known to have heart disease. Experimentally,
it appears that regular exercise in dogs prevents
ischemia-induced ventricular fibrillation and death
by increasing vagal activity.8 Thus, it may be
that regular exercise decreases cardiovascular
morbidity and mortality, whereas vigorous exercise, particularly in
untrained individuals, may have an adverse effect. The annual incidence
of sudden cardiac death during exercise is 1 per 200 000 to 250 000
healthy young people,1 whereas in competitive
athletes, sudden cardiac death is very rare, despite the publicity,
with only 20 to 25 sports-related sudden cardiac deaths from cardiac
causes annually in the United States.9 In young
athletes (Figure 3), sudden cardiac death
most often occurs from hypertrophic cardiomyopathy,
and in older athletes, from coronary heart
disease.10 Interestingly, in Europe, particularly
in northern Italy, arrhythmogenic right ventricular
dysplasia, possibly congenital, is the predominant anatomic finding in
athletes with sudden cardiac death.11 Commotio
cordis, that is, concussion of the heart from nonpenetrating blunt
trauma to the anterior chest, can lead to fatal cardiac arrest, due to
either myocardial trauma or the mechanoelectrical triggering of a
ventricular tachyarrhythmia during the
vulnerable period of the T wave.12 As with some
other risk factors, the overall impact of activity on sudden cardiac
death may be small. In the Maastricht Sudden Death study, 67% of the
sudden death victims were physically inactive at the time of the
event.3
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Anatomy
Anatomic findings at autopsy include acute changes in
coronary plaque morphology, such as thrombus, plaque
disruption, or both, in >50% of cases of sudden coronary
death, whereas in hearts with myocardial scars and no acute infarction,
active coronary lesions are identified in 46% of cases.
Erosion of proteoglycan-rich and smooth muscle cell–rich plaques
lacking a superficial lipid core, or plaque rupture, is a frequent
pathological finding.13 Plaque rupture appears to
be more common in older women.14
Apoptosis may participate in the genesis and pathophysiology of
some cardiac arrhythmias or conduction disturbances
responsible for sudden cardiac death.15 However,
these anatomic abnormalities are not represented by
specific clinical risk factors different from those that identify
patients with coronary heart disease in general. In addition,
because mechanisms responsible for sudden cardiac death depend in part
on anatomic substrate, which naturally varies from one individual to
another, the usefulness of risk assessment modalities varies from one
patient and particular type of anatomic substrate to another.
Furthermore, in addition to interpatient variations, there may be
intrapatient variation due to temporal changes in specific diseases
(Figure 1
).
Other Risk Factors
Age, hypertension, left ventricular
hypertrophy, intraventricular
conduction block, elevated serum cholesterol, glucose
intolerance, decreased vital capacity, smoking, relative weight, and
heart rate identify individuals at risk for sudden cardiac death
(Figure 4). Smoking is an important risk
factor. In the Framingham study, the annual incidence of sudden cardiac
deaths increased from 13 per 1000 in nonsmokers to almost 2.5 times
that for people who smoked >20 cigarettes per day. Stopping
smoking promptly reduced this risk, which may be mediated by an
increase in platelet adhesiveness, release of
catecholamines, and other mechanisms. Elevated serum
cholesterol appears to predispose patients to rupture of
vulnerable plaques, whereas cigarette smoking predisposes patients to
acute thrombosis.16 Female survivors of cardiac
arrest are less likely to have underlying coronary artery
disease, even though coronary artery disease status is the most
important predictor of cardiac arrest in women; impaired left
ventricular function appears to be the most important
predictor in men.17 In patients with severe heart
failure, nonsustained ventricular tachycardia
may be an independent marker of increased mortality due to sudden
cardiac death.18 According to one
study,19 sudden coronary deaths are less
likely to occur at home than nonsudden coronary deaths, whereas
individuals who die of sudden coronary death are more likely to
have been current cigarette smokers. However, in the Maastricht
study,3 80% of sudden cardiac deaths occurred at
home. Emotional stress can be an important trigger for sudden cardiac
death, as shown by the Northridge earthquake that struck the Los
Angeles area at 4:31 AM January 17,
1994.20 Depression in a patient in the hospital
after myocardial infarction is a significant predictor of the 18-month
post–myocardial infarction cardiac mortality, and the risk associated
with depression was greatest among patients with frequent premature
ventricular complexes. Socioeconomic factors are also
important; sudden cardiac death after myocardial infarction increases
3-fold in men with low levels of education and complex
ventricular ectopy compared with better educated men who
have the same arrhythmias.
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History can provide clues to the high-risk patient. For example, in patients with ventricular tachycardia after myocardial infarction, on the basis of clinical history, the following 4 variables identify patients at increased risk of sudden cardiac death: (1) syncope at the time of the first documented episode of arrhythmia, (2) NYHA class III or IV, (3) ventricular tachycardia/fibrillation occurring early after myocardial infarction (3 days to 2 months), and (4) history of previous myocardial infarctions.21 In some patients, family history can be important.22
Left ventricular dysfunction is a major independent predictor of total and sudden cardiac mortality in patients with ischemic and nonischemic cardiomyopathy.23 For example, in survivors of cardiac arrest who have a left ventricular ejection fraction <30%, the risk of sudden cardiac death exceeds 30% over 1 to 3 years if the patients do not have inducible ventricular tachycardia, whereas it ranges between 15% and 50% in those who have inducible ventricular tachyarrhythmias despite therapy with drugs that suppress the inducible arrhythmias or with empirical amiodarone.24 25 Whether an ICD will reduce total mortality in patients with severe left ventricular dysfunction alone is the subject of several prospective trials, including the Multicenter Automatic Defibrillator Implantation Trial (MADIT II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).26 These patients have competing causes of death, and unless death is caused primarily by a ventricular tachyarrhythmia that can be terminated by prompt defibrillation, the ICD may not have an important impact. Although prompt defibrillation generally restores sinus rhythm with a very high success rate, it may not be as successful in patients with very advanced ventricular dysfunction.
Certain ECG abnormalities can help identify patients at increased risk
for sudden cardiac death. These include the presence of AV block or
intraventricular conduction defects and QT
prolongation, an increase in resting heart rate to >90 bpm, and
increased QT dispersion in survivors of out-of-hospital cardiac arrest.
A recent study failed to support the usefulness of QT dispersion in
predicting risk in patients after myocardial
infarction.27 The presence of complex
ventricular arrhythmias, such as nonsustained
ventricular tachycardia, is also a
marker1 (Figure 5).
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Transient Risk Factors
Unfortunately, most of these more stable risk factors lack
sufficient sensitivity, specificity, and predictive accuracy to
pinpoint the patient at risk with a degree of accuracy that would
permit using a specific therapeutic intervention before an actual
event. This probably relates, at least in part, to the transient nature
of many risk factors, such as myocardial ischemia and
reperfusion; hemodynamic dysfunction; abnormalities in
electrolytes, such as hypokalemia and hypomagnesemia, often due to
diuretics; changes in pH or
PO2; the influence of central and
peripheral neurophysiological actions;
and the transient effects of toxins such as
drugs28 or alcohol.1 2
Structural cardiac abnormalities of the myocardium,
coronary arteries, or cardiac nerves provide the substrate on
which a transient risk factor operates. Although it is possible that
intense functional changes alone may create electrical instability of
the normal heart to the degree that a ventricular
tachyarrhythmia can be provoked, the vast majority of
cardiac arrests occur in patients with hearts that have structural
abnormalities. One group that was identified before a cardiac arrest
with sufficient accuracy to warrant ICD placement was the MADIT
population,29 who were post myocardial infarction
and had spontaneous nonsustained ventricular
tachycardia, inducible sustained ventricular
tachycardia not suppressed by intravenous
procainamide, and an injection fraction <35%.
As noted earlier, the most common structural abnormality is
coronary atherosclerosis and its consequences,
such as myocardial infarction. Interestingly, only 20% of patients
who survive cardiac arrest develop features of a transmural myocardial
infarction, and it is assumed that transient myocardial
ischemia, perhaps caused by coronary spasm or unstable
platelet thrombi,13 30 plays an important
role in precipitating a lethal ventricular
tachyarrhythmia. Myocardial hypertrophy,
congestive heart failure, and cardiac
dilation,31 32 as well as regional autonomic
dysfunction,33 34 all may be important. Although
almost 50% of deaths in heart failure patients are sudden, among
patients with cardiomyopathies, those with
better-preserved functional capacity (NYHA functional classes I and II)
have lower total death rates, but the fraction of all deaths that are
sudden and unexpected is higher; among class IV patients, total death
rates are higher, but the fraction of sudden deaths is lower; thus, the
impact of reducing sudden cardiac death in this population will be
influenced by competing causes of other mechanisms of
death.1 2 Time of day is also important, with
more sudden cardiac deaths, strokes, and myocardial infarctions
occurring in the morning on arising from bed, perhaps related to
increased sympathetic discharge in response to venous pooling that then
triggers increased blood viscosity and platelet
aggregation.35 The lack of association between
the times of day in almost 600 patients who had at least 2 separate
cardiac arrests supports the hypothesis that a person's activity may
also play a role in triggering the cardiac
arrest.36
Thus, if structural factors for the most part only create a substrate on which the transient factors operate to initiate a ventricular tachyarrhythmia, risk identification requires finding those subjects whose inherent physiological characteristics make the initiation of electrophysiological instability more likely when these conditions are met. This requires clinically identifiable, genetically based or acquired, individual differences in the responses of membrane channels, receptors, exchangers, and pumps in the susceptible individual,2 a formidable challenge at present. Patients with the congenital long-QT syndrome (see below) serve as the prototypic example of the interaction between a molecular myocardial abnormality, an "ionopathy," and an inciting event, eg, exercise in LQT1 and sleep/rest in LQT3.37 Some patients may have a non–clinically manifest abnormality in repolarization, a latent form of long-QT syndrome, that becomes provoked only by exposure to certain drugs.37 Thus, molecular abnormalities in the long-QT syndrome, as well as in conditions such as hypertrophic cardiomyopathy,38 help provide genetic markers of patients at increased risk.
An antiarrhythmic drug can create the abnormality on which a transient risk event, such as ischemia, interacts to provoke a lethal arrhythmia.39 For example, in the CAST experience, despite the increased risk of sudden cardiac death established by the presence of complex forms of ventricular ectopy, particularly in older age groups and in patients post myocardial infarction, suppression of those ventricular arrhythmias with encainide and flecainide conferred an increased risk of death and/or no improvement in survival with moricizine.40 Death among those treated with an antiarrhythmic drug may have resulted from an interaction between the substrate of coronary artery disease, the transient risk factor of acute myocardial ischemia, and the exacerbation of ischemia-induced conduction slowing produced by drugs with negative dromotropic actions, such as encainide or flecainide.41 The results of CAST taught us at least 3 important lessons: (1) that mechanisms responsible for premature ventricular complexes, which were suppressed, were different from mechanisms that caused sudden cardiac death, presumably from a ventricular tachyarrhythmia, which was increased; (2) that proarrhythmia from an antiarrhythmic agent could occur months after drug initiation and was not always an early event; and (3) that antiarrhythmic drugs could become a risk factor when the myocardial substrate changed, presumably when ischemia developed.
Electrophysiological End Points
Two tests that reflect autonomic actions on the sinus node can
also be useful risk stratifiers. Baroreflex sensitivity, reflecting a
vagal response to acute blood pressure elevation, is reduced in
patients at risk of sudden cardiac death,42 and
heart rate variability, a measure of beat-to-beat variations of
sinus-initiated RR intervals, with its Fourier-derived
parameters, is also blunted in these
patients.43 It is important to stress that both
of these parameters judge autonomic modulation at the sinus
node, which is taken as a surrogate for autonomic actions at the
ventricular level. Autonomic effects at the sinus node and
ventricle can easily be dissociated
experimentally44 and may possibly be a cause of
false-positive or false-negative test results.
According to chaos theory, apparently irregularly irregular events, such as ventricular ectopy, are nonrandomly distributed in time, and their clustering can be quantified by fractal geometric analysis, which may help identify patients at risk for sudden cardiac death.45 Late potentials, which are electrical activity in the microvolt range extending the duration of a filtered QRS complex and detected by signal-averaged ECG, has good negative predictive value but low positive predictive value in patients after myocardial infarction.1 More recently, late potentials were not found to be useful in identifying patients who might benefit from ICD implantation and who were undergoing coronary artery bypass surgery.46 T-wave alternans, that is, T-wave changes in alternate beats, can at times be visible in the scalar ECG and, when present, denote patients with an electrically unstable ventricle. Recently, T-wave alternans detectable only by computer averaging techniques has been used to identify patients at risk for subsequent ventricular arrhythmias.47 Finally, electrophysiological studies to induce sustained ventricular arrhythmias can be useful to help select appropriate therapy, including drug therapy, catheter ablation, surgery, or ICD implantation, and in identifying high-risk patients such as those suitable for treatment with an ICD.29
Disease States
Coronary Artery Disease
As indicated earlier, at least 80% of patients who experience
sudden cardiac death have coronary artery disease as the
underlying anatomic substrate due to atherosclerotic changes of the
coronary arteries. Nonatherosclerotic coronary artery
abnormalities are important in only a very small number of sudden
cardiac deaths and include problems such as coronary arteritis,
embolism, dissection, and congenital malformations of anomalous origin
of a left coronary artery from the pulmonary artery or
of a left coronary artery from the right or noncoronary
aortic sinus of Valsalva, passing between the aortic and
pulmonary artery roots.1 2
In survivors of cardiac arrest, coronary heart disease with
vessels exhibiting more than 75% cross-sectional stenosis are
found in 40% to 86% of patients, depending on age and sex of the
population studied. Although <50% of the patients resuscitated from
ventricular fibrillation evolve evidence of myocardial
infarction by elevated cardiac enzymes and <25% have Q-wave
myocardial infarction, autopsy studies have reported that a recent
occlusive coronary thrombus was found in 15% to 64% of
victims of sudden cardiac death, caused by ischemic heart
disease, with many hearts showing plaque fissuring, hemorrhage,
and thrombosis.48 There appears to be no specific
pattern of distribution of coronary artery lesions that favors
the development of sudden cardiac death. Abrupt changes in regional
myocardial blood flow due to alterations in coronary artery
structure and/or function, such as spasm, platelet thrombi,
dissection, plaque rupture, or other vasoactive events can provoke
acute ischemia.13 30 Transition of stable
atherosclerotic plaques by fissuring that leads to platelet
activation and aggregation followed by thrombosis formation, as well as
other biochemical events that can have a direct effect on
electrophysiological properties of the
heart, may be important in provoking ventricular
arrhythmias.13 30 Healed infarctions are
present in 
50% of hearts of sudden cardiac death victims at
autopsy and in those of survivors of cardiac arrest. Interestingly,
chronic ischemia may exert a protective effect by causing the
development of coronary collaterals that can help mitigate the
extent of ischemia produced by sudden coronary
occlusion. Therefore, an acute occlusion of a minimally stenosed
coronary artery can result in a more disastrous outcome than
occlusion of a severely stenosed coronary artery with the
jeopardized myocardium protected by collaterals.
Cardiomyopathy
Cardiomyopathies represent the second
largest group of patients who experience sudden cardiac death.
Hypertrophic cardiomyopathy has a prevalence of
2 in 1000 young adults and an incidence of sudden cardiac death of
2% to 4% per year in adults and 4% to 6% per year in children and
adolescents49 (Figure 3). In patients with
hypertrophic cardiomyopathy, a history of sudden
cardiac death or sustained ventricular
tachycardia, family history of sudden cardiac death, a
diverse genotype, recurrent syncope, multiple episodes of
nonsustained ventricular tachycardia, and
massive left ventricular hypertrophy are the
strongest risk factors for sudden cardiac
death.38 49 Multiple mechanisms may be
responsible, including arrhythmias, abrupt
hemodynamic deterioration, and/or ischemia.
Hemodynamic and echocardiographic
variables are generally not useful in identifying patients at high
risk for sudden cardiac death, and the results of ambulatory ECG
monitoring and invasive
electrophysiological study are
controversial.49 The presence of mutations in the
-tropomyosin as well as in the ß-myosin heavy chain gene has been
associated with sudden cardiac death.38 49
Idiopathic dilated cardiomyopathy is a substrate
for 10% of sudden cardiac deaths in the adult population. Mortality
in patients with idiopathic dilated cardiomyopathy
ranges from 10% to 50% annually, depending on the severity of the
disease. In a compilation of 14 studies including 1432 patients, mean
mortality rate after a follow-up of 4 years was 42%, with 28% of
deaths classified as sudden.50 The presence of
nonsustained ventricular tachycardia in this
group identifies a population at high risk of sudden death, presumably
on the basis of a ventricular
tachyarrhythmia.18 Bundle-branch
reentry can be an important cause of ventricular
tachycardia in patients with dilated
cardiomyopathy.51 The
terminal event can also be asystole or electromechanical dissociation,
particularly in patients with advanced left ventricular
dysfunction.23 Multiple triggering events in
heart failure patients include myocardial stretch, neuroendocrine
factors, electrolyte abnormalities, proarrhythmic effects of
antiarrhythmic drugs, and excessive activation of the sympathetic and
renin-angiotensin systems.31 Syncope
in heart failure patients appears to be an important clinical
variable that also identifies patients with a higher risk of sudden
cardiac death.50
Arrhythmogenic right ventricular dysplasia is a particular
kind of cardiomyopathy responsible for sudden death
in young individuals and adults, with a gene defect recently localized
to chromosomes 1 and 14 q23-q24.11 52 It occurs
as a familial disorder in 30% of cases, with autosomal dominant
inheritance. Exercise can precipitate ventricular
tachycardia in these patients, with an annual incidence of
sudden death estimated to be 2%. Two pathological patterns, fatty
and fibrofatty myocardial infiltration, have been identified. In the
fibrofatty variety, myocardial atrophy appears to be the consequence of
acquired injury and myocyte death and repair by fibrofatty replacement,
mediated by patchy myocarditis. Apoptosis may be important. The
left ventricle and ventricular septum can be involved in
50% to 67% of cases, often later in the disease, confirming a poor
prognosis.52 ECG during sinus rhythm often
exhibits T-wave inversion in V1 to
V3 or complete or incomplete right bundle-branch
block, and the ventricular tachycardia has a
left bundle-branch block contour, with the frontal-plane axis
reflecting the site of origin in 1 of 3 predilection sites for
ventricular fatty degeneration: right
ventricular inflow and outflow tracts and apex, the
so-called "triangle of dysplasia." During sinus rhythm,
intraventricular conduction may be sufficiently
slow as to produce a terminal notch on the QRS complex that Fontaine
called an epsilon wave (Figure 6).
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Left Ventricular Hypertrophy
Left ventricular hypertrophy, whether
established by ECG or by cardiac echo, is a strong independent risk
factor for cardiovascular deaths and, in particular,
sudden cardiac death in patients who also had a history of
hypertension. Multiple disease states can result in
hypertrophy, including valvular heart disease,
obstructive and nonobstructive hypertrophic
cardiomyopathy, primary pulmonary
hypertension with right ventricular
hypertrophy, and various congenital heart disorders.
Although ventricular repolarization (QT interval) is
prolonged in hypertensive hearts, potentially setting the stage for
triggered activity (see below), myocardial ischemia,
interstitial fibrosis, and electrolyte disturbances
can all contribute to the genesis of ventricular
tachyarrhythmias.1
Valvular Disease
The risk of sudden death in asymptomatic patients with
aortic valve disease appears to be low. After prosthetic or
heterograft aortic valve replacements, patients remain at some risk for
sudden cardiac death caused by arrhythmias, prosthetic
valve dysfunction, or coexistent coronary artery
disease. Hence, sudden cardiac death has been reported to be the second
most common mode of death after valve replacement surgery, with an
incidence of 2% to 4% over a follow-up of 7 years, accounting for
20% of the postoperative deaths.1
Whether mitral valve prolapse causes sudden cardiac death is unresolved. Its prevalence is so high that its presence may be just a coincidental finding in victims of sudden cardiac death and not causally related.1 However, patients with mitral valve prolapse who have mitral regurgitation and left ventricular dysfunction or myxomatous degeneration of the valve are clearly at higher risk for complications, such as infective endocarditis, cerebroembolic events, and sudden cardiac death.
Congenital Heart Disease
An increased risk of sudden cardiac death due to
arrhythmias has been found predominantly in 4 congenital
conditions, including tetralogy of Fallot, transposition of the great
arteries, aortic stenosis, and pulmonary vascular
obstruction. Sudden cardiac death has also been described as a late
complication after surgical repair of complex congenital cardiac
lesions, such as tetralogy of Fallot and transposition of the great
arteries, and in patients with primary or secondary pulmonary
hypertension. In tetralogy of Fallot, QRS prolongation relates to right
ventricular size and predicts patients at risk for sudden
cardiac death.53
Primary Electrophysiological Abnormalities
Patients with primary
electrophysiological abnormalities
represent a group in whom mechanical function of the
myocardium is normal and an
electrophysiological derangement
represents the primary cardiac problem. This includes patients
with the congenital long-QT syndrome, Wolff-Parkinson-White syndrome,
several types of distinctive ventricular
tachycardias, idiopathic ventricular
fibrillation54 (including a newly described
entity characterized by right bundle-branch block and ST-segment
elevation, Brugada's syndrome),55 congenital
complete AV block, and a variety of acquired abnormalities, such as the
acquired long-QT syndrome and acquired diseases of the sinus node, AV
node, and His-Purkinje system, such as Lenegre's disease or Lev's
disease.2 Isolated cardiac conduction
disturbances can be due to an autosomal dominant defect that
includes various combinations of bundle-branch or fascicular
blocks.56 It is important to remember that the
absence of structural abnormalities is established by relatively gross
tests, such as cardiac catheterization and
echocardiography. Other imaging techniques, for
example, those that evaluate sympathetic neural function, are often
abnormal in these patients.57 With the
development and validation of new diagnostic tools,
including autonomic imaging by positron emission tomography, genetic
testing,58 and magnetic resonance imaging, many
forms of "idiopathic" sudden cardiac death in patients with
apparently structurally normal hearts may have to be reclassified,
because these patients may become identified as having a specific
structural and/or genetic abnormality. A fascinating recent discovery
is that the gene responsible for the Brugada syndrome, the cardiac
sodium channel gene SCN5A on chromosome
3,58 is the same gene, with different defects,
that causes LQT3 syndrome37 (Table 1).
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The idiopathic (congenital) long-QT syndrome is caused by prolongation
of repolarization due to abnormal movement of sodium ions into or
potassium ions out of the cardiac myocyte, creating prolonged periods
of intracellular positivity.37 Such prolongation
of repolarization can lead to the development of early
afterdepolarizations (Figure 7). A
specific kind of ventricular tachycardia called
torsade de pointes occurs in patients with the long-QT syndrome,
whether congenital or acquired (Figure 8). In addition to prolonged
repolarization, ECG characteristics of this congenital disorder include
abnormal T-wave contours, T-wave alternans, a relative sinus
bradycardia, and torsade de pointes that can produce syncope and sudden
cardiac death. Genetic heterogeneity (Table 1) may make
therapies specifically targeted for the
electrophysiological abnormality somewhat
difficult. Syndromes LQT1 through LQT5 are inherited as
autosomal dominants, whereas the Jervell-Lange-Nielsen syndrome,
dominant for the long-QT manifestation, is recessive for the associated
deafness and appears to be due to the presence of both alleles
responsible for LQT1. The incidence of cardiac events is higher
in LQT1 and LQT2 than in LQT3, whereas the lethality of cardiac events
is higher in LQT3 than in LQT1 and LQT2
patients.37 Interestingly, atrial
tachyarrhythmias, induced in an animal model by
mechanisms similar to those that cause torsade de pointes in the
ventricles,59 do not seem to be important
clinically, even though the same ionopathy affecting the ventricles
should be present in the atria.
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Patients with the Wolff-Parkinson-White syndrome have a risk of sudden
cardiac death <1 per 1000 patient-years of follow-up. Almost all
survivors of sudden cardiac death with Wolff-Parkinson-White syndrome
have had symptomatic arrhythmias before the event,
but up to 10% experience sudden cardiac death as their first
manifestation of the disease.60 The responsible
mechanism most probably is the development of atrial fibrillation, with
rapid conduction to the ventricles over the accessory pathway that
produces ventricular rates so rapid that the rhythm
degenerates to ventricular fibrillation (Figure 9). The best predictor for development of
ventricular fibrillation is a rapid ventricular
response over the accessory pathway during atrial fibrillation, with
the shortest interval between ventricular beats conducted
over the accessory pathway 250 ms. Although this response identifies
virtually 100% of patients at risk for developing
ventricular fibrillation, its specificity is low, because
it may be found in 20% of asymptomatic patients with
Wolff-Parkinson-White conduction and 50% of those with mild to
moderate symptoms due to atrioventricular reentrant
tachycardia.
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Idiopathic ventricular tachycardias with monomorphic contours that occur in patients with apparently structurally normal hearts include paroxysmal and repetitive forms that originate from the region of the right ventricular outflow tract. This ventricular tachyarrhythmia characteristically has a left bundle-branch block contour and inferior axis and possesses the unique quality of termination with vagal maneuvers such as adenosine infusion.61 Far less common is a ventricular tachycardia from the left ventricular outflow tract. A left septal ventricular tachycardia arises in the left posterior septum and is sometimes called a fascicular tachycardia because it is often preceded by a fascicular potential. It has a right bundle-branch block, left-axis-deviation contour. Calcium channel blockers characteristically suppress this arrhythmia. Sudden cardiac death rarely occurs in this population.
Several types of idiopathic polymorphic ventricular tachycardias have been described and are associated with a less favorable outcome than the idiopathic monomorphic ventricular tachycardias noted above. They may occur as sporadic or familial forms, frequently precipitated by catecholamine release during physical or emotional stress. Patients with catecholaminergic polymorphic ventricular tachycardia apparently have a favorable response to ß-blockade therapy, whereas those with idiopathic ventricular fibrillation or short coupled torsade de pointes may not. Sudden cardiac death can occur in patients with polymorphous ventricular tachycardia who have normal QT intervals and normal systolic cardiac function; closely coupled premature complexes can initiate the spontaneous episodes.62 Perhaps related is a similar ventricular tachyarrhythmia characterized by a torsade de pointes contour and normal QT interval and initiated by premature ventricular complexes with extremely short coupling intervals.63
Sudden cardiac death due to primary ventricular
fibrillation, ie, without apparent evidence of structural heart disease
(see above),54 occurs in 5% of victims of
sudden cardiac death. Preliminary data suggest that these patients have
a 30% recurrence rate of ventricular fibrillation,
syncope, and cardiac arrest, and it is important to stress that their
survival is largely related to potentially controllable or reversible
electrophysiological disturbances
rather than death due to advanced heart disease. ICDs should be
particularly useful in these patients.64
Sudden unexplained nocturnal death can occur in young, apparently healthy, males of Southeast Asian origin and has several names, such as lai-tai (sleep death, Laos), pokkuri (sudden and unexpected death, Japan), and bangungut (to rise and moan in sleep, Philippines). The cause(s) is unknown.
Drugs
Antiarrhythmic drugs have long been known to be capable of
provoking ventricular tachyarrhythmias and
sudden cardiac death. Nonantiarrhythmic drugs that prolong
repolarization (Table 2), along with
class IA antiarrhythmic agents, can cause torsade de pointes. Class IC
drugs in the CAST study were mentioned earlier. Drug-drug interactions
during poly-pharmacy can be dangerous, even with apparently innocuous
medications.28 Phosphodiesterase
inhibitors and other positive inotropic agents that
increase intracellular calcium loading have also been demonstrated to
exert proarrhythmic actions and increase the risk of sudden cardiac
death.1 Hypokalemia (in some instances provoked
by potassium-wasting diuretics), hypomagnesemia, and increased
intracellular calcium concentration may be important as primary or
triggering events. It is sometimes difficult to determine whether a
patient resuscitated from ventricular fibrillation had the
arrhythmia provoked by hypokalemia, because in the
postresuscitation period, serum concentrations of potassium may be
reduced because of the effects of catecholamine release
after the cardiac arrest. Thus, unless there is a history of
electrolyte imbalance, drugs known to deplete potassium, special diets
such as the liquid protein diet, or documented electrolyte
abnormalities when the patient is in a steady state, the diagnosis of
hypokalemia may be in doubt.
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Autonomic Nervous System
Abnormalities of the autonomic nervous system appear to be
involved in the genesis of sudden cardiac death.8
Myocardial infarction, for example, produces regional cardiac
sympathetic and parasympathetic dysfunction not only in the infarcted
area but also in regions apical to the infarct, presumably because of
interruption of afferent and efferent nerve fibers traversing the
infarct (Figure 10). Similar changes
have been found in patients after myocardial
infarction.8 Denervated regions show
supersensitivity to catecholamine infusion, with
disproportionate shortening of refractoriness that creates autonomic
heterogeneity, resulting in dispersion of
refractoriness and/or conduction, which can be conducive to development
of ventricular arrhythmias.8
Similar increased dispersion of refractoriness can occur after
ventricular dilation and heart failure. Any process that
creates electrical heterogeneity favors the development
of ventricular fibrillation. Recent data indicate that
sympathetically denervated ventricular
myocardium demonstrates abnormal oxygen utilization, which
could also affect arrhythmogenesis (G.D. Hutchins, PhD, unpublished
observations, 1998).
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Most data suggest that vagal stimulation, profibrillatory for the atria, mitigates the development of ventricular arrhythmias in a variety of experimental situations. Whether parasympathetic stimulation is protective because of a direct electrophysiological effect on ventricular myocardium, by opposing sympathetic actions, or by albeit minimally prolonging refractoriness8 is not known. Because it is difficult to study the effects of vagal activity on ventricular electrophysiological properties noninvasively in humans, the behavior of the sinus node has been used as a surrogate for ventricular actions by measurement of indices of heart rate variability (reflecting primarily tonic vagal action) and evaluation of baroreflex sensitivity (as a measure of reflex vagal activity). Responses can be misleading because vagal actions at the sinus node and ventricles can easily be dissociated,44 as mentioned earlier. Reductions in heart rate variability,43 as well as baroreflex sensitivity,42 identify patients at risk for a subsequent cardiac event. An increase in vagal tone in animals66 and patients67 has been achieved by scopolamine patches, without a clear benefit on preventing ventricular arrhythmias. In contrast, exercise conditioning in animals, demonstrated to increase vagal "tone," has been shown to have a protective effect on preventing ventricular fibrillation in dogs with coronary occlusion.8 Naturally, exercise conditioning does many things that may be unrelated to neural function. Vagal stimulation can terminate a specific type of ventricular tachycardia originating in the right ventricular outflow tract,61 but neural innervation at that site may be unique.8
Mechanisms
In one sense, sudden cardiac death can be considered an electrical
accident because, although many individuals have anatomic and
functional substrates conducive to developing a life-threatening
ventricular tachyarrhythmia and many
patients have transient events that could predispose to the initiation
of ventricular tachycardia or
ventricular fibrillation, only a relatively small number of
patients actually do develop sudden cardiac death. It is this interplay
between the anatomic and functional substrates, modulated by the
transient events that perturb the balance, and the impact of all 3 on
the underlying potential arrhythmia mechanisms possessed by all
hearts that precipitates sudden cardiac
death1 2 35 (Figure 11). Understanding this is critical to
understanding the pathophysiology of sudden cardiac death.
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The figure also indicates the complexity as well as the potential
variations in the inciting factors, because each category in the Venn
diagram can interact with the others in almost endless permutations and
combinations. Most often, interaction of a single item in each circle
with a single item in the other circle (points at which only 2 circles
overlap) may normally be insufficient to produce sudden cardiac death,
unless the single abnormality is extremely severe. For example, mild
electrolyte abnormalities, such as a potassium concentration of 2.7
mEq/L, alone are usually insufficient to cause a problem. Even in a
patient with stable coronary artery disease, that combination
may not necessarily be lethal. However, if the patient had preexisting
reentry pathways in the ventricular myocardium,
perhaps due to an old infarction, then the combination of the 3, ie,
coronary artery disease, scarred myocardium, and
hypokalemia, might now be sufficient to provoke a
ventricular tachyarrhythmia, causing sudden
cardiac death. Changes in the anatomic substrate can alter the
susceptibility of the myocardium to the effects of the
transient initiating events. For example, experimental studies indicate
that hypertrophied myocardium, as well as
myocardium after a healed myocardial infarction, exhibits a
greater arrhythmogenic response than normal tissue to the same extent
of acute ischemia.2
Catecholamine release can modulate some of the effects of
acute coronary occlusion and reperfusion, and reduction in
sympathetic action with drugs introduced to the pericardial sac to
superfuse sympathetic nerves68 can prevent
ventricular arrhythmias. Conversely, acute
ischemia alone, involving a sufficiently large area of
myocardium in an otherwise normal ventricle, can
precipitate ventricular fibrillation without interplay with
other factors, although it is interesting to consider the many balloon
angioplasties performed and the infrequent occurrence of
ventricular fibrillation during that procedure. Perhaps the
duration of the ischemia is too short to initiate
ventricular fibrillation. Although unquestionably the above
logic represents a very simplistic synthesis (Figure 11) and
actual mechanisms are more complex, nevertheless it offers a conceptual
framework to understand the interactive forces precipitating sudden
cardiac death.
In the experimental animal, a very definite set of arrhythmogenic intervals has been described after acute coronary occlusion, including an arrhythmogenic interval within the first few minutes after coronary occlusion that begins to abate after 30 minutes and reappears after several hours. In addition, the initial 30 minutes of arrhythmias can be divided into the first 10 minutes, presumably directly related to the initial ischemic injury, and the second 20 to 30 minutes, related to either reperfusion or the evolution of different injury patterns in the epicardial and endocardial muscles and Purkinje fibers.1 2 In the ischemic myocardium, a dramatic reduction in tissue pH to <6.0, an increase in interstitial potassium levels to values >15 mmol/L, increases in intracellular calcium concentration, and neurohumoral changes all contribute to creating electrophysiological changes characterized by slowed conduction, reduced excitability and prolonged refractoriness, cell-to-cell uncoupling, and the generation of spontaneous electrical activity.69 Other metabolic changes, such as accumulation of free fatty acids and their metabolites, formation of lysophosphoglycerides, and impaired myocardial glycolysis, may contribute to the development of electrical instability leading to cardiac arrhythmias.1 2 Although reentry is considered to be a dominant mechanism responsible for ventricular fibrillation, regional changes in automaticity, as well as triggered activity due to afterdepolarizations, are probably important as well. Reperfusion can also be arrhythmogenic, although the seriousness of this problem appears to be greater in the experimental animal than clinically.
Cardiac arrest due to severe bradycardia, asystole, or pulseless electrical activity (electromechanical dissociation) appears to be more common in severely diseased hearts, probably representing more global myocardial dysfunction.23 The outlook for patients exhibiting these disturbances at the time of attempted resuscitation is worse than for patients who exhibit ventricular fibrillation at that time.
A major, if not the major,
electrophysiological feature responsible
for the initiation of ventricular fibrillation appears to
be electrical heterogeneity. A heart that is totally
homogeneous electrically, that is, all cells are at the
same stages of depolarization and repolarization and conduct normally
without delay or block, very probably cannot develop
ventricular fibrillation. However, even in the normal
state, these conditions do not exist, because various cell types, eg,
ventricular muscle versus Purkinje fibers, exhibit
different action potential characteristics, refractoriness, and
conduction velocities. However, when heterogeneity
becomes extreme, for instance, if one region of the
myocardium exhibits ischemia-induced conduction
delay and/or block that is different from neighboring regions, or when
there is regional sympathetic dysfunction8 or
unequal stretch70 that can produce regional
electrophysiological alterations, the stage
becomes set for development of ventricular fibrillation.
Such alterations can be provoked by anatomic/functional substrates and
by transient initiating events and can modulate basic
arrhythmia mechanisms of reentry, automaticity, and triggered
activity to provoke ventricular arrhythmias (Figure 11). Reentry appears to be the major mechanism responsible for
ventricular arrhythmias due to acute and chronic
coronary disease and must be dependent on
heterogeneity. While we know a great deal about the
electrophysiological alterations that
accompany acute and chronic ischemia in a variety of
experimental preparations, the events surrounding the onset of
ventricular fibrillation in humans, even after 50 years of
study, remain fairly opaque. The "holy grail" of the
electrophysiologist to match a particular antiarrhythmic drug that has
a specific mechanism of action to an arrhythmia caused by a
unique set of electrophysiological
alterations has, to date, still proved elusive. In fact, the only drugs
shown to reduce mortality from sudden cardiac death are ß-blockers
and amiodarone (by
meta-analysis).71 Neither drug has
specific and single ion channel actions. The reason ICDs are so
successful is that a "dose of electricity" is generic; ie, the
mechanism causing the ventricular
tachyarrhythmia and the nature of the underlying heart
disease, both critical for antiarrhythmic drug effectiveness, are
largely irrelevant.
Treatment
Because different electrophysiological
mechanisms in the presence of different types of cardiac disease can
cause sudden cardiac death and because many of the victims do not have
symptoms or signs identifying them as being at high risk before the
event, a preventive approach to the problem becomes complicated.
Furthermore, to test the value of primary preventive measures such as
abstinence from smoking, exercise, weight reduction, control of high
blood pressure, and lipid abnormalities in patients without a history
of cardiac disease, studies have to be performed in communities in
which it is possible not only to randomize to preventive versus no
preventive measures but also to register all cases of sudden deaths
accurately, including the unwitnessed ones. Naturally, this is
difficult, if not impossible. However, because most cases of sudden
cardiac death occur in the population with coronary artery
disease, it is logical that in recent years most attention has been
given to secondary preventive therapy in patients with proven
coronary artery disease and especially to survivors of a
myocardial infarction.
Risk Stratification for Treatment
During the past 2 decades, a number of tests have been developed
to stratify cardiac patients as to their risk of dying suddenly. As
shown in Table 3, these tests address
different cardiac and noncardiac factors that have been shown to affect
mortality. The relatively low positive predictive accuracy of these
tests adversely affects their usefulness. At best, alone or in
combination, the tests reach a positive predictive accuracy of 30%,
indicating that if adequate protective treatment were available, 10
patients would have to be treated to save 3. Although this may not be a
problem when low-cost, effective therapy free of adverse effects is
possible, unfortunately, this is not the case.
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Pharmacological Treatment
Of the different drugs that have been evaluated, only ß-blockers
and amiodarone have reduced sudden death in the myocardial
infarction survivor.40 Class I drugs (mexiletine,
encainide, flecainide, moricizine), calcium antagonists,
and class III drugs (d-sotalol, dofetilide) all failed to
reduce or even increased the incidence of sudden cardiac death after a
myocardial infarction.40 41 71 72 A major problem
in drug treatment, as shown by the ESVEM study,73
is that noninvasive (Holter) and invasive (programmed stimulation of
the heart) tests allow identification of an effective antiarrhythmic
drug regimen in only a minority of patients with documented
life-threatening ventricular arrhythmias. In a
study from South America that included patients with different causes
of cardiac disease and diminished left ventricular function
(ejection fraction, <35%), empirical amiodarone was shown to
beneficially affect mortality.18 This was not
confirmed in a multicenter VA trial, CHF-STAT.74
Two recent studies using amiodarone in patients with reduced
left ventricular function after a myocardial infarction
showed a reduction in sudden (presumably arrhythmic) deaths but not in
total number of deaths.75 76 Importantly, these
studies showed no increase in mortality compared with placebo for
patients treated with amiodarone, whereas a
meta-analysis from 13 trials of 6500 patients treated with
amiodarone after myocardial infarction or with heart failure
showed a reduction in all-cause mortality, death from
arrhythmia, or sudden death.71 Some data
suggest that amiodarone may be more effective when used for
patients with high (>90 bpm) resting heart rates. Preliminary data
also suggest increased effectiveness when amiodarone is
combined with a ß-blocker. Both of these observations need further
testing before adoption. The BHAT study showed that ß-blockade with
propranolol reduced all-cause mortality by 25% and that
the drug was especially useful in patients with diminished left
ventricular function and/or ventricular
arrhythmias. No evidence indicates that selective ß-blockers
are better than nonselective ones. Although ß-blocker therapy has
been shown to be advantageous and should be prescribed for most
patients after a myocardial infarction unless contraindicated, in most
countries a fraction of all patients who should receive a ß-blocker
after a myocardial infarction actually do so. This is especially true
for women, diabetics, and the elderly.77
In view of the complexity of the mechanisms involved in sudden cardiac
death, there has been growing interest in the use of measures that may
halt or delay progress of cardiac disease or prevent
disturbances in the autonomic balance of the heart, such as the
administration of anti-ischemic drugs, drugs to prevent plaque
rupture or thrombus formation, and drugs that stabilize the autonomic
balance or improve pump function (Table 4). With this number and diversity of
drugs, it has become increasingly difficult, if not impossible, to
evaluate the individual contribution of each drug to the reduction in
sudden cardiac death. Aggressive therapy using
thrombolysis in acute ischemic syndromes or
intracoronary interventions resulting in reduction of
myocardial damage and scar formation and prevention of
ventricular remodeling13 30 will
diminish the occurrence of some of the mechanisms that play a role in a
fatal arrhythmia. The role of specific potassium channel
blockers like dofetilide and azimilide needs to be established in the
future.
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Implantable Cardioverter-Defibrillator
For many patients who die suddenly, ventricular
fibrillation is the culprit arrhythmia. Superiority of an ICD
over antiarrhythmic drug therapy (predominantly amiodarone) has
been shown recently in the AVID trial64 in this
patient population. Results consistent with the AVID study were
also reported from the CIDS78 and the
CASH79 studies. At present, it is quite clear
that an ICD is the initial treatment of choice for patients
resuscitated from documented ventricular fibrillation not
related to a reversible or transient cause such as an acute myocardial
infarction, in patients with hemodynamically poorly
tolerated VT, and probably in patients with a history of unexplained
syncope in the presence of impaired ventricular function in
whom a sustained ventricular arrhythmia can be
induced during electrophysiological testing
(Figure 12). The MADIT study included
patients after a myocardial infarction with a left
ventricular ejection fraction <35% and spontaneously
occurring nonsustained VT in whom a sustained monomorphic VT could be
initiated by programmed electrical stimulation of the heart and not
prevented by procainamide
administration.29 Patients randomized to the
defibrillator arm had an 80% reduction in sudden and a 54% reduction
in total mortality compared with patients treated with conventional
antiarrhythmic drug therapy after 2 years of follow-up, thus showing
the benefit of prophylactic ICD placement in a high-risk
population. In the CABG Patch study, patients with left
ventricular ejection fraction of <36% and abnormal
signal-averaged ECG who were undergoing elective coronary
bypass surgery were randomized to ICD or no antiarrhythmic therapy.
CABG Patch showed no difference in survival between the two groups and
concluded appropriately that if a patient's risk of dying is not from
a ventricular tachyarrhythmia, then the ICD
conferred no benefit.46
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The value of the ICD in patients with markedly diminished ventricular function in the absence of ventricular fibrillation, VT, or syncope, with or without a previous myocardial infarction, and with or without ambient ventricular ectopy is currently being evaluated. Trials like MUSST, MADIT-2, DEFINITE (Danish Investigations on Arrhythmias and Mortality on Dofetilide), ALIVE (azimilide postinfarct survival evaluation), and SCD-HeFT26 all address patients with a 10% to 30% chance of dying within 2 years.80
Again, we should realize that patients included in these trials
represent a minority of the total number of patients who die
suddenly out-of-hospital (Figure 1). Protection against sudden cardiac
death by ICD implantation is expensive, as shown in the MADIT study
($27 000 per life year saved),81 in which 100
devices had to be implanted to prevent 10 patients from dying suddenly,
and therefore selection of the high-risk population must have very high
predictive accuracy.
Out-of-Hospital Resuscitation
The majority of sudden cardiac death victims have no symptoms and
are not identified as being at high risk before the
event.82 This stresses the enormous importance of
improving the outcome of resuscitation attempts outside the hospital
(Figure 13). There is growing awareness
that major changes are necessary to reach that goal. The short time
frame after cardiac arrest during which circulation has to be restored
to prevent death or irreversible cerebral damage is
essential.83 In the so-called chain of survival,
several steps are crucial. The first step is to identify and locate the
sudden cardiac arrest victim. In the Maastricht study, 80% of cardiac
arrests occurred at home, and 40% were
unwitnessed.3 Therefore, we must have warning
systems able to recognize cardiac arrest, to raise an alarm, and to
transmit the exact location of the victim to providers of basic and
advanced life support. Much attention has recently been given to public
access defibrillation, allowing nonphysicians to use widely distributed
automated external defibrillators to
defibrillate.84 In fact, it was suggested several
years ago that external defibrillators be made "as common as fire
extinguishers,"85 and they may have to be, to
cover all the places a cardiac arrest can
occur.86 This idea has aroused a groundswell of
enthusiasm but will obviously have the greatest impact when the sudden
cardiac arrest victim is identified and located as soon as possible.
The approach must be coupled with education, perhaps during the 4 years
of high school,85 as well as legislative changes.
When they function properly, devices that document cardiac arrest and
locate the victim might be distributed initially to cohorts with known
cardiac disease and then among asymptomatic people with
risk factors for the development of cardiac disease. It will be more
expensive for standard emergency medical systems to carry a
defibrillator, but the potential impact on survival should warrant this
approach.
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Conclusions
Sudden cardiac death continues to be a major health issue. At
present, although insight into mechanisms and circumstances of
sudden cardiac death is increasing, our methods for identifying the
high-risk candidate and predicting efficacy of measures to prevent
sudden cardiac death are still inadequate. Because many victims are not
known to suffer from heart disease and/or are considered to be at low
risk for dying suddenly, more efforts are needed to improve
out-of-hospital resuscitation by better warning systems and widespread
availability of automated defibrillation devices. It is likely that
these measures could increase the number of survivors of cardiac
arrest. Implantation of the ICD, in many instances probably combined
with an antiarrhythmic drug like amiodarone, would then be used
to maintain survival. Until we have better risk stratifiers and better
methods of preventing ventricular
tachyarrhythmias, the 2 major goals of the
cardiologist/electrophysiologist, that approach should still receive a
major emphasis.
Acknowledgments
This study was supported in part by the Herman C. Krannert Fund; by grant HL-52323 from the National Heart, Lung, and Blood Institute of the National Institute of Health, Bethesda, Md; and by the Wijnand N. Pon Foundation.
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C. M. Gibson, Y. B. Pride, J. L. Buros, E. Lord, A. Shui, S. A. Murphy, D. S. Pinto, P. J. Zimetbaum, M. S. Sabatine, C. P. Cannon, et al. Association of impaired thrombolysis in myocardial infarction myocardial perfusion grade with ventricular tachycardia and ventricular fibrillation following fibrinolytic therapy for ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol., February 5, 2008; 51(5): 546 - 551. [Abstract] [Full Text] [PDF]
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B. M. Tice, B. Rodriguez, J. Eason, and N. Trayanova Mechanistic investigation into the arrhythmogenic role of transmural heterogeneities in regional ischaemia phase 1A Europace, November 1, 2007; 9(suppl_6): vi46 - vi58. [Abstract] [Full Text] [PDF]
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H. L. Lujan, V. J. Kramer, and S. E. DiCarlo Sex influences the susceptibility to reperfusion-induced sustained ventricular tachycardia and beta-adrenergic receptor blockade in conscious rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2799 - H2808. [Abstract] [Full Text] [PDF]
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P. B. Tabereaux, G. P. Walcott, J. M. Rogers, J. Kim, D. J. Dosdall, P. G. Robertson, C. R. Killingsworth, W. M. Smith, and R. E. Ideker Activation Patterns of Purkinje Fibers During Long-Duration Ventricular Fibrillation in an Isolated Canine Heart Model Circulation, September 4, 2007; 116(10): 1113 - 1119. [Abstract] [Full Text] [PDF]
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J.-P. Empana, P. Duciemetiere, B. Balkau, and X. Jouven Contribution of the metabolic syndrome to sudden death risk in asymptomatic men: the Paris Prospective Study I Eur. Heart J., May 1, 2007; 28(9): 1149 - 1154. [Abstract] [Full Text] [PDF]
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D. Goltz, J.-H. Schultz, C. Stucke, M. Wagner, P. Bassalay, A. P. Schwoerer, H. Ehmke, and T. Volk Diminished Kv4.2/3 but not KChIP2 levels reduce the cardiac transient outward K+ current in spontaneously hypertensive rats Cardiovasc Res, April 1, 2007; 74(1): 85 - 95. [Abstract] [Full Text] [PDF]
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J.-q. Zhong, G. Laurent, P. P.-S. So, Xudong Hu, J. K. Hennan, and P. Dorian Effects of Rotigaptide, a Gap Junction Modifier, on Defibrillation Energy and Resuscitation From Cardiac Arrest in Rabbits Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 69 - 77. [Abstract] [PDF]
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