REVIEW

Sudden Cardiac Death From the Perspective of

Coronary Artery Disease
Jaskanwal D. Sara, MBChB; Mackram F. Eleid, MD; Rajiv Gulati, MD, PhD;
and David R. Holmes Jr, MD

Abstract

Sudden cardiac death accounts for approximately 50% of all deaths attributed to cardiovascular disease in the
United States. It is most commonly associated with coronary artery disease and can be its initial manifestation
or may occur in the period after an acute myocardial infarction. Decreasing the rate of sudden cardiac death
requires the identification and treatment of at-risk patients through evidence-based pharmacotherapy and
interventional strategies aimed at primary and secondary prevention. For this review, we searched PubMed for
potentially relevant articles published from January 1, 1970, through March 1, 2014, using the following key
search terms: sudden cardiac death, ischemic heart disease, coronary artery disease, myocardial infarction, and
cardiac arrest. Searches were enhanced by scanning bibliographies of identified articles, and those deemed
relevant were selected for full-text review. This review outlines various mechanisms for sudden cardiac death in
the setting of coronary artery disease, describes risk factors for sudden cardiac death, explores the management
of cardiac arrest, and outlines optimal practice for the monitoring and treatment of patients after an acute
ST-segment elevation myocardial infarction to decrease the risk of sudden death.
ª 2014 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2014;89(12):1685-1698

S
udden cardiac death (SCD) accounts for
nearly half of all deaths from cardiovas-
cular disease in the United States.1 In
this review, we discuss the current under-
standing of SCD mechanisms and risk factors,
along with contemporary management and
preventive strategies in patients with estab-
lished coronary artery disease (CAD). We
searched PubMed for potentially relevant arti-
cles published from January 1, 1970, through
March 1, 2014, using the following key search
terms: sudden cardiac death, ischemic heart dis-
ease, coronary artery disease, myocardial infarc-
tion (MI), and cardiac arrest. Searches were
enhanced by scanning bibliographies of identi-
fied articles, and articles deemed relevant were
selected for full-text review.
DEFINITION OF SCD
The definition of SCD has been explored many
times in the literature. The most recently
accepted definition describes it as a natural
death due to cardiac causes, heralded by abrupt
loss of consciousness and occurring within 1
hour of the onset of symptoms.2 It may occur
in patients with previously documented CAD
or may be an initial event. Earlier studies have
used less stringent criteria and included patients
who died within 24 hours of the onset of symp-
toms.3 Additional criteria for SCD include the
absence of trauma as a mechanism and the unex- From the Division of
Cardiovascular Diseases,
pected timing and mode of death. A population- Mayo Clinic, Rochester,
based study in Maastricht, Netherlands, found MN.
that 21% of deaths in men and 14.5% of deaths
in women were sudden and unexpected (ie, not
preceded by other symptoms).4 These findings
raise the problem of how to characterize such
deaths, and in this setting, investigators tend to
err on the side of caution and label these events
as SCDs, which may overestimate rates and
possibly confuse our understanding of the un-
derlying mechanisms involved.
The incidence of SCD ranges from 0.36 to
1.28 per 1000 persons per year,5-8 with approx-
imately 400,000 deaths annually in the United
States alone.2,9 Using data from the Oregon Sud-
den Unexpected Death Study, Stecker et al10
estimated the public health burden of SCD
and compared it with death rates for other dis-
eases using national databases such as the US
Census Bureau and the National Program of
Cancer Registries. The age-adjusted national
incidence of SCD was 60 per 100,000 persons.
The burden of premature death was greater for
men than for women (2.04 million [95% CI,
1.86-2.23 million] vs 1.29 million [95% CI,

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ARTICLE HIGHLIGHTS
n Sudden cardiac death (SCD) is currently defined as a natural
death from cardiac causes occurring within 1 hour of symptom
onset and heralded by abrupt loss of consciousness.
n Sudden cardiac death accounts for 400,000 deaths annually in
the United States.
n Coronary artery disease is the most common cause of SCD.
n Identifying clinical, angiographic, and electrical variables that
confer increased risk of SCD remains an ongoing challenge.
n Prompt management of cardiac arrest with bystander-
administered cardiopulmonary resuscitation, appropriate defi-
brillator shocks, and pharmacotherapy is critical.
n Increases in timely myocardial reperfusion, use of preventive
pharmacotherapies, and defibrillator implantation have under-
pinned the decreased incidence of SCD.
1.13-1.45 million]). Sudden cardiac death
accounted for approximately half of all years of
potential life lost due to heart disease and
exceeded that for all individual cancers and
most other leading causes of death, including
chronic lower respiratory tract disease and cere-
brovascular disease.
PATHOLOGIC MECHANISMS RELATED
TO CAD
Autopsy studies have found approximately two-
thirds of unexpected deaths to be cardiac in
origin, with CAD related to atherosclerosis ac-
counting for most of these deaths. For example,
Thomas et al11 reported that 54% (189 of 350)
of consecutive cases of “natural” sudden death
in adults living in the United Kingdom that
occurred within 6 hours of symptom onset
were related to ischemic heart disease. Similarly,
Leach et al12 found that 62% (206 of 333) of
randomly selected out-of-hospital deaths in the
United Kingdom were related to ischemic heart
disease. In the same studies, 5% to 10% of sud-
den deaths occurred with no evidence of CAD or
congestive heart failure. In patients who have
survived cardiac arrest, 40% to 86% have CAD
with more than 75% cross-sectional stenosis.13
Nonatherosclerotic CAD is unusual and in-
cludes causes such as dissection, embolism,
and arteritis. Acute coronary lesions including
plaque disruption or thrombus have been noted
n n
1686 Mayo Clin Proc. December 2014;89(12):1685-1698
MAYO CLINIC PROCEEDINGS
in more than 50% of SCDs related to CAD and
in 46% of hearts with evidence of myocardial
scarring in the absence of acute ischemia.14 Pla-
que rupture appears to be more common in
older women,15 and the probability of finding
an acute coronary lesion appears to be greater
with increasing duration of prodromal
symptoms.12,16
Identification of active coronary lesions at
autopsy of patients with SCD is highly variable,
with rates ranging from less than 20% to more
than 80%.17,18 Variation in reported rates of
CAD are most likely related to differences in
the accepted definition of SCD among studies,
variability in autopsy practices, and temporal
changes in population health such as changes
in smoking patterns and treatment of CAD.
For example, in Olmsted County, Minnesota,
as well as in other places, when smoking was
banned in public places, the incidence of SCD
substantially decreased within approximately 2
years.19 Furthermore, improvements in primary
and secondary pharmacotherapy have resulted
in decreasing mortality rates from CAD in the
contemporary era.20 In addition, several
population-based studies have found a 15% to
19% decrease in the incidence of SCD related
to CAD since the 1980s.21
Stable risk factors that contribute to SCD
include anatomic defects, myocardial scarring,
CAD, and abnormalities in cardiac nerves.13
Superimposed on these tangible abnormalities
are “transient” factors that precipitate SCD.
These factors include changes in local oxygen
tension and pH, electrolyte imbalances such as
hypokalemia and hypomagnesemia, ischemia
and/or reperfusion, hemodynamic changes,
and toxins and drugs such as alcohol and nega-
tively inotropic medications.13 One or several of
these transient factors may occur to precipitate
electrical instability and thereby a terminal event
in isolation. For example, one study found that
SCD in the setting of acute thrombotic occlusion
of a major coronary vessel in the absence of pre-
vious MI was usually due to an arrhythmia.22
Indeed, SCD in patients with CAD could
result from acute ischemia without infarction,
acute infarction, electrical instability due to struc-
tural abnormalities induced by CAD, or some
other problem entirely, in which CAD is an inci-
dental finding. In one study in which the hearts
of 270 persons who died of SCD were examined
along with analysis of their clinical data, 14 (5%)
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SUDDEN CARDIAC DEATH AND CORONARY ARTERY DISEASE

TABLE 1. Electrical and Nonelectrical Mechanisms of Sudden Cardiac Death

Mechanism Arrhythmia Electrocardiographic characteristics Potential causes
Electrical Pulseless VT Organized ventricular pattern, heart rate Ischemia, scar-mediated reentry, free wall rupture, papillary
>100 bpm, and absence of a palpable muscle rupture, acute ventricular septal defect
central pulse
VF Absence of organized ventricular Ischemia, scar-mediated reentry, free wall rupture, papillary
depolarization muscle rupture, acute ventricular septal defect
Nonelectrical PEA Organized, usually wide, QRS complexes Ischemia, cardiac tamponade, pulmonary embolism, tension
Primary cardiac (regular or irregular) and absence of a pneumothorax, medications, electrolyte imbalance, acidosis
(initial arrhythmia) palpable central pulse
Primary noncardiac
Secondary postshock
Asystole Absence of ventricular activity (not including Ischemia, medications, electrolyte imbalance, acidosis
fine VF)
bpm ¼ beats per minute; PEA ¼ pulseless electrical activity; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

had no structural abnormalities.23 In half of these
patients, SCD was the first manifestation of dis-
ease. Thus, the underlying mechanism in this sub-
set of patients remains poorly understood and
may relate once again to a combination of a trig-
gering event and a susceptible myocardium. Iden-
tification of the latter may depend on molecular
analysis and genetic typing.24-26 Of the remaining
patients with structurally normal hearts in that
study,23 potential mechanisms of SCD may relate
to their comorbid conditions such as obesity and
epilepsy, electrocardiographic findings such as
fusion complexes, or family histories of SCD.
Nevertheless, SCD is usually associated
with preexisting underlying structural heart
disease. Even in the setting of underlying struc-
tural heart disease such as scarred myocardium
in the setting of one of the aforementioned tran-
sient factors, many patients still do not have
SCD. This finding implies that specific combi-
nations of factors occurring in temporal and
spatial association are required to produce
SCD. Alternatively, a third specific arrhythmic
mechanism, such as automaticity or reentry
circuits, may be necessary to cause SCD.13
ELECTRICAL VS NONELECTRICAL
MECHANISMS FOR SCD
Causes of SCD can be broadly divided into electri-
cal and nonelectrical categories (Table 1). Ventric-
ular tachyarrhythmias account for most electrical
causes of cardiac arrest. In one study in which pa-
tients underwent clinically indicated Holter
monitoring, 64.4% of monitored sudden deaths
were preceded by ventricular fibrillation (VF),
16.5% by bradyarrhythmias, 12.7% by torsades
de pointes, and 8.3% by ventricular tachy-
cardia.27 Furthermore, ischemic ST-segment
changes before the arrhythmia were uncommon,
which suggests that alternative transient factors
may be involved. The study, however, was
confounded by selection bias because patients
were given Holter monitors on the basis of clinical
need, which thus potentially overestimates the
contribution of ventricular arrhythmia as a termi-
nal mechanism in this setting. Prodromal symp-
toms such as palpitations, light-headedness,
presyncope, and syncope lack satisfactory predic-
tive capacity, and as such, the only definitive way
to prove the terminal event to be arrhythmic is
through electrocardiographic monitoring or ven-
tricular electrograms from implanted devices.
Nontachyarrhythmic electrical presenta-
tions of SCD, including pulseless electrical ac-
tivity (PEA) and asystole, can have multiple
potential etiologies. Although the incidence of
ventricular tachyarrhythmias has steadily
decreased, the incidence of arrhythmias such
as PEA has not changed over the past few de-
cades, which has resulted in their increased
overall proportional contribution to SCD rates.
Data from the Seattle, Washington, emergency
rescues system revealed that of the cardiac ar-
rests they responded to, ventricular tachycardia
or VF was identified as the initial rhythm in
61% between 1979 and 1980 compared with
41% between 1999 and 2000.28 Conversely,
PEA was the initial rhythm in 17% of cases in
the first period compared with 28% in the latter
period.28 This difference may be explained
by a wider deployment of emergency medical
services resulting in longer response times,

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prolonged resuscitation attempts, or the chang-
ing myocardial substrate of an aging population
with a greater prevalence of chronic heart
disease.29 Other possible explanations include
the increased use of implantable cardioverter-
defibrillators in patients with systolic heart fail-
ure30 and enhanced use of pharmacotherapy to
manage heart failure, particularly b-blockers.31
Cardiac events that may result in nontachyar-
rhythmic sudden death include MI, cardiac
free wall rupture, cardiac tamponade, and
aortic rupture, whereas noncardiac-related
events include rupture of subarachnoidal aneu-
rysms and massive pulmonary emboli.
In the setting of acute MI, acute changes in
myocardial blood flow from the disruption of cor-
onary atherosclerotic plaques and formation of
platelet thrombi is likely to precipitate local elec-
trical instability, which may instigate arrhythmia
and subsequent SCD. This effect may be some-
what mitigated in the setting of chronic myocar-
dial ischemia from variably occluded coronary
vessels. The generation of collateral circulation
may maintain local oxygen tension and adequate
myocardial perfusion even in the setting of acute
coronary artery flow disruption, thereby protect-
ing against arrhythmogenic SCD.
RISK FACTORS FOR SCD
Risks Pertaining to CAD
Although evidence of CAD is detected subse-
quently in 80% of SCDs,13 most of these deaths
occur in apparently normal, asymptomatic adults
with no documented history of CAD. High-risk
groups such as patients who have had acute MI
within the previous year have SCD rates higher
than 30% but account for a small minority of
the total number of cases per year.2 Managing
traditional risk factors for CAD through primary
and secondary preventive methods, such as
smoking cessation, exercise, Mediterranean-
style diet, and appropriate pharmacotherapy,
may decrease the prevalence of CAD and, in
turn, decrease the incidence of SCD. Asymptom-
atic persons without known heart disease are an
important group to target, and yet they remain
the most difficult to identify. In one study of
young adults hospitalized with their first MI,
less than 25% would have qualified for lipid-
lowering therapy on the basis of the guidelines
available at the time, which highlights the limita-
tions of risk-based identification algorithms.32
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MAYO CLINIC PROCEEDINGS
Determination of cardiovascular risk and
institution of appropriate statin and antiplatelet
therapy is one of the most effective primary pre-
vention strategies to lower CAD mortality.33
Risk stratification tools such as the Framingham
risk score are helpful in identifying at-risk
groups at the population level but have limited
utility in individual patients because they fail to
include all known “conventional” cardiovascular
risk factors, such as family history of premature
CAD, and do not incorporate “nonconventional”
risk factors, such as body mass index, that are
also clinically relevant.34 Additional screening
tools for subclinical atherosclerosis, including
computed tomographic coronary calcium sco-
ring and carotid intima-media thickness,35 may
also facilitate the identification of at-risk
individuals who may otherwise be unidentified
using traditional risk scores. In one study, pa-
tients 65 years and younger without diabetes
mellitus who were not taking statins underwent
ultrasonography to assess carotid intima-media
thickness.36 Of 441 patients, 336 had a low-
risk Framingham score (5% risk of cardiovas-
cular disease within 10 years), but 38% of this
group had increased carotid intima-media thick-
ness on ultrasonography, which has been shown
to predict a higher risk of future MI in several
studies.37,38 In light of these findings, the preven-
tive regimens were intensified in 70% of this
apparently low-risk group through initiation of
lipid-lowering therapy, aspirin, or both. In keep-
ing with the National Cholesterol Education Pro-
gram guidelines, only 4.7% of patients with a low
Framingham score in this study would have been
candidates for lipid-lowering therapy.36
Traditional Risk Factors
Traditional risk factors remain important predic-
tors of SCD both in the primary care setting and
after MI. These factors include older age, male
sex, a personal history of hypertension, diabetes
mellitus, and dyslipidemia, a family history of
premature CAD, and current or past smoking.
The incidence of SCD increases with age and,
overall, is 3 to 4 times more common in men
than in women, reflecting a similar pattern for
CAD.2 These factors remain similar in the
post-MI setting. In addition, white men have
the highest death rates, followed by men of other
races, women of non-white races, and lastly,
white women. Table 2 displays the composite
hazard ratio for arrhythmic mortality for several
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SUDDEN CARDIAC DEATH AND CORONARY ARTERY DISEASE

risk factors as determined in a meta-analysis39

TABLE 2. Risk Factors for Arrhythmic Mortality at 2 Years in Patients Surviving
of several trials (European Myocardial Infarct
45 Days After MI
Amiodarone Trial, Canadian Amiodarone
Myocardial Infarction Trial, Survival With Oral Factor Arrhythmic mortality, HR (95% CI)
D-Sotalol trial, Trandolapril Cardiac Evaluation, Age, 10-y increases 1.28 (1.08-1.52)
and Dofetilide in Patients With Acute Myocar- Male sex 1.62 (1.10-2.38)
Smoker, current or former 1.04 (0.70-1.53)
dial Infarction and Left Ventricular Dysfunction
Previous MI 1.70 (1.25-2.30)
Trial). These data indicate that traditional risk
HTN 1.70 (1.23-2.34)
factors are important predictors of arrhythmic History of angina 1.59 (1.13-2.23)
(and sudden cardiac) death in the post-MI DM 1.30 (0.89-1.88)
setting among patients with ejection fractions Systolic BP, 10% increases 0.84 (0.77-0.92)
(EFs) of less than 35% or premature ventricular Heart rate, 10% increases 1.12 (1.03-1.22)
complexes. NYHA class, compared with level 0
I 1.72 (0.80-3.73)
Nontraditional Risk Factors II 2.77 (1.28-6.01)
III 3.21 (1.38-7.47)
Left ventricular EF remains the most important IV 3.53 (1.09-11.45)
predictor of SCD after MI. Pooled data from Pathologic Q wave 0.67 (0.49-0.92)
several trials revealed that left ventricular Atrial fibrillation 0.99 (0.60-1.63)
EF significantly predicted 2-year all-cause
BP ¼ blood pressure; DM ¼ diabetes mellitus; HR ¼ hazard ratio; HTN ¼ hypertension;
arrhythmic and cardiac mortality. 40 For every MI ¼ myocardial infarction; NYHA ¼ New York Heart Association.
10% increase in EF, the hazard ratio for all- Adapted from Clin Cardiol,39 with permission from John Wiley & Sons.
cause mortality was 0.58 (95% CI, 0.49-0.68;
P<.001) and the hazard ratio for arrhythmic
mortality was 0.61 (95% CI, 0.48-0.78; The role of exercise in SCD has received
P<.001). Reduced EF satisfies the need for an much public attention. The incidence of SCD
underlying “structural” heart defect that forms during exercise is between 1 per 200,000 and
one of the prerequisites for a terminal cardiac 1 per 250,000 healthy young people per year.9
event. Other transient factors and arrhythmic In cardiac rehabilitation programs, however,
mechanisms are also likely to be necessary, cardiac arrest rates range between 1 in 12,000
which is why decreased EF should be consid- and 1 in 15,000, whereas during cardiac stress
ered in addition to other factors when identi- testing these rates increase further to 1 per
fying high-risk patients. 2000. Vigorous exercise may therefore have a
Increased heart rate is also associated with role in causing SCD, particularly in previously
an increased risk of SCD.41-44 The GISSI-2 inactive patients, possibly related to increased
(Gruppo Italiano per lo Studio della Streptochi- myocardial oxygen demand and platelet aggreg-
nasi nell’Infarto Miocardico) trial found that an ability. A population-based study,4 however,
increased heart rate at discharge after MI was an found that of all persons with SCD, 67% were
independent risk factor for all-cause mortality, inactive at the time of the event. In contrast,
and that 50% of all deaths were sudden.45 The moderate exercise of approximately more than
high proportion of sudden deaths may, in part, 60 min/wk has been reported to be associated
reflect that reduced vagal activity to the heart is with a decreased risk of SCD,4 further illus-
associated with increased rates of SCD and trating the similarities between risk factors for
non-SCD. This contention is supported by CAD and SCD.
the findings of the Autonomic Tone and Re- Heavy alcohol consumption has also been
flexes After Myocardial Infarction trial,46 which associated with increased rates of SCD,41,47
documented increased 1-year mortality after although the role of moderate consumption re-
MI from 1% to 15% in the presence of mains uncertain. Prospective studies have
depressed heart rate variability and barore- revealed a lower risk of incident CAD48 and a
ceptor sensitivity, 2 factors associated with decreased case fatality rate for a first major cor-
decreased vagal activity. Indeed, derangements onary event41 among persons who consume
in each factor were independently associated moderate amounts of alcohol compared with
with increased mortality (hazard ratios of 3.2 those who abstain entirely. The observational
and 2.8, respectively).46 design of these studies, however, may lead to

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confounding and makes it difficult to establish a
causal protective relationship between alcohol
consumption and CAD. Subsequent meta-
analyses have aimed to investigate these issues.
In one of these studies, the pooled adjusted rela-
tive risk for incident CAD among consumers of
light to moderate amounts of alcohol, compared
with abstainers, was 0.71 (95% CI, 0.66-
0.77).49 The investigators controlled for con-
founders such as smoking, diet, and exercise
and concluded that any potential unmeasured
confounders would need to be very strong to
minimize the association. Other meta-analyses
found favorable changes to both lipid profiles50
and biomarkers associated with cardiovascular
disease51 among consumers of moderate
amounts of alcohol compared with abstainers,
findings that may provide potential mechanistic
explanations for this effect.
Cocaine is an important cause of drug-
related deaths; in one study, it was implicated
as the cause of sudden death in 3.1% of
autopsies.52 Although metabolic, respiratory,
and cerebrovascular causes may be relevant,
cocaine-induced sudden deaths mainly result
from cardiovascular complications and may
relate to coronary artery vasoconstriction,
accelerated atherosclerosis, and intravascular
thrombosis53 leading to ischemia and cardiac
arrest.
Electrocardiographic Risk Factors
Several electrocardiographic changes have been
associated with SCD, including the presence of
ST-segment depression and T-wave inver-
sion.54 A prolonged QT interval or a prolonged
QTc is associated with an increased risk of SCD
de novo55 and in the post-MI setting.56 The
cause of this increased risk may be related to
congenital channelopathies, which may lead to
the underlying structural defect necessary for
an SCD to occur or may be related to transient
factors such as myocardial ischemia, electrolyte
imbalance, and QT-prolonging drugs. These
QT-prolonging drugs include antiarrhythmic
medication (typically those in category III of
the Vaughan-Williams classification system),
antibiotics including macrolides such as eryth-
romycin and clarithromycin or fluoroquino-
lones such as levofloxacin, and psychiatric
medications, including tricyclic antidepressants
such as amitriptyline, doxepin, and imipra-
mine, selective serotonin-reuptake inhibitors
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MAYO CLINIC PROCEEDINGS
such as citalopram, fluoxetine, and sertraline,
and antipsychotics such as risperidone.57 What-
ever the origin of a prolonged QT interval, its
likely mechanism for precipitating SCD is
through its propensity to transform into lethal
ventricular arrhythmias rather than as a direct
consequence of the factors that cause it. Effec-
tively using this parameter in risk stratification,
however, remains difficult because it requires
multiple measurements to generate accurate fig-
ures. This issue has led to the concept of QT
dispersion, a parameter that as yet has uncertain
prognostic implications.
Other indicative electrocardiographic find-
ings include the presence of premature ventricu-
lar complexes. The GISSI-2 study found that
frequent premature ventricular complexes are
an independent risk factor for SCD within the
first 6 months after MI.58 The role of episodes
of nonsustained ventricular tachycardia (NSVT)
remains less clear. The GISSI-2 trial failed to
show NSVT to be predictive of SCD after MI.58
In contrast, both the MADIT (Multicenter Auto-
matic Defibrillator Implantation Trial)59 and the
MUSTT (Multicenter Unsustained Tachycardia
Trial)60 studies documented the importance of
identifying NSVT in patients who have had MI
and considering it in their treatment. Patients at
high risk for arrhythmic death were identified
through having NSVT, decreased EF, and posi-
tive findings on electrophysiologic studies. These
patients benefitted from prophylactic implant-
able cardioverter-defibrillator insertion with
decreased mortality; the hazard ratios for all-
cause mortality were 0.46 (95% CI, 0.26-0.82)
in the MADIT study59 and 0.24 (95% CI,
0.13-0.45) in the MUSTT study.60 These studies
have revealed that it is far more important to
consider multiple risk factors for each patient
group rather than any one in isolation. This
concept provides a more reasoned approach to
the management of patients’ conditions and en-
hances the predictive capacity for risk factors,
which independently have limited utility.
Furthermore, these trials examined the use of
electrophysiologic studies to induce sustained
monomorphic ventricular tachycardia for post-
MI risk stratification. As yet, the routine use of
these studies in the post-MI setting has not
been proven to be beneficial. Nevertheless, their
inclusion in this review once again reiterates the
importance of considering multiple different risk
factors as well as the findings of various tests
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SUDDEN CARDIAC DEATH AND CORONARY ARTERY DISEASE
when making management decisions to decrease
SCD rates in patients after an MI.
INITIAL MANAGEMENT AND SURVIVAL
AFTER OUT-OF-HOSPITAL SCD
In excess of 300,000 Americans are estimated to
have an out-of-hospital cardiac arrest each year,
with a survival rate nationally of 7.9%.61 The
Resuscitation Outcomes Consortium evaluated
data on 14,420 adult patients who had cardiac
arrests in nonhospital settings and were treated
by emergency medical services from 7 American
and 3 Canadian centers between December
2005 and April 2007.62 A total of 12,930 arrests
(89.7%) had a known or shockable rhythm ac-
cording to bystander-administered automated
external defibrillator (AED) data; 74% of these
events occurred in private homes, 10% in
nursing homes or residence facilities, and 16%
in public places. Of those who sustained arrests
in public locations, 17% survived to hospital
discharge compared with 6% for those occur-
ring in homes and 3% for those in residential
or other private facilities.62
Survival until hospital discharge was more
common for patients who had an AED applied
by a bystander in a public location compared
with at home (34% vs 12%; P¼.04), a difference
that may be attributed to a concomitant observa-
tion of a higher incidence of shockable arrhyth-
mias occurring in public places compared with
in private or residential/nursing homes.62 In a
study of cardiac arrests in casinos identified by
video surveillance, those who had a cardiac ar-
rest and received AED shocks had a survival
rate of 53%.63 Similarly, patients with cardiac ar-
rests occurring in Chicago, Illinois, airports that
were managed by AED shocks delivered by by-
standers had a survival rate of 60%,64 which
compares favorably with a survival rate of 42%
among individuals who received AED shocks
in public places as determined by the Resuscita-
tion Outcomes Consortium study.62 Automated
external defibrillator rhythm detection and
shock advisory algorithms are highly sensitive
and specific.65,66 It has been suggested that
AEDs should be “as common as fire extin-
guishers”67 to cover all potential locations of ar-
rests, but this plan would be most effective if
combined with effective means of promptly
recognizing, localizing, and responding to out-
of-hospital cardiac arrests and educating the
public in basic life support.13
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Bystander cardiopulmonary resuscitation
(CPR) can more than double survival rates68
yet has a low prevalence (27%-33%) in most
cities.69,70 Swor et al69 found that bystanders
trained in CPR most often cited fear of causing
harm as preventing them from performing
CPR. Improved public awareness and more
widespread and simplified training in CPR
may allow more people to learn and perform
this important skill.71
ADJUNCTIVE TREATMENT AFTER SCD
In addition to the delivery of appropriate and
timely shocks, pharmacotherapy has an impor-
tant role in the setting of cardiac arrest. Resus-
citation guidelines advocate the use of repeated
doses of epinephrine. Vasoconstrictors have
been found to improve blood flow and survival
in animals, but improved survival has not been
documented in clinical trials.29 Vasopressin
may be used as an alternative to epinephrine
in shock-refractory VF, PEA, and asystole. In
one study, vasopressin and epinephrine per-
formed similarly in VF and PEA arrests, but
vasopressin performed better in asystole.72 In
contrast, another study found no added benefit
from combining the drugs.73 Once advocated
in the setting of PEA, atropine is no longer rec-
ommended in this setting.74
Therapeutic hypothermia after return of
spontaneous circulation also has improved
outcomes. In a prospective study performed
at 9 centers in 5 European countries, patients
who experienced return of spontaneous
circulation and had persistent coma after VF
cardiac arrest were randomly assigned to hy-
pothermia treatment (32 C-34 C achieved
within 4 hours, maintained for a 24-hour
period, and followed by passive rewarming)
or normothermia.75 In total, 55% of the hy-
pothermia group had a favorable neurologic
outcome at 6 months compared with 39%
in the normothermia group (risk ratio, 1.40;
95% CI, 1.08-1.81). Furthermore, at 6
months, 41% of patients in the hypothermia
group had died compared with 55% in the
normothermia group (risk ratio, 0.74; 95%
CI, 0.58-0.95).75 Similarly favorable data
were seen in a randomized trial in Australia.76
Early implementation may augment benefits
further. One study found that intra-CPR hy-
pothermia in the setting of coronary occlu-
sion in an animal model decreased infarct
1691

size.77 This strategy needs further evaluation
to facilitate its effective implementation in
the setting of cardiac arrest.
FACTORS RELATED TO TREATMENT OF
ACUTE MI
Important considerations when managing CAD
include the early management of MI, secondary
preventive pharmacotherapy including the pre-
vention of plaque progression and instability,
and the control of neuroendocrine factors.
Antiarrhythmic medications also have an
important role in this setting but are beyond
the scope of this review.
Reperfusion
Thrombolysis as the treatment of acute ST-
segment elevation MI has been associated
with up to a 50% decrease in death rates.78-81
In light of several limitations including risk of
bleeding, multiple cautions disqualifying
some patients from having the treatment, and
delayed presentation of symptoms, thromboly-
sis has been superseded by the new standard in
therapydpercutaneous coronary interven-
tion.82 Timely reperfusion therapy is known
to decrease in-hospital mortality during MI
through decreased rates of arrhythmogenic
death (typically VF) and structural death (typi-
cally cardiogenic shock).83 Prevention of the
former is particularly time-critical. Other ben-
efits of achieving patency of culprit vessels
include preservation of left ventricular func-
tion and limitation of ventricular remodel-
ing.84,85 Furthermore, the use of stents in
acute MI has been associated with reduced
early occlusion86 and late restenosis.87 The ef-
fect of primary percutaneous coronary inter-
vention on mortality in patients with
ST-segment elevation MI highlights the
important effect of early reperfusion on pre-
venting the myocardial substrate from trans-
forming into a medium conducive to
arrhythmia by restricting infarct size and scar-
ring and limiting ventricular remodeling. The
Figure summarizes best practice management
of acute ST-segment elevation MI. Implantable
cardioverter-defibrillator placement has been
addressed only briefly in this review but has
been found by the MADIT-2 study to improve
post-MI survival in patients who have a
decreased EF and episodes of NSVT de novo
and during electrophysiologic studies.88
n n
1692 Mayo Clin Proc. December 2014;89(12):1685-1698
MAYO CLINIC PROCEEDINGS
Timely subspecialist input is crucial in deter-
mining the suitability of individual patients
for such treatment.
Secondary Prevention
Pharmacotherapy has a key role in secondary
prevention after acute MI. Angiotensin-
converting enzyme inhibitors reduce the pro-
gression to overt heart failure after MI and
have decreased mortality due to progressive
heart failure. In one prospective, double-blind
study, 1556 patients with symptoms of an acute
anterior MI were randomly assigned within 24
hours of presentation to receive either zofeno-
pril or placebo for 6 weeks.89 Those taking zofe-
nopril had a cumulative decrease in the risk of
death or severe congestive heart failure of 34%
(95% CI, 8%-54%; P¼.02). The studies by
Ambrosioni et al89 and Pfeffer et al90 also
revealed a decrease in the rate of SCD by
as much as 54%. Therefore, angiotensin-
converting enzyme inhibitors form an impor-
tant component of treatment after MI. These
drugs, however, can only suppress aldosterone
in acute and subacute settings, after which aldo-
sterone levels increase and exert deleterious
neuroendocrine effects and possibly deleterious
effects on the myocardium itself; this limited
time frame of effectiveness may then explain
the additive benefit provided by aldosterone an-
tagonists. The Randomized Aldactone Evalua-
tion Study91 found that adding an aldosterone
antagonist to the treatment regimen of patients
with progressive heart failure after MI was asso-
ciated with reduced mortality, including SCD.
In fact, the trial was discontinued early because
interim analysis at a mean follow-up of 24
months revealed that patients randomly
assigned to treatment with spironolactone had
a 30% decrease in the risk of death (95% CI,
18%-40%; P<.001) compared with those not
taking spironolactone.
The Long-term Intervention with Pravasta-
tin in Ischaemic Disease92 and the Scandina-
vian Simvastatin Survival Study93 trials both
found decreased mortality and SCD rates after
MI in patients who were treated with a statin.
In the latter study,93 patients with angina pec-
toris or previous MI and serum cholesterol
levels of 5.5 to 5.8 mmol/L were randomly
assigned to simvastatin or placebo. Those tak-
ing simvastatin had a relative risk of coronary
death of 0.58 (95% CI, 0.46-0.73). That study
http://dx.doi.org/10.1016/j.mayocp.2014.08.022
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SUDDEN CARDIAC DEATH AND CORONARY ARTERY DISEASE
Patient seeks care for chest pain/anginal
symptoms suggestive of STEMI
Obtain 12-lead ECG
(within 5 minutes of arrival in the ED)
history and physical examination
laboratory tests
SL nitroglycerin as required for pain
81 mg x 4 chewable aspirin
ECG diagnostic of STEMI
1. ST-segment elevation ≥2 mm in
V2-V3 and ≥1 mm in all other
contiguous leads. or
2. New/presumed new LBBB with
clinical status in keeping with acute MI
Timely access to PPCI? No
Yes
Patient candidate for invasive No
procedure?
Yes
Activate STEMI system
Give:
1. Ticagrelor 180 mg (preferred) or
clopidogrel 600 mg orally
2. Unfractionated heparin or bivalirudin
3. SL nitroglycerin as required for pain
4. IV morphine or fentanyl for pain
5. Oxygen via nasal cannula
FIGURE. Algorithm outlining optimal management of acute ST-segment elevation myocardial infarction (STEMI). aPTT ¼ activated
partial thromboplastin time; BP ¼ blood pressure; Cath Lab ¼ catheterization laboratory; ECG ¼ electrocardiogram; ED ¼ emer-
gency department; EP ¼ electrophysiology; IV ¼ intravenously; LBBB ¼ left bundle branch block; MI ¼ myocardial infarction;
PPCI ¼ primary percutaneous coronary intervention; SL ¼ sublingual.
also found decreased rates of heart failure,
largely attributable to reduced rates of reinfarc-
tion, which reinforces that statins confer bene-
fits through stabilization of lipid-rich coronary
plaques in addition to control of serum lipid
levels. Treating all patients who have experi-
enced MI with aspirin decreases all-cause mor-
tality and has the additional benefit of reducing
the likelihood of ischemic stroke and reinfarc-
tion through antiplatelet effects.94 In one early
trial evaluating the role of aspirin in secondary
prevention after MI, patients randomly
assigned to aspirin for 1 year had an overall
decrease in total mortality and a hospital
Mayo Clin Proc. n December 2014;89(12):1685-1698
www.mayoclinicproceedings.org
No
Nondiagnostic ECG with clinical status Contraindication to
thrombolytics? Thrombolytic therapy
suggestive of evolving infarct:
1. Serial ECGs every 5-10 min
2. Chest pain/other observation unit
3. Treat comorbid conditions Yes
(eg, low BP.)
Yes
4. Consider the differential diagnosis
<2 h onset of No Patient candidate for
Give:
symptoms? invasive procedure?
1. Unfractionated heparin or bivalirudin
2. Heparin infusion (12 U/kg/h IV initially, up
to a maximum of 1000 U/h, and then
No
adjust to maintain aPTT in therapeutic Yes
range
3. SL nitroglycerin as required for pain
4. IV morphine or fentanyl for pain
5. Oxygen via nasal cannula
1. PPCI
Medical therapy
2. Don’t give thrombolytics
as before
3. Medical therapy as before
Give:
1. Ticagrelor 180 mg (preferred) or
clopidogrel 600 mg orally
2. Unfractionated heparin or bivalirudin
3. Heparin infusion (12 U/kg/h IV initially,
up to a maximum of 1000 U/h,
and then adjust to maintain aPTT in
therapeutic range)
4. SL nitroglycerin as required for pain 1. Transfer to coronary care unit
2. Secondary prevention
5. IV morphine or fentanyl for pain
pharmacotherapy
6. Oxygen via nasal cannula
3. Cardiac rehabilitation, including advice
on lifestyle modifications and
medication compliance
4. Early echocardiography to assess
Transfer to cath lab ejection fraction
(within 30 minutes of arrival in the ED) 5. Timely and appropriate input from
heart failure and EP teams
readmission rate of 28% compared with those
given a placebo (P<.05).95 b-Blockers also
reduce all-cause mortality and the risk of rein-
farction in the post-MI period and may
decrease the rates of SCD by 40% to 55%.96 Pa-
tients with decreased left ventricular function
have the greatest benefit.97 In one multicenter,
randomized, placebo-controlled trial, patients
with proven acute MI and left ventricular EF
of 40% or less who were randomly assigned
to receive carvedilol had a lower rate of all-
cause mortality than did those given placebo
(12% vs 15%) (hazard ratio, 0.77; 95% CI,
0.60-0.98; P¼.03).98 Table 3 summarizes the
n http://dx.doi.org/10.1016/j.mayocp.2014.08.022 1693

TABLE 3. Risk of Death After MI Following Administration of Various
Therapeutic Agents or Interventionsa
Agent/intervention Death after MI, RR (95% CI)b
ACE inhibitors 0.83 (0.71-0.97)
Aldosterone antagonists 0.70 (0.60-0.82)
Statins 0.71 (0.64-0.80)
Nitrates 0.94 (0.90-0.98)
Aspirin 0.75 (0.71-0.79)
b-Blockers 0.77 (0.70-0.84)
Thrombolytics 0.82 (0.77-0.87)
PTCA 0.66 (0.46-0.94)
a
ACE ¼ angiotensin-converting enzyme; MI ¼ myocardial infarction; PTCA ¼ percutaneous
transluminal coronary angioplasty; RR ¼ relative risk.
b
Risk of all-cause mortality, not sudden cardiac death.
Adapted from Eur Heart J,83 with permission from Oxford University Press for the European
Society of Cardiology.
findings of several meta-analyses evaluating
the roles of the drug classes discussed herein
after MI.
Other Considerations
Mortality after MI has decreased in the contem-
porary era. In the prethrombolytic era, rates
during the first 21/2 years after MI were higher
than 15%, and 75% of deaths were attributed to
arrhythmia105 compared with 5% in the throm-
bolytic era.106,107 Reperfusion strategies to limit
infarct size are most likely responsible for the
observed decrease in mortality after MI and
SCD rates, the mechanism for which may relate
to improved overall electrical stability in the
myocardium or specifically in the myocytes
adjacent to the infarcted territory. Achieving
successful reperfusion of an infarct-related ar-
tery appears to be associated with a decreased
incidence of ventricular tachyarrhythmias and
SCD; one study found it to be the only factor
among several variables examined, including
EF lower than 40% and ventricular arrhyth-
mias, to predict arrhythmic events within 12
months of follow-up after MI.108 Ejection frac-
tion has traditionally been viewed as the single
best predictor of outcomes after MI. In fact, the
same study indicated that an occluded infarct-
related artery had superior sensitivity as a risk
factor predicting arrhythmic events compared
with EF less than 40% (78% vs 58%) but a
concomitant inferior specificity (61% vs
83%).108 Thus, ensuring patency of the culprit
artery is an important part of disease manage-
ment in these patients to decrease SCD rates
n n
1694 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
and should be combined with appropriate
pharmacotherapy to prevent and manage inci-
dental heart failure.
Reference The poor positive predictive value for SCD
99 of many of the risk factors we have discussed in
91 this review (14% for occlusion of infarct-related
100
artery and 21% for EF <40%) is a pervasive
101
problem and relates in an important way to
102
96
modern treatment strategies. Timely reperfu-
103 sion and diligent use of pharmacotherapy
104 have decreased the incidence of both all-cause
mortality and SCD after acute MI, the result
of which is that accepted risk factors now pro-
vide important predictive capacity when used
alone. At the same time, aggressive primary
and secondary prevention strategies have
resulted in a changing population with CAD
and its complications, which also challenges
the utility of conventionally accepted risk fac-
tors when predicting risk for SCD. The best
way to circumvent this problem is to combine
and use the predictive capacity of multiple
risk factors to account for the holistic array of
causative mechanisms, as described in this
review.
CONCLUSION
Sudden cardiac death remains a major source
of morbidity and mortality in the developed
world. Most cases are related to CAD, and
because many of the risk factors for SCD paral-
lel those of CAD, it is important to promptly
identify and aggressively manage the condi-
tions of those deemed to be at risk. Advances
in the recognition and initial management of
SCD have appeared to improve outcomes in
these patients. In the setting of acute MI, timely
reperfusion, careful monitoring, and evidence-
based pharmacotherapy to reduce mortality
form the cornerstone of sound management.
Successful implementation of these strategies
to date has resulted in the fortunate decrease
in rates of SCD, which highlights the impor-
tance of maintaining high clinical standards in
identifying at-risk patients and managing their
conditions as such. Actually identifying these
at-risk patients, however, has been difficult
because most cases of SCD occur in asymptom-
atic persons who have not been diagnosed as
having cardiac disease, CAD or otherwise.
Further studies to improve screening methods
for identifying at-risk individuals for SCD are
needed.
December 2014;89(12):1685-1698 http://dx.doi.org/10.1016/j.mayocp.2014.08.022
www.mayoclinicproceedings.org
SUDDEN CARDIAC DEATH AND CORONARY ARTERY DISEASE
Abbreviations and Acronyms: AED = automated external
defibrillator; CAD = coronary artery disease; CPR = car-
diopulmonary resuscitation; EF = ejection fraction; MADIT =
Multicenter Automatic Defibrillator Implantation Trial; MI =
myocardial infarction; NSVT = nonsustained ventricular
tachycardia; PEA = pulseless electrical activity; SCD = sud-
den cardiac death; VF = ventricular fibrillation
Correspondence: Address to David R. Holmes, Jr, MD, Di-
vision of Cardiovascular Diseases, Mayo Clinic, 200 First St
SW, Rochester, MN 55905 (holmes.david@mayo.edu).
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