Fibrilacion Ventricular

CHAPTER
Ventricular Fibrillation
Introduction, Principles of Practice: Paul Dorian
Etiology and Pathology: Saroja Bharati
Epidemiology: Robert J. Myerburg
46
Basic Electrophysiology: David Rosenbaum, Kara J. Quan, and Mariah L. Walker
Clinical Electrocardiography: Bruce D. Lindsay
Diagnostic Evaluation: L. Brent Mitchell
Electrophysiological Testing: William G. Stevenson
Evidence-Based Therapy: Paul Dorian and Michael Domanski
Ventricular fibrillation (VF) is the most serious cardiac arrhyth- may occur in acute myocarditis of any etiology. However,
mia and has a primary role in mediating sudden cardiac death intractable VT with recurrent cardiac arrest refractory to medica-
(SCD). It leads to immediate circulatory arrest with cardiovascu- tions or defibrillator device implantation may be related to chronic
lar collapse. A variable period may elapse, but cardiac asystole myocarditis (Figure 46-2).4-6
usually supervenes (Figure 46-1). Spontaneous termination of VF,
which is seen in animal experiments, is rare in humans. VF is
often preceded by an organized, rapid ventricular tachycardia Pathology
(VT) of variable duration; recordings from implantable devices
have now substantiated this. Ischemic injury may trigger VF. If The anatomic basis for VF in acquired heart diseases is similar to
untreated, this leads to irreversible end-organ damage, including that of VT. In this chapter, emphasis is given to the morphologic
cerebral and myocardial damage after 5 to 7 minutes of VF. Even findings for VF in athletes or healthy youths who were seemingly
with optimally performed basic cardiopulmonary resuscitation living a “normal, asymptomatic” life and died suddenly. In addi-
(CPR), the mortality rate is greater than 95% if defibrillation is tion, familial occurrences of SCD caused by recurrent VT degen-
delayed by more than 10 minutes. The rule of survival from out- erating to VF is briefly discussed.1-3,5,6
of-hospital VF is that survival decreases by 10% for each minute
before defibrillation. The sine qua non of effective resuscitation
Sudden Cardiac Death in Athletes or the Young
from VF is thus prompt defibrillation, delivered as early as pos-
and Healthy
sible. Importantly, however, a brief period of CPR before defibril-
lation in out-of-hospital cardiac arrest, especially if the arrest is The conduction system has been carefully studied in several
more than 4 minutes in duration, may increase survival rates. young persons who were living a “normal” life and died suddenly.
Routine autopsies are often unremarkable. In the majority, the
heart is hypertrophied and enlarged to a mild, moderate, or
Etiology marked extent; however, at the gross level, no significant abnor-
malities were seen.3 A serial section examination of the conduc-
VF occurs in many disease states of the myocardium and the tion system and the surrounding myocardium reveals varying
conduction system and can be broadly grouped under two catego- types of abnormalities, either of a congenital or acquired nature.
ries: (1) genetic/familial and (2) acquired. Genetically based Congenital abnormalities can exist in the sinoatrial (SA) node,
abnormalities of the myocardium or the specialized conduction atrioventricular (AV) node, or the AV bundle and the bundle
fibers or both may give rise to the clinical manifestations of famil- branches (Figure 46-3). Abnormal formation of the SA or AV
ial occurrence of VT and VF. In most cases, the initial arrhythmia nodes, such as a double SA node, a double AV node, or the abnor-
is one of various forms of VT (monomorphic or polymorphic VT, mal location of the SA and AV nodes in unexpected areas, can be
which then degenerates to VF). However, acquired cardiac dis- seen pathologically. The AV bundle may be considerably frag-
eases such as coronary artery disease (CAD), hypertensive heart mented into several components, abnormally located, or both. In
disease, cardiomyopathy of any etiology with or without heart addition, acquired pathologic findings exist in the form of focal
failure, and other miscellaneous disease states (see Chapter 47) myocardial disarray, fat, or fibrosis to varying degrees, disrupting
are the most common causes of VF and SCD.1-3 VT leading to VF or replacing parts of the specialized conduction fibers and the
681
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682 Cardiac Rhythms and Arrhythmias
Polymorphic VT VF
VF Asystole
FIGURE 46-1 Evolution of polymorphic ventricular tachycardia (VT) into ventricular fibrillation (VF) and subsequent development of cardiac asystole.
surrounding myocardium (see Figure 46-3) with arteriolosclerosis

(small vessel disease) of the ventricular septum. In general, the
Epidemiology
findings in the conduction system are accompanied by pathologic
Ventricular Fibrillation and Sudden Cardiac Death
findings in the surrounding myocardium. Mononuclear cell infil-
tration in the approaches to the SA node and in the SA node itself The epidemiology of VF intertwines with the available data on
is present.3 SCD (or cardiac arrest) and its documentation by emergency
Despite such pathologic findings in and around the conduction medical system (EMS) personnel.9 In 1998, an epidemiologic pro-
system, these persons were considered to be asymptomatic, and spective study from northeast Italy reported an incidence of
SCD was the first manifestation of the disorder. Clinically, in cardiac arrest of 95 of 100,000 persons per year.10 In this study,
almost all, VF was the only common denominator observed by VF accounted for 30.2% of the initially recorded rhythms, asystole
the paramedics at the time of resuscitation. It can be hypothesized for 48.3%, and pulseless electrical activity for 21.5%. A similar
that varying types of congenital or acquired pathologic findings study of out-of-hospital cardiac arrest confirmed VT or VF as the
in and around the conduction system may remain “silent,” and initial rhythm in 59 (30%) of 197 patients of a patient cohort from
these individuals are asymptomatic for long periods. Other dis- the Los Angeles area.11 Although VT and VF were consistently
orders (e.g., right ventricular cardiomyopathy, hypertrophic car- more likely to be associated with return of spontaneous circula-
diomyopathy, idiopathic dilated cardiomyopathy) can lead to VT tion in these two studies, the time dependency of the initial
degenerating to VF, the first evident manifestation of the disease. recorded rhythm is still debated. The Ontario Prehospital
During an altered physiological or metabolic state, anatomic find- Advanced Life Support (OPALS) study quoted an annual inci-
ings, pathologic findings, or both may trigger an arrhythmia that dence of 58 out-of-hospital cardiac arrests per 100,000 persons,
progresses to VT, VF, and SCD.3 and in the subgroup of EMS-witnessed cardiac arrests, VT and
VF accounted for 34.2% of cases.12 However, a recent analysis
from Sweden estimated that patients with an electrocardiogram
Familial Sudden Cardiac Death
(ECG) taken within the first 10 minutes from a witnessed cardiac
A genetic tendency for the development of an abnormal conduc- arrest have an incidence of VF of 50% to 60%. Linear regression
tion system, the surrounding myocardium, or both may also lead further estimated that ECGs taken within the first 4 minutes
to VT, VF, and SCD (Figure 46-4).5,6 Familial occurrence of ven- should have an incidence of 75% to 80%.13
tricular arrhythmias may be related to the many genetic muta-
tions associated with congenital long QT syndrome (LQTS) or
Ventricular Fibrillation and Population Considerations
Brugada syndrome. These disorders of ion channel function may
also lead to cellular dysfunction and pathologic changes such as Despite the debate on the true proportion and incidence of VF in
fatty infiltration, fibrosis, and disruption of the conduction system prehospital cardiac arrest, event rates range from 250,000 to more
and the adjoining myocardium.7,8 These disorders are discussed than 450,000 per year in the United States.14 This absolute number
in other chapters in this text and are alluded to in subsequent is heavily influenced by population dynamics and the defined
sections of this chapter. subpopulation being discussed.
Of note, in many cases of SCD in young patients, no gross The median incidence of cardiac arrest in 10 large Canadian
anatomic or histologic abnormalities are identified. and U.S. communities is 52 cases per 10,000 annually.15 The
Ventricular Fibrillation 683
46
Fi
Fi
Fi,
Fi
Fi
Fi
FIGURE 46-2 Chronic myocarditis in a 35-year-old man with

polymorphic sustained drug-refractory ventricular tachycardia FIGURE 46-3 Conduction system and adjoining myocardial disease
associated with multiple cardiac arrests, uncontrolled by β-blockers, in a 25-year-old man who collapsed while playing basketball. He was
antiarrhythmic drugs, and defibrillator insertion. The patient found to be in ventricular fibrillation and could not be resuscitated.
underwent heart transplantation. The explanted heart revealed Photomicrograph of the left bundle branch shows falling out of cells.
myocarditis of a chronic or smoldering type in the approaches to the Note the endocardial thickening and numerous focal areas of fibrosis
atrioventricular (AV) node, the AV node, and beginning of the right of the ventricular septum (Weigert-van Gieson stain ×30). Arrows point
bundle branch. The AV bundle revealed fibro-fatty change and was to the loss of left bundle branch fibers. E, Endocardium; V, ventricular
left sided. There was marked fibrosis of the left bundle branch, chronic septum; Fi, fibrosis. (From Bharati S, Lev M: The cardiac conduction
epicarditis, arteriolosclerosis of the summit of the ventricular septum, system in unexplained sudden death, Mount Kisco, NY, 1990, Futura.)
and fibrosis on both sides of the septum. (Weigert-van Gieson stain
×45). Arrows point to arteriolosclerosis. Fi, Fibrosis in the myocardium;
V, ventricular septum. (From Bharati S, Olshansky B, Lev M: Pathological
study of an explanted heart due to intractable ventricular fibrillation, J
Cardiovasc Electrophysiol 3:437–441, 1992.) artery calcification in an autopsy series of SCD victims.18 The two
risk assessment methods had modest correlation with each other
(63%). Of the cases, 83.5% had a coronary artery calcification
score or Framingham risk index above average for age. The
remaining 17.5% highlight the need for exploration of new cardiac
risk factors (e.g., fibrinogen, homocysteine, infectious agents, or
well-documented high-risk subgroups (ischemic heart disease ion channel abnormalities) that could be applied to the population
with low left ventricular ejection fraction [LVEF], complex ven- at large.
tricular ectopy, prior hospital admission for congestive heart The high-risk subpopulations have been targeted in recent
failure [CHF], or previous cardiac arrest) contribute a minority of publications for epidemiologic analysis. The Worcester Heart
the total number of cardiac arrests, although the subgroup percent Attack Study described a relatively fixed incidence rate of 4.7% for
incidence per year is the highest (Figure 46-5). VF in hospitalized patients with validated acute myocardial
A screening tool or preventative intervention would need to infarction (MI) over a 22-year period (1975 to 1997).19 The
be applied to 999 of 1000 persons to influence the 1 of 1000 previ- Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
ously unidentified persons destined for a cardiac arrest. The Miocardico (GISSI-2) database reported an incidence of early-
Framingham study demonstrated a large disparity from the onset VF (<4 hours after onset of acute MI) and late VF (>4 to 48
highest to lowest decile (14-fold increase in risk) for SCD measur- hours) of 3.1% and 0.6%, respectively. In-hospital prognosis was
ing the well-known risk factors such as age, family history, gender, worse in patients with VF than without VF, but the postdischarge
tobacco use, hyperlipidemia, and hypertension.16 Electron beam to 6-month mortality rate was similar for both VF subgroups and
computed tomography for the detection of coronary artery calci- controls.20 The patient with prior cardiac arrest has a similar “time
fication has been correlated to coronary event risk.17 A recent dependence” of risk of recurrent events, as was presented by
publication compared the Framingham risk index and coronary Furukawa et al (Figure 46-6).21
report, there was a 23% relative reduction in all-cause mortality

with the ICD compared with placebo (7.2% to 5.8% per year), and
no reduction in mortality rate with amiodarone compared with
placebo. The most recent developments in assessing risk of
cardiac arrest have been in the blossoming technology of molecu-
lar genetics. The familial types of LQTS and their respective
genetic bases have been well described elsewhere. An increasingly
recognized syndrome of right bundle branch block (RBBB), ST
segment elevation, and aborted SCD (Brugada syndrome) has
also been ascribed to a genetic mutation in the gene encoding the
cardiac sodium channel. Its prevalence in a European study by
ECG screening was estimated at 0.1% of the general population.24
If the only effective therapy for the syndrome is ICD implantation,
the economic impact on the public health budget is obvious.
A trial of the automated external defibrillator (AED) to be used
in the home by trained spouses or cohabitants of individuals with
prior anterior MI (the Home Automated External Defibrillator
Trial [HAT]) was not able to show a reduction in mortality rate,
in part because of the unexpectedly low incidence of VF as the
initial recorded arrhythmia in these patients.25
The epidemiology of VF and SCD are closely aligned. From a
public health perspective, the largest number of cardiac arrest
survivors will have the well-described cardiac risk factors from
the Framingham study (e.g., hypertension, hyperlipidemia). An
intervention for the population as a whole, however, will require
treatment of a vast majority to prevent a single cardiac arrest. The
high-risk subset of pre–cardiac arrest (although a minority of the
total number) is currently undergoing research investigating pro-
FIGURE 46-4 Cardiac conduction system histology in a 16-year-old phylactic ICD implantation and the cost effectiveness of such a
girl with a familial history of alternating bi-directional tachycardia who practice. New screening tools that are widely applicable, eco-
died suddenly. Fatal ventricular arrhythmias occurred in three nomical, and cost-effective are needed for future progress in SCD
generations, including two siblings and the mother. The conduction prevention.
system revealed degenerative changes. Photomicrograph
demonstrates vacuolar degeneration of left bundle branch
(hematoxylin-eosin stain ×104). Arrows point to vacuolar degeneration Basic Electrophysiology
of main left bundle branch. (From Gault JH, Cantwell J, Lev M, Braunwald
E: Fatal familial cardiac arrhythmias, Am J Cardiol 29:548–553, 1972.)
During VF, the myocardium fails to contract effectively and cir-
culate blood. Although certain species such as rats can spontane-
ously revert from VF to normal sinus rhythm, in humans, VF is
lethal if not treated promptly. Thus, analysis of the electrophysi-
Low LVEF was a strong predictor of the highest risk of recur- ological mechanisms culminating in VF is critical to effective
rence (11% in the first 6 months). Persistent inducibility at elec- therapy.
trophysiological study (EPS) was the better predictor for recurrent Ventricular arrhythmias can develop by three major mecha-
events from 6 to 42 months, but the subsequent risk fell to 0.8% nisms. Abnormal impulses may be initiated by (1) triggered
over the final 6 months of the study period. In the patients who activity (early or delayed afterdepolarizations); (2) abnormal auto-
entered the Antiarrhythmics Versus Implantable Defibrillators maticity, which refers to the inherent ability of various regions of
(AVID) study with VF, the survival curve shows the same early myocardium (other than the SA node) to act as pacemakers; and
recurrence (<6 months) in the patients treated with antiarrhyth- (3) re-entry. Re-entrant excitation is believed to be the primary,
mic drugs as those who did not receive this therapy and most clinically relevant, mechanism for VF and is therefore
(Figure 46-7).22 the focus of this chapter.
Clinical trials are assessing the “static” risk of cardiac events
outside the setting of acute hospitalization.23 The Multicenter
Dynamics of Re-entrant Ventricular Fibrillation
Automatic Defibrillator Implantation Trial (MADIT-II) trial
tested implantable cardioverter-defibrillator (ICD) therapy versus VF is generated by self-sustained re-entrant circuits that turn
standard medical therapy in patients with ischemic heart disease, around regions of conduction block. In some circumstances, the
an LVEF less than 30%, and previous MI. It showed a 31% relative zone of conduction block can be anatomic in nature, such as the
risk reduction with ICD therapy. The Sudden Cardiac Death in site of a healed infarct or a region of fibrosis. In such cases,
Heart Failure Trial (SCD-HeFT) trial compared three arms of the re-entrant circuit is anchored to the site of block and results
therapy in patients with congestive heart failure and LVEF less in a stable rotor and monomorphic VT. When the zone of con-
than 30%: best conventional heart failure therapy with placebo, duction block is functional in nature, the region of refractoriness
best conventional heart failure therapy with amiodarone, and best is transient both spatially and temporally. Re-entrant circuits that
conventional heart failure therapy with ICD.23 In a preliminary form around such zones can therefore meander freely or change
46
SUDDEN DEATH–INCIDENCE AND TOTAL EVENTS
Overall incidence
in adult population
High coronary
risk sub-group
Any prior
coronary event
EF <30%;
heart failure
Out-of-hospital
FIGURE 46-5 Risk of sudden cardiac death,
cardiac arrest
survivors with influence of pre-existing heart disease on
magnitude of risk in middle-aged and older
Convalescent phase adults. The prevalent etiologies are a function
VT/VF after MI of age. EF, Ejection fraction; VT/VF, ventricular
tachycardia/ventricular fibrillation; MI,
0 1 2 5 10 20 30 0 100 200 300 myocardial infarction. (Modified from Myerburg
Percent/year Events/year RJ, Kessler K, Castellanos A: Sudden cardiac death:
Structure, function and time-dependence of risk,
(×1000) Circulation 85[suppl I]:2–10, 1992.)
RECURRENCES AMONG CARDIAC ARREST SURVIVORS
11.2%
100
3.3%
3.3%/
90
6 months
0.8%/
6 months
FIGURE 46-6 Risk of recurrent cardiac arrest among
Percent
80
survivors of out-of-hospital cardiac arrest. The highest
EF risk of recurrent cardiac arrest is within the first 12 to
(<35%) 24 months. In the earlier part of that period, ejection
70 fraction (EF) is the most powerful predictor, whereas
Persistent inducibility persistent inducibility of ventricular tachyarrhythmias
during electrophysiological studies becomes an
60 important predictor beyond that period.
n = 101 Nonetheless, EF remains a predictor throughout. F/U,
at t = 0 Follow-up. (Modified from Furukawa T, Rozanski JJ,
Nogami A, et al: Time-dependent risk of and predictors
0
for cardiac arrest recurrence in survivors of out-of-
0 6 12 18 24 30 36 42
hospital cardiac arrest with chronic coronary artery
Months (F/U) disease, Circulation 80:599–608, 1989.)
in size, providing an important mechanism for VF. However, the coworkers to explain atrial fibrillation (AF).26 This hypothesis
nature of re-entrant waves and the mechanisms by which they states that a re-entrant circuit is the smallest pathway in which the
lead to VF are still not entirely clear. impulse can continue to circulate and that the core is kept perma-
nently refractory (i.e., there is no excitable gap) (Figure 46-8).
However, Janse questioned whether the core is truly refractory
Nature of Fibrillatory Wavefronts
during re-entry, since membrane potential is relatively normal in
Re-entrant excitation is the fundamental mechanism responsible this region and diastolic intervals are relatively long.27 Further-
for VF. The precise nature of these wavefronts, their formation, more, the presence of an excitable gap allows wavefronts (sponta-
and sustainability are key to understanding VF. Various theories neous or induced) to invade the area and terminate or entrain the
exist regarding the nature of re-entrant waves. One such theory is re-entrant circuit; Allessie et al were able to terminate tachycardia
the leading circle hypothesis, originally put forward by Allessie and with premature beats (i.e., anti-tachycardia pacing).26 It now
appears that in most cases of VF, an excitable gap does exist; because curvature is negatively related to conduction velocity
however, there may still be room for leading circle re-entry in a (because of the source-sink relationship). As a result, the wave is
subset of arrhythmic phenomena, particularly with regard to AF.28 highly curved near the core and moves slowly, but at the distal
An alternative mechanism for VF is spiral wave re-entry. This end the wave speed increases, resulting in a spiral shape. Two-
theory suggests that the wavefront curves, or forms a spiral, dimensional spiral waves may theoretically exist in surviving two-
dimensional layers overlying the healed myocardial infarcts,
although three-dimensional waves (i.e., scroll waves) are clearly
1.0 more relevant to cardiac arrhythmias. A scroll wave can be
thought of as a stack of spiral waves in which the cores line up to
form a “filament” at the center. Simple scroll waves, in which the
.8 filament forms a straight line, have been demonstrated during
VF.29 A scroll wave with a core that is perpendicular to the record-
Cumulative survival
ing surface will appear as a two-dimensional spiral wave, whereas

.6 Log rank P = .0019 a filament that is parallel to the recording surface will appear as
a plane wave. It has been suggested that during VF, scroll waves
are usually oriented parallel to the surface, which may explain why
.4 mapping studies sometimes fail to detect re-entry during VT or
VF. A scroll wave with a ring-shaped filament is called a scroll
Assigned therapy
ring. It is interesting to note that the cross-section of such a wave
.2 Drug
would represent classic figure-of-eight re-entry. Only indirect
Device
experimental evidence is available for the existence of scroll rings,
probably because of the difficulty of measuring them, because
0.0 they manifest only transmurally, never on the surface.30 The shape
0 6 12 18 24 30 36 42 48 of a scroll as it is initiated strictly depends on the shape of the
Months from randomization inexcitable obstacle encountered by the wavefront. Thus, fila-
ments of varying shape can readily develop in the myocardium.
FIGURE 46-7 Survival free of arrhythmic cardiac death in patients Scroll rings ultimately collapse on themselves, but simple scroll
with ventricular fibrillation who qualified for the Antiarrhythmics waves can be stabilized and maintained.31
Versus Implantable Defibrillators (AVID) study. Nonarrhythmic cardiac Numerous hypotheses have been offered regarding the nature
and noncardiac deaths are censored. (From the AVID Investigators:
of fibrillatory waves that underlie VF. Three of these theories are
Causes of death in the AVID study, J Am Coll Cardiol 34:1552–1559, 1999.)
illustrated in Figure 46-9: (1) the multiple wavelet hypothesis, (2)
40
0 mV 60
105 106
A
0 0 0 5
0 20 4
3
1 2 80
3 3 3 1
0
0
2
7 6 7 0 100
0
3
9 70 10 69 10
0
4
9 69 10 69 11
0
5
62 63
0
D
58 58 100 mV
50 ms 5 mm
FIGURE 46-8 Leading circle re-entry. Activation map (right) and action potential recordings (left) obtained during steady-state tachycardia in an
isolated rabbit atrial preparation. Cells in the central area of the re-entrant circuit show double potentials of low amplitude (tracings 3 and 4). A
schematic activation pattern is shown on the lower right. Double bars indicate conduction block; the black section is absolutely refractory; between the
head and tail of the re-entrant wavefront, relatively refractory tissue is present. Characteristics for leading circle re-entry are (1) the core is kept in a
permanent state of refractoriness by centripetal wavelets, and (2) the head of the leading circle bites into its own relative refractory tail. (From Allessie
MA, Bonke FI, Schopman FJ: Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The “leading circle” concept: A new model of circus
movement in cardiac tissue without the involvement of an anatomical obstacle, Circ Res 41:9–18, 1977.)
the meandering spiral wave hypothesis, and (3) the mother- myocardium (see Figure 46-9, B).33 According to this theory, the
daughter wavelet hypothesis. The multiple wavelet hypothesis was
put forward in the early 1960s by Moe and describes fibrillation
as consisting of multiple, nonstationary wavefronts that continu-
ously form, fractionate, and reform (Figure 46-9, A).32 Spatial
chaotic appearance of the ECG in VF is attributable to the mean-
dering of a single spiral wave rotor throughout the ventricular
myocardium. Jalife suggested that the mechanism of fibrillation
may consist of a stable, periodic re-entrant wave that gives off
46
dispersion of repolarization was an important condition for initi- “daughter wavelets” that meander and fractionate (see Figure
ating multiple wavelet VF. Others have suggested that VF is 46-9, C).34 According to this hypothesis, unstable daughter wave-
caused by spiral re-entrant waves that meander around the lets form because of local gradients of refractoriness and give rise
to the fibrillatory patterns of the ECG.
Substrates for Ventricular Fibrillation: Heterogeneities

of Repolarization and Refractoriness
Various anatomic and functional substrates can lead to the devel-
opment of the fibrillatory dynamics previously described. Early
studies of AF suggested that the heterogeneity of refractoriness
was a necessary substrate for fibrillation in the heart.32 Although
it was later shown that VF can occur in hearts without large
dispersions of refractoriness (i.e., in normal hearts), or in model-
ing studies using simulations of electrically homogenous tissue,
A Multiple wavelet hypothesis these studies may not be clinically relevant.35 It is more difficult
to initiate VF in a normal heart, and the vast majority of fibrilla-
tory episodes occur in diseased hearts, in which the gradients of
repolarization kinetics (and therefore refractoriness) are almost
certainly abnormal. The important role of repolarization in the
development of re-entrant substrates has recently been empha-
sized by studies demonstrating the inherent heterogeneities in
repolarization properties that exist transmurally.36 Antzelevitch
and others have demonstrated that trans-mural heterogeneities
of repolarization are critical in the development of the substrates
for re-entry under various drug-induced or disease-induced
conditions.37,38
Rosenbaum et al recently developed a hypothesis that explains
how the critical heterogeneities of repolarization that provide a
substrate for re-entry may occur.39 Beat-by-beat alternation of
cardiac action potential duration (APD) has been shown to
underlie T-wave alternans, an electrocardiographic indicator
B Meandering spiral wave hypothesis that correlates well with the risk of SCD.39 We have demonstrated
that when alternans occurs in various regions of the myocardium
in a “discordant” manner (i.e., some regions are on a long-short-
long cycle, and others are on a short-long-short cycle), steep
gradients of repolarization develop and reverse the direction on
a beat-by-beat basis, which can lead to conduction block, re-entry,
and VF.40
In related work, Laurita et al demonstrated that premature
beats modulate the dispersion of repolarization in a manner that
has direct effects on vulnerability to VF.41 As the S1-S2 interval is
shortened, gradients of repolarization decrease concomitant to a
decrease in vulnerability to VF, but then increase with a concomi-
tant increase in VF vulnerability as S1-S2 is further shortened
(Figure 46-10). Such biphasic modulation of dispersion relates
back to the concept of the “vulnerable period,” which arose from
critical studies by Moe, who described the window of time during
the ECG T wave when vulnerability to VF is greatest.32 Thus,
dispersion of repolarization and refractoriness appears to play a
major role in the mechanism of re-entrant VF.
C Mother-daughter wavelet hypothesis

Restitution Hypothesis
FIGURE 46-9 Various theories of fibrillatory wavefront behavior. Restitution is a property of cardiac myocytes that dictates the
A, Multiple wavelet hypothesis. B, Meandering spiral wave hypothesis.
APDs of a premature action potential after a period of steady-
C, Mother-daughter wavelet hypothesis.
state rhythm. The APD of the extrasystolic beat is determined not
used pharmacologic agents to flatten the restitution curve slope

110 240
and decrease vulnerability to VF. Koller et al showed that elevat-
220 ing extracellular potassium decreases the portion of the restitu-
S2-DISP (ms2) 100
S2-RT (ms)
tion curve where the slope is 1 or more and converts VF to a
200
90 periodic rhythm.43,44 Other investigators have shown that the
180 biphasic nature of a restitution curve, demonstrated in a number
80 S2-RT 160 of cardiac tissue types, is also an important determinant of vul-
S2-DISP nerability to VF.45 More recently, the restitution hypothesis has
A 70 140 been applied to restitution curves for both APD and conduction
velocity.46
14 Myocardial Ischemia
12 VF is commonly caused by acute myocardial ischemia. Under
S2-VFT (mA)
10 experimental conditions, it is often difficult to provoke VF in

8
normal tissue using premature stimuli; however, in ischemic
6
tissue, premature beats exacerbate dispersion of refractoriness
4
and readily lead to tachyarrhythmias.47 This is because of the
2
various electrical alterations that occur during ischemia and the
0
consequent formation of various substrates that promote re-entry
220 230 240 250 260 270 280 290 300
and VF.
B S1-S2 coupling interval (ms) At the cellular level, acute ischemia results in depolarization
of the resting membrane potential, decreased maximum rise rate
FIGURE 46-10 Modulated dispersion hypothesis and vulnerability to
and amplitude of the action potential, and decreased APD, as well
ventricular fibrillation. A, Dependence of mean repolarization (S2-RT,
as reduced intercellular coupling.48-53 Depolarization of the mem-
blue circles) and dispersion of repolarization (S2-DISP, red circles) on S1-S2
coupling interval. B, Dependence of arrhythmia vulnerability (S2-VFT) brane is attributed largely to accumulation of extracellular potas-
on premature coupling interval. Dispersion of repolarization sium, as is post-repolarization refractoriness.54,55 Acidosis can
(A, red circles) and vulnerability to fibrillation (B) were modulated in a produce a small depolarization of resting membrane potential and
similar biphasic fashion, with minimum vulnerability (i.e., maximum also decreases gap junction conductance and cell-to-cell cou-
S2-VFT) and minimum dispersion occurring at the same S1-S2 coupling pling.56 The net result of the electrical changes that occur during
interval (255 ms, dashed arrow). This inherent mechanism may provide ischemia is the formation of various substrates that can lead to
protection against premature stimuli delivered at moderate coupling re-entry and wavebreak, such as slowed conduction velocity,
intervals. (From Laurita KR, Girouard SD, Akar FG, et al: Modulated increased dispersion of refractoriness, and alternans.
dispersion explains changes in arrhythmia vulnerability during premature
stimulation of the heart, Circulation 98:2774–2780, 1998.)
Healed Myocardial Infarcts
The process of tissue healing and scar formation after an episode
of acute myocardial ischemia involves necrosis of the infarcted
region as well as swelling and hypertrophy of the noninfarcted
only by the S1-S2 interval but also by the APD of the pre- region as it attempts to compensate for the loss of cardiac muscle.57
extrasystolic beat. Furthermore, gradients of restitution kinetics Heterogeneity of repolarization may result from the uneven pro-
are known to exist across the epicardial surface such that cells in longation of APD in the hypertrophied post-MI ventricle, changes
different regions of the heart having equal baseline APDs could in expression of gap junction proteins, or both.58,59 A healed
have different extrasystolic APDs following the same S1-S2 inter- infarct may also provide an anatomic substrate for arrhythmias.
val.42 In theory, if gradients of restitution kinetics are steep Infarcts vary from simple surviving muscle bundles that form
enough, underlying heterogeneities of repolarization would not accessory pathways to complex subendocardial sheetlike struc-
be necessary to create dispersions of repolarization following a tures, which are linked to the surrounding myocardium by mul-
premature beat.42 However, cardiac tissue is known to exhibit tiple connecting bundles, creating complex matrices of conductive
repolarization heterogeneities across epicardial and trans-mural tissue that may promote multiple re-entrant circuits. In particular,
surfaces, so the role of restitution may be to enhance existing the combined effects of slowed conduction and the presence of
dispersion of repolarization and promote VF. structural anomalies is significant because in tissue where excit-
One possible mechanism to describe the role of restitution in ability is low, a wavefront breaking past an obstacle will curl at
VF is the restitution hypothesis, which states that when the res- the inner ends (where the break occurred) to create figure-of-
titution curve (a plot of APD vs. diastolic interval) has a slope eight re-entry, whereas in a normally excitable medium, the wave
greater than 1, VF may be initiated. For example, a wavefront tends to reform on the other side of the obstacle.60
encroaching on the tail end of a previous wave creates a gradient
of diastolic interval between the two (assuming the degree of
Autonomic Modulation of Ventricular Fibrillation
curvature is not identical); in regions of tissue where restitution
is steep, this will create large dispersions of APD along the second It has been well established that increases in sympathetic tone
wavefront. Some areas of the wave may have such a short dia- increase the risk for SCD, whereas vagal reflexes have the oppo-
stolic interval that they fail to propagate, resulting in wavefront site effect.61-63 Studies in dogs have shown that left cardiac sym-
fractionation. This was demonstrated by Garfinkel et al, who also pathetic denervation, or left stellectomy, increases survival and
decreases arrhythmias during acute MI.64 In contrast, unilateral

blockade of the right stellate ganglion by cooling increases the
number of arrhythmias after coronary occlusion.65 Many clinical
trials have shown that β-adrenergic receptor blocking drugs have
a potential benefit in preventing SCD in patients with MI,
Clinical Electrocardiography
The role of electrocardiography has been increasing in patients
presenting with VF. Certain ECG features may identify high-risk
46
whereas anti–α-adrenergic agents have not been shown to be patients or transient events that can result in VF, which may be
effective.66-69 preceded by VT (see Chapter 47).
It has been suggested that during acute MI, sympathetic nerves
that traverse the myocardial wall are damaged, leading to dener-
Electrocardiographic Features of Patients at High Risk
vation hypersensitivity.70 This, in turn, leads to spatially inhomo-
for Ventricular Fibrillation
geneous responses to β-adrenergic stimulation across the
ventricle, forming potential substrates for re-entrant excitation. Electrocardiographic recordings obtained at the onset of VF
Further investigation is required to elucidate fully the mechanistic provide insight into events that precipitate SCD. Documentation
role of β-adrenergic stimulation and arrhythmogenesis. of these events has been obtained by continuous monitoring in
hospital telemetry units and by ambulatory monitoring. The
patients involved in these studies had a high incidence of CAD,
Genetic Substrates for Ventricular Fibrillation
and most had frequent or complex ventricular ectopy. The termi-
Brugada syndrome is a cardiac disease characterized by an ele- nal events were associated with sinus arrest, complete heart
vated ST segment that is unrelated to ischemia, Q-T interval block, or ventricular asystole in approximately 10% of patients; in
prolongation, electrolyte abnormalities, or structural heart 90%, VF was preceded by VT or ventricular flutter of variable
disease.71 Patients with Brugada syndrome are at increased risk of duration.77-80 ST segment and T-wave changes indicative of isch-
SCD from VF. The syndrome is caused by a mutation in the gene emia related to acute MI or coronary spasm have also been
encoding the cardiac sodium channel (SCN5A) and is common reported to precede terminal ventricular arrhythmias.77-80 Other
in Southeastern Asia, where it is the second highest cause of death studies indicate that bradycardia and electromechanical dissocia-
among young men.72 In Europe, gender specificity is less distinct, tion are important causes of SCD in patients with advanced heart
although affected women tend to be less symptomatic than failure and nonischemic cardiomyopathy.81 These observations
affected men. Patients with Brugada syndrome often die in their have significant implications for strategies to reduce mortality
sleep, and a possible relationship to sudden infant death syn- rates in patients at risk for SCD.
drome has been suggested.73 The diagnostic role of the ECG in identifying patients with
It is believed that the mechanism of VF in patients with genetic disorders associated with SCD from ventricular arrhyth-
Brugada syndrome is related to reduced function of the mutant mias has continued to evolve over the past decade. The electro-
late inward sodium current, forcing the balance of plateau cur- cardiographic characteristics of LQTS, Brugada syndrome, and
rents in favor of repolarization. This is why any further impair- arrhythmogenic right ventricular cardiomyopathy (ARVC) have
ment of sodium channel function (e.g., by sodium-blocking gained widespread attention. This is vital to the prevention of
drugs) can exacerbate the electrocardiographic and arrhythmo- SCD in young patients with these disorders, particularly if these
genic phenotype in this disorder.74 Because epicardial, not endo- patients participate in athletics. A recent study has suggested a
cardial, cells possess the transient outward current (Ito), they are higher incidence of early repolarization changes in the inferolat-
most susceptible to the repolarizing effect of the sodium channel eral leads (J-point elevation and notching in the terminal portion
mutation in Brugada syndrome. Marked and selective shortening of the QRS complex) among survivors of cardiac arrest caused by
of epicardial action potentials relative to endocardial action idiopathic VF when compared with control subjects.82
potentials produces a transmural voltage gradient during the The pattern of early repolarization associated with highest risk
plateau that, in turn, is believed to account for the characteristic seems to be global or inferolateral early repolarization with prom-
pattern of ST segment elevation seen in these patients.75 inent J waves on the resting ECG.83 It is not clear if a single dis-
Transmural action potential gradients also account for the pre- order of repolarization causes at least some of the cases previously
sumed mechanism of VF (i.e., phase 2 re-entry). labeled “idiopathic VF,” or, as seems more likely, a spectrum of
In a recent provocative study, Haisaguerre et al identified a disorders is associated with abnormal and heterogeneous repo-
select group of patients with recurrent idiopathic VF that seemed larization that predisposes otherwise normal individuals to VF.
to originate with premature beats emanating from the distal His- These disorders have been collectively named early repolarization
Pukinje system; these patients were successfully treated with disease.84
radiofrequency ablation targeting the originating premature Although the prevalence of repolarization abnormalities in
beats, with a low rate of VF recurrence.76 patients resuscitated from VF with no evident structural heart
In summary, VF is a complex arrhythmia associated with many disease is higher than expected, these abnormalities are also
distinct electrophysiological mechanisms that no doubt highly common in young, healthy individuals. The sensitivity, specificity,
depend on the disease state in question. Although most often and predictive accuracy of this finding are not clear. The risk of
associated with acute ischemia or healed MI, VF can occur in the cardiac arrest in asymptomatic patients with early repolarization
absence of any structural heart disease, such as heritable disorders is likely very low.
(e.g., Brugada syndrome). Greater understanding of these various
mechanisms is required to guide the development of novel phar-
Long QT Syndrome
macologic approaches and targets that can ultimately be used in
the treatment and prevention of VF. Until then, clinicians will The electrocardiographic manifestations of LQTS include QT
have to rely on electrical defibrillation, which is highly effective prolongation, abnormalities in T-wave morphology, increases
irrespective of the underlying VF mechanism. in QT dispersion, T-wave alternans, and a relative degree of
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
2 A– H– S– F+ Sf23 H442 #31926
FIGURE 46-11 Twelve-lead electrocardiogram of a patient with familial long QT syndrome. Note the prolonged Q-T interval and T-wave
abnormalities.
bradycardia in children (Figure 46-11). The upper limits of normal characterized by the undulating amplitude of the QRS complex,
for the QTc values are 460 to 470 ms for females and 440 to 460 which gives the appearance of twisting about its axis. The onset
ms for males.85,86 Longer QT values may be observed in normal is frequently associated with pause-dependent ventricular ectopy
women after puberty.87 The degree of QT prolongation does not that falls on the T wave.96-98
directly correspond with the risk of syncope, but malignant ven-
tricular arrhythmias are more frequent when the QTc exceeds 600
Brugada Syndrome
ms.87 A diagnostic dilemma is that the Q-T interval shows tem-
poral variations in patients with this syndrome, and the QTc may The ECG patterns associated with Brugada syndrome are (1) a
fall within the normal range on a random recording.88 Garson terminal R′ in lead V1 with complete or incomplete RBBB; (2)
reported that 6% of LQTS patients had a normal Q-T interval, convex downward (coved) ST segment elevation equal to 0.1 mV
and data from the International Registry showed that 10% of in lead V1 or leads V1 and V2; convex upward (saddle-shaped)
family members with a QTc less than 440 ms had a cardiac ST-segment elevation equal to 0.1 mV; and (3) J-point elevation
arrest.89,90 Thus, an ECG with a normal QTc does not exclude the followed by a downsloping ST segment ending in a negative
diagnosis if strong suspicion exists that a patient has the syn- deflection (triangular shape).98 Serial ECGs performed on the
drome, especially if the QTc is on the border of normal. same patient may show variation from one pattern of ST-segment
The effect of exercise increases the QTc in patients with LQTS, elevation to another, normalization, and progressive development
but this effect is less apparent in patients with LQT3 than in those of RBBB. Figure 46-12 shows examples of variable Brugada ECG
with other genotypes.91 Approximately 62% of patients with LQTS patterns that occurred during an ajmaline test in the same
exhibit T waves that are biphasic or notched, and a higher inci- patient.99,100 The prevalence of the Brugada ECG pattern is
dence of these abnormalities is seen in patients with cardiac reported to be 0.07% to 0.7%, and there is a male predominance
events.92 The characteristic features are most pronounced in pre- that is especially marked in Asians.101-106 The range in prevalence
cordial leads V2 to V5. The appearance of notched T waves may appears to depend on the criteria used to make the diagnosis. The
be provoked by exercise. The degree of QT dispersion is measured saddleback ST-segment elevation is more common. The typical
by the difference between the longest and shortest Q-T intervals coved pattern was found in 0.1% to 0.26% of community-based
on the 12-lead ECG and is prolonged in patients with LQTS.93 It populations in Japan and Europe.104-106 In a Japanese study popula-
is thought to represent increased dispersion of repolarization. tion that underwent ECGs during health examinations, the preva-
Patients who show no change in the degree of QT dispersion lence of all types of Brugada ECG patterns was 0.7%.103 The
when they are treated with β-blockers appear to be at increased coved-type ST-segment elevation was found in 38% of subjects
risk for cardiac events.90,94 T-Wave alternans is a beat-to-beat with the Brugada pattern, and the saddleback-type ST-segment
alternation in the amplitude or polarity of the T wave. It appears elevation was seen in 62%. In the same study, the rsR′ pattern in
to be a marker of electrical instability that may precede torsades lead V1 was observed in 41%, and the Rsr′ pattern was recorded
de pointes.94 Children with LQTS often have resting heart rates in 59%. The prevalence of the coved pattern was 0.26%, and the
that are lower than normal and may exhibit a blunted chrono- typical Brugada ECG pattern with coved ST-segment elevation
tropic response to exercise.87,95 Torsades de pointes, and the rsR′ pattern in lead V1 was 0.12%. If only male subjects
which is the ventricular arrhythmia associated with LQTS, is were considered, the criteria for a Brugada ECG pattern was met
in 2.14% of the population, but the typical pattern in males was studies by Miyasaka, Takenaka, or Priori.104,105,107 In the Osaka
0.38%.104 In a European population studied by Hermida, the prev-
alence of ST segment elevation was 6.1%; however, only 1 (0.1%)
of the 61 subjects who met the study’s criteria for the Brugada
pattern had the coved pattern. All of the others had the saddle-
population, one SCD occurred among the 98 subjects with the
Brugada ECG pattern during a mean follow-up of 2.6 years.104 A
3-year follow-up reported by Atarashi of patients with a Brugada
ECG pattern found cardiac event–free rates of 67.6% in symptom-
46
back pattern.103 atic patients and 93.4% in an asymptomatic group.108 Coved-typed
The prognostic significance of the Brugada ECG pattern is ST segment elevation appeared to be related to cardiac events.
difficult to assess. Brugada reported an 8% incidence of arrhyth- The higher incidence in hospital-based studies may reflect referral
mic events in an asymptomatic hospital-based population.106 The patterns based on a family history of SCD. Differences in criteria
degree and type of ST segment elevation require further study for or ECG interpretation affect the diagnosis of this pattern, and the
risk stratification of asymptomatic individuals in community- follow-up in most studies is too short to draw definitive conclu-
based populations. Matsuo evaluated mortality in patients sions about the long-term prognosis.
younger than 50 years who had ECGs recorded during biannual
examinations from 1958 through 1999.107 A total of 32 patients
Arrhythmogenic Right Ventricular Cardiomyopathy
were identified with the Brugada ECG pattern. Seven of these
patients died suddenly or died of an unexplained accident. ECG recordings during sinus rhythm in patients with ARVC have
Although total mortality was not increased in patients with the several distinctive features (Figure 46-13).109 The QRS may be
Brugada ECG pattern, the mortality rate from unexpected death prolonged in the right precordial leads to a greater extent than in
was significantly higher. No increase in mortality was observed in leads I or V6. The QRS is often greater than 110 ms in lead V1
Baseline ajmaline test

I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
V1
A
FIGURE 46-12 Serial changes in a Brugada pattern electrocardiogram recorded in a patient during an ajmaline test. Twelve-lead ECGs are recorded at
baseline (A), followed by ajmaline infusion. At 2 minutes, ST-segment elevation that is coving upward is seen in the right precordial leads (B), followed
by marked ST-segment elevation in leads V1 to V3 (C).
Continued
Ajmaline test—2 min

I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
V1
B
FIGURE 46-12, cont’d
(sensitivity, 55%), and a pattern of incomplete RBBB is observed.110 V1 with a variable axis. Nava published a clinical profile and long-
In 30% of cases, the delay in conduction over the right ventricle term follow-up of 37 families with ARVC that demonstrated a
results in a small potential at the terminal portion of the QRS in correlation between the severity of echocardiographic findings
lead V1 that has been termed an epsilon (ε) wave, which can be and the severity of ventricular arrhythmias, which were seen in all
amplified with bipolar recordings over the inferior and superior patients with the severe form of the disease, in 82% with moderate
aspects of the sternum.109 This can be achieved by repositioning disease, and in 23% in those with mild disease.112 Overall, 60 (45%)
the left arm lead over the xiphoid process, positioning the right of 132 affected living members had ventricular arrhythmias. These
arm lead over the manubrium sternum, and applying the left leg included VF in 1, sustained VT in 14, nonsustained VT in 8, ven-
lead at the position customarily used for lead V4 or V5.111 The tricular couplets and triplets in 16, and frequent ventricular pre-
other major feature of ECGs recorded from patients with ARVC mature depolarizations in 8. Exercise-induced polymorphic VT
is inversion of the T waves in the precordial leads, which is was observed in 13 patients with no other documented arrhyth-
observed in 42% to 54% of patients.111,112 Metzger assessed the mias. Only one patient who was judged to have mild disease had a
value of serial 12-lead ECGs in 20 patients to recognize progres- sustained ventricular arrhythmia. Although the data from this
sion of ARVC over a mean of 71 ± 48 months.113 Abnormalities study showed a low incidence of VF, the incidence may be higher.
were detected in 90% of the patients. The most frequent abnor- In 19 of the 37 families, the proband died at a young age, and the
mality was T-wave inversion in the precordial leads. No correla- diagnosis was made at autopsy. One may speculate that some of
tion was demonstrated between the ECG and the extent of disease these subjects had VF. Figure 46-14 shows electrograms recorded
detected by echocardiography. In the 14 patients who had several from an ICD implanted in a teenager (male) with ARVC and fre-
ECGs recorded over time, no clear progression of electrocardio- quent nonsustained ventricular arrhythmias. The recording shows
graphic abnormalities was observed. the sudden onset and successful termination of VF, which occurred
The ventricular arrhythmias associated with ARVC typically at night while he was asleep. He had no prior history of syncope
show a morphology resembling left bundle branch block in lead or sustained ventricular arrhythmias.
46
Ajmaline test—3 min
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
V1
C
FIGURE 46-12, cont’d
few focused investigations. Electrolyte abnormalities are

Diagnostic Evaluation identified with serum electrolyte testing performed as soon as
possible after resuscitation. The most common electrolyte abnor-
Investigation of patients who have been resuscitated from an malities leading to VF are hypokalemia, hypomagnesemia, or
episode of spontaneous VF is directed toward determining both. When considering the temptation to ascribe an episode
whether the episode of VF had a transient or reversible cause, of VF wholly to hypokalemia, hypomagnesemia, or both, one
identifying the type and extent of underlying structural heart must recall that the adrenergic discharge state during resuscitated
disease, documenting the mechanism of VF, identifying coexist- VF results in redistribution of extracellular potassium and
ing disease states that may interact with future antiarrhythmic magnesium into the intracellular compartment. Accordingly, rela-
therapies, and assessing and monitoring selected antiarrhythmic tive hypokalemia, hypomagnesemia, or a combination is very
therapy. In each instance, the importance of a complete history common after VF.115 Only marked hypokalemia, hypomagnese-
and physical examination is well established and needs no further mia, or both and confidence that future episodes can be prevented
discussion. should prompt the belief that the episode of VF had a reversible
cause.
The early performance of a 12-lead ECG and serum markers
Evaluation of Transient or Reversible Causes
of myocardial necrosis (creatine kinase [muscle or brain type],
VF that occurs secondary to a reversible or transient cause troponin) will permit identification of the patient whose VF has
may be adequately treated by correction of the reversible cause occurred in the acute phase (first 48 hours) of an MI. Evidence
or by short-term therapy or close observation while awaiting that acute MI produces an environment that constitutes only a
spontaneous resolution of the transient cause.114 The causes of transient risk of VF is most convincing for a Q-wave MI.116 Nev-
VF with these characteristics are usually readily identified with a ertheless, the risk of VF may also be transient in the setting of a
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
II
FIGURE 46-13 Twelve-lead electrocardiogram recorded from a 19-year-old man with arrhythmogenic right ventricular cardiomyopathy. An ε wave is
present in lead V1 at the end of the QRS.
non–Q-wave MI.117 However, the practitioner must avoid the physiological derangement required administration of sympatho-
temptation to ascribe an episode of VF wholly to an acute MI if mimetic agents.
the only evidence of acute myocardial necrosis is a marginal eleva-
tion in a serum marker of necrosis; such elevations may be sec-
Identification of Structural Heart Disease
ondary to the VF-induced cardiac arrest rather than represent its
cause. The diagnosis of MI in the setting of out-of-hospital cardiac In most of the world, the most common forms of structural heart
arrest from VF is made difficult by the usual absence of a history disease that precipitate VF are atherosclerotic CAD and either
of chest pain, frequent nondiagnostic ECG abnormalities that congestive or hypertrophic cardiomyopathy. Accordingly, most
may be a consequence of the myocardial ischemia resulting from patients who have been resuscitated from VF require an echocar-
the global “no-flow or low-flow state” during VF, and the absence diographic examination, an exercise test (with or without myo-
of a specific cut-off for the degree of cardiac enzyme elevation cardial perfusion imaging), and cardiac catheterization with
that separates MI causing VF from VF causing myocardial necro- coronary angiography.
sis. In general, the presence of a culprit lesion (coronary thrombus The echocardiogram primarily serves as an adjunct to the
or ulcerated plaque) on angiography early after cardiac arrest and physical examination for identification of myocardial or valvular
well-preserved or normal left ventricular function suggests an structural heart disease. It is particularly suited to the documenta-
ischemic or infarction-related cause. tion of hypertrophic cardiomyopathy and for the detection of
The other common reversible or transient cause of VF is the other forms of structural heart disease that have escaped clinical
use of a proarrhythmic drug: a classic antiarrhythmic drug, other detection. Although the echocardiogram is also useful to quanti-
drugs with electrophysiological effects, and recreational drugs, tate left ventricular systolic function, radionuclide ventriculogra-
particularly cocaine.118 Use of these agents is determined from the phy, cardiac computed tomography, cardiac magnetic resonance
history. However, if the practitioner believes that a report of such imaging, and contrast ventriculography may provide more accu-
drug use will not be forthcoming from a high-risk individual, rate determinations of this important prognostic variable. Of
a toxicology screen is advised. When therapeutic drug use is importance, the echocardiogram is not very sensitive for the
reported, early determination of a serum concentration of the detection of early arrhythmogenic right ventricular dysplasia.
agent may be important when toxicity related to that agent has a Exercise testing of the patient who has been resuscitated from
relationship to serum concentrations (i.e., digitalis). an episode of VF provides information about the inducibility of
Finally, an episode of VF may be considered reversible if both exercise-related myocardial ischemia and exercise-related
it accompanies a state of extreme physiological derangement that arrhythmias.119 The sensitivity, specificity, and spatial localization
is not expected to be recurrent. Such states include that seen of reversible myocardial ischemia can be enhanced by coupling
in the immediate postoperative period, with sepsis, and with the exercise test with radionuclide or echocardiographic imaging
hemodynamic instability, especially when the treatment of the techniques.
46
1 mV/mm
U U U U U F F F F F F F F F F F F F F F F F F F F F F F F F U U
5 5 5 3 2 3 4 3 5 3 6 8 5 9 7 7 7 6 6 5 5 4 4 5 3 3 3 2 2 3 2 3
1646 1286 5 4 3 2 3 2 3 2 2 1 1 2 1 1 2 2 1 2 1 2 2 1 2 1 1 1 2 2 2
5 1 0 1 2 5 5 4 0 9 9 2 8 9 1 4 9 1 9 0 5 9 0 9 9 9 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 5 5 5
1 1 1 1 3 3 3 1 1 2 1 3 3 2 1 1 1 1 2 1 1 1 2 2 1 1 4 2 4 1230 6 6 6
9 9 8 4 5 7 3 9 9 0 7 4 6 2 9 8 9 9 0 9 7 8 2 0 4 7 0 3 5 0 0 6
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
FIGURE 46-14 Electrograms recorded from an implantable cardioverter-defibrillator (ICD) in a patient with arrhythmogenic right ventricular
cardiomyopathy. The continuous recordings document the sudden onset of ventricular fibrillation, followed by an ICD shock and conversion to sinus
rhythm. The upper channel represents the stored intracardiac electrogram. The lower channel marks sensed events and displays the cycle length.
Despite the availability of these noninvasive diagnostic proce- a high index of suspicion exists. These procedures include cardiac
dures, the critical importance of accurate and complete anatomic magnetic resonance imaging, catheter endomyocardial biopsy, or
and functional diagnosis of structural heart disease in a patient both for the diagnosis of arrhythmogenic right ventricular dyspla-
who has been resuscitated from VF usually necessitates cardiac sia (ARVD), cardiac magnetic resonance imaging, catheter endo-
catheterization and coronary angiography. Occasionally, the com- myocardial biopsy, or both for the diagnosis of myocarditis; signal
bination of information available from the history of events sur- averaged electrocardiography for the diagnosis of ARVD; infusion
rounding the spontaneous episode of VF (especially when of a class I antiarrhythmic agent for the diagnosis of Brugada
preceded by physical or emotional stress accompanied by angina), syndrome; and infusion of epinephrine for the diagnosis of LQTS.
evidence of reversible myocardial ischemia on exercise testing To date, genetic testing has not yet reached the maturity at which
(especially when associated with evidence of ventricular electrical it can be recommended for diagnostic purposes in patients with
instability), and documentation of CAD (especially when not VF. However, the future promise of genetic testing in this regard
associated with severe left ventricular dysfunction) will suggest is high.
the possibility that the episode of VF was caused by reversible
myocardial ischemia that can be corrected. Although coronary
Documentation of the Mechanism of Ventricular Fibrillation
revascularization in this setting has been reported to prevent
further episodes of VF in some patients, the effect is not neces- The debate on the advisability of offering a baseline transvenous
sarily predictable.120 Accordingly, it has become customary to catheter EPS to all patients who have had an episode of VF in the
either assume that the revascularization procedure was insuffi- absence of a reversible or transient cause is still ongoing.121 The
cient for the prevention of VF recurrences or document that VT major potential advantage of an EPS for patients with VF is
or VF is not inducible by programmed stimulation performed the possibility of demonstrating that the VF was caused by
during a transvenous catheter EPS study after the revasculariza- another arrhythmia that would be treated in another way. Of
tion procedure—preferably after a preoperative catheter EPS course, VF may result from the degeneration of other tachyar-
documented the inducibility of sustained VT or VF. rhythmias best treated by trans-catheter ablation procedures such
On occasion, specialized procedures are required to identify as supraventricular tachyarrhythmias (including AF in the setting
underlying structural heart disease in selected patients for whom of ventricular pre-excitation) and certain VTs (including bundle
branch re-entrant VT). EPS may also help distinguish patients catheterization are all important diagnostic tools. If myocardial
with a permanent VT substrate (typically those with a myocardial ischemia is demonstrated, revascularization (percutaneous or
scar who have inducible VT) from those without a permanent VT surgical) can improve long-term survival.125,126
substrate (typically those without a myocardial scar who do not
have inducible monomorphic VT). This distinction may assist the
Induction of Ventricular Tachycardia Versus
practitioner in the selection of treatment modalities. For example,
Ventricular Fibrillation
revascularization of CAD is rarely, if ever, useful in the former
circumstance. Finally, EPS may also provide information regard- After defining the underlying heart disease, EPS is important for
ing optimal programming of a subsequently implanted ICD. Nev- risk stratification for primary VF. It is believed that VF is often
ertheless, each of these potential advantages is more likely to be preceded by VT, which degenerates into VF, so the induction of
had by the patient who presents with VT. VT in the electrophysiological laboratory is indicative of the clini-
cal rhythm (Figure 46-15). Therefore, the principal goal at EPS is
the induction of sustained monomorphic VT. In the setting of a
Identification of Other Disease States
healed MI, VT can be induced at EPS in 20% to 45% of patients.
Identification of other disease states that interact with antiar- The anatomic and electrophysiological substrate of VT is well
rhythmic therapies to be prescribed for the treatment of VF is described. Areas of healed MI, regions of slow conduction, and
an important goal of the investigations performed in this patient inhomogeneities of refractoriness all contribute to the specific
population. Screening biochemical investigations for renal or responses to programmed stimulation and the induction of VT.
hepatic dysfunction are indicated before the prescription of anti- As the induction of VT at EPS is already well described (see
arrhythmic drugs that depend on the renal or hepatic metabo- Chapters 25, 26, and 47), the focus of this section is induction
lism. Similarly, prescription of those therapies with adverse of VF.
effect profiles that include interaction with other organ systems The correlation between the induction of VF in the electro-
should be preceded by screening of the integrity of that organ physiology laboratory and the incidence of VF as the presenting
system (e.g., thyroid function testing and pulmonary function arrhythmia is limited, perhaps because of transient factors or
testing in preparation for amiodarone therapy). These screening prior VT in either situation.127 Among patients with previous
examinations are then be repeated as necessary during follow-up cardiac arrest, 20% to 50% do not have VF induced at EPS. VF is
and can be compared with the baseline evaluations to substanti- inducible in up to 25% of cardiac arrest survivors compared with
ate change. 3% of patients who presented with monomorphic VT. This sug-
gests that induction of VF in patients who present clinically with
VF may be specifically predictive of spontaneous VF episodes,
Assessment and Monitoring of Selected
whereas induction of VF in patients who presented with VT may
Antiarrhythmic Therapy
represent a nonspecific response to programmed electrical
The assessment and monitoring of some forms of antiarrhythmic stimulation.128
therapy require other selected investigations. Although now In patients with asymptomatic nonsustained VT, CAD, and an
infrequently used, the selection of antiarrhythmic drug therapy ejection fraction less than 40%, VF or polymorphic VT is induced
by suppressing ventricular premature beats requires a baseline in up to 6% of cases.129 Clinical variables often fail to distinguish
EPS as well as antiarrhythmic drug–free, and drug assessment patients with inducible arrhythmias from those without inducible
24-hour ambulatory ECG examinations along with exercise toler- arrhythmias. Ejection fraction is not significantly different in
ance tests.119,122 Similarly, the selection of antiarrhythmic drug patients with no inducible arrhythmia, inducible nonsustained
therapy using the approach of suppression of ventricular tachyar- VT, inducible sustained monomorphic VT, or inducible VF
rhythmias induced by programmed stimulation requires a base- (Figure 46-16). Of the 6% of patients in whom VF or polymorphic
line EPS as well as antiarrhythmic drug–free and drug assessment VT was induced, 17% died suddenly during follow-up.126 The
EPSs.123,124 Of course, the follow-up of patients with a treated presence of inducible sustained ventricular arrhythmias and the
propensity to VF usually requires long-term surveillance—most persistence of inducible sustained ventricular arrhythmias on
commonly with repeated 24-hour ambulatory ECG examinations. therapy were significant univariate predictors of SCD. However,
However, no direct evidence suggests that such surveillance is of only the persistence of inducible sustained arrhythmias on therapy
value to the patient with VF. was an independent predictor of SCD (Figure 46-17).
Electrophysiological Characteristics Associated with

Electrophysiological Study Induction of Ventricular Fibrillation
The role of EPS in the patient with VF depends on the etiology of It is not well understood why VF is induced in some patients in
the arrhythmia. Secondary VF is associated with acute reversible the clinical electrophysiology laboratory and not in others.
derangement such as ischemia, electrolyte imbalance, or cardiac Because VF can be induced in perfectly normal hearts by using
trauma. In contrast, primary VF is not associated with any acute either multiple closely coupled premature stimuli or by shocks
precipitant. In secondary VF, the best approach is to treat the applied on the T wave, induction of VF by catheter stimulation is
specific precipitant responsible for VF. The role of EPS is often not necessarily associated with a poor prognosis. Several potential
limited in secondary VF. Therefore, the focus of this section is on reasons exist for the nonspecific response of induction of VF at
the approach to primary VF in the electrophysiology laboratory. EPS, including local graded response in normal muscle or decre-
In the setting of primary VF, it is imperative to first define the mental conduction block caused by short coupling intervals. This
anatomic substrate. Because healed MI is the most common appears to have less to do with dispersion of refractoriness or
cause of primary VF, echocardiography, stress testing, and cardiac propagation and more to do with local graded responses in
I 1000 ms
46
aVF
V1
V6
HIS p
RV
S1
S1 S1 S1 S1 S1 S1 S2 S3 S4
STIM A1
10:48:12 AM 10:48:14 AM 10:48:16 AM 10:48:18 AM 10:48:20 AM
A
1000 ms
I
aVF
V1
V6
HIS p
ABL d
S1 S1 S1 S1 S1 S1 S1 S1 S2 S3 S4
STIM A1
10:57:08 AM 10:57:10 AM 10:57:12 AM 10:57:14 AM 10:57:16 AM
B
FIGURE 46-15 A, Induction of rapid monomorphic ventricular tachycardia with triple ventricular extrastimuli in a patient with cardiac arrest.
B, A subsequent induction attempt with triple extrastimuli resulted in induction of ventricular fibrillation.
40% 100
90
80
Survival (percent)
70
30% 60
50
40 Noninducible (N = 57, SD/CA = 2)
Ejection fraction
Inducible/suppressed (N = 20, SD/CA = 1)

30
Inducible/not suppressed (N = 20, SD/CA = 7)
20% 20 P < .001
10
4 8 12 16 20 24
Follow-up (mo)
10%
FIGURE 46-17 Actuarial incidence of sudden cardiac death or
cardiac arrest in 97 patients, stratified by treatment subgroup. Three
24 ± 8% 26 ± 7% 25 ± 8% patients with cardiac arrest during serial drug testing were not
included in analysis. CA, Cardiac arrest; SD, sudden cardiac death. (From
Wilber DJ, Olshansky B, Moran JF, Scanlon PJ: Electrophysiological testing
NI NSVT SMVT VF and nonsustained ventricular tachycardia: Use and limitations in patients
(N = 39) (N = 18) (N = 37) (N = 6) with coronary artery disease and impaired ventricular function,
Induced arrhythmia 82[2]:350–358.)
FIGURE 46-16 Scatterplot of left ventricular ejection fraction

stratified by baseline-induced ventricular arrhythmia. Vertical bars are
the mean ± SD of each group. Circled dots represent patients in whom operating room and have been cured by endocardial resection.
inducible arrhythmias were suppressed. P = not significant among These findings have not been observed in patients with a normal
groups. NI, Noninducible; NSVT, nonsustained ventricular tachycardia; heart and inducible polymorphic VT or VF. Therefore, use of a
SMVT, sustained monomorphic ventricular tachycardia; VF, ventricular type I antiarrhythmic agent may be helpful in differentiating
fibrillation. (From Wilber DJ, Olshansky B, Moran JF, Scanlon PJ: between a nonspecific finding from a significant one in the elec-
Electrophysiological testing and nonsustained ventricular tachycardia: Use trophysiology laboratory.
and limitations in patients with coronary artery disease and impaired
ventricular function, 82[2]:350–358, 1990.)
Prognosis and Clinical Relevance
The prognostic value of electrophysiological evaluation has been
extensively studied in survivors of cardiac arrest. The reproduc-
normal muscle. For this reason, premature coupling intervals are ibility of inducible VF is strongly predictive of recurrent cardiac
usually not shortened below 180 ms to avoid inducing VF that has arrest. However, the failure to induce arrhythmias with pro-
no diagnostic value.129 Other causes of nonspecific responses to grammed stimulation may not necessarily be associated with a
programmed stimulation and induction of VF include increased benign prognosis. In a specific subset of patients with CAD, LVEF
conduction latency and prolongation of local activation time in less than 40%, asymptomatic nonsustained VT, and no inducible
proximity of the stimulus electrode. Induction of VF is preceded arrhythmias, the relative risk of death was 1.8.125
by increased latency (Figure 46-18).130 In addition, several secondary prevention trials have supported
Another hypothesis suggesting why VF is induced with closely the efficacy of defibrillator implantation in out-of-hospital VF
coupled premature beats during programmed stimulation is survivors irrespective of the outcome of EPS. Results of the
delayed conduction. Conduction slowing by itself causes disper- Cardiac Arrest Study Hamburg (CASH), AVID, and the Canadian
sion of activation time between sites near the stimulating elec- Implant Defibrillator Study (CIDS) support defibrillator place-
trode and distant sites. Also, conduction slowing of a premature ment in cardiac arrest survivors who have no reversible cause of
beat allows distant sites to have a longer coupling interval of the VF.133,134
premature beat compared with that from the pacing site. These In summary, the usefulness of EPS in patients with VF is evolv-
factors result in dispersion of refractoriness, with the refractory ing. If a clearly reversible cause of secondary VF is identified,
periods following the premature beat being longer at distant sites correction of the underlying problem is needed. With primary VF,
than at the pacing site. This, in turn, allows additional premature it may be reasonable to consider EPS. The specificity of induction
beats to induce VF. Therefore, the measurement technique itself of VF by programmed stimulation varies with the patient’s clinical
alters what we are attempting to measure (Table 46-1).131 In addi- presentation. The induction of VF may be related to areas of slow
tion, indirect evidence suggests that the mechanism of VF in the conduction or healed MI, local graded responses, decremental
setting of a healed MI may be related to areas of slow conduction conduction block caused by short coupling intervals, and
and stable re-entrant circuits. Occasionally, polymorphic VT or increased latency and prolongation of activation time. Defibrilla-
VF can transform to monomorphic VT by type I antiarrhythmic tor insertion may be indicated despite a negative EPS result in
medications.132 These tachycardias have been mapped in the these patients.
trained lay rescuers with manually operated semiautomated
46
VT
external defibrillators. These are deployed in locations readily
1 accessible to rescuers in proximity to patients experiencing
cardiac arrest. The best and most publicized examples of these
anticipatory strategies include the provision of semiautomated
external defibrillators and trained lay operators in casinos, air-
2
ports, and on long-haul airplane flights and sophisticated tiered
V1 S1 S1 S2 S3 S4 therapy programs with EMS programs. Therapy for VF includes
both defibrillation and adjunctive therapies such as measures to
support the failing circulation during CPR as well as antiarrhyth-
mic drug therapy to enhance the probability of successful resus-
VF citation from VF.
Evidence-Based Therapy
S1 S1 S2 S3 S4 Rescue of the Patient with Ventricular Fibrillation
Optimal resuscitation from VF requires restoring a perfusing
cardiac rhythm as early as possible as well as providing the
No VT/VF maximum possible cerebral and coronary blood flow during the
resuscitation process. Mechanical aids, which improve cardiac
output during CPR, have consistently shown improved outcomes
in experimental settings and have shown, in limited human
clinical trials, improved early resuscitation and improved survival
to hospital admission.135 However, definitive clinical trials
with respect to improving survival to discharge from hospital
S1 S1 S2 S3 S4 are lacking although such interventions may be able to improve
long-term outcomes in patients with VF, particularly if the inter-
100 ventions are begun relatively early (e.g., at 5 to 10 minutes) after
ms the onset of cardiac arrest from VF.
Mechanical interventions of this type include the active
compression-decompression CPR device, interposed abdominal
FIGURE 46-18 Tracings of electrocardiogram leads I, II, and V1 and
and chest compression devices, the impedance threshold valve,
ventricular electrograms. Top, Tracing of the last two ventricular stimuli
from the drive (S1) and the triple extrastimuli that result in the mechanical or pneumatically driven chest compression devices,
induction of sustained monomorphic ventricular tachycardia. Middle, or devices inserted into the chest cavity to assist in direct cardiac
Induction of ventricular fibrillation. Bottom, No induction of ventricular compression.136 All these devices increase cardiac output by
tachycardia or ventricular fibrillation. VF, Ventricular fibrillation, paper increasing intrathoracic pressure during the compression phase
speed 100 ms/cm; VT, ventricular tachycardia. (From Avitall B, McKinnie of CPR or by increasing venous return during the decompression
J, Jazayeri M, et al: Induction of ventricular fibrillation versus monomorphic phase, either by positive abdominal pressure or by negative intra-
ventricular tachycardia during programmed stimulation: Role of thoracic pressure during the decompression phase of CPR. The
premature beat conduction delay, Circulation 85:1271–1278, 1992.) recent Prehospital Resuscitation Using an Impedance Valve and
Early vs. Delayed Analysis Impedance Threshold Device (ROC
PRIMED ITD) study was stopped at the recommendation of the
Data and Safety Monitoring Board; the ITD did not improve
Principles of Practice survival to hospital discharge (see www.nih.gov/news/health/
nov2009/nhlbi-06.htm).
The main strategic approaches to preventing death from VF
include prevention and treatment. Preventive therapies of proven
Drug Therapy in Acute Management
benefit include β-blocker therapy in patients with MI or heart
of Ventricular Fibrillation
failure; angiotensin-converting enzyme inhibition in patients with
left ventricular dysfunction; spironolactone therapy in patients The benefit of pharmacologic therapy as an adjunct to defibrilla-
with moderate or severe heart failure; revascularization (bypass tion in out-of-hospital VF is incompletely established. Despite
surgery in patients with left main or severe three vessel disease, many decades of use and ample laboratory experimental evidence
especially with left ventricular dysfunction); and possibly amioda- of benefit, controlled clinical trials have not provided any clear
rone therapy. No other antiarrhythmic drug has been shown in evidence that either low-dose or high-dose epinephrine is benefi-
any controlled study to reduce the likelihood of VF, SCD, or cial in the treatment of patients with out-of-hospital VF.137
overall mortality. Anticipatory therapy for VF (i.e., treating those Vasopressin, which appears to be superior to epinephrine in
patients at particularly high risk for this arrhythmia) may include experimental models of cardiac arrest in improving survival from
the implantation of an ICD; providing family members with a experimental VF, appears to be superior to epinephrine in some
semiautomatic external defibrillator; using “wearable” AEDs; and, studies but not in others.138-140 However, vasopressin has also not
from a public health perspective, providing EMS personnel or been proven superior to placebo in randomized controlled trials.
Table 46-1 Normalized Latency and Activation Times for S1-S2, S1-S2-S3, and S1-S2-S3-S4 Used to Derive Cumulative Latency and Activation Times
LATENCY ACTIVATION TIME
VT VF NO VT OR VF VT VF NO VT OR VF
S2 4 ± 4* 17 ± 13 1 ± 6* 2 ± 6* 43 ± 27 1 ± 12*
S2 5 ± 5 10 ± 14 1 ± 6* 6 ± 10* 22 ± 20 1 ± 12†
S3 4 ± 5* 14 ± 23 5 ± 12* 8 ± 15* 31 ± 32 10 ± 15*
S2 4 ± 8 8 ± 10 1 ± 6* 4 ± 9† 16 ± 15 1 ± 12†
S3 12 ± 14 20 ± 20 5 ± 12* 17 ± 17† 37 ± 26 10 ± 15†
S4 7 ± 18 14 ± 27 7 ± 13 8 ± 22† 33 ± 36 14 ± 17‡
Normalized latency and activation times for S1-S2, S1-S2-S3, and S1-S2-S3-S4 used to derive cumulative latency and activation times (in ms). Sustained monomorphic ventricular
tachycardi was initiated with lower latency times than the induction of ventricular fibrillation. Total activation times were longer in the inducible ventricular fibrillation group with
single, double, and triple premature stimuli.
VT, Ventricular tachycardia; VF, ventricular fibrillation.
*P < .01 vs. ventricular fibrillation.
†P < .001 vs. ventricular fibrillation.
‡P < .05 vs ventricular fibrillation.
From Avitall B, McKinnie J, Jazayeri M, et al: Induction of ventricular fibrillation versus monomorphic ventricular tachycardia during programmed stimulation. Role of premature beat
conduction delay, Circulation 85:1271–1278.
Similarly, the evidence base regarding antiarrhythmic therapy recurrences of VF as much as to assist in defibrillation. In particu-
is incomplete. The standard therapy used to assist electrical defi- lar, patients with frequent recurrences of VF may benefit from
brillation has been lidocaine; no evidence from controlled clinical intensive antiadrenergic therapy, IV amiodarone therapy, and
trials is available to suggest that lidocaine is superior to placebo occasionally from anti-ischemic therapy, revascularization
or any other agent in improving survival to hospital admission or therapy, or therapy with an intra-aortic balloon pump.148,149
survival to hospital discharge.141 In a meta-analysis of prophylactic
lidocaine used in the post-infarction period, lidocaine may reduce
“Non-antiarrhythmic” Drugs that Prevent Sudden
the incidence of primary VF but appears to increase mortality
Cardiac Death
rate.142 Lidocaine likely increases defibrillation thresholds and
may increase the incidence of asystole. Magnesium is not superior In the setting of heart failure, a cascade of neurohumoral activa-
to placebo in in-hospital cardiac arrest caused by VF.143-145 Brety- tion initially supports perfusion.150 Over time, however, the bio-
lium, although studied in VF, is no longer available. logically active molecules released in the neurohumoral activation,
Intravenous (IV) amiodarone for VF resistant to three defibril- including the sympathetic nervous system and the renin-
lation shocks was compared with placebo in a blinded, random- angiotensin-aldosterone system, result in progressive left ven-
ized clinical trial by Kudenchuk et al.146 The 246 patients with tricular dysfunction. Pharmacologic antagonism of these two
shock-resistant, out-of-hospital VF were randomized to 300 mg systems has proven to be an effective treatment paradigm.
amiodarone by IV bolus versus placebo; the primary study end-
point was survival to hospital admission, achieved in 44% of
β-Blockers
amiodarone-treated patients versus 34% of placebo-treated
patients. In a related study, IV amiodarone was compared with IV Strong evidence for a beneficial effect of β-blocker treatment in
lidocaine in a blinded, randomized trial of patients with VF per- patients following an MI was reported in 1981 by the Norwegian
sisting after three shocks, IV epinephrine, and a further defibril- Multicenter Study Group.68 In their study, 1884 patients were
lation shock. Survival to hospital admission was achieved in 23% randomly assigned to treatment with timolol (10 mg twice a day)
of amiodarone-treated patients versus 12% of lidocaine-treated or to placebo. Mortality in rate the control group was 16% com-
patients (P = .009).147 Although neither of these studies demon- pared with 10% in the timolol group (P = .0001), and a reduction
strated statistically significant improvements in survival to hospi- in SCD from 13.9% to 7.7% (P = .0001) was observed. In the fol-
tal discharge, if any antiarrhythmic drug is to be used in lowing year, the Beta-Blocker Heart Attack Trial (BHAT) reported
out-of-hospital VF, on the basis of these studies it seems reason- a comparison of propranolol and placebo in patients with prior
able to consider amiodarone as the drug of choice. MI.66 In that study, 3837 patients were randomized to treatment
It is important to note that resuscitation from VF is a dynamic with propranolol or placebo 5 to 10 days after an MI. The trial
clinical situation, and many patients will have multiple recur- was stopped 9 months early after an average follow-up of 25
rences of VF in the seconds to minutes after initial defibrillation months because of a highly significant difference in mortality in
and also undergo multiple transitions among VF, asystole, pulse- favor of propranolol (7.2% in the propranolol group vs. 9.8% in
less electrical activity, and a perfusing organized rhythm during the placebo group). These trials, along with a series of subsequent
the course of a protracted cardiac arrest. The use of adjunctive studies, were combined in a meta-analysis confirming that
drug therapy can therefore be considered a means to prevent β-blockers reduce both total mortality and SCD.153
More recently, two studies investigating treatment of patients associated with a reduction in total mortality and SCD.165 A mul-
with heart failure have suggested the benefit of β-blockers with
respect to reduction of total mortality and prevention of SCD.154,155
The Cardiac Insufficiency Bisoprolol Study II (CIBIS II) trial ran-
domized 2647 patients with an LVEF of 35% or less and New York
tivariate analysis of the 6797 participants in the Studies of Left
Ventricular Dysfunction (SOLVD) demonstrated that both anti-
platelet and anticoagulant therapies were associated with a reduc-
tion in the risk of SCD.166 This provides a rationale for
46
Heart Association (NYHA) functional class III or IV heart failure anti-thrombotic therapy, anti-platelet therapy, or a combination
to the β1-selective agent bisoprolol or placebo.156 All-cause mor- of both in patients with left ventricular dysfunction.
tality was reduced from 17.3% in the placebo group to 11.8% in
the bisoprolol group (P < .0001). Significantly fewer SCDs
Antiarrhythmic Drugs
occurred in bisoprolol-treated patients compared with placebo-
treated patients (3.6% vs. 6.3%; P = .0011). The Metoprolol Ran- The importance of ventricular ectopy as a risk factor for SCD in
domized Intervention Trial in Congestive Heart Failure patients with coronary disease is well established. It was therefore
(MERIT-HF) randomized 3991 patients with LVEF of 40% or less reasonable to hypothesize that suppression of premature ven-
in NYHA functional class II to IV heart failure to treatment with tricular complexes (PVCs) using standard antiarrhythmic agents
the β1-selective agent metoprolol, in its controlled release or that block sodium or potassium channels might reduce the risk
extended release form, or placebo.155 All-cause mortality was 7.2% of SCD.
per year in the metoprolol group and 11% in the placebo group
(P = .00009). A reduction in SCD was seen in metoprolol-treated
Class I Agents
patients (odds ratio [OR], 0.59; confidence interval [CI], 0.45 to
0.78). The Cardiac Arrhythmia Suppression Trial (CAST) studied
patients with a history of MI and frequent PVCs that were sup-
pressible with encainide, flecainide, or moricizine (type IC agents
Angiotensin-Converting Enzyme Inhibitors
that are sodium channel blockers).167 More than 90 days after MI,
The survival advantage conferred by angiotensin-converting patients were also required to have an LVEF of 40% or less.
enzyme (ACE) inhibitors in patients with heart failure has been Despite suppression of PVCs, the encainide and flecainide arms
demonstrated in a number of studies.156-159 However, only in the of the trial were stopped early because of increased mortality in
Tandolapril Cardiac Evaluation Trial (TRACE) did the reduction patients treated with antiarrhythmic drugs. The moricizine arm
in SCD reach statistical significance.160 A recently published was subsequently stopped because it became clear there would
meta-analysis has now clearly demonstrated that ACE inhibitors be no benefit and because of concern about an apparent early
reduce SCD.160 In this study, 15,104 patients from 15 trials were increase in mortality.168
studied. The relative risk of SCD in ACE inhibitor–treated patients The CAST trial provided four important insights: (1) the
was 0.80 (95% CI, 0.70 to 0.92). mechanism causing PVCs was different from that causing the
arrhythmia (presumably a ventricular tachyarrhythmia) that pro-
voked SCD; (2) ventricular ectopy is not an appropriate surrogate
Aldosterone Antagonism
endpoint for SCD in clinical trials; (3) antiarrhythmic drugs could
The effect of spironolactone on survival was studied in the Ran- be proarrhythmic, even months after initiation; and (4) a change
domized Aldactone Evaluation Study (RALES).161 A total of 822 in the myocardial substrate, presumably ischemia, could make the
patients on an ACE inhibitor with an LVEF of 35% or less and antiarrhythmic drug proarrhythmic.
severe heart failure symptoms were randomly assigned to treat-
ment with spironolactone or placebo. After a mean follow-up of
New Class III Drugs
24 months, the mortality rate was 46% in the placebo group and
35% in the spironolactone group (P < .001). The relative risk of In the Survival with Oral D-Sotalol (SWORD) study, the impact
SCD in spironolactone-treated patients was 0.71 (CI, 0.54 to on SCD of d-sotalol, a potassium channel blocker without
0.95). β-blocker properties, was studied.3,127,169 Patients with a history of
Recent studies have confirmed these findings and extended MI and LVEF less than 40% were randomly assigned to d-sotalol
the benefit to patients with mild heart failure, in whom eplere- or placebo. The study was terminated because of an excess risk of
none, a selective aldosterone inhibitor, reduces all-cause mortal- mortality in d-sotalol–treated patients (relative risk [RR], 1.65; P
ity. A total of 12.5% of patients receiving eplerenone and 15.5% = .006). Dofetilide was also evaluated in patients with CHF.170 In
of those receiving placebo died (hazard ratio [HR], 0.76; 95% CI, a study of 1518 patients with symptomatic CHF and severe left
0.62 to 0.93; P = .008).162 Taken together, the data confirm that ventricular dysfunction randomized to dofetilide or placebo, no
antagonizing the various components of the neuroendocrine acti- difference in mortality rate was seen, although dofetilide was suc-
vation that accompanies heart failure results in a reduction in cessful in converting AF to sinus rhythm. Similar results were
SCD. obtained in patients with prior MI but without CHF.171 These data
suggest that although dofetilide has no role in the prevention of
SCD, it may be a useful treatment option in patients with AF who
Anti-thrombotic and Anticoagulant Therapy
are also at risk for SCD because it did not increase mortality rate
Accumulated data have suggested that ischemia caused by throm- in these patients. A meta-analysis performed by Teo et al of anti-
bus formation in stenotic coronary arteries may result in SCD. arrhythmic trials was reported in 1993. Data were drawn from
On the basis of pathologic examinations, greater than 80% of SCD 138 trials and 98,000 patients.172 The mortality rate of patients
cases in patients with ischemic heart disease may be associated randomized to receive class I agents was significantly higher than
with thrombus formation or plaque fissuring.163,164 In the Second that of patients receiving placebo (OR, 1.14; 95% CI, 1.01 to 1.28;
International Study of Infarct Survival (ISIS-2), aspirin use was P = .03).
Given the data presented, it is reasonable to ask whether the (P = .05). All the mortality benefit occurred in amiodarone-
reason for the failure of these antiarrhythmic drugs to prevent treated patients, who were also treated with a β-blocker. In
SCD is the intrinsic ineffectiveness of drug action or the method CAMIAT, 1202 patients with a history of MI and frequent ven-
of guiding selection of the drug. If the problem were the method tricular ectopy (>10 PVCs per hour or at least one episode of
of guiding selection of potentially effective drugs, it would be VT) were randomized to receive amiodarone or placebo. A reduc-
expected that although the drugs might not prevent an arrhyth- tion was seen in the endpoint of resuscitated VF or arrhythmic
mia, at least they would not be proarrhythmic. However, most death from 6% in the placebo group to 3.3% in the amiodarone
antiarrhythmic drugs other than amiodarone were shown to group (P = .03). No difference in total mortality was observed.
provoke SCD in clinical trials. This suggests that the failure to As in EMIAT, only amiodarone-treated patients who were also
prevent SCD is based on the molecule rather than the selection on a β-blocker appeared to derive any benefit. Two recent meta-
paradigm. The results of the Electrophysiologic Study Versus analyses that provide a quantitative overview of the available
Electrocardiographic Monitoring (ESVEM) study provide support randomized trials have been published. The Amiodarone Trials
for this view.122 In this study, 486 patients with sustained mono- Meta-Analysis Investigators examined 13 randomized trials
morphic VT, inducible with programmed electrical stimulation involving 6553 patients.177 Five trials of patients with CHF and
(PES) and 10 PVCs or more per hour on Holter monitoring, were eight trials involving patients with previous MI were included.
randomly assigned to guidance by demonstrating suppression of The mean LVEF in this population was 0.31. They found a 29%
PES-stimulated VT or Holter recording suppression of ventricu- reduction in SCD (OR, 0.71; 95% CI, 0.59 to 0.85). No difference
lar ectopy. Although the PES protocol used in ESVEM was was seen between the post-MI and CHF populations. Sim et  al
limited, the results in ESVEM were no different in either arm, studied 15 randomized trials of amiodarone to prevent SCD using
indicating that PES guidance was not better than Holter guidance. the random effects model.178 Amiodarone was found to signifi-
In contrast, the Calgary study, using a standard PES protocol, cantly reduce the risk of total mortality (OR, 0.77; 95% CI, 0.66
showed superior results with PES-guided therapy for the preven- to 0.89; P < .001) and SCD (OR, 0.70; 95% CI, 0.58 to 0.85; P <
tion of recurrent VT or VF in less drug-refractory patients.123,124 .001).
It can be concluded from the studies presented that the antiar- These data suggest that, unlike other antiarrhythmic drugs,
rhythmic drugs, excluding amiodarone, that have been tested may amiodarone may reduce arrhythmic death in the post-MI popula-
not prevent death from ventricular arrhythmias and, depending tion and that its effect appears to be greater if there is concomitant
on the drug, may even increase it. As a result, antiarrhythmics β-blocker therapy.
other than amiodarone that have been studied have a limited role In the Optimal Pharmacological Therapy in Cardioverter Defi-
in the prevention of SCD and should be considered after other, brillator Patients (OPTIC) trial, amiodarone was more effective
better treatments have been rejected. that β-blockers alone or sotalol in preventing ICD discharges for
ventricular arrhyhthmias.179 However, amiodarone is rarely rec-
ommended as the sole therapy for the secondary prevention of
Amiodarone
SCD in patients with a history of VF not caused by a reversible
A number of early studies suggested that amiodarone, unlike cause, the ICD being the therapy of choice. The fact that the
other antiarrhythmics, may have a role in suppressing VTs in the reduction in arrhythmic death is not easily translated into an
post-MI population. The Basel Antiarrhythmic Study of Infarct improvement in total mortality is likely attributable to the limited
Survival (BASIS) randomized 312 patients with previous MI and protective effect of amiodarone. SCD-HeFT did not show any
complex ventricular ectopy to amiodarone, individualized drug mortality benefit from amiodarone versus placebo; the HR for
therapy starting with procainamide, or no antiarrhythmic drug mortality in 845 amiodarone-treated patients followed up to 5
therapy.173 After 1 year of follow-up, amiodarone-treated patients years versus the 847 patients treated with placebo was 1.06 (97.5%
had a significantly greater survival compared with patients treated CI, 0.86 to 1.30).
with no antiarrhythmic therapy (95% vs. 87%; P = .048).
Amiodarone-treated patients also had better survival compared
with patients who received individualized therapy, but this did Nonpharmacologic Therapy
not reach statistical significance. Ceremuzynski et al randomized
Revascularization
613 patients with previous MI who were ineligible to receive
β-blockers to amiodarone or placebo.174 A statistically significant As previously discussed, ischemia appears to be a precipitating
(P = .048) reduction in cardiac mortality was seen in amiodarone- event in SCD and is frequently caused by plaque disruption and
treated patients, although the reduction in total mortality did not coronary thrombus formation. Data supporting the usefulness of
achieve statistical significance. The meta-analysis by Teo et al, anti-thrombotic agents suggest a potential antiarrhythmic role for
discussed earlier, showed a significant mortality reduction in revascularization. Interestingly, trial-derived data bearing directly
amiodarone-treated patients with previous MI.172 Taken together, on the issue of revascularization are rare. In the Coronary Artery
these studies suggested that amiodarone may reduce arrhythmic Surgery Study (CASS) registry, revascularization was indepen-
death. dently associated with improved survival free of SCD (SCD
This picture was further clarified by the European Myocardial occurred in 4.9% of patients assigned to medical therapy and 1.6%
Infarction Amiodarone Trial (EMIAT) and the Canadian Amio- of patients assigned to surgical therapy).180 Garan et al showed
darone Myocardial Infarction Trial (CAMIAT).175,176 EMIAT that myocardial revascularization can result in elimination of
randomized 1486 patients who had an LVEF of 40% or less, 5 PES-inducible ventricular tachyarrhythmias.181 Hii et al found
to 21 days after an MI, to treatment with amiodarone or placebo. that a patent infarct-related artery was associated with the effec-
No difference was observed in the primary endpoint of total tive drug suppression of inducible VT at PES.182 In sum, data
mortality or in cardiac mortality. Arrhythmic death was reduced supporting a role for ischemia in the production of ventricular
from 7% in the placebo group to 4% in the amiodarone group arrhythmias and studies suggesting a positive treatment effect of
eliminating the ischemia lead to the conclusion that elimination CABG-PATCH, 71% of the deaths were nonarrhythmic, which
of inducible ischemia should be a component of treatment to
prevent SCD.
accounts for the absence of benefit from the ICD.187 It is possible
that the revascularization reduced the frequency of VTs by
removing the contributing role of inducible ischemia. The results
of this trial do not provide support for the use of the signal-
46
Implantable Cardioverter-Defibrillator
averaged ECG in risk stratification.
Since the first implantation of an ICD by Mirowski in 1980, these The Multicenter Unsustained Tachycardia Trial (MUSTT)
systems have continued to evolve.183 Today, they are generally studied patients with CAD, an LVEF of 40% or less, and nonsus-
placed transvenously, with an implantation-related mortality rate tained VT on Holter recording and who had inducible, sustained
of less than 1%.184 Current systems are capable of defibrillation of monomorphic VT or VF.188 Patients were randomized to standard
VF, tiered therapy of VT (competitive pacing, synchronized car- therapy for coronary disease or standard therapy with a PES-
dioversion, defibrillation), and antibradycardia pacing. Increas- guided attempt to suppress inducible VT or VF. Patients in whom
ingly sophisticated electrogram storage and telemetry are useful inducible VT or VF was suppressed or whose VT was hemody-
for rhythm diagnosis. namically tolerated were treated with the drug that suppressed
A number of randomized, controlled clinical trials in patients the VT (or rendered it tolerable). Patients who continued to be
with malignant ventricular arrhythmias, including SCD, have inducible to a sustained VT at PES that was hemodynamically
been performed and have provided an increasingly clear picture intolerable had an ICD placed. The primary endpoint of the study
of the appropriate role of and considerations for the ICD (Box was cardiac arrest or death. A total of 704 patients were random-
46-1). The AVID trial was a secondary prevention study that ized. The patients who received the ICD because of nonsuppress-
randomized patients with a history of symptomatic VT or VF to ibility would be expected to be the highest risk group, but they
ICD implantation or to antiarrhythmic therapy.131 Randomized had a better survival compared with patients not receiving antiar-
patients must have been resuscitated from VF or have had an rhythmic therapy and those who were suppressible with PES-
episode of VT that was hemodynamically compromising or that guided antiarrhythmic therapy (RR, 0.24; 95% CI, 0.13 to 0.45; P
was associated with an LVEF less than 40%. A total of 1016 < .001). No difference was seen in mortality rate or cardiac arrest
patients were randomized to immediate ICD implantation or between patients who received no antiarrhythmic therapy and
antiarrhythmic drug therapy. Although sotalol or amiodarone was those with antiarrhythmic drug suppression of inducibility. Inter-
permitted in the antiarrhythmic drug arm, only 2.6% of patients estingly, unlike the other ICD trials, it is possible to compare ICDs
randomized to antiarrhythmic drug were discharged on sotalol. with standard treatment without an antiarrhythmic drug in
Thus, for all practical purposes, this was an amiodarone versus patients who have had a demonstrated VT (in this case, at PES).
ICD trial. The trial was stopped early because of significantly These data suggest that the ICD is the most effective approach to
better survival in ICD-treated patients (75.4% vs. 64.1% at 3 years; preventing SCD in these patients. Also, they proved an important
P < .02). Similar patient populations were studied in CIDS and additional demonstration of the ineffectiveness of PES-guided
CASH, with results similar to AVID.134,135 antiarrhythmic drug selection. The conclusions drawn from
MADIT was a primary prevention trial that studied 196 MUSTT suggest that the potentially large group of coronary
patients with previous MI, nonsustained VT, and an LVEF of 35% patients with depressed ejection fraction and nonsustained VT
or less who were inducible to a sustained monomorphic VT at who are inducible into a sustained monomorphic VT or VF by
PES not suppressible by procainamide.185 This population was PES should have an ICD inserted. MADIT-II randomized patients
different from the AVID patients in that they did not have a with previous MI and an LVEF of 30% or less to ICD or standard
spontaneous sustained ventricular arrhythmia but had shown therapy.189 The primary endpoint was total mortality. Most
that VT could be induced by PES. These patients were randomly patients were in NYHA class I or II. The ICD arm had a 31%
assigned to immediate ICD implantation or antiarrhythmic drug relapse risk reduction in total mortality, suggesting that an impor-
therapy. At 1-month follow-up, 74% of the patients in the antiar- tant role for SCD prevention exists in this population.189 However,
rhythmic drug therapy group were on amiodarone. Survival was most of the benefit was seen in patients with a prolonged QRS
significantly better in the ICD group than in patients treated with complex on the resting ECG. In summary, the accumulated data
an antiarrhythmic drug (mostly amiodarone) (HR for overall mor- suggest that the ICD reduces mortality in patients at high risk for
tality, 0.46; 95% CI, 0.26 to 0.82; P = .009). a fatal VT and that it is more effective than amiodarone in doing
All the ICD trials (AVID, MADIT, CIDS, CASH) presented so.
thus far entered patients known to be at high risk for a fatal A consideration of these facts leads to the current management
arrhythmia because they had a history of prior VT, either as a approach to patients at risk for SCD:
presenting problem or at PES. The Coronary Artery Bypass Graft
PATCH (CABG-PATCH) trial examined patients at risk of SCD 1. Patients resuscitated from VF or with VT associated with
because of the presence of coronary disease for which they were hemodynamic compromise or reduced LVEF (≤0.40) should
to undergo coronary artery bypass grafting (CABG), who had an have an ICD inserted. They should also be treated with aspirin,
LVEF of 35% or less, and who had an abnormal signal-averaged β-blockers, and ACE inhibitors, as tolerated, as well as revas-
ECG.186 In contrast to the patients presented in the other studies, cularization if inducible ischemia is present.
these patients had no history of a sustained VT that occurred
spontaneously or at PES. This study randomly assigned 900 2. Patients with coronary disease, reduced LVEF (31% to 40%),
patients to ICD implantation or no implantation at the time of and nonsustained VT who have a sustained monomorphic VT
CABG. During an average follow-up of 32 ± 16 months, no sig- induced by PES should also have an ICD placed. They should
nificant difference was seen in mortality between patients assigned be treated with aspirin, β-blockers, and ACE inhibitors, as
to ICD and those assigned to no ICD. The HR for total mortality tolerated, as well as revascularization if inducible ischemia is
with ICD placement was 1.07 (95% CI, 0.81 to 1.42). In present. The presence of nonsustained VT may be useful as a
Box 46-1 Indications for Implantable Cardioverter-Defibrillator Therapy for Patients at Risk of Ventricular Fibrillation
CLASS I
1. ICD therapy is indicated in patients who are survivors of cardiac arrest due to VF or hemodynamically unstable sustained VT after evaluation to
define the cause of the event and to exclude any completely reversible causes. (Level of Evidence: A)
2. ICD therapy is indicated in patients with syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF
induced at electrophysiological study. (Level of Evidence: B)
3. ICD therapy is indicated in patients with LVEF less than 35% due to prior MI, at least 40 days after MI, and who are in NYHA functional class II or III.
(Level of Evidence: A)
4. ICD therapy is indicated in patients with nonischemic DCM who have an LVEF 35% or less and who are in NYHA functional class II or III. (Level of
Evidence: B)
5. ICD therapy is indicated in patients with left ventricular dysfunction caused by prior MI, at least 40 days after MI, and who have an LVEF less than
30%, and are in NYHA functional class I. (Level of Evidence: A)
6. ICD therapy is indicated in patients with nonsustained VT from prior MI, LVEF less than 40%, and inducible VF or sustained VT at electrophysiological
study. (Level of Evidence: B)
CLASS IIA
1. ICD implantation is reasonable for patients with unexplained syncope, significant left ventricular dysfunction, and nonischemic DCM. (Level of
Evidence: C)
2. ICD implantation is reasonable for patients with HCM who have 1 or more major† risk factors for SCD. (Level of Evidence: C)
4. ICD implantation is reasonable for the prevention of SCD in patients with ARVD/C who have 1 or more risk factors for SCD. (Level of Evidence: C)
5. ICD implantation is reasonable to reduce SCD in patients with long QT syndrome who are experiencing syncope, VT, or both while receiving
β-blockers. (Level of Evidence: B)
6. ICD implantation is reasonable for nonhospitalized patients awaiting transplantation. (Level of Evidence: C)
7. ICD implantation is reasonable for patients with Brugada syndrome, who have had syncope. (Level of Evidence: C)
8. ICD implantation is reasonable for patients with cardiac sarcoidosis, giant cell myocarditis, or Chagas disease. (Level of Evidence: C)
CLASS IIB
1. ICD therapy may be considered in patients with nonischemic heart disease, who have an LVEF of 35% or less and who are in NYHA functional class
I. (Level of Evidence: C)
2. ICD therapy may be considered for patients with long QT syndrome and risk factors for SCD. (Level of Evidence: B)
3. ICD therapy may be considered in patients with syncope and advanced structural heart disease, in whom thorough invasive and noninvasive
investigations have failed to define a cause. (Level of Evidence: C)
4. ICD therapy may be considered in patients with a familial cardiomyopathy associated with SCD. (Level of Evidence: C)
5. ICD therapy may be considered in patients with left ventricular noncompaction. (Level of Evidence: C)
CLASS III
1. ICD therapy is not indicated for patients who do not have a reasonable expectation of survival with an acceptable functional status for at least 1
year, even if they meet ICD implantatio criteria specified in the class I, IIa, and IIb recommendations above. (Level of Evidence: C)
2. ICD therapy is not indicated for patients with incessant VT or VF. (Level of Evidence: C)
3. ICD therapy is not indicated in patients with significant psychiatric illnesses that may be aggravated by device implantation or that may preclude
systematic follow-up. (Level of Evidence: C)
4. ICD therapy is not indicated for NYHA class IV patients with drug-refractory congestive heart failure who are not candidates for cardiac
transplantation or CRT-D. (Level of Evidence: C)
5. ICD therapy is not indicated for syncope of undetermined cause in a patient without inducible ventricular tachyarrhythmias and without structural
heart disease. (Level of Evidence: C)
6. ICD therapy is not indicated when VF or VT is amenable to surgical or catheter ablation (e.g., atrial arrhythmias associated with the Wolff-Parkinson-
White syndrome, righty or left ventricular outflow tract VT, idiopathic VT, or fascicular VT in the absence of structural heart disease). (Level of
Evidence: C)
7. ICD therapy is not indicated for patients with ventricular tachyarrhythmias from a completely reversible disorder in the absence of structural heart
disease (e.g., electrolyte imbalance, drugs, or trauma). (Level of Evidence: B)
ARVD/C, Arrhythmogenic right ventricular dysplasia or cardiomyopathy; CRT-D, cardiac resynchronization therapy–defibrillator; DCM, dilated cardiomyopathy;
HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association;
SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.
Adapted from Epstein, AE, DiMarco, JP, Ellenbogen, KA, et al: ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: American College of
Cardiology/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic
Surgeons, J Am Coll Cardiol 51:1–62, 2008.
Primary Prevention of Sudden Cardiac Death

screening tool for detecting higher risk for sustained ventricu-
lar arrhythmias but is likely superfluous in a patient with a At this point, no doubt exists about the capacity of the ICD to
history of sustained arrhythmia, including at PES. prevent arrhythmic death. This means that any patient destined
to have a potentially fatal ventricular arrhythmia (in spite of oth-
3. Patients with CAD, prior MI, and severe left ventricular dys- erwise appropriate medical therapy) could potentially benefit
function (LVEF <30%) should be risk stratified (e.g., by QRS from having an ICD in place. A central issue for future investiga-
width and ≥120 ms) or otherwise considered for ICD therapy. tion is the identification of patients at sufficiently high risk of SCD
to justify the morbidity and cost of placing a device. Some sub- Cobb LA, Fahrenbruch CE, Walsh TR, et al: Influence of cardiopulmonary
46
populations of patients described earlier may be effectively treated resuscitation prior to defibrillation in patients with out-of-hospital ven-
with amiodarone. For instance, a post hoc analysis of the AVID tricular fibrillation, JAMA 281:1182–1188, 1999.
Connolly SJ, Dorian P, Roberts RS, et al: Comparison of beta-blockers,
database suggests that ICDs have no benefit over amiodarone for
amiodarone plus beta-blockers, or sotalol for prevention of shocks from
patients with LVEF greater than 35%.190 A randomized trial in implantable cardioverter defibrillators: The OPTIC Study. A random-
such patients would be needed to make definitive treatment ized trial, JAMA 295:165–171, 2006.
recommendations. Domanski M, Saksena S, Epstien A, et al, for the AVID Investigators:
Certain populations of patients are known to be at risk for Relative effectiveness of the implantable cardioverter-defibrillator and
SCD, but because of competing risks of death, it is not clear antiarrhythmic drugs in patients with varying degrees of left ventricular
whether the ICD will confer a benefit to the population as a whole. dysfunction who have survived malignant ventricular arrhythmias, J
The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) Am Coll Cardiol 34:1090–1095, 1999.
study used a risk factor representing autonomic dysfunction as a Dorian P, Cass D, Schwartz B, et al: Amiodarone as compared with lido-
risk stratifier to allow defibrillation therapy to more effectively caine for shock-resistant ventricular fibrillation, N Engl J Med 346:884–
890, 2002.
focus on the highest-risk patients. A reduction in heart rate vari-
Furukawa T, Rozanski J, Nogami A, et al: Time-dependent risk of and
ability (HRV) has been shown to portend a worse prognosis in predictors for cardiac arrest recurrence in survivors of out-of-hospital
patients with CAD.191-193 Patients in DINAMIT had low HRV and cardiac arrest with chronic coronary artery disease, Circulation
an ejection fraction of 35% or less. They were within 40 days of 80:599–608, 1989.
an acute MI. No mortality benefit was seen in patients random- Haissaguerre M, Derval N, Sacher F, et al: Sudden cardiac arrest
ized to the ICD (n = 332) compared with control patients (n = associated with early repolarization, N Engl J Med 358(19):2016–2023,
342), with an HR for all-cause death of 1.08 (95% CI, 0.76 to 1.55) 2008.
in the ICD versus control groups, over 30 ± 13 months of Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R,
follow-up.194 Fain E, Gent M, Connolly SJ. Prophylactic use of an implantable
In the Defibrillators In Non-Ischemic Cardiomyopathy Treat- cardioverter-defibrillator after acute myocardial infarction, N Engl J
Med 351:2481–2488, 2004.
ment Evaluation (DEFINITE) study, 458 patients with nonisch-
Kannel W, Thomas H: Sudden coronary death: The Framingham study,
emic cardiomyopathy, an LVEF of 35% or less, and more than 10 Ann N Y Acad Sci 382:3–21, 1982.
PVCs per hour or any episode of unsustained VT were random- Kober L, Torp-Pederson C, Carlsen J, et al for the Trandolapril Cardiac
ized to standard medical therapy versus standard therapy plus Evaluation (TRACE) Study Group: A clinical trial of the ACE inhibitor
ICD. The HR for all-cause mortality after 29 ± 14.4 months of Trandolapril in patients with left ventricular dysfunction after myocar-
follow-up in the ICD versus control groups was 0.65 (95% CI, 0.4 dial infarction, N Engl J Med 333: 1670–1676, 1995.
to 1.06; P = .08).195 Kowey PR, Levine JH, Herre JM, et al: Randomized, double-blind com-
The entire discussion to this point has focused on populations parison of intravenous amiodarone and bretylium in the treatment of
known to be at high risk for SCD. Myerberg and others have patients with recurrent, hemodynamically destabilizing ventricular
emphasized the fact that the majority of cardiac arrests occur in tachycardia or fibrillation. The Intravenous Amiodarone Multicenter
Investigators Group, Circulation 92:3255–3263, 1995.
the low-risk, but very large, population of patients whose increased
Luu M, Stevenson WG, Stevenson LW, et al: Diverse mechanisms of
risk has not come to clinical recognition.196 To make major inroads unexpected sudden cardiac arrest in advanced heart failure, Circulation
into the prevention of SCD, learning how to screen the asymp- 80:1675–1680, 1989.
tomatic population inexpensively, but safely and effectively, will Mason J for the Electrophysiologic Study Versus Electro cardiographic
be necessary. Identifying high-risk patients in the low-risk, Monitoring Investigators: A comparison of electrophysiologic testing
asymptomatic population and identifying members of known with Holter monitoring to predict antiarrhythmic drug efficacy for
high-risk populations who are not at high enough risk to justify ventricular tachyarrhythmias, N Engl J Med 329:445–451, 1993.
ICD placement is the next frontier in SCD prevention. Mitchell LB, Duff HJ, Manyari DE, Wyse DG: A randomized clinical trial
of the noninvasive and invasive approaches to drug therapy ventricular
tachycardia, N Engl J Med 317:1681–1687, 1987.
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arrhythmias, N Engl J Med 337:1576–1583, 1997. Moss AJ, Schwartz PJ, Crampton RS, et al: The long QT syndrome: Pro-
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341:1882–1890, 1999. ity in patients with left ventricular dysfunction after myocardial infarc-
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arrhythmic agent moricizine on survival after myocardial infarction, N J Med 327:669–677, 1992.
Engl J Med 327:227–233, 1992. Pitt B, Zannad F, Remme W, et al for the Randomized Aldactone Evalua-
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1981. com.

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CHAPTER

surrounding myocardium (see Figure 46-3) with arteriolosclerosis

FIGURE 46-2 Chronic myocarditis in a 35-year-old man with

report, there was a 23% relative reduction in all-cause mortality

RECURRENCES AMONG CARDIAC ARREST SURVIVORS

ing surface will appear as a two-dimensional spiral wave, whereas

Substrates for Ventricular Fibrillation: Heterogeneities

C Mother-daughter wavelet hypothesis

used pharmacologic agents to flatten the restitution curve slope

10 experimental conditions, it is often difficult to provoke VF in

decreases arrhythmias during acute MI.64 In contrast, unilateral

2 A– H– S– F+ Sf23 H442 #31926

Baseline ajmaline test

Ajmaline test—2 min

few focused investigations. Electrolyte abnormalities are

Electrophysiological Characteristics Associated with

10:48:12 AM 10:48:14 AM 10:48:16 AM 10:48:18 AM 10:48:20 AM

10:57:08 AM 10:57:10 AM 10:57:12 AM 10:57:14 AM 10:57:16 AM

Inducible/suppressed (N = 20, SD/CA = 1)

FIGURE 46-16 Scatterplot of left ventricular ejection fraction

trained lay rescuers with manually operated semiautomated

LATENCY ACTIVATION TIME

S3 4 ± 5* 14 ± 23 5 ± 12* 8 ± 15* 31 ± 32 10 ± 15*

S3 12 ± 14 20 ± 20 5 ± 12* 17 ± 17† 37 ± 26 10 ± 15†

Primary Prevention of Sudden Cardiac Death

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