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905
Point of View
Nonischemic Sudden Tachyarrhythmic Death
in Atherosclerotic Heart Disease
Marc D. Meissner, MD; Masood Akhtar, MD; and Michael H. Lehmann, MD
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Sudden cardiac death victims have a high prevalence of significant coronary arterial
stenoses.12 This association has led, in part, to
the belief that acute ischemia is frequently responsible for the occurrence of sustained ventricular tachyarrhythmias that result in sudden cardiac death.
Although evidence for acute myocardial infarction as
a precursor is present in only approximately one third
of cases,1, 3the occurrence of antecedent chest pain in
as many as 60% of sudden coronary deaths56 further
implicates acute ischemia as an important precipitant
of fatal ventricular tachyarrhythmias-even when
such ischemia is not sufficiently prolonged to result in
myocardial necrosis.
Nevertheless, ischemia remains far from established as a universal mechanism for sudden tachyarrhythmic death in patients with atherosclerotic heart
disease (ASHD). We critically assess this controversial issue in light of recent investigations, and focus
on the importance of the nonischemic route to sudden tachyarrhythmic death in the setting of ASHD.
Evidence Against Ischemia as the Requisite
Preterminal Cause of Sudden Cardiac
Death in ASHD
From a purely anatomic standpoint, the lack of a
preterminal ischemic process in many sudden cardiac
death victims with ASHD is suggested by the observations that coronary artery segment cross-sectional
area narrowing of at least 50% (at autopsy) is absent
in 30% of cases,4 whereas angiographically significant
stenoses are absent in as many as 10% of cases.7,8
Although Davies et a19 found that "acute" coronary
arterial lesions (plaque fissuring, mural thrombi, or
occlusive thrombi) were detectable in 95% of sudden
coronary deaths (6-hour definition of "sudden"),
that study included victims of whom one third had an
acute myocardial infarction (M.J. Davies, personal
communication). In a more recent and larger study
From the Department of Internal Medicine (M.D.M., M.H.L.),
Division of Cardiology, Wayne State University/Harper Hospital,
Detroit, Mich., and the University of Wisconsin-Milwaukee Clinical Campus (M.A.), Sinai-Samaritan Medical Center, Milwaukee,
Wis.
Address for reprints: Marc D. Meissner, MD, Division of
Cardiology, Harper Hospital, 3990 John R, Detroit, MI 48201.
The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
by the same investigators,10 an acute coronary lesion
was absent in 42% of sudden death victims who had
neither preterminal chest pain nor acute infarction.
Acknowledging the lack of proof that plaque-fissuring alone can precipitate ventricular fibrillation, Davies et al10 noted that after excluding abnormalities
limited to these lesions, acute coronary pathology
was absent in one fourth of all "ischemic" sudden
deaths studied. These findings challenge the notion
that an acute coronary event represents a necessary
precondition for sudden cardiac death in ASHD.
Data from the clinical arena are also relevant. For
example, it has been well established that most
sudden cardiac deaths do not occur in the setting of
strenuous exercise.11,12 Furthermore, approximately
40% of victims are asymptomatic before collapse.5,6
Particularly striking is the finding that during treadmill testing, ST segment depression is absent in more
than half of the ASHD patients who have survived
out-of-hospital cardiac arrest.12 These collective findings argue strongly against overt and/or demand-type
ischemia as a lethal triggering mechanism in a significant proportion of ASHD patients prone to sudden
cardiac death.
Could silent myocardial ischemia1314 play a role in
the genesis of sudden cardiac death in ASHD? In
some instances, probably SO.15-17 However, based on
validated methods of Holter ST segment analysis18
and -to the extent that Holter-based ST deviation is
a sensitive index of ischemia-many studies have
shown that silent ischemia is absent as a precursor to
spontaneously occurring sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) in approximately 90% of monitored sudden deaths.19-21
Thus, evidence for either manifest or occult ischemia
is commonly lacking as a precursor to terminal
tachyarrhythmias in ASHD.
If ischemia were the exclusive cause of sustained
ventricular tachyarrhythmias in patients with ASHD,
one might expect adequate anti-ischemic therapy to
drastically reduce the mortality rate of sudden death.
Although the Beta-Blocker Heart Attack Trial22
clearly demonstrated a protective effect of ,8-blockade in these patients, 72% of sudden deaths after
myocardial infarction were not prevented. Furthermore, there was no significant reduction in sudden or
arrhythmic death in patients receiving diltiazem com-
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Circulation Vol 84, No 2 August 1991
TABLE 1. Nonischemic Mechanisms and Factors That May Contribute to Spontaneous Onset of Sustained Monomorphic Ventricular
Tachycardia Arising From a Myocardial Scar
Mechanisms of spontaneous sustained monomorphic ventricular tachycardia initiation
Creation of unidirectional block during penetration of ventricular tachycardia circuit by ventricular premature depolarizations (single
or multiple; monomorphic or polymorphic-but different from ultimate sustained ventricular tachycardia morphology)7071
Breakthrough to normal myocardium and perpetuation of concealed reentry, following invasion of the ventricular tachycardia circuit
by sinus beats (no difference in morphology between first and subsequent beats of ventricular tachycardia)7071
Facilitating factors
Changes in autonomic tone,40,73-75 including direct or indirect effects (e.g., altered heart rate)
Antiarrhythmic drugs (i.e., proarrhythmia)76
Postextrasystolic increase in dispersion of refractoriness within the ventricular tachycardia circuit ("short-long" phenomenon)77'78
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pared with those receiving placebo in the Multicenter
Diltiazem Postinfarction Trial.23 Finally, it is relevant
to mention the relation between coronary revascularization and sudden death. Although surgery (compared with medical treatment) decreased the cumulative risk of sudden cardiac death in the European
Coronary Surgery Study (ECSS),24 the 10-year follow-up of the Coronary Artery Surgery Study (CASS)
randomized trial failed to demonstrate such a benefit.25 It should be noted, however, that whereas the
ECSS consisted entirely of patients with normal left
ventricular function (ejection fraction 50% or more),
the CASS included patients with left ventricular
dysfunction and scar.
Pathophysiological Delineation of Ischemic and
Nonischemic Pathways to Sudden
Tachyarrhythmic Death in ASHD
Of the terminal tachyarrhythmias seen by emergency medical personnel during attempted resuscitations, VF constitutes approximately 80-90% of cases,
and sustained VT constitutes the remainder.26-28
Analysis of available data strongly suggests that for
patients with ASHD, VF may develop via two major
mechanistic pathways. 1) The acute ischemia-related
pathway is exemplified by the occurrence of VF during
an abrupt decline in coronary artery blood flow29 (e.g.,
spasm30 and other acute coronary occlusive phenomena), when blood supply fails to meet increased myocardial oxygen demands,15 or in the setting of early
reperfusion.31-33 Under these various conditions, VF
may be preceded by polymorphic VT unassociated
with a prolonged QT interval.3435 Although monomorphic VT has also been reported, it has usually
been unsustained.30,36 Acute ischemia-related ventricular tachyarrhythmias may derive, in part, from electrophysiological derangements in the "border
zone."37,38 2) Nonischemic processes involving scarred
myocardium (discussed below) sometimes directly
give rise to polymorphic VT and VF3940 but more
often give rise to sustained monomorphic VT that
degenerates into NF, as documented by Holter studieS.2040-45 These mechanistic pathways - ischemic versus nonischemic-constitute two distinct poles defining a continuum of pathophysiological scenarios that
may culminate in cardiac arrest.
Sustained Monomorphic Ventricular Tachycardia:
A Nonischemic Precipitant of Cardiac Arrest
That sustained monomorphic VT is infrequently, if
ever, the result of acute ischemia is supported by the
former's virtual absence from the reported spectrum
of sustained ventricular arrhythmias caused by coronary artery spasm.46 Furthermore, sustained VT
failed to occur in at least 85% of treadmill tests
performed in patients with ASHD and previously
demonstrated "malignant" ventricular arrhythmias
(three fourths were sustained VT or NF)47'48; although significant ST depression occurred in 10% of
such tests, there were no associated episodes of
sustained VT.47
The entity of sustained monomorphic VT encompasses a clinical spectrum whose manifestations may
vary from minimal associated symptoms to cardiac
arrest.26,27,49,50 Tachycardia rate is only one factor contributing to hemodynamic collapse in patients prone to
developing sustained VT.50 Other factors include left
ventricular systolic and diastolic dysfunction, asvnchronous ventricular contraction, tachycardia-induce,' mitral regurgitation, and lack of atrioventricular synchrony.50-52 Hemodynamic compromise during rapid VT
may secondarily precipitate ischemia, further potentiating a vicious cycle that rapidly culminates in cardiac
arrest. The fact that some VTs are very poorly tolerated
may explain why cardiac arrest victims may not have a
history of recurrent sustained VT, as sudden death may
be their first and only presentation.
Our understanding of the pathophysiology of sustained VT derives from a spectrum of VTs in animal
models; in humans, this knowledge has, of necessity,
been collected from patients with well-tolerated sustained monomorphic VT and extrapolated to hemodynamically poorly tolerated sustained monomorphic VT.
Reentry occurring near or within a site of prior
myocardial infarction is thought to be the most likely
mechanism of sustained monomorphic VT in
ASHD.53 Support for the latter conclusion comes
from the tachycardia response to paced stimuli (e.g.,
entrainment,54 resetting55) and to drug effects,56,57
and activation mapping during sustained VT.58-61
Conditions favoring reentry include areas of heterogeneous refractoriness that are prone to developing
unidirectional block62 and areas of slow conduction
that permit reentrant excitation of the former re-
Meissner et al Nonischemic Tachyarrhythmic Death in ASHD
gions.63 Histopathology of such loci of reentry in the
vicinity of preexisting infarcted myocardium demonstrates myocytes encased in fibrous tissue,64,65 tortuously interconnected muscle bundles, and a ragged,
irregular infarct edge.66 The resultant poor intercellular electrical coupling as well as the presence of
inexcitable scar tissue and possibly altered cellular
electrophysiological properties67,68 help set the stage
for occurrence of reentrant circuits based on functional abnormalities (nonuniform anisotropic conduction), anatomic obstacles, or both.64'69
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Nonischemic Mechanisms and Factors
Contributing to Spontaneous Onset of Sustained
Monomorphic Ventricular Tachycardia Arising
From a Myocardial Scar (Table 1)
If sustained monomorphic VT in patients with
ASHD rarely (if ever) requires an ischemic trigger,
how then does it begin? Conceptually, the "awakening" of a previously dormant reentrant VT circuit
may be no more unusual than the new appearance of
other common reentrant arrhythmias (e.g., atrioventricular nodal reentrant tachycardia) where ischemia
is not a requisite trigger.
The traditional mechanism for this phenomenon
follows the paradigm of programmed electrical stimulation and involves penetration of the reentrant
circuit by one or more spontaneous ventricular premature beats, which precipitate unidirectional block
and slow conduction, thereby permitting initiation of
reentry. Such a scenario is supported, albeit not
proven, by electrocardiographic recordings of spontaneous sustained monomorphic VT onset that demonstrate a morphology of the first premature beat
differing from that of subsequent tachycardia beats.70
An unsustained initiating salvo of premature ventricular beats can be either monomorphic or polymorphic.39'40'70 Whether single or repetitive, such initiating beats may be reentrant in origin, but could result
from abnormal automaticity or triggered activity.
A more recently proposed mechanism involves the
notion of "concealed slow conduction" within the VT
circuit occurring during each sinus beat.70'71 According to this concept, each sinus impulse invades the
putative reentrant circuit, resulting in block along
one limb and conduction that is insufficiently slow
along the other limb to allow for recovery at the site
of block. Were exit of the impulse to recovered
myocardium to occur, at least one ventricular premature depolarization would be generated; if the circuit
then permitted perpetuation of reentrant activation,
sustained monomorphic VT would ensue. This mechanism is strongly suggested by electrocardiographic
recordings of spontaneous onset of sustained VT,
which demonstrate that the "initiating" premature
beat is usually late-coupled (not "R-on-T") and often
morphologically identical to subsequent beats of the
tachycardia.70,71
The processes that might account for sudden
breakthrough and perpetuation of a concealed reentrant impulse after a prolonged quiescence (some-
907
times lasting years) are not well understood, but may
involve time-dependent changes of local tissue properties to facilitate exit of the reentering impulse. In
addition, autonomic or neurohormonal influences
may play a role. For example, elevations in serum
epinephrine levels can have significant electrophysiological effects,72 including facilitation of reentry in
patients with VT.73,74 Regional sympathetic denervation can occur in humans after myocardial infarction,75 a phenomenon that may also affect the spontaneous initiation of sustained monomorphic VT.
Antiarrhythmic drugs, especially class IC agents, can
facilitate reentry (proarrhythmic effect) by slowing
conduction within the circuit, thus allowing recovery
of excitability ahead of the advancing wave front.76
The likelihood of occurrence of unidirectional
block is generally enhanced by factors that increase
dispersion of refractoriness between components of a
reentrant VT circuit. Recent research supports the
concept that extrasystole-induced short-to-long cycle
length changes may promote such dispersion,77'78 as
manifest in electrocardiographic recordings that reveal the onset of sustained VT following a postextrasystolic sinus beat.19'40 This phenomenon could facilitate occurrence of sustained VT regardless of
whether initiated on an ongoing concealed basis or by
premature ventricular beats.
Clinical Characterization of the Arrhythmic
Substrate for Sustained Monomorphic
Ventricular Tachycardia
The arrhythmic substrate described above can
permit the reproducible induction of sustained
monomorphic VT (or, much less often, VF). Premature paced ventricular beats may elicit unidirectional
block while adding to conduction delays already
present during sinus rhythm. This phenomenon is the
basis for the clinical utility of programmed electrical
stimulation, because sustained monomorphic VT is
virtually never induced in the normal ventricle.79-81
Induction of sustained monomorphic VT in patients with ASHD rarely requires antecedent acute
ischemia. On a clinical level, this is attested to by the
nearly universal absence of chest pain or ST segment
shifts during VT induction in the electrophysiology
laboratory (unpublished observations). Findings
pointing to more subtle (e.g., biochemical) evidence
of myocardial ischemia remain controversial. For
example, Morady et al reported that net myocardial
lactate production was present in nearly 50% of
cardiac arrest survivors during induction of sustained
monomorphic VT.82 However, in another study,83
whereas nifedipine frequently eliminated metabolic
evidence of ischemia during programmed electrical
stimulation, induction of sustained monomorphic VT
was independent of the presence or absence of
ischemia. Further evidence against an acute ischemic
basis for sustained monomorphic VT comes from
observations that inducibility of this arrhythmia
failed to be eradicated in 80% of patients with
sustained VT who underwent coronary artery bypass
908
Circulation Vol 84, No 2 August 1991
surgery.84 Similarly, intravenous propranolol was
strikingly ineffective in suppressing induction of sustained VT in patients with ASHD.85
Although programmed electrical stimulation can
provide important information about the arrhythmic
substrate, signal-averaged electrocardiography can
noninvasively do likewise. This diagnostic technique
exploits the fact that fractionated electrograms often
occur over a relatively large area around the border
of infarcted myocardium,86-88 reflecting slow, inhomogeneous conduction.63,88 Late potentials (low-amplitude, high-frequency signals) appear to correlate
with delayed and fragmented ventricular activation
recorded from the epicardium and endocardium of
patients with sustained monomorphic VT.89,90 A
strong correlation in these patients has also been
observed between the presence of an abnormal signal-averaged electrocardiogram (delayed ventricular
activation) and VT inducibility by programmed electrical stimulation.91,92
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The Arrhythmic Substrate in ASHD Patients Who
Have a Cardiac Arrest
Healed infarction is present in a mean of nearly
60% (range, 44-82%) of postmortem hearts of sudden death victims with ASHD.1,93-95Among coronary
patients surviving cardiac arrest in the absence of
acute infarction, an average of 78% of patients
(range, 38-91%) have evidence of prior myocardial
scarring,32627'96-101 and one third (range, 18-56%)
have left ventricular aneurysms.26'27'96'9799 -101
Electrophysiologic derangements related to scarring
from prior infarction contribute importantly to an arrhythmic substrate in these patients. Localized conduction abnormalities or late potentials may be noninvasively detected with the signal-averaged electrocardiogram in approximately 40% of ASHD survivors of
out-of-hospital VF.102 Furthermore, ventricular tachyarrhythmias are inducible in more than three fourths
(range, 58-90%) of ASHD patients surviving cardiac
arrest unrelated to acute infarction.26-28,96,97,100,101,103,104
On the average, sustained monomorphic VT accounts
for 63% (range, 59-77%), sustained polymorphic VT
or VF accounts for approximately 18%, and unsustained VT accounts for 19% (range, 5-22%) of these
tachyarrhythmias.26-28,96,97,100,101,103,104 Induction of VF,
sustained polymorphic or unsustained VT may be indicative of an arrhythmic substrate, but the clinical
significance of these induced tachycardias remains controversial. Rates of induced sustained monomorphic
VT are faster in patients with aborted sudden death
than in those presenting with sustained (usually well
tolerated) VT.105,106 This difference may contribute to a
poorer outcome in the former group of patients.107-110
The inducibility of ventricular tachyarrhythmias
during electrophysiologic testing attests to the importance of an arrhythmic substrate in cardiac arrest
survivors with underlying ASHD and is well correlated with subsequent sudden death rate, independent of ventricular function.26 Left ventricular ejection fraction of less than 35% and persistent
inducibility of ventricular tachyarrhythmias were also
found to be independent predictors for recurrent
early and late cardiac arrest, respectively, in patients
with ASHD who had survived a prior tachyarrhythmic arrest unrelated to acute infarction.27
While the aforementioned data help to define
patients with ASHD and prior cardiac arrest who are
at higher risk for recurrences, some factors are
known that delineate a group at increased risk for
sudden tachyarrhythmic death as a first event; these
include impairment of left ventricular function and
frequent complex and repetitive ectopy.111 The prognostic value of electrophysiological testing and signal-averaged electrocardiography in these patients is
being investigated.
Prototypical Features of "Purely" Ischemic Cardiac
Arrest-Unrelated to Acute Infarction-in
Patients With ASHD
In contradistinction to the primary scar-related
setting for sudden tachyarrhythmic death in patients
with ASHD, the clinical profile corresponding to a
purely ischemic cardiac arrest is characterized by a
greater likelihood of preterminal exertional angina,103112,113 absence of a myocardial scar,103 noninducibility of sustained VT by programmed electrical stimulation,103"112'113 and favorable long-term arrest-free
outcome in survivors treated with medical or surgical
anti-ischemic therapy alone.84'103,112"13 As reflected in
large reported series, this purely ischemic profile is
present in approximately 10-15% of patients with
ASHD resuscitated from cardiac arrest unrelated to
acute infarction.26,27
Ischemia Superimposed on Scar and Other
Mechanistic Scenarios
In an area as complex as that of sudden cardiac
death, it would be an oversimplification to present
only the prototypes of nonischemic versus ischemic
arrhythmogenic processes. Therefore, it is important
to acknowledge scenarios in which multiple mechanisms may be operative.
Of particular importance is the situation of acute
ischemia superimposed on prior infarction. Several
experimental models of acute ischemia superimposed
on healing or healed myocardial infarction have
demonstrated in vitro and in vivo electrophysiological
abnormalities,114-117 many of which probably relate
to anatomic and histological derangements.67 The
arrhythmogenic potential of such experimental preparations can be significantly modulated by changes or
disturbances in the autonomic nervous system.118 It is
noteworthy that the tachyarrhythmia observed in
these models is almost exclusively VF,118 thus indirectly supporting the concept that sustained monomorphic VT is not primarily ischemic in origin.
Polymorphic VT unrelated to QT prolongation is
another arrhythmic entity that may eventuate in VF,
although this phenomenon often appears to be related to acute myocardial ischemia,34,35,119 typically in
patients who have had prior infarction.34,35 We have
Meissner et al Nonischemic Tachyarrhythmic Death in ASHD
yet to achieve a complete understanding of the
mechanistic basis of this type of polymorphic VT and
its role as a precursor to VF or even to sustained
monomorphic VT.39 Finally, in the setting of acute
ischemia, various other factors such as myocardial
hypertrophy,120 autonomic heterogeneity,121 sympathetic-parasympathetic interactions,122 and hypokalemia123 may promote the occurrence of VF.
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Conclusions and Implications
Acute ischemia, with or without progression to infarction, certainly plays an important role in causing
cardiac arrest among patients with ASHD. This relation probably accounts for the ability of anti-ischemic
therapy to reduce, albeit modestly, the incidence of
sudden death in postinfarction patients.22
However, there is impressive evidence for the
occurrence of lethal sustained ventricular tachyarrhythmias independent of an acute ischemic process in
a significant subset of coronary artery disease patients. It can be conservatively estimated that this
phenomenon accounts for at least 20-40% of sudden
tachyarrhythmic deaths unrelated to acute infarction
in patients with ASHD.26,27 These nonischemic tachyarrhythmic deaths appear to result mainly from
poorly tolerated sustained VT, often degenerating to
VF, arising from myocardial regions electrophysiologically altered by remote infarction. An additional
one third to two thirds of resuscitated victims of
cardiac arrest unassociated with acute infarction
have a scar-related arrhythmic substrate coexistent
with potentially treatable ischemic disease.26'27 The
presence of such a substrate continues to predispose
these patients to recurrent sustainedventricular tachyarrhythmias and sudden death if therapeutic measures are limited to the prevention of myocardial
ischemia.124-126
Despite significant progress, much research is
needed to better define the relative contributions of
acute ischemia versus chronic arrhythmic substrate in
the genesis of sudden cardiac death in ASHD. Further
advances in our understanding of this complex area will
require clinical studies to incorporate comprehensive
and objective assessments of both the ischemic burden
and the arrhythmic substrate, as well as hemodynamic
parameters and indexes of autonomic imbalance. By
targeting diagnostic and therapeutic approaches to
each of these components, we may be more successful
in combating the major public health problem posed by
sudden cardiac death.
Acknowledgment
The authors wish to thank Ms. Karen Beal for her
excellent secretarial assistance.
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KEY WORDS * sudden cardiac death * atherosclerotic heart
disease * arrhythmia
Nonischemic sudden tachyarrhythmic death in atherosclerotic heart disease.
M D Meissner, M Akhtar and M H Lehmann
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Circulation. 1991;84:905-912
doi: 10.1161/01.CIR.84.2.905
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