Abstract

Aims: We sought to define reperfusion-induced ventricular arrhythmias (VAs)

more precisely through simultaneous angiography, continuous ST-segment
recovery, and beat-to-beat Holter analyses in subjects with anterior ST-elevation
myocardial infarction (STEMI) undergoing primary angioplasty [percutaneous
coronary intervention (PCI)].
Methods and Results: All 157 subjects with final TIMI 3 flow had continuous 12-
lead electrocardiography with simultaneous Holter recording initiated prior to PCI
for continuous ST-segment recovery and quantitative VA analyses. Ventricular
arrhythmia bursts were detected against subject-specific background VA rates
using a statistical outlier method. For temporal correlations, timing and quality of
reperfusion were defined as first angiographic TIMI 3 flow with 50% stable ST-
segment recovery. Almost all subjects had VAs [156/157 (99%)], whereas VA
bursts during or subsequent to reperfusion occurred in 97/157 (62%). The
majority of VA bursts (72%) arose within 20 min of reperfusion (95% CI: 26.7, 72),
with onset at a median of 4 min post-reperfusion (IQR: 0-43) Bursts comprised a
median of 1290 ventricular premature complexes (VPCs) (IQR: 415-4632) and
persisted for a median of 105 min (IQR: 35-250). Most background VAs occurred
as single VPCs; bursts typically comprised runs of three or more VPCs. Subjects
with bursts had higher absolute peak ST segments and more frequent worsening
of ST elevation immediately after reperfusion.
Conclusion: Ventricular arrhythmia bursts temporally associated with TIMI 3 flow
restoration and stable ST-segment recovery (reperfusion VA bursts) can be
precisely defined in subjects with anterior STEMI and may constitute a unique
electric biosignal of myocellular response to reperfusion.

Introduction
Reperfusion-induced ventricular arrhythmias (VAs) have interested researchers
since their first description in 1935.[1] Preclinical models of reperfusion arrhythmias
explored patho- and electrophysiological mechanisms and assessed anti-
arrhythmic drug efficacy,[2] generating concern about possible initiation of
malignant arrhythmias with intracoronary thrombolytic therapy in patients with ST-
elevation myocardial infarction (STEMI).[3] Clinical experience, however, proved
reassuring.[3,4]Widespread use of intravenous thrombolytics saw reperfusion VAs
[particularly accelerated idioventricular rhythms (AIVRs)] regarded optimistically
as a non-invasive electric biomarker of successful epicardial reperfusion.[5] More
recently, it has been suggested that the presence of reperfusion-induced VAs
following primary percutaneous coronary intervention (PCI) reflects an adverse
cellular response to epicardial recanalization,[6] although this is controversial.[7,8]

The mechanistic and prognostic implications of reperfusion VAs hinge upon

precisely defining the timing and quality of epicardial reperfusion, and on
capturing arrhythmias and differentiating those specifically correlated with
reperfusion. Previous studies lack angiographic documentation of reperfusion;
many used sporadic sampling or otherwise highly selected sustained VAs,[9-
12]
while only a few smaller reports correlated angiographic recanalization and
continuous rhythm capture.[5,6,13,14] Further, VAs can result from ischaemia and
infarction as well as from reperfusion, but such distinctions have never been
reported in human subjects.

We sought to develop a more precise definition for reperfusion-induced VAs in

human subjects by using simultaneously acquired angiographic and 24 h
continuous high-fidelity electrocardiography (ECG) recordings to characterize the
timing and quality of reperfusion, correlated with quantitative analysis of all VAs
observed in a cohort of subjects with anterior STEMI treated with primary PCI

Study Population
The data used for this retrospective analysis were obtained from subjects
participating in the CAldaret ST-Elevation Myocardial Infarction (CASTEMI) study,
which has been previously reported.[15] Briefly, CASTEMI was a multicentre,
randomized, double-blind trial that evaluated adjunctive MCC-135 (caldaret) in
subjects undergoing primary PCI for acute STEMI, defined as >20 min of chest
pain with onset <6 h from presentation, with >10 mm ST-segment elevation
summed over the presenting 12-lead ECG. No drug effect was detected; thus, for
this analysis, data for all CASTEMI patients with anterior MI and final TIMI grade
3 flow after primary PCI were pooled. Data were collected by an independent
clinical research organization and subjected to quality control and validation
procedures.

Angiographic Analysis for TIMI Flow

TIMI flow grades, as determined by coronary angiography in the setting of primary
PCI, were assessed by an independent angiographic core laboratory blinded to all
data apart from coronary angiograms (Bio-Imaging Technologies, Leiden, The
Netherlands). TIMI flow grade was determined according to classifications used in
the Thrombolysis In Myocardial Infarction (TIMI) trial.[16]
Electrocardiographic Data Acquisition
All subjects received continuous 24 h digital 12-lead ECG monitoring (NEMON
180+, NorthEast Monitoring, Inc., Maynard, MA, USA) initiated prior to PCI. [17] The
NEMON system acquires and stores a standard digital 12-lead ECG every 60 s in
high-fidelity 720 Hz mode. The system simultaneously records continuous 3-lead
beat-to-beat Holter rhythm on a digital clock that supports precise temporal
correlations (Figure 1). Each research site's NEMON clock was synchronized to
the catheterization laboratory clock so that ECG changes, rhythm changes, and
changes in infarct-related artery (IRA) flow could be precisely correlated.
Continuous digital ECG and Holter data were encrypted and blinded to the clinical
team. Encrypted data were sent to the eECG core laboratory (eECG Core
Laboratory, Duke Clinical Research Institute, Durham, NC, USA) for independent,
blinded, continuous ST-segment recovery and quantitative arrhythmia analyses.

(Enlarge Image)

Figure 1.

Three-dimensional graphic output from 12-lead digital ECG monitor (NEMON 180+, NorthEast
Monitoring, Inc.), showing ST-segment level (mm) (y-axis) for all 12 leads (z-axis) with respect to
time (x-axis) in a study subject with anterior STEMI treated with primary PCI presented as abrupt
ST-segment resolution anterior myocardial wall leads V2-V6; V4 is the peak ST lead. The
substantial data gap in the graphic at the time of ST-elevation resolution was caused by a sudden
increase ('bursts') of VAs from which ST-segment levels were excluded for graphic three-
dimensional continuous ST-segment recovery visualization.

Continuous ST-segment Recovery Analysis

Continuously updated 12-lead ST-segment recovery analysis criteria and their
correlations with infarct artery patency and myocardial reperfusion have been
described in detail.[18,19] Briefly, determination of peak ST-segment deviation is
based on the lead with greatest deviation, taken from the most abnormal ECG
recorded during the monitoring period. Transitions between periods of 50%
recovery from the immediately preceding peak or ST-segment re-elevation of
>150 V over preceding recovered ST-segment levels are continuously updated
until stable 50% recovery, with stable defined as sustained for at least 4 h
(Figure 1).

Quantitative Rhythm Analysis

Quantitative beat-to-beat rhythm analysis was performed on all digital 3-lead
Holter recordings using Holter 5 software (NorthEast Monitoring, Inc.) with full
disclosure visualization, waveform superimposition, and digitally sorted ECG
morphology 'bins'. All automatically assigned waveform labels were manually
verified for every cardiac cycle from each subject, and VAs were discriminated
from other sinus, supraventricular, aberrant, or pacemaker rhythms. Ventricular
premature complexes (VPCs) were defined as premature beats with QRS-
complex morphology that differed from baseline and had a width of at least 120
ms without an associated preceding P wave.[20] A fusion beat (normal beat
morphology fused with VPC morphology) was also considered a VPC. VAs were
further categorized as isolated, couplets, or runs of three or more consecutive
VPCs [including non-sustained and sustained AIVRs and ventricular tachycardias
(VTs)], and total VPCs (sum of all isolated VPCs plus VPCs in couplets or runs).
To generate quantitative VA rates over 24 h, total VPC counts were bundled into
5 min blocks for temporal correlation with stable ST-segment recovery and
angiographic observations. Episodes of ventricular fibrillation in these recordings
were also verified and documented. Ventricular fibrillation was defined as irregular
undulations of varying shape and amplitude on ECG without discrete QRS or T
waves, followed by visible direct-current cardioversion on Holter monitoring.[21]

Terminology and Definitions

Ventricular Arrhythmia Bursts. Quantitative VA rates over the course of Holter
recordings were used to characterize subject-specific background VA density.
Ventricular arrhythmia bursts above this background were detected using an
automated statistical outlier method, described in detail below. Once quantitative
beat-to-beat Holter analysis for VAs was completed, subjects could be
dichotomously classified as having or not having VA bursts. In all patients with VA
bursts, timing (by onset) after reperfusion, duration, quantity, and density (per 5
min block) of VPCs, and ventricular rhythmic content (isolated VPCs, VPCs in
couplets, or runs of three or more consecutive VPCs) of the bursts could be
defined.

Reperfusion. Anatomic reperfusion was defined angiographically as the time of

first documented re-establishment of TIMI 3 flow in the IRA, based on data
recorded by the site. Physiological reperfusion was evaluated with continuous ST-
segment recovery analysis as a non-invasive method not only for confirming
angiographic IRA patency but also as a reflection of the reversal of ischaemia in
the infarct zone. Physiological reperfusion was defined by stable ST-segment
recovery, with timing defined as the transition from the peak ST-segment level
immediately preceding 50% stable ST-segment recovery. We considered first
documentation of TIMI 3 flow restoration in the IRA (anatomic reperfusion)
associated with stable ST-segment recovery (physiological reperfusion) as the
measure of timing ('zero time') and quality of reperfusion for temporal correlations
with quantitative analysis of VAs (VA bursts).

Statistical Methods
Outlier Detection Methodology. This method uses all VA counts obtained over
the course of the Holter recording for a patient and automatically separates
outliers (VA burst counts), if any, from background VA counts. Background counts
are considered to arise from a Poisson distribution with mean . A VA count is
considered an outlier when it is statistically significantly large enough that it likely
does not arise from background VA activity. To establish which VA counts are
significantly large, we considered type I error =0.01 with a conservative
Bonferroni adjustment for multiplicity of comparisons by dividing by 288 [the
number of 5 min intervals in a 24 h Holter recording (288=24*60/5)]. Thus, a VA
count above cutoff C() equal to the (1 - /288) quantile of the background count
distribution with mean is considered an outlier. This method is based on the
forward search and is an iterative process, because it is unknown a priori which
VA counts form the background VA activity.[22] To form the initial background
collection of VA counts, we chose a low mean =1 corresponding to a cutoff
equal to seven VAs/5 min interval. Ventricular arrhythmia counts below this initial
cutoff level were considered as initial 'background,' which was required to contain
at least 10% of the recorded VA counts; rarely, few next-smallest VA counts >7
were added to the initial 'background' collection to satisfy this requirement. Based
on the current set of background counts, a new background average was
computed and the next (higher) cutoff point C() was determined as before,
based on this new higher mean . If any VA count currently outside the
background collection was below the new cutoff level, the smallest such count
was added to the existing background collection and the next average with the
next cutoff C() was computed. The iteration was repeated until the background
could not be enlarged, either because all recorded VA counts were already in the
background (i.e. no outliers, and thus, no bursts detected), or VA counts not
currently in the background were all above the current cutoff C() and thus were
identified as outliers forming the initial VA bursts. For patients with initial bursts, a
statistical smoothing of counts over the duration of Holter recording was
performed, and single-burst counts or groups of time-contiguous burst counts with
maximum smoothed value below the last cutoff C() were eliminated. The
resulting collection of burst counts, if any remained, formed the subject's final VA
bursts.

Other Statistical Analyses. Univariable comparisons of patient characteristics

between subjects with reperfusion bursts vs. those without were performed with
the 2-sample Wilcoxon rank sum test for continuous variables and the Fisher
exact test for dichotomous variables. A P value <0.05 was considered statistically
significant.Continue Reading

Ventricular Arrhythmia Bursts and Reperfusion

Ventricular arrhythmias were present on Holter in 156/157 (99.3%) subjects; VA
bursts concomitant with or subsequent to reperfusion occurred in 97/157 (62%) of
the subjects. A study subject with VA bursts concomitant with angiographic TIMI 3
flow restoration (anatomic reperfusion) associated with stable ST recovery
(physiological reperfusion) is visually presented in Figure 2. The distribution of
time intervals between onset of reperfusion (defined as first angiographic TIMI 3
flow with 50% stable ST-segment recovery) and VA bursts is summarized in
Figure 3. Of all VA bursts, 72% occurred within 20 min of onset of reperfusion
(95% CI: 26.7, 72).

(Enlarge Image)

Figure 2.

Concomitantly acquired (A) coronary angiography assessments of pre- and post-primary PCI
TIMI flow grades in a study subject with a total occlusion in the proximal left anterior descending
(LAD) artery; (B) continuous digital 12-lead ECG monitoring for ST-segment recovery analysis;
and (C) complete beat-to-beat Holter monitoring for quantitative rhythm analysis to identify VA
bursts in excess of established patient-specific background rates of VAs using statistical outlier
detection methodology. Cx, circumflex artery.

(Enlarge Image)

Figure 3.

Distribution of time interval between onset of reperfusion to first VA burst in all subjects with VA
bursts.
Characteristics of Reperfusion Ventricular Arrhythmia Bursts
The characteristics of VA bursts during or subsequent to reperfusion (reperfusion
VA bursts) are summarized in Table 1 . The median time from onset of
reperfusion to first VA burst was 4 min (IQR: 0-43.3). VA bursts comprised a
median total of 1290 VPCs (with a median of 97 VPCs per 5 min interval) and
persisted for a total median duration of 105 min. Runs of three or more VPCs
appeared to be more common in VA bursts than were isolated VPCs or couplets;
in background VAs, however, isolated VPCs were more common (Figure 4).

(Enlarge Image)

Figure 4.

Contribution of isolated VPCs (yellow bars), VPC couplets (blue bars), or runs of three or more
VPCs (red bars) to all background VAs (lower grey bars) or VA bursts (upper grey bars).

Correlation With Key Subject Characteristics

Demographic and clinical descriptors for subjects with or without VA bursts during
or subsequent to reperfusion are listed in Table 2 . Characteristics were generally
well-matched between the groups. Subjects with bursts had significantly higher
absolute peak ST-segment levels (P<0.001) and showed possible trends towards
earlier clinical presentations, with shorter time from onset of chest pain to first
angiographic evidence of blood flow in the IRA (P=0.05).

Timing of Anatomic and Physiological Reperfusion

Temporal association between concomitantly acquired anatomic evidence of
reperfusion with angiography and physiological evidence of reperfusion with
continuous ST recovery monitoring is summarized for all subjects in Figure 5A. As
can be seen in Figure 5B, the curve for subjects with reperfusion bursts is right-
shifted relative to those without, indicating that subjects with bursts more
frequently had further ST-segment deviation after angiographic reperfusion than
those without bursts (P=0.064).
 (Enlarge Image)

Figure 5.

(A) Temporal correlation between concomitantly acquired anatomic onset of reperfusion (defined
as angiographic documentation of re-establishment of blood flow in the IRA), and physiological
onset of reperfusion (defined as time of transition from peak ST level immediately preceding
50% stable ST-segment recovery). (B) Delay from time of onset of anatomic reperfusion,
defined as angiographic documentation of re-establishment of flow in the IRA, to onset of
physiological reperfusion, defined as time of transition from peak ST level immediately preceding
50% stable ST-segment recovery in subjects with reperfusion VA bursts vs. subjects without
bursts.
Discussion
Our analysis shows that with simultaneous angiographic TIMI flow grading,
continuous high-fidelity 12-lead ST-segment recovery, and beat-to-beat Holter
rhythm analysis, reperfusion-induced VAs can be defined more precisely in
subjects with anterior STEMI. Our data suggest that VA bursts in excess of
subject-specific background VA rates are temporally associated with angiographic
TIMI 3 flow restoration (anatomic reperfusion) and stable ST-segment recovery
(physiological reperfusion). We therefore consider reperfusion-induced VAs in
human subjects to be defined by the presence of these reperfusion VA bursts.
This definition provides a uniquely quantitative characterization of VAs specifically
related to both epicardial recanalization and myocardial reperfusion. Unlike
previous definitions, reperfusion VA bursts are statistically defined as outliers
relative to a quantified, patient-specific background VA density and can thus
include any of the many ventricular rhythms, from isolated VPCs to sustained fast
VTs, that may comprise reperfusion arrhythmias. This definition may also be
especially relevant to modern primary PCI therapy for STEMI, as both
angiographic and ECG monitoring signals are technologies already routinely used
in managing these patients.

From the earliest days of thrombolytics to the modern era of primary PCI for
STEMI, reperfusion arrhythmias have sustained a wide range of mechanistic and
prognostic interests.[3,5,6,8-14,23-29] A major barrier to advancing understanding in this
area, or even to achieving a meaningful synthesis of available reports, is the
present heterogeneity of definitions used for reperfusion as well as for reporting
and timing of VAs, or the correlation of the two. Observational reports of
arrhythmias in large cohorts receiving thrombolytics almost certainly include
arrhythmias from patients who never reperfuse, as recanalization rates with
thrombolytics exceeding 75% of the patients treated have never been reported. [30-
35] In addition, sporadic capture of arrhythmias in some reports is likely subject to

observational bias,[35,36] whereas other reports, which include only sustained

arrhythmias requiring cardioversion/defibrillation, will by definition exclude other
potentially important, albeit less life-threatening, electrophysiological signals
directly related to reperfusion.[7,37]

Our Holter data show that virtually all subjects experienced VAs in the course of
infarction; however, this was not necessarily related to reperfusion per se. This is
consistent with the report of Miller et al.,[13]who analysed Holter data in patients
with simultaneous angiographic observations associated with delivery of
intracoronary thrombolytics, and it was found that quantification of VAs, both
overall and by specific category, could not distinguish patients who reperfused
from those who did not. Ventricular arrhythmia bursts may provide a conceptual
framework for identifying unique events useful for specifically characterizing
reperfusion-related electrophysiological signals above the background activity
level.

The temporal proximity of such bursts to reperfusion events, whether defined

anatomically or physiologically, supports the hypothesis that such sudden outlier
rates of ventricular ectopic activity, identified through simultaneously acquired
continuous ECG and angiographic data (obtained by protocol from all CASTEMI
subjects) can be used to better define reperfusion VAs.

We should emphasize that our goal in defining reperfusion VA bursts is not to

discriminate between successful and failed reperfusion; rather, in an era in which
primary PCI produces TIMI 3 flow in more than 80% of the patients treated, our
objective is to extend understanding of the electromechanical events that
constitute the cellular response to TIMI 3 reperfusion. Thus, as in the primary
analysis of the CASTEMI study, we have examined only subjects in whom final
TIMI 3 flow was achieved.

It is generally understood that cohorts characterized by epicardial recanalization

and TIMI 3 flow are not actually homogeneous.[38] Populations with TIMI 3 flow
can be meaningfully stratified by both microvascular 'blush' and ST-segment
recovery, reflecting microvascular distribution of contrast and physiological
cellular response to reperfusion, respectively.[39-41] Well-defined reperfusion VA
bursts may provide an additional 'electric biomarker' reflecting cellular signals that
can be used to characterize quality of reperfusion. Engelen et al.[6] studied acute-
phase Holter data in anterior STEMI patients with successful TIMI 3 reperfusion
and ST-segment recovery who were followed up for 6 months with serial
echocardiographic measurement of infarct zone contractility and found that
quantitative Holter characterization of VA density was highly predictive of failure
to recover LV function.

Although our objective in performing this analysis of subjects with anterior STEMI
from the CASTEMI cohort was not to establish mechanistic or clinical outcome
correlations to reperfusion VA bursts, nonetheless, the observed correlation of
such bursts with higher ST peak deviation and with the 'right-shift' of the time
delay from anatomic to physiological reperfusion peak is noteworthy. Worsening
of ST-segment elevation following angiographic reperfusion has been previously
reported as a marker of adverse cellular response to reperfusion. [24,25,42] The
greater tendency for patients with reperfusion VA bursts to show delayed peaking
of ST injury current following angiographic reperfusion compared with patients
without such bursts suggests a mechanistic effect consonant with the findings of
Engelen et al.; i.e. that reperfusion followed by additional ST-segment elevation
and reperfusion VA bursts may indicate patients with cytotoxic reperfusion
responses who are less likely to recover mechanical function of the infarct zone.

Limitations
Our study has a number of limitations, chief among which is the fact that our
analysis is intended to provide observational details and a novel definition for
reperfusion VA bursts. As such, our findings, although suggestive, cannot fully
elucidate the mechanistic or prognostic significance of the observed
phenomenon. Further, our study is retrospective, albeit prospectively planned
across blinded core laboratory and data coordinating centre angiographic, ST-
segment recovery, Holter arrhythmia, and clinical descriptor datasets. Finally, our
findings are drawn from a modest cohort of subjects with anterior STEMI
undergoing primary PCI. Important subgroup analyses are limited by cohort size,
logistical consideration, and by the limitations inherent in the data collected for the
study that formed the basis of our retrospective analysis; thus, the generalizability
of our observations to non-anterior MIs or to patients treated with thrombolytic
therapy and other medication must be regarded with caution.

Mechanistic questions remain as well. Although heart rate variability data were
not available from the eECG Core laboratory in these studies, the relationship
between heart rate behaviour and reperfusion VA bursts is interesting for future
research. Even with continuous ECG monitoring and early angiography
associated with primary PCI in the CASTEMI study, it is conceivable that some
patients had transient or 'cyclic' changes in IRA patency prior to enrollment and
monitoring. Whether or not such events might be protective, or might
'precondition' the infarct zone substrate, cannot be determined from our
data.Continue Reading

Conclusions
In the current era of primary PCI for STEMI characterized by final TIMI 3 flow
success rates of >80%, short- and long-term implications of reperfusion VAs
cannot be imputed from existing literature, primarily due to limitations in existing
definitions. By combining concomitant ECG monitoring and angiographic
evidence of epicardial recanalization in conjunction with a patient-specific
statistical definition of VA bursts outside of background ventricular ectopy rates,
we have developed a novel definition of reperfusion arrhythmias that is more
quantitative, comprehensive, and specific than any hitherto described. Further
testing in larger patient cohorts is necessary in order to assess the degree to
which this definition enables further insight into the mechanistic and prognostic
implications of VAs in the modern era of STEMI therapy.

The Scientific World Journal

Volume 2013 (2013), Article ID 160380, 7 pages
http://dx.doi.org/10.1155/2013/160380
Clinical Study

Arrhythmias following Revascularization Procedures in the

Course of Acute Myocardial Infarction: Are They Indicators
of Reperfusion or Ongoing Ischemia?
Ersan Tatli,1,2 Gray Alicik,1 Ali Buturak,3 Mustafa Yilmaztepe,1 and Meryem Aktoz1
1Department of Cardiology, Trakya University Hospital, Edirne, Turkey
2Department of Cardiology, Ada Tp Hospital, Sakarya, Turkey
3Cardiology Department, Acibadem University School of Medicine, Istanbul,

Turkey
Received 17 December 2012; Accepted 16 January 2013
Academic Editors: C. Spaulding and X. L. Tang
Copyright 2013 Ersan Tatli et al. This is an open access article distributed under
the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is
properly cited.

Abstract
Objective. The most important step in the treatment of ST elevation myocardial
infarction is to sustain myocardial blood supply as soon as possible. The two main
treatment methods used today to provide myocardial reperfusion are
thrombolytic therapy and percutaneous coronary intervention. In our study,
reperfusion arrhythmias were investigated as if they are indicators of coronary
artery patency or ongoing ischemia after revascularization. Methods. 151 patients
with a diagnosis of acute ST elevation myocardial infarction were investigated. 54
patients underwent primary percutaneous coronary intervention and 97 patients
were treated with thrombolytic therapy. The frequency of reperfusion arrythmias
following revascularization procedures in the first 48 hours after admission was
examined. The relation between reperfusion arrhythmias, ST segment regression,
coronary artery patency, and infarct related artery documented by angiography
were analyzed. Results. There was no statistically significant difference between
the two groups in the frequency of reperfusion arrhythmias (). Although
angiographic vessel patency was higher in patients undergoing percutaneous
coronary intervention, there was no significant difference between the patency
rates of each group with and without reperfusion arrythmias. Conclusion. Our
study suggests that recorded arrhythmias following different revascularization
procedures in acute ST elevation myocardial infarction may not always indicate
vessel patency and reperfusion. Ongoing vascular occlusion and ischemia may lead
to various arrhythmias which may not be distinguished from reperfusion
arrhythmias.

1. Introduction
The term, reperfusion arrhythmias, was used in the first studies of thrombolytic
therapy guided revascularization in acute myocardial infarction. To confirm the
presence of vessel patency and successful reperfusion of the myocardiumfollowing
thrombolytic therapy, electrocardiographic data in addition to clinical and
laboratory measures are used by the clinicians. These include normalization or
more than 50% regression of ST elevation, T-wave inversion, and any other
arrythmia observed in electrocardiography. The most frequently observed
arrhytmias that are defined as reperfusion arrhytmias are ventricular premature
contractions, sustained or nonsustained episodes of ventricular tachycardia,
accelerated idioventricular rhythm, atrial fibrillation, and ventricular fibrillation.
These arrhythmias are thought to be indicators of successful reperfusion.
However, in some studies it was mentioned that these arrhytmias may be due to
ongoing myocardial cell damage and ischemia [1].
In acute myocardial infarction, ventricular tachycardia (VT) and ventricular
fibrillation (VF) may occur due to either complete occlusion or reperfusion.
Rhythm disorders associated with coronary occlusion are defined as ischemic
arrhytmias, whereas arrhythmias occurring as the result of increased myocardial
perfusion are called reperfusion arrhythmias [2]. Accelerated idioventricular
rhythm may be a marker of early reperfusion and continuing arterial patency. In a
previous study, the presence of accelerated idioventricular rhytm combined with
normalization of ST segments was demonstrated to indicate successful reperfusion
in patients treated with thrombolytics and there was no requirement for
emergency coronary angiography and rescue percutaneous coronary intervention
(PCI) in this group of patients [3].
The aim of our study is to observe the arrhythmias after application of different
revascularization treatment modalities (thrombolysis or primary) and investigate
whether these are indicators of arterial patency or ischemia due to ongoing
vascular occlusion by reviewing the arrhythmias recorded in the first 48 hours. In
addition, reperfusion arrhythmias observed after thrombolysis and percutaneous
revascularization were compared in this study.

2. Material and Methods

2.1. Patient Groups and Clinical Features
The data of patients treated by either thrombolysis or percutaneous coronary
intervention with a diagnosis of acute ST elevation myocardial infarction followed
in our clinic between the years 2008 and 2010 were evaluated retrospectively in
this study. Patients with non-ST elevation myocardial infarction, unstable angina
pectoris, cardiac conduction system disorders, permanent pacemakers,
mechanical ventilation support, cardiogenic shock, and survivors of cardiac arrest
due to acute myocardial infarction were excluded from the study group in addition
to the individuals to whom rescue PCI was performed following the first 24 hours
of thrombolytic therapy. The diagnosis of STEMI was based on recently published
criteria of the European guidelines [4]. Time of diagnosis, patient age, gender,
height, weight, hypertension, diabetes mellitus, history of previous MI, smoking,
ECG, lipid profile, urea, creatinine, blood glucose, troponin I, and potassium values
were recorded. The patients blood samples were analyzed by Siemens ADVIA
1800 autoanalyzer (Siemens Healthcare Diagnostics, Tarrytown NY). Same brand
of kits were used for each patient.
Thrombolytic therapy was applied to 97 patients within 12 hours after the onset
of chest pain. Coronary angiography was performed at a median of 112 minutes
after the initiation of thrombolytic therapy. We did not give thrombolytic therapy
to patients after 12 hours after the onset of symptoms because no mortality benefit
has been demonstrated.
2.2. Electrocardiographic and Echocardiographic Data
GEM ECG-9020 Cardiofax Nihon Kohden (Tokyo, Japan) system was used to obtain
a twelve lead electrocardiography. Infarct localizations were classified according
to the place of ST segment elevations in ECG derivations as anterior, inferior, right
ventricular inferior, and lateral MI. After the treatment, ST segment regression
ratio was defined in derivations with ST segment elevation. ST segment regression
ratio was classified as over 50% and less than 50%. Echocardiographic
examination was performed by Vivid 7 (General Electric Medical Systems,
Milwaukee, WI, USA).
2.3. Cardiac Catheterization, Coronary Intervention, and Assessment of
Coronary Flow
Coronary angiography and percutaneous coronary interventions were performed
with Philips Integris H 3000 (Eindhoven, The Netherlands). Coronary angiography
was performed via the femoral artery; 4000 units of heparin and an intracoronary
bolus of 100g glyceryl trinitrate were given to all patients before angiography.
Infarct related arteries were classified as LAD (left anterior descending artery), CX
(circumflexartery), proximal RCA (right coronary artery), and distal RCA. After the
diagnostic angiography, PCI was performed in the usual manner with balloon
catheters with or without stenting. This was performed after the administration of
additional heparin to maintain the activated clotting time at >300 seconds. After
the PCI, heparin was continuously infused to the patients for 48 hours and was
adjusted to maintain the activated clotting time at >180 seconds. The two groups
received acetyl salicylic acid and clopidogrel. Patients received conventional drug
therapy based on individual needs. Beta-blocker therapy (metoprolol) was
initiated to patients without contraindications in the early course of acute
myocardial infarction in the two groups. After the treatment the patency of the
infarct related artery was determined by evaluating TIMI flow ratesof coronary
angiography images [5].
2.4. ECG Monitorization and Definitions
Arrhythmias, recorded in the first 48 hours by Nihon Kohden Brand ECG
monitoring system (BSM-5105 Tokyo-Japan), were evaluated. Whether the
reperfusion arrhythmias have occurred or not was determined by examining each
patients records individually. Frequent Ventricular Premature Beat (VPB) was
defined as more than 5 VPBs per minute. Accelerated Idioventricular Rhythm
(AIVR) was defined as a ventricular rhythm with a rate of 60 to 125 beats/minute
and frequent episodes of slow ventricular tachycardia. Nonsustained ventricular
tachycardia (VT) was defined as 3 or more consecutive ventricular ectopic beats at
a rate >100 beats/minute and lasting <30 seconds. Sustained VT was defined as
the last longer than 30 seconds or cause hemodynamic compromise that requires
intervention. Ventricular fibrillation was recognized by the presence of irregular
ondulations of varying contour and amplitude. The conduction blocks at the
atrioventricular (AV) node or intraventricular conduction systems were assessed.
2.5. Statistical Analysis
NCSS (Number Cruncher Statistical System) Statistical Software 2007 & PASS 2008
(Utah, USA) program was used for statistical analysis (NCSS 2007 serial number:
N7H5-J8E5-D4G2-H5L6-W2R7). Descriptive statistical methods were used for
evaluating data from the study groups (mean, standard deviation). For the
comparison of two groups, data showing normal distribution were compared by
students t-test and data not displaying normal distribution were compared by
Mann-Whitney U-test. For the comparison of qualitative data, chi-square test and
Fishers exact chi-square tests were used. was considered statistically significant.

3. Results
151 patients with STEMI were included in the study. To 54 (35.8%) cases primary
PCI was performed, and 97 (64.2%) cases were given thrombolytic drug therapy.
The age of patients ranged between 26 and 88 years. Mean age was years. 118
patients (78.1%) were male and 33 (21.9%) were female (Table 1). There was not
any statistically significant difference between primary PCI and thrombolytic
treatment groups in terms of age, height, weight, and body mass index. And also
mean levels of demographic data were not significantly different between the men
and women (). There was no statistically significant difference between the two
groups in hypertension, diabetes mellitus, smoking, history of coronary artery
disease, preinfarction angina, and previous history of MI (). Systolic blood
pressures, inhospital cardiovascular events, ejection fractions, onset of chest pain,
and time to implementation of treatment (pain-reperfusion period) did not show
a significant difference between the two groups (). The time from onset of pain to
treatment time in the primary PCI and thrombolytic groups was,
respectively, hours and hours (). Tables 1 and 2 show demographic and clinical
characteristics of both groups.

Table 1: Demographic and clinical characteristics of patients.

Table 2: Laboratory measures of patients.

Statistically significant differences were not found in terms of the incidence of
reperfusion arrhythmias between two treatment modalities (). In the primary PCI
group, 45 patients (83.3%) displayed reperfusion, while in 86 patients (88.7%) of
the trombolytic group, reperfusion arrhytmias were observed (). When we
evaluate the incidence of reperfusion arrhytmias separately, the rate of AIVR in the
thrombolytic group was significantly higher than the PCI group: 71 patients
(73.2%) and 27 patients (50%), respectively, with a (Table 3). The rate of atrial
fibrillation was significantly higher in thrombolytic treatment group compared to
primary PCI group: 26 patients (26.8%) and 7 patients (13%), respectively, (). No
statistically significant difference between the two groups in terms of sustained
ventricular tachycardia, nonsustained ventricular tachycardia, ventricular
fibrillation, frequent ventricular premature beats, and atrioventricular block was
found (). ST segment regression more than 50% after revascularization was found
significantly higher in primary PCI group compared with thrombolytic therapy
group (Table 4). TIMI flow was assessed in both groups and no difference was
found according to the type of treatment. The association of ST segment regression
and reperfusion arrythmias was compared between the two groups. A statistically
significant relationship was found in the thrombolytic therapy group () compared
with the primary PCI group (). The patients with more than 50% ST segment
regression who received thrombolytic therapy exhibited significantly higher rates
of reperfusion arrhythmias (Table 5). In addition, TIMI flow rates and reperfusion
arrhythmias were examined (Table 6). There was no relationship between TIMI
flow and reperfusion arrhythmias in primary PCI group (). On the contrary,
reperfusion arrhythmia frequency was significantly lower for the patients with
TIMI 1 flow in thrombolytic threapy group (). There was no statistically significant
relationship between TIMI 0, TIMI 2, TIMI 3 flow rates and reperfusion
arrhythmias (). Interestingly, the frequency of reperfusion arrhythmias was higher
in the patients whose infarct related artery was left anterior descending artery
(LAD) in primary PCI group (, Table 7).
Table 3: Comparison of the frequency of various reperfusion arrythmias between
primary percutaneous coronary intervention and thrombolytic treatment groups
of patients.

Table 4: Comparison of electrocardiographic ST segment regression, TIMI flow

grades, and the presence of collateral circulation between two treatment groups.

Table 5: Association between the occurrence of reperfusion arrythmias and ST

segment regression in primary PCI and thrombolytic treatment groups.

Table 6: The relationship between presence of reperfusion arrythmias and TIMI

flow grades in different treatment groups.

Table 7: Infarct related artery and presence of reperfusion arrythmias in both

treatment groups.

4. Discussion
In our study, the incidence of reperfusion arrhythmias detected in the first 48
hours did not differ significantly between the two treatment groups. 83.3% of
patients in primary PCI group and 88.7% of the thrombolytic group, had at least
one reperfusion arrhythmia. When the rates of different arrhythmia findings were
examined separately, the ratio of sustained VT, nonsustained VT, VF, frequently
VEA, and AV block was similar between the two groups. However AIVR and AF
ratio were higher in the thrombolytic group.
The incidence of the development of AF in acute MI is about 510% and it is known
that AF development in acute MI is usually due to impaired left ventricular function
or poor reperfusion [5]. Celik et al. reported that in patients who underwent PTCA,
p dispersion was reduced, showing that successful reperfusion may reduce the
likelihood of development of AF [6]. On the contrary, the incidence of AF could
increase in patients with poor reperfusion. The left ventricular functions in both
groups of patients were normal in this study. Therefore, the cause of AF was
thought to be residuel ischemia or poor reperfusion instead of impaired left
ventricular functions. Unlike thrombolytic group, we observed significantly lower
rates of AF in PTCA group. Six et al. investigated the predictive value of ventricular
arryhtmias as an indicator of angiographic arterial patency after thrombolytic
therapy. Among these, AIVR was the most sensitive and specific arrythmia in cases
of successful reperfusion [7]. In contrast, Bonnemeier et al. demonstrated that only
19 of 125 patients who were successfully treated with primary PCI exhibited AIVR
which indicated a poor relationship between TIMI 2 or 3 flow and reperfusion
arrhythmia and declared that AIVR may not be used as a reperfusion criteria [8].
Terkelsen et al. mentioned that although AIVR does not meet criteria for
reperfusion, it may be an indicator of more extensive myocardial damage and
delayed microvascular reperfusion in a study of 503 patients who were treated by
primary PTCA [9]. In another study, Gibson et al. [10] exhibited the development
of VT and VF in 3491 patients with STEMI after thrombolytic therapy, and reported
that cases who developed VT or VF had TIMI 02 flow.
The relationship between arterial patency rates demonstrated via coronary
angiography (TIMI flow grades). The analysis of TIMI flows allows better
understanding of the relationship between arterial patency rates and reperfusion
arryhtmias.
In the primary PCI group, TIMI 3 patency was obtained in 83.3% of cases. There
was no statistically significant relation between the presence of reperfusion
arryhtmia and TIMI flow grades in primary PCI group although reperfusion
arryhtmia was observed with a ratio of 82.2% in these patients with TIMI 3 flow.
42.3% and 38.1% of the patients who had received thrombolytic therapy had TIMI
3 and TIMI 2 flow, respectively. The incidence of reperfusion arryhthmia observed
in the group of patients with TIMI 1 flow was significantly lower in thrombolytic
therapy arm. On the other hand, there was no relationship between the presence
of reperfusion arryhthmia and higher TIMI flow grades (TIMI 2 and TIMI 3) in the
same group.
Wehrens et al. [11] compared the electrocardiographic changes following
reperfusion in AMI patients to whom thrombolytic therapy, primary PTCA, or
rescue PTCA were performed. The researchers demonstrated that
electrocardiographic changes as a noninvasive tool associated with reperfusion
did not provide sufficient information to clinicians to distinguish TIMI 2 and 3
flows from each other after thrombolytic therapy. This result is compatible with
our results. Gressin et al., investigated the relationship between ventricular
arrhytmias and arterial patency by recording ventricular arrhytmias in the first 24
hours and examining the angiographic views in a group of patients with acute
myocardial infarction treated with thrombolytic therapy [12]. On the basis of
ventricular arrhythmias detected; arryhtmia rates, in patients with TIMI 2 and 3
flow grades and in those without arterial patency (TIMI 0 or 1 flow grades), was
found to be similar. These results suggest that some arrythmias may be due to
different reasons such as ongoing ischemia or metabolic abnormalities. However,
in another study, rates of sustained VT or AIVR occurring in the first 6 hours were
found significantly higher in patients with arterial patency and these arrhytmias
were defined as noninvasive indicators of early coronary reperfusion [13]. But it
must be emphasized that the results and assessment of this study were limited to
 the detection of arrythmias in the first 6 hours, which is different from previous
studies.
Engelen et al. demonstrated that at least 97% of patients developed one ventricular
reperfusion arrhythmia in a study group of 62 patients with acute anterior
myocardial infarction who underwent primary PCI. Nonsustained VT, AIVR, and
frequent VEA were the most frequently arrhythmias (similar to our findings) and
ventricular arrhytmias were correlated with reduced and worsening left
ventricular functions after the acute phase of myocardial infarction among this
group of patients treated via primary PCI and concluded that reperfusion
arrhythmias are noninvasive indicators of myocardial cell damage [14].
4.1. Study Limitations
The main limitation of the present study resides in its retrospective design. Larger
scale studies may provide additional information for clinical applications.

5. Conclusion
In conclusion, reperfusion arrhytmia frequency is not significantly different
between patients treated by primary PCI and thrombolytics although PCI is known
to provide better arterial patency. AIVR, which is so far known as a reperfusion
arrhytmia, may indicate myocardial damage and ongoing ischemia rather than
vascular patency. Further larger prospective studies are required to validate this
hypothesis.

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Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last
updated: Wed Oct 05 00:00:00 GMT 2005 (More)

INTRODUCTION Life-threatening ventricular arrhythmias ventricular tachycardia

(VT) and ventricular fibrillation (VF) are infrequent but serious complications of an
acute myocardial infarction (MI). The largest experience on the incidence of VT and VF
during an acute ST elevation MI comes from the GUSTO-1 trial of 40,895 patients who
were treated with thrombolytic therapy [1]. The overall incidence of sustained VT or VF
was 10.2 percent: 3.5 percent developed VT, 4.1 percent VF, and 2.7 percent both VT
and VF. Approximately 80 to 85 percent of these arrhythmias occurred in the first 48
hours.

Sustained ventricular arrhythmias are less common in patients with an acute non-ST
elevation MI or unstable angina, as illustrated in a pooled analysis of four major trials of
over 25,000 such patients [2]. The overall incidence of VT or VF was 2.1 percent, lower
than the 10.2 percent incidence in GUSTO-1 in STEMI [3]. VT occurred in 0.8 percent, VF
in 1 percent, and VT and VF in 0.3 percent. The median time to arrhythmia was 78
hours.

Sustained VT and VF in the setting of myocardial infarction result from the complex
interaction of multiple factors, including myocardial ischemia, necrosis, reperfusion,
healing, and scar formation. These events produce the mechanisms that initiate
arrhythmias and the substrate for arrhythmia perpetuation. Arrhythmia pathogenesis
varies at different stages in this process. For ventricular arrhythmias occurring more than
48 to 72 hours after an acute myocardial infarction (MI), scar formation is of primary
importance.

Ventricular arrhythmias during acute MI are typically classified based upon their time of
onset. This scheme is useful clinically because VT and VF occurring early (24 to 48
hours) have been thought to be epiphenomena of the MI and do not require long-term
therapy because they are not associated with a worse prognosis after hospital discharge.
In contrast, VT or VF occurring later is generally thought to reflect the development of
arrhythmic substrate, and require chronic therapy because of an increased risk of sudden
cardiac death. (See "Clinical features and treatment of ventricular arrhythmias during
acute myocardial infarction".)

This topic will review the mechanisms of arrhythmogenesis during acute MI, with
particular attention to serious ventricular arrhythmias occurring in the first 48 to 72
hours. The clinical features and management of these arrhythmias are discussed
separately. (See "Clinical features and treatment of ventricular arrhythmias during acute
myocardial infarction".)

MECHANISMS OF ARRHYTHMIA FORMATION Life-threatening periinfarction

ventricular arrhythmias result from an interplay among three basic components:

The damaged myocardium, which produces a substrate capable of developing

reentrant circuits. Complex ventricular arrhythmias are associated with larger
infarctions and with early left ventricular dilatation and remodeling, perhaps due
to ventricular stretching and electromechanical feedback [4,5].
Arrhythmia triggers, including spontaneous ventricular arrhythmias, variations in
cycle length, and heart rate.
 Modulating factors, such as electrolyte imbalance (eg, hypokalemia), dysfunction
of the autonomic nervous system (eg, increased sympathetic activity), continued
ischemia, impaired left ventricular function, and elevated plasma levels of free
fatty acids [6]. These factors may act on both substrate and triggers to induce
arrhythmias.

The proper milieu for the development and maintenance of ventricular arrhythmias is
ultimately based upon the rapid and profound effects that acute myocardial ischemia has
on the electrophysiologic characteristics of the myocyte. Changes in the resting
membrane potential and in the inward and outward ionic fluxes during the action
potential lead to alterations in conduction, refractoriness, and automaticity of cardiac
muscle cells, all of which contribute to the occurrence of ventricular arrhythmias [7].

An increase in QT dispersion on the electrocardiogram, which reflects differences in

ventricular repolarization times between normal myocardium and myocardium within the
periinfarction ischemic zone, may predict an increase in risk for VF early in the course of
a myocardial infarction [8]. Early coronary reperfusion after an acute myocardial
infarction reduces QT dispersion which may diminish electrical instability [9]. (See "QT
dispersion: Measurement and interpretation" and "QT dispersion: Clinical
applications" and "Coronary artery patency and outcome after myocardial infarction".)

Changes in the resting membrane potential Experimental coronary artery

occlusion and resulting ischemia causes the resting membrane potential to become less
negative via the following mechanisms [10,11]. (See "Myocardial action potential and
action of antiarrhythmic drugs".)

Loss of the energy dependent sodium-potassium-ATPase pump

A decrease in potassium influx
An increase in potassium efflux

The net increase in potassium leakage out of the cells leads to a rise in the local
extracellular potassium concentration from 4 to 15 meq/L within 15 minutes of coronary
occlusion [12]. Potassium accumulation occurs in two phases, since blood flow is absent
[11,13,14]:

The first phase is reversible with reperfusion, provided it occurs within 15 minutes
of occlusion.
The second phase is irreversible and represents permanent cellular damage.

Animal experiments have shown that the Na-K-ATPase pump is only mildly depressed in
the early stages of ischemia (approximately 10 minutes) [7]. It has therefore been
suggested that initial potassium loss is secondary to increased permeability of the cell
membrane to anions, such as inorganic phosphate and lactate, or to the development of
an intracellular acidosis [12,15].

Other products accumulating in the ischemic myocardium are lysophosphoglycerides

(LPGs), which may mediate the following adverse electrophysiologic changes [3]:

Isolated normal myocardium and Purkinje fibers exposed to LPGs show electrical
changes that are similar to those seen in ischemic myocardium [16-18].
 Small amounts of LPGs augment the effect of hypoxia and elevated potassium,
effects that are intensified by acidosis [19].
High concentrations of LPGs cause disruption of the cell membrane, contributing
to massive calcium entry and cell death [20,21].

The metabolic changes and acidosis that accompany occlusion and ischemia can be
altered by multiple brief occlusions, as may occur in the patient with unstable angina or
an acute myocardial infarction with ongoing episodes of ischemia. Studies using
repetitive occlusions lasting less than five minutes have demonstrated a reduced
incidence of VF; this phenomenon has been termed "ischemic preconditioning" [22].
(See "Clinical implications of ischemic preconditioning".)

However, longer periods of occlusion may not produce the same results. One animal
study, for example, evaluated the effect of repetitive 15 minute coronary occlusions
followed by 45 minute reperfusions on the incidence of occlusion and release arrhythmias
[23]. Repetitive occlusions were associated with progressively higher ST segment
elevation, more frequent ST segment alternans, and a greater incidence of VF,
suggesting increasing metabolic derangement. However, there was also faster
normalization of the ECG and a reduced incidence of ventricular fibrillation during
repetitive reperfusions, suggesting a progressively faster resolution of the metabolic
derangements.

Changes in the action potential Acute ischemia significantly reduces the amplitude,
upstroke velocity, and duration of the action potential. The changes vary based upon the
area of involvement.

The central ischemic zone has the largest alteration, consisting of a decrease in
impulse velocity and an increase in the refractory period.
The areas of normal myocardium surrounding the main area of infarction have an
increase in impulse conduction velocity (due to catecholamines) and a shortened
refractory period.
The ischemic tissue at the border zone of the infarct manifests electrophysiologic
changes that are intermediate between those found in the other two regions. This
inhomogeneity is partly caused by diffusion of potassium that has leaked out of
the cells in the ischemic areas toward more normal myocardium. In animals,
ischemia at the border zone of a one-month old infarction is more arrhythmogenic
that ischemia at a distance from the infarction zone [24].

Changes in the characteristics of the action potential upstroke cause a reduction in

conduction velocity by approximately 50 percent during the first 5 to 10 minutes of
ischemia. If ischemia continues, coupling resistance increases rapidly, indicating
irreversible injury with a further reduction in impulse conduction between cells [7].

Acute phase (first 30 minutes) arrhythmias A distinction must be made between

the acute phase of myocardial ischemia (during the first 30 minutes) and the subacute or
delayed phase (6 to 48 to 72 hours post-MI) when considering the mechanisms
responsible for periinfarction ventricular arrhythmias. Acute and delayed arrhythmias are
distinguished by clinical arrhythmia type, cellular mechanisms, and immediate prognostic
implications.
Arrhythmias occurring within the first 30 minutes of experimental coronary artery
occlusion demonstrate the following bimodal distribution [25]:

Arrhythmias occurring after the first 2 to 10 minutes are known as "immediate" or

phase 1a ventricular arrhythmias and have a peak incidence after five minutes of
ischemia.
"Delayed" or phase 1b arrhythmias occur after approximately 10 to 60 minutes of
coronary artery occlusion.

Experimental studies suggest that phase 1a and 1b arrhythmias arise via different
mechanisms.

Phase 1a arrhythmia Phase 1a arrhythmias occur when there is marked conduction

slowing and delayed activation in the subepicardium, coincident with the decrease in
resting membrane potential, partial membrane depolarization, and consequent reduction
in membrane action potential amplitude [26]. This results in marked slowing of impulse
conduction and is detected as fractionation of local electrograms [27]. One phenomenon
associated with the fractionated electrogram is diastolic bridging, which often precedes
sustained ventricular arrhythmia [28].

On the basis of these electrocardiographic findings, it has been postulated

that reentry is the dominant mechanism behind phase 1a arrhythmias [27,29-31].
(See "Reentry and the development of cardiac arrhythmias".) It has also been suggested
that during phase 1a, a nonreentry mechanism initiates isolated premature ventricular
beats (VPBs), which in turn may precipitate reentrant arrhythmias.

The possible origin for this series of events is a focal mechanism such as triggered
activity secondary to afterdepolarizations and abnormal automaticity. The latter changes
result from spontaneous impulse formation based upon phase 4 depolarization in cells
with reduced resting membrane potential [32]. The occurrence of a focal mechanism is
supported by a canine study using three dimensional activation mapping, which found
that 60 percent of ventricular tachycardias in the early ischemic period were of focal
Purkinje origin [33]. (See "Enhanced cardiac automaticity".)

Phase 1b arrhythmia The mechanism that gives rise to phase 1b arrhythmias has
not been fully elucidated, but they may reflect abnormal automaticity, induced by left
ventricular wall stress [34] or the increased catecholamine release that occurs after 15 to
20 minutes of ischemia [35-37].

These observations suggests that sustained VT within the first few hours after MI may be
the result of transient arrhythmogenic mechanisms, possibly resulting from ischemia, and
its predictive value for sudden death is low. Consistent with this hypothesis is a report in
which sustained monomorphic VT could not be induced in seven patients who had
sustained monomorphic VT within 24 hours of the acute insult [38].

Delayed phase (6 to 72 hours) arrhythmias Delayed phase arrhythmias generally

occur between three to six hours and as long as two to three days after the onset of the
MI. The most frequently observed ventricular arrhythmias are [39,40]:

VPBs
Nonsustained VT (three to four beats)
Accelerated idioventricular rhythm, which occurs in up to 50 percent of patients
It is generally believed that delayed arrhythmias arise from surviving Purkinje
cells located within the subendocardium that display abnormal automaticity [7,41].
These cells have an increased sensitivity to catecholamines, and delayed arrhythmias can
be provoked by stimulation of the sympathetic nervous system.

An animal model suggested an alternative mechanism for arrhythmia occurring soon

after acute MI [42]. Four days after MI, prior to the development of fibrosis, there was
marked disruption of gap-junctional distribution due to early remodeling of the
myocardium. This resulted in nonuniformity of anisotropic conduction, which may lead to
reentrant VT if the disruption extends through the full thickness of the myocardium.
(See "Reentry and the development of cardiac arrhythmias".)

Chronic phase arrhythmias During the chronic, healing phase of an acute MI (more
than 72 hours), the typical patient with sustained monomorphic VT has had a large, often
complicated infarct with a left ventricular ejection fraction (LVEF) 30 percent [43,44].
The VT is often quite rapid in this setting, with a roughly equal distribution of heart rates
above 220 beats/min, between 180 to 220 beats/min, and below 180 beats/min [43].
(See "Sustained monomorphic ventricular tachycardia in patients with a prior myocardial
infarction: Treatment".)

New ischemia can be superimposed upon this substrate with the appearance of a variety
of ventricular arrhythmias including nonsustained, sustained monomorphic, and
polymorphic VT. Thus, revascularization and antiischemic therapy may be part of the
antiarrhythmic regimen. Autonomic imbalance, electrolyte abnormalities, and the
proarrhythmic effects of antiarrhythmic drugs can also contribute to the appearance of
sustained monomorphic VT or other ventricular arrhythmias.

Transient events, such as ischemia, autonomic surges, or VPBs may be difficult to

document but may be important in selected patients:

In a series of 53 patients with spontaneous VT (44 with remote MI), the heart rate
rose and measures of heart rate variability indicated a rise in sympathetic activity
before the onset of the arrhythmia [45]. (See "Heart rate variability: Technical
aspects".)
One report evaluated the role of VPBs in 52 patients, 40 with CHD, who had an
implantable cardioverter-defibrillator (ICD) [46]. Two-thirds of VT episodes were
provoked by VPBs, which were most often multiple and had a morphology that
was different from the VT. In another study using detailed electroanatomic
mapping, 29 patients with ischemic cardiomyopathy and repeated episodes of VF
were evaluated [47]. In all subjects, VF was initiated by monomorphic VPBs
originating in the border zone of the infarct scar. (See "Clinical significance and
treatment of ventricular premature beats".)
Inducibility and reentry Sustained monomorphic VT can be initiated during
electrophysiology study in approximately 90 to 95 percent of these patients
[43,48,49]. The arrhythmia usually remains inducible after coronary artery bypass
graft surgery [49]. Patients who have noninducible sustained monomorphic VT
have a decreased probability of spontaneous VT, suggesting that the substrates
for inducible and spontaneous VT may evolve in parallel over time [50].

These findings support the hypothesis that late sustained monomorphic VT is typically
reentrant in origin. Experimental evidence in both the subacute and chronic phases after
MI suggest that scar with the interdigitation of viable myocardium may provide the
substrate for reentry [51,52]. Late potentials and slow conduction can occur in areas with
normal action potentials; thus, slow conduction may be due to disruption of the gap
junctional connections between cells by the collagen of the scar, resulting in
nonuniformity of anisotropic conduction [53].

Reentry may occur around the area of infarction with a single circuit or two circuits. In a
canine model of VT in healing MI, observed reentry circuits included [54]:

Figure of eight
Functional with long lines of functional block
Short lines of functional block with slow conduction transverse to fiber orientation
(anisotropic reentry)
Leading circle reentry

(See "Reentry and the development of cardiac arrhythmias".)

Remodeling Left ventricular remodeling after an MI produces structural changes

in the myocardium that may also be a factor in the pathogenesis of ventricular
arrhythmia. In an analysis from the Survival and Ventricular Enlargement (SAVE)
trial, transthoracic echocardiograms and 24-hour ambulatory ECG monitoring
were performed at baseline and at one and two years in 263 patients [55]. Left
ventricular size, muscle mass, and function were significantly correlated with the
incidence of VT and with frequent VPBs. A similar correlation was found between
ventricular arrhythmia and changes in left ventricular size and function over the
two years of the study. (See "Cardiac remodeling: Basic aspects".)

Role of the autonomic nervous system A relative excess of sympathetic compared

to vagal activity may be an important factor in genesis of ventricular arrhythmias during
acute MI [56,57]. Autonomic imbalance can increase Na-K-ATPase pump activity and
enhance potassium conductance of the myocardial cell membrane, both of which lead to
hyperpolarization of the membrane [58].

Support for the role of the sympathetic nervous system comes from a study of 49
patients who had electrical storm, defined as multiple recurrent episodes of VF,
associated with an acute MI [59]. Compared to patients receiving antiarrhythmic therapy,
those treated with sympathetic blockade (beta blockers or stellate ganglionic blockade)
had a lower one week mortality (22 versus 82 percent) and overall mortality at one year
(33 versus 95 percent).

The longer term important of the role of sympathetic activity comes from the clear
evidence of reduced mortality, including arrhythmic death, in patients treated with beta
blockers (figure 1) [60]. (See "Beta blockers in the management of acute coronary
syndrome".)

Indirect clinical evidence supporting a role for reduced parasympathetic tone are the
observations that decreased baroreflex sensitivity and impaired heart rate variability
(which reflect reduced vagal activity) are associated with increased inducibility of
sustained monomorphic VT and with sudden death during the first 6 to 12 months after a
myocardial infarction [61-63]. However, extrapolation of these findings to the acute
phase of MI is at present not justified. (See "Incidence of and risk stratification for
sudden cardiac death after acute myocardial infarction".)

Abnormalities in cardiac innervation Myocardial infarction may be associated with

inhomogeneous distribution of sympathetic fibers. Regions with necrosis and dense
scarring show myocardial denervation. In contrast, other regions of the myocardium may
show an increase in sympathetic innervation, possibly the result of injury-related nerve
sprouting. Immunocytochemical staining of tissue from patients with severe heart failure,
due to either an idiopathic cardiomyopathy or a myocardial infarction, found that patients
with a history of spontaneous ventricular arrhythmias had regional hyperinnervation,
with an increase in sympathetic nerve fibers in the perivascular regions and the periphery
of injured myocardium [64].

Sympathetic efferent fibers en route to the left ventricle cross at the atrioventricular
groove, travel within the superficial subepicardium in a base-to-apex direction, and
penetrate the myocardium to innervate the endocardium. A transmural MI can damage
the sympathetic fibers and result in functional denervation of the myocardium apical to
the area of the infarction. The following observations illustrate the range of findings:

Animal and human studies have shown that, after an infarction, regions of the
ventricular myocardium below the infarcted zone have no uptake of iodine-123-
metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is
actively taken up by sympathetic nerve terminals, even though this tissue remains
viable, as indicated by persistent thallium uptake [65-67].
Denervated regions show denervation hypersensitivity to infused norepinephrine
or isoproterenol, as manifested by a greater shortening in refractoriness
compared to normal myocardial tissue or easier inducibility of sustained VT during
sympathetic stimulation [68,69]. The resulting heterogeneity in refractoriness
induced by circulating catecholamines is a potential mechanism for
arrhythmogenicity after infarction that can be minimized by beta blockers [68]. In
comparison, regional denervation may not affect the inducibility of sustained VT at
electrophysiology study [67].
Reinnervation of the periinfarction area, but not the infarcted tissue, and the loss
of supersensitivity occur within 12 months after the infarction [70].

Role of thrombus and ischemic preconditioning The incidence of life-threatening

ventricular arrhythmias in the presence of intracoronary thrombus is greater than that
associated with coronary artery ligation or balloon occlusion, despite a similar amount of
ischemia [71,72]. In an animal study, for example, an increased incidence of VF due to
more conduction slowing during the first few minutes was noted with ischemia induced
by intracoronary thrombus compared to coronary artery ligation [72]. The
electrophysiologic effect of the thrombus lasted only a few minutes, suggesting an
association between thrombin and the rapid release of ischemic metabolites, such as
LPGs and lysophosphatidylcholines, and their accumulation in ventricular myocytes
[16,17,73].

The profibrillatory effect of the thrombus in the above report was not detectable after
ischemic preconditioning [72]. This may account, in part, for the observation that a
sudden obstruction of the coronary artery without preexisting coronary artery narrowing
is associated with a higher incidence of ventricular fibrillation compared to an obstruction
occurring in association with preexisting stenoses. (See "Clinical implications of ischemic
preconditioning".)

Reperfusion arrhythmias Ventricular arrhythmias in some patients have been

thought to be related to reperfusion, occurring within a period of minutes after
reperfusion has been achieved [74-76]. The evidence is best for an accelerated
idioventricular rhythm (AIVR) as a reperfusion arrhythmia [75-79], although AIVR is
neither a sensitive nor very specific marker for successful reperfusion. The most common
reperfusion changes involve the ST segment and T waves (eg, ST segment elevation
resolution) [79]. (See "Fibrinolytic (thrombolytic) agents in acute ST elevation myocardial
infarction: Markers of efficacy".)

Serious ventricular arrhythmia induced by reperfusion does not appear to a major

problem [79-81]. As an example, large trials of intravenous thrombolytic therapy did not
demonstrate any increase in life-threatening arrhythmias that could be attributed to
reperfusion, although frequent VPBs and accelerated idioventricular rhythms did occur
and might have been a marker of reperfusion [82,83]. Similar findings have been noted
after primary percutaneous coronary intervention [79]. Although sustained VT and VF
may be associated temporally with reperfusion, they are often associated with persistent
occlusion not patency of the infarct-related artery [77,84].

Pathophysiology Reperfusion arrhythmias may be one manifestation of reperfusion

injury, which also includes vascular damage (no reflow phenomenon), myocardial
stunning, accelerated necrosis of reversibly damaged cells, and cell swelling and
accelerated necrosis of irreversibly damaged myocytes [85]. Reperfusion injury is
thought to be mediated by three main mechanisms, although angiotensin II also may
contribute. (See "Ischemic reperfusion injury of the heart".)

The calcium paradox - The calcium paradox occurs when calcium is restored to
the extracellular space after having been depleted by ischemia. This ensuing
accumulation of calcium in the cell causes damage to the respiratory chain and
decreases ATP production, leading to depletion of mitochondrial energy [86].
Severe cell damage ensues with muscle contracture and cell death.
The oxygen paradox - The oxygen paradox is closely linked to the calcium
paradox since oxygen mediates the uptake of calcium by the mitochondria [87].
Recycling of calcium occurs when ATP is restored during reperfusion, with the
subsequent possibility of developing calcium-dependent arrhythmias [88,89].
Oxygen also leads to cell damage during reperfusion by the formation of oxygen
free radicals [90].
The production of oxygen free radicals - The role of oxygen free radicals in the
genesis of reperfusion arrhythmias is uncertain. Free radical-induced membrane
damage occurs 5 to 10 minutes after reperfusion [91], and reduced levels of free
radical scavengers have been observed within three hours of angioplasty in
patients with an infarction [92]. Reperfusion arrhythmias, however, usually occur
within seconds after abrupt restoration of blood flow. The observation that free
radicals reduce the occurrence of reperfusion ventricular fibrillation is also against
their playing a primary role in reperfusion arrhythmias [93].
Angiotensin II - A role for angiotensin II in reperfusion arrhythmias was suggested
by studies in angiotensin II type 1a receptor knockout mice which, compared to
wild-type mice, showed less reperfusion arrhythmia despite a similar infarct size.
Furthermore, administration with a selective angiotensin II type 1 receptor before
 ischemia blocked reperfusion arrhythmias in the wild-type mice [94].
(See "Actions of angiotensin II on the heart".)

The incidence of reperfusion arrhythmias is influenced by the severity and duration of

ischemia. The concept that reperfusion arrhythmias are energy-dependent and arise from
salvaged myocardium is supported by the observation that arrhythmias do not arise from
dead cells.

The occurrence of reperfusion arrhythmias follows a bell-shaped curve: as the duration of

ischemia increases in experimental animals, so do reperfusion arrhythmias. The peak
incidence occurs at 5 to 10 minutes after the onset of ischemia, presumably due to
depletion of ATP stores [87,89].

Summary Clinical experience is different from these largely experimental

observations of reperfusion arrhythmias. Thrombolytic therapy is typically given more
than two to four hours after the onset of coronary occlusion, when significant infarction is
already present; the same is true of primary percutaneous coronary intervention. It
therefore seems likely that ischemia rather than reperfusion is responsible for the
majority of serious ventricular arrhythmias seen in patients with acute MI [84].

Arrhythmias that may be due to reperfusion should be managed in an identical fashion to

other arrhythmias in the acute MI setting. (See "Clinical features and treatment of
ventricular arrhythmias during acute myocardial infarction".)

At present, there are no prophylactic therapeutic maneuvers that have been proven to
reduce the incidence of these events, but there is interest in the possible efficacy of
calcium channel blocking agents and free radical scavengers, such as superoxide
dismutase and adenosine. As an example, dipyridamole, an inhibitor of cellular uptake of
adenosine that may reduce intracellular calcium, was evaluated in a study of 61 patients
undergoing primary angioplasty for an acute anterior wall myocardial infarction [78].
Pretreatment with dipyridamole prevented all episodes of AIVR and VT, which occurred in
18 and 8 percent, respectively, of patients not receiving pretreatment. In addition,
dipyridamole terminated arrhythmia in all nine patients who developed a sustained
ventricular tachyarrhythmia after reperfusion
Clinical features and treatment of ventricular arrhythmias during acute
myocardial infarction

Authors
Philip J Podrid, MD
Leonard I Ganz, MD, FHRS, FACC

Section Editor
James Hoekstra, MD

Deputy Editor
Brian C Downey, MD, FACC

Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last
updated: Mon Feb 07 00:00:00 GMT 2011 (More)

INTRODUCTION Death from a ventricular tachyarrhythmia in the setting of an acute

myocardial infarction (MI) has historically been one of the most frequent causes of
sudden cardiac death (SCD) [1,2]. In a 1985 report, for example, 60 percent of deaths
associated with acute MI occurred within the first hour and were attributable to a
ventricular arrhythmia, in particular ventricular fibrillation (VF) [3]. However, subsequent
improvements in arrhythmia detection and treatment have had a major impact on the
outcome of ventricular arrhythmias associated with acute MI. As a result, both
arrhythmic and overall in-hospital mortality from acute myocardial infarction (MI) have
fallen significantly [4-6]. (See "Prognosis after myocardial infarction".)

The incidence, clinical features, and treatment of ventricular tachyarrhythmias associated

with acute MI will be reviewed here. Risk stratification for life-threatening ventricular
arrhythmias after MI, prophylactic treatment of ventricular arrhythmias following MI, and
the management of ventricular arrhythmias in the setting of chronic coronary heart
disease are discussed separately. (See "Incidence of and risk stratification for sudden
cardiac death after acute myocardial infarction" and "Prophylaxis against ventricular
arrhythmias following myocardial infarction" and "Role of antiarrhythmic drugs for
ventricular arrhythmias in patients with a prior myocardial infarction" and "Sustained
monomorphic ventricular tachycardia in patients with a prior myocardial infarction:
Treatment" and "Role of implantable cardioverter-defibrillators for the secondary
prevention of sudden cardiac death".)

INCIDENCE While many studies have evaluated the incidence of ventricular

arrhythmias in the peri-infarct period, comparison of these studies is difficult due to
differences in populations (percutaneous intervention therapy versus fibrinolytic therapy
versus no therapy), type of infarct (ST segment elevation MI versus non-ST segment
elevation MI versus both) and arrhythmia reported (ventricular tachycardia versus VF
versus both).

Ventricular arrhythmias, ranging from isolated ventricular premature beats to ventricular

fibrillation, are common in the immediate postinfarction period. Observations in the
prefibrinolytic era found the following range of incidence [7,8]:

Ventricular premature beats (VPBs) 10 to 93 percent

Ventricular tachycardia (VT) 3 to 39 percent
Ventricular fibrillation (VF) 4 to 20 percent

Early series underestimated the incidence of unstable VT and VF, because they did not
include patients whose MI resulted in out-of-hospital sudden cardiac death (SCD) [9].
The incidence of ventricular arrhythmias appears to be higher with ST elevation (Q wave)
than non-ST elevation (non-Q wave) infarctions (STEMI and NSTEMI).

VT is less common than VF in the periinfarction period. This is probably due to the fact
that VT usually requires a reentrant circuit and a fixed arrhythmic substrate, such as the
scar from a healed MI. When VT occurs during an acute MI, it may reflect triggered
activity, enhanced automaticity, or a prior infarction. (See "Pathogenesis of ventricular
tachycardia and ventricular fibrillation during acute myocardial infarction".)

ST elevation MI Data regarding the incidence of ventricular arrhythmias at the time

of acute STEMI come from studies of patients treated with either fibrinolysis or primary
percutaneous coronary intervention (PCI). Although the incidence of ventricular
arrhythmias is probably lower with contemporary therapies [10-15], these data also
probably underestimate the true incidence of arrhythmias because patients with pre-
hospital sudden cardiac death may not have been included in studies of fibrinolysis or
primary PCI. The risk factors for and the prognosis of early VT or VF in patients with
STEMI are discussed separately. (See 'Prognosis after early VT' below and 'Prognosis
after early VF' below.)

Fibrinolytic therapy Among patients with acute MI in the fibrinolytic era, the
incidence of VF has ranged from 3.7 to 6.7 percent in large studies [12-17].

The largest experience in patients (40,895) with acute STEMI treated with fibrinolytic
therapy comes from the GUSTO-1 trial [13]. The overall incidence of sustained VT or VF
was 10.2 percent (3.5 percent developed VT, 4.1 percent VF, and 2.7 percent both VT
and VF). Approximately 80 to 85 percent of these arrhythmias occurred in the first 48
hours.

A similar frequency of VF was noted in a report from the GISSI-2 database of 9720
patients with a first MI treated with a fibrinolytic agent [12].

Early (4 hours) primary VF (ie, VF in the absence of heart failure or shock)

occurred in 3.1 percent. VF recurred during the hospitalization in 11 percent of
these patients.
Late VF (>4 to 48 hours) occurred in 0.6 percent and was recurrent in 15 percent.

Two problems with fibrinolytic trials bring into question the validity of their reported
arrhythmia incidence. First, by nature of their patient inclusion and consent issues,
patients who died of SCD in the prehospital arena were excluded from the trial
denominator. Secondly, fibrinolysis and reperfusion may lead to reperfusion arrhythmias,
falsely increasing the incidence of MI associated arrhythmias. Given the reduced
incidence of VT and VF compared to older studies, it seems likely that reperfusion does
not necessarily increase the overall incidence of VF or sustained VT. Ventricular
premature beats (VPBs) and accelerated idioventricular rhythm (AIVR) have been
thought to be a marker of reperfusion following fibrinolysis [18]. (See "Pathogenesis of
ventricular tachycardia and ventricular fibrillation during acute myocardial infarction",
section on 'Reperfusion arrhythmias'.)

Primary PCI Among 5745 STEMI patients with planned percutaneous coronary
intervention (PCI) enrolled in the APEX AMI trial, VT or VF occurred in 329 (5.7 percent)
[19]. The arrhythmia was noted before catheterization in 25, during catheterization in
180, and after catheterization but before discharge in 170 patients. Most events (282)
occurred within the first 48 hours. (See "Primary percutaneous coronary intervention in
acute ST elevation myocardial infarction: Determinants of outcome".)

Non-ST elevation MI The best data on the incidence of sustained ventricular

arrhythmias in patients with acute NSTEMI or unstable angina comes from a pooled
analysis of four major trials of over 25,000 patients with a non-ST elevation acute
coronary syndrome (NSTEMI or unstable angina) [14]. The overall incidence of sustained
ventricular tachycardia (VT) or ventricular fibrillation (VF) was 2.1 percent, which is lower
than the 10.2 percent STEMI incidence in GUSTO-1 [13]. VT occurred in 0.8 percent, VF
in 1 percent, and VT and VF in 0.3 percent. The median time to arrhythmia was 78
hours.

Temporal trends There is conflicting evidence regarding changes in the incidence of

ventricular fibrillation (VF) with advancements in care for acute MI. One series showed no
difference in the incidence between 1975 and 1997 [3], while a second report noted a
reduction in nonprimary VF, but no change in primary VF (ie, VF in the absence of heart
failure or shock), between 1979 and 1998 [15]. Improvements in therapy have led to a
reduction in the in-hospital mortality in those who develop VF from approximately 50
percent in 1975 to 20 percent in 1997 [3].

FAMILIAL PREDISPOSITION There may be inherited factors that predispose some

individuals to ventricular arrhythmias and sudden cardiac death (SCD) in the setting of
an MI. This possibility was supported by two case-control studies in slightly different
populations:

Among patients presenting with a first ST elevation MI, 330 survivors of primary
VF (ie, VF in the absence of heart failure or shock) were compared to 372 controls
[20]. A family history of SCD was more common among those who experienced
primary VF (odds ratio 2.7, 95% confidence interval 1.8 to 4.0, compared to
controls).
In a Finnish series of consecutive SCD victims who underwent autopsy (which is
mandatory for unexplained SCD in Finland), 138 were identified who had an acute
coronary event, but no history of prior MI [21]. These cases were compared to
two control groups; 254 consecutive patients surviving an acute MI, and 470
healthy subjects. A history of SCD in first-degree relatives was ascertained in each
group. The incidence of SCD was significantly higher in the relatives of SCD
victims than in those of the acute MI survivors or the control subjects (5.6, 3.3,
and 1.6 percent, respectively).

Although these observations are intriguing, this study design is subject to the possibility
of recall bias, which could lead to an overestimation of the familial risk.

VENTRICULAR PREMATURE BEATS The presence of ventricular premature beats

(VPBs) after acute MI is associated with an increased total mortality in some patients,
particularly those with larger infarctions and impaired left ventricular function. It is
uncertain if the increased risk is attributable to VPBs alone or only to repetitive forms,
which often occur in association with frequent VPBs. (See "Incidence of and risk
stratification for sudden cardiac death after acute myocardial infarction".)

Pre-thrombolytic era Prior to the widespread use of thrombolytic therapy for

treatment of acute ST elevation myocardial infarction (STEMI), a number of reports found
that repetitive ventricular premature beats (VPBs), but not frequent VPBs alone, were
associated with an increased risk among post-MI patients [22-25]. In the largest of these
series, the prognostic significance of VPBs detected in a one hour electrocardiogram
monitoring session was evaluated in 1739 men with a recent MI [22]. At a mean follow-
up of two years, patients with ventricular bigeminy, couplets, or multiform VPBs had a
three-fold increase in sudden death and a two-fold increase in all-cause mortality. In
comparison, this was not noted in those who had only simple VPBs, regardless of
frequency. The increase in risk persisted at later follow-up at five years [23].

In contrast, other studies have found that an increased frequency of VPBs alone may be
associated with an increased mortality risk [26-28]. As an example, the European
Infarction Study Group noted a 4 percent two-year mortality in post-MI patients with
more than 10 VPBs per hour, a value significantly higher than in that seen in those with
no or fewer VPBs [27]. The two-year mortality was much greater in patients with
ventricular couplets (22 and 10 percent if more than ten and one to nine couplets per
day, respectively).

There are also conflicting data as to whether the effect of VPBs upon sudden death in
post-MI patients is independent of left ventricular dysfunction. It is possible, for example,
that VPBs may only signify the presence of a severe myocardial process and may not be
an independent provoker of a terminal electrical event [29]. However, although a
relationship exists between the frequency of ventricular arrhythmias and the degree of
left ventricular dysfunction, the results of several large well-designed studies have found
that an increased frequency of complex VPBs is an important risk factor independent of
the degree of myocardial damage [24,30,31].

Thrombolytic era Studies of patients with an ST elevation myocardial infarction

(STEMI) treated in the thrombolytic era have also noted an increased mortality rate
associated with ventricular premature beats (VPB) in the post infarction period [32-34].

A review from the GISSI-2 trial evaluated 8676 patients with STEMI treated with
thrombolytic therapy undergoing 24-hour Holter monitoring before discharge: 64 percent
had at least one VPB per hour and 20 percent had more than 10 VPBs per hour [32]. At
six months, the mortality rate was 5.5 percent in patients with more than 10 VPBs per
hour compared to 2.0 and 2.7 percent in patients without ventricular arrhythmia or with
1 to 10 VPBs per hour, respectively. After adjusting for risk factors, more than 10 VPBs
per hour remained a significant predictor for both total (relative risk 1.62, 95% CI 1.16-
2.26) and sudden mortality (RR 2.24, 95% CI 1.22-4.08).

As in the prethrombolytic era, it is uncertain if the increase in risk after thrombolysis is

attributable to VPBs themselves or to the presence of repetitive forms that occur in
association with frequent VPBs. In the GISSI-2 analysis, the presence of complex VPBs
and the occurrence of more than 10 VPBs per hour were associated with a similar six-
month mortality (4.8 and 5.4 percent) [32,33].

The findings were different in the Canadian Assessment of Myocardial Infarction (CAMI)
study, which included 3178 patients with either an STEMI or a non-ST elevation
myocardial infarction (NSTEMI) [35]. Although cardiac mortality increased progressively
with increasing frequency of VPBs, VPBs alone had no independent predictive value in
multivariate analysis.

Primary PCI era Very limited data have been published assessing VPBs following
primary percutaneous coronary intervention (PCI). One single-center study of 44
consecutive STEMI patients treated with primary PCI measured the frequency of VPBs in
the first 24 hours post-PCI [36]. Compared to historical controls treated with
thrombolysis, no significant difference was seen in the frequency of VPBs in the initial 24
hours post-PCI, although there was a trend toward fewer VPBs in the patients treated
with PCI.

Treatment of VPBs Suppression of VPBs with antiarrhythmic drugs does not improve
either short- or long-term outcomes, and, with some drugs, may actually increase
mortality [37,38]. Thus, treatment for the suppression of asymptomatic VPBs
is not recommended [39]. (See "Prophylaxis against ventricular arrhythmias following
myocardial infarction".)

NONSUSTAINED VENTRICULAR TACHYCARDIA Ventricular tachycardia (VT) is

defined as three or more consecutive beats originating below the atrioventricular node,
with a heart rate greater than 100 or 120 beats/min. There is some disagreement as to
whether 100 or 120 beats/min represents the upper limit for an accelerated
idioventricular rhythm. VT is considered nonsustained if it terminates spontaneously in
less than 30 seconds. The incidence of nonsustained VT (NSVT) following MI ranges from
1 to 7 percent [40,41]. In the first 24 to 48 hours after an infarction, NSVT is usually due
to abnormal automaticity or triggered activity in the region of ischemia or infarction. In
comparison, NSVT that occurs later is more often due to reentry. Thus, the probable
mechanism and the prognostic significance of NSVT depends upon the time at which it
occurs in relation to infarction. (See "Incidence of and risk stratification for sudden
cardiac death after acute myocardial infarction", section on 'NSVT on
monitoring' and "Prognosis of nonsustained VT in the presence of structural heart
disease", section on 'Coronary heart disease'.)

Treatment of NSVT As with ventricular premature beats (VPBs), antiarrhythmic

drugs for the suppression of NSVT is not recommended [39]. In the rare case when
NSVT is frequent and causes hemodynamic compromise, treatment may be reasonable.
In such patients, additional beta blockade or, if necessary, amiodarone or procainamide,
may be useful. (See "Management of nonsustained ventricular tachycardia".)

ACCELERATED IDIOVENTRICULAR RHYTHM An accelerated idioventricular rhythm

(AIVR), which has also been called "slow ventricular tachycardia," arises below the
atrioventricular node and has, by definition, a rate between 50 and 100 or 120 beats/min
(figure 1) [42]. It may be the result of pacemaker failure, and therefore be an escape
rhythm, or it may represent an abnormal ectopic focus in the ventricle that is accelerated
by sympathetic stimulation and circulating catecholamines.

AIVR occurs in up to 50 percent of patients with acute MI. Some studies have suggested
an association with reperfusion following fibrinolytic therapy [18]. However, AIVR is
neither a sensitive nor very specific marker for successful reperfusion.
(See "Pathogenesis of ventricular tachycardia and ventricular fibrillation during acute
myocardial infarction", section on 'Reperfusion arrhythmias'.)

Treatment of AIVR Most episodes of accelerated idioventricular rhythm (AIVR) are

transient and require no treatment. Furthermore, treatment is contraindicated if AIVR is
an escape rhythm, since suppression of the ectopic pacemaker focus will result in
asystole [39]. There are no convincing data linking AIVR to sustained VT or VF.
(See "Role of antiarrhythmic drugs for ventricular arrhythmias in patients with a prior
myocardial infarction", section on 'Accelerated idioventricular rhythm'.)

SUSTAINED VENTRICULAR TACHYCARDIA Ventricular tachycardia (VT) is defined

as three or more consecutive beats originating below the atrioventricular node, with a
heart rate greater than 100 or 120 beats/min. There is some disagreement as to whether
100 or 120 beats/min represents the upper limit for an accelerated idioventricular
rhythm. VT is considered sustained if it lasts more than 30 seconds or if it causes
instability that requires termination (eg, cardioversion) within 30 seconds.

Sustained monomorphic VT (SMVT) in the periinfarction period (ie, within the first 48
hours after the infarct) occurs in approximately 2 to 3 percent of patients with an ST
elevation MI (STEMI) [13,43] and less than 1 percent with a non-STEMI or unstable
angina [14]. SMVT is associated with larger MI size [43]. The factors responsible for
SMVT differ in the very early (30 minutes) and later phases (6 to 48 hours) of the early
post-MI period. (See "Pathogenesis of ventricular tachycardia and ventricular fibrillation
during acute myocardial infarction".)

The clinical presentation may include palpitations, worsening ischemic symptoms due to
the elevated heart rate, and hemodynamic compromise or collapse. Patients with faster
tachycardias and worse left ventricular function are less likely to tolerate the arrhythmia.

Morphology Ventricular tachycardia (VT) is called monomorphic if the QRS complexes

are all of one morphology and polymorphic if the QRS morphology varies during an
episode (figure 2A-B). (See "Pathogenesis of ventricular tachycardia and ventricular
fibrillation during acute myocardial infarction".)

Monomorphic VT The presence of a single, consistent QRS morphology suggests that

each beat arises from the same location and activates the ventricle in the same
sequence. This uniformity should be present in all 12 electrocardiogram (ECG) leads. As
a result, a 12 lead ECG should be obtained in stable patients in order to fully characterize
the VT morphology.

In the early stage of an evolving infarction (ie, the first 6 to as many as 48 hours),
monomorphic VT may result from transient arrhythmogenic phenomena in ischemic and
infarcting tissue, such as abnormal automaticity, triggered activity, and reentrant circuits
created by heterogeneous conduction and repolarization.

SMVT in any other setting is considered a marker of permanent arrhythmic substrate and
an increased long-term risk of arrhythmia recurrence and SCD. Because of the
physiologic and mechanistic link between SMVT and permanent substrate, it is not clear
that SMVT at any point, even early after an MI, should be attributed to transient
phenomena. Furthermore, SMVT in the setting of an acute MI may reflect permanent
substrate from a prior infarction. As a result, the prognostic significance of SMVT in the
early period after an MI is unclear. This issue is discussed in greater detail below.
(See 'Prognosis after early VT' below.)

Polymorphic VT Polymorphic ventricular tachycardia (VT) is an unusual arrhythmia

during acute MI, occurring in 0.3 percent of patients in one report [44]. Like VF and
accelerated idioventricular rhythm (AIVR), it is usually due to abnormal automaticity or
triggered activity associated with ischemia or reperfusion. When polymorphic VT does
occur early after an acute MI, it is typically associated with symptoms or signs of
recurrent myocardial ischemia [44]. The typical features associated with polymorphic VT,
or torsades de pointes, in other settings are not present (eg, prolonged QT interval, sinus
bradycardia, preceding sinus pauses, or electrolyte abnormalities).

Some patients (8 of 434 consecutive patients in one series) do develop typical pause-
dependent torsades de pointes in association with progressive QT interval prolongation
[45]. This pattern of events occurs during the healing phase of an infarct, usually days 3
to 11, and does not suggest recurrent ischemia. (See "Acquired long QT syndrome".)

Prognosis after early VT Early sustained monomorphic ventricular tachycardia

(SMVT) is associated with a higher in-hospital mortality due to cardiac arrest and
possibly to exacerbation of ischemia and extension of the infarct [13,15,40,43,46-48].
Whether early SMVT is associated with an increased long-term mortality risk among
patients who survive to hospital discharge is unclear [13,15,19,40,46]. Because SMVT
usually reflects myocardial scar and permanent arrhythmic substrate, this arrhythmia,
even early after an acute MI, may have different implications than nonsustained VT or
ventricular fibrillation (VF).

The following observations illustrate the range of findings:

A case-control study compared 162 patients with sustained or nonsustained VT

within 48 hours after an acute MI to 2578 post-MI patients without VT [40]. VT
was not associated with an increase in long-term mortality, but the majority of
these patients had nonsustained VT (only 28 patients had sustained VT).
In the TIMI phase II trial, excluding patients with hypotension or heart failure, 1.9
percent of patients developed sustained VT or VF in the first 24 hours [46]. These
patients had higher in-hospital mortality (20.4 versus 1.6 percent) but, for those
who survived 21 days, there was no increase in late mortality compared to
patients who did not have ventricular arrhythmias. The implication of these results
for patients with monomorphic VT is uncertain, however, because patients with
sustained VT and VF were analyzed as a single group.
In a study limited to patients with a non-STEMI, SMVT was a significant predictor
of increased mortality at both 30 days and six months (adjusted hazard ratio 8
and 5, respectively) [14]. However, the increase in risk was largely due to more
deaths in the first 30 days, and the prognostic implications of early VT in patients
who survive the post-MI period were not addressed.
The APEX AMI trial data was used to evaluate the prognosis of 329 STEMI patients
scheduled for PCI who had sustained VT or VF, either before the end of
catheterization (early) or after catheterization but before discharge (late) [19]. At
90 days the frequency of death was significantly worse in patients with versus
those without VT/VF (23.2 versus 3.6 percent) and outcomes were significantly
worse if the VT/VF was late as opposed to early (33.3 versus 17.2 percent).

Due to the relatively small numbers of patients and the combined analysis of patients
with VT and VF or nonsustained VT and sustained VT, these studies did not adequately
address the long-term prognostic significance of SMVT in the early post-MI setting. As
noted above, there are physiologic reasons to suggest that SMVT has different
implications than VF or nonsustained VT.

Somewhat different findings were noted in the analysis of over 40,000 patients in
GUSTO-I, illustrated by the following results [13] (figure 3):

Similar to prior reports, the in-hospital mortality was significantly higher in

patients who had SMVT alone (18.6 percent) or SMVT and VF (44.0 percent)
compared to those without sustained ventricular arrhythmia (4.2 percent).
Among those who survived 30 days, one-year mortality was significantly higher
among patients who had SMVT alone (7.1 percent) or SMVT with VF (6.4 percent)
compared to those without sustained ventricular arrhythmias (2.7 percent). This
finding is in contrast to the earlier studies, in which early VT did not predict worse
outcomes among patients who survived the early post-MI period (eg, to hospital
discharge).
Patients with early VF alone had an increased rate of in-hospital mortality (19.8
percent) but, among those who survived 30 days, the one-year mortality was the
same as that in patients without ventricular arrhythmias (approximately 2.8
percent in both groups).
These findings support the hypothesis that SMVT and VF have distinct mechanisms and
prognoses. The reasons for the discrepancies in the long-term significance of early SMVT
between GUSTO-I and the prior studies are uncertain. However, GUSTO-I was larger,
analyzed arrhythmias separately, and utilized reperfusion and adjuvant therapies that are
closer to contemporary practice than the earlier reports. As a result, some experts
consider SMVT, regardless of the temporal relationship to a recent infarction, to reflect
fixed substrate for ventricular arrhythmias and therefore to be predictive of a high risk of
future arrhythmias and SCD. (See 'Ventricular fibrillation' below.)

Acute treatment The acute treatment of sustained ventricular arrhythmias is

discussed in detail separately. The following discussion addresses issues associated with
acute MI, and is in broad agreement with 2010 advanced cardiac life support (ACLS)
guidelines published by the American Heart Association (AHA) [49,50], and with
ACC/AHA guidelines for the management of acute MI [39]. (See "Advanced cardiac life
support (ACLS) in adults".)

Polymorphic VT and unstable monomorphic VT Unstable, poorly-tolerated

arrhythmias are a life-threatening emergency that are treated according to established
ACLS protocols [50].

Sustained polymorphic VT and pulseless monomorphic VT should be treated

with unsynchronized electrical shocks. If available, a biphasic waveform
defibrillator is preferable since the success rate for defibrillation is higher than
with monophasic waveforms. For biphasic defibrillators, the initial shock should be
at 120 to 200 joules, with subsequent shocks at the highest available biphasic
energy level (200 joules for most devices). For monophasic defibrillators,
nonescalating shocks beginning at 360 joules should be used.
Sustained monomorphic VT associated with angina, pulmonary edema, or
hypotension (systolic blood pressure <90 mmHg) should be treated immediately
with synchronized electrical cardioversion using an initial energy of 100 joules.
Subsequent shocks at increasing energy can be given as necessary. Brief
anesthesia is desirable if hemodynamically tolerable.

Stable monomorphic VT Even when hemodynamically tolerated, sustained VT in the

periinfarction period must be treated urgently because of its deleterious effect on cardiac
output, possible exacerbation of myocardial ischemia, and the risk of deterioration into
ventricular fibrillation. However, if the patient is stable and asymptomatic, cardioversion
may be deferred for several minutes, during which an electrocardiogram (ECG) should be
obtained and intravenous amiodarone initiated. During this time, preparations should
simultaneously be made for urgent electrical cardioversion or defibrillation if the patient
deteriorates.

A 12-lead ECG can help to distinguish VT from supraventricular tachycardia with

aberrant conduction. However, a wide complex tachycardia occurring in the
setting of an acute MI should always be considered ventricular in origin unless
there is irrefutable evidence to the contrary. Perhaps more important in this
setting, the ECG provides information regarding the location of origin of the VT,
which may facilitate later diagnostic studies and treatment. (See "Approach to the
diagnosis and treatment of wide QRS complex tachycardias".)
 Sustained monomorphic VT that is hemodynamically tolerated and asymptomatic
can be treated initially with intravenous amiodarone. Synchronized electrical
cardioversion with brief anesthesia should be performed if VT persists after the
administration of the initial 150 mg of amiodarone.

Recurrent arrhythmias Recurrent arrhythmias should prompt an urgent evaluation

for underlying causes, including recurrent ischemia.

Recurrent SMVT or ventricular fibrillation (VF) that is not due to a reversible

cause, such as hypokalemia, ischemia, or heart failure, can be treated with
intravenous amiodarone (150 mg over 10 minutes, followed by an intravenous
infusion 1 mg/min for six hours, then 0.5 mg/min for 18 hours) [51,52].
(See "Clinical uses of amiodarone" and "Major side effects of amiodarone", section
on 'Intravenous amiodarone'.)
In patients with refractory polymorphic VT, aggressive attempts should be made
to reduce myocardial ischemia and adrenergic stimulation [39]. These efforts
include therapies such as beta blockade, use of an intraaortic balloon pump, and
consideration of emergency revascularization.
If the patient has refractory polymorphic VT in the setting of bradycardia to a rate
less than 60 beats per minute or a long QTc, temporary pacing at a higher rate
may be instituted.
Electrolytes should be aggressively repleted (serum potassium goal >4.0 meq/L
and serum magnesium goal >2.0 mg/dL) [39].

Intravenous procainamide is an alternative to amiodarone that can be administered in a

number of ways. The standard method is an infusion of 20 mg/min until the arrhythmia
terminates, hypotension ensues, the QRS is prolonged by more than 50 percent, or a
total of 17 mg/kg (1.2 g for a 70 kg patient) has been given.

The 2010 AHA guidelines give a weak recommendation regarding the use of
intravenous lidocaine for the treatment of recurrent sustained VT, stating it should only
be considered for use if amiodarone is not available [50]. However, lidocaine is a
relatively safe agent that has no adverse hemodynamic effects and a rapid onset of
action, and therefore may be useful in some patients. If lidocaine is used, it should be
administered by intravenous push in a dose of 0.5 to 0.75 mg/kg; this dose is repeated
every 5 to 10 minutes as needed. At the same time, a continuous intravenous lidocaine
infusion of 1 to 4 mg/min is begun. The maximum total dose is 3 mg/kg over one hour.

VENTRICULAR FIBRILLATION Ventricular fibrillation (VF) is the most frequent

mechanism of sudden cardiac death (SCD). It is a rapid, disorganized ventricular
arrhythmia, resulting in no uniform ventricular contraction, no cardiac output, and no
recordable blood pressure. The electrocardiogram in VF shows rapid (300 to 400
beats/min), irregular, shapeless QRST undulations of variable amplitude, morphology and
interval (figure 4). Over time, these wave forms decrease in amplitude. Ultimately,
asystole occurs.

The majority of episodes of VF occur within the first 48 to 72 hours after the onset of
symptoms [12-14]. It is presumably a manifestation of ischemia and is associated with
lack of perfusion via the infarct-related artery [46,53].
Primary and nonprimary VF Ventricular fibrillation (VF) can be further subclassified
as primary or nonprimary:

Primary VF refers to VF that occurs early (usually <48 hours post myocardial
infarction), and is not associated with recurrent ischemia or heart failure. This
category is defined to identify patients who experience VF despite a relatively
uncomplicated myocardial infarction (ie, as a primary electrical event).
Nonprimary VF refers to all other episodes. VF is more common in patients with
myocardial infarctions that are complicated by heart failure or recurrent ischemia.

VF Predictors There are no clinical features that reliably identify the individual patient
who is likely to develop ventricular fibrillation (VF) in the periinfarction period. However,
retrospective analyses of several clinical trials and a large meta-analysis of both clinical
trials and observational series have identified some factors that are associated with an
increased risk of early VF [12,14,54,55]. These include:

ST elevation myocardial infarction (STEMI) In a meta-analysis including 57,158

patients, the presence of ST elevations was the most powerful predictor of
primary VF (odds ratio [OR] 3.35 compared to non-STEMI, 95% CI 2.43 to 4.62)
[14,55].
Hypokalemia In the GISSI-2 trial the incidence of VF among patients with a
serum potassium <3.6 meq/L was nearly twice that seen in patients with a higher
serum potassium [12,55].
Hypotension defined as systolic blood pressure 120 mmHg on admission [12].
Larger infarcts (based upon myocardial enzyme levels) [55].
Male sex (OR 1.27, 95% CI 1.12 to 1.43) [55].
History of smoking (OR 1.26, 95% CI 1.04 to 1.53) [55].
Preinfarction angina Preinfarction angina may protect against out-of-hospital VF
(OR 0.25, 95% CI 0.10 to 0.66, and OR 0.84, 95% CI 0.77 to 0.99 for two
different studies, respectively) [54,55]. This effect is presumably due to ischemic
preconditioning. (See "Clinical implications of ischemic preconditioning".)

In the APEX AMI trial of STEMI patients with planned PCI, multivariate analysis identified
the following significant predictors of early (prior to the end of cardiac catheterization) VF
or sustained VT [19]:

Pre-PCI Thrombolysis in MI (TIMI) flow grade 0 (HR 2.94, 95% CI 1.93 to 4.47)
Inferior infarction (HR 2.16, 95% CI 1.58 to 2.93)
Total baseline ST segment deviation (HR 1.39, 95% CI 1.19 to 1.63)
Killip Class (table 1) greater than I (HR 1.88, 95% CI 1.29 to 2.76).

In this same study, the following predictors of late (after the end of catheterization but
before discharge) VF or sustained VT were found [19]:

ST resolution less than 70 percent (HR 3.17, 95% CI 1.60 to 6.28)

Total baseline ST deviation (HR 1.43, 95% CI 1.14 to 1.79)
Post-PCI TIMI flow less than grade 3 (HR 2.09, 95% CI 1.24 to 3.52)
Pre-PCI TIMI flow grade 0 (HR 2.12, 95% CI 1.20 to 3.75)
Beta blockers in the first 24 hours (HR 0.52, 95% CI 0.32 to 0.85)
Prognosis after early VF The occurrence of ventricular fibrillation (VF) among
patients with an acute MI, if occurring within the first 48 hours, is associated with an
increase in early mortality (eg, in-hospital mortality), but little or no increase in mortality
at one to two years among patients who survive to hospital discharge [12,13,46-48,56].

A report from the GISSI-2 trial evaluated the prognostic significance of ventricular
arrhythmias in 9720 patients with a first ST elevation MI (STEMI) who were treated with
fibrinolytic therapy [12]. Arrhythmias were characterized as primary VF (occurring in the
absence of heart failure or shock), nonprimary VF (all other VF), and VT. Primary VF was
further characterized as early (within 6 hours), or late (between 6 and 48 hours). This
distinction is in contrast to most other reports, in which the term "late VF" usually refers
to events that occur more than 48 to 72 hours after the MI. The following findings were
noted (figure 5):

Both early and late primary VF (ie, all events occurring within the first 48 hours)
were associated with a significant increase in in-hospital mortality.
The mortality rate from discharge to six months was not affected by primary VF.
Mortality from discharge to six months was markedly increased in those with
nonprimary VF.

Similar findings were noted in the GUSTO-I trial cited above, which included over 40,000
patients with STEMI who were treated with fibrinolytic therapy [13]. The 1229 patients
with early (first 48 hours) VF alone (ie, without VT) had an increased rate of in-hospital
mortality (19.8 versus 4.2 percent in those without sustained ventricular arrhythmia);
however, among those who survived 30 days, the one year mortality was the same as
that in patients without ventricular arrhythmias (2.7 percent in both groups) (figure 3).

Data are more limited in patients with a non-STEMI. In the pooled analysis noted above
of patients with non-ST elevation MI or unstable angina, VF was a significant predictor of
increased mortality at both 30 days and six months (adjusted hazard ratio 23 and 15,
respectively) [14]. The increase in risk was largely due to more deaths in the first 30
days.

Additional information on the prognosis of patients with early VF comes from the APEX
trial. (See 'Prognosis after early VT' above.)

Acute therapy Ventricular fibrillation (VF) is almost universally lethal if not treated,
with very few spontaneous reversions to sinus rhythm. Defibrillation is the definitive
therapy for VF. If available, a biphasic waveform defibrillator is preferable since the
success rate for defibrillation is higher than with monophasic waveforms. (See "Basic
principles and technique of cardioversion and defibrillation", section on 'Monophasic
versus biphasic waveforms'.)

The 2010 AHA guidelines for adult advanced cardiac life support (ACLS) recommended
that, for biphasic defibrillators, the initial shock should be at 120 to 200 joules, with
subsequent shocks at the highest available biphasic energy level (200 joules for most
devices) [50]. For monophasic defibrillators, nonescalating shocks beginning at 360
joules should be used. (See "Advanced cardiac life support (ACLS) in adults".)
Following successful reversion to sinus rhythm, patients should be treated with
intravenous amiodarone for 24 to 48 hours. The dosing schedule is similar to that used
for sustained VT (see 'Sustained ventricular tachycardia' above). At present, an ICD is
not generally appropriate for VF occurring in the first 24 to 48 hours of an acute MI.

The approach to VF that persists after three rapid shocks delivered in a row is discussed
in detail separately. (See "Supportive data for advanced cardiac life support in adults
with sudden cardiac arrest".)

Electrical storm Electrical storm is defined as multiple recurrent episodes of

ventricular fibrillation (VF). The optimal therapy of this problem in patients with an acute
myocardial infarction (MI) is uncertain. (See "Electrical storm and incessant ventricular
tachycardia".)

Two approaches warrant comment:

One modality that is of benefit is sympathetic blockade. This was illustrated in a

report of 49 patients with a recent MI (mean 11 days) who had electrical storm,
which was defined as 4 VT/VF episodes per hour or 20 per day [57]. Compared
to 22 patients receiving ACLS-guided antiarrhythmic therapy, those treated with
sympathetic blockade (beta blockers in 21 and stellate ganglionic blockade in six)
had a lower mortality at one week (22 versus 82 percent). Patients who survived
the initial electric storm event did well over the one-year follow-up.

Radiofrequency catheter ablation may be used as a bailout therapy in patients

with refractory electrical storm who may otherwise require cardiac
transplantation. The potential efficacy of this approach was illustrated in a report
of four patients (out of 2340 seen with an acute MI) with persistent electrical
storm despite beta blockers and amiodarone [58]. All episodes were triggered by
monomorphic ventricular premature beats (VPBs) with a right bundle branch block
morphology. Activation mapping of the VPBs identified the sites of earliest
activation with Purkinje potentials at the same sites. Six to thirty radiofrequency
applications abolished these local potentials and suppressed VPBs in all patients,
who subsequently remained free of VT or VF for 5 to 33 months. This surprisingly
favorable course following discharge is similar to that described in the preceding
report with sympathetic blockade.

TREATMENT OF ISCHEMIA Patients with ventricular arrhythmias in the setting of an

acute myocardial infarction (MI) should receive aggressive treatment for both the
arrhythmia and ischemia. Therapy for ischemia usually includes either primary
percutaneous coronary intervention (PCI) or fibrinolysis.

The outcomes in patients who are resuscitated from a cardiac arrest in the setting of an
ST elevation MI who undergo emergent primary PCI were illustrated in a multicenter
series of 186 patients [59]:

PCI was successful in 87 percent of cases.

Rates of six-month survival and six month survival free of neurological sequelae
were 54 and 46 percent, respectively.
 Predictors of six-month survival were shorter intervals between cardiac arrest and
the arrival of first responders and shorter intervals between cardiac arrest and the
return of spontaneous circulation.

The 2006 ACC/AHA/ESC guidelines for the management of ventricular arrhythmias made
the following recommendations [60]:

Patients with ventricular arrhythmias should be treated aggressively for

myocardial ischemia, if present. (See "Overview of the acute management of
acute ST elevation myocardial infarction" and "Overview of the acute management
of unstable angina and acute non-ST elevation myocardial infarction".)
Patients with evidence of myocardial ischemia that precedes ventricular fibrillation
should undergo coronary revascularization for the purpose of reducing the risk of
SCD.

LATE ARRHYTHMIAS In most cases, patients with sustained ventricular tachycardia

(VT) or ventricular fibrillation (VF) that occurs after the early acute MI period are
considered survivors of sudden cardiac death (SCD). As such, they are treated according
to secondary prevention protocols, usually with an implantable cardioverter-defibrillator
(ICD). The definition of "early" versus "late" arrhythmias varies among cardiologists and
electrophysiologists, and is also receding with time. Whereas in the past the line was
often drawn at 48 to 72 hours, many now consider late arrhythmias to be those that
occur beyond 24 to 48 hours post-MI. (See "Role of implantable cardioverter-
defibrillators for the secondary prevention of sudden cardiac death".)

Late VT "Late" VT (ie, VT that occurs after the first 24 to 48 hours) is most often
related to healing of the infarct and may reflect the development of an arrhythmogenic
substrate that promotes the development of VT (eg, scar tissue). The associated fibrosis
leads to areas of conduction block with interdigitation of viable myocardium; the ensuing
slowing of conduction at the border of the infarct can lead to stable reentry circuits and
VT [61]. (See "Pathogenesis of ventricular tachycardia and ventricular fibrillation during
acute myocardial infarction", section on 'Chronic phase arrhythmias'.)

Late VT is a predictor of a worse prognosis [13,17,62]. The following findings were noted
in the patients with late ventricular arrhythmia in the GUSTO-I trial [13]:

The in-hospital mortality was significantly higher in patients who had late
sustained VT alone (37.5 percent) or VT and VF (57.0 percent) compared to those
without sustained ventricular arrhythmia (4.2 percent).
The one-year mortality of 30 day survivors was significantly higher among those
who had late VT alone (24.7 percent) compared to those without sustained
ventricular arrhythmia (2.7 percent).

A similar adverse effect was noted in the GISSI-3 trial in which late VT occurred in 1
percent of patients between 48 hours and six weeks [62]. Late VT was associated with a
more complicated in-hospital and six-week posthospital course, a higher incidence of
pump failure, atrial arrhythmias, asystole, atrioventricular block, and VF, and a higher
mortality at six weeks (35 versus 5 percent without VT, hazard ratio 6.13).
(See "Sustained monomorphic ventricular tachycardia in patients with a prior myocardial
infarction: Treatment".)
Late VF Patients who develop sustained VF more than 48 hours after their MI ar1e
also thought to be at risk for recurrent ventricular tachyarrhythmias and to have a worse
prognosis [13,17,62]. Such patients typically receive an ICD as well as revascularization
and optimal medical therapy [39]. (See "Implantable cardioverter-defibrillators: Clinical
trials of secondary prevention of sudden cardiac death".)

Treatment The 2004 ACC/AHA guidelines on STEMI gave a class I recommendation to

the insertion of an implantable cardioverter-defibrillator (ICD) in patients with
hemodynamically significant sustained VT more than two days after an MI, provided that
the arrhythmia is not judged to be due to transient or reversible ischemia or reinfarction
[39]. (See "Implantable cardioverter-defibrillators: Clinical trials of secondary prevention
of sudden cardiac death".)

SUMMARY

Ventricular arrhythmias, ranging from isolated ventricular premature beats (VPBs)

to ventricular fibrillation (VF), are common in the immediate postinfarction period.
(See 'Incidence' above.)
In patients with asymptomatic VPBs in the peri-infarct period, attempting to
suppress these with antiarrhythmic drugs does not improve outcomes, and, with
some drugs, may actually increase mortality. Thus, we do not routinely treat
asymptomatic VPBs with antiarrhythmic medications during the peri-infarct
period. (See 'Ventricular premature beats' above.)
In patients with asymptomatic nonsustained ventricular tachycardia (NSVT) in the
peri-infarct period, suppression with antiarrhythmic drugs has not been shown to
improve outcomes. Thus, we do not routinely treat asymptomatic NSVT with
antiarrhythmic medications during the peri-infarct period. However, in the rare
case when NSVT is frequent and/or causes hemodynamic compromise, treatment
with additional beta blockade or, if necessary, amiodarone or procainamide, may
be useful. (See 'Nonsustained ventricular tachycardia' above and "Management of
nonsustained ventricular tachycardia".)
VF is the most frequent mechanism of sudden cardiac death, with the majority of
VF occurring within the first 48 to 72 hours after the onset of symptoms.
(See 'Ventricular fibrillation' above.)
In patients with ST elevation myocardial infarction (STEMI) treated with
fibrinolysis, the incidence of sustained VT or VF is approximately 10 percent, with
80 to 85 percent occurring in the first 48 hours. (See 'Fibrinolytic therapy' above.)
In patients with STEMI treated with primary percutaneous coronary intervention
(PCI), VT or VF occurs in approximately 6 percent, with 85 percent occurring in
the first 48 hours. (See 'Primary PCI' above.)
Following non-STEMI, patients have a much lower incidence of sustained VT or VF
(2 percent), with the majority of these arrhythmias occurring after 72 hours.
(See 'Non-ST elevation MI' above.)
The development of VF among patients with an acute MI, if occurring within the
first 48 hours, is associated with an in-hospital mortality rate of approximately 20
percent. (See 'Prognosis after early VF' above.)
Patients who develop early VT (within 48 hours) have markedly higher rates of
30-day mortality (as high as 40 percent mortality compared to 2 to 4 percent
mortality in those without VT). (See 'Prognosis after early VT' above.)
 In accordance with the 2006 ACC/AHA/ESC guidelines, patients with ventricular
arrhythmias should be treated aggressively for myocardial ischemia, if present,
and should undergo coronary revascularization for the purpose of reducing the
risk of sudden cardiac death. (See 'Treatment of ischemia' above and "Overview
of the acute management of acute ST elevation myocardial
infarction" and "Overview of the acute management of unstable angina and acute
non-ST elevation myocardial infarction".)

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Coronary artery patency and outcome after myocardial infarction

Authors
Richard C Becker, MD
Carey Kimmelstiel, MD

Section Editor
Freek Verheugt, MD, FACC, FESC

Deputy Editor
Gordon M Saperia, MD, FACC

Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last
updated: Fri Oct 08 00:00:00 GMT 2010 (More)

INTRODUCTION It is widely accepted that the likelihood of death after myocardial

infarction (MI) correlates inversely with left ventricular performance. In turn, the degree
of left ventricular dysfunction is determined by the extent of myocardial necrosis or
infarct size. Thus, pump failure and increased mortality result when the infarct is large
and ventricular compromise is severe [1,2].

Prompt and sustained coronary arterial patency has repeatedly been found to limit infarct
size. Among patients with an acute ST elevation (Q wave) MI, over 90 percent have
complete occlusion of the culprit artery, patency can be achieved by fibrinolysis, primary
percutaneous coronary intervention (PCI), or a combination of both modalities. In
addition, there are many factors (hemodynamic, anatomic, cellular) that influence
coronary artery patency regardless of the technique used (figure 1). (See "Characteristics
of fibrinolytic (thrombolytic) agents and clinical trials in acute ST elevation myocardial
infarction" and "Primary percutaneous coronary intervention in acute ST elevation
myocardial infarction: Determinants of outcome" and "Primary percutaneous coronary
intervention versus fibrinolysis in acute ST elevation myocardial infarction: Clinical
trials".)

TIMI FLOW GRADE The degree of perfusion in the infarct-related artery (IRA) is
typically described by the TIMI flow grade:

TIMI 0 refers to the absence of antegrade flow beyond a coronary occlusion.

TIMI 1 flow is faint antegrade coronary flow beyond the occlusion, although filling
of the distal coronary bed is incomplete.
TIMI 2 flow is delayed or sluggish antegrade flow with complete filling of the distal
territory.
TIMI 3 flow is normal flow which fills the distal coronary bed completely.

(See "Fibrinolytic (thrombolytic) agents in acute ST elevation myocardial infarction:

Markers of efficacy", section on 'TIMI flow grade'.)

OPEN VESSEL HYPOTHESIS In the early 1940s, the possible relationship between a
patent IRA, myocardial damage, and mortality was first advanced in the open vessel
hypothesis. This theory holds that early reperfusion results in myocardial salvage,
preserves ventricular performance, and is ultimately responsible for improved patient
survival.

The foundation for the open vessel hypothesis came from the demonstration in dogs that
the extent of infarction was affected by the duration of coronary arterial occlusion. As a
result of this and subsequent investigations, the clinical importance of a patent, as
opposed to an occluded infarct-related coronary artery, is now widely accepted.

The impact of reperfusion of the infarct-related artery with either fibrinolysis or

angioplasty on survival may be due to both time-dependent and time-independent
mechanisms. Time independent mechanisms possibly responsible for improved survival
include [3-15]:

Effects on post-MI left ventricular remodeling, such as a reduction in infarction

expansion, ventricular dilatation, and aneurysm formation, resulting in better left
ventricular function and a smaller wall motion abnormality [14]
Improvement in diastolic function [13]
Effects on infarct healing
Electrophysiologic effects and electrical stability, including a reduction in the
incidence and duration of sustained ventricular arrhythmias [15], lower incidence
of induced ventricular tachycardia, a reduced frequency of late potentials on a
signal averaged ECG, and reduction in QT dispersion
Perfusion of hibernating myocardium
Collateral blood supply to distant ischemic myocardium (see "Coronary collateral
circulation")

Patent artery and degree of residual stenosis Analysis of coronary angiograms

obtained in 2119 patients entered into the TIMI 4, 10A, 10B, and 14 trials found the
following results at 90 minutes after fibrinolytic therapy [16]:
 Only 9 percent of patients had a patent culprit artery and <50 percent residual
luminal diameter stenosis
71 percent had a patent artery and 50 percent residual stenosis,
20 percent had a totally occluded vessel

Compared to those with a patent artery and 50 percent residual stenosis, those with
mild residual stenosis were younger, had fewer prior infarctions, and fewer eccentric or
ulcerated lesions, but also had a greater thrombus burden. A milder residual stenosis was
associated with a lower incidence of in-hospital death, myocardial infarction, or heart
failure (2.8 versus 7 percent).

Predictors of early IRA patency In order to establish variables of greatest

importance for determining early IRA patency, defined as TIMI grade 3 flow after
fibrinolysis, the GUSTO 1 angiographic substudy analyzed data from 1030 patients [17].
Predictors of TIMI grade 3 flow at 90 minutes included (figure 2) [17]:

Use of an accelerated alteplase regimen

The IRA (right and circumflex versus left anterior descending)
History of cigarette smoking

ST segment resolution and IRA ST segment resolution also correlates with IRA
patency and TIMI flow grade (figure 3). This was seen in the TIMI 14 trial of 444 patients
with interpretable ECGs who underwent angiography at 90 minutes [18]. Seventy-nine
percent of those with complete (70 percent) ST segment resolution had TIMI grade 3
flow and their 30-day mortality was 1 percent. In contrast, patients with partial or no ST
segment resolution were less likely to have TIMI grade 3 flow (50 and 44 percent,
respectively) and had a higher 30-day mortality (4.2 and 5.9 percent, respectively)
(figure 4). Although patients without ST segment resolution may still have a patent
coronary artery, they are nevertheless at increased risk for mortality, which is likely due
to extensive microvascular and tissue injury. (See "Fibrinolytic (thrombolytic) agents in
acute ST elevation myocardial infarction: Markers of efficacy".)

Coronary artery patency versus perfusion Despite angiographic evidence of an

open infarct-related coronary artery, patients may have slow coronary artery flow (TIMI
grade 2 flow) and a mismatch between patency and myocardial perfusion may be
observed (no-reflow phenomenon), resulting in persistent left ventricular dysfunction;
this may be due to irreversible myocardial necrosis, to reversible myocardial injury or
stunning, to macro or microcirculatory perfusion abnormalities (microvascular
dysfunction), or to a residual stenosis. Improvement after stenting is expected in
patients with a residual stenosis but not in those with evidence of microvascular damage
[19]. Optimal therapy of no-reflow is uncertain. (See "Suboptimal reperfusion after
primary percutaneous coronary intervention in acute ST elevation myocardial infarction",
section on 'No-reflow phenomenon'.)

Blood flow in nonculprit artery Although reperfusion trials have focused on blood
flow in the culprit artery, flow in the nonculprit arteries is also of importance. It has been
assumed that flow in these arteries is normal, but data are limited. One report measured
the corrected TIMI frame count (ie, the number of frames required for contrast to reach a
standardized distal landmark) in 1817 nonculprit arteries of patients entered into the
TIMI 4, 10A, 10B, and 14 fibrinolytic trials [20]. At 90 minutes, blood flow in the
nonculprit vessels was 45 percent slower than normal flow in the absence of a myocardial
infarction. Patients with reduced blood flow in nonculprit arteries had a higher incidence
of regional wall motion abnormalities within the distribution of the nonculprit vessel.
Culprit and nonculprit blood flows were directly related at baseline, and relief of the
residual stenosis in the culprit artery with angioplasty restored its flow to a level equal to
the nonculprit artery; however, after angioplasty, blood flow in both culprit and
nonculprit arteries remained 45 percent below normal.

Correlates of slower nonculprit artery flow included:

Pulsatile flow pattern (systolic flow reversal) in the nonculprit artery

Left anterior descending culprit artery location
Decreased systolic blood pressure
Reduced cardiac output on ventriculography
Decreased double product
Greater percent of stenosis in the nonculprit artery
Greater percent of the culprit artery bed lying distal to the stenosis

Microvascular dysfunction As described above, successful reperfusion after an

acute MI has generally been defined as restoration of normal flow in the infarct-related
epicardial coronary artery. (See 'TIMI flow grade' above.) However, even after
restoration of patency in the IRA, there may be a persistent impairment in tissue
perfusion due to microvascular dysfunction. This has been called the no-reflow
phenomenon and has been a particular problem after primary PCI. (See "Suboptimal
reperfusion after primary percutaneous coronary intervention in acute ST elevation
myocardial infarction", section on 'No-reflow phenomenon'.)

Microvascular dysfunction is also a component of ischemia-reperfusion injury. Brief

periods of ischemia at the onset of reperfusion, a phenomenon called ischemic
postconditioning, may improve microvascular flow and reduce infarct size. (See "Clinical
implications of ischemic preconditioning", section on 'Ischemic
postconditioning' and "Definition and pathogenesis of ischemic preconditioning".)

SPONTANEOUS REPERFUSION Spontaneous reperfusion occurs in both ST elevation

and non-ST elevation MI.

ST elevation MI Although primary PCI or fibrinolysis is standard therapy for acute ST

elevation MI, spontaneous reperfusion occurs in an increasing proportion of patients over
time. It has been estimated that, in the absence of reperfusion therapy, the proportion of
patients with an ST elevation MI who have an occluded IRA falls from 87 percent at four
hours to 65 percent at 12 to 24 hours to 45 percent at one month [1,21].

As described below, the attainment of a patent IRA after fibrinolysis is associated with
lower rates of morbidity and mortality. Outcomes are also improved with spontaneous
reperfusion [22,23].

In the PAMI trials, for example, 16 percent of patients had TIMI 3 (normal) flow before
PCI (ie, spontaneous reperfusion) [22]. The patients with TIMI 3 flow had the following
significant benefits: greater clinical and angiographic evidence of myocardial salvage; a
lesser likelihood of presenting in or developing heart failure; and a lower rate of early
and late mortality (six month mortality: 0.5 versus 2.8 and 4.4 percent with TIMI grade
2 and 0/1 flow, respectively).
Non-ST elevation MI Spontaneous early reperfusion is much more common in
patients with non-ST elevation acute coronary syndromes. Coronary arteriography,
performed during the acute period in these disorders, demonstrates that the IRA is not
occluded in 60 to 85 percent of cases [24-27]. The nonoccluding thrombi that are present
are primarily grayish-white (ie, platelet-rich), and therefore less likely to respond to
fibrinolytic therapy [28], in contrast to being almost always reddish (ie, fibrin-rich) in
patients with ST elevation MI [29]. In addition, microvascular perfusion is often reduced
in patients with non-ST elevation acute coronary syndromes; as a result, the ongoing
mechanism of ischemia is more likely embolization than epicardial vessel occlusion [27].
(See "Fibrinolytic (thrombolytic) agents in unstable angina and acute non-ST elevation
myocardial infarction".)

IRA PATENCY AND OUTCOME AFTER FIBRINOLYSIS Patency of the IRA after
fibrinolytic therapy appears to have beneficial effects on both the short and long term
outcome of patients with acute MI. This is most likely to occur when therapy is given
within two to three hours of symptom onset (figure 5). A meta-analysis from the
Fibrinolytic Therapy Trialists' (FTT) Collaborative Group found that the absolute mortality
benefit from fibrinolytic therapy at five weeks was 3 percent for those presenting within
six hours from symptom onset, 2 percent for those presenting within 7 to 12 hours, and
a nonsignificant 1 percent for those presenting within 13 to 18 hours [30].
(See "Fibrinolytic (thrombolytic) agents in acute ST elevation myocardial infarction:
Therapeutic use", section on 'Time to therapy (door-to-needle time)'.)

As noted above, spontaneous reperfusion before fibrinolytic therapy or PCI is also

associated with a better prognosis. (See 'Spontaneous reperfusion' above.)

Short-term morbidity and mortality Evidence supporting a beneficial effect of early

IRA patency on mortality date back to the initial fibrinolytic trials. In the Western
Washington Intracoronary Streptokinase trial, for example, patients with a patent IRA
had a mortality at one month that was one-half that of patients with a closed artery. The
difference in mortality between the two groups persisted at one year follow-up, as
patients with patent IRAs had less than one-fifth the mortality of those with occluded
arteries. Similar results were seen in the TIMI 1 trial, with impressive reductions in 21-
day and one-year mortality in patients with patent IRAs [31].

The beneficial effect of coronary artery patency on short-term mortality suggested by

early fibrinolytic trials was supported by an overview of four German multicenter clinical
trials which included early coronary angiography [32]. Complete reperfusion of the IRA
as determined by coronary angiography 90 minutes after the initiation of fibrinolytic
therapy was associated with the significant reduction in in-hospital mortality. In addition,
only TIMI grade 3 flow conferred a survival benefit (2.7 percent); patients with TIMI
grade 2 flow fared no better than those with TIMI 0/I flow (6.6 and 7.1 percent,
respectively).

This important observation has subsequently been confirmed by data from a number of
other trials (figure 6) [32-36]. GUSTO 1, for example, tested the hypothesis that early
and sustained patency of an infarct-related vessel is associated with improved survival
[34-36]. Forty-one thousand patients in over 1,000 hospitals in 15 countries with
evolving myocardial infarction presenting within six hours of symptom onset were
randomized to streptokinase (1.5 million units over 60 minutes) plus either subcutaneous
heparin (12,500 units BID) or intravenous heparin (5,000 unit bolus followed by 1,000
units per hour), or to accelerated alteplase (recombinant tissue-type plasminogen
activator or tPA) with intravenous heparin (accelerated refers to the rate at which
alteplase is given). (See "Fibrinolytic (thrombolytic) agents in acute ST elevation
myocardial infarction: Therapeutic use".) A fourth arm consisted of a combination of
streptokinase and alteplase.

Alteplase was associated with a 1 percent absolute reduction in mortality (6.3 versus 7.3
percent) compared to streptokinase. The mortality benefit for alteplase was greatest in
patients less than 75 years old and in those with anterior wall infarctions. The time of
fibrinolysis was also important, independent of the fibrinolytic agent used (alteplase or
streptokinase) [37]. Early fibrinolysis was associated with a lower 30 day mortality rate
(less than two hours 5.5 percent; greater than four hours 9.0 percent).

In the angiographic substudy, accelerated alteplase produced TIMI 3 flow at 90 minutes

in 54 percent compared to only 30 to 33 percent for the streptokinase groups. Patency
rates for streptokinase and alteplase were only different at the 90 minute mark. Over
time, streptokinase "caught up" with alteplase so that patency for both agents was
similar at four hours. The earlier and more complete infarct vessel patency associated
with alteplase at 90 minutes appears to contribute to the lower mortality [34-36].

When data from 11,228 patients enrolled in GUSTO 1 were analyzed, 45 percent of
patients overall had an open IRA, defined as the presence of TIMI grade 3 flow [38].
Those with an open artery had a lower 30 day mortality (1.5 versus 6.3 percent for a
closed artery) even after adjusting for baseline clinical predictors of outcome including
ejection fraction. At one year, the mortality rate among those surviving after the first 30
days was still lower for those with an open vessel (3.3 versus 8.8 percent); however,
after adjusting for clinical variables, patency was no longer a significant predictor and the
only predictor of mortality was the left ventricular ejection fraction (LVEF) (figure 7).

Patency also is associated with lower morbidity. This was illustrated in a study of 327
patients who received fibrinolysis [39]. Those with coronary artery reperfusion based
upon clinical markers (eg, relief of pain, 50 percent reduction in the sum of ST segment
elevation, and abrupt initial release of creatine kinase levels >2 fold over normal) not
only had a lower 30-day mortality (3.8 versus 16.2 percent for those without evidence of
reperfusion), but also had a lower incidence of heart failure (10.5 versus 23.1 percent)
and less often progressed to cardiogenic shock (0.5 versus 12.8 percent).

Long-term mortality Improved long-term prognosis attributable to patency of the

infarct-related artery is supported by several studies which analyzed different types of
patients [40-47].

Single-vessel coronary disease One study retrospectively analyzed patients with

single-vessel coronary artery disease who underwent cardiac catheterization following
myocardial infarction [41]. These patients had not received a fibrinolytic agent. Patients
with partial or complete anterograde flow were compared to those with minimal or no
flow through the infarct-related artery. Survival correlated most significantly with a
patent IRA. Over a five-year follow-up period, no patients with a patent IRA died
compared to an 18 percent mortality observed in those with minimal IRA perfusion
(p<0.001) (figure 8). Heart failure, unstable angina, and recurrent MI were also more
common in patients with minimal perfusion.
TIMI flow The GUSTO 1 trial evaluated the importance of TIMI flow grade in 2431
patients with a myocardial infarction who received fibrinolysis [47]. The two-year
mortality for those with TIMI 3 flow was 7.9 percent compared to 15.7 percent for those
with lesser flow grades (hazard ratio 0.48) [47]. When survival after 30 days was
analyzed separately, there was an additional 3.3 percent mortality in those with TIMI 3
flow compared with 8.3 percent for lesser flow grades (hazard ratio 0.39); thus, the
benefit of having TIMI 3 flow continued after the acute phase (a gain of 5 lives per 100
during this period) (figure 9). This benefit was independent of left ventricular ejection
fraction.

Anterior MI and LAD perfusion In the ISAM (Intravenous Streptokinase Acute

Myocardial infarction) trial, 368 patients in whom reperfusion was achieved were
subsequently followed for approximately three years [43]. Angiographic evaluation was
generally performed one month following MI. Using a strict definition of patency that
incorporated both TIMI flow grade and stenosis severity of the IRA, mortality in patients
with an anterior MI who had a patent LAD was 8 percent compared with 28 percent in
those with an occluded artery (p<0.03).

Left ventricular dysfunction The potential importance of IRA patency in patients

with left ventricular (LV) dysfunction was illustrated in a study of over 300 patients
treated with fibrinolytic therapy who had coronary angiography performed one month
following MI [45]. Employing an occlusion score that considered both TIMI flow grade and
the amount of myocardium supplied by the IRA, the investigators confirmed that patients
with a LV ejection fraction (LVEF) less than 50 percent who had an occluded IRA (defined
as less than TIMI 3 grade flow) experienced an adverse prognosis regardless of the
myocardial distribution. In those with LVEF >50 percent, an occluded vessel was
associated with a poor prognosis when it supplied approximately 25 percent of the LV.
The study clearly highlights the independent long-term prognostic importance of arterial
patency in addition to LV function following fibrinolytic therapy.

TIMI frame count The clear correlation between coronary flow and patient survival
has stimulated enthusiasm for the development of more quantitative and precise
measures than the semi-quantitative TIMI flow scale. It is hoped that increasingly
accurate measures of coronary arterial flow velocity will minimize the limitation resulting
from interobserver variability seen with the present system. The TIMI frame count, which
is the number of cine frames required for dye to first reach standardized distal coronary
landmarks, has shown great promise, particularly in defining low-risk and high-risk
patient subsets [48].

One study measured the TIMI frame count in 1248 patients treated with fibrinolytic
agents in the TIMI 4, 10, and 10B trials [49]. The following findings were noted (figure
10):

Patients who died in the hospital had a higher frame count (slower flow)
compared to survivors (70 versus 50); a higher frame count was also observed in
those who died by 30 to 42 days. In a multivariate model that excluded the TIMI
flow grade, there was a 0.7 percent increase in absolute mortality for every 10-
frame rise.
The frame count further stratified patients with TIMI grade 3 flow. Although a
frame count 40 is associated with TIMI grade 3 flow, those with a frame count
20 had a 7.9 percent incidence of in-hospital adverse events (death, recurrent
 infarction, shock, congestive heart failure or left ventricular ejection fraction 40
percent) compared to 15.5 percent for those with a frame count between 21 and
40.
Patients who had an adverse in-hospital outcome (death, recurrent infarction,
shock, heart failure, or ejection fraction 40 percent) had a slower global TIMI
frame count (ie, the average of all three coronary arteries) [20].

Another small study of 104 patients with a first MI found that a lower TIMI frame count
(faster flow) immediately after successful PCI (TIMI flow grade 3) predicted recovery of
regional LV function [50].

Although intraobserver and interobserver reproducibility of the TIMI frame count is good,
there are factors that can introduce variability and decrease the TIMI frame count,
including nitrate use, increasing heart rate, and injection of dye during the beginning of
diastole (versus the beginning of systole) [51].

Assessing myocardial perfusion The assessment of myocardial perfusion is highly

relevant because tissue level blood flow is a major determinant of ventricular salvage and
viability following acute MI. The TIMI myocardial perfusion grade (TMPG) is as follows:

Grade O - Indicates the failure of contrast dye to enter the microvasculature

Grade 1 - The dye slowly enters the microvasculature but fails to exit
Grade 2 The dye entry to and exit from the microvasculature is delayed (in
comparison to the noninfarct-related areas)
Grade 3 - The dye enters and exits the microvasculature normally. A relationship
between myocardial perfusion and clinical outcome has been reported [52].

Further work in this area is needed, particularly if angiographic flow grade is to be used
as a surrogate end point in the development of new fibrinolytics and adjunctive
treatment strategies.

Plaque morphology and coronary blood flow The relationship between plaque
rupture and coronary thrombosis among patients with acute coronary syndromes is well
established. Rupture involving the proximal aspect of an atheromatous plaque, compared
to mid-or distal plaque rupture is much more likely to cause occlusive thrombus, TIMI O
blood flow and ST-segment elevation MI. A larger proportion of fibro-fatty material, as
determined by intravascular ultrasound and greater overall plaque burden associated
with reduced myocardial blood flow (myocardial blush grade) and no reflow in patients
with MI and TIMI 3 coronary artery blood flow following primary PCI [53-55].

Coronary no reflow, thrombus characteristics and outcome The absence of

successful myocardial perfusion despite infact-related vessel patency (no reflow
phenomenon) is associated with large infarction size, reduced left ventricular
performance, clinical congestive heart failure and increased mortality. In addition to
platelet, leukocyte and atheromatous debris, as well as endothelial cell swelling, patients
with no reflow exhibit a more compact fibrin network and resistance to fibrinolysis [56].

IRA PATENCY AND OUTCOME AFTER PCI There are two issues related to IRA
patency and PCI: reocclusion after PCI; and late PCI to open an occluded artery.

Reocclusion after PCI Late reocclusion after successful PCI has a negative impact on
long-term survival. This was illustrated in a review of 528 patients with a patent IRA
after a successful PCI who underwent a repeat angiogram at six months [57]. At 5.7 year
follow-up, those with reocclusion had a higher actuarial eight year total mortality rate (28
versus 10 percent) and higher cardiovascular mortality (25 versus 7 percent) compared
to those without reocclusion; the impact on long-term survival was greater in those with
an anterior wall MI (figure 11).

LATE PCI TO OPEN AN OCCLUDED ARTERY This section will address the difficult
issue of when to consider percutaneous coronary intervention (PCI) later than 24 hours
after STEMI. The discussion of when to consider PCI between 12 and 24 hours after
STEMI is found elsewhere. (See "Selecting a reperfusion strategy for acute ST elevation
myocardial infarction", section on 'Delayed presentation'.)

Fibrinolytic therapy administered more than 24 hours after the onset of acute ST
elevation MI does not improve clinical outcome (figure 5), possibly because it does not
restore artery patency. Although early PCI is also optimal, some have suggested that late
PCI to open an occluded artery might be of benefit. (See "Fibrinolytic (thrombolytic)
agents in acute ST elevation myocardial infarction: Therapeutic use", section on 'Time to
therapy (door-to-needle time)' and "Primary percutaneous coronary intervention in acute
ST elevation myocardial infarction: Determinants of outcome", section on 'Time from
hospital arrival (door-to-balloon time) on outcomes'.)

Recovery of left ventricular function decreases with later PCI [58], but late PCI may still
be beneficial at a time when fibrinolytic therapy is no longer effective [59]. This is an
important issue, since registry data suggest that 9 to 31 percent of patients with an
STEMI present more than 12 hours after the onset of symptoms [60,61]. It has been
estimated that, in the absence of reperfusion, an occluded IRA is present in 87 percent of
patients with an STEMI at four hours, 65 percent at 12 to 24 hours, and 45 percent at
one month [1,21].

A possible mechanism for benefit from late PCI is residual antegrade or collateral blood
flow, which was present in 73 percent of patients in the BRAVE-2 trial cited below [62].
The low rate of persistent flow may maintain myocardial viability and therefore infarct
size until blood flow is restored by PCI [63,64]. Mechanisms other than myocardial
salvage, such as prevention of ventricular remodeling, also may be involved [65,66].

There are two settings in which late PCI might be performed: in previously untreated
patients, which will be reviewed here; and in patients previously treated with fibrinolytic
therapy, which is a form of adjunctive or early elective PCI that will be discussed
separately. (See "Percutaneous coronary intervention after fibrinolysis for acute ST
elevation myocardial infarction", section on 'Adjunctive or early elective PCI'.)

A potential benefit of late PCI was suggested by observational data from the National
Registry of Myocardial Infarction (NRMI)-2 of 7358 patients with acute STEMI who
presented more than 12 hours after symptom onset [67]. Patients undergoing PCI (22
percent of the group) had a significantly lower incidence of recurrent ischemia or angina,
recurrent MI, and in-hospital mortality (3.4 versus 6.6 percent without PCI); the
association between PCI and lower mortality persisted after adjusting for factors
associated with a higher in-hospital mortality (odds ratio 0.67, 95% CI 0.49-0.92). With
a propensity analysis, which helps to adjust for treatment selection bias, there was still a
significant reduction in recurrent ischemia with PCI (10.8 versus 14.6 percent), and a
strong trend toward a reduction in in-hospital mortality (odds ratio 0.73, 95% CI 0.53-
1.01).
The randomized trials BRAVE-2, DECOPI, and OAT that have evaluated late PCI
have included patients at different time periods after symptom onset, ranging from more
than 12 hours to up to 28 days. Some have demonstrated an improvement in left
ventricular function with intervention, but none has demonstrated a significant benefit on
hard clinical outcomes.

The SWISSI II trial, which randomly assigned patients with both STEMI (including many
treated with fibrinolytic therapy) and NSTEMI to late PCI or medical therapy is discussed
separately. (See "Silent myocardial ischemia: Prognosis and therapy", section on
'Treatment with revascularization'.)

The BRAVE-2 trial evaluated 365 patients who presented with an acute STEMI 12 to 48
hours (median 23 hours) after the onset of symptoms [62]. The patients, who were no
longer symptomatic, were randomly assigned to an invasive strategy, which primarily
consisted of PCI with stenting, or conventional conservative therapy. The primary end
point was infarct size at 5 to 10 days as determined by Tc-99m sestamibi SPECT
imaging. There were two major findings:

Final left ventricular infarct size was significantly smaller in the late PCI group
(median 8 versus 13 percent). The size of the infarct with conservative therapy
was smaller than the expected value of 20 percent and may have reflected some
antegrade flow and some collateral flow to the infarct zone.
The secondary end point of death, recurrent MI, or stroke occurred less often with
late PCI (4.4 versus 6.6 percent). Although this difference was not significant
(relative risk 0.67, 95% CI 0.27-1.62), the study was underpowered to detect
such a modest difference in clinical outcomes.

The efficacy of primary PCI performed even later was evaluated in the DECOPI and OAT
trials. Neither showed a mortality benefit from intervention. In DECOPI, 212 patients with
a first STEMI and an occluded infarct-related artery who were seen 2 to 15 days (mean 5
days after symptom onset) underwent coronary angiography and were randomly
assigned to continued medical therapy or PCI [68]. Most patients had single vessel
disease and only 13 percent had been treated with fibrinolytic therapy.

At six months, more patients in the intervention group had a patent infarct-related artery
(82 versus 34 percent) and the LVEF was 5 percent higher (59 versus 54 percent), a
benefit seen only in those with patent infarct-related arteries. However, at a mean
follow-up of 34 months, the primary end point (a composite of cardiac death, nonfatal
MI, or ventricular tachyarrhythmia) was not significantly different in the two groups (7.3
versus 8.7 percent).

The much larger Occluded Artery Trial (OAT) included 2166 stable patients who had an
occluded IRA as determined by cardiac catheterization performed 3 to 28 days after
acute STEMI [69]. The patients were randomly assigned to optimal medical therapy alone
or with routine PCI with stenting. Important characteristics of the patients in this trial
included high-risk features (left ventricular ejection fraction [LVEF] less than 50 percent
or proximal occlusion of a major epicardial vessel) and the absence of recurrent clinical
ischemia or the demonstration of severe ischemia on stress testing. Twenty percent had
received fibrinolytic therapy.

The primary end point was a composite of death, myocardial reinfarction, or New York
Heart Association class IV heart failure (table 1). At four years, the rate of the composite
end point was not statistically different between the PCI and the medical therapy groups
(17.2 and 15.6 percent, respectively). It should be emphasized that this neutral result
was obtained despite the presence of retained viability in about 600 of patients. What
remains to be determined is whether the extent of viability could have an impact upon
outcomes, even if not shown in this study. In addition a quality of life substudy found
there was no significant difference between the two groups in measures of cardiac
physical function or psychological well-being at two years [70].

The logic for attempts to demonstrate the value of late opening of an occluded IRA in the
OAT trial was based upon the presumption that treated patients would have an
improvement in LVEF compared to patients who did not undergo PCI. TOSCA-2, an
angiographic follow-up substudy of 381 patients in OAT, was not able to demonstrate a
greater improvement in LVEF in patients with PCI than in those receiving medical therapy
[71]. At one year, there was no significant difference between the PCI and medical
therapy groups with regard to the increases seen in LVEF (48.3 to 52.5 and 48.0 to 51.2
percent, respectively).

Meta-analysis The above trials demonstrated an improvement in left ventricular

function with PCI, but not a significant benefit on hard clinical outcomes such as
mortality. An attempt to further evaluate this discrepancy was made in a meta-analysis
of ten trials (including OAT, DECOPI, BRAVE II and SWISSI II) in which 3,560 stable
patients were randomly assigned to either late (12 hours to 26 days) PCI or medical
therapy after acute MI [72]. At an average follow-up of 2.8 years patients who
underwent late PCI had a significantly better long-term survival than those who received
medical therapy (6.3 versus 8.4 percent, odds ratio for death 0.49, 95% CI 0.26 to 0.
94). However, the results of this meta-analysis need to be interpreted with extreme
caution as the trials included were very heterogeneous. Indeed, 16 percent of the
patients had an open artery at the time of angiography.

Summary The evidence that can be applied to answer the question of whether late
PCI (after 24 hours) of the infarct related artery in stable patients improves outcomes
does not allow for a firm conclusion. We agree with recommendations made in the 2007
American College of Cardiology/American Heart Association focused update of prior
STEMI guidelines (not changed in the 2009 focused update) [73]:

A weak recommendation for PCI of a hemodynamically significant stenosis in a

patent infarct artery
A strong recommendation against PCI of a totally occluded infarct artery in
asymptomatic, stable patients who have no evidence of severe ischemia and have
one or two vessel disease.

The 2008 European Society guidelines on the Management of acute myocardial infarction
in patients presenting with persistent ST-segment elevation does not address this issue
and states that there is limited experience with PCI in STEMI patients presenting more
than 12 hours after onset of symptoms [74].

The optimal approach to similar patients who present between 12 and 24 hours is also
not known.

LONG-TERM VALUE OF A PATENT IRA Among the best data on the long-term
prognostic importance of IRA patency comes from the SAVE trial. In the SAVE trial of
post-MI patients with LV dysfunction, an occluded IRA was an independent predictor of
all-cause mortality (24 versus 14 percent for patients with an occluded or patent IRA,
respectively), cardiovascular mortality (23 versus 12 percent), and the composite end
point of cardiovascular mortality or morbidity (51 versus 37 percent) at an average
follow-up of 3.5 years.

The salutary effects of IRA patency in SAVE were independent of the benefits associated
with medical therapy (which included angiotensin-converting enzyme inhibition and beta
blockade). This study differed from other studies in that IRA patency was a prespecified
ancillary end point; the analysis was restricted to post-MI patients with LV dysfunction
without clinically apparent ischemia or heart failure, baseline coronary anatomy was
known in all patients, a variety of treatment strategies culminating in IRA patency were
included, and corrections for clinical variables, including LV function, were made.