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In spite of recent improvement in overall cardiovascular mortality,
post-hospital mortality remains high in survivors of acute myocardial infarction (AMI). Approximately one third
of late deaths in survivors of AMI are sudden and unexpected and the risk of sudden death persists for years after
the AMI1,2. Prevention of sudden cardiac death (SCD), which, in the majority of cases is due to malignant
ventricular tachyarrhythmias (VT – defined as hypotensive ventricular tachycardia/ventricular fibrillation) in
survivors of AMI remains a formidable clinical challenge. Management strategy of this major health care
problem has centered over the years on two closely related aspects: one, how to identify those at risk of SCD,
and two, what are the best management modalities, vis-a-vis pharmacotherapy or the implantable cardioverter
defibrillation (ICD). Following recent publications of the results of several multicenter studies, pharmacotherapy,
mainly antiarrhythmic drugs, has not proven, so far, to be an effective management modality for those at risk of
SCD.This cleared the way for more widespread use of the ICD as the sole, or main, management modality.
Primarily because of the high cost of the ICD, and the invasive nature of this therapeutic modality, the
prophylactic use of the device for primary prevention of SCD did not gain momentum until recently. This aspect
of management strategy for SCD is still in the clinical research domain with several primary ICD prevention trials
currently underway. However, this trend has highlighted the urgent need for more powerful risk stratification
algorithms for SCD in this population.
The most recent results of the MADIT3 and
AVID4 trials on one hand and the CABG-PATCH
trial5 on the other
hand, underscored the point that the ICD works only when implanted in patients at high risk of arrhythmic death.
Besides the invasive electrophysiologic study (EPS), commonly utilized non invasive risk stratifiers include; left
ventricular ejection fraction (LVEF), ventricular arrhythmias on ambulatory Holter recording, signal averaged
electrocardiography (SAECG), heart rate variability (HRV), baroreflex sensitivity (BRS), QT dispersion, and T
wave alternans (TWA). In addition, there is a number of other less commonly utilized markers of arrhythmic
death. However, with the exception of LVEF, none of the other tests, at present, has proven to be solely
adequate as a powerful risk stratifier. An optimal algorithm that combines more than one index of high risk has
not yet been identified or agreed upon.
LVEF-LV
It is one of the best predictors of cardiac mortality and morbidity in
patients with coronary artery disease (CAD), especially after AMI. For example, in the Multicenter Postinfarction
Study, patients with LVEF<20% had an approximately 45% 1-year mortality rate, compared to a 4% rate in
patients with LVEF>40%6. However, LV systolic dysfunction is not a very sensitive marker of sudden or arrhythmic
death7. The combination of severely depressed LVEF and NYHA class IV seems to identify patients who will die
from pump failure or electromechanical dissociation rather than from malignant VT. On the other hand, in
patients with moderate-to-severe LV dysfunction, approximately one third die suddenly, relatively independent
of the severity of LVF dysfunction7. It is important to remember that the extent of LV dysfunction can influence
significantly the predictive power of other risk stratifiers, such as the SAECG and EPS.
Ambulatory Holter recording
The finding of complex ventricular arrhythmias on a Holter recording is not specific enough to identify individual
patients at high risk of SCD. Spontaneous variation from day to day in the incidence of complex ventricular
arrhythmias makes interpretation of the results of therapy guided by Holter recording subject to large errors. A
more difficult question that remains unanswered at present is the relationship of asymptomatic complex
ventricular arrhythmias to symptomatic VT. It is not clear whether these rhythm disorders are related
mechanistically, and therefore whether alterations in spontaneous ectopy by antiarrhythmic therapy will impact
on the prognosis.
SAECG
The SAECG appears useful in risk stratification of post-MI patients. Late potentials have been shown to predict
future arrhythmic events8,9. However, a recent NIH study has shown that time-domain (TD) SAECG indices of late
potentials do not provide the best prediction criteria for serious arrhythmic events in the first year post-MI, but
rather the filtered QRS duration at 40 Hz10. The SAECG has some limitations; although it appears to have an
excellent negative predictive value, both its sensitivity and positive predictive value are low. Recently, combined
time- and frequency-domain analysis of the SAECG was shown to improve its overall predictive accuracy11,12.
The rationale for combined time; and frequency-domain analysis of the SAECG is the observation that TD
analysis has a high incidence of false positive results in patients with inferior wall MI, while spectral turbulence
analysis (STA) has high incidence of false positive results in anterior MI. In a recent study of 602 post-MI patients,
receiver operated characteristics curves were utilized to optimize cutoff values for each SAECG parameter
separately, and also for the combined TD+STA model12. The negative predictive accuracy of all three analysis
was high (98%). On the other hand, the positive predictive accuracy of TD (19.6%) or STA (18.3%) was quite low,
and significantly improved to 35.8% by combined TD+STA analysis. The best results were obtained in patients
with LVEF<40%, where the positive predictive accuracy of combined TD+STA analysis was 51.2%. The study
concluded that combined TD+STA analysis of the SAECG significantly improves risk stratification power for VT
in post-MI patients compared to TD and STA separately.
HRV and BRS
Many studies have revealed an association between the autonomic nervous system and SCD13. Both HRV and
BRS are measures of the sympathovagal balance. Methods to analyze HRV employ both time- and
frequency-domain measurements that quantify periodicities in the data. Prognostic information to risk stratify
patients for future VT or other cardiac events leading to premature death may be possible by quantifying
HRV14,15. Baroreflex sensitivity assessed with phenylephrine injection is an alternative non invasive test to
evaluate sympathovagal balance16. Two major questions concerning HRV remain to be clarified. First, many
methods to measure HRV have been reported, and it is very difficult to conclude which one is most appropriate
for establishing normal values and for particular patient subgroups. There is a need to standardize the
measurement of HRV and to quantify normal values under various circumstances, including patient age and
gender. A recent effort in this regard is the report of the Task Force of the European Society of Cardiology and
the North American Society of Pacing and Electrophysiology17. Low HRV is associated with increased all-cause
mortality in middle aged and elderly men18. HRV did not add independent prognostic value to LV function and
ventricular arrhythmias on predischarge Holter recording19. On the other hand, in the ATRAMI study, low values
of BRS and HRV were significantly associated with an increased mortality risk in a multivariate model in which
LVEF and premature ventricular complexes were included16.
QT interval and QT dispersion
Previous studies have shown that prolongation of the QT interval is a risk factor for VT and SCD in patients with
previous MI20, but there has been some controversy as to the predictive accuracy of the prolonged QT interval.
QT dispersion may be a more powerful predictor of susceptibility to VT, suggesting that inhomogeneity of
repolarization is more closely associated with arrhythmic risk than is prolongation of repolarization itself21.
Spatial dispersion of recovery times may be a fundamental electrophysiologic substrate for the genesis of
reentrant VT. Day et al first proposed that interlead variability of QT interval in 12-lead electrocardiograms, QT
dispersion, reflects dispersion of ventricular recovery time, thus providing a convenient tool for clinical studies22.
However, the role of QT dispersion for risk stratification of SCD remains controversial which, in large measure,
may be due to methodologic discrepancies.Some studies suggest that increased QT dispersion is related to
susceptibility to VT, independent of the degree of LV dysfunction or clinical characteristics of the patients21.
Other studies have shown that determination of QT dispersion from the surface ECG, even when performed with
the best available methodology, failed to predict subsequent risk in post-MI patients23. Some investigators have
found an association between measures of dispersion of ventricular repolarization and susceptibility to
ventricular fibrillation24. However, because of considerable overlap between groups, these measures failed to
provide a useful marker for the risk of SCD.
TWA
Alternation of the configuration and/or duration of the repolarization wave of theECG, usually referred to as TWA,
is seen under diverse experimental and clinical conditions25. Interest in repolarization alternans is attributed to
the hypothesis that it may reflect underlying dispersion of repolarization in the ventricle, a well recognized
electrophysiologic substrate for reentrant VT. Although overt TWA in the ECG is not common, in recent years
digital signal-processing techniques capable of detecting subtle degrees of TWA have suggested that the
phenomenon may be more prevalent than previously recognized and could represent an important marker of
vulnerability to VT26. The electrophysiological basis of arrhythmogenicity of QT/T alternans in long QT syndrome
has been recently investigated in an experimental surrogate model of long QT syndrome27. The
arrhythmogenicity of QT/T alternans was primarily due to the greater degree of spatial dispersion of
repolarization during alternans than during slower rates not associated with alternans. The dispersion of
repolarization was most marked between midmyocardial and epicardial zones in the LV free wall. In the
presence of a critical degree of dispersion of repolarization, propagation of the activation wavefront could be
blocked between these zones to initiate reentrant excitation and polymorphic VT. An important observation was
that marked repolarization alternans could be present in local electrograms without manifest alternation of the
QT/T segment in the surface ECG.The latter was seen at critically short cycle lengths associated with reversal of
the gradient of repolarization between epicardial and midmyocardial sites, with a consequent reversal of
polarity of the intramyocardial QT wave in alternate cycles.These observations provide a strong impetus for
studies that explore the use of microvolt TWA as a strong predictor for SCD.
Recent technical improvements allow the detection of microvolt TWA during sinus rhythm with the heart rate
moderately elevated using bicycle exercise test. Several studies have shown that microvoltTWA detected with
heart rate elevation with bicycle exercise is a strong predictor of arrhythmia inducibility at EPS28,29. In a
prospective multicenter study of 148 patients, the relationship between TWA and the induction of VT on EPS was
assessed. TWA was a moderately sensitive but specific predictor of the results of EPS. However, TWA more
accurately predicted future arrhythmic events compared to EPS29. TWA compared favorably with EPS and other
non invasive risk markers in predicting recurrence of VT in ICD recipients30. The heart rate at the onset of TWA
in normals and in patients with VT was also investigated31. False positive TWA developed in 7% of age-matched
normal subjects at higher heart rate compared to patients with VT. A target heart rate of 110 beats/min was found
to be highly sensitive and specific. However, because of their lower symptom limited heart rate, many patients
may not be able to achieve the target heart rate associated with TWA resulting in an indeterminate test. In these
patients, non invasive or pharmacologic means to increase heart rate may be considered.
EPS
The role of EPS in risk stratification of post-MI patients for arrhythmic events remains controversial. Inducible VT
were reported in 9-20% of survivors of recent MI by EPS and after a follow-up period of one to two years, serious
arrhythmic events occurred in 14-36% of patients with inducible sustained VT32-34. In the MADIT study, patients
with one or more prior MI, LVEF£35%, non-sustained VT and inducible nonsuppressible VT had significantly
improved survival with the ICD compared to conventional medical therapy3. The MUSTT study investigated a
very similar population (the only difference was an LVEF£40%) and found that in patients with inducible VT,
EP-guided antiarrhythmic therapy improved survival primarily due to therapy with the ICD rather than “effective”
antiarrhythmic drugs35. In this study, the 5-year arrhythmic death or cardiac arrest in patients who had no
inducible VT was 26% compared to 32% in patients with inducible VT who were followed on no antiarrhythmic
therapy. However, the 5-year total mortality was similar (48%). Both MADIT and MUSTT trials failed to shed light
on the one crucial question regarding the future role of EPS in risk stratification, namely, whether non
inducibility of VT in post-MI patients is a strong marker of low risk independent of other variables, such as the
degree of LV dysfunction, TWA, etc.
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