What is the role of risk stratification for sudden death in the defibrillator era?
1 Department of Cardiology, Academic Hospital Villingen, Vöhrenbacherstr. 23, 78050 Villingen-Schwenningen, Germany
2 Department of Cardiology, Clinic of Cardiovascular Medicine, Salzburger Leite 1, 97616 Bad Neustadt/Saale, Germany
* Corresponding authors. Tel: +49 7721 933001; fax: +49 7721 933099. E-mail address: werner.jung{at}sbk-vs.de (W.J.) Tel: +49 9771 66 2602; fax: +49 9771 66 2605.E-mail address: schumacher{at}kardiologie-bad-neustadt.de (B.S.)
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Abstract |
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 Top Abstract The need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Accurate and timely prediction of sudden cardiac death (SCD) is a necessary prerequisite for effective prevention and therapy. Although the largest numbers of SCD events occur in patients without overt heart disease, there are currently no tests that are of proven predictive value in this population. Efforts in risk stratification for SCD have focused primarily on predicting SCD in patients with known structural heart disease. Despite the ubiquity of tests that have been purported to predict SCD vulnerability in such patients, there is little consensus on which test, in addition to the left ventricular ejection fraction, should be used to select patients for implantable cardioverter defibrillators (ICDs). Effective therapy exists for SCD but it is costly and is associated with potential complications. Currently used strategies for selection of the best candidates for ICDs are imperfect and leave many high-risk patients unprotected. At the same time, some patients who receive ICDs will never develop ventricular tachyarrhythmia requiring ICD intervention. This article summarizes the current status and applicability of the non-invasive and invasive tests used for SCD risk assessment.
Key Words: Risk stratification • Sudden cardiac death • Implantable cardioverter defibrillator • Non-invasive tests
Risk stratification for sudden cardiac death (SCD) has been studied primarily in patients with a history of acute myocardial infarction (AMI) and/or congestive heart failure (CHF). Because survivors of AMI and patients with CHF have long been known to be at an increased risk for SCD, randomized clinical trials of implantable cardioverter defibrillator (ICD) therapy have focused on these patients.1–7 Although most of these trials have shown a significant reduction in SCD and all-cause mortality with an ICD, most patients enrolled in those trials did not receive therapy (ICD shock or antitachycardia pacing) during study follow-up.3–6 Some have argued that this observation is evidence that, for many patients, the implantation of an ICD was not necessary; however, this argument does not take into account the trials’ limited duration of follow-up.8 Several tests have been claimed to predict SCD risk in survivors of AMI and in patients with CHF; however, there is little agreement on which test, in addition to the left ventricular ejection fraction (LVEF), should be used in clinical decision making.9
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The need for sudden cardiac death risk assessment |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Risk assessment strategies need to be re-evaluated in light of new evidence about the effectiveness of preventive therapy. Although pharmacological therapy for SCD has failed to demonstrate survival enhancement, several recent randomized clinical trials in primary SCD prevention populations have demonstrated a reduction in total mortality with use of an ICD.1–7 When applied in populations with proven benefit, ICD therapy seems to represent good value for money using conventional benchmarks, despite the high initial cost of the ICD.10
Nevertheless, many involved in the care of high-risk patients have expressed concern that the number needed to treat with a primary prevention ICD is too high and that further risk stratification, beyond that used in the trials, must be devised. The basis for these concerns is contained in several observations.
First, although clinical trials demonstrate a mortality benefit at the population level, many of the individual patients in each of the trials did not receive tachycardia therapy from the device during the trial's follow-up period. For instance, in MADIT-II and SCD-HeFT, <40% of patients received an appropriate ICD shock therapy for ventricular arrhythmias during the first 4 years of follow-up.4,6 In most trials of preventive therapy, the individuals who benefit cannot be identified, even in retrospect; so it is assumed that the benefits of intervention apply equally to all eligible patients. The ICD however is a unique preventive therapy because patients who received no benefit from therapy are identifiable as individuals, namely, those who did not receive appropriate therapy from the device. This clear difference in identifying treatment benefit at the individual level rather than only at the population level provides a unique opportunity for improving patient management through more targeted device implantation. Although the risks associated with ICD implantation and follow-up have been small in the clinical trials, device complications are more common when used in broad community practice among less selected patients.10
Secondly, although ICD implantation in specific primary prevention populations may be a cost-effective use of society's resources,10 these analyses assumed all patients in the primary prevention populations had equivalent risk of sudden death and did not evaluate the value of selecting patients most likely to benefit. Furthermore, the patient population potentially eligible for primary prevention is so large that provision of ICD therapy will strain financial resources and the pool of trained personnel. Resource expenditure could be optimized by improved risk assessment.
Finally, although clinical evidence at present supports prophylactic implantation of ICDs in specific primary prevention populations,1–6 current practice has not followed published recommendations. At present, most patients who might benefit from prophylactic ICD placement do not receive a device. There are several potential reasons for this gap including difficulties identifying patients who would benefit from an ICD, patients with co-morbidities that limit potential benefit, the scarcity of qualified providers to implant ICDs and offer follow-up services, the cost of ICD devices, and the scepticism from some providers and patients regarding the value of ICD therapy.10 Another important potential reason for this gap may be that clinicians and policy makers do not feel that trial evidence can be generalized to real-world ICD use in the community. Finally, the recent release of information on ICD failures may lead patients and providers to be concerned about the reliability of devices. Evidence-based risk assessment strategies that accurately indicate which patients are at highest and lowest risk for SCD and provide better targeting of populations for primary prevention ICD use might address some of the existing barriers to ICD use.
Given the limitations of current stratification strategies for defining patients at risk for SCD, the costs associated with current treatments, our limited health care resources, and the current barriers to widespread implementation of the evidence, development and evaluation of additional risk assessment strategies are needed.
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Populations at risk |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Risk assessment strategies for the primary prevention of SCD can target two distinct patient populations. The first population consists of those patients who are currently perceived as ‘high risk’ and therefore eligible for ICD implantation under current guidelines. In these patients, better risk stratification could in principle enable identification of a subset of these patients perceived to be at high risk in which an ICD is unlikely to be effective. The second population consists of those patients now considered as ‘low risk’ and, therefore, not currently eligible for treatment. In this population, risk assessment tools could be used to identify a subgroup that would benefit from ICD prophylaxis. The low-risk population includes both the majority of patients and the majority of the annual sudden deaths10—yet the incidence of sudden death in this population is the lowest.
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Assessment of sudden cardiac death risk factors |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Several risk markers and risk assessment strategies for SCD are discussed below (Table 1).9,11
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Left ventricular systolic ejection fraction |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Depressed LV systolic function is the most consistent and powerful predictor of cardiac mortality regardless of its aetiology.11 This association remains true despite the dramatic improvements in the therapy for acute and chronic phases of coronary artery disease, which is the most common cause of depressed LV function.
The proportion of patients dying from arrhythmia decreases with declining pump function and clinical progression of heart failure. However, even in the most advanced stages of LV dysfunction, up to 50% of deaths are still attributed to arrhythmic events. EF is the most often used indicator of LV systolic performance. It is easy to measure, noninvasive, and reasonably reproducible. Given the inverse relationship between EF and increasing mortality risk noted in the observational studies, EF was incorporated as a risk stratification tool in multiple trials assessing the impact of therapies on SCD and total mortality.
In most ICD trials of primary SCD prevention, an inclusion criterion of an EF 
0.40 selected a high-risk group who benefited from the intervention.1–6 The MADIT II trial used an EF 0.30 in patients with coronary artery disease as the sole risk stratification criterion and showed a significant reduction in SCD and total cardiac mortality with ICD implantation.4 On the other hand, most patients who survive cardiac arrest have only mildly depressed or near-normal EF.12–14 Moreover, in certain populations, EF was an insufficient risk stratification tool for predicting benefit from ICD intervention. Notably, in the CABG-Patch trial, an EF 0.35 combined with abnormal signal averaged electrocardiography (SAECG) and surgical revascularization was inadequate to predict the benefit of ICD therapy.2 More recently, the DINAMITE study used an EF 0.35 for risk stratification in patients with impaired cardiac autonomic function early post myocardial infarction (MI). Decreased arrhythmic death was noted with ICD intervention, although no difference in the total mortality was reported.7 Among patients with nonischaemic cardiomyopathy, depressed EF correlates well with increasing total mortality risk; however, the association of low EF and arrhythmic death risk is not sufficiently studied in these patients.15 Available data from ICD interventional trials suggest that in patients with nonischaemic cardiomyopathy and low EF, SCD risk is reduced by ICD implantation.5,6 This is clear when symptomatic heart failure is present, as shown in the SCD-HeFT trial;6 but the data are less clear in the absence of such symptoms.
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New York Heart Association class |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Heart failure symptoms, as reflected in the New York Heart Association (NYHA) functional class provide a potent risk stratification tool. Despite its obvious subjective and imprecise nature, this simple bedside assessment remains useful even in the current era of sophisticated tests and biomarkers. Patients with NYHA Class II and III symptoms are at a higher risk for SCD than death from progressive pump failure. In contrast, patients with NYHA Class IV symptoms are less likely to die suddenly and are much more likely to die of pump failure.16
These observations have been the subject of ongoing debate, especially in light of the results of SCD-HeFT, in which a subgroup analysis showed significant benefit from an ICD in patients with NYHA Class II symptoms but not in those with NYHA Class III symptoms.6 Nevertheless, patients with NYHA Class III symptoms were well represented in other trials of ICD therapy and appeared to derive benefit from an ICD. Indeed, an analysis that combined data from the MADIT-I and II, MUSTT, SCD-HeFT, DEFINITE, DINAMIT, and COMPANION trials showed a significant improvement in survival with an ICD in patients with NYHA Class III symptoms (HR 0.66, 95% CI 0.46–0.95).17
Although no clinical trials have been exclusively performed in patients with NYHA Class I symptoms, such patients were well represented in MADIT-I, MADIT-II, and MUSTT (36, 37, and 36%, respectively), all of which showed a significant improvement in survival with an ICD.1,3,4
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Electrophysiology study/programmed ventricular stimulation |
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Electrophysiology study is commonly used in SCD risk evaluation. Inducibility of monomorphic ventricular tachycardia (VT) with programmed ventricular stimulation predicts a high risk of future arrhythmic events among patients with a history of MI and reduced LVEF,1,3 ischaemic cardiomyopathy presenting with syncope,18 resuscitated cardiac arrest,12–14 or asymptomatic nonsustained VT.19 Although inducibility of ventricular arrhythmia is a powerful marker of SCD risk, noninducibility may not necessarily confer a benign prognosis. Several studies found that patients with ischaemic cardiomyopathy who are noninducible at electrophysiological programmed stimulation (EPS) remain at high risk of sudden death.3,4 The predictive value of EPS among patients with nonischaemic or hypertrophic cardiomyopathy is limited.11 Monomorphic VT is inducible in the minority of these patients; polymorphic VT and ventricular fibrillation are frequently induced, but are considered a nonspecific endpoint without significant predictive value. A history of syncope carries particularly adverse prognosis in patients with nonischaemic cardiomyopathy. In the small cohorts of patients with nonischaemic cardiomyopathy and syncope, risk stratification with programmed ventricular stimulation had no value in predicting SCD risk; however, a very high incidence of recurrent arrhythmic events was observed.20 In addition to evaluation for ventricular tachyarrhythmias, EPS may detect occult conduction system disease or concomitant supraventricular arrhythmias, thus facilitating selection of the appropriate therapy.
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Nonsustained ventricular tachycardia (Holter monitoring) |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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A few studies have suggested an association between post-AMI nonsustained ventricular tachycardia (NSVT) and an increased risk of mortality; however, the value of NSVT in predicting SCD has not been consistently demonstrated.9 In a large study of 2130 post-AMI patients, although the presence of NSVT on 24 h electrocardiographic (ECG) recordings predicted SCD, it could not discriminate between risk of SCD and risk of non-SCD. In addition, NSVT was not a significant predictor of SCD in patients with an LVEF
35% in that study.21
The predictive value of NSVT in patients with nonischaemic cardiomyopathy is also uncertain. In MACAS, NSVT was not a significant predictor of SCD.15 However, further analysis of the MACAS database showed that 
10 beat runs of NSVT were associated with a higher risk of major arrhythmic events than 5–9 beat runs of NSVT or no NSVT (10, 5, and 2%, respectively, P < .05).9
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Measures of cardiac autonomic modulation |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Many measures of cardiac autonomic modulation have been proposed to risk stratify patients for SCD. These include heart rate variability (HRV), baroreflex sensitivity (BRS), heart rate turbulence (HRT), and deceleration capacity of heart rate.
HRV can be measured by calculating time domain indices or performing spectral (frequency) analysis of an array of R-R intervals on 0.5–5 min ECG segments or on 24 h ECG recordings. Reduced HRV has been associated with an increased risk of mortality among survivors of AMI.9 HRV was examined in such patients in the ATRAMI study. This study enrolled 1284 survivors of AMI within 28 days of their infarction. Mean follow-up was 21 months, and the primary study outcome was cardiac mortality. A low HRV significantly predicted a high risk of cardiac mortality independently of LVEF and spontaneous ventricular tachyarrhythmias. SCD was not examined in that study.22
Information acquired from ambulatory electrocardiography may be used for evaluation of cardiac autonomic tone. Multiple reports confirm the association of impaired HRV, HRT, and BRS with increased risk of death especially in patients post MI with depressed LV function. Despite the experimental data linking abnormal autonomic balance with arrhythmogenesis, the clinical value of these methods in predicting arrhythmic events is not confirmed and requires further investigation. Some measures of cardiac autonomic modulation are predictive of all-cause or cardiac mortality; however, these measures do not appear to be significant predictors of SCD.
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Resting electrocardiogram (QRS duration, QT interval and derivatives) |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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The resting ECG as routinely performed measures several variables of prognostic value but is not often considered as part of SCD risk stratification. For example, QRS duration is a simple measure that reflects intraventricular conduction time and identifies delays and blocks when present. Prolonged conduction creates increased dispersion of depolarization and repolarization, thus promoting ventricular arrhythmias. Furthermore, electrical delays often result in cardiac dyssynchrony, which not only contributes to mechanical ventricular dysfunction but may also have a proarrhythmic effect.
Observational studies among patients with coronary heart disease suggest that QRS duration is a predictor of cardiac mortality, especially in populations with depressed LV systolic function and CHF.11 However, QRS duration tends to increase in parallel with declining LVEF; and in some studies, it was not found to be an independent risk factor of cardiac mortality.
The prognostic value of QRS duration has been studied in multiple randomized controlled trials of ICD therapy for primary SCD prevention. In a subgroup analysis of MUSTT, QRS duration and presence of left bundle branch block were found to be independent predictors of SCD and total mortality.23 The initial report from MADIT-II investigators and subsequent analyses arrived at different conclusions.4,24 Whereas the MADIT-II investigators reported QRS duration to have no significant predictive value despite a trend suggesting higher mortality in the presence of QRS prolongation, early reimbursement decisions were made allowing for payment preferentially for subjects with QRS duration >120 ms. Preliminary data presented from the SCD-HeFT trial did not find QRS duration to have a strong role in predicting cardiac mortality. Marginal effects could be shown only if specific QRS cut-off points were selected for statistical analysis. The data for patients with nonischaemic cardiomyopathy are more sparse, albeit more consistent. In both the observational studies and the few available published reports from randomized controlled trials, QRS duration was not shown to have significant predictive value for selecting patients at increased risk of SCD or total cardiac mortality.5,15
The QT interval is a measure of slowed or inhomogeneous ventricular repolarization. The association between prolonged QT interval (either measured directly or more commonly after correction for the heart rate, QTc) and increased mortality was first noted among patients with acute MI.11 Subsequently, large population studies among patients with and without known coronary disease reported a two- to three-fold increase in cardiac mortality risk when QTc was >420–440 ms.11 Prospective evaluations of high-risk patients with LV systolic dysfunction did not corroborate these findings, although a modest predictive value was demonstrated in some studies.11
QT dispersion index (maximal interlead QT interval variability in a 12-lead ECG) was proposed to be a better estimate of repolarization inhomogeneity, and thus a better predictor of arrhythmic risk. When applied to the general population, abnormal QT dispersion confers increased risk of cardiac and total mortality.11 However, similar to QT interval, QT dispersion is not an independent mortality predictor in high-risk populations of patients with prior MI and CHF.11
Although a long QT interval, QT dispersion, and QT variability have been shown in a few epidemiological studies to be associated with an increased risk of SCD, they, like other risk stratification tests, have not been proven to be clinically useful.
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Signal-averaged electrocardiography |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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The signal-averaged ECG (SAECG) is used to detect low amplitude, high-frequency electrical signals at the end of the QRS complex, known as late potentials. Late potentials correlate with local areas of delayed activation in working ventricular myocardium. Because such local areas may constitute part of the substrate (slow conduction) required to initiate and sustain reentry, many investigators have postulated that an abnormal SAECG may be a strong predictor of SCD in survivors of AMI. Although many studies have proven the prognostic value of SAECG in post-MI patients, the positive predictive value of SAECG in all of these studies was <30%.9
The prognostic value of SAECG was examined in the MUSTT study that enrolled patients with a history of coronary artery disease, a LVEF <40%, and nonsustained asymptomatic VT. In MUSTT, patients with an abnormal SAECG had a significantly higher 5-year rate of arrhythmic death (28% vs. 17%, P < .01) and all-cause mortality (43% vs. 35%, P < .01) than did patients with a normal SAECG.25 SAECG seems to be a relatively specific predictor of arrhythmic events; however, as with other risk stratifying tests, the performance of SAECG alone is suboptimal. The prognostic value of SAECG in patients with nonischaemic cardiomyopathy is uncertain. In MACAS, an abnormal SAECG was not a significant predictor of major arrhythmic events.15
The value of SAECG in risk stratification of patients without coronary disease is less well studied, and the available data are conflicting.11 Newer methods using spectral analysis of SAECG, such as wavelet decomposition analysis, were developed to circumvent some of the methodological limitations; but their utility requires further studies. Some reports suggest these methods may be useful in risk stratification of patients with nonischaemic cardiomyopathies; however, in this population, abnormal wavelet analysis was predictive of progression of pump failure and total cardiac mortality rather than the risk of arrhythmic death.11
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Exercise electrocardiogram (exercise stress test, heart rate recovery, T-wave alternans) |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Exercise stress testing is the most common procedure to identify the presence and magnitude of myocardial ischaemia. Exercise-induced ventricular ectopy and sustained ventricular arrhythmias are rare in healthy subjects; however, their incidence increases dramatically among patients with structural heart disease.11 In addition, exercise commonly serves as a trigger for some forms of VT occurring in patients with structurally normal hearts, for example, right ventricular outflow tract, or idiopathic VT. Historically, the presence of complex ventricular ectopy during exercise stress testing early after MI was associated with increased total mortality.11 However, these observations are no longer valid in patients treated with modern reperfusion strategies, as ventricular arrhythmias early after MI are much less common and are not predictive of subsequent mortality and arrhythmic events.11 Exercise stress testing may still be useful when combined with microvolt T-wave alternans (MTWA) evaluation.
MTWA is defined as a change in T-wave amplitude, width, or shape that occurs in alternate beats and can be detected with careful computerized signal processing techniques. Although the pathophysiology of this phenomenon in humans remains uncertain, it is believed to reflect both temporal and/or spatial heterogeneity of dispersion of repolarization in the ventricles. This dispersion can be associated with reentrant ventricular arrhythmias.9 Digital processing techniques have been developed to allow the detection of TWA at a microvolt level. MTWA is a heart rate dependent measure with maximal predictive accuracy at sustained regular heart rates between 100 and 120 b.p.m.9 These rates can be achieved either by exercise or by atrial pacing.
MTWA has been found to be a predictor of ventricular tachyarrhythmic events.9 Data from 19 studies were combined in a meta-analysis involving 2608 patients. Exercise-induced MTWA was found to have a negative predictive value (NPV) of 97.2% (95% CI 96.5–97.9), a positive predictive value of 19.3% (95% CI 17.7–21.0), and an RR of 3.8 (95% CI 2.4–5.9) for arrhythmic events. Patients with an indeterminate MTWA test result were excluded from the analysis. The predictive value of MTWA varied significantly, depending on the type of patients being studied. In post-MI patients, the NPV of MTWA was 99.4% compared with 95.2% in patients with CHF due to nonischaemic cardiomyopathy and 91.6% in patients with CHF due to ischaemic cardiomyopathy.26
Since the publication of this meta-analysis, two studies have been published. One of them explored the predictive value of MTWA in 768 patients with ischaemic cardiomyopathy (LVEF 35%) and no prior ventricular tachyarrhythmias. An abnormal MTWA test was associated with a significantly higher risk of all-cause mortality but only a trend towards increased risk of arrhythmic mortality.9 Another study examined the role of MTWA in patients with either ischaemic or nonischaemic cardiomyopathy (LVEF V40%) and no history of ventricular tachyarrhythmias. An abnormal MTWA test was associated with a significant increase in the incidence of a composite endpoint of all-cause mortality or nonfatal sustained ventricular tachyarrhythmias.9
The SCD-HeFT MTWA substudy examined the role of MTWA in risk-stratifying patients with ischaemic or nonischaemic cardiomyopathy, NYHA Class II or III symptoms, and LVEF of <35%. Of 2521 patients enrolled in SCD-HeFT, 490 underwent MTWA testing at baseline. An indeterminate MTWA test was observed in 41% of the patients. The incidence of the composite endpoint of SCD, sustained ventricular tachyarrhythmias, or appropriate ICD discharges was not significantly different between the alternans-positive and alternans-negative patients (P= 0.56).27
The ABCD trial, a noninferiority study comparing MTWA with electrophysiology study (EPS), enrolled 566 patients with coronary artery disease, EF <40%, and NSVT. All patients underwent an EPS and MTWA testing and were divided into six groups based on the results of these tests (MTWA+ and EPS+; MTWA– and EPS+; MTWA+ and EPS–; MTWA– and EPS–, MTWA indeterminate, EPS+, MTWA indeterminate, and EPS–). Patients with a positive result in either test had to have an ICD implanted. The primary endpoint of the study was ventricular tachyarrhythmic events, and median follow-up was 1.9 years. The incidence of ventricular arrhythmic events was 12.6% in patients with MTWA+ and EPS+, compared with 5.0% in patients with MTWA+ and EPS– and 2.3% in patients with MTWA– and EPS–.28
One limitation of MTWA testing is the high percentage of indeterminate tests (20–40%), which is usually due to atrial fibrillation, frequent ventricular ectopy, or patients’ inability to exercise or to attain the target heart rate. Other limitations include uncertainty regarding the usefulness of MTWA testing in patients with a prolonged QRS duration and uncertainty surrounding the effect of medications, such as beta-blockers and antiarrhythmic medications, on the predictive value of MTWA. The greatest limitation of MTWA is the absence of prospective, randomized clinical trials of ICD therapy in which randomization was guided by the result of MTWA testing. Although TWA testing is promising, these limitations, along with the discordant findings from studies to date, support the need for additional data before establishing the use of MTWA in clinical decision making.9
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Imaging studies |
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Data from some investigations suggest that imaging studies are likely to play an important role in SCD risk stratification not only by measuring the LVEF but also by detecting scar. In that regard, magnetic resonance imaging (MRI) may have the highest clinical use. Improving the accuracy of LVEF assessment with MRI may enhance the role of the LVEF in SCD risk stratification.9 Furthermore, contrast enhanced cardiac MRI can detect myocardial scars with high precision.9 Because myocardial scar is an important part of the anatomical substrate for malignant reentrant ventricular tachyarrhythmias, the correlation between the presence of myocardial scar and the risk of SCD has been the focus of some investigations. At least one of these investigations has suggested an association between scar surface area or mass as detected by MRI and inducibility of VT on EPS.29 However, the significance of these findings is uncertain especially in light of these studies' small sample size and the EPS's inability to predict SCD. Studies linking scar characteristics with risk of SCD are needed.
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Genetic testing |
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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Genetic testing has the potential to help in SCD risk stratification. Several genetic markers of SCD have been identified in LQTS, Brugada syndrome, arrhythmogenic right ventricular dysplasia, catecholaminergic polymorphic VT, and hypertrophic cardiomyopathy.9,30 Mutations in cytoskeletal proteins such as dystrophin and desmin have been associated with an increased risk of SCD in inherited dilated cardiomyopathy.9 No genetic markers of SCD have been identified in patients with coronary artery disease, CHF, or ischaemic cardiomyopathy. The slow progress in identifying genetic markers of SCD in such conditions may be due to the observation that many genetic changes can result in the same phenotype. To identify genetic variations that are important contributors to SCD risk, large prospective community-based case-control studies are needed.
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Serum markers |
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A few serum markers of SCD risk have been proposed. One such marker is brain natriuretic peptide. In one study of 521 survivors of AMI, an elevated brain natriuretic peptide level was associated with a 3.9-fold increase in the risk of SCD.31 This finding needs to be validated by other studies. Another serum marker proposed to have value in the prediction of SCD is C-reactive protein (CRP). In a study of 3435 white men from Germany, although an elevated CRP level was associated with a significant increase in the risk of coronary events, separate data on the risk of SCD were not provided. The relationship between CRP and risk of SCD deserves further study.9
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Conclusions |
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Historical data suggest that the most important risk factor for cardiac mortality and SCD after AMI is the extent of myocardial injury, characterized by a reduction in EF and increased end-systolic and end-diastolic volumes.32 These indexes of LV function have been shown to be consistent, although nonspecific, predictors of mortality after AMI. Other factors associated with risk of SCD include the QRS duration, ventricular arrhythmias at electrophysiological testing or during 24 h ambulatory monitoring, TWA, exaggerated QT dispersion, HRV, and persistently elevated neuroendocrine and troponin levels. However, because of inconsistency in the accurate prediction of subsequent clinical events, these factors are difficult to use alone and may theoretically be best applied in a multi-factorial model, although such models have major limitations. Unfortunately, we have to accept that currently available techniques are unable effectively to stratify patient risk for SCD, and although genetic approaches to the problem are intriguing and a promising focus of investigation, their utility in a clinical setting has yet to be defined. For these reasons, the major inclusion criterion in the large randomized trials has been a reduction in EF in combination with other risk factors.32
There is currently no single test capable of accurate prediction of the SCD risk in various clinical settings and patient populations. The risk itself is nonlinear and changes dynamically with the progression of disease and therapies applied. Presently available tests offer valuable information but often suffer from the limited positive predictive value and are not adequately investigated in many categories of patients with structural heart disease. In clinical practice, LVEF, coronary artery disease, and clinical symptoms (CHF, syncope) are used as main determinants of primary prevention therapy. More sophisticated noninvasive tests are likely to be best used in combination together with the best clinical judgment of an experienced clinician. Furthermore, the available therapies proven to reduce SCD are expensive and carry their own risks. Additional research is needed to limit the imprecision and subjectivity of the current SCD risk stratification process and improve cost effectiveness of the existing and future therapeutic options.
Efforts should focus on examining existing and novel markers in patients meeting the inclusion criteria of published clinical trials of ICD therapy to identify those who will benefit from an ICD. In this regard, risk modelling is likely to be needed. Whether predictors differ significantly between ischaemic and nonischaemic cardiomyopathy remains unknown. The identification of asymptomatic subjects in the general population who will experience SCD as their first manifestation of heart disease remains problematic, and no satisfactory solutions have so far been achieved.
Conflict of interest: none declared.
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TopAbstractThe need for sudden...Populations at riskAssessment of sudden cardiac...Left ventricular systolic...New York Heart Association...Electrophysiology...Nonsustained ventricular...Measures of cardiac autonomic...Resting electrocardiogram (QRS...Signal-averaged...Exercise electrocardiogram...Imaging studiesGenetic testingSerum markersConclusionsReferences |
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