Preventing Sudden Cardiac Death in Patients with Ischaemic Cardiomyopathy

Login or register to view PDF.
Abstract

Sudden cardiac death (SCD) is an important cause of mortality. In this article, we review the definition, impact and underlying aetiology of SCD. Ventricular tachyarrhythmia accounts for the majority of SCDs and can be caused by various underlying heart diseases, the most frequent being ischaemic cardiomyopathy. The most effective ways to reduce the risk of SCD in ischaemic cardiomyopathy are the optimal prevention of recurrent coronary ischaemia and the use of an implantable cardioverter-defibrillator (ICD) in high-risk patients. We discuss current patient selection for ICD implantation and focus on the need for, and possibilities to improve, SCD risk stratification.

Acknowledgements: The research leading to the results presented here has received funding from the Belgian Science Policy programme (IAPP36/10). Rik Willems is supported as a clinical researcher by the Fund for Scientific Research Flanders. The University of Leuven receives unconditional research funding from Boston Scientific and Medtronic Belgium.

Disclosure
Vincent Floré has no conflicts of interest to declare. Rik Willems has received speaker and consultancy fees from, and participated in clinical trials by, different implantable cardioverter-defibrillator manufacturers (Biotronik, Boston Scientific, Medtronic, Sorin, St Jude Medical).
Correspondence
Rik Willems, Division of Cardiology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E: rik.willems@uzleuven.be
Received date
29 February 2012
Accepted date
15 March 2012
DOI
https://doi.org/10.15420/ecr.2012.8.2.134

Sudden cardiac arrest (SCA) can be defined as the abrupt cessation of cardiac activity due to an underlying cardiac cause, occurring instantaneously in a previously stable patient and in the absence of non-cardiovascular causes (e.g., trauma, intoxication, drowning, electrocution).1,2 SCA will lead to loss of consciousness within the minute due to insufficient cerebral perfusion. If no immediate action is taken to restore circulation – e.g., defibrillation – SCA will invariably lead to sudden cardiac death (SCD). In this article, we will use SCD as the common term for both SCA and SCD.

A Major Cause of Death with a High Impact on Daily Life

The mechanism underlying SCD is arrhythmic in the majority (80–90 %) of cases3 and over 80 % of the arrhythmic episodes are ventricular arrhythmia (VA): ventricular tachycardia (VT) or ventricular fibrillation (VF).4 As, in many cases, the deadly event is not witnessed (e.g., occurring during sleep and/or out of hospital), no definition of SCD is 100 % accurate.1 This explains why epidemiological data vary from report to report. However, it is clear that SCD is a very frequent cause of mortality worldwide. Incidence estimates from large population studies in the 1990s were as high as 450,000 SCD cases per year in the US,5 400,000 in Europe6 and 3,000,000 worldwide.7 SCD accounts for over 50 % of all cardiac-related deaths in the US8,9 and it is the second leading cause of death after all cancers combined.10 Even though, during the last 20 years, the significant decrease in the incidence of cardiovascular mortality has also been observed for SCD,11 SCD remains a very important health issue. Not only because its incidence remains high, but also because the abrupt and unforeseeable character of the condition leads to very low (less than 10 %) out-of-hospital survival rates11 and loss of life for people who were often free of morbidity up until right before the event.

A Prism of Possible Underlying Causes

The underlying conditions that form the substrate of, and the trigger for, VA leading to SCD are very diverse. In less than 10 % of the patients experiencing SCD, no macroscopic structural heart disease is found.12 This subgroup consists of patients with congenital electrophysiological anomalies, such as the congenital long and short QT syndromes, Brugada syndrome, catecholaminergic polymorphic VT and idiopathic VF. These conditions are a particularly important cause of death in young people. The current knowledge about the origin, detection and treatment of these individual conditions, which is continuously evolving, is beyond the scope of this article.

The majority of SCD cases are accompanied by structural cardiac abnormalities of which SCD is often the first presentation. These abnormalities can be divided between coronary artery disease (myocardial ischaemia and infarction), congestive heart failure, ventricular hypertrophy, arrhythmogenic ventricular cardiomyopathy or a combination of these. Up to 70 % of all SCDs are related to myocardial ischaemia or subsequent infarction and heart failure. SCD in turn is the cause of mortality in up to 50 % of all deaths due to ischaemic heart disease.13 In this article, we will focus on the prevention of SCD in ischaemic cardiomyopathy.

Arrhythmogenic Mechanisms Specific to Ischaemic Cardiomyopathy

SCD is caused in the majority of cases by VA – that is, by VT, VF or VT degenerating into VF. Arrhythmogenesis results from the interaction between a transient initiating event, a cardiac substrate and an arrhythmic mechanism.14 In ischaemic cardiomyopathy, two specific underlying pathophysiological mechanisms leading to VA predominate.

First, acute myocardial ischaemia due to insufficient coronary blood supply and post-ischaemic reperfusion can induce VA through abnormal automaticity.14 This mechanism is responsible for the high incidence of VA during the first 48 hours after acute myocardial infarction (MI). Since the 1980s, strategies for rapid coronary reperfusion, continuous electrocardiogram (ECG) monitoring within specialised coronary care units and early external defibrillation when needed have resulted in a drastic decrease in mortality in the acute phases of acute MI.11 Improved protection against this arrhythmia mechanism is offered by the elimination of behavioural cardiovascular risk factors (e.g., smoking and obesity), optimal reperfusion therapy and the pharmacological prevention of recurrent coronary ischaemia (through, for example, statins, platelet aggregation inhibitors, beta-blockers and angiotensin-converting enzyme [ACE] inhibitors).14

The other main arrhythmic mechanism in ischaemic heart disease is re-entry in myocardium scarred by infarction. It is believed that the conditions for re-entry are established through disruption and reorganisation of the intercellular gap junctions in the border zone of healing infarcts.15 In contrast to abnormal automaticity induced by acute ischaemia, this substrate is not transient but permanent and it is responsible for the ‘late’ presentation of SCD in patients with previous MI. The presence of this substrate for re-entry will put patients at permanent risk of developing life-threatening arrhythmia, in spite of an optimal reduction in recurrent ischaemia risk as discussed above.

Prevention of Sudden Cardiac Death in Ischaemic Cardiomyopathy

In the last 20 years, several options have been developed to prevent and treat VA leading to SCD.

Pharmacological Strategies

The prevention of recurrent ischaemia to prevent SCD in ischaemic cardiomyopathy has already been mentioned. Given that scar tissue is a chronic substrate of re-entry VA, pharmacological therapies limiting myocardial injury and adverse remodelling also reduce the risk of SCD. This was repeatedly proven for ACE inhibitors, making them a cornerstone of post-infarct treatment.16 During the last 20 years, there has been an extensive quest to find an anti-arrhythmic agent that can reduce SCD risk once the arrhythmic substrate is present. Only beta-blockers have been shown to reduce SCD in patients with previous MI.17 This is due to their protective effect against recurrent ischaemia and alleviation of sympathetic tone, but probably also to intrinsic electrophysiological effects.18 The results with other anti-arrhythmic agents have been disappointing. Class I (mexiletine, encainide, flecainide, moricizine), class III (sotalol, dofetilide) and class IV (calcium antagonists) drugs have all failed to reduce, or have even increased, the incidence of SCD after MI.14 Finally, even amiodarone, having the most potent antiarrhytmic effects with almost no proarrhythmic risk (but frequent and important negative side effects), failed to reduce mortality in several large randomised controlled trials (RCTs).19

Implantable Cardioverter-defibrillators

The implantable cardioverter-defibrillator (ICD), a subcutaneous implanted device that detects VA through a lead placed in the right ventricle (see Figure 1) and automatically treats these arrhythmias by delivering anti-tachy pacing or ultimately a high power DC shock, emerged in clinical practice in the early 1980s. This therapy does not prevent VA, but it does prevent SCD following VA. The benefit on mortality was convincingly shown in survivors of a previous sustained VA20,21 and has led to guidelines regarding ICD implantation for secondary prevention that are relatively straightforward and effective (see Table 1). The extremely high mortality of SCD at its very first presentation implied that ICD therapy should not be restricted to survivors of previous VA.11 The first and second Multicenter Automatic Defibrillator Implantation

Trial (MADIT I & II), the Multicenter Unsustained Tachycardia Trial (MUSTT) and the Sudden Cardiac Death in Heart Failure Trial (SCD HeFT) were landmark RCTs all showing significantly improved survival in patients who had suffered an MI and were considered to be at high risk of SCD based on a limited number of parameters – of which depressed left ventricular ejection fraction (LVEF) was the most important (see Table 2).19,22–24 The forthcoming guidelines regarding the primary prevention of SCD were somewhat more complex than those for secondary prevention ICD implantation (see Table 1) but still allowed implementation in daily clinical routine.

Radiofrequency Ablation

Radiofrequency ablation for VA is another recently studied approach. The rationale is straightforward: through the creation of lesions on critical points in the scar tissue, the circuit allowing re-entry is interrupted and the risk of VA lowered. The technique has been shown to significantly reduce VT recurrence in patients with previous MI.25 Unfortunately, it has only proven effective in the limited subset of patients with stable VT. Its impact on SCD-related mortality or the possibility to avoid ICD implantation have currently not been investigated. And it seems less likely to help in patients with the more complex arrhythmic substrates which are more prone to cause SCD.

Risk Stratification for Implantation of a Cardioverter-defibrillator in Primary Prevention of Sudden Cardiac Death
Does the Current Risk Stratification Need to Be Improved?

Although backed by sound scientific evidence, the current identification of candidates for an ICD for the primary prevention of SCD is far from optimal. A meta-analysis of the above-mentioned large RCT showed that, with the current risk stratification, only approximately one in four patients (22.9 %, range 17.8–31.4 %) received appropriate and possibly life-saving intervention in the form of an ICD.26 Combined with the important upfront financial cost, the need for frequent follow-up and the inevitable complications of a device featuring intracardiac leads, this makes the cost-effectiveness of ICD therapy a polemical issue among today’s health economics. Gaining one quality-adjusted life year has been estimated to cost around €30,000 and the cost estimates have been repeatedly challenged, making decisions regarding reimbursement difficult in this era of economic uncertainty.27 Moreover, although the risk stratification that is being used does identify a subpopulation in which the incidence of SCD is higher than in the general population, the absolute number is only a minority compared with the number of SCD cases in a broader population without depressed LVEF or even without ischaemic cardiomyopathy.28

The quasi-monopoly of reduced LVEF in the risk stratification for a primary prevention ICD implantation (see Table 2) has the advantage of simplicity, but also has major drawbacks. The rationale behind its use as a predictor of SCD is that reduced LVEF reflects advanced cardiac remodelling leading to an arrhythmic substrate. Nevertheless, LVEF has relatively low sensitivity and specificity for arrhythmia leading to SCD: the majority of SCD patients do not have low ejection fraction and the majority of patients with low LVEF will never experience SCD.29 Another important issue is the strong predictive value of low LVEF for total mortality, as patients with low LVEF are also at high risk of non-sudden cardiac death. SCD and non-sudden cardiac death risks are to be seen as competing:30 a very high risk of dying from heart failure will prevent an ICD implantation from being useful.31,32 Thus, very low LVEF might rather be a marker of particular ICD-resistant mortality.

The Quest for the Telltale of Specific Arrhythmic Risk

The efficacy of ICD implantation can only be improved if it is possible and easy to identify patients at high risk of arrhythmia but at low risk of non-arrhythmic death. This ‘electrophysiologist’s holy grail’ has urged many to look for new, preferentially non-invasive approaches to detect factors that act as a trigger for, or create a substrate for re-entry leading to, VA and subsequent SCD. The most important pathophysiological factors that have been identified are ventricular ectopy, myocardial scar, slowed ventricular conduction, imbalance in autonomic tone and heterogeneity in ventricular repolarisation. Here we briefly present the rationale and – where already known – the value of these factors (in a systematic structure similar to that used in a consensus document issued by the American Heart Association, American College of Cardiology and Heart Rhythm Society33).

Ventricular Ectopy

Ambulatory ECG (Holter) monitoring can easily detect ventricular premature beats (VPBs) and non-sustained VT (NSVT). The presence of 10 VPBs or more per hour in post-MI patients correlated with higher total mortality: the negative predictive value was over 90 % whereas the positive predictive value ranged from 5–15 %.34 This predictive value became stronger when combined with a reduction of LVEF.33 Holter has proven to be clinically useful to guide ischaemic cardiomyopathy therapy in the subgroup of patients with an LVEF between 35 and 40 %: if NSVT is recorded, an electrophysiological study should be performed. If the latter is positive, ICD implantation has shown to improve survival (see Table 1).

Extent of Myocardial Damage and Scar Formation

More myocardial damage means a higher chance of developing a re-entrant substrate. Lower LVEF is reflecting myocardial damage (its value has been discussed above). Magnetic resonance imaging with delayed contrast enhancement (DE-MRI) is a more direct measurement of the extent of myocardial scar. A large observational study evaluating the correlation between MRI and outcomes measured LVEF and scar size, and showed that, even in patients with near-normal LVEF, significant damage identifies a cohort at high risk of early mortality.34 The extent of scar on DE-MRI has been correlated with ICD interventions for VA in post-MI patients.36 No data on MRI-guided anti-arrhythmic therapy are available.

Slowed Ventricular Conduction

QRS duration can be obtained easily from a standard electrogram. A broadened QRS complex is a marker of high total mortality in ischaemic cardiomyopathy patients with depressed LVEF.37 A broad QRS reflects slow conduction, which has been suggested to be a direct cause of arrhythmogenic dispersion of ventricular recovery,38 but no data warrant the use of QRS duration as a specific marker for SCD.

Signal-averaged ECG (SAECG) is a technique that allows noise reduction and amplification of an ECG signal in order to detect late potentials. These subtle signals at the end of the QRS indicate prolonged activation of small parts of the myocardium, typically in infarct regions, and were shown by some to correlate with re-entry substrate. Abundant clinical data show that abnormal SAECG may identify MI patients at risk of SCD, but no proof of the superiority of SAECG-guided ICD therapy is available.33

Mechanical dispersion of contraction measured by echocardiographic strain imaging is a technique that has been developed only recently. It has been shown to correlate with higher VA risk in post-MI patients.39

Imbalance in Autonomic Tone

The heart rate variability (HRV) is calculated with several different techniques on long-term ambulatory ECG (Holter) registrations and reflects the vagal and sympathetic influences on the heart. The theoretical link between abnormal HRV, autonomic tone and arrhythmogenesis has not been observed in clinical cohorts.

Nevertheless, depressed HRV was clearly related to higher total mortality. Although a limited number of studies have been performed, the same assumptions can currently be made about heart rate turbulence (HRT). This elegant technique measures the slope of return to normal heart rate after the parasympathetic slowing of the heart in answer to a VPB. A higher slope indicates more parasympathetic tone and is believed to correlate with better prognosis.33

Heterogeneity in Ventricular Repolarisation

The QT interval can easily be measured from a surface ECG. In large study populations, a prolonged QT interval correlated with increased total mortality. The benefit of QT interval length in specific SCD risk prediction has only been demonstrated in patients with long QT syndrome.33 The same holds true for QT variability, a parameter defined as the slope of the QT/RR interval relationship. QT dispersion is defined as the maximal difference between QT intervals in the surface ECG. It is unclear whether this parameter represents a spatial heterogeneity in ventricular repolarisation, and studies investigating its relationship with outcomes have been contradictory.33

T-wave alternans (TWA) is beat-to-beat alternating of the amplitude of T-wave, measurable on a microvolt level by spectral analysis techniques. Protocols of both a positive and negative clinical TWA test are displayed in Figure 2. The phenomenon was related to increased clinical VA risk for the first time in 1994.40 Since then, extensive clinical and experimental research has been conducted to understand this phenomenon. Experimental research has shown that repolarisation alternans at cellular level can amplify electrical heterogeneities between cells that can directly cause arrhythmia.41 A meta-analysis of 19 studies investigating the clinical value of TWA showed strong predictive value (relative risk 2.42, 95 % confidence interval 1.3–4.5) for arrhythmic events in ischaemic cardiomyopathy patients.42 Unfortunately, not all recent studies were equally positive43 and no definitive proof that TWA is predicting a benefit from ICD implantation is currently available.

Conclusion

SCD is an important cause of mortality because of its very high incidence and its unexpected way of taking lives with previously little morbidity. Ventricular tachyarrhythmia accounts for the majority of SCD events and can be caused by various heart diseases, the most frequent being ischaemic cardiomyopathy. The most effective ways to reduce SCD risk in ischaemic cardiomyopathy are the optimal prevention of recurrent coronary ischaemia and the use of an ICD in high-risk patients. The cost-effectiveness of the latter, which is an expensive therapy, relies primordially on the identification of patients at high risk of SCD and low risk of non-arrhythmic mortality. The current risk stratification rests mainly on depressed LVEF and needs to be improved. There has been an extensive quest for alternative risk-stratifiers. Despite providing new insights in the mechanisms leading to SCD, this quest has, up to now, failed to provide a clinically useful tool to identify non-invasively patients at high risk of SCD.

References
  1. Siscovick DS, Challenges in cardiac arrest research: data collection to assess outcomes, Ann Emergency Med, 1993;22:92–98.
    Crossref | PubMed
  2. Buxton AE, Calkins H, Callans DJ, et al., ACC/AHA/HRS 2006 key data elements and definitions for electrophysiological studies and procedures: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology), J Am Coll Cardiol, 2006;48:2360–96.
    Crossref | PubMed
  3. Albert CM, Chae CU, Grodstein F, et al., Prospective study of sudden cardiac death among women in the United States, Circulation, 2003;107:2096–101.
    Crossref | PubMed
  4. Bayés de Luna A, Coumel P, Leclercq JF, Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases, Am Heart J, 1989;117:151–9.
    Crossref | PubMed
  5. Zheng ZJ, Croft JB, Giles WH, Mensah GA, Sudden cardiac death in the United States, 1989 to 1998, Circulation, 2001;104:2158–63.
    Crossref | PubMed
  6. De Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al., Out-of-hospital cardiac arrest in the 1990’s: a population-based study in the Maastricht area on incidence, characteristics and survival, J Am Coll Cardiol, 1997;30:1500–5.
    Crossref | PubMed
  7. Myerberg RJ, Catellanos A, Cardiac arrest and sudden cardiac death, In: Braunwald E (ed), Heart Disease: A Textbook of Cardiovascular Medicine, 5th edn, New York: WB Saunders, 1997;742–79.
  8. Centers for Disease Control and Prevention (CDC), State-specific mortality from sudden cardiac death – United States, 1999, MMWR Morb Mortal Wkly Rep, 2002;51:123–6.
    PubMed
  9. Fox CS, Evans JC, Larson MG, et al., Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999: the Framingham Heart Study, Circulation, 2004;110:522–7.
    Crossref | PubMed
  10. Anderson RN, Deaths: leading causes for 1999, Natl Vital Stat Rep, 2001;49:1–88.
    PubMed
  11. Lloyd-Jones D, Adams RJ, Brown TM, et al., Executive summary: heart disease and stroke statistics – 2010 update: a report from the American Heart Association, Circulation, 2010;121:948–54.
    Crossref | PubMed
  12. Chugh SS, Kelly KL, Titus JL, Sudden cardiac death with apparently normal heart, Circulation, 2000;102:649–54.
    Crossref | PubMed
  13. Adabag AS, Peterson G, Apple FS, et al., Etiology of sudden death in the community: results of anatomical, metabolic, and genetic evaluation, Am Heart J, 2010;159:33–39.
    Crossref | PubMed
  14. Zipes DP, Wellens HJ, Sudden cardiac death, Circulation, 1998;98:2334–51.
    Crossref | PubMed
  15. Peter NS, Wit AL, Myocardial architecture and ventricular arrhythmogenesis, Circulation, 1998;97:1746–54.
    Crossref | PubMed
  16. Domanski MJ, Exner DV, Borkowf CB, et al., Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials, J Am Coll Cardiol, 1999;33:598–604.
    Crossref | PubMed
  17. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF), Lancet, 1999;353:2001–7.
    Crossref | PubMed
  18. Berruezo A, Brugada J, Betablockers: is the reduction of sudden death related to pure electrophysiologic effects? Cardiovasc Drugs Ther, 2008;22:163–4.
    Crossref | PubMed
  19. Bardy GH, Lee KL, Mark DB, et al., Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure, N Engl J Med, 2005;352:225–37.
    Crossref
  20. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from nearfatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators, N Engl J Med, 1997;337:1576–83.
    Crossref | PubMed
  21. Kuck KH, Cappato R, Siebels J, Rüppel R, Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest : the Cardiac Arrest Study Hamburg (CASH), Circulation, 2000;102:748–54.
    Crossref | PubMed
  22. Moss AJ, Hall WJ, Cannom DS, et al., Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators, N Engl J Med, 1996;335:1933–40.
    Crossref | PubMed
  23. Buxton AE, Lee KL, Fisher JD, et al., A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators, N Engl J Med, 1999;341:1882–90.
    Crossref | PubMed
  24. Moss AJ, Zareba W, Hall WJ, et al., Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction, N Engl J Med, 2002;346:877–83.
    Crossref | PubMed
  25. Kuck KH, Schaumann A, Eckardt L, et al., Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial, Lancet, 2010;375:31–40.
    Crossref | PubMed
  26. Theuns DA, Smith T, Hunink MG, et al., Effectiveness of prophylactic implantation of cardioverter-defibrillators without cardiac resynchronization therapy in patients with ischaemic or non-ischaemic heart disease: a systematic review and meta-analysis, Europace, 2010;12:1564–70.
    Crossref | PubMed
  27. Cowie MR, Marshall D, Drummond M, et al., Lifetime cost-effectiveness of prophylactic implantation of a cardioverter defibrillator in patients with reduced left ventricular systolic function: results of Markov modelling in a European population, Europace, 2009;11:716–26.
    Crossref | PubMed
  28. Myerburg RJ, Mitrani R, Interian A Jr, Castellanos A, Interpretation of outcomes of antiarrhythmic clinical trials: design features and population impact, Circulation, 1998;97:1514–21.
    Crossref | PubMed
  29. Buxton AE, Risk stratification for sudden death: do we need anything more than ejection fraction?, Card Electrophysiol Rev, 2003;7:434–7.
    Crossref | PubMed
  30. Koller MR, Schaer B, Wolbers M, et al., Death without prior appropriate implantable cardioverter-defibrillator therapy: a competing risk study, Circulation, 2008;117:1918–26.
    Crossref | PubMed
  31. Clarke B, Howlett J, Sapp J, et al., The effect of comorbidity on the competing risk of sudden and nonsudden death in an ambulatory heart failure population, Can J Cardiol, 2011, 27:254–61.
    Crossref | PubMed
  32. Marijon E, Trinquart L, Otmani A, et al., Competing risk analysis of cause-specific mortality in patients with an implantable cardioverter-defibrillator: The EVADEF cohort study, Am Heart J, 2009;157:391–7.e1.
    Crossref | PubMed
  33. Goldberger JJ, Cain ME, Hohnloser SH, et al., American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on Noninvasive Risk Stratification Techniques for Identifying Patients at Risk for Sudden Cardiac Death. A scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention, J Am Coll Cardiol, 2008;52:1179–99.
    Crossref | PubMed
  34. Crawford MH, Bernstein SJ, Deedwania PC, et al., ACC/AHA Guidelines for Ambulatory Electrocardiography. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the Guidelines for Ambulatory Electrocardiography). Developed in collaboration with the North American Society for Pacing and Electrophysiology, J Am Coll Cardiol, 1999;34:912–48.
    Crossref | PubMed
  35. Klem I, Shah DJ, White RD, et al., Prognostic value of routine cardiac magnetic resonance assessment of left ventricular ejection fraction and myocardial damage: an international, multicenter study, Circ Cardiovasc Imaging, 2011;4:610–9.
    Crossref | PubMed
  36. Scott PA, Morgan JM, Carroll N, et al., The extent of left ventricular scar quantified by late gadolinium enhancement MRI is associated with spontaneous ventricular arrhythmias in patients with coronary artery disease and implantable cardioverter-defibrillators, Circ Arrhythm Electrophysiol, 2011;4:324–30.
    Crossref | PubMed
  37. Shamim W, Francis DP, Yousufuddin M, et al., Intraventricular conduction delay: a prognostic marker in chronic heart failure, Int J Cardiol, 1999;70:171–8.
    Crossref | PubMed
  38. Akar FG, Spragg DD, Tunin RS, et al., Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy, Circ Res, 2004;95:717–25.
    Crossref | PubMed
  39. Haugaa KH, Smedsrud MK, Steen T, et al., Mechanical dispersion assessed by myocardial strain in patients after myocardial infarction for risk prediction of ventricular arrhythmia, JACC Cardiovasc Imaging, 2010;3:247–56.
    Crossref | PubMed
  40. Rosenbaum DS, Jackson LE, Smith JM, et al., Electrical alternans and vulnerability to ventricular arrhythmias, N Engl J Med, 1994;330:235–41.
    Crossref | PubMed
  41. Pastore JM, Girouard SD, Laurita KR, et al., Mechanism linking T-wave alternans to the genesis of cardiac fibrillation, Circulation, 1999;99:1385–94.
    Crossref | PubMed
  42. Gehi AK, Stein RH, Metz LD, Gomes JA, Microvolt T-wave alternans for the risk stratification of ventricular tachyarrhythmic events: a meta-analysis, J Am Coll Cardiol, 2005;46:75–82.
    Crossref | PubMed
  43. Chow T, Kereiakes DJ, Onufer J, et al., MASTER Trial Investigators, Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischaemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial, J Am Coll Cardiol, 2008;52:1607–15.
    Crossref
  44. Epstein AE, DiMarco JP, Ellenbogen KA, et al., ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons, Circulation, 2008;117:e350–e408.
    Crossref | PubMed