Authors
- Obias-Manno, Dulce RN, BSN, MHSA
- Wijetunga, Mevan MD
Abstract
The initial challenge in primary prevention of sudden cardiac death (SCD) lies in identifying those at greatest risk, before the index event. Ventricular fibrillation is the leading cause of SCD; however, many clinical conditions predispose fatal ventricular dysrhythmias. In patients with structural heart disease, left ventricular dysfunction is the strongest predictor of SCD. Noninvasive markers such as nonsustained ventricular tachycardia, delayed potentials, decreased heart rate variability and baroreflex sensitivity, and repolarization alternans are further observed to assess risk in ischemic cardiomyopathy; however, most of these markers have poor positive predictive value and lack specificity. The electrophysiologic study has strong positive predictive value, but remains a costly and invasive method for risk stratification. In patients with normal hearts, genetic predisposition may identify patients at risk but clinical markers are not readily recognized. The implantable loop recorder is a useful tool in detecting dysrhythmic causes of syncope and identifying patients at risk for SCD.
The past decade has produced evidence that the implantable cardioverter defibrillator is superior to antiarrhythmic drugs or conventional therapy in reducing sudden death in cardiomyopathy, particularly of ischemic origin. Increasing public awareness and wide public access to automated external defibrillator (AED) may further improve the survival in the general population.
Article Content
Definition and Significance of Sudden Cardiac Death
Sudden cardiac death (SCD) is defined as an unheralded, fatal outcome in an individual with previously stable clinical status, with symptoms occurring less than one hour into demise. It is the most lethal, and not infrequently the only manifestation of structural heart disease and of primary electrical disorders in normal hearts. Early studies on resuscitative efforts and epidemiological studies have revealed ventricular fibrillation as its principal underlying cause. 1-4 Electrophysiologic testing has further elucidated ventricular tachycardia (VT), a precursor of ventricular fibrillation (VF), as the culprit dysrhythmia associated with SCD, particularly in chronic ischemic heart disease.
The impact of sudden death on the society is incalculable. Ostensibly, healthcare costs are less, compared to a chronic illness, but personal stakes are higher. Immediate disruption of family economics is threatened with the unanticipated loss of livelihood, sometimes during the most productive years of an individual's life. The survivors of the decedent are often emotionally overwhelmed when death is unexpected. 5 As contrasted to a lingering illness, the decedent usually does not have a chance to put his or her matters in order and the family does not have the opportunity to provide terminal care for their loved ones, which would otherwise help survivors cope with their loss. In witnessed events, sudden death denies the decedent of death with dignity, as the bystander(s) attempt a resuscitation in public view. In the emergency department, healthcare workers are often at a loss when notifying family of sudden death occurrence or providing care for the bereaved. 6 Many aspects of sudden death are yet to be explored but the main consideration remains primary prevention. Table 1 provides definition of terms related to sudden death.
Incidence
The incidence of SCD ranges from 300,000 to 450,000 cases per year in the United States. 7,8 Findings from vital statistics of deaths occurring out of hospital, in the emergency room, or as dead-on-arrival in 1998 included the following: 9
* 63% of total deaths (456,076 out of 719,456) were defined as SCD
* of all SCD, 62% were associated with coronary heart disease
* among 35- to 44-year-old decedents, 74% were classified as SCD
* SCD rates were higher in men than women in age group <85 years
* >50% of cardiac death in women were out of hospital
* SCD rates were higher in African Americans.
The incidence of SCD is increased four to six times in those with a previous myocardial infarction (MI) and two- to fourfold in the presence of coronary heart disease risk factors. 7,10 In people diagnosed with congestive heart failure (CHF), the risk of sudden death is six to nine times the rate of the general population. 7 The risk of SCD is higher in mild to moderate heart failure (New York Heart Association class II and III) compared to severe class IV CHF. Nonsudden progressive heart failure, bradycardia, electromechanical dissociation, and asystole may account for two thirds of the mode of death in advanced heart failure. 11
The clinical diseases associated with SCD in the adolescent and young adult group are markedly diverse and distinctly different from the older age group. Mortality risks may have genetic predetermination. 12 Recent studies indicate that 36% of SCD in young athletes are probably associated with hypertrophic cardiomyopathy, a disorder caused by a mutation encoding the proteins of the heart muscle fibers. 7
Medical conditions associated with dysrhythmic death encompass structural and nonstructural heart disease 11-22 (Tables 2 and 3). In normal hearts, clinical markers are not readily recognizable.
Risk Stratification: Physiologic, Clinical, and Investigational Markers
Coronary Heart Disease Risk Factors
Approximately 80% of SCD is attributed to coronary artery disease and its sequelae. 12 Consequently, in the absence of population based screening tools for SCD, it is reasonable to employ coronary risk factors to predict SCD. The modifiable traditional coronary risk factors include hypertension, dyslipidemia, obesity, tobacco smoking, and sedentary lifestyle. 23,24
Left Ventricular Dysfunction
Several studies have implicated left ventricular (LV) dysfunction as the most powerful independent predictor of sudden and non-SCD in patients with both ischemic and nonischemic cardiomyopathy. The risk for death increases substantially in patients with ejection fraction (EF) <30%. 25 In the clinical setting, EF is commonly measured by 2D-echocardiography, nuclear perfusion gated imaging, radiocontrast ventriculography, or cardiac magnetic resonance imaging. Despite the utility of EF as an independent predictor of SCD, clinical decisions are often not based on merely meeting the requisite value of EF <30%, due to variability in measurement methods and results. Clinical prudence dictates, in some cases, assessing the degree of functional impairment (ie, NYHA functional class), to substantiate the severity of LV dysfunction.
Ventricular Dysrhythmias
In the post-MI population, LV dysfunction is closely associated with frequent premature ventricular contractions (PVCs) and increased cardiac mortality. 26,27 Many studies with a post-MI population used evidence of frequent PVCs and nonsustained VT (NSVT) as clinical markers of risk (Tables 4 and 5). There are suggestions, but no definitive data, supporting the prognostic value of NSVT in idiopathic cardiomyopathy. In the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial, a study of the effect of low-dose Amiodarone in moderate to severe CHF (EF <35%), NSVT was noted to correlate closely with total (all cause) mortality. 28 Conversely, the absence of NSVT conferred low probability of sudden death. However, in two other CHF trials, NSVT was not an independent predictor of SCD or total mortality 29,30 One might consider that the difference lies in the heterogeneity of the population studied (non-is-chemic/idiopathic vs. ischemic), or within the variables analyzed.
PVCs have always been regarded as a harbinger of dysrhythmic risk but it is unknown if it is an independent predictor of SCD in those with normal hearts. In long QT syndrome, PVCs may presage torsades des pointes; however, prolonged QT intervals, rather than PVCs, are the hallmark of this syndrome. 31 In Brugada syndrome, PVCs have been observed transiently but not universally. 32 In idiopathic VT, particularly Right Ventricular Outflow Tract (RVOT) tachycardia, PVCs may originate from the tachycardia circuit and can be used for mapping the location during ablation. (RVOT tachycardia is discussed in a separate article of this issue of the journal.)
There are data supporting NSVT as independent predictor of SCD risk in hypertrophic cardiomyopathy in the young, but association of risk with frequency, rate, and duration are not demonstrated. 33-35
Electrocardiographic Markers
Analysis of the 12-lead electrocardiogram is a simple and important first step in identifying risk in those with a strong family history of sudden death in patients without structural heart disease. The QRS width and morphology, QT interval prolongation, ST segment and EKG patterns, as in Wolff-Parkinson-White (WPW), Long QT, and Brugada syndromes may provide important clues to genetic predisposition (Table 3). It is important to note that absence of these EKG manifestations does not always imply absence of risk for SCD. 36
Autonomic Markers
Multiple studies validate the role of the autonomic nervous system as a trigger of SCD. 37 In post-MI patients, imbalance of vagal and sympathetic output may result in sympathetic dominance, leading to an increased risk of ventricular dysrhythmias. Of the non-invasive markers of autonomic activity, heart rate variability (HRV) has received most attention in the recent investigations. HRV indicates the beat-to beat variability of heart rate (R-R interval) and reflects the tonic vagal action on the sinus node. High HRV is associated with an increased parasympathetic tone and is generally considered a sign of sound cardiovascular health. Attenuated HRV has been described in patients after MI, in which it is considered a prognostic indicator of SCD. 38 HRV is commonly measured with spectral analysis during Holter monitoring. It is frequently described as the reciprocal of R-R interval and is calculated as the standard deviation of all normal beats over a specified time period. 39
Baroreflex sensitivity is another marker of autonomic function. It measures the ability of autonomic reflexes to increase vagal activity and decrease sympathetic activity in response to a sudden increase in blood pressure. It is measured by spectral analysis of R-R interval and systolic arterial pressure. A recent trial showed that reduction in baroreflex sensitivity is associated with increased risk of subsequent cardiac events in post MI patients. 40
Despite the recent progress in this field, autonomic markers have yet not gained widespread clinical applicability and popularity in the risk stratification of SCD. Abnormality in autonomic markers can be present in several conditions, including hypertension, diabetes mellitus, autonomic dysfunction, and even in healthy, middle-aged adults. Furthermore, use of beta-adrenergic blockade after MI results in blunting of sympathetic activity and reduction in heart rate, which confounds the interpretation and predictive power of autonomic markers. 41
Signal Averaged Electrocardiogram
Signal averaged electrocardiogram (SAECG) involves high gain amplification and filtering of the cardiac electrical impulse, facilitating the detection of low amplitude electrical signals (referred to as "late potentials") in the terminal part of the QRS complex. These potentials are thought to reflect areas of slowed conduction, a substrate for ventricular reentrant dysrhythmias, as typified in a healed myocardial scar. 42 SAECG has a high negative predictive value, particularly in ischemic heart disease. It has been used in isolated cases, as an extra measure of assurance; when found negative in patients, who might otherwise appear to belong to a moderate risk category. Because it also has low positive predictive value, it is of limited clinical utility in appraising risk for primary prevention of SCD. Furthermore, SAECG results are uninterpretable in patients with bundle branch block and conduction delay.
Microvolt T Wave Alternans
T wave alternans (TWA) is described as changes in the contour, amplitude, or polarity of the T wave in every other heart beat indicating electrical instability. TWAs on ECG often predict the occurrence of lethal dysrhythmias but are not always manifest, or readily detectable due to surface artifact. The detection of microvolt-level TWA has been facilitated by the advent of modern signal processing techniques and high-resolution electrodes, which significantly filter out the background noise. Several studies have shown that TWA has a high sensitivity and negative predictive value for predicting SCD in heart failure, dilated cardiomyopathy, and after MI. 43-45 It has been hypothesized that alterations in the ion channels lead to the development of TWA by heterogeneous prolongation and increased dispersion of repolarization, rendering the myocardium susceptible to reentrant activity. 46
TWA is generally measured during exercise, pharmacological stress, or atrial pacing as its maximum predictive accuracy is achieved at heart rates between 100 and 120. Recent studies suggest that TWA, with a negative predictive value greater than 90%, may help to further delineate patients (among the moderate risk group of ischemic and nonischemic cardiomyopathy) who would not benefit from prophylactic ICD implantation. 47 The ongoing Alternans Before Cardioverter Defibrillator (ABCD) trial may help to further define the clinical applications of TWA as a risk marker of SCD in the setting of post MI ventricular dysfunction.
Programmed Electrical Stimulation
Electrophysiologic studies (EPS) with programmed electrical stimulation employ pacing techniques, based on the principles of reentry, to initiate and reproduce ventricular dysrhythmias in the invasive laboratory. In patients with LV dysfunction and NSVT, induction of sustained monomorphic VT during EPS identifies patients at risk for SCD. 47 Induction of polymorphic VT with aggressive stimulation protocols is a nonspecific finding in most entities. The positive predictive value and sensitivity of EPS is highest in ischemic heart disease. However, when used alone, LVEF is superior to EPS in predicting arrhythmic events post-MI. 48
The response to programmed stimulation is more variable in patients with nonischemic dilated cardiomyopathy, presenting with nonsustained dysrhythmia or syncope. Inducibility of monomorphic VT is much lower in these patients compared to those with ischemic cardiomyopathy; hence, the negative predictive value of EPS in this population is poor. The utility of EPS to determine prognosis and to guide therapy remains more limited in this patient population compared to those with ischemic heart disease. 49
In patients with hypertrophic cardiomyopathy (HCM), EPS has been largely abandoned as a routine strategy in risk profiling because of the nonspecificity of provoked ventricular tachyarrhythmias. 50 In patients with structurally normal hearts, EPS is of low utility, although there are anecdotal data suggesting its utility for risk stratification in Brugada syndrome. 51 In patients with syncope, EPS may be useful in implicating an arrhythmic basis for the clinical events. 52
Implantable Loop Recorder
The implantable loop recorder (ILR) is a subcutaneously implanted cardiac rhythm monitor, which, when activated through a radio frequency transmitter, can store rhythm strips for symptom related events. It can also automatically store rhythm strips meeting programmed criteria such as rapid or slow heart rates even when the patient is asymptomatic. In patients with infrequent but recurrent syncope, it provides the opportunity for an extended view when limited by Holter or external recording. In patients where a dysrhythmic basis is suspected but not confirmed, after other conventional tests have been utilized, ILR enhances the diagnostic yield and assists in risk stratification (Figure 1). In a pilot study of post acute MI patients, clinically significant dysrhythmias were recorded in a large number of patients with depressed LV function. 53
Primary Prevention
General Population: Risk Factor Behavior Modification and Public Education
Aggressive attempts to reduce modifiable risk factors of coronary artery disease in the general population, along with moderate regular exercise result in improved survival. 54-57 Conventional wisdom supports that a low-fat, low-cholesterol diet reduces risk in ischemic heart disease. Preliminary data suggest that increased consumption of n-3 polyunsaturated fatty acids, found primarily in fish oil, is associated with a decreased incidence of ischemia induced ventricular dysrhythmias. 58 However, recent data have failed to corroborate this. In recently released data from a randomized trial of patients with implantable cardioverter defibrillator (ICDs), patients who took fish oil had more episodes of VT/VF compared to those on placebo. 59 Subgroup analysis, to look for confounding variables, may shed light on the conclusions drawn from this study. In contrast, a recent meta analysis concluded that n-3 polyunsaturated fatty acids reduce the sudden death by 30%, among people with coronary heart disease. 60 It has been postulated that this beneficial effect of fish oil may be due to the modulation of myocyte ion channels resulting in an increase of HRV. 61 In addition, there is epidemiologic evidence that Indo-Mediterranean diet and light to moderate alcohol intake are associated with reduced risk of SCD. 62-65
Public education is a potent, underused tool in the prevention of sudden death. Education is a prerequisite to behavioral modification. It facilitates public awareness of the risks and strategies toward SCD prevention. Early intervention with AEDs can save many lives. The initial results of the Public Access Defibrillation Trial (PAD), presented at the American Heart Association Annual Scientific Session in November 2003, disclosed that trained laypersons could double the rate of survival from cardiac arrest, with cardiopulmonary resuscitation (CPR) and AED, compared to CPR alone. 66 Not surprisingly, more victims were identified and treated with AED in public, rather than in residential units. A separate and ongoing NIH-funded study, the HAT (Home AED Trial,) will determine whether training family or residential companions on the use of home installed AEDs can reduce SCD of post MI patients. 67 Communal training will become imperative as more AEDs are made available.
Primary Prevention in Ischemic Cardiomyopathy
Randomized clinical trials are our best source of evidence in primary prevention strategies. Postinfarction studies provided data supporting LV dysfunction and frequent complex PVCs as independent predictors of cardiac mortality. 25,68 As a corollary to this, the hypothesis that suppression of complex PVCs in patients with poor LV function would prevent SCD was tested in the Cardiac Arrhythmia Suppression Trial (CAST). Three class I antiarrhythmic drugs (encainide, flecainide, and moricizine) were initially tested in open label titration. The patients whose PVCs were suppressed effectively, as assessed by 24-hour Holter recording, were randomized to either active drug or placebo. The CAST study was terminated prematurely when interim analysis revealed that dysrhythmic death were more common in patients taking active drugs encainide or flecainide compared to those on placebo. 69 Thus, CAST results refuted the hypothesis that effective reduction of a clinical risk marker (PVC suppression) confer clinical benefit (improved survival from SCD). In fact, treatment with antiarrhythmic drugs like encainide and flecainide may even be harmful, in patients with ischemic heart disease. CAST II study continued with moricizine versus placebo but was again discontinued because of a trend toward mortality in the treatment arm. 70
Further studies of other classes of antiarrhythmic agents were undertaken to assess their effect on survival in the ischemic heart disease population. 71-74 The only drugs of the Vaughan Williams classification that showed benefit for SCD prevention in the post-MI population were amiodarone and beta-blockers 74-76 (Table 4).
Subsequent to the recognition of deleterious outcomes from Class I antiarrhythmic therapy, clinical trials on implantable cardioverter defibrillator (ICD) therapy were conducted and outcomes were consistent. In Multicenter Automatic Defibrillator Implantation Trial (MADIT), patients with previous MI, documented NSVT, and LV dysfunction (EF <=35%) were risk stratified with EPS. Those with inducible VT were randomized to either ICD implant or conventional therapy, including antiarrhythmic therapy. MADIT, as well as a similarly designed study, Multicenter UnSustained Tachycardia Trial (MUSTT), showed significant all cause mortality reduction in the subjects randomized to ICD implant compared to no ICD or antiarrhythmic therapy. 47,77 MADIT II later confirmed the same outcomes; however, in MADIT II, patients with previous MI and EF <=30% did not undergo risk stratification with EPS and did not require NSVT as entry criteria. 78
Substudy analysis in MADIT II further defined those with EF <25% and wide QRS (>=150 ms) to be at highest risk. 78 Based on this subgroup analysis and as of this writing in March 2004, the Center for Medicare and Medicaid Services has currently endorsed reimbursement for ICD implantation in the MADIT II population if the patient has bundle branch block (QRS >=120 ms). The expenses related to the ICD implantation in patients with MADIT I criteria are reimbursed, provided VT is inducible at EPS (Table 5).
In the chronic post MI/LV dysfunction population, prophylactic ICD implantation provides significant reduction in cardiac and all-cause mortality compared to EP guided antiarrhythmic therapy or conventional therapy 47,76-79 (Table 6). However, in recently released data of prophylactic ICD implantation shortly after acute MI, ICD did not show overall survival benefit. 80
Primary Prevention in Congestive Heart Failure
In patients with CHF, improvement in survival has been demonstrated with the use of angiotensin converting enzyme (ACE) inhibitors, beta blockers, and nitrates in combination with hydralazine. 81 The utility of prophylactic antiarrhythmic therapy, specifically amiodarone, in this population has been uncertain. In clinical trials of patients with CHF, amiodarone showed discordant effects on survival. 82,83
To date, prophylactic use of ICDs has been unsettled in patients with idiopathic dilated, or nonischemic cardiomyopathy in class II-III CHF (Table 7). In small, randomized studies comparing amiodarone or conventional therapy to prophylactic ICD, no benefit could be detected from either treatment group. 84,85 The initial results of Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial presented at the American Heart Association scientific sessions in November 2003 revealed significant reduction in dysrhythmic but not all-cause mortality in the ICD group compared to conventional therapy. 86 Moreover, the initial results of a large multicenter trial, Sudden Cardiac Death in Heart Failure (SCD-HEFT), presented at the American College of Cardiology in March 2004, conclude prophylactic ICD significantly reduces SCD in patients with EF <35% and class II-III CHF of both ischemic and nonischemic etiology. 83 In subgroup analysis, the hazard ratio of either subgroup does not reach statistical significance but remains on the beneficial side of unity. 83 The results of this large trial may signal expanding the coverage of prophylactic ICD implantation to nonischemic cardiomyopathy population. (Clinical trials with cardiac resynchronization therapy in patients with moderate to severe CHF are discussed elsewhere in this issue of the journal.)
Primary Prevention in Hypertrophic Cardiomyopathy, Brugada, Long QT, and Wolff-Parkinson-White Syndrome
Prospective primary prevention trials in Hypertrophic Cardiomyopathy (HCM) have not been done because of the lower prevalence in cardiology practice and clinical heterogeneity. In a small retrospective study of patients identified at risk who had ICDs implanted, a 5% per year appropriate discharge rate was observed. 87 In Defibrillator versus Beta-blockers for Unexplained Death in Thailand (DEBUT), a clinical trial of patients with structurally normal hearts surviving cardiac arrest or with inducible VF and Brugada pattern on ECG, patients randomized to ICD had higher survival compared to treatment with beta blockers. 88 Although this was not purely a primary prevention trial, there were patients included who had not had their primary event but were nonetheless identified at high risk. This study highlights the familial component of Brugada syndrome, where patients are identified among specific ethno-genetic groups. In Wolff-Parkinson-White Syndrome, patients at risk (ie, those who have rapid conduction in atrial fibrillation over accessory pathway) are cured by catheter ablation of the accessory pathway. 22
In dysrhythmia substrates with genetic predisposition, the key to primary prevention would invariably lie in identifying the gene locus, as in Long QT syndrome. (An in-depth discussion of inherited dysrhythmias and genetic subtyping is included in a featured article elsewhere in this journal.) In the absence of genetic testing protocols, patients who have multiple risk markers need vigilant risk stratification. Early identification of risk is critical in primary prevention. There are multiple web based ongoing registries of these uncommon disorders, which will help in mapping epidemiological data.
Conclusion
Despite substantial advances made in dysrhythmia research in recent decades, the mechanisms leading to SCD remain incompletely understood. This is particularly true in nonischemic cardiomyopathy and primary electrical disorders. Precise mechanistic definition is critical in further identifying clinical risk markers of these patients.
Although several noninvasive risk markers have been tested in the setting of ischemic cardiomyopathy, the relatively low positive predictive accuracy of these modalities has affected their clinical usefulness. Of the noninvasive risk markers, LVEF remains the most widely used clinical parameter of increased risk of SCD. A prediction model using a stepwise approach appears to be a logical sequence in risk stratification, using a composite of noninvasive and invasive markers. Further clinical evaluations are forthcoming.
Preventive strategies targeting modifiable coronary risk factors and lifestyle changes have been shown to decrease cardiac mortality in the general population. As the understanding on human genomics increases, genetic screening may be proven useful in early identification of individuals who are at risk of developing SCD.
Primary prevention trials in the ventricular dysfunction populations, ischemic or idiopathic, demonstrate the superiority of ICDs to antiarrhythmic and conventional therapy in improving survival, resulting in a surge of ICD implantation. Cost, access to care, and potential complications dissuade from universal acceptance of the ICD, despite its effectiveness. Furthermore, rapid technology advancement can create a knowledge gap among patients and healthcare providers. This gap needs to be reduced for optimization of care.
The role of the AED in primary SCD prevention remains to be explored. Initial results of lay person use of AEDs are promising. Increased public awareness with wider access to AED in the community and proper training on the use of AEDs may further improve the survival associated with SCD in the general population.
Acknowledgments
The authors thank Susan O'Donoghue, MD, and Joseph Lindsay, MD, for their expert advice and critical review of this manuscript.
References
1. Schaffer WA, Cobb LA. Recurrent ventricular fibrillation and modes of death in survivors of out-of-hospital ventricular fibrillation. N Engl J Med. 1975;293(6):259-262. [Context Link]
2. Baum RS, Alvarez H 3rd, Cobb LA. Survival after resuscitation from out-of-hospital ventricular fibrillation. Circulation. 1974;50(6): 1231-1235. [Context Link]
3. Eisenberg, Mickey S. The Quest to Reverse Sudden Death in Cardiac Arrest: The Science and Practice of Resuscitation Medicine. Balti-more, Md: Williams and Wilkins; 1996:1-27 [Context Link]
4. Cobb LA, Baum RS, Alvarez H 3rd, Schaffer WA. Resuscitation from out-of-hospital ventricular fibrillation: 4 years follow-up. Circulation. 1975;52(6 Suppl):III223-III235. [Context Link]
5. Wright B. Responding to autonomy and dis-empowerment at the time of a sudden death. Accid Emerg Nurs. 1999;7(3):154-157. [Context Link]
6. Iverson KV. The gravest words: sudden-death notifications and emergency care. Ann Emerg Med. 2000;36(1):75-77. [Context Link]
7. American Heart Association. Heart Disease and Stroke Statistics-2003 Update. Dallas, Tex: American Heart Association; 2002. [Context Link]
8. Goraya TY, Jacobsen SJ, Kottke TE, et al. Coronary heart disease death and sudden cardiac death: a 20-year population-based study. Am J Epidemiol. 2003;157(9):771-773. [Context Link]
9. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation. 2001;104(18):2158-2163. [Context Link]
10. Kuller, LH Sudden death-definition and epidemiologic considerations. Prog Cardiovasc Dis. 1980;23(1):1-12. [Context Link]
11. Krishnan SC, Schuger CD, Goldstein S. Sudden death in heart failure: underlying electro-physiological mechanisms. Heart Fail Rev. 2002;7(3):255-260. [Context Link]
12. Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol. 2001;12(3):369-381. [Context Link]
13. Maron BJ. Risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Cardiol Rev. 2002;10(3):173-181. [Context Link]
14. Corrado D, Basso C, Nava A, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: current diagnostic and management strategies. Cardiol Rev. 2001;9(5):259-265. [Context Link]
15. Moncrieff J, McGavigan AD, Dunn FG. Arrhythmias, sudden death and syncope in hypertensive cardiovascular disease. Card Electrophysiol Rev. 2002;6(1-2):36-41. [Context Link]
16. Petersen EC, Engel JA, Radio SJ, Canfield TM, McManus BM. The clinical problem of occult cardiac amyloidosis. Forensic implications. Am J Forensic Med Pathol. 1992;13(3):225-229. [Context Link]
17. Veinot JP, Johnston B. Cardiac sarcoidosis-an occult cause of sudden death: a case report and literature review. J Forensic Sci. 1998 May;43(3):715-717. [Context Link]
18. Cox GF, Kunkel LM. Dystrophies and heart disease. Curr Opin Cardiol. 1997;12(3):329-343. [Context Link]
19. Meyer JS, Mehdirad A, Salem BI, Kulikowska A, Kulikowski P. Sudden arrhythmia death syndrome: importance of the long QT syndrome. Am Fam Physician. 2003;68(3):483-488. [Context Link]
20. Haverkamp W, Monnig G, Schulze-Bahr E, Haverkamp F, Breithardt G. Physician-induced torsade de pointes-therapeutic implications. Cardiovasc Drugs Ther. 2002;16(2): 101-109. [Context Link]
21. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002;105(11):1342-1347. [Context Link]
22. Grogin HR, Scheinman MM. Advances in evaluating and treating Wolff-Parkinson-White syndrome. Curr Opin Cardiol. 1992;7(1):30-36. [Context Link]
23. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497. [Context Link]
24. Graves KD, Miller PM. Behavioral medicine in the prevention and treatment of cardiovascular disease. Behav Modif. 2003;27(1):3-25. [Context Link]
25. Stevenson WG, Stevenson LW, Middlekauff HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation. 1993;88(6):2953-2961. [Context Link]
26. Buxton AE, Lee KL, Hafley GE, et al. MUSTT investigators relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation. 2002;106(19):2466-2472. [Context Link]
27. Bigger JT Jr. Relation between left ventricular dysfunction and ventricular arrhythmias after myocardial infarction. Am J Cardiol. 1986;57(3):8B-14B. [Context Link]
28. Doval HC, Nul DR, Grancelli HO, et al. Non-sustained ventricular tachycardia in severe heart failure. Independent marker of increased mortality due to sudden death. GESICA-GEMA Investigators. Circulation. 1996;94(12):3198-3203. [Context Link]
29. Singh SN, Fisher SG, Carson PE, Fletcher RD. Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. Department of Veterans Affairs CHF STAT Investigators. J Am Coll Cardiol. 1998;32(4):942-947. [Context Link]
30. Teerlink JR, Jalaluddin M, Anderson S, et.al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators. Circulation. 2000;101(1):40-46. [Context Link]
31. Vos MA, Gorenek B, Verduyn SC, et al. Observations on the onset of torsade de pointes arrhythmias in the acquired long QT syndrome. Cardiovasc Res. 2000;48(3):421-429. [Context Link]
32. Morita H, Nagase S, Kusano K, Ohe T. Spontaneous T wave alternans and premature ventricular contractions during febrile illness in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 2002;13(8):816-818. [Context Link]
33. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003;42(5):873-879. [Context Link]
34. Kuck KH. Arrhythmias in hypertrophic cardiomyopathy. Pacing Clin Electrophysiol. 1997;20(10 Pt 2):2706-2713. [Context Link]
35. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36(7):2212-2218. [Context Link]
36. Marcus FI. Electrocardiographic features of inherited diseases that predispose to the development of cardiac arrhythmias, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy/dysplasia, and Brugada syndrome. J Electrocardiol. 2000;33 Suppl:1-10. [Context Link]
37. Zipes DP. Autonomic modulation of cardiac arrhythmias and sudden cardiac death. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside, 2nd ed, Philadelphia, Pa: Saunders:441-453. [Context Link]
38. Kleiger RE, Miller JP, Bigger JT, Moss AJ: Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256-262. [Context Link]
39. Carlson MD, Krishen A. Risk assessment for ventricular arrhythmias after extensive myocardial infarction: What should I do?ACC Current Journal Review. 2003;12(2):90-93. [Context Link]
40. La Rovere MT, Pinna GD, Hohnloser SH, et.al. and ATRAMI Investigators. Autonomic tone and reflexes after myocardial infarction. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation. 2001;103(16):2072-2077. [Context Link]
41. Huikuri HV, Tapanainen JM, Lindgren K, et al. Prediction of sudden cardiac death after myocardial infarction in the beta-blocking era. J Am Coll Cardiol. 2003;42(4):652-658. [Context Link]
42. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345(20):1473-1482. [Context Link]
43. Klingenheben T, Zabel M, D'Agostino RB, Co -wave alternans for arrhythmic events in patients with congestive heart failure. Lancet. 2000;356(9230):651-652. [Context Link]
44. Hohnloser SH, Klingenheben T, Bloomfield D, Dabbous O, Cohen RJ. Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study. J Am Coll Cardiol. 2003;41(12):2220-2224. [Context Link]
45. Hohnloser SH, Ikeda T, Bloomfield DM, Dabbous OH, Cohen RJ. T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation. Lancet. 2003;362(9378):125-126. [Context Link]
46. Armoundas AA, Tomaselli GF, Esperer HD. Pathophysiological basis and clinical application of T-wave alternans. J Am Coll Cardiol. 2002;40:207-217. [Context Link]
47. 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(26):1933-1940. [Context Link]
48. Caruso AC, Marcus FI, Hahn EA, Hartz VL, Mason JW. Predictors of arrhythmic death and cardiac arrest in the ESVEM trial. Electrophysiology study versus electromagnetic monitoring. Circulation. 1997;96:1888-1892. [Context Link]
49. Hsia HH, Marchlinski FE. Electrophysiology studies in patients with dilated cardiomyopathies. Card Electrophysiol Rev. 2002;6(4): 472-481. [Context Link]
50. Maron BJ, Mark Estes, NA, Maron MS, Almquist AK, Link MS, Udelson JE. Primary prevention of sudden cardiac death as a novel treatment strategy in hypertrophic cardiomyopathy. Circulation. 2003;107:2872-2875. [Context Link]
51. Brugada P, Brugada R, Mont L, Rivero M, Geelen P, Brugada J. Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart. J Cardiovasc Electrophysiol. 2003;14(5):455-457. [Context Link]
52. Garcia-Civera R, Ruiz-Granell R, Morell-Cabedo S, et.al. Selective use of diagnostic tests inpatients with syncope of unknown cause. J Am Coll Cardiol. 2003;41(5):787-790. [Context Link]
53. Huikuri HV, Mahaux V, Bloch-Thomsen PE. Cardiac arrhythmias and risk stratification after myocardial infarction: results of the CARISMA pilot study. Pacing Clin Electrophysiol. 2003;26(1 Pt 2):416-419. [Context Link]
54. De Backer G, Kornitzer M, Dramaix M, Kittel F, Thilly C, Graffar M, Vuylsteek K. The Belgian Heart Disease Prevention Project: 10-year mortality follow-up. Eur Heart J. 1988;9(3):238-242. [Context Link]
55. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coll Cardiol. 1985;5(6 Suppl):141B-149B. [Context Link]
56. Lemaitre RN, Siscovick DS, Raghunathan TE, Weinmann S, Arbogast P, Lin DY. Leisure-time physical activity and the risk of primary cardiac arrest. Arch Intern Med. 1999;159(7):686-690. [Context Link]
57. Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med. 1984;311(14):874-877. [Context Link]
58. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312(19):1205-1209. [Context Link]
59. Omega-Clinical Trial. Clinical Trial Updates. Available at: http://www.hrsonline.org/professional_education/learning_categories/clinical_tri. Accessed June 14, 2004. [Context Link]
60. Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112(4):298-304. [Context Link]
61. Christensen JH, Skou HA, Fog L, Hansen V, et al. Marine n-3 fatty acids, wine intake, and heart rate variability in patients referred for coronary angiography. Circulation. 2001;103(5):651-657. [Context Link]
62. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99(6):779-785. [Context Link]
63. Singh RB, Dubnov G, Niaz MA, et al. Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): a randomised single-blind trial. Lancet. 2002 Nov 9;360(9344):1455-1461. [Context Link]
64. Siscovick DS, Weiss NS, Fox N. Moderate alcohol consumption and primary cardiac arrest. Am J Epidemiol. 1986;123(3):499-503. [Context Link]
65. Albert CM, Manson JE, Cook NR, Ajani UA, Gaziano JM, Hennekens CH. Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation. 1999;100(9):944-950. [Context Link]
66. PAD: The Public Access Defibrillation Trial. Presenter: Joseph P. Omato, MD, Virginia Commonwealth University (Richmond). Available at: http://www.medscape.com/viewarticle/464582. Accessed March 22, 2004. [Context Link]
67. Bardy GH. Home Automated External Defibrillator Trial. Available at: http://www.sicr.org/hatmain.html. Accessed March, 22, 2004 [Context Link]
68. Brezinski D, Stone PH, Muller JE, et al. Prognostic significance of the Karnofsky Performance Status score in patients with acute myocardial infarction: comparison with the left ventricular ejection fraction and the exercise treadmill test performance. The MILIS Study Group. Am Heart J. 1991;121(5):1374-1381. [Context Link]
69. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving en-cainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324(12):781-788. [Context Link]
70. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II Investigators. N Engl J Med. 1992;327(4):227-233. [Context Link]
71. International Mexiletine and Placebo Antiarrhythmic Coronary Trial (IMPACT): II. Results from 24-hour electrocardiograms. IMPACT Research Group. Eur Heart J. 1986;7(9):749-759. [Context Link]
72. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet. 1996;348(9019):7-12. [Context Link]
73. Kober L, Bloch Thomsen PE, Moller M, et al. Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet. 2000;356(9247):2052-2058. [Context Link]
74. Morganroth J, Lichstein E, Byington R. Beta-Blocker Heart Attack Trial: impact of propranolol therapy on ventricular arrhythmias. Prev Med. 1985;14(3):346-357. [Context Link]
75. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet. 1997;349(9053):675-682. [Context Link]
76. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet. 1997;349 (9053):667-674. [Context Link]
77. Lee KL, Hafley G, Fisher JD, et al. Multicenter Unsustained Tachycardia Trial Investigators. Effect of implantable defibrillators on arrhythmic events and mortality in the multicenter unsustained tachycardia trial. Circulation. 2002;106(2):233-238. [Context Link]
78. Moss AJ, Zareba W, Hall WJ, Klein H, et al. Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877-883. [Context Link]
79. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med. 1997;337(22):1569-1575. [Context Link]
80. Stuart J. Connolly, Stefan H. Hohnloser, on behalf of the DINAMIT Steering Committee and Investigators. DINAMIT: Randomized Trial of Prophylactic Implantable Defibrillator Therapy Versus Optimal Medical Treatment Early After Myocardial Infarction: The Defibrillator in Acute Myocardial Infarction Trial. Available at: http://www.cardiosource.com/meetings. Accessed March, 2004. [Context Link]
81. Naccarelli GV, Wolbrette DL, Dell'Orfano JT, Patel HM, Luck JC. Amiodarone: what have we learned from clinical trials?Clin Cardiol. 2000;23(2):73-82. [Context Link]
82. Hammill SC, Packer DL. Amiodarone in congestive heart failure: unravelling the GESICA and CHF-STAT differences. Heart. 1996;75(1):6-7. [Context Link]
83. Gust H. Bardy, Kerry L. Lee, Daniel B. Mark, et al. and The SCD-HeFT Investigators. Available at: http://www.cardiosource.com/meetings. Accessed March 20, 2004. [Context Link]
84. Strickberger SA, Hummel JD, Bartlett TG, et al. AMIOVIRT Investigators. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVIRT. J Am Coll Cardiol. 2003;41(10): 1707-1712. [Context Link]
85. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002;105(12):1453-1458. [Context Link]
86. DEFINITE: Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation. Luis Gruberg, MD, Presenter: Alan H. Kadish, MD, Northwestern University Feinberg School of Medicine. Available at: http://www.medscape.com/viewarticle/464653. Accessed March 20, 2004. [Context Link]
87. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342(6):365-373. [Context Link]
88. Nademanee K, Veerakul G, Mower M, et al. Defibrillator Versus beta-Blockers for Unexplained Death in Thailand (DEBUT): a randomized clinical trial. Circulation. 2003;107 (17):2221-2216. [Context Link]