1. 1
    Definition and Causes

    Sudden cardiac death is defined as abrupt, unexpected natural death occurring within a short time period (generally <1 hour) after onset of acute symptoms. Primary cardiac arrhythmia is responsible for most of the cases, but acute severe myocardial dysfunction, intracardiac obstruction, and acute aortic dissection are other important causes (Table 1). Structural abnormalities of the myocardium resulting from hypertrophy, scarring, and fibrosis serve as substrates for malignant arrhythmias. The majority of patients who die suddenly have atherosclerotic coronary artery disease (CAD). However, only about 20% of those who survive a cardiac arrest demonstrate evidence of an acute myocardial infarction. Instead, a large number have evidence of prior myocardial infarction and LV dysfunction. It is now recognized that chronic LV dysfunction is the most important predictor of sudden death in ischemic and nonischemic cardiomyopathy.

    Table 1

    Causes of Sudden Cardiac Death

    Coronary artery disease

    Atherosclerotic disease

    Congenital anomalies Spasm




    Primary cardiomyopathies

    Nonischemic dilated cardiomyopathy

    Hypertrophic cardiomyopathy


    Valvular heart disease

    Arrhythmogenic right ventricular dysplasia

    Electrophysiologic abnormalities

    Conduction system disease involving the His-Purkinje conduction system

    Primary ventricular arrhythmia associated with the following cardiac conditions:

    Abnormalities of the QT interval

    Brugada syndrome

    Wolff-Parkinson-White syndrome

    Catecholaminergic ventricular tachycardia

    Idiopathic ventricular fibrillation and early repolarization syndromes

    Malignant ventricular arrhythmia resulting from metabolic abnormalities

    Commotio cordis Pulmonary hypertension Hypertensive heart disease

    Congenital heart disease

    Noncompaction of the left ventricle

    Inflammatory and infiltrative diseases of the myocardium


    Chagas’ disease



    Hydatid cyst

    Neuromuscular diseases

    Muscular dystrophy

    Myotonic dystrophy

    Kearns-Sayre syndrome

    Friedreich’s ataxia

    Intracardiac obstruction

    Primary cardiac tumors (e.g., myxoma)

    Intracardiac thrombus

    Massive pulmonary embolism

    Acute aortic dissection

    A significant number (10%) of sudden deaths occur in the absence of obvious structural heart disease. Young, active, and otherwise healthy individuals are often the victims. Inherited or spontaneous mutations in genes coding for ion channels are responsible for most of these cases. A number of specific syndromes have been recognized, allowing for screening of relatives.

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  2. 2
    Tests to Identify Risk for Sudden Death

    Electrocardiography (ECG) and echocardiography can provide several clues. Assessment of ventricular function provides the most information in determining the risk for sudden death.

    Several noninvasive tests, including detection of microvolt T-wave alternans, signal-averaged ECG, and heart rate variability, have been developed to predict the future risk of sudden death. These tests have poor generalized applicability because of their low positive predictive value. In addition, most have not been coupled with a therapeutic intervention to show that therapy based on them can reduce the risk of dying. Cardiac MRI showing evidence for myocardial scar is emerging as a useful tool for predicting risk.

    Intracardiac electrophysiologic testing has retained some value, especially in patients with CAD. Inducibility of a sustained arrhythmia can be a marker for arrhythmic events, and therapy based on results of electrophysiologic testing has been shown to reduce mortality.

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  3. 3

    This article summarizes the treatment modalities that have been shown to be effective in the various conditions leading to sudden cardiac death. Data based on randomized clinical trials are limited to common conditions such as CAD and the cardiomyopathies. The rarer diseases lack large clinical experience, and recommendations are based on the current consensus.

    Acute Management of Survivors of Cardiac Arrest

    Once stabilized with the use of standard advanced cardiac life support guidelines, patients should undergo cardiac evaluation by echocardiography and cardiac catheterization. Electrolyte abnormalities should be sought and corrected. Mild hypokalemia (3.0–3.5 mmol/L) is common after a cardiac arrest and resuscitation and is related to hypotension and transient acidosis. Hence, it is often the result and not the cause of the cardiac arrest. Similarly, in the acute phase after resuscitation, it is not uncommon to find global LV hypokinesis, but this should not be taken as a marker for preexisting heart disease. LV function tends to improve over the next 24 to 48 hours and should then be reassessed.

    Ventricular fibrillation that occurs during the acute phase of a myocardial infarction (within the first 24–48 hours) is presumed to be secondary to electrical instability resulting from myocardial ischemia and reperfusion. If treated promptly by defibrillation, this arrhythmia has little prognostic value so long as overall myocardial function is preserved.

    If acute ischemia or infarction is the documented cause of a cardiac arrest, revascularization by percutaneous angioplasty or coronary bypass surgery is the best treatment. The risk of recurrence is determined by the residual LV ejection fraction. In the Antiarrhythmic Versus Implantable Defibrillator (AVID) trial and Canadian trial of Implantable Defibrillators (CIDS), ICDs did not offer any survival benefit for patients with preserved LV function (>35%). Therefore, postrevascularization electrophysiologic evaluation is recommended only for patients with impaired ejection fraction or significant LV scarring.

    Survivors of a malignant arrhythmia other than that due to a reversible cause such as severe metabolic disturbance, toxic drug effect, or acute myocardial infarction are best treated with an ICD. In the largest prospective, randomized trial of drugs versus an ICD (the AVID trial), the ICD reduced mortality by 39% at 1 year and by 31% at 3 years, compared with amiodarone (Cordarone) or sotalol (Betapace). In the absence of specific contraindication, ICD therapy is currently the standard of care for secondary prevention of life-threatening ventricular arrhythmias. However, a permanent ICD is best reserved for patients who are expected to survive with a reasonable quality of life for a year or more. Temporary protection against ventricular arrhythmic death can be afforded by the use of a wearable defibrillator (LifeVest) when a permanent implant has to be delayed for reasons such as an ongoing infection or when awaiting recovery of cardiac function after an MI or revascularization procedure such as CABG or PTCI.

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  4. 4
    Primary Prevention of Ventricular Arrhythmias and Sudden Cardiac Death

    Coronary Artery Disease

    There are considerable data to guide efforts at primary prevention of sudden death in patients with CAD. β-Adrenergic blockers and angiotensin-converting enzyme inhibitors reduce mortality after myocardial infarction and should be routinely prescribed in the absence of major contraindications (Table 2). Part of the benefit on mortality offered by these drugs is achieved through reduction of the incidence of sudden death. There is no role for the use of antiarrhythmic drugs in primary prevention. Amiodarone, sotalol, and dofetilide (Tikosyn) have largely neutral effects, but class 1 antiarrhythmic drugs such flecainide (Tambocor) and propafenone (Rythmol) are clearly harmful and increase mortality in patients with ventricular dysfunction.

    Table 2

    Drugs That Have Been Shown to Reduce Sudden Cardiac Death

    β-Adrenergic blockers: metoprolol (Lopressor), carvedilol (Coreg)

    Angiotensin-converting enzyme inhibitors

    Angiotensin receptor blockers

    Aldosterone antagonists

    Antiplatelet drugs

    Lipid-lowering agents Fish oil1

    1  Not FDA approved for this indication.

    Ventricular arrhythmias occurring late (>24 hours) after a myocardial infarction usually indicate a persisting propensity for recurrent arrhythmia and risk of death. Commonly, these patients have impaired LV function and benefit from treatment with an ICD; an intracardiac electrophysiologic study is helpful in determining the risk of recurrence. Inducibility of ventricular tachycardia (VT) on electrophysiologic study is considered a predictor of sudden death, and treatment of such patients with an ICD lowers mortality.

    For the stable patient with CAD, depressed ejection fraction and nonsustained VT are recognized risk factors for sudden death. If severe LV dysfunction is present (ejection fraction <30%), implantation of an ICD will significantly reduce sudden death. In the presence of moderate LV dysfunction (ejection fraction ≤35%), a defibrillator is indicated if patients have New York Heart Association class II or III heart failure symptoms. Nonsustained VT occurring in the context of moderate LV dysfunction warrants an intracardiac electrophysiologic study (Table 3). In all cases ICD should be avoided in patients where meaningful survival is limited to less than a year from nonarrhythmic causes.

    Table 3

    Indication for ICD Therapy Based on the ACC/AHA 2008 Guidelines

    Abbreviations: ACC/AHA = American College of Cardiology/American Heart Association Task Force; ICD = implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; VF = ventricular fibrillation; VT =   ventricular tachycardia.

    †  There is good clinical evidence and general agreement that ICD is beneficial.

    †  There is inadequate data or some divergence of opinion regarding ICD  benefit.

    Idiopathic Dilated Cardiomyopathy

    Unlike CAD, nonischemic dilated cardiomyopathy is more variable in its course. This is partly because the etiology is often unclear; the disease process may be progressive in some and self-limited with spontaneous improvement in others. Consequently, benefit from ICD therapy is not as convincing as in patients with CAD. Nonsustained VT, syncope, and heart failure symptoms are predictors of high risk of sudden death in this population. In the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation trial (DEFINITE), implantation of an ICD based on the presence of LV dysfunction, symptomatic heart failure, and nonsustained VT resulted in a reduction in arrhythmic mortality. The Sudden Death in Heart Failure trial (SCD Heft) showed that ICDs reduce mortality in the presence of heart failure symptoms and an LV ejection fraction of 35% or less.

    Syncope in the presence of cardiomyopathy can be a harbinger of sudden death and merits the use of ICD therapy if another cause of syncope cannot be identified.

    Hypertrophic Cardiomyopathy

    Hypertrophic cardiomyopathy is a genetically heterogenous disease with an autosomal dominant mode of inheritance caused by mutations in genes coding for sarcomeric proteins. Unrecognized hypertrophic cardiomyopathy is a frequent cause of sudden death in young athletes.

    Sudden death in hypertrophic cardiomyopathy is caused by ventricular arrhythmias and can be prevented by implantation of an ICD. A number of risk factors for sudden death have been identified in retrospective studies and are outlined in Table 4. The presence of any one of the major risk factors is an indication for ICD implantation. Electrophysiologic testing has no major value in risk stratification.

    Table 4

    Clinical Risk Factors for Sudden Death in Hypertrophic Cardiomyopathy

    Major Risk Factors

    Cardiac arrest

    Spontaneous sustained or nonsustained ventricular tachycardia

    History of sudden cardiac death in first-degree relatives Syncope

    Left ventricular thickness ≥30 mm

    Abnormal blood pressure response to exercise

    Possible Risk Factors

    Atrial fibrillation

    Myocardial ischemia

    Left ventricular outflow obstruction

    High-risk mutations

    Intense (competitive) physical exertion

    Genetic abnormalities do not always correlate with phenotypic expression of disease, and some abnormalities in the troponin gene may have minimal clinical features but high risk for arrhythmias.

    Genetic testing of the index case is useful in screening of family members.

    Arrhythmogenic Right Ventricular Dysplasia

    Arrhythmogenic right ventricular dysplasia is characterized by progressive replacement of myocytes with fibrofatty tissue due to an inherited autosomal dominant abnormality in the genes coding for cell-to-cell junction proteins. Typically, the right ventricle is involved, but progressive involvement of the LV has been described. Right bundle branch blockade with late potentials (epsilon wave) and T- wave inversion in the precordial lead may be present on ECG. Ventricular arrhythmia and sudden death are common modes of presentation between the ages of 20 and 40 years, although occasionally heart failure is the presenting symptom.

    Patients presenting with stable VT may respond to radiofrequency ablation and antiarrhythmic therapy, but the recurrence rates are high. Consequently, most patients will require ICD therapy. ICD is the first line of treatment for patients with prior cardiac arrest, inducible ventricular arrhythmias on electrophysiologic study, and unexplained syncope.


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  5. 5
    Sudden Death Associated with Abnormalities of the QT Interval

    Congenital long QT (LQT) syndrome is commonly caused by inherited abnormalities of the potassium channel (e.g., LQT1 and LQT2) or of the sodium channel (e.g., LQT3) that result in abnormal cardiac repolarization. These patients carry a risk of developing torsades de pointes VT. Torsades de pointes can lead to syncope but is frequently self-limited. However, the arrhythmia can degenerate to ventricular fibrillation, and sudden death may be the initial manifestation.

    The mortality rate is high in untreated patients (approximately 1% per year). Once syncopal episodes begin, the risk of death increases; in one study, 20% of patients had died within 1 year after a syncopal spell. However, ideal management of the congenital LQT syndrome remains controversial. β-Adrenergic blockers and left stellate ganglionectomy, at times in conjunction with cardiac pacing, have been shown to reduce symptoms and mortality. However, the response to beta blockers may vary based on the type of genetic mutations. Because most patients are children or teenagers at the time of diagnosis, there is concern about long-term therapy with implantable devices because of the need for generator changes, potential lead malfunction, and risk of infection. ICD therapy is currently reserved for high-risk patients identified by prior cardiac arrest, recurrent syncope, or VT while on β-blockers, QTc exceeding 500 msec, siblings with sudden death, and symptoms in the patient with LQT3 and possibly LQT2.

    One of the major precipitants of torsades in the asymptomatic patient is iatrogenic effects. Numerous drugs have the potential to prolong the QT interval (Table 5). In addition, hypokalemia and hypomagnesemia can induce QT prolongation and torsades de pointes.

    Table 5

    Drugs Known to Cause QT Prolongation and Torsades de Pointes



    Sotalol (Betapace)

    Dofetilide (Tikosyn)

    Ibutilide (Corvert)

    Disopyramide (Norpace)

    Procainamide (Pronestyl)

    Less Common

    Amiodarone (Cordarone)

    Antibiotics: clarithromycin (Biaxin), erythromycin, pentamidine (Pentam), sparfloxacin (Zagam)2

    Antiemetic agents: domperidone (Motilium),2 droperidol (Inapsine)

    Antipsychotic agents: chlorpromazine (Thorazine), haloperidol (Haldol), mesoridazine (Serentil),2 thioridazine (Mellaril)

    2  Not available in the United States.

    In patients without a recognized QT abnormality, drug-induced torsades is treated by discontinuation and avoidance of the offending drug. A number of risk factors have been recognized for drug-induced torsades. They include female gender, hypokalemia and hypomagnesemia, bradycardia, congestive heart failure, baseline QT prolongation, and high drug concentrations (with the exception of quinidine). Conversion of atrial fibrillation with rapid heart rates to sinus rhythm in the presence of a QT-prolonging drug is a known risk for torsades because of the relative bradycardia interacting with QT prolongation. Administration of class III antiarrhythmic drugs such as sotalol, ibutilide (Corvert), and dofetilide used for conversion and prevention of atrial fibrillation should be commenced under telemetric monitoring. The potential for accumulation of antiarrhythmic drugs in the face of renal dysfunction (e.g., sotalol, dofetilide) should be recognized and dosing adjusted.

    A familial form of the short QT syndrome associated with sudden death has been described. A family history of sudden death appears to confer a high risk of sudden arrhythmic death in these patients, warranting ICD therapy.

    Brugada Syndrome

    Brugada syndrome is characterized by ECG features of incomplete right bundle branch block, J-point elevation with ST-segment elevation in the right precordial leads, normal QT interval, and risk of ventricular fibrillation. The condition has been shown to be caused by an inherited abnormality of the sodium channel involving the same gene (SCN5A) that is responsible for LQT3. The clinical features share similarities with those of LQT3: relative inefficacy of β-blockade, high mortality in symptomatic patients, and sudden death occurring during rest or sleep. Diagnostic criteria are equivocal. ST-segment abnormalities may be transient and dynamic and tend to be augmented by administration of sodium channel blockers.

    The general consensus is that symptomatic patients should be treated with an ICD. Asymptomatic patients with a malignant family history should also be considered for ICD therapy. As with the LQT syndromes, drugs have a potential for provoking arrhythmias; sodium channel blockers, including tricyclic antidepressants, have the potential for inducing ventricular arrhythmias and are best avoided in these patients.

    Catecholaminergic Ventricular Tachycardia

    Inherited defects in genes coding for handling of calcium by the sarcoplasmic reticulum result in ventricular arrhythmia triggered by exercise or emotional stress. The resting ECG is normal. Children are usually affected, but late onset of this condition has been recognized. An autosomal dominant form is caused by mutations in the gene coding for the cardiac ryanodine receptor. The autosomal recessive form is caused by mutation in the gene encoding for calsequestrin, a calcium-buffering protein in the sarcoplasmic reticulum. β-Blockers are the primary form of treatment. However, those patients who have had ventricular fibrillation or continue to have VT or syncope despite β-blocker therapy are considered to be at high risk and should receive ICD therapy.

    Wolff-Parkinson-White Syndrome

    In the Wolff-Parkinson-White (WPW) syndrome, atrial fibrillation can be conducted rapidly via an accessory pathway with a short refractory period, resulting in ventricular fibrillation and death. The risk of sudden death in patients with WPW syndrome is estimated to be less than 1 in every 1000 patient-years of follow-up. Although the risk is reportedly very low among asymptomatic patients, a potentially lethal arrhythmia can be the initial manifestation in a small number of patients (up to 10%).

    The treatment of choice for WPW syndrome is catheter ablation of the accessory pathway; this is successful in 95% of patients. If ablation is ineffective or preferentially avoided because of a high risk of heart block, use of antiarrhythmic drugs such as flecainide or propafenone is an alternative. Rarely, amiodarone may be required to suppress arrhythmias including atrial fibrillation.

    Management in the asymptomatic individual who exhibits the WPW pattern on ECG is controversial. Until recently, the consensus was that asymptomatic patients did not require invasive evaluation. Patients with intermittent ventricular preexcitation and those in whom the refractory period of the accessory pathway can be determined to be long are at low risk for sudden death. If a benign nature of the accessory pathway cannot be confirmed by noninvasive evaluation, intracardiac electrophysiologic testing should be considered, with radiofrequency ablation if appropriate. A recent study showed that prophylactic ablation in asymptomatic patients younger than 35 years of age significantly reduced subsequent arrhythmias. Prophylactic ablation should also be considered for individuals in situations in which there is minimal tolerance of a potential for arrhythmias, such as in airline pilots.

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    Idiopathic Ventricular Fibrillation

    A small number of patients who are resuscitated from sudden death episodes have no identifiable structural or electrical abnormalities.

    The term idiopathic ventricular fibrillation is applied to these patients. Clinically silent focal myocarditis, cardiomyopathy, or unrecognized ionic channel abnormalities may be responsible and may become apparent during subsequent follow-up. The current consensus is that drug therapy is ineffective, and ICD therapy is the safest and most effective secondary prevention strategy. An early repolarization pattern on ECG with >0.1mV J-point elevation in the inferior and lateral leads has recently been associated with vulnerability to VF but the prognostic significance of this pattern in the general population is uncertain.

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  7. 7
    Adult Congenital Heart Disease

    A number of congenital heart diseases can be corrected or palliated by surgery, and survival into adulthood is common. However, sudden arrhythmic cardiac death is a leading cause for late mortality.

    Unexplained syncope in such patients warrants evaluation by electrophysiologic testing. Intracardiac repair of tetralogy of Fallot has been accomplished since the mid-1950s, with favorable long-term outcome. Risk of late arrhythmic death increases with wide QRS duration, right ventricular dilatation from pulmonary regurgitation, and LV dysfunction. Ventricular arrhythmias or complete heart block may lead to sudden death. Syncope in such patients is an ominous symptom and should be investigated by electrophysiologic evaluation. Pulmonary valve replacement is known to reduce subsequent arrhythmia risk. Inducible VT and evidence for spontaneous ventricular arrhythmias should prompt the consideration of ICD therapy.

    A rare condition called noncompaction, caused by an arrest in development of the LV, is known to be associated with sudden death. Prophylactic ICD implantation is recommended.

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    Neuromuscular Diseases

    Some neuromuscular diseases are associated with conduction system disease and ventricular arrhythmias leading to sudden death.

    Myotonic dystrophy and Kearns-Sayre syndrome are situations in which prophylactic cardiac pacing at the first sign of conduction system disease can be lifesaving. If evidence of cardiac disease precedes the onset of respiratory muscle disease, the risk of cardiac arrhythmia is high, and ICD implantation is often necessary.

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  9. 9

    Bradyarrhythmias resulting from atrioventricular blockade below the atrioventricular node is a cause for sudden death. Most cases of Mobitz type II block or complete heart block below the His bundle are caused by sclerodegenerative changes in the specialized conduction system. Occasionally, cardiac sarcoid or other infiltrative diseases may be responsible. Chagas’ disease is a common cause in endemic areas in South America. A familial form of progressive heart block caused by a defect in the SCN5A gene has been identified in some families.

    Symptomatic bradyarrhythmias and heart block due to disease in the His-Purkinje system are indications for permanent cardiac pacing. In the absence of the other structural heart disease, permanent cardiac pacing can restore longevity to match that of age-matched controls.

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  10. 10

    Antiarrhythmics Versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near fatal ventricular arrhythmias. N Engl J Med.


    Ezekowitz J.A., Armstrong P.W., McAlister F.A. Implantable cardioverter defibrillators in primary and secondary prevention: A systematic review of randomized, controlled trials [see comments]. Ann Intern Med. 2003;138:445–452.

    Goldberg I., Moss A.J., Peterson D.R., et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long QT syndrome. Circulation.


    Pappone C., Santinelli V., Manguso F., et al. A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome. N Engl J Med. 2003;349:1803–1811.

    Priori S.G., Schwartz P.J., Napolitano C., et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348:1866–1874.

    Santinelli V., Radinovic A., Manguso F., et al. The natural history of asymptomatic ventricular pre-excitation: A long-term prospective follow-up study of 184 asymptomatic children. J Am Coll Cardiol. 2009;53:275–280.

    Zipes D.P., Camm A.J., Borggrefe M., et al. ACC/AHA/ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.

    Circulation. 2006;114(10):e385–484.

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