AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Sudden cardiac death (SCD) is an unexpected death due to cardiac causes occurring in a short time period (generally within 1 h of symptom onset) in a person with known or unknown cardiac disease in whom no previously diagnosed fatal condition is apparent. Most cases of SCD are related to cardiac arrhythmias. Approximately half of all cardiac deaths can be classified as SCDs. SCD occurs as the first expression of cardiac disease in many individuals presenting as out-of-hospital patients with cardiac arrest. This article explores the epidemiology, pathophysiology, diagnostic approach, and treatment of patients who experienced SCD in the United States.

Pathophysiology

The most common electrophysiologic mechanisms leading to SCD are tachyarrhythmias such as VF or VT. Interruption of tachyarrhythmias, using either an automatic external defibrillator (AED) or an implantable cardioverter defibrillator (ICD), has been shown to reduce mortality and morbidity from SCD. Patients with tachyarrhythmias, especially VT, carry the best overall prognosis of SCD patients because of the success of defibrillation. In patients with ischemic heart disease, the most common form of VT is monomorphic, which arises from a reentrant circuit.

Approximately 20-30% of patients from all documented sudden death events have bradyarrhythmia or asystole at the time of initial contact. Oftentimes, it is difficult to determine with certainty the initiating event in a patient presenting with a bradyarrhythmia because asystole and pulseless electrical activity (PEA) may result from a sustained VT. Conversely, an initial bradyarrhythmia producing myocardial ischemia may then provoke VT or VF.

Most cases of SCD occur in patients with structural abnormalities of the heart, related to either a prior myocardial infarction (MI) or a congenital abnormality. Acute thrombosis in an atherosclerotic coronary artery may present as unstable angina, acute myocardial infarction (MI), or SCD. Although more than 80% of SCD events occur in individuals with coronary artery disease (CAD), evidence of acute MI is far less common. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) both are associated with increased risk of SCD. Heart failure and various valvular diseases such as aortic stenosis are associated with increased risk of SCD. The strongest predictor of SCD is left ventricular dysfunction of any cause. Acute illnesses, such as myocarditis, may provide both an initial and sustained risk of SCD due to inflammation and fibrosis of the myocardium.

Less commonly, SCD happens in patients who may not have apparent structural heart disease. These conditions usually are inherited arrhythmia syndromes.

At the molecular level, VT and VF can be caused by altered Ca hemodynamics, neurohormonal changes, altered K hemodynamics especially in ischemia, or mutations resulting in dysfunction of a sodium channel (Na channelopathy) resulting in enhanced automaticity or reentry with unidirectional block. In patients who survive a myocardial infarction (MI), it has been demonstrated that the presence of premature ventricular contractions (PVCs), particularly complex forms, such as multiform PVCs, short coupling intervals (R-on-T phenomenon), or VT (salvos of 3 or more ectopic beats), reflect an increased risk of sudden death.

Even though many patients have anatomic and functional cardiac substrates that predispose them to develop ventricular arrhythmias, only a small percentage develop SCD. The interplay between the regional ischemia, LV dysfunction, and transient inciting events (eg, worsened ischemia, acidosis, hypoxemia, wall tension, drugs, metabolic disturbances) has been proposed as being the precipitator of sudden death (see Image 1).

Frequency

United States

SCD accounts for approximately 325,000 deaths per year in the United States; more deaths are attributable to SCD than to lung cancer, breast cancer, or AIDS. This represents an incidence of 0.1-0.2% per year in the adult population. SCD commonly is the first expression of CAD and is responsible for approximately 50% of deaths from CAD.

In several population-based studies, the incidence of out-of-hospital cardiac arrest has been noted as declining in the past 2 decades, but the proportion of sudden CAD deaths in the United States has not changed. Looking at population subgroups, a high incidence of SCD occurs among certain groups (congestive heart failure [CHF] with ejection fraction <30%, convalescent phase after MI, patients who survived cardiac arrest). Unfortunately, only a small percentage of total SCD events occur in these patients. The time dependence of risk for SCD has been noted in several studies, with an increased number of events in the first 6-24 months after surviving a major cardiovascular event.

International

The frequency of SCD in Western industrialized nations is similar to that in the United States. The incidence of SCD in other countries varies as a reflection of CAD prevalence in those populations. The trend toward increasing SCD events in developing nations of the world is thought to reflect a change in dietary and lifestyle habits in these nations.

Mortality/Morbidity

Of the 325,000 deaths attributed to SCD in the United States each year, a large portion (as many as 40%) are unwitnessed. For most people who experience SCD, their survival depends on the presence of individuals who are competent in performing basic life support, the rapid arrival of personnel and apparatus for defibrillation and advanced life support, and transfer to a hospital. Even under ideal circumstances, only an estimated 20% of patients who have out-of-hospital cardiac arrest survive to hospital discharge. In a study of out-of-hospital cardiac arrest survival in New York City, only 1.4% of patients survived to hospital discharge. Other studies in suburban and rural areas have indicated higher rates of survival (as high as 35%). Placement of automatic external defibrillators throughout communities and training people to use them has the potential to markedly improve outcomes from SCD.

• Upon emergency department (ED) presentation, the most important determinants of survival include (1) an unsupported systolic blood pressure (SBP) greater than 90 mm Hg, (2) a time from loss of consciousness to return of spontaneous circulation (ROSC) of less than 25 minutes, and (3) some degree of neurological responsiveness.
• A major adverse outcome from a SCD event is anoxic encephalopathy, which occurs in 30-80% of cases.

Race

Most studies demonstrate inconclusive data with regard to racial differences as they relate to the incidence of sudden death. Some studies suggest that a greater proportion of coronary deaths were "sudden" in blacks compared to whites. In a report by Gillum et al on SCD from 1980-1985, the percentage of CAD deaths occurring out of the hospital and in EDs was found to be higher in blacks than in whites (see Image 2).

Sex

Men have a higher incidence of SCD than women, with a ratio of 3:1. This ratio generally reflects the higher incidence of CAD in men. Recent evidence suggests that a major sex difference may exist in the mechanism of MI. Basic and observational data point to the fact that men tend to have coronary plaque rapture, while women tend to have plaque erosion. Whether this biologic difference accounts for the male predominance of SCD is unclear.

Age

The incidence of SCD parallels the incidence of CAD, with the peak of SCD occurring in people aged 45-75 years. The incidence of SCD increases with age in men, women, whites, and nonwhites as the prevalence of CAD increases with age. However, the proportion of deaths that are sudden from CAD decreases with age. In the Framingham study, the proportion of CAD deaths that were sudden was 62% in men aged 45-54 years, but this percentage fell to 58% in men aged 55-64 years and to 42% in men aged 65-74 years. According to Kuller et al, 31% of deaths are sudden in people aged 20-29 years.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Obtaining a thorough history from the patient, family members, or other witnesses is necessary to obtain insight into the events surrounding the sudden death. Patients at risk for SCD may have prodromes of chest pain, fatigue, palpitations, and other nonspecific complaints. History and associated symptoms, to some degree depend on the underlying etiology of SCD. For example, SCD in an elderly patient with significant CAD may be associated with preceding chest pain due to a massive myocardial infarction, while SCD in a young patient may be associated with history of prior syncopal episodes and/or a family history of syncope and SCD and due to inherited arrhythmia syndromes. As many as 45% of persons who have SCD were seen by a physician within 4 weeks before death, although as many as 75% of these complaints were not related to the cardiovascular system. A prior history of LV impairment (ejection fraction <30-35%) is the single greatest risk factor for sudden death.

Risk factors that relate to CAD and subsequent MI and ischemic cardiomyopathy also are important and include a family history of premature CAD, smoking, dyslipidemia, hypertension, diabetes, obesity, and a sedentary lifestyle. Specific considerations include the following:

• Coronary artery disease
• • Previous cardiac arrest
  • Syncope
  • Prior MI, especially within 6 months
  • Ejection fraction less than 30-35%
  • History of frequent ventricular ectopy (more than 10 PVCs per h or nonsustained VT)
• Dilated cardiomyopathy
• • Previous cardiac arrest
  • Syncope
  • Ejection fraction less than 30-35%
  • Use of inotropic medications
• Hypertrophic cardiomyopathy
• • Previous cardiac arrest
  • Syncope
  • Family history of SCD
  • Symptoms of heart failure
  • Drop in SBP or ventricular ectopy upon stress testing
  • Palpitations
  • Most are asymptomatic
• Valvular disease
• • Valve replacement within 6 months
  • Syncope
  • History of frequent ventricular ectopy
  • Symptoms associated with severe uncorrected aortic stenosis or mitral stenosis
• Long QT syndrome
• • Family history of long QT and SCD
  • Medications that prolong the QT interval
  • Bilateral deafness
• Wolff-Parkinson-White (WPW) syndrome (with atrial fibrillation or atrial flutter with extremely rapid ventricular rates): With extremely rapid conduction over an accessory pathway, degeneration to VF can occur.
• Brugada syndrome, arrhythmogenic right ventricular (RV) cardiomyopathy/dysplasia, others

Physical

The physical examination may reveal evidence of underlying myocardial disease or may be entirely normal, depending on the underlying cause. Initial evaluation studies show that patients who survive to ED presentation can be stratified by a cardiac arrest score, which has excellent diagnostic value. The cardiac arrest score, developed by Thompson and McCullough, can be used for patients with witnessed out-of-hospital cardiac arrest and is defined by the following criteria:

• Clinical characteristic points
• • ED SBP greater than 90 mm Hg = 1 point
  • ED SBP less than 90 mm Hg = 0 points
  • Time to ROSC less than 25 minutes = 1 point
  • Time to ROSC more than 25 minutes = 0 points
  • Neurologically responsive = 1 point
  • Comatose = 0 point
  • Maximum score = 3 points
• Patients with a score of 3 points can be expected to have an 89% chance of neurologic recovery and an 82% chance of survival to discharge (see Image 3).
• Recent work from McCullough indicates that even in the setting of ST elevation and early invasive management with primary angioplasty and intraaortic balloon pump insertion, patients with low cardiac scores are unlikely to survive.
• Severe anoxic encephalopathy in patients with scores of 0, 1, or 2 mitigates conservative management with empiric supportive and medical therapy. Given the very poor actuarial survival rates for these patients, invasive management with catheterization and electrophysiology studies (EPS) is rarely justified.

Causes

• Ischemic heart disease: Cardiac arrest due to ventricular arrhythmias may be due to chronic scar or to acute MI/ischemia. A chronic infarct scar can serve as the focus for reentrant ventricular tachyarrhythmias. This can occur shortly after the infarct or years later. Many studies support the relationship of symptomatic and asymptomatic ischemia as markers of myocardium at risk for arrhythmias. Patients resuscitated from out-of-hospital cardiac arrest represent a group of patients with increased recurrence of cardiac arrest and have been shown to express an increased incidence of silent ST-segment depression. Experiments inducing myocardial ischemia in animal models have a strong relationship with the development of VF.
• • In postmortem studies of people who have died from SCD, extensive atherosclerosis is the most common pathologic finding. In survivors of cardiac arrest, coronary heart disease with vessels showing greater than 75% stenosis is observed in 40-86% of patients, depending on the age and sex of the population studied. Autopsy studies show similar results; in one study of 169 hearts, approximately 61% of patients died of SCD, and more than 75% stenosis in 3 or 4 vessels and similar severe lesions were present in at least 2 vessels in another 15% of cases. No single coronary artery lesion is associated with an increased risk for SCD. Despite these findings, only approximately 20% of SCD-related autopsies have shown evidence of a recent MI. A greater proportion of autopsies (40-70%) show evidence of a healed MI. Many of these hearts also reveal evidence of plaque fissuring, hemorrhage, and thrombosis.
  • The Cardiac Surgery Study (CASS) showed that improving or restoring blood flow to an ischemic myocardium decreased the risk of SCD, especially in patients with 3-vessel disease and heart failure, when compared with medical treatment over a 5-year period. This suggests that transient acute ischemia is one of the major triggering events for sudden arrhythmic death.
  • The efficacy of beta-blocking agents, such as propranolol, in decreasing sudden death mortality, especially when administered to patients who had MI with VF, VT, and high-frequency PVCs, is thought to be due in part to the ability of beta-blockers to decrease ischemia. Beta-blockers also increase the VF threshold in ischemic animals and decrease the rate of ventricular ectopy in patients who had MI.
  • Reperfusion of ischemic myocardium with thrombolysis or direct angioplasty can induce transient electrical instability by several different mechanisms. Coronary artery spasm is a condition that exposes the myocardium to both ischemia and reperfusion insults. The exact mechanism of coronary artery spasm is not known.
  • Roles of the autonomic nervous system, especially the alpha-adrenergic activity, vagal activity, vessel susceptibility, and humoral factors, particularly associated with platelet activation and aggregation, are being investigated as possible mechanisms of coronary vasospasm.
  • Nonatherosclerotic coronary artery abnormalities, including congenital lesions, coronary artery embolism, coronary arteritis, and mechanical abnormalities of the coronary artery, have been associated with an increased incidence of sudden death.
• Nonischemic cardiomyopathies: Patients with nonischemic cardiomyopathies represent the second largest group of patients who experience SCD. Nonischemic myopathies, for the purpose of this article, can be divided into the categories dilated and hypertrophic
• • Dilated cardiomyopathy
  • • Dilated cardiomyopathy can result from prior ischemia and myocardial infarction or from nonischemic causes. Nonischemic dilated cardiomyopathy (DCM) is becoming increasingly more common, with an incidence of approximately 7.5 cases per 100,000 persons each year. Of cases of SCD, 10% are estimated to be attributable to DCM. The prognosis is very poor for these patients, with a 1-year mortality rate of 10-50%, depending on the New York Heart Association functional class; approximately 30-50% of these deaths are SCD.
    • The causes of DCM are uncertain; viral, autoimmune, genetic, and environmental (alcohol) origins are implicated. The predominant mechanism of death appears to be ventricular tachyarrhythmia, although bradyarrhythmia and electromechanical dissociation also have been observed, especially in patients with advanced LV dysfunction. Extensive fibrosis of the subendocardium, leading to dilated ventricles and subsequent generation of reentrant tachyarrhythmias, is a proposed mechanism for sudden death. Multiple factors have been shown to contribute to increased risk for SCD in this population. The most important hemodynamic predictor is an increase in end-diastolic pressure and subsequent wall tension. Other important factors are increased sympathetic tone, neurohumoral activation, and electrolyte abnormalities.
    • Many drugs used in the treatment of heart failure, such as antiarrhythmics, inotropic agents, and diuretics, have proarrhythmic properties, which may provoke arrhythmias in some cases.
    • Nonsustained ventricular tachycardia (NSVT) is common in patients with dilated cardiomyopathy and approximately 80% of persons with DCM have abnormalities on Holter monitoring. Although NSVT may be a marker, it has not been shown to be a reliable predictor of SCD in these patients. Recent studies have shown possibility of increased mortality following suppression of NSVT by antiarrhythmic medications due to proarrhythmic properties of these medications and lack of benefit of suppressing NSVT. Given the possibility of sustained VT being the underlying cause, a history of syncope should be aggressively pursued. Unexplained syncope, especially in patients with class 3 or 4 heart failure, has been shown to be a powerful predictor of SCD in most patients with cardiomyopathy.
  • Hypertrophic cardiomyopathy
  • • Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant, incompletely penetrant genetic disorder resulting from a mutation in one of the many (>45) genes encoding proteins of the cardiac muscle sarcomere. Among the genetic abnormalities described, mutations in the genes coding for the beta-myosin heavy chains, and cardiac troponin T make up most cases. Other mutations may include alpha-myosin heavy chain MYH6), cardiac troponin C (TNNC1), alpha-tropomyosin (TPM1), myosin binding protein-C (MYBPC3), cardiac troponin (TNNI3), essential and regulatory light-chain genes (MYL3 and MYL2, respectively), cardiac alpha-actin gene (ACTC), and titin (TTN). The incidence of SCD in this population is 2-4% per year in adults and 4-6% per year in children and adolescents. HCM is the most common cause of SCD in people younger than 30 years.
    • The vast majority of young people who die of HCM are previously asymptomatic. Most experience SCD while at rest or with mild exertional activity; however, in a significant portion of these patients, the SCD event occurs after vigorous exertion. HCM is the single greatest cause of SCD in young athletes and, hence, is the major entity for which to screen during the physical examination of an athlete.
    • The mechanism of SCD in HCM is not entirely understood. Initially, it was thought to be due to obstruction of the outflow tract because of catecholamine stimulation. However, later studies suggested that individuals with nonobstructive HCM are at high risk for SCD, primarily related to VT or VF. The mechanism of arrhythmia in this setting is not clear, and hypertrophy may provide the substrate for lethal arrhythmia.
    • Rapid or polymorphic symptomatic NSVT may have better predictive value compared with asymptomatic and monomorphic NSVT. Other clinical markers that may have predictive value for SCD in patients with HCM are young age at onset, thickness of the septum, and family history of SCD.
  • Arrhythmogenic right ventricular dysplasia
  • • Arrhythmogenic RV dysplasia is characterized by replacement of the RV wall with fibrofatty tissue. Involvement of the interventricular septum and left ventricle is associated with poorer outcomes.
    • About 30-50% of cases occur as a familial disorder. Several genetic defects, including mutations in the desmoplakin domain locus on chromosome 6 and the ryanodine receptor locus on chromosome 1, have been correlated with SCD. Gap junction remodeling may contribute to arrhythmogenicity, and fibrosis provides substrate for macroreentry leading to lethal arrhythmias. Autosomal dominant inheritance is common, but autosomal recessive transmission has been reported for select mutations. The autosomal recessive form (Naxos disease) has been reported in a geographically isolated area mainly in Mediterranean countries and is usually associated with wooly hair and palmoplantar keratoderma or similar skin disorder.
    • Arrhythmogenic RV dysplasia affects men more often than women. The annual incidence rate of SCD in this population is approximately 2%. Patients may present with signs and symptoms of RV hypertrophy and dilation, often with sustained monomorphic or polymorphic VT of a left bundle-branch block morphology with an axis usually between negative 90-100°.
    • Atrial arrhythmias may be present in as many as 25% of patients. Syncope and sudden death often are associated with exercise. In many patients, sudden death is the first manifestation of the disease. Clinicians should be alerted to the epsilon wave finding on ECG studies (see Image 4). The epsilon wave can be present in as many as 23% of patients after the first VT event. The percentage of patients with the epsilon wave finding on ECG increases to 27% and 34% at 5 and 10 years, respectively, after the first VT event.
    • Uhl anomaly is a condition in which the RV wall is extremely thin secondary to apposition of endocardial and epicardial layers.
• Valvular disease
• • Aortic stenosis
  • • Prior to the advent of surgical therapy for valvular heart disease, SCD was fairly common in patients with progressive aortic stenosis.
    • Most aortic stenosis deaths were sudden. In a study by Chizner et al of 42 patients who had isolated aortic stenosis and did not undergo valve replacement, as many as 56% of deaths were sudden at 5 years of follow-up. Of these 42 patients, 32 were symptomatic and 10 were asymptomatic.
    • The mechanism of sudden death is unclear, and both malignant ventricular arrhythmia and bradyarrhythmia have been documented.
    • The incidence of SCD has decreased significantly with advent of aortic valve replacement. However, it still accounts for the second most common cause of death postoperatively in this population and especially in those with prosthetic and heterograft aortic valve replacement. The incidence of SCD after aortic valve surgery is highest in the first 3 weeks after the procedure and then plateaus at 6 months of follow-up.
  • Other valvular lesions: The risk of SCD is much lower in other valvular diseases compared with aortic stenosis.
  • • Aortic insufficiency usually presents with signs of heart failure and progressive LV dilatation. As part of this process, reentrant or automatic ventricular foci may develop and ultimately lead to a symptomatic ventricular arrhythmia. After valve replacement, LV wall tension can be expected to reduce and the risk of arrhythmia can be expected to decrease.
    • Mitral stenosis is becoming increasingly uncommon in the United States because of widespread use of antibiotics in primary streptococcal infections. SCD due to mitral stenosis is very rare.
    • The incidence of SCD is low in patients with mitral valve prolapse (MVP). MVP has a 5-7% incidence in the general population. In clinically significant MVP, the risk of SCD seems to rise along with total mortality. Kligfield et al estimated that the incidence of sudden death varies with the presence of symptoms and the severity of mitral regurgitation. Ventricular tachyarrhythmias are the most frequent arrhythmia in patients with SCD. Risk factors for SCD to consider in these patients include a family history of SCD, echocardiographic evidence of a redundant mitral valve, repolarization abnormalities, and lengthening of the corrected QT interval (>420 ms in women and >450 ms in men).
• Congenital heart disease: In the pediatric and adolescent age groups, SCD occurs with an incidence of 1.3-8.5 cases per 100,000 patients annually, accounting for approximately 5% of all deaths in this group. The causes of SCD are much more diverse in children than adults. In reviewing 13 studies involving 61 children and adolescents with SCD, Driscoll found 50% of cases were due to HCM; 25% were due to anomalous origin of the left coronary artery; and the remaining patients had aortic stenosis, cystic medial necrosis, and sinus node artery obstruction. The following is a classification of SCD in the pediatric population:
• • In patients with known, previously recognized (including repaired) heart disease, congenital causes of SCD include the following:
  • • Tetralogy of Fallot
    • Transposition of the great arteries
    • Fontan operation
    • Aortic stenosis
    • Marfan syndrome
    • Mitral valve prolapse
    • Hypoplastic left heart syndrome
    • Eisenmenger syndrome
    • Congenital heart block
    • Ebstein anomaly
  • In patients with known, previously recognized (including repaired) heart disease, acquired causes of SCD include the following:
  • • Kawasaki syndrome
    • DCM or myocarditis
  • In patients with previously unrecognized heart disease who have structural heart disease, causes of SCD include the following:
  • • HCM
    • Congenital coronary artery abnormalities
    • Arrhythmogenic RV dysplasia
  • In patients with previously unrecognized heart disease who do not have structural heart disease, causes of SCD include the following:
  • • Long QT syndrome
    • WPW syndrome
    • Primary VT and VF
    • Primary pulmonary hypertension
    • Commotio cordis - Traumatic blow to the chest wall (eg, from a hockey puck or baseball) causing VT/VF and SCD in the absence of significant identifiable trauma
  • The predominant mechanism is ventricular arrhythmias. In tetralogy of Fallot after postoperative correction of the anomaly, as many as 10% of these patients have VT and the incidence of sudden death is 2-3%. In the Fontan procedure, ie, to correct a physiologic single ventricle, even atrial arrhythmias can cause severe hemodynamic compromise and arrhythmic death. Patients who develop secondary pulmonary hypertension (Eisenmenger syndrome), despite attempted correction of the anatomic defects, have a very poor prognosis. The terminal event may be bradycardia or VT progressing to VF.
• Primary electrophysiologic abnormalities: This generally represents a group of abnormalities in which patients have no apparent structural heart disease but have a primary electrophysiologic abnormality that predisposes them to VT or VF. Some imaging techniques have detected abnormal sympathetic neural function in these patients. An ECG study can provide clues to the diagnosis; consider a familial component to these conditions.
• • Long QT syndrome
  • • Idiopathic long QT syndrome, in which patients have a prolonged QT with a propensity to develop malignant ventricular arrhythmias, is a rare familial disorder.
    • Two forms of congenital long QT syndrome have been described. The Jervell-Lange-Nielsen syndrome, associated with congenital deafness, has an autosomal-recessive pattern of inheritance. The Romano-Ward syndrome is not associated with deafness and has an autosomal dominant pattern of inheritance with variable penetration. This syndrome accounts for 90% of long QT syndrome cases. More than 200 mutations in the 7 genes related to long QT syndrome have been found. Among the most common are mutations of SCN5A on chromosome 3, the HERG gene on chromosome 7, and the KVLTQT1 gene on chromosome 11.
    • Alteration in the function of a myocellular channel protein that regulates the potassium flux during electrical repolarization is thought to be causative, though in some subsets of long QT syndrome, such as those with mutations in SCN5A (long QT3), Na channels are primarily impaired. A relationship with sympathetic nervous system imbalance also appears to exist. The prolongation that occurs makes these patients susceptible to develop a specific form of VT called torsade de pointes.
    • The clinical course of patients with long QT syndrome is quite variable, with some patients remaining asymptomatic while others develop torsade de pointes with syncope and sudden death. Symptoms and SCD are more common among homozygous individuals (those with two copies of the mutant allele), compared with heterozygous individuals (who have a single mutant allele). The risk of SCD is impacted by environmental factors such as hypokalemia, medications and the presence of sinus pauses. SCD in these patients also has been associated with emotional extremes, auditory auras or stimulation, and vigorous physical activity. Symptoms usually begin in childhood or adolescence.
    • The probability of having congenital long QT syndrome is divided to low, intermediate, and high probability based on the following criteria: (1) ECG criteria including long QT, torsade de pointes, notched T wave, T wave alternans, bradycardia for age; (2) clinical criteria including syncope with or without stress, deafness; and (3) family history of long QT syndrome or SCD.
    • When measuring QTc, selecting rhythm strips that have minimal variability of RR intervals and a stable heart rate is important.
    • Treatment for long QT syndrome includes beta-blockers, pacemaker placement, and ICD implantation. Beta-blockers decrease the overall mortality in patients with long QT syndrome. However, they do not eliminate the risk of syncope, cardiac arrest, and SCD completely. They are not effective in patients with mutation in Na channel genes (long QT3). Torsade de pointes in patients with long QT is associated with bradycardia and pauses. Therefore, a pacemaker can prevent torsade de pointes in these patients by preventing bradycardia. ICD therapy may be indicated in patients with recurrent symptoms despite treatment with beta-blockers.
  • Acquired long QT syndrome
  • • A number of antiarrhythmics (especially class Ia and class III) and other medications, electrolyte abnormalities, cerebrovascular diseases, and altered nutritional states are known to cause QT prolongation and put patients at risk for torsade de pointes. This usually occurs when QT prolongation is associated with a slow heart rate and hypokalemia.
    • The QT interval is prolonged in as many as 32% of patients with intracranial hemorrhage (especially in subarachnoid hemorrhages). Lesions in the hypothalamus are thought to lead to this phenomenon.
    • Reports of sudden death due to ventricular arrhythmia in patients with hypocalcemia, hypothyroidism, nutritional deficiencies associated with modified starvation diets, and in patients who are obese and on severe weight-loss programs have been reported.
    • Class Ia antiarrhythmic drugs that cause acquired long QT syndrome include quinidine, disopyramide, and procainamide. Class III antiarrhythmic drugs that cause acquired long QT syndrome include sotalol, N-acetyl procainamide, bretylium, amiodarone, and ibutilide.
    • Other drugs that cause acquired long QT syndrome include bepridil, probucol, tricyclic and tetracyclic antidepressants, phenothiazines, Haldol, antihistamines (eg, terfenadine, astemizole), antibiotics (eg, erythromycin, sulfamethoxazole/trimethoprim), chemotherapeutics (eg, pentamidine, anthracycline), serotonin antagonists (eg, ketanserin, zimeldine), and organophosphorus insecticides.
    • Electrolyte abnormalities that cause acquired long QT syndrome include hypokalemia, hypomagnesemia, and hypocalcemia.
    • Altered nutritional states and cerebrovascular disease that cause acquired long QT syndrome include intracranial and subarachnoid hemorrhages, stroke, and intracranial trauma.
    • Hypothyroidism and altered autonomic status (eg, diabetic neuropathy) can cause acquired long QT syndrome.
  • Short QT Syndrome:
  • • The short QT syndrome is a newly recognized syndrome, first time described in 2000, which can lead to lethal arrhythmias and SCD. Three mutations in potassium channels have been described that lead to gain of function in potassium channels and shortening of action potential and decreased QT interval.
    • To diagnose short QT syndrome, the QTc should be less than 330 msec and tall and peaked T waves should be present. Clinical manifestations are variable from no symptoms, to palpitation due to atrial fibrillation, syncope due to VT, and SCD. VF is easily inducible at electrophysiology study in these patients, and SCD can happen at any age.
    • Although antiarrhythmic medications, such as sotalol, ibutilide, and procainamide, have been proposed as a therapy (to prolong the QT), data to support this approach are insufficient at present. ICD placement may be considered to prevent VT and SCD, although T-wave oversensing, resulting in inappropriate ICD discharges, has been problematic.
  • Wolff-Parkinson-White syndrome
  • • WPW syndrome is a recognized cause of sudden death. Existence of an atrioventricular accessory pathway in this syndrome results in ventricular preexcitation, which appears with short PR interval, wide QRS complex, and delta wave on ECG. The refractory period in the anterograde direction of accessory pathway determines the ventricular rate in the setting of atrial fibrillation and WPW. Most patients with WPW syndrome and SCD develop atrial fibrillation with a rapid ventricular response over the accessory pathway, which induces VF (see Image 5). In a study by Klein et al of 31 patients with VF and WPW syndrome, a history of atrial fibrillation or reciprocating tachycardia was an important predisposing factor. The presence of multiple accessory pathways, posteroseptal accessory pathways, and a preexcited R-R interval of less than 220 ms during atrial fibrillation are associated with higher risk for SCD.
    • Symptomatic patients should be treated by antiarrhythmic medications (eg, procainamide), catheter ablation of the accessory pathway, or electrical cardioversion depending on the severity and frequency of symptoms. Asymptomatic patients may be observed without treatment.
    • Medications such as digoxin and verapamil that block the AV node are contraindicated in patients with WPW and atrial fibrillation because they may accelerate conduction through the accessory pathway causing VF and SCD.
  • Brugada syndrome
  • • In 1992, Brugada and Brugada described a syndrome of a specific ECG pattern of right bundle-branch block and ST-segment elevation in leads V₁ through V₃ without any structural abnormality of the heart that was associated with sudden death.
    • In 25-30% of these patients, a mutation in SCN5A on chromosome 3 is detected. This mutation results in a sodium channelopathy. The most common clinical presentation is syncope, and this mutation is most common in young males and in Asians. It is associated with VT, VF, and SCD.
    • Three ECG types of Brugada pattern are described. Only type 1,- which consists of a coving ST elevation in V1 to V3 with downsloping ST segment and inverted T waves, pseudo RBBB pattern with no reciprocal ST changes and normal QTc, is specific enough to be diagnostic for Brugada syndrome when it is associated with symptoms. The other two ECG patterns of Brugada are not diagnostic, but they merit further evaluation.
    • The Brugada ECG pattern can be dynamic and not found on an index ECG. When clinical suspicion is high, a challenge test with procainamide or some other Na channel blockers may be diagnostic by reproducing the type 1 ECG pattern.
    • Although antiarrhythmic medications, catheter ablation and pacemaker therapies all have potential, in young and symptomatic patients, an ICD should be implanted to prevent VF and SCD. ICD therapy is the only proven treatment up to date. Whether ICD placement is indicated in older or asymptomatic patients is controversial at present.
  • Catecholaminergic polymorphic ventricular tachycardia
  • • Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a syndrome that presents with polymorphic VT, syncope, or SCD, and in about half of these patients, a mutation in one of two different genes have been detected.
    • The polymorphic VT is characteristically induced by emotional or physical stress (eg, exercise stress test). The medical therapy of choice is administration of beta-blockers, and ICD may be indicated.
• Primary ventricular fibrillation occurs in a structurally normal heart due to idiopathic etiology.
• • An estimated 3-9% of cases of VT and VF occur in the absence of myocardial ischemia. As many as 1% of patients with out-of-hospital cardiac arrest have idiopathic VF with no structural heart disease. As many as 15% of patients younger than 40 years who experience VF have no underlying structural heart disease. Viskin and Behassan noted that of 54 patients with idiopathic VF, 11 patients had histologic abnormalities on endomyocardial biopsy.
  • SCD is often the first presentation of VF in patients at risk but who have had no preceding symptoms. In those patients who survive, VF may reoccur in as high as one third of patients.
  • The options for medical therapy include beta-blockers and class 1A antiarrhythmic drugs, but limited data are available regarding their efficacy. The mainstay of treatment is preventing VF by ICD placement. Mapping and radiofrequency ablation of the triggering foci is an option for those patients who experience frequent episodes of VF following ICD placement.
• Right ventricular outflow tract ventricular tachycardia
• • Right ventricular outflow tract (RVOT) tachycardia is the most common form of idiopathic VT, comprising 70-80% of all idiopathic VTs. RVOT tachycardia is a rare cause of SCD. It also has been referred to as exercise-induced VT, adenosine-sensitive VT, and repetitive monomorphic VT.
  • RVOT tachycardia occurs in patients without structural heart disease and arises from the RV outflow region. Current data suggest that triggered activity is the underlying mechanism of RVOT tachycardia. RVOT tachycardia is believed to be receptor-mediated because exogenous and endogenous adenosine can terminate this process. Maneuvers that increase endogenous acetylcholine also have been demonstrated to antagonize this process.
  • Symptoms typical of RVOT tachycardia include palpitations and presyncope or syncope, often occurring during or after exercise or emotional stress. VT also can occur at rest. The ECG during VT displays a left bundle-branch block/inferior axis morphology.
  • Treatment is based on frequency and severity of symptoms. The first line of therapy is a beta-blocker or calcium channel blocker. Patients with symptoms not relieved by medical therapy are best treated with radiofrequency catheter ablation. Successful ablation is reported in 83-100% of cases.
• Other causes of sudden death: Two major causes of sudden cardiopulmonary death deserve mention.
• • Pulmonary embolism is a frequent cause of sudden death in people at risk. Risk factors include previous personal or family history of deep venous thromboembolism, malignancy, hypercoagulable states, and recent mechanical trauma such as hip or knee surgery.
  • Aortic dissection or aneurysmal rupture is the other major cause of out-of-hospital nonarrhythmic cardiovascular death. Predisposing factors for aortic dissection include genetic deficiencies of collagen such as Marfan syndrome, Ehlers-Danlos syndrome, and aortic cystic medial necrosis.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Arrhythmogenic RV dysplasia
Brugada syndrome

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Cardiac enzymes (creatine kinase, myoglobin, troponin): Elevations in these enzyme levels may indicate ischemia and MI. The extent of myocardial damage usually can be correlated to the extent of elevation in the enzyme levels. Patients are at increased risk for arrhythmia in the periinfarct period.
• Electrolytes, calcium, and magnesium: Severe metabolic acidosis, hypokalemia, hyperkalemia, hypocalcemia, and hypomagnesemia are some of the conditions that can increase the risk for arrhythmia and sudden death.
• Quantitative drug levels (quinidine, procainamide, tricyclic antidepressants, digoxin): Drug levels higher than the levels indicated in the therapeutic index may have a proarrhythmic effect. Subtherapeutic levels of these drugs in patients being treated for specific cardiac conditions also can lead to an increased risk for arrhythmia. Most of the antiarrhythmia medications also have a proarrhythmic effect.
• Toxicology screen: Looking for drugs, such as cocaine, that can lead to vasospasm-induced ischemia is warranted if suspicion exists. Obtaining levels of drugs (antiarrhythmics) also may be warranted.
• Thyroid-stimulating hormone: Hyperthyroidism can lead to tachycardia and tachyarrhythmias. Over a period of time, it also can lead to heart failure.
• Brain natriuretic peptide (BNP): BNP has predictive value especially in post MI patients and in patients with HF. Although preliminary and not conclusive, emerging data support the notion that an elevated BNP level may provide prognostic information on the risk of SCD, independent of clinical information and LVEF.

Imaging Studies

• Chest x-ray: This may reveal whether someone is in congestive heart failure. It also can show signs of LV hypertrophy or RV hypertrophy. Signs of pulmonary hypertension also may be evident on the chest x-ray.
• Echocardiography: Two-dimensional echocardiography with Doppler is essential in the evaluation of SCD. A number of studies have demonstrated that the use of 2-dimensional echocardiogram to evaluate left wall motion abnormalities after an acute MI (using the LV wall-motion score index) is useful in predicting the risk for major cardiac events, including sudden death. A decrease in the ejection fraction and worsening wall motion abnormalities upon exercise echocardiography in patients who have had an MI has been suggested to confer increased risk of cardiac death.
• Nuclear imaging techniques: Resting thallium or technetium-99m scintigraphy is helpful in assessing myocardial damage after MI. A larger defect has been associated with greater risk for future cardiac events. Exercise nuclear scintigraphy is very sensitive when detecting the presence, extent, and location of myocardial ischemia. Gibson et al found that pharmacologic-stress nuclear (dipyridamole or adenosine) scintigraphy was better than submaximal exercise ECG and coronary angiography in predicting cardiac death and other cardiac events. These tests can be very helpful in patients with low functional capacity such as chronic obstructive pulmonary disease, peripheral vascular disease, or orthopedic problems. The Multi-Center Post-Infarction Research Group provided evidence that resting ejection fraction was the most important noninvasive predictor of SCD and other cardiac events in patients with MI.

Other Tests

• Electrocardiogram: This study is indicated in all patients. Evidence of MI, prolonged QT interval, short QT interval, epsilon wave, Brugada sign, short PR, a WPW pattern, or other conditions should be sought.
• Signal-averaged ECG (SAECG) has been variably reported to be useful in analysis of patients with SCD. What appears to be more useful is analysis of T wave alternans in patients with VT, VF, and/or SCD. Small changes in T amplitude are not detected in 12-lead ECG. Microvolt T wave alternans (MTWA) amplifies the alternans and may be used in the workup to predict the risk of SCD.
• Genetic testing: The value of genetic testing in conditions such as congenital long QT and HCM is still being evaluated. Some studies have recommended the testing of siblings and close relatives of people with SCD due to these conditions.

Procedures

• Coronary angiography: Perform cardiac catheterization in patients who survive SCD to assess the state of ventricular function and the severity and extent of CAD.
• • The number of vessels with severe obstruction and the degree of LV dysfunction are important variables in predicting cardiac events. Ejection fraction is the best predictor of significant cardiac events and survival.
  • Coronary angiography also can help identify coronary anomalies and other forms of congenital heart disease.
  • Angiography is performed with the aim of identifying patients who may benefit from revascularization. Revascularization is the single greatest treatment for the underlying substrate of VT/VF, ischemic myocardium.
• Electrophysiology studies: In targeted patients, EPS play diagnostic, prognostic, and therapeutic roles. EPS usually are performed after ischemic and structural heart disease has been diagnosed and addressed. These studies have been used to identify patients who have inducible versus noninducible sustained monomorphic VT. The presence of inducible sustained VT, at baseline or when the patient is on antiarrhythmic medications, confers a higher risk for sudden death. Significantly lower ventricular function also has been observed in patients with inducible sustained VT. Inducible bundle-branch reentrant VT can be seen in patients with DCM and in the postoperative period after valvular replacement. As many as 20% of patients with HCM have inducible sustained monomorphic VT. The identification of accessory pathways also is possible with these studies. EPS are performed with an eye toward the following:
• • Ablation of VT foci, eg, bundle branch VT, RVOT VT, and some cases of idiopathic LV tachycardia
  • ICD implantation, which generally is the case in survivors of SCD

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• Advanced cardiac life support (ACLS): In the event of cardiac arrest, the immediate implementation of ACLS guidelines is indicated. Widespread interest in improving rates of public ACLS training with a special emphasis on use of early defibrillation by public service personnel (eg, police, fire, airline attendants) exists. Through these measures, the greatest public health benefits can be achieved in the fight against sudden death.
• Medical stabilization: Careful postresuscitative care is essential to survival because studies have shown a 50% repeat in-hospital arrest rate for people admitted after an SCD event. Treatment of myocardial ischemia, heart failure, and electrolyte disturbances are all justified by the results of multiple acute MI and CHF randomized trials. Empiric beta-blockers are reasonable in many circumstances because of favorable properties discussed in Causes. Empiric antiarrhythmics, including amiodarone, should not supersede ICD implantation unless control of recurrent VT is needed while the patient is in the hospital.

Surgical Care

• Radiofrequency ablation: Radiofrequency ablation, now routinely available, may be indicated for patients with atrioventricular bypass tracts, bundle-branch block VT, RVOT VT, idiopathic LV tachycardia, and more rare forms of automatic foci VT. Unfortunately, most cases of SCD are not amenable to radiofrequency ablation and require ICD implantation. Radiofrequency ablation may be useful in the treatment of patients with SCD who experience frequent recurrent VT/VF after ICD placement, especially those who require frequent defibrillation.
• Several multicenter trials examining the prophylactic use of cardioverter defibrillator therapy in patients at high risk for SCD have been performed.
• • The annual SCD rate in patients with these devices has been reduced from 25% to 1-2%. Studies have shown that in patients at high risk in whom electrophysiologic-guided therapy with antiarrhythmics has failed, ICD placement is beneficial. In several studies comparing ICD placement to antiarrhythmic therapy in patients with VT and/or prior cardiac arrest, ICD placement has been shown to be associated with decreased mortality.
  • The use of ICDs as primary prevention for SCD is now standard care for anyone with LVEF less than 35%. Newer ICDs have pacing capabilities and have addressed bradyarrhythmias either causing or complicating VT or VF.
• Cardiac surgery can be a primary treatment for SCD via a variety of strategies.
• • Surgical treatment in patients with ventricular arrhythmias and ischemic heart disease includes coronary artery bypass grafting (CABG). The CASS study illustrated that patients with significant CAD and operable vessels who underwent CABG had a decrease in the incidence of sudden death when compared to patients on conventional medical treatment. The reduction was most evident in patients who had 3-vessel disease and CHF.
  • Surgical treatment of ventricular arrhythmias in patients with nonischemic heart disease includes excision of VT foci after endocardial mapping and excision of LV aneurysms. This is performed with decreasing frequency, because of perioperative mortality and the alternative, transvenous ICD implantation.
  • Aortic valve replacement is associated with improved outcome in patients with hemodynamically significant valvular stenosis and well-preserved ventricular function. In patients with MVP associated with significant valvular regurgitation and LV dysfunction, malignant tachyarrhythmias and SCD have been reported. These patients are candidates for mitral valve replacement.
  • Orthotopic heart transplantation is indicated in cases of SCD and refractory heart failure in which significant improvement in actuarial survival is expected. Given a limited donor service, this form of treatment is expected to be beneficial for very few people who survive SCD.
  • Patients with long QT syndrome who do not respond to beta-blockers are candidates for ICD implantation or high thoracic left sympathectomy.

Consultations

• A cardiologist always should be participating in the care of these patients. Cardiac electrophysiologists should be involved in the care of these patients, which generally involves ICD implantation.
• Other consultations for expertise include an interventional cardiologist and cardiac surgeon and are made on an individual basis.

Diet

• Patients with CAD are advised to follow a diet low in fat and cholesterol. Patients with severe heart failure should monitor their fluid and sodium intake.

MEDICATION

Section 7 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medications are prescribed on an individual basis, depending on the underlying cause of SCD.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Transfer

• Patients should be at centers where intensive cardiac monitoring and appropriate invasive and noninvasive studies can be performed. In general, a cardiovascular service, including interventional cardiology, electrophysiology, and cardiac surgery, is needed.

Prognosis

• Prognosis of morbidity and mortality for people who have had SCD can be made using the cardiac arrest score developed by McCullough and Thompson (see Physical). The detection of the underlying cause of SCD and available treatment options play an important role in the natural history and prognosis of SCD.
• SCD is a frequently encountered problem for emergency physicians, internists, and cardiologists. Ischemic cardiomyopathy in all adult cases and HCM in pediatric and adolescent cases are at the top of the differential diagnosis.
• • The clinical course, once the patient is resuscitated, largely is predicted by the ED presentation of hemodynamic stability, early neurologic recovery, and the duration of the resuscitation.
  • Patients who survive the initial phases require a systematic evaluation of LV performance, myocardial perfusion, and electrophysiologic instability. Survivors of SCD have a recurrence rate on the order of 20-25% per year, making ICD implantation important in the majority of patients.
  • Modern treatment with ICD implantation has saved lives and likely will be an area of continued clinical growth.
  • Preventive measures, at their roots, are measures of CAD prevention. Efforts to inform and train the public about external defibrillator use likely will have the greatest public health impact on improving survival rates of SCD.

Patient Education

• For excellent patient education resources, visit eMedicine's Heart Center and Public Health Center. Also, see eMedicine's patient education articles Chest Pain, Heart Rhythm Disorders, Coronary Heart Disease, Heart Attack, and Cardiopulmonary Resuscitation (CPR).

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize and initiate early management of patients with ischemic heart disease is a pitfall. The importance of this cannot be overestimated because approximately 80% of SCD cases can be attributed to ischemic heart disease.
• Failure to use appropriate medical therapy for ischemic heart disease (eg, beta-blockers) can be a pitfall.
• Involving a specialist in cardiovascular disease in the care of patients who have had a cardiac arrest or have symptoms of ischemic heart disease, valvular disorders, or presentations with complex arrhythmias is very important.
• Failure to educate patients about the consequences of noncompliance with medical therapy is an important pitfall to avoid.
• Survivors of SCD should be carefully considered for ICD implantation.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Krishna Malineni, MD to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Interplay of various risk factors that can lead to sudden cardiac death.
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Media file 2:  Cardiac death, sudden. Plots of mortality rates (deaths per 1000 persons) for ischemic heart disease occurring out of the hospital or in the emergency department (top) and occurring in the hospital (bottom) by age, sex, and race in 40 states during 1985.
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Media file 3:  Cardiac death, sudden. Figure a shows neurologic outcome stratified by initial cardiac arrest score. Neurologic recovery is defined as discharged home and able to care for self. Figure b shows overall survival stratified by initial cardiac arrest score.
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Media type:  Graph

Media file 4:  Cardiac death, sudden. Epsilon wave in a patient with arrhythmogenic right ventricular dysplasia.
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Media type:  ECG

Media file 5:  Cardiac death, sudden. Ventricular fibrillation appeared during rapid atrial fibrillation in a patient with Wolff-Parkinson-White syndrome.
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Media type:  Rhythm Strip

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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