• Unexpected death occurring within an hour of onset of symptoms.
  
• Primary electrical mechanisms include ventricular fibrillation, ventricular tachycardia, asystole, and pulseless electrical activity.

Each year in the United States, more than 350,000 individuals die suddenly of some form of cardiovascular disease. Because of the many advances made during the past 30 years in clinicians’ ability to identify and modify the risk factors associated with sudden death, to resuscitate victims of cardiac arrest, and to prescribe specific antiarrhythmic therapy to prevent recurrences, age-adjusted sudden death mortality rates have declined dramatically. However, the number of elderly individuals in the population has increased, and sudden cardiac arrest remains an important problem.

For general clinical purposes, the term “sudden cardiac death” is usually reserved for those deaths in which the patient had stable cardiac function until the terminal event, with death occurring within a short time (often defined as less than 1 hour) of the onset of symptoms. Some experts prefer the term “instantaneous death,” namely, death with immediate collapse without preceding symptoms. Instantaneous death is usually assumed to be due to a primary arrhythmia, but other catastrophic events, such as a massive pulmonary embolism, the rupture of an aortic aneurysm, or a stroke, can also cause instantaneous death. It is also important to note that not all arrhythmic deaths are sudden. For example, a patient who is resuscitated from a cardiac arrest may die days or weeks later from complications of the arrest. This death would be due to an arrhythmia but would not meet the standard time-based definition for instantaneous or sudden death.

Effective evaluation and treatment of patients at risk for cardiac arrest and sudden death require an understanding of the responsible pathophysiologic mechanisms, the strategies proposed for primary prevention, the techniques and results of resuscitation, and the treatment modalities for secondary prevention in survivors of an initial episode.

A number of different electrophysiologic mechanisms may be responsible for sudden cardiac death. When ambulatory electrocardiographic (ECG) recordings from the time of an out-of-hospital cardiac arrest are examined, ventricular fibrillation and rapid ventricular tachycardia are the most commonly documented initial arrhythmias. Bradyarrhythmias, including atrioventricular block, asystole, or electromechanical dissociation, are also observed. The prevalence of these latter arrhythmias is higher in the setting of progressive and advanced underlying heart disease; in the elderly, and in patients whose sudden death is precipitated by an acute catastrophe, such as a pulmonary embolism, an acute myocardial infarction, rupture of a major vessel, or a major neurologic insult. Extrapolation of the mortality rate from data recorded by the Resuscitation Outcomes Consortium suggests that 382,800 people experience out-of-hospital cardiac arrests in the United States each year. Among out-of-hospital cardiac arrests treated by emergency medical personnel, only 23% have an initial rhythm of ventricular tachycardia or ventricular fibrillation or are shockable by an automated external defibrillator. Interestingly, the incidence of cardiac arrest with an initial rhythm of ventricular fibrillation has decreased over time, although the incidence of cardiac arrest with any rhythm has not decreased. The focus of this chapter will be principally those sudden deaths for which an arrhythmia was the primary cause.

Coronary Artery Disease

Although sudden death occurs in all forms of heart disease, in the United States and Europe, coronary artery disease is the most common cardiac diagnosis seen in sudden death victims (Table 15–1). Several mechanisms can produce potentially fatal arrhythmias among patients with coronary artery disease, and it is often difficult to define the precise factors that gave rise to a given episode. At one extreme is the patient with a previously normal ventricle who has an acute occlusion of a major epicardial coronary artery in whom ventricular fibrillation then develops during the first minutes of an acute infarction. This patient represents an example of pure ischemic injury without associated prior scar. At the other end of the spectrum is the patient with a history of a single-vessel occlusion and an old myocardial infarction, in whom postinfarction scarring has provided the anatomic substrate for a rapid reentrant ventricular tachycardia that results in hemodynamic collapse and sudden death. Acute ischemia need not be involved as a trigger in the latter situation. In coronary artery disease, the individuals at highest risk for sudden death have both multivessel disease and myocardial scarring from one or more prior infarctions. Even in such individuals, sudden cardiac arrest may be the first clinical manifestation of the disease. As treatment of acute myocardial infarction has become more aggressive during the past 20 years, the nature of the typical scar that results from a myocardial infarction has also changed. Dense scar tissue with aneurysm formation, the classic substrate associated with uniform morphology ventricular tachycardia, is now seen less often. After early pharmacologic or mechanical reperfusion, the current standards of therapy, the infarct zone shows mostly patchy fibrosis, and in such areas, disorganized arrhythmias predominate. In patients with this complex substrate, sudden death is thought to result from a complex interaction between some triggering event, such as ischemia, autonomic nervous system dysfunction, electrolyte imbalance, or drug toxicity, and the unstable electrophysiologic milieu created by prior infarction.

Autopsy and clinical studies have highlighted this complexity. Coronary artery thrombi or plaque rupture may be detected in up to 50% of sudden death victims, but new Q-wave myocardial infarctions will develop in only about 25% of patients resuscitated from an out-of-hospital cardiac arrest. Angiographic studies in cardiac arrest survivors have shown that a high proportion of persons have long, diffusely irregular, and ulcerated coronary lesions similar to those seen in patients with acute coronary syndromes. It has also been demonstrated that therapy directed at ischemia reduces the incidence of sudden death. Aggressive surgical revascularization has been shown to decrease late sudden death mortality. In the Coronary Artery Bypass Graft (CABG-Patch) trial, no survival benefit over control was seen in patients who received an implantable cardioverter-defibrillator (ICD) at the time of their revascularization surgery. Based on this confusing overall picture, it is prudent in any individual with coronary disease to consider ischemia as an important, potentially reversible risk factor for sudden death, even in the absence of clinical angina. In previously asymptomatic individuals, coronary artery disease may still be the cause of sudden death. Significant coronary artery disease may be asymptomatic or unrecognized, and the general population contains a large number of such individuals. Up to 50% of all sudden cardiac deaths due to coronary artery disease may occur in individuals not previously known to have the condition.

Other diseases of the coronary arteries are rare causes of sudden death. An anomalous origin of a coronary artery may give rise to either myocardial scarring with late ventricular tachycardia or to arrhythmias mediated by acute intermittent ischemia. Similar mechanisms affecting patients with coronary artery spasm, embolism, trauma, dissections, or arteritis may cause sudden death.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder with an estimated prevalence of 1 in 500. In hypertrophic cardiomyopathy, sudden death tends to occur in young adults who often have had no prior cardiac symptoms. There appears to be an excess of events during vigorous exercise, and hypertrophic cardiomyopathy is the leading cause of sudden death among competitive athletes in the United States. Teenagers or young adults in some kindreds with familial hypertrophic cardiomyopathy have a higher incidence of sudden death than do older members. In other families, sudden death in young adults is uncommon but may occur after heart failure has developed.

Several clinical risk factors for sudden death in patients with hypertrophic cardiomyopathy have been determined. These include a family history of sudden death; recurrent, unexplained syncope; nonsustained ventricular tachycardia during ambulatory monitoring; hypotension during exercise; and severe (> 30 mm) left ventricular hypertrophy. The presence of myocardial scarring on a magnetic resonance scan is a new risk factor that has recently been identified. Hypertrophic cardiomyopathy is a genetic disease primarily affecting the cardiac sarcomere with 60–70% of cases accounted for by sarcomere mutations. Genetic studies of patients with hypertrophic cardiomyopathy have revealed more than 900 mutations in 13 different genes. Some mutations (eg, those in troponin T) may be associated with a high risk of sudden death even in the absence of marked left ventricular hypertrophy. Polymorphic ventricular tachycardia or ventricular fibrillation, rather than monomorphic ventricular tachycardia with a scar-related intramyocardial circuit, is thought to be the initial arrhythmia at the time of cardiac arrest in patients with hypertrophic cardiomyopathy. Due to the severe hypertrophy and conduction system disease seen in patients with hypertrophic cardiomyopathy, sustained ventricular tachycardia due to reentry in the His-Purkinje system may occur and result in hemodynamic collapse with sudden death. Patients with hypertrophic cardiomyopathy are also at risk for sudden death due to atrioventricular block and supraventricular arrhythmias because any change in rhythm that produces significant ischemia in the hypertrophied ventricular wall may degenerate to a fatal arrhythmia.

Nonischemic Dilated Cardiomyopathy

Nonischemic dilated cardiomyopathy is the primary cardiac diagnosis in about 10% of patients who have been resuscitated after cardiac arrest. Sudden death accounts for about half of all deaths in patients with this diagnosis. In contrast to the situation in some forms of hypertrophic cardiomyopathy, sudden death tends to occur relatively late in the course of dilated cardiomyopathy, after hemodynamic symptoms have been present for some time. A variety of arrhythmias have been implicated in patients with this condition; both monomorphic and polymorphic ventricular tachycardias are seen in patients with nonischemic dilated cardiomyopathies. Intraventricular conduction delays may lead to ventricular tachycardia caused by macroreentry in the His-Purkinje system. In patients with this arrhythmia, catheter ablation of one of the bundle branches may be curative. In patients with cardiomyopathies and very advanced heart failure, bradyarrhythmias, rather than tachyarrhythmias, are the initial recorded rhythm in up to 50% of cardiac arrests. Some forms of familial dilated cardiomyopathy (eg, lamin A/C mutation carriers) are associated with markedly increased risks for sudden death, and such patients will often require intervention outside of standard guidelines.

Other Cardiac Diseases

In valvular heart disease, sudden death can occur in several ways. Sudden death is usually related to exertion in young adults with congenital aortic stenoses. In other forms of valvular heart disease, sudden death is usually a late occurrence seen in patients with advanced heart failure and ventricular hypertrophy. Although symptomatic atrial and ventricular arrhythmias are common in patients with mitral valve prolapse, truly life-threatening arrhythmias are rare, except in the presence of some complicating condition, such as a LQTS, electrolyte imbalance, or drug toxicity. In pulmonary hypertension, sudden death may occur from hemodynamic causes, bradyarrhythmias, or tachyarrhythmias.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a regional myopathy with primarily right ventricular involvement. When genetic studies have been performed, mutations in one of the desmosomal proteins are often found. These patients usually have left bundle branch block morphology ventricular tachycardias. Symptoms and signs of right ventricular dysfunction may or may not be present in patients with ARVC and ventricular tachycardia, and the clinical course is highly variable. It has been suggested that ARVC with extensive disease (including left ventricular involvement), one or more affected family members with sudden death, or undiagnosed syncope (when ventricular tachycardia or ventricular fibrillation has not been excluded as the cause of syncope) may indicate an increased risk of sudden death and prompt consideration for a primary prevention ICD.

In most forms of congenital heart disease, sudden arrhythmic death in the absence of severe heart failure, ventricular hypertrophy, or hypoxemia is uncommon. However, late ventricular tachycardia that arises from the right ventriculotomy scar or the septal repair may develop in some patients who have undergone a successful surgical repair of Fallot tetralogy.

Inherited Arrhythmia Syndromes

The congenital long QT syndrome (LQTS) is a family of disorders characterized by prolongation of cardiac repolarization with a prolonged QT interval on the scalar ECG and a tendency to develop polymorphic ventricular tachycardia that may degenerate to ventricular fibrillation. It occurs with an estimated prevalence of 1 in 3000 to 5000 in the general population. The most common types of the LQTS are caused by mutations in genes that encode ion channel proteins. The resultant ion channel dysfunction causes a prolonged repolarization phase of the ventricular action potential. This promotes polymorphic ventricular tachycardia triggered by oscillations in the action potential called early after-depolarizations. Electrolyte imbalance, bradycardia or pauses, sudden sympathetic stimulation, and drug effects all may further prolong repolarization in individuals with these mutations and trigger acute episodes. Factors significantly affecting outcome include QTc duration (ie, increased risk of ventricular arrhythmias with QTc > 500 ms); age-gender interactions (increased event rate in males during childhood and females after onset of adolescence); LQTS genotype (LQT3 responds less well to β-blocker therapy); and syncope despite treatment with a β-blocker. Interestingly, family history of sudden death does not seem to be a marker of life-threatening cardiac events in LQTS patients. It is important to recognize patients with LQTS because standard antiarrhythmic drugs may worsen their condition and other QT-prolonging agents must be avoided.

A short QT syndrome caused by a gain in function mutation in a repolarizing potassium current that is associated with sudden death has also been described. The syndrome is characterized by short QT intervals (< 350 ms) and high incidence of syncope, sudden death, and atrial fibrillation.

The Brugada syndrome is another familial condition associated with sudden death. These individuals have an incomplete or complete right bundle branch block on their ECG with ST segment elevation in V1 and V2. These patients will manifest spontaneous episodes of polymorphic ventricular tachycardia and ventricular fibrillation, often during sleep. Some patients with Brugada syndrome have a mutation in the sodium channel gene (SCN5A) with a decrease in the inward sodium current during the plateau phase of the action potential. The unusual ECG manifestations are believed to be due to more pronounced ion channel dysfunction in the right ventricular epicardium.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare syndrome in which bursts of rapid ventricular tachycardia occur during sympathetic stimulation or exercise. This syndrome is genetically heterogenous, with mutations in the genes encoding the cardiac ryanodine receptor type II and calsequestrin. These genetic mutations result in deranged calcium homeostasis with increased intracellular calcium, thereby predisposing to an increased risk of ventricular arrhythmias. β-Blockers are indicated for symptomatic patients. An ICD may be indicated for CPVT patients with syncope or sustained ventricular tachycardia despite treatment with β-blockers.

Advancements in genetic testing have facilitated the diagnosis and risk stratification of patients with inherited arrhythmia syndromes. Most of these diseases are caused by single genetic mutations that are heritable (often in an autosomal dominant fashion). However, the genetic cause has been identified for only a portion of these life-threatening disorders (up to 75% of LQTS cases; 65% of hypertrophic cardiomyopathy; 50% of ARVC and CPVT; and 25 to 30% of dilated cardiomyopathy and Brugada syndrome). Genome-wide association studies (GWAS) analyze the entire human genome in large cohorts seeking to establish a correlation between common genetic mutations and disease. Specifically, GWAS assess the impact of single nucleotide polymorphisms (SNPs; genetic mutations that are common [> 1%] in the general population) on the susceptibility to arrhythmias. GWAS have identified mutations that affect the QT interval and may modulate the risk of sudden cardiac death in the LQTS. Further research may identify mutations that influence the risk of sudden death in other cardiac conditions as well as the susceptibility to drug-induced QT prolongation and torsade de pointes.

Drug-Induced Arrhythmias

Drug toxicity can also result in sudden death. A variety of medications can affect cardiac electrophysiology and lead to fatal arrhythmias. Even when prescribed for atrial fibrillation or supraventricular tachycardia, all antiarrhythmic drugs may be associated with a proarrhythmic response in the ventricle. Other cardiac and noncardiac drugs can also cause arrhythmias. The most common mechanism is IKr blockade. Multiple factors are often required for drug-induced proarrhythmia. Risk factors include electrolyte disturbances, age, female gender, genetic polymorphisms or mutations, left ventricular hypertrophy, and bradycardia.

Patients with severe electrolyte disturbances and abnormal dietary histories (eg, anorexia nervosa and liquid protein diets) are also susceptible to potentially fatal ventricular arrhythmias even in the absence of significant heart disease.

Other Arrhythmias