Edmond M. Cronin
Sudden Cardiac Death
I. DEFINITION AND EPIDEMIOLOGY.
Sudden cardiac death (SCD) is defined as death following cardiac arrest in a patient with or without known preexisting heart disease in whom the mode and time of death are unexpected (1). The generally accepted timeframe between the onset of symptoms and loss of consciousness is 1 hour, although some patients who receive medical interventions may live for much longer after the initiating event before expiring. If the patient survives the event, due to defibrillation or spontaneous recovery, it is labeled sudden cardiac arrest (SCA). The incidence of SCD in the United States is estimated at 460,000 cases per annum, accounting for 10% to 15% of all deaths from natural causes and about 50% of all cardiac deaths. SCD exhibits a bimodal age distribution with peaks between birth and 6 months of age and then rises steadily from age 30. A male preponderance is observed in all age groups, narrowing after age 65, and is attributable to an increased incidence of coronary artery disease (CAD). While the absolute risk of SCD is greater among high-risk populations, most SCDs occur in patients who have not been identified as being at risk, being the first presentation of cardiovascular disease in approximately 25% of patients.
It is likely that ventricular fibrillation (VF) or ventricular tachycardia (VT) is the initiating rhythm in most cases of SCA. As the time from onset and rhythm identification increases, the proportion of VF decreases. This suggests that asystole and pulseless electrical activity (PEA) are frequently the result of prolonged VF and resultant ischemia and hypoxia. However, a significant proportion of SCA is due to bradyarrhythmias and pump failure. The proportion of these deaths is slightly higher in patients with advanced heart failure, although tachyarrhythmias still predominate.
II. CAUSES OF SCD
A. Coronary artery disease
accounts for 80% or more of episodes of SCD in Western societies, and SCD is the first presentation of CAD in 20% to 25% of patients. However, the extent to which acute ischemia plays a role in initiating a trigger for SCD is unclear. Autopsy data have demonstrated a recent occlusive thrombus in only about 15% to 20% of patients, while evidence of a remote infarct is identified in 40% to 70% of cases. The majority (80%) of SCD episodes in patients with CAD are considered to be primary (i.e., no precipitating factor can be identified), whereas secondary causes like myocardial ischemia/infarction, drug toxicity or proarrhythmia, decompensated heart failure, or electrolyte imbalance can be identified in the minority. Patients with reduced left ventricular ejection fraction (LVEF) and frequent premature ventricular contractions (PVCs) are identified as a particularly high-risk subgroup. A study of patients implanted with a loop recorder with recent myocardial infarction (MI) and ejection fraction (EF) ≤ 40% found that the termi nal rhythm was VF in 86% of sudden deaths, and 50% of all deaths, with bradyarrhythmias in the remaining 50%.
B. Cardiomyopathies
1. Dilated cardiomyopathy (DCM).
Patients with DCM represent the second largest group of patients who experience SCD, accounting for approximately 10% of cases. The annual mortality from DCM is 11% to 15%, with SCD accounting for about 30% of all deaths in this population. The presence of reduced LVEF and syncope are markers of a high risk of SCD in these patients. There is also a higher incidence of sudden deaths related to bradyarrhythmias and PEA in patients with advanced disease.
2. Hypertrophic cardiomyopathy (HCM).
The incidence of SCD in patients with HCM is 2% to 4% per year in adults and 4% to 6% per year in children and adolescents. Risk factors that identify a high-risk population in patients with HCM include prior SCA, family history of SCD, sustained or nonsustained VT (NSVT), syncope, a drop in blood pressure with exercise, and septal hypertrophy ≥ 30 mm. Myocardial scar, detected by late gadolinium enhancement on magnetic resonance imaging (MRI), is also emerging as a predictor of risk. SCD usually results from ventricular arrhythmias, but occasionally it may be precipitated by atrial fibrillation, bradyarrhythmias, or myocardial ischemia.
3. Arrhythmogenic right ventricular dysplasia (ARVD).
ARVD is a rare genetic disorder characterized by heart failure, ventricular arrhythmias, and SCD. Mutations involving the desmosome are manifested by fibrofatty infiltration of the right ventricle. The incidence of SCD is approximately 2% per year and is mainly due to ventricular tachyarrhythmia. Patients are identifiable by right bundle branch block (RBBB), T-wave inversion in V1 through V3 and epsilon waves on the electrocardiogram (ECG), regional right ventricular akinesia, dyskinesia, or aneurysm on echo or MRI, and findings on endomyocardial biopsy.
C. The channelopathies
1. The congenital long QT syndrome (LQTS).
LQTS is a familial disease with a prevalence of about 1:2,000, characterized by an abnormally long QT interval, leading to the development of early afterdepolarizations and torsades de pointes.
The two variants of the syndrome include the more common autosomal dominant form (Romano-Ward syndrome) and the less common recessive form (Jervell and Lange-Nielsen syndrome), which is associated with congenital deafness. To date, mutations at 12 different LQTS susceptibility genes have been identified. The most common, accounting for over 50% of cases, is a mutation in KCNQ1, which encodes the α-subunit of the potassium channel conducting the slow delayed rectifier current (IKs). This mutation produces LQT1, which is characterized clinically by broad-based T waves and exercise-induced arrhythmic events (especially swimming). LQT2 (35% to 40% of cases) is caused by mutations in the KCNH2 gene encoding the HERG protein (IKr current) and presents with low-amplitude, notched T waves and auditory arrhythmogenic triggers. LQT3 is caused by a gain-of-function mutation in the sodium channel gene SCN5A and manifests a long, isoelectric ST segment and SCD events during sleep.
The mortality rate for LQTS is estimated to be about 1% per year. High-risk patients include those with a corrected QT interval > 500 milliseconds, a history of syncope or SCA, male sex in children and female sex in adults (especially after menopause), and the LQT2 or LQT3 genotype. It has been postulated that 11% to 13% of sudden infant death syndrome cases could be caused by LQTS. All patients are treated with β-blocker therapy; however, genotype-specific and individualized therapies are evolving. Symptomatic patients who are either refractory to or intolerant of medical therapy, or who have other high-risk markers for SCD, should be considered for implantable cardioverter—defibrillator (ICD) implantation and left cardiac sympathetic denervation. It seems increasingly likely that many patients who suffer cardiac events due to drug-induced or other acquired QT prolongation have a forme fruste of LQTS.
The very rare short QT syndrome is caused by mutations in genes encoding the potassium channel, resulting in shortening of the action potential duration and vulnerability to VF.
2. Brugada syndrome.
The Brugada syndrome is an autosomal dominant arrhythmogenic disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel, which predisposes patients to develop polymorphic VT or VF. The arrhythmias commonly occur at rest or during sleep, and the risk of SCA is up to 30% at 3 years in untreated symptomatic patients. Incomplete RBBB with coved ST elevation in the right precordial leads is diagnostic and, although often transient, may be elicited by a drug challenge. Atrial fibrillation and conduction abnormalities are frequently associated. Symptomatic patients (syncope or SCA) should undergo ICD implantation; risk stratification for asymptomatic patients is controversial.
3. Catecholaminergic polymorphic ventricular tachycardia (CPVT)
is due to mutations in the ryanodine receptor and calsequestrin and results in a malignant phenotype of bidirectional VT during emotional or physical stress. Treatment is with β-blockers and ICD, and recent evidence suggests an emerging role for flecainide.
D. Others.
The risk of SCD is also higher in patients with Wolff-Parkinson-White (WPW) syndrome, especially if they have rapidly conducting accessory pathways, when atrial fibrillation can be associated with very rapid ventricular rates and degeneration to VF. An RR interval ≤ 220 milliseconds during spontaneous AF indicates a higher risk. The incidence of SCD is 0.05% to 0.1% per year and is higher in males in their second and third decades, but the phenomenon is easily identifiable and manageable. When no cause of SCA can be found, the label idiopathic VF is applied. In some cases, VF is triggered by a PVC which is amenable to catheter ablation. Recent evidence suggests that early repolarization on ECG denotes a higher risk of SCD in the presence of proarrhythmic triggers, and the clinical implications of this are still being clarified. Some of the other cardiac and noncardiac causes of SCD are presented in Table 23.1.
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III. DIAGNOSTIC AND PROGNOSTIC TESTING.
Survivors of SCA should have a detailed cardiovascular evaluation. Reversible precipitating factors must be identified and corrected. Underlying diseases must be identified and managed, and the risk of recurrent SCD must be determined. Diagnostic and prognostic testing appropriate for the survivor of SCA includes the following:
A. ECG
for the evidence of MI or ischemia, intraventricular conduction delay, acces sory pathway (WPW syndrome), prolonged QT interval, epsilon waves, Brugada pattern, and left ventricular hypertrophy.
B. Laboratory data
to rule out reversible causes, such as cardiac biomarkers (cre atine kinase—myocardial band, troponin T, and troponin I), abnormal electrolytes, antiarrhythmic drug levels for toxicity, and urine screening for illicit drugs such as cocaine.
C. ECG monitoring
to assess frequency, duration, and symptomatology of arrhythmias.
D. Twenty-four-hour ambulatory electrocardiography
during normal activities can be useful in predicting the risk of recurrent SCA.
E. Echocardiography
for the assessment of left ventricular function, valvular disease, cardiomyopathy, and hypertrophy. Nuclear or angiographic determinations of left ventricular function may be used but do not provide as much information as echocardiography. The LVEF continues to be the most potent predictor of SCD, behaving as a continuous variable with markedly increased risk < 40%. However, nonsudden death also increases with declining EF, meaning that the likely mode of death cannot be predicted. LVEF is also limited by poor sensitivity—from 22% to 59% in studies in the last decade.
F. Coronary angiography
for the assessment of CAD or coronary anomalies.
G. Exercise or pharmacologic stress testing
with radionuclide imaging or echocar diography if CAD is present and myocardial ischemia and/or viability is in question.
H. Electrophysiologic (EP) testing
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