Approach to sudden cardiac arrest in the absence of apparent structural heart disease

INTRODUCTION — Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of cardiac activity with hemodynamic collapse due to sustained pulseless ventricular tachycardia/fibrillation, pulseless electrical activity (PEA), or asystole. The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation) restores circulation. The event is called SCD if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest persists by convention. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Definitions'.)

SCA and SCD occur most commonly in patients with structural heart disease (including previously undiagnosed heart disease), particularly coronary artery disease. SCD in the apparently normal heart (at autopsy) is less common and is responsible for, as previously reported, 10 to 15 percent of cases of SCD [1,2]. However, series of SCD in the young show increasing percentages of SCA with an apparently normal hearts, with up to 40 percent of SCD with a normal heart [3,4]. Thus, SCA with an apparently normal heart is more common in younger arrest victims. The majority of SCD patients without apparent structural heart disease likely do not actually have "normal" hearts, but our diagnostic tools limit identification of structural or functional abnormalities. In the past, the etiology of many of these deaths was unknown and deemed "idiopathic." However, more complete evaluation has identified the cause of death as a primary electrical disorder (ie, long QT, Wolff-Parkinson-White [WPW], catecholaminergic polymorphic ventricular tachycardia [CPVT], and Brugada syndrome) in many of these patients [1,2,5]. (See "Pathophysiology and etiology of sudden cardiac arrest".)

SCD in the apparently normal heart will be reviewed here. SCD in patients with heart disease, and the evaluation and options for the management of survivors of SCD, are discussed separately. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Etiology' and "Pathophysiology and etiology of sudden cardiac arrest", section on 'Etiology of SCD' and "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".)

In addition, sudden death may occur from noncardiac causes (eg, trauma, pulmonary embolism, seizure), and these topics are discussed separately. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults" and "Sudden unexpected death in epilepsy".)

EPIDEMIOLOGY — Based upon a review of death certificates in the United States during 1998 and 1999, sudden cardiac death (SCD) accounted for over 450,000 deaths annually, which represented 63 percent of cardiac deaths among adults ≥35 years of age [6]. The incidence of SCD is increased six- to ten-fold in the presence of clinically recognized heart disease (figure 1); it also increases with age and is two to three times more common in men than women (figure 2) [7].

Although the risk of SCD is higher in patients with structural heart disease, SCD events occur in individuals with apparently normal hearts. In a series of 121 SCD cases where data on left ventricular function was available, 48 percent had normal left ventricular function [8]. Among these patients, one-half had no history of established coronary heart disease.

Autopsy studies of subjects with a presumed diagnosis of SCD have shown high variability in the numbers of subject without a demonstrable cardiac abnormality [1,9-12]. A lower value of about 5 percent has been described in autopsy studies and among survivors of SCD when older patients are included, a population in which coronary heart disease (CHD) is more prevalent but not necessarily the cause of SCD [1,10]. In an autopsy series of 902 cases of SCD (mean age 38 years), 187 (21 percent) had no evidence of cardiac pathology that could cause SCD [11]. In a separate autopsy series of 967 cases of SCD referred to a tertiary cardiac pathologist between 1994 and 2010, 45 percent of cases had a normal cardiac postmortem examination [12]. Atherosclerotic CHD at autopsy is much more commonly found in SCD victims who are older than 35 years (incidence 13.7 per 100,000 person-years versus 0.7 per 100,000 person years without CHD), yet causality is not always clear as autopsy rates of coronary artery disease (CAD) would be high in this age group regardless of cause of death [11].

The distribution of cardiac causes of SCD varies with age, the population studied, and geography. While CAD is listed as the underlying cause of SCD on the majority of death certificates among the general population in the United States, younger patients, athletes, and those without known prior disease often have a different distribution of causes. The etiology of SCD is discussed in greater detail elsewhere. (See "Pathophysiology and etiology of sudden cardiac arrest".)

EVALUATION OF SURVIVORS — The evaluation of survivors of sudden cardiac arrest (SCA) with apparently normal hearts involves a variety of tests, generally including multiple of the following tests:

●Laboratory studies to assess electrolytes

●Electrocardiogram

●Echocardiogram

●Coronary angiography

●Cardiac magnetic resonance imaging

●Provocative testing for primary electrical disease

●Genetic analysis

These tests are performed in an effort to find underlying structural heart disease, primary electrical diseases, and drug or toxin exposure that may have contributed to SCA. In addition, a rigorous search for the known causes of SCA should be performed in the apparently healthy person prior to making the diagnosis of idiopathic ventricular fibrillation [2]. An extensive discussion of the evaluation of SCA survivors is presented separately. (See "Cardiac evaluation of the survivor of sudden cardiac arrest".)

AUTOPSY AND MOLECULAR GENETIC TESTING — Patients who experience sudden cardiac death (SCD), particularly young patients, should undergo an autopsy with extensive cardiac evaluation to evaluate for the presence of structural heart disease. This has importance not only for the proband, but also for the family. Autopsies may demonstrate that there was an underlying heart disease such as hypertrophic cardiomyopathy (HCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC), Wolff-Parkinson-White syndrome (WPW), congenital heart disease coronary anomalies, coronary artery disease, or dilated cardiomyopathies. Subtle cases of these diseases may be missed, particularly with standard autopsies. As noted, inherited arrhythmia syndromes are common in individuals who experience SCD but whose autopsy reveals no evidence of structural heart disease. Diagnosing such a syndrome would have significant implications for surviving family members, particularly if a specific genetic defect could be identified. (See 'Evaluation of family members' below.)

In general, genetic testing of the victim of SCD with a structurally normal heart should occur, ideally prior to the declaration of death, but it may also be done as part of an autopsy if resuscitation is unsuccessful. Although interpretation may be limited by the large number of candidate genes, the number of known mutations in each of these genes and variable gene expression and penetrance, continued development and knowledge of the gene pool database will be important for the management of the surviving relatives.

As both genetic testing techniques and our understanding of these heritable disorders improve, genetic screening at specialized centers has yielded diagnoses in up to one-third of young SCD victims without structural heart disease [13-16].

In the largest reported series of 302 cases of sudden death with negative autopsy and negative toxicologic evaluation (median age 24 years, 65 percent male), molecular autopsy was performed, with sequencing for a panel of 77 genes associated with primary electrical disorders and cardiomyopathies [16]. Pathogenic or likely pathogenic variants were identified in 40 patients (13 percent), most commonly variants associated with catecholaminergic polymorphic ventricular tachycardia and congenital long QT syndrome (17 and 11 patients, respectively). When results from the molecular autopsy were combined with clinical evaluation in the screening of surviving family members, the likelihood of making a significant clinical diagnosis increased from 26 to 39 percent. In a study from the Paris Sudden Death Center which included 88 SCA VF survivors with a negative workup after ECG, angiography, and echocardiography, MRI was abnormal in 25 of these (myocarditis = 13, HCM = 4, ARVC = 4, DCM = 2 and CAD = 2) [17]. Additionally, ergonovine caused vasospasm in 12, and pharmacologic provocative testing was positive with ajmaline in one (Brugada) patient and with catecholamine in one (CPVT) patient.

POTENTIAL CAUSES — Several major diseases must be considered as possible causes of sudden cardiac death (SCD) in patients without evidence of structural heart disease [2]. Many of these disorders are familial and therefore are associated with an increased risk of SCD in first-degree relatives. In multiple series of intensive evaluation, including genetic analysis, the LQTS and CPVT are the most frequently found causes [16,18-20].

Prolonged QT interval — Long QT can be primary (genetic/inherited) (the long QT syndrome [LQTS]) or secondary (acquired) (table 1) and may be associated with a specific form of polymorphic ventricular tachycardia (VT) called torsades de pointes (waveform 1). Among patients with inherited LQTS, the precipitating factors and prognosis vary with the genetic abnormality. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Pathophysiology and genetics" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

The majority of secondary causes of prolonged QT interval result from an interaction with a drug/electrolyte which interferes with an ion channel involved in repolarization, the same ion channels involved in LQTS. Most of the pharmaceutical agents are prescription drugs; a list can be found at crediblemeds.org, which should be consulted before prescribing new drugs for anyone with a long QT or on another drug known to prolong the QT. Common drugs that increase the QT are anti-psychotics, anti-emetics, quinolones, anti-arrhythmics, and methadone [21]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

Polymorphic VT with normal QT interval — Polymorphic VT with a normal QT interval is largely due to either acute cardiac ischemia or catecholaminergic polymorphic VT (CPVT). Ischemia is the cause in the majority of these patients, and thus prompt evaluation for cardiac ischemia is warranted. In those without cardiac ischemia, CPVT, an inherited channelopathy, may be the cause. Affected patients typically present with life-threatening polymorphic VT or ventricular fibrillation occurring during emotional or physical stress, with syncope often being the first manifestation of the disease. Although sporadic cases occur, this is a largely familial disease. The majority of known cases are due to mutations in the cardiac ryanodine receptor, which is the cardiac sarcoplasmic calcium release channel. One report suggested that this disorder may account for at least one in seven cases of sudden unexplained death [13]. (See "Catecholaminergic polymorphic ventricular tachycardia".)

Brugada syndrome — The Brugada syndrome is characterized by the electrocardiographic findings of right bundle branch block and ST-segment elevation in leads V1 to V3 (waveform 2), and an increased risk of sudden cardiac death. Brugada syndrome is due to a functional abnormality in repolarization. There may be some overlap with an early subclinical manifestation of arrhythmogenic right ventricular cardiomyopathy (ARVC). The Brugada syndrome occurs in families, with genetic transmission consistent with autosomal dominant inheritance with variable penetrance. Mutations in the cardiac sodium channel gene, SCN5A, have been found in several families. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'SCN5A' and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".)

A sudden unexpected nocturnal death syndrome (SUNDS) has also been described in young, apparently healthy males from Southeast Asia. This disorder is closely related and indeed may be the same as Brugada syndrome since a majority of affected patients have the ECG manifestations of the Brugada syndrome and the same mutations in the sodium channel gene.

Different mutations of the same SCN5A gene have been found in a number of cardiac disorders, including the long QT syndrome, and a unique allele found in African Americans, Y1102. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 3 LQTS (LQT3)'.)

Commotio cordis — Commotio cordis is defined as sudden cardiac death secondary to relatively innocent chest wall impact due to ventricular fibrillation. Affected patients have no underlying heart disease and there is no structural damage to the chest wall, thoracic cavity, or the heart. Early defibrillation of commotio victims is lifesaving, despite historical evidence that resuscitation may be more difficult in commotio cordis than in other forms of SCD. Commotio cordis is discussed in detail separately. (See "Commotio cordis".)

WPW and other forms of SVT — Both Wolff-Parkinson-White (WPW) syndrome and, very rarely, other forms of supraventricular tachycardia (SVT) can cause sudden cardiac death (SCD). The frequency with which this occurs was assessed in a report of 290 patients with aborted SCD. The mechanism was an arrhythmia associated with the WPW syndrome in 2.1 percent; atrial fibrillation (AF) with a rapid ventricular response was the most common [22]. A similar incidence of preexcitation (3.6 percent) was noted in a report of 273 children and young adults with SCD [23]. The epidemiology and clinical manifestations of the WPW syndrome are discussed in greater detail separately. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis".)

Most patients who have been resuscitated from ventricular fibrillation (VF) secondary to preexcitation have a previous history of syncope, atrioventricular reciprocating tachycardia, and/or AF [24]. However, preexcitation and arrhythmias have been previously undiagnosed in up to 25 percent of such individuals [25,26]. Among patients with WPW syndrome who survive an episode of SCD, ablation of the accessory pathway is the treatment of choice. Treatment options for persons with the WPW syndrome are discussed in detail separately. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome".)

Early repolarization syndrome — Early repolarization pattern on ECG is common. In 2008 a higher frequency of early repolarization was described in 206 survivors of cardiac arrest without apparent heart disease (31 to 5 percent of controls; p<0.001) [27]. These survivors tended to have increased incidences of recurrent VF compared with those SCA survivors with normal hearts and no early repolarization. Subsequent studies have confirmed the higher incidence of early repolarization in SCA survivors with normal hearts. Early repolarization in the inferior and lateral leads is associated with an increased risk of SCA. However, large population studies continue to describe a 5 to 10 percent incidence of early repolarization, and when found in the absence of a SCA it is thought benign [28]. Early repolarization ECG pattern is especially common in athletes, and in these individuals it is nearly always benign [29]. An expert consensus panel does not recommend any specific treatment for those with early repolarization without SCA [30]. (See "Early repolarization".)

VF secondary to PVCs — Short coupled PVCs have been described as a trigger of VF [31]. Generally these arise from the Purkinje fibers, but PVCs from papillary muscles have also been described to trigger VF. Ablation of these triggering PVCs may eliminate recurrent episodes of VF [32].

Idiopathic VF — If the above disorders are excluded and the heart is structurally normal, the diagnosis of primary electrical disease is made [2,33,34]. More commonly referred to as idiopathic ventricular fibrillation (VF), this entity is estimated to account for 5 percent of cases of sudden cardiac death (SCD) [33]. In a review of 54 published cases with presumed idiopathic VF, the mean age was 36 years with a male-to-female ratio of 2.5-to-1 [34]. A history of syncope preceded the episode of VF in 25 percent. In a meta-analysis of 639 patients with idiopathic VF from 23 studies, among whom 80 percent had an implantable cardioverter-defibrillator for secondary prevention, 31 percent of patients had recurrent ventricular arrhythmias over a mean follow-up of five years [35]. Other registries have shown a similar high incidence of arrhythmias over time, and pediatric patients appear to have a higher incidence of ICD-treated arrhythmias [36,37].

The diagnosis and treatment of idiopathic VF, particularly as they relate to the early repolarization syndrome, are presented in greater detail separately. (See "Early repolarization".)

Familial SCD — A family history of sudden cardiac death (SCD) in the absence of apparent structural heart disease is associated with an increased risk for primary SCD [38-40]. It has been estimated that the adjusted relative risk for SCD, compared with controls, is 1.6 to 1.8 in individuals without apparent structural heart disease in whom a first-degree relative had SCD [38,39]. However, the absolute increase in risk is quite small since primary SCD is rare in the general population. The increase in risk is incompletely understood. Some of these families have an inherited cardiac disease, as illustrated in a report in which 147 first-degree relatives of 32 patients with SCD underwent detailed cardiac assessment [40]. Seven (22 percent) of the 32 families had an inherited cardiac disease, including four with long QT syndrome, one with myotonic dystrophy, and one with hypertrophic cardiomyopathy.

Genome-wide association studies have demonstrated an increased risk with several loci [41].

Short QT syndrome — Short QT syndrome (SQTS) is an extremely rare inherited channelopathy associated with markedly shortened QT intervals and SCD in individuals with a structurally normal heart. In contrast to long QT syndrome, ion channel defects associated with SQTS lead to abnormal abbreviation of repolarization, predisposing affected individuals to a risk of atrial and ventricular arrhythmias. SQTS is discussed in detail separately. (See "Short QT syndrome".)

EVALUATION OF FAMILY MEMBERS — As noted above, many causes of sudden cardiac death (SCD) in patients with structurally normal hearts are familial, and therefore are associated with an increased risk of SCD in first-degree relatives. In families of victims of unexplained SCD, a general cardiology evaluation of first- and second-degree relatives can yield diagnosis of a heritable disease in up to 40 percent of families. A discussion of the evaluation of family members of victims of unexplained SCD is presented separately. (See "Cardiac evaluation of the survivor of sudden cardiac arrest", section on 'Evaluation of family members'.)

SUMMARY AND RECOMMENDATIONS

●Background – Sudden cardiac death (SCD) refers to the sudden cessation of cardiac activity with hemodynamic collapse, often due to sustained pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF). SCD is the most common cause of cardiovascular death in the developed world. (See 'Introduction' above.)

●Epidemiology – Although the risk of SCD is higher in patients with structural heart disease, as many as 10 to 15 percent of SCDs occur in individuals with apparently normal hearts. (See 'Epidemiology' above.)

●Potential causes – Causes of SCD with a normal heart are (see 'Potential causes' above):

•Prolonged QT interval (congenital [long QT syndrome] or acquired)

•Catecholaminergic polymorphic VT with normal QT interval

•Brugada syndrome

•Commotio cordis

•Wolff-Parkinson-White syndrome

•Short QT syndrome

•Early repolarization syndrome

•Short coupled PVCs

●Family history – A family history of SCD (in first-degree relatives) in the absence of apparent structural heart disease is associated with an increased risk for primary SCD. (See 'Familial SCD' above.)

●Role of autopsy – Patients who experience SCD, particularly young patients, should undergo an autopsy with particular attention to the heart to evaluate the presence of structural heart disease. In young patients, if there is no clear diagnosis after autopsy, genetic testing now can yield a diagnosis in up to one third of young SCD victims and should generally be performed. (See 'Autopsy and molecular genetic testing' above.)

●SCA survivors – Survivors of sudden cardiac arrest (SCA) should undergo extensive testing to exclude drug or toxin exposure or underlying structural heart disease that may have contributed to SCA. Therapy with an implantable cardioverter-defibrillator should generally be recommended in survivors of SCA. (See "Cardiac evaluation of the survivor of sudden cardiac arrest".)

●Evaluation of family members – In families of victims of unexplained SCD, a general cardiology evaluation of first- and second-degree relatives can yield diagnosis of a heritable disease in up to 40 percent of families. (See "Cardiac evaluation of the survivor of sudden cardiac arrest", section on 'Evaluation of family members'.)