Arrhythmias that cause cessation of cardiac mechanical activity^2,4,9 include tachyarrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF), and bradyarrhythmias. VT, VF, and bradyarrhythmias are acutely reversible with defibrillation or pacing and may be caused by myocardial injury via acquired cardiac disease (eg, ischemia, inflammation, pressure overload), inherited cardiac disease (eg, arrhythmia syndromes), acute electrolyte imbalance (eg, hyperkalemia due to kidney failure), or autonomic dysregulation. Approximately 10% of persons who have had cardiac arrests out of the hospital have pulseless electrical activity,⁸ characterized by the absence of a palpable pulse in an unconscious person with organized electrical activity other than VT or VF on electrocardiogram (ECG).³⁸ Underlying conditions responsible for pulseless electrical activity include acute heart failure, cardiac tamponade, acidosis, hemorrhage, hypoxia, or tension pneumothorax. Asystole is defined as a complete absence of electrical and mechanical cardiac activity.

These terminal rhythms can be due to unrecognized underlying structural heart disease such as CAD or cardiomyopathy, arrhythmia syndromes such as long QT syndrome (LQTS) or Brugada syndrome, and conditions that predispose to arrhythmias such as muscular dystrophies³⁹ but may also be caused by noncardiac conditions such as neurocardiogenic VF due to intracranial hemorrhage,⁴⁰ bradyarrhythmias secondary to opioid overdose,¹⁸ and serum electrolyte disorders.⁴¹ Opioids, stimulants (eg, cocaine), or supplements (eg, herbal medications, energy drinks)^42,43 can also cause sudden cardiac arrest via QT prolongation,⁴⁴ predisposing to polymorphic VT, also called torsades de pointes. Congenital conditions such as anomalous coronary artery origin with a course between the aorta and pulmonary artery can predispose to cardiac arrest via myocardial ischemia.⁴⁵

The most common etiologies of out-of-hospital cardiac arrest in US adults aged 25 to 35 years are CAD (43%), followed by sudden unexplained death (14%).¹¹ In a Canadian study, the most common etiologies of cardiac arrest among 131 individuals aged 25 through 34 years were structural heart disease (including cardiomyopathy and myocarditis) and sudden unexplained death, each accounting for 28%.⁴⁶ Among hospitalizations in the US for overdoses, opioid-associated out-of-hospital cardiac arrest increased from 1% of hospitalizations in 2000 to 2% in 2013,^47,48 although recent CDC data show a decrease in opioid overdose deaths from 84 181 in 2022 to 81 083 in 2023.⁴⁹ Positive drug toxicology was reported in 17.1% of out-of-hospital cardiac arrests among persons aged 1 to 50 years (median, 42.4 years) in an Australian study from April 2019 to April 2021.²⁹

A retrospective observational cohort study from the CARES registry reported 101 968 out-of-hospital cardiac arrests in the US from 2006 through 2013, of which approximately 6% occurred among individuals aged 20 through 39 years; survival rate to hospital discharge ranged from 11% (30–39 years) to 16% (20–24 years).⁵⁰ Approximately 85% to 95% of out-of-hospital cardiac arrest survivors aged 20 through 49 years were discharged with good neurological outcome, as defined by a Cerebral Performance Categories scale of 1 or 2.^2,50,51 In an Australian registry conducted from 2000 through 2009 involving 3912 patients aged 16 though 39 years with out-of-hospital cardiac arrest, the survival rate was 8.8%.⁵² The overall survival rate of young adults experiencing out-of-hospital cardiac arrest was 9% in a prospective US study from 2005 through 2007 involving 665 persons aged 20 through 39 years, and increased to 34.8% for those with bystander-witnessed VT or VF who were more likely to receive prompt initial cardiopulmonary resuscitation (CPR) or automated external defibrillator use⁵³ (Figure 1).

The worldwide incidence of presumed sudden cardiac death is 4.2 to 7.8 per 100 000 person-years in adults younger than 40 years and 23 to 34 per 100 000 person-years in adults aged 40 through 49 years (Table 1).^{12,18,30–32} In a US study from 1999 through 2015 (n = 31 492) with race determined by examination of death certificates, Black individuals younger than 34 years had a higher incidence of presumed sudden cardiac deaths (1.88 per 100 000 person-years in 2015) than Hispanic individuals (0.66 per 100 000 person-years), and White individuals (1.17 per 100 000 person-years),⁵⁴ which may be due to inequitable access to care⁵⁵ and racial disparities among out-of-hospital resuscitation attempts. Several US studies have found that White individuals were more likely to receive bystander CPR after a witnessed cardiac arrest and postresuscitation care than were Black and Hispanic persons.^56,57 Incidence of presumed sudden cardiac death among adults younger than 40 years in Cameroon was higher at 12 to 42 per 100 000 person-years (Table 1).¹⁰

Over a 3-year study period (2011–2014), autopsies of 32 persons aged 18 through 39 years with presumed sudden cardiac deaths in San Francisco demonstrated that 40% had a noncardiac cause.¹⁸ Even when a lethal rhythm is documented at the time of sudden death, including VT or VF⁴⁰ or complete heart block,¹⁸ death may be due to underlying noncardiac causes, such as intracranial hemorrhage or drug overdose. Autopsy rates to confirm the cause of presumed sudden cardiac death after an out-of-hospital cardiac arrest vary widely depending on sex, country, region, and study.⁵⁸ Combined data from 4 autopsy-based studies worldwide that include 529 presumed sudden cardiac deaths among those aged 14 through 44 years, with autopsy rates ranging from 43% to 100%, demonstrated that cardiac causes accounted for 64% of sudden deaths. The most frequent cardiac causes were coronary artery disease (22% of all presumed sudden cardiac deaths), sudden arrhythmic death syndrome (16%), hypertrophic cardiomyopathy (12%), and cardiomyopathy (11%). The most frequent noncardiac causes were neurological (9.3%), pulmonary (8.1%), overdose (4.7%), and infection (4.7%).^18,24,33,34

The incidence of sudden cardiac death defined by autopsy for individuals younger than 40 years is 1.1 to 5.8 per 100 000 person-years (Table 1).^{20–23,35,36} The distribution of underlying causes of sudden cardiac arrest in resuscitated patients differs from those who were not resuscitated (ie, sudden cardiac death) with significantly more noncardiac causes in the latter.⁵⁹ Among autopsy studies of persons younger than age 30 years who had sudden cardiac death, the most common cause was sudden arrhythmic death syndrome with normal heart on postmortem examination (36%−49%).^20,21 The proportion of cases attributable to CAD increased with age, from 6% to 14% in persons younger than 30 years and to 19% to 46% in persons aged 30 years or older.^20,21,35,36 Unexpected myocarditis is another relatively common underlying cause of sudden cardiac death in young adults.^20,21,35 Autopsy-confirmed dilated cardiomyopathy was more frequently identified among individuals who were older than 30 years (10%) than individuals who were younger than 30 years (5%).^20,21 In 1 study of sudden cardiac death in young adults (n = 2006, median age, 28 years), CAD was more common in males (44%) than in females (27%), whereas unspecified cardiomyopathy (5% males vs 7% females, P = .04), myocarditis (9% males vs 14% females, P < .001), and valvular heart disease (2% males vs 7% females, P < .001) were more common in young females.²²

Autopsy-based studies of individuals with sudden cardiac death aged 18 to 50 years reported that 65% to 78% had at least 1 known cardiovascular disease (CVD) risk factor (ie, hypertension, diabetes, dyslipidemia, obesity, smoking) before death.^18,60 In these studies, compared with the reported prevalence of individual risk factors in the general US population among those aged 20 through 44 years,⁶¹ the reported prevalence of hypertension and diabetes was higher among those with sudden cardiac death (22%−24% vs 12% and 12%−19% vs 4%, respectively).

In young adults, sudden cardiac arrest occurs more frequently at rest and during sleep than during exercise. In a study in which 153 persons aged 19 to 34 years, only 8 (5.2%) occurred during sports-related activity.⁶² Other studies have found that among young adults, the sudden cardiac death occurred during exercise in 7% to 15%, whereas 30% to 40% died during sleep.^{20–23,35,36}

Sudden cardiac death during sexual intercourse is rare. An autopsy-based study involving 6847 persons with sudden cardiac death in the UK reported that 17 (0.2%) occurred during or within an hour of sexual intercourse. The mean age of the 17 who died suddenly was 38 years, 11 (65%) of whom were men. The autopsy results showed that 9 cases (53%) had a structurally normal heart consistent with sudden arrhythmic death syndrome.⁶³

Figure 2 shows an overview of the evaluation of young adults who had been resuscitated from sudden cardiac arrest. Emergency workup includes a 12-lead electrocardiogram (ECG) after return of spontaneous circulation, toxicology testing, a bedside neurological assessment, and neuroimaging (eg, head computed tomography [CT]) after the patient has stabilized. If ECG shows STEMI or unstable arrhythmia, the patient should be referred for emergency coronary angiography. Complete coronary revascularization should be performed for acute ischemia causes, including surgery if coronary anomaly is found. Figure 3 shows representative ECGs of high-risk arrhythmia conditions: LQTS (present in 13% of young adults resuscitated from sudden cardiac arrest),⁶⁴ Wolff-Parkinson-White syndrome (5%−12%),^64,65 arrhythmogenic right ventricular cardiomyopathy (10%),⁶⁴ and Brugada syndrome (<1%).⁶⁶ Repeating 12-lead ECGs are important during evaluation because ECG waveforms, particularly type 1 waveform in Brugada syndrome⁶⁷ and the QT interval, may show day-to-day and circadian variation⁶⁸ and variation after the initial resuscitation due to ischemia, autonomic fluctuations, and electrolyte derangements (eg, hypokalemia, hypomagnesemia) after sudden cardiac arrest.⁶⁹

If the corrected QT interval remains at 460 milliseconds or longer for females or 450 milliseconds or longer for males⁷⁰ beyond 6 days after resuscitation,⁷¹ patients should be evaluated for LQTS, the most common arrhythmia syndrome causing sudden cardiac arrest.⁶⁴ In patients with LQTS, a prolonged QT interval results in the end of the T wave often exceeding half of the RR interval, along with broad, biphasic, or notched T waves with beat-to-beat alternans (Figure 3A).⁷² In a study of 647 untreated patients older than 28 years with LQTS, 13% experienced out-of-hospital cardiac arrest or sudden death before age 40 years.⁷³ LQTS can be either congenital or acquired, most commonly due to drugs such as anti-arrhythmics, antipsychotics, antidepressants, or antibiotics (a continuously updated list can be found at https://crediblemeds.org/). However, some acquired LQTS cases may have underlying congenital LQTS unmasked by drugs or other predisposing factors such as electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia) or bradyarrhythmias. Evaluation for acquired LQTS should be reassessed after resolution of these factors.⁷⁴

In Brugada syndrome, type 1 pattern (ie, coved shape of ST segment) in leads V1 and V2 can sometimes be recorded when these leads are moved to the second or third intercostal spaces instead of the typical fourth intercostal space (Figure 3B).⁷⁴ In preexcitation syndromes (ie, Wolff-Parkinson-White), the observed delta waves are a marker for potential atrioventricular reentrant tachycardia or VF via preexcited atrial fibrillation (Figure 3C).⁷⁵ In some cases of arrhythmogenic right ventricular cardiomyopathy, epsilon waves that represent delayed right ventricular conduction can be observed in the ST segment in the right precordial leads (Figure 3D).⁷⁶

Clinicians evaluating persons hospitalized after resuscitation from out-of-hospital cardiac arrest should review documented cardiac rhythm from EMS records and the circumstances of arrest, including witness accounts. They should obtain a family history of heart disease for at least 3 generations, syncope, sudden cardiac arrest, or sudden cardiac death and should evaluate for use of QT-prolonging medications, substance use (eg, cocaine, methamphetamine, or ketamine), and supplements (eg, kratom, tianeptine).^43,77,78 If the cause is not determined with initial laboratory tests (eg, serum electrolytes or troponin), coronary angiography, or imaging examinations (eg, chest x-ray for pneumothorax, bedside ultrasound for pericardial tamponade, aortic dissection, or hemorrhage, and head-to-pelvis CT scan for intracranial or chest or pelvis emergencies), transthoracic echocardiography should be performed to screen for structural heart disease such as unsuspected cardiomyopathy or valvular disease such as mitral valve prolapse, a condition in young persons (especially females) that can precipitate sudden cardiac death due to VF or sustained VT.⁷⁹

If transthoracic echocardiography reveals a normal structural heart and ECG shows no findings consistent with an arrhythmia syndrome, further evaluation with electrophysiological study (EPS), sodium channel blocker challenge, or stress ECG testing may be performed (Figure 3). Because delta waves in Wolff-Parkinson-White syndrome and Brugada pattern may not be apparent on initial ECGs after resuscitation, an EPS can identify and treat accessory pathways responsible for cardiac arrest.⁸⁰ A sodium channel blocker challenge during EPS involves administration of drugs such as flecainide, ajmaline, and pilsicainide to unmask a type 1 Brugada ECG pattern.⁷⁴ Stress ECG testing can identify catecholaminergic polymorphic VT (CPVT) if bidirectional VT is observed during exercise, or LQTS if the QT interval does not shorten with exercise or remains prolonged during the recovery phase.^74,81

An estimated 60% to 78% of young adults hospitalized after resuscitation from sudden cardiac arrest do not survive to hospital discharge (Figure 1).^52,53,82 This in-hospital mortality rate is similar to that of older adults who were resuscitated to hospitalization (≈ 65%).⁵⁹

For certain noncardiac causes of out-of-hospital cardiac arrest (eg, hemorrhage, infection, hypoxia) or reversible cardiac causes (eg, acute ischemia due to ST-segment elevation MI or coronary anomaly), treatment of the underlying condition reduces risk of recurrent sudden cardiac arrest. For patients who survived an out-of-hospital cardiac arrest that involved stimulants or supplements, avoidance of these substances can prevent recurrence. For patients with an event caused by an opioid overdose, counseling, education, and medications to treat opioid use disorder (eg, buprenorphine, methadone, and naltrexone) are recommended to decrease the risk of recurrence.⁴⁸ Survivors with a previously undiagnosed seizure disorder should be treated and closely followed up given a more than 20-fold higher risk of sudden unexplained death in persons with epilepsy compared with the general population.⁸³ For survivors with coronary anomalies such as congenital atresia of the left main artery and anomalous aortic origin of a coronary artery, surgical intervention is recommended to prevent recurrent sudden cardiac arrest.^74,80,84 Among persons presenting with VF due to acute MI with coronary plaque rupture and/or thrombus (typically <48 hours), risk of a recurrent event is reduced after early revascularization such as percutaneous coronary intervention. Implantable cardioverter-defibrillator (ICD) is not indicated for secondary prevention.^74,85

Sudden cardiac arrest survivors in whom noncardiac or reversible causes are excluded remain at high risk of recurrent ventricular arrhythmias.⁸⁶ Based on landmark trials in the 1990s and 2000s, ICD implants as secondary prevention is indicated for these patients,^87–89 particularly for those diagnosed with structural heart disease, such as dilated cardiomyopathy, or arrhythmia syndromes, such as LQTS, Brugada syndrome, and CPVT (Figure 2, Table 2). An alternative to conventional ICD with transvenous leads is a subcutaneous ICD in which the lead is tunneled subcutaneously instead of passing through the blood vessels. Subcutaneous ICDs have fewer long-term lead-related complications than conventional ICDs, so they may be reasonable for younger patients with primary arrhythmia syndromes. However, according to recent European Society of Cardiology guidelines (class IIa, level B), conventional transvenous ICDs are recommended for patients who require pacing for bradyarrhythmias or LQTS, cardiac resynchronization therapy with coronary sinus lead, or antitachycardia pacing for VT.^74,90 Despite ICD implants, survivors remain at risk of spontaneous VT or VF, with a reported recurrence rate of 37% during a 2-year follow-up among Australian adults.⁹¹ Thus, adjunctive pharmacotherapy, especially amiodarone,^92,93 or catheter ablation^92,94,95 may be used in combination with ICD.

A summary of recent European recommendations for secondary prevention of recurrence in survivors of sudden cardiac arrest is shown in Table 2.⁷⁴ Certain medications and lifestyle habits such as exercise should be avoided in patients with specific primary arrhythmia syndromes. For patients with LQTS, QT-prolonging medications (eg, ciprofloxacin and odansetron) and genotype-specific triggers that increase ventricular arrhythmia risk (strenuous exercise in LQT type 1 [LQT1]; emotions such as extreme stress or fear, and sudden loud noise in LQT2) should be avoided. Individuals with Brugada syndrome should avoid excessive alcohol use and certain drugs (eg, tricyclic antidepressants, class 1A or class 1C antiarrhythmics such as procainamide or flecainide, cocaine, and other drugs; see https://www.brugadadrugs.org/drug-lists/). Fever (temperature >38.0 °C) can increase risk of VF in patients with Brugada syndrome so should be promptly reduced with antipyretics.^74,96 For patients with CPVT, strenuous exercise and high psychological stress may increase adrenergic activity and should be avoided.

The 10-year survival rate of sudden cardiac arrest survivors aged 40 years or younger was 90% in an Australian registry.⁹⁷ The rate of recurrent arrest (both out of and in the hospital) or death in survivors aged 18 to 39 years in a Swedish registry was approximately 15% a year after the out-of-hospital cardiac arrest.⁹⁸ One-year overall mortality of subcutaneous ICD recipients aged 15 to 34 years was 4.3% in one cohort,⁹⁰ whereas the VT or VF recurrence rate estimated by subcutaneous ICD recording in secondary prevention recipients (age not reported) in a separate study was 9.9% at 1 year and 15.8% at 3 years.⁹⁹

Postmortem genetic testing to investigate the association between gene variants (genotype) and etiology assessments by autopsy (phenotype) has increased recently for research purposes and to inform family members about potentially inherited disease. Genetic studies of sudden deaths in young adults demonstrate that the genetic yield for pathogenic or likely pathogenic variants in autopsy-confirmed sudden cardiac deaths ranged from 13% to 34% (see eTable 1 in the Supplement).^20,100–103 These yields are obtained after careful etiologic assessment by comprehensive postmortem investigation (including toxicology) for accurate genotype-phenotype correlation.

Sudden arrhythmic death without an apparent cause identified by autopsy is often attributed to arrhythmia syndromes. Of 490 prospectively ascertained sudden cardiac deaths by autopsy in persons aged 1 to 35 years in Australia,²⁰ 113 were adjudicated as sudden arrhythmic death syndrome (ie, normal structural heart) and underwent genetic testing. Clinically relevant pathogenic or likely pathogenic variants in cardiac genes were found in 27%; major associated disorders included LQTS, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and CPVT. Another study of 103 sudden cardiac deaths defined by autopsy in persons aged 1 to 44 years without known CVD referred from 24 US medical examiners’ offices identified pathogenic or likely pathogenic variants associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, LQTS, and arrhythmogenic right ventricular cardiomyopathy in 13%.¹⁰³ However, the total number of eligible sudden deaths was not reported, so it is unclear how this applies to all young adults with sudden cardiac death. A single center prospective study in the UK revealed that among 303 referred family members of individuals who had sudden arrhythmic death syndrome, 128 (42%) were diagnosed with inherited cardiac diseases including Brugada syndrome, LQTS, and dilated cardiomyopathy.¹⁰⁴

Genetic testing of sudden cardiac arrest survivors and additional cardiac screening of family members may detect previously unknown cardiomyopathy, such as dilated cardiomyopathy, hypertrophic cardiomyopathy, or primary arrhythmia syndrome.^64,101,103 In the 2020 Asian Pacific Heart Rhythm Society and Heart Rhythm Society expert consensus statement, genetic testing of survivors is recommended if the results are likely to aid diagnosis, management, or family screening (class I, level B).¹⁰⁵ However, the yield of genetic testing from studies of survivors with clinically unexplained VT/VF targeting arrhythmia and cardiomyopathy genes ranged from 2% to 22%, which is lower than the percentage of pathogenic or likely pathogenic variants in cardiac genes among those who had sudden cardiac death (ie, nonsurvivors).^106–109

In a Canadian study of 63 patients with unexplained cardiac arrest due to VT or VF (although toxicology was not performed), genetic testing of family members (mean age, 30 years) identified causative genetic variants for LQTS, Brugada syndrome, and CPVT in 24%.⁶⁴ If the phenotype in a patient resuscitated after sudden cardiac arrest is established, a recent expert consensus statement¹⁰⁵ recommends genetic testing focused on potential candidate genes and clinical evaluation of family members to identify relatives who have or are at risk of developing the same condition. If the cause of sudden cardiac arrest is not determined, first-degree relatives may undergo clinical evaluation, including ECG, cardiac imaging, ambulatory monitoring, and provocative testing. In addition, psychological evaluation and treatment of grief and posttraumatic stress in survivors and their immediate family members by trained mental health professionals is recommended.¹⁰⁵