Seventy to eighty percent of SCA is attributed to ischemic heart disease and in up to half of cases, SCA is the initial presentation of underlying coronary disease. Autopsy findings reveal a high incidence of multivessel disease. In those with myocardial scar
but no evidence of acute infarction, half will have active coronary lesions. Coronary revascularisation, secondary prevention medical therapy, and optimal treatment of heart failure all reduce SCA events in patients with ischemic heart disease, but are not the focus of this chapter. A brief description of some of the less common causes of SCA follows.

Structural heart disease, such as nonischemic dilated cardiomyopathy (DCM), accounts for 15% to 20% of SCA. DCM may be idiopathic, inherited, or due to one of many secondary causes, including infection, endocrine disorders, long-standing tachycardia, rheumatologic disorders, and nutritional deficiencies. Left-ventricular noncompaction may also present with a decreased ejection fraction and is associated with an increased risk of SCA. The risk of SCA increases with worsening LV function. Certain genetic causes of cardiomyopathy (e.g., laminopathy) have also been particularly associated with an increased risk of arrhythmia and may be collectively termed “arrhythmic cardiomyopathies.” Optimal medical therapy for heart failure will reduce the chance of SCA in some patients. Device therapy both in the form of implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy (CRT), for those eligible, also reduces sudden death in nonischemic cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by ventricular arrhythmias with exercise and right ventricular dilatation due to fibro fatty infiltration and progressive myocardial thinning. The underlying pathology is impaired cell-cell adhesion between cardiomyocytes due to mutations in genes encoding components of the cardiac desmosome. SCA, syncope, or palpitations attributed to ventricular tachycardia may be the presenting event. A diagnosis of ARVC requires evidence of mechanical and/or electrical signs of the disease. A combination of noninvasive imaging abnormalities, electrocardiographic conduction and repolarization abnormalities, and observed arrhythmias as well as family background, genetics, and histopathology form the internationally recognised Task Force Criteria scoring system for the diagnosis of ARVC. Poor prognostic signs include prior syncope or cardiac arrest, evidence of significant left or right ventricular systolic impairment, or symptomatic heart failure. Genetic features that may increase the risk of arrhythmic events include multiple mutations and autosomal recessive forms. Mutations in the TMEM43 gene (ARVC5) are associated with higher risk than other ARVC genotypes. Male gender and diagnosis at a younger age are also associated with an increased risk of sudden death. Beta-blockers are recommended as secondary prevention in those with symptomatic arrhythmias and sotalol may be used when standard β-blockers are insufficient. All cardiac arrest survivors with ARVC should receive an ICD. Adjunctive ablation of ventricular tachycardia (VT) circuits can reduce future shocks but does not eliminate the need for an ICD. Exercise may be the trigger for arrhythmic events and evidence suggests that increased lifetime exercise exposure worsens the ARVC phenotype in gene-positive individuals. Therefore, patients are advised to avoid strenuous endurance exercise, although these recommendations must always follow a full discussion with the patient.

Hypertrophic cardiomyopathy (HCM) is a genetic defect of the cardiac sarcomere resulting in marked hypertrophy of the left ventricle. This population carries a well-defined risk of SCA, with an annual rate as high as 4%, depending on the patient’s risk profile. An individual’s risk is affected by several variables. Agreed markers of poor prognosis include increasing septal wall thickness and associated outflow tract gradient, prior syncope or cardiac arrest, and documented nonsustained VT. A family history of SCA due to HCM has a moderate impact on prognosis. These and other risk factors have been incorporated into an SCD risk calculator that is recommended in the European HCM guidelines. Alternatively, the American Heart Association state that ICD implantation is reasonable or may be considered in the presence of a single major risk factor. Management of HCM is complex and beyond the remit of this chapter. It is recommended that those at risk of SCD have an ICD implanted.

The long QT syndrome (LQTS) is the most common ion channelopathy diagnosed in cardiac arrest survivors. A deficiency in net repolarizing currents causes prolongation of the cardiomyocyte action potential. This in turn leads to the hallmark features of prolongation of the QT interval and polymorphic ventricular tachycardia (torsades de pointes). Although the diagnosis is primarily based upon a prolonged QTc interval on the resting electrocardiogram (ECG), significant overlap exists between resting QTc measurements in the general population and in those with LQTS. Therefore a scoring system, taking in to account clinical and family background, documented arrhythmia, T-wave morphology and QT response to exercise (the modified Schwartz score) can be used to aid diagnosis of LQTS. Alternatively, the diagnosis can be made when an unequivocally pathogenic genetic variant is identified. Genetic testing is positive in around 75% of LQTS patients. The majority of cases are LQTS type 1 (LQTS1), due to loss-of-function mutations in the KCNQ1 gene, and clinically associated with cardiac arrests triggered by exercise, particularly swimming. LQT2 and LQT3 (KCNH2 and SCN5A genes, respectively) are associated with cardiac arrests at night or, in LQTS 2, with sudden auditory stimuli. LQT3 is associated with a higher risk of sudden death than LQT1 or LQT2. Additional risk factors include increased QTc duration, infero-lateral early repolarization on the resting ECG, multiple mutations or homozygous carrier state, presentation at a young age, and ongoing symptoms despite treatment. Age and sex also have an effect: prepubertal males with LQT1 and postpubertal females with LQT2 appear to be at higher risk.

Treatment of a cardiac arrest survivor diagnosed with LQTS comprises lifestyle advice, medical therapy, and ICD implantation. All patients should avoid drugs known to cause QT prolongation (www.crediblemeds.org) and should be aware of, and correct, possible causes of electrolyte disturbance such as gastrointestinal disturbance. Historical guidance has been to avoid sporting activity, particularly in LQT1; however, recent data suggest that event rates in those who continue to compete may be lower than previously expected. Patients are advised to discuss sports participation with their care team that should ideally be experienced in managing such cases. It may be recommended to continue unless a specific risk has been identified in an individual patient while on optimal therapy. Beta-blockers are the first-line treatment and are almost universally indicated, particularly in those with prior cardiac arrest. There is evidence that nadolol has superior efficacy but due to the limited availability in some
countries, propranolol may be used as an alternative and is preferred over atenolol or metoprolol. Individuals who suffer recurrent events despite β-blockers may be considered for an ICD and may potentially require left cardiac sympathetic denervation (LCSD).

Brugada syndrome (BrS) is estimated to be responsible for 4% of sudden deaths. There is no precise data on the prevalence of BrS although it is highest in South East Asia where an estimated 1:2,000 individuals are affected. The majority of sudden death victims are males aged 30 to 50 years and events typically occur during sleep, where vagal tone is thought to play a pathogenic role. The underlying mechanisms in BrS are not fully understood. It is agreed that abnormalities of the right ventricular outflow tract (RVOT) are responsible both for the characteristic ECG changes and the development of polymorphic VT or ventricular fibrillation (VF); however, there is much debate as to the relative roles of depolarization and repolarization abnormalities. Evidence is also emerging of a subtle cardiomyopathic process with fibrosis of the epicardial RVOT in some cases. BrS is diagnosed by the presence of a specific ECG pattern: The “type 1 Brugada pattern” is discussed in detail below. Established risk factors for SCD include prior arrhythmic syncope and the presence of a spontaneous type 1 Brugada ECG pattern (i.e., not induced by class 1 sodium channel blocking drugs or a fever). Family history of sudden death has been shown not to be relevant. There has been much debate on the prognostic role of programmed ventricular stimulation with recent evidence suggesting it may have a modest role in asymptomatic individuals with a spontaneous type 1 pattern. Other minor risk factors may include fragmentation of the surface QRS complex, the inferolateral ER pattern, and a ventricular effective refractory period ≤200 ms.

Mutations in the sodium channel gene SCN5A account for the vast majority of gene-positive cases. However, the yield of a positive finding is currently only 25% and further causative genes continue to be identified. ICD implantation is the only proven intervention for prevention of sudden death in BrS and should be offered to all cardiac arrest survivors. Quinidine can be used for those who receive ICD shocks although its use is often limited by availability in many countries, and patients may experience gastrointestinal side effects. Epicardial ablation of the RVOT has shown promise as a therapy for those with recurrent ICD shocks but is not yet widely undertaken. In the setting of VT/VF storms due to BrS, isoproterenol effectively suppresses ventricular arrhythmias.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare ion channelopathy (estimated prevalence ˜1:10,000) characterized by syncope, cardiac arrest, or sudden death during physical exertion in the context of a structurally normal heart and normal resting ECG. It typically presents during childhood and VF is the first presentation in as many as 30% of cases. The pathognomonic feature is bidirectional during exercise; however, premature ventricular contractions (PVCs) and polymorphic VT can also be seen. In survivors of unexplained cardiac arrest, epinephrine infusion may be used as a provocative test where exercise testing is not possible (discussed below).

CPVT is caused by excess calcium release within the cardiomyocyte in response to catecholamine release. The majority of gene-positive cases (yield of genetic testing up to 65%) are due to mutations in RYR2 that encodes the ryanodine receptor, integral
to calcium-mediated-calcium-release in the cardiomyocyte, and show an autosomal dominant pattern of inheritance.

Cardiac arrest survivors diagnosed with CPVT should receive an ICD and be initiated on β-blockers, with nadolol showing superior efficacy. Adjunctive therapy with flecainide may be considered. Left cardiac sympathetic denervation (LCSD) reduces events in patients who remain symptomatic despite β-blockers although the number of patients with long-term follow-up is small. All patients with CPVT should be counselled regarding avoiding competitive sport and strenuous exercise and limiting exposure to stressful environments.

The early repolarization (ER) pattern was described as an electrocardiographic entity more than 50 years ago, and was originally thought to be entirely benign. Recent evidence, however, has shown that ER is more common in survivors of otherwise unexplained VF. ER is defined as ≥0.1 mV J-point elevation in at least two inferior leads (II, III, aVF), lateral leads (I, aVL, V_4-6), or both. ER in the inferior leads, associated with a horizontal ST segment and of higher amplitude, is associated with a higher risk of VF. There may be further augmentation of the J-point elevation immediately preceding VF.

Diagnosis of early repolarization syndrome (ERS) can be made when the ER pattern is present on the ECG of a cardiac arrest survivor in the absence of an alternative cause. However, the high prevalence of the ER pattern in the general population (5% in middle-aged individuals and up to 20% in athletic young adults) warrants caution when making the diagnosis. ER has also been shown to be associated with a higher risk of sudden death when seen in patients with other cardiac conditions including acute coronary syndrome, LQTS and BrS. The underlying pathophysiology remains incompletely understood but may be related to differential repolarizing currents between the endo- and epicardium. While some familial cases have been reported, a reliable genetic locus has not yet been identified.

Cardiac arrest survivors diagnosed with ERS should receive an ICD. Quinidine may be useful in those with recurrent episodes of VF and may reduce or eliminate the ER pattern on the resting ECG.

Short QT syndrome (SQTS) is a very rare cause of SCA associated with a short QT interval on the resting ECG. There is some debate among experts as to the absolute limit that should be considered diagnostic due principally to the very small numbers of cases upon which to base recommendations. The most recent expert consensus suggests that a QTc ≤330 ms is diagnostic. Gain of function mutations in potassium channel genes account for up to 20% of index cases of SQTS. ICD implantation is recommended for those who have survived a cardiac arrest and quinidine may also be beneficial. Class III anti-arrhythmics including sotalol do not prolong the QT interval in SQTS.

The role of premature ventricular contractions (PVCs), originating from the Purkinje network, in triggering VF was first described in 2002. Short-coupled VF (SC-VF) is
diagnosed in cardiac arrest survivors when VF is seen to be initiated by single PVCs occurring early after the preceding QRS, and no other phenotype can be identified despite systematic investigation. It has previously been called idiopathic VF, but the authors believe this label should be avoided due to confusion with unexplained cardiac arrest. The underlying pathophysiology remains unclear, although the transient outward current (I_to) is thought to play a role. Mutations in DPP6, which binds K⁺ channels involved in I_to have been identified in familial cases in the Netherlands. SCN5A mutations have also been reported in familial cases. Treatment aims to suppress ventricular ectopy. Quinidine has shown to be effective while catheter ablation can be considered in cases with a single, reproducible PVC. Neither of these treatments precludes the need for an ICD in cardiac arrest survivors, however.

Other causes of SCA include congenital heart disease, anomalous coronary arteries, and valvular heart disease. The management of such patients focuses on management of the underlying pathology and so they are not covered in detail here. In the absence of coronary artery disease or LV dysfunction, no cause can be found in approximately half of SCA survivors. Recurrence rates remain high in unexplained cardiac arrest (UCA) survivors and long-term follow-up is recommended as a definitive phenotype may present even years after the initial event.