The incidence of SCD increases with age in men and women, both white and nonwhite, because the prevalence of ischemic heart disease increases with age. For people under 35, the peak incidences of SCD are between ages 25 and 35 years, if sudden infant death syndrome cases are excluded. For people 35 and older, SCD is most likely to occur between 75 and 85 years. The incidence of SCD is 2.28/100,000 person-years in persons <35, 4.40/100,000 person-years in the 25–35 group, and 100/100,000 person-years in adults older than 35 [5, 17]. However, the proportion of SCD caused by CAD decreased with age from approximately 75 % at ages 35–42 to approximately 50 % at ages 75–84 [16].

Sudden cardiac death is more common among black Americans than white and Hispanic Americans. Hispanic Americans have lower SCD rates than non-Hispanic populations [18]. Moreover, survival rates after in-hospital cardiac arrest are lower for black American patients [19]. A large study in Chicago concluded that the incidence of cardiac arrest was significantly higher for African Americans than for white Americans in every age group [20]. The survival rate after cardiac arrest was 2.6 % in white patients, compared with 0.8 % in black patients. When African Americans had cardiac arrest, the event was significantly less likely to be witnessed than when white or Hispanic patients had cardiac arrest. Likewise, black patients who had SCD were significantly less likely to receive standard-initiated cardiopulmonary resuscitation or have a favorably initial rhythm on admittance to the hospital than white or Hispanic patients with SCD. When black patients were admitted, they were half as likely to survive and had lower rates of postresuscitation care than white patients [19, 20].

The annual incidence of SCD is three to four times higher in men than in women; approximately 75 % of SCDs occur in men. This can be explained by the higher incidence of CAD in men than in women and the protection from atherosclerosis that estrogen gives to premenopausal women. After 20 years of follow-up in the Framingham Heart Study, there was a 3.8-fold excess incidence of SCD in men compared with women. The excess rate in men peaked at 6.75:1 in the 55–64 age group and then fell to 2.17:1 in the 65–74 age group [11].

As discussed earlier, CAD is the most common cause of SCD in Western countries. Approximately 80 % of patients who experience SCD have a history of CAD. Death in this population may occur in the acute ischemia phase or long after a previous MI. In an autopsy-based study of 902 cases of adjudicated unanticipated sudden cardiac death, 79.3 % of SCD victims had underlying cardiac pathology. Coronary artery disease was the cause of 73.2 % of SCD among persons 35 or older and 23.2 % in those under 35 [62].

Coronary artery disease with more than 75 % cross-sectional stenosis is found in 40–86 % of SCD survivors, depending on the age and sex of the study population [2]. Autopsy studies have reported that a recent occlusive coronary thrombus was found in 15–64 % of victims of SCD caused by ischemic heart disease. A study by Roberts and associates [63] found intraluminal thrombi in 29 % of victims of SCD. However, the thrombus was nonocclusive in more than 80 % of this group. In a study of 90 persons who died as a result of SCD, acute MI was present in 21 % and healed MI in 41 %; no MI was observed in 38 % of the examined hearts [64]. Active coronary lesions (plaque rupture or coronary thrombosis) were identified in 57 % of the entire group of sudden coronary death victims. These data suggest that myocardial ischemia is a major cause of SCD in patients with CAD. Evidence of MI on the basis of elevated cardiac enzymes occurs in less than 50 % of patients with VF, and less than 25 % have Q-wave MI [2]. Many factors can play a role in the process of SCD in patients with a history of CAD. The main factors are acute MI, ischemia without infarction, electrical instability, and structural alterations, such as left ventricular dysfunction [34].

Observation during the ambulatory monitoring of victims of SCD with a history of previous MI showed that the most common mode of death was either VF or VT deteriorating to VF. In the prethrombolytic era, the expected mortality during the first 2–5 years after MI was a little greater than 15 % [65], with three quarters of all deaths being arrhythmic and about 70 % of them being witnessed. Studies in the postthrombolytic era have shown that the incidence of cardiac and arrhythmic death after MI have been substantially reduced, with figures of about 5 and 2 %, respectively, at 2.5 years’ follow-up [66, 67]. Data from more recent studies indicate that the incidence of SCD after MI has declined significantly over the past 30 years because of advances in managing acute MI and now is less than 1 % per year among patients who receive standard medical therapy and revascularization [68].

Mapping of ventricular activation during VT [69] showed the presence of fragmented, repetitive, low-voltage electrical activity in the area of abnormal impulse formation covering most of the interval between two successive tachycardia beats. This was initially interpreted as an indication of reentry circuit with a zone of slow conduction [70]. However, it was later shown that although the cells incorporated in the circuit may have a normal intracellular structure with normal electrical properties, they have lost lateral intercellular connections that lead to a long, maze-type circuit, suggesting a marked slowing of conduction velocity in the circuit [71, 72]. Sudden death due to VF is most common in the 6 months after MI. It is independently predicted by LVEF [38, 73], extent of CAD, premature ventricular beats [74], evidence of ischemia during post-MI exercise testing [75], late potentials [76], and decreased heart rate viability [77]. Approximately one-third of SCD survivors were not inducible during EP testing despite aggressive programmed stimulation [78, 79]. This may represent a population in whom ischemia is important as a trigger or to facilitate the induction of reentrant arrhythmias through modulation of the underlying EP substrate [4].

The incidence and importance of bradyarrhythmias as a mechanism of SCD is difficult to assess. Severe bradycardia, asystole, or electromechanical dissociation is generally considered to account for about 25 % of SCD [80]. In patients with advanced heart failure who are scheduled for cardiac transplantation, this percentage may be as high as 62 % [81]. However, these data supporting a bradyarrhythmic origin of SCD were derived primarily from small groups of patients undergoing long-term ECG recordings at the time of death.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiac muscle disorder caused by mutations in genes that affect sarcomeric/myofilament, Z-disc, and calcium-handling proteins [82]. It results in small-vessel disease, myocyte and myofibrillar disorganization, and fibrosis with or without myocardial hypertrophy [83]. These features may result in significant cardiac symptoms and are a potential substrate for arrhythmias. The estimated prevalence of HCM is approximately 1 in 500 [37, 83]. The incidence of SCD associated with HCM has been reported to be 2–4 % per year [84–86]. According to more recent studies, the incidence of SCD is almost 1 % per year among HCM patients [87–89]. The authors attributed previous reported excess mortality rates to selection and referral bias [90]. The incidence of SCD is higher in young patients than in elderly patients with HCM. It is the most common cause of sudden death in competitive athletes younger than 35 years of age (Fig. 24.6) [91].

Since most sudden deaths occur in young asymptomatic or mildly symptomatic individuals, a major focus of managing HCM is identifying people at increased risk for SCD. Despite intense investigation, identifying persons at high risk remains a challenge. The variety and interrelation of mechanisms that can result in SCD represent different aspects of the same phenomenon. Variables that seem to identify patients at increased risk include prior cardiac arrest, spontaneous sustained VT, family history of sudden death, high-risk genotype, multiple repetitive nonsustained VT (NSVT) on ambulatory Holter monitoring or during exercise testing, recurrent syncope, and severe LVH of more than 3 cm [83, 92, 93]. Although the magnitude of the LV outflow gradient was initially considered a risk for sudden death, data have not shown an association [94].

During upright exercise testing, HCM patients commonly show an abnormal blood pressure response, with either a fall or failure of blood pressure to rise. This vascular response is useful in assessing SCD risk predominantly by virtue of a normal test result identifying the low risk young subsets. The absence of an abnormal blood pressure response has a negative predictive value for sudden death, which is 97 % in the young population [83, 95]. This vascular response can be detected in 25 % of HCM patients; thus, its positive predictive accuracy for SCD is low at 15 % [83, 95]. It is a more sensitive indicator of risk in patients younger than 40 years and is associated with sudden death, although the relative risk is low (1.8) [96]. Therefore, a positive result should be used in conjunction with other risk factors.

An angiographic study of children with HCM suggested that myocardial bridging was a significant risk factor for SCD [97]. However, by virtue of having to undergo angiography, these children constituted a highly select group. They were examined retrospectively, making these findings difficult to extrapolate to the general pediatric HCM population. The significance of myocardial bridging and ischemia in initiating secondary arrhythmias remains unknown. However, the available data do not provide sufficient justification for routine angiography.

Other noninvasive electrophysiologic investigations have been used to assess the risk stratification with little success. Furthermore, there is no convincing evidence that EP testing has an important role in identifying patients with hypertrophic cardiomyopathy who are at high risk for sudden death [93].

Some studies [98] have suggested that inducible VT/VF during programmed electrical stimulation in an EP lab in a patient with HCM is associated with a higher risk of cardiac events. However, the response to programmed stimulation is highly dependent on the protocol used. An aggressive protocol using three or more premature stimuli can be expected to produce sustained polymorphic VT in up to 40 % of patients with low predictive accuracy for SCD [99, 100]. Therefore, the hazard and inconvenience of electrophysiologic studies cannot be justified in this population. Available data on genetic markers of SCD in patients with high-risk HCM suggest that β-myosin heavy chain mutations may account for 30–40 % of cases of familial HCM [80, 81, 101]. The prognosis for patients with different myosin mutations varies considerably. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. Nevertheless, the genotype-phenotype relation has to be clarified further to allow proband risk prediction, as the existing data have been elicited from select groups of patients and their families. β-myosin mutations are heterogeneous in their associated levels of risk. The ARG-403GLN, ARG453CYS, and ARG719TRP mutations in the β-myosin heavy chain are associated with a high incidence of SCD, while the VAL606MET mutation appears to carry a better prognosis.

Troponin-T mutations can be exceptionally lethal and appear to be more homogeneous in their high level of risk than prognostic allelic heterogenicity, which characterizes the other sarcomeric gene abnormalities. Troponin-T patients tend to exhibit a mild degree of hypertrophy [102] but with significant myocyte disarray and therefore may be at high risk of SCD without conspicuous evidence of disease.

All HCM patients should undergo a comprehensive assessment of SCD risk factors (Table 24.1) [103]. Implantable cardioverter-defibrillator implantation is the most effective therapy for HCM patients at high risk of SCD. The 2011 ACCF/AHA guidelines state that an ICD is reasonable in patients with family history of SCD, severe LVH, or unexplained syncope and can be useful in individuals with nonsustained ventricular tachycardia (NSVT) or abnormal systolic blood pressure response to exercise (ABPRE) in the presence of other risk factors. Implantable cardioverter-defibrillators D are not recommended in the absence of risk factors, and the benefit of ICD in HCM patients with only NSVT or ABPRE is uncertain [104, 105].

A higher incidence of coronary anomalies has been consistently observed in young victims of sudden death than in adults undergoing routine autopsy (4–15 % in the young vs. 1 % in adults) [106]. Coronary artery anomalies are the second most common underlying pathology associated with SCD among young competitive athletes, accounting for 15–25 % of cases [107]. There is an increased risk of SCD in patients with an anomalous origin of the left main coronary artery from the right (anterior) sinus of Valsalva, with passage of the left main coronary artery between the aorta and the pulmonary trunk. About 75 % of patients reported with this malformation die before age 20, usually during or soon after vigorous exertion [108]. The mirror image coronary anomaly, in which the right coronary artery originates from the left sinus of Valsalva, has also been associated with an increased risk for SCD, although the risk is not as high as the former congenital anomaly [109]. Other unusual variants of coronary artery anomalies, including hypoplasia of the right coronary and the left circumflex arteries [85], the left or right coronary artery originating from the pulmonary trunk, and coronary arterial intussusception that causes coronary lumen occlusion [110], could be rarely associated with SCD. Myocardial bridges have also been associated with SCD during exercise in healthy individuals [111]. It has been suggested that dynamic mechanical obstruction may cause myocardial ischemia. However, evidence that myocardial bridges are responsible for sudden death remains controversial [112]. Coronary dissection with or without aortic dissection occurs in patients with Marfan syndrome [113]. Among other rare mechanical causes of SCD is a rupture of the sinus of Valsalva aneurysm with involvement of the coronary arteries [114]. Prolapse of myxomatous polyps from the aortic valve into coronary arteries has also been reported as a rare cause of SCD [115]. Coronary spasm can cause ischemia and SCD [116]. Vasculitis of coronary arteries, as seen in polyarteritis nodosa, can be associated with SCD [117], and Kawasaki disease can cause SCD through involvement of the coronary arteries [118].

Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by ventricular arrhythmias and specific right ventricular cardiomyopathy that shows fatty infiltration on the right ventricle [119]. The term arrhythmogenic right ventricular dysplasia was first proposed in 1977 by Fontaine and colleagues [119] in a report of six patients with sustained VT who were resistant to medical therapy and did not have overt heart disease. In the three patients who underwent surgery, the right ventricle was dilated and had paradoxical wall motion. Arrhythmogenic right ventricular dysplasia should be considered as a possible differential diagnosis in patients with frequent premature ventricular beats or VT, particularly if the ventricular arrhythmias have a left bundle branch block morphology [120]. It is a rare but important cause of sudden death in young, otherwise healthy populations and an insidious cause of congestive heart failure (CHF) [121].

The estimated prevalence of ARVD in the general population is 1:1,000–1:5,000 and typically occurs in young adults. It affects men more frequently than women, with an approximate ratio of 3:1 [122]. The disease is common in northern Italy, where it has a prevalence of 1 in 1,000 [123]. Arrhythmogenic right ventricular dysplasia is an inherited cardiomyopathy with incomplete penetrance typically caused by mutations in genes encoding elements of the cardiac desmosome [124]. It is an autosomal dominant disease in almost 50 % of cases. An autosomal recessive variant of ARVD that is associated with wooly hair and palmoplantar keratoderma has been reported from the Greek island of Naxos [125].

The most common form of presentation includes ventricular arrhythmias, ranging from symptomatic to asymptomatic isolated ventricular extrasystoles to sustained poorly tolerated VT with left bundle branch morphology. Sudden unexpected death could be the first presentation of the disease [126]. Ventricular fibrillation and SCD may be observed during competitive sports and strenuous exercise [127], but they can also occur at rest or even during sleep [128]. The data suggest that, like other inherited cardiomyopathies, it is one of the major causes of SCD in people <35 years old, accounting for up to 25 % of deaths in young athletes [129–131].

The ECG in sinus rhythm shows changes compatible with right-sided abnormality. The first signs to attract medical attention are repolarization abnormalities in terms of T-wave inversion in precordial leads beyond V₁ and particularly between V₁ and V₃, which are observed in 54 % of cases [123]. Extension of T-wave inversion in all precordial leads had a positive correlation with left ventricular involvement [132]. In patients with suspected ARVD, a QRS duration of more than 110 ms in leads V₁ to V₃ has a sensitivity of 55 % and a specificity of 100 % for this condition [133]. In 25–33 % of ARVD patients, a more specific change with the presence of a discrete just beyond the QRS complex at the beginning of ST segment can be observed during standard ECG evaluation. This deflection has been named the epsilon wave (Fig. 24.7). These waves represent potentials of small amplitude, suggesting delayed ventricular activation of some portion of the right ventricle.

Aortic stenosis was one of the most common noncoronary causes of SCD in the pre–valvular surgery era. However, the risk of sudden cardiac death [134] is less than 1 % per year in patients with asymptomatic aortic stenosis. Both ventricular arrhythmias and bradyarrhythmias have been associated with SCD in this population. The primary cause of ventricular arrhythmia in this population is believed to be subendocardial ischemia due to LVH and high end-diastolic intracavitary pressure. The arrhythmia may be due to atrioventricular block caused by calcium penetration in the conduction system or neurocardiogenic mechanism. Patients with aortic valve replacement remain at some risk for SCD caused by arrhythmias, prosthetic valve dysfunction, or coexistent CAD [135]. Sudden cardiac death has been reported to be the second most common mode of death after valve replacement surgery, with an incidence of 2–4 % over a follow-up period of 7 years, accounting for 21 % of postoperative deaths. The incidence peaked 3 weeks after surgery and then plateaued after 8 months [136].

It is not clear whether mitral valve prolapse can cause SCD. Its prevalence is so high that its presence may be just a coincidental finding in victims of SCD. Severe mitral regurgitation, LV dysfunction, and myxomatous degeneration of the valve can be markers for patients with higher risk for complications such as endocarditis, cerebral embolic events, and SCD [2]. It has been shown that patients who have valvular heart disease may develop bundle branch reentrant tachycardia, particularly after valvular replacement [137, 138]. The arrhythmia usually occurs in the immediate postoperative period and can result in either cardiac arrest or syncope [138]. Almost all VTs occurred within 4 weeks after surgery (median of 10 days). Because of the proximity of the His-Purkinje system, valvular surgery may result in His-Purkinje system conduction abnormalities that facilitate bundle branch reentry.

Dilated cardiomyopathy (DCM) is the most common type of nonischemic cardiomyopathy, and approximately 10 % of SCDs in the adult population occur in patients with DCM [139, 140]. Overall survivor rates after clinical diagnosis have been reported to be 70 % at 1 year and 50 % at 2 years [141, 142]. The annual mortality in DCM has been reported to range from 10 to 50 %, depending on the severity of disease, with up to 28 % of deaths classified as sudden [2, 142]. More recent studies of the DCM patients on optimal medical therapy have reported considerably lower mortality rates of around 7 % at 2 years [143]. Mortality rates increased with higher New York Heart Association (NYHA) class, but the proportion of patients dying suddenly rather than from progressive pump failure is highest among those with less severe heart failure (NYHA class II or III) [144]. Sudden cardiac death accounts for at least 30 % of all deaths in DCM and may occur in patients with advanced as well as mild disease and in those who appear clinically and echocardiographically to have recovered.

In DCM, malignant ventricular arrhythmias are not the only cause of SCD. Reports vary on the extent to which other mechanisms could be responsible for SCD. In advanced forms of DCM, other causes, such as bradyarrhythmias, systemic embolization, pulmonary emboli, or pulseless electrical activity, may account for up to 50 % of cardiac arrests [142, 145]. However, malignant ventricular arrhythmia is the single most common cause of SCD in DCM. Predictors of overall mortality include EF, end-diastolic dimension or volumes, male sex, old age, hyponatremia, persistent third heart sound, sinus tachycardia, elevated pulmonary/capillary wedge pressure, systemic hypertension, and atrial fibrillation [146].

In a study of noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy, Grimm and associates [147] concluded that reduced LVEF and lack of beta-blocker use were important arrhythmia risk predictors in idiopathic DCM, whereas signal averaged ECG, baroreflex sensitivity, heart rate variability, and T-wave alternans do not seem to be helpful for arrhythmia risk stratification. The major shortcoming of EF and other variables that reflect disease severity is the lack of specificity for arrhythmic death.

Other investigators have focused on syncope and ventricular arrhythmia. In a study by Middlekauff and associates [148], the probability of SCD was 45 % among patients with NYHA functional class III to IV who had unexplained syncope in 1 year. This risk factor was specific for SCD and did not predict the risk of dying from progressive heart failure. Nonsustained VT correlates with disease severity and is seen during ECG monitoring in approximately 20 % of asymptomatic or mildly symptomatic patients and in up to 70 % of severely symptomatic patients [149, 150]. Kron and colleagues reported that NSVT was a sensitive (80 %) but not specific (31 %) marker of SCD [149]. A significant association between the presence of couplets, NSVT, or PVCs of more than 1,000 per day and SCD was reported in a study of 74 patients with dilated cardiomyopathy, NYHA class II to III, 12 of who died suddenly [150]. Inducibility of VT during programmed electrical stimulation predicts sudden death [151], but failure to induce VT does not guarantee that the patient will not have an SCD [149]. In a meta-analysis of 6 programmed electrical stimulation (PES) studies, which included a total of 288 DCM patients, PES failed to identify 75 % of patients who died suddenly [152]. The role of microwave T-wave alternans for arrhythmia risk stratification in DCM patients has to be determined. Several studies evaluated its role for risk stratification of SCD. Klingenheben et al. [153] observed 13 arrhythmic events in 107 patients with CHF of mixed pathogenesis, including 40 patients with nonischemic DCM. Of the 13 patients with arrhythmic events during follow-up in this study, 11 had positive T-wave alternans, and 2 had indeterminate T-wave alternans results, although a negative T-wave alternans test predicted freedom of arrhythmic event in all patients. Kitamura et al. [154] investigated 104 patients with DCM and observed major arrhythmic events in 12 of 83 patients (14 %) during a mean follow-up of 21 months after 21 patients with an indeterminate T-wave alternans test had been excluded from the analysis. As a result, Kitamura et al. found that 11 of 12 arrhythmic events occurred in patients with a positive T-wave alternans test, with additional arrhythmia risk for patients with an onset heart rate of T-wave alternans of ≤100 beats per minute (bpm). Finally, Hohnloser et al. [155] found that a positive microvolt T-wave alternans analysis was the only significant arrhythmia risk predictor by multivariate analysis in 137 patients with DCM during mean follow-up of 14 months. In contrast to these studies, the study by Grimm et al. [147] did not find a positive T-wave alternans to be associated with an increased arrhythmia risk in this population, whereas a negative T-wave alternans test showed a trend toward decreased arrhythmia risk by univariate analysis but not by multivariate analysis.

Stable CAD is the leading cause of SCD, even in patient populations that did not have a premorbid diagnosis of CAD [156, 157]. A healed MI has been found in up to 70 % of patients with SCD [158]. The incidence of SCD after MI has decreased during last 30 years and now is less than 1 % per year among patients who receive optimal medical therapy and revascularization [4]. Although there is a strong association between CAD and SCD [159], the role of ischemia in SCD is less clear. The results of pathologic studies of victims of SCD have been mixed [160, 161], with some studies showing that as few as 20 % of victims have acute coronary thrombosis and others showing an incidence greater than 95 %. Stable plaques and chronic changes were observed among 50 % of SCD patients with CAD in autopsy-based studies [64, 162, 163].

Evidence does not suggest a clinical progression of ischemic symptoms before SCD [164], and it has been uncommon for monitored patients to show ischemic changes before VF [165, 166]. Ischemia leads to a cascade of events that include calcium overload, decrease in pH, and inhibition of the sodium-potassium pump, all of which may then lead to triggered activity in the form of delayed afterdepolarizations [167, 168]. Delayed afterdepolarizations are associated with any state of calcium overload and therefore can trigger VF [169].

Transient ischemia in the setting of a previous myocardial scar is extremely arrhythmogenic and could account in part for the low incidence of acute coronary occlusion in some studies [170]. Alternatively, spontaneous thrombolysis may explain the lower incidence of acute thrombosis [13].

Hypertrophic cardiomyopathy (HCM) is the most common cause of SCD in young athletes [125]. The incidence of SCD in people with HCM is approximately 1 % per year [89]. Most people who die from SCD caused by HCM had no symptoms before death. Deaths caused by HCM usually occur during start-stop sports like soccer and football and rarely occur during endurance events, such as long-distance cycling and running [171]. Although there is a correlation between the degree of hypertrophy and the incidence of SCD, the actual mechanism leading to SCD has not been clearly established. There is no clear association between diminished LV filling, LV noncompliance, or outflow tract gradients and SCD [172, 173]. Patients with SCD and HCM have a higher incidence of myofibrillar disarray than patients with HCM who die of heart failure [174]. It is thought that such disarray increases anisotropic conduction and acts as the substrate for microreentrant circuits and VF [175]. Recent studies suggested that ventricular tachyarrhythmia and/or VT is the most probable mechanism of SCD in HCM [176, 177].

Patients with CHF have up to a ninefold increase in the risk of SCD compared to the general population [178]. Prolongation of the action potential duration (APD) is a uniform finding in failing hearts [179]. This is in part due to the down regulation in potassium channels, which leads to APD prolongation by delaying the repolarization phase of the action potential (AP) [180, 181]. Furthermore, this change in APD is not uniform throughout the myocardium [182]. The role of APD prolongation in the onset of VF has not been clearly defined, but the extent to which dispersion of repolarization accompanies such changes may be a determining factor [53].

Changes in calcium homeostasis may also play a role in SCD [53]. The calcium channels show a slower rate of decay [183], and the calcium transient’s amplitude is decreased [184]. However, these changes are also nonuniform [185], thus raising the possibility that further perturbations in AP dynamics are created [186].

Slowed conduction and poor electrical coupling have been shown consistently in patients with CHF [187]. These factors facilitate reentry and increase the likelihood of SCD. Conduction velocity is associated with sodium channel current, and the levels of these currents have been found to be attenuated in heart failure [188, 189]. Fibrosis leads to the same findings and is associated with a decreased safety factor for propagation [190]. If conduction fails (blocks), one of the criteria for initiation of reentry has been satisfied. This also predisposes the heart to reentrant ventricular arrhythmias.

Finally, neurohumoral factors may play a role in the onset of ventricular arrhythmias [191]. Activation of the renin-angiotensin-aldosterone system is well documented in these patients, and the blockade of these systems has been shown to decrease overall mortality and SCD [192, 193]. The failing heart has heterogeneities of sympathetic innervation that are thought to be Arrhythmogenic [194, 195].

Ventricular fibrillation is the most common cause of SCD. It is the first rhythm documented in approximately 75 % of patients with cardiac arrest [196]. However, it is most likely that the actual dysrhythmia originates as ventricular tachycardia that subsequently degenerates into VF. A study of 157 patients with ambulatory Holter monitors during cardiac arrest found this to be the case in 62 % of patients [197]. Ventricular fibrillation without antecedent VT occurred in only 8 % of cases.

Bradycardia is not thought to be as common an initiating rhythm of SCD as ventricular arrhythmias [198], although it appears to be the presenting dysrhythmia in patients with more advanced heart failure more often [199]. Bradyarrhythmia and asystole account for 10 % of SCD cases [200]. The role of pulseless electrical activity (PEA) or asystole is more prominent in SCD in people older than 65 [201]. Bradyarrhythmia is more often seen with a nonischemic cardiomyopathy, but asystole or PEA is commonly associated with pulmonary embolism [202].

After coronary occlusion, there are two peaks in the acute incidence of ventricular arrhythmias [203]. The first occurs 10 min before occlusion and the second at 15–20 min after occlusion. These are typically polymorphic VT, presumably due to the acute ischemia-induced derangements in membrane depolarization, repolarization, and refractoriness.

Subsequently, VF can occur within the first 4 days after infarction. These are usually initiated by PVCs, the mechanism of which is thought to be abnormal automaticity [204]. The macroreentrant circuits leading to monomorphic VT evolve during chronic stages after the myocardium has healed and scar tissue has developed [64].

The GUSTO-1 trial showed that the overall incidence of VT or VF was 10.2 % (VF: 4.1 %, VT: 3.5 %, both VT and VF: 2.7 %) among patients with acute ST elevation MI and approximately 80 % of them occurred within 2 days after acute MI [205]. In another study, the overall incidence of VT or VF was reported as 2.1 % (VF: 1 %, VT: 0.8 %, both VT and VF: 0.3 %) after non-ST elevation acute coronary syndrome. The median time of arrhythmia occurrence was 78 h [206].

An ECG is helpful in diagnosing underlying CAD and MI. Furthermore, it provides other helpful markers, such as QT interval (prolonged QT interval in acquired and congenital LQTS, short QT interval in short QT syndrome), delta wave (a clue to Wolf-Parkinson-White syndrome), epsilon wave (in ARVD), and right bundle branch block and ST segment elevation in V₁ to V₃ (in Brugada syndrome). An ECG is also a specific but insensitive tool with which to evaluate LVH.

Echocardiography provides information regarding LVEF, one of the most powerful predictors of recurrent cardiac arrest [209]. Left ventricular ejection fraction is an independent predictor of death. An LVEF ≤0.40 indicates an increased risk of death by at least three- to fourfold [210].

However, when the LVEF is severely depressed (≤15–20 %), the prevailing mode of cardiac death is not sudden. When it is sudden, it is often related to bradyarrhythmias or electromechanical dissociation rather than ventricular tachyarrhythmias. The meta-analysis of pooled data from the European Myocardial Infarction Amiodarone Trial (EMIAT), the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), Survival with Oral d-Sotalol (SWORD), Trandolapril Cardiac Evaluation (TRACE), and the Danish Investigations of Arrhythmia and Mortality on Dofetilide study group (DIAMOND) assessed the risk of death in patients who survived at least 45 days after MI [211]. The prognostic value of EF was adjusted for treatment and other demographic factors associated with survival. The meta-analysis confirmed that LVEF significantly predicted 2-year, all-cause arrhythmic and cardiac mortality. A 10 % absolute increase in EF reduced the mortality at 2 years with a hazard ratio of 0.61. The EF is usually combined with other risk factors. While it is unclear which combination of noninvasive variables provides the strongest risk prediction in the current thrombolytic era, combining the variables that reflect different factors linked to SCD is logical. These factors could include the substrate (EF), the trigger (ventricular premature beats, NSVT), or the modulator (autonomic dysfunction).

As discussed earlier, the ATRAMI investigators showed that a combination of low values of autonomic markers and reduced EF identified a group of post-MI patients at highest risk for sudden death. The results from another study [212] confirmed prethrombolytic era findings [213] that echocardiographic LV end-systolic and end-diastolic volumes were strong predictors of mortality at 6 months after acute MI. Echocardiography can also be used to evaluate segmental wall motion abnormalities associated with CAD, significant valvular dysfunction, evidence of hypertrophic cardiomyopathy, pericardial disease, intracardiac tumors, and congenital heart disease. The presence of LV dysfunction precludes the use of certain antiarrhythmic agents that can produce a negative inotropic effect or a proarrhythmic event.

Exercise stress testing is a recognized prognostic test in survivors of acute MI. Several studies have shown that the presence of ST segment changes, the occurrence of exercise-induced angina, inappropriate blood pressure response, and exercise-induced ventricular arrhythmia in post-MI patients during submaximal predischarge stress testing are predictors of recurrent ischemic events, the need for revascularization, and overall cardiac mortality rates. Several authors have reported that these findings are predictive of ventricular arrhythmia and sudden death [213–216]. However, other investigators have not found exercise test results to specifically predict the risk of SCD [75, 217, 218]. Exercise testing also helps identify patients with exercise-induced or exercise-aggravated ventricular tachycardia [219–221]. Stress testing is most commonly used as a noninvasive test to evaluate the presence of CAD in patients with chest pain. The sensitivity and the specificity of stress tests improve when the tests are combined with nuclear methods.

Radionuclide angiography is another noninvasive method that can be used to quantitatively assess LV function. It can also provide information regarding regional LV performance and myocardial viability.

Magnetic resonance imaging can provide information about myocardial viability, LV function, and LV end-diastolic and end-systolic volumes. Furthermore, as discussed earlier, MRI can be a useful tool for evaluating patients with suspected ARVD.

The role of Holter monitoring in the evaluation of patients with arrhythmias has been the subject of multiple studies, particularly those of MI patients. Several studies confirmed the prognostic significance of frequent premature ventricular complexes and NSVT in post-MI patients [222, 223]. However, the specificity of a spontaneous ventricular ectopy is limited [224].

Mortality rates are not influenced by the frequency, duration, or rate of NSVT [222, 223]. However, all of the above-mentioned studies were performed in the prethrombolytic era. In the thrombolytic era, the risk associated with the presence of NSVT is currently unknown. The GISSI-II study investigators reported that the prevalence of NSVT was only 6.8 % and its presence was not predictive of SCD at 6 months after MI [225]. In another study, there was a low prevalence (9 %) of NSVT shortly after acute MI. At multivariate analysis, NSVT was not an independent predictor of SCD, unlike heart rate variability, EF, or status of the infarct artery. More recent data from primary prevention of SCD by prophylactic ICD implantation have shown that the combination of NSVT with other variables, including reduced EF and electrophysiologic testing after acute MI, was effective in identifying post-MI patients at high risk of arrhythmic death.

Low-amplitude, fragmented, and delayed electrical activity can be recorded from areas bordering the infarction in an experimental model of MI. The signal-averaged ECG (SAECG) records this delayed fractionated activity from the body surface. A number of studies have evaluated the prognostic significance of this SAECG alone or in combination with Holter monitoring or LVEF in the post-MI population [66, 76, 226, 227]. In these studies, the sensitivity during a follow-up period of 6–24 months in patients who experienced sustained VT or SCD was between 50 and 90 %. Its primary benefit was its excellent negative predictive value, reported to be about 95 %. However, the positive predictive value of SAECG (the risk of arrhythmia in a patient with positive results) has been lower, averaging 20 % in these studies.

Kuchar and colleagues [227] risk-stratified patients after an acute MI by using SAECG, Holter monitoring, and radionuclide ventriculography. The patients were followed for a median of 14 months for an arrhythmic event, defined as sudden death or sustained VT. The results of each of these three tests were independently predictive of arrhythmic events. An LVEF <40 % was the most powerful predictor of an arrhythmic event. Adding a positive SAECG to the LVEF further increased the probability of predicting an event (from 4 % for LVEF of <40 % alone to 34 % with LVEF <40 % plus a positive SAECG). An SAECG is more predictive of arrhythmic events in inferior infarction and is less useful in anterior infarctions. This difference is probably due to the fact that the peri-infarct tissue in anterior infarction is activated relatively early in the sequence of ventricular activation, which makes detecting late potentials difficult.

A meta-analysis of all available prospective studies during the prethrombolytic era on the use of SAECG after MI showed that the SAECG predicted a sixfold increase in risk of arrhythmic events independent of LV function and an eightfold increase in risk of arrhythmic events independent of Holter results [228]. Beta blockers and successful thrombolysis/revascularization reduce the frequency of late potentials after acute MI and significantly diminish the prognostic power of SAECG [229, 230]. Some studies supported the concept that SAECG is an independent predictor of arrhythmic events after MI [230, 231]. The CARISMA study showed that a filtered QRS duration in the SAECG ≥120 ms predicted VF or symptomatic sustained VT after acute MI [232].

Heart rate viability (HRV) is a measure of beat-to-beat variation of sinus-initiated RR intervals. It has been evaluated as an indicator of decreased parasympathetic tone, which is associated with poor prognosis in post-MI patients. Schneider and Costiloe [233] evaluated the relationship between sinus arrhythmia and prognosis after MI and concluded that sinus arrhythmia decreases in normal patients with age, that sinus arrhythmia is less evident after MI, and that patients with the least evidence of sinus arrhythmia had the worst prognosis during follow-up.

Kleiger and colleagues [234] examined the relationship between increased mortality rates and decreased heart rate viability in a study of 808 post-MI patients. They showed that HRV has a significant relation with other prognostic indicators, relating directly to LVEF and exercise capacity. However, HRV correlated to a much lower degree with ventricular ectopy, suggesting that these two factors acted independently. Farrell and associates [235] observed that the sensitivity of HRV in predicting arrhythmic events (sudden death and sustained VT) was higher than that of other risk factors, including exercise testing, LVEF, ventricular ectopy, and SAECG. In the analysis of a combination of risk factors, the combination of decreased HRV and the presence of late potentials in SAECG was more predictive of arrhythmic events than other combinations. The decrease in HRV suggests a relative decrease in parasympathetic tone [236]. Another possible explanation is that increased vagal tone protects against VF in the presence of ischemia.

As we discussed earlier, the ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) investigators [60] studied HRV and baroreceptor sensitivity on 1,284 patients in the first month after MI. They concluded that these variables were significant predictors of cardiac mortality. They showed that, during 21 months of follow-up, depressed HRV and baroreceptor sensitivity carried a significant multivariate risk of cardiac mortality of 3.2 and 2.8, respectively. The combination of low HRV and depressed baroreceptor sensitivity further increased the risk. One-year mortality increased from 1 % when both markers were well preserved to 15 % when both were depressed. Furthermore, the investigators showed that the predictive power of baroreceptor sensitivity declined much more markedly than HRV in patients older than 65. The ATRAMI investigators have shown that after MI, the analysis of the autonomic markers has significant prognostic value independent of established clinical predictors, such as EF and ventricular arrhythmias. Furthermore, the combination of low values of autonomic markers and reduced EF identifies a group of post-MI patients at high risk for SCD.

Huikuri and his team [237] showed that HRV and heart rate turbulence increased over time after MI in the CARISMA and REFINE studies and attenuated recovery of autonomic function after MI was associated with a 9.4-fold higher risk of ECG-documented sustained VT or VF in CARISMA and a 7.0-fold higher risk of fatal or near-fatal events in REFINE.

Cardiac catheterization should be performed in almost all survivors of SCD to establish the presence, extent, and severity of CAD. It can also exclude congenital coronary vessel anomalies in younger SCD survivors. Cardiac catheterization can confirm the results of noninvasive studies for evaluation of LV function, wall motion abnormalities, and valvular disease.

Wellens and colleagues [238] showed that programmed stimulation could safely and reproducibly initiate VT in most patients who experienced sustained VT. Subsequent studies confirmed this observation. Between 60 and 90 % of patients who survive sudden death unassociated with acute MI are inducible during EP study [225, 238–240]. Sustained monomorphic VT can be induced during EP study in 50–60 % of cardiac arrest survivors, and polymorphic VT or VF can be induced in an additional 10–20 % [241–243]. However, in the thrombolytic era, EP testing for risk stratification of patients has progressively lost favor. Nearly half of all reported trials found inducibility of sustained VT during programmed stimulation unable to predict later mortality or arrhythmic events [244]. Many post-MI patients with SCD have negative predischarge electrophysiologic tests, resulting in a low negative predictive accuracy [245]. Furthermore, when used alone, EF is superior to EP testing in predicting arrhythmic events after acute MI [246]. Therefore, a 2-step strategy using EF ≤40 % and ventricular arrhythmias on Holter monitoring and then electrophysiologic testing significantly improved the positive predictive accuracy of risk stratification process but only to a moderate level of 18.2 % [247].

Moreover, evidence from primary prevention trials (Multicenter Automatic Defibrillator Implantation Trial [MADIT] and Multicenter UnSustained Tachycardia Trial [MUSTT]) confirmed that a 2-step risk stratification procedure using reduced EF and nonsustained VT followed by EP testing was helpful in selecting a high-risk subgroup of patients who benefited from prophylactic ICD implantation for the primary prevention of SCD. However, the precise value of VT inducibility is uncertain. Data from the MADIT-II trial showed that EP testing had moderate predictive value for the occurrence of monomorphic VT, but incidence of VT and VF were not significantly different between inducible and noninducible patients in 2-year post-MI follow-up [248].

Microvolt T-wave alternans (TWA) is beat-to-beat variability in the T wave [249]. Its precise mechanism remains unclear, but one proposed mechanism is beat-to-beat changes in the intracellular levels of Ca²⁺. The beat-to-beat variability in intracellular Ca²⁺ leads to modulation of repolarization currents, which may contribute to TWA [250]. Metabolic disturbances during ischemia lead to microvolt TWA [251]. T-wave alternans is thought to contribute to induction of malignant arrhythmias by leading to dispersion of refractoriness [252]. This in turn can lead to functional block and induction of reentrant arrhythmias.

Using the spectral method and sophisticated signal-processing techniques, microvolt TWA is analyzed during standard stress exercise protocols, treadmill stress echocardiography, pharmacologic stress testing, or atrial pacing in the electrophysiology lab [253]. A positive test is the presence of significant sustained alternans measured in any three orthogonal leads or two adjacent precordial leads. It should be present for at least 1 min with an onset at a HR >110 bpm [253]. Microvolt TWA testing is a reliable marker for late post-MI risk stratification, but there is some controversy about its accuracy in patients with recent infarction [254–258]. In patients with idiopathic dilated cardiomyopathy, it has shown promise as a clinically important risk stratifier [253]. Despite promising results in previous studies, data from more recent studies failed to prove reliability of microvolt TWA as a predictor of serious arrhythmic events [259]. There are only limited data for microvolt TWA testing in patients with hypertrophic cardiomyopathy or the inherited arrhythmic disorders.