SD is a natural phenomenon interrupting life instantaneously. The widely accepted definition is a death occurring unexpectedly, within 1 h from the onset of symptoms, in healthy even vigorous people or in people whose preexisting morbid conditions did not foresee such an abrupt outcome [1–18]. This temporal definition refers to witnessed SD, whereas it should be extended to 24 h for unwitnessed SD victims known to be alive and healthy one day prior to being found dead [3–7]. Since up to one third of SDs are unwitnessed, exclusion of these SDs would seriously bias a study by underrepresenting this quote. In nearly two third of cases, SD is the first cardiac event, whereas in one third it is predictable because the patient is at high risk. SD which takes place in the hospital has to be excluded, whereas that occurring in the emergency room is included.

SD may occur along with all the human life, even in prenatal time: up to 50 % of stillborn die suddenly in utero (sudden intrauterine unexplained death, i.e., SIUD, or stillbirth) [19]. Sudden unexpected infant death (SUID) affects infants with an incidence up to 1.5 % and may find an explanation at autopsy in unrecognized malformations, infections, or, not so rarely, following abuse [20]. Within SUID group, sudden infant death syndrome (SIDS) refers to SUID babies, 1–12 months old, found dead (“cot death”), in whom a cause is not discovered at autopsy. Nowadays, the incidence of SIDS varies from 0.3 to 1 % and is declining, following preventive measure with the supine position while sleeping.

A recent systematic review of the publications dealing with the incidence of cardiac SD the United States clearly showed that very few studies have reported estimates from primary sources of data and that the stated definitions of cardiac SD and cardiac arrest are not standardized across the medical community [11].

In adolescents and young adults (<35 years) the incidence varies from 0.5 to 8/100,000/year in the reported epidemiological studies, and cardiomyopathies, myocarditis, premature coronary artery disease, congenital coronary artery anomalies, and channelopathies play a major causative role (Fig. 2.1) [2, 6–9, 21–23].

We carried out a prospective study in the Veneto Region, Northeast Italy, which holds a mean 4,379,900 overall population. Young population (12–35 years old) was 1,386,650 and young athletes 112,790, according to Italian Census Bureau & Sports Medicine database 1978–1999 [24]. The cumulative incidence of SD was 1/100,000/year. Among the non-athletic young people the incidence was 0.9/100,000/year, whereas in the athlete it was 2.3/100,000/year. Thus, the incidence of SD in athletes was 2.5-fold, clearly indicating that effort is at risk in people affected by hidden morbid entities, simply by unmasking them.

With age, the incidence of SD in general population is increasing, mostly due to coronary atherosclerosis but also to degenerative valve disease, like mitral valve prolapse and aortic stenosis [6–8]. However, coronary atherosclerosis may account for premature SD as early as at 25 years of age [25–28].

In the general population, SD may reach an incidence of 1 per 1000/year in the age interval 35–40 years, and 2 per 1000/year by 60 years [3, 8].

In the elderly (>60 years), SD is the mode of death in 25 % of cases, with an incidence up to 10–25 per 100/year in people affected by advanced ischemic heart disease. The incidence of SD increases dramatically as a function of advancing life, in parallel with the age-related increase of total coronary heart disease deaths. Overall, incidence of SD is 1 per 1000/year during the first year of life, 0.01 per 1000/year in adolescents and young adults (<35 years), 2 per 1000/year in adults, and 200 per 1000/year in the elderly.

There are two ages of peak of incidence of postnatal SD, one between 1 and 12 months (SUID and SIDS) and another over 45 years [8].

Nearly 50 % of all coronary heart disease deaths are sudden – unexpected and in two third SD is the first coronary event [6]. Half occurs out of the hospital or in emergency room and nearly 50 % of them have prior myocardial infarction. Diffuse obstructive coronary atherosclerosis and scars following previous myocardial infarction are the usual arrhythmogenic substrates found at autopsy. Coronary artery disease is the dominant cause of SD in the adult–elderly population (up to 80 %) [3–18].

The risk of coronary SD is 4–7 times greater in males compared to females in the young adult – middle-age population, because of the hormonal protection in females [3, 28, 29]. This does not exclude that classical coronary risk factors are predictor of events even in female (cigarette smoking, obesity, diabetes, hypertension, oral contraceptives) [6]. Smoking is the most important risk factor for SD even in women. Blood pressure levels and left ventricular hypertrophy have been also associated with a higher risk of SD [3].

Of course, the distribution of SD risk varies according to clinical and population profiles. The overall estimated incidence in the population is 0.1–0.2 % year, with total events of 300,000–350,000 deaths per year in the United States [10, 15] and nearly 50,000–60,000 deaths per year in Italy. Overall, event rates in Europe are similar to those in the United States [4], with significant geographic variations reported.

Obviously, the risk increases in higher-risk subgroups. For instance, the SD incidence is 1–2 %/year in people with coronary risk profile, 5 %/year in those with a prior coronary event, 15 %/year in those with congestive heart failure and ejection fraction (EF) <35 %, 25 %/year in cardiac arrest survivors. Combination of prior myocardial infarction, low EF, and ventricular tachycardia accounts for a risk of nearly 35 %/year [7] (Figs. 2.2 and 2.3).

These figures are now influenced by the benefit of drug (ß-blockers, amiodarone) and especially by implantable cardioverter defibrillator (ICD), according to evidence-based risk stratification.

However, nearly two third of SDs occur as the first clinical manifestation or, in the setting of known cardiac disease, in the absence of risk predictors. The cause is acute coronary thrombosis which precipitates upon nonobstructive, unstable atherosclerotic plaque, an event still unpredictable. Noteworthy, it is well known that 13–17 % of persons resuscitated from cardiac arrest develop an acute myocardial infarction [30, 31].

Although the final pathway of SD is always cardiac arrest, the pathophysiologic mechanism may be cerebral, respiratory, and cardiovascular in origin when considering the primary loss of vital function [25–27, 32, 33].

Cerebral SD occurs as a consequence of cerebral hemorrhage, either intraparenchymal (usually hypertension) or subarachnoid (rupture of a congenital berry aneurysm). The latter is much more frequent in the young and may be considered the consequence of congenital dysplasia of the cerebral artery wall. The berry aneurysms are located throughout the cerebral circle of Willis, more frequently in the middle cerebral artery and in the anterior communicating artery (Fig. 2.4). Extensive hemispheric infarction after embolic occlusion of a carotid or cerebral artery may also account for SD. Brain injury occurs with cerebral edema, hernia of cerebellar tonsils into the occipital foramen, and injury of brain stem cardio-respiratory centers, with cardiac asystole as final mechanism of death.

Respiratory SD is the consequence of an abrupt obstruction of the airways, hindering lung ventilation and alveolar gas exchange. Suffocation and foreign body occlusion of upper airways (larynx, trachea, and bronchi) are accidental phenomena. Infectious inflammatory disease of the upper airways may lead to edema of the larynx with obstruction. However, the most common and frequent cause of respiratory SD in the young is allergic asthma, with bronchospasm and obstruction of the bronchi because of increased mucous secretion by bronchial glands (Fig. 2.5). The bronchial wall, with typical thickening of basal membrane and plugs in the bronchial lumen due to hypersecretion of the mucinous glands, appears infiltrated by eosinophils with amines release, accounting for bronchospasm. While in cerebral and cardiac SD loss of consciousness occurs immediately, during allergic asthma attack the patient is conscious and faces frightened the incoming death, becoming progressively cyanotic. Lack of blood oxygenation may contribute to slowdown of sinus node function and cardiac asystole.

SD in epilepsy (also known as sudden unexpected death in epilepsy, i.e., SUDEP) usually occurs during or immediately after an epileptic attack, through either cerebral or respiratory mechanism, insofar as the tonic–clonic seizure may jeopardize the brain stem respiratory centers or otherwise block the chest muscles with unpaired ventilation [34]. The risk of SD is 20 times higher than in the general population.

Cardiac arrest may be mechanical, when the heart function stops because of mechanical reasons. This is the case of pulmonary thromboembolism, when blood circulation is interrupted by the sudden occlusion of the pulmonary artery usually from a venous source (Fig. 2.6). In the young, it is often observed in women using estroprogestin drugs for therapeutic or contraceptive purpose, in obese people, and those with acquired or inherited hypercoagulable conditions, factor V Leiden being the most common [35].

Another circumstance of mechanical cardiovascular SD is hemopericardium with cardiac tamponade (Fig. 2.7). The amount of blood required to constrict the heart and impair diastolic ventricular filling is about 300–500 ml. Cause of hemopericardium may be cardiac rupture, complicating acute myocardial infarction; it usually occurs 2–4 days after the onset of myocardial infarcts, most often in the intensive coronary care unit (Fig. 2.8) and, as such, does not fit the definition of SD as an unpredictable event.

Instead, intrapericardial aortic rupture, due to aortic dissection, occurs suddenly and unexpectedly (whether due to hypertension, pregnancy, Marfan syndrome, or bicuspid aortic valve, with or without isthmic coarctation – see Chap. 7) (Fig. 2.9). In particular, while hypertension is the leading cause in the adult–elderly population, congenital or genetic diseases prevail in the young. Among the latter, Marfan syndrome is a genetic disorder, autosomal dominant, due to a mutation of fibrillin, a protein in the aortic wall tunica media connecting smooth muscle cells and elastic lamellae [36]. Besides extracardiac anomalies (lens luxation, arachnodactyly, laxity of the joints), it shows a peculiar cardiovascular involvement with progressive dilatation of the ascending aorta, accounting for aortic valve incompetence and eventually aortic dissection due to severe elastic disruption and medial necrosis in the tunica media [37]. A cut off of 5 cm aortic diameter is considered as the threshold for indication to surgery, to prevent the occurrence of aortic dissection and death.

Rupture of a concealed mycotic aneurysm into the pericardial sac may also account for cardiac tamponade (Fig. 2.10).

There are other circumstances which can abruptly interfere with blood circulation and vital organ perfusion. This is the case of acute hemorrhage, due to external rupture of either dissecting (usually thoracic) or atherosclerotic (either abdominal or thoracic) aortic aneurysm into the pleural cavity (which can host up to 2 liters of blood) or into the retroperitoneal space (Fig. 2.11), respectively. In both instances, which are almost exclusively observed in the adult–elderly population, hypovolemic shock occurs with cardiac asystole and death.

Acute mitral valve incompetence due to spontaneous rupture of chordae tendineae and mitral valve stenosis due to impingement of a huge left atrial myxoma are also exceptional causes of acute pulmonary edema and mechanical cardiac SD (Fig. 2.12).

SD may also occur in patients after heart valve replacement due to prosthetic valve dysfunction [38, 39]. Massive thrombosis with poppet block and embolization, as well as anticoagulation-related hemorrhage, are well-known complications. In cases of mechanical valve prostheses, abrupt detachment of annular suture anchorage, strut fracture, and tab fracture with valve leaflet escape (Fig. 2.13) are the main reported causes. In bioprostheses, sudden commissural tearing, either mechanical (Fig. 2.14) or related to calcification, is the equivalent of a strut fracture. These causes usually account for acute pump failure and pulmonary edema.

Gastric or duodenal perforating ulcers may lead to a massive gastroduodenal hemorrhage and hypovolemic shock as well.

Shock may be septic in case of Waterhouse–Friderichsen syndrome, with bilateral adrenal hemorrhage, usually following meningococcal infection (Fig. 2.15). In this circumstance, shock is due to extreme dilatation of systemic microcirculation because of acute adrenal insufficiency. The overall size of blood circuit becomes exceedingly wider than the blood content, thus leading to severe hypotension, hypoxia, and eventually cardiac asystole.

However, the vast majority of primary cardiac SDs (more than 90 %) are arrhythmic (“electric cardiac SD”) [3]. The pathophysiology may be asystole, due to sino-atrial or atrioventricular (AV) block; or, in the vast majority (>80 %), ventricular fibrillation (VF) (Fig. 2.16). Another mechanism is electromechanical dissociation, when electrical activity of the heart, still present, does not couple with contractility (pulseless electrical activity, PEA).

Also known as “heart delirium,” VF is the most common final pathway of cardiac SD. There are several heart diseases which may complicate with VF and cardiac arrest: ischemic heart disease, cardiomyopathies, valve abnormalities, conduction system disorders, and ion channel diseases.

When recorded by ECG, often an early premature ventricular beat (R on T) is seen to trigger ventricular tachycardia (200–300 beats/min), which degenerates into ventricular flutter/VF (400–500 beats/min). The heart rate is too high and incompatible with an adequate diastolic filling/systolic stroke volume, thus leading to abrupt cessation of blood circulation and cerebral perfusion, loss of consciousness, and death in a few minutes.