In contrast with SCD in the adult and elderly, thrombotic occlusion of a main subepicardial coronary artery is not the rule. Only 25–30 % of cases present with recent occlusive thrombosis [2, 4].

The phenomenon is mostly focal, consisting of a single vessel disease in contrast with the adult and elderly population where a diffuse, multivessel involvement is typically found (Fig. 3.1). The obstructive (>75 % lumen stenosis), usually eccentric, atherosclerotic plaque is often located in the proximal tract of the anterior descending branch of the left coronary artery [2, 4] (Fig. 3.2).

The culprit lesion rarely shows the classic features of vulnerable atherosclerotic plaque (necrotic core covered by a thin fibrous cap) [1, 5–8] (Figs. 3.3 and 3.4). It is mostly fibrocellular, due to recent smooth muscle cell growth indicating an accelerated proliferative phenomenon [2, 4, 9–15] (Figs. 3.1, 3.5, 3.6, and 3.7).

When thrombotic occlusion is observed, the thrombosis rarely precipitates as a consequence of plaque rupture or fissuring of the atherosclerotic plaque with thin fibrous cap [2, 4] (Figs. 3.8, 3.9, and 3.10). The thrombus is a mixture of platelets and fibrin entrapping red cells (Fig. 3.11). More frequently, endothelial erosion accounts for thrombogenicity [16, 17] (Figs. 3.12 and 3.13) and inflammation of the superficial layer of the intima (“endothelitis”) is often observed as a cause of endothelial cell detachment (Fig. 3.14). In the setting of endothelial erosion due to extensive T-lymphocytes and macrophage infiltration, molecular pathology investigation can help in detecting viral infection as a cause of coronary plaque instability precipitating thrombotic occlusion [18] (Fig. 3.15). The thrombosis may be occlusive or mural (Fig. 3.16). In both conditions, detachment of thrombus fragments may lead to embolism into the distal coronary small arteries (Fig. 3.17).

In the absence of an organic occlusion of a coronary artery, as in the case of a single obstructive atherosclerotic plaque, a transient ischemic attack, most probably due to vasospasm, has been demonstrated to occur just before cardiac arrest, with ST segment elevation on ECG like in Prinzmetal variant angina [12, 14, 19, 20] (Figs. 3.18 and 3.19). Reperfusion, following release of vasospasm, entails life-threatening electrical instability, because of massive calcium cellular inflow, due to damage of sarcolemma following transient myocardial ischemia.

Risk factors for accelerated atherosclerotic coronary artery disease leading to SCD in the young are not easily recognizable, due to the almost absent clinical information, including laboratory tests, in this apparently healthy population. Among the risk factors, cocaine and other drug addiction are well known particularly in young adults [21, 22]. Systematic toxicology investigation indicated that about 3 % of SCD are cocaine-related, and premature coronary artery atherosclerosis, with or without lumen thrombosis, is a frequent finding that may account for myocardial ischemia at risk of cardiac arrest in cocaine addicts [21] (Fig. 3.20). Small vessel disease is quite often associated with epicardial atherosclerotic coronary artery disease in this population (Fig. 3.21).

In our extensive experience of SCD in the young, an overt acute myocardial infarction was rarely observed, even at histology, and myocardial scar due to previous infarction was also quite rare (Fig. 3.22) [4], in contrast with the adult elderly population [1, 23, 24] (Figs. 3.1 and 3.23). Because of the instantaneous death, it is impossible to predict whether these young people would have developed overt myocardial infarction, if resuscitated. Certainly, in case of fresh occlusive thrombosis, the occurrence of cardiac arrest due to ventricular fibrillation is most probably equivalent to that occurring within the first hour of myocardial infarction with out-of-the-hospital fatal outcome [25–28]. In case of transient coronary artery occlusion following vasospasm, it is also impossible to establish whether the constriction time would have been long enough to precipitate an acute myocardial infarction, either subendocardial or even transmural. It is well known that histological evidence of myocardial infarction is detectable not before 3–4 h from the time of coronary occlusion. It is highly probable that, like in experimental ligation of the descending coronary artery in the dog which immediately triggers ventricular fibrillation, transient ischemia due to vasospasm may be enough to threaten the regular electrical impulse transmission or favor ectopic ventricular tachycardia by triggered activity. A genetic predisposition to ventricular fibrillation has been suggested with a specific single nucleotide polymorphism in chromosome 21q21 [29]. A pathological substrate in the myocardium, consistent with a reentry mechanism for ventricular arrhythmias, is lacking in the absence of fibrous scars (Fig. 3.23) and the hypothesis that transient ischemia may precipitate an ion channel disorder cannot be ruled out.

Origin of a main coronary artery from the opposite (wrong) sinus. This is the case of origin of the right coronary artery from the left aortic sinus or origin of the left coronary artery for the right anterior sinus [62–65] (Figs. 3.38 and 3.39). The latter is much more malignant because the anteroseptal and lateral walls of the left ventricle are perfused by this artery, whereas the former has been reported also as incidental finding in noncardiac deaths. They may be well visualized in vivo by coronary angiography or even noninvasively by two-dimensional echocardiography, cardiac magnetic resonance or computed axial tomography [65]. The anomalous origin of the coronary artery from the wrong sinus is a cause of ischemia, especially during effort, through several mechanisms (Figs. 3.40, 3.41, and 3.42):

They all contribute to precipitate a discrepancy between coronary blood flow demand during effort and effective coronary blood perfusion across the stenotic proximal coronary segment. Repeated prolonged efforts create focal myocardial ischemic injury that with time precipitates patchy, highly arrhythmogenic fibrotic scars (Fig. 3.43). Combination of acute and chronic myocardial damage is a cocktail of malignant substrate with life-threatening electrical turmoil.

Origin of the left circumflex artery from the right coronary artery or directly from the right sinus of Valsalva (Fig. 3.44). This is the most frequent coronary anomaly and a source of controversy, because it is usually considered a benign variant. However, cases in which this coronary anatomy pattern was the only abnormality found at autopsy of SCD (Fig. 3.45) have been observed, associated even with myocardial infarction just in the related left lateral myocardial region and in the absence of atherosclerotic obstructive disease [66, 67] (Fig. 3.46).

High takeoff of a coronary artery. Usually the coronary ostia are located just underneath or above the sino-tubular junction [68] (Fig. 3.35). There are cases of SCD, in which the sole abnormality is an origin of the coronary artery from the tubular part of the aorta, 1–2 cm above the sino-tubular junction [53, 54] (Figs. 3.47 and 3.48). This is usually the case of the right coronary artery, which, by reaching the right AV groove, presents with a vertical course within the aortic tunica media, a condition which clearly impairs coronary blood flow at the time of increased demand during effort, as it is with a coronary artery arising from a wrong sinus.

Myocardial bridge. Intramyocardial course of a major coronary artery, particularly the left anterior descending branch, is quite common (nearly 30 % of people) as to be considered a variant of normal. There are cases, however, with angina and ECG ST segment alterations, in the absence of other explanation but a “milking effect” at coronary angiography. The intramyocardial course is deep and long, constricted also during diastole, when coronary perfusion occurs [69]. Histologically, the coronary segment is not simply covered by a myocardial fascicle (“bridge”) but also surrounded by a sheath of myocardium acting as sphincter [70] (Figs. 3.49 and 3.50).

In the AECVP guidelines for the investigation of SCD, this substrate is classified among those of uncertain significance in terms of risk [61]. Noteworthy, by reviewing with attention the illustrations of reported cases of SCD with myocardial bridge, they were cases of hypertrophic cardiomyopathy with myocardial bridge [71, 72] and now it is well known that myocardial bridge is part of the phenotypic expression of hypertrophic cardiomyopathy [73].