It is a major cause of SCD during effort and thus the leading cause of cardiac arrest in athletes in countries such as the United States, where ECG is not employed at the pre-participation screening [4–6]. It is a genetically determined disease, with autosomal dominant pattern of inheritance, mostly due to mutations of genes encoding sarcomeric proteins, and characterized by asymmetrical hypertrophy of the left ventricle, usually septal or apical [7, 8] (Figs. 4.1 and 4.2). Concentric, symmetrical hypertrophy may be also observed.

In case of asymmetrical septal hypertrophy, a fibrous endocardial plaque is usually present in the subaortic position, as a consequence of the friction of the anterior mitral leaflet with the endocardium of the ventricular septum, due to systolic anterior motion of the leaflet, which itself appears thickened (Figs. 4.2 and 4.3).

The histology discloses myocardial disarray, with variously oriented cardiomyocytes crossing each other (either single cell or fascicular), cardiomyocyte hypertrophy with bizarre nuclei, interstitial fibrosis, and dysplastic and frequently obstructed, intramural small arteries [9–16] (Fig. 4.4).

There are several structural substrates which explain why HCM is highly arrhythmogenic and at risk of life-threatening ventricular arrhythmias and SCD:

Observation of scars within the hypertrophy is almost regular at autopsy of cases with HCM and SCD, even when the wall thickness and the heart weight are not particularly increased [16]. In support of the ischemic etiology of replacement-type fibrosis, all the stages of ischemic myocardial injury are seen in the hearts of people dying suddenly with HCM, including interstitial edema, myocyte coagulative necrosis, neutrophilic infiltrates, and myocytolysis, eventually leading to scarring [15] (Fig. 4.10). By the way, the progressive scarring accounts for the evolution of HCM into a dilated, end-stage form [17].

Disarray and replacement-type fibrosis appear to be a malignant arrhythmic combination. Replacement-type fibrosis is easily identified in vivo by contrast-enhanced cardiac magnetic resonance imaging [18].

A so-called idiopathic left ventricular hypertrophy has been reported in young people and athletes who died suddenly [4–6]. The degree of hypertrophy is beyond that seen in the cardiac hypertrophy of the trained athlete, with left ventricular thickness exceeding 15 or 16 mm. It is a diagnosis by exclusion, after ruling out other conditions that would predispose to left ventricular hypertrophy (e.g., aortic valve stenosis, isthmic aortic coarctation, systemic hypertension). Unlike HCM, idiopathic left ventricular hypertrophy is concentric and symmetric and there is no evidence of subaortic plaque and mitral valve disease, myocardial disarray, and familial transmission. Whether this condition should be considered a distinct entity at risk of SCD is still a matter of debate, and differential diagnosis with “athlete heart” remains a challenge not only in the clinical setting but also at postmortem [19–21].

It is the leading nonischemic cause of SCD in the young and in the athletes in Italy [22, 23]. In contrast with HCM, which is a sarcomeric disease mostly affecting the left ventricle, AC is a desmosomal disease and has been viewed as a disease of the right ventricle [22–30]. The fibrofatty replacement starts from the subepicardium and deepens as a wave-front phenomenon, reaching the subendocardium, to become transmural [22, 31, 32]. In SCD series, both segmental (Figs. 4.11 and 4.12) and diffuse (Figs. 4.13 and 4.14) forms of AC are described and even cases with early stages of myocardial injury (Fig. 4.15), preceding the mature fibrofatty tissue [22, 24, 31–35]. Biventricular or even isolated or dominant left ventricular forms have also been reported [31, 32, 35–37] (Figs. 4.16 and 4.17). Left ventricular free wall involvement has been observed in up to 70 % of autopsy reports [31, 32], whereas the ventricular septum only in 20 % [31]. In the left ventricle, the subepicardium of the posterolateral wall is typically affected. When the biventricular involvement is diffuse, AC may mimic dilated cardiomyopathy with congestive heart failure, so severe as to require cardiac transplantation. Cases with predominant fatty tissue replacement with preserved wall thickness or even pseudo-hypertrophy do also exist (Fig. 4.18). However, isolated fatty tissue at postmortem cannot be regarded as a pathognomonic feature of the disease [19, 38], in order to avoid a misdiagnosis of AC at autopsy, with forensic and preventive implications, since the postmortem diagnosis must guide cascade investigation of family members [39].

Endomyocardial biopsy is frequently employed to detect fibrofatty replacement in vivo and an amount of residual myocardium less than 60 % is considered diagnostic [40]. Clinical diagnosis is challenging and there is no single gold standard [41]. Typically, the ECG discloses depolarization abnormalities, QRS widening, epsilon waves, and repolarization changes with inverted T waves on precordial leads. In the classical variant, ventricular arrhythmias present a left bundle branch block morphology indicating the right ventricular origin. Low voltage areas by electro-anatomic mapping and late enhancement by contrast cardiac magnetic resonance are now very helpful clinical imaging surrogates of myocardial atrophy [42, 43].

The pathobiological phenomenon consists of a transmural fibrofatty replacement of the ventricular free wall, as a repair consequence of a progressive cardiomyocyte death, either by necrosis or apoptosis [44, 45] (Fig. 4.19). In advanced forms, the myocardium may almost disappear and the free wall looks parchment like. This process accounts for the dilatation of the ventricular cavity and the development of wall aneurysms. In contrast with HCM, where the cardiomyocyte death is mostly ischemic in origin because of impairment of microcirculation due to hypertrophy and wall stiffness constricting the small arteries, in AC, cell death with myocardial loss is genetically determined, due to cell junction vulnerability [44]. AC is indeed a genetic disorder of desmosomes [24–30, 46, 47]. Mutations of genes encoding desmosomal proteins account for a vulnerable intercalated disk, which appears disrupted at electron microscopy [48, 49]. Stretch, due to increased ventricular preload during effort, facilitates both cell death and onset of arrhythmias. Although AC is genetically determined, there is an age and gender related penetrance of the phenotype and SCD typically occurs during adolescence or early adulthood, even as first manifestation of the disease [24–26, 50, 51].

The following substrates of the disease should be considered arrhythmogenic [51]:

It is still a matter of debate whether electrical instability at risk of SCD might occur also in the pre-phenotypic stage of the disease, before structural abnormalities of the myocardium, due to a cross-talk between mechanical junction and ion channels. Experimental studies demonstrated that intercellular space widening at the level of the intercalated disk and a concomitant reduction in action potential upstroke velocity, as a consequence of lower sodium current density, lead to slowed conduction and increased arrhythmia susceptibility at disease stages preceding the onset of necrosis and replacement fibrosis [49]. However, no single SCD case has been reported so far in the pre-phenotypic stage of AC.

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