ARVC is a genetic cardiomyopathy in which mutations of the genes encoding proteins of the desmosome have been identified [2]. As discussed above, ARVC is currently considered to be a disease of myocyte adhesion caused by defects at the intercellular junction. Cardiac myocyte-to-myocyte adhesion is maintained by desmosomes, adherens, and gap junctions, which together comprise the intercalated disc [30, 31]. The desmosomes have a complex structure (Fig. 16.3) that includes adhesion molecules of the cadherin (desmoglein-DSG and desmocollin-DSC), plakin (desmoplakin-DSP), and catenin (plakophilin-PKP, and plakoglobin-JUP) families, which link intermediate filaments of the cytoskeleton to the desmosomal cadherins [32, 33].

Five of the known ARVC genes encode proteins of cell–cell junctions at the intercalated disc: plakoglobin (JUP) [34], desmoplakin (DSP) [35], plakophillin-2 (PKP2) [36], desmoglein-2 (DSG2) [37], and desmocollin-2 (DSC2) [38]. Mutations in PKP2 are the most common reported in ARVC [36]. Desmoplakin mutation carriers have echocardiographic, cardiac MRI, and ECG signs of a more severe involvement of the left ventricle [5]. JUP gene variants in recessive families are a well recognized cause of ARVC [34], as discussed below. Recently, a dominant mutation of JUP has also been reported in a German family with ARVC without cutaneous abnormalities [39].

Naxos disease is a rare subset of ARVC notable for an autosomal recessive inheritance pattern and a complex syndromic phenotype with skin (palmoplantar keratoderma) and hair abnormalities (woolly hair), due to homozygous mutations in the JUP gene, encoding junctional plakoglobin [34] (Table 16.4). The syndrome takes its name from the Greek island of Naxos, where its prevalence exceeds 1 in 1,000 despite the autosomal recessive inheritance. The cutaneous phenotype is expressed from infancy, facilitating recognition of affected individuals, whereas the cardiac symptoms characteristically develop from adolescence to the fourth decade of life. Following successful linkage mapping of the disease locus to 17q21, a homozygous two-base-pair deletion in the plakoglobin gene (JUP) was identified as the causal mutation [40]. Plakoglobin is a key constituent of desmosomes, the specialized intercellular junctions of cardiac and epithelial tissue, and its isolation in Naxos disease let to the discovery of the other desmosomal genes associated with ARVC.

Carvajal syndrome is another syndromic recessive cardiocutaneous syndrome, described in families from India and Ecuador, caused by DSP mutations. The causal homozygous DSP mutation results in truncation of the C terminus at the tail end of the protein [41]. The phenotype of Carvajal syndrome consists of palmoplantar keratoderma, woolly hair, and LDAC, which was initially labeled dilated cardiomyopathy [41]. Clinical and pathological characterization of this entity is more limited, but frequent and complex ventricular arrhythmias and precordial T-wave inversion have been reported [42] along with ARVC, woolly hair, skin features localized in the extremities, and vesicular lesions similar to pemphigus foliaceus (Table 16.4) [43].

Several non-desmosomal genes have been reported as disease-causing: transforming growth factor beta-3 (TGFB3), cardiac ryanodine receptor (RYR2), transmembrane protein 43 (TMEM43), tumor protein p63 (TP63), desmin (DES), lamin A/C (LMNA), alpha T-catenin (CTNNA3), and phospholamban (PLN). Thus far, more than 800 genetic variants have been identified in 12 genes, yet only around 300 have been classified as clearly pathogenic [3].

Concerning TGFB3 [44] and TMEM43 [45], the mechanism leading to ARVC is still unknown, although there are some hypotheses. The TGFB3 gene encodes TGF-β3, a cytokine that stimulates fibrosis, influences cell adhesion [46] and modulates expression of genes for desmosomal proteins [47]. Regarding the TMEM43 gene, this gene contains a response element for an adipogenic transcription factor, which might correlate with the histopathology of ARVC. The S358L mutation in TMEM43, identified in the Newfoundland founder population, causes a fully penetrant non-classic form of the disease associated with a high incidence of premature sudden cardiac death and heart failure in survivors [45, 48].

Other genes have been reported as possible candidates for causing ARVC: the RYR2 gene encodes for ryanodine receptor 2, which regulates mechanisms of calcium handling. This gene has been described as a cause of ARVC [49] and of a distinct clinical entity, polymorphic ventricular tachycardia (ARVD2), characterized by juvenile sudden cardiac death and effort-induced polymorphic ventricular tachycardia [50].

Among extra-desmosomal genes, lamin A/C (LMNA) mutations are known to cause a diverse range of clinical phenotypes, including dilated cardiomyopathy, which may in some cases show severe skeletal muscle involvement. These patients characteristically show atrial arrhythmias or atrioventricular blocks as the early signs and progression to heart failure and a high incidence of sudden cardiac death later in the disease [51, 52]. Pathological examination of hearts usually shows four-chamber dilation, cardiomyocytes hypertrophy and fibrosis without inflammation, although there have been reports of cases presenting with a phenotype compatible with restrictive cardiomyopathy, right ventricular dilation, left ventricular non-compaction and, recently, ARVC [53]. Patients with a presumed diagnosis of ARVC but with mutations in the LMNA gene were more likely to show either atrial tachycardia or conduction disease in comparison to genetically confirmed ARVC patients [54].

Finally, mutations in the TTN gene encoding for the giant sarcomeric protein titin have been recently described in ARVC [4]. The possible mechanism, which could explain the association between the disease and this gene, is the connection between a structurally altered titin to the transitional junction at intercalated disks. This discovery provides novel insights into the pathophysiology of ARVC, a complex disease with variable expression and a variety of genes as possible candidates for its etiology.

Idiopathic RV outflow tract–ventricular tachycardia (RVOT-VT) is a mostly benign condition not associated with structural heart disease. In early stage ARVC can be difficult to distinguish from RVOT-VT in the absence of structural changes. The differential diagnosis is based on the fact that RVOT-VT is non-familial and patients do not have the characteristic ECG/SAECG abnormalities of ARVC (inversion T waves in V1–V3, epsilon waves, QRS duration >110 ms) (Table 16.5).

Brugada syndrome is an inherited cardiac condition that, similarly to ARVC, is transmitted with an autosomal dominant pattern, which can lead to sudden cardiac death from malignant ventricular arrhythmias. This syndrome is characterized by a distinct typical ECG pattern with a “J wave” in precordial leads, and by the absence of morphological echocardiographic features.

Dilated cardiomyopathy can be also an inherited condition in a large proportion of patients, and may be difficult to distinguish from ARVC when presenting with biventricular involvement, especially in its advanced stage. In its late phase, signs and symptoms of RV and/or LV failure are present and finally severe biventricular congestive heart failure can occur. In the absence of classic ARVC hallmarks (RV aneurisms, bulging), there are no other echocardiographic diagnostic features [57]. In 30 % of patients with dilated cardiomyopathy, the right ventricular function is significantly depressed and a biventricular dysfunction is not rare [58]. However, a predominant RV dilation and dysfunction is rare in dilated cardiomyopathy and in these cases, the diseases is more probably caused by ARVC with biventricular involvement. There are two possible mechanisms underlying RV dysfunction in dilated cardiomyopathy: intrinsic characteristics of the disease which can affect both ventricles and/or the presence of pulmonary hypertension due to dysfunction of the left ventricle with consequent afterload increase [59]. A severely depressed RV ejection fraction (<35 %) and/or the presence of biventricular dysfunction have been demonstrated to be independent predictors of more severe prognosis if compared to patients with isolated LV involvement [60–62]. In patients with dilated cardiomyopathy and biventricular dysfunction, RV function can be improved by the use of optimized medical treatment with ACE inhibitors and beta-receptor blockers; the persistence of RV dysfunction despite optimized treatment predicts a high risk of death and is an indication for heart transplantation [63].

Cardiac sarcoidosis, a condition with a strong genetic component, can mimic ARVC. Sarcoidosis is a systemic inflammatory disease with formation of noncaseating granulomas in the reticuloendothelial system, and skin. Approximately 5 % of patients with sarcoidosis have clinically relevant cardiac findings. Therefore, cardiac sarcoidosis has to be considered if conduction defects with a high-grade atrioventricular block are present. A global RV hypokinesia or some regional wall motion abnormalities can be present, due to the patchy nature of the granulomatous infiltration. The echocardiographic presentation of cardiac sarcoidosis includes normal or dilated ventricular chambers and normal or reduced systolic function. The ventricle may be globally hypokinetic or the patchy nature of sarcoid infiltration of the heart may result in regional wall motion abnormalities. Segmental wall motion abnormalities characteristically do not conform to any particular coronary distribution [64]. Two-dimensional echocardiographic characteristics of cardiac sarcoid vary according to the disease activity and include wall thickening due to granulomatous expansion and wall thinning due to fibrosis [65]. A typical but uncommon finding is the thinning of the basal anterior septum, the appearance of which in a young patient with a dilated cardiomyopathy is highly suggestive of sarcoidosis [66]. Scar retraction and aneurysms may develop, especially if the patient has been treated with corticosteroids. Pulmonary involvement occurs in 90 % of patients with sarcoidosis, thus Doppler echocardiographic examination should include the assessment of pulmonary pressures and right ventricular function to detect early signs of pulmonary hypertension [67]. In patients with extra cardiac sarcoidosis, advanced echocardiography can be useful to detect, in asymptomatic patients, early alterations in strain and rotational indices [68]. Newly diagnosed sarcoid patients appear to have lower global longitudinal strain, despite having a well-preserved global systolic myocardial function. Moreover, twist appears increased in the patient population with respect to the control population. MRI is another imaging test used to establish the diagnosis; both cardiac sarcoidosis and ARVC are progressive diseases and the accuracy of cardiac MRI can vary, depending on the stage of the disease at which the cardiac MRI data are acquired. Interestingly, myocardial fat infiltrates are absent in cardiac MRI in patients with sarcoidosis [69].