Firstly considered a congenital malformation, nowadays it is known that ACM is a genetically inherited disease, in most cases autosomally dominant, which develops after birth. This knowledge stems from the recognition of two recessively inherited cardiocutaneous syndromes, namely Naxos [2] and Carvajal [3] diseases, whose affected individuals share a common phenotype characterized by palmoplantar keratoderma, woolly hair and arrhythmogenic right ventricular cardiomyopathy. The identification of these syndromes led to the discovery of the responsible mutated genes: plakoglobin (JUP) for Naxos disease and desmoplakin (DSP) for Carvajal disease.

Plakoglobin and desmoplakin are components of a transmembrane complex named desmosome. Other elements include desmoglein-2 (DSG2) [4], desmocollin-2 (DSC2) [5] and plakophilin-2 (PKP2) [6]. As its name suggests (“binding body”), the role of the desmosome is to mediate adhesion between cells. However, it also has much more complex functions such as anchoring cytoskeleton to cell membrane, intracellular signaling and electrical coupling by organizing gap junctions and ion channels [7].

In the context of altered desmosome structure and function, cardiomyocytes are prone to loose adhesion to each other [8], a process that is amplified by mechanical stress. This leads to altered intracellular signaling with suppression of the Wnt/$\beta$-catenin pathway resulting in apoptosis and up-regulation of adipogenesis transcriptional factors. Plakoglobin shares structural and functional properties with $\beta$-catenin. In cultured DSP-deficient atrial myocytes [9] and heterozygous cardiac-specific DSP-knockout mouse models [10], it shows increased nuclear translocation where it can compete with $\beta$-catenin for binding to transcription factors, resulting in decreased expression of Wnt target genes (c-Myc and cyclin-D1). Interestingly, inhibition of glycogen synthase kinase-3 beta (GSK-3$\beta$), which targets $\beta$-catenin for degradation, reversed desmosomes and gap junctions remodeling and prevented cardiac dysfunction [11].

Desmosome interacts with connexin 43 (Cx43) and sodium channel Na${}_v$1.5 possibly implying a role in arrhythmogenesis. Heterozygous knockout PKP2 and DSP mice models have indeed shown altered sodium currents kinetics and induction of ventricular arrhythmias without overt histological alterations [12].

Mutations of desmosome components are the most commonly observed in ACM patients, with PKP2 being the most frequent. Nonetheless, a wealth of mutations also in non-desmosomal proteins have been described:

- N-Cadherin (CDH2) is a transmembrane adherens junction which provides calcium-dependent adhesion, connects actin filament between sarcomeres, stabilises gap junctions and has many roles in embryogenesis. In 2017 a novel variant of CDH2 was found in a South African ARVC-affected family [13].

- Lamins are nuclear intermediate filament proteins, encoded in the LMNA gene, that have suppressive effects on the expression of many genes [14]. Pathogenic variants of LMNA have been described in a variety of cardiac manifestations: atrial fibrillation [15], conduction disease, ventricular arrhythmias and dilated cardiomyopathy [16, 17]. Its role in ACM is not completely understood, though. The high incidence of SCD in these families has led to recommendations to consider prophylactic implantable cardioverter defibrillators (ICD) for SCD prevention [18].

- Desmin (DES) is a muscle-specific intermediate filament protein which is involved in linking Z-disk to nuclear and cellular membranes, sarcomere synthesis, nuclear positioning, sarcoplasmic reticulum and T-tubular system. DES mutations have been reported in all phenotypes of cardiomyopathy as well as skeletal myopathies, but they are frequently associated to DCM typically exhibiting a high incidence of conduction system disease and arrhythmias [19, 20]. ACM DES-mutated carriers have been described to show a fully penetrant variable cardiac phenotype with a propensity for left ventricular involvement [21].

- Filamin C (FLNC) in an actin cross-linking protein found in striated muscle cells. Truncating variants of this gene have been associated with a left dominant ACM [22] with an elevated risk of SCD. Other variants have been reported in restrictive [23] and hypertrophic [24] cardiomyopathies.

- Transmembrane 43 is a nuclear membrane protein known to bind with Lamin and other nuclear proteins. Mutations of this protein, firstly described in Newfoundland, have been found to cause a fully penetrant biventricular ACM [25, 26] with a substantial risk for SCD in males.

- Phospholamban (PLN) is a sarcoplasmic homopentameric protein involved in calcium homeostasis by regulating the activity of sarcoplasmic reticulum Ca${}^{2+}$- ATPase (SERCA). PLN mutations make its product unable to be inactivated through cAMP-protein kinase mediated phosphorylation [27]. In the unphosphorylated state, phospholamban inhibits SERCA-mediated Ca${}^{2+}$ re-uptake back in the sarcoplasmic reticulum. Thereby, cytosolic calcium increases, which is known to cause delayed after depolarization (DAD), possibly triggering arrhythmias. PLN p.R14del mutation carriers are quite common in the Netherlands (1 in 1500 Dutch people). In 2012 a cohort a DCM and ARVC were screened for this specific mutation, and it was found in 15% and 12% respectively [28]. Affected individuals show a variable phenotype with right, left, or biventricular involvement. The high incidence of SCD in affected individuals led to ICD implant recommendation similar to LMNA-related cardiomyopathy.

- Voltage-gated sodium channel (encoded by SCNA5) mutations are known to cause Brugada syndrome (loss of function) and type 3 long QT syndrome (gain of function). Both types of mutations can lead to DCM [29] with no apparent fibrosis and frequent conduction disease and ventricular arrhythmias. However, it is not clear whether the DCM phenotype is due to genetic defect or consequent to frequent ventricular arrhythmias.

- Mutations of Titin (TTN), the biggest human protein and essential component of sarcomere, have been reported in 7 out of 38 families suffering from ARVC with negative desmosomal genetic testing [30]. The clinical history was characterised by high penetrance (86%) with SCD, severe myocardial dysfunction leading to death or heart transplantation, and conduction system disease. TTN nonsense mutations are also the first genetic cause of DCM [31, 32].

- RBM20 encodes an RNA-binding protein involved in constitutive and alternating splicing of key cardiac genes including sarcomeric proteins and ion regulating proteins. Loss of function mutations leads to missplicing of these proteins. Affected patients present with an early-onset and fastly-progressing disease with severe heart failure, high arrhythmic burden and SCD [33, 34].

Other implicated genes with limited evidence are CTNNA3, TJP1, RYR2, NKX2-5, BAG3, TGF$\beta$3 [35].

Genetic mutations, though important, cannot explain the entire disease pathogenesis. In fact, they can be found in about 60% ACM patients, with desmosomal genes accounting for the majority of them [36]. Owing to the development of next generation sequencing and of genome-wide association studies, variants of potential culprit genes keep being discovered and reported, but in many cases their pathogenicity is of uncertain significance. On the other hand, pathogenic variants can be found in healthy controls and relatives of affected individuals who show no signs of the disease. Other factors are involved in the development and progression of the disease, for instance mutations of genes encoding factors limiting disease expression. Patients with multiple mutations (compound heterozygosity, digenic heterozygosity) are known to have a higher penetrance and an earlier onset of disease [37], but their frequency is low, ranging from 4% to 10%.

Genetic tests for ACM range from small panels of specific diseases to exome and genome sequencing. The more extensive the search, the greater the risk of identifying variants of uncertain significance that make it more difficult to interpret the results. However, advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions. This is driving a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes [36, 38].

The observation that a disproportionate number of ACM patients are athletes led to the hypothesis that physical exercise may be a risk factor for disease development and progression with an incremental effect [39]. In a group of 47 athletes with a definite or probable diagnosis of ARVC, 41 of them practiced endurance sports [40]. Furthermore, desmosomal mutations were found in only six patients, of which two had a family history of ARVC. In addition, the higher the exercise load, the lower the rate of desmosomal mutations. So, it was inferred that high-intensity exercise could mimic the ARVC phenotype even in subjects with no known mutations [41, 42, 43, 44]. Ruwald et al. [45] evaluated via questionnaire the relationship between sport, age of its onset and arrhythmia risk in 108 probands. They noticed that those who took part in competitive sports had a lower age at diagnosis and higher risk of ventricular arrhythmias/SCD compared to those who were inactive or engaged in recreational activities. Later studies confirmed the results and added further knowledge. The John Hopkins group evaluated the safety of AHA minimum recommended physical activity in healthy carriers of desmosomal mutations [46]. To do so, they interviewed 28 relatives of 10 probands. Healthy carriers who restricted physical exercise to minimum recommended had no arrhythmic events. On the other hand, probands were found to have undergone a more intensive exercise load than their relatives; a later observation by the same group showed that the arrhythmic risk is dramatically reduced by exercise restriction once the diagnosis is made.

Male ACM patients have a higher arrhythmic risk compared to females. This may be due to the propensity of males to engage heavier in sports. Hormonal influence may play a role too: androgenic hormones trigger adipogenesis, which can enhance disease progression and may also explain why ACM tends to manifest between the twenties and the forties, being exceedingly rare before puberty [47].

The observation of inflammatory infiltrates in up to two-thirds of autoptic ARVC diagnosis implies that inflammation may have a role in ACM pathogenesis [48]. Protonotarios et al. [49] retrospectively analysed 16 ARVC patients referred for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)—a validated technique for detecting myocardial inflammation in suspected myocarditis. Despite a few study limitations, the group proved 36% of their ARVC patients on FDG-PET had active myocardial inflammation. Inflammatory cytokines have been found at higher levels in the serum of ARVC patients. In addition, there is gathering evidence of autoimmunity [50] being involved, as inferred by the identification of anti-desmosome antibodies that could be produced by the unmasking of epitopes caused by the disease. Indeed, a myocarditis-like clinical presentation is increasingly reported in ACM patients, either being the initial trigger of the disease or a transient “hot phase” along its clinical continuum [51]. To further complicate things, there is clinical and pathological overlap between ACM and sarcoidosis, another inflammatory myocardial disease (Fig. 4) [52, 53]. Thus, ACM diagnosis remains clinical challenging both in the early stages when myopericarditis, sarcoidosis, or other inflammatory disease need to be ruled out, and at later stages when ischemic/nonischemic dilated cardiomyopathies are concerned.

The first detailed pathological description of arrhythmogenic right ventricular cardiomyopathy (ARVC) dates back to the XIX century treatise “De l’auscultation médiate ou traité du diagnostic des maladies des poumons et du Coeur”, describing the association of myocardial fat accumulation and right ventricular wall thinning with sudden death. Although this condition has been known for a long time, the diagnosis of ARVC still constitutes a challenge owing to the phenotypic overlap with other causes of right ventricular enlargement or dysfunction such as pre-mitral left-to-right shunts and cardiac sarcoidosis [53]. ARVC diagnosis is mainly suspected based on its phenotypic expression rather than on its genotype, so a subset of clinical features were identified as disease markers. In 1994, a first ARVC diagnostic score was developed based on qualitative parameters including family history, ECG abnormalities, arrhythmic events, and cardiac functional and structural abnormalities. The imaging diagnostic criteria gained by echocardiography, cardiac magnetic resonance (CMR), invasive cardiac angiography (ICA) or nuclear imaging focused on the evidence of RV dilation, reduced RV systolic function (in the absence of or with only mild LV impairment), regional RV motion abnormalities (i.e., small aneurysms, akinetic or dyskinetic areas with diastolic bulging). When addressing the ARVC diagnostic pathway, myocardial fibro-fatty replacement at biopsy (major criterion) was not considered sufficient to diagnose ARVC as this finding can be observed in several other conditions. Furthermore, given the typical segmental pattern of fibro-fatty replacement in ARVC, the histological diagnosis is burdened by a low sensitivity. However, it retains a high clinical value when alternative diagnostic hypotheses like sarcoidosis or myocarditis are considered.

Electrocardiographic criteria for right ventricular involvement included relatively specific depolarization abnormalities such as: (1) epsilon waves (small depolarization signal between the end of the QRS complex and the beginning of the T wave) and QRS prolongation in right precordial leads (Major criteria); (2) late potentials on signal-averaged ECG; (3) repolarization abnormalities like isolated T wave inversions in right precordial leads; (4) left bundle branch block (LBBB) type ventricular tachycardia, and frequent ventricular extrasystoles ($>$10,000/24 h). Lastly, histological confirmation of the disease in a close relative was considered a major criterion [54].

Given the high specificity but low sensitivity of these criteria, they were revisited in 2010 with the addition of genetic and quantitative structural and functional parameters. In particular, the evidence of pathogenic variants in ARVC-related genes was introduced as a major diagnostic criterion [55]. Despite these additions, a 2020 review paper by a group of international experts outlined a number of shortcomings of the current diagnostic system. Firstly, the 2010 criteria had been developed for those cases with exclusive RV involvement and therefore cannot aid the diagnosis of left dominant and biventricular forms. Secondly, the role of genetic analysis, introduced in the 2010 diagnostic score as a major criterion, was questioned given the high uncertainty surrounding several genetic variants linked to ACM as these are often non-specific and can also be found in healthy subjects. Eventually, despite the introduction of morphological and functional CMR features in the 2010 criteria, tissue characterization was not included [56].

The 2020 development of the “Padua Criteria” aimed at overcoming precisely these diagnostic weaknesses by including left ventricular diagnostic parameters. These criteria keep the previous score system’s outline based on major and minor diagnostic criteria divided into six groups (morphological and functional ventricular abnormalities, structural myocardial abnormalities, repolarization abnormalities, depolarization abnormalities, ventricular arrhythmias, family history and genetics) [57]. According to this update, ARVC diagnosis should be regarded as certain in the presence of two major criteria, or one major and two minor criteria, probable in the presence of one major and one minor criterion or three minor criteria from different categories, and possible in the presence of one major or two minor criteria from different categories.

ALVC is on the contrary diagnosed in the presence of one structural criterion for left-ventricle (LV) involvement (with or without the association of morphological and functional abnormalities) and the demonstration of an associated genetic mutation, in the absence of RV involvement. Based on the histologic/CMR correlations observed in ARVC, the clinical entity of LV fibro-fatty involvement at the epicardial/midventricular layers coupled with ventricular arrhythmias and with varying degrees of LV dysfunction is currently investigated as a suspected ALVC in a view to determine its possible genetic basis.

ECG abnormalities for ALVC are nonspecific and include inverted T waves in left precordial leads (V4–V6) in the absence of complete LBBB, low voltage QRS in limb leads and ventricular arrhythmias with right bundle branch block (RBBB) morphology (Table 1).

Finally, to diagnose biventricular forms of ACM at least one morphological/functional or structural criterion for both the right and the left ventricle are needed [57]. As can be noted, ARVC diagnosis is mainly based on phenotype and clinical manifestations, whereas genotype assessment plays a predominant role in ALVC diagnosis, as many etiologies/genetic mutations can subtend a similar phenotype. So, ARVC and ALVC can hardly be considered as the same disease with different clinical presentations, given the broad spectrum of manifestations and the different genetic alterations supposed to be disease-causative.

A further source of complexity emerges from the 2019 HRS consensus definition of ACM, extending the definition of ACM to all types of arrhythmogenic heart muscle disorders that are not explained by ischemic, hypertensive, or valvular aetiologies [58].

The pitfalls of previous diagnostic scores and the limited adoption of Padua criteria to date, as well as the nosological ambiguity surrounding ACM, strongly demand a shared diagnostic approach to this uncharted field of cardiology.

Imaging techniques play a fundamental role in the diagnosis and follow-up of ACM patients. Indeed, these are not limited to the assessment of morphological and functional abnormalities of the heart, but extend also to tissue characterisation and in particular to myocardial fibro-fatty replacement. Nowadays, echocardiography and Cardiac MRI (CMR) are the most important techniques, while right ventriculography is outdated.

This study is a retrospective analysis of the data of consecutive patients with confirmed diagnosis of ACM based on the proposed Padua Criteria, who were referred to our centre from January 1992 to October 2021. The aim of this study was to identify characteristics of ventricular arrhythmias and treatment in patients with ACM.

Clinical information regarding demographics, symptoms, 12-lead ECG, echocardiogram, CMR, and genetics were collected. In addition, data regarding ICD therapies and arrhythmia occurrence were obtained for each patient. Decisions regarding ICD programming were made by the managing cardiologist and/or electrophysiologist, namely VF+ single VT zone (conditional shocking zone for S-ICD), or VF + 2 VT zones based on available clinical data. Ventricular tachycardia (VT) detection was programmed at a cutoff rate as 171 bpm for a duration of 20–25 seconds, while VF detection was set at 231 bpm for a duration of at least 9 seconds, arrhythmia discriminators turned ON at their best possible performance [88, 89, 90, 91, 92]. When a slow VT zone was programmed in the range 120–170 bpm, detection was at least 35 seconds; shock therapy in this zone was programmed only after the arrhythmia had proved to cause severe hypotension or cardiogenic shock.

Anti-tachycardia pacing (ATP), either as Burst (minimum 2 attempts) and Ramp (minimum 1 attempt) pacing, was programmed as first delivered therapy in the VT zone, whereas it was delivered either before or during shock charging in the VF zone (according to each manufacturer specificity), while shock therapy was available in both VT and VF zone. Arrhythmia history and delivered therapy were analyzed either at in-clinic and at remote patients’ follow-ups. Clinical assessment, drugs and antiarrhythmic drug prescription were evaluated at twice yearly follow-up unless more frequent examinations were deemed necessary. Arrhythmia analysis was carried out by 5 experienced electrophysiologists based on stored intra-cardiac electrograms (EGMs).

Ventricular arrhythmia (VA) was defined as a regular or irregular ventricular tachycardia at cycle length 430 ms; life-threatening ventricular arrhythmia (LT-VA) was defined as an irregular or regular tachycardia with a mean cycle length (CL) of $\le$300 ms. Appropriate ICD intervention was defined as an ICD therapy for VA/LT-VA. An inappropriate intervention was defined as therapy delivery because of supraventricular tachycardia or oversensing due to either cardiac or non-cardiac signals.

Continuous variables are summarized as either mean $\pm$ SD or median (interquartile range) and compared across groups using a Mann–Whitney or Kruskal-Wallis test. Categorical variables are reported as frequency (percentage) and compared between groups by a $\chi$${}^2$ or Fisher exact test. The cumulative probability of survival free from first appropriate ICD intervention (VA/LT-VA) and from intervention for VA/LT-VA was determined by the Kaplan–Meier method, and differences in survival between groups were evaluated with the log-rank test. In patients without an ICD intervention, follow-up was to the most recent evaluation, transplantation, or date of death, whichever came first. All analyses were performed using SPSS 23.0 (SPSS Statistics/IBM Corp, Chicago IL, USA). A p $\le$ 0.05 was considered significant.

The patient population consisted of 72 patients with diagnosis of ACM, confirmed using retrospectively the proposed Padua Criteria. Of these, 29 patients (40.3%) were initially diagnosed using 1994 ITF Diagnostic Criteria for ARVC and 18 (25%) using the 2010 Proposed Modification of the Task Force Criteria. Twenty-two (30.6%) patients with exclusive left ventricle involvement were diagnosed as ALVC according to the characteristic ring-like LGE LV pattern at CMR associated genetic mutation and/or familial history of AC and/or red flags for ALVC (i.e., negative T waves in V4-6/aVL, low voltages in limb leads, right bundle branch block-like ventricular tachycardia) or defined on microscopic analysis in explanted heart examinations. Three (4.1%) patients were diagnosed after the introduction of Padua Criteria.

At the time of ICD implant, 29 patients (40.3%) had right ventricular involvement, 24 (33.3%) had a dominant LV involvement, and 19 (26.4%) had biventricular involvement. During follow-up, 6 ARVC patients and 2 ALVC patients evolved to a biventricular pattern.

The mean age at implant was 46 $\pm$ 16 years; 48 patients (66%) were males, 68/72 implanted at our centre. The patients were followed for a median follow-up of 6.1 years [IQR: 2.5–9.9], genetic testing was performed in 45 patients (62.5%) and a pathogenic mutation was observed in 35 (80%) of these patients. The genes most frequently involved were desmoplakin (41.7%) and plakophillin2 (22.2%); 7 patients (20%) had more than one mutation.

Following the diagnostic criteria themselves, and the more recent enrolment, patients with ALVC had a better genetic characterization, compared to ARVC and biventricular ACM.

Population characteristics at implant are described in Table 2.

Primary prevention devices were implanted in 46 patients (63.9%), whereas 26 (36.1%) received a device for secondary prevention of SCD. A transvenous ICD was implanted in 51 patients (70.8%); single chamber ICD was the most frequent (39; 54.2%). Only 3 patients (4.2%) received a CRT-D, but during follow-up there were 3 up-grades from single-chamber to CRT-D. Eighteen patients (25%) underwent implantation of a subcutaneous ICD, 1 patient had an epicardial ICD (1.4%), and 2 patients (2.8%) received an extravascular ICD.

During follow-up, 34 patients (47.2%) had ventricular arrhythmias treated by the ICD. Fig. 5 shows the Kaplan–Meier analysis of cumulative survival from first appropriate ICD therapy on VA and LT-VA. Overall, the cumulative survival free from appropriate ICD interventions was 81%, 64% and 53% at 1, 2 and 5 years, respectively. Considering only life-threatening events (cycle length $\le$300 ms), 27 patients (37.5%) received appropriate therapy. Overall, the cumulative survival free from appropriate ICD interventions on LT-VA was 87%, 72% and 61% at 1, 2 and 5 years, respectively (Fig. 5). Within the three phenotypic variants (ARVC, ALVC and biventricular) there were no significant differences in the incidence of appropriate ICD intervention on VA or LT-VA (Fig. 5). ICD intervention characteristics are described in Table 3. The 34 patients who received an appropriate ICD activation had 919 therapies delivered because of VA, in total. Of these 34 patients, 27 had 314 episodes of LT-VA. The mean cycle length of LT-VA was 248 $\pm$ 25 ms. LT-VA was the first arrhythmic episode treated by ICD in 18 patients (52.6%). Of the 919 VA, 914/919 (99.4%) occurred in patients with an ICD capable of delivering ATP, while 5 (0.6%) occurred in s-ICD recipients. Considering only the 32 patients with an ICD capable of delivering ATP, 735 VA (80.4%) were successfully terminated with ATP; 179 VA (18.6%) did not respond to ATP and were treated with a shock. Of the 309 episodes of LT-VA, 201 (65%) of the 309 episodes of LT-VA (65%) were terminated by ATP and 108 (35%) by a shock, respectively. In 29/32 patients (91%) ATP terminated at least one episode of VA and in 14/25 (56%) at least one episode of LT-VA. The median cycle length of ATP-terminated vs non-terminated VA was respectively 310 [279–350] vs 278 [250–326] ms (p 0.001); the distribution is reported in Fig. 6. Two patients in the end-stage of biventricular ACM had a slow VT zone programmed to treat monomorphic VAs in the range 120–170 bpm recurrent despite ablation, which were managed by drug therapy and ATP. Shock was disabled in this VT zone. VT ablation was carried out in four patients with ARVC (3 endocardial, 1 epi/endocardial), 3 of them having recurrences at a different cycle length and morphology at follow up: 2 died after 6 and 13 months after ablation. A single ALVC patient with an S-ICD underwent endo-epicardial VT ablation proving non-inducibility, but had 3 VA recurrences in the 190–220 bpm range in the first year, requiring electrical cardioversion; no VAs have been recorded 2 years after the procedure.

In S-ICD recipients (18 patients) there were 5 shocks on LT-VA in 2 patients. One had a VA below the detection rate which was treated by electrical cardioversion (CVE) for clinical instability and was treated by ablation as aforementioned.

16 patients (22.2%) had inappropriate ICD therapy, including 10 because of supraventricular arrhythmias (7 atrial fibrillation, 2 sinus tachycardia, 1 atrial tachycardia), 4 because of oversensing (T wave or muscular activity in 2 S-ICD patients, lead noise in 2 transvenous ICD recipients). Nine patients (12.5%) needed reintervention because of loss of ventricular sensing (3 patients), infection (3 cases), insulation defect in a Riata lead (2), lead dislodgement (1 extravascular ICD patient). No re-interventions occurred in the S-ICD subgroup.

At last follow-up, 61 patients (84.7%) were alive and 11 (15.3%) had died: 7 related to heart failure, 1 for stroke, 3 due to non cardiovascular causes. Eight patients (11.1%) underwent heart transplantation due to refractory heart failure at a relatively young age (Fig. 7A,B). Mean patients age at cardiac transplantation was 38.6 $\pm$ 10.8 years. None of them required invasive mechanical assistance before transplant. One patient died over the complications of a CMV donor-driven primary infection.