Left-dominant Arrhythmogenic Cardiomyopathy Research Articles

MYOCARDITIS: VIRUS OR DESMOSOME?

Abstract Patient Profile Female, 56 yo, arterial hypertension, FH of autoimmune diseases, no history of sudden death. Medical History: • At the age of 46: Hospitalized for chest pain. Coronary angiography: negative. Diagnosis: myocardial ischemia with normal coronary arteries. • 2018: Hospitalized again for angina. ECG showed low voltages, flat T–waves in the inf–lat. leads. Coronary angiography: negative. Biopsy Mild hypertrophy and cytoplasmic vacuolization, minimal increase in interstitial fibrosis, no necrosis or inflammatory infiltrates. Mild nonspecific cardiomyopathy. Viral DNA test positive for HHV–6. Serology: HHV–6 in blood (neg), IgG HHV–6 (pos), IgM (neg). Diagnosis: myocarditis due to HHV–6. • San Camillo Cardiomyopathy Center: Echocardiogram: basal ant–lat. hypokinesia, EF 60%. Therapy: Bisoprolol 3.75 mg, Ramipril 5 mg, Ranolazine 1000 mg. MRI: basal transmural ant–lat. and subepicardial lateral LGE. Oedema and hypokinesia coexists. Subacute myocarditis. MRI at 1 year: mild left ventricular dilation, EF 60%, meso–subepicardial LGE in the ant–lat and inf mid–basal regions without oedema. Serial Holter ECGs: frequent polymorphic ventricular ectopics, couplets, and runs. CPET: normal exercise capacity, pVO2 19.4 (ml/min)/kg (90%). Genetic testing VUS in DSC, probably pathogenic, and VUS in ABCC9, PKP2, DSP (2 mutations) with uncertain clinical significance. • In 2022: Readmitted for angina. Elevated Troponin levels. Coro CT angiography: negative. MRI: EF 45%, akinesia of the apex and apical lat. wall; diffuse LGE and edema. Pericardial effusion. Patient refused biopsy. Discharged after recovery (EF 52%) with the diagnosis of recurrent myocarditis. Empagliflozin added. • Follow up. ECG: progression of repolarization abnormalities (TWI in V1–V3 + inf.–lat. leads). Biopsy: fibroadipose replacement, no necrosis or inflammatory infiltrates. Chronic myocarditis and sequels. Viral tests: negative. CPET and stress echo: VO2peak 20.7 (ml/kg)/min (88%), normal work capacity. Very rare monomorphic PVCs. EF 50%, preserved contractile reserve. Conclusions Diagnosis of left dominant arrhythmogenic cardiomyopathy with a typical pattern for hot phases of myocardial inflammation. The first episode could have been triggered by a viral infection on a predisposing genetic substrate. Nadolol 40 mg x2 was introduced. The possibility of ICD implantation was discussed, and patient refused. A six–month follow–up was planned. Family screening results were negative.

Diagnostic delay in arrhythmogenic cardiomyopathy.

Diagnosis of arrhythmogenic cardiomyopathy (ACM) may be challenging, as it comprises diverse phenotypes (right dominant, biventricular, and left dominant), and each may overlap with other clinical entities. The issue of differential diagnosis with conditions mimicking ACM has been previously highlighted; however, a systematic analysis of ACM diagnostic delay, and of its clinical implications, is lacking. Data of all ACM patients from three Italian Cardiomyopathy Referral Centres were reviewed to assess the time from first medical contact to definitive ACM diagnosis; a significant diagnostic delay was defined as a time to ACM diagnosis ≥2 years. Baseline characteristics and clinical course of patients with and without diagnostic delay were compared. Of 174 ACM patients, 31% experienced diagnostic delay, with a median time to diagnosis of 8 years (20% in right-dominant ACM, 33% in left-dominant ACM, and 39% in biventricular). Patients with diagnostic delay, when compared with those without, more frequently exhibited an ACM phenotype with left ventricular (LV) involvement (74 vs. 57%, P = 0.04) and a specific genetic background (none had plakophilin-2 variants). The most common initial (mis)diagnoses were dilated cardiomyopathy (51%), myocarditis (21%), and idiopathic ventricular arrhythmia (9%). At follow-up, all-cause mortality was greater in those with diagnostic delay (P = 0.03). Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in specific clinical settings are of key importance for the timely identification of ACM.

Role of cardiac magnetic resonance in the differential diagnosis between arrhythmogenic cardiomyopathy with left ventricular involvement and previous infectious myocarditis.

AimsArrhythmogenic cardiomyopathy with left ventricular involvement (ACM-LV), particularly in case of isolated left ventricular involvement (i.e. left dominant arrhythmogenic cardiomyopathy, LDAC) and previous infectious myocarditis (pIM) may have overlapping clinical and cardiac magnetic resonance (CMR) features. To date, there are no validated CMR criteria for the differential diagnosis between these conditions. The present study aimed to identify CMR characteristics to distinguish ACM-LV from pIM. Methods and resultsThis observational, retrospective, single-centre study included 30 pIM patients and 30 ACM-LV patients. In ACM-LV patients CMR was performed at diagnosis; in patients with pIM, CMR was performed six months after acute infection. CMR analysis included quantitative assessment of left ventricle (LV) volumes, systolic function and wall thicknesses, qualitative and quantitative assessment of late gadolinium enhancement (LGE) sequences. Compared with pIM, ACM-LV patients showed slightly larger LV volumes, more frequent regional wall motion anomalies and reduced wall thicknesses. ACM-LV patients had higher amounts of LV LGE and extension. Notably, the LDAC subgroup had the highest amount of LV LGE. LV LGE amount > 15 g and a LV LGE percentage > 30% of LV mass discriminated ACM-LV from pIM with a 100% specificity. LGE segmental distribution was superimposable among the groups, except for septal segments that were more frequently involved in ACM-LV and LDAC patients. ConclusionsA great extension of LV LGE (a cut-off of LGE >15 g and a percentage above 30% of LV LGE in relation to total myocardial mass) discriminates ACM-LV from pIM with extremely high specificity.

787 A CASE OF LEFT-DOMINANT ARRHYTHMOGENIC CARDIOMYOPATHY

Abstract The case we present involves a 45-years-old male patient who presented to the Emergency Department of our Hospital complaining of epigastric increasing pain associated with nausea and vomiting since the previous afternoon. During night patient had a syncopal episode after having had the feeling of pounding heart at the moment he was having a diarrheal bowel movement. Blood test showed no HS-Troponin nor D-dimer increase. Consultant cardiologist decided to test patient with an exercise test that showed polymorphic ventricular ectopic beats thus leading to hospitalization in our Cardiology Unit. Here patient was asymptomatic and hemodynamically stable during the whole period. He underwent an echocardiography showing no abnormal findings. For this reason, our team decided to perform a Cardiac Magnetic Resonance that showed LGE at subepicardial level in mid-apical segment of inferior wall and apical segment of interventricular septum. What's more, “India ink artifact” as of intramyocardial adipose infiltration was evident. Not having made a final diagnosis we decided to implant a Loop Recorder and asked patient to wear a wearable cardiac defibrillator. Genetic testing was also ordered to search for common mutations involved in Arrhythmogenic cardiomyopathy. At discharge, a therapy with metoprolol 50 mg twice per day was prescribed. Two months later, the result of genetics confirmed the diagnosis of Arrhythmogenic Cardiomyopathy with left ventricular involvement and the patient entered our Unit to undergo Implantable Cardioverter-Defibrillator (ICD) positioning for primary prevention of sudden cardiac death (SCD). Arrhythmogenic Cardiomyopathy (AC) is a genetic heart muscle disorder whose main pathological feature is normal myocardial tissue replacement by fibrofatty scar tissue and clinical presentation with life-threatening ventricular arrhythmias associated or not with global or regional ventricular systolic dysfunction. Although it was firstly described a predominant right ventricle involvement, nowadays it is known the existence of biventricular and even left-dominant phenotype. Prevalence is estimated between 1:1000 and 1:5000. AC occurs all over the world but has an increased prevalence in Northeastern Italy area. Pathologically fibrofatty tissue replacement begins from the subepicardial layers of myocardium towards subendocardial to become transmural. Diagnosis is made following a scoring system firstly created in 1994, then revised in 2010 and again in 2020, when the so-called Padua criteria were proposed. They are divided in 6 different categories: morpho-functional ventricular abnormalities, structural myocardial abnormalities, repolarization and depolarization abnormalities, ventricular arrhythmias, genetics. Demonstration of mutation in left-dominant AC related genes is mandatory for diagnosis because clinical and imaging features are not specific for this condition. Our case demonstrates a challenging diagnosis of left-dominant AC with a perfect example of Padua criteria implementation, because our patient had structural myocardial abnormalities as LGE by CMR plus had a positive molecular genetic testing.

310 CLINICAL COURSE AND CHARACTERISTICS OF ADVANCED HEART FAILURE ASSOCIATED WITH ARRHYTHMOGENIC CARDIOMYOPATHY

Abstract Background The prevalence and course of heart failure (HF) in arrhythmogenic cardiomyopathy (ACM) is unresolved, and previous studies have mostly focused on the right-dominant variant of the disease, less prone to HF. Conversely, ACM variants with left ventricular (LV) involvement are now increasingly recognized, often initially ‘mis-diagnosed’ as dilated cardiomyopathy. Aim of this study was therefore to describe the prevalence and clinical course of advance HF in the full clinical spectrum of ACM. Methods We retrospectively reviewed records of all ACM patients diagnosed before 2021 from 3 Italian Cardiomyopathy Referral Centres (Azienda Ospedaliero Universitaria Careggi; Policlinico Sant’Orsola; Azienda Ospedaliero Universitaria Sant’Andrea). LV involvement was diagnosed in the presence of subepicardial late gadolinium enhancement (LGE) in at least 3 contiguous segments in the same short-axis slice at cardiac magnetic resonance, independent of whether it fulfilled the 2010 Task Force criteria for right-dominant ACM (biventricular ACM) or not (left-dominant ACM); in this latter case, diagnosis was reached after careful exclusion of other differential diagnosis, and only when at least one of the following features was present: likely pathogenic/pathogenic genetic variant associated with ACM; familial history of ACM; electrocardiographic abnormalities suggestive of ACM with LV involvement. Advanced HF was defined as NYHA functional class III/IV and/or referral for heart transplantation. Median follow-up was 6 years. Results Forty-four out of 174 ACM patients (25%) developed advanced HF: 10 right-dominant ACM and 34 with LV involvement. Twenty ACM patients were initially diagnosed with dilated cardiomyopathy; as such, development of advanced HF in 17 cases preceded the diagnosis of ACM. Five patients were diagnosed with ACM after heart transplantation, by histological examination. In the other 22, median time from ACM diagnosis to advanced HF development was 4 years. As compared to those without, advanced HF patients were more likely to present LV involvement. During clinical course, 20 (46%) advanced HF patients received at least one appropriate ICD intervention, with 13 experiencing an electrical storm. Twenty-six (59%) patients required HF-related hospitalization, and 32 (72%) were referred for heart transplantation with 25 ultimately receiving it. ACM patients with advanced HF, compared to those without, experienced a higher rate of mortality (36% vs. 6%; OR 3.5 [95%CI: 1.4-8.7], p=0.01) and ventricular arrhythmic events (41% vs. 11%; OR 2.4 [95%CI: 1.1-5.0], p=0.02). Conclusions Advanced HF progression in ACM is not rare, and occurs more frequently in variants with LV involvement. Advanced HF is associated with increased mortality and arrhythmic risk.

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies

BackgroundDiverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. ObjectivesWe sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. MethodsDilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure–related death (DHF)/HT/left ventricular assist device implantation (LVAD). ResultsSurvival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. ConclusionsGenotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

Loss-of-Function FLNC Variants Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population.

The FLNC gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy, which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in FLNC (FLNCLOF) would have increased odds for arrhythmogenic cardiomyopathy-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort. We identified rare, putative FLNCLOF among 171 948 individuals with exome sequencing linked to health records. Associations with arrhythmogenic cardiomyopathy phenotypes from available diagnoses and cardiac evaluations were investigated. Sixty individuals (0.03%; median age 58 years [47-70 interquartile range], 43% male) harbored 27 unique FLNCLOF. These individuals had significantly increased odds ratios for dilated cardiomyopathy (odds ratio, 4.9 [95% CI, 2.6-7.6]; P<0.001), supraventricular tachycardia (odds ratio, 3.2 [95% CI, 1.1-5.6]; P=0.048), and left-dominant arrhythmogenic cardiomyopathy (odds ratio, 4.2 [95% CI, 1.4-7.9]; P=0.03). Echocardiography revealed reduced left ventricular ejection fraction (52±13% versus 57±9%; P=0.001) associated with FLNCLOF. Overall, at least 9% of FLNCLOF patients demonstrated evidence of penetrant disease. FLNCLOF variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of FLNC for actionable secondary findings.

Cardiac magnetic resonance features of left dominant arrhythmogenic cardiomyopathy: differential diagnosis with myocarditis

Cardiac magnetic resonance features of left dominant arrhythmogenic cardiomyopathy: differential diagnosis with myocarditis

Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP).

Background:Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC.Methods:We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with “pathogenic” or “likely pathogenic” variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected.Results:Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%).Conclusions:Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.

The 2020 "Padua Criteria" for Diagnosis and Phenotype Characterization of Arrhythmogenic Cardiomyopathy in Clinical Practice.

Arrhythmogenic Cardiomyopathy (ACM) is a heredo-familial cardiac disease characterized by fibro-fatty myocardial replacement and increased risk of sudden cardiac death. The diagnosis of ACM can be challenging due to the lack of a single gold-standard test: for this reason, it is required to satisfy a combination of multiple criteria from different categories including ventricular morpho-functional abnormalities, repolarization and depolarization ECG changes, ventricular arrhythmias, tissue characterization findings and positive family history/molecular genetics. The first diagnostic criteria were published by an International Task Force (ITF) of experts in 1994 and revised in 2010 with the aim to increase sensitivity for early diagnosis. Limitations of the 2010 ITF criteria include the absence of specific criteria for left ventricle (LV) involvement and the limited role of cardiac magnetic resonance (CMR) as the use of the late gadolinium enhancement technique for tissue characterization was not considered. In 2020, new diagnostic criteria (“the Padua criteria”) were proposed. The traditional organization in six categories of major/minor criteria was maintained. The criteria for identifying the right ventricular involvement were modified and a specific set of criteria for identifying LV involvement was created. Depending on the combination of criteria for right and LV involvement, a diagnosis of classic (right dominant) ACM, biventricular ACM or left-dominant ACM is then made. The article reviews the rationale of the Padua criteria, summarizes the main modifications compared to the previous 2010 ITF criteria and provides three examples of the application of the Padua criteria in clinical practice.

Cardiac magnetic resonance features of left dominant arrhythmogenic cardiomyopathy: differential diagnosis with myocarditis

Cardiac magnetic resonance (CMR) findings suggesting a suspected left-dominant arrhythmogenic cardiomyopathy (LDAC) may be difficult to distinguish from those related to previous myocarditis; however, especially in patients with ventricular arrhythmias (VA) with ECG morphology consistent with a left ventricle (LV) origin differential diagnosis is fundamental. Aim of the study was to identify potential imaging features at CMR specific for LDAC diagnosis. Between January 2011 and December 2019, we enrolled 15 consecutive stable patients with a recent diagnosis of significant VA and ECG morphology consistent with a LV origin, detection of potential LV arrhythmic substrate at CMR and undergoing a clinically-indicated LV endomyocardial biopsy showing tissue abnormalities consistent with the diagnosis of LDAC. From the same CMR-endomyocardial biopsy registry, a second group of 30 consecutive patients who underwent CMR and biopsy with a histological diagnosis of previous myocarditis were identified. (1) Subepicardial LGE at the level of the posterolateral wall of the LV was detected in 13 cases of LDAC vs. 21 cases of myocarditis; (2) fat infiltration, and particularly subepicardial posterolateral fat infiltration, was found in almost all LDAC patients vs. one myocarditis only (p < 0.01). (3) No differences in other CMR findings or in any clinical or echocardiographic parameters were found between patients with a biopsy consistent with LDAC vs. myocarditis. In patients with significant VA and ECG morphology consistent with a LV origin, the presence of morpho-functional involvement of the subepicardial layer of LV posterolateral wall at CMR (LGE, fat infiltration, wall dyskinesis) supports LDAC diagnosis.

Evolution of diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy and their application in clinical practice

This article describes evolution of criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The novel diagnostic criteria for ARVD/C published in 2020 are analyzed in detail, among which biventricular and leftdominant arrhythmogenic cardiomyopathy are identified for the first time. The need to develop novel criteria was fed on the accumulation of new data on ARVD/C, in particular, significant advances in magnetic resonance imaging technologies. The novel criteria retained high sensitivity and specificity in relation to traditional right ventricular disease form and became more sensitive in relation to the biventricular and left-dominant arrhythmogenic cardiomyopathy.Nevertheless, the addition of left-dominant disease forms reduces the criteria specificity in general, since left ventricle involvement with a similar clinical performance can have different etiology that goes beyond the ARVD/C, even when mutations are detected in typical genes, which is demonstrated by case reports described in the article. Like the previous two versions, the novel criteria will be fully assessed only with a large sample of patients after their introduction into the routine cardiology clinical practice.

Use of 3D computed tomography to image fatty tissue: a case of left-dominant arrhythmogenic cardiomyopathy

Use of 3D computed tomography to image fatty tissue: a case of left-dominant arrhythmogenic cardiomyopathy

A paradigm shift in the concept of arrhythmogenic cardiomyopathy: expanding the clinical and genetic spectrum, new diagnostic criteria for left ventricular phenotypes

Recent multicenter studies using high-tech cardiac imaging and novel translational technologies have shown that cardiac fibrofatty replacement, characteristic of arrhythmogenic cardiomyopathy (ACM), is observed in both ventricles; left ventricular (LV) involvement may be minimal, on par with the right ventricle (RV), or dominant. In 2019, the Heart Rhythm Society (HRS) proposed a new approach to the assessment of arrhythmic and genetic diseases with the inclusion of new phenotypes — left-dominant ACM and biventricular ACM. In 2020, to improve the diagnosis of left ventricular phenotypes, European experts revised ACM criteria (based on the 2010 ITF criteria), which are called the Padua criteria.The presented article highlights the clinical and genetic aspects of the new concept and the difficulties in ACM diagnosis, the practical experience of using new diagnostic algorithm. To help practitioners, step-by-step differential diagnosis and risk stratification of right and left ventricular phenotypes are presented using clinical examples (leftdominant ACM with a pathogenic variant in the LMNA gene; right-dominant ACM associated with a desmoplakin gene mutation, with predominant RV and moderate LV involvement; and an isolated RV ACM associated with a mutation in the plakophilin 2 gene).

Cardiac magnetic resonance features of left dominant arrhythmogenic cardiomyopathy: differential diagnosis with myocarditis

Abstract Objectives To identify potential imaging features at cardiac magnetic resonance (CMR) specific for left-dominant arrhythmogenic cardiomyopathy (LDAC) diagnosis. Materials and methods Between January 2011 and May 2016, we considered 36 consecutive stable patients with a recent diagnosis of significant VA and ECG morphology consistent with a LV origin, detection of potential LV arrhythmic substrate at CMR, undergoing a clinically-indicated LV endomyocardial biopsy. Exclusion criteria were history of known cardiac disease, contraindications to CMR and impaired CMR image quality. After application of these criteria, in 9 patients endomyocardial biopsy showed tissue abnormalities consistent with the diagnosis of LDAC. From the same CMR-endomyocardial biopsy registry, a second group of 9 consecutive patients with a histological diagnosis of previous myocarditis were identified. Results Mid-wall LGE in the interventricular septum was detected in 5 myocarditis, without findings in LDAC group (p=0.03), whereas subepicardial LGE at the level of posterolateral wall of LV was detected in 8 cases of LDAC vs. 2 cases of myocarditis (p=0.02). Fat infiltration, and particularly subepicardial posterolateral fat infiltration, was found in all LDAC patients vs. one myocarditis only (p&amp;lt;0.01). No differences in other CMR findings or in any clinical or echocardiographic parameters were found between patients with a biopsy consistent with LDAC vs. patients in whom biopsy suggested myocarditis. Conclusions In patients with significant VA and ECG morphology consistent with a LV origin, identification of morpho-functional involvement of the subepicardial layer of LV posterolateral wall at CMR (LGE, fat infiltration, wall dyskinesis) is consistent with a diagnosis of LDAC. Funding Acknowledgement Type of funding source: None

Emerging concepts in arrhythmogenic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) represents one of the primary cardiomyopathies and may lead to heart failure and sudden death. Until recently, ventricular arrhythmias were considered to be a direct consequence of the systolic dysfunction of the left ventricle (LV) and guidelines for implantable cardioverter defibrillator implantation were established on this basis. However, the identification of heritable dilated cardiomyopathy phenotypes that presented with mildly impaired or moderate LV dysfunction, with or without chamber dilatation, and ventricular arrhythmias exceeding the degree of the underlying morphological abnormalities lead to the identification of the arrhythmogenic phenotypes and genotypes of DCM. This subset of DCM patients presents phenotypic and in many cases genotypic overlaps with left dominant arrhythmogenic cardiomyopathy (LDAC). LMNA, SCN5A, FLNC, TTN, and RBM20 are the main genes responsible for arrhythmogenic DCM. Moreover, desmosomal genes such as DSP and other non-desmosomal such as DES and PLN have been associated with both LDAC and arrhythmogenic DCM. The aim of this review is to highlight the importance of genetic profiling among DCM patients with disproportionate arrhythmic burden and the significance of the electrocardiogram, cardiac magnetic resonance, Holter monitoring, detailed family history, and other assays in order to identify red flags for arrhythmogenic DCM and proceed to an early preventive approach for sudden cardiac death. A special consideration was given to the phenotypic and genotypic overlap with LDAC. The role of myocarditis as a common disease expression of LDAC and arrhythmogenic DCM is also analyzed supporting the premise of their phenotypic overlap.

Long-term follow-up analysis of a highly characterized arrhythmogenic cardiomyopathy cohort with classical and non-classical phenotypes-a real-world assessment of a novel prediction model: does the subtype really matter.

To provide long-term outcome data on arrhythmogenic cardiomyopathy (ACM) patients with non-classical forms [left dominant ACM (LD-ACM) and biventricular ACM (Bi-ACM)] and an external validation of a recently proposed algorithm for ventricular arrhythmia (VA) prediction in ACM patients. Demographic, clinical, and outcome data were retrieved from all ACM patients encountered at our institution. Patients were classified according to disease phenotype (R-ACM; Bi-ACM; LD-ACM). Overall and by phenotype long-term survival were calculated; the novel Cadrin-Tourigny et al. algorithm was used to calculate the a priori predicted VA risk, and it was compared with the observed outcome to test its reliability. One hundred and one patients were enrolled; three subgroups were defined (R-ACM, n = 68; Bi-ACM, n = 14; LD-ACM, n = 19). Over a median of 5.41 (2.59-8.37) years, the non-classical form cohort experienced higher rates of VAs than the classical form [5-year freedom from VAs: 0.58 (0.43-0.78) vs. 0.76 (0.66-0.89), P = 0.04]. The Cadrin-Tourigny et al. predictive model adequately described the overall cohort risk [mean observed-predicted risk difference (O-PRD): +6.7 (-4.3, +17.7) %, P = 0.19]; strafing by subgroup, excellent goodness-of-fit was demonstrated for the R-ACM subgroup (mean O-PRD, P = 0.99), while in the Bi-ACM and LD-ACM ones the real observed risk appeared to be underestimated [mean O-PRD: -20.0 (-1.1, -38.9) %, P < 0.0001; -22.6 (-7.8, -37.5) %, P < 0.0001, respectively]. Non-classical ACM forms appear more prone to VAs than classical forms. The novel prediction model effectively predicted arrhythmic risk in the classical R-ACM cohort, but seemed to underestimate it in non-classical forms.

Left-Dominant Arrhythmogenic Cardiomyopathy: A Rare and Frequently Misdiagnosed Cardiomyopathy Associated with Heart Failure

Left-Dominant Arrhythmogenic Cardiomyopathy: A Rare and Frequently Misdiagnosed Cardiomyopathy Associated with Heart Failure

P178The "rat-bite sign". An additional clue in the diagnosis of left-dominant arrhythmogenic cardiomyopathy

P178The "rat-bite sign". An additional clue in the diagnosis of left-dominant arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management

### Learning objectives Phenotype is defined as a set of observable characteristics of an individual resulting from the interaction of their genotype with the environment. It differs from ‘disease’ in...