Extracellular vesicles (EVs) are membrane-bound particles released by all cells under physiological and pathological conditions. EVs constitute a potential tool to unravel cell-specific pathophysiological mechanisms at the root of disease states and retain the potential to act as biomarkers for cardiac diseases. By being able to carry bioactive cargo (such as proteins and miRNAs), EVs harness great potential as accessible \"liquid biopsies\", given their ability to reflect the state of their cell of origin. Cardiomyopathies encompass a variety of myocardial disorders associated with mechanical, functional and/or electric dysfunction. These diseases exhibit different phenotypes, including inappropriate ventricular hypertrophy, dilatation, scarring, fibro-fatty replacement, dysfunction, and may stem from multiple aetiologies, most often genetic. Thus, the aims of this narrative review are to summarize the current knowledge on EVs and cardiomyopathies (e.g., hypertrophic, dilated and arrhythmogenic), to elucidate the potential role of EVs in the paracrine cell-to-cell communication among cardiac tissue compartments, in aiding the diagnosis of the diverse subtypes of cardiomyopathies in a minimally invasive manner, and finally to address whether certain molecular and phenotypical characteristics of EVs may correlate with cardiomyopathy disease phenotype and severity.

Arrhythmogenic cardiomyopathy is a genetic heart muscle disease that typically affects the right ventricle. However, 2 other phenotypes affecting the left ventricle were recently discovered. Here, we report the case of an 18-year-old patient with biventricular arrhythmogenic cardiomyopathy, highlighting the challenges encountered in establishing this diagnosis. Diagnostic criteria for the left-sided phenotypic variants of arrhythmogenic cardiomyopathy were only introduced in 2020 by an international expert consensus document, known as the \"Padua criteria,\" they are divided in 6 categories with an emphasis on morpho-functional ventricular abnormalities and structural myocardial tissue alterations to diagnose biventricular arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients has been reported, suggesting a possible role of inflammation in the pathophysiology of the disease. Furthermore, chest pain episodes accompanied by electrocardiographic changes and troponin release have been observed and defined as the \"hot-phase\" phenomenon. The aim of this critical systematic review was to assess the clinical features of ACM patients presenting with \"hot-phase\" episodes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: \"arrhythmogenic cardiomyopathy\"; \"myocarditis\" or \"arrhythmogenic cardiomyopathy\"; \"troponin\" or \"arrhythmogenic cardiomyopathy\"; and \"hot-phase\". A total of 1433 titles were retrieved, of which 65 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, 9 papers reporting 103 ACM patients who had experienced hot-phase episodes were selected for this review. Age at time of episodes was available in 76% of cases, with the mean age reported being 26 years ± 14 years (min 2-max 71 years). Overall, 86% of patients showed left ventricular epicardial LGE. At the time of hot-phase episodes, 49% received a diagnosis of ACM (Arrhythmogenic left ventricular cardiomyopathy in the majority of cases), 19% of dilated cardiomyopathy and 26% of acute myocarditis. At the genetic study, Desmoplakin (DSP) was the more represented disease-gene (69%), followed by Plakophillin-2 (9%) and Desmoglein-2 (6%). In conclusion, ACM patients showing hot-phase episodes are usually young, and DSP is the most common disease gene, accounting for 69% of cases. Currently, the role of \"hot-phase\" episodes in disease progression and arrhythmic risk stratification remains to be clarified.

Arrhythmogenic cardiomyopathy (AC) is a rare, heritable myocardial disorder that is a leading cause of ventricular arrhythmia and sudden cardiac death (SCD) in young people. Desmoplakin (DSP) mutations account for 3-20% of AC cases. However, the number of patients with DSP mutations is extremely small in all published reports and genotype-phenotype correlations are scant and mostly non-gene-specific.
A 45-year-old man was admitted after an out-of-hospital cardiac arrest, with documented ventricular fibrillation. He had no previous history of heart disease or family history of SCD or cardiomyopathy. The cardiac magnetic resonance showed a mildly dilated left ventricle with an ejection fraction of 30% and a non-dilated right ventricle with mildly depressed systolic function, and extensive subepicardial late gadolinium enhancement. Genetic screening identified a heterozygote nonsense mutation in DSP (NM_004415.2: c.478 C > T; p.Arg160Ter). Cascade genetic screening of the relatives revealed a high prevalence of the genotype and cutaneous phenotype, but a very low penetrance of the cardiac phenotype.
We report a case of SCD and an autosomal dominant mutation in DSP that causes arrhythmogenic dilated cardiomyopathy/AC. Like the recessive mutation in DSP known to cause Carvajal syndrome, Arg160Ter may be associated with cutaneous abnormalities.

Sudden cardiac death (SCD) in young athletes represents a challenging issue in forensic practice. The pathologist is frequently asked to establish the cause of death basing upon anatomical findings and to evaluate the role of the physician in preparticipation evaluation (PPE) and eligibility decision. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of SCD during sport activity. However, in the last few years, forms with predominant or even isolated involvement of the left ventricle (LV) have progressively been correlated with a high risk of SCD. We present a case of SCD in an apparently healthy 19-year-old semi-professional football player. Annual PPEs performed in accordance with international and Italian recommendations, were unremarkable. At autopsy, a 1-cm area of subepicardial fibro-fatty replacement was observed at the postero-lateral wall of the LV. The finding was diagnostic of arrhythmogenic left ventricular cardiomyopathy (ALVC). A review of this rare pathology has been performed under a forensic perspective, focusing on the evaluation of the medico-legal responsibility of the physician in the PPE and on the morphological aspects of the disease. Current diagnostic criteria and recommendations result to be focused on the right ventricular pattern, with a risk of misdiagnosis for isolated LV forms. Furthermore, few detailed autopsies cases concerning ALVC have been published. There is a need, therefore, to study this rare disease with a careful and revised approach.

Speckle tracking echocardiography (STE) has gained importance in the evaluation of adult inherited cardiomyopathies, but its utility in children is not well characterized. We conducted a systematic review to evaluate the role of STE in pediatric inherited cardiomyopathies. PubMed, EMBASE, Web of Science, Scopus, CENTRAL and CINAHL databases were searched up to May 2020, for terms related to inherited cardiomyopathies and STE. Included were dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC) and arrhythmogenic cardiomyopathy (ACM). A total of 14 cohorts were identified, of which six were in DCM, four in HCM, three in LVNC and one in ACM. The most commonly reported STE measurements were left ventricular longitudinal strain (Sl), circumferential strain (Sc), radial strain (Sr) and rotation/torsion/twist. Sl, Sc and were abnormal in all DCM and LVNC cohorts, but not in all HCM. Apical rotation and twist/torsion were increased in HCM, and decreased in LVNC. Abnormal STE parameters were reported even in cohorts with normal non-STE systolic/diastolic measurements. STE in childhood cardiomyopathies can detect early changes which may not be associated with changes in cardiac function detectable by non-STE methods. Longitudinal and circumferential strain should be introduced in the cardiomyopathy echocardiography protocol, reflecting current practice in adults.

BACKGROUND: Naxos disease is a rare entity that manifests with woolly hair, keratosis of extremities, and cardiac manifestations that resemble arrhythmogenic right ventricular cardiomyopathy. It is inherited in an autosomal recessive pattern and mutations affecting plakoglobin and desmoplakin have been identified. There is an increased risk of arrhythmias, including sudden cardiac death at a young age. Right ventricular systolic dysfunction often progresses and left ventricular involvement may also occur.
UNASSIGNED: This article reviews historic background, epidemiology, clinical characteristics, genetics, and pathogenesis as well as therapeutic management and future perspectives.
UNASSIGNED: The principles of evaluation and treatment are based on arrhythmogenic right ventricular cardiomyopathy (ARVC) and general heart failure guidelines, because specific data on Naxos disease are limited. Therefore, larger registries on Naxos disease are welcome in order to gain more knowledge about clinical course and risk stratification. Translational research on pathophysiological mechanisms has evolved, including promising approaches using stem cells for novel targets.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.

Desmosomes have long been appreciated as intercellular junctions that are vital for maintaining the structural integrity of stratified epithelia. More recent clinical investigations of patients with diseases such as arrhythmogenic cardiomyopathy have further highlighted the importance of desmosomes in cardiac tissue, where they help to maintain coordination of cardiac myocytes. Here, we review clinical and mechanistic studies that provide insight into the functions of desmosomal proteins in skin and heart during homeostasis and in disease. While intercellular junctions are organized differently in cardiac and epithelial tissues, studies conducted in epithelial systems may inform our understanding of cardiac desmosomes. We explore traditional and non-traditional roles of desmosomal proteins, ranging from adhesive capacities to nuclear functions. Finally, we discuss how these studies can guide future investigations focused on determining the molecular mechanisms by which desmosomal mutations promote the development of cardiac diseases.