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Myocarditis has increased with Covid-19 and Covid-19 vaccines. Precise diagnosis relies on endomyocardial biopsy, but MRI and myocardial markers may be used. Treatment depends on the cause and degree of functional compromise.

Arrhythmogenic right ventricular cardiomyopathy is a rare inherited heart-muscle disease that is a cause of sudden death in young people and athletes. Causative mutations in genes encoding desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy. Clinical diagnosis can be achieved by demonstrating function and structure changes of the right ventricle, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias, and fibrofatty replacement through endomyocardial biopsy. Although specific, the standardised diagnostic criteria lack sensitivity for early disease and their primary application remains in establishing the diagnosis in probands. However, the main clinical targets are early detection of concealed forms and risk stratification for preventive strategies, which include physical exercise restriction, antiarrhythmic drugs, and implantable cardioverter-defibrillator therapy. Cascade genetic screening of family members of gene-positive probands allows the identification of asymptomatic carriers who would require lifelong follow-up due to the age-related penetrance.

Arrhythmogenic cardiomyopathy (AC) is a clinically heterogeneous cardiac disease that is associated with ventricular arrhythmias and sudden cardiac death. The authors discuss the diagnosis and genetic basis of AC, and how disruption of desmosomal crosstalk with the nucleus, gap junctions, and ion channels might underlie the pathophysiology of this condition. Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous disorder of heart muscle that is associated with ventricular arrhythmias and risk of sudden cardiac death, particularly in the young and athletes. Mutations in five genes that encode major components of the desmosomes, namely junction plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2, have been identified in approximately half of affected probands. AC is, therefore, commonly considered a 'desmosomal' disease. No single test is sufficiently specific to establish a diagnosis of AC. The diagnostic criteria for AC were revised in 2010 to improve sensitivity, but maintain specificity. Quantitative parameters were introduced and identification of a pathogenic mutation in a first-degree relative has become a major diagnostic criterion. Caution in the interpretation of screening results is highly recommended because a 'pathogenic' mutation is difficult to define. Experimental data confirm that this genetically determined cardiomyopathy develops after birth because of progressive myocardial dystrophy, and is initiated by cardiomyocyte necrosis; cellular and animal models are necessary to gain insight into the cascade of underlying molecular events. Crosstalk from the desmosome to the nucleus, gap junctions, and ion channels is under investigation, to move from symptomatic to targeted therapy, with the ultimate aim to stop disease onset and progression. Key Points Arrhythmogenic cardiomyopathy (AC) is a familial heart-muscle disease that is usually inherited with an autosomal-dominant pattern; mutations in desmosomal-protein genes are found in approximately 50% of probands The 1994 diagnostic criteria were updated in 2010 to increase their sensitivity, but maintain their specificity; differential diagnosis with AC 'phenocopies' is mandatory when dealing with sporadic forms of AC Emerging tools offer the possibility to visualize the fibrofatty scar, as either low-voltage myocardial areas using electroanatomical mapping, or areas of delayed contrast-enhancement with cardiac MRI Genotype–phenotype studies show that the clinicomorphological spectrum of AC is wider than originally thought, and includes variants with predominant or even isolated left ventricular involvement within a single family Animal and cellular models indicate that both abnormal biomechanical properties and crosstalk from the desmosome to the nucleus, gap junctions, and ion channels are implicated in the pathobiology of AC Electrical instability is the main clinical manifestation of AC; in addition to re-entry arrhythmias caused by fibrofatty replacement, current hypotheses implicate acute cell death, gap-junction remodeling, and ion-channel crosstalk

Since cardiac hypertrophy may be considered a cause of death at autopsy, its assessment requires a uniform approach. Common terminology and methodology to measure the heart weight, size, and thickness as well as a systematic use of cut off values for normality by age, gender, and body weight and height are needed. For these reasons, recommendations have been written on behalf of the Association for European Cardiovascular Pathology. The diagnostic work up implies the search for pressure and volume overload conditions, compensatory hypertrophy, storage and infiltrative disorders, and cardiomyopathies. Although some gross morphologic features can point to a specific diagnosis, systematic histologic analysis, followed by possible immunostaining and transmission electron microscopy, is essential for a final diagnosis. If the autopsy is carried out in a general or forensic pathology service without expertise in cardiovascular pathology, the entire heart (or pictures) together with mapped histologic slides should be sent for a second opinion to a pathologist with such an expertise. Indication for postmortem genetic testing should be integrated into the multidisciplinary management of sudden cardiac death.

Ischemic heart disease is one of the leading causes of morbidity and death worldwide. Consequently, myocardial infarctions are often encountered in clinical and forensic autopsies, and diagnosis can be challenging, especially in the absence of an acute coronary occlusion. Precise histopathological identification and timing of myocardial infarction in humans often remains uncertain while it can be of crucial importance, especially in a forensic setting when third person involvement or medical responsibilities are in question. A proper post-mortem diagnosis requires not only up-to-date knowledge of the ischemic coronary and myocardial pathology, but also a correct interpretation of such findings in relation to the clinical scenario of the deceased. For these reasons, it is important for pathologists to be familiar with the different clinically defined types of myocardial infarction and to discriminate myocardial infarction from other forms of myocardial injury. This article reviews present knowledge and post-mortem diagnostic methods, including post-mortem imaging, to reveal the different types of myocardial injury and the clinical-pathological correlations with currently defined types of myocardial infarction.

Introduction Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterised by substitution of the ventricular myocardium by fibrofatty tissue.1 The disease was originally termed ‘arrhythmogenic right ventricular (dysplasia/) cardiomyopathy’ (ARVC) to define a condition which distinctively affected the right ventricle (RV) and predisposed to potentially fatal ventricular arrhythmias, particularly in young individuals and athletes.2–4 New insights arising from postmortem investigations, genotype–phenotype correlation studies and myocardial tissue characterisation by contrast-enhanced cardiac magnetic resonance (CMR) led to increased awareness that the disease often also involves the left ventricle (LV).5–11 The current designation of ‘arrhythmogenic cardiomyopathy’ better reflects the evolving concept of a heart muscle disease affecting both ventricles, with some phenotypic variants characterised by a parallel or predominant involvement of the LV. According to the HRS document, the vague common denominator of this miscellaneous group of ‘arrhythmogenic cardiomyopathies’ was the ‘clinical presentation with symptoms or documentation of atrial fibrillation, conduction disease, and/or RV and/or LV arrhythmia’. CMR studies in living patients fulfilling the 2010 International Task Force (ITF) criteria have consistently shown that LV involvement in terms of morphofunctional (LV global or regional systolic dysfunction) and/or structural (LV late gadolinium enhancement (LGE)) abnormalities is identified in more than half of patients.9 22 24 According to the available findings of clinical studies, phenotypic features of left-sided ACM include the following (figure 1): (1) ECG abnormalities such as low-amplitude QRS complexes (peak to peak <0.5 mV) in limb leads and T-wave inversion or flattening in the lateral (or inferolateral) leads, although the ECG is often normal; (2) ventricular arrhythmias with a right bundle branch block (RBBB) morphology of the ectopic QRS (denoting the origin from the LV); (3) normal or slightly depressed LV systolic function with no (or mild) dilatation; (4) large amount of myocardial fibrosis evidenced by contrast-enhanced CMR as LGE; and (5) ‘non-ischemic’ pattern of LGE, predominantly involving the subepicardial layers of the inferior and the inferolateral regions. A number of human DSP gene mutations have been linked with ACM, which manifest characteristically with early LV involvement occurring in isolation or preceding RV disease.28 Of note, in the initial report of the DSP gene mutation responsible for ‘Carvajal syndrome’, the cardiac phenotype resembled that of DCM as opposed to the classic ARVC phenotype.29 Phospholamban normally inhibits the sarcoendoplasmic reticulum calcium transport ATPase, and PLN gene mutations cause dysregulated calcium flux, predisposing to prominent arrhythmia and ventricular dysfunction.

In sudden cardiac death, an autopsy is an essential step in establishing a diagnosis of inherited cardiac disease and identifying families that require cardiac screening. To evaluate aspects of post-mortem practice in Europe, a questionnaire was designed and circulated to both clinical and forensic pathologists. There was a 48% response rate and information was obtained from 17 countries. The results showed a wide variety in the management of sudden cardiac death, with a general tendency towards a lack of thorough investigation. In up to 40% of cases, autopsies were not performed in subjects less than 50 years who may have died from cardiac disease. Reasons for this were lack of finance and lack of interest from police, legal authorities, and doctors. Only 50% of pathologists seem to follow a standard protocol for autopsy examination, apparently due to lack of expertise and/or training. When autopsies were performed, histology and toxicology were almost always taken, genetic studies were generally available and retention of the heart for specialist study was usually permitted. Our results suggest that although the standard of practice is appropriate in many centres, many more cases should have autopsies, especially in sudden deaths in subjects less than 50 years.

Despite advances in non-invasive methods, endomyocardial biopsy (EMB) remains essential for definitive diagnosis of amyloidosis in many cases. Traditionally, Congo red birefringence (CRB) has been crucial for identifying amyloid deposits but is challenging to capture digitally. Emerging fluorescent Congo red imaging (CRF) overcomes this problem and holds promise in image analysis and AI applications. The diagnostic performance of CRF on virtual slides was evaluated in a cohort of EMB and autopsy cases. The feasibility of developing AI algorithms applicable to centers lacking a fluorescence scanner was investigated leveraging a computational pipeline that enables fluorescence outcome visualization in brightfield. The study analyzed 43 digital myocardial slides stained with Congo Red, acquired using a fluorescent Texas Red filter. Among these, 28 (65%) were diagnosed with amyloidosis, with complete diagnostic agreement with original diagnosis. AI achieved an AUC-ROC of 0.87, 0.86 and 0.79 on the training, validation and test set, respectively, in tile-level classification for amyloidosis positivity and IoU and Dice scores indicating partial but reasonable overlap between predictions and ground truth in amyloid segmentation. The study underscores CRF’s transformative impact on virtual slides and AI integration for diagnosing cardiac amyloidosis, showcasing high reliability and diagnostic accuracy. These advancements promise a more quantitative and precise approach, facilitating the histological study of the disease in the digital transition era of pathology labs.

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.

In the WHO 1996 classification of cardiomyopathies, myocarditis is defined as an “inflammatory disease of the myocardium associated with cardiac dysfunction” and is listed among “specific cardiomyopathies”. Myocarditis is diagnosed on endomyocardial biopsy (EMB) by established histological, immunological, and immunohistochemical criteria, and molecular techniques are recommended to identify viral etiology. Infectious, autoimmune, and idiopathic forms of inflammatory cardiomyopathy are recognized that may lead to dilated cardiomyopathy. According to Dallas criteria, myocarditis is diagnosed in the setting of an “inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of ischemic damage associated with coronary artery disease”. The majority of experts in the field agree that an actual increase in sensitivity of EMB has now been reached by using immunohistochemistry together with histology. A value of >14 leukocytes/mm 2 with the presence of T lymphocytes >7 cells/mm 2 has been considered a realistic cut off to reach a diagnosis of myocarditis. The development of molecular biological techniques, particularly amplification methods like polymerase chain reaction (PCR) or nested-PCR, allows the detection of low copy viral genomes even from an extremely small amount of tissue such as in EMB specimens. Positive PCR results obtained on EMB should always be accompanied by a parallel investigation on blood samples collected at the time of the EMB. According to the recent Association for European Cardiovascular Pathology guidelines, optimal specimen procurement and triage indicates at least three, preferably four, EMB fragments, each 1–2 mm in size, that should immediately be fixed in 10 % buffered formalin at room temperature for light microscopic examination. In expected focal myocardial lesions, additional sampling is recommended. Moreover, one or two specimens should be snap-frozen in liquid nitrogen and stored at −80 °C or alternatively stored in RNA-later for possible molecular tests or specific stains. A sample of peripheral blood (5–10 ml) in EDTA or citrate from patients with suspected myocarditis allows molecular testing for the same viral genomes sought in the myocardial tissue.