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• Early EMB is associated with a higher rate of survival free of HTx/LVAD at one year compared with delayed EMB. [ABSTRACT FROM AUTHOR]

• Histological examination of endomyocardial biopsy or myocardium at autopsy is key to the diagnosis of myocarditis. • There is currently extensive variability in criteria used by pathologists to diagnose myocarditis. • It is difficult to achieve a consensus diagnosis of myocarditis, even amongst experienced cardiovascular pathologists. Histological examination of endomyocardial biopsy or myocardium at autopsy is key to the diagnosis of myocarditis. Among pathologists there is currently extensive variability in routine practice and criteria used to define, diagnose, and report myocarditis as well as to achieve consensus on cases. Two manuscripts emphasizing the need to standardize and implement histopathological diagnostic criteria for myocarditis are reviewed. [ABSTRACT FROM AUTHOR]

• Pathologists worldwide report various biopsy practice of myocarditis diagnosis. • There are regional differences in adopting diagnostic criteria and ancillary testing. • Non-uniformity in current criteria hinders comparative and multicenter studies. Dallas criteria (DC) and European Society of Cardiology criteria (ESCC) have provided valuable frameworks for the histologic diagnosis and classification of myocarditis in endomyocardial biopsy (EMB) specimens. However, the adaptation and the usage of these criteria are variable and depend on local practice settings and regions/countries. Moreover, several ancillary tests that are not included in the current criteria, such as immunohistochemistry (IHC) or viral polymerase chain reaction (PCR), have proven useful for the diagnosis of myocarditis. As a joint effort from the Association for European Cardiovascular Pathology (AECVP) and the Society for Cardiovascular Pathology (SCVP), we conducted an online survey to understand the current practice of diagnosing myocarditis. A total of 100 pathologists from 23 countries responded to the survey with the majority practicing in North America (45%) and Europe (45%). Most of the pathologists reported to examine less than 200 native heart biopsies per year (85%), and to routinely receive 3-5 fragments of tissue per case (90%). The number of hematoxylin-eosin-stained levels for each case varies from 1 to more than 9 levels, with 20% of pathologists routinely asking for more than 9 levels per case. Among the 100 pathologists, 52 reported to use the DC alone, 12 the ESCC alone, 28 both DC and ESCC and 8 reported to use neither the DC nor the ESCC. Overall, 80 pathologists reported to use the DC and 40 the ESCC. Use of DC alone is more common among North American pathologists compared to European ones (80% vs 32.6%) while use of ESCC alone is more common in Europe (20.9% vs 2.5%). IHC is utilized in either every case or selected cases by 79% of participants, and viral PCR is performed by 35% of participants. Variable terminologies are used in reporting, including both histological and clinical terms. The diagnosis of myocarditis is rendered even in the absence of myocyte injury (e.g., in cases of borderline or inactive/chronic myocarditis) by 46% respondents. The majority of the participants think it is time to update the current criteria (83%). The survey data demonstrated that pathologists who render a myocarditis diagnosis practice with variable tissue preparation methods, use of ancillary studies, guideline usage, and reporting. This result highlights the clinically unmet need to update and standardize the current diagnostic criteria for myocarditis on EMB. Additional studies are warranted to establish standard of practice. [ABSTRACT FROM AUTHOR]

• One hundred digital cases were evaluated by cardiovascular pathologists • Consensus was achieved on 90 cases • Subtle forms of myocarditis are challenging to diagnose The two histopathology benchmarks used to diagnose myocarditis are the Dallas Criteria, developed in 1984 and the European Society of Cardiology criteria, developed in 2013, which added immunohistochemistry for the detection of CD3+ T cells (lymphocytes) and CD68+ macrophages. Despite their near universal acceptance, the extent to which pathologists use these criteria or their own criteria to consistently render the diagnosis of myocarditis on endomyocardial biopsy (EMB) is unknown. We digitally scanned slides from 100 heart biopsies, including a trichrome stain and immunostaining, that were chosen as representative of myocarditis, non-myocarditis, and borderline myocarditis, as diagnosed per one institution's use of the Dallas Criteria. Eight blinded international cardiovascular experts were asked to render diagnoses and offer a confidence score on each case. No clinical histories were shared. There was full initial agreement across all experts on 37 cases (16 myocarditis and 21 non-myocarditis) and moderate consensus on 35 cases. After individual inquiries and group discussion, consensus was reached on 90 cases. Diagnostic confidence was highest among the myocarditis diagnoses, lowest for borderline cases, and significantly different between the three diagnostic categories (myocarditis, borderline myocarditis, non-myocarditis; P -value=8.49 × 10−57; ANOVA). Diagnosing myocarditis, particularly in cases with limited inflammation and injury, remains a challenge even for experts in the field. Intermediate cases, termed "borderline" in the Dallas Criteria, represent those for which consensus is particularly hard to achieve. To increase consistency for the histopathologic diagnosis of myocarditis, we will need more specifically defined criteria, more granular descriptions of positive and negative features, clarity on how to incorporate immunohistochemistry findings, and improved nomenclature. [ABSTRACT FROM AUTHOR]

Diagnosis of myocarditis as the cause of death in the forensic setting at post-mortem is currently determined by a forensic pathologist. There is no systematic method for diagnosis and thus the determination is subject to inter-observer variability and is often non-reproducible. The primary aim of this study was to investigate the differences in the amount of inflammation between cases where myocarditis was deemed the cause of death, compared to cases where myocardial inflammation was incidentally present at autopsy, but not determined to be the cause of death. Participants were sourced from the Victorian Institute of Forensic Medicine (VIFM) database, from full autopsies conducted on reportable death in Victoria, Australia between the years 2011 and 2021. Cases of fatal myocarditis were significantly more likely to experience infection-like symptoms prior to death, and to be in hospital at the time of death. Histopathological examination revealed fatal cases had a significantly higher inflammatory index compared to the incidental group. Lethal cases were also significantly more likely to have myocyte necrosis, and a diffuse pattern of inflammation. There are significant differences between cases where myocardial inflammation has been determined to be the cause of death and cases where inflammation in the myocardium was an incidental finding. These results could be used in the forensic autopsy to help pathologists determine if inflammation should be considered fatal or incidental. [ABSTRACT FROM AUTHOR]

• There is no current reproducible method for diagnosis of myocarditis in the post-mortem setting, it is up to the forensic pathologist • There is no system to determine whether inflammation in the heart was the cause of death, or an incidental finding at autopsy. • Variables to distinguish between fatal and incidental myocarditis have not been widely researched and requires further investigation Diagnosis of myocarditis as the cause of death at post-mortem is currently determined by a forensic pathologist. There is no systematic method for diagnosis and thus the determination is subject to inter-observer variability and is non-reproducible. Postmortem studies often rely on the clinical method of diagnosis, which is inaccurate. Furthermore, there is no current standardized method of distinguishing between myocarditis as cause of death, and myocardial inflammation as an incidental finding post-mortem. Only a few studies have investigated a method of quantifying this difference using variables such as number of inflammatory cells and presence of myocyte necrosis, however, there are several limitations hindering the reproducibility of this research. This review investigates the current practices and limitations associated with the diagnosis of myocarditis as cause of death in the autopsy setting [ABSTRACT FROM AUTHOR]

• The histologic diagnosis of myocarditis warrants revisiting in light of questions raised preceding and during the pandemic. • Interobserver variability remains high, with divergent practices in different regions of the world. • The diagnosis and implications of myocarditis are reviewed in conjunction with two relevant articles. The histologic criteria for myocarditis are a focal point of scientific debate in the wake of the SARS-CoV-2 pandemic. Variable methodologies have evolved in an evaluation already plagued by high intraobserver variability and low sensitivity. In this commentary, two topical manuscripts are reviewed in the context of this unfolding discussion. [ABSTRACT FROM AUTHOR]

• Single myocyte necrosis is a relatively specific finding in Covid-19 decedents. • Epicardial macrophages are elevated in the setting of single myocyte necrosis. • Epicardial and myocardial macrophages are increased in Covid-19 decedents' hearts. SARS-Cov-2 infection is not limited to the respiratory tract and can involve other organs including the heart, blood vessels, kidneys, liver, gastrointestinal tract, placenta, and skin. Covid-19 patients with cardiac involvement usually have higher morbidity and mortality compared to those without cardiac involvement. The frequency and the specificity of the myocardial pathological changes in patients who die after documented infection with SARS-Cov-2 is uncertain. Macrophages can be found in the normal heart (interstitium, around the endothelial cells and in the epicardial adipose tissue), and they are considered part of the major immune cell population in the heart. In this case-control autopsy study, we compare the gross and microscopic cardiac findings, and the available clinical characteristics between a group of 10 Covid-19 decedents and a control group of 20 patients who died with non-SARS-Cov-2 severe bronchopneumonia and/or diffuse alveolar damage. The objectives of this semi-quantitative study are to study single myocyte necrosis and its relation to the strain on the heart caused by lung injury as a causative mechanism, and to study the density of myocardial and epicardial macrophages in Covid-19 hearts in comparison to the control group, and in Covid-19 hearts with single myocyte necrosis in comparison to Covid-19 hearts without single myocyte necrosis. Lymphocytic myocarditis was not identified in any of the hearts from the Covid-19 or the control group. Single myocyte necrosis is more frequent in the Covid-19 group compared to the control group, suggesting that it is unrelated to the strain on the heart caused by underlying lung injury. The density of the macrophages in the epicardium and myocardium in the hearts of the Covid-19 group is higher compared to those in the control group. The density of epicardial macrophages is higher in the Covid-19 hearts with single myocyte necrosis than in those without. These observations contribute to our increasing appreciation of the role of macrophages in the pathophysiologic response to infection by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

• Mechanisms of myocardial injury as a complication of COVID-19 have not been well understood. • We experienced a case with cardiogenic shock infected by COVID-19. • With endomyocardial biopsy, there was no sign of typical active myocarditis. • Ischemic changes were found at microvascular level accompanied by microthrombi. • Microvascular thrombotic injury is shown as a cause of fulminant myocarditis-like presentation. Myocardial injury has been reported as a complication of COVID-19. Although several mechanisms have been proposed as its cause, they are mostly based on autopsy studies, We report a 49-year-old male with COVID-19-associated myocardial injury presented like fulminant myocarditis. We performed endomyocardial biopsy on day 2 and we confirmed the presence of microthrombosis histologically. He died on day 5 due to cardiogenic shock. [ABSTRACT FROM AUTHOR]

• Endomyocardial biopsy results are integral for diagnosis and management of myocarditis. Current diagnostic classifications of myocarditis are based on the microscopic and immunochemical characterization of inflammation do not include monocyte/macrophage-predominant (i.e. "histiocytic") myocarditis as a histologic subtype. We describe 6 cases of patients with acute heart failure whose endomyocardial biopsies showed predominant inflammation with macrophages and monocytes identified by immunopositivity for CD68. • Our cases were both cardiac limited (i.e. primary) and associated with systemic disease, including autoimmune disease. Some biopsies showed coagulative necrosis, and some showed features resembling antibody mediated rejection of cardiac allografts. Clinical outcomes ranged from spontaneous resolution to persistent heart failure. • Histiocytic myocarditis appears to be a distinct histopathological subtype associated with heterogeneous clinical contexts and outcomes, and its presence may reflect antibody mediated myocardial injury. Endomyocardial biopsy results are integral for diagnosis and management of myocarditis. Current diagnostic classifications of myocarditis are based on the microscopic and immunochemical characterization of inflammation do not include monocyte/macrophage-predominant (i.e. "histiocytic") myocarditis as a histologic subtype. Endomyocardial biopsies from 6 patients with sudden heart failure were reviewed by 3 cardiac pathologists. Routine stains and immunostains to identify T cells and monocytes/macrophages, complement C4d, and endothelium were applied. Electron microscopy was performed in 2 cases. The 6 patients included 2 with diagnoses of systemic lupus erythematosus (SLE) and 4 without known disease. Microscopy showed space-occupying inflammation in 2 cases and interstitial inflammation in 4. No giant cell myocarditis or eosinophilic myocarditis was found. Immunostains showed infiltration predominantly by macrophages and/or monocytes with markedly fewer T cells. In 4 of 6 cases necrotic cells were immunopositive for complement C4d. Monocytes we identified immunochemically within the microvasculature in 5 cases and by electron microscopy in 2. Patients with SLE had microvascular C4d positivity or interstitial/sarcolemmal staining. Clinical outcomes ranged from spontaneous resolution to persistent heart failure requiring an internal cardioverter/defibrillator. (1) Heart failure with CD68 predominant inflammation ("histiocytic" myocardial inflammatory disease, HMID) occurs with variable clinical presentation and outcome; (2) HMID may be primary or secondary; (3) some cases of HMID show features suggestive of antibody and/or complement mediated myocardial injury, and (4) HMID is a diagnosis distinct from those in classification systems currently in use. [ABSTRACT FROM AUTHOR]

• Myocarditis is an uncommon but potentially life-threatening disease • Clinical onset varies from subclinical disease to sudden death • The evolution of myocarditis ranges from complete recovery to dilated cardiomyopathy • It is crucial to identify predictors of short and long-term outcomes • A correct diagnostic evaluation is crucial to provide an appropriate treatment Although it has been recognized for almost two centuries, myocarditis is still a challenging diagnosis due to the wide heterogeneity of its clinical manifestations and evolution. Moreover, the diagnostic gold standard, endomyocardial biopsy (EMB), is infrequently used, making hard to determine the exact incidence of myocarditis. Clinical presentation includes a wide range of symptoms, ranging from asymptomatic or subclinical disease with mild dyspnea and chest pain to sudden death, due to cardiogenic shock or malignant ventricular arrhythmias. Equally, the evolution of myocarditis largely varies: albeit short-term prognosis is usually good, with complete or partial recovery, dilated cardiomyopathy with chronic heart failure is the major long-term consequence of myocarditis, developing often several years after the acute onset. This narrative review aims to summarize the current knowledge about myocarditis, with a particular attention to predictors of short- and long-term prognosis, in order to provide a rational and practical approach to the diagnosis, evaluation and treatment of suspected myocarditis. [ABSTRACT FROM AUTHOR]

• A significant decrease in QRS duration and R-amplitude occur in VM mice. • A strong correlation between ECG alteration and inflammation in the ventricles. • No correlation between ECG alteration and lesion size/ fibrosis in the ventricles. • The inflammation can form an important arrhythmogenic substrate in mild VM. Viral myocarditis (VM) can induce changes in myocardial electrical conduction and arrhythmia. However, their relationship with myocarditis-associated arrhythmic substrates in the heart such as inflammation and fibrosis is relatively unknown. This we have analyzed in the present study. C3H mice were infected with 1×105 plaque-forming units Coxsackievirus B3 (CVB3, n=68) and were compared with uninfected control mice (n=10). Electrocardiograms (ECGs) were recorded in all conscious mice shortly before sacrifice and included heart rate; P-R interval; QRS duration; QTc interval and R-peak amplitude of lead II and aVF. Mice were sacrificed at 4, 7, 10, 21, 35 or 49 days post-infection. Cardiac lesion size, calcification, fibrosis and cellular infiltration of CD45+ lymphocytes, MAC3+ macrophages, Ly6G+ neutrophils and mast cells were quantitatively determined in cross-sections of the ventricles. Putative relations between ECG changes and lesion size and/or cardiac inflammation were then analyzed. Significant transient reductions in QRS duration and R-peak amplitude occurred between 4 and 14 days post-infection and returned to baseline values thereafter. The magnitude of these ECG changes strongly correlated to the extent of lymphocyte (days 7 and 14), macrophage (days 7 and 10) and neutrophil (days 7) infiltration. The ECG changes did not significantly correlate with lesion size and fibrosis. VM induces transient changes in myocardial electrical conduction that are strongly related to cellular inflammation of the heart. These data show that even in mild VM, with relatively little cardiac damage, the inflammatory infiltrate can form an important arrhythmogenic substrate. [ABSTRACT FROM AUTHOR]

• Endomyocardial biopsy remains a valuable diagnostic tool in patients with suspected myocarditis. • Seventy-five percent of our patients with a diagnostic biopsy for myocarditis had a Class I or IIa indication for biopsy. • ↑ age and ventricular arrhythmias associated with ↑ mortality in diagnostic biopsy myocarditis. • Twenty-five percent of diagnostic biopsy myocarditis patients did not have a 2007 guideline indication for biopsy. • Diagnostic biopsy myocarditis patients more frequently required inotropes + advanced therapies. Diagnostic endomyocardial biopsy (EMB) in patients with suspected myocarditis helps to direct therapy and guide prognosis. This study aimed to investigate the correlation between the 2007 clinical guideline indications for EMB and the presence of a diagnostic biopsy result and associated outcomes in patients with suspected myocarditis in a national quaternary referral center in a contemporary cohort. All cases of suspected myocarditis referred to the National Cardiac Transplant Centre who underwent EMB between 2009 and 2019 were identified retrospectively through pathology records. Outcomes including subsequent need for inotrope and/or mechanical circulatory support (MCS), heart transplantation and in-hospital mortality were recorded. In total, 25 (68% male, mean age of 45 ± 15 years) EMBs were performed for this indication across this time period, 64% (n = 16) of which demonstrated diagnostic results, the majority (75%, n = 12) identifying acute lymphocytic myocarditis, 13% (n = 2) giant cell, one patient (6.3%) eosinophilic and one (6.3%) an immune checkpoint inhibitor myocarditis. The majority of those with histologically confirmed myocarditis had a Class I or IIa guideline indication for EMB (n = 12, 75%). The remaining 4 patients (25%), either met Class IIb criteria (n = 2) or would not have been accounted for in this guideline. The majority of patients requiring inotropes and/or MCS (n = 9/11), and/or heart transplant (n = 3/4), or who later died (n = 4/5) were in the diagnostic biopsy group. In this 10-year National referral sample, 75% of patients with histologically confirmed myocarditis had a Class I or IIa indication for EMB, reinforcing the usefulness of traditional guidelines in this contemporary era. However, 25% of patients with a subsequent confirmed histological diagnosis had either none or a less well-established indication for EMB, highlighting the need for clinical suspicion outside of accepted clinical scenarios. [ABSTRACT FROM AUTHOR]

• COVID-19 hearts do not exhibit typical inflammatory myocarditis. • COVID-19 hearts are associated with increased numbers of CD68+ cells compared to appropriate control hearts and with hearts with myocarditis. • The role of CD68+ cells in the cardiac pathophysiology of COVID-19 needs more investigation. COVID-19 has a significant effect upon the cardiovascular system. While a number of different cardiovascular histopathologies have been described at post-mortem examination, the incidence of typical viral myocarditis in COVID-19 positive patients appears very low [1–3]. In this study, we further characterize and quantify the inflammatory cell infiltrate in a COVID-19 study cohort and compare the findings to both an age and disease matched control cohort and a cohort of patients diagnosed with typical inflammatory myocarditis. All study and control cohorts had 1 or more of the comorbidities most commonly associated with severe disease (hypertension, type II diabetes, obesity, or known cardiovascular disease). The results demonstrate a skewed distribution of the number of CD68+ cells in COVID-19 hearts, with upper quantiles showing a significant increase as compared to both matched control hearts, and those with myocarditis. In contrast, hearts from typical inflammatory myocarditis contained increased numbers of CD4+, and CD8+ cells compared to both COVID-19 and control cohorts. In conclusion, the presence of an increased number of CD68+ cells suggests that COVID-19 may incite a form of myocarditis different from typical viral myocarditis, and associated with diffusely infiltrative cells of monocytes/macrophage lineage. [ABSTRACT FROM AUTHOR]