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Background Pentraxin 3 (PTX3) is an acute phase protein, which regulates the outcomes of inflammation. Currently, there are no myocarditis-typical biomarkers that allow a non-invasive diagnosis, and endomyocardial biopsy (EMB) is still the gold standard. Finally, risk stratification is often challenging in these patients. Aim To investigate whether PTX3 could be expressed in cardiomyocytes and released during myocarditis, serving as a novel and independent diagnostic indicator of myocardial inflammation, and contributing to prognosis prediction. Methods Fifty-five patients with a diagnosis of acute or chronic active myocarditis proven by cardiac magnetic resonance (CMR) and/or endomyocardial biopsy (EMB), were included. First, we evaluated tissue PTX3 expression by immunohistochemistry (IHC). Then, we assessed circulating blood PTX3 by ELISA technique. Results On cardiac tissue, PTX3 at IHC did not localize in the interstitium, and showed an inconstant expression in the vascular endothelium, but a marked staining by cardiomyocytes in all myocarditis patients. The only exception was represented by two patients with systemic COVID-19, with SARS-CoV-2 and PVB-19 intracardiac genomes, respectively, who showed a diffuse cardiac PTX3 expression. Remarkably, at semi-quantitative pixel analysis, viral aetiology showed higher levels of tissue expression, rather than the autoimmune one. Circulating PTX3 levels were significantly higher in myocarditis patients than controls, with pathologic values in 87% of myocarditis patients, and none among controls. Remarkably, plasma PTX3 proved to be more sensitive in myocarditis detection than CRP, ESR, troponin T, and NT-proBNP. As regards of prognosis, we observed that patients with heart failure (HF) presentation all had elevated PTX3 levels, as compared with chest pain or arrhythmia. Remarkably, patients with reduced LVEF ( Conclusions Tissue PTX3 is mostly expressed by cardiomyocytes in patients with active myocarditis on EMB samples. In addition, plasma PTX3 is a sensitive diagnostic and prognostic marker in patients with inflammatory cardiomyopathy.

Background Preclinical data support the rationale for targeting myocardial inflammation in genetic nonischemic cardiomyopathies. However, no consistent clinical reports have been provided so far. Methods We describe a series of patients (n=25) with genetic cardiomyopathy and active myocardial inflammation (AMI) proven by multimodal diagnostic workup. Patient-tailored immunosuppressive therapy was empirically started to target myocardial inflammation whenever feasible. Multiple outcomes were retrospectively assessed by a dedicated multidisciplinary disease unit. Results Patients carrying desmosomal (DGV), cytoskeletal (CGV) and membrane gene variants (MGV), were 12 (48%), 10 (40%), and 3 (12%), respectively. DGV carriers uniformly presented with myocarditis-like chest pain and ventricular arrhythmias, whereas heart failure symptoms were found only in CGV carriers. Dilated cardiomyopathy phenotype and ring-like pattern on cardiac magnetic resonance allowed the best discrimination among genotypes. AMI was proven by endomyocardial biopsy in all cases, and by noninvasive imaging in 21 (83%). IST was started in 17 patients (71%) with no safety issues. By the end of follow-up (median 69 months, range 21-182), signs of AMI were documented in 6/18 IST receivers (33%) and 4/7 untreated cases (57%). For most genotypes, paucity of adverse events was noted while on immunosuppression as compared to the off-treatment period. Conclusion Our preliminary data provide the clinical rationale for the research and targeting of AMI in a spectrum of genetic nonischemic cardiomyopathies.

Brugada syndrome (BrS) is an inherited autosomal dominant genetic disorder responsible for sudden cardiac death from malignant ventricular arrhythmia. The term “channelopathy” is nowadays used to classify BrS as a purely electrical disease, mainly occurring secondarily to loss-of-function mutations in the α subunit of the cardiac sodium channel protein Nav1.5. In this setting, arrhythmic manifestations of the disease have been reported in the absence of any apparent structural heart disease or cardiomyopathy. Over the last few years, however, a consistent amount of evidence has grown in support of myocardial structural and functional abnormalities in patients with BrS. In detail, abnormal ventricular dimensions, either systolic or diastolic dysfunctions, regional wall motion abnormalities, myocardial fibrosis, and active inflammatory foci have been frequently described, pointing to alternative mechanisms of arrhythmogenesis which challenge the definition of channelopathy. The present review aims to depict the status of the art of concealed arrhythmogenic substrates in BrS, often resulting from an advanced and multimodal diagnostic workup, to foster future preclinical and clinical research in support of the cardiomyopathic nature of the disease.

Brugada syndrome (BrS) is an inherited autosomal dominant cardiac channelopathy. Pathogenic rare mutations in the SCN5A gene, encoding the alpha-subunit of the voltage-dependent cardiac Na+ channel protein (Nav1.5), are identified in 20% of BrS patients, affecting the correct function of the channel. To date, even though hundreds of SCN5A variants have been associated with BrS, the underlying pathogenic mechanisms are still unclear in most cases. Therefore, the functional characterization of the SCN5A BrS rare variants still represents a major hurdle and is fundamental to confirming their pathogenic effect. Human cardiomyocytes (CMs) differentiated from pluripotent stem cells (PSCs) have been extensively demonstrated to be reliable platforms for investigating cardiac diseases, being able to recapitulate specific traits of disease, including arrhythmic events and conduction abnormalities. Based on this, in this study, we performed a functional analysis of the BrS familial rare variant NM_198056.2:c.3673G>A (NP_932173.1:p.Glu1225Lys), which has been never functionally characterized before in a cardiac-relevant context, as the human cardiomyocyte. Using a specific lentiviral vector encoding a GFP-tagged SCN5A gene carrying the specific c.3673G>A variant and CMs differentiated from control PSCs (PSC-CMs), we demonstrated an impairment of the mutated Nav1.5, thus suggesting the pathogenicity of the rare BrS detected variant. More broadly, our work supports the application of PSC-CMs for the assessment of the pathogenicity of gene variants, the identification of which is increasing exponentially due to the advances in next-generation sequencing methods and their massive use in genetic testing.

Background: both myocarditis and mitral valve prolapse (MVP) are known uncommon causes of ventricular arrhythmias in young patients. Aim: to report the first clinical case of endomyocardial biopsy (EMB)-proven autoimmune myocarditis and associated arrhythmogenic MVP in a patient with recurrent ventricular fibrillation (VF) episodes. Methods: myocarditis was diagnosed both by cardiac magnetic resonance (CMR) and EMB. Arrhythmogenic MVP was documented by transthoracic echocardiogram, CMR, and electroanatomical mapping of the trigger premature ventricular contractions (PVCs). Results: a 22-year-old woman underwent immunosuppressive therapy after EMB-proven diagnosis of autoimmune myocarditis with VF onset and early implantable cardioverter defibrillator (ICD) placement. Three years later, she experienced two VF recurrences and persistent PVCs, despite no signs of myocarditis recurrence. An echocardiogram revealed bileaflet MVP with high arrhythmic risk features. Finally, electroanatomical mapping and ablation of the trigger PVC were successfully performed. Conclusion: in patients with recurrent VF episodes despite evidence-based medical treatment for myocarditis, MVP should be considered as an alternative arrhythmogenic substrate, and warrants early ICD implant and PVC-targeted therapy.

Background Arrhythmic risk of patients with left ventricular arrhythmogenic cardiomyopathy (LVAC) is unpredictable. Purpose To identify risk facors associated with major ventricular tachyarrhythmias (VTA) in clinically-suspected LVAC patients. Methods We enrolled 127 consecutive patients (69% males, age 46±13 y, LVEF 54±7%) with clinically-suspected LVAC. All patients presented with either major (VT, VF) or minor VTA (NSVT, frequent VEB), and underwent extensive diagnostic workup to rule-out alternative diagnoses. Medical treatment and ICD implant were clinically-driven. Prospective follow-up was obtained via sequential 24h-Holter ECG (2–4/y) with or without continuous arrhythmia monitoring (ICD or implantable loop recorders, ILR). The primary endpoint was occurrence of major VTA (VT/VF/ICD therapy) by 24-month follow-up. Results At presentation, 56 (44%) and 71 patients (56%) had, respectively, major and minor VTA. Variants in desmosomal genes were identified in 7 of the 9 patients with clinically-indicated genetic test. Delayed gadolinium enhancement (DGE, average 23±12% of the LV mass) had anteroseptal distribution in 43 cases (34%). Monitoring strategy included ICD (n=64), ILR (n=33), or sequential Holer ECGs (n=30). By 24-month follow-up, major VTA occurred in 32 patients (25%). At univariable anlysis, major VTA onset (HR 16.8, 95% CI 5.4–52.2, p Conclusion Our preliminary experience suggests that, in patients with clinically-suspected LVAC, major VTA onset and anteroseptal DGE are relevant risk factors for major arrhythmic events by 24-month follow-up. Funding Acknowledgement Type of funding sources: None.

Background. Exercise stress test (EST) has been scarcely investigated in patients with arrhythmic myocarditis. Objectives. To report the results of EST late after myocarditis with arrhythmic vs. nonarrhythmic presentation. Methods. We enrolled consecutive adult patients with EST performed at least six months after acute myocarditis was diagnosed using gold-standard techniques. Patients with ventricular arrhythmia (VA) at presentation were compared with the nonarrhythmic group. Adverse events occurring during follow-up after EST included cardiac death, disease-related rehospitalization, malignant VA, and proven active myocarditis. Results. The study cohort was composed of 128 patients (age 41 ± 9 y, 70% males) undergoing EST after myocarditis. Of them, 64 (50%) had arrhythmic presentation. EST was performed after 15 ± 4 months from initial diagnosis, and was conducted on betablockers in 75 cases (59%). During EST, VA were more common in the arrhythmic group (43 vs. 4, p < 0.001), whereas signs and symptoms of ischemia were more prevalent in the nonarrhythmic one (6 vs. 1, p = 0.115). By 58-month mean follow-up, 52 patients (41%) experienced adverse events, with a greater prevalence among arrhythmic patients (39 vs. 13, p < 0.001). As documented both in the arrhythmic and nonarrhythmic subgroups, patients had greater prevalence of adverse events following a positive EST (40/54 vs. 12/74 with negative EST, p < 0.001). Electrocardiographic features of VA during EST correlated with the subsequent inflammatory restaging of myocarditis. Nonarrhythmic patients with uneventful EST both on- and off-treatment were free from subsequent adverse events. Conclusions. Late after the arrhythmic presentation of myocarditis, EST was frequently associated with recurrent VA. In both arrhythmic and nonarrhythmic myocarditis, EST abnormalities correlated with subsequent adverse outcomes.

Background. Myocarditis lacks systematic characterization in COVID-19 patients. Methods. We enrolled consecutive patients with newly diagnosed myocarditis in the context of COVID-19 infection. Diagnostic and treatment strategies were driven by a dedicated multidisciplinary disease unit for myocarditis. Multimodal outcomes were assessed during prospective follow-up. Results. Seven consecutive patients (57% males, age 51 ± 9 y) with acute COVID-19 infection received a de novo diagnosis of myocarditis. Endomyocardial biopsy was of choice in hemodynamically unstable patients (n = 4, mean left ventricular ejection fraction (LVEF) 25 ± 9%), whereas cardiac magnetic resonance constituted the first exam in stable patients (n = 3, mean LVEF 48 ± 10%). Polymerase chain reaction (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome in one of the six cases undergoing biopsy: in the remaining patients, myocarditis was either due to other viruses (n = 2) or virus-negative (n = 3). Hemodynamic support was needed for four unstable patients (57%), whereas a cardiac device implant was chosen in two of four cases showing ventricular arrhythmias. Medical treatment included immunosuppression (43%) and biological therapy (29%). By the 6-month median follow-up, no patient died or experienced malignant arrhythmias. However, two cases (29%) were screened for heart transplantation. Conclusions. Myocarditis associated with acute COVID-19 infection is a spectrum of clinical manifestations and underlying etiologies. A multidisciplinary approach is the cornerstone for tailored management.

Background Procalcitonin (PCT) is an established predictor of bacterial infections and sepsis. However, PCT involvement in cardiovascular diseases has been scarcely investigated so far. In particular, no studies at all ever addressed the role of PCT in myocarditis patients. We aimed at evaluating PCT in myocarditis patients, as a potential biomarker of: a) aetiologic diagnosis; b) prognosis. Methods A cohort of 130 consecutive patients with a novel diagnosis of myocarditis confirmed by both endomyocardial biopsy and cardiac magnetic resonance were included in the study. Patients with known bacterial infections or bacterial myocarditis were excluded (n=5). PCT concentration was measured on admission in all patients. Prospective follow-up (FU) was performed every 6 months up to 5 years. Results Of 125 patients analyzed (mean age 45±15 years, males 62%, mean LVEF 48±15%), 22 (18%) had fulminant myocarditis (FM). The remaining 103 cases had non-fulminant myocarditis (NFM), including infarct-like presentation and non-malignant arrhythmias. Aetiology was viral or virus-negative in 23 and 102 patients, respectively. The mean PCT value was 0.44±0.18 mcg/ml, with no significant differences between viral and virus-negative myocarditis (0.43±0.19 vs. 0.44±0.18 mcg/ml, p=0.90). Baseline PCT concentration was significantly higher in FM patients (0.69±0.21 vs. 0.39±0.16 mcg/ml, p=0.07). Consistently, PCT was higher in patients with LVEF 400 pg/mL) NT-proBNP (0.55±0.19 vs. 0.36±0.17 mcg/ml, p=0.03). As for inflammatory biomarkers, patients with high ESR (>20 mm/h) had also higher PCT values (0.56±0.20 vs. 0.37±0.16 mcg/ml, p=0.03). By converse, no association was found between PCT and CRP abnormal values (p>0.05). At univariate analysis, high PCT (≥0.20 mcg/ml) was predictive of heart failure recurrence (OR 2.77, 95% CI 1.18–6.48, p=0.02) or arrhythmic cardiac arrest (OR 3.22, 95% CI 1.19–8.71, p=0.02) by discharge, with overall hospitalization prolonged by 10±4 days (p Conclusions In myocarditis patients, elevated PCT values at presentation are not associated with myocarditis aetiology. Nonetheless, PCT suggests a worse short-term clinical outcome, and also a higher risk of myocarditis recurrences at long-term FU. Funding Acknowledgement Type of funding source: None

Background: Little is known about the risk stratification of patients with myocarditis undergoing ventricular tachycardia (VT) ablation. Objectives: This study sought to describe VT ablation results and identify factors associated with arrhythmia recurrences in a cohort of patients with myocarditis. Methods: The authors enrolled 125 consecutive patients with myocarditis, undergoing VT ablation. Before ablation, disease stage was evaluated, to identify active (AM) versus previous myocarditis (PM). The primary study endpoint was assessment of VT recurrences by 12-month follow-up. Predictors of VT recurrences were retrospectively identified. Results: All patients (age 51 ± 14 years, 91% men, left ventricular ejection fraction 52% ± 9%) had history of myocarditis diagnosed by endomyocardial biopsy (59%) and/or cardiac magnetic resonance (90%). Furthermore, all had multiple episodes of drug-refractory VTs. Multimodal pre-procedural staging identified 47 patients with AM (38%) and 78 patients with PM (62%). All patients showed low-voltage areas (LVA) at electroanatomical map (97% epicardial or endoepicardial); of them, 25 (20%) had wide borderzone (WBZ, constituting >50% of the whole LVA). VT recurrences were documented in 25 patients (20%) by 12 months, and in 43 (34%) by last follow-up (median 63 months; interquartile range: 39 to 87). At multivariable analysis, AM stage was the only predictor of VT recurrences by 12 months (hazard ratio: 9.5; 95% confidence interval: 2.6 to 35.3; p < 0.001), whereas both AM stage and WBZ were associated with arrhythmia recurrences anytime during follow-up. No VT episodes were found after redo ablation was performed in 23 patients during PM stage. Conclusion: Our findings suggest that VT ablation should be avoided during AM, but is often of benefit for recurrent VT after the acute phase of myocarditis.