Active Myocarditis Research Articles

The diagnostic value of endomyocardial biopsy in the era of precision medicine: data from over 8,000 patients with comprehensive biopsy diagnostics

Abstract Background Endomyocardial biopsy (EMB) is an important diagnostic tool for evaluating various cardiac diseases such as myocarditis and storage disorders as well as for the monitoring heart transplant patients. Despite advances in non-invasive imaging techniques to characterize myocardial tissue, EMB remains the gold standard for definitive diagnosis and initiation of specific therapy. Here we report EMB laboratory results from over 8,000 patients and demonstrate the diagnostic utility of EMB. Methods and results We retrospectively reviewed EMB analyses performed at our institution. EMBs for monitoring graft rejection were not included in this study. Clinical data, suspected clinical diagnoses and EMB-based laboratory results were collected. Histopathological, immunohistochemical and molecular biology biopsy findings were recorded and reviewed for degree of concordance with clinical diagnosis. In total, EMBs from N=8,085 consecutive patients with unexplained heart failure were analyzed. The comprehensive EMB analysis revealed that N=616 (7.6%) patients had cardiac storage disease, most of whom had cardiac amyloidosis (N=606). N=357 (4.4%) patients were diagnosed with acute forms of myocarditis, including N=95 cases with active myocarditis, N=148 cases with giant cell myocarditis, N=95 cases with sarcoidosis and N=19 cases with eosinophilic myocarditis. A total of N=3,392 (42%) patients were found to have inflammatory heart disease such as inflammatory cardiomyopathy and borderline myocarditis, whereby a differentiation of the inflammatory infiltrates revealed considerable differences in the quality of inflammation. Viral genomes were found in the myocardium of N=6,072 (75%) patients, with treatment-relevant viral infections detected in N=2,015 (25%) cases. The remaining N=1,705 (21%) patients were diagnosed with other cardiomyopathies, including dilated cardiomyopathy (N=1,252), heart failure with preserved ejection fraction (N=325), hypertrophic cardiomyopathy (N=117) and arrhythmogenic right ventricular cardiomyopathy (N=11). Conclusions This retrospective study of over 8,000 patients with heart failure clearly shows that a definitive diagnosis is only possible with a comprehensive EMB diagnosis and leads to specific therapy in 79% of the cases. In the remaining 21% of patients, infectious and inflammatory causes could be excluded in order to initiate standard heart failure therapy. It is important to emphasize here that the quality of the inflammation and therapy-relevant viral infections cannot be detected with imaging techniques, which underlines the clinical-therapeutic importance of endomyocardial biopsy.

Protease-activated receptor 2 (PAR2) inhibition reduces complement-associated cardiac remodelling in obesity-related heart failure

Abstract Background and Aims Obesity is considered a major risk factor for the development of heart failure (HF) due to lipid accumulation, oxidative stress and inflammation which results in cardiac remodeling. Protease activated receptor 2 (PAR2) has been linked to various cardiovascular and inflammatory diseases. The role of PAR2 has not yet been studied in obesity-related HF. Methods In the experimental mouse study, we used 1-year-old ApoE knockout (ApoE-/-) and ApoE PAR2 double knockout (ApoE-/-PAR2-/-) mice with a C57BL/6J background on a high fat (HF) diet (n=5/ group). Cell culture experiments were performed with human primary cardiac fibroblasts and HepG2 hepatocytes. Patients (n=50) included in the clinical study had a BMI > 25kg/m², symptoms of heart failure (HF), coronary angiography (CA) that excluded coronary artery disease (CAD) and endomyocardial biopsy (EMB) that confirmed the absence of active myocarditis or primary cardiac amyloidosis. Patients were divided into PAR2low (n=22) and PAR2high (n=22) based on the median PAR2 expression measured via qPCR in the EMB of the cohort, and six patients served as healthy controls. Results Evaluation of endomyocardial biopsies (EMB) from overweight/ obese non-ischemic cardiomyopathy (NICM) patients with heart failure (HF) (n=44) revealed that a reduced cardiac PAR2 expression is associated with less cardiac C3 (p≤0.054), C4 (p≤0.041) and C5 gene expression (p≤0.045), as well as plasma levels of complement C3 (1.1g/l± 0.7 vs 2.1g/l±0.2; p≤0.016) and C5b-9 (303.4ng/ml± 215.7 vs 992.7ng/ml± 756.2; p≤0.0002) and as a result, better systolic function i.e. LVEF (46.1%±17.1 vs 36.8%±15.2; p≤0.046) and LV GLS (-14.9%± 5.7 vs -9.5%± 4.6; p≤0.009), less cardiac remodeling and damage. Correspondingly, aged ApoE-/-PAR2-/-mice on a Western diet showed less hepatic and cardiac complement expression (i.e. C1q, C3, C4, C5, C9), cardiac C3 deposition (p≤0.047) and C5b-9 plasma levels (p≤0.049), as well as less cardiac necrosis (p≤0.046) and lower BNP (p≤0.016) than ApoE-/-. PAR2 overexpression in human cardiac fibroblasts (HCFs) independently enhanced and PAR2 antagonism reduced interferon γ (IFNγ)-mediated STAT1-dependent complement C3, C4 and C5 expression. Conclusions Protease-activated receptor 2 regulates complement-mediated cardiac damage and remodeling in HF. The PAR2-IFNγ/STAT1/C3-C4-C5 complement-axis might be a promising prognostic and therapeutic approach to identify and treat high-risk cases of HF in overweight/obese patients.

Long-term efficacy and safety of tailored immunosuppressive therapy in immune-mediated biopsy-proven myocarditis: A propensity-weighted study.

Standardized immunosuppressive therapy (IS) had been previously investigated in biopsy-proven (BP) lymphocytic myocarditis with heart failure (HF). This study evaluated efficacy and safety of tailored IS in BP immune-mediated myocarditis, irrespective of histology and clinical presentation. Consecutive BP myocarditis patients treated with long-term tailored IS on top of optimal medical therapy (OMT), were compared with OMT non-IS controls using propensity-score weighting. The primary outcome was a composite of death or heart transplant, the secondary outcome was a composite of biventricular function, New York Heart Association (NYHA) class variation, and relapse. IS was managed by a multidisciplinary Cardioimmunology Team, involved a safety checklist and active patients' education. Ninety-one IS patients were compared with 267 non-IS patients. IS patients more frequently had systemic immune-mediated diseases (35% vs. 9.7%), lower baseline echocardiographic left ventricular ejection fraction (35% vs. 43%), lower right ventricular fractional area change (34% vs. 41%) and higher frequency of active lymphocytic, eosinophilic and giant cell myocarditis (71% vs. 58%, 12% vs. 1.1%, and 6.6% vs. 1.5%, respectively). At 5-year follow up, no difference was observed in the primary outcome (survival rate 93% in IS vs. 87% in non-IS), but IS patients had a higher relapse rate. Thus, IS patients, with a lower biventricular function and a higher risk profile at baseline, presented similar biventricular function and NYHA class to non-IS patients at follow-up. Minor adverse drug reactions occurred in 13% of patients, all resolved with therapy switch. Prolonged tailored IS is effective and safe in BP immune-mediated myocarditis irrespective of histology and clinical presentation.

Post-COVID-19 myocardium and coronary involvement in a young patient: differential diagnosis and comprehensive treatment

The state of the heart after a coronavirus disease 2019 (COVID-19, coronavirus disease 2019) is very diverse and in some cases requires a complex differential diagnosis. We described a 35-year-old smoking male patient who, by the end of the first month after COVID-19, developed left ventricular dysfunction with decrease in ejection fraction to 25-30% and persistent left bundle branch block (LBBB). Echocardiography also detected local contractility disorders. A significant increase in blood anticardiac antibody titers was noted. Myocardial biopsy revealed active lymphocytic myocarditis, coronavirus ribonucleic acid, while coronary angiography revealed extensive stenosis of the anterior interventricular artery. On the first day after balloon angioplasty and stenting, the disappearance of LBBB block was noted with the appearance of deep negative T waves in the precordial leads, which did not allow ruling out a previous myocardial infarction. As a result of treatment of heart failure and steroid therapy, the structural and functional cardiac parameters and the electrocardiography were completely normalized by the end of the second year of treatment. Only a transient LBBB remained at high loads. Cardiac computed tomography after 2 years showed no delayed contrast agent accumulation in the myocardium, and coronary stenosis up to 30%.The mechanisms of complex myocardial and coronary damage (including the role of coronaritis in the atherosclerosis progression) after COVID-19 are discussed.

Echocardiographic predictors of positive left ventricular remodeling in patients with a history of active myocarditis.

Myocarditis may be difficult to diagnose because of the variety of its clinical manifestations, and the clinical course of the disease can be unpredictable. Nevertheless, some patients may exhibit partial or full contractile recovery following myocarditis. Standard and speckle-tracking echocardiography may serve as tools to follow this recovery. We aimed to evaluate predictors of positive left ventricular (LV) remodeling after active myocarditis (AM). A database of a high‑volume, tertiary cardiology center was searched for patients with AM hospitalized between 2016 and 2019. They were included in the analysis based on clinical manifestations and presence of at least 1 of the following diagnostic criteria: positive findings on electrocardiography / Holter monitoring, echocardiography, elevated troponin T/I levels, functional or structural abnormalities on cardiac imaging, or tissue characterization by cardiac magnetic resonance. LV global longitudinal strain and mechanical dispersion (MD; defined as SD of the time to peak longitudinal strain derived from all LV segments in 3 apical views) were determined. Echocardiographic response (positive LV remodeling measured by transthoracic echocardiography) was defined as end‑systolic volume (ESV) reduction by 15% or greater or end-diastolic volume (EDV) reduction by 15% or greater from the baseline values. A total of 61 consecutive patients were recruited. The median follow‑up was 1.4 years (range, 0.3-4). The mortality rate was 1.6%. Echocardiographic response was noted in 24 patients (39.4%). A multivariable Cox regression model including significant baseline differences as covariates showed that QRS duration (hazard ratio [HR], 1.31; 95% CI, 1.17-1.57; P = 0.049), MD (HR, 1.03; 95% CI, 1.01-1.07; P = 0.04), and mineralocorticoid receptor antagonist [MRA] use (HR, 8.60; 95% CI, 1.50-46.49; P = 0.01) were independently associated with positive LV remodeling with ESV reduction. MD (HR, 1.04; 95% CI, 1.02-1.06; P = 0.04) was also independently associated with positive LV remodeling with EDV reduction. Mechanical dispersion, QRS duration, and MRA use are independent predictors of positive LV remodeling in individuals with a history of AM.

COVID-19 vaccine-associated myocarditis in an adolescent after the third vaccine dose. Case report with follow-up

We report on the case of a 16-year-old boy with myocarditis developing after the third dose of COVID-19 mRNA vaccine. The patient presented with fever and retrosternal chest pain two days after immunisation. On admission, the boy was in good condition, with stable vitals. Elevated serum troponins and electrocardiographic repolarisation abnormalities with normal echocardiographic contractility were noted. Cardiac magnetic resonance imaging revealed active myocarditis in form of oedema with late gadolinium enhancement in five segments of the left ventricle myocardium. During further hospitalisation, rapid improvement in the patient’s general condition with normalisation of troponin level, and regression of electrocardiographic abnormalities were observed. In follow-up reassessments at three and nine months, cardiac magnetic resonance revealed residual myocardial lesions. No symptoms and abnormalities in laboratory tests, electrocardiography, or echocardiography were found. It is imperative to exercise full vigilance for COVID-19 vaccine-associated myocarditis when chest pain appears following vaccination, even in the absence of alarming symptoms after previous vaccine doses.

Interleukin 17A-correlated myocarditis in patients with psoriasis: cardiac recovery following secukinumab administration

Abstract Background Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has been rarely suggested. Purpose Report of PS-related myocarditis. Methods One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with moderate-severe form showed a dilated cardiomyopathy (LVEF <35%) with normal coronary arteries and valves. They underwent a left ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which plays a major role in psoriasis pathogenesis; real-time PCR for cardiotropic viruses and Western blot analysis for myocardial expression of IL-17A. Patients’ sera were tested for anti-heart autoantibodies. Results An active lymphocytic myocarditis was revealed in all 5 patients, characterized by absence of viral genomes at PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A at western blot analysis showing a 2,48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a 6-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/Kg daily for 4 weeks, tapered to 0.33 mg/Kg) + azathioprine (2 mg/Kg, daily) in 3 pts or secukinumab (SK, 100 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (-14% and + 118%, respectively) while completely recovered (LVEF> 50%) in the last 2 pts on SK. Conclusion IL-17A-related myocarditis can occur in up-to 5% of patients with psoriasis. It manifests as a progressive dilated cardiomyopathy. It may completely recover following SK administration. Figure Legend Endomyocardial biopsy findings from pt 5 with PS-related myocarditis including histology (panel A). Immune-histochemistry for IL 17-A (panel B) and anti-heart abs (panels C, D). It shows an active lymphocytic myocarditis with overexpression of IL 17-A and positive anti-heart abs (panel C), cross-reacting with skeletal muscle (panel D).

Abstract 11836: A Rare Cause of Recurrent Myocardial Infarction: Genetic Testing Cracks the Case

A 29-year-old man presented to our institution with acute, severe substernal chest pain. An ECG on arrival revealed 3mm ST-elevations in the lateral leads with reciprocal depressions in the inferior leads. Troponin-I was above assay (>50 ng/mL). Emergent coronary angiography showed normal coronary arteries, and left ventriculogram showed no wall motion abnormalities. A transthoracic echocardiogram showed normal biventricular size, wall thickness, and ejection fraction (EF). This was his fifth episode of chest pain over the past 10 years, consistent with prior presentations of ST-elevation myocardial infarction and angiographically normal coronary arteries. A prior cardiac magnetic resonance imaging (MRI, 6 years before the current presentation) revealed increased T2 signal intensity and subepicardial late gadolinium enhancement (LGE) in the septum, inferior, and inferolateral walls, suggestive of nonischemic acute myocardial injury. A repeat cardiac MRI during the current presentation showed mildly reduced biventricular systolic function (LVEF 52%, RVEF 36%), and again showed increased T2 signal intensity and subepicardial LGE involving the septum, inferior and inferolateral walls. The anterior and anterolateral walls were also now involved. Endomyocardial biopsy (EMB) showed focal interstitial fibrosis with no evidence of active myocarditis. On telemetry he was noted to have runs of non-sustained ventricular tachycardia (NSVT). Serologic evaluation was negative for parvovirus, cytomegalovirus, and Chagas disease. Erythrocyte sedimentation rate and C-reactive protein levels were normal. Genetic testing was performed at our newly established cardiovascular genetics program, which showed a pathogenic truncating mutation in the desmoplakin gene (DSP). DSP cardiomyopathy (CM) is an LV-predominant arrhythmogenic CM, which can present with episodic myocardial injury, and has a high disposition for ventricular arrhythmias with subepicardial LGE pattern often proceeding LV systolic dysfunction. A primary prevention implantable cardioverter-defibrillator was placed given extent of LGE and NSVT burden in the context of DSP variant. This case illustrates the importance of genetic testing in identifying rare CM phenotypes.

Can FDG PET Serve as a Clinically Relevant Tool for Detecting Active Non-sarcoidotic Myocarditis?

Can FDG PET Serve as a Clinically Relevant Tool for Detecting Active Non-sarcoidotic Myocarditis?

COVID-19 as a potential trigger for refractory arrhythmias and electrical storm in a patient with dilated cardiomyopathy: a case report

Arrhythmias occur both in the acute coronavirus disease 2019 (COVID-19) and in the post-acute period, which may be associated with the long-term SARS-CoV-2 persistence. In a case report, patient with primary dilated cardiomyopathy, an implanted cardioverter-defibrillator, recurrent ventricular arrhythmias, and an electrical storm are presented. The patient was repeatedly hospitalized in a city hospital, where electrical cardioversion, antiarrhythmic therapy, radiofrequency ablation of recurrent ventricular tachycardia regions, including emergency ("lifesaving") combined catheter radiofrequency destruction of the electrical storm substrate, was performed. Subsequently, against the background of ongoing postoperative therapy, massive pulmonary embolism (PE) suddenly developed, which led to the death. Autopsy established that the cause of the patient’s death was massive pulmonary embolism; SARS-CoV-2 and enterovirus was detected in the myocardium. Based on an autopsy study, the patient was diagnosed with primary dilated cardiomyopathy with secondary active chronic lymphocytic myocarditis.

Cardiac MRI Findings in Patients Clinically Referred for Evaluation of Post-Acute Sequelae of SARS-CoV-2 Infection.

Persistent or recurrent cardiovascular symptoms have been identified as one of the hallmarks of long-COVID or post-acute sequelae of SARS-CoV-2 infection (PASC). The purpose of this study was to determine the prevalence and extent of cardiac abnormalities in patients referred for cardiac MRI due to clinical evidence of PASC. To investigate this, two tertiary care hospitals identified all patients who were referred for cardiac MRI under the suspicion of PASC in a 2-year period and retrospectively included them in this study. Patients with previously known cardiac diseases were excluded. This resulted in a total cohort of 129 patients (63, 51% female; age 41 ± 16 years). The majority of patients (57%) showed normal cardiac results. No patient had active myocarditis or an acute myocardial infarction. However, 30% of patients had evidence of non-ischemic myocardial fibrosis, which exceeds the prevalence in the normal adult population and suggests that a possible history of myocarditis might explain persistent symptoms in the PASC setting.

Interleukin-17A-Correlated Myocarditis in Patients with Psoriasis: Cardiac Recovery following Secukinumab Administration.

(1) Background: Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has rarely been suggested. (2) Aims: Report of PS-related myocarditis. (3) Methods and Results: One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with a moderate-severe form of PS showed dilated cardiomyopathy (LVEF < 35%) with normal coronary arteries and valves. They underwent a left-ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which play a major role in PS pathogenesis. Real-time PCRs were carried out for cardiotropic viruses, and Western blot analysis was conducted for myocardial expression of IL-17A. Patients' sera were tested for anti-heart autoantibodies. Active lymphocytic myocarditis was revealed in all five patients, characterized by an absence of viral genomes with PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A during western blot analysis, showing a 2.48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a six-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/kg daily for 4 weeks, tapered to 0.33 mg/kg) and azathioprine (2 mg/kg, daily) in 3 pts or secukinumab (SK, 150 mg/weekly for 4 weeks followed by 150 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (-14% and + 118%, respectively), while they completely recovered (LVEF > 50%) in the last 2 pts on SK. (4) Conclusions: IL-17A-related myocarditis can occur in up to 5% of patients with PS. It manifests as progressive dilated cardiomyopathy. It may completely recover following SK administration.

Laboratory biomarker galectin-3 in the diagnostics of myocardial inflammatory changes in patients with atrial fibrillation

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Numerous data indicate a significant contribution of myocardial inflammatory changes in the development and progression of AF. The search for new laboratory biomarkers to assess the activity of myocardial inflammatory processes, and the study of their diagnostic significance for noninvasive diagnosis in patients with AF is relevant. Therefore, the aim was to study the features of the serum level of the biomarker Gal-3 and to identify its relationship with inflammatory changes in the myocardium in patients with AF. Depending on the results of histological studies, the patients were divided into 2 groups: group 1 – with morphologically verified active lymphocytic myocarditis (ALM), group 2 – with lymphocytic infiltration (LI). Analysis of the frequency of detection and severity of the inflammatory process in the myocardium showed that activity of 4-5 scores was detected only in group 1. In 2nd group, activity of the inflammatory process in most patients was 1 score. All patients with LI mild interstitial inflammation were showed. In the ALM group moderate and severe interstitial inflammation was detected. A high number of CD3+ and CD45+ cells were found in 1st group compared to group 2 (p &lt; 0.001).There were no significant intergroup differences in the serum level of Gal-3. At the same time, in 1st group showed a significant decrease in Gal-3 in 6 months after treatment (p = 0.028). Positive correlations of Gal-3 with the severity of the inflammatory process and endocardial involvement were revealed in patients with ALM. The association of serum Gal-3 levels with CD68+ levels in 1st group was detected (R = 0.48, p = 0.030). In 2nd group, a correlation between the level of Gal-3 in 6 months after ablation with infiltration of CD45+ cells was found (R = 0.69, p = 0.003). Thus, in patients with AF and active lymphocytic myocarditis, significant associations were established between biomarkers of Gal-3 and inflammatory changes in the myocardium. This confirms the important role of Gal-3 as a participant in the inflammatory process.

Comparative Study of the Myocardium of Patients from Four COVID-19 Waves.

Few studies have compared COVID-19 patients from different waves. This study aims to conduct a clinical and morphological analysis of patients who died from COVID-19 during four waves. The study involved 276 patients who died from COVID-19 during four waves, including 77 patients in the first wave, 119 patients in the second wave, and 78 patients in the third wave. We performed a histological examination of myocardium samples from autopsies and additionally analyzed the samples by PCR. We conducted immunohistochemistry of the myocardium for 21 samples using antibodies against CD3, CD45, CD8, CD68, CD34, Ang1, VWF, VEGF, HLA-DR, MHC1, C1q, enteroviral VP1, and SARS-CoV-2 spike protein. We also did immunofluorescent staining of three myocardial specimens using VP1/SARS-CoV-2 antibody cocktails. Further, we ran RT-ddPCR analysis for 14 RNA samples extracted from paraffin-embedded myocardium. Electron microscopic studies of the myocardium were also performed for two samples from the fourth wave. Among the 276 cases, active myocarditis was diagnosed in 5% (15/276). Of these cases, 86% of samples expressed VP1, and individual cells contained SARS-CoV-2 spike protein in 22%. Immunofluorescence confirmed the co-localization of VP1 and SARS-CoV-2 spike proteins. ddPCR did not confidently detect SARS-CoV-2 RNA in the myocardium in any myocarditis cases. However, the myocardium sample from wave IV detected a sub-threshold signal of SARS-CoV-2 by qPCR, but myocarditis in this patient was not confirmed. Electron microscopy showed several single particles similar to SARS-CoV-2 virions on the surface of the endothelium of myocardial vessels. A comparison of the cardiovascular complication incidence between three waves revealed that the incidence of hemorrhage (48 vs. 24 vs. 17%), myocardial necrosis (18 vs. 11 vs. 4%), blood clots in the intramural arteries (12 vs. 7 vs. 0%), and myocarditis (19 vs. 1 vs. 6%) decreased over time, and CD8-T-killers appeared. Immunohistochemistry confirmed the presence of endotheliitis in all 21 studied cases. This study compared myocardial damage in patients who died during three COVID-19 waves and showed a decrease in the incidence of endotheliitis complications (thrombosis, hemorrhage, necrosis) and myocarditis over time. However, the connection between myocarditis and SARS-CoV-2 infection remains unproven.

Multimodality Screening For (Peri)Myocarditis In Newly Diagnosed Idiopathic Inflammatory Myopathies: A Cross-Sectional Study.

Cardiac involvement in idiopathic inflammatory myopathy (IIM or "myositis") is associated with an approximate 4% mortality, but standardised screening strategies are lacking. We explored a multimodality screening on potentially reversible cardiac involvement -i.e. active (peri)myocarditis -in newly diagnosed IIM. We included adult IIM patients from 2017 to 2020. At time of diagnosis, patients underwent cardiac evaluation including laboratory biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR). Based on 2019 consensus criteria for myocarditis, an adjudication committee made diagnoses of definite, probable, possible or no (peri)myocarditis. We explored diagnostic values of sequentially added diagnostic modalities by Constructing Classification and Regression Tree (CART) analysis in patients with definite/probable versus no (peri)myocarditis. We included 34 IIM patients, in whom diagnoses of definite (six, 18%), probable (two, 6%), possible (11, 32%), or no (peri)myocarditis (15, 44%) were adjudicated. CART-analysis showed high-sensitivity cardiac troponin T (cut-off value < 2.3 times the upper limit of normal (xULN)) ruled out (peri)myocarditis with a sensitivity of 88%, while high-sensitivity troponin I (cut-off value > 2.9 xULN for females and > 1.8 xULN for males) ruled in (peri)myocarditis with a specificity of 100%. Applying high-sensitivity cardiac troponins with these cut-off values in a diagnostic algorithm without and with a CMR to the total population of 34 patients demonstrated a diagnostic accuracy for a clear diagnosis of probable/definite or no (peri)myocarditis of 59% and 68%, respectively. A diagnostic algorithm for detection of (peri)myocarditis in adult IIM may consist of sequential testing with high-sensitivity cardiac troponins and CMR.

Different Phases of Disease in Lymphocytic Myocarditis: Clinical and Electrophysiological Characteristics.

Endomyocardial biopsy (EMB) is required to make a definite diagnosis of lymphocytic myocarditis (LM), to identify its etiology, and to classify LM into different phases. This study aims to characterize and compare clinical and electrophysiological characteristics of different biopsy-proven LM phases, namely acute myocarditis (AM), chronic active myocarditis (CAM), and healed myocarditis (HM). All patients with a diagnosis of LM at 3 Italian referral centers were prospectively enrolled. According to EMB findings, LM was classified as AM, CAM, or HM; per-group comparisons of clinical presentations, noninvasive, and invasive findings are reported. Among the 122 enrolled patients (AM, n=44; CAM, n=42; HM, n=36), complex ventricular arrhythmias were very common overall (n=109, 89%), but ventricular fibrillation was slightly more prevalent in AM (P=0.028). Cardiac magnetic resonance imaging showed late gadolinium enhancement in more patients with HM and CAM than AM (94.4% vs 92.9% vs 50%; P< 0.001), whereas edema was more common in AM than in CAM, being absent in HM (90.9% vs 50% vs 0%; P< 0.001). Accordingly, edema was the strongest independent clinical predictor of EMB-proven active inflammation. Electroanatomical mapping revealed a lower prevalence of low-voltage areas in AM than in CAM or HM. We observed a strong association between edema at a specific myocardial segment and normal voltages at that site (odds ratio: 0.24; 95%CI: 0.10-0.54; P< 0.01), as well as between late gadolinium enhancement and low-voltage areas (odds ratio: 2.86; 95%CI: 1.19-6.97; P=0.019). LM is a highly heterogeneous disease, and its different phases are characterized by diverse clinical, morphological, and electrophysiological features. Further research is required to identify electroanatomical markers of inflammation.

Cardiac Magnetic Resonance Findings in Patients Recovered from COVID-19 Pneumonia and Presenting with Persistent Cardiac Symptoms: The TRICITY-CMR Trial.

The prevalence and clinical consequences of coronavirus disease 2019 (COVID-19)-related non-ischemic cardiac injury are under investigation. The main purpose of this study was to determine the occurrence of non-ischemic cardiac injury using cardiac magnetic resonance (CMR) imaging in patients with persistent cardiac symptoms following recovery from COVID-19 pneumonia. We conducted a single-center, cross-sectional study. Between January 2021 and May 2021, we enrolled 121 patients with a recent COVID-19 infection and persistent cardiac symptoms. Study participants were divided into those who required hospitalization during the acute phase of SARS-CoV-2 infection (n = 58; 47.9%) and those non-hospitalized (n = 63; 52.1%). Non-ischemic cardiac injury (defined as the presence of late gadolinium enhancement (LGE) lesion and/or active myocarditis in CMR) was detected in over half of post-COVID-19 patients (n = 64; 52.9%). LGE lesions were present in 63 (52.1%) and active myocarditis in 10 (8.3%) post-COVID-19 study participants. The majority of LGE lesions were located in the left ventricle at inferior and inferolateral segments at the base. There were no significant differences in the occurrence of LGE lesions (35 (60.3%) vs. 28 (44.4%); p = 0.117) or active myocarditis (6 (10.3%) vs. 4 (6.3%); p = 0.517) between hospitalized and non-hospitalized post-COVID-19 patients. However, CMR imaging revealed lower right ventricular ejection fraction (RVEF; 49.5 (44; 54) vs. 53 (50; 58) %; p = 0.001) and more frequent presence of reduced RVEF (60.3% vs. 33.3%; p = 0.005) in the former subgroup. In conclusion, more than half of our patients presenting with cardiac symptoms after a recent recovery from COVID-19 pneumonia had CMR imaging abnormalities indicating non-ischemic cardiac injury. The most common finding was LGE, while active myocarditis was detected in the minority of patients. CMR imaging abnormalities were observed both in previously hospitalized and non-hospitalized post-COVID-19 patients. Further research is needed to determine the long-term cardiovascular consequences of COVID-19 infection and the optimal management of patients with suspected post-COVID-19 non-ischemic cardiac injury.

369 PENTRAXIN 3 AS A DIAGNOSTIC AND PROGNOSTIC MARKER OF ACTIVE MYOCARDITIS

Abstract 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 (&amp;lt;50%) at admission who recovered during follow-up had higher baseline PTX3 levels, rather than those whose systolic function did not improve. 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.

433 A PRO-ARRHYTHMIC DOUBLE HIT

Abstract A 42-year-old man went to the emergency room complaining about dyspnea and palpitations. He reported an episode of atrial fibrillation (AF) with symptoms of dizziness 8 years before. He had a family history of ischemic cardiopathy, his father has suffered from AF since a young age.Acute course: The ECG revealed AF at high ventricular frequency. The echocardiography demonstrated mild reduction of the left ventricular function (EF 45%) with diffuse hypokinesis, and mitral valve prolapse (MVP) with mild mitral regurgitation. The blood tests showed a troponin peak of 750 ng/L (n.v. 0–34 ng/L). The suspect was acute coronary syndrome. Thus, he was treated with dual antiplatet therapy and low doses of beta-blockers, and he underwent coronarography, which demonstrated no significant lesions. So, after a transesophageal echocardiography that excluded thrombosis, and a loading dose of amiodarone, a successful electrical cardioversion was performed. The discharge diagnosis was AF with mild left ventricular disfunction. Three months later: He came back to the emergency room because of suffering some days of progressive epigastric and retrosternal pain radiating to the shoulders. The ECG and the echocardiography were unchanged, the troponin-I values were 79 ng/L-74 ng/L. Therefore, he underwent cardiac magnetic resonance (CMR), which showed normal biventricular dimensions and function (LVEF 64%, LVEDV 80 ml/mq), MVP with mitral annular disjunction (MAD) and curling of the infero-lateral basal wall (Figure A). The native T1, T2 and ECV values were increased, and there was a wide left ventricular subepicardial late gadolinium enhancement (LGE). The conclusion was MVP and active myocarditis. Moreover, he underwent endomyocardial biopsy that revealed focal lymphocytic infiltration, PCRs for common cardiotropic viruses or bacteria were negative. Six months later: The basal ECG was characterized by low QRS voltages in limb leads (Figure B). The CMR revealed a wide left ventricular non-ischemic fibrosis with a ring-like pattern (Figure C). The 24-hours Holter ECG showed premature ventricular beats with a right bundle branch block/superior and inferior axis morphology (Figure D), in keeping with MVP. The next step was the genetic testing that resulted positive for a Filamin-C (FLNC) mutation associated with cardiomyopathy. The final diagnosis was “Hot-phase of Left Ventricular Arrhythmogenic Cardiomyopathy (ACM), MVP and paroxysmal AF”. Discussion: The ACM is a rare hereditary heart muscle disease, and the “hot phase” represents its uncommon clinical presentation. Mutations in FLNC gene could be involved in the pathogenesis of ACM. Moreover, there are few cases in literature about the correlation between FLNC mutations and MVP. FLNC mutation may be a cross-sectional substrate for both these pro-arrhythmic conditions.

493 A CASE REPORT OF SUBACUTE INFLAMMATORY HEART DISEASE WITH AN ATYPICAL ONSET

Abstract Background Inflammatory heart disease is a heterogeneous process with variegate clinical manifestations. The acute phase is characterized by a sudden injury involving cardiomyocytes, cardiac conduction system and/or pericardium, with different pathophysiological implications. Case Summary A 26-year-old previously healthy woman presented for worsening fatigue and bradycardia. The ECG at admission showed total heart block with infra-Hisian escape rhythm, heart rate was 36 bpm. She reported no history of tick bite or recent inflammatory event; body temperature was 36,8 °C. Laboratory assessment showed persistently raised troponin (28943 -&amp;gt; 32632 ng/l), C-reactive protein was 0,70 mg/l, white blood cells 4,86×10^3/µl, procalcitonin 0,03 µg/l, interleukin-6 was 60,5 pg/ml (n.v. &amp;lt;28,0) and NT-pro-BNP was 312 pg/ml. Borrelia, Salmonella, Ricketsiae, Toxoplasma screening was negative for acute infection as well as any other viral serology. Comprehensive laboratory autoimmunity assessment was negative. Echocardiography revealed normal biventricular volume and kinetics, no valvulopathies and no pericardial effusion. Coronary angiogram was normal. The cardiac magnetic resonance showed extensive oedema and contextual late gadolinium enhancement predominantly in the interventricular septum and mid segment of the anterior wall. Serum angiotensin-converting enzyme concentration was normal. Due to persistent heart block, after 5 days the patient underwent endomyocardial biopsy that showed slight oedema and mild fibrosis without lymphocytic infiltration nor histochemical findings suggestive of active myocarditis. Granulomas were absent. Viral analysis on myocardium was negative. An intermediate dose of steroids was started with a progressive restoration of 1:1 atrioventricular conduction and shortening of QRS up to incomplete right bundle branch block, hence the patient was discharged without pacemaker implantation. Discussion In heart inflammatory diseases with bradyarrhythmic onset, atrioventricular conduction may be restored with targeted therapy. Multimodality assessment is crucial in the diagnostic and therapeutic work-up of these cases.