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Background Clinically manifest cardiac sarcoidosis (CS) has a prevalence of 5%, but is more frequent in autoptic series (25%). Diagnosis is multiparametric and relies on clinical criteria and imaging findings, although a certain diagnosis, especially in the case of isolated CS (ICS), can only be based on endomyocardial biopsy. Cardiovascular magnetic resonance (CMR) has a comprehensive role in the assessment of CS: left ventricular (LV) dysfunction and extent of late gadolinium enhancement (LGE)are important predictors of prognosis, T2 mapping provides information on disease activity and global longitudinal strain (GLS) analysis can uncover subclinical LV impairment. Purpose To assess the prevalence of CS by CMR in patients with biopsy-proven extracardiacsarcoidosis (ECS); to describe the imaging characteristics of patients with ECS and those with high clinical suspicionof ICS; to investigate the contribution of more recent techniques to the diagnosis of CS alongside traditional LGE assessment. Methods We retrospectively enrolled 84 patients (66% males, mean age 59±13 years) referred to our centreforsuspected CS (biopsy-proven ECS, n=61; clinical presentation suggestive of CS,, n=23). CMR was performed on a 1.5T scanner, with a protocol comprehensive of biventricular functional assessment and post-contrast images; T2-STIR images (n=30), native myocardial T1 mapping (n=24) and T2 mapping (n=19) were also performed in selected patients. Tissue tracking analysis was perfomed in all patients using a dedicated software. Results Based on CMR findings, 35 patients (42%) with ECS did not show cardiac involvement (SS), 26 (31%) showed both cardiac and systemic involvement (CS-SS) and 23 (27%) had evidence of ICS (ICS). 43% of patients had history of arrhythmias, but life-threatening tachyarrhythmiaswere more frequent in patients with CS (p=0.02).Patients with CS had significantly lower LVEF (p Conclusions CMR findings consistent with CS were found in 49 patients referred for suspected CS. Patients with cardiac involvement, particularly if isolated, had significantly lower LVEF, greater LV volumes and more impaired GLS. Patients with SS, despite a normal LV function, showed mildly impaired GLS, subtending subclinical cardiac involvement. Funding Acknowledgement Type of funding source: None

Background Myocarditis is an infectious or autoimmune inflammatory disease of the myocardium; diagnosis relies on the exclusion of an acute coronary syndrome, and is confirmed by endomyocardial biopsy (EMB). Prognosis is highly variable, outcome predictors are not well defined. Purpose To identify clinical, imaging and immunological predictors of death, heart transplantation (HTx) and relapse in patients with myocarditis in the pre-immunosuppression era. Methods From 1993 to 2012 we consecutively enrolled 466 patients (68% male, mean age 37±17 years), 216 with clinically suspected and 250 with EMB-proven myocarditis. All patients underwent coronary angiogram and transthoracic echocardiogram, 44% of patients underwent cardiac magnetic resonance (CMR). Circulating auto-antibodies were measured in patients' sera by indirect immunofluorescence. All patients were prospectively followed-up at the local Cardio-immunology outpatient clinic. Results After a median follow-up of 50 months (IQR 25–75), 366 patients (79%) were alive, while 42 (9%) were dead or underwent HTx; 58 were lost to follow-up. Ten-year survival free from death or HTx was overall 83%, but was lower in patients with EMB-proven myocarditis (76% vs 94% in patients with clinically suspected myocarditis, p Conclusions In the pre-immunosuppressive era, young age and a previous episode of myocarditis were independent predictors of relapse, female gender, left ventricular dysfunction at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features in myocarditis predict worse prognosis. Funding Acknowledgement Type of funding source: None

Background Risk stratification for death and heart transplantation (HTx) in myocarditis is complex. A random forest (RF) is a tree-based machine learning technique (MLT) which is being increasingly used for clinical data analysis; it allows the detection of complex relationships between the outcome of interest and the covariates, overcoming the limits of traditional statistical analysis (i.e. regression approaches). Purpose To assess the potential role of clinical and diagnostic features at presentation as predictors of death and HTx in biopsy (Bx)-proven myocarditis using RF. Methods From January 1993 to August 2019, we consecutively enrolled 357 patients with Bx-proven myocarditis (65% male, median age 39 years, interquartile range (IQR) 26–51). An RF approach for survival data was used. Variables included in the analysis were: histology type by Bx, NYHA, type of presentation (infarct-like, arrhythmia, heart failure), viral genome detection on Bx, serum antiheart (AHA), antiintercalated disk (AIDA), anticardiac endothelial cells (AECA), antinuclear (ANA) autoantibodies, immunosuppressive therapy, cardiac catheterisation (left ventricular enddiastolic volume (LVEDV), mean capillary wedge pressure, right and left ventricular enddiastolic pressure) and 2-D echocardiographic measures (LVEDV, left ventricular ejection fraction (LVEF) at presentation and at follow-up, right ventricular fractional area change (FAC%), right ventricular diastolic area). Results The median follow-up time was of 1352 days (IQR 423.25–2535.75). At the end of follow-up, 42 patients were dead or transplanted. The 1-year, 5-year, and 10-year survival probabilities were of 0.928, 0.854, and 0.817, respectively. The most relevant predictors of death or HTx identified by the RF algorithm (according to the variable importance measure) were histological type, NYHA, clinical presentation, LVEF, and FAC%. Among the circulating auto-antibodies AECA were found to be the most important. Histological type was the strongest predictor of death/HT (100% relative importance, (RI)), giant cell myocarditis having a lower survival probability compared to other types. The next stronger predictors were advanced (III-IV) NYHA and heart failure presentation with lower survival probabilities (90% and 84% RI respectively). AECA-positive patients had lower survival probability compared to AECA negative ones (20% RI). The RF algorithm revealed an excellent predictive performance in the correct identification of all alive patients, with only 5 dead patients being misclassified (balanced accuracy 94%). Conclusions Autoimmune features, i.e Giant cell myocarditis and AECA, as well as severity of heart failure and of left ventricular disfunction at presentation were the strongest predictors of dismal prognosis. Our RF approach provides a new automated powerful tool for accurate risk stratification for death/HTx in Bx-proven myocarditis. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Budget Integrato per la Ricerca dei Dipartimenti (BIRD, year 2019), Padova University, Padova, Italy (project Title: Myocarditis: genetic background, predictors of dismal prognosis and of response to immunosuppressive therapy.)

Background Cardiovascular magnetic resonance (CMR) is an accurate diagnostic tool providing detailed myocardial tissue characterization. Correlates of late gadolinium enhancement (LGE) with clinical and diagnostic features are poorly defined in endomyocardial biopsy (EMB)-proven myocarditis. Purpose We sought to identify clinical, laboratory and imaging correlates of LGE in patients with EMB-proven myocarditis. Methods We analyzed our prospective cohort of patients with EMB-proven myocarditis (n=366) to identify patients who underwent CMR (n=154, aged 39±13, 108 males). Presence of LGE was qualitatively assessed. CMR and EMB were performed in all cases at the time of hospitalization. Clinical, laboratory, and imaging features at diagnosis were analyzed to identify correlates of LGE presence. Results Demographic characteristics (age, gender), cardiovascular risk factors (hypertension, diabetes) and cardiovascular therapy did not differ between patients with and without LGE. Patients with history of myocarditis tended to have a higher prevalence of LGE (25 vs 4 patients, p=0.07). There was a trend towards a higher prevalence of LGE in patients presenting with heart failure or acute coronary syndrome (p=0.07) as opposed to those presenting with arrhythmias. Patients with LGE were more symptomatic in the 6 months preceding diagnosis (palpitations, p=0.03, chest pain p=0.02). Clinical left and right ventricular systolic dysfunction at presentation were more common in patients with LGE (p=0.02, p=0.02 respectively). LGE presence failed to distinguish patients according to EMB findings (active vs. borderline myocarditis) (p=0.66) or to the histological type of myocarditis. Troponin I levels were higher in patients with LGE (p=0.03). There was no difference in bi-ventricular volumes and function, as assessed both by echocardiography and heart catheterization. There was no correlation between anti-heart antibodies and LGE presence, nor were patients with LGE more likely to receive immunosuppressive therapy; however, response to immunosuppression tended to be more common in patients without LGE (13/13 vs 29/38 patients, p=0.09). The rate of heart transplant, death and myocarditis relapse did not differ between patients with and without LGE. Conclusions Presence of LGE on CMR was associated with longer symptom duration before diagnosis, presentation with heart failure and higher troponin release, but failed to correlate with specific EMB features or myocarditis aetiopathogenetic markers. Acknowledgement/Funding None

Background Myocarditis is an insidious and potentially fatal illness with different clinical presentations and an unpredictable course. Prompt recognition of high risk patients is of paramount importance in preventing major adverse events. Purpose To identify predictors of dismal prognosis in a large cohort of patients with biopsy proven myocarditis. Methods Univariate analysis was used to identify predictors of death and heart transplant in a prospective cohort of 366 patients with biopsy proven myocarditis (aged 38±17, male 66%) using student's test and contingency tables as appropriate. Results At the time of follow up 46 patients (13%) were dead or received heart transplant (DHTX), 283 (77%) were alive (A) and 37 (10%) lost at follow up. Age at presentation was 33±20 y in DHTX v.s 39±15 in A cohort (p=0.057). Clinical features predicting adverse prognosis included female gender (p=0.002), heart failure at presentation (p=0.000), NYHA class II to IV (p=0.000). Clinical and radiographic signs of both left and right heart failure suggested worse outcome (p=0.000) as well as ongoing anticoagulation therapy (p=0.009). On ECG right (R) or left (L) axis deviation was a strong predictor of events (p=0.000). From an echocardiography perspective the presence of mild to severe mitral regurgitation (p=0.03), reduced left ventricular systolic function (FE) (p=0.000), reduced right ventricular fractional area change (FAC) (p=0.035) was strongly correlated to death or heart transplant. On cardiac catheterization the variables predicting unfavourable outcome included reduced left ventricular systolic pressure (LVSP) (p=0.000), reduced mean aortic pressure (mAP) (p=0.002), increased mean right atrial pressure (RAP) (p=0.001), FE on angiography (p=0.000). On cardiac biopsy (Bx) negative predictors were giant cell histology type (p=0.000) and PCR positive for viral genome (p=0.02) particularly for parvovirus B19 (p=0.04), adenovirus (p=0.04), and Epstein Barr virus (EBV) (p=0.03). See Tab 1 Table 1 Conclusion Female gender, HF like presentation, reduced LV and RV systolic function, R or L axis deviation on ECG, presence of viral PCR or giant cell histology on Bx, reduced LVSP and mAP; increased RAP may be useful parameters to identify high risk patients on presentation. This may increase clinical efforts and surveillance in this subgroup in order to reduce the incidence of major adverse events.

Background Sarcoidosis is an immune-mediated disease; cardiac involvement, a granulomatous form of myocarditis, is under-recognised and prognostically relevant, as it can present with significant morbidity and mortality. Anti-heart autoantibodies (AHA) and anti-intercalated disk autoantibodies (AIDA) are reliable autoimmune markers in non-sarcoidosis myocarditis forms. Purpose The aim of this study was to assess the potential role of serum AHA and AIDA in cardiac sarcoidosis. Methods This is a cross-sectional study on a series of 29 patients with biopsy proven extra-cardiac sarcoidosis and with biopsy-proven or clinically suspected cardiac involvement, who were tested for AHA and AIDA. Patients were recruited in two recruiting tertiary centres, in USA and Italy. AHA and AIDA were detected by indirect immunofluorescence on human myocardium and skeletal muscle. Controls included sera from patients with non-inflammatory cardiac disease (NICD) (n=160), with ischemic heart failure (IHF) (n=141) and normal blood donors (NBD) (n=270). Results The frequencies of AHA and of AIDA were higher in sarcoidosis (86%; 62%) than in NICD (8%; 4%), IHF (7%; 2%), NBD (9%; 0%) (p=0.0001; p=0.0001 respectively). Sensitivity and specificity were: 86% and 92% for positive AHA and 62% and 98% for positive AIDA, respectively (see figure). Figure 1 Conclusions The detection of serum AHA and AIDA in biopsy-proven or clinically suspected cardiac sarcoidosis supports the involvement of heart-specific autoimmunity in the majority of our cases and may provide a novel non invasive diagnostic marker.

Background Biopsy-proven myocarditis may be infectious or autoimmune. Risk stratification in biopsy-proven myocarditis and the role of immunosuppressive therapy in autoimmune forms have not been completely defined. Purpose To identify clinical, instrumental and immunological predictors of death, cardiac transplantation and relapse in a prospective cohort of 314 biopsy-proven myocarditis patients, and describe the effect of immunosuppressive treatment on secondary outcome measures, e.g. left ventricular ejection fraction (LVEF), in a subgroup of 45 consecutive patients with biopsy-proven autoimmune myocarditis diagnosed in our Cardiology Clinic. Methods Univariate and multivariate Cox regression analysis were used to identify predictors of death, heart transplant, and relapse in a cohort of 314 patients with biopsy-proven myocarditis (male 75%, median age 37). Actuarial survival free from death or transplant was calculated by the Kaplan-Meier method. Results Actuarial survival free from death or heart transplantation was 83% at 5 years. Among the clinical, instrumental and immunological features at diagnosis, independent predictors of death or heart transplantation by multivariable analysis were a lower transthoracic echocardiographic biplane LVEF% (p=0.001) and high serum titre for anti-nucler (ANA) and anti-cardiac endothelial cell autoantibodies (AECA). The only independent predictor of relapse was previous history of myocarditis. Immunosuppressive therapy was associated with a significantly favorable effect on LVEF (LVEF pre-therapy 37% (26; 50 interquartile range) vs. LVEF post-therapy 59% (48; 65 interquartile range), respectively, p=0.000). Conclusions In biopsy-proven myocarditis left ventricular dysfunction at diagnosis and autoimmune pathogenesis are associated with dismal prognosis, immunosuppressive therapy with improved LVEF in autoimmune patients.