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Objective: Cardiovascular magnetic resonance (CMR) is increasingly used in the diagnosis of myocarditis, with myocardial injury and systolic dysfunction playing key roles in the prognosis of this clinical setting. The clinical determinants of myocardial injury and systolic impairment in acute myocarditis are poorly defined. The aim of the current study is to assess the association of laboratory markers, late gadolinium enhancement (LGE) and left ventricular ejection fraction (LVEF) in patients with acute myocarditis., Methods: We completed a retrospective cohort study from a tertiary referral centre in London with CMR and acute myocarditis. Cases with cardiomyopathy were excluded. Missing data was imputed for selected clinical variables. We evaluated the association between peak troponin and LGE extent and LVEF. We adjusted the models for age, sex and time to CMR with a sensitivity analysis adjusting for body mass index and cardiovascular risk factors including hypertension, dyslipidaemia, diabetes mellitus and smoking., Results: 127 patients had abnormal T2-weighted imaging/mapping results with 118 (93%) presenting with chest pain and/or shortness of breath. Left ventricular LGE was identified in 118 (93%) patients and LVEF was 58±11%. The median time from the peak troponin to CMR was 1 day (IQR 0-6 days). The highest tertile of peak troponin was associated with more LGE (incident rate ratio 1.33, 95% CI: 1.07 to 1.64) and a lower LVEF (coefficient -5.3%, 95% CI: -9.5% to -1.1%). Diabetes was also associated with more LGE (incident rate ratio 1.90, 95% CI: 1.37 to 2.61) and lower LVEF (coefficient -8.9%, 95% CI: -14.7% to -1.8%)., Conclusions: Peak troponin is associated with more LGE and a lower LVEF even after accounting for demographics and comorbidities. Myocardial injury and systolic dysfunction play key roles in prognosis and future work incorporating clinical features into a risk prediction model may enable better risk stratification in acute myocarditis., Competing Interests: Competing interests: SEP reports a consultancy for Circle Cardiovascular Imaging, Inc., Calgary, Alberta, Canada., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Myocarditis is a common disease of the cardiovascular and immune systems, but the relationship between relevant blood metabolites and the risk of myocarditis has not been well-established. To identify potential biometabolic markers associated with myocarditis, we conducted a two-sample Mendelian randomization (MR) study. We performed preliminary MR analysis using the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode methods to adjust for false discovery rate (FDR). Confounders were screened using the GWAS Catalog website. Sensitivity analyses included Cochrane Q-test, Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), scatterplots, funnel plots, and forest plots. For genetic and directional analysis, we employed co-localization analysis and the Steiger test. MR analysis was performed using the FinnGen database and meta-analysis was performed using the IEU database. MR analysis identified significant correlations for five metabolic biomarkers after FDR correction. These included four known metabolites: kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, and 5-acetylamino-6-formylamino-3-methyluracil, as well as one unknown metabolite, X-25,422. Among these, kynurenine (OR = 1.441, 95%CI = 1.089-1.906, p-value = 0.018) and 1-stearoyl-GPE (18:0) (OR = 1.263, 95%CI = 1.029-1.550, p-value = 0.029) were identified as risk factors for myocarditis, while deoxycarnitine (OR = 0.813, 95%CI = 0.676-0.979, p-value = 0.029), 5-acetylamino-6-formylamino-3-methyluracil (OR = 0.864, 95% CI = 0.775-0.962, p-value = 0.018), and X-25,422 (OR = 0.721, 95%CI = 0.587-0.886, p-value = 0.009) were found to be protective factors. No evidence of heterogeneity, horizontal pleiotropy, or sensitivity issues was observed, and no shared genetic factors between exposure and outcome were detected. The causality was in the correct direction. Meta-analysis further confirmed the causal relationship between the five metabolites and myocarditis. This study identifies a causal relationship between five circulating metabolites and myocarditis. Kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, X-25,422, and 5-acetylamino-6-formylamino-3-methyluracil may serve as potential drug targets for myocarditis, providing a theoretical basis for the prevention, diagnosis, and treatment of the condition., (© 2024. The Author(s).)

Objective: To evaluate the association between vitamin D status and CV disease after COVID-19 in college athletes., Design: Retrospective cohort study., Setting: National College Athletic Association Division-I college athletes from a single academic institution., Patients: A total of 157 athletes (60 female; median age: 20 years) from 9 sports with a positive SARS-CoV-2 test, cardiac magnetic resonance imaging (CMR), and vitamin D level., Independent Variables: Serum 25-hydroxyvitamin D level (primary); age, sex (regression models)., Main Outcomes Measures: Differences in age, sex, race, ethnicity, myocarditis, pericarditis, and CMR metrics by vitamin D status were analyzed. Regression models were used to assess the relationship between vitamin D status and CMR metrics accounting for age and sex., Results: Low vitamin D (LVD) was found in 33 (21.0%) of athletes, particularly Black males ( P < 0.001). Athletes with LVD had higher biventricular and lower mid-ventricular extracellular volumes, but these differences were not significant when corrected for age and sex. Athletes with LVD had higher left ventricle (LV) mass ( P < 0.001) and LV mass index ( P = 0.001) independent of age and sex. Differences in global circumferential strain were noted but are likely clinically insignificant. Vitamin D status did not associate with myocarditis and pericarditis ( P = 0.544)., Conclusions: LVD is common in athletes, particularly in Black males. Although athletes with LVD had higher LV mass, cardiac function and tissue characterization did not differ by vitamin D status. Future studies are needed to determine if the differences in LV mass and LV mass index by vitamin D status are clinically significant. This study suggests that vitamin D status does not impact the development of myocarditis or pericarditis after COVID-19 infection., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To study the concentration of immunoglobulin free light chains (FLCs) in patients with myocarditis in comparison with non-inflammatory heart diseases, their relationship with inflammatory markers and the severity of chronic heart failure (CHF)., Material and Methods: This study included 77 patients (31 women, mean age 54.1±13.3 years): 41 patients with myocarditis verified by myocardial biopsy (n=18) or using a noninvasive diagnostic algorithm, 31 patients with noninflammatory CHF (comparison group), and 5 patients with monoclonal gammopathy identified during the study (4 of them were diagnosed with AL amyloidosis with heart damage). In the myocarditis group, CHF was diagnosed in 29 patients, mean stage IIA, functional class (FC) 2-3, with a mean left ventricular ejection fraction 43%. In the comparison group, patients had predominantly IIA stage, FC 2-3 CHF without systolic dysfunction. The blood concentration of kappa and lambda FLC types was measured with Cloneus S-FLC-K TIA Kit and Cloneus S-FLC-L TIA Kit. Concentrations were considered normal at FLC-kappa 4.84-14.20 mg/l, FLC-lambda 7.03-22.50 mg/l, and the FLC-kappa/lambda ratio 0.426-1.050., Results: Increased FLC concentrations were found in 58% of patients with myocarditis and in 77% of patients in the comparison group. The FLC-lambda concentration was significantly higher in the comparison group; there were no significant differences between the groups in FLC-kappa and their ratio. The closest significant correlations in both groups and the entire cohort were noted between FLCs of either type and CHF, as well as the requirement for loop diuretics (correlation coefficients, 0.60-0.90), independent on the severity of systolic dysfunction. Myocarditis patients also showed correlations of FLCs with the titer of antibodies to cardiomyocyte nuclear antigens, levels of C-reactive protein, leukocytes, neutrophils, erythrocyte sedimentation rate, and the concentration of N-terminal fragment of brain natriuretic peptide. In a subgroup of 10 myocarditis patients who were treated with immunosuppressants, FLCs of both types were significantly lower than in the comparison group; only with the persistence of severe CHF was an increase in FLCs noted., Conclusion: An increased FLC concentration can be considered as an important pathogenesis component that reflects both the specific mechanisms of myocarditis and the severity of CHF. In the absence of a statistically significant increase in general inflammatory markers in the blood of myocarditis patients, the measurement of FLCs can be used as an additional diagnostic marker and predictor of the decompensated variant of the course of myocarditis. However, the diagnostic and prognostic significance of FLC concentration in patients without CHF requires a further study.

Pentraxin 3 (PTX3) is an acute phase protein produced in various tissues in response to microbial and sterile stimuli, which regulates the inflammation outcomes. PTX3 has not been investigated in myocarditis. Our aim was to assess circulating and cardiac tissue expression of PTX3 in 55 patients with myocarditis proven by magnetic resonance and/or endomyocardial biopsy. A major proportion of patients with myocarditis displayed significantly increased plasma PTX3 levels as compared with controls (26/30 vs. 0/10), with higher diagnostic yield than conventional biomarkers in the study group. Cardiac tissue analysis revealed PTX3 expression in all patients (40/40), with viral myocarditis exhibiting higher signal intensity than autoimmune myocarditis, and with a predominant localization in cardiomyocytes. Abnormal plasma PTX3 was associated with systolic dysfunction and heart failure at presentation. Interestingly, patients who recovered by 12 months had higher baseline PTX3 levels. Our preliminary data support the potential use of PTX3 as a biomarker in myocarditis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR)., Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis., Conclusions: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

Background: Biomarkers simplifying the diagnostic workup by discriminating between non-ST-segment-elevation myocardial infarction (NSTEMI) and infarct-like myocarditis are an unmet clinical need., Methods and Results: A total of 105 subjects were categorized into groups as follows: ST-segment-elevation myocardial infarction (n=36), NSTEMI (n=22), infarct-like myocarditis (n=19), cardiomyopathy-like myocarditis (n=18), and healthy control (n=10). All subjects underwent cardiac magnetic resonance imaging, and serum concentrations of matrix metalloproteinase-1 (MMP-1) and procollagen type I carboxy terminal propeptide (PICP) were measured. Biomarker concentrations in subjects presenting with acute coronary syndrome and non-ST-segment-elevation, for example NSTEMI or infarct-like myocarditis, categorized as the non-ST-segment-elevation acute coronary syndrome-like cohort, were of particular interest for this study. Compared with healthy controls, subjects with myocarditis had higher serum concentrations of MMP-1 and PICP, while no difference was observed in individuals with myocardial infarction. In the non-ST-segment-elevation acute coronary syndrome-like cohort, MMP-1 concentrations discriminated infarct-like myocarditis and NSTEMI with an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI, 0.89-1.00), whereas high-sensitivity cardiac troponin T performed inferiorly (AUC, 0.74 [95% CI, 0.58-0.90]; P =0.012). Application of an optimal MMP-1 cutoff had 94.4% sensitivity (95% CI, 72.7%-99.9%) and 90.9% specificity (95% CI, 70.8%-98.9%) for the diagnosis of infarct-like myocarditis in this cohort. The AUC of PICP in this context was 0.82 (95% CI, 0.68-0.97). As assessed by likelihood ratio tests, incorporating MMP-1 or PICP with age and C-reactive protein into composite prediction models enhanced their diagnostic performance., Conclusions: MMP-1 and PICP could potentially be useful biomarkers for differentiating between NSTEMI and infarct-like myocarditis in individuals with non-ST-segment-elevation acute coronary syndrome-like presentation, though further research is needed to validate their clinical applicability.

Purpose: Immune checkpoint inhibitors-related myocarditis (ICI-M) is one of the immune-related adverse events (irAEs), which is rare and highly lethal. This study aimed to establish nomograms based on ratio biomarkers to predict the severity and prognosis of ICI-M., Methods: We retrospectively examined patients with advanced cancers who were also diagnosed with ICI-M at the Fourth Hospital of Hebei Medical University. The patients of ICI-M were divided into mild and severe groups and a 40-day following up was carried out. The major adverse cardiovascular events(MACEs) were regarded as the endpoint. Nomogram-based models were established and validated., Results: Seventy-seven patients were involved, including 31 severe cases(40.3%). Lactate dehydrogenase-to-albumin ratio(LAR) combined with the change rate from baseline to onset of LAR( ▵ LAR) which performed best to diagnose the severe ICI-M was identified to establish the nomogram-based model. The bootstrap-corrected concordance index [0.752 95% confidence interval (CI): 0.635 - 0.866] and calibration plot with good degree of fitting confirmed this diagnostic model. Neutrophil-to-high-density lipoprotein cholesterol ratio(NHR) and LAR were also screened into the nomogram-based model for 40-day MACEs after ICI-M, which performed well by validating for concordance index(0.779 95% CI: 0.677 - 0.865)and calibration plots after being bootstrap-corrected. Moreover, a  ≥ 101% increase in LAR significantly separated patients in MACE-free survival., Conclusion: Ratio indexes at onset and their change rates from baseline showed good diagnostic value for the severity of ICI-M and prognostic value for subsequent MACEs, particularly LAR, NHR and their change rates. The nomogram-based models of ratio indexes could provide a potential choice for early detection and monitor of the severe ICI-M and subsequent MACEs., (© 2024. The Author(s).)

Acute myocarditis remains a diagnostic issue with a wide spectrum of clinical manifestations that could mimic ST-elevation myocardial infarction (STEMI). We present a case of a 26-year-old male with left-sided intense squeezing chest pain associated with elevated troponin, ST-segment elevations, and reduced ejection fraction. The patient was initially suspected of having a STEMI with non-obstructed coronary arteries (MINOCA). However, due to positive pair troponin tests, increased inflammatory markers there was suspected myocarditis and cardiac MRI confirmed this diagnosis. This case highlights the clinical significance of assessment of laboratory markers and cardiac MRI in diagnostics of myocarditis.

Aim: Myocarditis, an inflammatory disease of the myocardium, can range from asymptomatic cases to severe forms such as fulminant myocarditis. The systemic immune-inflammation index (SII) has emerged as a potential biomarker for various inflammatory diseases. This study aimed to determine the effect of SII on the prognosis of young adults with acute myocarditis and compare it with other cardiac markers. Methods: We retrospectively analyzed patients aged 18-40 years who were admitted to the emergency department with a diagnosis of acute myocarditis between January 2014 and January 2024. Patients were divided into non-fulminant and fulminant myocarditis groups based on diagnostic criteria. Results: SII, troponin I and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were significantly higher in the fulminant myocarditis group ( p  < 0.001 for all). Logistic regression analysis identified SII and NT-proBNP as independent predictors of fulminant myocarditis but not for troponin I ( p  = 0.064). The optimal cutoff value for SII in diagnosing fulminant myocarditis was 1020, with a sensitivity of 91% and specificity of 83%, outperforming troponin I. Patients with SII ≥1020 had a significantly higher risk of adverse outcomes. Conclusion: The SII enables early detection of adverse outcomes and is an independent predictor of prognosis in young adults with myocarditis.

Aims: Myocardial inflammation is increasingly detected noninvasively by tissue mapping with cardiovascular magnetic resonance (CMR). Intraindividual agreement with endomyocardial biopsy (EMB) or markers of myocardial injury, high-sensitive cardiac troponin (hs-cTnT) in patients with clinically suspected viral myocarditis is incompletely understood., Methods: Prospective multicenter study of consecutive patients with clinically suspected myocarditis who underwent blood testing for hs-cTnT, CMR, and EMB as a part of diagnostic workup. EMB was considered positive based on immunohistological criteria in line with the European Society of Cardiology (ESC) definitions. CMR diagnoses employed tissue mapping using sequence-specific cut-off for native T1 and T2 mapping; active inflammation was defined as T1 ≥2 standard deviation (SD) and T2 ≥2 SD above the mean of normal range. Hs-cTnT of greater than 13.9 ng/L was considered significant., Results: A total of 114 patients (age (mean ± SD) 54 ± 16, 65% males) were included, of which 79 (69%) had positive EMB criteria, 64 (56%) CMR criteria, and a total of 58 (51%) positive troponin. Agreement between EMB and CMR diagnostic criteria was poor (CMR vs ESC: area under the curve (AUC): 0.51 (0.39-0.62)). The agreement between a significant hs-cTnT rise and CMR-based diagnosis of myocarditis was good (AUC: 0.84 (0.68-0.92); p < 0.001), but poor for EMB (0.50 (0.40-0.61). Hs-cTnT was significantly associated with native T1 and T2, high-sensitive C-reactive protein, and N-terminal pro-hormone brain natriuretic peptide (r = 0.37, r = 0.35, r = 0.30, r = 0.25; p < 0.001), but not immunohistochemical criteria or viral presence., Conclusion: In clinically suspected viral myocarditis, all diagnostic approaches reflect the pathophysiological elements of myocardial inflammation; however, the differing underlying drivers only partially overlap. The EMB and CMR diagnostic algorithms are neither interchangeable in terms of interpretation of myocardial inflammation nor in their relationship with myocardial injury., Competing Interests: Declaration of competing interests The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth., Methods: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions., Results: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25)., Conclusions: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Although myocarditis following immune checkpoint inhibitor (ICI) therapy is rarely reported, it is considered clinically important because of its high mortality rate. Although various tests may be used for early diagnosis, abnormalities suggestive of myocarditis may not be detected. We report a case of ICI-induced myositis and concurrent asymptomatic myocarditis with mild cardiac marker elevation following nivolumab therapy in a 79-year-old man with metastatic gastric cancer. In this case, cardiac magnetic resonance imaging was useful for diagnosis. Treatment with oral prednisolone rapidly improved the patient's symptoms and creatine kinase levels. Follow-up examination revealed no flare-up of myositis and exacerbation of myocarditis. Since ICI-induced myositis is often complicated by myocarditis, this case report highlights the importance of detecting concurrent myocarditis in patients with ICI-induced myositis through intensive cardiac assessments to improve clinical outcomes.

Objective: Recent advances in cardiac MRI (CMR) and other diagnostic techniques have made it easier to identify subclinical cardiac inflammation and dysfunction in the idiopathic inflammatory myopathies (IIM). Herein, we systematically review the literature regarding cardiac involvement in IIM., Methods: We searched Medline and EMBASE from 1990 to 2020 using keywords related to IIM and cardiac disease. We included English language studies in adults with any immune-mediated, inflammatory muscle pathology., Results: We identified 10 425 potentially relevant abstracts, of which 29 were included. Most frequently these included patients with PM or DM without symptomatic myocarditis. Five categories of cardiac investigation were used in these patients: cardiac enzyme testing, ECG, transthoracic echocardiography, CMR and nuclear medicine testing. Patients with clinical myocarditis had universally abnormal cardiac troponin levels and ECG. Elevated cardiac troponin T was more common than cardiac troponin I and may correlate with disease activity, whereas cardiac troponin I was more specific for cardiac involvement. Non-specific ECG changes were common. The major finding on transthoracic echocardiography was abnormal ejection fraction. Gross systolic dysfunction was unusual, but subclinical systolic dysfunction was reported in several studies. Abnormal diastolic function was common and may be associated with disease duration. Late gadolinium enhancement (reflecting regional necrosis or scarring) and abnormal myocardial mapping parameters (reflecting myocardial inflammation, fibrosis and oedema) were frequently identified on CMR, suggesting significant subclinical myocardial pathology (despite typically normal ejection fraction)., Conclusion: Abnormal cardiac investigations are commonly found in asymptomatic IIM patients, which has potential prognostic and treatment implications., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We sought to describe the tendency and extent of high-sensitivity cardiac troponin I (hs-cTnI) changes in patients with fulminant myocarditis (FM) after admission and to explore the relationship between the in-hospital mortality of FM and the absolute and relative changes in hs-cTnI within 24 h and 48 h after admission., Methods: In the retrospective study, the object are patients diagnosed with FM in our single centre. The value of cardiac troponin was recorded after patients admitted to hospital in succession. The absolute and relative changes in hs-cTnI within 24 h and 48 h were described as range distributions. Receiver operating characteristic (ROC) curve and Cox analyses were performed to determine the relationship between in-hospital mortality of FM and hs-cTnI changes., Results: A total of 83 FM patients admitted to our centre from January 1, 2010 to December 31, 2019 were included; 69 patients survived and 14 patients died. In the survival group, 78% of patients experienced a decline in hs-cTnI within 24 h, while 36% of the mortality group exhibited a declining tendency in hs-cTnI (P = 0.003). Nearly 60% of survival group had a 0-2000 ng/l reduction in troponin from baseline within 24 h of admission. However, troponin levels of 50% of patients in the mortality group were 0-10,000 ng/ L higher than baseline 24 h after admission. Multivariable logistic analysis revealed that the declining tendency of hs-cTnI within 24 h, in addition to time from onset to admittance to hospital, intravenous immunoglobulin treatment and the abnormal level of creatinine, were associated with the in-hospital mortality of FM (for the declining tendency of hs-cTnI within 24 h, OR = 0.10, 95% CI 0.02-0.68, P = 0.018). The ROC curve revealed optimal cut-off values of - 618 ng/l for absolute change within 24 h (AUC = 0.800, P < 0.01), - 4389 ng/l for absolute change within 48 h (area under the curve = 0.711, P < 0.01), - 28.46% for relative change within 24 h (AUC = 0.810, P < 0.01), and - 52.23% for relative change within 48 h (AUC = 0.795, P < 0.01). Absolute changes and relative changes in hs-cTnI within 24 h and 48 h were strong predictors of in-hospital mortality by Cox regression analysis after adjustment for sex, time from onset to admission, and occurrence of ventricular tachycardia or ventricular fibrillation., Conclusion: Most FM patients who survived experienced a decline in hs-cTnI within 24 h. The absolute and relative changes in hs-cTnI within 24 h and 48 h were strong predictors of in-hospital mortality., (© 2021. The Author(s).)

Objective: To better define the clinical distinctions between the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related paediatric inflammatory multisystem syndrome (PIMS) and Kawasaki disease (KD)., Methods: We compared three groups of patients: group 1, cases from our national historic KD database (KD-HIS), before the SARS-CoV-2 pandemic; group 2, patients with KD admitted to an intensive care unit (KD-ICU) from both our original cohort and the literature, before the SARS-CoV-2 pandemic; and group 3, patients with PIMS from the literature., Results: KD-HIS included 425 patients [male:female ratio 1.3, mean age 2.8 years (s.d. 2.4)], KD-ICU 176 patients [male:female ratio 1.3, mean age 3.5 years (s.d. 3.1)] and PIMS 404 patients [male:female ratio 1.4, mean age 8.8 years (s.d. 3.7)]. As compared with KD-HIS patients, KD-ICU and PIMS patients had a higher proportion of cardiac failure, digestive and neurological signs. KD-ICU and PIMS patients also had a lower frequency of typical KD-mucocutaneous signs, lower platelet count, higher CRP and lower sodium level. As compared with KD-HIS and KD-ICU patients, PIMS patients were older and more frequently had myocarditis; they also had fewer coronary abnormalities and lower sodium levels. Unresponsiveness to IVIG was more frequent in KD-ICU than KD-HIS and PIMS patients., Conclusion: On clinical grounds, KD-HIS, KD-ICU and PIMS might belong to a common spectrum of non-specific pathogen-triggered hyperinflammatory states. The causes of increasing inflammation severity within the three entities and the different effects on the heart remain to be determined., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Immune checkpoint inhibitors (ICIs) have improved the management and the prognosis of patients with cancer but are associated with an increased risk of toxicities that can affect every organ. ICI-associated myocarditis has a low incidence (< 1%) but a high fatality rate (30%-50%). Herein we report a patient treated with ICI admitted for suspicion of myocarditis. Cardiac magnetic resonance imaging (cMRI) was normal. An endomyocardial biopsy (EMB) was in favour of ICI-related myocarditis with cardiac lymphohistiocytic infiltrate. This case highlights the role of a systematic evaluation with electrocardiography and troponin and the potential value of EMB in patients without a suggestive cMRI., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) are associated with the severity of various diseases. The aim of this study was to demonstrate the relationship of NLR and MLR with the severity of myocarditis. 202 consecutive patients with myocarditis were retrospectively enrolled in this study. Laboratory parameters and clinical data were extracted from hospital records and discharge letters. Median NLR was 2.48 (IQR 1.55-4.58) and median MLR was 0.42 (IQR 0.39-0.58). NLR and MLR correlated with HF, CRP and leukocyte count, MLR further correlated inversely with LV systolic function (rs = - 0.379, p = 0.030). Both ratios correlated better with length of hospital stay (NLR: rs = 0.435, p = 0.003; MLR: rs = 0.534, p < 0.0001) than CRP, leukocyte count, IL-6 or procalcitonin. AUCs for the prediction of prolonged hospital stay (NLR = 0.75, MLR = 0.80), and optimal cut-offs therefor were calculated. Patients who had in-hospital complications showed a higher NLR, however, this remained statistically insignificant. NLR and MLR correlated with the length of stay, as well as with several clinical and laboratory parameters in patients with myocarditis. Since white blood cell differentials are relatively easy and fast to perform, both ratios could facilitate further risk stratification in affected patients., (© 2021. The Author(s).)

Trichinellosis is a parasitic infection that is associated with the consumption of raw meat. The specific genotype Trichinella nativa has been found in raw bear meat. The most common genotype that has been linked with myocarditis is T spiralis. We present a case of T nativa myocarditis secondary to consumption of raw bear meat. The clinical manifestations as well as therapy of this specific genotype is outlined., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The treatment of myopericarditis is different than that of acute myocardial infarction (AMI). However, since their clinical presentation is frequently similar it may be difficult to distinguish between these entities despite a disparate underlying pathogenesis. Myopericarditis is primarily an inflammatory disease associated with high C-reactive protein (CRP) and relatively low elevated troponin concentrations, while AMI is characterized by the opposite. We hypothesized that evaluation of the CRP/troponin ratio on presentation to the emergency department could improve the differentiation between these two related clinical entities whose therapy is different. Such differentiation should facilitate triage to appropriate and expeditious therapy., Methods: We evaluated the CRP/troponin ratio on presentation among patients consecutively included in a large single center registry that included 1898 consecutive patients comprising 1025 ST-elevation myocardial infarction (STEMI) patients, 518 Non-STEMI (NSTEMI) patients, and 355 patients diagnosed on discharge as myopericarditis. CRP and troponin were sampled on admission in all patients and their ratio was assessed against discharge diagnosis. ROC analysis of the CRP/troponin ratios evaluated the diagnostic accuracy of myopericarditis against all AMI, STEMI, and NSTEMI patients., Results: Median admission CRP/troponin ratios were 84, 65, and 436 mg×ml/liter×ng in STEMI, NSTEMI and myopericarditis groups, respectively (p<0.001) demonstrating good differentiating capability. The Receiver-operator-curve of admission CRP/troponin ratio for diagnosis of myopericarditis against all AMI, STEMI, and NSTEMI patients yielded an area-under-the curve of 0.74, 0.73, and 0.765, respectively. CRP/troponin ratio>500 resulted in specificity exceeding 85%, and for a ratio>1000, specificity>92%., Conclusion: The CRP/troponin ratio can serve as an effective tool to differentiate between myopericarditis and AMI. In the appropriate clinical context, the CRP/troponin ratio may preclude further evaluation., Competing Interests: The authors have declared that no competing interests exist.

Cardiac fibroblasts and cardiomyocytes are the main cells involved in the pathophysiology of myocarditis (MCD). These cells are especially sensitive to changes in iron homeostasis, which is extremely important for the optimal maintenance of crucial cellular processes. However, the exact role of iron status in the pathophysiology of MCD remains unknown. We cultured primary human cardiomyocytes (hCM) and cardiofibroblasts (hCF) with sera from acute MCD patients and healthy controls to mimic the effects of systemic inflammation on these cells. Next, we performed an initial small-scale ( n = 3 per group) RNA sequencing experiment to investigate the global cellular response to the exposure on sera. In both cell lines, transcriptomic data analysis revealed many alterations in gene expression, which are related to disturbed canonical pathways and the progression of cardiac diseases. Moreover, hCM exhibited changes in the iron homeostasis pathway. To further investigate these alterations in sera-treated cells, we performed a larger-scale ( n = 10 for controls, n = 18 for MCD) follow-up study and evaluated the expression of genes involved in iron metabolism. In both cell lines, we demonstrated an increased expression of transferrin receptor 1 (TFR1) and ferritin in MCD serum-treated cells as compared to controls, suggesting increased iron demand. Furthermore, we related TFR1 expression with the clinical profile of patients and showed that greater iron demand in sera-treated cells was associated with higher inflammation score (interleukin 6 (IL-6), C-reactive protein (CRP)) and advanced neurohormonal activation (NT-proBNP) in patients. Collectively, our data suggest that the malfunctioning of cardiomyocytes and cardiofibroblasts in the course of MCD might be related to alterations in the iron homeostasis.

Current reports concerning cardiac involvement in the novel corona virus disease (COVID-19) mostly document acute myocardial injury at presentation. Here, we present a healthy young male, with presumed acute myocarditis, presenting 20 days after initial diagnosis of COVID-19 - and after a clinical, and apparent laboratory, resolution of the original episode. His sole substantial clinical finding upon admission was fever, which was followed by a witnessed elevation in troponin-I., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors have improved the management of metastatic melanoma, however, we have witnessed an emergence of adverse cardiac events such as myocarditis., Objectives: We first aimed to assess the prevalence of adverse cardiac events in patients treated with anti-PD-1 for metastatic melanoma. Our second objective was to determine the role of troponin monitoring in the diagnosis of these events., Materials & Methods: We retrospectively analysed the prevalence of patients treated with anti-PD-1 in a real-life setting based on a cohort of 183 patients. We then performed a prospective cohort, in which clinical and biological profiles of patients were collected, along with monthly monitoring of troponin levels., Results: The prevalence of adverse cardiac events in the retrospective cohort was 2.2%, with three cases of myocarditis and one of myocardial infarction. In the prospective cohort, 14/52 patients had an abnormal baseline troponin T level. All patients had a history of cardiac or vascular complaints. Six patients showed an increase in troponin T level during follow-up, in two patients associated with clinical symptoms., Conclusion: Adverse cardiac events with immunotherapy are both frequent and life-threatening. Troponin T may be of interest to detect early adverse cardiac events before any clinical sign, however, the data supporting this remain to be confirmed.

C-reactive protein (CRP) is an acute phase reactant to be a marker of inflammation and has been correlated with the cardiac injury. An immunoassay was performed using anti-human CRP antibody on an InterDigitated electrode (IDE) sensor to determine and specify CRP concentration for diagnosing the condition of myocardial inflammation. To promote the detection, gold nanoparticle (GNP) was seeded on the aminated-IDE surface. Anti-CRP was hitched on the GNP-seeded surface and identified the abundance of CRP. The limit of quantification was found as 100 fM, and the higher current response was noticed by increasing CRP concentrations with the sensitivity at 1 pM. Furthermore, CRP-spiked human serum did not interfere the determination of CRP and increased the current response, indicating suitability for a real-life sample. Similarly, the control experiments with nonimmune antibody Troponin I are not showing the definite current responses, proving the selective identification of CRP. This method of diagnosing is needful to determine the cardiovascular injury at the right time., (© 2020 International Union of Biochemistry and Molecular Biology, Inc.)

Background: microRNAs (miRs) have emerged as important modulators of cardiovascular development and disease. Our aim was to determine whether cardiac-related miRs such as miR-21-5p and miR-1-3p were differentially expressed in acute viral myocarditis and whether any of them was related with the extent of myocardial damage and left ventricular dysfunction., Methods: We enrolled 40 patients with acute viral myocarditis. Blood samples were taken on admission and miRs expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction., Results: miR-21-5p, miR-1-3p were significantly elevated in acute myocarditis. miR-21-5p levels showed a strong correlation with global longitudinal strain ( r = 0.71, p < 0.01), while miR-1-3p had significant correlations with troponin I ( r = 0.79, p < 0.01)., Conclusions: The expression of miR-21-5p and miR-1-3p in peripheral blood is increased in acute viral myocarditis, and this increase is correlated with myocardial damage and indicative of left ventricular systolic dysfunction in these patients.

Background: This study aims to investigate the role of free triiodothyronine (fT3) in predicting poor prognosis of adult patients with acute myocarditis., Methods: A total of 173 consecutive adult patients with acute myocarditis completed thyroid function evaluations. They were divided into two groups according to fT3 levels: low fT3 group (n = 54, fT3 < 3.54 pmol/liter) and normal fT3 group (n = 119, fT3 ≥ 3.54 pmol/liter). The primary endpoint was major adverse cardiac events (MACE)., Results: During the 3.5 ± 2.8 years follow-up, the rate of MACE was 29.6% versus 3.5% in low fT3 group versus normal fT3 group, respectively ( P < 0.0001). Long-term at 8 years MACE-free survival were lower in low fT3 group versus normal fT3 group (52.9% versus 92.3%, log-rank P < 0.0001), respectively. Univariate Cox analysis showed that left ventricular ejection fraction (LVEF) < 50% [hazard ratio (HR) 10.231, 95% confidence interval (CI): 3.418-30.624, P < 0.0001) and low fT3 level (HR 0.360, 95% CI: 0.223-0.582, P < 0.0001) were strongest two predictors of MACE. After adjustment for traditional risk predictors, the prognostic value of fT3 status was still significant (HR 0.540, 95% CI: 0.316-0.922, P = 0.024). Compared with normal fT3 group, those in low fT3 group were at a much higher risk of MACE (HR 5.074, 95% CI: 1.518-16.964, P = 0.008)., Conclusions: Low T3 syndrome was a strong predictor of poor prognosis in adult patients with acute myocarditis. These findings suggest that fT3 level could serve as a biomarker for risk stratification in acute myocarditis patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Wang, Zhang and Tang.)

Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with Coronavirus Disease 2019 (COVID-19) still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia-induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel severe acute respiratory syndrome coronavirus 2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Here we present the case of a 37-year-old previously healthy man who developed fever, headache and a unilateral, painful neck swelling while working offshore. He had no known contact with anyone with COVID-19; however, due to the ongoing pandemic, a nasopharyngeal swab was performed, which was positive for the virus. After transfer to hospital for assessment his condition rapidly deteriorated, requiring admission to intensive care for COVID-19 myocarditis. One week after discharge he re-presented with unilateral facial nerve palsy. Our case highlights an atypical presentation of COVID-19 and the multifaceted clinical course of this still poorly understood disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Under physiological conditions, the myocardial extracellular matrix (ECM) is maintained by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). However, changes in the balance between MMPs and TIMPs can lead to pathological remodeling of the ECM, which contributes to cardiovascular and kidney diseases. The aim of our study was to assess levels of MMPs and TIMP-2 in patients with myocarditis and their relationship to renal function., Materials and Methods: Forty five patients with myocarditis who underwent CMR were included, comprising 11 with concurrent chronic kidney disease (CKD). Blood samples were obtained to assess serum levels of MMP-2, MMP-3, MMP-9, and TIMP-2., Results: Serum MMP-2, MMP-3, and TIMP-2 levels negatively correlated with the ejection fraction in patients with myocarditis, while MMP-3 levels correlated with longitudinal deformation (p < 0.05). Serum MMP-2, MMP-3, and TIMP-2 levels also negatively correlated with renal function, as assessed by the estimated glomerular filtration rate (eGFR) (p < 0.05). Patients with myocarditis and concurrent CKD had higher levels of MMP-2 and TIMP-2 than those without kidney damage., Conclusions: (1) We demonstrated that MMP-2, MMP-3, and TIMP-2 concentrations were related to left-ventricular ejection fraction, and MMP-3 levels correlated with longitudinal deformation, indicating MMPs play an important role in the post-inflammatory remodeling of the myocardium. (2) A negative correlation between the eGFR and MMP-2, MMP-3, and TIMP-2 and a positive correlation between creatinine and MMP-3 levels indicate the role of MMPs and TIMP-2 in renal dysfunction., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background Myocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event. Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune-related adverse events; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods and Results This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI immune-related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1-1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7-1.3 K/μL; P <0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3-5.4) to admission (6.6; interquartile range, 4.5-14.1; P <0.001). There was no statistically significant change in controls. In follow-up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P <0.001) or increases in NLR (156.5% versus 65.1%; P =0.019) were associated with major adverse cardiac events. Conclusions A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

This study sought to identify parameters that could guide towards an ischemic origin in patients hospitalized for myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA). MINOCA is challenging in clinical practice, as the pathophysiology is multifaceted. A total of 135 patients with MINOCA who underwent cardiovascular magnetic resonance imaging (CMR) in a single tertiary University Hospital, were retrospectively included. The study cohort was classified into 4 groups according to the CMR diagnosis (i.e., myocarditis, myocardial infarction, Takotsubo cardiomyopathy, normal or uncommon diagnosis). According to the CMR, 62% had myocarditis, 14.1% myocardial infarction, 4.4% of Takotsubo and 19.3% showed a normal CMR or uncommon diagnoses. In the multivariate analysis, three criteria were independently correlated with the underlying diagnosis of myocardial infarction: (1) the absence of inflammatory response (HR: 5.71 IC95% [1.79-18.28]; p = 0.002), (2) the presence of coronary atheroma in invasive coronary angiography (HR: 6.56 IC95% [2.27-18.92]; p = 0.001) and (3) a peak of troponin ratio elevated than normal levels of 150 (HR: 4.12 IC95% [1.45-11.65]; p = 0.01). The prevalence of myocardial infarction in MINOCA was 4.9% in the absence of these three criteria, 3.4% with one of the criteria present, 34.5% with two criteria present and 71.4% with all three criteria. The negative predictive value for MI was 96% in the presence of at least two criteria. Our study shows that the absence of inflammatory response, a high troponin and the presence of angiographic coronary atheroma are independently correlated with a myocardial infarction underlying cause of MINOCA.

Acute SARS-CoV-2 respiratory disease is an infectious respiratory disease caused by the virus SARS-CoV-2 belonging to the coronaviridae family. A pandemic is still present as of May 2020. In addition to causing pneumonia, SARS-CoV-2 may induce a direct damage to the heart, causing myocarditis, with significant impairment of cardiac contractility, and/or pericarditis. Elderly patients and those with cardiovascular risk factors, such as hypertension and diabetes mellitus, are at increased risk of heart complications from COVID-19. In this review, we focused on the correlation between COVID-19 infection and the high sensitivity troponin T and I, and their significance in the development of myocarditis. Data emerging from the studies so far conducted indicate that a high value of high-sensitivity troponin represents a negative prognostic indicator when associated with heart damage on an infectious-inflammatory basis (i.e. myopericarditis). We should identify a safe and clear diagnostic algorithm, possibly combining patient clinical history, troponin levels and cardiac ultrasound findings that could help us in the prediction of myopericarditis.

Coronavirus 2019 disease (COVID-19), caused by SARS-CoV-2, can lead to cardiac impairment with various types of clinical manifestations, including heart failure and cardiogenic shock. A possible expression of cardiac impairment is non-ischemic ventricular dysfunction, which can be related to different pathological conditions, such as myocarditis, stress and cytokine-related ventricular dysfunction. The diagnosis of these pathological conditions can be challenging during COVID-19; furthermore, their prevalence and prognostic significance have not been elucidated yet. The purpose of this review is to take stock of the various aspects of non-ischemic ventricular dysfunction that may occur during COVID-19 and of the diagnostic implications related to the use of cardiac imaging techniques.

There is an unmet need for accurate and practical screening to detect myocarditis. We sought to test the hypothesis that the extent of acute myocarditis, measured by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR), can be estimated based on routine blood markers. A total of 44 patients were diagnosed with acute myocarditis and included in this study. There was strong correlation between myoglobin and LGE (r s  = 0.73 [95% CI 0.51; 0.87], p < 0.001), while correlation was weak between LGE and TnT-hs (r s  = 0.37 [95% CI 0.09; 0.61], p = 0.01). Receiver operating curve (ROC) analysis determined myoglobin ≥ 87 μg/L as cutoff to identify myocarditis (92% sensitivity, 80% specificity). The data were reproduced in an established model of coxsackievirus B3 myocarditis in mice (n = 26). These data suggest that myoglobin is an accurate marker of acute myocarditis. Graphical Abstract Receiver operating curve analysis determined myoglobin ≥ 87 μg/L as cutoff to identify myocarditis and these data were reproduced in an established model of coxsackievirus B3 myocarditis in mice: CMRI, cardiac magnetic resonance imaging; Mb, myoglobin; LGE, late gadolinium enhancement; ROC, receiver operating curve analysis.

SARS-CoV-2 is the causative virus responsible for the COVID-19 pandemic. This pandemic has necessitated that all professional and elite sport is either suspended, postponed or cancelled altogether to minimise the risk of viral spread. As infection rates drop and quarantine restrictions are lifted, the question how athletes can safely resume competitive sport is being asked. Given the rapidly evolving knowledge base about the virus and changing governmental and public health recommendations, a precise answer to this question is fraught with complexity and nuance. Without robust data to inform policy, return-to-play (RTP) decisions are especially difficult for elite athletes on the suspicion that the COVID-19 virus could result in significant cardiorespiratory compromise in a minority of afflicted athletes. There are now consistent reports of athletes reporting persistent and residual symptoms many weeks to months after initial COVID-19 infection. These symptoms include cough, tachycardia and extreme fatigue. To support safe RTP, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of COVID-19 in elite athletes who place high demand on their cardiorespiratory system. As new evidence emerges, guidance for a safe RTP should be updated., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The cardiac involvement in Coronavirus disease (COVID-19) is still under evaluation, especially in severe COVID-19-related Acute Respiratory Distress Syndrome (ARDS). The cardiac involvement was assessed by serial troponin levels and echocardiograms in 28 consecutive patients with COVID-19 ARDS consecutively admitted to our Intensive Care Unit from March 1 to March 31. Twenty-eight COVID-19 patients (aged 61.7 ± 10 years, males 79%). The majority was mechanically ventilated (86%) and 4 patients (14%) required veno-venous extracorporeal membrane oxygenation. As of March 31, the Intensive Care Unit mortality rate was 7%, whereas 7 patients were discharged (25%) with a length of stay of 8.2 ±5 days. At echocardiographic assessment on admission, acute core pulmonale was detected in 2 patients who required extracorporeal membrane oxygenation support. Increased systolic arterial pressure was detected in all patients. Increased Troponin T levels were detectable in 11 patients (39%) on admission. At linear regression analysis, troponin T showed a direct relationship with C-reactive Protein (R square: 0.082, F: 5.95, p = 0.017). In conclusions, in COVID-19-related ARDS, increased in Tn levels was common but not associated with alterations in wall motion kinesis, thus suggesting that troponin T elevation is likely to be multifactorial, mainly linked to disease severely (as inferred by the relation between Tn and C-reactive Protein). The increase in systolic pulmonary arterial pressures observed in all patients may be related to hypoxic vasoconstriction. Further studies are needed to confirm our findings in larger cohorts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report a case of lethal myocarditis and myositis after pembrolizumab treatment for advanced upper urinary tract urothelial carcinoma. A 69-year-old man underwent pembrolizumab therapy as a second-line treatment. He had myalgia and a slightly elevated creatinine kinase (CK) on the day of the second administration of pembrolizumab. Five days later, the patient was admitted with severe fatigue and an abnormal gait. Physical examination revealed reduced muscle reflexes and proximal muscle weakness. An electrocardiogram (ECG) demonstrated a wide QRS complex ventricular rhythm. A marked elevation of cardiac enzymes, including CK, myoglobin, and cardiac troponin I, was detected. Myocardial biopsy revealed inflammatory cell infiltration and the partial impairment of myocardial tissue. The electromyogram was normal, but inflammation in myofibers was noted in a muscle biopsy. Myocarditis and myositis as immune-related adverse events (irAEs) were suspected, and the patient began intravenous steroid therapy and plasma exchange. However, the patient underwent cardiac arrest three days after admission and began extracorporeal membrane oxygenation and intra-aortic balloon pumping therapy. Despite steroid pulse therapy, the patient demonstrated no sign of improvement and subsequently died 17 days after admission. Immune-mediated myocarditis is a rare but fatal irAE of an immune checkpoint inhibitor (ICI). The present case suggests that myositis precedes myocarditis. Therefore, if myositis is suspected, subsequent myocarditis may need attention. In conclusion, we found that myositis and myocarditis developed in a patient with advanced urothelial carcinoma after pembrolizumab treatment. A routine follow-up of CK and cardiac troponin I, as well as an ECG, should be performed to identify any possible ICI-induced myocarditis and myositis quickly.