Myocarditis Patients Research Articles

Electrocardiogram changes in pediatric patients with myocarditis

BackgroundIt is traditionally taught that pediatric patients with myocarditis almost always have an abnormal electrocardiogram (ECG) at presentation. However, there has never been a study to objectively evaluate ECG changes in pediatric myocarditis patients compared to healthy controls or explore if specific ECG changes correlate with clinical outcomes. MethodsPediatric patients diagnosed with acute myocarditis were age and sex matched 1:2 with healthy controls in this retrospective case-control study spanning a seven-year period. ECGs from presentation through discharge were interpreted by electrophysiologists blinded to the patients' diagnoses. ResultsThirty-nine patients with myocarditis were identified. Twenty-eight (72%) had an abnormal ECG at presentation, 11 (28%) had a completely normal ECG. In this second group, six patients had an abnormal ECG at some point during their hospital course for a total of 34 (88%). Myocarditis patients who had an abnormal ECG at presentation spent more time in the hospital, 5 (2–19) versus 2 ((1–3) days (p < 0.01), and in the ICU, 1 (0–6) versus 0 (0–1) days (p < 0.01). Myocarditis patients were more likely to have ST elevation on their ECG compared to control patients (41% versus 17%, p < 0.01). Patients with ST elevation at presentation had a higher peak troponin level, 18.4 (5.8–31.0) versus 7.7 (0–19.1) ng/ml, (p < 0.01). ConclusionsOver a quarter of patients with myocarditis had a normal ECG at presentation to the emergency department. Patients with an abnormal ECG at presentation spent more time in the hospital. The presenting ECG, particularly the presence of ST elevation, may correlate with other clinical markers and help direct early management decisions.

Increased incidence of immune-mediated myocarditis in advanced skin malignancies treated with immune checkpoint inhibitors in the COVID-19 era.

2664 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results:A review of 361 patients that received ICI from 9/2014 – 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 – 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated AST:ALT ratio (median 1.58:1) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% pre-pandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and AST:ALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.

Characterization of the inflammasome IFN-dependent in hiPSC-derived endothelial cells from ICIs-induced myocarditis patients

Immune checkpoint inhibitors (ICIs) reactivate T cells to fight tumor cells, unraveling a new approach in cancer treatment. However, cardiovascular complications induced by these ICIs, especially myocarditis, have emerged as particularly dangerous complications with a mortality rate close to 50%. A recent study on cardiac biopsies showed that the IFN-γ pathway and inflammasome regulating proteins was specifically involved in myocarditis induced by ICIs treatment; this mechanism was not found in viral myocarditis and in dilated cardiomyopathies [1] . It is therefore crucial to set up models to study these pathophysiological mechanisms so that the benefit of immunotherapies is not compromised by their adverse cardiac effects. To better understand pathophysiological mechanisms of myocarditis induced by ICIs, we characterized the response to IFN-γ of endothelial cells (hiPSC-EC) generated from cells of patients with and without ICIs-induced myocarditis. We generated human-induced pluripotent stem cell (hiPSC), differentiated in hiPSC-EC, from cells of patients followed in the MediCO Center, Marseille. We considered two groups of patients: with myocarditis (Myoc) and without myocarditis (non-Myoc) following anti-PD-1/anti-CTLA4 immunotherapy. hiPSC-EC were treated with 10 ng/mL of IFN-γ during 48 h. Endothelial cells differentiated from hiPSC clones exhibited the characteristics expected for this cell type in all clones tested, both in the Myoc and non-Myoc patient groups. Stimulation by IFN-γ activated inflammatory intracellular signaling in hiPSC-EC, in particular overexpression of MHC class I and II, and PDL-1. Moreover, changes in the expression of genes of the JAK/STAT pathway and of the inflammasome, particularly the NLRP3 inflammasome, were observed in all groups of tested cells after the IFN-γ stimulation. However, the cells from Myoc patients seemed to be more impaired than those from non-Myoc patients. In particular, hiPSC-EC proliferation was more altered in this group by IFN-γ, and the expression of genes associated with the inflammatory response was strongly increased. Further analyses are in progress to confirm these preliminary data. These preliminary results, obtained in cells reprogrammed from cells of patients with immuno-induced myocarditis, are in agreement with the data published by Finke et al. (2021) in myocardial biopsies, indicating that these hiPSCs are a good model to study the pathophysiological mechanisms associated with the cardiotoxicitiy of anticancer immunotherapy.

Trends of Myocarditis and Endocarditis Cases before, during, and after the First Complete COVID-19-Related Lockdown in 2020 in France.

Background. The impact of the COVID-19 pandemic on hospitalization for cardiac infections is not well known. We aimed to evaluate the nationwide trends in hospital stays for myocarditis and endocarditis cases before, during and after the nationwide lockdown for the COVID-19 pandemic in France. We then aimed to describe the proportion of myocarditis and endocarditis patients with and without COVID-19 and their clinical characteristics. Methods. Hospitalized cases of cardiac infection were extracted from the French National Discharge database, which collects the medical records of all patients discharged from all public and private hospitals in France. Age, sex, and available cardiovascular risk factors were compared between stays with and without COVID-19 during the lockdown. Results. The number of myocarditis cases was 11% higher in 2020, compared to the average of the three prior years. In 2020, 439 of 3727 cases of myocarditis were associated with COVID-19. For endocarditis, there was an increase in cases by 7% in 2020 versus prior years. For endocarditis, 3% (240 of 8128 cases) of patients with endocarditis had COVID-19. For myocarditis, older age, hypertension, diabetes, obesity, and atrial fibrillation were more frequent in patients with COVID-19 than in those without. For endocarditis, only hypertension was more frequent in patients with COVID-19 than in those without. Conclusion. Our study reports an increase in hospitalizations for both myocarditis and endocarditis in 2020, possibly related to the COVID-19 pandemic. Interestingly, the trends differ according to the COVID-19 status. Knowledge of the factors associating myocarditis or endocarditis and COVID-19 may improve the quality and the type of monitoring for people with COVID-19, the identification of patients at risk of cardiac infections, and the treatment of COVID-19 patients.

Occurrence and predictors of severe arrhythmia in patients with myocarditis

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Patients with myocarditis are at risk for severe, life-threatening arrhythmia. However, predictors to identify high-risk patients are lacking. Purpose We investigated the occurrence and potential risk factors of severe arrhythmia in myocarditis patients. Methods 212 myocarditis patients that were hospitalized for arrhythmia monitoring at a tertiary university hospital were retrospectively enrolled. Non-sustained ventricular tachycardia (VT), sustained VT, ventricular fibrillation or cardiac arrest were considered as severe arrhythmia. We used a stepwise logistic regression model to investigate potential predictors. These included age, sex, clinical presentation (chest pain, palpitations, dyspnea, syncope, cardiac murmur, edema, pericardial friction, arrhythmia at presentation, Killip-class), comorbidities (hypertension, diabetes, coronary heart disease), imaging parameters (left ventricular ejection fraction [LVEF], pericardial effusion, edema and LGE on MRI), ECG variables (PQ depression, ST elevation, ST depression) and maximum levels of blood biomarkers (CRP, leukocytes, Troponin T, CK-MB). Results Mean age was 40.8 years, 73.1% were male and mean LVEF was 52.9%. During the hospital stay, 40 (18.9%) patients experienced severe arrhythmia: 33 (15.6%) non-sustained VT, 9 (4.2%) sustained VT, 1 (0.5%) ventricular fibrillation and 3 (1.4%) cardiac arrests (arrhythmia not mutually exclusive). Most arrhythmia occurred in the first 72h of monitoring (Figure). Significant predictors selected by the stepwise model (OR [95% CI]) for severe arrhythmia were LVEF (per 1% increase 0.95 [0.92; 0.99], p=0.005), syncope at presentation (7.9 [1.5; 40.4], p=0.01), any arrhythmia at first presentation (6.5 [1.3; 32.7], p=0.02) and CK-MB (per 10-unit increase 1.2 [1.1; 1.3], p=0.001). Conclusion(s) Myocarditis patients with low LVEF, presenting with arrhythmia and syncope and with increased CK-MB are at increased risk for severe arrhythmia and should be closely monitored. Further studies are needed to define, if patients without these risk factors might be safely discharged early.

COVID-19 Myocarditis: Prognostic Role of Bedside Speckle-Tracking Echocardiography and Association with Total Scar Burden.

SARS-CoV2 infection, responsible for the COVID-19 disease, can determine cardiac as well as respiratory injury. In COVID patients, viral myocarditis can represent an important cause of myocardial damage. Clinical presentation of myocarditis is heterogeneous. Furthermore, the full diagnostic algorithm can be hindered by logistical difficulties related to the transportation of COVID-19 patients in a critical condition to the radiology department. Our aim was to study longitudinal systolic cardiac function in patients with COVID-19-related myocarditis with echocardiography and to compare these findings with cardiac magnetic resonance (CMR) results. Patients with confirmed acute myocarditis and age- and gender-matched healthy controls were enrolled. Both patients with COVID-19-related myocarditis and healthy controls underwent standard transthoracic echocardiography and speckle-tracking analysis at the moment of admission and after 6 months of follow-up. The data of 55 patients with myocarditis (mean age 46.4 ± 15.3, 70% males) and 55 healthy subjects were analyzed. The myocarditis group showed a significantly reduced global longitudinal strain (GLS) and sub-epicardial strain, compared to the control (p < 0.001). We found a positive correlation (r = 0.65, p < 0.0001) between total scar burden (TSB) on CMR and LV GLS. After 6 months of follow-up, GLS showed marked improvements in myocarditis patients on optimal medical therapy (p < 0.01). Furthermore, we showed a strong association between baseline GLS, left ventricular ejection fraction (LVEF) and TSB with LVEF at 6 months of follow-up. After a multivariable linear regression analysis, baseline GLS, LVEF and TSB were independent predictors of a functional outcome at follow-up (p < 0.0001). Cardiac function and myocardial longitudinal deformation, assessed by echocardiography, are associated with TSB at CMR and have a predictive value of functional recovery in the follow-up.

Adenovirus increases arrhythmia susceptibility during acute cardiac infection

Myocarditis is responsible for 42% of sudden cardiac death in young adults, yet mechanisms underlying virally induced arrhythmia remain elusive. Adenovirus is a leading etiological agent of myocarditis but species‐specificity has limited development of animal disease models. Normal electrical impulse propagation in the heart is achieved through intercellular coupling via gap junctions, composed primarily of connexin43 (Cx43). Changes in Cx43 expression, localization, and/or function underlie the arrhythmias of sudden cardiac death. Given that gap junctions also propagate innate and adaptive antiviral immune responses, we hypothesized that adenovirus would target Cx43 to facilitate replication. Our prior work has demonstrated that Cx43 expression and function are indeed reduced rapidly during adenoviral infection limiting gap junction communication in human epithelial and cardiac cells. We are now employing a recently described cardiotropic strain of mouse adenovirus, MAdV‐3, to develop our work into whole animal studies and investigate virally‐induced alterations in cardiac electrophysiology and the molecular mechanisms of the resulting arrhythmogenic substrate. Adult mice were inoculated with MAdV‐3 and sampled after 7 days to model acute cardiac infection. We find MAdV‐3 viral genomes are specifically enriched in heart tissue, confirming cardiotropism. No cardiomyopathy was apparent by echocardiography or histopathology, consistent with human acute myocarditis patients. We find reductions in cardiac ion channel and connexin mRNA transcript levels after infection, and at the protein level, Cx43 is phosphorylated at residues known to reduce function. Ex vivo optical mapping experiments illustrate decreased conduction velocity in infected hearts. Turning to primary adult mouse cardiomyocytes, we detect prolonged action potential duration and impaired K+ current in infected cells by patch clamping. Confocal and super‐resolution localization microscopy of infected cardiac tissue and isolated cardiomyocytes reveals remodeling of gap junctions with alterations in complexing with scaffolding proteins and other ion channels at the cell‐cell junction. Finally, employing human iPSC‐derived cardiomyocytes and human adenovirus type‐5, we find increased Cx43 phosphorylation and, using optical mapping, perturbation of intercellular coupling during infection, just as we see with MAdV‐3. Our data demonstrate that reduced cellular coupling and ion channel function during adenoviral infection generates an arrhythmogenic substrate prior to an appreciable immune response or cardiomyopathy development. MAdV‐3 infection therefore provides a novel model of cardiac infection and myocarditis and provides physiologically relevant insight into mechanisms of virally‐induced arrhythmias.

Compensatory Upregulation of Anti-Beta-Adrenergic Receptor Antibody Levels Might Prevent Heart Failure Presentation in Pediatric Myocarditis.

BackgroundMyocarditis can be associated with severe heart failure and is caused by different inflammatory and autoimmune responses. The aim of this study was to describe the immunological response in children with myocarditis by analyzing anti-beta-adrenergic receptor antibodies (anti-β-AR Abs).MethodsSera of children who were hospitalized with biopsy-proven myocarditis were prospectively collected between April 2017 and March 2019. Anti-β1-AR Ab, anti-β2-AR Ab, and anti-β3-AR Ab were quantified by a CE-certified ELISA kit. According to normal values for immunoglobulin G (IgG), three age groups, <1, 1–5, and >5–17 years, were defined. Children without inflammatory cardiac pathology and no heart failure signs were served as a control group.ResultsWe compared 22 patients with biopsy-proven myocarditis and 28 controls. The median age (interquartile range) of the myocarditis group (MYC) was 12.1 (2.7–16.4) years, 13 men, left ventricular ejection fraction (LVEF) 51% and for control group, the median age was 5.0 (3.0–6.8) years, nine men, LVEF 64%. Myocarditis patients in the age group >5–17 years showed significantly higher anti-β3-AR Ab levels as compared to controls (p = 0.014). Lower anti-β2-AR Ab and anti-β3-AR Ab levels were significantly correlated with higher left ventricular diameters in myocarditis patients. The event-free survival using a combined endpoint (mechanical circulatory support [MCS], transplantation, and/or death) was significantly lower in myocarditis patients with antibody levels below the median as compared to myocarditis patients with antibody levels ≥ the median.ConclusionAnti-β-AR Ab levels are increased in children with myocarditis and >5 years of age. These antibodies might be upregulated compensatory to prevent further cardiac deterioration. A worse event-free survival in patients with lower anti-β-AR Ab levels might be a therapeutic target for immunoglobulin substitution.

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron and Other Variants in Serum From Children With Vaccination-Induced Myocarditis.

Our study demonstrates that children who developed SARS-CoV-2 vaccination-induced myocarditis and may not receive another vaccination, could be susceptible to infection with Omicron and emerging variants. We observed higher neutralizing antibody titers in myocarditis patients vs. healthy vaccinated children, but significantly lower neutralization titers against Omicron in both groups.

Patterns of cardiovascular magnetic resonance inflammation in acute myocarditis from South Asia and Middle East.

BackgroundCardiovascular magnetic resonance (CMR) is the test of choice for diagnosis and risk stratification of myocardial inflammation in acute viral myocarditis. The objective of this study was to assess patterns of CMR inflammation in a cohort of acute myocarditis patients from Northern Africa, Asia, and the Middle East using unsupervised machine learning.MethodsA total of 169 racially and ethnically diverse adults (18 years of age) with CMR confirmed acute myocarditis were studied. The primary outcome was a combined clinical endpoint of cardiac death, arrhythmia, and dilated cardiomyopathy. Machine learning was used for exploratory analysis to identify patterns of CMR inflammation.ResultsOur cohort was diverse with 25% from Northern Africa, 33% from Southern Asia, and 28% from Western Asia/the Middle East. Twelve patients met the combined clinical endpoint – 3 had arrythmia, 8 had dilated cardiomyopathy, and 1 died. Patients who met the combined endpoint had increased anterior (p = 0.034) and septal (p = 0.042) late gadolinium enhancement (LGE). Multivariable logistic regression, adjusted for age, gender, and BMI, found that patients from Southern Asia (p = 0.041) and the Middle East (p = 0.043) were independently associated with lateral LGE. Unsupervised machine learning and factor analysis identified two distinct CMR patterns of inflammation, one with increased LGE and the other with increased myocardial T1/T2.ConclusionsWe found that anteroseptal inflammation is associated with worsened outcomes. Using machine learning, we identified two patterns of myocardial inflammation in acute myocarditis from CMR in a racially and ethnically diverse group of patients from Southern Asia, Northern Africa, and the Middle East.

Heart and Lung Transplant for Mixed Connective Tissue Disease: Implications for Pre-Transplant Testing

<h3>Introduction</h3> We present a case of end-stage lung disease secondary to mixed connective tissue disease (MCTD) with concomitant myocarditis. <h3>Case Report</h3> The patient is a 37-year-old male initially diagnosed with interstitial lung disease due to MCTD at age 30. He was started on hydroxychloroquine (HCQ) at age 32 and later switched to mycophenolate mofetil (MMF). At that time, his left ventricular ejection fraction (LVEF) was 30%. His LVEF improved to 47% while on MMF and carvedilol but his pulmonary status worsened, and eventually he was placed on the lung transplant list. He was returned to HCQ due to progression while on MMF. A follow-up echocardiogram performed one year later for clinical decline revealed a LVEF of 15%. HCQ was discontinued for concern of cardiac toxicity and MMF was resumed. Repeat echocardiograms revealed improved LVEF although prohibitive for lung transplant alone. He was approved for heart and lung transplant, and soon thereafter, underwent successful transplant. Explant of lungs revealed extensive interstitial fibrosis with moderate chronic inflammation. Explant of heart revealed patchy lymphocytic myocarditis with myocyte damage and areas of fibrosis with myocyte hypertrophy. <h3>Summary</h3> MCTD is an autoimmune process that has a variety of end-organ manifestations, variably affecting the cardiovascular system and subsequently portending a poorer prognosis. Albeit rare, myocarditis is a known complication of MCTD. Because symptoms are insidious, we emphasize the importance of high clinical suspicion for myocarditis in patients with known MCTD. Diagnosis of myocarditis is made by biopsy, although imaging may be suggestive. The use of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging may be of value due to its ability to localize inflammation in the form of increased myocardial FDG uptake. In patients presenting with unexplained systolic dysfunction in the setting of MCTD, FDG-PET may be a screening tool and if myocardial inflammation is noted, there may be a role for increased immunosuppression. While this strategy was not employed in our patient, his improvement in LVEF while on MMF compared to HCQ and explant histology suggest a process that may have responded to escalation of immunosuppression. This has further implications as decision regarding single versus multi-organ transplant may be affected by medical therapy response.

Quantitative Assessment of Late Gadolinium Enhancement and Edema at Cardiac Magnetic Resonance in Low-Risk Myocarditis Patients.

In this study, we aimed to quantify LGE and edema at short-tau inversion recovery sequences on cardiac magnetic resonance (CMR) in patients with myocarditis. We retrospectively evaluated CMR examinations performed during the acute phase and at follow-up. Forty-seven patients were eligible for retrospective LGE assessment, and, among them, twenty-five patients were eligible for edema evaluation. Both groups were paired with age- and sex-matched controls. The median left ventricle LGE was 6.4% (interquartile range 5.0–9.2%) at the acute phase, 4.4% (3.3–7.2%) at follow-up, and 4.3% (3.0–5.3%) in controls, the acute phase being higher than both follow-up and controls (p < 0.001 for both), while follow-up and controls did not differ (p = 0.139). An optimal threshold of 5.0% was obtained for LGE with 87% sensitivity and 48% specificity; the positive likelihood ratio (LR) was 1.67, and the negative LR was 0.27. Edema was 12.8% (9.4–18.1%) at the acute phase, 7.3% (5.5–8.8%) at follow-up, and 6.7% (5.6–8.6%) in controls, the acute phase being higher than both follow-up and controls (both p < 0.001), while follow-up and controls did not differ (p = 0.900). An optimal threshold of 9.5% was obtained for edema with a sensitivity of 76% and a specificity of 88%; the positive LR was 6.33, and the negative LR was 0.27. LGE and edema thresholds are useful in cases of suspected mild myocarditis.

Prognosis Implication of N-Terminal Pro-B-Type Natriuretic Peptide in Adult Patients With Acute Myocarditis.

BackgroundThe aim of this study is to investigate the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in assessing the poor outcomes of adult patients with acute myocarditis.MethodsA total of 170 adult patients with available NT-proBNP information were included in the study. They were grouped according to quartiles of NT-proBNP concentrations at admission. Baseline and follow-up information was collected. Thirty-day major adverse cardiac events (MACE) were death and heart transplantation. Long-term MACE included all-cause death, heart transplantation, re-hospitalization due to heart failure, sustained ventricular arrhythmia, and myocarditis relapse.ResultsDuring a median follow-up of 3.8 years, patients in the highest NT-proBNP quartile suffered from the highest risk both of 30-day and long-term MACE (P < 0.001 by log-rank test). Multivariate analysis showed that apart from left ventricular ejection fraction (LVEF), an increased baseline NT-proBNP > 3,549 pg/mL (hazard ratio 3.535, 95% CI 1.316–9.499, P = 0.012) and NT-proBNP > 7,204 pg/mL (hazard ratio 22.261, 95% CI 1.976–250.723, P = 0.012) was independent predictor of long-term and 30-day MACE, respectively.ConclusionsHigher baseline NT-proBNP level was an independent predictor of poor outcomes in adult patients with acute myocarditis. Therefore, NT-proBNP may serve as a useful biomarker for risk stratification in acute myocarditis patients.

Consider Myocarditis When Patients Treated with Immune Checkpoint Inhibitors Present with Ocular Symptoms.

Immune checkpoint inhibitors (ICIs) have been associated with neurological immune related adverse events (irAE-N) and patients with ICI toxicity may present with neurological or ocular symptoms. Furthermore, patients on ICI may initially present to oncology or neurology. We report a case series of 3 patients treated with ICIs presenting with diplopia or ptosis, found to have concurrent myocarditis in addition to immune-related myopathy (irMyopathy) or myasthenia gravis (irMG). None of the patients described cardiac symptoms, underscoring the importance of screening for myocarditis in patients presenting with diplopia and/or other neuromuscular symptoms which may suggest either irMyopathy or irMG.

Long term prognosis of fulminant myocarditis and predictors related to impaired cardiac function post discharge

Objective: To compare the long-term prognosis of fulminant myocarditis (FM) and non-fulminant myocarditis (NFM) patients who survived and discharged from hospital, and to explore the factors associated with the long-term prognosis and impaired cardiac function. Methods: This study was a retrospective study. Consecutive patients with acute myocarditis hospitalized in Tongji Hospital from January 2017 to December 2020 were enrolled and divided into FM group and NFM group according to the type of myocarditis. Then, patients in the FM group were further divided into normal cardiac function group and impaired cardiac function group according the left ventricular ejection fraction (LVEF). All patients with acute myocarditis were treated with antiviral, immunomodulatory, immunosuppressive medications and symptomatic and supportive treatment, while FM patients were treated with comprehensive treatment plan. Clinical data at admission of enrolled patients were collected through the electronic medical record system. Patients were clinically followed-up at 1, 3, 6 and 12 months, then once a year after discharge by clinical visit. The primary endpoints included major cardiovascular events, impaired cardiac function was defined by LVEF<55%. Kaplan-Meier survival curve was used to analyze the occurrence of LVEF<55% and left ventricular enlargement during the follow-up of patients in FM group and NFM group, and Log-rank test was used for comparison between groups. Cox regression model was used to analyze the risk factors of impaired cardiac function in patients with FM during follow-up. Results: A total of 125 patients with acute myocarditis were enrolled (66 in FM group and 59 in NFM group). Compared with NFM group, the proportion of FM patients with the lowest LVEF<55% during hospitalization was higher (P<0.01), and the recovery time of normal LVEF during hospitalization was longer (P<0.01). The proportion of LVEF<55% at discharge was similar between the two groups (P=0.071). During the follow-up of 12 (6, 24) months, 1 patient (1.5%) died due to cardiac reasons in FM group after discharge, 16 patients (24.2%) had sustained LVEF<55% after discharge, and 8 patients (12.1%) had left ventricular enlargement. In NFM group, 3 patients (5.1%) had sustained LVEF<55%, and 1 patient (1.7%) had left ventricular enlargement. Kaplan-Meier survival curve analysis showed that the incidence of sustained LVEF<55% in FM group was higher than that in NFM group (P=0.003), and the incidence of left ventricular enlargement was also higher than that in NFM group (P=0.024). Subgroup analysis of patients in the FM group showed that, compared with the normal cardiac function group, the time from onset to admission was shorter (P=0.011), the proportion of LVEF<55% at discharge was higher (P=0.039), the proportion of coronary angiography was higher (P=0.014), and the LVEF recovery time during hospitalization was longer (P=0.036) in FM patients with impaired cardiac function. Multivariate Cox regression analysis showed that longer LVEF recovery time during hospitalization was an independent risk factor for cardiac function impairment after discharge of FM patients (HR=1.199, 95%CI 1.023-1.406, P=0.025). Conclusions: The incidence of reduced LVEF is significantly higher in FM patients than that in NFM patients. Longer LVEF recovery time during hospitalization is an independent risk factor for cardiac function impairment in FM patients after discharge.

Vaccination

Vaccination

Cardiac MRI in Suspected Acute Myocarditis After COVID-19 mRNA Vaccination.

To evaluate cardiac MRI characteristics in patients with suspected hypersensitivity myocarditis following mRNA COVID-19 vaccination. Patients clinically suspected of acute myocarditis after COVID-19 vaccination were retrospectively analyzed and compared against a healthy control group. Cardiac MRI protocol included parameters such as T1 and T2 relaxation times, extracellular volume (ECV), T2 signal intensity ratio, and late gadolinium enhancement (LGE). Lymph node size was assessed in the patient group on the injection side. Student t-test, analyses of variance (ANOVA) with Tukey post-hoc test, and χ2 test were used for statistical analysis. 20 patients with clinically suspected post-vaccine myocarditis (28 ± 12 years; 12 men) and 40 controls (31 ± 11years; 25 men) were evaluated. According to the 2018 Lake Louise criteria (LLC), patients with clinically suspected myocarditis were further subdivided into an LLC-positive group (n = 9) and an LLC-negative group (n = 11). The mean time of symptom onset after vaccination was 1.1 ± 1.2 days (LLC-positive) and 6.5 ± 9.2 days (LLC-negative). Group differences in inflammatory variables between myocarditis patients and control subjects were more pronounced in the LLC-positive group (e. g., T1 relaxation time: 1041 ± 61 ms [LLC positive] vs. 1008 ± 79 ms [LLC-negative] vs. 970 ± 25 ms [control]; p <.001; or T2 signal intensity ratio 2.0 ± 0.3 vs. 1.6 ± 0.3 [LLC-negative] and vs. 1.6 ± 0.3 [control], p = .012). LLC-positive patients were significantly faster in receiving an MRI after initial symptom onset (8.8 ± 6.1 days vs. 52.7 ± 33.4 days; p = .001) and had higher troponin T levels (3938 ± 5850 ng/l vs. 9 ± 11 ng/l; p <.001). LGE lesions were predominantly located at the subepicardium of the lateral wall. Axillary lymphadenopathy was more frequent in the LLC-positive group compared to the LLC-negative group (8/9 [89 %] vs. 0/11 [0 %], p < 0.001). Vaccine-induced myocarditis should be considered in patients with acute symptom onset after mRNA vaccination, especially if elevated serum troponin T is observed. Imaging findings of vaccine-induced myocarditis are similar to virus-induced myocarditis, allowing for the use of the Lake Louise Criteria for diagnostic purposes. · Vaccine-induced hypersensitivity myocarditis can be confirmed with cardiac MRI. · Especially patients with sudden onset of symptoms and elevated serum troponin T had positive cardiac MRI findings. · Cardiac MRI characteristics of vaccine-induced myocarditis are similar to those in virus-induced myocarditis. · Kravchenko D, Isaak A, Mesropyan N et al. Cardiac MRI in Suspected Acute Myocarditis After COVID-19 mRNA Vaccination. Fortschr Röntgenstr 2022; 194: 1003 - 1011.

Altered Phenotype of Circulating Dendritic Cells and Regulatory T Cells from Patients with Acute Myocarditis

Dendritic cells (DCs) and regulatory T cells (Tregs) play an essential role in myocarditis. However, a particular DC phenotype in this disease has not been assessed. Herein, we aim to evaluate myeloid (mDCs) and plasmacytoid DC (pDC) phenotype, as well as Treg levels from myocarditis patients and healthy controls. Using multiparametric flow cytometry, we evaluated the levels of myeloid DCs (mDCs), plasmacytoid DCs (pDCs), and Tregs in peripheral blood from myocarditis patients (n = 16) and healthy volunteers (n = 16) and performed correlation analysis with clinical parameters through Sperman test. DCs from myocarditis patients showed a higher expression of costimulatory molecules while a diminished expression of the inhibitory receptors, ILT2 and ILT4. Even more, Treg cells from myocarditis patients displayed higher levels of FOXP3 compared to controls. Clinically, the increased levels of mDCs and their higher expression of costimulatory molecules correlate with a worse myocardial function, higher levels of acute phase reactants, and higher cardiac enzymes. This study shows an activating phenotype of circulating DCs from myocarditis patients. This proinflammatory status may contribute to the pathogenesis and immune deregulation in acute myocarditis.

Morphologically, immunohistochemically and PCR proven lymphocytic viral peri-, endo-, myocarditis in patients with fatal COVID-19

BackgroundDespite a reported cardiac injury in patients with new coronavirus infection, the possibility and specifics of genuine viral myocarditis in COVID-19 remains not fully clear.PurposeTo study the presence of SARS-CoV-2 in the myocardium and the morphological properties of myocarditis in patients with severe coronavirus infection (COVID-19).MethodsAutopsy data of eight elderly patients (75.6 ± 7.4 years), four male and four female, with severe new coronavirus infection were studied. The lifetime diagnosis of COVID-19 is based on a positive result of the PCR study. The inclusion criterion was the presence of morphological signs of myocarditis according to the Dallas criteria. A standard histological examination included staining by hematoxylin and eosin, toluidin blue and Van Gieson. An immunohistochemical study was performed using antibodies to CD3, CD 68, CD20, perforin, toll-like receptor (TLR) types 4 and 9. PCR in real-time was performed to determine the viral RNA in the myocardium.ResultsAll patients had severe bilateral viral pneumonia. In all cases, myocarditis was not clinically diagnosed. Morphological examination of the heart found signs of active lymphocytic myocarditis. PCR identified the SARS-Cov2 RNA in all cases. There were also signs of destructive coronaritis in all cases, thrombovasculitis, lymphocytic pericarditis (in 3 cases) and endocarditis (in 2 cases). The absence of neutrophils confirms the aseptic nature of inflammation. An immunohistochemical study showed the CD3-positive T lymphocytes in the infiltrates. Increased expression of TLR type 4 and less 9 was also detected.ConclusionMorphological and immunohistochemical evidence of myocarditis in COVID-19 was presented. Lymphocytic infiltrations and positive PCR confirm the viral nature of inflammation. Myocarditis in COVID-19 is also characterized by coronaritis with microvascular thrombosis and associated with lymphocytic endo- and pericarditis.

Efficacy of a temporary CentriMag ventricular assist device in acute fulminant myocarditis patients revived with extracorporeal cardiopulmonary resuscitation

Although extracorporeal life support (ECLS) can provide emergency systemic perfusion for acute fulminant myocarditis (AFM), the mortality rate remains extremely high, especially in those undergoing extracorporeal cardiopulmonary resuscitation (ECPR). Temporary ventricular assist device (VAD) can provide a more physiological blood flow direction and better subsequent organ perfusion than ECLS. We investigated temporary VAD efficacy in ECPR-revived AFM patients. During January 2012-May 2019, we retrospectively recruited 22 AFM patients with hemodynamic collapse and ECPR; 11 underwent ECLS only and 11 underwent additional VAD support after ECLS. Systemic perfusion was compared via laboratory biochemistry at post-ECPR days 2 (D2) and 4 (D4). Consciousness and cardiac function were assessed through the Glasgow Coma Scale (GCS) and echocardiography, respectively. All major complications and causes of mortality were recorded; 30-day survival was analyzed and risk factors were predicted. The VAD group had significantly better hemodynamic improvement; more inotropes being tapered at D2 and D4; better data representative of systemic perfusion, including albumin, pH, bicarbonate, and lactate levels at D4; and better 30-day survival (72.7% vs. 27.2%, p=0.033). The causes of mortality included central failure, multiple organ failure, and bacteremia with sepsis. The risk factors included lethal dysrhythmia before ECLS, GCS <5at D2, and elevated cardiac enzymes at D4. For AFM patients, temporary VAD could provide better systemic perfusion and organ preservation than ECLS. VAD had better survival, including improved recovery and successful transplantation. Hence, temporary VAD should be considered if ECLS cannot revive the sustained cardiogenic shock.