Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry.

BACKGROUND AND AIMS: Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. METHODS: Prospective data were collected on individuals aged 1-<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014-December 2016). RESULTS: A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0-10] years, and there was a male predominance [n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P = .003]. Over a median follow-up of 12.5 months (IQR 11.3-15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). CONCLUSIONS: The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment.

Unraveling the Uncommon: A Case Report of Giant Cell Myocarditis and Examination of Existing Literature.

BACKGROUND Idiopathic giant cell myocarditis (IGCM) is an uncommon and frequently fatal type of myocarditis. It primarily affects young individuals and has the potential to result in heart failure and life-threatening arrhythmias. IGCM seems to be dependent on activation of CD4-positive T lymphocytes and can show improvement with treatment aimed at reducing T-cell function. We present a case of a 65-year-old patient who presented with features of acute heart failure refractory to guideline-directed medical therapy (GDMT), due to IGCM. A review of the natural history and treatment of IGCM is also presented. CASE REPORT A 65-year-old woman with multiple comorbidities was admitted to our hospital for ventricular tachycardia in the setting of progressive non-ischemic heart failure, unresponsive to GDMT. This led to further investigation, including an endomyocardial biopsy, which revealed inflammatory infiltration, with multinucleated giant cells and lymphocytes in the absence of granuloma formation, prompting a diagnosis of IGCM. An implantable cardioverter-defibrillator (ICD) was placed for secondary prevention of sudden cardiac death and the patient was initiated on combined immunosuppressive therapy. Owing to numerous comorbidities, she was determined to be unsuitable for a heart transplant. Unfortunately, she eventually died from complications secondary to the disease. CONCLUSIONS IGCM remains a challenging clinical diagnosis with a poor long-term outcome without heart transplantation. This case highlights the importance of considering atypical causes of heart failure in patients who do not respond to conventional therapies. Early recognition and appropriate management, involving medical and interventional approaches, are crucial in improving outcomes for patients with IGCM.

Cardiac Involvement in Patients With Multisystem Inflammatory Syndrome in Adults.

Multisystemic inflammatory syndrome in adults is a hyperinflammatory condition following (within 4-12 weeks) SARS-CoV-2 infection. Here, the dysregulation of the immune system leads to a multiorgan involvement often affecting the heart. Cardiac involvement in multisystemic inflammatory syndrome in adults has been described mainly in young men without other comorbidities and may present with different clinical scenarios, including acute heart failure, life-threatening arrhythmias, pericarditis, and myocarditis, with a nonnegligible risk of mortality (up to 7% of all cases). The heterogeneity of its clinical features and the absence of a clear case definition make the differential diagnosis with other postinfectious (eg, infective myocarditis) and hyperinflammatory diseases (eg, adult Still disease and macrophage activation syndrome) challenging. Moreover, the evidence on the efficacy of specific treatments targeting the hyperinflammatory response underlying this clinical condition (eg, glucocorticoids, immunoglobulins, and other immunomodulatory agents) is sparse and not supported by randomized clinical trials. In this review article, we aim to provide an overview of the clinical features and the diagnostic workup of multisystemic inflammatory syndrome in adults with cardiac involvement, highlighting the possible pathogenetic mechanisms and the therapeutic management, along with remaining knowledge gaps in this field.

Protective effect of low-intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation.

PURPOSE: Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. METHODS: An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. RESULTS: LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1-TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. CONCLUSION: LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

Clinical characteristics, diagnosis and management of nivolumab-induced myocarditis.

Nivolumab can cause fatal myocarditis. We aimed to analyze the clinical characteristics of nivolumab-induced myocarditis and provide evidence for clinical diagnosis, treatment, and prevention. Studies involving nivolumab-induced myocarditis were identified in electronic databases from 2000 to 2023 for retrospective analysis. A total of 66 patients were included, with a median age of 68 years. The median onset time of myocarditis is 11.5 days. The main organs affected in persons presented with myocarditis are heart (100.0%) and skeletal muscle (22.7%). The main clinical manifestations are dyspnea (49.2%), fatigue (47.6%), and myalgias (25.4%). The levels of troponin, troponin T, troponin I, creatine kinase, creatine kinase myocardial band, creatine phosphokinase, C-reactive protein, brain natriuretic peptide, and N-terminal brain natriuretic peptide precursor were significantly increased. Histopathology often shows lymphocyte infiltration, myocardial necrosis, and fibrosis. Myocardial immunological parameters usually present positive. Cardiac imaging often suggests complete heart block, intraventricular conduction delay, arrhythmia, myocardial infarction, edema, left ventricular ejection fractions reduction, ventricular dysfunction, and other symptoms of myocarditis. Forty-two (63.6%) patients achieved remission within a median time of 8 days after discontinuation of nivolumab and treatment with systemic corticosteroids, immunoglobulins, plasmapheresis, and immunosuppressant. Thirty-five patients eventually died attributed to myocarditis (68.6%), cancer (20.0%), respiratory failure (5.7%), and other reasons (5.7%). Nivolumab-induced myocarditis should be comprehensively diagnosed based on clinical symptoms, histopathological manifestations, immunological parameters, and cardiac function imaging examinations. Nivolumab should be discontinued immediately, plasmapheresis and systemic corticosteroids combined with immunoglobulins or immunosuppressants may be an effective treatment.

Myocarditis and Pericarditis.

Pericarditis typically presents with classic symptoms of acute sharp, retrosternal, and pleuritic chest pain. It can have several different underlying causes including viral, bacterial, and autoimmune etiologies. The mainstays of pericarditis treatment are nonsteroidal anti-inflammatory drugs and colchicine with glucocorticoids or other immunosuppressive drugs used for refractory cases and relapse. Myocarditis is an inflammatory disease of the cardiac muscle that is caused by a variety of infectious and noninfectious conditions. It mainly affects young adults (median age 30-45 years), and men more than women. The clinical manifestations of myocarditis are highly variable, so a high level of suspicion in the early stage of disease is important to facilitate diagnosis. The treatment of myocarditis includes nonspecific treatment aimed at complications such as heart failure and arrhythmia, as well as specific treatment aimed at underlying causes. Pericarditis and myocarditis associated with vaccine have been extremely rare before coronavirus disease 2019 (COVID-19). There is a small increase of incidence after COVID-19 messenger ribonucleic acid vaccine, but the relative risk for pericarditis and myocarditis due to severe acute respiratory syndrome coronavirus 2 infection is much higher. Therefore, vaccination against COVID-19 is currently recommended for everyone aged 6 years and older.

Exercise After Acute Myocarditis: When and How to Return to Sports.

Myocarditis is an inflammatory disease of the myocardium secondary to infectious and noninfectious insults. The most feared consequence of myocarditis is sudden cardiac death owing to electrical instability and arrhythmia. Typical presenting symptoms include chest pain, dyspnea, palpitations and/or heart failure. Diagnosis is usually made with history, electrocardiogram, biomarkers, echocardiogram, and cardiac MRI (CMR). Application of the Lake Louise criteria to CMR results can help identify cases of myocarditis. Treatment is usually supportive with medical therapy, and patients are recommended to abstain from exercise for 3 to 6 months. Exercise restrictions may be lifted after normalization on follow-up testing.

Contemporary Care and Outcomes of Critically-ill Children With Clinically Diagnosed Myocarditis.

PURPOSE: To describe contemporary management and outcomes in children with myocarditis who are admitted to a cardiac intensive care unit (CICU) and to identify the characteristics associated with mortality. METHODS: All patients in the Pediatric Cardiac Critical Care Consortium (PC4) registry between August 2014 and June 2021 who were diagnosed with myocarditis were included. Univariable analyses and multivariable logistic regression evaluated the factors associated with in-hospital mortality. RESULTS: There were 847 CICU admissions for myocarditis in 51 centers. The median age was 12 years (IQR 2.7-16). In-hospital mortality occurred in 53 patients (6.3%), and 60 (7.1%) had cardiac arrest during admission. Mechanical ventilation was required in 339 patients (40%), and mechanical circulatory support (MCS) in 177 (21%); extracorporeal membrane oxygenation (ECMO)-only in 142 (16.7%), ECMO-to-ventricular assist device (VAD) in 20 (2.4%), extracorporeal cardiac resuscitation in 43 (5%), and VAD-only in 15 (1.8%) patients. MCS was associated with in-hospital mortality; 20.3% receiving MCS died compared to 2.5% without MCS (P < 0.001). Mortality rates were similar in ECMO-only, ECMO-to-VAD and VAD-only groups. The median time from CICU admission to ECMO was 2.0 hours (IQR 0-9.4) and to VAD, it was 9.9 days (IQR 6.3-16.8). Time to MCS was not associated with mortality. In multivariable modeling of patients' characteristics, smaller body surface area (BSA) and low eGFR were independently associated with mortality, and after including critical therapies, mechanical ventilation and ECMO were independent predictors of mortality. CONCLUSION: This contemporary cohort of children admitted to CICUs with myocarditis commonly received high-resource therapies; however, most patients survived to hospital discharge and rarely received VAD. Smaller patient size, acute kidney injury and receipt of mechanical ventilation or ECMO were independently associated with mortality.

Sex differences in myocarditis hospitalizations: Rates, outcomes, and hospital characteristics in the National Readmission Database.

Inflammation of the myocardium, or myocarditis, presents with varied severity, from mild to life-threatening such as cardiogenic shock or ventricular tachycardia storm. Existing data on sex-related differences in its presentation and outcomes are scarce. Using the Nationwide Readmission Database (2016-2019), we identified myocarditis hospitalizations and stratified them according to sex to either males or females. Multivariable regression analyses were used to determine the association between sex and myocarditis outcomes. The primary outcome was in-hospital mortality, and the secondary outcomes included sudden cardiac death (SCD), cardiogenic shock (CS), use of mechanical circulatory support (MCS), and 90-day readmissions. We found a total of 12,997 myocarditis hospitalizations, among which 4,884 (37.6 %) were females. Compared to males, females were older (51 ± 15.6 years vs. 41.9 ± 14.8 in males) and more likely to have connective tissue disease, obesity, and a history of coronary artery disease. No differences were noted between the two groups with regards to in-hospital mortality (adjusted odds ratio [aOR] 1.20; confidence interval [CI] 0.93-1.53; P = 0.16), SCD (aOR:1.18; CI 0.84-1.64; P = 0.34), CS (aOR: 1.01; CI 0.85-1.20;P = 0.87), or use of MCS (aOR: 1.07; CI:0.86-1.34; P = 0.56). In terms of interventional procedures, females had lower rates of coronary angiography (aOR: 0.78; CI 0.70-0.88; P < 0.01), however, similar rates of right heart catheterization (aOR 0.93; CI:0.79-1.09; P = 0.36) and myocardial biopsy (aOR: 1.16; CI:0.83-1.62; P = 0.38) compared to males. Additionally, females had a higher risk of 90-day all-cause readmission (aOR: 1.25; CI: 1.16-1.56; P < 0.01) and myocarditis readmission (aOR:1.58; CI 1.02-2.44; P = 0.04). Specific predictors of readmission included essential hypertension, congestive heart failure, malignancy, and peripheral vascular disease. In conclusion, females admitted with myocarditis tend to have similar in-hospital outcomes with males; however, they are at higher risk of readmission within 90 days from hospitalization. Further studies are needed to identify those at higher risk of readmission.

Gene therapy vector-related myocarditis.

Gene therapy is a technique to correct genetic abnormalities, through introduction of a functional gene or through direct genome editing. Adeno-associated virus (AAV)-mediated gene replacement shows promise for targeted therapies in treatment of inherited cardiomyopathies and is the most used approach in clinical trials. However, immune responses from the host to the virus and gene product pose delivery and safety challenges. This review explores the immunological reactions to AAV-based gene therapy, their potential toxic effects, with a focus on myocarditis, and future directions for gene therapy.

Paradigm shift in myocarditis treatment.

Although most cases of myocarditis are self-limiting with a gradual improvement in cardiac function, the involvement of myocarditis in sudden cardiac death among children and young adults remains substantial, with rates of 3-17 % and 8.6-12 %, respectively. Moreover, the risk of developing chronic dilated cardiomyopathy ranges from 21 % to 30 % in all cases confirmed by biopsy. Current therapeutic strategies for myocarditis and its complications range from standard supportive care for heart failure and arrhythmias to etiologically oriented, case-based therapeutic options. For example, immunosuppression is indicated only in certain forms of acute myocarditis with clinical or endomyocardial biopsy evidence of immune checkpoint inhibitor-induced myocarditis and autoimmune diseases, including giant cell myocarditis, eosinophilic myocarditis, vasculitis, or cardiac sarcoidosis. However, our views on myocarditis treatment have changed considerably over the past two decades, thanks to the emergence of regenerative cells/tissues as well as drug and gene delivery systems. Cell-based therapies are now growing in popularity in any field of medicine. Studies evaluating the therapeutic efficacy of different stem cells in the treatment of acute myocarditis and its chronic complications have shown that although the experimental characteristics varied from study to study, in general, these strategies reduced inflammation and myocardial fibrosis while preventing myocarditis-induced systolic dysfunction and adverse remodeling in animal models.

Contemporary National Trends of Mechanical Circulatory Support Among Myocarditis Hospitalizations Before the Pandemic: A National In-patient Database (2005-2019) Study.

According to the Global Burden of Disease Project, the morbidity and mortality of myocarditis continue to be a significant worldwide burden. On October 1, 2015, hospital administrative data started using the International Classification of Diseases (ICD)-10 codes instead of the ICD-9. To our knowledge, nationwide trends of myocarditis have not been studied after this update. The NIS database from 2005-2019 was analyzed using ICD-9 and 10 codes. Our search yielded 141,369 hospitalizations due to myocarditis, with 40.9% females. There were 6627 (4.68%) patients who required mechanical circulatory support (MCS) using left ventricular assisted devices (LVAD), intra-aortic balloon pump (IABP), or extracorporeal membrane oxygenation (ECMO). The use of LVAD and ECMO increased significantly during the study period (p-trend 0.003 and <0.001, respectively), whereas the use of IABP decreased during the same period (p-trend 0.025). Our study demonstrated an overall increase in the use of MCS overall in myocarditis, with increasing utilization of more advanced MCS in the forms of LVAD and ECMO.

Novel insights on acute myocarditis in pediatric patients.

Acute myocarditis (AM) is an inflammatory affliction of the heart muscle characterized by recent onset with a broad spectrum of clinical manifestations that globally affect millions of individuals, notably children and young adults. The absence of distinct patterns of onset or predictable progression poses a significant threat to survival, potentially leading to advanced heart failure and malignant arrhythmias. Myocardial fibrosis, a hallmark of myocardial remodeling, is increasingly recognized as a contributor to adverse outcomes in acute myocarditis cases. Advances in molecular and immunological techniques have highlighted the intricate interplay between viral infections, dysregulated immune responses, and genetic susceptibility. Currently, there is no clear consensus for diagnosis or ongoing follow-up in pediatric patients. The conventional diagnostic tool, endomyocardial biopsy (EMB), considered the gold standard, has been complemented by the effectiveness of cardiac magnetic resonance imaging (CMRI) techniques. Given the procedural complexities and associated complications, there is a pressing need to explore non-invasive alternatives. In this context, biomarkers emerge as promising contenders by evaluating both the inflammatory processes and cardiac remodeling, providing valuable observations into disease severity, progression, and treatment response. Therapeutic strategies in these cases, focusing on the specific pathways or immune components associated with the etiologies, have exhibited promise for better outcomes. Acute myocarditis in children remains a multifaceted clinical challenge, necessitating a comprehensive understanding of its pathophysiology, diagnosis, and management. This review aims to delve into novel insights surrounding the pathophysiology, diagnosis, and management of acute myocarditis in pediatric patients.

[Long-term treatment of morphologically verified myocarditis: successes and probable errors. Case report].

Diagnosis and treatment of myocarditis can be challenging, including determining indications for heart transplantation. We present a 6-year medical history of a 54 years old patient with severe morphologically verified viral-negative lymphocytic myocarditis and systemic manifestations (onset of hemorrhagic vasculitis) combined with moderate coronary atherosclerosis, which regressed according to repeated coronary angiography. For 5 years, the patient received immunosuppressive therapy with methylprednisolone and azathioprine with a significant improvement. Repeated relapses of atrial fibrillation required correction of basic therapy and plasmapheresis. The disease was complicated by thyrotoxicosis and multi-organ dysfunction; the autopsy showed persistent myocarditis activity. The myocarditis is a chronic condition and requires a review of the treatment strategy at each stage.

Fulminant Lymphocytic Myocarditis Successfully Managed with Intra-Aortic Balloon Pump and Extracorporeal Membrane Oxygenation: A Case Report.

BACKGROUND Lymphocytic myocarditis (LM) is a rare inflammatory disease of the heart. The clinical presentation of LM varies from mild flu-like symptoms to fulminant myocarditis with cardiogenic shock. Fulminant myocarditis has a poor prognosis and the usual treatment is inotropes with or without ventricular assist devices such as intra-aortic balloon pump (IABP) and venoarterial extracorporeal membrane oxygenation (V-A ECMO). We report the case of fulminant LM with severe cardiogenic shock that was successfully treated with concomitant use of IABP and V-A ECMO. CASE REPORT A 32-year-old woman with no medical history presented to the Emergency Department (ED) with chest pain with irradiation to the left upper limb, worse when supine. The electrocardiogram (ECG) on admission showed sinus rhythm with nonspecific ST-T repolarization abnormalities, and laboratory results showed elevated ultrasensitive troponin and C-reactive protein. Transthoracic echocardiography (TTE) showed left ventricular ejection fraction (LVEF) of 25% and diffuse hypokinesis. On the next day, she developed cardiogenic shock requiring vasoactive drugs, IABP, and V-A ECMO. Pulse therapy with methylprednisolone was started. Endomyocardial biopsy (EMB) revealed acute LM, and intravenous human immunoglobulin was administered. The patient evolved with progressive clinical improvement, being discharged 56 days after admission, with an improvement in the LVEF to 55%. CONCLUSIONS Fulminant LM is a rare and potentially fatal condition that requires immediate intervention. The combination of IABP and V-A ECMO among patients with LM-cardiogenic shock may provide survival benefits.

Follow-up ICD generator explantation in tuberculous myocarditis induced ventricular tachycardia patient.

A rare case of ventricular tachycardia caused by extrapulmonary tuberculosis has been followed up. Automatic implantable cardioverter defibrillator implantation was done at the time of presentation. Following this, the patient is clinically well without any episodes of ventricular tachycardia and is considered for an implantable cardioverter defibrillator explantation.

Tolerated Re-Challenge of Immunotherapy in a Patient with ICI Associated Myocarditis: A Case Report and Literature Review.

Many different types of cancer can be treated with immunotherapy drugs called immune checkpoint inhibitors (ICIs). These drugs have altered the landscape of cancer treatment options since they function by triggering a stronger immune response to malignancy. As expected, ICIs' modification of immune regulatory controls leads to a wide range of organ/gland-specific immune-related side effects. These adverse effects are uncommonly deadly and typically improve by discontinuing treatment or administering corticosteroid drugs. As a result of a number of factors-including a lack of specificity in the clinical presentation, the possibility of overlap with other cardiovascular and general medical illnesses, difficulties in diagnosis, and a general lack of awareness-the true incidence of ICI-associated myocarditis is likely underestimated. Currently, protocols for the surveillance, diagnosis, or treatment of this condition are unclear. Several questions remain unanswered, such as how to best screen for this rare toxin, what tests should be run on patients who are suspected of having it, how to treat myocarditis once it has developed, and who is at most risk. In this article, we provide a case study of ICI-associated myocarditis and explain its key characteristics and treatment options.

Nursing Management of a Patient With Fulminant Myocarditis and Electrical Storm Receiving ECMO: A Case Report.

INTRODUCTION: Fulminant myocarditis is a devastating disease with significant mortality and complications. The care of patients with fulminant myocarditis is rarely reported. CLINICAL FINDINGS: A 17-year-old female patient was admitted to the emergency department with dizziness, amaurosis fugax, and chest tightness. Initial assessment revealed elevated levels of troponin T (4.753 ng/mL), troponin I (49.540 ng/mL), creatine kinase (1306 U/L), creatine kinase-MB isoenzymes (75.71 ng/mL), lactate dehydrogenase (509 U/L), and N-terminal pro-B-type natriuretic peptide (6345 pg/mL). The patient had recurrent ventricular tachycardia and failed to maintain a sinus rhythm after multiple electrical cardioversions. DIAGNOSIS: Echocardiography revealed a left ventricular ejection fraction of 34%. Magnetic resonance imaging results confirmed the diagnosis of myocarditis. INTERVENTIONS: The patient received extracorporeal membrane oxygenation for 6 days, intra-aortic balloon pump support for 7 days, and mechanical ventilation for 5 days. Norepinephrine and dopamine were used to keep circulation stable, lidocaine and amiodarone were used to control heart rate, and glucocorticoids and immunoglobulins were used to modulate immunity. OUTCOMES: The patient was discharged after 23 days. A month after discharge, echocardiography showed that the ejection fraction was 60%. The patient reported complete resolution of signs and symptoms of fulminant myocarditis at follow-up assessment. CONCLUSION: This case report presents the activities of bedside nurses in caring for a patient with fulminant myocarditis and broadens the literature describing nursing interventions for patients with fulminant myocarditis.