Revitalizing myocarditis treatment through gut microbiota modulation: unveiling a promising therapeutic avenue.

Numerous studies have demonstrated that gut microbiota plays an important role in the development and treatment of different cardiovascular diseases, including hypertension, heart failure, myocardial infarction, arrhythmia, and atherosclerosis. Furthermore, evidence from recent studies has shown that gut microbiota contributes to the development of myocarditis. Myocarditis is an inflammatory disease that often results in myocardial damage. Myocarditis is a common cause of sudden cardiac death in young adults. The incidence of myocarditis and its associated dilated cardiomyopathy has been increasing yearly. Myocarditis has gained significant attention on social media due to its association with both COVID-19 and COVID-19 vaccinations. However, the current therapeutic options for myocarditis are limited. In addition, little is known about the potential therapeutic targets of myocarditis. In this study, we review (1) the evidence on the gut-heart axis, (2) the crosslink between gut microbiota and the immune system, (3) the association between myocarditis and the immune system, (4) the impact of gut microbiota and its metabolites on myocarditis, (5) current strategies for modulating gut microbiota, (6) challenges and future directions for targeted gut microbiota in the treatment of myocarditis. The approach of targeting the gut microbiota in myocarditis is still in its infancy, and this is the study to explore the gut microbiota-immune system-myocarditis axis. Our findings are expected to pave the way for the use of gut microbiota as a potential therapeutic target in the treatment of myocarditis.

Myocarditis and autoimmunity.

INTRODUCTION: Autoimmune myocarditis may develop due to heterogeneous causes. Myocarditis is often caused by viral infections, but it can also be caused by systemic autoimmune diseases. Immune checkpoint inhibitors and virus vaccines induce immune activation, and they can cause the development of myocarditis, as well as several immune-related adverse events. The development of myocarditis is dependent on the genetic factors of the host, and the major histocompatibility complex (MHC) may be an important determinant of the type and severity of the disease. However, non-MHC immunoregulatory genes may also play a role in determining susceptibility. AREA COVERED: This review summarizes the current knowledge of the etiology, pathogenesis, diagnosis, and treatment of autoimmune myocarditis with a particular focus on viral infection, autoimmunity, and biomarkers of myocarditis. EXPERT OPINION: An endomyocardial biopsy may not be the gold standard for the diagnosis of myocarditis. Cardiac magnetic resonance imaging is useful in diagnosing autoimmune myocarditis. Recently identified biomarkers of inflammation and myocyte injury are promising for the diagnosis of myocarditis when measured simultaneously. Future treatments should focus on the appropriate diagnosis of the etiologic agent, as well as on the specific stage of the evolution of immune and inflammatory processes.

Repurposing Drugs for the Treatment of COVID-19 and Its Cardiovascular Manifestations.

COVID-19 is an infectious disease caused by SARS-CoV-2 leading to the ongoing global pandemic. Infected patients developed a range of respiratory symptoms, including respiratory failure, as well as other extrapulmonary complications. Multiple comorbidities, including hypertension, diabetes, cardiovascular diseases, and chronic kidney diseases, are associated with the severity and increased mortality of COVID-19. SARS-CoV-2 infection also causes a range of cardiovascular complications, including myocarditis, myocardial injury, heart failure, arrhythmias, acute coronary syndrome, and venous thromboembolism. Although a variety of methods have been developed and many clinical trials have been launched for drug repositioning for COVID-19, treatments that consider cardiovascular manifestations and cardiovascular disease comorbidities specifically are limited. In this review, we summarize recent advances in drug repositioning for COVID-19, including experimental drug repositioning, high-throughput drug screening, omics data-based, and network medicine-based computational drug repositioning, with particular attention on those drug treatments that consider cardiovascular manifestations of COVID-19. We discuss prospective opportunities and potential methods for repurposing drugs to treat cardiovascular complications of COVID-19.

Myocarditis: causes, mechanisms, and evolving therapies.

INTRODUCTION: Myocarditis is a severe lymphocyte-mediated inflammatory disorder of the heart, mostly caused by viruses and immune checkpoint inhibitors (ICIs). Recently, myocarditis as a rare adverse event of mRNA vaccines for SARS-CoV-2 has caused global attention. The clinical consequences of myocarditis can be very severe, but specific treatment options are lacking or not yet clinically proven. AREAS COVERED: This paper offers a brief overview of the biology of viruses that frequently cause myocarditis, focusing on mechanisms important for viral entry and replication following host infection. Current and new potential therapeutic targets/strategies especially for viral myocarditis are reviewed systematically. In particular, the immune system in myocarditis is dissected with respect to infective viral and non-infective, ICI-induced myocarditis. EXPERT OPINION: Vaccination is an excellent emerging preventative strategy for viral myocarditis, but most vaccines still require further development. Anti-viral treatments that inhibit viral replication need to be considered following viral infection in host myocardium, as lower viral load reduces inflammation severity. Understanding how the immune system continues to damage the heart even after viral clearance will define novel therapeutic targets/strategies. We propose that viral myocarditis can be best treated using a combination of antiviral agents and immunotherapies that control cytotoxic T cell activity.

Myocarditis related SARS-CoV-2 infection or vaccination: an expert consensus statement on its diagnosis and management.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has revealed several cardiovascular complications, including myocarditis caused by SARS-CoV-2 infection (COVID-19) or after messenger RNA vaccine administration. Because of the high prevalence of COVID-19, the expansion of vaccination programs, and the appearance of new information on myocarditis in these contexts, there is a need to condense the knowledge acquired since the start of the pandemic. To meet this need, this document was drafted by the Myocarditis Working Group of the Heart Failure Association of the Spanish Society of Cardiology, with the collaboration of the Spanish Agency for Medicines and Health Products (AEMPS). The document aims to address the diagnosis and treatment of cases of myocarditis associated with SARS-CoV-2 infection or messenger RNA vaccine administration.

Diagnosis and Treatment of Acute Myocarditis: A Review.

Importance: Acute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%. Observations: The most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear. Conclusions and Relevance: Acute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.

Application of Magnetocardiography to Screen for Inflammatory Cardiomyopathy and Monitor Treatment Response.

Background Inflammatory cardiomyopathy is one of the most common causes of sudden cardiac death in young adults. Diagnosis of inflammatory cardiomyopathy remains challenging, and better monitoring tools are needed. We present magnetocardiography as a method to diagnose myocardial inflammation and monitor treatment response. Methods and Results A total of 233 patients were enrolled, with a mean age of 45 (±18) years, and 105 (45%) were women. The primary analysis included 209 adult subjects, of whom 66 (32%) were diagnosed with inflammatory cardiomyopathy, 17 (8%) were diagnosed with cardiac amyloidosis, and 35 (17%) were diagnosed with other types of nonischemic cardiomyopathy; 91 (44%) did not have cardiomyopathy. The second analysis included 13 patients with inflammatory cardiomyopathy who underwent immunosuppressive therapy after baseline magnetocardiography measurement. Finally, diagnostic accuracy of magnetocardiography was tested in 3 independent cohorts (total n=23) and 1 patient, who developed vaccine-related myocarditis. First, we identified a magnetocardiography vector to differentiate between patients with cardiomyopathy versus patients without cardiomyopathy (vector of ≥0.051; sensitivity, 0.59; specificity, 0.95; positive predictive value, 93%; and negative predictive value, 64%). All patients with inflammatory cardiomyopathy, including a patient with mRNA vaccine-related myocarditis, had a magnetocardiography vector ≥0.051. Second, we evaluated the ability of the magnetocardiography vector to reflect treatment response. We observed a decrease of the pathologic magnetocardiography vector toward normal in all 13 patients who were clinically improving under immunosuppressive therapy. Magnetocardiography detected treatment response as early as day 7, whereas echocardiographic detection of treatment response occurred after 1 month. The magnetocardiography vector decreased from 0.10 at baseline to 0.07 within 7 days (P=0.010) and to 0.03 within 30 days (P<0.001). After 30 days, left ventricular ejection fraction improved from 42.2% at baseline to 53.8% (P<0.001). Conclusions Magnetocardiography has the potential to be used for diagnostic screening and to monitor early treatment response. The method is valuable in inflammatory cardiomyopathy, where there is a major unmet need for early diagnosis and monitoring response to immunosuppressive therapy.

COVID-19 Associated Myocarditis Clinical Outcomes among Hospitalized Patients in the United States: A Propensity Matched Analysis of National Inpatient Sample.

Coronavirus-19 (COVID-19), preliminarily a respiratory virus, can affect multiple organs, including the heart. Myocarditis is a well-known complication among COVID-19 infections, with limited large-scale studies evaluating outcomes associated with COVID-19-related Myocarditis. We used the National Inpatient Sample (NIS) database to compare COVID-19 patients with and without Myocarditis. A total of 1,659,040 patients were included in the study: COVID-19 with Myocarditis (n = 6,455, 0.4%) and COVID-19 without Myocarditis (n = 1,652,585, 99.6%). The primary outcome was in-hospital mortality. Secondary outcomes included mechanical ventilation, vasopressor use, sudden cardiac arrest, cardiogenic shock, acute kidney injury requiring hemodialysis, length of stay, health care utilization costs, and disposition. We conducted a secondary analysis with propensity matching to confirm results obtained by traditional multivariate analysis. COVID-19 patients with Myocarditis had significantly higher in-hospital mortality compared to COVID-19 patients without Myocarditis (30.5% vs. 13.1%, adjusted OR: 3 [95% CI 2.1-4.2], p < 0.001). This cohort also had significantly increased cardiogenic shock, acute kidney injury requiring hemodialysis, sudden cardiac death, required more mechanical ventilation and vasopressor support and higher hospitalization cost. Vaccination and more research for treatment strategies will be critical for reducing worse outcomes in patients with COVID-19-related Myocarditis.

A Successful Case of Cardiac Arrest due to Acute Myocarditis with COVID-19: 120 Minutes on Manual Cardiopulmonary Resuscitation then Veno-Arterial Extracorporeal Membrane Oxygenation.

Acute myocarditis is one of the common complications of coronavirus disease 2019 (COVID-19) with a relatively high case fatality. Here reported is a fulminant case of a 42-year-old previously healthy woman with cardiogenic shock and refractory cardiac arrest due to COVID-19-induced myocarditis who received veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) after 120 minutes of cardiopulmonary resuscitation (CPR). This is the first adult case of cardiac arrest due to COVID-19-induced myocarditis supported by ECMO that fully recovered with normal neurological functions. The success of the treatment course with full recovery emphasized the potential role of ECMO in treating these patients.

Severe COVID-19-associated myocarditis with cardiogenic shock - management with assist devices - a case report & review.

BACKGROUND: Primary viral myocarditis associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection is a rare diagnosis. CASE PRESENTATION: We report the case of an unvaccinated, healthy patient with cardiogenic shock in the context of a COVID-19-associated myocarditis and therapy with simultaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and percutaneous left ventricular decompression therapy with an Impella. The aim of this review is to provide an overview of therapeutic options for patients with COVID-19-associated myocarditis. CONCLUSIONS: The majority of patients required a combination of two assist devices to achieve sufficient cardiac output until recovery of left ventricular ejection fraction. Due to the rapid onset of this fulminant cardiogenic shock immediate invasive bridging therapy in a specialized center was lifesaving.

Myocarditis associated with COVID-19 and its vaccines - a systematic review.

Since the beginning of the COVID-19 (Coronavirus Disease of 2019) pandemic, myocarditis has received much attention and controversy as one of the more worrisome cardiovascular complications. After the availability of highly effective COVID-19 mRNA vaccines in late 2020, myocarditis was also appreciated as an important vaccine-related adverse event. Though the overall frequency of clinically evident viral myocarditis is rare in the general population, young males show a higher predilection for COVID vaccine-induced myocarditis. The severity of COVID-19 viral myocarditis is variable, ranging from very mild to severe, while vaccine-induced myocarditis is usually mild, and rarely a severe or fatal disease. The diagnosis of either COVID-19 or vaccine-induced myocarditis is based on typical clinical features, laboratory investigations, and imaging, preferably with cardiac magnetic resonance. The management of COVID-19 myocarditis is supportive care for mild or moderate disease. For the rare patient who develops severe disease, advanced heart failure therapies such as mechanical circulatory support devices may have to be employed and can be lifesaving. Avoidance of strenuous exercise during the bout of myocarditis and its recovery phase is important. Despite the small but finite risk of vaccine-induced myocarditis, the benefits of protection against COVID-19 disease and its attendant complications far outweigh the risks.

Hospital Outcomes Among COVID-19 Hospitalizations With Myocarditis from the California State Inpatient Database.

Many case reports have indicated that myocarditis could be a prognostic factor for predicting morbidity and mortality among patients with COVID-19. In this study, using a large database we examined the association between myocarditis among COVID-19 hospitalizations and in-hospital mortality and other adverse hospital outcomes. The present study was a retrospective analysis of data collected in the California State Inpatient Database during 2020. All hospitalizations for COVID-19 were included in the analysis and grouped into those with and without myocarditis. The outcomes were in-hospital mortality, cardiac arrest, cardiogenic shock, mechanical ventilation, and acute respiratory distress syndrome. Propensity score matching, followed by conditional logistic regression, was performed to find the association between myocarditis and outcomes. Among 164,417 COVID-19 hospitalizations, 578 (0.4%) were with myocarditis. After propensity score matching, the rate of in-hospital mortality was significantly higher among COVID-19 hospitalizations with myocarditis (30.0% vs 17.5%, p <0.001). Survival analysis with log-rank test showed that 30-day survival rates were significantly lower among those with myocarditis (39.5% vs 46.3%, p <0.001). Conditional logistic regression analysis showed that the odds of cardiac arrest (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.16 to 3.14), cardiogenic shock (OR 4.13, 95% CI 2.14 to 7.99), mechanical ventilation (OR 3.30, 95% CI 2.47 to 4.41), and acute respiratory distress syndrome (OR 2.49, 95% CI 1.70 to 3.66) were significantly higher among those with myocarditis. Myocarditis was associated with greater rates of in-hospital mortality and adverse hospital outcomes among patients with COVID-19, and early suspicion is important for prompt diagnosis and management.

Myocarditis and related complications of SARS-CoV-2 infection.

BACKGROUND: Myocarditis and pericarditis are associated with a wide range of presentations and have received renewed interest because of the association with SARS-CoV-2 infection. Some of these complications have also been reported with the mRNA vaccines used for preventing the infection, which has caused widespread anxiety and uncertainty in the community. OBJECTIVE: The aim of this article is to summarise an approach to the clinical problem of myocarditis and treatment/management of patients with myocarditis in the community. This article also discusses SARS-CoV-2 infection and vaccines. DISCUSSION: Myocarditis and pericarditis need to be considered as a differential, especially in all adolescents or young adults presenting with acute chest pain, shortness of breath or palpitations. Other serious causes of chest pain - such as acute myocardial infarction, pulmonary embolism, aortic dissection and pneumothorax - also need to be excluded. Initial electrocardiography, troponin and C-reactive protein tests are recommended, and cardiology advice should be sought for all suspected cases.

Phenotypic Heterogeneity of Fulminant COVID-19--Related Myocarditis in Adults.

BACKGROUND: Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19-related myocarditis. OBJECTIVES: This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19-related myocarditis fulfilling MIS-A criteria (MIS-A+) or not (MIS-A-). METHODS: A monocentric retrospective analysis of consecutive fulminant COVID-19-related myocarditis in a 26-bed intensive care unit (ICU). RESULTS: Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19-related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%. In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A- patients compared with MIS-A+ patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A- patients (31% vs 4%). MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A- had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A- patients (54%) but in none of the MIS-A+ patients. CONCLUSION: MIS-A+ and MIS-A- fulminant COVID-19-related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients' management and further understanding of their pathophysiology.

Management of myocarditis in clinical practice.

Myocarditis is an inflammatory heart muscle disease characterized by heterogeneous clinical presentation and outcome. Clinical heterogeneity of myocarditis, ranging from acute onset chest pain with electrocardiographic changes resembling an acute coronary syndrome, to arrhythmic storm and chronic decompensated heart failure, makes diagnosis challenging. However, a correct diagnosis is fundamental to proper patients' management and should always be seeked. Although a definite diagnosis is only provided by endomyocardial biopsy, the European Society of Cardiology task force on myocardial and pericardial diseases provided specific criteria for the diagnosis of clinically suspected myocarditis, which has been facilitated by the advent of noninvasive imaging tests (i.e. cardiovascular magnetic resonance based myocardial tissue characterization). Due to the heterogeneous presentation and disease course of myocarditis, a tailored treatment would be the best strategy, but a standardized management is still not available. However, over the years, new, promising therapies, such as antiviral and immune-suppressive treatment, have come side by side to the standard pharmacological heart treatment, i.e. antiheart failure medications. In this paper we will review the basic principles of myocarditis management in clinical practice, including diagnostic work-up, conventional and disease-specific therapy and patients' follow-up.

Diagnosis and Management of Myocarditis in Children: A Scientific Statement From the American Heart Association.

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.

COVID-19 Myocarditis: An Emerging Clinical Conundrum.

Coronavirus Disease 2019 (COVID-19) has been a significant cause of global mortality and morbidity since it was first reported in December 2019 in Wuhan, China. COVID19 like previous coronaviruses primarily affects the lungs causing pneumonia, interstitial pneumonitis, and severe acute respiratory distress syndrome (ARDS). However, there is increasing evidence linking COVID-19 to cardiovascular complications such as arrhythmias, heart failure, cardiogenic shock, fulminant myocarditis, and cardiac death. Given the novelty of this virus, there is paucity of data on some cardiovascular complications of COVID-19, specifically myocarditis. Myocarditis is an inflammatory disease of the heart muscle with a heterogenous clinical presentation and progression. It is mostly caused by viral infections and is the result of interaction of the virus and the host's immune system. There have been several case reports linking COVID-19 with myocarditis, however the true mechanism of cardiac injury remains under investigation. In this paper we review the clinical presentation, proposed pathophysiology, differential diagnoses and management of myocarditis in COVID-19 patients.

Fulminant Myocarditis Following SARS-CoV-2 Infection: JACC Patient Care Pathways.

A 60-year-old woman with a past medical history of asthma presented with fulminant myocarditis 9 days after testing positive for SARS-CoV-2 and 16 days after developing symptoms consistent with COVID-19. Her hospital course was complicated by the need for veno-arterial extracorporeal membrane oxygenation, ventricular arrhythmias, and pseudomonas bacteremia. She ultimately recovered and was discharged to home with normal left ventricular systolic function. Thereafter, she developed symptomatic ventricular tachycardia, for which she received an implantable cardioverter-defibrillator and antiarrhythmic drug therapy.