Myocarditis Review

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Introduction   

Myocarditis is an inflammatory disease of the heart muscle (myocardium), often triggered by infections or systemic inflammatory conditions such as autoimmune disorders that reduced the ability of the heart muscle to pump blood [1]. Myocarditis manifests in various forms, each with distinct characteristics and causes. Acute myocarditis refers to a sudden onset caused by a viral infection, with symptoms that may resolve [2]. Chronic myocarditis involves a prolonged course or recurrent symptoms, often due to autoimmune disorders where the immune system attacks healthy cells and tissues [3]. Lymphocytic myocarditis is a rare and severe form that can necessitate hospitalization, characterized by the infiltration of white blood cells (lymphocytes) into the heart muscle often following a viral infection [4].  

The classic symptoms of myocarditis include chest pain occurring 1-2 weeks after a viral infection of the upper respiratory or gastrointestinal tract [5]. Although viral infections are the primary cause, myocarditis can also result from bacteria, fungi, medications, toxins, bites from ticks, spiders, and other insects, as well as autoimmune conditions like lupus and rheumatoid arthritis [6][7]. Myocarditis is a diverse condition, presenting with symptoms that range from mild chest discomfort to severe cardiogenic shock. These symptoms often mimic those of coronary artery disease, complicating the diagnosis [8]. Modern diagnostic approaches include clinical assessments, laboratory tests, imaging techniques, and histological evaluations. While endomyocardial biopsy (EMB) remains the gold standard, cardiac magnetic resonance imaging (CMR) offers a non-invasive alternative [9].  

Epidemiological studies have highlighted the significant public health impact of myocarditis among young adults, where it is a leading cause of sudden cardiac death (SCD) [10]. Recent research efforts have revealed a wide range of prevalence rates, from 10.2 to 105.6 per 100,000 people worldwide, indicating potential underdiagnosis [8]. Experts estimate 1.8 million cases worldwide per year [11]. The ongoing COVID-19 pandemic has further emphasized the importance of understanding myocarditis and the associated heart damage [12].  

Various agents induce toxic myocarditis, including prescribed medications, recreational drugs, and environmental toxins. Known causes among prescribed medications include dobutamine, phenytoin, antibiotics (such as ampicillin, azithromycin, cephalosporins, tetracyclines), and psychiatric medications (like tricyclic antidepressants, benzodiazepines, clozapine). Recreational and illicit drugs, such as methamphetamine and cocaine, are also significant contributors. Exposure to heavy metals like copper, lead, and arsenicals, as well as antineoplastic agents (such as anthracyclines, cyclophosphamide, 5-fluorouracil, and tyrosine kinase inhibitors), can lead to the development of toxic myocarditis [8]. With the increasing use of immune checkpoint inhibitors (ICIs) for cancer treatment, there has been a rise in reports of lethal myocarditis as an adverse effect. The incidence of myocarditis associated with ICIs ranges from 0.04% to 1.14%. Despite being less common than other immune-related adverse events (irAEs), myocarditis linked to ICIs has a higher mortality rate, ranging from 25% to 50% [13]. 

Case Study: Diagnosis and Management of Myocarditis 

Patient Presentation 

A 28-year-old male presented to the emergency department with a 10-day history of mild flu-like symptoms, including fever, malaise, myalgia, vomiting, and diarrhea. He also reported intermittent chest pain and palpitations. There was no history of recent travel, tick bites, or use of recreational drugs. 

Initial Assessment 

• Vital Signs 

• Heart rate: 110 bpm 

• Blood pressure: 120/70 mmHg 

• Respiratory rate: 22 breaths/min 

• Oxygen saturation: 98% on room air 

• Temperature: 38.3°C 

• Physical Examination 

• Tachycardic with regular rhythm 

• Clear lung fields 

• No peripheral edema 

• No jugular venous distention 

• S3 gallop heard on cardiac auscultation 

Diagnostic Workup 

• Electrocardiogram (ECG) 

• Sinus tachycardia with nonspecific ST/T wave changes 

• Laboratory Tests 

• Elevated troponin I levels 

• Complete blood count (CBC): Elevated white blood cell count 

• Erythrocyte sedimentation rate (ESR): Elevated 

• C-reactive protein (CRP): Elevated 

• Viral antibody titers: Positive for Coxsackievirus B 

• Imaging 

• Transthoracic echocardiogram (TTE): Preserved left ventricular ejection fraction (LVEF) with global hypokinesis. 

• Cardiac MRI: Increased T2-weighted signal intensity indicating myocardial edema, and late gadolinium enhancement (LGE) suggesting myocyte necrosis and fibrosis. 

Diagnosis 

• Diagnosis 

• Acute viral myocarditis, confirmed by clinical presentation, elevated cardiac markers, and cardiac MRI findings consistent with myocarditis. 

• Differential Diagnosis [14]: 

• Carnitine deficiency 

• Coarctation of the aorta 

• Coronary artery anomalies 

• Cardiac tumor 

• Dilated cardiomyopathy 

• Endocardial fibroelastosis 

• Enteroviral infections 

• Genetic disorders (von Gierke disease, glycogen-storage disease type II) 

• Medial necrosis of coronary arteries 

• Nonviral myocarditis 

• Shock 

• Valvular aortic stenosis 

• Viral pericarditis 

Management 

Hospital Admission and Monitoring 

• Admit for continuous cardiac monitoring. 

• Perform serial troponin levels and ECGs to monitor cardiac status. 
• Limit activity  

Heart Failure Management 

• Initiated treatment with AE inhibitors and diuretics to manage ventricular dysfunction [15]. 

• Avoid cardiotoxic drugs and NSAIDs to prevent further myocardial damage [16]. 

• Withhold beta-blockers due to the presence of mild heart block on ECG. 

Physical Activity Restrictions 

• Advise the patient to avoid competitive sports and strenuous activities for at least 3 to 6 months. 

• Receive a comprehensive evaluation and functional testing prior to resuming any competitive sports. 

Arrhythmia Management 

• Given the risk of life-threatening arrhythmias, consider an automatic implantable cardioverter-defibrillator (AICD). 
• Monitor for signs of arrhythmias and deterioration. 

Follow-Up and Long-Term Management 

• Scheduled follow-up visits with repeat echocardiograms and cardiac MRI to assess recovery and cardiac function. 

• Refer patients with persistent symptoms or worsening heart function to a tertiary care center for advanced therapies and possible cardiac transplantation. 

Prognosis 

• Short-term: Expect a good short-term prognosis with appropriate supportive care and activity restriction. 

• Long-term: Prognosis depends on the severity of the inflammatory process and the presence of arrhythmias. Patients with severe disease and life-threatening arrhythmias may require mechanical assistance devices and cardiac transplantation [20]. 

Epidemiology 

Myocarditis is a disease with a wide range of clinical presentations, from asymptomatic cases to life-threatening conditions, including sudden death [2]. Myocarditis accounts for approximately 10% of sudden death cases [17]. Prospective studies using gold-standard biopsy parameters have reported that myocarditis progresses to dilated cardiomyopathy (DCM) in about 30% of cases [18]. Patients with post-myocarditis DCM have a poor prognosis, and often require heart transplantation for those in advanced stages of heart failure [18]. Viral myocarditis is the most frequent type, affecting children and young adults [5]. Studies indicate that 60% of children diagnosed with acute myocarditis have a transplant-free survival rate of 10 years [19].  

Global and Demographic Prevalence 

Myocarditis affects 82% of males and young adults, with an average age of 40 ± 16 for men and 40 ± 17 for women [8]. The high-income Asia-Pacific region had the highest age-standardized prevalence at 45.6 per 100,000 people [8]. Prevalence rates ranged from 10.2 per 100,000 people in Chile to 105.6 per 100,000 people in Albania [8].  

Inflammation and Gender Differences 

Endomyocardial biopsies (EMBs) reveal myocarditis in 1.4–63% of patients with unexplained congestive heart failure, ventricular arrhythmias, or “primary” atrial fibrillation [8]. 

The observation of inflammatory changes occurred in 22 of 35 patients with idiopathic congestive cardiomyopathy, suggesting a link between persistent myocardial inflammation and Dilated cardiomyopathy (DCM) [21]. Myocardial inflammation occurs in 13% to 27% of patients with idiopathic dilated cardiomyopathy (DCM). In Western Europe and North America, 10% to 50% of acute DCM cases are associated with myocarditis [8]. 

Studies show that myocarditis occurs more often in men than women, with a female-to-male sex ratio ranging from 1:2 to 1:4 [22]. In the distinction, women have a lower risk of death or requiring heart transplantation and a clinical presentation that tends to be more subtle leading to underdiagnosis [22][23]. 

Pathophysiology 

Myocarditis starts with the direct invasion and replication of an infectious agent within or around the myocardium, leading to myonecrosis and cardiac tissue destruction [24]. The host’s immune response, combined with the infectious agent, activates cytotoxic effects. The presence of a persistent virus in the myocardium leads to the progressive deterioration of heart muscle function [25]. Exogenous or endogenous chemicals produced by systemic pathogens might also induce toxic effects on myocytes [24]. 

Stages of Myocarditis 

1. Acute Stage (1-7 days): Myocarditis occurs when viruses damage heart muscle cells, causing necrosis and triggering the body’s innate immune response. In this phase, necrosis of the myocardium exposes host proteins, further activating the immune system [24]. The type of damage varies by virus: adenoviruses and enteroviruses cause direct cytotoxic effects on cells, parvoviruses infect endothelial cells and release pro-inflammatory cytokines, while influenza viruses prompt an inflammatory response regulated by T-cells. This combination of viral cytotoxicity and immune activation defines the progression and pathology of myocarditis [24]. 
2. Subacute Stage (1-4 weeks): During this stage, autoimmune-mediated injury intensifies as T cells and B cells become activated and produce antibodies. This process results in the formation of cardiac autoantibodies and the release of inflammatory proteins [24]. Patients suffering from myocarditis and dilated cardiomyopathy show higher levels of anti-beta-myosin antibodies compared to control groups [36]. This heightened immune response contributes significantly to the progression of myocardial damage and inflammation [24]. 
3. Recovery or Chronic Stage: The outcome of myocarditis depends on the elimination of the viral genome from the myocytes [24]. If the virus persists, T-cell-mediated inflammation can lead to cardiac remodeling and widespread myocardial fibrosis. This can progress to dilated cardiomyopathy (DCM) and result in complications such as congestive heart failure (CHF), ventricular arrhythmias, and abnormal electrocardiogram (ECG) findings [24]. Further studies into microRNAs (miRNAs) as immune response regulators during the subacute and chronic phases may offer more insight into patients with persistent and progressive cardiac dysfunction. 

Etiology 

Myocarditis classification can be based on the underlying cause, the severity of the disease, the predominant symptoms, and the histopathological findings [11]. These classifications help in understanding the diverse presentations and guiding appropriate treatment strategies. The traditional Dallas criteria use endomyocardial biopsy (EMB) to distinguish between active myocarditis and borderline myocarditis [34]. The classification of myocarditis includes lymphocytic, eosinophilic, polymorphic, giant cell, or granulomatous myocarditis [35]. Further classified includes acute myocarditis (AM), chronic myocarditis (CM), chronic inflammatory cardiomyopathy (CIC), or subacute myocarditis (SM) [2].  

A diagnosis of acute myocarditis occurs within one to three months of symptom onset and includes findings of active myocarditis [2]. Sub-acute myocarditis occurs one and three months after symptom onset, often showing healing myocarditis [2]. CM involves ongoing inflammation and fibrosis without necrosis, diagnosed after one to three months of symptoms [2]. CIC involves chronic inflammation with cardiomyocyte abnormality and ventricular remodeling, often presenting with dilated cardiomyopathy [11]. 

Cardiotropic viruses, which cause myocarditis by damaging cardiomyocytes, are the most frequent causes [11]. These viruses encompass enteroviruses like Coxsackie A and B viruses, echoviruses, and adenoviruses [11]. Genetic predisposition can increase susceptibility to infection by cardiotropic viruses and contribute to the development of chronic myocarditis [26].  

Vasculotropic viruses, such as parvovirus B19, and lymphotropic viruses, including herpes viruses, Epstein-Barr virus, and cytomegalovirus, can also lead to myocarditis. In heart transplant patients, cytomegalovirus, and Toxoplasma gondii are known potential causes of myocarditis [11]. Viruses can activate the immune system, causing a cytotoxic storm and immune mimicry. This includes pathogens like HIV, hepatitis C virus, influenza A and B viruses, and SARS-CoV-1 and SARS-CoV-2 [27]. 

Enteroviruses, often implicated in viral myocarditis, attach to specific receptors on heart muscle cells, replicate, and cause cell destruction. About half of the patients undergo spontaneous clinical recovery. However, if the viral genome remains in the myocardium, it often results in left ventricular dysfunction and a poorer prognosis [28]. Advancements in molecular technology have uncovered additional viral agents responsible for acute myocarditis (AM), including PVB19 and HHV61. PVB19, notably in children, can lead to systemic infection and is capable of causing both virus-mediated and virus-induced myocarditis [28]. 

Mechanisms of Myocardial Damage During Viral Infection 

The direct cytotoxic effect of myocarditis involves the virus penetrating myocytes, binding to specific receptors, replicating, and causing necrosis of myocytes [11]. Autoimmune-mediated injury intensifies as T cells and B cells become activated, generating antibodies. This process leads to the formation of cardiac autoantibodies and various inflammatory proteins, exacerbating the damage to the heart tissue [11].  

After the acute phase of viral-mediated myocarditis, three potential clinical outcomes can occur. First, the virus may eliminate without leaving behind any inflammation, leading to complete recovery [11]. Second, the viral infection might persist, with or without accompanying inflammation [11]. Third, the viral infection could trigger an autoimmune-mediated inflammatory response that continues after the clearing of the virus [11]. 

Cytokine release syndrome (CRS) represents a significant concern, marked by an inflammatory reaction that induces a massive cytokine release due to infection or drug treatment. Mild CRS often manifests with fever and flu-like symptoms, while severe CRS can result in hypoxia, left ventricular dysfunction, and hemodynamic instability [29]. This instability may include hypotension and rhythm disturbances. There are studies indicating that Myocarditis is a consequence of cytokine storms among patients with COVID-19 [29][30]. 

Eosinophilic myocarditis (EM) involves eosinophils infiltrating myocardial tissue, linked to conditions like hematologic disorders, hypersensitivity reactions, parasitic infections, malignancies, and systemic diseases [31]. One frequent cause of EM is drug reactions, including DRESS syndrome, manifest weeks to months after the administration of the offending drug. EM can escalate to severe heart failure, which is associated with high mortality rates [31]. 

Giant cell myocarditis (GCM) is an uncommon and fast-progressing form of myocarditis. It involves extensive damage to the heart muscle driven by cytotoxic T cells, macrophages, giant cells, and eosinophils. This condition frequently results in abrupt heart failure and persistent ventricular arrhythmias that are difficult to manage [32] 

Myocarditis associated with immune checkpoint inhibitors (ICIs) used in cancer treatment has increased, with acute myocarditis often occurring within the first month of drug administration [13]. Chimeric antigen receptor T cell (CAR-T) therapy, a cancer treatment, also links to myocarditis and cardiotoxicity [13]. 

Systemic diseases like systemic lupus erythematosus, scleroderma, and dermatomyositis can cause myocarditis through immune complex deposition and complement activation [33].  

Clinical Presentation and Diagnosis of Acute Myocarditis 

Acute myocarditis presents with diverse clinical symptoms. Patients describe a 7- to 14-day period of mild flu-like symptoms, including fever, fatigue, muscle aches, vomiting, and diarrhea [24].  

Clinical Presentation: 

• Adults: Common symptoms include chest pain (95%), dyspnea (45%), fatigue, syncope, palpitations, fever (18-35%), tachycardia, and tachypnea [24]. Hypotension may also be present. The presence of chest pain or congestive heart failure (CHF) symptoms often indicates a poor prognosis [24]. 

• Children: Symptoms include grunting respirations and intercostal retractions. 

• Infants: Infants with myocarditis often exhibit fulminant syndrome, marked by symptoms such as fever, hypoxia accompanied by cyanosis, respiratory distress, or failure, and, in some cases, cardiac arrest [24]. The severity of these initial symptoms is a strong indicator of the long-term prognosis [24]. 

Classification 

In 2013, the European Society of Cardiology classified acute myocarditis into three distinct profiles” 

1. Acute Coronary Syndrome-Like Presentation: Symptoms of myocarditis can include chest pain, alterations in ST/T waves on an electrocardiogram (ECG), elevated troponin levels, and abnormalities in wall motion [37]. 
2. New Onset Progressive Heart Failure: Myocarditis can result in impaired function of both the left and right ventricles, often manifesting as heart blocks or arrhythmias. The condition may also present with nonspecific changes on an ECG, complicating diagnosis, and management. This broad range of cardiac dysfunction underscores the importance of thorough diagnostic evaluation when suspecting myocarditis [37]. 
3. Severe Life-Threatening Fulminant Conditions: This condition encompasses severe scenarios such as cardiogenic shock that necessitates the use of vasopressors, mechanical life support interventions, and ventricular arrhythmias that demand defibrillation [37]. 

Patients diagnosed with fulminant myocarditis face an increased risk of cardiac death and require heart transplants within a five-year period [24]. This severe form of myocarditis demands prompt and aggressive treatment due to its rapid progression and high mortality rate [24]. Physical examination findings may include an S3 gallop, rales, tachycardia, and dependent edema, similar to CHF. 

Evaluation 

Patients exhibit nonspecific ECG abnormalities, including sinus tachycardia, wide QRS complexes, low voltage signals, prolonged QT intervals, and variable atrioventricular blocks [24]. The patterns can be indicative of acute myocardial infarction may also be present. These diverse ECG findings can complicate the diagnosis, necessitating a thorough clinical evaluation to differentiate myocarditis from other cardiac conditions [24]. Elevated troponin levels often signal myonecrosis and considerable damage to the heart muscle [24]. However, it is important to note that normal troponin levels do not exclude the presence of myocarditis [24]. Recommended diagnostic tests for myocarditis include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels [14][24]. While these tests may show elevated white blood cell counts, increased CRP levels, or a faster ESR, they are not definitive for diagnosing myocarditis [14][24]. These findings can indicate inflammation but do not provide conclusive evidence of myocarditis [24]. 

Order viral antibody titers for coxsackievirus group B, HIV, CMV, Epstein-Barr virus, hepatitis, and influenza viruses [38]. IgM titers increase four-fold during the acute phase and fall as the disease progresses, so serial titers may be helpful [24][38]. 

Imaging 

• Transthoracic Echocardiogram (TTE): Transthoracic echocardiogram (TTE) is the initial imaging choice for suspected myocarditis in unstable patients where cardiac MRI is not feasible [24]. 

• Advanced Echocardiography: Two-dimensional speckle-tracking echocardiography, real-time myocardial contrast echocardiography, and scintigraphy with Indium-111 labeled antimyosin antibodies offer additional insights by localizing and visualizing dead myocardial tissue, although their sensitivity and specificity are still under evaluation [24][37]. 

• Cardiac MRI: Cardiac MRI, based on the Lake Louise Criteria first introduced in 2009 and updated in 2018, serves as the best noninvasive imaging modality for diagnosing and monitoring myocarditis [24][39]. 

• Endomyocardial Biopsy (EMB): Considered the gold standard, limited use of EMB occurs due to its limited sensitivity and specificity; though recommended for patients with deteriorating conditions, severe heart failure, high-degree AV block, cardiogenic shock, suspected inflammatory cardiomyopathy and idiopathic causes [40]. 

Treatment & Management  

The treatment of myocarditis primarily focuses on supportive care aimed at preserving left ventricular function. This includes a range of strategies from activity limitation to rhythm control and heart failure (CHF) management. Due to the absence of large multicenter randomized control trials, treatment recommendations are primarily based on expert consensus. Admit patients suspected of having myocarditis, regardless of symptom severity for monitoring of arrhythmias and signs of decompensation. Obtain a transthoracic echocardiogram for patients presenting with chest pain upon admission and consider a coronary CT angiogram or cardiac catheterization [24]. 

Patients with heart failure and ventricular dysfunction should follow current heart failure guidelines, which often involve diuretics and inotropic support, with long-term treatment including ACE inhibitors [41]. Cardioprotective strategies, such as avoiding cardiotoxic drugs and NSAIDs, are essential to prevent exacerbation of inflammation and hindrance of myocardial healing [42]. Anticoagulation may be necessary for some patients, and the use of antiarrhythmics requires careful clinical judgment due to their potential negative inotropic effects [11]. Aspirin use in acute myocarditis is uncertain, and beta-blockers in patients with heart blocks or those who may require temporary or permanent pacemakers should be avoided [11][24]. 

During the acute phase of myocarditis, restrict physical activity and exercise. For patients experiencing cardiogenic shock that does not respond to medical treatment, consider advanced interventions such as intra-aortic balloon pump counterpulsation, the Impella system, and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) [43].  

Discharge patients with an LVEF of ≤35% with a wearable cardiac defibrillator for primary prophylaxis and reevaluate at three months for potential AICD implantation [44]. Professional athletes with an AICD should have it programmed for higher rate cutoffs and duration detection to reduce inappropriate shocks during physical activity [45]. 

Association of SARS-CoV-2 Infection and COVID-19 with Myocarditis 

SARS-CoV-2 damages cardiomyocytes by targeting Angiotensin II receptors. A link to COVID-19 mRNA and acute myocarditis may exist, though the exact cause is unclear [46] [49]. Explanations include immune reactivity to mRNA, antibodies against SARS-CoV-2 spike proteins, and hormonal differences influencing the immune response [46]. 

However, many early studies lacked detailed patient characteristics, cardiac imaging, or endomyocardial biopsy (EMB), leaving the exact cause of troponin elevation unclear. Given that myocarditis is a known complication of Middle East Respiratory Syndrome (MERS) and other coronaviruses, a connection between COVID-19 and myocarditis is plausible, though data remain preliminary [30][46]. 

COVID-19 patients experience cardiovascular complications such as thrombotic events, arrhythmias, and exacerbation of existing heart conditions, which can worsen myocardial damage and prognosis [47]. An autopsy study revealed myocardial damage and circulatory failure in only 7% of fatal cases [8]. Patients with underlying cardiovascular diseases are more to have a severe course of COVID-19 [48].  

Conclusion

Myocarditis, an inflammatory disease of the heart muscle triggered by various infections or systemic inflammatory conditions such as autoimmune disorders that weakens the heart muscle, reducing its ability to pump blood [1]. Myocarditis manifests in diverse forms: acute myocarditis, often caused by viral infections with symptoms that may resolve; chronic myocarditis, marked by prolonged or recurrent symptoms linked to autoimmune disorders; and lymphocytic myocarditis, a rare severe form characterized by white blood cell infiltration [11] [24]. Symptoms range from mild chest discomfort to severe cardiogenic shock, mimicking other cardiovascular diseases, complicating diagnosis. Advanced diagnostic approaches, including clinical assessments, laboratory tests, imaging techniques, and histological evaluations, have improved detection.  

Despite being less common, myocarditis has significant public health impacts among young adults and remains a leading cause of sudden cardiac death [10]. Recent increases in myocarditis cases linked to immune checkpoint inhibitors and the ongoing COVID-19 pandemic underscore the importance of continued research and improved diagnostic and therapeutic strategies. 

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