Introduction
Acute myocarditis, an inflammatory condition of the heart muscle, presents a significant diagnostic challenge in clinical practice. This serious condition, potentially affecting individuals across all age groups, is experiencing an increasing rate of hospital admissions in the UK, and likely worldwide. While primary diagnoses of myocarditis constituted approximately 0.04% of all hospital admissions in England between 1998 and 2017, this figure is widely considered to underestimate the true prevalence. The diverse range of underlying causes, encompassing infections, inflammatory processes, and toxic exposures, further complicates its identification. The clinical manifestations of acute myocarditis are varied and often mimic other acute cardiac emergencies, making accurate and timely diagnosis crucial. Cardiovascular Magnetic Resonance (CMR) imaging has emerged as the gold standard non-invasive diagnostic tool. While treatment strategies are often supportive, focusing on managing complications like heart failure and arrhythmias, targeted therapies addressing specific etiologies and emerging immunosuppressive approaches are gaining importance. Although the prognosis is generally favorable with most patients recovering, a notable proportion can progress to dilated cardiomyopathy, underscoring the importance of precise and early Acute Myocarditis Diagnosis. This review aims to provide a comprehensive overview of acute myocarditis diagnosis, encompassing clinical presentation, diagnostic modalities, and key considerations for clinicians.
Defining and Classifying Myocarditis
Myocarditis is characterized by inflammation of the myocardium, the heart’s muscular middle layer responsible for contraction. This inflammation can arise from various triggers, including infections, immune-mediated mechanisms, or exposure to toxic substances. The Global Burden of Disease study estimated an incidence of 22 cases per 100,000 individuals, based on hospital discharge data coded with International Classification of Diseases (ICD) codes from 1990 to 2013. Analysis of NHS England hospital admissions between 1998 and 2017 revealed 12,927 primary myocarditis diagnoses, representing 0.04% of all NHS admissions. This data also highlighted a concerning 88% increase in myocarditis-related admissions over the 19-year study period, significantly exceeding the 57% increase in overall cardiology admissions, suggesting a growing burden of myocarditis requiring hospitalization.
Forms of Myocarditis
Myocarditis can be categorized based on its clinical course into acute, fulminant, subacute, and chronic forms.
Acute Myocarditis
Acute myocarditis is typically defined by a symptom duration of less than one month.
Fulminant Myocarditis
Fulminant myocarditis represents a severe and rapidly progressive form of acute myocarditis. It is characterized by cardiogenic shock requiring inotropic support or mechanical circulatory assistance.
Subacute Myocarditis
Subacute myocarditis is marked by ongoing myocardial damage due to persistent or recurrent inflammatory stimuli. It can also describe a healing phase following active myocarditis or be defined by a symptom-to-diagnosis interval of 1 to 3 months.
Chronic Myocarditis
When symptoms persist beyond one month, the condition is considered chronic inflammatory cardiomyopathy, overlapping with the subacute myocarditis definition.
Histopathological Classification
Histopathologically, myocarditis is defined by an inflammatory cell infiltrate within the myocardium, potentially accompanied by cardiac myocyte injury. The type of cellular infiltrate aids in further classifying myocarditis:
Lymphocytic Myocarditis
This form is most commonly associated with viral pathogens, drugs, radiation exposure, and autoimmune disorders.
Eosinophilic Myocarditis
Eosinophilic myocarditis is a less common variant linked to parasitic infections, hypersensitivity reactions, eosinophilic inflammatory conditions, and rarely, neoplastic processes.
Giant-cell Myocarditis
Giant-cell myocarditis is predominantly idiopathic but can also be associated with autoimmune disorders like thyroid disease and inflammatory bowel diseases.
Granulomatous Myocarditis
Granulomatous myocarditis is primarily associated with sarcoidosis.
Clinical Presentation: Recognizing the Diverse Symptoms
The diagnosis of acute myocarditis is often challenging due to its diverse clinical presentations, affecting individuals across all ages, with typical symptom onset between 20 and 50 years. While myocarditis can be asymptomatic, chest pain (85–95% of cases), fever (approximately 65%), and dyspnea (19–49%) are the most common presenting symptoms.
Given these overlapping features, acute myocarditis diagnosis requires careful differentiation from acute coronary syndromes (ACS) and acute pericarditis. A detailed family history is also critical to exclude inherited cardiomyopathies, such as left-dominant arrhythmogenic cardiomyopathy, which may mimic or be misdiagnosed as acute myocarditis. Palpitations, syncope, and fatigue are additional presenting symptoms. Notably, up to 80% of acute myocarditis patients report prodromal symptoms, including preceding flu-like, respiratory, or gastrointestinal illnesses.
Physical examination may reveal limited findings. However, complications arise in approximately 26% of patients, including left ventricular systolic dysfunction, sustained ventricular arrhythmias, or fulminant presentations with low cardiac output syndrome. These patients may exhibit signs of heart failure, cardiogenic shock, or even cardiac arrest. Fulminant myocarditis must be distinguished from other causes of hemodynamic instability with acute myocardial dysfunction, such as septic shock.
Key Investigations for Diagnosis
Effective acute myocarditis diagnosis relies on a combination of investigations, starting with readily available tools.
Initial Investigations
Electrocardiogram (ECG)
The ECG, typically the initial investigation, is frequently abnormal in myocarditis. ST-segment elevation, often in inferior and lateral leads, mimicking ST-elevation myocardial infarction (STEMI), is a common finding. Other ECG abnormalities include bradycardia, tachycardia, atrioventricular block, and ventricular arrhythmias.
Full Blood Count
While often normal, a full blood count may reveal eosinophilia, suggesting eosinophilic myocarditis and warranting further investigation into the cause of eosinophilia.
C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR)
Inflammatory markers such as CRP and ESR are commonly elevated in myocarditis. CRP is elevated in over 80% of patients, and a persistently high ESR may suggest an underlying autoimmune etiology.
Cardiac Biomarkers (Troponin, BNP)
Plasma cardiac biomarkers, particularly troponins, are frequently elevated, indicating myocardial injury. However, a normal troponin level does not exclude myocarditis. Brain natriuretic peptide (BNP) levels are also generally measured, but similar to troponin, normal BNP levels do not rule out myocarditis. Significantly elevated cardiac biomarkers may prompt urgent further investigations like CMR or endomyocardial biopsy.
Differentiating Myocarditis from Pericarditis
The clinical overlap between myocarditis and pericarditis, especially in myopericarditis (concomitant myocarditis and pericarditis), poses a diagnostic challenge. ECG findings of ST-segment elevation can be present in both conditions, with pericarditis often exhibiting more widespread ST elevation. However, ECG features alone are insufficient for differentiation. Elevated troponin levels are more indicative of myocarditis or myopericarditis than isolated pericarditis.
Transthoracic Echocardiography (TTE)
Transthoracic echocardiography (TTE) is a standard component of the diagnostic workup for suspected myocarditis. Echocardiographic findings in acute myocarditis are broad and nonspecific, mirroring findings in other cardiac conditions. Possible TTE findings include reduced left ventricular ejection fraction (LVEF), diastolic dysfunction, increased cardiac wall thickness, segmental wall motion abnormalities, abnormal myocardial echogenicity, or pericardial effusion (in myopericarditis).
Cardiovascular Magnetic Resonance Imaging (CMR)
Cardiovascular magnetic resonance imaging (CMR) with intravenous gadolinium-based contrast agents is highly recommended for patients with suspected acute myocarditis diagnosis. CMR is particularly crucial in severe or fulminant cases, provided the patient is stable enough for the scan. CMR is considered the reference standard non-invasive modality for detecting myocardial inflammation and associated abnormalities. While CMR accuracy might be slightly reduced in the initial days of illness, it should ideally be performed within 2 to 3 weeks of symptom onset. CMR also plays a role in monitoring disease progression and activity.
Alt text: Table summarizing recommended laboratory and imaging investigations for acute myocarditis diagnosis, including blood tests like full blood count, liver and renal function tests, CRP, ESR, troponin, BNP and imaging tests like Chest X-ray, ECG, Echocardiography and CMR.
Endomyocardial Biopsy
Endomyocardial biopsy has historically been the gold standard diagnostic test for myocarditis. Biopsy specimens are typically analyzed using histology, immunohistochemistry, and polymerase chain reaction (PCR) to identify potential infectious agents and characterize the inflammatory infiltrate. It is valuable for confirming the acute myocarditis diagnosis and determining the specific etiopathogenic form (e.g., giant-cell, lymphocytic, or sarcoid myocarditis). Endomyocardial biopsy should be performed at experienced centers due to its invasive nature and potential risks, although complication rates are lower in high-volume centers. Complication risks can include cardiac complications (up to 9% in low-volume settings), peripheral vascular complications, arrhythmias, pneumothoraces, and post-procedure infections. Certain patients with suspected myocarditis may be unsuitable for endomyocardial biopsy. Furthermore, myocardial inflammation can be patchy, leading to false-negative results if unaffected tissue is biopsied. While the transfemoral approach is common, a transradial approach offers a similar complication profile. Despite increasing reliance on CMR, endomyocardial biopsy remains crucial in specific cases where it is likely to significantly impact patient management. ESC-HFA and ACCF/AHA guidelines outline indications for endomyocardial biopsy in acute myocarditis and chronic inflammatory cardiomyopathy:
- New-onset heart failure of less than two weeks duration unresponsive to usual therapy.
- Acute myocarditis or suspected chronic inflammatory cardiomyopathy associated with peripheral eosinophilia.
- Acute myocarditis or chronic inflammatory cardiomyopathy with persistent or relapsing myocardial necrosis biomarkers, particularly with autoimmune disorders, ventricular arrhythmias, or high-degree atrioventricular block.
- Myocarditis in the context of immune checkpoint inhibitor therapy, where definitive acute myocarditis diagnosis influences cancer therapy decisions.
Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)
Fluorodeoxyglucose positron emission tomography (FDG-PET) can detect myocarditis by identifying increased myocardial FDG uptake indicative of inflammation. FDG-PET is not routinely used but may be considered when CMR is inconclusive or when extra-cardiac inflammation, as in sarcoidosis, is suspected.
Box 1. Investigations Recommended in Suspected Myocarditis
(Content of Box 1 as in original article, already rendered as image above)
Unraveling the Etiology: Further Investigations
Determining the underlying cause is crucial for comprehensive acute myocarditis diagnosis and management. The patient’s history provides valuable clues to potential etiologies and guides further investigations. Viral infections are the most frequently identified cause, particularly coxsackieviruses, adenoviruses, and parvovirus B19. Recently, SARS-CoV-2 infection has emerged as a significant cause of cardiac inflammation and acute/fulminant myocarditis. Travel history is important to assess for travel-associated infections like dengue and Zika virus. A detailed drug history, including prescription, over-the-counter, and recreational drugs, and recent vaccination history are essential. Immunosuppression broadens the differential diagnosis, with agents like Epstein-Barr virus, cytomegalovirus, and fungi becoming more relevant. Assessing for autoimmune/inflammatory conditions (e.g., systemic lupus erythematosus, eosinophilic granulomatosis with polyangiitis) is important, as 7% of myocarditis patients have associated autoimmune disorders, potentially requiring specific therapies. Features suggestive of autoimmune/inflammatory conditions include fever, fatigue, musculoskeletal symptoms, lymphadenopathy, rashes, hair loss, mucosal ulceration, neuropathic pain, ocular manifestations (uveitis), altered bowel habits, renal dysfunction, peripheral eosinophilia, and a family history of autoimmune/inflammatory diseases. Sarcoidosis, a multisystem granulomatous disease, can present with these features, but can also be asymptomatic. Extra-cardiac features of sarcoidosis include erythema nodosum, respiratory symptoms (cough, dyspnea), and bilateral hilar adenopathy. Cardiac involvement occurs in approximately 5% of pulmonary/systemic sarcoidosis cases.
A wide range of potential triggers for acute myocarditis exist. Extensive testing for all potential causes is impractical. Therefore, further investigations, summarized in Table 1, are guided by a detailed history, thorough examination, and initial investigation findings.
Alt text: Table listing additional diagnostic investigations for suspected myocarditis based on specific clinical scenarios, including thyroid function tests, serum ACE level, drug screen, metanephrines, viral PCR, bacterial cultures, mycoplasma testing, blood borne virus screen, EBV/CMV/Parvovirus serology, autoantibodies, urine analysis, Borrelia serology, FDG-PET and endomyocardial biopsy.
Table 1. Additional Investigations to Consider in Patients with Suspected Myocarditis
(Content of Table 1 as in original article, already rendered as image above)
Box 2. Causes of Myocarditis
(Content of Box 2 as in original article, rendered as image below)
Alt text: Box outlining infectious and non-infectious causes of myocarditis, detailing viral, bacterial, fungal, protozoal, helminth, rickettsial, hypersensitivity, systemic inflammatory disorders, toxic, transplant rejection, and autoreactive causes.
Concomitant coronary artery disease should be considered and excluded in all patients presenting with suspected acute myocarditis diagnosis, either by CMR demonstrating a non-ischemic late enhancement pattern, or directly with CT coronary angiography or invasive coronary angiography.
Treatment Strategies and Management
Management of suspected myocarditis often necessitates a multidisciplinary approach involving cardiology, infectious diseases, rheumatology, immunology, and/or respiratory medicine specialists to determine etiology and guide treatment. When a specific cause is identified, treatment targets the underlying condition, such as anti-infective agents for treatable infections or corticosteroids/immunosuppressants for immune-mediated diseases. Immunosuppressive therapy is strongly supported in cardiac sarcoidosis, giant-cell myocarditis, and autoimmune rheumatic diseases. However, in many cases, the etiology remains unidentified or is viral, for which specific treatment is unavailable or unnecessary. Treatment in these cases is primarily supportive, managing complications like arrhythmias or heart failure, and severe cases may require intensive care unit (ICU) admission. Emerging evidence suggests potential benefits of selective immunosuppression in chronic myocarditis, but this remains non-routine and requires multidisciplinary team discussion. Empirical immunosuppression may be considered in critically ill patients unable to undergo endomyocardial biopsy, especially when giant-cell myocarditis is suspected.
Non-steroidal anti-inflammatory drugs (NSAIDs), commonly used in pericarditis, are generally contraindicated in myocarditis due to ineffectiveness and potential exacerbation in animal models, as well as the risk of worsening heart failure.
Patients with significant hemodynamic compromise or fulminant myocarditis may require inotropic support and, in some cases, temporary mechanical circulatory support like venoarterial extracorporeal membrane oxygenation (VA-ECMO) and rotary blood pumps. Early ICU review and admission for pharmacological or mechanical support is crucial. Cardiac transplantation or left ventricular assist device implantation may be considered for patients with refractory heart failure or arrhythmias despite these measures. Prompt discussion with a cardiac transplant center is essential in such cases.
Follow-up, Prognosis, and Potential Complications
Most patients with acute myocarditis recover, with spontaneous resolution of myocardial inflammation. Clinical improvement is indicated by decreasing inflammatory markers, cardiac biomarkers, improved cardiac function, and arrhythmia resolution. Follow-up by a consultant cardiologist within 3 months of discharge, ideally in a dedicated clinic, is recommended, with timing adjusted based on clinical condition at discharge. Competitive sports and vigorous exercise are discouraged for 3–6 months post-diagnosis to minimize cardiac remodeling and sudden cardiac death risk.
Baseline CMR at acute myocarditis diagnosis can identify predictors of adverse cardiovascular events, such as the presence and anteroseptal location of mid-wall late gadolinium enhancement, and low baseline LVEF. Repeat CMR, typically at 6–12 months, or sooner if clinically indicated, monitors disease progression. Persistent myocardial inflammation may warrant endomyocardial biopsy to guide further treatment.
Recurrence of acute myocarditis is rare (1.1%). However, up to 30% of biopsy-proven myocarditis cases progress to dilated cardiomyopathy, particularly with significantly impaired LVEF at presentation. UK NHS data indicate an approximate 4% all-cause mortality in hospitalized myocarditis patients, with 20% of these deaths attributed to non-ischemic dilated cardiomyopathy. Prognosis varies depending on etiology and classification, with giant-cell myocarditis historically exhibiting the poorest prognosis. However, outcomes in giant-cell myocarditis have significantly improved with immunosuppressive therapy, reducing the need for mechanical support and transplantation. Cardiac transplantation for giant-cell myocarditis shows favorable survival rates, but recurrence post-transplant (20–25%) often necessitates ongoing immunosuppression.
Conclusion: Key Takeaways for Acute Myocarditis Diagnosis
The burden of acute myocarditis is increasing. Its diverse etiologies and overlapping clinical features with other cardiac conditions make acute myocarditis diagnosis challenging. Endomyocardial biopsy remains the reference standard diagnostic test, while CMR is a crucial non-invasive modality. Treatment is primarily supportive, managing complications, with immunosuppressive therapies indicated in specific cases. Etiology-specific therapies may be appropriate when the trigger is identified. Overall prognosis is generally good, but a minority of patients develop long-term sequelae, often as dilated cardiomyopathy with associated heart failure and/or arrhythmias. Early and accurate acute myocarditis diagnosis is paramount for optimal patient outcomes.
Key Practice Points
- Consider acute myocarditis diagnosis in patients of all ages presenting with:
- Chest pain, fever, or breathlessness.
- Palpitations (arrhythmia).
- Syncope or cardiac arrest.
- Prodromal illness.
- ECG changes (e.g., ST-segment elevation).
- Elevated cardiac biomarkers (e.g., troponin).
- Regional or global cardiac contractile dysfunction.
- Detailed history and examination are crucial for guiding etiology investigations, focusing on recent/current infections (especially viral), autoimmune/inflammatory conditions, and toxic exposures (e.g., drugs).
- Myocarditis is defined histologically by myocardial inflammation on endomyocardial biopsy based on established criteria.
- Cardiovascular magnetic resonance imaging is the reference standard non-invasive test for acute myocarditis diagnosis.
- Unless a treatable specific cause is identified, acute myocarditis treatment is primarily supportive, managing heart failure and arrhythmias.
- NSAIDs are generally not recommended for acute myocarditis, unlike in acute pericarditis.
- Overall prognosis is favorable, with most patients recovering without long-term sequelae and low recurrence risk, but dilated cardiomyopathy can develop in up to 30% of biopsy-proven cases.
References
(References from original article to be included here)
