Acute Myocarditis

Etiology

The causes of acute myocarditis are broadly classified into infectious and non-infectious categories. In most cases (50%), no cause can be identified (idiopathic). The most implicated etiology in patients with an identified cause is a viral infection.[5]  

Infectious Causes

• Virus: Coxsackie and echoviruses are the most common cardiotropic viruses causing myocarditis. Other viral pathogens include the human immunodeficiency virus (HIV), adenovirus, hepatitis B and C, Parvovirus B19, poliovirus, Epstein-Barr virus, etc.[6]
• Bacteria: Bacteria notorious for causing myocarditis include legionella, staphylococci, Salmonella, Shigella, streptococci, Clostridium, tuberculosis, etc. 
• Parasites: Trichinosis, schistosomiasis. 
• Protozoa: Trypanosoma cruzi (causative agent of Chagas disease) and Toxoplasmosis gondii.
• Spirochetes: Borrelia burgdorferi.

Non-infectious Causes

Include a variety of causes such as eosinophilic myocarditis, collagen vascular diseases such as systemic lupus erythematosus, polymyositis, and dermatomyositis, cardiotoxic drugs, systemic diseases such as sarcoidosis, inflammatory bowel diseases, or giant cell arteritis, acute rheumatic fever, venoms and chemicals such as hydrocarbons and cellular rejection after a cardiac transplant.[7]  

Epidemiology

Given the variable clinical presentation and difficulty in clinical diagnosis, the exact prevalence of the disease is not known. The diagnosis is frequently missed, and it is difficult to estimate the true incidence and prevalence of acute myocarditis. Acute myocarditis is more common in younger adults and appears to affect both sexes and various races equally.[8][9] There is significant regional variation. 

According to the Global Burden of the Disease report (2019), the estimated rate of the disease is 6.1 per 100,000.[10] Some estimations have reported the incidence to be 10 to 22 per 100,000 cases, with an estimated 1.5 million cases worldwide in 2013.[11] 

It is also estimated that the myocardium is involved in up to 5% of patients who develop an acute viral illness. In patients presenting with angina-like symptoms, mildly elevated Troponin-I, and absence of coronary artery disease, the prevalence of myocarditis by cardiac magnetic resonance imaging is 13%.[12]

Pathophysiology

Acute myocarditis is an inflammatory cardiomyopathy. The inflammatory process is initiated after the entry of the virus into the myocardial cells. This entry leads to the activation of an innate immune response over the first week, followed by an adaptive immune response over the next 1-4 weeks. During the chronic stage, chronic inflammation and remodeling of the myocardium lead to myocardial dilation and cardiomyopathy.[5][13]

The cell damage caused by the virus leads to the release of interleukin and damage-associated molecular patterns (DAMP). These mediate the recruitment of inflammatory cells of the innate immune system. Additionally, any stress, such as pain or anxiety, triggers the medullary cells for monocytopoiesis. There is a release of myeloid progenitor cells. The spleen is activated to replenish the pro-inflammatory cells. These pro-inflammatory cells mobilize to the damaged myocardium, where interferon-gamma release leads to further recruitment. The exaggerated inflammatory response to the viral damage of the myocardium leads to chronic inflammation, myocardial remodeling, and ventricle dysfunction.[5]

There is also a role of autoimmunity in inflammatory myocarditis.[14] Autoantibodies against the cardiac myosin chain are found in more than half of cases of inflammatory myocarditis. Environmental factors further interplay with genes and contribute to inflammation.[5]

Histopathology

The histopathology of acute myocarditis is variable and depends on the organism and the extent of myocardial damage. The damage may be focal or diffuse. Necrosis with the involvement of the coronary vessels may also be seen. In long-standing cases, fibrosis may be evident. Endomyocardial biopsy is not routinely performed in nonfatal cases. Patients with myocarditis may or may not have evidence of viral genome by polymerase chain reaction (PCR). 

Dallas criteria (1987) is the most used by pathologists worldwide to diagnose myocarditis.[15] Dallas criteria define 'active myocarditis' as the histological evidence of myocyte damage in a pattern not suggestive of ischemic damage and characterized by mononuclear infiltrates (or sometimes neutrophilic or eosinophilic). The criteria define it as 'borderline myocarditis' if the mononuclear infiltrates are sparse. The absence of either of these changes is classified as 'no myocarditis.' The Dallas criteria carry a sensitivity and specificity of 60% and 80%, respectively. On subsequent biopsies, it further classifies biopsies into 'persistent, healing, or healed myocarditis' and 'with or without fibrosis.  

The WHO endorses a combination of histopathology and immunohistology to classify myocarditis. According to WHO Marbug criteria, in acute (active) myocarditis, there are more than 14 leukocytes per sqm, along with degeneration or necrosis. Chronic myocarditis has more than 14 leukocytes per sqm. However, necrosis or degeneration is usually absent. A leukocyte count of less than 14 per sqm suggests no myocarditis.[5]   

History and Physical

The clinical presentation of acute myocarditis is highly variable, ranging from asymptomatic or mild febrile illness to cardiogenic shock and sudden cardiac death. The presentation is acute or insidious in onset and progression. There are no pathognomonic clinical features.

Patients may present with fever, malaise, fatigue, chest pain, palpitations, dyspnea, orthopnea, presyncope, or syncope. The chest pain of acute myocarditis can mimic the pain of pericarditis (due to myopericarditis in at least 35% of patients) or occasionally be severe central pain mimicking the pain of acute coronary syndrome. In at least 60% of patients, a preceding history of a recent acute febrile illness, including respiratory tract infection, can be elucidated. 

The classic presentation of fulminant acute myocarditis is the same as acute decompensated heart failure of any etiology and includes respiratory distress, orthopnea, chest pain, palpitations, or syncope. There can be a hemodynamic compromise and lethal ventricular arrhythmias. In one study of clinically suspected cases, about a quarter of patients had reduced left ventricular ejection fraction (LVEF), sustained ventricular arrhythmias, or symptoms of low cardiac output.[16]

Physical examination is remarkable in patients with decompensated heart failure and includes S3 gallop, pulmonary rales, and peripheral edema. A frictional pericardial rub may be audible on auscultation in patients with pericardial involvement. Patients with ventricular dilatation may have a pansystolic murmur of mitral regurgitation. 

Patients may also have signs and symptoms of the systemic illnesses causing the myocarditis, such as lymphadenopathy in sarcoidosis, maculopapular rash in eosinophilic myocarditis, or erythema margenatum, chorea, polyarthralgia and subcutaneous nodules in acute rheumatic fever. Patients with Chagas disease (caused by Trypanosoma cruzi) may have associated dysphagia. Neurological symptoms can be found in patients infected with diphtheria. 

Evaluation

Diagnosis of acute myocarditis is challenging because of variable presentation and symptomatic overlap with other clinical entities. Acute myocarditis should be particularly suspected in patients with clinical signs and symptoms of the disease in absence of conventional risk factors for coronary artery disease, especially in young patients. A preceding acute febrile illness or viral prodrome or signs and symptoms of connective tissue disease should lead to the suspicion.[17][18][19]

The following investigations provide a comprehensive diagnosis and evaluation of acute myocarditis:

1. Complete blood picture: leukocytosis or occasionally eosinophilia (in eosinophilic myocarditis).

2. Inflammatory reactants: elevated C-reactive protein (CRP), interleukin, or interferon levels. Elevated erythrocyte sedimentation rate.  

3. Cardiac markers: More than half of patients with biopsy-proven myocarditis have elevated Troponin-I or T levels (good specificity but low sensitivity). An elevated pro-Brain natriuretic peptide may also be found.

4. EKG: often shows nonspecific ST changes; however, it may also show sinus tachycardia, ventricular arrhythmias, or bradyarrhythmia. There may be evidence of intraventricular conduction delay signifying diseased myocardium. Changes may also be suggestive of an acute coronary syndrome. In the presence of pericarditis, there can be diffuse ST elevation. 

5. Chest radiograph: is neither sensitive nor specific for myocarditis but may show an enlarged heart size, pulmonary vascular congestion, pulmonary edema, or pleural effusion. 

6. Echocardiogram: This is a readily available bedside investigation tool to assess myocardial function. It assesses the degree of myocardial damage and denotes the presence of valvular heart diseases or intracardiac thrombus. The ventricle dimensions are usually preserved in patients with fulminant myocarditis, whereas the septal thickness is increased. There is normal septal thickness and increased ventricle dimensions in acute myocarditis. 

7. Cardiac magnetic resonance (CMR): has emerged as a promising tool to evaluate patients with suspected myocarditis. Both T1 and T2 criteria are used in the updated Lake Louis criteria for diagnosing myocarditis.[20] T1 imaging shows increased T1 relaxation time. T2 imaging shows raised T2 relaxation time or Signal Intensity (SI). Gadolinium-enhanced CMR sequences show patchy hyperenhancement of the myocardium. 

8. Coronary angiography: this is the gold-standard test to rule out the presence of coronary artery disease, particularly if the clinical picture mimics acute coronary syndrome. CT coronary angiography (CTCA) may alternatively be used in patients with the absence of conventional contraindications.  

9. Viral antibody titers: are elevated at least four-fold in the acute phase. However, antibody testing is infrequently used. The specificity is low and often can result in a delay in diagnosis without any change in management.

10. Endomyocardial biopsy: Endomyocardial biopsy is the gold standard for diagnosing myocarditis. According to the consensus scientific statement, the class I indication for EMB is evidence of new-onset heart failure with a duration of fewer than two weeks, with preserved ventricle dimensions but compromised hemodynamics. EMB also has a class I indication in patients with new onset heart failure of 2 weeks to 3 months duration, dilated ventricle, evidence of tachyarrhythmia or bradyarrhythmia, and failure to respond to therapy in 1-2 weeks. Other indications include anthracycline toxicity, restrictive cardiomyopathy with no identifiable cause, arrhythmias with no identifiable trigger or cause, etc.[21] EMB has a limited role due to variable sensitivity (depending on the cause), inter-observer variability, high false negative rates, and invasive nature. 

Treatment / Management

General management of acute myocarditis is mainly supportive. The steps of management include the following. 

1. Heart failure management: The overall management of HF encompasses drugs used for managing heart failure due to any cause. The main medications used include beta-blockers, renin-angiotensin-aldosterone (RAAS) inhibitors, mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors), and diuretics. Heart failure (HF) management depends on the severity and hemodynamic status. In patients with acute heart failure, beta-blockers are withheld. Depending on volume status, diuretics are given. In hemodynamically stable patients and left ventricle dysfunction, early initiation of renin-angiotensin-aldosterone inhibitor is recommended. As the hemodynamic and clinical status allows, a beta-blocker is started. In severe cases, mechanical support devices such as an intra-aortic pump or left ventricular assist devices can also be used.[22]
2. Arrhythmia management: Acute myocarditis can be complicated by ventricular or atrial arrhythmias or heart block. For patients with hemodynamically stable tachyarrhythmia and the absence of signs of peripheral hypoperfusion, initiation of a beta-blocker is recommended. Amiodarone and dofetilide may also be used for sustained ventricular arrhythmias. If indicated, heart block is managed with a temporary pacemaker and a permanent pacemaker. An implantable cardioverter defibrillator is indicated in the chronic stage, as per standard recommendations, once the acute illness has settled. 
3. Other agents: Immunosuppressive therapy has not shown clinical benefit and, therefore, should not be used routinely except in patients with underlying systemic autoimmune or granulomatous inflammatory diseases. Although viral etiology is the most identified cause, the efficacy of antiviral therapy is unknown, and routine antiviral treatment is not recommended. Non-steroid anti-inflammatory agents should be avoided in the acute setting as they may impair the healing of the myocardium. Anticoagulation is indicated in patients with evidence of atrial or ventricular thrombus or atrial fibrillation, as per standard recommendations.
4. Exercise limitation: In acute myocarditis, activity restriction is recommended. Patients should not participate in competitive sports for at least three to six months after acute myocarditis.[23] Further recommendation depends on serial follow-up for clinical assessment, echocardiogram, and Holter monitoring.[24][25]
5. Alcohol restriction: Alcohol intake should be restricted to one drink per day (14 to 15 grams).
(B3)

Differential Diagnosis

• Acute coronary syndrome
• Coronary vasospasm
• Stress cardiomyopathy

Prognosis

Given the variable presentation, disease severity, and underlying etiology, the prognosis is also variable. Generally, patients with acute decompensated heart failure, sustained arrhythmias, and a left ventricle ejection fraction of less than 50%, or those requiring inotropes, vasopressors, or mechanical cardiac support, have adverse cardiovascular outcomes.[26] Patients who survive the acute stage have favorable outcomes. At least half of patients develop cardiomyopathy on long-term follow-up. The one-year mortality rate for acute myocarditis is 20%, increasing to 56% on four-year follow-up.[27]

Patients with fulminant myocarditis have a higher mortality rate and a lower transplant-free survival rate.[28] The persistence of the viral genome on subsequent EMB is a poor prognostic factor and determines response to therapy.[29] The prognosis of eosinophilic myocarditis and giant cell myocarditis is generally poor. Those who exhibit the soluble Fas-ligand at presentation tend to have a good prognosis, whereas those who have anti-myosin autoantibodies have a worse outcome.[24][30]

Complications

• Left ventricle dysfunction
• Right ventricle failure
• Arrhythmia
• Death