Viral Myocarditis

Etiology

Myocarditis is thought to be caused by various infectious and noninfectious causes. Among the infectious causes, viruses are presumed to be the most common pathogen. In North America and Europe, the most frequently implicated viruses are parvovirus B-19 and human herpesvirus 6 (HHV 6), followed by Epstein-Barr virus, enterovirus, human cytomegalovirus, and adenovirus. Other pathogens that have been implicated include various bacteria, fungi, protozoa, and helminths. Multiple case reports of COVID-19 and influenza-associated myocarditis have recently been reported in the medical literature. Other common noninfectious causes of myocarditis include autoimmune disorders such as systemic lupus erythematosus, Wegener granulomatosis, and giant cell arteritis. In some patients, viral particles may be found in biopsy specimens. In almost 50% to 80% of cases, no cause is ever found.

Damage to the myocardium occurs in the following ways:

• Direct damage by the offending agent
• Secondary immune response triggered by the offending agent
• Expression of cytokines in the myocardium, which leads to an inflammatory process 
• Premature or aberrant induction of apoptosis

Epidemiology

The incidence of myocarditis is approximately 1.5 million cases worldwide annually, and the overall incidence is unknown and probably underdiagnosed. In the United States, the frequency of myocarditis is difficult to ascertain as many cases are subclinical. In community-based populations, the prevalence and outcomes of myocarditis are unknown as epidemiologic studies suggest that most Coxsackie B virus infections, a significant cause of myocarditis, are subclinical, thus following a benign course.

According to some estimates, 1% to 5% of all patients with acute viral infections may involve the myocardium. Most patients are young and healthy. Susceptible individuals include children, pregnant women, and those who are immunocompromised.

COVID-19 and Myocarditis

The true epidemiology of COVID-19–associated cardiac diseases is difficult to establish. In a study by Shi S et al, cardiac injury was reported in 19% to 28% of COVID-19 patients in Wuhan, China, and was found to be associated with worse patient outcomes.[4]  In a Global health research network retrospective cohort study, 5% of COVID-19 patients had new onset myocarditis, and 6 months of all-cause mortality was 3.9%.[5] Patients with COVID-19 have a 16 times increased risk of myocarditis compared without COVID-19. The diagnosis of COVID-19 myocarditis is proportional to increased hospitalizations from COVID-19 infection in 2020 to 2021.[6] The incidence of myocarditis after COVID-19 mRNA vaccinations is extremely low at 0.3 to 5 cases per 100,000 in the USA and Israel, mostly in young men within a week after the second dose, with a self-limiting course.[7][8] The incidence of myocarditis associated with COVID-19 infection is 100 times higher than the mRNA vaccination.[9]

Pathophysiology

Myocarditis begins with the direct invasion of an infectious agent and its subsequent replication within or around the myocardium, causing myonecrosis leading to the destruction of the cardiac tissue from the infiltration and replication of the infectious agent.[10][11]

Later, the host cellular immune response and the offending agent activate the cytotoxic effects of host immunity. Persistence of the virus in the myocardium is associated with progressive deterioration of heart muscle function, ie, left ventricle. Marked improvement in heart function is seen once the viral genome is eliminated.[12] Exogenous or endogenous chemicals produced by the systemic pathogen might induce a toxic effect directly on the myocyte.

Three stages of the disease process are listed below.

• Acute stage (1-7 days): Defined by direct viral cytotoxicity and focal or diffuse necrosis of the myocardium with subsequent exposure to host proteins and activation of the innate immune response. Adenovirus and enterovirus cause direct cell toxicity, whereas parvovirus infests endothelium and releases pro-inflammatory cytokines. Influenza causes T-cell–regulated inflammatory response. 
• Subacute stage (1-4 weeks): An increase in autoimmune-mediated injury with activated T cells and B cells and subsequent antibody production, creating cardiac autoantibodies and inflammatory proteins. There are higher concentrations of anti-b-myosin antibodies in patients with myocarditis with dilated cardiomyopathy than in control groups.
• Recovery or chronic: Depends on the presence or elimination of the viral genome in the myocyte. Chronic T-cell–mediated inflammation results in remodeling and diffuse myocardial fibrosis, affecting cardiac dysfunction and leading to dilated cardiomyopathy and its sequelae, such as CHF, ventricular dysrhythmias, and abnormal ECG findings. Th17 cells are believed to play a significant role in this chronic phase of myocarditis.[13]

The chronicity of viral myocarditis depends on the favorable host genetic background based on a study by Artico et al, where 31% of patients are carriers of pathogenic genes like titin, filamin C, and desmoplakin.[14] Further knowledge of micro RNAs (miRNA) as immune response regulators in the subacute and chronic phases might shed more light on patients with persistent and progressive cardiac dysfunction.[15]

COVID-19 and Myocarditis

The exact pathophysiology mechanism of COVID-19 infection and myocarditis needs to be better established. The direct role of angiotensin-converting enzyme-2 receptors and hyperimmune response are plausible theories causing myocarditis with COVID-19.[16] COVID-19 mRNA vaccines are also associated with acute myocarditis, and the etiology is unknown. The role of mRNA immune reactivity, antibodies to SARS-CoV-2 spike proteins, and hormonal differences (ie, immune response) might be the most likely explanation.[17]

Histopathology

Endomyocardial biopsy is typically recommended after other causes of heart failure, such as ischemic heart disease, valvular lesions, and other causes of cardiomyopathy, have been excluded. Endomyocardial biopsy is recommended should the likelihood of the results change management or impact prognosis.

Classic histologic examination of an endomyocardial biopsy will reveal cellular infiltrates, usually histiocytic and mononuclear, with or without associated myocyte damage. Specific findings include eosinophilic, granulomatous, and giant-cell myocarditis. The infiltrates are highly variable and often associated with varying degrees of myonecrosis. With subacute and chronic myocarditis, interstitial fibrosis may result from the previous insult of the myocardial cytoskeleton.

Toxicokinetics

Toxic drug-induced myocarditis is a term used to describe myocarditis caused by illicit drugs or drugs used as part of chronic medical management. Many drugs, including but not limited to cocaine, phenothiazines, alcohol, tricyclic antidepressants, and lithium, are known to cause myocarditis over time. Frequently, toxic myocarditis will run an insidious course, resulting in CHF and dilated cardiomyopathy, often irreversible.Post-mortem examinations have revealed that cocaine abusers often display myocarditis. The cause of this condition is not entirely clear, but it is thought to be linked to the drug's strong sympathomimetic effect, high levels of oxidative stress, and how metabolites interact with ion channels. Myocarditis may be responsible for structural alterations predisposing the patient to ventricular dysrhythmias associated with sudden deaths.

History and Physical

Viral myocarditis is typically seen in young males with varied clinical presentations. Patients typically present with a 7- to 14-day history of mild flulike illness, including fever, malaise, myalgia, vomiting, and diarrhea. Rarely do they have debilitating symptoms like dyspnea at rest, palpitations, and sudden cardiac death.

• Adults typically present with chest pain (95%), dyspnea (45%), fatigue, syncope, palpitations, fever (18-35%), tachycardia, and tachypnea. Hypotension may be seen. The presence of chest pain or CHF symptoms often indicates a poor prognosis.
• Children often present with grunting respirations and intercostal retractions. Infants often present with fulminant syndrome, including fever, hypoxia with cyanosis, respiratory distress or failure, and occasionally cardiac arrest. Much like adults, long-term prognosis correlates with the severity of their initial presentation.

The 2013 European Society of Cardiology classified acute myocarditis into 3 profiles.[3]

1. Acute coronary syndrome-like presentation, including chest pain, ST/T wave changes on electrocardiogram (ECG), troponin elevation, and wall motion abnormalities
2. New onset progressive heart failure, which includes impaired left and right ventricular dysfunction, nonspecific ECG changes, heart blocks, or arrhythmias
3. Severe life-threatening fulminant conditions, such as cardiogenic shock requiring vasopressors, mechanical life support, and ventricular arrhythmias requiring defibrillation 

Patients with fulminant myocarditis have a higher rate of cardiac death and often require heart transplants within 5 years.

The physical examination findings are similar to CHF and may include an S3 gallop, rales, tachycardia, and dependent edema. 

Special cases of myocarditis include the following:

• Sarcoid myocarditis presents with heart block and associated lymphadenopathy.
• Giant cell myocarditis presents with ventricular tachycardia and heart failure.
• Acute rheumatic fever presents with chorea, erythema marginatum, polyarthritis, and subcutaneous nodules.

Evaluation

Most patients will present with nonspecific ECG findings like sinus tachycardia, wide QRS patterns, low voltage, prolonged QT, variable atrioventricular (AV) blocks, and acute myocardial infarction patterns.[18]

The stage of the disease process in which cardiac markers like troponin may be elevated is unclear. Elevated troponin levels may suggest more damage to the heart muscle, indicating myonecrosis. However, negative levels do not necessarily rule out the possibility of this diagnosis. Tests to determine complete blood count (CBC), erythrocyte sedimentation rate (ESR), and c-reactive protein (CRP) levels are recommended. Elevated white blood cell and CRP levels or faster ESR might occur but are inconclusive for diagnosing the condition.[19]

Viral antibody titers should also be ordered, including coxsackievirus group B, HIV, CMV, Epstein-Barr virus, hepatitis, and influenza viruses. IgM titers typically increase 4-fold during the acute phase, with a gradual fall as the disease progresses; therefore, serial titers may be helpful.[20]

Transthoracic echocardiogram (TTE) is usually the first imaging modality of choice in suspected myocarditis, specifically in unstable patients where cardiac MRI cannot be performed. However, TTE has limited diagnostic accuracy because myocarditis does not have specific echocardiographic findings. The most common finding includes preserved left ventricular ejection fraction (LVEF) without regional wall motion abnormalities. It may show nonspecific findings such as reduced left ventricular function, global hypokinesis, and regional wall motion abnormalities. When the left ventricle appears globally hypokinetic but not dilated and demonstrates increased wall thickness and echogenicity (edema), and right ventricular dysfunction is observed, it may indicate the presence of fulminant myocarditis.

Two-dimensional speckle-tracking echocardiography is a diagnostic and prognostic tool for patients with suspected viral myocarditis.[21] Additionally, real-time myocardial contrast echocardiography can offer further insight into the ventricles' inflammatory process, although its sensitivity and specificity have yet to be determined.[22][21] Scintigraphy with Indium-111 labeled antimyosin antibodies can localize and visualize dead myocardial tissue areas by highlighting the intracellular proteins because of loss of cell membrane integrity.[23] 

Cardiac MRI is the best noninvasive imaging modality for both diagnosis and follow-up. The diagnosis of myocarditis through cardiac MRI relies on the Lake Louise Criteria, initially released in 2009 and later revised in 2018. The original Lake Louise Criteria (2009) proposed a clinical cardiac MRI protocol for evaluating the principal tissue targets in myocarditis, including:

• Myocardial edema - increased T₂ weighted signal intensity 
• Hyperemia and capillary leak - early gadolinium enhancement (EGE)
• Myocyte necrosis and fibrosis - late gadolinium enhancement (LGE)

Supportive criteria include associated impairment of global or regional systolic left ventricular function and pericardial effusion. The presence of 2 of the 3 criteria supports the diagnosis of myocarditis with 74% sensitivity and 86% specificity.[24]

In the subsequent decade, significant advancements in cardiac MRI technology enabled high-resolution and clinically applicable quantitative T1-and T2-mapping techniques. These are particularly sensitive in detecting significant increases in myocardial free water content, hence their utility in detecting myocarditis. Accordingly, the Lake Louise Criteria were updated in 2018 to include parametric mapping.

According to the revised Lake Louise Criteria 2018, in the setting of clinically suspected acute myocarditis, cardiac MRI findings are consistent with myocardial inflammation if both T₁- and T₂-based criteria are present, as follows:

• T2-based imaging: regional or global increase in myocardial T2 signal, either on T2-weighted imaging or T2-mapping
• T1-based imaging: regional or global increase in myocardial T1-signal, either on native myocardial T1-mapping, extracellular volume (ECV) quantification, or LGE imaging in a predominantly non-ischemic pattern

Supportive criteria include:

• The presence of pericardial effusion in cine cardiac MRI images or high signal intensity of the pericardium in LGE images, T1 mapping or T2 mapping
• The presence of systolic left ventricular wall motion abnormality in cine cardiac MRI images

Most cases of acute myocarditis have normal LVEF with no wall motion abnormalities. Myocardial tissue characterization is crucial for diagnosis; therefore, MRI is of immense value. In patients with contraindications to cardiac MRI, a PET scan using 18F-fluoro-2-deoxyglucose can be used, although it may be nonspecific.[25]

Endomyocardial biopsy, considered the gold standard for diagnosis, is rarely utilized. Endomyocardial biopsy has limited sensitivity and specificity, as inflammation across the myocardium may be diffuse or focal in myocarditis. More importantly, histologic diagnosis rarely has an impact on therapeutic approaches. However, according to 2020 expert consensus, biopsy should be performed if a patient's condition is deteriorating. Other indications for endomyocardial biopsy are severe heart failure, high-degree AV block, cardiogenic shock, suspected inflammatory cardiomyopathy, and idiopathic causes. The Heart Failure Society of America does recommend a myocardial biopsy.[26] An endomyocardial biopsy within 2 weeks of symptom onset with the collection of 4 to 6 specimens for the best yield is recommended. Cardiac catheterization may be required in some patients to rule out coronary artery disease.

Treatment / Management

For the most part, treatment of myocarditis is supportive and aimed at preserving left ventricular function. Treatments range from activity limitation to rhythm control and CHF management. Due to the lack of large multicenter randomized control trials, treatment recommendations for myocarditis are primarily based on expert consensus. Any patient suspected of having myocarditis, whether they are symptomatic or not, should be admitted to the hospital. The patient should be monitored for arrhythmias and signs of decompensation. A transthoracic echocardiogram should be obtained. Patients experiencing chest pain upon admission should be considered for a coronary CT angiogram or cardiac catheterization.

Along with providing supportive care, patients who present with heart failure and ventricular dysfunction should be treated according to current heart failure guidelines. Patients with heart failure often require diuretics and inotropic support. Long-term treatment with ACE inhibitors is recommended. Avoid cardiotoxic drugs and NSAIDs, as they can hinder the healing of the myocardium and exacerbate the inflammatory process. Some patients may require anticoagulation. The use of antiarrhythmics requires good clinical judgment, as many of these agents also have negative inotropic effects that may worsen heart failure. The use of aspirin is uncertain when it comes to acute myocarditis. Beta-blockers should be avoided in patients with heart blocks. Patients with a heart block may need a temporary pacemaker, while a permanent pacemaker is recommended if symptoms persist and the patient is ready to be discharged home.[27] (B3)

Physical activity should be limited during the acute phase of the disease. Exercise or nuclear stress testing should be avoided with acute symptoms. Intra-aortic balloon pump counterpulsation, Impella system, and veno-arterial extracorporeal oxygenation should be considered in patients with cardiogenic shock refractory to medical therapy.

Multicenter trials evaluating antivirals and immunosuppressive therapies, such as IVIG, have shown no benefit. Management of chronic viral myocarditis is similar to current heart failure guidelines. Viral myocarditis was initially thought to be fully reversible, but recent literature proves this may not be true. The prognosis of patients with myocarditis depends on the severity of the inflammatory process and the presentation of symptoms. Patients with severe disease and life-threatening arrhythmias have a poor prognosis and will likely require a mechanical assist device.[28] In this case, they will need to be considered for cardiac transplantation, but this is only an option if a suitable donor is found.(B2)

European guidelines suggest waiting for the resolution of the acute phase before implantation of an automatic implantable cardioverter defibrillator (AICD). Still, more recent data from the Lombardy registry and a study by Rosier et al. showed that the patients presenting with ventricular tachyarrhythmia in the acute phase of myocarditis who have received AICD implantation early for secondary prophylaxis had a high risk of recurrence for major arrhythmic events over a follow-up of 3 years.[29][30] On the other hand, patients presenting with sustained ventricular tachycardia or ventricular fibrillation will benefit from AICD implantation during the acute phase at discharge from the hospital for secondary prophylaxis. Patients with LVEF of less than or equal to 35% with acute myocarditis should be discharged with a wearable cardiac defibrillator for primary prophylaxis and optimal medical therapy and then reevaluated at 3 months for AICD implantation.[31] Professional athletes with an AICD should have it programmed for higher rate cutoffs and duration detection to help reduce inappropriate shocks during physical activity.[32] 

Patients with mild symptoms do improve spontaneously, but recovery can take months. Repeat assessment with echocardiograms is necessary. Patients who continue to do poorly should be referred to a tertiary care center where assist devices and transplant services are available.

Differential Diagnosis

The following conditions must be ruled out when diagnosing of myocarditis.

• Carnitine deficiency

• Coarctation of the aorta

• Coronary artery anomalies

• Cardiac tumor

• Dilated cardiomyopathy

• Endocardial fibroelastosis

• Enteroviral infections

• Genetics of von Gierke disease

• Genetics of glycogen-storage disease type II

• Medial necrosis of coronary arteries

• Nonviral myocarditis

• Shock

• Valvar aortic stenosis

• Viral pericarditis

Prognosis

Patients with mild myocarditis usually have a good prognosis. Poor prognostic factors include low ejection fraction, left bundle branch block, and syncope. The patients may also develop varying degrees of heart block and require permanent pacing. Cardiogenic shock is the most common cause of death, with the highest mortality rates in postpartum cardiomyopathy.

Cardiac MRI is an effective tool for predicting adverse events and diagnosing viral myocarditis. LGE on cardiac MRI within 5 days of the patient's presentation was strongly associated with poor outcomes, including sudden cardiac death, sustained ventricular tachycardia, hospitalization, and transplantation, even in those with a normal LVEF.[33] On cardiac MRI at 6-month follow-up, the finding of LGE without edema favors definitive fibrosis, indicating a poorer prognosis.[34] Evaluating left ventricular global longitudinal strain through speckle tracking echocardiography and cardiac MRI has a prognostic value. In cases of myocarditis, a decrease in this strain predicts a higher risk of experiencing nonsustained ventricular tachycardia in the future. The presence of LGE with decreased global longitudinal strain portends a poor prognosis, whereas the absence of LGE with increased global longitudinal strain suggests a favorable prognosis.[35]

Patients with acute fulminant myocarditis have an excellent long-term prognosis if the disease is recognized quickly and appropriate supportive care is initiated early. In one study, a survival rate of 93% at 11 years was demonstrated. The long-term prognosis of those with less severe disease was generally good, with a 3- to 5-year survival rate of 56% to 83%.

Complications

Excessive physical activity during acute myocarditis may increase the risk of sudden cardiac death. Professional athletes should refrain from competitive events for at least 3 to 6 months from the onset of myocarditis, regardless of the severity of symptoms, age, and sex. Before resuming participation in competitive sports, a complete evaluation and functional testing should be performed.

Life-threatening arrhythmias should be treated appropriately with AICD. The most likely mechanism for arrhythmias in acute myocarditis includes pathogen-mediated cell lysis, inflammatory changes, increased edema, cytokine release, gap junction dysfunction, and abnormal calcium handling secondary to iron channel impairment. Chronic myocarditis can also pose a risk for arrhythmias secondary to ongoing chronic inflammation, scar formation, and ventricular dysfunction.