Myocarditis

Acute myocarditis is inflammation of the myocardium with associated necrosis or degeneration, or both - it is typically seen in young patients but can occur at any age. It most commonly results from a viral illness but can also be due to non-infectious etiologies. The disease is also known as inflammatory cardiomyopathy (or myocarditis with cardiac dysfunction in the WHO 1995 classification for cardiomyopathy).

It has a very variable clinical presentation, so the diagnosis is frequently missed. The initial clinical presentation includes febrile illness, mild chest pain, arrhythmias, heart failure, cardiogenic shock or death. The clinical diagnosis is often challenging, and the management if usually supportive - it is a significant source of morbidity and mortality.

The clinicopathologic classification of myocarditis is revelant but not widely used:

1. Fulminant myocarditis - 17% : Indistinct onset. Results in complete, spontaneous resolution or rapid deterioration and death due to cardiac compromise. Multiple active foci of inflammatory infiltrate that completely resolve

2. Acute myocarditis - 65% : Indistinct onset, with moderate cardiovascular compromise and incomplete recovery, often resulting in cardiac dysfunction or subsequent death. Active or borderline inflammatory infiltrates that resolve completely over time.

3. Chronic active myocarditis - 11% : Presents similar to acute, but the chronic form usually progresses to only mild or moderate cardiac dysfunction with restrictive physiology. Histological examination shows ongoing fibrosis.

4. Chronic persistent myocarditis - 7%: Indistinct onset, with nonresolving active or borderline inflammatory infiltrates. There is no cardiovascular compromise.

Etiology

The causes of acute myocarditis are broadly classified into infectious and non-infectious causes. In 50% of cases, the myocarditis is idiopathic. The most implicated etiology in patients with an identified cause is a viral infection.

Coxsackie (specifically, coxsackie group B) and echoviruses are the most common cardiotropic viruses causing myocarditis. It may cause direct cardiotoxic injuries, cytokine activation and cytoskeletal damage, and autoimmune response. Data suggests the incidence of myocarditis after infection is lower than previously projected. Viral myocarditis is considered when accompanied by a clinical picture of recent febrile illness, often with prominent myalgias, followed by rapid onset of cardiac symptoms. Many cases of idiopathic dilated cardiomyopathies have been attributed to antecedent viral myocarditis. Antiviral therapies have not proven to be useful.

Chagas disease is a cardiomyopathy caused by Trypanosoma cruzi in South and Central America, particularly in persons aged 30 to 50 years. It is estimated that 16-18 million persons are infected with T.cruzi in Latin America. Cardiac involvement usually appears after initial treatment, and is the leading cause of death of persons aged 30 to 50 years in the endemic areas.

HIV is an important cause of dilated cardiomyopathy, with a 1.6% incidence. HIV type 1 virions appear to infect myocardial cells in patchy distributions, leading to cytokine activation and progressive tissue damage. Cardiac autoimmunity, nutritional deficiencies and drug toxicity (mitochondrial damage from zidovudine and vasculitis/coronary artery disease from HARRTs may contribute). EBV, coxsackie and cytomegalovirus has been isolated from endomyocardial biopsy of HIV-positive patients with myocarditis - suggesting that opportunistic viral infections may play an important role in the pathogenesis of this type of cardiomyopathy.

GCM (pernicious myocarditis, Fiedler myocarditis, granulomatous myocarditis or interstitial myocarditis) is a rare disorder with an unclear origin - the hallmark is the presence of fused, multinucleated (>20 nuclei) epithelioid giant cells within a diffuse, intramyocardial inflammatory infiltrate with lymphocytes.

Hypersensitive reactions (eosinophilic myocarditis), is part of Loeffler endomyocardial fibrosis, occurs as a major complication of idiopathic hypereosinophilic syndrome as a result of direct toxic damage caused by eosinophil granule proteins within the heart. Drug-induced eosinophilic myocarditis is independent of cumulative dose and duration of therapy. Collagen vascular diseases may also lead to eosinophilic myocarditis. In systemic autoimmune disorders with myocarditis, the histologic appearance of myocarditis occurring as part of SLE, sarcoidosis or polymyositis is similar to that seen in isolated myocarditis. Nonetheless, the natural history is different - systemic causes of myocarditis often respond poorly to medical therapy and cardiac transplantation. Their prognoses are often unfavourable. However, small retrospective surveys and case series have identified a significant decrease in mortality and improved clinical course among cardiac sarcoid patients treated with corticosteroids and other immunosuppressive strategies.

Pathophysiology

Acute myocarditis is an inflammatory cardiomyopathy - the inflammatory process in infectious causes is initiated after the entry of the virus into myocardial cells. This entry leads to 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 remodelling of the myocardium leads to myocardial dilation and cardiomyopathy.

The cell damage caused leads to the release of interleukin and damage-associated molecular patterns (DAMP). These mediate the recruitment of inflammatory cells of the innate immune system. Any stress, such as pain or anxiety, triggers the medullary cells for monocytopoiesis. There is a release of myeloid progenitor cells, and the spleen is activated to replenish the pro-inflammatory cells. These pro-inflammatory cells mobile 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 remodelling and ventricular dysfunction.

Morphology and Histopathology

The Dallas classification (1986) is used for myocarditis:

1. Initial biopsy

   1. Myocarditis: Myocardial necrosis or degeneration, or both, in the absence of significant CAD with adjacent inflammatory infiltrates or fibrosis, or both

   2. Borderline myocarditis: Inflammatory infiltration too sparse or myocyte damage not apparent.

   3. No myocarditis: No inflammatory infiltration or myocyte damage

2. Subsequent biopsy

   1. Ongoing (persistent) myocarditis or fibrosis, or both

   2. Resolving (healing) myocarditis or fibrosis, or both

   3. Resolved (healed) myocarditis or fibrosis, or both

There is also the World Health Organisation Marbug Criteria (1996):

• A minimum of 14 infiltrating leukocytes per mm, preferably T-lymphocytes, and up to four macrophages may be included.

Presentation and History

Myocarditis can be totally asymptomatic or can manifest with chest pain syndromes ranging from mild persistent chest pain of acute myopericarditis (35% of cases) to severe symptoms that mimic acute myocardial infarction. Due to this presence of acute myopericarditis in 35% of cases, it may mimic the pain of pericarditis. Chest pain associated with coronary artery vasospasm may rarely occur in patients with myocarditis. Alternatively, chest pain may be more typical for pericarditis, suggesting pericardial involvement. 60% of patients have antecedent arthralgias, malaise, fever, sweats or chills consistent with viral infections 1 to 2 weeks before onset.

The hallmark symptoms are those of heart failure - dyspnea, fatigue, reduced exercise tolerance and edema. This is a classic presentation of a fulminant acute myocarditis. However, diffuse, severe myocarditis can progress rapidly and result in acute myocardial failure and cardiogenic shock. In some instances, patients may present with arrhythmia in the form of syncope, palpitations caused by heart block (Stokes-Adams attack), ventricular tachyarrhythmia, or even sudden cardiac death. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias. Palpitations secondary to premature atrial or ventricular extrasystoles are common. In one study of clinically suspected cases, about a quarter of patients have reduced left ventricular ejection fraction (LVEF), sustained ventricular arrhythmias and symptoms of low cardiac output.

Patients who present with signs of signs of acute decompensated heart failure, examination is remarkable. A S3 gallop, pulmonary rales, raised JVP and peripheral oedema may be seen. 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.

In patients with a non-infectious cause, there will be specific findings in special cases:

1. Sarcoid myocarditis : Lymphadenopathy, also with arrythmias, and sarcoid involvement in other organs (up to 70%)

2. Acute Rheumatic Fever (Affects the heart in 50% to 90% of cases): Associated signs such as erythema marginatum, polyarthralgia, chorea and subcutaneous nodules (Jones criteria)

3. Hypersensitive or eosinophilic myocarditis: Pruritic maculopapular rash and history of onset temporally related to initiation of potential culprit medications

4. Giant cell myocarditis (GCM): Sustained ventricular tachycardia in rapidly progressive heart failure

5. Peripartum cardiomyopathy: Heart failure developed in the last month or pregnancy or within 5 months of delivery

Investigations and diagnosis

Diagnosis of acute myocarditis is challenging due to 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 CAD. A preceding acute febrile illness or viral prodrome or signs and symptoms of connective tissue disease should lead to the suspicion of acute myocarditis.

An ECG should be done all patients with cardiac pain or a suspected cardiac disease. The ECG often shows sinus tachycardia, although the presence of nonspecific ST-segment and T-wave abnormalities may represent focal or global ischemia. The changes in ECG are suggestive of an acute MI and may include ST-segment elevation. Pericarditis can accompany myocarditis and is often manifested in pericarditis like changes seen on ECG. The sensitivity of ECG for myocarditis is low (47%). In some cases, fascicular block or AV conduction disturbances and ventricular tachyarrhythmia may be hemodynamically significant.

Bloods

• Full blood count (FBC) : Leukocytosis is common (often lymphocytic) although the presence of eosinophils may suggest hypersensitive eosinophilic myocarditis

• CRP/ESR : Elevated acute phase reactants are good monitors of clinical progression or response to therapy, but they have low specificity for myocarditis. Novel inflammatory markers under investigation include TNF-a, interleukins, interferon-gamma, serum-soluble Fas, and soluble Fas ligand levels. Elevation of these markers confer a worse prognosis.

• Cardiac markers: More than half of patients with biopsy-proven myocarditis have elevated Troponin I levels; it has a good specificity but a low sensitivity. An elevated proBNP may also be found. Creatinine kinase (myoglobin subfraction) is elevated in only 7.5% of patients with biopsy-proven myocarditis.

• Serum viral antibody titers: Usually increased fourfold or more acutely and gradually fall during convalescence (recovery). However, measurement of antibody titers is rarely indicated.

• We may consider rheumatological screening if it is indicated:

  • SLE : anti-dsDNA (reported positive anti-Ro/SSA and anti-La/SSB in lupus carditis in children

  • Polymyositis: anti-Jo₁

  • Wegener granulomatosis: c-ANCA (antineutrophil cytoplasmic antibody)

  • Scleroderma: anti-Scl₇₀

Imaging

• Echocardiogram: A complete echo is standard procedure for patients with suspected myocarditis in order to exclude alternative causes, detect the presence of intracardiac thrombi and associated valvular disease, and quantify the degree of left ventricular (LV) dysfunction to monitor response to therapy. It also helps identify focal wall motion abnormalities and presence of pericardial fluid.

  • Fulminant myocarditis is often characterised by near-normal diastolic dimensions and increased septal wall thickness, whereas acute myocarditis often has increased diastolic dimensions but normal septal wall thickness.

  • In a series of 23 patients with biopsy-proven myocarditis, significant reduction in right ventricular function was a powerful predictor of death or the need for cardiac transplantation.

• Gadolinium-enhanced magnetic resonance imaging (MRI) is being used more frequently for diagnosis based on several small observational studies that have found up to 100% sensitivity and specificity depending on the protocol. In one study, MRI was also used for guiding biopsy to areas of focal increased uptake of gadolinium in patients with clinically suspected myocarditis with significantly higher diagnostic yield compared with those who did not have enhancing areas with which to guide the bioptome.

• Coronary angiography may be indicated to rule out coronary artery disease as the cause of new-onset heart failure especially if there are focal wall motion abnormalities and localising electrocardiographic changes.

A endomyocardial biopsy (EMB) is the gold standard for diagnosing myocarditis. According to the consensual scientific opinion, the class I indication for EMB is evidence of new-onset heart failure with a duration of fewer than two weeks, with persevered ventricular 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 with dilated ventricle, evidence of tachyarrhythmia or bradyarrhythmia and failure to respond to therapy in 1 to 2 weeks. Other indications include anthracycline toxicity, restrictive cardiomyopathy with no identifiable trigger or cause. EMB has limited roles due to variable sensitivity, inter-observer variability, high false negative rates and the invasive nature.

Management and treatment

All patients should be managed with fluids and supportive care. The care of myocarditis is mostly supportive with control of symptoms.

Heart failure management

Standard heart failure therapy (according to guidelines - European society of Cardiology) consists of diuretics, ACE-inhibitors, B-blockers and aldosterone antagonists. Studies have not been done to determine when and how to discontinue standard heart failure therapy in patients who recover LV function. Digoxin should be avoided due to its proarrhythmic properties in animal models (At toxic levels, digoxin is proarrhythmic. An impaired ventricle is more prone to ventricular tachyarrhythmias and ectopy). MRA and SGLT-2 can also be used to manage heart failure. In patients who are hemodynamically unstable, beta-blockers should not be used until stable. In severe cases, mechanical support devices such as an intra-aortic pump or left ventricular assist device may be used. Extracorporeal membrane oxygenation may also be used.

Early consideration for cardiac transplantation should be given, especially for patients with progressive, biopsy-proven GCM or peripartum cardiomyopathy. However, patients with myocarditis have increased rates of rejection and reduced survival after heart transplantation compared with those without myocarditis, and recurrent disease may affect the allograft.

Arrhythmia management

Antiarrhythmics provide first-line treatment using standard therapy such as B-blockers, amiodarone and sotalol. ICDs are used for patients stabilized in the chronic phase with persistently low ejection fraction for those with malignant arrhythmias that are refractory to treatment. Permanent pacemakers may be used for heart block or bradyarrhythmias.

Exercise limitations

In patients with acute myocarditis, activity restriction is recommended. Patients should not participate in competitive sports for 3-6 months after acute myocarditis. Further recommendation depends on serial follow-up for clinical assessment, echocardiogram and Holter monitoring.

Other agents

There are no established benefits for antiviral regimens or NSAIDs. The most recent guidance do not recommend routine use of immunosuppressive agents in myocarditis - more work is needed to identify patient cohorts who will benefit from tailored antiviral and immunosuppressive therapy.

Anticoagulation is indicated in patients with evidence of atrial or ventricular thrombus or atrial fibrillation.

Prognosis

Adults may present with heart failure after the initial event of myocarditis - up to 12.8% of patients with idiopathic dilated cardiomyopathy has presumed prior myocarditis in one case series. The outlook is poor in the acute phase regardless of classification or cause. The 1-year mortality rate was reported as 20%, and the 4-year 56% in one study. Up to one half of patients with myocarditis develop subsequent cardiomyopathy over a range of 3 months to 13 years.

Unfavourable factors for survival include extremes of ages, ECG abnormalities, syncope and specific diagnosis (etc GCM). Favourable factors include normal ventricular function, shorter clinical history and fulminant presentation at onset.

Clinical follow up should be close as there is a risk of persistent chronic inflammation, which may lead to dilated cardiomyopathy. 1 to 3 month intervals should be used for drug and exercise titrations. Serial echocardiograms are required for ventricular structure and function, although there is no agreement regarding the frequency of echocardiographic assessment after myocarditis.