Myocarditis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Varun Kumar, M.B.B.S.

Overview

Myocarditis is inflammation of the myocardium. It may present with chest pain, ST segment elevation, elevated biomarkers of myonecrosis, heart failure, and / or sudden death.

Pathophysiology

During either an infection or a hypersensitivity reaction, the inflammatory response may cause myonecrosis either directly or indirectly as part of an autoimmune reaction. Myocarditis is a continuum of three phases of the disease processes with each one evolving into the next:

Phase I: Viral Infection and Replication

Viruses such as coxsackie and enterovirus, get internalized in peripheral tissues and activate the immune system. A few of these viral genomes attach to the immunologic cells which circulate throughout the body and lodge in other organs such as the heart where they further replicate and cause localized tissue destruction.

Phase II: Autoimmune Injury

After the host immune system eliminates the viral genomes from the body, the immune system may remains activated in patients who develop myocarditis. This leads to the development of an autoimmune reaction where T-cells and cytokines target the host tissue such as the myocardium which causes further myocyte damage.

Phase III: Dilated Cardiomyopathy

Cytokines, which are produced in reaction to infection and cell death, are a leading cause of dilated cardiomyopathy. Matrix metalloproteinases, such as gelatinase, collagenases, and elastases may also be activated by cytokines during the autoimmune phase. Protease produced by coxsackie virus can also modify the sarcoglycan complex in myocytes leading to ventricular dilation.

Eosinophilic and hypersensitive myocarditis may occur secondary to parasitic infections, drug hypersensitivity or hypereosinophilic syndrome. Eosinophilic infiltration in myocardium lead to release of eosinophilic proteins which increase cellular membrane permeability which in turn leads to cell death.

Epidemiology and Demographics

In developed countries, myocarditis is generally due to viral infections such as coxsackie B, enterovirus,adenovirus, parvovirus B19, hepatitis C, and herpes virus 6. In developing countries, myocarditis is generally due to HIV and rheumatic heart disease. In routine autopsies, 1-9% of all patients had evidence of myocardial inflammation. In young adults, up to 20% of all cases of sudden death are due to myocarditis. There is a male predominance.

Natural History, Complications & Prognosis

Myocarditis is usually self limiting and is associated with a good prognosis especially if it is secondary to a viral infection. Patients rarely develop cardiac failure, pulmonary edema, arrhythmias or cardiogenic shock. In some instances, myocarditis may be associated with sudden death. Patients with fulminant myocarditis have a good long term prognosis if they survive the acute phase of the disease . The prognosis of fulminant myocarditis is better than that of either acute myocarditis or giant cell myocarditis.

The presence of left bundle branch block, q waves, AV block, syncope and a left ventricular ejection fraction < 40% are associated with sudden death and cardiac transplantation.

Clinicopathological classification

• Fulminant myocarditis - Fulminant myocarditis occurs following a viral prodrome. Fulminant myocarditis presents as acute severe cardiovascular compromise with ventricular dysfunction. The prognosis is good if the patient survives the acute illness. On endomyocardial biopsy, there are multiple focci of inflammation. Fulminant myocarditis is associated with a non-dilated hypocontractile left ventricle with thick interventricular septum while acute myocarditis (see below) is associated with a dilated hypocontractile left ventricle with normal interventricular septum.

• Acute myocarditis - Acute myocarditis presents with a less distinct onset of the illness. When the patient does present, there is already a decline in left ventricular dysfunction. Acute myocarditis may progress to dilated cardiomyopathy.

• Chronic active myocarditis Chronic active myocarditis has a less distinct onset of the illness. There are clinical and histologic relapses and the development of ventricular dysfunction. Histologically, chronic inflammatory changes with mild to moderate fibrosis may be present.

• Chronic persistent myocarditis - Chronic persistent myocarditis has a less distinct onset ff the illness. Histologically it is characterized by persistent infiltration and myocyte necrosis. Despite the presence of symptoms, ventricular dysfunction is absent.

Differential Diagnosis of the Underlying Causes of Myocarditis

(By organ system)

Cardiovascular	Acute rheumatic fever, Dressler syndrome
Chemical / poisoning	Arsenic, Carbon monoxide, Lead
Dermatologic	Scleroderma, Systemic lupus erythematosus
Drug Side Effect	Drugs are known to cause hypersensitive myocarditis. Peripheral eosinophilia and eosinophilic myocardial infiltrates may be seen on myocardial biopsy. Some of the common drugs are: Amphetamines, Benzodiazepines, Carbamazepine, Chloramphenicol, Clozapine, Cocaine, Cyclophosphamide, Dobutamine, Methyldopa, Penicillin, Phenytoin, Spironolactone, Streptomycin, Sulfonamides, Tricyclic antidepressants.
Ear Nose Throat	No underlying causes
Endocrine	Thyrotoxicosis
Environmental	Heatstroke, Scorpion stings, snake bites, bites from black widow spider, wasp venom, tick paralysis
Gastroenterologic	Celiac disease, Crohn disease, Ulcerative colitis
Genetic	Haemochromatosis, Friedreich ataxia
Hematologic	No underlying causes
Iatrogenic	Inflammatory myocarditis may be seen in post transplant rejection.
Infectious Disease	Viral: The idiopathic myocarditis is the most common type of myocarditis and is often suspected to be secondary to viral infection. Common virus associated with myocarditis are- Adenovirus, Arbovirus, Coxsackie B, Cytomegalovirus, Echovirus, Enterovirus, Epstein-Barr virus, Herpes simplex virus, Hepatitis B, Hepatitis C, HIV-1, Influenza, Mumps, Parvovirus B19, Poliomyelitis, Rabies, Respiratory syncytial virus, Rubeola, Varicella, Variola/vaccinia, Viral hepatitis, Yellow fever virus Bacterial: Borrelia burgdorferi, Brucellosis, Clostridia, Diphtheria, Melioidosis, Meningococci, Mycoplasma pneumoniae, Psittacosis, Salmonella typhi, Staphylococci, Streptococci, Tuberculosis Fungal: Actinomycosis, Aspergillosis, Blastomycosis, Candidiasis, Coccidioidomycosis, Cryptococcosis, Histoplasmosis, Mucormycosis Parasitic: Balantidiasis, Chagas disease, Cysticercosis, Echinococcosis, Filariasis, Heterophyiasis, Leishmaniasis, Malaria, Sarcosporidiosis, Schistosomiasis, Toxoplasmosis, Trichinosis, Trypanosomiasis, Visceral larva migrans Rickettsial: Q fever, Rocky mountain spotted fever, Scrub typhus, Typhus fever Spirochetal: leptospirosis/Weil disease, Lyme disease, relapsing fever/Borrelia, Syphilis
Musculoskeletal / Ortho	Rheumatoid arthritis
Neurologic	Friedreich ataxia
Nutritional / Metabolic	Amyloidosis, Haemochromatosis
Obstetric/Gynecologic	Peripartum cardiomyopathy
Oncologic	No underlying causes
Opthalmologic	No underlying causes
Overdose / Toxicity	Doxorubicin, Radiation exposure
Psychiatric	No underlying causes
Pulmonary	Aspergillosis, Sarcoidosis
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	Crohn disease, Dressler syndrome, Giant cell myocarditis, Kawasaki disease, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Systemic lupus erythematosus, Thyrotoxicosis, Ulcerative colitis, Wegener granulomatosis
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	Amyloidosis, Heatstroke, Hyperthermia, Radiation exposure

Diagnosis

Symptoms

The symptoms and the intensity of symptoms associated with myocarditis are variable. Myocarditis may be associated with no symptoms. If symptoms are present,they may be similar to the flu. Patients may present with chest pain as a result of the inflammatory process involving the myocardium or with symptoms of congestive heart failure. Patients may complain of palpitations, a racing heart or syncope. In fulminant myocarditis, patients present with the abrupt onset of flu-like symptoms and the abrupt onset of heart failure symptoms. In chronic and acute myocarditis, the onset of symptoms may be more insidious. Symptoms may include:

• Palpitations
• Chest pain
• Fatigue
• Fever and other signs of infection including headache, muscle aches, sore throat, diarrhea, or rashes
• Joint pain or swelling
• Pedal edema
• Shortness of breath
• Fainting, often related to irregular heart rhythms
• Low urine output

Physical examination

Physical examination in patients with myocarditis may reveal tachycardia, a cardiac gallop, mitral regurgitation and pulmonary edema suggestive of cardiac failure. A pericardial friction rub may be noted in presence of concomitant pericarditis, a condition sometimes referred to as myopericarditis.

Electrocardiographic Findings

The ECG findings in myocarditis are similar to those in pericarditis and myocardial infarction. Myocarditis should be suspected in patients who are at low risk for ischemic heart disease and MI and in those patients with normal coronary arteries on coronary angiography.

The ECG findings most commonly seen in myocarditis are:

• Sinus tachycardia
• Diffuse T wave inversions
• ST segment elevation without reciprocal depression. This helps in differentiating myocarditis from infarction particularly when EKG changes are diffuse.
• Low voltage of the QRS complexes may be observed.
• Arrhythmias such as atrial and ventricular ectopic beats, atrial and ventricular tachycardias and atrial fibrillation may also be present and are common in Chagas heart disease.
• Heart block is frequently observed in giant cell myocarditis and cardiac sarcoidosis.

These EKG changes may persist for several months before they resolve spontaneously.

The presence of ST segment elevation in patients with myocarditis can mimic pericarditis and myocardial infarction. Arrhythmias and heart blocks may also be observed in myocarditis patients. Myocarditis can be distinguished from pericarditis by the presence of PR depression in the patient with pericarditis.

Echocardiography

Echocardiography in patients with myocarditis allows for serial assessment of left ventricular dysfunction, and can be used to distinguish fulminant (non-dilated hypocontractile left ventricle with thick interventricular septum) from acute myocarditis (dilated hypocontractile left ventricle with normal interventricular septum).

Echocardiographic findings in myocardits include:

• Wall motion abnormalities.
• Systolic dysfunction.
• Diastolic dysfunction.
• Changes in image texture on echocardiogram, i.e. increase in brightness, heterogeneity, and contrast.
• Pericardial effusion
• Functional regurgitation through the AV valves may be noted due to ventricular dilation.

In general, left ventricular function improves in fulminant myocarditis over a course of approximately 6 months.

Endomyocardial Biopsy

Endomyocardial biopsy remains the gold standard test to evaluate for the presence of and to subclassify the type of myocarditis. A small tissue sample of the endocardium and myocardium is obtained via right sided cardiac catheterization. The sample is then evaluated by a pathologist using immunochemistry and special staining techniques as necessary. Histopathological features include abundant edema in the myocardial interstitium and an inflammatory infiltrate which is rich in lymphocytes and macrophages. Focal destruction of myocytes as a result of the inflammatory process results in left ventricular dysfunction. Endomyocardial biopsy is recommended when the results would identify an underlying disease that is amenable to therapy. Routine performance of endomyocardial biopsy is not recommended in all patients with myocarditis.

2009 ACC / AHA Guidelines for Endomyocardial Biopsy

“

Class IIa Endomyocardial biopsy can be useful in patients presenting with heart failure when a specific diagnosis is suspected that would influence therapy. (Level of Evidence: C) Class III Endomyocardial biopsy should not be performed in the routine evaluation of patients with heart failure. (Level of Evidence: C)

”

The AHA/ACCF/ESC Scientific Statement: The role of Endomyocardial Biopsy in fourteen clinical scenarios

“

Class I 1. New-onset heart failure of <2 weeks’ duration associated with a normal-sized or dilated left ventricle and hemodynamic compromise. (Level of Evidence: B) 2. New-onset heart failure of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual care within 1 to 2 weeks. (Level of Evidence: B) Class IIa 1. Heart failure of >3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual care within 1 to 2 weeks. (Level of Evidence: C) 2. Heart failure associated with a DCM of any duration associated with suspected allergic reaction and/or eosinophilia. (Level of Evidence: C) 3. Heart failure associated with suspected anthracycline cardiomyopathy. (Level of Evidence: C) 4. Heart failure associated with unexplained restrictive cardiomyopathy. (Level of Evidence: C) 5. Suspected cardiac tumors. (Level of Evidence: C) 6. Unexplained cardiomyopathy in children. (Level of Evidence: C) Class IIb 1. New-onset heart failure of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle, without new ventricular arrhythmias or second- or third-degree heart block, that responds to usual care within 1 to 2 weeks. (Level of Evidence: B) 2. Heart failure of >3 months’ duration associated with a dilated left ventricle, without new ventricular arrhythmias or second- or third-degree heart block, that responds to usual care within 1 to 2 weeks. (Level of Evidence: C) 3. Heart failure associated with unexplained HCM. (Level of Evidence: C) 4. Suspected ARVD/C. (Level of Evidence: C) 5. Unexplained ventricular arrhythmias. (Level of Evidence: C) Class III 1. Unexplained atrial fibrillation. (Level of Evidence: C)

”

Complications of Endomyocardial Biopsy

Complications may be as high as 6% as observed in a series where 546 patients with cardiomyopathy underwent right ventricular endomyocardial biopsy. Several other studies reported the incidence of complications to be 0.5 to 1.5%.

• Myocardial perforation leading to pericardial tamponade
• Heart block
• Pulmonary embolization
• Pneumothorax
• Nerve injury
• Hematoma
• Tricuspid valve damage
• Arteriovenous fistula
• Deep venous thrombosis
• Bleeding at the puncture site (venous/arterial due to accidental arterial puncture)
• Arrhythmias (supraventricular tachycardia/ventricular tachycardia/complete heart block)
• Tricuspid valve damage
• Coronary artery to right ventricle fistula

Coronary Angiography

Coronary angiography may be helpful in excluding either myocardial ischemia or infarction as the cause of ST segment elevation, elevated cardiac biomarkers, or left ventricular dysfunction.

Cardiac Magnetic Resonance Imaging

Cardiac MRI findings associated with myocarditis include myocardial inflammation, myocardial edema, capillary leak, and reduced left ventricular function. While the cMRI pattern of gadolinium hyperenhancement in ST segment elevation myocardial infarction is transmural and extends from the endocardium to the epicardium, the patchy, non-segmental hyperenhancement pattern in myocarditis in contrast involves the epicardium and spares the subendocardium.

Laboratory Findings

Myocardial inflammation can be suspected on the basis of the clinical history along with elevations of:

• Biomarkers of myocardial damage such as troponin or creatine kinase
• Antibodies against viruses known to affect the myocardium and cause myocarditis
• ESR
• C-reactive protein
• Auto antibodies such as ANA and rheumatoid factor

Differentiating Myocarditis from Pericarditis and Myocardial Infarction

Myocarditis presents with chest pain and ST segment elevation. Myocarditis must be distinguished from pericarditis and the life threatening condition of ST elevation myocardial infarction.

Differentiating Myocarditis from ST Segment Elevation Myocardial Infarction

Both diseases present with chest pain, elevated cardiac biomarkers, and focal left ventricular dysfunction. There are two studies that can be used to distinguish the two syndromes:

Coronary Angiography

Coronary angiography can be performed to distinguish myocarditis from ST segment elevation myocardial infarction. ST segment elevation myocardial infarction is associated with either complete or subtotal occlusion of an epicardial coronary artery on coronary angiography.

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging is also useful in distinguishing between the two syndromes as well. On cardiac MRI, myocarditis is associated with patchy, non-sentimental, hyperenhancement which is confined to the epicardial layer of the myocardium. In contrast, in ST segment elevation myocardial infarction there is confluent hyperenhancement extending from the endocardium in a distribution that mimics the distribution of the epicardial coronary arteries.

Differentiating Myocarditis from Pericarditis

Both diseases present with chest pain and ST segment elevation. The two conditions can be distinguished by the following studies:

Electrocardiogram

While both disorders are associated with ST segment elevation, pericarditis is also associated with PR segment depression.

Cardiac Biomarkers

Myocarditis is associated with elevations of the CK-MB and the troponin, while pericarditis is not. If pericarditis is associated with underlying inflammation of the myocardium, then this is called myopericarditis. If there is concomitant involvement of both the pericardium and myocardium in myopericarditis, then there are elevations of the cardiac biomarkers.

Echocardiography

In patients with myocarditis there will be a focal wall motion abnormalities, while these will be absent in the patient with pericarditis.

Treatment

Bacterial infections are treated with antibiotics, dependent on the nature of the pathogen and its sensitivity to antibiotics. As most viral infections cannot be treated with directed therapy, symptomatic treatment is the only form of therapy for those forms of myocarditis, e.g. diuretics and/or inotropes for ventricular failure. ACE inhibitor therapy may aid in left ventricular remodeling after the inflammation has begun to resolve.

According to 2010 HFSA guidelines, routine use of immunosuppressive therapies in management of myocarditis is not recommended (Strength of Evidence A). Immunotherapy is beneficial in giant cell myocarditis. Other alternative therapy in severe myocarditis is transplantation.