MyocarditisDept. Cardiology , Fac. of Medicine USUAdam Malik Hospital

BackgroundMyocarditis is collection of diseases of infectious, toxic, and autoimmune etiologies characterized by inflammation of the heart. Subsequent myocardial destruction can lead to dilated cardiomyopathy. Myocarditis is an elusive illness to study, diagnose, and treat because the clinical presentation may range from nearly asymptomatic to overt heart failure requiring transplantation; a myriad of causes exist, and it is occasionally the unrecognized culprit in cases of sudden death.

Pathophysiology (1)Myocarditis is defined as inflammatory changes in the heart muscle and is characterized by myocyte necrosis.Animal models of viral myocarditis have lead to a much greater understanding of the pathophysiology of acute, severe myocarditis and correlate with the findings in susceptible patients who apparently uptake viral RNA and develop a cytotoxic necrosis and rapid (1-2 d) cell death without the appearance of the interstitial infiltrate usually associated with myocarditis.

Pathophysiology (2)

Over 4-14 days, those cells that survive the initial insult, in response to macrophage activation and cytokine expression, develop the classic, histologically apparent infiltration of mononuclear cells. In this subacute viral-clearing phase:Natural killer cells target myocardium expressing viral RNA and continue myocyte necrosis. Tumor necrosis factor is also involved in rapidly clearing virus, but its involvement results in the further recruitment of inflammatory cells, activates endothelial cells, and has negative inotropic effects. In the latter stages of the subacute process, cytotoxic T lymphocytes infiltrate the myocardium and direct lysis of cardiocytes, which present virus fragments via the histocompatibility complex on the surface of myocyte membrane. Neutralizing antiviral antibodies also develop to assist in the clearing of virus.

Pathophysiology (3)In the chronic phases, the deleterious effects of either inadequate or inappropriately abundant immune response can lead to the unfortunate long-term sequelae of dilated cardiomyopathy and heart failure. In animal models of insufficient immune response, viral replication can continue and cause chronic destruction of myocytes. Biopsy results of patients with acute myocarditis who develop dilated cardiomyopathy demonstrate changes consistent with those seen in polymerase chain reaction (PCR) amplifying RNA from enteroviruses. On the opposite spectrum of immune activity, overabundant T cells may continue activity into the chronic phase and also may cause tissue destruction and heart failure.

The pathogenesis of myocarditis.

FrequencyUnited StatesThe true incidence of myocarditis is unknown because many cases are asymptomatic, and some symptoms related to significant morbidity may not be appropriately credited. One major urban US medical examiners office attributed 1.3% of sudden and unexpected deaths to myocarditis1, consistent with other autopsy studies that demonstrate evidence of myocardial inflammation in 1-1.5% of deaths. In the United States, viral and medication-related cases are the most commonly identified causes.InternationalInternationally other etiologies (ie, Chagas disease, diphtheria) play a greater role than in the United States, and true frequency of disease is even more difficult to appreciate.

Mortality/MorbidityBecause of its difficulty in diagnosis, the large number of cases that likely never come to medical attention, and its previously underappreciated role in sudden dysrhythmic death, morbidity and mortality data are difficult to construct. Rarely, acute myocarditis is fulminant and leads rapidly to death. Mortality for clinically significant and biopsy proven myocarditis varies widely. Recent studies have demonstrated death to be as low as 4% of cases for patients without heart failure and with no persistent viral genome expression. On the opposite end of the spectrum, in patients with persistent viral genome expression, myocarditis related mortality may be as high as 25%.The appropriate delicate balance of the immune response to viral invasion of myocytes indicates that a certain number of individuals, perhaps with genetic predispositions, will advance to dilated cardiomyopathy and heart failure, the most common long-term sequelae in those patients who do not recover completely.

Sex and AgeSexThe male-to-female ratio is 1.5:1.AgeThe average age of patients with myocarditis is 42 years. It is a prominent cause of sudden cardiac death in young adults, accounting for 8-12% of such deaths.

History (1)Many patients present with a nonspecific illness characterized by fatigue, mild dyspnea, and myalgias. A few patients present acutely with fulminant congestive heart failure (CHF) secondary to widespread myocardial involvement. Small and focal areas of inflammation in electrically sensitive areas may be the etiology in patients whose initial presentation is sudden death.Most cases of myocarditis are subclinical; therefore, the patient rarely seeks medical attention during acute illness. These subclinical cases may have transient ECG abnormalities.An antecedent viral syndrome is present in more than one half of patients with myocarditis. The appearance of cardiac-specific symptoms occurs primarily in the subacute virus-clearing phase; therefore, patients commonly present 2 weeks after the acute viremia.

History (2)Fever is present in 20% of patients.Other symptoms include fatigue, myalgias and arthralgias, and malaise.Chest painChest discomfort is reported in 35% of patients.The pain is most commonly described as a pleuritic, sharp, stabbing precordial pain.It may be substernal and squeezing and, therefore, difficult to distinguish from that typical of ischemic pain.Dyspnea on exertion is common.

History (3)Orthopnea and shortness of breath at rest may be noted if CHF is present.Palpitations are common. Syncope in a patient with a presentation consistent with myocarditis should be carefully approached because it may signal high-grade atrioventricular (AV) block or risk for sudden death.Pediatric patients, particularly infants, present with nonspecific symptoms, including the following:FeverRespiratory distressPoor feeding or, in cases with CHF, sweating while feedingCyanosis in severe cases

Physical (1)Physical findings can range from nearly normal examination findings to signs of fulminant CHF.Patients with mild cases of myocarditis have a nontoxic appearance and simply may appear to have a viral syndrome.Tachypnea and tachycardia are common. Tachycardia is often out of proportion to fever.More acutely ill patients have signs of circulatory impairment due to left ventricular failure.

Physical (2)A widely inflamed heart shows the classic signs of ventricular dysfunction including the following:Jugular venous distention Bibasilar crackles Ascites Peripheral edema S3 or a summation gallop may be noted with significant biventricular involvement.Intensity of S1 may be diminished.Cyanosis may occur.

Physical (3)Hypotension caused by left ventricular dysfunction is uncommon in the acute setting and indicates a poor prognosis when present.Murmurs of mitral or tricuspid regurgitation may be present due to ventricular dilation.In cases where a dilated cardiomyopathy has developed, signs of peripheral or pulmonary thromboembolism may be found.Diffuse inflammation may develop leading to pericardial effusion, without tamponade, and pericardial and pleural friction rub as the inflammatory process involves surrounding structures.

Causes (1)The causes of myocarditis are numerous and can be roughly divided into:infectious, toxic, and immunologic etiologies, with viral etiologies.

Causes (2)Amongst the infectious causes, viral acute myocarditis is by far the most common.Identification of the coxsackie-adenovirus receptor protein explains the prevalence of these viruses as a frequent cause. The receptor is the common target of coxsackievirus B of the enterovirus family and serotypes 2 and 5 of the adenovirus family.Other viruses implicated in myocarditis include influenza virus, echovirus, herpes simplex virus, varicella-zoster virus, hepatitis, Epstein-Barr virus, and cytomegalovirus. Hepatitis C, in particular, is becoming a major focus of research.Human immunodeficiency virus (HIV) deserves special mention because it seems to function differently than other viruses. Although some evidence indicates that HIV directly invades myocytes, HIV genomes can be amplified from patients without histologic signs of inflammation. In addition, in patients who are infected with HIV, T-cell mediated immune suppression increases the risk of contracting myocarditis due to other infectious causes.

Causes (3)Toxic myocarditis has a number of etiologies including both medical agents and environmental agents.Among the most common drugs that cause hypersensitivity reactions are clozapine, penicillin, ampicillin, hydrochlorothiazide, methyldopa, and sulfonamide drugs. Numerous medications (eg, lithium, doxorubicin, cocaine, numerous catecholamines, acetaminophen) may exert a direct cytotoxic effect on the heart. Zidovudine (AZT) has been associated with myocarditis.Environmental toxins include lead, arsenic, and carbon monoxide. Cases have been attributed to Chinese sumac.Wasp, scorpion, and spider stingsRadiation therapy may cause a myocarditis with the development of a dilated cardiomyopathy.

Causes (4)Immunologic etiologies of myocarditis encompass a number of clinical syndromes and include the following:Connective tissue disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and dermatomyositis that can often result in a dismal prognosisIdiopathic inflammatory and infiltrative disorders such as Kawasaki disease, sarcoidosis, and giant cell arteritis

Lab StudiesCardiac enzyme levelsThese levels are only elevated in a minority of patients.Normally, a characteristic pattern of slow elevation and fall over a period of days occurs; however, a more abrupt rise is observed in patients with acute myocardial infarction.Cardiac troponin I may be more sensitive because it is present for longer periods after myocardial damage from any cause.2Erythrocyte sedimentation rate (ESR) is elevated in 60% of patients with acute myocarditis.Leukocytosis is present in 25% of cases.

Imaging Studies (1)Chest radiographyA chest radiograph often reveals a normal cardiac silhouette, but pericarditis or overt clinical CHF is associated with cardiomegaly.Vascular redistributionInterstitial and alveolar edemaPleural effusion

Myocarditis Infectious/Inflammatory

Imaging Studies (2)EchocardiographyImpairment of left ventricular systolic and diastolic functionSegmental wall motion abnormalitiesImpaired ejection fractionA pericardial effusion may be present, although findings of tamponade are rare.Ventricular thrombus has been identified in 15% of patients studied with echocardiography.

Imaging Studies (3)MRI is capable of showing abnormal signal intensity in the affected myocardium.Cardiac MRI is an emerging field in general, and contrast-enhanced T1- weighted MRI has been shown to have sensitivities and specificities approaching 100% for diagnosis.3MRI can demonstrate nodular and patchy areas of inflammation, often seen first in the lateral and inferior wall and can be used to guide later biopsy.MRI is also one of the modalities used in the evaluation of young patients with apparently idiopathic dysrhythmias, and this imaging study can differentiate focal and diffuse inflammation from the rare electrically significant myocardial tumor.

Other Test (1)Electrocardiography Sinus tachycardia is the most frequent finding.ST-segment elevation without reciprocal depression, particularly when diffuse, is helpful in differentiating myocarditis from acute myocardial infarction.Decreased QRS amplitude and transitory Q-wave development is very suggestive of myocarditis.As many as 20% of patients will have a conduction delay, including Mobitz I, Mobitz II, or complete heart block.Left or right bundle-branch block is observed in approximately 20% of abnormal ECG findings and may persist for months.

Example

Other Test (2)Viral isolation from other body sites may be supportive of the diagnosis.Polymerase chain reaction (PCR) identification of a viral infection from myocardial tissue, pericardial fluid, or other body fluid sites can be helpful. Persistent viral genome, as detected by PCR, has been identified as one marker of increased incidence of dilated cardiomyopathy and mortality.If a systemic disorder (eg, SLE) is suspected, antinuclear antibody (ANA) and other collagen vascular disorder laboratory investigations may be useful.

ProceduresCardiac catheterization usually reveals normal coronary vessels and regional wall motion abnormalities with diminished ejection fraction. It has no benefit over noninvasive echocardiography. Endomyocardial biopsy continues to be of use in diagnosing myocarditis The Dallas criteria, the classic histological criteria required for diagnosis of myocarditis, are no longer broadly accepted due to stated biopsy sample errors, problems with inter-rater reliability, and the identification of alternate patterns of inflammation besides the previously defined lymphocytic infiltrate with myocyte necrosis.4 The use of MRI to target biopsy, immunohistochemical staining, and the ability to identify viral genome by PCR has allowed endomyocardial biopsy to remain a powerful tool. In one study of nearly 900 patients, biopsy altered diagnosis in 21% of patients.

Emergency Department Care (1)Because many cases of myocarditis are not clinically obvious, a high degree of suspicion is required to identify acute myocarditis. Fortunately, most patients have mild symptoms consistent with viral syndromes, and they recover with simple supportive care on an outpatient basis. Standard treatment of clinically significant disease includes the detection of dysrhythmia with cardiac monitoring, supplemental oxygen, and managing fluid status. Left ventricular dysfunction developing from myocarditis should be approached in much the same manner as other causes of CHF with some exceptions (see Medication).

Emergency Department Care (2)In general, sympathomimetic drugs should be avoided because they increase the extent of myocardial necrosis and mortality. Beta-blockers should be avoided in the acutely decompensating phase of illness, but studies that have used carvedilol have shown decreases in the expression of several different histochemicals, subsequent inflammatory myocyte infiltrate, and mortality. Patients who present with Mobitz II or complete heart block require pacemaker placement. Some authors also suggest the placement of automatic implantable cardioverter-defibrillators (AICDs) in patients with significant, persistent decreases in left ventricular (LV) function.

ConsultationsPatients who require emergency room treatment for new-onset CHF, dysrhythmia, or cardiogenic shock should be admitted to the hospital with continuous cardiac monitoring and cardiology consultation.

MedicationMedical therapy for myocarditis is an area of avid research interest but with little success in human trials. Treatment primarily involves managing the complications of myocarditis, chiefly thromboembolism, dysrhythmia, and CHF, and is addressed in detail in the corresponding eMedicine Journal articles; little is specific to myocarditis except for a few specific aspects of the treatment of myocarditis-related CHF.

Drug CategoryAngiotensin converting enzyme inhibitors. Ex. : Captopril (Capoten).Calcium channel blockers. Ex. : Amlodipine (Norvasc).Loop diuretics. Ex. : Furosemide (Lasix).Cardiac glycosides. Ex. : Digoxin (Digitek, Lanoxicaps, Lanoxin)Beta-adrenergic blockers. Ex. : Carvedilol (Coreg)

Further Inpatient Care (1)Patients admitted to the hospital are treated for the complications of myocarditis.The increased use of MRI for targeting biopsy, novel immunohistochemical staining, and PCR for viral genome detection have lead to improved accuracy of the technique of endomyocardial biopsy and have secured its continued place in the evaluation and treatment of patients with suspected myocarditis.Although temporary pacemaker placement for advanced degrees of heart block is indicated, in the setting of myocarditis, these conduction disturbances are usually transitory. Therefore, permanent pacemaker placement usually is not necessary.

Further Inpatient Care (2)Bedrest with restriction of activity and sodium intake is beneficial.Mechanical assist devices and extracorporeal membrane oxygenation are growing in use as bridges to recovery or heart transplant.Patients with fulminant heart failure may require transplantation, which can be life saving. Unfortunately, these patients have a higher rate of rejection than patients whose underlying cause of heart failure is not myocarditis.

Further Outpatient CareThe clinician may consider the placement of a Holter monitor to recognize dysrhythmias on an outpatient basis.This may be undertaken after the initial ED evaluation of a patient who shows no sign of acute dysrhythmia, CHF, or other complication.A Holter monitor may also be placed after the initial inpatient treatment.Upon discharge from the hospital, all patients with myocarditis should have follow-up visits with a cardiologist.Recovered patients should have restricted activity for 6 months because rapid return to activity has provoked recurrent inflammation in animal models.

In/Out Patient MedsTreatment of pain with a narcotic analgesic (eg, acetaminophen with codeine) is appropriate.Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), which are relatively contraindicated in this condition.Other outpatient medications are associated with managing the resultant CHF and are discussed in Medication.

ComplicationsCongestive heart failurePulmonary edema Cardiogenic shock Cardiac failure Dilated cardiomyopathyDysrhythmiasRecurrent myositis

Prognosis (1)Most cases are believed to be clinically silent and resolve spontaneously without sequelae; therefore, making accurate statements concerning the prognosis of myocarditis is difficult.Patients who present with CHF experience morbidity and mortality based on the degree of left ventricular dysfunction.Of patients who present with cardiogenic shock, elderly patients and patients with giant cell arteritis have a poor prognosis.

Prognosis (2)Patients with HIV and persistent viral genome expression from myocytes have dismal outcomes.One half of patients who present with new-onset CHF experience considerable improvement of cardiac function with treatment. One fourth of patients who present with CHF stabilize with compromised cardiac function. The conditions of the remaining one fourth of patients continue to deteriorate.Patients who require transplantation have an increased risk of recurrent myocarditis and graft rejection.

Patient EducationPatients are advised to restrict activity since studies have shown that increased activity promotes progression of inflammation.

Medical/Legal PitfallsMyocarditis may present subtly, but it should be considered in the patient who presents with dyspnea and chest discomfort, particularly if the history includes a recent viral illness.Careful physical examination looking for signs of CHF and pericarditis is helpful. Electrocardiography, ESR, and cardiac enzyme levels are useful screening tools. Patients with evidence of dysrhythmia, CHF, or thromboembolism must be admitted.

Thank you

ReferencesThis 12th edition of Hursts The Hearthttp://www.emedicine.com/emerg/topic326.htmhttp://www.nature.com