WORKUP	Section 5 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab Studies:

• CBC count - Leukocytosis (may demonstrate eosinophilia)

• Elevated erythrocyte sedimentation rate (and other acute phase reactants such as C-reactive protein)

• Rheumatologic screening - To rule out systemic inflammatory diseases

• Elevated cardiac enzymes (creatine kinase or cardiac troponins)

• These are an indicator for cardiac myonecrosis. Cardiac troponin (troponin I or T), in particular, is elevated in at least 50% of patients with biopsy-proven myocarditis.

• The test has 89% specificity and 34% sensitivity and increases more frequently than creatine kinase MB subunits (elevated in only 5.7% of patients with biopsy-proven myocarditis).

• Giant cell myocarditis - Associated with increased tissue cytokine levels that decrease with immunosuppressive treatment

• Serum viral antibody titers for viral myocarditis

• Titers increase 4-fold or more with gradual fall during convalescence (nonspecific).

• This test is rarely indicated, however, in the diagnosis of viral myocarditis or any dilated cardiomyopathies, owing to its low specificity and the delay of rising viral titers, which would have no impact on therapeutic decisions.

Imaging Studies:

• Echocardiography: This is performed to exclude other causes of heart failure (eg, valvular, amyloidosis, congenital) and to evaluate the degree of cardiac dysfunction (usually diffuse hypokinesis and diastolic dysfunction). It also may allow gross localization of the extent of inflammation (ie, wall motion abnormalities, wall thickening, pericardial effusion). In addition, echocardiography may distinguish between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis (versus increased left ventricular diastolic dimensions and normal septal thickness in acute myocarditis), with marked improvement in systolic function in time.

• Antimyosin scintigraphy (using antimyosin antibody injections): Antimyosin scintigraphy can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28-33%).

• Gallium scanning: This technique is used to reflect severe myocardial cellular infiltration and has a good negative predictive value, although specificity is low.

• Gadolinium-enhanced MRI: This imaging technique is used for assessment of the extent of inflammation, although it is still nonspecific and investigational.

• Cardiac angiography often is indicated to rule out coronary ischemia as a cause of new-onset heart failure, especially when clinical presentation mimics acute myocardial infarction. It usually shows high filling pressures and reduced cardiac outputs.

Other Tests:

• Electrocardiogram - Often nonspecific (eg, sinus tachycardia, nonspecific ST or T-wave changes)

• Occasionally, heart block (atrioventricular block or intraventricular conduction delay), ventricular arrhythmia, or injury patterns with ST- or T-wave changes mimicking myocardial ischemia or pericarditis (pseudoinfarction pattern) may indicate poorer prognosis.

• Arrhythmia is common in Chagas heart disease. The following may be seen: right bundle-branch block with or without bifascicular block (50%), complete heart block (7-8%), atrial fibrillation (7-10%), and ventricular arrhythmia (39%).

Procedures:

• Right ventricular endomyocardial biopsy (EMB): This is the criterion standard for diagnosis of myocarditis, although it still has limited sensitivity and specificity, as inflammation can be diffuse or focal. Routine EMB in establishing diagnosis of myocarditis rarely is helpful clinically, however, since histologic diagnosis seldom has an impact on therapeutic strategies, unless giant cell myocarditis is suspected.

• Because of sampling technique, sensitivity may increase with multiple biopsies (50% for 1 biopsy, 90% for 7 biopsies). The standard is to obtain at least 4 or 5 biopsies, although false-negative rates still may be as high as 55%.

• False-positive rates are also high, owing to small numbers of normally occurring lymphocytes in the myocardium and the difficulty in distinguishing between lymphocytes and other cells (such as eosinophils in hypersensitive/eosinophilic myocarditis).

• Wide interobserver variability in histologic interpretations is also a factor.

• Noncaseating granulomas for sarcoid myocarditis are found in only 5% of cases by biopsies, and in as many as 27% in autopsy series.

• Persisting viral mRNA can be found in only 25-50% of patients with biopsy-proven acute myocarditis, and persistent viral mRNA often confers a poor prognosis. Recent epidemiological results from the European Study on the Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) database found that only 11.8% of patients with suspected acute or chronic myocarditis and reduced ejection fractions had detectable viral genomes in biopsy samples.

Histologic Findings: Biopsy specimens from EMB should reveal the simultaneous findings of lymphocyte infiltration and myocyte necrosis.

Staging: The Dallas classification (1987) and the World Health Organization (WHO) Marburg classification (1996) are commonly used.

• Cell types - Lymphocytic, eosinophilic, neutrophilic, giant cell, granulomatous, or mixed

• Amount - None (grade 0), mild (grade 1), moderate (grade 2), or severe (grade 3)

• Distribution - Focal (outside vessel lumen), confluent, diffuse, or reparative (in fibrotic areas)

• Dallas classification (1987)

• Initial biopsy
  • Myocarditis - Myocardial necrosis, degeneration, or both, in the absence of significant coronary artery disease with adjacent inflammatory infiltrate with or without fibrosis

  • Borderline myocarditis - Inflammatory infiltrate too sparse or myocyte damage not apparent

  • No myocarditis

• Subsequent biopsy
  • Ongoing (persistent) myocarditis with or without fibrosis

  • Resolving (healing) myocarditis with or without fibrosis

  • Resolved (healed) myocarditis with or without fibrosis

• WHO Marburg criteria (1996) defines myocarditis as a minimum of 14 infiltrating leukocytes/mm², preferably T cells (CD45RO), with as many as 4 macrophages possibly included.

	TREATMENT	Section 6 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical Care: Treatment of myocarditis includes supportive therapy for symptoms of acute heart failure with use of diuretics, nitrates/sodium nitroprusside, and angiotensin-converting enzyme (ACE) inhibitors (see Pulmonary Edema, Cardiogenic). Inotropic drugs (eg, dobutamine, milrinone) may be necessary for severe decompensation, although they are highly arrhythmogenic. Long-term treatment follows the same medical regimen, including ACE inhibitors, beta-blockers, and aldosterone receptor antagonists. However, in some instances, some of these drugs cannot be implemented initially because of hemodynamic instability.

• Withdrawal of the offending agent is called for, if applicable (eg, cardiotoxic drugs, alcohol). Treat underlying infectious or systemic inflammatory etiology. Nonsteroidal anti-inflammatory agents should be avoided in the acute phase, as their use may impede myocardial healing and actually exacerbate the inflammatory process and increase the risk of mortality.

• Anticoagulation may be advisable as a preventive measure, as in other causes of heart failure, although no definitive evidence is available.

• Antiarrhythmics can be used cautiously, although most antiarrhythmic drugs have negative inotropic effects that may aggravate heart failure.

• Supraventricular arrhythmias should be converted electrically.

• High-grade ventricular ectopy and ventricular tachyarrhythmia should be treated cautiously with beta-blockers and antiarrhythmics.

• Patients are usually very sensitive to digoxin and should use it with caution and in low doses. (Digoxin increases expression of proinflammatory cytokines and mortality rate in animal models.)

• Complete heart block is an indication for temporary transvenous pacing.

• Implantable defibrillators rarely are indicated in lymphocytic myocarditis unless extensive scarring has occurred.

• This condition carries a low threshold for ventilatory and circulatory support (such as intra-aortic balloon pump) because of the rapidly progressive course of decompensation and the potential for reversal.

• Immunosuppression has not been demonstrated to change the natural history of infectious myocarditis. Three large-scale prospective clinical trials on immunosuppressive strategies have been performed in patients with myocarditis, none of which showed significant benefits (National Institutes of Health [NIH] prednisone trial, Myocarditis Treatment Trial, and Intervention in Myocarditis and Acute Cardiomyopathy [IMAC] trial). Empirical treatment with immunosuppression for systemic autoimmune disease, especially in giant cell myocarditis and sarcoid myocarditis, is often given based on evidence from small series.

• No benefit has been established for the use of antiviral agents, although some small series have demonstrated their efficacy (the efficacy of interferon-alpha will be evaluated in the ongoing ESETCID).

Surgical Care:

• Left ventricular assistive devices (LVADs) and extracorporeal membrane oxygenation (ECMO) may be indicated for short-term circulatory support if needed for cardiogenic shock.

• Cardiac transplantation

• Survival rates have not been shown to be decreased in patients with acute myocarditis, although retrospective observations have been made that more posttransplant acute rejections and subsequent posttransplant vasculopathy may occur in these patients.

• Transplantation has been shown to be particularly beneficial to those with biopsy-proven giant cell myocarditis; the 5-year survival rate after transplantation was 71%, despite a 25% incidence of posttransplantation recurrence, as seen in 9 of 34 patients in the Multicenter Giant Cell Myocarditis study.

Consultations:

• Cardiothoracic surgery

• Infectious disease and/or rheumatology consultations

Diet: Low-sodium diet similar to that of heart failure management

Activity: Bedrest and avoidance of athletic activities are recommended from anecdotal experiences (with lower incidence of arrhythmia).

	MEDICATION	Section 7 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

In general, treatment of both acute and chronic myocarditis is aimed at reducing congestion and improving cardiac hemodynamics in heart failure, as well as providing supportive therapy with the hopes of prolonging survival (see Treatment). Treatment of heart failure follows the same treatment regimen regardless of the underlying cause (ie, ACE inhibitors, beta-adrenergic blockers).

Intensive immunosuppressive therapy (eg, corticosteroids, azathioprine, cyclosporine, muromonab-CD3/OKT3) has been shown to have some benefit only in small-scale clinical studies in treatment of giant cell myocarditis and has not been validated in large clinical trials. At this time, immunosuppressive therapy is not recommended for myocarditis until clear evidence is available from the results of multicenter trials.

Drug Category: Vasodilators -- Reduce systemic vascular resistance, allowing more forward flow and improving cardiac output. This in turn improves myocardial oxygen supply, resulting in dilatation of epicardial and collateral vessels, improving blood supply to the ischemic myocardium.

Drug Name	Nitroglycerin (Tridil, Nitro-Bid IV) -- DOC for patients who are not hypotensive. Provides excellent and reliable preload reduction. Higher doses provide mild afterload reduction. Has rapid onset and offset (both within minutes), allowing for rapid clinical effects and rapid discontinuation of effects in adverse reactions.
Adult Dose	Mild-to-moderately severe respiratory distress: 1-2 inches topically if good skin perfusion; not effective in peripheral vessel vasoconstriction resulting from shock Moderate-to-severe respiratory distress: 0.3-0.4 mg SL q3-5min Severe distress: 10-20 mcg/min IV, titrate 5- to 10-mcg increments q5min as BP tolerates
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypotension; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage
Interactions	Sildenafil (Viagra) taken within 24 h may induce precipitous decreases in BP; aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in right ventricular infarction or severe aortic stenosis because of importance of maintaining adequate preload in maintaining cardiac output

Drug Name	Sodium nitroprusside (Nitropress) -- Considered an afterload reducer. Potent direct smooth muscle–relaxing agent that results primarily in afterload reduction but can cause mild preload reduction. Produces improved cardiac output but also can cause precipitous decreases in BP. Intra-arterial BP monitoring strongly recommended. Excellent medication in critically ill patients because of rapid onset and offset of action (within 1-2 min). Excellent for use in cardiogenic pulmonary edema associated with relative hypertension in myocarditis.
Adult Dose	0.1-0.3 mcg/kg/min continuous IV infusion initial, titrate q5-10min; not to exceed 5-10 mcg/kg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe aortic stenosis or idiopathic hypertrophic subaortic stenosis
Interactions	Not established in short-term (<24 h) use for stabilization; combined use with other vasodilators may induce significant decreases in BP (continuous hemodynamic monitoring by arterial line is imperative)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can result in precipitous decreases in BP; coat drug reservoir and tubing with opaque material (eg, aluminum foil) to protect against light sensitivity; adverse effects may include thiocyanate toxicity (symptoms include headache, nausea, vomiting); monitor thiocyanate levels in prolonged use (24 h or 6-12 h in renal failure); fetal cyanide toxicity is concern in prolonged use during pregnancy, convert to oral vasodilator once condition stable

Drug Category: ACE inhibitors -- Following stabilization of heart failure symptoms, initiation of ACE inhibitors is the standard of care to delay disease progression in heart failure. Beta-adrenergic antagonists should be used only following resolution of congestive symptoms and clinical stabilization of the patient's condition.

Drug Name	Enalapril (Vasotec) -- Competitive inhibitor of angiotensin-converting enzymes. Reduces angiotensin II levels, causing decrease in aldosterone secretion.
Adult Dose	1.25 mg IV q6h 2.5-20 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, pregnancy; renal insufficiency; history of angioedema or ACE inhibitor allergy; hypotension
Interactions	NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; diuretics may enhance hypotensive effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment, severe aortic stenosis, or severe congestive symptoms in heart failure; may cause hypotension

Drug Category: Diuretics -- Reduce preload. The initial drop in cardiac output produced by diuresis causes a compensatory increase in peripheral vascular resistance. With continuing diuretic therapy, the extracellular fluid volume and plasma volume return almost to pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline.

Drug Name	Furosemide (Lasix) -- Most commonly used loop diuretic. Increases excretion of water by interfering with chloride-binding cotransport system, resulting in inhibition of sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Reduces preload through diuresis in 20-60 min. May contribute to more rapid preload reduction through direct vasoactive mechanism, but this is controversial. As many as half of all patients with cardiogenic pulmonary edema (CPE) are total-body euvolemic. Generally administered to all patients with CPE but probably is most useful in patients with total-body fluid overload. PO form has slower onset of action, and therefore, generally not considered appropriate for treating these patients.
Adult Dose	1 mg/kg or 40-80 mg IV push; in severe cases may be given in continuous IV drip format, starting 10-20 mg/h IV gtt
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; aminoglycosides increase risk of auditory toxicity—hearing loss of varying degrees may occur; may increase anticoagulant activity of warfarin; may increase plasma levels and toxicity of lithium
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patients with anuria will not produce urine in response to furosemide; some clinicians believe acute use of furosemide in these patients is appropriate because of direct vasoactive effect; perform frequent serum electrolyte, bicarbonate, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

	FOLLOW-UP	Section 8 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Outpatient Care:

• Ongoing chronic inflammation may cause dilated cardiomyopathy and subsequent heart failure. Patients with a history of myocarditis should be monitored at intervals of 1-3 months initially, with gradual return of physical activity.

Deterrence/Prevention:

• Vaccination should reduce the incidence of myocarditis caused by measles, rubella, mumps, poliomyelitis, and influenza. Development of vaccines for other cardiotropic viruses may prevent viral myocarditis in the future.

Complications:

• Cardiogenic shock may occur in fulminant cases of myocarditis.

• Severe heart block requiring permanent pacemaker placement occurred in 1% of patients in the Myocarditis Treatment trial.

Prognosis:

• Patients who have survived fulminant myocarditis have a good prognosis. In a study of 147 cases of myocarditis monitored for an average of 5.6 years, 93% of the 15 patients with fulminant disease were alive without transplant 11 years after biopsy, compared with 45% of the 132 patients with less severe disease. Left ventricular dilation was not as severe in the fulminant cases as in the nonfulminant ones.

• Expression of soluble Fas and Fas ligands at initial presentation appears to be a good serologic marker to predict the prognosis of acute myocarditis, while antimyosin autoantibodies are associated with development of worse cardiac dysfunction in chronic myocarditis.

• Predictors of death or need for heart transplantation after acute myocarditis in multivariate analyses include syncope, low ejection fraction, and left bundle-branch block, all indicators of advanced cardiomyopathy.

	MISCELLANEOUS	Section 9 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

• High clinical suspicion of acute myocarditis is required for young and otherwise healthy individuals who develop heart failure with a rapid deteriorating course.

• Young patients presenting with cardiogenic shock with classic ECG changes of myocardial infarction but febrile may suffer from pseudomyocardial infarction, which is consistent with myocarditis. These people certainly need cardiac catheterization to rule out ischemic causes, despite the possibility of myocarditis.

• Close follow-up care is needed for patients who survive acute myocarditis, despite full initial recovery, as persistent chronic inflammation may lead to subsequent dilated cardiomyopathy and heart failure.

• Giant cell myocarditis has a more aggressive course and may require prompt surgical support (LVAD, transplant).

	BIBLIOGRAPHY	Section 10 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

• Aretz HT, Billingham ME, Edwards WD, et al: Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol 1987 Jan; 1(1): 3-14[Medline].
• Badorff C, Knowlton KU: Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside. Med Microbiol Immunol (Berl) 2004 May; 193(2-3): 121-6[Medline].
• Bowles NE, Towbin JA: Molecular aspects of myocarditis. Curr Opin Cardiol 1998 May; 13(3): 179-84[Medline].
• Cooper LT Jr, Berry GJ, Shabetai R: Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 1997 Jun 26; 336(26): 1860-6[Medline].
• D'Ambrosio A, Patti G, Manzoli A, et al: The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review. Heart 2001 May; 85(5): 499-504[Medline].
• Dec GW Jr, Palacios IF, Fallon JT, et al: Active myocarditis in the spectrum of acute dilated cardiomyopathies. Clinical features, histologic correlates, and clinical outcome. N Engl J Med 1985 Apr 4; 312(14): 885-90[Medline].
• Feldman AM, McNamara D: Myocarditis. N Engl J Med 2000 Nov 9; 343(19): 1388-98[Medline].
• Frustaci A, Chimenti C, Calabrese F, et al: Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 2003 Feb 18; 107(6): 857-63[Medline].
• Fuse K, Kodama M, Okura Y, et al: Predictors of disease course in patients with acute myocarditis. Circulation 2000 Dec 5; 102(23): 2829-35[Medline].
• Hufnagel G, Pankuweit S, Richter A, et al: The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID). First epidemiological results. Herz 2000 May; 25(3): 279-85[Medline].
• Karjalainen J, Heikkila J: Incidence of three presentations of acute myocarditis in young men in military service. A 20-year experience. Eur Heart J 1999 Aug; 20(15): 1120-5[Medline].
• Kawai C: From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 1999 Mar 2; 99(8): 1091-100[Medline].
• Kuhl U, Pauschinger M, Noutsias M, et al: High prevalence of viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular dysfunction. Circulation 2005 Feb 22; 111(7): 887-93[Medline].
• Lauer B, Schannwell M, Kuhl U, et al: Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis. J Am Coll Cardiol 2000 Jan; 35(1): 11-8[Medline].
• Mason JW, O'Connell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 1995 Aug 3; 333(5): 269-75[Medline].
• McCarthy RE 3rd, Boehmer JP, Hruban RH, et al: Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000 Mar 9; 342(10): 690-5[Medline].
• McNamara DM, Starling RC, Dec GW: Intervention in myocarditis and acute cardiomyopathy with immune globulin: results from the randomized placebo controlled IMAC trial. Circulation 1999; 100(suppl): I-21.
• Oakley CM: Myocarditis, pericarditis and other pericardial diseases. Heart 2000 Oct; 84(4): 449-54[Medline].
• Parrillo JE, Cunnion RE, Epstein SE, et al: A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989 Oct 19; 321(16): 1061-8[Medline].
• Pulerwitz TC, Cappola TP, Felker GM, et al: Mortality in primary and secondary myocarditis. Am Heart J 2004 Apr; 147(4): 746-50[Medline].
• Rosenstein ED, Zucker MJ, Kramer N: Giant cell myocarditis: most fatal of autoimmune diseases. Semin Arthritis Rheum 2000 Aug; 30(1): 1-16[Medline].
• Wakafuji S, Okada R: Twenty year autopsy statistics of myocarditis incidence in Japan. Jpn Circ J 1986; 50: 1288-1293[Medline].

Myocarditis excerpt