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A. Disease Descriptionnavigator

  1. Inflammation of cardiac myocytes
  2. Usually leads to myocyte cell death and reduced cardiac function
  3. Variety of inflammation triggers
  4. Epidemiology
    1. Asympatomic disease in most cases, making early identification difficult
    2. Responsible for 10-25% of cases of progressive severe congestive heart failure (CHF)
    3. Autopsy series show ~5% of persons have myocardial inflammation
  5. Outcomes
    1. Full recovery (over months) in many patients
    2. Apparent recovery in short term, followed by latent period and subclinical progression
    3. Rapid progression to CHF with development of dilative cardiomyopathy
    4. Myocarditis associated with sudden death in young adults in 20% of cases [3]
  6. Definitive diagnostis requires myocardial biopsy

B. Etiology navigator

  1. Idiopathic
    1. Lymphocytic Type (most common)
    2. Giant Cell Type (uncommon; possibly related to sarcoidosis)
  2. Infectious [2]
    1. Viral: CMV, Coxsackievirus Group B > A, ECHO virus, influenza, poliovirus, HIV, others
    2. Chronic: Chagas' Disease, Lyme Disease, Diphtheria, Salmonella typhi, many others
    3. Rickettsia: Coxiella, spotted fever (R. rickettsii), R. helvetica, R. typhis, others [13]
    4. Fungal: actinomyces, aspergillus, blastomyces, candida, nocardia, histoplasmosis, others
    5. Bacterial Toxin mediated - diphtheria
    6. Smallpox (live attenuated) vaccine - myopericarditis 7.8 per 100,000 primary vaccinees [18]
  3. Viral Myocarditis
    1. Less than 3% of people with Coxsackievirus B infection develop myocarditis
    2. Some 10-20% of myocarditis is associated with Coxsackievirus
    3. Cytomegalovirus (CMV) also found in 10-20% of patients with myocarditis
  4. Drug Reaction [5]
    1. Direct cardiac muscle toxic effects versus inflammatory reactions
    2. Direct drug toxic effects:
    3. Anthracycline Chemotherapies: doxorubicin, daunorubicin, idarubicin, epirubicin
    4. Trastuzumab (Herceptin®) anti-her2/neu, mainly after anthracycline therapy
    5. Observed with very high dose ifosfamide or cyclophosphamide
    6. Alcohlism - usually with chronic abuse of ethanol
    7. Interleukin 2
    8. Inflammatory / Hypersensitivity Reactions
    9. Penicillins: ampicillin, penicillins, others
    10. Sulfa Drugs: hydrochlorothiazide, sulfamethoxazole
    11. Cardiac Medications: methyldopa, dobutamine, thiazides
    12. Nonsteroidal anti-inflammatory drugs
    13. Antiepileptics: phenytoin, carbamazepine
    14. Cocaine
    15. Low incidence of severe idiopathic myocarditis / cardiomyopathy with clozapine [14]
    16. Variety of other agents [19]
    17. Drug induced myocarditis often accompanied by eosinophilia
  5. Autoimmune Diseases [11]
    1. Vasculitis: Giant Cell, Takayasu, Churg-Strauss, Wegener's Granulomatosis
    2. Dermatomyositis, Polymyositis
    3. Systemic Lupus Erythematosus (SLE) - uncommon [17]
    4. Sjogren Syndrome
    5. Scleroderma (pericarditis more common)
    6. Sarcoidosis (often with giant cells)
  6. Alcohol - especially heavy intake, may contribute [4]
  7. Postpartum
  8. Familial Cardiomyopathies
  9. Postmyocardial infarction syndrome
  10. Cardiac Allograft Rejection
  11. Plasma Cell Dyscrasias [9]
    1. May be associated with myelomas or monoclonal gammopathies
    2. Pathological classification is necrobiotic xanthogranuloma
    3. Includes childhood forms and Erdheim-Chester Syndrome
  12. Acute Rheumatic Fever

C. Pathologynavigator

  1. Myocardial biopsy is required to assess pathologies
  2. Lymphocytic Myocarditis
    1. Most common finding in human cardiac tissue biopsies in patients with myocarditis
    2. Of all patients with cardiomyopathy, ~10% have lymphocytic myocarditis
    3. Myocyte necrosis, degeneration or both with adjacent inflammatory infiltrate
    4. Absence of significant coronary artery disease
    5. Predominance of lymphocytes and some monocytes without significant eosinophils
    6. Likely related to viral or other infection
  3. Eosinophilic Myocarditis [5,6]
    1. Usually due to drug allergic effects
    2. Perivascular infiltrates with eosinophil predominance, lymphoyctes, macrophages
    3. Usually with peripheral eosinophilia, rash and/or fever
    4. Sometimes called "Loffler" Myocarditis
  4. Giant Cell Myocarditis [7,10]
    1. Rare condition usually associated with systemic illnesses
    2. Infections: tuberculosis, endocarditis, fungi, syphilis, leprosy
    3. Rheumatologic: rheumatoid arthritis, lupus, vasculitides, polymyositis, dermatomyositis
    4. Gastrointestinal: Crohn Disease, ulcerative colitis, chronic hepatitis
    5. Autoantibody Associated: myasthenia gravis, Hashimoto thyroiditis
    6. Sarcoidosis - probably separate entity, rare eosinophilia
    7. Often associated with conduction abnormalities, may have rapid progression
    8. Necrotizing or non-necrotizing granulomas are found, often with eosinophilia
    9. T cell infiltrates have been documented and anti-CD3 Ab therapy may be effective [10]
    10. Idiopathic type is most often progressive and may require cardiac transplant
    11. Patients are usually young, present with heart failure or ventricular arrhythmias
  5. Peripartum Myocarditis
    1. Found in <10% of women with peripartum cardiomyopathy
    2. May be a variant of lymphocytic myocarditis, worsened in pregnant condition
  6. AIDS-Related Myocarditis
    1. Likely due to direct cardiac muscle toxic effects of HIV
    2. Coinfections with other viruses (cytomegalovirus, Coxsackie B virus) may contribute
    3. Cytokine mediated injury (e.g. tumor necrosis factor) may play a role as well
    4. Inflammatory infiltrates seen in cardiac tissue, usually CD8+ T lymphocytes

D. Pathophysiology navigator

  1. Myocarditis Definition
    1. Myocardial inflammation and injury without ischemia
    2. May present as angina, myocardial infarction, heart failure, severe fatigue
  2. Infiltration of cardiac tissue with lymphocytes and monocytes most common
    1. T cells appear to be prominant initiating cells, both CD4+ and CD8+
    2. Production of inflammatory mediators
    3. IL-2 itself can be toxic to cardiac myocytes
  3. Autoantibodies
    1. Animal models do not often correlate with human disease findings
    2. Antimyosin Abs
    3. Antisarcolemmal and antimyolemmal Abs
    4. Anti-ß-adrenergic receptor Abs
  4. Myocardial Injury
    1. Inflammatory mediators - macrophage derived, antibody/complement, etc.
    2. Toxic oxygen metabolites
    3. Physical disruption of myocytes by inflammatory cells
    4. Proliferation of interstitial cells, increased fibrous matrix
    5. Dilative (or restrictive) cardiomyopathy may result
  5. Myocarditis is likely to account for ~25% of cases of idiopathic dilated cardiomyopathy

E. Symptoms and Signs [4]navigator

  1. Non-specific chest symptoms (may be asymptomatic)
  2. Shortness of breath, dyspnea on exertion
  3. Palpitations
  4. Fever, myalgias, arthralgias, malaise (flu-like symptoms)
  5. Tachycardia
  6. Symptoms of congestive heart failure
  7. Clinical Classification at presentation has prognostic significance [15]:
    1. Acute subfulminant forms ~90% of cases - poorer prognosis long term
    2. Fulminant myocarditis in ~10% of cases - initially more severe but better recovery

F. Laboratorynavigator

  1. Leukocytosis may occur, usually with increased ESR
  2. Serum Analysis
    1. Increased creatine kinase MB fraction - rare
    2. Elevated levels of serum cardiac troponin I in ~30% of persons with biopsy myocarditis [4]
  3. Electrocardiogram (ECG)
    1. ST segment elevation - diffuse, "pseudoinfarct" pattern
    2. PR depression is nearly pathognomonic for pericarditis (which may also be present)
    3. Variable degrees of heart block may be present
  4. Echocardiography - dilated, diffusely hypokinetic heart
  5. Chest Radiograph - cardiomegaly, pulmonary congestion
  6. Diagnosis is made by biopsy of left or right ventricle
    1. Hallmark is myocardial necrosis
    2. Inflammatory infiltrate is present during active disease

G. Treatment [2]navigator

  1. Supportive Care [15]
    1. Intensive care often required in fulminant (~10%) forms of myocarditis
    2. However, recovery from fulminant myocarditis is often very good
    3. Subfulminant (acute) myocarditis (~90%) often with progressive worsening
  2. Glucocorticoids
    1. Recommended in (viral) idiopathic myocarditis if ongoing muscle inflammation
    2. No clear benefit in multiple randomized trials
    3. Probably most effective in eosinophilic (Loffler) myocarditis [6]
    4. High doses usually effective in myocarditis associated with SLE [17]
  3. Immunosuppressives [12]
    1. No role at this time for immunosuppressive agents for common types of myocarditis
    2. Randomized trial of prednisone + azathioprine or cyclophosphamide versus placebo [8]
    3. 111 patients with ejection fraction <45% received 24 weeks of therapy
    4. Mean initial ejection fraction 25%, increased to 34% overall in both groups
    5. No difference in ejection fraction change in placebo vs. treated group
    6. No change in mortality rates: 20% at 1 year and 56% at 4.3 years
    7. Steroids + azathioprine or cyclosporine recommended for idiopathic giant cell type [7]
  4. Intravenous Immuniglobulin (IVIg) [16]
    1. IVIg is useful in variety of inflammatory and autoimmune conditions
    2. 400mg/kg daily x 5 days effective in case reports
    3. Well tolerated and should be considered in acute myocarditis
  5. Treatment of CHF
    1. Diuretics for symptomatic relief
    2. ACE Inhibitor therapy is highly recommended
    3. Aggressive therapy for CHF is very important
    4. Ventricular support, including assist devices, are strongly recommended in severe disease
    5. Ventricular assist devices can help restore normal cardiac function
    6. Patients should be followed for progression of disease
  6. Pacemaker may be required for heart block
  7. Myocarditis implicated in ~20% of sudden cardiac death in young adults [3]

References navigator

  1. Pisani B, Taylor DO, Mason JW. 1997. Am J Med. 102(5):459 abstract
  2. Feldman AM and McNamara D. 2000. NEJM. 343(19):1388 abstract
  3. Eckart RE, Scoville SL, Campbell CL, et al. 2004. Ann Intern Med. 141(11):829 abstract
  4. Leeper NJ, Wener LS, Dhaliwal G, et al. 2005. NEJM. 352(14):1474 (Case Discussion) abstract
  5. Lee EY, Cibull ML, Hanzlick R, et al. 1997. Arch Intern Med. 157(18):2044 abstract
  6. Galiuto L, Enriquez-Sarano M, Reeder GS, et al. 1997. Mayo Clin Proc. 72(7):603 abstract
  7. Cooper LT, Berry GJ, Shabetai R. 1997. NEJM. 336(26):1860 abstract
  8. Mason JW, O'Connell JB, Herskowitz A, et al. 1995. NEJM. 333(5):269 abstract
  9. Winkelmann RK, Litzow MR, Umbert IJ, Lie JT. 1997. Mayo Clin Proc. 72:1028 abstract
  10. Levy NT, Olson LJ, Weyand C, et al. 1998. Ann Intern Med. 128(8):648 abstract
  11. Ledford DK. 1997. JAMA. 278(22):1962 abstract
  12. Garg A, Shiau J, Guyatt G. 1998. Ann Intern Med. 129(4):317 abstract
  13. Nilsson K, Lindquist O, Pahlson C. 1999. Lancet. 354(9185):1169 abstract
  14. Kilian JG, Kerr K, lawrence C, Celermajer DS. 1999. Lancet. 354(9193):1841 abstract
  15. McCarthy RE III, Boehmer JP, Hruban RH, et al. NEJM. 342(10):690
  16. Tedeschi A, Airaghi L, Giannini S, et al. 2002. J Intern Med. 251(2):169 abstract
  17. Wijetunga M and Rockson S. 2002. Am J Med. 113(5):419 abstract
  18. Halsell JS, Riddle JR, Atwood JE, et al. 2003. JAMA. 289(24):3283 abstract
  19. Sabatine MS, Poh KK, Mega JL, et al. 2007. NEJM. 357(21):2167 (Case Record) abstract