Written by Leslie T. Cooper, MD & DeLisa Fairweather, PhD
What is “chronic myocarditis”?
A: Chronic diseases are by definition diseases that develop or progress slowly and are difficult to treat. Acute diseases occur suddenly and last for a relatively short period. “Myocarditis” usually refers to “acute myocarditis” and the term “chronic myocarditis” is used if acute myocarditis does not disappear quickly or if myocarditis symptoms reappear later after an episode of acute myocarditis.
What causes “chronic myocarditis”?
A: Many different environmental agents can trigger myocarditis including viral or bacterial infections, toxins, and drugs 7. The reasons why some persons recover and others do not is an area of active investigation.
How is chronic myocarditis diagnosed?
A: Examination of heart tissue under a microscope is the only way to prove the diagnosis of chronic myocarditis. Up to 40% of patients with chronic dilated cardiomyopathy (large, poorly functioning hearts) who have symptoms of heart failure despite standard medical care can have myocarditis when special techniques are used to study heart tissue.
Magnetic resonance imaging (MRI) of the heart is under evaluation to aid in the diagnosis of chronic myocarditis. The sensitivity and specificity of MRI for the diagnosis of myocarditis varies with the duration of illness and the sequences used.
Blood tests that measure damage to heart muscle cells (e.g. troponin T) can also be elevated in chronic myocarditis, but the levels may be normal or only minimally elevated.
The electrocardiogram has nonspecific changes in the majority of myocarditis cases. There are also no specific echocardiographic features of chronic myocarditis.
Which viruses cause myocarditis?
The known viral causes of myocarditis include:
Parvovirus B19 spreads via respiratory droplets that are expelled when infected people cough, sneeze, or speak. Approximately half the population carries its antibodies. It is the cause of fifth disease, sometimes called slapped cheek syndrome for the red facial rash caused in children ages six to 10. Teens and adults typically experience rashes elsewhere, especially the hands and feet. Symptoms of infection usually occur within a week of exposure and last for approximately one week. Parvovirus B19 has also been associated with:
- Severe birth defects
- Infection in patients with acquired immunodeficiency syndrome (AIDS), arthritis, and aplastic anemia (lack of red blood cell production)
At this time, there is no vaccination against parvovirus B19.
Human Herpes Virus 6
This virus is transmitted via saliva and often presents with a rash and fever. It is so common that most infants are exposed by 13 months of age, although infection may occur during the first weeks of life. Approximately 20% of infant emergency department visits are linked to fevers caused by human herpes virus 6. Conditions associated with this virus include:
- Sixth disease (roseola infantum)
- Multiple sclerosis
- Chronic fatigue syndrome
- And more…
Once contracted, the virus remains in the salivary glands and bone marrow for life.
These viruses include Coxsackie A virus, or hand, foot, and mouth disease, and Coxsackie B virus, which typically presents as a mild rash, nasal and throat infections, and symptoms commonly associated with colds. It has been known to cause not just myocarditis but also:
- Pericarditis, or the inflammation of the membrane that surrounds the heart
- Meningitis, or inflammation of the spinal cord’s outer membranes
- Pancreatitis, or inflammation of the pancreas
Is chronic myocarditis associated with other diseases?
A: Non-infectious causes of myocarditis are uncommon, and include myocarditis associated with connective tissue diseases such as systemic lupus erythematosus or rheumatoid arthritis. Myocarditis can also develop in patients who have rare primary disorders of immune regulation.
Is “chronic myocarditis” related to dilated cardiomyopathy and heart failure?
A: Yes, most patients with chronic myocarditis also have dilated cardiomyopathy, or an enlarged heart 6. Having an enlarged heart places the patient at a greater risk for developing heart failure. Because of this, and the difficulty of treating dilated cardiomyopathy, patients may need a heart transplant. However, there are other causes of dilated cardiomyopathy and heart failure besides myocarditis.
How is chronic myocarditis treated?
A: There is no established treatment for chronic myocarditis. However, studies in patients with chronic heart failure that did not respond to usual care suggest a limited role for immunosuppression. Randomized trials of patients with chronic myocarditis (diagnosed by special stains of heart biopsy tissue) immunosuppression with azathioprine and prednisone resulted in an improvement in quality of life and left ventricular ejection fraction. This treatment strategy is now under evaluation in well-designed, multicenter trials. Other studies seek to evaluate antiviral therapy in patients with evidence of chronic viral heart infections.
Does everyone who has myocarditis progress to “chronic myocarditis”?
A: No, most patients with myocarditis resolve the disease relatively quickly. Only certain susceptible individuals progress from acute to chronic myocarditis and dilated cardiomyopathy 1. Research has shown that susceptibility to develop “chronic myocarditis” depends on the type of immune response an individual has in response to infections, chemicals, or physical damage to the heart2,3,8-10.
How can “chronic myocarditis” occur later after “acute myocarditis”?
A: Research in animal models has shown that myocarditis can be a biphasic disease, meaning that acute myocarditis can resolve and then several weeks or months later it can reappear 1. Researchers have found that proteins called cytokines that are released from inflammatory cells during acute myocarditis begin to cause changes in heart structure that only appear several weeks or months later 2-5. This process is called “remodeling” and leads to fibrosis (i.e. scar tissue in the heart) and dilated cardiomyopathy (i.e. an enlarged heart). However, it is important to note that only some individuals progress from acute to chronic myocarditis, while most patients with acute myocarditis do not develop the chronic phase of the disease.
Is “chronic myocarditis” an autoimmune disease?
A: In most cases, chronic myocarditis involves autoimmunity 16. An autoimmune response occurs when the immune system attacks the cells and tissues of our body. The immune system does this in an attempt to heal the damage induced by infections or chemicals, for example, but can end up causing damage itself. This results in chronic inflammation and may involve the deposition of proteins called autoantibodies on cardiac tissue that can adversely affect heart function and further promote inflammation 16-18.
Am I at a greater risk of heart failure with “chronic myocarditis”?
A: Not necessarily. Patients are at a risk for heart failure during acute and chronic myocarditis, but for different reasons. For example, patients may be at heightened risk for heart failure during “acute myocarditis” because of the release of cytokines (which are immune signaling proteins) that adversely affect cardiac function, but at risk for heart failure during “chronic myocarditis” more because of poor cardiac function due to myocardial scarring 5.
Is there a sex difference in “chronic myocarditis”?
A: Yes. Chronic myocarditis, dilated cardiomyopathy, and heart failure occurs more frequently in men than women. Recently two studies were published finding that myocardial recovery after acute myocarditis and transplant-free survival occurred much less frequently in men than women with myocarditis 6,11. Another study found that men are two times more likely to develop myocardial fibrosis (i.e. scarring) following myocarditis than women 12. Fibrosis is a scar that develops in the cardiac muscle that makes it more difficult for the heart to pump efficiently and usually leads to dilated cardiomyopathy, or an enlarged heart, and may progress to heart failure. Researchers have found that elevated testosterone levels in males directly promote the type of inflammation that leads to increased myocarditis, fibrosis, dilated cardiomyopathy, and heart failure 4,8,13-15.
- Fairweather D, Rose NR (2007) Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity. Methods 41:118-122.
- Fairweather D, Frisancho-Kiss S, Gatewood S, Njoku D, Steele R, Barrett M, Rose NR (2004) Mast cells and innate cytokines are associated with susceptibility to autoimmune heart disease following coxsackievirus B3 infection. Autoimmunity 37:131-145.
- Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Gatewood SJL, Njoku DB, Rose NR (2004) IFN-g protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines TGF-b1, IL-1b, and IL-4 in the heart. Am J Pathol 165:1883-1894.
- Coronado MJ, Brandt JE, Kim E, Bucek A, Bedja D, Abston ED, Shin J, Gabrielson KL, Mitzner W, Fairweather D (2012) Testosterone and interleukin-1b increase cardiac remodeling during acute coxsackievirus B3 myocarditis via serpin A 3n. Am J Physiol Heart Circ Physiol 302:H1726-H1736.
- Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P (2012) Inflammatory cytokines in heart failure: mediators and markers. Cardiology 122:23-35.
- McNamara DM, Starling RC, Cooper LT, Boehmer JP, Mather PJ, Janosko KM, Gorcsan J 3rd, Kip KE, Dec GW; IMAC Investigators (2011) Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Coll Cardiol 58:1112-1118.
- El Amm C, Fairweather D, Cooper LT Jr (2012) Pathogenesis and diagnosis of myocarditis. Heart 98:835-840.
- Onyimba JA, Coronado MJ, Garton AE, Kim JB, Bucek A, Bedja D, Gabrielson KL, Guilarte TR, Fairweather D (2011) The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice. Biol Sex Differ 2:2.
- Abston ED, Coronado MJ, Bucek A, Bedja D, Shin J, Kim JB, Kim EY, Gabrielson KL, Georgakopoulos D, Mitzner W, Fairweather D (2012) Th2 regulation of viral myocarditis in mice: different roles for TLR3 vs. TRIF in progression to chronic disease. Clin Dev Immunol 2012:129486.
- Abston ED, Barin JG, Cihakova D, Bucek A, Coronado MJ, Brandt JE, Bedja D, Kim JB, Georgakopoulos D, Gabrielson KL, Mitzner W, Fairweather D (2012) IL-33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function. Circ Heart Fail 5:366-375.
- Cooper LT, Mather PJ, Alexis JD, Pauly DF, Torre-Amione G, Wittstein IS, Dec GW, Zucker M, Narula J, Kip K, McNamara DM; IMAC2 Investigators (2012) Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women. J Card Fail 18:28-33.
- Cocker MS, Abdel-Aty H, Strohm O, Friedrich MG (2009) Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study. Heart 95:1925-1930.
- Huber SA, Kupperman J, Newell MK (1999) Hormonal regulation of CD4+ T cell responses in coxsackievirus B3-induced myocarditis in mice. J Virol 73:4689-4695.
- Huber SA (2005) Increased susceptibility of male BALB/c mice to coxsackievirus B3-induced myocarditis: role for CD1d. Med Microbiol Immunol 194:121-127.
- Frisancho-Kiss S, Coronado MJ, Frisancho JA, Lau VM, Rose NR, Klein SL & Fairweather D (2009) Gonadectomy of male BALB/c mice increases Tim-3+ alternatively activated M2 macrophages, Tim-3+ T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun 23:649-657.
- Fairweather D, Petri MA, Coronado MJ & Cooper LT Jr (2012) Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis. Expert Rev Clin Immunol 8:269-284.
- Li Y, Heuser JS, Cunningham LC, Kosanke SD, Cunningham MW (2006) Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol 177:8234-8240.
- Burgstaler EA, Cooper LT, Winters JL (2007) Treatment of chronic dilated cardiomyopathy with immunoadsorption using the staphylococcal A-agarose column: a comparison of immunoglobulin reduction using two different techniques. J Clin Apher 22:224-232.
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