Nonviral Myocarditis

Etiology

The cause of myocarditis is most commonly viral, and most prominently linked with enteroviruses like Coxsackie B,[3] but also associated with parvovirus B19 (PVB19), adenovirus, influenza A virus, human herpesvirus (HHV), Epstein–Barr virus, cytomegalovirus, hepatitis C virus, and HIV.[4]

The non-viral causes of myocarditis can broadly classify into infectious, immune-mediated, and toxic.[5]

Infectious causes include:

• Bacterial pathogens like group A Streptococci, which can cause rheumatic myocarditis, characterized by Aschoff nodules on histopathology; Corynebacterium diphtheriae associated with toxin-mediated myocarditis; Mycobacterium, and Mycoplasma pneumoniae. Other bacteria which may lead to myocarditis include Staphylococcus, Gonococcus, Meningococcus, Pneumococcus, Hemophilus influenzae, and Brucella. There are also a few reported cases of myocarditis associated with non-typhi Salmonella species like S. enteritidis and S. berta, and rarely with typhoid fever[6][7][8][9]
• Spirochetes like Borrelia burgdorferi, which causes Lyme myocarditis and may correlate with atrioventricular conduction abnormalities; Leptospira, associated with Weil's disease; and rarely Treponema pallidum, causing gummatous myocarditis in tertiary syphilis
• Protozoa like Trypanosoma cruzi, causing Chagas' disease, which could present as acute myocarditis or chronic cardiomyopathy; Toxoplasma gondii, associated with post-cardiac transplant myocarditis and rejection; Entameba histolytica, which often also causes acute pericarditis; Leishmania; and Naegleria fowleri[10]
• Parasitic causes like cysticercosis because of Tenia solium; Trichinella-associated eosinophilic myocarditis, larva migrans, and Echinococcus granulosus
• Fungi like Aspergillus, Candida, Actinomyces, Blastomyces, Coccidioides, Histoplasma, Cryptococcus, Mucormycosis, Nocardia, and Sporothrix
• Rickettsial diseases like Q fever, caused by Coxiella burnetii; or Rocky Mountain spotted fever, due to R. rickettsii

Immune-mediated myocarditis could be due to:

• Autoimmune causes, like giant cell myocarditis and infection-negative lymphocytic myocarditis; or associated with immunologic syndromes like systemic lupus erythematosus, Churg-Strauss syndrome, Wegener’s granulomatosis, rheumatoid arthritis, Kawasaki disease, inflammatory bowel disease, celiac disease, systemic sclerosis, polymyositis, myasthenia gravis, Type 1 diabetes mellitus, thyrotoxicosis or sarcoidosis
• Hypersensitivity reaction to drugs like sulfonamides, penicillin, cephalosporins, furosemide, thiazide, digoxin, dobutamine, tricyclic antidepressants, isoniazid, tetracycline, phenytoin, phenylbutazone, and methyldopa; or serum sickness-like reaction to toxoids or vaccines
• Allograft rejection after a cardiac transplant

Toxic myocarditis may be caused by:

• Drugs, like amphetamines, cocaine, ethanol, chemotherapeutic agents (anthracyclines, trastuzumab, cyclophosphamide), antipsychotic medications (clozapine, lithium) and interleukin-2
• Heavy metal toxicity with copper, iron, lead
• Metabolic causes like pheochromocytoma, thyrotoxicosis, hemochromatosis, or beriberi

Epidemiology

Myocarditis is a significant cause of sudden death and nonischemic dilated cardiomyopathy, especially in the young. It was recently ranked as the third leading cause of sudden cardiac death in competitive athletes by the American Heart Association and the American College of Cardiology, and it is considered the most common known cause of dilated cardiomyopathy in children less than 18 years of age.[11] However, the actual burden of myocarditis is challenging to determine and is likely under-reported. Prevalence estimated from autopsy studies of young people with sudden cardiac death is highly variable ~ 2 to 42%.

Whereas neonates and children are more susceptible to viral-induced fulminant myocarditis,[12] acute lymphocytic and giant cell myocarditis are more commonly seen in adults with a median age of 43 years.[13] Men have a slightly higher prevalence of myocarditis than females, which is believed to be due to the natural hormonal variations that promote a proinflammatory Th1-type immune response in men, in contrast to the FOXP3+, CTLA4+ regulatory T cell response in women.[14]

Unlike viral myocarditis, there is a lot of variation in the distribution of non-viral pathogens causing myocarditis. Rheumatic heart disease and tertiary syphilis are rare in the developed nations because of better access to healthcare and early administration of antibiotics. Enteric pathogens and parasitic infestations are more prevalent in regions with poor sanitation, whereas diphtheritic myocarditis is limited to populations with poor immunization coverage.

Some pathogens are endemic to certain geographic regions, such as follows:

• Borrelia burgdorferi, Babesia, and Anaplasma species, associated with Ixodes tick (northeastern United States)
• Trypanosoma cruzi (rural areas of Central and South America)
• Coccidioides immitis (the southwestern United States and northern Mexico)
• Histoplasma capsulatum (central and eastern United States, most prevalent in the Ohio and Mississippi river valley
• Blastomyces dermatitidis (eastern North America, around St. Lawrence and Mississippi river systems)

Pathophysiology

Most studies have focused on the pathogenesis of viral myocarditis, using murine models. However, barring a few differences, most cases of myocarditis develop from the same three-step sequence of events[15][16]:

1. Acute injury because of infectious or non-infectious causes, leading to myocardial damage
2. Myocytolysis causing the release of intracellular antigens and cytoskeletal proteins like cardiac myosin
3. Activation of the innate immune response against cardiac self-antigens, followed by CD4+ T cell activation, clonal expansion of B cells, and production of cardiac autoantibodies.

Rheumatic carditis occurs because of molecular mimicry of streptococcal antigens (like M protein) with cardiac antigens such that anti-streptococcal antibodies cross-react with cardiac myosin and valvular endothelium[17]; however, their role in myocardial injury is debatable.[18] Intracellular pathogens like Borrelia, Trypanosoma, or Toxoplasma cause myocyte injury by direct invasion and intracellular proliferation[10] However, the pathogenesis of Chagas' myocarditis is much more complicated and possibly involves multiple other mechanisms like parasite-mediated myocytolysis, antibody-mediated cytotoxicity, and parasite-induced autoimmunity.[10][19] Spirochetal diseases like Lyme carditis can sometimes worsen after the initiation of antibiotics because of the release of endotoxin-like products from widespread microbial killing, which triggers proinflammatory cytokines (Jarisch-Herxheimer reaction).[20] Parasitic diseases could be secondary to encystment in the cardiac muscle itself (as seen in cysticercosis) or from activation of immune response leading to eosinophilic myocarditis.[10] Toxicity with heavy metals like copper or iron (including hemochromatosis) and certain chemotherapeutic agents like trastuzumab or anthracycline agents (doxorubicin, daunorubicin) can also cause myocyte injury. Cocaine and amphetamines can cause myocarditis because of catecholamine excess, which can induce apoptosis through ß1-receptor and also increase oxidative stress and local inflammation by inactivating superoxide dismutase.[21] This enzymatic inactivation might also be the mechanism behind pheochromocytoma or thyrotoxicosis-induced myocarditis. The pathogenesis of giant cell myocarditis is unknown; however, many ascribe it to autoimmune origins because of its association with thymomas and other autoimmune disorders.[22][13]

Studies have implicated both cell-mediated, and antibody-mediated immune responses in the pathogenesis of myocarditis, and CD4+ T cells play a major role in both pathways.[23][24] The Th1 subtype of CD4+ T cells activate the CD8+ cytotoxic T cells whereas the Th2 cells induce antibody production by the B cells. Some of these autoantibodies have a cytopathic or cardio-depressant effect,[25][26], while others might just be markers of inflammation. An abnormal immunologic response causes incomplete microbial clearance and/or persistent autoimmune myocyte injury and inflammation leading to chronic myocarditis.[27][28][29] This condition may be chronic microbial myocarditis (ongoing inflammation with detectable microbes and no autoantibodies), chronic autoreactive myocarditis (persistent inflammation and autoantibodies without microbes), and chronic microbial and immune myocarditis (ongoing inflammation in the presence of both microbes and autoantibodies).[5] Dilated cardiomyopathy develops when the inflammation resolves, but there is a persistence of myocyte destruction and cardiac remodeling.[5]

Histopathology

Aretz et al. proposed the Dallas criteria in 1986 for the histopathologic diagnosis of acute myocarditis, which requires evidence of inflammatory cellular infiltrate and myocyte necrosis for a diagnosis of acute myocarditis; whereas borderline myocarditis describes an inflammatory infiltrate in the absence of myocyte necrosis.[30][31] However, studies have shown this classification to be inadequate because of interobserver variability in interpretation and poor sensitivity because of sampling error.[32][33] It also provides no prognostic information because of the lack of characterization of the infiltrate. In contrast, the use of immunohistochemical staining for cell surface antigens (like CD3 and CD4 for T cells, CD20 for B cells, and CD68 for macrophages) and human leukocyte antigens (HLA-DR, which are often over-expressed in non-infective autoimmune myocarditis, and may influence treatment decisions) not only makes EMB more sensitive but also helps classify myocarditis as lymphocytic, granulomatous or giant cell or eosinophilic. A new immunohistochemical criterion proposed in a report by the European Society of Cardiology involves the detection of =14 leucocytes/mm including up to 4 monocytes/mm with the presence of CD3 positive T-lymphocytes =7 cells/mm.[5] Chronic myocarditis also displays areas of fibrosis and remodeling besides active inflammation.

Some types of myocarditis have very characteristic morphologies. Aschoff nodules with central fibrinoid necrosis and Anitschkow cells are the hallmark findings of rheumatic carditis, typically seen in perivascular regions. Patients with toxoplasma myocarditis may have pseudocysts containing Toxoplasma tachyzoites in the non-inflamed regions of the myocardium.[34][35] Giant cell myocarditis has multinucleated giant cells on a biopsy whereas cardiac sarcoidosis may reveal noncaseating granulomas. Myocarditis because of drug hypersensitivity, parasitic infections, hypereosinophilic syndrome, Loffler syndrome, and Churg-Strauss syndrome display a predominantly eosinophilic infiltrate with variable myocyte necrosis and may involve endocardial and valvular fibrosis.[36][37][38]

History and Physical

Myocarditis can present with a broad spectrum of symptoms of varying severity. From being asymptomatic to mild nonspecific symptoms like fever, myalgias, decreased exercise tolerance, or pleuritic chest pain, it can also mimic angina/MI and heart failure, or present with life-threatening arrhythmia or cardiogenic shock. In their position statement on myocardial and pericardial diseases, the European Society of Cardiology broadly grouped myocarditis symptoms into four classes[5]:

1. Acute coronary syndrome-like presentation, associated with ST-T wave changes, the elevation of troponins, and even regional or global wall motion abnormalities on echocardiography, but with no evidence of CAD on coronary angiography. A respiratory or gastrointestinal illness often precedes symptoms by approximately 1-4 weeks.
2. New onset or worsening heart failure lasting for fewer than 3 months, in the absence of CAD or known causes of heart failure, with symptoms of dyspnea, orthopnea, palpitations, pedal edema, fatigue, and chest discomfort. Physical examination may reveal a distressed, tachypneic individual with sinus tachycardia, an audible S3, bilateral crackles, or jugular venous distension. An echocardiogram can show impaired left or right ventricular systolic function with or without increased wall thickness or ventricular dimensions, and patients might have associated atrioventricular or bundle branch blocks.;
3. Chronic heart failure with symptoms lasting for over 3 months, in the absence of CAD or known causes of heart failure
4. Life-threatening conditions like ventricular arrhythmias or cardiogenic shock with severely reduced ejection fraction.

Patients might also display signs and symptoms of the causative disease. For example, a patient with Chagas’ disease might present with swelling at the infection site (chagoma), fever, myalgia, rash, lymphadenopathy or eyelid swelling (Romaña's sign) in the acute phase; or with dysphagia (megaesophagus), constipation (megacolon) or orthostatic hypotension (dysautonomia) in the chronic phase. Similarly, Lyme carditis may present with rash, flu-like symptoms, joint pain, facial palsy, or neuropathy.

Liebermann et al. introduced a clinicopathologic classification in 1991 that utilized clinical presentations to differentiate fulminant myocarditis from active lymphocytic myocarditis (acute, chronic active, or chronic persistent).[39] Fulminant myocarditis has an acute onset of two to three days, with severe decompensation of ventricular function that may require circulatory support, but typically resolves spontaneously. A viral prodrome might precede fulminant myocarditis. Conversely, giant cell myocarditis and cardiac sarcoidosis might have a more protracted course but lead to worse outcomes. They can cause sustained ventricular tachycardias, high degree heart blocks, and progressively worsening heart failure refractory to therapy which may require a cardiac transplant.[40][41]

Evaluation

Myocarditis typically causes nonspecific changes in the EKG but can include diffuse ST-segment elevations that are typically concave (as opposed to convex morphology in STEMI). Lyme carditis, giant cell myocarditis, and cardiac sarcoidosis often present with AV blocks or bundle branch blocks. Patients with a prolonged QRS duration have a greater risk of cardiac transplant or death in the setting of clinically suspected myocarditis.[42]

Myocarditis may cause elevation of cardiac biomarkers like troponin T or troponin I, but this is more sensitive than specific.[43] Troponin I is more commonly elevated compared to creatinine kinase MB.[43][44] Patients with heart failure symptoms might have an elevated brain natriuretic peptide (BNP) level. Acute phase reactants like ESR or CRP may also be elevated, but are non-specific. A complete blood count may reveal eosinophilia in eosinophilic myocarditis.

An echocardiogram may or may not reveal an impairment of ventricular function, with or without global or regional wall motion abnormalities. Both acute and chronic myocarditis can present with an increase in the size of the ventricular chambers; acute myocarditis can have a normal-to-thickened myocardium whereas chronic myocarditis more commonly correlates with thinning and scarring of the ventricular walls. However, it can morphologically resemble any of the three cardiomyopathies (dilated, restrictive, or hypertrophic).[45] Fulminant myocarditis causes decreased contractility because of interstitial edema in the myocardium; there might also be a slight thickening of the ventricular walls because of the edema, but the ventricles remain non-dilated.[46] Chronic Chagas’ myocarditis can cause an apical ventricular aneurysm in up to 55% of cases.[10] Additionally, echocardiography can rule out other causes of heart failure like valvular diseases.

Microbial diagnosis of myocarditis requires respective serologies. A patient with acute myocarditis will have IgM immunoglobulins whereas chronic microbial myocarditis will show IgG antibodies. Adding viral PCR for DNA or RNA on the EMB specimen may improve the diagnostic yield.

Studies have linked several autoantibodies with myocarditis; some target cardiac and muscle-specific antigens like anti-heart antibodies (AHA), anti-intercalated disk antibodies (AIDA), and anti-sarcolemmal antibodies (ASA).[5] AHA and AIDA are also predictors of the development of dilated cardiomyopathy in relatives.[26] Others like anti-muscarinic acetylcholine receptor-2 and anti-adenine nucleotide translocator (anti-ANT) antibodies exert a negative inotropic effect such that immunoadsorption leads to improvement of cardiac function.[26][47] However, there is no commercially available assay so far that can reliably diagnose myocarditis.

Nuclear imaging with Gallium-67 scintigraphy, Thallium-201 scan, or 18-fluorodeoxyglucose positron emission tomography have poor specificity but can help detect sarcoidosis in its acute phase and also be useful in monitoring the progression of the disease.[48][49]

Cardiac MRI (CMR) has developed as a promising mode of non-invasive diagnosis of myocarditis. In patients with clinically suspected myocarditis, the Lake Louise criteria help determine if the CMR findings are consistent with myocarditis.[50] These criteria require at least two out of the following three criteria:

1. Increase in global or regional myocardial signal intensity in T2-weighted images, suggestive of myocardial edema
2. Early gadolinium enhancement of the myocardium suggestive of hyperemia and capillary leakage (markers of inflammation), and an increased ratio of signal intensity between myocardium and skeletal muscles in T1-weighted gadolinium-enhanced images
3. At least one focal lesion of late gadolinium enhancement (in inversion recovery-prepared gadolinium-enhanced T1-weighted images) is suggestive of myocyte injury and/or scar due to myocarditis; this must be in the non-ischemic regional distribution (sub-epicardium or mid-wall, rather than the sub-endocardium which is involved in myocardial infarction)

If high clinical suspicion exists for myocarditis with recent onset of symptoms, but the CMR does not meet the Lake Louise criteria, then the CMR must be repeated in 1-2 weeks.

 Endomyocardial biopsy (EMB) is the only means of a definitive diagnosis of myocarditis and must fulfill the histologic and immunohistochemical criteria discussed before. Since it is an invasive procedure with significant morbidity, it is not feasible in every patient. The European Society of Cardiology proposes that EMB should be performed in patients with clinically suspected myocarditis after ruling out ischemia with coronary angiography.[5]

The patient has clinically suspected myocarditis if he has one or more "clinical presentations" with one or more "diagnostic criteria"; or if he/she is asymptomatic, he/she must meet 2 or more "diagnostic criteria" from different categories.[5] Clinical presentations include:

1. Acute chest pain (which can be pericarditic or pseudo-ischemic)
2. New onset/ acute worsening (<3 months)
3. Chronic (>3 months) heart failure (with dyspnea and/or fatigue with or without the left and/or right heart failure signs)
4. Arrhythmias (palpitations, syncope, other unexplained arrhythmia symptoms, or aborted sudden cardiac death)
5. Unexplained cardiogenic shock

Diagnostic criteria include:

1. Newly abnormal 12-lead EKG, Holter or stress testing
2. Elevated myocytolysis markers like Troponin T or Troponin I,
3. New and otherwise unexplained functional and structural abnormalities on cardiac imaging (echocardiography, angiography, or MRI)
4. Tissue characterization by CMR (including edema and/or late gadolinium enhancement of myocarditis pattern). 

All patients raising clinical suspicion of myocarditis should be admitted to the hospital for observation. Patients must have a 12-lead EKG testing and a transthoracic echocardiogram and should be considered for coronary angiography to rule out ischemic heart disease. If the patient is clinically stable, a cardiac MRI may precede EMB for further characterization; but if the patient has a life-threatening presentation, he/she must undergo an EMB without delay.[5] An EMB supplemented with immunohistochemical staining, PCR, and HLA typing can identify the etiology (microbial versus autoimmune) and the type of inflammatory response (lymphocytic, eosinophilic, giant cell, and sarcoidosis), and can guide the treatment and prognosis. 

Treatment / Management

Treatment of myocarditis can be symptomatic or etiologic. Symptomatic treatment involves the management of heart failure and arrhythmias based on current guidelines.

Hemodynamically unstable patients need intensive care and may require inotropic support, ventricular assist devices, or extracorporeal membrane oxygenation (ECMO) in cases of severe ventricular dysfunction as a bridge to cardiac transplant or recovery.[51][52] Hemodynamically stable patients with ventricular dysfunction are treatable with angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), or angiotensin receptor- neprilysin inhibitors (ARNI), along with beta-blockers, aldosterone receptor antagonists, and diuretics as per the ACC/AHA/HFSA heart failure recommendations.[53](B2)

Myocarditis patients may present with conduction abnormalities like complete A-V blocks, which can rapidly evolve into life-threatening arrhythmias. As a result, temporary or permanent pacing may be necessary. Ventricular tachycardias can be treated with amiodarone or may require an implantable cardioverter-defibrillator (ICD) as a bridge to transplant or recovery.[54] Radio-frequency catheter ablation can also be used to control recurrent ventricular arrhythmias.[54] A wearable cardioverter-defibrillator is another bridging alternative for the control of transient arrhythmias.[55] Patients with cardiac sarcoidosis require an ICD if their left ventricular ejection fraction is less than 35% and their life expectancy is greater than 1 year.[54](A1)

Etiologic management includes appropriate antimicrobial therapy for infective causes (like ceftriaxone or doxycycline in Lyme carditis, benznidazole, or nifurtimox for Chagas disease).[10] Drug hypersensitivity reactions and toxic myocarditis respond to the cessation of the offending agents.  Autoimmune myocarditis, including giant cell myocarditis, shows a variable response to immunosuppressive therapy.[56][57][58] Common regimens include steroids alone, azathioprine and steroids, or cyclosporine A, azathioprine, and steroids. A trial of immunomodulatory therapies like intravenous immunoglobulins (IVIG) may be given in patients that do not respond to conventional immunosuppression.[59] Many have studied the role of antiviral therapies in the treatment of viral myocarditis; however, there are no clear guidelines so far; infectious disease specialists should be consulted for the initiation of therapy.[5] Similarly, while immunoadsorption of certain antibodies has shown an improvement of cardiac function in small randomized controlled trials, there are no current recommendations for their routine use.(A1)

Non-steroidal anti-inflammatory drugs (NSAIDs) do not seem to have any benefit in myocarditis; in fact, their use in myocarditis correlates with greater mortality.[5][60][15] Patients must avoid physical activity because of a greater risk for sudden cardiac death[61]; an exercise stress test must not be performed for the evaluation of coronary artery disease.(B3)

Differential Diagnosis

Myocarditis mimics several conditions; therefore, one must carefully consider its differential diagnoses. Acute coronary syndrome, valvular disease, infective endocarditis, cardiac tamponade, and pericarditis must be ruled out. Right ventricular myocarditis can present like arrhythmogenic right ventricular cardiomyopathy.[62][63] Other conditions that may resemble myocarditis include hypertrophic cardiomyopathy, restrictive diseases like cardiac amyloidosis, ischemic cardiomyopathy, coronary artery vasospasm, peripartum cardiomyopathy, ventricular tachycardia, interstitial pulmonary fibrosis, and high altitude-induced pulmonary edema.

Prognosis

The prognosis of myocarditis varies by the type and etiology of the disease. Viral myocarditis usually resolves spontaneously. Even fulminant myocarditis which is marked by severe ventricular impairment and multiple foci of myocarditis (while it might require aggressive interventions during the active phase of the disease) eventually resolves completely.[64][65] However, the persistence of the viral genome on PCR is a marker of a worse prognosis.[66] Acute lymphocytic myocarditis is a broad category that includes immune-mediated causes and has worse outcomes compared to fulminant myocarditis.[64][65] Giant cell myocarditis has very poor outcomes including higher incidences of arrhythmias, sudden cardiac death, and refractory heart failure requiring a cardiac transplant.[40] There might be a recurrence of giant cell myocarditis in the donor heart after transplantation; however, the disease in the allograft responds favorably to treatment.[58] Eosinophilic myocarditis has a variable prognosis; drug hypersensitivity syndromes, hyper-eosinophilic, and parasitic myocarditis may resolve with drug cessation, antimicrobial therapy, and corticosteroid therapy respectively. There is a rarer, more aggressive entity called acute necrotizing eosinophilic myocarditis that correlates with higher death rates.[67]

The presence of biventricular dysfunction at the time of diagnosis is a major predictor of death or the need for a cardiac transplant.[66] Right ventricular dysfunction is an independent predictor of adverse outcomes.[68] Myocarditis can also cause deterioration of concomitant cardiac conditions like cardiac amyloidosis and hypertrophic cardiomyopathy, especially in cases with persistent viral genome. Some studies have linked elevated serum soluble Fas (sFas) and soluble Fas ligand (sFasL) levels at the time of presentation with an increased risk of death.[69][70][71]

Complications

Immediate complications of myocarditis include cardiogenic shock, ventricular arrhythmias, and sudden cardiac death. Unresolved myocarditis can progress to dilated cardiomyopathy, heart failure with reduced ejection fraction, areas of focal hypokinesis, and ventricular aneurysms that may also lead to intracardiac thrombi, which may further result in a stroke or MI. Dilated cardiomyopathy is perhaps the most common sequelae of myocarditis that develops in up to 30% of biopsy-proven cases of myocarditis.[5][72][11] Cases of eosinophilic myocarditis may also cause endocardial fibrosis and lead to valvular diseases.[73]