Acute Myocarditis – Causes, Symptoms, Treatment

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Acute Myocarditis/Inflammatory cardiomyopathy (ICM) is defined as inflammation of the heart muscle associated with impaired function of the myocardium, which has most often the morphology of dilated cardiomyopathy. Inflammation of the heart muscle itself, that is, myocarditis may have many infectious (viral, bacterial, and protozoal infections) and noninfectious causes (e.g., myocarditis accompanying autoimmune disease or hypersensitivity to certain noxious substances).

Myocarditis knew as inflammatory cardiomyopathy is an uncommon, potentially life-threatening disease significant cause of sudden death and nonischemic dilated cardiomyopathy, especially in the young. It include bacterial and protozoal infections, toxins, drug reactions, autoimmune diseases, giant cell myocarditis, and sarcoidosis and has a very diverse and sometimes, nonspecific presentation, and can mimic various disease entities. Although viral myocarditis is the most common type, nonviral myocarditis also must be considered. Nonviral myocarditis comprises several infectious and autoimmune etiologies that should not be overlooked; recognition is critical for a timely intervention.

Synonyms of Myocarditis

  • Inflammatory cardiomyopathy
  • Idiopathic myocarditis
  • Viral cardiomyopathy

Subdivisions of Myocarditis

  • Viral myocarditis
  • Giant cell myocarditis
  • Lymphocytic myocarditis
  • Eosinophilic myocarditis
  • Granulomatous myocarditis

Types of Myocarditis

  • Acute Lymphocytic Myocarditis – Acute lymphocytic myocarditis is characterized by a predominant myocardial patchy infiltration of T lymphocytes, typically identified in immunohistochemistry [IHC] by CD3 expression, with minimal fibrosis. As expected, areas of lymphocyte infiltration co-localize with CD68+ macrophages. This is the most common pathologic type of myocarditis and is most frequently of viral etiology, mainly Coxsackievirus B and adenoviruses [, ].
  • Chronic Lymphocytic Myocarditis (CLM) – CLM is thought to be a chronic stage of acute lymphocytic myocarditis; this entity is pathologically characterized by existence of myocardial fibrosis but still accompanied by leukocyte infiltration. The timing for such progression from acute to chronic inflammation is variable and currently unpredictable. In this case, the areas of fibrosis are consequence of the persistent evolution of the inflammatory processes [].
  • Giant Cell Myocarditis – Giant cell myocarditis is characterized by unique histological features and particular aggressiveness and capacity to progress to chronic and subacute life-threatening complications like DCM. The prevalence of progression to DCM is considered to be up to 80% []. In fact, despite immunosuppressive therapy, two studies have shown that only around 10% of giant cell myocarditis patients survive 4 years without transplantation, compared with 44% of lymphocytic myocarditis [, ].
  • Sarcoidosis – This is a systemic “idiopathic” disease in the frontier between autoimmunity and autoinflammatory disease, characterized by an antigen presenting cells (APC) dys-function, generating chronic tissue inflammation and granulomatous lesions in organs like the lung, kidney, and heart. Sarcoidotic myocarditis display extensive infiltration by activated macrophages, leading to chronic inflammation and tissue damage [, ].
  • Eosinophilic Myocarditis – This form of myocarditis is observed in entities associated with peripheral eosinophilia (like primary idiopathic hypereosinophilia or chronic eosinophilia due to infectious causes). Eosinophilic myocarditis may also appear as a primary disease, most likely of autoimmune origin. Its landmark is the presence of eosinophils in significant proportions in myocardial infiltrates. This entity, like the giant cell myocarditis, shows also a poor long-term prognosis despite broad immunosuppressive treatment [, , ].

Three stages of the disease process

  • Acute – defined by direct viral cytotoxicity and focal or diffuse necrosis of the myocardium
  • Subacute – defined by an increase in autoimmune-mediated injury with activated T cells and B cells and subsequent antibody production creating cardiac autoantibodies along with inflammatory proteins. There are higher concentrations of anti-b-myosin antibodies in patients with myocarditis with dilated cardiomyopathy than in control groups.
  • Chronic –  defined by diffuse myocardial fibrosis and cardiac dysfunction that may lead to dilated cardiomyopathy and its sequelae such as CHF, ventricular dysrhythmias, and abnormal ECG findings.

Causes of Acute Myocarditis

A large number of causes of myocarditis have been identified, but often a cause cannot be found. In Europe and North America, viruses are common culprits. Worldwide, however, the most common cause is Chagas disease, an illness endemic to Central and South America that is due to infection by the protozoan Trypanosoma cruzi.[rx] In viral myocarditis, the Coxsackie B family of the single-stranded RNA viruses, in particular, the plus-strand RNA virus Coxsackievirus B3 and Coxsackievirus B5 are the most frequent cause.[rx] Many of the causes listed below, particularly those involving protozoa, fungi, parasites, allergy, autoimmune disorders, and drugs are also causes of eosinophilic myocarditis.

Viruses/disorders Bacteria/disorders Cardiotoxins Hypersensitivity
Adenovirus* Chlamydia Ethanol* Cephalosporins
Coxsackievirus B* Cholera Anthracycline drugs* Clozapine
Cytomegalovirus* Mycoplasma Arsenic Diuretics
Epstein–Barr virus Neisseria Carbon monoxide Insect bites
Hepatitis C virus Salmonella Catecholamines Lithium
Herpes simplex virus Staphylococcus Cocaine* Snake bites
HIV* Streptococcus Heavy metals Sulfonamides
Influenza virus Tetanus Copper Tetanus toxoid
Mumps Tuberculosis Mercury Tetracycline
Parvovirus B19 Lead
Poliovirus Spirochetal Systemic disorders
Rabies Leptospirosis Protozoa Hypereosinophilia
Rubella Lyme disease Chagas disease Kawasaki disease
Varicella zoster virus Relapsing fever Leishmaniasis Sarcoidosis
Yellow fever Syphilis Malaria Wegener granulomatosis

Infections

Bacterial myocarditis is rare in patients without immunodeficiency.

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 pneumonia. Other bacteria which may lead to myocarditis include Staphylococcus, Gonococcus, Meningococcus, Pneumococcus, Hemophilus influenza, 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 Bacterial Brucella, Corynebacterium diphtheriae, gonococcus, Haemophilus influenza, Actinomyces, Tropheryma whipplei, Vibrio cholerae, Borrelia burgdorferi, leptospirosis, Rickettsia, Mycoplasma pneumonia
  • Viral – adenovirus,[rx] parvovirus B19, coxsackievirus, rubella virus, poliovirus, Epstein-Barr virus, hepatitis C, severe acute respiratory syndrome coronavirus 2[rx]
  • Fungal –  Fungi like Aspergillus, Candida, Actinomyces, Blastomyces, Coccidioides, Histoplasma, Cryptococcus, Mucormycosis, Nocardia, and Sporothrix
  • 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
  • Parasitic – Ascaris, Echinococcus granulosus, Paragonimus westermani, Schistosoma, Taenia solium, Trichinella spiralis, visceral larva migrans, Wuchereria bancrofti. Parasitic causes like cysticercosis because of Tenia solium; Trichinella-associated eosinophilic myocarditis, larva migrans, and Echinococcus granulosus
  • Rickettsial diseases – like Q fever, caused by Coxiella burnetti; or Rocky Mountain spotted fever, due to R. rickettsii. Coxiella burnetii (Q fever), Orientia tsutsugamushi (scrub typhus), Rickettsia prowazekii (typhus), Rickettsia rickettsii (Rocky Mountain spotted fever)
  • HelminthicAscaris, Echinococcus granulosus, Heterophyes, Paragonimus westermani, Schistosoma, Strongyloides stercoralis, Taenia solium (cysticercosis), Toxocara canis (visceral larva migrans), Trichinella spiralis, Wuchereria bancrofti (filariasis)

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. Drugs, including alcohol, anthracyclines and some other forms of chemotherapy, and antipsychotics, e.g., clozapine, also some designer drugs such as mephedrone[rx]azithromycin, benzodiazepines, clozapine, cephalosporins, dapsone, dobutamine, gefitinib, lithium, loop diuretics, methyldopa, mexiletine, nonsteroidal anti-inflammatory drugs, penicillins, phenobarbital, smallpox vaccination, streptomycin, sulfonamides, tetanus toxoid, tetracycline, thiazide diuretics, tricyclic antidepressants
  • Heavy metal – toxicity with copper, iron, lead
  • Metabolic – causes like pheochromocytoma, thyrotoxicosis, hemochromatosis, or beriberi.
Immunologic
  • Allergic (acetazolamide, amitriptyline)
  • Rejection after a heart transplant
  • Autoantigens (scleroderma, systemic lupus erythematosus, sarcoidosis, systemic vasculitis such as eosinophilic granulomatosis with polyangiitis, and granulomatosis with polyangiitis, Kawasaki disease, idiopathic hypereosinophilic syndrome)[16]
  • Toxins (arsenic, toxic shock syndrome toxin, carbon monoxide, or snake venom)
  • Heavy metals (copper or iron)

Physical agents

  • Electric shock, hyperpyrexia, and radiation

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 dermatitis (eastern North America, around St. Lawrence and Mississippi river systems)

Symptoms of Acute Myocarditis

The signs and symptoms associated with myocarditis are varied and relate either to the actual inflammation of the myocardium or to the weakness of the heart muscle that is secondary to the inflammation. Signs and symptoms of myocarditis include the following:[rx]

  • Chest pain (often described as “stabbing” in character)
  • Congestive heart failure (leading to swelling, shortness of breath, and liver congestion)
  • Palpitations (due to abnormal heart rhythms)
  • Dullness of heart sounds
  • Shortness of breath, especially after exercise or when lying down
  • Fatigue
  • Heart palpitations
  • Chest pain or pressure
  • Lightheadedness
  • Swelling in the hands, legs, ankles, and feet
  • A sudden loss of consciousness
  • Sudden death (in young adults, myocarditis causes up to 20% of all cases of sudden death)[rx]
  • Fever (especially when infectious, e.g., in rheumatic fever)
  • Symptoms in young children tend to be more nonspecific, with generalized malaise, poor appetite, abdominal pain, and chronic cough. Later stages of the illness will present with respiratory symptoms with increased work of breathing and is often mistaken for asthma.

European Society of Cardiology broadly grouped myocarditis symptoms into four classes:

  • 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.
  • 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.;
  • Chronic heart failure with symptoms lasting for over 3 months, in the absence of CAD or known causes of heart failure
  • Life-threatening conditions like – ventricular arrhythmias or cardiogenic shock with severely reduced ejection fraction.

Myocarditis is often associated with pericarditis, and many people with myocarditis present with signs and symptoms that suggest myocarditis and pericarditis at the same time

Diagnosis of Acute Myocarditis

Myocardial inflammation can be suspected on the basis of electrocardiographic (ECG) results, elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), and increased IgM (serology) against viruses known to affect the myocardium. Markers of myocardial damage (troponin or creatine kinase cardiac isoenzymes) are elevated.

  • The ECG findings – most commonly seen in myocarditis are diffuse T wave inversions; saddle-shaped ST-segment elevations may be present (these are also seen in pericarditis).[rx]
  • A Chest X-Ray – A chest X-ray produces an image on film that outlines your heart, lungs, and other structures in your chest. From a chest X-ray, your physician learns information such as the size and shape of your heart.
  • An Echocardiogram (abbreviated echo) – Sound waves (too high-pitched to be heard) are used to make an image of your heart or analyze blood flow. The sound waves are sent into your body from a transducer, a small plastic device. The sound waves are reflected back from internal structures, returning to the transducer and producing images of the heart and its structures.
  • Electrocardiography – Electrocardiography (ECG) has a low sensitivity for diagnosing myocarditis. Non-specific ECG changes in myocarditis patients include sinus tachycardia, ST and T wave abnormalities, and ST elevations mimicking an acute myocardial infarction and occasionally atrial or ventricular conduction delays, as well as supraventricular and ventricular arrhythmias.
  • MRI – Cardiac MRI will show your heart’s size, shape, and structure. This test can show signs of inflammation of the heart muscle.
  • Blood tests – This measures white and red blood cell counts, as well as levels of certain enzymes that indicate damage to your heart muscle. Blood tests can also detect antibodies against viruses and other organisms that might indicate a myocarditis-related infection. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually elevated but nonspecific.
  • Cardiac catheterization and endomyocardial biopsy – A small tube (catheter) is inserted into a vein in your leg or neck and threaded into your heart. In some cases, doctors use a special instrument to remove a tiny sample of heart muscle tissue (biopsy) for analysis in the lab to check for inflammation or infection.
  • 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). AHA and AIDA are also predictors of the development of dilated cardiomyopathy in relatives. Patients with myocarditis often develop autoantibodies against cardiac myosin or the β-adrenergic receptor. Anti-myosin antibodies are associated with left ventricular systolic dysfunction and diastolic stiffness in patients with chronic myocarditis.
  • Anti-muscarinic acetylcholine receptor-2 test –  and anti-adenine nucleotide translocator (anti-ANT) antibodies exert a negative inotropic effect such that immunoadsorption leads to improvement of cardiac function. 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.
  • 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.
  • 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 for 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.
  • CT angiography – to evaluate for other causes of chest pain may be indicated. Percutaneous coronary angiography is indicated in patients at high risk for coronary artery disease to help rule out an ischemic cause of cardiac dysfunction in the right setting. Cardiac magnetic resonance imaging seems to be promising and may help differentiate ischemic from non-ischemic etiologies of dilated cardiomyopathy.
  • Serum biomarkers – Serum biomarkers provide valuable information for the diagnosis of CVDs including myocarditis. For a biomarker to be clinically useful it should fulfill several criteria: (1) biomarker levels should be able to be accurately assessed using widely available and cost-efficient methods; (2) biomarkers should provide additional information from the tests already conducted such as MRI; and (3) biomarker information should aid in medical decision making.
  • Troponins I and T – The release of cardiac troponins (I and T) from cardiomyocytes signals cell damage or death. Unfortunately, most studies suggest that a single value of troponin used for the diagnosis of suspected myocarditis has a low sensitivity.
  • BNP and NT-proBNP – B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are important indicators of cardiovascular stress and have the advantage of being able to distinguish acute from chronic heart failure. In contrast to troponins that are released due to cell wall compromise, BNP is synthesized in healthy cardiac myocytes from its precursor NT-proBNP. The prohormone BNP is only released to the circulation when the ventricles become dilated, hypertrophic, or during other conditions that induce wall distension and stretching, and by neurohormonal activation.
  • Coronary angiography is indicated to exclude coronary artery disease (CAD) as one of the possible causes of the symptoms and should be done in all patients at risk of CAD regardless of the symptoms, which means also in patients without chest pain.
  • Endomyocardial biopsy is still considered as the gold standard and the only method for definitive diagnosis in vivo. The sample can be obtained from the left or right ventricle (or both); the diagnostic yield probably depends on the number of samples, not on the particular site of EMB [rx, rx] despite the fact that some studies showed higher sensitivity in left ventricular and biventricular biopsy than only right ventricular one [rx, rx]. Unlike the presence of infiltrating cells, which is comparable in both ventricles, some characteristics differ between the two chambers; for example, the degree of fibrosis is more pronounced in LV [rx].

Treatment of Acute Myocarditis

If your heart is weak, your doctor might prescribe medications to reduce your heart’s workload or help you eliminate excess fluid, including:

  • 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.
  • Antimicrobial therapy – for infective causes (like ceftriaxone or doxycycline in Lyme carditis, and benznidazole or nifurtimox for Chagas’ disease). Drug hypersensitivity reactions and toxic myocarditis respond to the cessation of the offending agents.
  • Immunosuppression therapy – Autoimmune myocarditis including giant cell myocarditis shows a variable response to immunosuppressive therapy. Common regimens include steroids alone, azathioprine and steroids, or cyclosporine A, azathioprine, and steroids such as (prednisone, prednisolone), [, ].  A trial of immunomodulatory therapies like intravenous immunoglobulins (IVIG) may be given in patients that do not respond to conventional immunosuppression.
  • Immune modulating agents – allow for a more targeted approach with reduced side effects. An anti-CD3 monoclonal antibody (muronumab) suppresses lymphocyte activation and proliferation. IL-6 antibody blocks the Il-6 receptor and has been shown to be beneficial in viral myocarditis [].
  • Angiotensin-converting enzyme (ACE) inhibitors – These medications, such as enalapril (Vasotec), captopril (Capoten), lisinopril (Zestril, Prinivil), and ramipril (Altace), relax the blood vessels in your heart and help blood flow more easily. The use of candesartan improved survival in a murine model of viral myocarditis (60%, vs. 18% with no candesartan treatment).
  • Angiotensin II receptor blockers (ARBs) – These medications, such as losartan (Cozaar) and valsartan (Diovan), relax the blood vessels in your heart and help blood flow more easily.
  • Beta-blockers – Beta-blockers, such as metoprolol (Lopressor, Toprol-XL), bisoprolol, and carvedilol (Coreg), work in multiple ways to treat heart failure and help control arrhythmias.
  • Diuretics – These medications, such as furosemide (Lasix), relieve sodium and fluid retention.
  • Antiviral – The main antiviral drugs studied in myocarditis have been acyclovir, peramivir, ganciclovir, ribavirin, and artesunate, in well-defined viral myocarditis patients (etiology was specifically determined: parvovirus B19, influenza, cytomegalovirus, parainfluenza, herpesvirus, respectively) [, , ].
  • Plasmapheresis/immunoadsorption – has been studied by several groups. A consistent benefit was observed in hemodynamic terms, mainly improvement of ejection fraction. Those protocols include the coadministration of immunoglobulin

Treating severe cases

In some severe cases of myocarditis, aggressive treatment might include:

  • Intravenous (IV) medications. These might improve the heart-pumping function more quickly.
  • Ventricular assist devices. Ventricular assist devices (VADs) are mechanical pumps that help pump blood from the lower chambers of your heart (the ventricles) to the rest of your body. VADs are used in people who have weakened hearts or heart failure. This treatment may be used to allow the heart to recover or while waiting for other treatments, such as a heart transplant.
  • Intra-aortic balloon pump. Doctors insert a thin tube (catheter) in a blood vessel in your leg and guide it to your heart using X-ray imaging. Doctors place a balloon attached to the end of the catheter in the main artery leading out to the body from the heart (aorta). As the balloon inflates and deflates, it helps to increase blood flow and decrease the workload on the heart.
  • Extracorporeal membrane oxygenation (ECMO). With severe heart failure, this device can provide oxygen to the body. When blood is removed from the body, it passes through a special membrane in the ECMO machine that removes carbon dioxide and adds oxygen to the blood. The newly oxygenated blood is then returned to the body.

Surgery

People who do not respond to conventional therapy may be candidates for bridge therapy with left ventricular assist devices. Heart transplantation is reserved for people who fail to improve with conventional therapy.[rx] Extracorporeal membrane oxygenation may be used in those who are about to go into cardiac arrest.[rx]

References

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