Eosinophilic myocarditis


Eosinophilic myocarditis is inflammation in the heart muscle that is caused by the infiltration and destructive activity of a type of white blood cell, the eosinophil. Typically, the disorder is associated with hypereosinophilia, i.e. an eosinophil blood cell count greater than 1,500 per microliter. It is distinguished from non-eosinophilic myocarditis, which is heart inflammation caused by other types of white blood cells, i.e. lymphocytes and monocytes, as well as the respective descendants of these cells, NK cells and macrophages. This distinction is important because the eosinophil-based disorder is due to a particular set of underlying diseases and its preferred treatments differ from those for non-eosinophilic myocarditis.
Eosinophilic myocarditis is often viewed as a disorder that has three progressive stages. The first state of eosinophilic myocarditis involves acute inflammation and cardiac cell necrosis; it is dominated by symptoms characterized as the acute coronary syndrome such as angina, heart attack and/or congestive heart failure. The second stage is a thrombotic stage wherein the endocardium of the diseased heart forms blood clots which break off, travel in, and block blood through systemic or pulmonary arteries; this stage may dominate the initial presentation in some individuals. The third stage is a fibrotic stage wherein scarring replaces damaged heart muscle tissue to cause a clinical presentation dominated by a poorly contracting heart and cardiac valve disease. Perhaps less commonly, eosinophilic myocarditis, eosinophilic thrombotic myocarditis, and eosinophilic fibrotic myocarditis are viewed as three separate but sequentially linked disorders in a spectrum of disorders termed eosinophilic cardiac diseases. The focus here is on eosinophilic myocarditis as a distinct disorder separate from its thrombotic and fibrotic sequelae.
Eosinophilic myocarditis is a rare disorder. It is usually associated with, and considered secondary to, an underlying cause for the pathological behavior of the eosinophils such a toxic reaction to a drug, the consequence of certain types of parasite and protozoan infections, or the result of excessively high levels of activated blood eosinophils due to a wide range of other causes. The specific treatment of eosinphilic myocarditis differs from the specific treatment of other forms of myocarditis in that it is focused on relieving the underlying reason for the excessively high numbers and hyperactivity of eosinophils as well as on inhibiting the pathological actions of these cells.

Signs and symptoms

Symptoms in eosinophilic myocarditis are highly variable. They tend to reflect the many underlying disorders causing eosinophil dysfunction as well as the widely differing progression rates of cardiac damage. Before cardiac symptoms are detected, some 66% of cases have symptoms of a common cold and 33% have symptoms of asthma, rhinitis, urticarial, or other allergic disorder. Cardiac manifestations of eosinophilic myocarditis range from none to life-threatening conditions such as cardiogenic shock or sudden death due to abnormal heart rhythms. More commonly the presenting cardiac symptoms of the disorder are the same as those seen in other forms of heart disease: chest pain, shortness of breath, fatigue, chest palpitations, light headedness, and syncope. In its most extreme form, however, eosinophilic myocarditis can present as acute necrotizing eosinophilic myocarditis, i.e. with symptoms of chaotic and potentially lethal heart failure and heart arrhythmias. This rarest form of the disorder reflects a rapidly progressive and extensive eosinophilic infiltration of the heart that is accompanied by massive myocardial cell necrosis.
Hypereosinophilia or, less commonly, eosinophilia are found in the vast majority of cases of eosinophilic myocarditis and are valuable clues that point to this rather than other types of myocarditis or myocardial injuries. However, elevated blood eosinophil counts may not occur during the early phase of the disorder. Other, less specific laboratory findings implicate a cardiac disorder but not necessarily eosinophilic myocarditis. These include elevations in blood markers for systemic inflammation, elevations in blood markers for cardiac injury ; and abnormal electrocardiograms.

Eosinophilic coronary periarteritis

Eosinophilic coronary periarteritis is an extremely rare heart disorder caused by extensive eosinophilic infiltration of the adventitia and periadventitia, i.e. the soft tissues, surrounding the coronary arteries. The intima, tunica media, and tunica intima layers of these arteries remain intact and are generally unaffected. Thus, this disorder is characterized by episodes of angina, particularly Prinzmetal's angina, and chaotic heart arrhythmias which may lead to sudden death. The disorder is considered distinct from eosinophilic myocarditis as well as other forms of inflammatory arterial disorders in that it is limited to the coronary artery system.

Cause

There are many causes of eosinophilia that may underlie eosinophilic myocarditis. These causes are classified as primary, secondary, or idiopathic. Non-idiopathic causes of the disorder are sub-classified into various forms of allergic, autoimmune, infectious, or malignant diseases and hypersensitivity reactions to drugs, vaccines, or transplanted hearts. While virtually any cause for the elevation and activation of blood eosinophils must be considered as a potential cause for eosinophilic myocarditis, the follow list gives the principal types of eosinophilia known or thought to underlie the disorder.
Primary conditions that may lead to eosinophilic myocarditis are:
Secondary conditions that may lead to eosinophilic myocarditis are:
The DRESS syndrome is a severe immunological drug reaction. It differs from other drug reactions in that it: a) is caused by a particular set of drugs; b) typically occurs after a delay of 2 to 8 weeks following intake of an offending drug; c) presents with a specific set of signs and symptoms ''' involves reactivation of latent viruses, most commonly human herpesvirus 6 or more rarely human herpes virus 5, human herpesvirus 7, and human herpesvirus 4. These virus usually become dormant after infecting humans but under special circumstances, such as drug intake, are reactivated and may contribute to serious diseases such as the DRESS syndrome.

Pathophysiology

Eosinophils normally function to neutralize invading microbes, primarily parasites but also certain types of fungi and viruses. In conducting these functions, eosinophils normally occupy the gastrointestinal tract, respiratory tract, and skin where they produce and release on demand a range of toxic reactive oxygen species and also release on demand a preformed armamentarium of chemical signals including cytokines, chemokines, growth factors, lipid mediators, and toxic proteins. These agents serve to orchestrate robust inflammatory responses that destroy invading microorganisms. Eosinophils also participate in transplant rejection, Graft-versus-host disease, the destruction or walling off of foreign objects, and the killing of cancer cells. In conducting these functions, eosinophils enter tissues that they do not normally occupy.
When overproduced and over-activated, such as in cases of eosinophilic myocarditis, eosinophils behave as though they were attacking a foreign or malignant tissue: they enter a seemingly normal organ such as the heart, misdirect their reactive oxygen species and armamentarium of preformed molecules toward seemingly normal tissue such as heart muscle, and thereby produce serious damage such as heart failure. Animal model studies suggest reasons why eosinophils are directed to and injure the heart muscle. Mice made hypereosinophilic by the forced overexpression of an interleukin-5 transgene develop eosinophilic myocarditis. A similar eosinophilic endocarditis occurs in mice immunized with the cardiac muscle protein, mouse myosin. In the latter model, endocarditis is reduced by inhibiting the cytokine interleukin-4 or eosinophils and is exacerbated by concurrently blocking two cytokines, interferon gamma and interleukin-17A. Finally, certain eosinophil-attracting agents, viz., eotaxins, are elevated in the cardiac tissue of myosin-immunized mice that are concurrently depleted of interferon gamma and interleukin-17A. Eotaxins are also elevated in the cardiac muscle biopsy specimens of individuals with eosinphilic myocarditis compared to their levels in non-eosinophiliic myocarditis. These findings suggest that eosinophilic myocarditis is caused by the abnormal proliferation and activation of eosinophils and that their directional migration into the heart is evoked by a set of cytokines and chemoattractants in mice and possibly humans.

Diagnosis

In eosinophilic myocarditis, echocardiography typically gives non-specific and only occasional findings of endocardium thickening, left ventricular hypertrophy, left ventricle dilation, and involvement of the mitral and/or tricuspid valves. However, in acute necrotizing eosinophilic myocarditis, echocardiography usually gives diagnostically helpful evidence of a non-enlarged heart with a thickened and poorly contracting left ventricle. Gadolinium-based cardiac magnetic resonance imaging is the most useful non-invasive procedure for diagnosing eosinophilic myocarditis. It supports this diagnosis if it shows at least two of the following abnormalities: a) an increased signal in T2-weighted images; b) an increased global myocardial early enhancement ratio between myocardial and skeletal muscle in enhanced T1 images and c) one or more focal enhancements distributed in a non-vascular pattern in late enhanced T1-weighted images. Additionally, and unlike in other forms of myocarditis, eosinophilic myocarditis may also show enhanced gadolinium uptake in the sub-endocardium. However, the only definitive test for eosinophilic myocarditis is cardiac muscle biopsy showing the presence of eosinophilic infiltration. Since the disorder may be patchy, multiple tissue samples taken during the procedure improve the chances of uncovering the pathology but in any case negative results do not exclude the diagnosis.

Treatment

Due to its rarity, no comprehensive treatment studies on eosinophilic myocarditis have been conducted. Small studies and case reports have directed efforts towards: a) supporting cardiac function by relieving heart failure and suppressing life-threatening abnormal heart rhythms; b) suppressing eosinophil-based cardiac inflammation; and c) treating the underlying disorder. In all cases of symptomatic eosinophilic myocarditis that lack specific treatment regimens for the underlying disorder, available studies recommend treating the inflammatory component of this disorder with non-specific immunosuppressive drugs, principally high-dosage followed by slowly-tapering to a low-dosage maintenance corticosteroid regimens. It is recommended that afflicted individuals who fail this regimen or present with cardiogenic shock be treated with other non-specific immunosuppressive drugs viz., azathioprine or cyclophosphamide, as adjuncts to, or replacements for, corticosteroids. However, individuals with an underlying therapeutically accessible disease should be treated for this disease; in seriously symptomatic cases, such individuals may be treated concurrently with a corticosteroid regimen. Examples of diseases underlying eosinophilic myocarditis that are recommended for treatments directed at the underlying disease include:
The prognosis of eosinophilic myocarditis is anywhere from rapidly fatal to extremely chronic or non-fatal. Progression at a moderate rate over many months to years is the most common prognosis. In addition to the speed of inflammation-based heart muscle injury, the prognosis of eosinophilc myocarditis may be dominated by that of its underlying cause. For example, an underlying malignant cause for the eosinophilia may be survival-limiting.

History

In 1936, the famed Swiss physician Wilhem Löffler first described heart damage that appeared due to massive cardiac eosinophil infiltrations and was associated with excessively high levels of blood eosinophils. Subsequent cases of this disorder, termed Loeffler endocarditis, were found to occur in about 20% of individuals diagnosed with the hypereosinophilic syndrome. Loeffler's and the latter cases had pathological features of eosinophil infiltrations not only into the heart's myocardium but also its epicardium. Although eosinophilic myocarditis due to other underlying causes may show little or no eosinophil infiltrations into the endocardium, Loeffler endocarditis is considered an important form of the disorder.