Hypersensitivity myocarditis. High magnification of myocardium with perivascular infiltrates rich in eosinophils. This patient had a clinical history compatible with drug-induced hypersensitivity myocarditis.
Myocarditis, a disease of adult and pediatric patients, is an inflammatory disorder of the myocardium that is typically caused by a viral infection. Necrosis of the myocytes and associated inflammatory infiltrate are seen in this disorder. (See Etiology.)[1]
Myocarditis particularly arises from adenovirus and enterovirus infections (eg, coxsackievirus), although many infectious organisms commonly seen in infants and children have been implicated in the disease. Occasionally, myocarditis may be a manifestation of drug hypersensitivity or toxicity. (See Etiology.)
Although the use of myocardial biopsy is debated, suspected myocarditis can be classified into the following 3 types based on pathologic findings as defined in the Dallas Criteria (1987) (See Workup.)[2] :
If an active or borderline inflammatory process is found, follow-up biopsy findings can be subclassified into ongoing, resolving, or resolved myocarditis. (See Workup and Treatment.)
Myocarditis generally results in a decrease in myocardial function, with concomitant enlargement of the heart and an increase in the end-diastolic volume caused by increased preload. Normally, the heart compensates for dilation with an increase in contractility (Starling law), but because of inflammation and muscle damage, a heart affected with myocarditis is unable to respond to the increase in volume.
In addition, inflammatory mediators, such as cytokines and adhesion molecules, as well as apoptotic mechanisms, are activated. The progressive increase in left ventricular end-diastolic volume increases left atrial, pulmonary venous, and pulmonary arterial pressures, resulting in increasing hydrostatic forces. These increased forces lead to pulmonary edema and congestive heart failure. Without treatment, this process may progress to end-stage cardiac failure and death.
Adenovirus and Ebstein-Barr virus have been considered the most common viruses that cause myocarditis. However, studies have found that, using polymerase chain reaction (PCR) assay for the diagnosis, parvovirus B19 and human herpesvirus 6 are the most frequent pathogens in patients with acute myocarditis.[3, 4, 5]
Infecting organisms include the following:
The coxsackievirus and adenovirus receptor acts as the receptor for the 4 most common viruses that cause human myocarditis: type C (type 2 and type 5) adenovirus and coxsackievirus B3 and B4. Coxsackievirus B serotypes 1-6 have been associated with human myocarditis, but the most serious cases have been attributed to types 3 and 4.
In 1973, Lerner and Wilson developed an animal model of myocarditis using mice inoculated with coxsackievirus B3.[7] This model was characterized by an early and a late phase. Following inoculation of the mice with the virus, initial replication of the virus occurred, with maximum replication within 3-5 days. By day 5, focal myocyte necrosis was evident. On day 7, most mice showed no further inflammation, and no organisms could be recovered; however, some mice showed ongoing, worsening inflammation similar to that seen in humans.
The primary response to the early phase of viral infection is the release of natural killer (NK) cells, which lyse infected myocytes. This helps to clear the virus from the system.
NK cells also induce the expression of major histocompatibility complex antigens on myocytes by releasing cytokines, which prepare the NK cells to interact with T lymphocytes. Animal models depleted of NK cells develop a more severe form of myocarditis.
The late phase, or second wave of T lymphocytes (CD4, CD8), begins approximately 1 week after the mouse has been inoculated with the virus. T lymphocytes can injure cells in the following 3 ways:
These ongoing processes are considered to be genetically mediated autoimmune processes. Two different strains of cytolytic T cells have been recognized; one strain attacks virus-infected myocytes and the other strain attacks uninfected cells.
Apoptosis, as well as enzymatic cleavage by viral proteins of cytoskeletal proteins, appears to play a role in development of dilated cardiomyopathy.
Various kinds of autoantibodies have been found in as many as 60% of patients with myocarditis. These include complement-fixing antimyolemmal antibodies, complement-fixing antisarcolemmal antibodies, antimyosin heavy chain antibodies, and anti–alpha myosin antibodies. Although their role in the disease is not completely understood, their presence may serve as a marker for diagnosing myocarditis in the future.
Myocarditis is a rare disease. The World Health Organization (WHO) reports that the incidence of cardiovascular involvement after enteroviral infection is 1-4%, depending on the causative organism. Incidence widely varies among countries and is related to hygiene and socioeconomic conditions. Availability of medical services and immunizations also affect incidence. Occasional epidemics of viral infections have been reported with an associated higher incidence of myocarditis. Enteroviruses (eg, coxsackievirus, echovirus) and adenoviruses, particularly types 2 and 5, are the most commonly involved organisms.
No sex predilection is observed in humans in viral myocarditis, but some research in laboratory animals suggests that the disease may be more aggressive in males than in females. Certain strains of female mice had a reduced inflammatory process when treated with estradiol. In other studies, testosterone appeared to increase cytolytic activity of T lymphocytes in male mice.
No age predilection is noted in viral myocarditis. However, younger patients, especially newborns and infants, as well as immunocompromised patients, may have increased susceptibility to myocarditis.
Studies give a wide spectrum of mortality and morbidity statistics. With suspected coxsackievirus B, the mortality rate is higher in newborns (75%) than in older infants and children (10-25%).[8]
Complete recovery of ventricular function has been reported in as many as 50% of patients. Some patients develop chronic myocarditis (ongoing or resolving), and an association has been suggested between myocarditis and the development of dilated cardiomyopathy. Those who develop dilated cardiomyopathy may require a heart transplant.
Viral myocarditis may be a fatal disease during pregnancy; however, pregnant women are not at a higher risk of developing viral myocarditis compared with the general population.
Complications of myocarditis may include the following:
Clinical presentation of viral myocarditis widely varies. In mild forms, few or no symptoms are noted. In severe cases, patients may present with acute cardiac decompensation and progress to death usually weeks after the initial viral infection and prodromal symptoms.
Heart failure is the most common presenting picture in all ages. The condition of patients who present with heart failure may rapidly deteriorate even with supportive care. Neonates and young children have higher mortality rates than older patients. Rapid supportive care with blood pressure support, afterload reduction, diuretic therapy, and control of arrhythmia may prevent early death.
Although rare in young children, chest pain may be the initial presentation for older children, adolescents, and adults. Chest pain may be due to myocardial ischemia or concurrent pericarditis.
Patients can present with any type of dysrhythmia, including atrioventricular conduction disturbances. Sinus tachycardia is typically a compensatory mechanism in patients with myocardial dysfunction, and the rate is faster than expected for the degree of fever present, which is typically low-grade. Junctional tachycardia is also seen and can be difficult to control medically.
The debate continues over whether myocarditis progresses to dilated cardiomyopathy. Many investigators believe that dilated cardiomyopathy is a direct result of a previously burned-out myocarditis episode.
Initial symptoms in infants include the following:
Older children present with similar symptoms and may experience lack of energy and general malaise. Parents of pediatric patients may refer to a recent, nonspecific, flulike illness, gastrointestinal (GI) symptoms, poor feeding, or rapid breathing.
Signs of diminished cardiac output, such as tachycardia, weak pulse, cool extremities, decreased capillary refill, and pale or mottled skin, may be present (see the Cardiac Output calculator). Heart sounds may be muffled, especially in the presence of pericarditis. An S3 may be present, and a heart murmur caused by atrioventricular valve regurgitation may be heard. Hepatomegaly may be present in younger children. Rales may be heard in older children. Jugular venous distention and edema of the lower extremities may be present in older patients.
Neonates may seem irritable, be in respiratory distress, and exhibit signs of sepsis. Somnolence, hypotonia, and seizures can be associated if the central nervous system (CNS) is involved.
Hypothermia or hyperthermia, oliguria, elevated liver enzymes, and elevated blood urea nitrogen (BUN) and creatinine levels caused by direct viral damage, low cardiac output, or both may be present.
Signs include failure to thrive, anorexia, tachypnea, tachycardia, wheezing, and diaphoresis with feeding. End-organ damage may develop because of direct viral infestation or because of low cardiac output. CNS involvement may also develop. In severe cases, low cardiac output may progress to acidosis and death.
The presentation of viral myocarditis may be similar to that in younger children but with a more prominent decrease in exercise tolerance, lack of energy, malaise, chest pain, low-grade fever, arrhythmia, and cough. End organ damage and low cardiac output may be present.
Perform a complete blood count (CBC) with differential. Acute anemia of any origin may cause heart failure, and chronic anemia exacerbates heart failure; both respond to blood transfusion. The presence of lymphocytosis or neutropenia supports diagnosis of a viral infection. In addition, perform blood cultures; ruling out any bacterial infection is important.[9]
Additional tests to perform are as follows:
Other techniques are under investigation to determine a specific viral etiology of myocarditis, such as immunohistochemical stains, inflammatory mediators, and autoantibody measurements.
On chest radiography, cardiomegaly and pulmonary edema may be depicted. Incidentally noted cardiomegaly on chest radiography may be the initial presentation.
Magnetic resonance imaging (MRI) with gadolinium can be used to evaluate the cardiac muscle inflammation via a special protocol for myopericarditis.
Echocardiography is the most cost-effective test used for evaluation of myocardial function. It is sensitive but not specific. Findings include the following:
Radionuclide imaging may be helpful as a screening tool. Gallium 67 (67 Ga) citrate myocardial scintigraphy is useful for revealing chronic inflammatory processes. It is a sensitive test but is limited by its low specificity and predictive value.
Indium 111 (111 In) antimyosin antibody imaging is highly sensitive for myocardial necrosis, but it has a high incidence of false-positive results. However, absence of antimyosin uptake is highly predictive of negative biopsy findings (92-98%).
Myocardial perfusion imaging with technetium 99m–labeled methoxyisobutyl isonitrile single-photon emission computed tomography (99m Tc-MIBI SPECT) scanning is usually a tool used to evaluate the severity of myocardial ischemia.[12] Because the uptake and clearance of99m Tc-MIBI is affected by cell viability and membrane integrity, clinicians have also used it as a marker for the severity of myocardial necrosis and inflammation in patients with myocarditis, with results comparable to those obtained with enzymatic cell damage markers.
In some patients with mild cardiac involvement, electrocardiographic changes may be the only abnormal findings suggestive of myocarditis. Low-voltage QRS (< 5 mm throughout the limb leads) is the classic pattern. Pseudoinfarction patterns with pathologic Q waves and poor progression of R waves in the precordial leads may also be present. T-wave flattening or inversion is a common finding associated with small or absent Q waves in V5 and V6.
Left ventricular hypertrophy with strain may be present. Other, nonspecific findings include prolonged PR segment and prolonged QT interval.[13]
Sinus tachycardia is the most common finding. Premature ventricular contractions and atrial tachycardias have been reported. Junctional tachycardia is common and may worsen congestive heart failure. Occasional second-degree and third-degree atrioventricular block may be present, requiring temporary pacing. Ventricular tachycardia may be associated with active myocardial inflammation early in the disease process or occur late in the course of the disease when myocardial fibrosis has developed.
Right ventricular endomyocardial biopsy is the criterion standard for the diagnosis of myocarditis.[14] Myocardial biopsy findings establish diagnosis and classify disease stage. Biopsy is a relatively safe and effective way to sample heart muscle in older children; however, a risk of perforation in sick or younger infants is observed.
The use of endomyocardial biopsy is controversial because of the possibility of a high false-negative result rate and because no proven therapy is available, even when a positive biopsy finding is obtained. Some advocate using radionuclide imaging techniques as screening tools before considering endomyocardial biopsy.
Biopsy specimens may be useful for PCR assay diagnosis of viral etiology. Viral serology in adults has been shown to have poor sensitivity and specificity compared with endomyocardial biopsy with PCR assay detection of the viral genome under diagnostic testing.[15]
Gross evaluation of the heart reveals flabby and pale muscle with petechiae. Ventricular muscle is usually thin and may be hypertrophied. Heart valves and the endocardium are not usually involved, but in cases of chronic myocarditis, they might appear as they appear in endocardial fibroelastosis. Some experts believe that endocardial fibroelastosis is a result of viral myocarditis that occurred much earlier.
The microscopic hallmark of acute myocarditis is focal or diffuse interstitial infiltrate of mononuclear cells, lymphocytes, plasma cells, and eosinophils. Viral particles are rarely seen unless searched for with special techniques (ie, PCR assay). Necrosis and disarrangement of the myocytes are typical and often are seen with coxsackievirus infection. In the chronic and healing stages, myocytes are replaced by fibroblasts (scar tissue).[16]
In adenoviral myocarditis, the infiltrate seen histologically is less severe than is seen in cases of enteroviral infection.
In the acute phase of viral myocarditis, the patient should be admitted to the hospital, even if only mild signs of respiratory distress or congestive heart failure are present. Rapid progression to overt heart failure, hemodynamic collapse, or both may occur. Consultation with a cardiologist is indicated. Transfer to a facility with intensive and cardiology care may be required.
Medical care is aimed at minimizing the body’s hemodynamic demands. No specific proven therapy is available to prevent myocardial damage, but maintenance of tissue perfusion is the goal to avoid further complications. Normal arterial blood oxygen levels should be maintained with supplemental oxygen as needed.
Conventional management of viral myocarditis includes the use of digoxin, diuretics, and afterload reduction. Severe cases with hemodynamic compromise may require intravenous inotropic agents, afterload reduction, vasodilators, and anticoagulation. Discharge patients with viral myocarditis when they are stable on oral medications.
Extracorporeal membrane oxygenation (ECMO) has been used as an interim treatment to provide rest to the heart and as a bridge for transplant in selected patients with good results. Left ventricular assist devices may also be utilized in those patients with poor left ventricular function that does not recover and as a bridge to transplantation.
A low-salt diet is recommended for patients with congestive heart failure. Bed rest is necessary during the acute phase of the illness and may slow the intramyocardial replication of the virus. Activity is permitted as partial or complete recovery is achieved. Restrict patient activity based on performance after the acute phase.
Monitor medication doses and adverse effects. Serial echocardiography is useful in monitoring ventricular function. Avoid negative inotropes. Be aware of the possibility of a further decrease in ventricular function.
If congestive heart failure is present in a patient with viral myocarditis, digitalis may be useful in maintaining adequate function. Diuretics can be given concomitantly to remove excess extracellular fluid and to decrease preload. Caution should be exercised, because removal of fluid may cause low cardiac output and shock (see the Cardiac Output calculator). A higher venous-filling pressure may be necessary to maintain an adequate cardiac output. Intracardiac pressure monitoring can facilitate maintenance of adequate filling pressures.
Inotropic agents are used when cardiac output cannot be maintained by less invasive measures. Dopamine, dobutamine, inamrinone (formerly amrinone), and milrinone are the most commonly used vasopressors.
Afterload reduction is most important in treating acute myocarditis and is used when hypotension is not present. This decreases the workload for the compromised myocardium and can allow patients to recover from the acute phase of illness. Agents that reduce afterload improve cardiac output by decreasing systemic arterial resistance. Intravenous medications such as nitroprusside, inamrinone, and milrinone can be replaced with oral angiotensin-converting enzyme (ACE) inhibitors when the patient stabilizes.
The use of immunosuppressive agents for the treatment of viral myocarditis is still controversial. Some animal studies revealed an exacerbation of viral cytotoxicity when subjects were treated with immunosuppressive agents. Small series in humans have shown that the condition of patients improves when the patients are treated with these agents.
In a randomized study of 111 patients, the Multicenter Myocarditis Treatment Trial found that left ventricular function and survival did not significantly differ between patients given any of the following 3 treatment modalities[17] :
Intravenous gamma globulin may be important in the treatment of acute myocarditis.[18, 19] It has been associated with improved left ventricular function and improved survival.
New therapeutic agents are being studied as candidates for the treatment of myocarditis. These include agents that inhibit the virus entrance to the cells; antiviral agents that inhibit translation, transcription, or both; and interferon, among others. However, these strategies are still in early stages, and although they have shown promising results, some time may go by before they are widely accepted.
Pleconaril, an investigational agent that inhibits viral attachment to host cell receptors, has broad antienteroviral activity and, in clinical trials, has demonstrated benefit in children with enteroviral meningitis. This medicine is being tested in children with myocarditis. Pleconaril is currently an investigational drug from Schering-Plough Corporation.
Clinical Context: Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Digoxin's indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
These agents may improve left ventricular function by increasing myocardial contraction through inhibition of the sodium/potassium adenosine triphosphatase (ATPase) pump. This leads to sodium accumulation within the myocyte, which stimulates the sodium-calcium exchange. The increased intracellular calcium increases the force of contraction.
Clinical Context: This loop diuretic is the diuretic of choice in pediatric patients. It increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule.
Clinical Context: This is a thiazide diuretic. If given with furosemide, it may decrease hypercalciuria. Chlorothiazide inhibits sodium reabsorption at the distal tubule in the kidney.
Clinical Context: Spironolactone is a potassium-sparing diuretic. It acts on the distal convoluted tubule of the kidney as an aldosterone antagonist.
Hypoperfusion of the kidneys causes retention of sodium and water, which produces peripheral and pulmonary edema. Diuretics decrease the intravascular volume overload.
Clinical Context: Captopril reduces afterload and myocyte necrosis. It is beneficial in all stages of chronic heart failure. The drug's pharmacologic effects result in a decrease in systemic vascular resistance, reducing blood pressure, preload, and afterload. Dyspnea and exercise tolerance are improved.
Clinical Context: A competitive ACE inhibitor, enalapril reduces angiotensin II levels, decreasing aldosterone secretion. The drug lowers systemic arterial blood pressure, reducing injury caused by elevated blood pressure. It may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms. Enalapril may be used every day or twice per day, which may improve compliance in comparison with a 3-time-per-day medication, such as captopril.
Cardiac output and systemic resistance determine blood pressure. When systemic resistance is decreased with afterload reduction, myocardial shortening and stroke volume improve. Therefore, cardiac output can be maintained at a lower heart rate with lower myocardial oxygen demand. ACE inhibitors decrease the production of angiotensin II, a potent vasoconstrictor. High levels of angiotensin II have also been associated with cellular damage in patients with myocarditis.
Clinical Context: At lower doses, this drug stimulates beta1-adrenergic and dopaminergic receptors (renal vasodilation, positive inotropism); at higher doses, it stimulates alpha-adrenergic receptors (renal vasoconstriction).
Clinical Context: Dobutamine stimulates beta1-adrenergic receptors. It has less alpha1 stimulation than dopamine; therefore, it produces less of an increase in systemic vascular resistance.
Dopamine is a precursor to epinephrine; thus, it augments the endogenous release of catecholamines. It also stimulates specific dopamine receptors. Dobutamine does not promote the release of endogenous epinephrine; it predominantly augments myocardial contractility via beta1 stimulation.
Clinical Context: Inamrinone produces vasodilation and increases the inotropic state. This agent is more likely to cause tachycardia than dobutamine is, and it may exacerbate myocardial ischemia.
Clinical Context: Milrinone is a bipyridine with positive inotropic and vasodilator effects and little chronotropic activity. Milrinone is different in mode of action from digitalis glycosides and catecholamines.
Inotropic effects occur through the inhibition of cyclic adenosine monophosphate (c-AMP) phosphodiesterase, which increases the cellular levels of c-AMP. The sodium-potassium pump is not affected, as with digitalis. Vasodilatory activity is related to the direct relaxation effect on vascular smooth muscle.
Clinical Context: Use of these agents in myocarditis is not widely accepted. Clinical studies have shown that intravenous immunoglobulin (IVIG) may improve left ventricular function and survival in children.
Immunoglobulin is a purified preparation of gamma globulin. It is derived from large pools of human plasma and consists of 4 subclasses of antibodies, approximating the distribution of human serum.
Hypersensitivity myocarditis. High magnification of myocardium with perivascular infiltrates rich in eosinophils. This patient had a clinical history compatible with drug-induced hypersensitivity myocarditis.
