Myocarditis: Difference between revisions

The incidence of myocarditis is largely unknown because of difficulties establishing the diagnosis and the lack of a gold standard other than myocardial biopsy, which has a low sensitivity, mostly due to sampling error.  In a recent large registry evaluation of sudden cardiac death in 1866 athletes, myocarditis was considered causative in 6 percent of cases. (Circulation. 2009;119:1085-1092) Endomyocardial biopsy revealed myocarditis in 9% of 1230 patients with idiopathic heart failure. (N Engl J Med 2000 Apr 13;342(15):1077-84) As in the ‘myocarditis treatment trial (N Engl J Med 1995 Aug 3;333(5):269-75), the true prevalence of myocarditis is probably underestimated in patients with ‘idiopathic’ heart failure in these studies. This was recently suggested in a study showing high prevalence of viral genomes in myocardial biopsies of 245 patients with unexplained cardiomyopathy (median ejection fraction 35%). (Circulation. 2005;111:887-893.) See Figure 1.

Most often, myocarditis results from common viral infections. In developed countries, the most frequently identified viruses were enteroviruses (including coxsackievirus) until the 1990s. Now parvovirus B19 and Human Herpes Virus 6 are the viruses most frequently found in patients with acute and chronic cardiomyopathy (Figure 1). PCR of endomyacardial biopsies in 624 patients (approximately 60% children)  with idiopathic heart failure and biopsy-proven myocarditis showed viral genomes in 38% of cases, whereas viral genomes could only be shown in 20% in myocarditis-negative biopsies of 149 patients with heart failure (J Am Coll Cardiol 2003 Aug 6;42(3):466-72). Interestingly, although adenovirus and enterovirus were the most encountered pathogens in both groups, PCR showed other pathogens only in the patients with biopsy-proven myocarditis. Some of these pathogens, especially Parvovirus B19 end Human Herpes Virus-6, were predominantly present in a more recent study, investigating only adult patients (Figure1). There are several potential mechanisms by which a viral myocarditis might cause acute or chronic DCM, including direct viral damage or as a result of humoral or cellular immune responses to persistent viral infection (Figure 2).Our understanding of the pathogenesis of viral myocarditis comes almost entirely from experimental models of acute coxsackie B virus infection. The initial change is myocyte damage in the absence of a cellular immune response. The myocyte injury may be mediated through direct viral toxicity, perforin-mediated cell lysis, and cytokine expression. The second phase which rapidly follows is an innate immune response comprised of altered regulatory T cell function, NK cells, interferon gamma, and nitric oxide. In the third phase, a heart specific immune response is characterized by antibodies to pathogen and host cardiac proteins and autoreactive T cells. Most subjects recover with few consequences, but a minority either die from arrhythmias or progress onto a phase of chronic heart failure. Hemodynamic and neurohumoral stresses lead to ventricular dilatation.

Idiopathic giant cell myocarditis is a rare, virulent, and frequently fatal type of myocarditis that may respond to immunosuppressive therapy. (Am J Cardiol. 2008 Dec 1;102(11):1535-9. Epub 2008 Sep 18.) The pathogenesis of this disorder is not known. In an animal model, a disorder similar to giant cell myocarditis was induced by immunization with cardiac myosin. In this model, myocardial damage is primarily mediated by T lymphocytes.

This is a protozoan infection due to Trypanosoma cruzi; it is a major public health problem in endemic areas in many South American countries. Morbidity is primarily related to three problems: megaesophagus, megacolon, and cardiac disease. Chagas' myocarditis is by far the most common form of cardiomyopathy in Latin American countries. It is estimated that over 750 thousand years of productive life are lost annually, because of premature deaths due to this disorder. In the acute phase it is characterized by intense and diffuse myocarditis with mononuclear infiltrates. The most characteristic cardiac anatomic lesion in the chronic phase is the ventricular apical aneurysm which, in one series, was noted in 52 % of 1078 autopsied Chagasic patients (Br Heart J 1981 Oct;46(4):432-7).

In symptomatic patients, the cardiac presentation is frequently one of acute heart failure , although a syndrome mimicking acute myocardial infarction or a tachyarrhythmia, including sudden death, or high-grade heart block may occur. If the epicardium is involved, the syndrome of myopericarditis develops, often with pleuritic chest pain and pericardial effusion. Severe illness with systemic manifestations of viral disease and heart failure, often referred to as ‘fulminant myocarditis’, may resolve without symptoms but may also lead to heart failure in a limited number of patients. Prognosis seems relatively good compared to ‘Acute Myocarditis’, presenting with heart failure as the main symptom (N Engl J Med 2000 Mar 9;342(10):690-5.). See Figure 3. Most people with myocarditis who present with acute dilated cardiomyopathy have relatively mild disease that resolves with few short-term sequelae, but certain clinical clues signify those at high risk for more difficulty (Table 2). Rash, fever, peripheral eosinophilia, or a temporal relation with recently initiated medications or the use of multiple medications suggest a possible hypersensitivity myocarditis. Giant-cell myocarditis should be considered in patients with acute dilated cardiomyopathy associated with thymoma, autoimmune disorders, ventricular tachycardia, or high-grade heart block. An unusual cause of myocarditis, such as cardiac sarcoidosis, should be suspected in patients who present with chronic heart failure, dilated cardiomyopathy and new ventricular arrhythmias, or second-degree or third-degree heart block or who do not have a response to standard care. Many symptomatic cases of postviral or lymphocytic myocarditis present with a syndrome of heart failure and dilated cardiomyopathy. In  patients who develop heart failure, fatigue and decreased exercise capacity are the most common initial manifestations. However, diffuse, severe myocarditis, if rapid in evolution, can result in acute myocardial failure and cardiogenic shock. Signs of right ventricular failure include increased jugular venous pressure, hepatomegaly, and peripheral edema. The decline in right ventricular function "protects" the left side of the circulation so that signs of left ventricular failure may not be seen. If, however, there is predominant left ventricular involvement, the patient may present with the symptoms of pulmonary congestion: dyspnea, orthopnea, pulmonary rales, and, in severe cases, acute pulmonary edema. Chest pain is usually associated with concomitant pericarditis. However, myocarditis can mimic myocardial ischemia and/or infarction both clinically and on the electrocardiogram, particularly in younger patients. Myocarditis may present with unexpected sudden death, presumably due to ventricular tachycardia or fibrillation. A number of other arrhythmias may be seen. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias, while palpitations secondary to premature atrial or, more often, ventricular extrasystoles are common. The electrocardiogram may be normal or abnormal in myocarditis. However, the abnormalities are nonspecific unless there is pericardial involvement. The changes that may be seen include nonspecific ST abnormalities, single atrial or ventricular ectopic beats, complex ventricular arrhythmias (couplets or nonsustained ventricular tachycardia), or, rarely, atrial tachycardia or atrial fibrillation. High grade heart block is uncommon in lymphocytic myocarditis, but common in cardiac sarcoidosis and idiopathic giant cell myocarditis. Myocarditis can, in some patients, exactly simulate the ECG pattern of acute pericarditis or acute MI. Like acute MI, myocarditis may be associated with regional ST elevations and Q waves. Myocarditis should be suspected in young patients who present with a possible MI but have a normal coronary angiogram. The chest radiograph is variable, ranging from normal to cardiomegaly with or without pulmonary vascular congestion and edema. Considerable biventricular cardiomegaly may be associated with the total absence of pulmonary congestion due to the presence of right ventricular failure and/ or moderate or severe tricuspid regurgitation. Cardiac enzyme elevations are seen in some but not all patients with myocarditis. Persistent elevations in cardiac enzymes are indicative of ongoing necrosis.

Table 2 : Clinical scenarios (N Engl J Med. 2009 Apr 9;360(15):1526-38)

The standard Dallas pathological criteria for the definition of myocarditis require that an inflammatory cellular infiltrate with or without associated myocyte necrosis be present on conventionally stained heart-tissue sections. Criteria are limited by variability in interpretation, lack of prognostic value, and low sensitivity, in part due to sampling error. These limitations have led to alternative pathological classifications with criteria that rely on cell-specific immunoperoxidase stains for surface antigens, such as anti-CD3, anti-CD4, anti-CD20, anti-CD68, and anti–human leukocyte antigen. Criteria that are based on immunoperoxidase staining have greater sensitivity and may have prognostic value. The lack of consensus regarding the value of invasive studies such as endomyocardial biopsy and the overall good prognosis for patients with mild, acute dilated cardiomyopathy who have suspected myocarditis have led to recent recommendations that endomyocardial biopsy should be considered on the basis of the likelihood of finding specific treatable disorders. (Circulation 2007;116:2216-2233). See Table 3. A presumptive diagnosis of myocarditis may be made on the basis of the clinical and laboratory presentations delineated above. This presumption may be strengthened if an echocardiogram or cardiac magnetic resonance imaging is characteristic and does not reveal evidence of other forms of heart disease. Cardiac magnetic resonance (CMR) imaging can detect myocardial edema and myocyte injury in myocarditis. Findings include increase in focal and global T2 signal intensity , increase in focal and global early myocardial contrast enhancement relative to skeletal muscle, and presence of late gadolinium enhancement (LGE) . Late gadolinium enhancement appears to be less sensitive than global relative enhancement or edema ratio for detection of myocarditis, so lack of LGE does not exclude myocarditis. The best diagnostic performance may be obtained by requiring positivity of any two of these three sequences which yielded a 76 percent sensitivity and 96 percent specificity. (J Am Coll Cardiol 2005 Jun 7;45(11):1815-22)

CMR studies have demonstrated that myocarditis often begins as a focal process: In a study using gadolinium-enhanced CMR imaging, 19 patients with clinically suspected myocarditis were compared with 18 normal volunteers. Initial focal increase in relative myocardial enhancement consistent with inflammation became global in serial studies over four weeks. The extent of relative myocardial enhancement correlated with clinical status and left ventricular function. (Circulation 1998 May 12;97(18):1802-9) In a report of 32 patients with clinically suspected myocarditis, 28 (88 percent) had one or more foci of LGE, most often in the left ventricular free wall. Active myocarditis was found in 19 of 21 patients in whom endomyocardial biopsy was performed in the LGE region and in only one of 11 patients in whom the biopsy was performed outside the LGE region. Thus, use of CMR data to guide endomyocardial biopsy may increase the diagnostic yield. (Circulation 2004 Mar 16;109(10):1250-8) The pattern of LGE in myocarditis can generally be distinguished from that in ischemic cardiomyopathy. In myocarditis, LGE preferentially involves the epicardium and mid myocardium with sparing of the endocardium. In ischemic cardiomyopathy, LGE reflects the distribution of myocardial infarction which typically involves the endocardium with variable extension into the mid myocardium and epicardium. Different viral pathogens may produce different focal patterns of myocardial injury. Patients with parvovirus B19 (PVB19) have left ventricular lateral wall subepicardial LGE, while patients with human herpes simplex virus 6 (HHV6) and especially HHV6/PVB19 have septal LGE and heart failure. (Circulation. 2006 Oct 10;114(15):1581-90) See Figure 3. These patterns also seem to be predictive for recovery of myocarditis.

There are a number of causes (primarily infectious) of myocarditis for which there is specific therapy, such as Mycoplasma or Lyme disease (Borrelia burgdorferi). There seems to be a role for antiviral therapy (interferon) in acute and fulminant myocarditis but early results need to be confirmed in larger studies. (Circulation 2003 Jun 10;107(22):2793-8) Immunosuppressive therapy by corticosteroids, cyclosporine and azathioprine does not seem to influence prognosis in general and has been shown to exacerbate murine viral myocarditis. (Circulation 1986 May;73(5):1058-64) Moreover, the high rate of spontaneous recovery may have clouded the results in human trials. Patients with evidence of chronic inflammation, however, may respond favourably to immunosuppressive therapy. (Circulation 2001 Jul 3;104(1):39-45) Unlike lymphocytic myocarditis, patients with Giant cell myocarditis treated with certain immunosuppressive regimes may have a significantly improved survival compared to patients who do not receive immunosuppressive treatment . Among 22 patients treated with immunosuppressive medications the average transplant-free survival was 13 months compared with only three months among 30 patients who did not receive therapy. (N Engl J Med 1997 Jun 26;336(26):1860-6). Myocarditis characterized by a predominantly eosinophilic infiltrate may occur in association with malignancy, parasite infection, hypersensitivity myocarditis (HSM), endomyocardial fibrosis, and with the idiopathic hypereosinophilic syndrome. HSM presents as sudden death or rapidly progressive heart failure sometimes with rash, fever and peripheral eosinophilia. Necrotizing eosinophilic myocarditis has an exceptionally poor prognosis with most cases diagnosed at autopsy. Eosinophilic myocarditis associated with the hypereosinophilic syndrome typically evolves over weeks to months. The presentation is usually biventricular heart failure, although arrhythmias may lead to sudden death. Treatment usually consists of high dose steroids and removal of the offending drug in the case of HSM or treatment of the underlying disorder. Sarcoid myocarditis may respond to treatment with corticosteroids if given before the development of extensive fibrosis of the LV. It is less clear if steroid therapy prevents conduction disease or ventricular arrhythmias. Some recommend an implantable cardioverter-defibrillator (ICD) as primary therapy of ventricular tachycardia since there is a high rate of recurrence of ventricular tachycardia with antiarrhythmic drug therapy, even when guided by electrophysiologic testing.