Vedide Tavlı¹ and Murat Muhtar Yılmazer²
Şifa University of Medicine, Department of Pediatric Cardiology, İzmir –TURKEY
Dicle University, Heart Center , Department of Pediatric Cardiology, Diyarbakır-TURKEY
Myocarditis is an inflammatory process of the heart with necrosis and degeneration of adjacent myocytes by immune-mediated responses frequently resulting from viral infections, systemic diseases, toxins and drugs. In most children, myocarditis is triggered by an infection agent. Among the viral agents, enteroviruses (particularly Coxsackie) and adenovirus were recognized as the major cause of viral myocarditis (Baboonian&Treasure, 1997; Pauschinger et al, 1999). Despite the development of diagnostic and therapatic modalities, acute myocarditis continues to be a significant cause of morbidity and mortality among children and young adults. The true overall incidence of myocarditis remain obscure due to inconsistency of its definition and clinical manifestation in the paediatric population. Post-mortem study from Sweden reported incidence of myocarditis to be 1.06 % in 12.747 consecutive autopsies (Gravanis & Sternby, 1991). Annual incidence was estimated as 1 per 100 000 (Karjalainen et al., 1999, Lipshultz SE., 2003, Levine et al., 2010).However myocarditis continues to be implicated in 8.6 to 12% of sudden cardiac deaths in young adults (Fabre et al., 2006). A significant part of the cases with myocarditis progress to a dilated cardiyomyopathy (DCM) which is currently the most frequent reason for heart transplantation (Maron et al.,2006, Kindermann et al., 2012). It seems that persistence of viral yine expression in myocytes and the accompanying immune response may cause a more chronic dilated type of cardiomyopathy (Kearney et al., 2001). A clinical picture of myocarditis is extremely variable, ranging from asymptomatic ECG abnormalities to heart failure (Dec et al., 1985, Bowles et al., 2003).The diagnosis should be suspected when an infant presents with poor feeding, irritability or listlessness, diaphoresis, apnea and episodic pallor or a child presents with viral prodrome of flu-like illness, shortness of breath, fatigue, an unexplained new arrhythmia or acute cardiac failure (Levine et al., 2010, Kindermann et al., 2012, Tavli et al., 2012). Recent history of viral disease 10 to 14 days preceding presentation typically occurs in older children and adolescents (Friedman et al., 1998). Although viral infections are the most suspected triggers in etiology ,the utility of viral serology in the diagnosis of myocarditis remains controversial.Therefore, other non-invasive methods such as echocardiography, magnetic resonance imaging, electrocardiograhy are usually available at the initial phase. The increasing use of these methods allows the initiation of medical treatment without a significant delay from the onset of the initial infection. However, endomyocardial biopsy (EMB) remains the gold standard in diagnosis of myocarditis. Recently, the use of some immunohistological methods in interpreting the biopsy specimens markedly increased the EMB revealing myocarditis. At present, diagnosis has been made by use of pathological classification, commonly referred to as Dallas criteria (Aretz et al., 1987). On the basis of these criteria, myocarditis is described as active or borderline myocarditis in accordance with the presence or absence, respectively, of myocardial necrosis.
Despite the evolving of treatment strategies for myocarditis due to improved understanding of pathophysiology, only supportive treatment is available in most cases.
Therapy with inotropes and afterload reduction drugs is mandatory for maintance of sufficient cardiac output. However administration of beta blokers has been found to be associated with improvement of left ventricle function and clinical symptoms. Since autoimmunity plays a key role in the pathogenesis of myocarditis, immune therapy with immune supressive agents have been tested for a long time, where the treatment with immune supressive agents have shown controversial results. Intravenous immunoglobulin (IVIG) treatment was observed to ameliorate myocardial injury in experimental autoimmune myocarditis. The results of a randomized clinical trail suggested that IVIG did not enhance an improvement in ejection fraction (EF) in adults. However, IVIG has demonstrated itself to be a promising treatment option
in children with acute myocarditis. Patients with myocarditis may recover, develop DCM, or die, in the follow-up. The purpose of this review is to give a brief and complete discussion of diagnosis and management of myocarditis in the light of the recent advances.
Diagnosis
Despite a variety of diagnostic methods for making diagnosis of the myocarditis. the diagnosis of myocarditis is often difficult to establish. The diagnosis of myocarditis requires a high index of suspicion, particularly in children, as it may mimic other common diseases (Baker E., 2010).World Health Organization (WHO)/International Society and Federation of Cardiology (ISFC) was defined myocarditis as an inflammatory disease of the heart muscle, diagnosed by established histological, immunological, and immunohistochemical criteria (Richardson P et al., 1996 ). Since there are no specific test for myocarditis, the best way that help support a suspected diagnosis may be through a clinical symptoms, followed by a thorough medical history and physical examination. However the diagnosis of myocarditis based on the clinical presentation alone is usually not possible (Kindermann et al., 2012), because clinical manifestation of myocarditis varies with a broad spectrum of symptoms including asymptomatic courses. Several diagnostic methods can be performed that help support a suspected diagnosis of myocarditis. Endomyocardial biopsy is most frequently used to establish a definitive diagnosis of myocarditis. Dallas criterions were proposed in 1986 (Aretz et al., 1987) provide standardised histopathological categorizations for defining myocarditis according to the presence of histological evidence of an inflammatory infiltrate in myocites and associated myocyte necrosis or damage not due to ischaemia.Unfortunately myocardial biopsy is diagnostically sensitive in a few number of cases. A large number of biopsy specimens should be taken to increase the sensitivity of EMB. Appropriate diagnostic methods include the following
Electrocardiography and chest radiography
Electrocardiography (ECG) and chest radiography can be used as first line diagnostic. modality after clinical assessment. Previous studies have reported a high incidence of ECG
abnormalities in myocarditis.( Di Bella et al., 2012, Dec et al., 1992, Morgera et al., 1992). Generally, patients can exhibit dysrhythmias, conduction system abnormalities. The most common ECG abnormality in myocarditis is sinus tachycardia with nonspecific ST/T-wave changes (Punja et al., 2010). Other electrocardiographic changes include pathological Q waves, T wave inversion,low QRS voltages and atrial, ventricular, or intraventricular conduction delays, (Ukena et al., 2011, Morgera et al., 1992, Pauschinger et al., 2006). These ECG patterns, none of which are pathognomonic but most of these can also be observed in the acute coronary syndrome and pericarditis (Di Bella et al., 2012, Brady et al., 2001, Wang et al., 2003 ). Myocarditis is usually characterized by patchy lesions that differs from myocardial ischemic damage which results in a continous lesions (Di Bella et al., 2012, de Werf F et al., 2008, Magnani et al., 2006). However the ECG findings are also limited in myocarditis to identified the location of myocardial involvement (Di Bella et al., 2012.) While the high prevalence of repolarization abnormalities (40.2% of all patients) and Q-waves (12.8% of all patients) in myocarditis was confirmed, only a prolonged QRS interval proved to independently predict cardiac death and heart transplantation in a recent study (Ukena et al., 2011) that included a large cohort of patients. Moreover,evidence from previous studies suggests that the presence of northwest axis deviation, new left bundle branch block and abnormal QRS complexes is correlated with higher rates of transplantation or death (Magnani et al., 2006, Morgera et al.,1992, Nakashima et al., 1998,Greenwood et al. 1976).
In the majority of cases of myocarditis (up to 90%), abnormal chest radiography was documented (Durani et al., 2009, Freedman et al., 2007). Most common chest radiography finding is cardiomegaly, followed by pulmonary edema and pulmonary infiltrate. However the heart size may be olağan in whom with acute, haemodynamically compromising left ventricular dysfunction (Baker E., 2010).
Laboratory findings
Despite the markers for inflammation such as C-reactive protein and erythrocytic sedimentation rate are commonly elevated, they are not usually helpful in confirming the diagnosis of myocarditis. Cardiac biomarkers of myocardial injury such as troponin I and T and cardiac isoform of creatine kinase (CK-MB) may be of use. Elevations of serum CK and CK-MB have been previously reported in myocarditis (Bachmaier et al., 1995, Dec et al., 1985). However elevation of CK and CK-MB levles are less sensitive and specific than troponin (Bachmaier et al., 1995, Baker E, 2010) .Therefore these are not clinically useful for screening of myocarditis.Cardiac troponin I, subunit of thin filament of contractile element of the myocardium, has high specificity (89%) and low sensitivity (34%) (Baker E, 2010) in adult patients with acute myocarditis, whereas cTnT has been documented to have a specificity of 83% and sensitivity of 71% in children. Cardiac troponin t (cTnT) has also been investigated as a diagnostic marker foracute myocarditis since 1990’s. cTnT, a contractile protein unique to cardiac muscle, is vastly concentrated in the myocytes and will be released into the blood within hours after heart muscle injury. Following myocardial cell necrosis an increased concentration of cTnT is noticable in blood for more than a week. Cardiac troponin T measurements are especially useful in clinical settings in which traditional enzyme determinations fail to diagnose myocardial cell damage effectively. Braın natrıuretıc peptıde (BNP) ıs also cardıac hormone that levels increase in patients with congestive heart failure and in acute myocardial infarction. Previous studies shown that plasma BNP levels increased in the acute phase of myocarditis in Kawasaki disease. .Even Kawamura et al observed when the BNP titer is over 50 pg/ml, the patient with Kawasaki disease probably has an abnormal electrocardiogram and is most likely to have myocarditis in the acute phase of disease (Kawamura et al., 2002, Kishimoto et al., 2011). Therefore, the concentration of BNP or its N-terminal segment (NT-proBNP) can be a useful biochemical marker for the myocarditis. Nasser et al. also reported that NT-proBNP is a good marker for persistent left ventricular dysfunction in children who have had myocarditis or cardiomyopathy(Nasser et al., 2006). Kim et al. also reported that NT-proBNP concentrations and left ventricular fractional shortening (FS) were valuable prognostic factors for acute myocarditis (Kim et al., 2010). Further examinations are needed to determine the usefulness of plasma BNP levels in in the myocarditis . Freedman et al. demonstrated that the most sensitive marker for myocarditis was an increased aspartate transaminase (AST). AST elevation was found in 85% of probable and definite cases of myocarditis (Freedman et al., 2007). But similar to other cardiac biomarkers AST elevations are not specific to myocarditis and do occur in other conditions. In patients with idiopathic DCM , autoantibodies against cardiac antigens such as contractile and structural proteins, proteins of energy metabolism/transfer, ion channels, and sarcolemmal receptors have been identified. (Lappé et al., 2008, Caforio et al., 2008, Caforio & Iliceto 2008). However elevated levels of interleukin-10 (IL-10) and TNF appears to be predictor of fulminant myocarditis. Besides this, increase of serum Fas and Fas ligand levels, as well as immunohistological signs of inflammation (CD3 and/or CD68) on initial presentation are associated with fatal outcome in patients with acute myocarditis (Tavli&Güven, 2011).
Viral Serology
Viral serological analyses in suspected myocarditis are still widely used, although their utility remains unproven. Recent study. (Mahfoud et al., 2011) investigated the diagnostic value of viral serology in comparison to EMB findings including viral genome detection in patients with clinically suspected myocarditis. Only 4% of patients had serological evidence of an infection with the same virus that was detected by nested PCR in EMB. Since myocarditis is underdiagnosed disease, patients are referred with a significant delay from the onset of the initial infection. Since acute viral infection have already resolved when patients referred to the hospital, the virus titre could not detected high sufficiently in serum samples. Although most viruses involved in the pathogenesis of myocarditis are highly prevalent in the population, the diagnostic value of viral serology is also limited (Mahfoud et al., 2011, Kindermann et al., 2012)
Echocardiography
The diagnostic value of conventional echocardiography seems limited because echocardiography is entirely olağan in a few patients and patterns of echocardiographic images in myocarditis could mimic other myocardial diseases. However, echocardiography allows the evaluation of cardiac chamber sizes, wall thickness, cardiac muscle functions include systolic and diastolic function and as well as associated valvar insufficiency in patients with myocarditis. Classical echocardiographic findings include impaired left ventricular systolic performance, with reduced FS and EF and functional mitral regurgitation, in the setting of left ventricular dilation.In addition pericardial effusion and intracardiac thrombi, which have been noted in up to 25% of patients (Blauwet et al., 2010) can revealed by echocardiography..Focal inflammation leads to local cell necrosis and tissue edema, often before küresel LV dilatation or dysfunction are evident in early stages of myocarditis (Skouri et al., 2006., Durani et al. showed that the echocardiography would be abnormal in 98% of cases of pediatric myocarditis, and segmental wall motion abnormalities (hypokinesia, akinesia and dyskinesia) were the most common findings in acute myocarditis (Durani et al., 2009). During active myocarditis, remodeling of the left ventricle occurs and shown to be associated with chamber dilatation and the development of a spherical shape. Mendes et al reported the degree of baseline left ventricular sphericity was correlated with more severely depressed left ventricular systolic function (Mendes et al., 1999). However they suggested only initial left ventricular EF was an independent predictor of survival. Ventricular wall thickening can be determined in the acute phase, but it is usually normalized during the convalescent phase of myocarditis (Hauser et al., 1983, Matsuoka et al., 1989). Hiramitsu et al reported that left ventricular wall thickening in the setting of acute myocarditis is caused by interstitial edema (Hiremitsu et al., 2001). Patients with fulminant myocarditis often have an increased septal thickness than patients with acute myocarditis. (Felker et al., 2000). Myocarditis can mimic symmetrical or asymmetrical hypertrophic cardiomyopathy in some cases (Skouri et al., 2006, Hauser et al., 1983, Matsuoka et al., 1989). However, dilated, hypertrophic, restrictive and ischemic echocardiographic patterns were reported in histologically proven myocarditis (Pinamonti et al., 1988). Right ventricular function have also investigated in some previus studies. Mendes et al.assessed right ventricular systolic function and observed the initial LV EF was significantly lower in myocarditis patients with depressed right ventricular function (Mendes et al., 1994). They finally suggested that right ventricular function is an independent predictor of death or cardiac transplantation in acute myocarditis.
Tissue Doppler imaging (TDI) can also be used to evaluate the regional and küresel myocardial contraction in acute myocarditis. Particularly diastolic velocities of both mitral and tricuspid annulus usually reveal markedly abnormal which shows impaired longitudinal and circumferential myocardial function in myocarditis (Adsett et al., 2003). Although the usability of TDI in myocarditis remains an active investigation.area, it is a promising non-invasive method for helping decision especially in patients without typical echocardiographic signs.
Speckle-tracking echocardiography is a new noninvasive ultrasound imaging technique for the objective and quantitative evaluation of küresel and regional myocardial regional and küresel myocardial function, may have a clinical utility in this setting (Cate FE et al., 2012, Geyer et al., 2010, Hsiao et al., 2012). Hsiao et al observed longitudinal and circumferential strain and strain rate can predict major clinical events in patients with decreased or olağan left ventricular EF in acute myocarditis (Hsiao et al., 2012). Therefore this imaging technique appears to be promising prognostic tools, even in those patients with preserved left ventricular EF.
CARDIAC MAGNETIC RESONANCE (CMR) IMAGING
Recent interest has focused on the use of cardiac magnetic resonance imaging (CMR) evolving as a noninvasive and valuable clinical tool for the diagnosis of myocarditis. However, CMR may help to increase the diagnostic yield of biopsy for detecting myocarditis due to guiding for EMB sampling (Skouri et al., 2006)
CMR with a unique potential for tissue characterization, particularly with the utilization of T1 and T2 weighted images, can assess 3 markers of tissue injury, which is, hyperemia and capillary leakage, necrosis and fibrosis and intracellular and interstitial edema (Friedrich et al., 2009). CMR visualizes the entire myocardium, recognizing borders of inflammation from later modeling. Gagliardi et al. (published the first description of T2-weighted CMR findings in children with myocarditis in 1991 (Gagliardi et al., 1991). In this study, T2-weighted spin echo CMR sequences were observed to have a 100% specificity and 100% sensitivity. T2-weighted imaging sensitively detects tissue edema as a marker of acute but not chronic myocardial injury using the long T2 of water-bound protons. (Friedrich et al,. 2009).
High Transmural T2 signal can also accurately identifiy the area of the acute event (delayed). In addition, T2-weighted CMR abnormalities significantly correlated with laboratory markers of acute myocarndial injury was reported (Abdel-Aty et al.,2005). Myocardial hyperemia and regional vasodilatation leads to an increased blood volume in the inflamed area. Therefore gadolinium-based contrast agents distribute quickly into the interstitial space after administration (Friedrich et al,. 2009). ECG-triggered T1- weighted images that obtained both prior to and within 1 min after gadoliniumdiethylenetriaminepentacetate (Gd-DTPA) infusion was titled “myocardial early gadolinium enhancement are used to assess myocardial hyperemia which is usually early change in acute myocarditis (Kindermann et al., 2012, Friedrich et al.,1998 and 2009). Nevertheless specificity of contrast-enhanced T1-weighted sequences may decrease due to abnormally increased skeletal muscle enhancement.and focal myocardial inflammatory process in the early stages(Abdel-Aty et al.,2005). Delayed enhancement images permit visualization of the necrotic and fibrotic myocardium (Friedrich et al., 2009) that mostly indicates irreversible myocardial injury (Abdel-Aty et al.,2005). The observations obtained from the studies late gadolinium enhanced (LGE) MRI indicate that pattern of myocarditic lesions occur predominantly in the lateral free wall and get localized to the subepicardial or intramyocardial regions (Mahroldt et al., 2004, Friedrich et al., 1998). The finding of lateral free wall involvement (subepicardial region) partially explain why some young patients with acute myocarditis can present with only ST elevation on ECG . Postmortem studies also showed that lateral wall was the preferred location in myocarditis (Theleman et al., 2001, Shirani et al., 1993). Subendocardial region involvement pattern which is typical for myocardial infarction was never seen in patients with acute myocarditis (Mahroldt et al., 2004).Late gadolinium enhancement was exhibited an excellent specificity (100%) but a low sensitivity (44%), resulting in an overall diagnostic accuracy of 71% (Skouri et al., 2006, Abdel-Aty et al.,2005). Therefore, the combined use of different CMR sequences may provide a higher diagnostic accuracy than single sequences (Skouri et al., 2006). However LGE may provide additional significant prognostic information.Abd-el Aty postulated that myocarditis patients with positive LGE may be more likely to develop dilated cardiomyopathy (Abdel-Aty et al.,2005). In a retrospective study published in 2009, researchers found that myocarditis in children is characterized mainly by subepicardial and transmural enhancement. Küresel hypokinesia, left ventricular dilatation, EF less than 30% and transmural myocardial involvement were discovered to be associated with poor outcome (Vashist et al., 2009).
Due of the lack of large-scale multi-center veri, recently, International Consensus Group on Cardiovascular Magnetic Resonance suggested the diagnostic criteria, known as ‘’Lake Louis Consensus Criteria’’ (Friedrich et al., 2009). Cardiac MRI should be made in the setting of clinically suspected myocarditis according to these criteria. It was also stated that maximum diagnostic accuracy can be accomplished with the presence of any two or more of the following criteria: Regional or küresel myocarditis signal increases in T2 weighted images, increased küresel myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle (T1 weighted images) or presence of at least one focal lesion with nonischemic regional distribution (late gadolinium enhancement).
In summary, three CMR techniques have been performed in myocarditis: 1) T2-weighted images for assessment of myocardial edema; 2) T1-weighted sequences before and after gadolinium injection for detection of myocardial hyperemia and 3) late gadolinium
enhancement sequences for detection of myocardial necrosis and/or fibrosis
Combined use of all three CMR techniques and two or more of the three tissue-based criteria are positive, myocardial inflammation has been proposed to be predicted or ruled out with a diagnostic accuracy of 78% if only LGE imaging is performed, the diagnostic accuracy is 68% (Friedrich et al., 2009).
Myocardial Scintigraphy
Inflammation-sensitive radioisotopic imaging has been used as an adjunct to other diagnostic methods in the diagnosis of myocarditis. myocardial scanning using gallium-67 citrate has been suggested as a useful tool in the detection of myocarditis (O’Connell et al.,1984, Matsuura et al., 1987 ,Hung et al., 2007) Matsura et al. also showed the usefulness of gallium-67 imaging, especially in identifying myocarditis in the acute phase of Kawasaki disease (Matsuura et al., 1987). Indium-111 antimyosin antibodies have been also used to detect myocardial injury in acute myocarditis (Skouri et al., 2006, Margari et al. 2003 ). A positive antimyosin scintigraphy accompanied by olağan or mildly dilated LV could be considered suggestive of AM during the early phase of the disease course (Margari et al. 2003 ). However, the usefulness of scintigraphy is limited in the diagnosis of acute myocarditis by several technique-dependent sources of error, low specificity, radiation exposure and expense and increase of the diagnostic value of CMR (Skouri et al., 2006, Friedrich et al.,1998).
Endomyocardial Biopsy (EMB)
Endomyocardial biopsy is still considered to be the gold standard for diagnosis of myocarditis. The histological changes of myocarditis are usually patchy and scattered in the myocardium (Towbin JA, 2008, Baker E, 2010) so it is very difficult to diagnose with a single biopsy. The Dallas criteria were proposed in 1986 and provided a histopathological criterias in the diagnosis of myocarditis. (Aretz et al., 1987). Acute myocarditis is defined by focal or diffuse mononuclear cell (T lymphocytes and macrophages) infiltrates in association with associated myocyte necrosis or damage of adjacent myocytes not characteristic of an ischemic damage (Kindermann et al., 2012, Towbin JA, 2008). Borderline myocarditis is characterized by a less intense inflammatory infiltrate and no evidence of myocyte necrosis (Baughman et al.,2006). Myocardial tissue obtained by EMB is considered to be inflamed by mononuclear infiltrates with >14 cells/ mm2, in addition to enhanced expression of HLA class II molecules (Kindermann et al., 2012).Previously reported that 17 or more specimens must be obtained to identify 80% of cases (chow et al., 1989, Hauck et al., 1989). A scientific statement from the American Heart Association, The American College of Cardiology and European Society of Cardiology published in 2007 proposed that the number of samples obtained should range from 5 to 10, and each sample should be 1 to 2 mm³ in size (Cooper et al., 2007). After the sampling for the assessment of suspected infiltrative disorders such as amyloidosis, glycogen storage diseases, lysosomal storage diseases transmission electron microscopy may also be useful (Cooper et al., 2007). The use of quantitative (qPCR) and qualitative (nested PCR) molecular biological techniques for detection of of cardiotropic viruses has substantially increased. Various studies reported a wide range of viruses, including enteroviruses, adenoviruses, parvovirus B19, cytomegalovirus,influenza and respiratory syncytial virus, herpes simplex virus, Epstein-Barr virus, human herpesvirus 6, HIV, and hepatitis C that was detected by using nested PCR technique (Cooper et al., 2007).
Sampling error, high interobserver variability in interpreting biopsy specimens, variance with other markers of viral infection and immune activation in the heart are limitations of EMB procedure (Kindermann et al., 2012, Baughman , 2006). EMB usually is performed safely under fluoroscopy..However some complications such as pneumothorax, dysrhythmia, perforation and death, may occur during the EMB , and it can be hazardous for particularly pediatric patients (Pophal et al., 1999). In a retrospective review analyzing the morbidity and mortality of EMB in children, highest risk was found in children with suspected myocarditis on inotropic support (Pophal et al., 1999). Authors also found that risk of biopsy in small children (< 10 kg) or sick infants was extreme. Compared with established risk of EMB in adults, there is an increased risk in children. Therefore careful performance of the technique can minimize the procedural risks.
Treatment
Treatment strategy for myocarditis is evolving with the improved understanding of pathophysiology of disease. Specific causative therapy may be used if a causative organism or diseases such as sarcoidosis and giant cell myocarditis has been identified. However, this is rare and in most cases only supportive treatment is available. Therefore treatment should be focused to aim the maintenance of cardiac output due to lowering the cardiac pre- and afterload, and to prevent complications such as heart failure and rhythm disturbances.Most patients with acute myocarditis presenting with dilated cardiomyopathy respond favorably to standard anticongestive therapy including afterload reduction, diuretics, angiotensin converting enzyme inhibitors and the introduction of β blockers such as carvedilol or metoprolol succinate evvel the acute phase is controlled (Tavli&Güven, 2011). However, digitalis may be used and has effected dramatic improvement in some cases with congestive heart failure (Parillo et al., 1998). Since the myocardium may be hypersensitive to digitalis during the acute phase, rapid administration should be avoided. However patients may deteriorate despite the optimal medical treatment and mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may be required to bridge the patient to recovery or heart transplantation. Several studies have examined the utility of adjuvant therapeutic agents focused at preventing longterm cardiac recovery. Intravenous immunoglobulin and immunsupressive agents have been the most common studied. The value of drugs that suppress the inflammatory reaction is unclear (Baker E, 2010). Some reports have demonstrated increased survival with IVIG therapy especially among children with myocarditis (Robinson et al., 2005, Drucker et al., 2004). Experimental animal studies suggest that bed rest may prevent an increase in intramyocardial viral replication in the acute stage (Towbin A, 2008)). Some authors are advised bedrest for at least 14 days in the acute stage for reduce the workload of the heart (Baker E, 2010). Cardiac transplantation is also option for patients who are intractable with medical management and mechanical circulatory support.
Treatment of heart failure
Advances in treatment strategies of myocarditis are still limited despite the significant progress in understanding the mechanisms of pathogenesis in last two decades. Since no pathogen-specific therapy of viral myocarditis has been shown to improve survival free of HF, symptomatic treatment and supportive deva is mandatory fort this patients (Kindermann et al., 2012). Heart failure should be managed according to the current guidelines (Swedberg et al., 205, Dickstein et al., 2008, Jessup et al., 2009) Standart pharmacological treatment of HF including, diuretics, angiotensinconverting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs), beta-blockers and positive inotropic agents. The ACE inhibitor captopril as well as the ARBs losartan and olmesartan were reported that effective at reducing myosin-induced experimental autoimmune myocarditis or virus-induced myocarditis
(Godsel et al., 2003, Reyes et al.,1998, Bahk et al., 2008, Seko Y, 2006).The exact mechanism by which captopril reduces myocarditis is not known. ACE inhibition and its consequent reduction in Ang II receptor signaling seemed a probable mechanism by which the drugs reduces inflammation, necrosis, fibrosis and cardiac hypertrophy. Although beta-blocker treatment recommended to avoid in the acute phase of decompensated HF previously, there is consensus that a beta-blocker and an ACE inhibitor should both be started as soon as possible after diagnosis of HF with reduced EF (McMurray et al., 2012) reported at the last guideline of ESC. ACE inhibitors have a modest effect on LV remodelling whereas beta-blockers often lead to a substantial improvement in EF (McMurray et al., 2012). Various experimental studies with β adrenoreceptor inhibitors or agonists showed different effects in acute myocarditis. Treatment with propranolol in mice infected with encephalomyocarditis virus (EMCV) reduced the severity of myocarditis and mortality (Wang et al., 2005). On the other hand, carvedilol, non-selective β blocker, improved the survival and decreased the virus replication of mice infected with EMCV through the enhancement of IL-12 and IFN-γ production, whereas metoprolol had no effect on this murine model (Nishio et al., 2003).In suspected myocarditis, the presence of beta-blocker therapy was observed that associated with a good prognosis, whereas a lack of beta-blocker treatment was associated with poor outcome (Kindermann et al., 2008). Despite the lack of extensive studies in pediatric patients,
administration of carvedilol has been found to be associated with improvement of left
ventricle function and clinical symptoms and normalization of antioxidant enzyme activity
(Bajcetic et al., 2008). Phosphodiesterase inhibitors such as milrinone, if well tolerated, can be used to provide both inotropy and afterload reduction (Towbin JA, 2008, Tavlı&Güven, 2011).A recent multi-institutional analysis revealed that milrinone was used most often for vasoactive support in children (Klugman et al., 2010). Digoxin should be used in low dose and with caution in patients with viral myocarditis since high dose digoxin was proven to increase mortality in animals with EMVC induced myocarditis as well as elevate intracardiac production of cytokines (Matsumori et al., 1999). Furthermore digoxin may restrict the maximal tolerated dose of betablocker due to bradycardia or heart block (Kindermann et al., 2012). Diuretics are also used to prevent fluid overload by reducing water retention in HF. Despite the widespread use of furosemide in the treatment of heart failure associated DCM, Torasemide is reportedly more effective in chronic heart failure with respect to reducing symptoms, admissions and other adverse cardiovascular events (Veeraveedu et al., 2008, Murray et al., 2001; Spannheimer et al., 1998). Furthermore, Torsemide was reported to reduce the progression of myocarditis to DCM in a rat model of inflammatory cardiomyopathy (Veeraveedu et al., 2008). The use of aldosterone antagonists such as spironolactone and eplerenone is recommended in HF (McMurray et al., 2012). Previously reported that mast cells play an important role in myocardial remodeling and fibrosis after myocardial ischemia (Frangogiannis et al., 1998, Higuchi et al., 2008). Eplerenone was reported to improve survival of mice infected with EMC virüs by inhibition of mast cell-derived proteinases and resulted in an improvement of myocardial remodeling by suppressing fibrosis (Xiao et al., 2009).
Supportive Care
Avoidance of aerobic physical activity is recommended in acute phase of myocarditis. Bedrest is advised for at least 14 days in the acute stage (Baker E, 2010). Sleeping pulse rate of less than 100 beats per minute in children is related a good response (Baker E, 2010). Myocarditis is shown a relevant cause of sudden death in young athletes. Therefore, all patients with presumed or definite myocarditis discontinue competitive sports and undergo a prudent convalescence period around six months after the onset of clinical manifestations (maron et al., 2005).Athletes may return to sports activity evvel LV function, dimensions and wall motions return to olağan, markers of imflammation in blood have resolved, 12-lead ECG has normalized and clinically relevant arrhythmias are absent on Holter ECG or graded exercise testing (Maron et al., 2005).
Despite administiration of optimal medical treatment, patients with acute myocarditis may detoriate and require mechanical circulatory support. In general, patients who present as cardiogenic shock due to acute fulminant myocarditis require mechanical circulatory support or extracorporeal membrane oxygenation that serve to bridge the patient to recovery or heart transplantation (Cooper et al., 2009). Ventilation and oxygenation could be best achieved with
continuous positive airway pressure (CPAP) or other non-invasive methods. CPAP, unloads
inspiratory muscles and leads to decreased left ventricular afterload without compromising
cardiac index via increasing intrathoracic pressure. Medications used for intubation can
cause hypotension and acute cardiovascular collapse, thus CPAP also avoids this and is an
outstanding adjunctive therapy for cardiac failure and myocarditis (Bradley et al., 1992,
Naughton et al., 1995). ECMO is used effectively to support cardiorespiratory collapse in children and young adults with myocarditis (Rajagopal et al., 2010). Various studies showed that 60 % to %80 of patients requiring ECMO or ventricular-assist devices (VADs) were survived (Duncan et al., 2001, Mirabel et al., 2011, Chen et al., 1999) Rajagopal et al also reported the ECMO is a valuable tool to rescue children with severe cardiorespiratory compromise related to myocarditis and increased mortality during ECMO were associated with female gender, arrhythmia on ECMO, and need for dialysis. (Rajagopal et al., 2010). Consequently, mechanical circulatory support systems should be considered early for patients with fulminant acute myocarditis when optimal medical therapy has failed.
Immune therapy
Autoimmunity plays a key role in the pathogenesis of myocarditis. It was reported that the severity of myocarditis is regulated by T cells (Kishimoto et al.,2003). It is well known that the long term morbidity and mortality following viral myocarditis seem to be dependent on cellular and humoral immunity abnormalities.Since there have been a few published controlled studies, the use of immunosuppressive agents (cyclosporine, prednisolone, azathioprine) in the treatment of acute myocarditis have shown controversial results (Hufnagel et al., 2000, Mason et al., 1995, Chan et al., 1991). Initial adult studies investigating the effect of prednisone with or without azathioprine and cyclosporine demonstrated a slight improvement in left ventricular function. But, this improvement was temporary. (Mason et al., 1995, Parillo et al., 1989). In 1995, the National Institutes of Health–supported US MyocarditisTreatment Trial were published by Mason et al. The patients were randomized to conventional therapy or an immunosuppressive regimen of steroids combined with either azathioprine or cyclosporine in this trial. They found a similar degree of recovery of ventricular function in both groups, and there was no difference in mortality. Therefore, they concluded that immunosuppressive therapy is not beneficial in most patients with histologically confirmed myocarditis. Although a few uncontrolled studies showed benefit with several immune suppressive agents, meta analysis of adult studies did not confirm a significant favourable effect of immunosuppression (Garg et al., 1998, Maisch et al., 1998).There were also investigations to evaluate the results of immune suppressive regime in children with acute myocarditis (Chan et al., 1991, Camargo et al., 1995). Previous report by Chan et al. included 13 infants and children with biopsy-proved myocarditis also suggested that immunosuppressive therapy is effective in reducing myocardial inflammation, lessening symptoms and improving cardiac function in children (Chan et al., 1991). Better outcome was also observed in a meta analysis (Hia et al., 2004) assessing the impact of immunosuppression on the outcome of acute myocarditis in children which was published in 2004. Similarly, Camargo et al. suggested that children with DCM but ongoing inflammatory myocardial disease responded positively to immunosuppressive therapy, regardless of the persistence of viral genomes. (Camargo et al., 2011 ) However, studies in children are inadequate and yet, no randomized controlled trials are present. In a randomized, placebo-controlled adult study by Wojnicz et al. also suggested that a short-term immunosuppressive therapy with steroids and azathioprine may provide long-term benefit in patients with chronic heart failure and immunohistologically proven myocarditis (Wojnicz et al., 2001). They concluded that if patients are selected for immunosuppression on the basis of HLA upregulation on EMB specimens, immunosuppressive therapy may significantly improve clinical status. The randomized, double-blind, placebo-controlled trial included 85 patients with virus-negative inflammatory cardiomyopathy was published in 2009 (Frustaci et al., 2009). Results from this trial was confirmed the positive effect of immunosuppressive treatment on recovery of LV function in a high rate (88%) of patients during treatment and in the following 6 months.
Intravenous immunoglobulin has been recommended in the treatment of several autoimmune conditions, including idiopathic thrombocytopenic purpura, systemic vasculitis and Kawasaki disease (Rosen et al., 1993, Wolf et al., 1996, Kishimoto et al., 2003). IVIG has been shown to improve myocardial function in myocarditis associated with Kawasaki disease (Newburger et al., 1989) due to its antiviral or immunsupressive effect. Although little is known about the exact mechanisms, administration of IVIG may lead to decrease cardiac inflammation or to downregulate the inflammatory cytokines that have direct negativeinotropic effects through its modulation ability of immune response (Drucker et al., 1994). The previous study in pediatric population suggested that high dose IVIG treatment was associated with improved recovery of left ventricular function and with a tendency of better survival (Drucker et al., 1994.) Nevertheless, immunoglobulin treatment was observed to ameliorate myocardial injury in experimental autoimmune myocarditis associated with suppression of reactive oxygen species and reduction of neurohumoral activity. (Kishimoto et al., 2012). It seems that the cardioprotection of IVIG is associated with its immunmodulatory effects and as well as the suppression of cytotoxic myocardial injury. The results of a randomized clinical trail suggested that IVIG did not enhance an improvement in EF in adults with recent onset DCM (McNamara et al., 2001). However, in this cohort, EF was increased considerably during follow-up and short term prognosis remained favourable. A systemic review conducted by Robinson et al., evaluated the use of IVIG therapy in acute myocarditis in both adults and children (Robinson et al., 2005). They determined that IVIG might be useful in the presence of ongoing or active infection which may be causing obstinate cardiac failure. Immunoglobulin therapy was shown to suppress virus induced myocarditis and sufficiently (Kishimoto et al., 2001) prevent the development of congestive heart failure failure in experimental studies with mice. Unfortunately, up-to-date human studies a different from experimental trials do not include definite results against usefulness of IVIG treatment in myocarditis. Currently, there are no prospective, randomized, controlled studies evaluating the efficacy of IVIG treatment in children with acute myocarditis. However IVIG seems to be a promising agent in the therapy of acute myocarditis especially in children by way of suppression of inflammatory cytokines associated with the reduction of oxidative stress (Kishimoto et al., 2003)
IMMUNOADSORPTION
A number of cardiac antibodies against cardiac cell proteins such as surface receptors, mitochondrial proteins, sarcolemmal proteins, (Limas et al., 1989, Caforio et al., 1992, Magnusson et al., 1994) play an active role in the pathogenesis of DCM (Felix et al., 2002). Disturbances in humoral and cellular immunity may contribute to cardiac dysfunction in patients with myocarditis and DCM (Klappacher et al., 1993, Limas et al., 1995). Since The functional role of cardiac autoantibodies is still unclear, immunoadsorption for the elimination of anticardiac antibodies may be applied for its potential benefits in myocarditis and recent-onset DCM. The result from the first uncontrolled pilot study showed that immunoadsorption induced significant decrease in immunoglobulin IgG levels and as well as improvement of hemodynamics in patients with DCM (Dörffel et al., 1997). A number of adult studies asserted that removal of circulating antibodies by immunoadsorption in DCM improved cardiac function as well as hemodynamic parameters (Felix et al., 2000 and 2002, Herda et al., 2010). However Bulut et al also demonstrated the improvement of LV systolic function after protein A immunadsorption in patients with inflammatory cardiomyopathy (Bulut et al., 2010). Further randomized, placebocontrolled studies are needed to demonstrate the potential beneficial effect of immunadsorption therapy. Currently, A multicenter, randomized, double-blind, prospective trial concerning the effects of immunoadsorption on cardiac function in patients with DCM is ongoing (NCT00558584)
Antiviral treatment & vaccines
The logical basis of using antiviral drugs results from the knowledge that most common causes of myocarditis are viral triggers. It is obvious that studies using polymerase chain reaction identified viral genomes in patients with acute myocarditis (Bowles et al., 2003). Enteroviruses and adenoviruses are the most common associated pathogens in myocarditis. It is shown that the existing of enteroviral genomes in the myocardium is associated with a worse prognosis and an independent predictor of clinical outcome (Why et al., 1994, Fujioka et al., 2000, Kühl et al., 2003). Therefore, studies have been conducted regarding a specific antiviral therapy in patients with myocarditis or DCM. Experimental studies in murine models usually conducted with interferone treatment for coxackievirus b (CVB). Coxackievirus B3 (CVB3) as a member of the enterovirus genus of the picornavirus family, is one of the most important infectious agents in the pathogenesis of myocarditis. Since the main pathogenic process in the early stages of CVB3 infection is the direct attack on myocardial cells, antivirus treatment at this phase is very important to prevent the development of myocardial injury(Dennert et al., 2008). Type I interferons (IFN), including IFN-beta and IFN-alfa demonstrated to protect cells from viral infections with direct antiviral effect (Samuel CE , 2001). However, IFN also has an immunomodulatory function by modulating both B- and T-lymphocyte responses (Wang et al., 2007). Although , interferon (IFN)-beta and IFN-alpha2 therapy were shown to prevent myocyte injury with decreasing inflammatory cell infiltrates, only administration of IFN-beta reduced cardiac viral load (wang et al., 2007) in murine Balb/c mice. Kühl et al. designed the study in patients with persistence of LV dysfunction and PCR–proven enteroviral or adenoviral myocarditis were treated with IFN-beta (Beneferon) subcutaneously for 24 weeks (Kühl et al., 2003). Veri from this study suggest that treatment with IFN-beta resulted in an elimination of viral genomes in all patients and an improvement of LV function in 15 of 22 patients. Therefore authors asserted that antiviral therapy with IFN- is safe and may achieve virus clearance in association with hemodynamic improvement in patients with proven viral myocarditis. In addition to IFN, several promising new agents including peroxisome proliferator activated gamma receptor activator, rapamycine, pycogenol, SUNC8079 and mycophenol mofetil have been studied in murinemodels of myocarditis during the last decade (Komiyoshi et al., 2005, Ellis&DiSalvo, 2007, Matsumori, 2007). It has been demonstrated that these agents decrease the severity of myocarditis and improve cardiac function, blocks activation of NF-ê, blocks mRNA expression of key cytokines (IL-1, IL-6 and TNF) and stabilizes mast cell (Matsumori, 2007). Synergistic effect of IFN- á and ribavirin has been demonstrated against both EMCV and coxsackie virus infection (Okada et al., 1992, Matsumori, 2007). Up to date, antiviral therapy cannot be recommended routinely for the treatment of acute myocarditis; however, IFN therapy for more chronic myocarditis with persistent viral genomes seems to be more effective and is a subject of active clinical investigation.
Vaccination has been used successfully to prevent viral diseases. Vaccination against mumps, rubella, poliomyelitis, measles and influenza has made myocarditis consequent to these infections quite rare and increases the arguments on whether vaccination against other cardiotropic viruses might prevent myocarditis in the future. Immunization against CVB3 was shown to protective against entoroviral heart disease in mice. Recently, Zhang et al demonstrated the vaccination against CVB3 elicits humoral immune response and protects mice against myocarditis. (Zhang et al., 2012) At the present time, there have been no vaccination trial againts viral myocarditis in humans regardless of age.
References:
Abdel-Aty H, Boye P, Zagrosek A, et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparison of different approaches. J Am Coll Cardiol 2005;45:1815–22.
Adsett M, West MJ, Galbraith A, et al. Eosinophilic heart: marked left ventricular wall thickening and myocardial dysfunction improving with corticosteroid therapy. Echocardiography 2003;20:369 –74.
Aretz HT, Billingham ME, Edwards WD, Parker MM, Factor SM, Fallon JT & Fenoglio JJ. Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Pathol. 1987;1:3–14.
Baboonian C, Treasure T. Meta-analysis of the association of enteroviruses with human heart disease. Heart. 1997;78:539–543.
Bachmaier K, Mair J, Offner F. Serum cardiac troponin T and creatine kinase-MB elevations in murine autoimmune myocarditis. Circulation. 1995 Oct 1;92(7):1927-32.
Bahk TJ, Daniels MD, Leon JS, et al. Comparison of angiotensin converting enzyme inhibition and angiotensin II receptor blockade for the prevention of experimental autoimmune myocarditis. Int J Cardiol 2008;125:85–93.
Bajcetic M, Kokic Nikolic A, Djukic M et al. Effects of carvedilol on left ventricular function and oxidative stress in infants and children with idiopathic dilated cardiomyopathy: a 12-month, two-center, open-label study. Clin Ther. 2008;30:702-14.
Baughman KL. Diagnosis of Myocarditis : Death of Dallas Criteria. Circulation. 2006;113:593-595
Blauwet LA, Cooper LT. Myocarditis. Prog Cardiovasc Dis 2010; 52:274–88.
Bowles NE, Ni J, Kearney DL, Pauschinger M, et al. Detection of viruses in myocardial tissues by polymerase chain reaction: evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol. 2003;42:466–472.
Bradley TD, Holloway RM, McLaughlin PR, et al. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992; 145:377–382.
Brady WJ, Perron İSİM, Chan T. Electrocardiographic STsegment elevation: correct identification of acute myocardial infarction (AMI) and non-AMI syndromes by emergency physicians. Acad Emerg Med 2001;8:349–360
Bulut D, Scheeler M, Wichmann T, Borgel J, Miebach T, Mugge A. Effect of protein A immunoadsorption on T cell activation in patients with inflammatory dilated cardiomyopathy. Clin Res Cardiol 2010; 99:633– 8.
Caforio AL, Grazzini M, Mann JM, et al. Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation 1992;85:1734–42.
Caforio AL, Tona F, Bottaro S, et al. Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy. Autoimmunity. 2008 Feb;41(1):35-45
Caforio AL, Iliceto S. Genetically determined myocarditis: clinical presentation and immunological characteristics. Curr Opin Cardiol. 2008 May;23(3):219-26.
Camargo PR, Okay TS, Yamamoto L, et al. Myocarditis in children and detection of viruses in myocardial tissue: implications for immunosuppressive therapy. Int J Cardiol. 2011 14;148:204-208
Camargo PR, Snitcowsky R, da Luz PL, et al: Favorable effects of immunosuppressive therapy in children with dilated cardiomyopathy and active myocarditis. Pediatr Cardiol 1995;16:61-68.
Chan KY, Iwahara M, Benson LN, Wilson GJ, Freedom RM.Immunosuppressive therapy in the management of acute myocarditis in children: a clinical trial. J Am Coll Cardiol. 1991;17:458-60.
Chen YS, Wang MJ, Chou NK, et al. Rescue for acute myocarditis with shock by extracorporeal membrane oxygenation. Ann Thorac Surg.1999;68:2220-2224.
Chow LH, Radio SJ, Sears TD, et al. Insensitivity of right ventricular biopsy in the diagnosis of myocarditis. J Am Coll Cardiol 1989;14:915-920.
Cooper LT Jr. Myocarditis. N Engl J Med 2009;360:1526 –38.
Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914 –31.
Dec GW Jr, Waldman H, Southern J, et al. Viral myocarditis mimicking acute myocardial infarction. J Am Coll Cardiol 1992;20:85–89
Dec GW, Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DC, Johnson RA. Active myocarditis
Dennert R, Crijns HJ, Heymans S: Acute viral myocarditis. Eur Heart J 2008;29:2073-2082.
Di Bella G, Florian A, Oreto L Electrocardiographic findings and myocardial damage in acute myocarditis detected by cardiacmagnetic resonance. Clin Res Cardiol. 2012;101:617-624
Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Eur Heart J 2008;29:2388–442.
Dörffel WV, Felix SB, Wallukat G, et al. Short-term hemodynamic effects of immunoadsorption in dilated cardiomyopathy. Circulation 1997;95:1994 –7.
Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 1994; 89:252–257.
Duncan BW, Bohn DJ, Atz AM, et al. Mechanical circulatory support for the treatment of children with acute fulminant myocarditis. J Thorac Cardiovasc Surg 2001;122:440–448
Durani Y, Egan M, Baffa J, et al. Pediatric myocarditis: presenting clinical characteristics. Am J Emerg Med 2009; 27:942–947.
Edward J. Baker. Non-rheumatic Inflammatory Diseases of the Heart. In: Anderson RH, Baker EJ, Penny D editors. Paediatric Cardiology. Churchill Livingston, Elsevier; 2010. p.1079-1089.
Ellis CR, Di Salvo T. Myocarditis: basic and clinical aspects. Cardiol Rev 2007; 15: 170–177.
Fabre A, Sheppard MN. Sudden adult death syndrome and other non-ischaemic causes of sudden cardiac death. Heart 2006;92:316–320.
Felix SB, Staudt A, Dorffel WV, et al. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study. J Am Coll Cardiol 2000;35:1590–8.
Felix SB, Staudt A, Landsberger M, et al. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption.J Am Coll Cardiol 2002;39:646 –52.
Felker GM, Boehmer JP, Hruban RH Echocardiographic findings in fulminant and acute myocarditis. J Am Coll Cardiol. 2000 Jul;36(1):227-32.
Frangogiannis NG, Perrard JL, Mendoza LH, et al. Stem cell factor induction is associated with mast cell accumulation after canine myocardial ischemia and reperfusion. Circulation. 1998;98:687– 698.
Freedman SB, Haladyn JK, Floh A, et al. Pediatric myocarditis: emergency department clinical findings and diagnostic evaluation. Pediatrics 2007;120:1278–1285.
Friedman RA, Schowengerdt KO, Towbin JA. Myocarditis. In: Bricker JT, Garson A Jr, Fisher DJ, et al., eds. The Science and Practice of Pediatric Cardiology. 2nd ed. Baltimore: Williams & Wilkins, 1998: 1777-1794.
Friedrich MG, Sechtem U, Schulz-Menger J, et al: Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53:1475-1487.
Friedrich MG, Strohm O, Schulz-Menger J, et al: Contrast media enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation 1998;97:1802-1809.
Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J. 2009;30:1995-2002.
Fujioka S, Kitaura Y, Ukimura A, et al. Evaluation of viral infection in the myocardium of patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2000;36:1920–1926.
Gagliardi MG, Bevilacqua M, Di Renzi P et al. Usefulness of magnetic resonance imaging for diagnosis of acute myocarditis in infants and children, and comparison with endomyocardial biopsy. Am J Cardiol. 1991;68:1089-91.
Garg A, Shiau J, Guyatt G. The ineffectiveness of immunosuppressive therapy in lymphocytic myocarditis: an overview. Ann Intern Med 1998; 129: 317–322.
Geyer H, Caracciolo G, Abe H, et al. Assessment ofmyocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr 2010;23:351–69.
Godsel LM, Leon JS, Wang K, et al. Captopril prevents experimental autoimmune myocarditis. J Immunol 2003;171:346 –52.
Gravanis, MB. ; Sternby, NH. (1991) Incidence of myocarditis. A 10-year autopsy study from Malmö, Sweden. Archives of Pathology & Laboratory Medicine, Vol.115 No. 5, (April 1991), pp. 390-392, ISSN 1543-2165.
Greenwood RD, Nadas AS, Fyler DC: The clinical course of primary myocardial disease in infants and children. Am Heart J 1976;92:549-560.
Hauck AJ, Kearney DL, Edwards WD. Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocarditis: Implications for role of sampling error. Mayo Clin Proc 1989;64:1235-1245.
Hauser AM, Gordon S, Cieszkowski J, Timmis GC: Severe transient left ventricular ‘hypertrophy’ occurring during acute myocarditis. Chest 1983;83: 275– 277
Herda LR, Trimpert C, Nauke U, et al. Effects of immunoadsorption and subsequent immunoglobulin G substitution on cardiopulmonary exercise capacity in patients with dilated cardiomyopathy. Am Heart J 2010;159:809 –16.
Hia CP, Yip WC, Tai BC, et al. Immunosuppressive therapy inacute myocarditis: an 18 year systematic review. Arch Dis Child 2004; 89: 580–584.
Higuchi H, Hara M, Yamamoto K, et al. Mast cells play a critical role in the pathogenesis of viral myocarditis. Circulation. 2008;118:363-72.
Hiramitsu S, Morimoto S, Kato S et al. Transient ventricular wall thickening in acute myocarditis: a serial echocardiographic and histopathologic study. Jpn Circ J. 2001;65:863-6.
Hsiao JF, Koshino Y, Bonnichsen CR et al. Speckle tracking echocardiography in acute myocarditis. Int J Cardiovasc Imaging. 2012 Jun 27. DOI 10.1007/s10554-012-0085-6
Hufnagel G, Pankuweit S, Richter A, Schonian U, Maisch B. The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID). First epidemiological results. Herz 2000;25:279–85.
Hung MY, Hung MJ, Cheng CW. Use of gallium 67 scintigraphy to differentiate acute myocarditis from acute myocardial infarction. Tex Heart Inst J. 2007;34(3):305-9.
in the spectrum of acute dilated cardiomyopathies: clinical features, histologic correlates, and clinical outcome. New England Journal of Medicine. 1985;312:885–890.
interferon for coxsackievirus B3 replication. J Lab Clin Med 1992;120:569–73.
Jessup M, Abraham WT, Casey DE, et al; American College of Cardiology. American Heart Association Task Force on Practice Guidelines (2009 Writing Committee to update the 2005 Guidelines for the Evaluation and Management of Heart Failure). 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009 Apr 14;119:1977-2016.
Kamiyoshi Y, Takahashi M, Yokoseki O, et al. Mycophenolate mofetil prevents the development of experimental autoimmune myocarditis. J Mol Cell Cardiol. 2005;39:467– 477.
Karjalainen J, Heikkila J. Incidence of three presentations of acute myocarditis in young men in military service. A 20-year experience. Eur Heart J 1999;20:1120–1125.
Kawamura T, Wago M.Brain natriuretic peptide can be a useful biochemical marker for myocarditis in patients with Kawasaki disease.Cardiol Young. 2002;12:153-158.
Kearney MT, Cotton JM, Richardson PJ, Shah AM. Viral myocarditis and dilated cardiomyopathy : mechanisms, manifestations, and management. Postgrad Med J 2001; 77:4–10.
Kim HJ, Yoo GH, Kil HR. Clinical outcome of acute myocarditis in children according to treatment modalities. Korean J Pediatr. 2010;53:745-52.
Kindermann I, Kindermann M, Kandolf R, et al. Böhm M. Predictors of outcome in patients with suspected myocarditis. Circulation 2008;118:639–648.
Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol. 2012 Feb 28;59(9):779-92.
Kishimoto C, Takada H, Kawamata H, Umatake M, Ochiai H. Immunoglobulin treatment prevents congestive heart failure in murine encephalomyocarditis viral myocarditis associated with reduction of inflammatory cytokines.J Pharmacol Exp Ther. 2001 ;299:645-51
Kishimoto C, Shioji K, Kinoshita M, et al Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress. Int J Cardiol. 2003;91:173-178
Kishimoto S, Suda K, Teramachi Y, et al. Increased plasma type B natriuretic peptide in the acute phase of Kawasaki disease.Pediatr Int. 2011;53:736-741
Kishimoto C, Nimata M, Okabe TA, Shioji K. Immunoglobulin treatment ameliorates myocardial injury in experimental autoimmune myocarditis associated with suppression of reactive oxygen species. Int J Cardiol. 2012 Jan 12. [Epub ahead of print]
Klappacher G, Mundigler G, Papousek A, et al. Elevated circulating levels of beta-2 microglobulin in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 1993;71:119–22.
Klugman D, Berger JT, Sable CA, He J, Khandelwal SG, Slonim İSİM. Pediatric patients hospitalized with myocarditis: a multi-institutional analysis. Pediatr Cardiol. 2010;31:222-8.
Kondo M, Takahashi M, Shimono Y, et al. Reversible asymmetric septal hypertrophy in acute myocarditis. Serial findings of two-dimensional echocardiogram and thallium-201 scintigram. Jpn Circ J 1985;49:589 –93.
Kühl U, Pauschinger M, Schwimmbeck PL,Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation. 2003;107:2793-8.
Lappé JM, Pelfrey CM, Tang WH. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. J Card Fail. 2008;14:521-30.
Levine MC, Klugman D, Teach SJ.Update on myocarditis in children. Curr Opin Pediatr. 2010;22:278-83.
Limas CJ, Goldenberg IF, Limas C. Autoantibodies against betaadrenoceptors in human idiopathic dilated cardiomyopathy. Circ Res 1989;64:97–103.
Limas CJ, Goldenberg IF, Limas C. Soluble interleukin-2 receptor levels in patients with dilated cardiomyopathy: correlation with disease severity and cardiac autoantibodies. Circulation 1995;91:631–4.
Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 2003;348:1647–1655.
Magnani JW, Dec GW. Myocarditis: current trends in diagnosis and treatment. Circulation 2006;113:876–890
Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, Hoebeke J. Autoimmunity in idiopathic dilated cardiomyopathy: characterization of antibodies against the beta1-adrenoceptor with positive chronotropic effect. Circulation 1994;89:2760–67.
Mahfoud F, Gartner B, Kindermann M, et al. Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2011;32:897–903.
Mahrholdt H, Goedecke C, Wagner A, et al: Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology.Circulation 2004;109: 1250-1258.
Maisch B, Herzum M, Hufnagel G, et al. Immunosuppressive treatment for myocarditis and dilated cardiomyopathy. Eur Heart J 1995; 16 Suppl O: 153–161.
Margari ZJ, Anastasiou-Nana MI, Terrovitis J, et al. Indium-111 monoclonal antimyosin cardiac scintigraphy in suspected acute myocarditis: evolution and diagnostic impact. Int J Cardiol. 2003;90:239-45.
Maron BJ, Ackerman MJ, Nishimura RA, et al: Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005;45:1340-1345.
Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: a
