**3. Pathogenesis**

Special attention to understanding the mechanism and pathogenesis of myocarditis have been increased since Gore and Saphir showed in 1947 that diphteric and rheumatic carditis separately comprised only 10% of a series of 1402 patients of myocarditis (Gore & Saphir, 1947). In 1970's, several investigators demonstrated the persistence of neutralizing antibodies to coxsackie B (CVB) in cases with cardiomyopathy than healthy subjects (Kawai, 1971, Kawai et al., 1978, Toshima et al., 1979). This finding supported the hypothesis of a viral cause underlying the pathogenesis of cardiomyopathy. Evidence from murine models helped understanding pathogenesis of myocarditis (Liu&Mason, 2001). Myocarditis in susceptible mice is characterized by 3 separate disease processes, direct viral or other infectious agent access to myocardium tissue rapidly evolves into the second phase (Figure 2). In second phase, also called autoimmune phase of disease, immunological activation is the main feature. During the last phase, signs of myocarditis usually disappear and the damaged myocytes are substituted by diffuse fibrosis. Misdiagnosis and inappropriate therapy are especially possible at the time of transitional period among the 3 phases. In the case of reinfection and autoimmune recurrence, confusion can be compounded.

#### **3.1 Viremia**

Currently, there are two models of coxsackie B virus 3 induced myocarditis. The first one provokes acute viral myocarditis with a significant damage to myocytes and sudden death of animals within a week of infection (Fuse et al., 2005). In the second model, some degree of mice seemed to advance acute viral myocarditis following an infection with a cardiotropic strain of CVB3 (Fairwather&Rose, 2007). There also models with CMV, HIV and adenovirus (O'Donoughe et al., 1990, Salone et al., 2003, Beischel et al., 2004). During the time of active viremia, cardiotropic RNA virus (Coxsackie B) is taken into cells by receptor mediated endocytosis and are directly translated interior to the cells to produce protein (Huber, 1993). The virus enters the cell by endothelial receptors, particularly coxsackie-adenovirus receptor (CAR). Additionally, coxsackie B1, B3 and B5 uses decay accelerating factor (Shafren et al., 1995); adenoviruses uses αv integrin as coreceptors for viral entry (Wickham et al., 1994). It has been shown that CAR is highly expressed in the heart and brain, peaking in the perinatal period with subsequently declining with age and it is identified on the entire surface of the myocardium (Kashimura et al., 2004). Therefore, one can explain the susceptibility of neonates and infants to coxsackie B 3 myocarditis on the basis of expression level and the location of CAR. Titers of viral antigens in the myocardium is highest on the fourth day of inoculation of virus (Tomioka et al., 1986). No neutralizing antibodies to the virus were present until day 4. The antibody titers elevate promptly on day 8 and 10 reach the highest level on day 14 (Kawai, 1999). The emergence of a rising antibody titers is closely linked to elimination of the virus from the myocardium.

Fig. 2. Schematic drawings of pathophysiological processes of viral myocarditis. NO: Nitric oxide, NK: Natural killer cells.

#### **3.2 Autoimmunity**

44 Myocarditis

viral myocarditis, in particular of that due to mumps virus. Based on the chronology of the fading of the disease, Ni et al. suggested that it is likely that vaccination was responsible for the remarkable decrease in documented case of EFE. So it is logical to think that vaccination against parvovirus B19, echovirus and adenovirus could diminish cases of myocarditis and

Special attention to understanding the mechanism and pathogenesis of myocarditis have been increased since Gore and Saphir showed in 1947 that diphteric and rheumatic carditis separately comprised only 10% of a series of 1402 patients of myocarditis (Gore & Saphir, 1947). In 1970's, several investigators demonstrated the persistence of neutralizing antibodies to coxsackie B (CVB) in cases with cardiomyopathy than healthy subjects (Kawai, 1971, Kawai et al., 1978, Toshima et al., 1979). This finding supported the hypothesis of a viral cause underlying the pathogenesis of cardiomyopathy. Evidence from murine models helped understanding pathogenesis of myocarditis (Liu&Mason, 2001). Myocarditis in susceptible mice is characterized by 3 separate disease processes, direct viral or other infectious agent access to myocardium tissue rapidly evolves into the second phase (Figure 2). In second phase, also called autoimmune phase of disease, immunological activation is the main feature. During the last phase, signs of myocarditis usually disappear and the damaged myocytes are substituted by diffuse fibrosis. Misdiagnosis and inappropriate therapy are especially possible at the time of transitional period among the 3 phases. In the case of reinfection and autoimmune recurrence,

Currently, there are two models of coxsackie B virus 3 induced myocarditis. The first one provokes acute viral myocarditis with a significant damage to myocytes and sudden death of animals within a week of infection (Fuse et al., 2005). In the second model, some degree of mice seemed to advance acute viral myocarditis following an infection with a cardiotropic strain of CVB3 (Fairwather&Rose, 2007). There also models with CMV, HIV and adenovirus (O'Donoughe et al., 1990, Salone et al., 2003, Beischel et al., 2004). During the time of active viremia, cardiotropic RNA virus (Coxsackie B) is taken into cells by receptor mediated endocytosis and are directly translated interior to the cells to produce protein (Huber, 1993). The virus enters the cell by endothelial receptors, particularly coxsackie-adenovirus receptor (CAR). Additionally, coxsackie B1, B3 and B5 uses decay accelerating factor (Shafren et al., 1995); adenoviruses uses αv integrin as coreceptors for viral entry (Wickham et al., 1994). It has been shown that CAR is highly expressed in the heart and brain, peaking in the perinatal period with subsequently declining with age and it is identified on the entire surface of the myocardium (Kashimura et al., 2004). Therefore, one can explain the susceptibility of neonates and infants to coxsackie B 3 myocarditis on the basis of expression level and the location of CAR. Titers of viral antigens in the myocardium is highest on the fourth day of inoculation of virus (Tomioka et al., 1986). No neutralizing antibodies to the virus were present until day 4. The antibody titers elevate promptly on day 8 and 10 reach the highest level on day 14 (Kawai, 1999). The emergence of a rising antibody titers is closely

dilated cardiomyopathy.

confusion can be compounded.

linked to elimination of the virus from the myocardium.

**3.1 Viremia** 

**3. Pathogenesis** 

First phase terminates with the stimulation of the host immune response that weakens viral proliferation but may also augment viral entry. Under ideal circumstances, immune system should normalize to a resting state once viral proliferation is limited. However, if host immune system stimulation persists unrestricted even with the elimination of the virus, autoimmune disease may develop, activating the second phase. This phase is distinguished by inflammatory cellular infiltration with natural killer cells and macrophages, then consequent expression of proinflammatory cytokines, especially interleukin-1, interleukin-2, TNF and interferon γ (Kawai, 1999, Matsumori et al., 1994). It has been shown that TNF triggers endothelial cells, recruits further inflammatory cells, more enhances cytokine production and has direct negative inotropic effects (Feldman&McNamara, 2000). Cytokines can also induce macrophages to express inducible nitric oxide synthase (NOS) in heart cells (Zaragoza et al., 1998). The role of NO in myocarditis is complicated. NO can reduce viral replication, and peroxynitrate production has strong antiviral effects (Zaragoza et al., 1997). Mice deficient in NOS were found to have greater viral titers and more widespread myocyte injury (Padalko et al., 2004). Alternatively, myosin induced autoimmune myocarditis animal model showed us that NOS expression in myocytes and macrophages is related with more severe inflammation, where NOS inhibitors can have potential to reduce myocarditis severity (Zaragoza et al., 1998, Mikami et al., 1997). Furthermore, improvement in myocarditis of the mouse model has been demonstrated by blocking IL-1b or TNF-a at the onset of the disease (Fairweather et al., 2004). Cihakova et al. also showed that the severity of CVB3 induced myocarditis as well as myosin-induced myocarditis is associated with the levels of IL-1b and IL-18 in the myocardium (Cihakova et al., 2008). T cells are activated in viral myocarditis by classical cell-mediated immunity. Viral peptide fragments are processed in the Golgi apparatus of the myocyte and presented to the cell. These prepared T-cells are capable of identifying the viral antigen and destroy the infected myocyte by

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 47

Several remodelling mechanisms leading to dilated cardiomyopathy may be particular to myocarditis. The association of myocarditis to dilated cardiomyopathy has been moderately elucidated by molecular techniques. Badorff and Knowlton, demonstrated that dystrophin is cellular target for coxsackie B3 viral protease (Badorrff&Knowlton, 1999). It may provide one of the molecular mechanisms clarifying the significant ventricular dilatation that may develop immediately following viral infection. Furthermore, it was found that dystrophin deficiency augments host vulnerability to coxsackie virus infection (Xiong et al., 2002). This conclusion may result from the findings that more efficient liberation of the virus from the infected myocytes and is related with an increase in virus-mediated cytopathic effects. Proteases from other viruses (adenovirus and HIV) may also cleave cytoskeletal proteins

Identification of viral RNA at early, intermediate and late stages of myocarditis has been demonstrated in animal models. That persistent myocyte viral gene expression may be a cause of progressive dilated cardiomyopathy. Some findings propose that the persisting viral RNA seems to be capable of replication. In 172 patients with biopsy-confirmed viral infection, persistent viral genome of enterovirus, parvovirus B19, and HHV-6 was found to be associated with on-going impairment in ejection fraction (Kuhl et al., 2005); But, in the lack of measurable virus titers, it appears likely that the replication can be done in a limited or transformed manner (Klingel et al., 1992). All the more so, such replication might produce novel antigenic non-infectious or defective interfering viral elements, sufficient to cause evolving myocardial injury (Kawai, 1999). Cytokines possibly will participate in the development of dilated cardiomyopathy (Ono et al., 1998). During the second phase, they stimulate the matrix metalloproteinases, such as elastase, colleganases and gelatinase. Moreover, various reports suggest that several different viruses perform as a trigger for apoptosis. In addition to an immune-mediated mechanism activated by viral infection and persistent viral RNA in the myocardium, apoptosis may provide the third mechanism to

It is not fully understood which factors may define susceptibility to viral myocarditis and the development of cardiomyopathy. There are still remaining issues to be answered as why is it that who are in proximity to each other may be infected with the identical virus, but all do not develop myocardial injury? Why do certain infected cases continue to develop mild versus severe myocarditis or cardiomyopathy. But, up to date, the presence of genetic and environmental factors have been documented that influence particularly to viral myocarditis. Risk factors associated with severe myocarditis include age, viral variant, exercise, mouse strain and sex (Woodruff, 1980). Biochemical alterations such as selenium deficiency, vitamin E deficiency (Beck et al., 2003) and mercury exposure (Illback et al., 1996) have been documented to increase the viral virulence. Host genetic configuration not only influences the pathogenic mechanism of disease but also affects the severity of myocarditis. HLA-DQ locus and CD45 polymorphisms were to found to be essential determinants for early viral infection (Tchilian et al., 2006). Several investigations documented the significant association between dilated cardiomyopathy and MHC class II antigens, primarily HLA DR4 (Carlquist et al., 1991, Limas&Limas, 1989). In the study published in the Annals of Human Genetics, it is documented that HLA-DQA1\* 0501 and DQB1\*0303 are related to genetic susceptibility to idiopathic dilated cardiomyopathy (IDC), while DQA1\* 0201, DQB1\*

**3.3 Dilated cardiomyopathy** 

(Chen et al., 1999, Shoeman et al., 1993).

elucidate the development of dilated cardiomyopathy.

**3.4 Host factors** 

means of cytokine and perforine secretion (Ayach et al., 2003). But, persistent excited stimulation of the T cells is eventually harmful to the host, due to both direct T-cell mediated and cytokine-mediated cell damage diminish the number of contractile elements. Continuous T-cell activation is induced through antigens intrinsic to the myocardium that share molecular mimicry with viral peptides. The virus may also prompt a TH2 reaction, stimulating more CD8 killer cells in the process. It can be explained partially by the presence of evidence that CD4/CD8 or p56lck knockout animals have a much better survival following coxsackie infection (Liu et al., 1995). Recently, it has been shown that CD4+ Th cell subset, referred as Th17 cells, are involved in several inflammatory diseases, including experimental autoimmune myocarditis and collagen induced arthritis (Aggarwal et al., 2003, Chen et al., 2006). In addition to the proinflammatory effects, evidence from previous works suggested that Th17 cells may facilitate the production of autoantibodies in the development of acute viral myocarditis (Yuan et al., 2009). In experimental study published last year (Yuan et al., 2010), they showed that IL-17 produced by Th17 may take part in the regulation of the equilibrium between antiviral immunity and autoimmunity in CAVB3-induce acute viral myocarditis and IL-17 will be a new therapeutic goal for viral myocarditis in future (Milenkovic et al., 2010).

Although the activation of CD4 cells also leads to B-cell clonal expansion and antibody production, antibodies might not be the critical initiating factor that directs the advancing of the myocarditis. The severity of myocarditis was also found to be dependent on the responding T-cell subset in T-cell knockout mice (Opavsky et al., 1999). But, it has been shown that antibodies are a significant modifier of the disease phenotype. In a study conducted in 1982, it was found that among 30% of cases with suspected myocarditis, as well as in 18/19 patients with proven viral infection due to coxsackie, influenza A or mumps virus (Maisch et al., 1982). They also showed that antimyolemmal antibodies was correlated with the degree of in vitro induced cytolysis of rat myocytes.

Adenoviral myocarditis differs from coxsackie virus in the setting of pathogenesis (Hayder&Müllbacher, 1996). The amount of CD2, CD3 and CD45ROt lymphocytes detected in the adenovirus-infected cases was decreased compared with those patients who had myocarditis with other pathogens (Pauschinger et al., 1999). It was also demonstrated that 71% of PCR-positive adenoviral did not have inflammation histologically (Martin et al., 1994). One of the strategies of adenovirus for modulating immune response is that interaction of adenoviral encoded proteins with host immune components. These proteins may protect cells from tumor necrosis factor mediated lysis, as well as downregulation of major histocompatibility complex class I antigen expression. On the other side, adenoviral E1a encoded proteins are able to encourage the induction of apoptosis and inhibition of interleukin-6 (IL-6) expression (Davison et al., 2003). Besides this, it restricts IL-6 signal transduction pathways. These functions of E1A may be relevant to the occurrence of dilated cardiomyopathy. HIV has been identified within myocytes and is related with interference of myocyte integrity and replacement of endocardial fibrosis. Therefore, it was suggested that HIV myocarditis may share similar pathogenic mechanism of those of coxsackie (d'Amati et al., 2001).

It should be underlined that the natural killer (NK) cells is also important in the pathogenesis of myocardial inflammation. These finding corroborate those observed in a prior animal study, in which animals depleted of their NK cells previous to infection with coxsackievirus develop a more severe myocarditis (Godeny et al., 1987). The NK cells particularly reduce the nonenveloped virus infection by destroying the infected cells.

#### **3.3 Dilated cardiomyopathy**

46 Myocarditis

means of cytokine and perforine secretion (Ayach et al., 2003). But, persistent excited stimulation of the T cells is eventually harmful to the host, due to both direct T-cell mediated and cytokine-mediated cell damage diminish the number of contractile elements. Continuous T-cell activation is induced through antigens intrinsic to the myocardium that share molecular mimicry with viral peptides. The virus may also prompt a TH2 reaction, stimulating more CD8 killer cells in the process. It can be explained partially by the presence of evidence that CD4/CD8 or p56lck knockout animals have a much better survival following coxsackie infection (Liu et al., 1995). Recently, it has been shown that CD4+ Th cell subset, referred as Th17 cells, are involved in several inflammatory diseases, including experimental autoimmune myocarditis and collagen induced arthritis (Aggarwal et al., 2003, Chen et al., 2006). In addition to the proinflammatory effects, evidence from previous works suggested that Th17 cells may facilitate the production of autoantibodies in the development of acute viral myocarditis (Yuan et al., 2009). In experimental study published last year (Yuan et al., 2010), they showed that IL-17 produced by Th17 may take part in the regulation of the equilibrium between antiviral immunity and autoimmunity in CAVB3-induce acute viral myocarditis and IL-17 will be a new therapeutic goal for viral myocarditis in future

Although the activation of CD4 cells also leads to B-cell clonal expansion and antibody production, antibodies might not be the critical initiating factor that directs the advancing of the myocarditis. The severity of myocarditis was also found to be dependent on the responding T-cell subset in T-cell knockout mice (Opavsky et al., 1999). But, it has been shown that antibodies are a significant modifier of the disease phenotype. In a study conducted in 1982, it was found that among 30% of cases with suspected myocarditis, as well as in 18/19 patients with proven viral infection due to coxsackie, influenza A or mumps virus (Maisch et al., 1982). They also showed that antimyolemmal antibodies was

Adenoviral myocarditis differs from coxsackie virus in the setting of pathogenesis (Hayder&Müllbacher, 1996). The amount of CD2, CD3 and CD45ROt lymphocytes detected in the adenovirus-infected cases was decreased compared with those patients who had myocarditis with other pathogens (Pauschinger et al., 1999). It was also demonstrated that 71% of PCR-positive adenoviral did not have inflammation histologically (Martin et al., 1994). One of the strategies of adenovirus for modulating immune response is that interaction of adenoviral encoded proteins with host immune components. These proteins may protect cells from tumor necrosis factor mediated lysis, as well as downregulation of major histocompatibility complex class I antigen expression. On the other side, adenoviral E1a encoded proteins are able to encourage the induction of apoptosis and inhibition of interleukin-6 (IL-6) expression (Davison et al., 2003). Besides this, it restricts IL-6 signal transduction pathways. These functions of E1A may be relevant to the occurrence of dilated cardiomyopathy. HIV has been identified within myocytes and is related with interference of myocyte integrity and replacement of endocardial fibrosis. Therefore, it was suggested that HIV myocarditis may share similar pathogenic mechanism of those of coxsackie

It should be underlined that the natural killer (NK) cells is also important in the pathogenesis of myocardial inflammation. These finding corroborate those observed in a prior animal study, in which animals depleted of their NK cells previous to infection with coxsackievirus develop a more severe myocarditis (Godeny et al., 1987). The NK cells

particularly reduce the nonenveloped virus infection by destroying the infected cells.

correlated with the degree of in vitro induced cytolysis of rat myocytes.

(Milenkovic et al., 2010).

(d'Amati et al., 2001).

Several remodelling mechanisms leading to dilated cardiomyopathy may be particular to myocarditis. The association of myocarditis to dilated cardiomyopathy has been moderately elucidated by molecular techniques. Badorff and Knowlton, demonstrated that dystrophin is cellular target for coxsackie B3 viral protease (Badorrff&Knowlton, 1999). It may provide one of the molecular mechanisms clarifying the significant ventricular dilatation that may develop immediately following viral infection. Furthermore, it was found that dystrophin deficiency augments host vulnerability to coxsackie virus infection (Xiong et al., 2002). This conclusion may result from the findings that more efficient liberation of the virus from the infected myocytes and is related with an increase in virus-mediated cytopathic effects. Proteases from other viruses (adenovirus and HIV) may also cleave cytoskeletal proteins (Chen et al., 1999, Shoeman et al., 1993).

Identification of viral RNA at early, intermediate and late stages of myocarditis has been demonstrated in animal models. That persistent myocyte viral gene expression may be a cause of progressive dilated cardiomyopathy. Some findings propose that the persisting viral RNA seems to be capable of replication. In 172 patients with biopsy-confirmed viral infection, persistent viral genome of enterovirus, parvovirus B19, and HHV-6 was found to be associated with on-going impairment in ejection fraction (Kuhl et al., 2005); But, in the lack of measurable virus titers, it appears likely that the replication can be done in a limited or transformed manner (Klingel et al., 1992). All the more so, such replication might produce novel antigenic non-infectious or defective interfering viral elements, sufficient to cause evolving myocardial injury (Kawai, 1999). Cytokines possibly will participate in the development of dilated cardiomyopathy (Ono et al., 1998). During the second phase, they stimulate the matrix metalloproteinases, such as elastase, colleganases and gelatinase. Moreover, various reports suggest that several different viruses perform as a trigger for apoptosis. In addition to an immune-mediated mechanism activated by viral infection and persistent viral RNA in the myocardium, apoptosis may provide the third mechanism to elucidate the development of dilated cardiomyopathy.

#### **3.4 Host factors**

It is not fully understood which factors may define susceptibility to viral myocarditis and the development of cardiomyopathy. There are still remaining issues to be answered as why is it that who are in proximity to each other may be infected with the identical virus, but all do not develop myocardial injury? Why do certain infected cases continue to develop mild versus severe myocarditis or cardiomyopathy. But, up to date, the presence of genetic and environmental factors have been documented that influence particularly to viral myocarditis. Risk factors associated with severe myocarditis include age, viral variant, exercise, mouse strain and sex (Woodruff, 1980). Biochemical alterations such as selenium deficiency, vitamin E deficiency (Beck et al., 2003) and mercury exposure (Illback et al., 1996) have been documented to increase the viral virulence. Host genetic configuration not only influences the pathogenic mechanism of disease but also affects the severity of myocarditis. HLA-DQ locus and CD45 polymorphisms were to found to be essential determinants for early viral infection (Tchilian et al., 2006). Several investigations documented the significant association between dilated cardiomyopathy and MHC class II antigens, primarily HLA DR4 (Carlquist et al., 1991, Limas&Limas, 1989). In the study published in the Annals of Human Genetics, it is documented that HLA-DQA1\* 0501 and DQB1\*0303 are related to genetic susceptibility to idiopathic dilated cardiomyopathy (IDC), while DQA1\* 0201, DQB1\*

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 49

to a physician in 83% of cases. In a retrospective review, of 31 children with probable and definite myocarditis, 57% were initially diagnosed as suffering pneumonia or asthma (Freedman et al., 2007). One point that deserves attention in these studies is the absence of other signs of congestive heart failure in the majority of cases with myocarditis. Only 50% of children had hepatomegaly and 34% had abnormal chest radiography. The electrocardiographic changes include sinus tachycardia with low voltage QRS complexes, inverted T waves typically occur in the clinical setting of myocarditis (Durani et al., 2009). Wide Q waves and ST segment changes as a pattern of myocardial infarction also may be observed. Supraventricular tachycardia, ventricular tachycardia or atrial fibrillation, as well as atrioventricular block may occur (Friedman et al., 1994). Of note, the sensitivity of electrocardiography in myocarditis is only 47% (Morgera et al., 1992). However, Freedman and colleagues found that sensitivity of electrocardiography as a screening test was 93% (Freedman et al., 2007). Additional interesting finding that is worth to mentioning that the presence of axis deviation (%37) in children with myocarditis. Although ventricular tachycardia is a rare initial manifestation of myocarditis, it may often develops in long-term

Myocarditis imitating an acute coronary syndrome has also been defined. Viral genomes were demonstrated in 71% of adult cases with normal coronary anatomy, clinically mimicking myocardial infarction. Parvovirus B19 was most common agent identified in this study (Kuhl et al., 2003). ECG criteria (wide Q waves in I, avL, V5 and V6, ST segment change > 2 mm, ventricular arrhythmias) was described for the diagnosis of myocardial infarction in children (Towbin et al., 1992). However, similar ECG findings can occur in myocarditis (Durani et al., 2009). Most common ECG findings in adult patients with myocarditis include ST segment elevation(55%), T wave inversion (27%), ST segment depression (27%) and pathological Q waves (%18) (Dec et al., 1992, Angelini et al., 2000). Myocardial infarction and myocarditis in neonates overlap and mimic each other (deVetten et al., 2011). Despite angiographically normal coronary anatomy, global or segmental wall motion abnormalities are commonly obvious (Angelini et al., 2000). Physicians should always bear in mind the possibility of acute myocarditis in younger cases who present with acute coronary syndromes when coronary risk factors are lacking, global rather than segmental left ventricular dysfunction is evident on echocardiography or ECG abnormalities

Although the misdiagnosis of the myocarditis is common, several diagnostic methods can

Fig. 3. 12 lead ECG in children with myocarditis. Negative T wave in DI, aVL, ST-T changes

follow up and may occasionally result in sudden death (Drory et al., 1991).

encompass beyond a single coronary artery zone (Magnani&Dec, 2006).

aid physicians in making diagnosis of the myocarditis.

**5. Diagnosis** 

were noted in precordial leads.

0502 and DQB1\* 0504 present protection from IDC (Liu et al., 2005). However, associations of MHC class II alleles with dilated cardiomyopathy are possibly affected by ethnicity, sex, age and geographical variations. Besides the MHC haplotype, non- MHC genes should be considered (Neu et al., 1987). Two non-MHC loci on murine chromosomes 1 and 6, referred as Eam1 and Eam2, respectively, might influence autoimmune myocarditis (Guler et al., 2005). These loci intersect with loci implicated in other autoimmune diseases, such as lupus and diabetes, might give a clue that various autoimmune disease could be controlled by related genetic mechanisms. Initial antiviral response by the host has been recognized to be mediated at least in part by Toll-like receptors. TLR3 was found to play a significant role in the host innate immune response to infection with several cardiotropic viruses. Recent data suggests that variations in TLR3 alter the innate immune response and might change host susceptibility to increased cardiovascular pathology (Gorbea et al., 2010).
