**4. Conclusions**

338 Myocarditis

Atherosclerosis is a major initiator of thrombi formation that can restrict blood flow and lead to a heart attack (Carter, 2005). Cardiac mural thrombi can arise from a myocardial infarction, infection, inflammation (e.g. myocarditis) or rheumatic heart disease, for example. Although research has led to a clear understanding of conditions that induce thrombosis, the precise pathology leading to disease remains unclear. Thrombi can develop anywhere in the cardiovascular system like in the ventricular or atrial chambers, arteries, veins or capillaries. The size and shape of individual thrombi vary depending on the circumstances leading to their development. They often are found at sites of endothelial injury. Once thrombi have formed (acute) they may accumulate more platelets and fibrin and grow larger, or dislodge and travel to other sites, or be removed by fibrinolytic activity, and finally they can attract inflammation, undergo remodeling with deposition of collagen

and be reincorporated into the vessel or myocardium (Kumar et al., 2005) (Figure 6).

Fig. 6. Mural thrombi develop during acute CVB3 autoimmune myocarditis in mice and reincorporate into the myocardium. Male BALB/c mice were infected intraperitoneally with heart-passaged coxsackievirus B3 (CVB3) containing infectious CVB3 (103 plaque forming units) and heart proteins on day 0 and thrombus formation examined at day 10 post

infection (pi) during acute myocarditis (**A**) or during chronic myocarditis/DCM at day 35 pi (**B**). H&E staining shows ventricular mural thrombus at day 10 pi (magnification, x100) (**A**). Masson's trichrome stains bright blue revealing collagen composition of mural integrated

Damage of cardiac tissue by viruses and inflammation is known to release tissue factor (TF), the main initiator of the coagulation cascade that results in the formation of fibrin and thrombotic clots (Mackman, 2009). Mural thrombi are known to occur in viral models of myocarditis in mice as well as in myocarditis patients (Antoniak et al., 2008; Kojima et al., 1988; Kuh & Seo, 2005). Furthermore, DCM patients demonstrate a high frequency of LV thrombi and prothrombotic characteristics like high levels of circulating fibrinogen and antithrombin III (Abdo et al., 2010). Many studies have shown that TF can increase inflammation by stimulating release of IL-6, a cytokine that along with TNF and IL-1 has been strongly associated with poor CVD outcome (Braunwald, 2008; Carter, 2005; Mackman, 2009; Rao et al., 2006). Complement components also contribute to thrombosis by depositing at sites of tissue damage and by activating platelets (Fairweather et al., 2006; Peerschke et al.,

ventricular thrombus at day 35 pi (magnification, x100) (**B**).

**3.4 Thrombosis biomarkers** 

Biomarkers are an important clinical tool for assessing progression to heart failure. DCM often leads to HF, and myocarditis is an important cause of acute (sudden death) and chronic (arising from DCM) forms of HF. Even though myocarditis is known to be an important cause of HF, few clinical studies have been conducted to determine the presence or usefulness of HF biomarkers in predicting adverse outcomes in myocarditis patients. Studies that have been conducted in myocarditis/DCM patients or animal models suggest that many of the biomarkers used to assess the likelihood of progression to heart failure in other CVDs will also provide useful information in myocarditis/DCM patients. More studies examining the ability of circulating HF biomarkers to predict poor outcome and HF in animal models of myocarditis/DCM are needed. Animal models will also provide valuable information on the potential role of HF biomarkers in the pathogenesis of disease. This knowledge is critical in determining the ability of therapies targeted to these biomarkers to prevent disease progression.
