**2. Experimental evidence**

### **2.1 Overview**

Our previous studies indicated that catecholamines exacerbate the severity of viral myocarditis in a murine model (Soodini & Morgan, 2001; Wang & Morgan, 2003; Wang et al., 2002a, 2002b, 2005). We performed studies with a variety of agents known to enhance the adrenergic tone, all of which exacerbated myocarditis in our viral model; in contrast, treatment with propranolol ameliorated the severity of myocarditis. Tobacco smoke has also been demonstrated to increase adrenergic activation in animals and patients, in part due to its content of nicotine (Cavarra et al., 2001; Pomerleau, 1992; Su, 1982) which in turn may exacerbate the severity of viral myocarditis in a murine model through adrenergically mediated mechanisms (Bae et al., 2010). As a more generalized hypothesis, exposure to tobacco smoke may be an important and as yet underappreciated cause of heart failure in patients receiving treatments with pro-inflammatory drugs (i.e. clozapine) or who are exposed to pathogens (i.e. viruses) or physical factors (i.e. radiotherapy) that can produce a level of myocarditis susceptible to exacerbation.

Sympathomimetic agents have the potential to produce toxic effects on the heart through a variety of mechanisms that are summarized in Figure 1. Note the overlap with mechanisms

Table 2. Sympathomimetic agents that may initiate or exacerbate myocarditis.

1997; Sofuoglu et al., 2006; Marano et al., 1999, Wang et al., 2005).

**2. Experimental evidence** 

level of myocarditis susceptible to exacerbation.

**2.1 Overview** 

associated increases in heart rate, blood pressure and coronary vasoconstriction (Haass & Kϋbler, 1997, Adamopoulos et al., 2008, Shinozaki et al., 2008). Nicotine may also potentiate catecholamine actions, perhaps via effects on nitric oxide synthesis or release (Haass & Kϋbler, 1997). The adrenergic actions of nicotine can be attenuated or blocked by administration of beta-adrenergic antagonists, although it has been proposed that the drug may act by additional mechanisms to activate the beta-adrenergic pathway (Haas & Kϋbler,

Our previous studies indicated that catecholamines exacerbate the severity of viral myocarditis in a murine model (Soodini & Morgan, 2001; Wang & Morgan, 2003; Wang et al., 2002a, 2002b, 2005). We performed studies with a variety of agents known to enhance the adrenergic tone, all of which exacerbated myocarditis in our viral model; in contrast, treatment with propranolol ameliorated the severity of myocarditis. Tobacco smoke has also been demonstrated to increase adrenergic activation in animals and patients, in part due to its content of nicotine (Cavarra et al., 2001; Pomerleau, 1992; Su, 1982) which in turn may exacerbate the severity of viral myocarditis in a murine model through adrenergically mediated mechanisms (Bae et al., 2010). As a more generalized hypothesis, exposure to tobacco smoke may be an important and as yet underappreciated cause of heart failure in patients receiving treatments with pro-inflammatory drugs (i.e. clozapine) or who are exposed to pathogens (i.e. viruses) or physical factors (i.e. radiotherapy) that can produce a

Sympathomimetic agents have the potential to produce toxic effects on the heart through a variety of mechanisms that are summarized in Figure 1. Note the overlap with mechanisms attributed to tobacco smoke exposure in Table 1, most notably with regard to myocarditis, their effects on inflammation, immune function, and factors associated with cardiac and vascular dysfunction. Although multiple factors undoubtedly contribute to the exacerbation of myocarditis we have observed with tobacco smoke exposure, it is reasonable to propose that catecholamine-related effects play a central role.

Fig. 1. Direct and indirect effects of catecholamines and related sympathomimetic agents on the heart.
