**4. Conclusions**

Evidence from our laboratory and elsewhere (summarized above) indicates that both mainstream and secondhand tobacco smoke exposure can exacerbate viral myocarditis. Induction of a systemic inflammatory response appears to be a central initiating mechanism responsible for myocarditis, an effect that can be mediated by a cardiotropic viral infection itself and exacerbated by additional factors, most notably, catecholamines and other sympathomimetic agents, (Figure 2).

There appears to be an additive or synergistic effect of factors producing inflammation, which in turn can enhance viral load in the myocytes and exacerbate the extent and severity of myocarditis. Severe cardiac dysfunction and clinical heart failure may result. Our data suggest that disruption of gap junctions plays an important role in this regard (Figure 1). Moreover, to the extent that catecholamines are responsible, beta-adrenergic antagonists can attenuate the effect. Although the results presented in this review are consistent with a primary pathogenic role of catecholamines in the exacerbation of myocarditis by tobacco smoke, they do not exclude other factors that may operate through different mechanisms.

increase in mortality among mice that were pre-exposed to smoke compared to the virus alone. Tobacco smoke alone did not affect mortality. There was a significant increase in

In this study, we also investigated the rate of apoptosis 5 days after ί.ρ. injection of virus. Viral exposure alone significantly increased the number of apoptotic cells. The number of apoptotic cells was increased further by smoke exposure prior to viral injection. Viral injection increased the translocation of apoptosis-inducing factor from mitochondria, a hallmark of caspace-independent apoptosis activation. Exposure to tobacco smoke exacerbated these effects without changing the total expression of apoptosis-inducing factor

Apoptosis has been shown to play an important role in human and animal heart failure (Kang et al., 2000; Kang & Izumo, 2003). Other investigators have demonstrated EMCVinduced apoptosis in the hearts of mice and pigs (for example, see Mizutani et al., 1996 and Brewer et al., 2001). Activation of caspaces may be a critical facilitator of viral infection in cardiomyocytes (DeBiasi et al., 2004, Kyoto et al., 2004). In fact, DeBiasi et al., have shown that inhibition of caspaces effectively blocks virus-induced apoptosis in vitro, although caspace-independent factors also appeared to be involved. Apoptosis-inducing factor release from mitochondria is one important caspace-independent factor, and appears to play an important role in EMCV-infection related apoptosis, as shown in our study. These data were later to show that viral infection induced a significant increase in apoptosis, through caspace-independent apoptosis, and that preexposure to tobacco smoke exacerbated this

Several studies have shown a relationship between myocyte apoptosis and increased sympathetic activity in patients with underlying heart disease, most commonly heart failure (Singh et al., 2001). Communal et al., 1998 showed that over-stimulation by norepinephrine produced apoptosis in ventricular myocytes of adult rats and blocking the beta-receptor decreased apoptosis. These data are consistent with our hypotheses that catecholamines are a major factor inducing inflammation and cell death in tobacco smoke exposed animals.

Evidence from our laboratory and elsewhere (summarized above) indicates that both mainstream and secondhand tobacco smoke exposure can exacerbate viral myocarditis. Induction of a systemic inflammatory response appears to be a central initiating mechanism responsible for myocarditis, an effect that can be mediated by a cardiotropic viral infection itself and exacerbated by additional factors, most notably, catecholamines and other

There appears to be an additive or synergistic effect of factors producing inflammation, which in turn can enhance viral load in the myocytes and exacerbate the extent and severity of myocarditis. Severe cardiac dysfunction and clinical heart failure may result. Our data suggest that disruption of gap junctions plays an important role in this regard (Figure 1). Moreover, to the extent that catecholamines are responsible, beta-adrenergic antagonists can attenuate the effect. Although the results presented in this review are consistent with a primary pathogenic role of catecholamines in the exacerbation of myocarditis by tobacco smoke, they do not exclude other factors that may operate through different mechanisms.

virus load among hearts from mice exposed to S+V compared to V alone.

suggesting activation of caspace-independent apoptotic pathways as well.

effect.

**4. Conclusions** 

sympathomimetic agents, (Figure 2).

Additional animal and human studies will be necessary to further elucidate the several factors that may be involved. However, taken together, the available data indicate that tobacco smoke can exacerbate myocarditis which in turn may result in irreversible cardiac dysfunction and failure. Even in the absence of additional data, these results provide another example of the adverse effects of tobacco smoke and strengthen the argument for minimizing exposure to this agent in our environment.

Fig. 2. Proposed primary mechanism for exacerbation of viral myocarditis by tobacco smoke exposure: the catecholamine hypothesis.
