**1. Introduction**

168 Myocarditis

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#### **1.1 Tobacco smoke exposure and cardiovascular disease**

More than 1 in every 10 cardiovascular deaths in the world during the year 2000 were attributable to smoking, demonstrating that it is an important preventable cause of cardiovascular mortality (Ezzati et al., 2005). It has been clearly established that exposure to environmental tobacco smoke increases the risk of cardiovascular disease among persons who have never smoked (Steenland, 1992). The cardiovascular effects of secondhand smoke are nearly as large as those confronting the principal smoker (Barnoya & Glantz, 2005). Non-smokers living with smokers have about a 25% increase in risk of death from heart disease and are more likely to suffer a stroke. Exposure to secondhand smoke may increase the risk of heart disease by non-smokers as much as 60% (Whincup et al., 2004). In 2004, Ong & Glantz estimated that only about 69% of U.S. indoor workers were covered by a smoke-free workplace policy. Making all workplaces smoke free as been accomplished for the commercial aircraft industry (Repace, 2004) would in one year prevent about 1500 myocardial infarctions and 350 strokes, and result in nearly 49 million dollars in savings in direct medical costs. These estimates are supported by reports of reduced incidence of admissions for myocardial infarction associated with smoking bans (Sargent et al., 2004). The cardiovascular effects of tobacco smoke exposure have been summarized in several excellent reviews (for example, see Barnoya and Glantz, 2005). Among the strongest pathophysiological correlates of tobacco smoking are accelerated endothelial dysfunction (Puranik & Celermajer, 2003) and acute clinical events, the latter being largely thrombotic (Ambrose & Barus, 2004). Recent studies indicate that increased oxidative stress is a

potential mechanism for initiating cardiovascular dysfunction (Yang et al., 2004; Talukder et al, 2011). Tobacco smoke has also been demonstrated to increase inflammatory markers in patients exposed to secondhand smoke, including homocysteine, C-reactive protein, fibrinogen, and oxidized LDL cholesterol, (Panagiotakos et al., 2004) suggesting that an increased inflammatory response may contribute to accelerated atherosclerosis. Clearly, the incidence of ischemic coronary and peripheral vascular disease is increased in patients exposed to tobacco smoke, either as smokers or through exposure to secondhand tobacco smoke (Ambrose & Barus, 2004; Benowitz, 2003; Law & Wald, 2003; Burns, 2003; Leone et al., 2004). The cardiovascular effects of tobacco smoke exposure are summarized in Table l.

Exacerbation of Viral Myocarditis by

catecholaminergic effects in the development of myocarditis.

It has been estimated that there are over 4,000 chemical constituents in cigarette smoke. Of these, about 400 have been measured or estimated in mainstream or sidestream smoke; of the 400, a significant amount of toxicology data exists for less than 100 (Fowles & Bates, 2000). Nicotine is the most comprehensively studied constituent of cigarette smoke, and has been shown to act primarily on nicotinic acetylcholine receptors in autonomic ganglia and in the brain (Benowitz, 2008; Mobascher & Winterer, 2008). This results in activation of the sympathetic nervous system, increasing the release of epinephrine (EPI) and norepinephrine (NE) from adrenergic nerve endings and the adrenal medulla, both systemically and into the local milieu of adrenergically innervated organs, including the heart (Haass & Kϋbler, 1997; Adamopoulos, et al., 2008; Shinozaki et al., 2008). Cigarette smoke also contains monoamine oxidase inhibitors (Cooper & Magwere, 2008; Fowles & Bates, 2000; Herraiz et al., 2005). Cigarette smoke has been shown to increase norepinephrine and epinephrine levels with

**1.4 Adrenergic activation by cigarette smoke** 

Tobacco Smoke: The Catecholamine Hypothesis 171

been shown to increase catecholamine levels in the blood (Wong et al, 2007). The most direct evidence arises from carefully controlled studies of murine myocarditis indicting that hypercatecholaminergeic states, secondary to pheochromocytoma and during infusion with sympathomimetic drugs, can cause or significantly exacerbate myocarditis (Cho et al., 1987; Van Vliet et al., 1966; Bindoli et al., 1992; Kammermeier & Grobecker, 1995; Davila et al., 1995; Prichard et al., 1991; Brown & O'Connell, 1995; Siltanen et al., l982; Haft, 1974; Noda, 1970; Morin & Cote, 1972; Seta et al., 1997; Nash & Carter, 1967; Karch, 1987; Krentz et al., 2001; Rezkalla et al., 1988). Reports of a prospective study by Karch (Karch, 1987) showed significantly elevated levels of epinephrine and norepinephrine in a group of patients who presented with cardiac symptoms immediately after using cocaine. Moreover, sympatholytic agents and states may ameliorate the manifestations of myocarditis and decrease mortality, although this effect is controversial (Rezkalla et al., 1988; Anandasabapathy & Frishman, 1998; Mehes et al., 1966; Dunn & Vickers, 1994). We have shown a beneficial effect of beta blockade, ameliorating cocaine and catecholamine exacerbation of myocarditis in a murine model (Wang et al., 2005). It is provocative to consider that many of the interventions shown to ameliorate viral myocarditic pathgenicity, including calcium channel blockers, act predominantly to attenuate sympathomimetic effects on the heart (Dong et al., 1992; Hiraoka et al., 1996; Lowenstein et al., 1996; Wang et al., 1997; Keaney et al., 1996). Additional evidence includes the observation that, among commonly abused substances in the general population (alcohol, nicotine, caffeine, marijuana, and cocaine), cocaine has been most strongly associated with an increased incidence of myocarditis, suggesting that its unique sympathomimetic properties, not shared with these other agents, may be the causative factor. Moreover, in the clinical area, it has been accepted clinical practice for many years to restrict the activities of patients with myocarditis, primarily based on animal studies and circumstantial clinical evidence in man that exercise exacerbates the disease (Abelmann, 1966; Cabinian et al., 1990; Gatmaitan et al., 1970; Friman et al., 1983; Kiel et al., 1989; Tilles et al., 1964; Elson & Abelmann, 1965; Hosenpud et al., 1987). In addition to directly increasing the work of the heart, normal exercise is associated with a marked increase in circulating catecholamine levels (Cabinian et al., 1990; Gatmaitan et al., 1970; Friman et al., 1983; Kiel et al., 1989). While the cardiac effects of sympathomimetic drugs and interventions using sympatholytic agents require additional testing in animal models of myocarditis and in man, the available evidence points to

Table 1. Cardiovascular effects of tobacco smoke exposure.

#### **1.2 Tobacco smoke exposure and heart failure**

National hospital discharge surveys estimate that 4.8 million Americans have heart failure, which has become an increasingly frequent reason for inpatient admission (Ho et al., 1993). One recent study estimated that among individuals aged 55 and older almost 1 in 3 will develop heart failure during their remaining lifespan. Heart failure is a fatal disease, with only 35% surviving 5 years after diagnosis (Bleumink et al., 2004). Coronary disease and diabetes mellitus along with hypertension are the leading causes of heart failure in the United States and it is therefore not surprising that tobacco smoke exposure has been identified as an independent risk factor for developing heart failure (Kannel et al., 1994; He et al., 2001). However, in at least 5% of patients, the cause of heart failure is initially unknown (Baldasseroni et al., 2002) and it has been estimated that myocarditis or inflammation of the heart muscle, may account for some 9% of these cases (Felker et al., 2000). Although estimates vary, these figures indicate that hundreds of thousands of Americans and millions of patients worldwide with heart failure may have myocarditis as a primary or exacerbating cause. The true incidence of myocarditis from any cause among the general population is unknown and most patients do not develop clinical manifestations of heart failure (Olinde & O'Connell, 1994). However, the Myocarditis Treatment Trial in which endomyocardial biopsy was performed in over 2,200 patients with unexplained heart failure of less than two years duration indicated a prevalence of 10%, implicating myocarditis as a potential cause of heart failure in hundreds of thousands of patients (Mason et al., 1995). Since only around 5% of patients systemically infected with a cardiotropic virus (Coxsakie β) may develop cardiac involvement, it is important to determine what factors may increase the risk of cardiac involvement (Grist & Bell, 1969; Gerzen et al., 1972; Rodeheffer & Gersh, 1996).

#### **1.3 Catecholamines exacerbate myocarditis**

Evidence from several different sources indicates that catecholamines may exacerbate viral myocarditis in animals and patients. A variety of sympathomimetic agents have been reported to induce or exacerbate myocarditis (Table 2). It is also important to note that nicotine has

National hospital discharge surveys estimate that 4.8 million Americans have heart failure, which has become an increasingly frequent reason for inpatient admission (Ho et al., 1993). One recent study estimated that among individuals aged 55 and older almost 1 in 3 will develop heart failure during their remaining lifespan. Heart failure is a fatal disease, with only 35% surviving 5 years after diagnosis (Bleumink et al., 2004). Coronary disease and diabetes mellitus along with hypertension are the leading causes of heart failure in the United States and it is therefore not surprising that tobacco smoke exposure has been identified as an independent risk factor for developing heart failure (Kannel et al., 1994; He et al., 2001). However, in at least 5% of patients, the cause of heart failure is initially unknown (Baldasseroni et al., 2002) and it has been estimated that myocarditis or inflammation of the heart muscle, may account for some 9% of these cases (Felker et al., 2000). Although estimates vary, these figures indicate that hundreds of thousands of Americans and millions of patients worldwide with heart failure may have myocarditis as a primary or exacerbating cause. The true incidence of myocarditis from any cause among the general population is unknown and most patients do not develop clinical manifestations of heart failure (Olinde & O'Connell, 1994). However, the Myocarditis Treatment Trial in which endomyocardial biopsy was performed in over 2,200 patients with unexplained heart failure of less than two years duration indicated a prevalence of 10%, implicating myocarditis as a potential cause of heart failure in hundreds of thousands of patients (Mason et al., 1995). Since only around 5% of patients systemically infected with a cardiotropic virus (Coxsakie β) may develop cardiac involvement, it is important to determine what factors may increase the risk of cardiac involvement (Grist &

Evidence from several different sources indicates that catecholamines may exacerbate viral myocarditis in animals and patients. A variety of sympathomimetic agents have been reported to induce or exacerbate myocarditis (Table 2). It is also important to note that nicotine has

Table 1. Cardiovascular effects of tobacco smoke exposure.

**1.2 Tobacco smoke exposure and heart failure** 

Bell, 1969; Gerzen et al., 1972; Rodeheffer & Gersh, 1996).

**1.3 Catecholamines exacerbate myocarditis** 

been shown to increase catecholamine levels in the blood (Wong et al, 2007). The most direct evidence arises from carefully controlled studies of murine myocarditis indicting that hypercatecholaminergeic states, secondary to pheochromocytoma and during infusion with sympathomimetic drugs, can cause or significantly exacerbate myocarditis (Cho et al., 1987; Van Vliet et al., 1966; Bindoli et al., 1992; Kammermeier & Grobecker, 1995; Davila et al., 1995; Prichard et al., 1991; Brown & O'Connell, 1995; Siltanen et al., l982; Haft, 1974; Noda, 1970; Morin & Cote, 1972; Seta et al., 1997; Nash & Carter, 1967; Karch, 1987; Krentz et al., 2001; Rezkalla et al., 1988). Reports of a prospective study by Karch (Karch, 1987) showed significantly elevated levels of epinephrine and norepinephrine in a group of patients who presented with cardiac symptoms immediately after using cocaine. Moreover, sympatholytic agents and states may ameliorate the manifestations of myocarditis and decrease mortality, although this effect is controversial (Rezkalla et al., 1988; Anandasabapathy & Frishman, 1998; Mehes et al., 1966; Dunn & Vickers, 1994). We have shown a beneficial effect of beta blockade, ameliorating cocaine and catecholamine exacerbation of myocarditis in a murine model (Wang et al., 2005). It is provocative to consider that many of the interventions shown to ameliorate viral myocarditic pathgenicity, including calcium channel blockers, act predominantly to attenuate sympathomimetic effects on the heart (Dong et al., 1992; Hiraoka et al., 1996; Lowenstein et al., 1996; Wang et al., 1997; Keaney et al., 1996). Additional evidence includes the observation that, among commonly abused substances in the general population (alcohol, nicotine, caffeine, marijuana, and cocaine), cocaine has been most strongly associated with an increased incidence of myocarditis, suggesting that its unique sympathomimetic properties, not shared with these other agents, may be the causative factor. Moreover, in the clinical area, it has been accepted clinical practice for many years to restrict the activities of patients with myocarditis, primarily based on animal studies and circumstantial clinical evidence in man that exercise exacerbates the disease (Abelmann, 1966; Cabinian et al., 1990; Gatmaitan et al., 1970; Friman et al., 1983; Kiel et al., 1989; Tilles et al., 1964; Elson & Abelmann, 1965; Hosenpud et al., 1987). In addition to directly increasing the work of the heart, normal exercise is associated with a marked increase in circulating catecholamine levels (Cabinian et al., 1990; Gatmaitan et al., 1970; Friman et al., 1983; Kiel et al., 1989). While the cardiac effects of sympathomimetic drugs and interventions using sympatholytic agents require additional testing in animal models of myocarditis and in man, the available evidence points to catecholaminergic effects in the development of myocarditis.

### **1.4 Adrenergic activation by cigarette smoke**

It has been estimated that there are over 4,000 chemical constituents in cigarette smoke. Of these, about 400 have been measured or estimated in mainstream or sidestream smoke; of the 400, a significant amount of toxicology data exists for less than 100 (Fowles & Bates, 2000). Nicotine is the most comprehensively studied constituent of cigarette smoke, and has been shown to act primarily on nicotinic acetylcholine receptors in autonomic ganglia and in the brain (Benowitz, 2008; Mobascher & Winterer, 2008). This results in activation of the sympathetic nervous system, increasing the release of epinephrine (EPI) and norepinephrine (NE) from adrenergic nerve endings and the adrenal medulla, both systemically and into the local milieu of adrenergically innervated organs, including the heart (Haass & Kϋbler, 1997; Adamopoulos, et al., 2008; Shinozaki et al., 2008). Cigarette smoke also contains monoamine oxidase inhibitors (Cooper & Magwere, 2008; Fowles & Bates, 2000; Herraiz et al., 2005). Cigarette smoke has been shown to increase norepinephrine and epinephrine levels with

Exacerbation of Viral Myocarditis by

the heart.

**chronic viral myocarditis** 

that catecholamine-related effects play a central role.

Tobacco Smoke: The Catecholamine Hypothesis 173

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

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

**2.2 Propranolol ameliorates and epinephrine exacerbates progression of acute and** 

Recent studies point to important interactions between proinflammatory cytokines and neurohumoral mediators in heart failure. We investigated the influence of the β-adrenergic system on cytokines and neurohumoral factors and the sequelae of viral myocarditis (Wang et al., 2005). In an experimental model with virus-infected BALB/c mice, we studied the acute and chronic effects of epinephrine and propranolol on myocardial morphology, cytokine gene expression, and survival. BALB/c mice were inoculated with the encephalomyocarditis virus (EMCV) or sham inoculated with saline and followed for 30 days. Epinephrine increased the severity of inflammatory cell infiltration and myocardial necrosis induced by EMCV-inoculated mice. Survival rate after 30 days was reduced to 40% in epinephrine-treated EMCV-inoculated mice compared with 70% in untreated EMCVinoculated mice (P<0.05). Treatment with the β-blocker propranolol significantly decreased


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

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