*2.4.1.1 Inflammatory cardiomyopathy*

DCM can occur after a cardiac infection or inflammation as an early (e.g. giantcell myocarditis) or late stage disease. Typically, the active or fulminant myocarditis appears with preserved left ventricular size, while in contrast inflammatory DCM is defined as the presence of chronic inflammatory cells in association with left ventricular dilatation and reduced fraction [3]. The inflammatory myocarditis can result from an infection or may be mediated by autoimmune mechanisms. The infectious myocarditis is commonly caused by viral pathogens as an acute or chronic disease [24]. In the developed countries until the 1990s, the most frequently reported viruses were adenoviruses and enteroviruses. Recently, parvovirus B12 and human herpes virus-6 are increasingly reported causing DCM [25]. In the acute phase, the virus replicates actively within the myocardium. This leads to dysfunction of cardiomyocytes and endothelial cells, and thus triggering the immune response [23]. Commonly, the innate immune system clears the viral load whereas insufficient immune response results in viral persistence and progressive myocyte destruction [25]. The secondary effect is triggered by primed T-cells. In addition, some host myocardial cellular antigens may share epitopic similarities with viral antigens and induce an autoimmune response with further destruction of cardiomyocytes [23].

**43**

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

Another important viral-related form of DCM is HIV syndrome. DCM in HIV patients is called HIV-associated cardiomyopathy. Autopsies demonstrated histological evidence of myocarditis in around 50% of patients, who died of AIDS-related illness [26]. Bacterial infections such as brucellosis, diphtheria, psittacosis, and typhoid fever are also known to cause (peri-) myocarditis [27–30]. In addition, E. coli bacteraemia have been described to induce myocarditis [31]. Spirochaetal myocarditis may be encountered in the setting of the Lyme disease (Borrelia burgdorferi), the Weil disease (Leptospirosis), and syphilis (Treponema pallidum) [32]. In endemic areas, the protozoan parasite Trypanosoma cruzi is a typical cause of DCM due to acute cardiac infection (perimyocarditis), as well as chronic myocardial fibrosis leading to DCM [33]. There are several proposed mechanisms leading to DCM in autoimmune disorders. These include immune-mediated myocarditis, progressive fibrosis, apoptosis with resultant restrictive and dilated phenotypes, and progressive atherosclerosis with subsequent ischemic cardiomyopathy [26]. Other causes for a non-infectious myocarditis are: Kawasaki disease in children with coronary vasculitis and systemic lupus erythematosus, which can affect the myocardium without involvement of the pericardium. In rare cases, connective tissue diseases such as scleroderma, rheumatoid arthritis, and polyarteritis nodosa may lead to DCM [26]. The non-infectious etiologies of myocarditis include drug-induced hypersensitivity and hypereosinophilic syndromes, as well as giant-cell myocarditis, which is one of the most aggressive non-infectious autoimmune disorders with rapid and devastating

Peripartum cardiomyopathy (PPCM) affects predisposed teenagers and older women during the last month of pregnancy or within 5 months of delivery with typical signs and symptoms of HF [34, 35]. Suspected etiological factors include inflammatory myocarditis, autoimmunity caused by chimerism of hematopoietic lineage cells from the fetus, hemodynamic stress during pregnancy, and toxicity caused by an abnormal cleavage product of prolactin [3, 36]. Furthermore, genetic

A number of chemical compounds are responsible for DCM. In western and developing countries, alcoholic cardiomyopathy (ACM) represents one of the most common forms of secondary cardiomyopathies resembling IDC with an estimated prevalence of 23–40% [24, 38]. More than women, men are affected by ACM and the occurrence correlates with a daily level and the duration of alcohol consumption [39]. However, the prevalence of ACM is variable and the mean daily amount of alcohol consumption, duration of regular intake, and patients' individual characteristics, including genetic susceptibility, are all related to the development of a respective cardiomyopathy [26]. Alcohol may result in both acute and chronic depression of myocardial contractility. Street drugs such as cocaine and methamphetamines are potent sympathomimetic drugs that induce inotropic and chronotropic effects. Mechanisms of cardiac toxicity include myocardial ischemia from increased oxygen consumption, prothrombotic effects, coronary vasospasms, and acceleration of coronary atherosclerosis [24]. Anthracycline-based chemotherapeutic agents are known to induce cardiac dysfunction. Acute or subacute injury can occur immediately after treatment with transient arrhythmias, pericarditis, and myocarditis [38]. The time course of chronic development of HF varies from an early onset (<1 year) to late onset (>1 year) or chronic progressive cardiomyopathy,

*DOI: http://dx.doi.org/10.5772/intechopen.83567*

outcome if not treated appropriately [24, 26].

predisposition seems to be important [37].

*2.4.1.3 Toxic cardiomyopathies*

*2.4.1.2 Peripartum cardiomyopathy*

**Figure 1.** *Etiologies of the dilated cardiomyopathy.*

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83567*

Another important viral-related form of DCM is HIV syndrome. DCM in HIV patients is called HIV-associated cardiomyopathy. Autopsies demonstrated histological evidence of myocarditis in around 50% of patients, who died of AIDS-related illness [26]. Bacterial infections such as brucellosis, diphtheria, psittacosis, and typhoid fever are also known to cause (peri-) myocarditis [27–30]. In addition, E. coli bacteraemia have been described to induce myocarditis [31]. Spirochaetal myocarditis may be encountered in the setting of the Lyme disease (Borrelia burgdorferi), the Weil disease (Leptospirosis), and syphilis (Treponema pallidum) [32]. In endemic areas, the protozoan parasite Trypanosoma cruzi is a typical cause of DCM due to acute cardiac infection (perimyocarditis), as well as chronic myocardial fibrosis leading to DCM [33]. There are several proposed mechanisms leading to DCM in autoimmune disorders. These include immune-mediated myocarditis, progressive fibrosis, apoptosis with resultant restrictive and dilated phenotypes, and progressive atherosclerosis with subsequent ischemic cardiomyopathy [26]. Other causes for a non-infectious myocarditis are: Kawasaki disease in children with coronary vasculitis and systemic lupus erythematosus, which can affect the myocardium without involvement of the pericardium. In rare cases, connective tissue diseases such as scleroderma, rheumatoid arthritis, and polyarteritis nodosa may lead to DCM [26]. The non-infectious etiologies of myocarditis include drug-induced hypersensitivity and hypereosinophilic syndromes, as well as giant-cell myocarditis, which is one of the most aggressive non-infectious autoimmune disorders with rapid and devastating outcome if not treated appropriately [24, 26].

#### *2.4.1.2 Peripartum cardiomyopathy*

*Visions of Cardiomyocyte - Fundamental Concepts of Heart Life and Disease*

As a consequence of the definition, the etiology of left ventricular dilatation and dysfunction is heterogeneous. In developed countries, CAD is the most common cause of left ventricular dilatation and dysfunction, and responsible for approximately 50–70% of HF patients. Therefore, potentially reversible myocardial ischemia must always be excluded for the diagnosis of DCM. The following section describes in detail the possible causes of the DCM (**Figure 1**). However, the current literature underscores that the cause of DCM remains unknown, that is, IDC, in

DCM can occur after a cardiac infection or inflammation as an early (e.g. giantcell myocarditis) or late stage disease. Typically, the active or fulminant myocarditis appears with preserved left ventricular size, while in contrast inflammatory DCM is defined as the presence of chronic inflammatory cells in association with left ventricular dilatation and reduced fraction [3]. The inflammatory myocarditis can result from an infection or may be mediated by autoimmune mechanisms. The infectious myocarditis is commonly caused by viral pathogens as an acute or chronic disease [24]. In the developed countries until the 1990s, the most frequently reported viruses were adenoviruses and enteroviruses. Recently, parvovirus B12 and human herpes virus-6 are increasingly reported causing DCM [25]. In the acute phase, the virus replicates actively within the myocardium. This leads to dysfunction of cardiomyocytes and endothelial cells, and thus triggering the immune response [23]. Commonly, the innate immune system clears the viral load whereas insufficient immune response results in viral persistence and progressive myocyte destruction [25]. The secondary effect is triggered by primed T-cells. In addition, some host myocardial cellular antigens may share epitopic similarities with viral antigens and induce an autoimmune response with further destruction of cardiomyocytes [23].

**2.4 Pathophysiological aspects and etiology**

half of the patients [23].

*2.4.1 Non-genetic causes of DCM*

*2.4.1.1 Inflammatory cardiomyopathy*

**42**

**Figure 1.**

*Etiologies of the dilated cardiomyopathy.*

Peripartum cardiomyopathy (PPCM) affects predisposed teenagers and older women during the last month of pregnancy or within 5 months of delivery with typical signs and symptoms of HF [34, 35]. Suspected etiological factors include inflammatory myocarditis, autoimmunity caused by chimerism of hematopoietic lineage cells from the fetus, hemodynamic stress during pregnancy, and toxicity caused by an abnormal cleavage product of prolactin [3, 36]. Furthermore, genetic predisposition seems to be important [37].

#### *2.4.1.3 Toxic cardiomyopathies*

A number of chemical compounds are responsible for DCM. In western and developing countries, alcoholic cardiomyopathy (ACM) represents one of the most common forms of secondary cardiomyopathies resembling IDC with an estimated prevalence of 23–40% [24, 38]. More than women, men are affected by ACM and the occurrence correlates with a daily level and the duration of alcohol consumption [39]. However, the prevalence of ACM is variable and the mean daily amount of alcohol consumption, duration of regular intake, and patients' individual characteristics, including genetic susceptibility, are all related to the development of a respective cardiomyopathy [26]. Alcohol may result in both acute and chronic depression of myocardial contractility. Street drugs such as cocaine and methamphetamines are potent sympathomimetic drugs that induce inotropic and chronotropic effects. Mechanisms of cardiac toxicity include myocardial ischemia from increased oxygen consumption, prothrombotic effects, coronary vasospasms, and acceleration of coronary atherosclerosis [24]. Anthracycline-based chemotherapeutic agents are known to induce cardiac dysfunction. Acute or subacute injury can occur immediately after treatment with transient arrhythmias, pericarditis, and myocarditis [38]. The time course of chronic development of HF varies from an early onset (<1 year) to late onset (>1 year) or chronic progressive cardiomyopathy,

which can occur 10–30 years after exposure. Both chronic forms tend to be irreversible, are dosage dependent and are associated with ultrastructural changes in the cardiac myocytes [40]. Trastuzumab, a monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2), is wildly used and very effective for the treatment of HER2-positive breast cancer. HER2 receptors are also localized on the cardiomyocyte. The inhibition of the Her2:Her4 signaling process in the myocardium is principally responsible for the cardiotoxicity [26]. In addition, a number of other, non-chemotherapeutical medications are associated with DCM, such as cyclophosphamide, phenothiazines, antidepressant drugs, carbon monoxide, lead, lithium, pseudoephedrine, ephedrine, cobalt, anabolic steroids, hydroxychloroquine, clozapine, and catecholamines [38, 41]. Possible causes of toxic cardiomyopathy are summarized in **Figure 2**.
