*2.4.1.5 Infiltrative diseases*

Several, systemic diseases may infiltrate the myocardium and result in DCM. Sarcoidosis, iron overload, and amyloidosis represent the most common clinical entities. Sarcoidosis is a multisystem inflammatory disease of unknown origin characterized by non-caseating granulomas in multiple organs. Sarcoidosis can progress to a fibrotic stage leading to DCM [26]. In the setting of iron overload, such as hereditary hematochromatosis, high blood volume, or parenteral iron infusions,

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*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

cardiac dysfunction and to DCM in very advanced stages [26].

disease), and l-carnitine being responsible for DCM [47, 48].

*2.4.2.1 Sarcomere protein location: force generation and transmission*

The sarcomere is the contracting unit of the myocyte. The thin filaments of the sarcomere emanate from the Z-disc. They consist of filamentous α-actin (gene name ACTC 1) and calcium-sensitive troponin-tropomyosin regulatory apparatus (encoded by TPM1), which includes the three troponin subunits (encoded by TNNT2, TNNC1, and TNNI3) [52, 53]. The thick filament core is formed by the β-myosin heavy chain (encoded by MYH7), the molecular motor of the thick filament, and the myosin-binding protein C (β-MYBPC3) [52, 53]. Titin (encoded by TTN), which is the largest human protein, spans the half length of the sarcomere,

the following section on genetic causes of DCM.

DCM may occur due to iron-induced reactive oxygen species with cellular oxidative stress and fibrosis [43]. Cardiac amyloidosis is the most common cause of infiltrative cardiomyopathy with poor prognosis. Amyloid is an extracellular tissue deposition of misfolded amyloid protein-fibrils [44]. Cardiac amyloidosis usually presents as a cardiomyopathy with restrictive pathophysiology and can progress to severe

Endocrinologic disorders rarely lead to the phenotype of DCM. Especially thyroid hormones have a significant impact on cardiac function and structure via regulation and expression of key structural and regulatory genes like myosin heavy chain and phospholamban. Therefore, excess or deficiency of triiodothyronine (T3) may lead to DCM in a late stage [45]. Growth hormone disorders, pheochromocytoma, and Cushing's disease are also very rare causes of DCM [26, 46]. Furthermore, the literature names nutritional deficiencies of thiamine (beriberi disease), selenium (Keshan

Neuromuscular disease like Duchenne's muscular dystrophy, Becker muscular dystrophy, and Emery-Dreifuss muscular dystrophy can affect the heart and induce DCM. Patients with DCM and muscular dystrophy commonly show X-linked mutations or autosomal recessive inheritance [24]. Further information is summarized in

In up to 30% of the cases, a gene mutation may be identified as the main cause of DCM [49]. Thanks to advances in next-generation sequencing technologies more than 40 genes have already been identified causing DCM [50]. Most commonly, familial DCM is inherited as an autosomal dominant pattern. Autosomal recessive, X-linked, and mitochondrial inheritance patterns are less common [24]. Most of the genes involved in the development of DCM encode structural elements of the cardiomyocytes. Mutations in genes encoding sarcomeric, cytoskeletal, desmosomal, nuclear membrane, mitochondrial, and RNA-binding proteins have all been linked to DCM [51]. Interestingly, several of the gene mutations linked to autosomal dominant DCM encode the same contractile proteins that are also responsible for the development of HCM [38]. As well, other affected genes are described in ARVC and left ventricular non-compaction cardiomyopathy (NCCM). In the following, we will describe the most investigated gene mutations and their consequences on the

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

*2.4.1.6 Endocrine/metabolic disorders*

*2.4.1.7 Neuromuscular disorders*

*2.4.2 Genetic causes of DCM*

cardiomyocyte functioning.

**Figure 2.** *Reasons for toxic cardiomyopathies.*

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

DCM may occur due to iron-induced reactive oxygen species with cellular oxidative stress and fibrosis [43]. Cardiac amyloidosis is the most common cause of infiltrative cardiomyopathy with poor prognosis. Amyloid is an extracellular tissue deposition of misfolded amyloid protein-fibrils [44]. Cardiac amyloidosis usually presents as a cardiomyopathy with restrictive pathophysiology and can progress to severe cardiac dysfunction and to DCM in very advanced stages [26].
