**3. α‐Cardiac actin (***ACTC***)**

Actin is a major constituent of the thin filament and spans the length of thin filament. Together with myosin, actin generates force and transmits this force from the sarcomere to the surrounding syncytium via the thin filament [23]. RCM mutations in the ACTC gene are extremely rare and only one ACTC mutation has been reported in RCM (nucleotide substitu‐ tion in exon 5 g. 4642G→C which lead to an Asp313His amino acid substitution). However, the significance of this variant is uncertain.

## **4. α‐Tropomyosin** *(TPM1***)**

In cardiac muscles, tropomyosin together with troponin forms the principal mechanism by which contractility is regulated in response to the Ca2+ concentration. In the absence of Ca2+, tropomyosin prevents productive myosin head binding. In systole, tropomyosin moves in response to Ca2+ binding to allow partial myosin attachment, which resulted in further shift of tropomyosin to expose fully the interaction site on actin [24]. Recently, a novel missense mutation in α‐tropomyosin, c.835A>C p.Asn279His has been identified in a patient with pri‐ mary RCM [25]. However, the significance of this variant is not clear since family evaluation did not show cosegregation.

### **5. β‐Myosin heavy chain (***MYH7***)**

Myosin is a dimeric protein consisting of two heavy chains and two associated pairs of light chains. The ~23‐kb long human *MYH7* gene, located on chromosome 14, contains 40 exons that direct the synthesis of the 1935 amino acid β‐myosin heavy chain [26]. Although over 500 disease‐causing point mutations have been found in human *MYH7* gene, most of them are reported in HCM, only four of these variants are identified in patients with primary RCM [27–32]. The understanding about the genotype‐phenotype correlation between the reported MYH7 mutation and RCM are very limited. MYH7 contains different functional domains, including the globular head domain (S1), the neck or hinge region (S2), and the tail (light meromyosin) [33, 34]. Although many mutations have been identified to cluster in functional hotspots due to the development of high throughput sequencing, all the above mentioned RCM‐related *MYH7* mutations located at regions where no definite function has been assigned to so far [28]. Besides, whether haploinsufficiency may contribute to the conse‐ quence of the variants is not clear.

### **6. Ventricular myosin essential light chain (***MYL3***) and ventricular myosin regulatory light chain (***MYL2***)**

Myosin assembles into hexamers comprising two heavy chains and two pairs of each light chain isoform. The light chain forms a stabilizing collar around the α‐helical neck of the heavy chain, a region of the myosin multimer thought to function as the level arm. Mutation in the gene encoding the essential light chain of myosin (*MYL3* Met149Val) and the regulatory light chain of myosin (MYL2 Glu22Lys) was previously reported to correlate with marked diastolic dysfunction and restrictive physiology both in human and transgenic mice [35]. Interestingly, carriers with simultaneous mutation in both *MYL3* and MYL2 showed different phenotypes. While patients with heterozygous mutation in MYL2 (p.Gly57Glu) and homozygous muta‐ tion in *MYL3* (p.Glu143Lys) had severe, early onset RCM, double heterozygote for these vari‐ ants have no evidence of cardiomyopathy [25, 36]. It is speculated that Glu143Lys substitution may be responsible for this heterogeneity through a loss of function mechanism. This specula‐ tion is based on (1) carriers with one mutant allele were clinically silent [36], while homozy‐ gotes for the mutation have severe, early‐onset cardiomyopathy [25]. If the cardiomyopathy was caused by a dominant‐negative mechanism, an intermediate phenotype in heterozygotes would be expected. (2) The substitution occurs in a surface‐exposed loop of the essential light chain [37], which makes it less likely to disrupt protein conformation or stability. The site‐ directed mutagenesis of the corresponding loop domain was confirmed to have no effect on binding between light and heavy chains [38]. Further study using transgenic animal models may help to answer this question.

### **7. Myosin‐binding protein C (***MYBPC3***)**

*2.1.1.3. Two deletion mutations*

176 Cardiomyopathies - Types and Treatments

*2.1.2. Troponin T mutation*

**3. α‐Cardiac actin (***ACTC***)**

**4. α‐Tropomyosin** *(TPM1***)**

did not show cosegregation.

**5. β‐Myosin heavy chain (***MYH7***)**

the significance of this variant is uncertain.

Deletion of nucleotides usually causes frame shift and the introduction of a premature stop codon. Two deletion mutations of *TNNI3* which impaired relaxation of myocardium and resulted in a restrictive filling pattern were reported to be located in exon 7 and cause trun‐ cation of C‐terminal portion of cTnI. The truncated cTnI which lost its C‐terminal portion is susceptible to degradation and has reduced inhibitory capacity on the thin filament since

cTnT anchors the troponin complex to Tm and plays a critical role in modulating ATPase activation when Ca2+ concentrations achieve threshold levels. Until now, three different muta‐ tions in the cTnT gene (*TNNT2*) linked to RCM have been identified. However, the molecular

Actin is a major constituent of the thin filament and spans the length of thin filament. Together with myosin, actin generates force and transmits this force from the sarcomere to the surrounding syncytium via the thin filament [23]. RCM mutations in the ACTC gene are extremely rare and only one ACTC mutation has been reported in RCM (nucleotide substitu‐ tion in exon 5 g. 4642G→C which lead to an Asp313His amino acid substitution). However,

In cardiac muscles, tropomyosin together with troponin forms the principal mechanism by which contractility is regulated in response to the Ca2+ concentration. In the absence of Ca2+, tropomyosin prevents productive myosin head binding. In systole, tropomyosin moves in response to Ca2+ binding to allow partial myosin attachment, which resulted in further shift of tropomyosin to expose fully the interaction site on actin [24]. Recently, a novel missense mutation in α‐tropomyosin, c.835A>C p.Asn279His has been identified in a patient with pri‐ mary RCM [25]. However, the significance of this variant is not clear since family evaluation

Myosin is a dimeric protein consisting of two heavy chains and two associated pairs of light chains. The ~23‐kb long human *MYH7* gene, located on chromosome 14, contains 40 exons that direct the synthesis of the 1935 amino acid β‐myosin heavy chain [26]. Although over

C‐terminal contains the second binding domain for actin and cTnC [19, 20].

pathogenesis of these cTnT mutations is not clear [20–22].

Cardiac myosin‐binding protein C is a modular polypeptide located at the C‐zone in the stri‐ ated muscles and binds myosin heavy chain in thick filament and titin in elastic filaments [39]. More than 150 mutations identified in MYBPC3 have been reported, which is the most com‐ mon genetic cause of HCM [40, 41]. Recently, variants of MYBPC3 have also been reported to be RCM‐causing mutation [42, 43].

### **8. Titin (***TTN***)**

The giant protein titin acts as the third filament system of the sarcomere, in addition to the actin and myosin filament. It physically connects myosin fibers to actin polymers and is attached to the Z‐line. Titin consists of four structurally and functionally distinct regions. (1) The N‐terminal titin binds to various Z‐disk proteins and acts as an anchor, which is composed of Z‐repeats and multiple immunoglobulin (Ig) domains. (2) Elastic I‐band region contains the important PEVK portion (proline, glutamate, valine, and lysine) and acts as the molecular spring. (3) Stabilizing A‐band region binds to the thick muscle filaments and contains Ig‐like, fibronectin type III (fibronection3) domain. (4) M‐band region contains the unique serine‐threonine kinase domain modulating titin expression and turnover, with C‐ terminus of titin embedding in the M‐line [44–46]. When the sarcomere is stretched during diastole, the I‐band segments gradually lengthen and develop passive tension and therefore, titin is a major determinant of the stiffness of myocardium [47].

Currently, two mechanisms are known to modulate titin's passive stiffness. (1) Titin‐based passive tension is critically defined by the ratio of the two major adult cardiac isoforms (N2BA and N2B). As a general rule, longer titin isoforms with longer PEVK repeats in the I‐band have more elasticity, whereas shorter isoforms provide more passive stiffness [48]. In adult cardiac muscle, two major isoforms are present: the long compliant N2BA and the shorter stiff N2B. In healthy adult, the ratio of N2BA to N2B in human left ventricle is 40:60 [49]. Moreover, the right ventricle expresses more N2BA than does the left ventricle [50]. In conditions with con‐ centric remodeling such as hypertension or aortic stenosis with diastolic function, a decreased N2BA:N2B ratio was shown [51, 52]. (2) Another more short‐term mechanism modulating titin's passive stiffness is caused by post‐translational modification influencing phosphoryla‐ tion states. Titin could be phosphorylated at the PEVK domain and the cardiac‐specific N2B domain, and phosphorylated titin exhibited decreased titin‐based passive tension [53].

Titin, known to be the major disease‐causing gene for DCM, is encoded by a single gene *TTN* on chromosome 2q31 [54]. Interestingly, recent clinical and genetic studies have estab‐ lished the role of titin defects in the pathophysiology of diastolic dysfunction and RCM. A de novo missense mutation of Titin c.22862A > G replacing adenine by guanine at position 109 of exon 226, resulting in the substitution of an evolutionally conserved tyrosine by cysteine (p.Y7621C) has been reported to result in early‐onset family RCM with severe heart failure [55]. Structural analysis revealed that p.Y7621C mutation is likely to disrupt the hydrophobic core within fibronectin3 domain, which locates in the A/I junction region [55]. However, how this *TTN* mutation might affect cardiac function and lead to the consecutive development of RCM is unknown.

### **9. Myopalladin (***MYPN***)**

Myopalladin (MYPN) is an Ig‐domain family member protein that has been reported to be a key intermediate molecule at the Z‐disc involved in sarcomere/Z‐disc assembly and regulation of gene expression in cardiac cells [56]. Through genetic screening for *MYPN* mutations in large cohorts of patients with cardiomyopathy, 15 *MYPN* variants were identified, of which a nonsense mutation (p.Q529X) was identified in an RCM family with variable penetrance [57]. Q529X was found to disturb different functional domains of MYNP. MYNP contains five Ig domains (two N‐terminal and three C‐terminal). Central and C‐terminal domains of MYPN bind at the Z‐disc to α‐actinin and nebulette (NEBL), respectively. This actinin‐MYPN‐ NEBL complex tethers actin and titin to the Z‐disc and may play roles in the signaling and regulation of gene expression in response to muscle stress. The N‐terminal domain of MYNP binds cardiac ankyrin repeat protein (CARP), which is involved in the control of muscle gene expression [58]. Q529X mutation truncates the C‐terminus of MYNP, including the NEBL‐ and α‐actinin‐binding domains. Comparative immunohistochemistry of human heart tissue was performed on specimens from the siblings with RCM and from normal control subjects without *MYPN* mutation as well as in neonatal rat cardiomyocytes (NRCs) expressing green fluorescent protein (GFP) chimeras of WT‐ and Q529X‐MYPN. Disrupted sarcomeric Z‐discs with abnormally diffuse MYPN codistributed focally with abnormal sarcomeric α‐actin, localization were seen in the specimen from siblings with RCM and NRCs expressing Q529X‐ MYPN [57]. Therefore, losing the NEBL and α‐actinin‐binding domain results in severe dis‐ turbance of sarcomere/Z‐disc assembly, which may have impact on early myofibrillogenesis and resulted in RCM. Besides, since MYPN localizes both at sarcoplasm and nucleus, mutant MPPN‐Q529X protein in the nucleus was reported to result in downregulation of CARP expression and upregulation of MLP and desmin, augmenting fibrotic restrictive remodel‐ ing [59]. In addition, truncated proteins are usually unstable due to decay of mRNA and/or protein degradation through the lysosome or ubiquitin‐proteasome system. Although *MYPN* mRNA was not affected by the Q529X‐MYPN mutation in the myocardium, mutant MYPN was relatively unstable compared with WT protein [57]. Therefore, insufficient quantities of the protein (haploinsufficiency) may be partly involved in dysfunction of the protein.

### **10. Mutations cause variable phenotypes**

**8. Titin (***TTN***)**

178 Cardiomyopathies - Types and Treatments

RCM is unknown.

**9. Myopalladin (***MYPN***)**

The giant protein titin acts as the third filament system of the sarcomere, in addition to the actin and myosin filament. It physically connects myosin fibers to actin polymers and is attached to the Z‐line. Titin consists of four structurally and functionally distinct regions. (1) The N‐terminal titin binds to various Z‐disk proteins and acts as an anchor, which is composed of Z‐repeats and multiple immunoglobulin (Ig) domains. (2) Elastic I‐band region contains the important PEVK portion (proline, glutamate, valine, and lysine) and acts as the molecular spring. (3) Stabilizing A‐band region binds to the thick muscle filaments and contains Ig‐like, fibronectin type III (fibronection3) domain. (4) M‐band region contains the unique serine‐threonine kinase domain modulating titin expression and turnover, with C‐ terminus of titin embedding in the M‐line [44–46]. When the sarcomere is stretched during diastole, the I‐band segments gradually lengthen and develop passive tension and therefore,

Currently, two mechanisms are known to modulate titin's passive stiffness. (1) Titin‐based passive tension is critically defined by the ratio of the two major adult cardiac isoforms (N2BA and N2B). As a general rule, longer titin isoforms with longer PEVK repeats in the I‐band have more elasticity, whereas shorter isoforms provide more passive stiffness [48]. In adult cardiac muscle, two major isoforms are present: the long compliant N2BA and the shorter stiff N2B. In healthy adult, the ratio of N2BA to N2B in human left ventricle is 40:60 [49]. Moreover, the right ventricle expresses more N2BA than does the left ventricle [50]. In conditions with con‐ centric remodeling such as hypertension or aortic stenosis with diastolic function, a decreased N2BA:N2B ratio was shown [51, 52]. (2) Another more short‐term mechanism modulating titin's passive stiffness is caused by post‐translational modification influencing phosphoryla‐ tion states. Titin could be phosphorylated at the PEVK domain and the cardiac‐specific N2B domain, and phosphorylated titin exhibited decreased titin‐based passive tension [53].

Titin, known to be the major disease‐causing gene for DCM, is encoded by a single gene *TTN* on chromosome 2q31 [54]. Interestingly, recent clinical and genetic studies have estab‐ lished the role of titin defects in the pathophysiology of diastolic dysfunction and RCM. A de novo missense mutation of Titin c.22862A > G replacing adenine by guanine at position 109 of exon 226, resulting in the substitution of an evolutionally conserved tyrosine by cysteine (p.Y7621C) has been reported to result in early‐onset family RCM with severe heart failure [55]. Structural analysis revealed that p.Y7621C mutation is likely to disrupt the hydrophobic core within fibronectin3 domain, which locates in the A/I junction region [55]. However, how this *TTN* mutation might affect cardiac function and lead to the consecutive development of

Myopalladin (MYPN) is an Ig‐domain family member protein that has been reported to be a key intermediate molecule at the Z‐disc involved in sarcomere/Z‐disc assembly and regulation of gene expression in cardiac cells [56]. Through genetic screening for *MYPN* mutations in

titin is a major determinant of the stiffness of myocardium [47].

The molecular mechanisms by which gene mutation cause cardiomyopathy can usually be explained by two alternative ways. One is mutation may cause structural and functional change in the protein, which should be analyzed in four different levels: (1) change in the deoxyribonucleic acid sequence, (2) the actual amino acid change, (3) the changes in Ca2+ sensitivity of force development and ATPase activity, and (4) the change in protein‐protein interaction. The other mechanism may involve insufficient quantities of the protein due to instability of the mutant protein leading to haploinsufficiency [23].

However, it is now evident that different mutations in one gene could cause multiple phe‐ notypes. It is also intriguing that even for a given single mutation and even within a sin‐ gle family disparate phenotypes can be seen. For example, the cTnT lle79Asn mutation has been shown to be associated with HCM, DCM, and RCM within a single pedigree [60]. This implies that factors just beyond the pathogenic sarcomere mutation influence the phenotype. Therefore, the model of sarcomeric cardiomyopathy as monogenic disease following simple Mendelian pattern of inheritance is an oversimplification. Theoretically, a discrete number of reasons can account for phenotypic diversity. (1) First of all, patients may carry more than one disease‐associated mutations, which is underestimated in most cases. Recent genotyping sug‐ gests that multiple cardiomyopathy patients have more than one mutation in the same gene or mutations in different genes. For example, in a study carried out in 292 HCM patients, 13 were found to carry at least 2 mutations [61, 62]. However, the number of patients carrying at least two mutations is likely to be significantly underestimated since many genetic studies typically investigate less than 15 genes for mutations associated with cardiomyopathy [63]. (2) Secondly, different expression and the incorporation rate of the mutant sarcomeric pro‐ teins in the heart may also contribute to the heterogeneity of the disease. A few examples in HCM have been published. Heterozygous individuals carrying the βMHC Lys207Gln muta‐ tion developed an HCM phenotype, but a homozygous individual developed a DCM‐like phenotype [61]. In another case, homozygous carriers of cTnT Ser179Phe mutation exhibited profound left and right ventricular hypertrophy [64] while heterozygous carriers had little or no hypertrophy [65]. (3) Third, mutant proteins are usually unstable due to decay of mRNA and/or degradation through the lysosome or ubiquitin‐proteasome system, especially in the case of nonsense mutation [66]. Because of genetic polymorphisms, individuals with RCM are likely to have substantial difference in their genome sequence including disease‐modifier genes which are involved in post‐translational or translational regulation, resulting in dif‐ ferent amounts of mutant protein. This mechanism may interfere with the development of the phenotype and explain different penetrance of a specific mutation. (4) Lastly, sarcomere gene mutation induces serials of maladaptive features, ranging from the prolongation of car‐ diomyocyte action potential to microvascular dysfunction, from intracellular calcium abnor‐ mality to dysregulation of collagen turn‐over, and from energetic derangement to abnormal sympathetic activation [67]. The extent and the rate at which each of these features occur and evolve are quite variable within individual patients. Therefore, the clinical heterogeneity of a specific sarcomere gene mutation may partly be ascribed to different stages of disease progression [68]. Although epigenetics and environmental factors are likely to be relevant in sarcomeric cardiomyopathies, there have been no studies yet describing how epigenetic modification and environmental factors may affect phenotype in sarcomeric RCM.

### **11. Phenotype transition**

Occasionally, with the progression of disease, "phenotype transition" may be seen in a given individual who was initially diagnosed with a specific type of cardiomyopathy. This situation could often be seen in patients who was initially diagnosed with HCM and gradually devel‐ oped into end‐stage of the disease. The morpho‐functional manifestation in this advanced stage usually exhibits two extremes: hypokinetic‐dilated from or hypokinetic‐restrictive form which could be hard to distinguish from primary DCM and RCM [68]. The "HCM to RCM" transition has been discussed above. There is another situation that patients initially diag‐ nosed with primary RCM could undergo persistent cardiac remodeling resulting atypical phenotype at a later stage of the disease. Although the main impairment of RCM is diastolic dysfunction, deterioration of systolic function has been observed in some patients. In a ret‐ rospective study, it was reported that 16% of 94 primary RCM patients was observed to have systolic dysfunction [69]. Another study carried out in pediatric RCM reveals that although all the 18 children had preserved ventricular systolic function at diagnosis, 6 of them later presented a deteriorated ventricular systolic function and eventually required inotropic sup‐ port [70]. In the RCM model using transgenic mice noticeable impaired systolic was observed over a time of 10 months. By the time, those RCM mice presented with signs of severely aggravated congestive heart failure and some of them died [71]. This disease progression is consistent with some of the clinical observation, suggesting that systolic dysfunction may be responsible for the end‐stage lethal heart failure. As for the mechanism, some proposed that ischemia may be a bridge between the progression of diastolic dysfunction and the develop‐ ment of systolic function, based on evidence of ischemia observed in hearts for autopsy from RCM patients and transgenic RCM mice [71–73]. Besides, it is presumed that reduced capil‐ lary density due to interstitial fibrosis and increased extravascular compressive force in the restrictive heart may also induce ischemia [74]. Of note, although an RCM patient may appear to have systolic dysfunction and low cardiac output, enlargement of ventricle is seldom seen, probably because the molecular mechanism and sarcomeric mechanics of RCM and DCM are opposite [75].

### **12. Summary**

reasons can account for phenotypic diversity. (1) First of all, patients may carry more than one disease‐associated mutations, which is underestimated in most cases. Recent genotyping sug‐ gests that multiple cardiomyopathy patients have more than one mutation in the same gene or mutations in different genes. For example, in a study carried out in 292 HCM patients, 13 were found to carry at least 2 mutations [61, 62]. However, the number of patients carrying at least two mutations is likely to be significantly underestimated since many genetic studies typically investigate less than 15 genes for mutations associated with cardiomyopathy [63]. (2) Secondly, different expression and the incorporation rate of the mutant sarcomeric pro‐ teins in the heart may also contribute to the heterogeneity of the disease. A few examples in HCM have been published. Heterozygous individuals carrying the βMHC Lys207Gln muta‐ tion developed an HCM phenotype, but a homozygous individual developed a DCM‐like phenotype [61]. In another case, homozygous carriers of cTnT Ser179Phe mutation exhibited profound left and right ventricular hypertrophy [64] while heterozygous carriers had little or no hypertrophy [65]. (3) Third, mutant proteins are usually unstable due to decay of mRNA and/or degradation through the lysosome or ubiquitin‐proteasome system, especially in the case of nonsense mutation [66]. Because of genetic polymorphisms, individuals with RCM are likely to have substantial difference in their genome sequence including disease‐modifier genes which are involved in post‐translational or translational regulation, resulting in dif‐ ferent amounts of mutant protein. This mechanism may interfere with the development of the phenotype and explain different penetrance of a specific mutation. (4) Lastly, sarcomere gene mutation induces serials of maladaptive features, ranging from the prolongation of car‐ diomyocyte action potential to microvascular dysfunction, from intracellular calcium abnor‐ mality to dysregulation of collagen turn‐over, and from energetic derangement to abnormal sympathetic activation [67]. The extent and the rate at which each of these features occur and evolve are quite variable within individual patients. Therefore, the clinical heterogeneity of a specific sarcomere gene mutation may partly be ascribed to different stages of disease progression [68]. Although epigenetics and environmental factors are likely to be relevant in sarcomeric cardiomyopathies, there have been no studies yet describing how epigenetic

modification and environmental factors may affect phenotype in sarcomeric RCM.

Occasionally, with the progression of disease, "phenotype transition" may be seen in a given individual who was initially diagnosed with a specific type of cardiomyopathy. This situation could often be seen in patients who was initially diagnosed with HCM and gradually devel‐ oped into end‐stage of the disease. The morpho‐functional manifestation in this advanced stage usually exhibits two extremes: hypokinetic‐dilated from or hypokinetic‐restrictive form which could be hard to distinguish from primary DCM and RCM [68]. The "HCM to RCM" transition has been discussed above. There is another situation that patients initially diag‐ nosed with primary RCM could undergo persistent cardiac remodeling resulting atypical phenotype at a later stage of the disease. Although the main impairment of RCM is diastolic dysfunction, deterioration of systolic function has been observed in some patients. In a ret‐ rospective study, it was reported that 16% of 94 primary RCM patients was observed to have

**11. Phenotype transition**

180 Cardiomyopathies - Types and Treatments

In the past decades, clinical and genetic studies suggest that primary RCM is part of a spec‐ trum of sarcomeric disease. Since RCM is associated with severe prognosis, ongoing and future basic science will continue to dissect the precise pathways driving how these muta‐ tions remodel the heart, and identify rational therapies targeting pathophysiological aspects to interrupt the emergency of pathology. On the other hand, it is also important to realize that genes contain information that is essential for the development of the phenotype but not neces‐ sarily complete. The final phenotype is determined not only by the causal mutation but also by the modifier genes, each exerting a modest effect, epigenetic factors, which link the gene to the phenotype, and the environmental factors, as in the case of complex phenotypes observed in single‐gene disorders with Mendelian pattern of inheritance. Thus, while advances in molecu‐ lar genetics of cardiovascular diseases are gradually changing our classical understanding of the disease and the phenotype‐based approach to the practice of medicine, currently they are unlikely to be sufficient to trigger a full switch from a phenotype‐based to genotyped‐based medicines. A comprehensive understanding of molecular mechanism of the pathogenesis integrating the genetic, epigenetic, transcriptomic, and proteomic profiles is necessary.

### **Author details**

Shuai Wang and Daoquan Peng\*

\*Address all correspondence to: pengdq@hotmail.com

1 Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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**Specific Cardiomyopathies**

#### **Chapter 10 Provisional chapter**

### **Infective Cardiomyopathy "Infective Cardiomyopathy"**

Agnieszka Pawlak and Robert Julian Gil Agnieszka Pawlak and Robert Julian Gil

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66095

#### **Abstract**

Both the infectious agent and development of inflammatory response to infection can lead to irreversible myocardial injury, which affects the outcome of short- and long-term prognosis. In the case of the rapid elimination of the infectious agent and rapid withholding of inflammatory process, changes in myocardium are small. If the immune response does not lead to complete elimination of infectious agent or inflammation progresses after removing the virus, chronic myocardial damage may develop. Persistence of the virus in myocardium, postinfectious immune reaction, autoimmunity, and primary cardiac damage may result in the development of progressive ventricular dysfunction, development of cardiac arrhythmias, and exacerbation of symptom. Because of the long-term consequences, it is important to diagnose infective cardiomyopathy (IC) quickly and start appropriate treatment. However, IC is still a diagnostic challenge. Infective cardiomyopathy is often underdiagnosed because of a wide spectrum of factors causing IC—infectious, toxic, immunologic, and various clinical manifestation. The processes responsible for the development of IC take place at the cellular level, which is why it is important to make the diagnosis not only based on clinical symptoms and imaging but also to confirm it with the use of histological, immunohistochemical, and molecular studies. Progress in the diagnosis and understanding of the pathomechanisms responsible for the development of IC contributed to the use of new therapeutic options. Immunosuppresive and immunomodulative treatment is still of limited use. However, in some cases of viral IC, targeted antiviral treatment can be added to the standard heart failure therapy resulting in improvement of the prognosis.

**Keywords:** myocarditis, infective heart disease, cardiomyoapthy

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

### **1. Introduction**

Infective cardiomyopathy (IC)is a disease in which structural or/and functional heart disorders are observed as a result of present or past infection caused by various infectious agents. In the course of infective cardiomyopathy heart chambers' dilatation, heart walls' hypertrophy or restriction may occur. A relation between infection and chronic heart disease was suggested as early as 1806, when Corvisart described a cardiac inflammatory disorder that could result in progressive abnormalities of cardiac function after all the evidence of the infective agent had disappeared [1]. Because of a variety of symptoms, diagnosis of IC can be difficult [2]. Usually, thesuspicionofICisbasedonclinicalpresentationandresultsofnoninvasivediagnosticimaging, e.g., cardiac magnetic resonance (CMR) [3]. Although endomyocardial biopsy (EMB), which can confirm myocarditis, is the gold standard in making a diagnosis, it is not often performed because of its still low availability and invasiveness. However, the interest in this method is increasing lately [2]. Although more is known about the pathophysiology of the disease, many questions remain unanswered. There are many controversions about the treatment of patients with IC, especially the most common form—viral myocarditis [3].

### **2. Etiology**

Infective cardiomyopathy may be caused by many etiological factors including viruses, bacteria, rickettsiae, fungi, protozoa, and parasites. However, the spectrum of pathogens has changed over the decades and also varies geographically as, for example, *Trypanosoma cruzi* [4]. Moreover, it can result from noninfectious agents, such as allergic agents, autoimmunity, toxins, and drugs [5]. Etiological factors that could cause IC are presented in **Table 1**.


**Table 1.** Etiological factors of IC.
