*2.4.2.5 Nuclear envelope: maintain structural organization*

The nuclear membrane protein complex contains emerin and lamin A/C (LMNA) [52, 55]. These two lamina proteins and nesprin-1 are part of the LINC complex that links the nucleus to the cytoplasm. Stress signals in the cytoplasm are hypothesized to act with the LINC complex, affecting gene expression in the nucleus. The LINC complex is crucial for an appropriate transcriptional response of the cell to mechanical stress [52]. Defects in emerin proteins can induce X-linked Emery-Dreifuss muscular dystrophy, joint contractures, conduction system disease, and DCM. Dominant lamin A/C (encoded by LMNA) mutations exhibit a more cardiac-restricted phenotype with fibrofatty degeneration of the myocardium and it is conducting system. More than 200 different lamin A/C (LMNA) mutations are associated with inherited cardiomyopathy, primarily DCM that may be associated with conduction system disease prior to the evidence of ventricular dilatation due to fibrofatty degeneration of the myocardium and conducting cells [52, 55]. Other diseases caused by lamin A/C mutations are Charcot-Marie-Tooth neuropathy, Dunningan partial familial lipodystrophy, progeria and other overlapping syndromes, all known as laminopathies [63].

### *2.4.2.6 Ion channel*

The function of sarcolemmal transmembrane cardiac voltage-gated sodium channel is crucial in the generation of cardiac action potentials. Some mutations in the encoding gene SCNA5 are implicated in DCM. SCN5A mutations causes high burden of arrhythmias. There are also many allelic variants in SCN5A, including those leading to Brugada syndrome, idiopathic ventricular fibrillation (VF), familial atrial fibrillation (AF), left ventricular non-compaction cardiomyopathy, and long QT syndrome type III [54, 59, 64].

### *2.4.2.7 Extracellular matrix-cell-adhesion and signaling*

Extracellular matrix proteins such as laminin alpha-4 (LAMA4) and Fukutin (FKTN) have been described in relation to DCM. They may lead to DCM phenotype by disrupting signaling pathways and modifying cell-surface molecules [50].

The genetic evaluation of DCM is summarized in **Table 2**.


are also associated with Noonan and Leopard Syndrome

**49**

**2.6 Screening**

**2.5 Diagnosis**

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

**Gene screening of DCM Genotype correlations of DCM**

system disease

is described in 4–8%

sudden cardiac death

• EMD mutations can lead to X-linked Emery-Dreyfuss muscular dystrophy, joint contractures and conduction

• Prevalence of genetic-related DCM due to LMNA mutation

• LMNA-related heart failure is often more resistant to heart failure therapy and has a high risk for arrhythmias and

• Mutations in LMNA can cause a severe and progressive DCM and can also lead to Charcot-Marie-Tooth neuropathy, Dunningan partial familial lipodystrophy, Emery-

Dreyfuss muscular dystrophy and progeria

• *SCN5A* mutations account for 2–3% of DCM, mutations are associated with Brugada syndrome, Long QT syndrome, atrial fibrillation and conduction defects • KCNQ1 mutations may induce atrial fibrillation, Long QT 1, Short QT1 and Jervell and Lange-Nielsen syndrome

• Extracellular matrix protein relation has been described

• FKTN and LAMA2 mutations can also cause congenital

Establishing the etiology is of great importance as it may influence treatment and prognosis of patients with DCM. Beside the conventional clinical tools, modern imaging and genetic tools are available to elucidate and ensure the correct diagnosis. The recently published statement for the diagnostic workup on DCM from the ESC working group on myocardial and pericardial diseases recommend the following steps: first the diagnostic evaluation should be start with in-depth personal and family history, followed by physical examination, an electrocardiogram (ECG), and echocardiography [8]. These steps often sufficiently differentiate between acquired and familial DCM. If there is no suspicion of an acquired DCM and if 'red flags' are recognized, the second-level diagnostic work-up should be added. 'Red flags' are defined as signs and suspicion on a specific etiology. Biochemical analyses, cardiac magnetic resonance imaging (CMR), endomyocardial biopsy (EMB), and genetic testing are recommended in a second step. However, the patient's age plays a crucial role in the decision-making during the diagnostic procedure and should be rated against the potential benefit of dedicated investigations. The detailed diagnostic

to DCM

muscular dystrophy

In common, DCM is a slowly progressive disease and screening is essential for an early diagnosis of asymptomatic family members. Currently, screening all first-degree family members of patients with genetic proven or non-genetic forms of DCM with a positive family history is recommended. The screening comprises

workup and possible red flags are presented in **Table 3**.

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

• Emerin (EMD) • Lamin A/C (LMNA)

• Sodium channel, voltagegated, type V, alpha subunit

• Potassium channel (KCNQ1)

• Laminin alpha-4 (LAMA4)

• Fukutin (FKTN)

*Genetic aspects of dilated cardiomyopathy.*

(SCNA5)

**Genetic evaluation of DCM**

Nuclear envelope and nucleus protein related genes

Ion channel protein related genes

Extracellular matrix protein related genes

**Table 2.**


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

#### **Table 2.**

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

**Gene screening of DCM Genotype correlations of DCM**

(TTN) mutations

of DCM

mutations

atrial fibrillation

muscular dystrophy

Naxos syndrome

palmoplantar keratoderma

• 12–25% of genetic related DCM are associated with titin

• α-Tropomyosin 1 (TPM 1) mutations are described in 1–2%

• Myosin heavy chain (MYH7)-mutations in 3–4% of DCM • 3% of DCM are linked to cardiac troponin T (TNNT2)

• Gene defects in sarcomere proteins are associated with defects in force generation and transmission • TNNI3K-mutations may cause conduction defects and

• Metavinculin (CVL) mutations are related to 1% of DCM • Dystrophin (DMD) mutations are associated with Duchenne/Becker muscular dystrophy

• Sacroglycan (SDC) mutations can cause Limb-girdle-

Prevalence of *Desmin (DES)* mutations in genetic related DCM is about 1–2%, the mutations are often related with myofibrillar myopathy, ARCV and cardiac conduction blocks

• Mutations in desmosomal genes are frequent in patients with advanced DCM undergoing cardiac transplantation • Desmosomal gene mutations are also linked to ARVC • Desmoplakin (DSP) causes 2% of genetic related DCM • Plakoglobin (JUP)-mutations are also associated with

• Desmocollin 2 (DSC2) mutations may lead to mild

• Specific mutations are associated with high risk of malignant ventricular arrhythmias and end-stage heart failure • Ryanodine receptor 2 (RyR2) correlates with cathecolaminergic polymorphic ventricular tachycardia and ARVC • Phospholamban (PLN) mutations can cause ARVC • Some other genes encoding for sarcoplasmic reticulum and cytoplasm related proteins like PTPN11, RAF1 and RIT1 are also associated with Noonan and Leopard Syndrome

**Genetic evaluation of DCM**

Sarcomere protein related genes

Cytoskeletal protein related genes: Z-disc Dystrophin complex Cytoskeleton

Desmosomal protein related genes

Sarcoplasmic reticulum related genes

• Titin (TNN) • α-Cardiac actin (ACTC 1 and ACTC 2) • α-Tropomyosin 1 (TPM 1) • Cardiac troponin subtypes (TNNT2, TNNC1, TNNI3) • Myosin heavy chains (MYH 6, MYH7)

(MYBPC)

(TNNI3K)

(PDLIM3)

SGCG) • Desmin (DES)

• Myosin-binding protein C

• α-Actinin 2 (ACTN 2) • Muscle LIM protein (MLP) • Cysteine- and glycine-rich protein 3 (CSPR3) • Telethonin (TCAP) • Cypher/Z-band (LDB3) • PDZ LIM domain protein 3

• Cardiac ankyrin repeat protein (CARP) • Myopalladin (MYPN) • Nexilin (NEXN) • Metavinculin (VCL) • Dystrophin (DMD) • Sacroglycan

(SGCA, SGCB, SGCD, and

• Ryanodine receptor 2 (RyR2) • Phospholamban (PLN) • SR proteins, Ca-ATPase pump

(SERCA2a)

• Plakoglobin (JUP) • Desmoplakin (DSP) • Desmocollin 2 (DSC2) • Desmoglein 2 (DSG2) • Plakophilin-2 (PKP2)

• Troponin I-interacting kinase

**48**

*Genetic aspects of dilated cardiomyopathy.*

### **2.5 Diagnosis**

Establishing the etiology is of great importance as it may influence treatment and prognosis of patients with DCM. Beside the conventional clinical tools, modern imaging and genetic tools are available to elucidate and ensure the correct diagnosis. The recently published statement for the diagnostic workup on DCM from the ESC working group on myocardial and pericardial diseases recommend the following steps: first the diagnostic evaluation should be start with in-depth personal and family history, followed by physical examination, an electrocardiogram (ECG), and echocardiography [8]. These steps often sufficiently differentiate between acquired and familial DCM. If there is no suspicion of an acquired DCM and if 'red flags' are recognized, the second-level diagnostic work-up should be added. 'Red flags' are defined as signs and suspicion on a specific etiology. Biochemical analyses, cardiac magnetic resonance imaging (CMR), endomyocardial biopsy (EMB), and genetic testing are recommended in a second step. However, the patient's age plays a crucial role in the decision-making during the diagnostic procedure and should be rated against the potential benefit of dedicated investigations. The detailed diagnostic workup and possible red flags are presented in **Table 3**.

#### **2.6 Screening**

In common, DCM is a slowly progressive disease and screening is essential for an early diagnosis of asymptomatic family members. Currently, screening all first-degree family members of patients with genetic proven or non-genetic forms of DCM with a positive family history is recommended. The screening comprises


#### **Table 3.**

*Diagnostic workup and possible red flags in dilated cardiomyopathy.*

physical examination, 12-lead ECG and transthoracic echocardiography as well as measurement of CK levels. The CK levels may help to identify subclinical skeletal muscle abnormalities and to provide supportive evidence for the presence of an inherited myopathy. If DCM is suspected in first-degree relatives, the screening should be repeated anually. Otherwise, asymptomatic first-degree relatives should be rescreened at three- to five-year intervals because of possible late onset of DCM phenotype [21].

**51**

*2.7.2 Anticoagulation*

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

Specific treatment is applicable in syndrome associated DCM, for example, infectious etiologies and infiltrative disorders. However, specific treatment is not available for most DCM patients. Therefore, the therapy focuses on improvement of clinical symptoms as well as on the control of disease progression and potential

Guidelines recommend the following treatment for acute HF, not including noncardiogenic shock: oxygen, non-invasive ventilation (NIV), intravenous diuretics (20–40 mg bolus furosemide at admission), and intravenous nitrates. Intravenous nitrates have long been described to improve hemodynamic and dyspnea in HF patients by many ways: decrease in systemic blood pressure and left ventricular afterload, substantial reduction preload and therefore of in right and left ventricular filling pressure, an increase in cardiac output, and little or no change in heart rate [65]. Improvement in cardiac output by intravenous nitrates is mostly related to the reduction in left ventricular afterload, but is also influenced by a decrease in pulmonary vascular resistance, improvement in myocardial oxygenation, and a reduction of mitral regurgitation. Administration of inotropes and/or vasopressors is recommended in patients with signs of low cardiac output [66]. However, application of inotropes and/or vasopressors is associated with an increased long-term mortality risk [67–69]. Additional treatment includes the optimal dosing of angiotensinconverting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). ACEI have been shown to reduce cardiovascular mortality and prevent rehospitalization in patients with HF in two key randomized controlled trails (CONSENSUS and SOLVD-Treatment) [70]. Likewise, ARB improve long-term outcome in HF patients [71]. Another essential component of HF therapy is spironolactone. The RALES study has shown a reduction in mortality after addition of 25 mg of spironolactone to the standard treatment in HF patients with an LVEF <35% [72]. The international guidelines recommend spironolactone in all patients presenting with moderate to severe HF symptoms. In the PARADIGM-HF trial, the use of angiotensin receptorneprilysin inhibitor (ARNI) (sacubitril/valsartan) showed a reduction of the composite endpoint of cardiovascular death or HF hospitalization by 20% compared with enalapril alone in symptomatic HF patients with reduced LVEF [73]. These study results are implemented in the updated ACC/AHA/HFSA guidelines on management of HF, which recommend to replace ACEI or ARB by sacubitril/valsartan in patients with reduced LVEF and ongoing symptoms [74]. Betablockers reduce mortality in HF patients even without reduced ejection fraction as has been demonstrated by multicenter placebo-controlled studies [75–77]. Because of the negative inotropic effect of betablockers, patients should not be treated in the very acute presentation with signs or symptoms of decompensation and initial doses should be low. Long-term goal is a heart rate below 70 bpm in sinus rhythm. If this is not obtainable with the maximum, or maximum tolerated dose of betablockers, the current European heart failure guidelines recommend the addition of Ivabradine [66]. In addition to pharmacological medication cardiac resynchronization therapy (CRT) has been shown to improve

cardiac performance, to reduce symptoms, morbidity, and mortality [78, 79].

The role of anticoagulation in DCM with sinus rhythm is unclear [80]. The prospective randomized trials were either underpowered or with a too short

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

complications such as sudden cardiac arrest.

*2.7.1 Heart failure treatment*

**2.7 Therapy**

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

#### **2.7 Therapy**

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

Degree of symptoms Travel history Inheritance pattern

organs

Personal and familial

24 h ambulatory blood pressure monitoring

Biochemistry Blood count

history

**Diagnostic tool Look for Red flags for specific disorders**

Intellectual and sensorineural disabilities

Repolarization disorders with non-coronary

Skin abnormities, for example, hyperpigmentation and palmoplantar keratoderma, butterfly-shaped face rash

Muscle weakness Myotonia Gait disturbances

Woolly hair

distribution Low QRS amplitude Bundle branch block Long QTc

Atrioventricular block

Ventricular arrhythmias

High levels of creatine kinase

Increased serum iron & ferritin levels Leucopenia or neutropenia Free light chains for amyloidosis Diabetes and lactatacidosis Thyroid disorders Infectious etiologies

Left ventricular hypertrabecularisation Segmental dysfunction with noncoronary

Patchy or inferobasal late gadolinium enhancement (LGE) distribution "Midwall sign" septal wall LGE distribution

Myoglobinuria

distribution

Toxin exposition Involvement of other

Electrocardiogram Low P-wave amplitude

24 h electrocardiogram Relevant brady- and tachyarrhythmias Relevant tachyarrhythmias

Exclude persistent hypertension

Serum iron, ferritin and electrophoresis

Urine chemistry and proteinuria Serum free light chains HIV and hepatitis serology Other specific serology tests in accordance symptoms and clinical

Right ventricular pathologies

Intramyocardial edema Intramyocardial iron deposit Right ventricular morphology

Electrolytes Renal function Cardiac biomarkers

TSH HbA1c

suspicion

Coronary angiography Exclude coronary artery disease CMR Late Gadolinium Enhancement

Valve diseases

Molly sequence

*Diagnostic workup and possible red flags in dilated cardiomyopathy.*

Echocardiography Ventricular dilatation

EBM Giant cell myocarditis Genetics Screening familial DCM

physical examination, 12-lead ECG and transthoracic echocardiography as well as measurement of CK levels. The CK levels may help to identify subclinical skeletal muscle abnormalities and to provide supportive evidence for the presence of an inherited myopathy. If DCM is suspected in first-degree relatives, the screening should be repeated anually. Otherwise, asymptomatic first-degree relatives should be rescreened at three- to five-year intervals because of possible late onset of DCM

**50**

**Table 3.**

phenotype [21].

Specific treatment is applicable in syndrome associated DCM, for example, infectious etiologies and infiltrative disorders. However, specific treatment is not available for most DCM patients. Therefore, the therapy focuses on improvement of clinical symptoms as well as on the control of disease progression and potential complications such as sudden cardiac arrest.

#### *2.7.1 Heart failure treatment*

Guidelines recommend the following treatment for acute HF, not including noncardiogenic shock: oxygen, non-invasive ventilation (NIV), intravenous diuretics (20–40 mg bolus furosemide at admission), and intravenous nitrates. Intravenous nitrates have long been described to improve hemodynamic and dyspnea in HF patients by many ways: decrease in systemic blood pressure and left ventricular afterload, substantial reduction preload and therefore of in right and left ventricular filling pressure, an increase in cardiac output, and little or no change in heart rate [65]. Improvement in cardiac output by intravenous nitrates is mostly related to the reduction in left ventricular afterload, but is also influenced by a decrease in pulmonary vascular resistance, improvement in myocardial oxygenation, and a reduction of mitral regurgitation. Administration of inotropes and/or vasopressors is recommended in patients with signs of low cardiac output [66]. However, application of inotropes and/or vasopressors is associated with an increased long-term mortality risk [67–69]. Additional treatment includes the optimal dosing of angiotensinconverting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). ACEI have been shown to reduce cardiovascular mortality and prevent rehospitalization in patients with HF in two key randomized controlled trails (CONSENSUS and SOLVD-Treatment) [70]. Likewise, ARB improve long-term outcome in HF patients [71]. Another essential component of HF therapy is spironolactone. The RALES study has shown a reduction in mortality after addition of 25 mg of spironolactone to the standard treatment in HF patients with an LVEF <35% [72]. The international guidelines recommend spironolactone in all patients presenting with moderate to severe HF symptoms. In the PARADIGM-HF trial, the use of angiotensin receptorneprilysin inhibitor (ARNI) (sacubitril/valsartan) showed a reduction of the composite endpoint of cardiovascular death or HF hospitalization by 20% compared with enalapril alone in symptomatic HF patients with reduced LVEF [73]. These study results are implemented in the updated ACC/AHA/HFSA guidelines on management of HF, which recommend to replace ACEI or ARB by sacubitril/valsartan in patients with reduced LVEF and ongoing symptoms [74]. Betablockers reduce mortality in HF patients even without reduced ejection fraction as has been demonstrated by multicenter placebo-controlled studies [75–77]. Because of the negative inotropic effect of betablockers, patients should not be treated in the very acute presentation with signs or symptoms of decompensation and initial doses should be low. Long-term goal is a heart rate below 70 bpm in sinus rhythm. If this is not obtainable with the maximum, or maximum tolerated dose of betablockers, the current European heart failure guidelines recommend the addition of Ivabradine [66]. In addition to pharmacological medication cardiac resynchronization therapy (CRT) has been shown to improve cardiac performance, to reduce symptoms, morbidity, and mortality [78, 79].

#### *2.7.2 Anticoagulation*

The role of anticoagulation in DCM with sinus rhythm is unclear [80]. The prospective randomized trials were either underpowered or with a too short

follow-up. At present, there are no trial data to guide anticoagulant treatment regime in DCM. Due to two studies (WATCH and WARCEF trial) showing a slight advantage of warfarin over aspirin, anticoagulation with warfarin is advised in patients with a history of thromboembolism or evidence of intracardiac thrombus [81, 82]. Current ACC/AHA HF guidelines do not recommend anticoagulation in reduced left ventricular function and sinus rhythm without prior thromboembolic events or known cardioembolic source [83]. Studies testing the non-vitamin K antagonist oral anticoagulants (NOACs) in patients with reduced left ventricular function are currently ongoing. In DCM patients with documented AF, oral anticoagulant is recommended with CHA2DS2-VASc score ≥ 2, as a class I indication and in men with a CHA2DS2-VASc score of 1 as class IIa with level of evidence B [66, 77, 83, 84].
