Clinical Applications of Electrocardiography

*Practical Applications of Electrocardiogram*

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**58**

Chapter 4

Abstract

variant maps

1. Introduction

the test results more conveniently.

61

Characteristics of Atrial Premature

Beat ECG Signals on Variant Maps

Premature heartbeat is also known as extrasystole. It means the foundation of sinus or ectopic heart rhythm, a certain pacemaker in the heart excitable earlier than the basic rhythm, cause the heart to be local or all happening prematurely remove pole. Premature atrial beats may lead to cardiomyopathy. The experimental data in this chapter are provided by Xishan People's Hospital of Wuxi city, including normal ECG signals and abnormal ECG signals (atrial premature beat). The two types of ECG data sequences are processed experimentally through the variant measurement model, and the differences in the variant maps are compared.

Keywords: atrial premature beat, ECG signal, data sequence, arrhythmia,

beat ECG signals obtained through variant measurement schemes.

of feature clustering to study the variant measurement of ECG signal data sequences. ECG signal utilizes multivalued logic function and variant principle to form variant logic symbol on n-element ECG signal sequence and output variant maps and observe the difference between different ECG signal data. The obtained variant maps can analyze the ECG data from the macroscopic level and express the information that cannot be reflected by the traditional ECG in an intuitive way. The application of variant maps in ECG signal is an extension of the original ECG signal methods. In practical applications, it is expected that the variant maps can assist the application of traditional ECG in the medical field and help clinicians to diagnose

Cardiovascular diseases are common diseases that seriously threaten human health [1], and the mortality rate caused by cardiovascular diseases continues to increase globally. ECG signal is the direct response of heart activity and the most effective way to analyze cardiovascular diseases. The object of this chapter is the atrial premature beat ECG signal in atrial arrhythmia. The experimental method is variant measurement model [2]. The provider of ECG data is Xishan People's Hospital of Wuxi city, Jiangsu Province China, and the later calibrator of ECG data is the First People's Hospital of Yunnan Province China. This chapter includes relevant background to introduce atrial premature beat [3], variant measurement model, experimental data, and variant maps of atrial premature beat signals. There is a significant difference between the variant maps of normal and atrial premature

This chapter uses the variant measurement model and the visualization method

Lihua Leng, Jeffery Zheng and Jing Zhang

#### Chapter 4

## Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

Lihua Leng, Jeffery Zheng and Jing Zhang

#### Abstract

Premature heartbeat is also known as extrasystole. It means the foundation of sinus or ectopic heart rhythm, a certain pacemaker in the heart excitable earlier than the basic rhythm, cause the heart to be local or all happening prematurely remove pole. Premature atrial beats may lead to cardiomyopathy. The experimental data in this chapter are provided by Xishan People's Hospital of Wuxi city, including normal ECG signals and abnormal ECG signals (atrial premature beat). The two types of ECG data sequences are processed experimentally through the variant measurement model, and the differences in the variant maps are compared.

Keywords: atrial premature beat, ECG signal, data sequence, arrhythmia, variant maps

#### 1. Introduction

Cardiovascular diseases are common diseases that seriously threaten human health [1], and the mortality rate caused by cardiovascular diseases continues to increase globally. ECG signal is the direct response of heart activity and the most effective way to analyze cardiovascular diseases. The object of this chapter is the atrial premature beat ECG signal in atrial arrhythmia. The experimental method is variant measurement model [2]. The provider of ECG data is Xishan People's Hospital of Wuxi city, Jiangsu Province China, and the later calibrator of ECG data is the First People's Hospital of Yunnan Province China. This chapter includes relevant background to introduce atrial premature beat [3], variant measurement model, experimental data, and variant maps of atrial premature beat signals. There is a significant difference between the variant maps of normal and atrial premature beat ECG signals obtained through variant measurement schemes.

This chapter uses the variant measurement model and the visualization method of feature clustering to study the variant measurement of ECG signal data sequences. ECG signal utilizes multivalued logic function and variant principle to form variant logic symbol on n-element ECG signal sequence and output variant maps and observe the difference between different ECG signal data. The obtained variant maps can analyze the ECG data from the macroscopic level and express the information that cannot be reflected by the traditional ECG in an intuitive way. The application of variant maps in ECG signal is an extension of the original ECG signal methods. In practical applications, it is expected that the variant maps can assist the application of traditional ECG in the medical field and help clinicians to diagnose the test results more conveniently.

#### 2. Relevant background

#### 2.1 Atrial premature beats

Atrial arrhythmia is the most common arrhythmia clinically, which refers to a kind of arrhythmia caused by conduction obstruction when ectopic excitations are located in the atrium or conduction system passing through the atrium. It is mainly active arrhythmia, and atrial premature beat is the most common type of atrial arrhythmia. Atrial premature beats can be seen in normal healthy people, but in healthy people, there are few frequent atrial premature beats [4]. Atrial premature beats is more common in organic heart disease patients, Hyperthyroidism, Coronary heart disease, Cardiomyopathy patients if frequent atrial premature beat, is the precursor of Atrial fibrillation, Acute myocardial infarction can also occur frequent atrial premature beat. Figure 1 shows the comparison between normal ECG and atrial premature beat ECG.

. The transformation rules of the four variant symbols are shown in Table 1. Therefore, in this chapter, long ECG signal is converted into long

The variant measurement model describes the measurement as the four meta symbols: . The 16 subsets of meta symbol set are as follows: , , , , , , , , , , , , , , , and .

If any measure is selected as the value of in the variant maps and any measure

quantity of is defined as 0 and the corresponding definitions of 16 variant

combinations of such two-dimensional maps, which are specifically shown in Table 3. In this chapter, the three-dimensional variant maps are also adopted, and the Z-axis is added on the basis of the two-dimensional maps. The selection princi-

Variant measurement structure is composed of three components: input, processing, and output. The input ECG signal is provided by Wuxi Xishan People's Hospital. The data processing module is the core module of variant measurement and consists of variant module, statistical measurement module, and visualization

Conversion type Variant sign Statistical sign Statistical total

Sign subset Variant measure Sign subset Variant measure

is selected as the value of in the variant maps, there are a total of

Here, the statistical

variant logical operator through variant logical function.

DOI: http://dx.doi.org/10.5772/intechopen.83551

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

The 16 subsets correspond to the 16 measures:

ple is the same as the selection method of and .

2.5 ECG signal variant measurement structure

2.4 Variant visualization

measures are shown in Table 2.

Table 1.

Table 2.

63

Definition of 16 variant measures.

Variant sign conversion rule.

The picture is the atrial premature beat ECG. Patient information: male, 46 years old, arrhythmia, mean heart rate 62 bpm, early occurrence of P<sup>0</sup> -QRS-T in limb leads, 160 ms in P'R interval, incomplete compensatory interval, such expression is a atrial premature beat.

#### 2.2 Variant measurement model

In 2010, variant model [5] was proposed with the stability of cellular automata as an example; the effect of variant and non-variant functions on binary logic functional space was explained. In 2011, the conditional probability statistical distribution of the variant measurement structure [6] is discussed. By simulating the two-state quantum interaction system, the variant two-path simulation model was established. With the continuous development of variant construction, this model has been applied in many fields: coding and non-coding DNA [7] sequence detection, random sequence testing [8], classification of cellular automata [7], classification of echolocation in bats [9], ECG signals [10, 11], and variant construction [12].

#### 2.3 Variant logic

The core theory of variant measurement model is variant logic, which is extended and evolved on the basis of classical logic. In the variant logic function, assuming that the input sequence is long , the output data sequence is N-1 according to the variant rule. On the basis of the variant logical function, the variant measurement model defines four basic variant logical symbols:

Figure 1. Atrial premature beats ECG.

. The transformation rules of the four variant symbols are shown in Table 1. Therefore, in this chapter, long ECG signal is converted into long variant logical operator through variant logical function.

#### 2.4 Variant visualization

2. Relevant background

Practical Applications of Electrocardiogram

2.1 Atrial premature beats

atrial premature beat ECG.

a atrial premature beat.

2.3 Variant logic

Figure 1.

62

Atrial premature beats ECG.

2.2 Variant measurement model

Atrial arrhythmia is the most common arrhythmia clinically, which refers to a kind of arrhythmia caused by conduction obstruction when ectopic excitations are located in the atrium or conduction system passing through the atrium. It is mainly active arrhythmia, and atrial premature beat is the most common type of atrial arrhythmia. Atrial premature beats can be seen in normal healthy people, but in healthy people, there are few frequent atrial premature beats [4]. Atrial premature beats is more common in organic heart disease patients, Hyperthyroidism, Coronary heart disease, Cardiomyopathy patients if frequent atrial premature beat, is the precursor of Atrial fibrillation, Acute myocardial infarction can also occur frequent atrial premature beat. Figure 1 shows the comparison between normal ECG and

The picture is the atrial premature beat ECG. Patient information: male, 46 years

leads, 160 ms in P'R interval, incomplete compensatory interval, such expression is

In 2010, variant model [5] was proposed with the stability of cellular automata

as an example; the effect of variant and non-variant functions on binary logic functional space was explained. In 2011, the conditional probability statistical distribution of the variant measurement structure [6] is discussed. By simulating the two-state quantum interaction system, the variant two-path simulation model was established. With the continuous development of variant construction, this model has been applied in many fields: coding and non-coding DNA [7] sequence detection, random sequence testing [8], classification of cellular automata [7], classification of echolocation in bats [9], ECG signals [10, 11], and variant construction [12].

The core theory of variant measurement model is variant logic, which is extended and evolved on the basis of classical logic. In the variant logic function, assuming that the input sequence is long , the output data sequence

function, the variant measurement model defines four basic variant logical symbols:

is N-1 according to the variant rule. On the basis of the variant logical


old, arrhythmia, mean heart rate 62 bpm, early occurrence of P<sup>0</sup>

The variant measurement model describes the measurement as the four meta symbols: . The 16 subsets of meta symbol set are as follows: , , , , , , , , , , , , , , , and . The 16 subsets correspond to the 16 measures:

Here, the statistical quantity of is defined as 0 and the corresponding definitions of 16 variant measures are shown in Table 2.

If any measure is selected as the value of in the variant maps and any measure is selected as the value of in the variant maps, there are a total of combinations of such two-dimensional maps, which are specifically shown in Table 3. In this chapter, the three-dimensional variant maps are also adopted, and the Z-axis is added on the basis of the two-dimensional maps. The selection principle is the same as the selection method of and .

#### 2.5 ECG signal variant measurement structure

Variant measurement structure is composed of three components: input, processing, and output. The input ECG signal is provided by Wuxi Xishan People's Hospital. The data processing module is the core module of variant measurement and consists of variant module, statistical measurement module, and visualization


#### Table 1.

Variant sign conversion rule.


Table 2. Definition of 16 variant measures.


#### Table 3.

Combinations of visualization of 256 variant measures.

#### Figure 2.

Structure diagram of ECG sequence variant measurement.

module. The final output is variant maps. The structure of ECG signal variant measurement is shown in Figure 2.

#### 2.6 Data processing module

The data processing module is divided into three parts: variant module, measurement statistics module, and visualization module. The variant module is the most important part of the variant measurement model. It is mainly responsible for transforming the original ECG signal sequence into the sequence of four basic variant logic symbols through mapping rules. The specific definitions of the parameters involved in the transformation process will be given in the core module. The measurement statistics module is mainly responsible for grouping the variant logical symbol sequence by setting a reasonable segment length M according to total length of the sequence. After grouping, the sequence in each group is counted and denoted as . The visualization module is to generate the final variant maps, in which the variant maps can be two-dimensional map and three-dimensional map. The specific visualization process will be given in the chapter of the core module. The structure diagram of the data processing module is shown in Figure 3.

#### 2.7 Core module

#### 2.7.1 Variant module

The variant module is the most core module in the variant measurement model. It is mainly responsible for converting the obtained ECG signal sequence into four variant logical symbol sequences through variant logic. The transformation process involves parameters , and the definition is shown in Eqs. (1)–(4).

$$X = A\_{i+1} \cdot A\_i \tag{1}$$

(3)

(4)

(5)

Considering that the difference value can reflect the increase or decrease of adjacent ECG data, the difference value of the overall ECG data can reflect the fluctuation of the sequence; the mean value can reflect the level of adjacent ECG data, so the mean value of the overall ECG data can reflect the overall level of the sequence. In the process of data transformation, the variant module selects the difference, global difference, mean, and global mean as the measurement parame-

parameter values can be calculated for the input n-long ECG signal sequence as the parameter support of the variant module. According to the mapping principle of Eq. (5), the original ECG sequence was mapped to sequence by setting

As shown in Figure 3, for n-1 long variant logic symbol sequence, set the segment length parameter , the number of groups is , and then . According to the grouping situation, the number of " " ," " ," " and " " in each group is recorded

ters. Using the parameters defined in Eqs. (1)–(4), the corresponding

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

DOI: http://dx.doi.org/10.5772/intechopen.83551

parameters.

65

Figure 3.

Structure diagram of ECG data processing.

2.7.2 Measurement statistics module

$$\mathbf{T} = \frac{\sum\_{l=1}^{N-1} |A\_{l+1} \cdot A\_l|}{N} \tag{2}$$

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps DOI: http://dx.doi.org/10.5772/intechopen.83551

Figure 3. Structure diagram of ECG data processing.

module. The final output is variant maps. The structure of ECG signal variant

... ... ... ... ... ...

length M according to total length of the sequence. After grouping, the

The data processing module is divided into three parts: variant module, measurement statistics module, and visualization module. The variant module is the most important part of the variant measurement model. It is mainly responsible for transforming the original ECG signal sequence into the sequence of four basic variant logic symbols through mapping rules. The specific definitions of the parameters involved in the transformation process will be given in the core module. The measurement statistics module is mainly responsible for grouping the variant logical symbol sequence by setting a reasonable segment

...

... ...

... ...

sequence in each group is counted and denoted as . The visualization module is to generate the final variant maps, in which the variant maps can be two-dimensional map and three-dimensional map. The specific visualization process will be given in the chapter of the core module. The structure diagram of the

The variant module is the most core module in the variant measurement model. It is mainly responsible for converting the obtained ECG signal sequence into four variant logical symbol sequences through variant logic. The transformation process involves parameters , and the definition is shown in Eqs. (1)–(4).

(1)

(2)

measurement is shown in Figure 2.

Combinations of visualization of 256 variant measures.

Practical Applications of Electrocardiogram

Structure diagram of ECG sequence variant measurement.

data processing module is shown in Figure 3.

2.7 Core module

64

2.7.1 Variant module

2.6 Data processing module

Table 3.

Figure 2.

$$\mathcal{L} = \frac{A\_l + A\_{l+1}}{2} \tag{3}$$

$$N = \frac{\sum\_{l=1}^{N-1} \frac{\{A\_l + A\_{l+1}\}}{Z}}{N} \tag{4}$$

Considering that the difference value can reflect the increase or decrease of adjacent ECG data, the difference value of the overall ECG data can reflect the fluctuation of the sequence; the mean value can reflect the level of adjacent ECG data, so the mean value of the overall ECG data can reflect the overall level of the sequence. In the process of data transformation, the variant module selects the difference, global difference, mean, and global mean as the measurement parameters. Using the parameters defined in Eqs. (1)–(4), the corresponding parameter values can be calculated for the input n-long ECG signal sequence as the parameter support of the variant module. According to the mapping principle of Eq. (5), the original ECG sequence was mapped to sequence by setting parameters.

$$\begin{cases} if \quad X > T \quad and \quad X > 0 \colon B\_{l} = + \\ if \quad X > T \quad and \quad X \le 0 \colon B\_{l} = - \\ if \quad X \le T \quad and \quad L > V \colon B\_{l} = \top \\ if \quad X \le T \quad and \quad L \le V \colon B\_{l} = \bot \end{cases} \tag{5}$$

#### 2.7.2 Measurement statistics module

As shown in Figure 3, for n-1 long variant logic symbol sequence, set the segment length parameter , the number of groups is , and then . According to the grouping situation, the number of " " ," " ," " and " " in each group is recorded as " ", " ", " " and " ", " " represents the number of statistics of the variant logic symbol " " in this group. After statistical process, the whole output group is generated . For each set of statistical results, including meet long variant logical symbol sequence is converted into S group statistical array .

4. Experimental results

Figure 5.

Figure 6.

67

4.1 Two-dimensional overall maps

DOI: http://dx.doi.org/10.5772/intechopen.83551

As shown in Figure 5, the red diagram on the left is a variant map of normal ECG signals; the blue on the right is a variant map of atrial premature ECG signals,

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

Overall two-dimensional maps of normal ECG data and atrial premature beat.

Two-dimensional combination maps of normal ECG data and atrial premature beat.

#### 2.7.3 Visualization module

The visualization module determines the selection of coordinates and generates a variant graph. According to the results obtained from the measurement statistics module and the definition of variant visualization, this chapter selects overall two-dimensional maps, two-dimensional combination maps, and threedimensional combination maps to display the visualization results. The overall twodimensional maps define normal and abnormal ECG signals as of 256 combinations, respectively. The two-dimensional combination maps is to form the scatter diagram of normal and abnormal ECG signals by the same mapping method, and it is easier to observe the differences between them on the same maps. Threedimensional combination maps are a combination method added on the basis of two-dimensional combination maps. In three-dimensional space, the characteristics between normal ECG signal and abnormal ECG signal are more abundant.

#### 3. Data sets

The ECG data is provided by the people's hospital of Wuxi Xishan. The CB series ECG review analyzer is used to measure blood pressure of ECG data. Through the system of the patient's ECG information is stored in 18 data files, one of .dat files is stored in the patient's ECG data, by reviewing the ECG blood pressure of CB series data of ECG analysis system is read as shown in Figure 4.

As shown in Figure 4, the patient's ECG was collected with three-lead, and the heart rate data of CH1 lead was recorded at a sampling point of 1.5 s on average. The ECG signal was imported into the database for variant measurement experiment. This set of ECG data includes 105 patients. By analyzing the diagnosis results of each patient, this data set can be divided into two categories: normal and abnormal. Abnormal ECG data includes four types of symptoms: atrial premature beat, 64 cases; ventricular/atrial premature beats and T changes, 9 cases; premature ventricular/atrial beats and complete right bundle branch conduction block, 4 cases; atrial fibrillation and ST-T changes, 4 cases; and normal, 24 cases. In this chapter, atrial premature beat and normal ECG data were selected for variant measurement.

Figure 4. ECG data diagram of Xishan People's Hospital.

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps DOI: http://dx.doi.org/10.5772/intechopen.83551

### 4. Experimental results

as " ", " ", " " and " ", " " represents the number of statistics of the variant logic symbol " " in this group. After statistical process, the whole output group is

meet long variant logical sym-

The visualization module determines the selection of coordinates and generates a variant graph. According to the results obtained from the measurement statistics module and the definition of variant visualization, this chapter selects overall two-dimensional maps, two-dimensional combination maps, and threedimensional combination maps to display the visualization results. The overall twodimensional maps define normal and abnormal ECG signals as of 256 combinations, respectively. The two-dimensional combination maps is to form the scatter diagram of normal and abnormal ECG signals by the same mapping method, and it is easier to observe the differences between them on the same maps. Threedimensional combination maps are a combination method added on the basis of two-dimensional combination maps. In three-dimensional space, the characteristics

generated . For each set of statistical results, including

bol sequence is converted into S group statistical array .

between normal ECG signal and abnormal ECG signal are more abundant.

data of ECG analysis system is read as shown in Figure 4.

The ECG data is provided by the people's hospital of Wuxi Xishan. The CB series ECG review analyzer is used to measure blood pressure of ECG data. Through the system of the patient's ECG information is stored in 18 data files, one of .dat files is stored in the patient's ECG data, by reviewing the ECG blood pressure of CB series

As shown in Figure 4, the patient's ECG was collected with three-lead, and the heart rate data of CH1 lead was recorded at a sampling point of 1.5 s on average. The ECG signal was imported into the database for variant measurement experiment. This set of ECG data includes 105 patients. By analyzing the diagnosis results of each patient, this data set can be divided into two categories: normal and abnormal. Abnormal ECG data includes four types of symptoms: atrial premature beat, 64 cases; ventricular/atrial premature beats and T changes, 9 cases; premature ventricular/atrial beats and complete right bundle branch conduction block, 4 cases; atrial fibrillation and ST-T changes, 4 cases; and normal, 24 cases. In this chapter, atrial premature beat and normal ECG data were selected for variant measurement.

2.7.3 Visualization module

Practical Applications of Electrocardiogram

3. Data sets

Figure 4.

66

ECG data diagram of Xishan People's Hospital.

#### 4.1 Two-dimensional overall maps

As shown in Figure 5, the red diagram on the left is a variant map of normal ECG signals; the blue on the right is a variant map of atrial premature ECG signals,

Figure 5. Overall two-dimensional maps of normal ECG data and atrial premature beat.

Figure 6. Two-dimensional combination maps of normal ECG data and atrial premature beat.

with the same mapping of , formed when the insets. At the top of each small map is the mapping mode corresponding to that diagram.

4.3 Three-dimensional combination maps

DOI: http://dx.doi.org/10.5772/intechopen.83551

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

sum of the three subsets.

Figure 8.

69

Three-dimensional combination maps of normal ECG data and atrial premature beat.

As shown in Figures 8–10, the three-dimensional combination maps are a combination of the normal ECG signal and the atrial premature beat ECG signal in the three-dimensional space. The mode of the (X, Y, Z) combination in Figure 8 is the combination of (X, Y, Z) in Figure 9 is and the

combination of (X, Y, Z) in Figure 10 is ; the values of X and Y are both defined as the sum of the two subsets, and the values of Z are all limited to the

#### 4.2 Two-dimensional combination maps

As shown in Figure 6, the two-dimensional combination maps put the results of the variant of the normal ECG signal and the atrial premature beat ECG signal in one picture, and the four combinations in Figure 6 are and ; the values of are all limited to the sum of the two subsets.

As shown in Figure 7, the two-dimensional combination maps also put the results of the variant of the normal ECG signal and the atrial premature beat ECG signal in a single graph. The 12 combinations in Figure 7 are

and

the value of is limited to the sum of two subsets, and the value of is limited to the sum of the three subsets.

Figure 7. Two-dimensional combination maps of normal ECG data and atrial premature beat.

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps DOI: http://dx.doi.org/10.5772/intechopen.83551

#### 4.3 Three-dimensional combination maps

with the same mapping of , formed when the

As shown in Figure 6, the two-dimensional combination maps put the results of the variant of the normal ECG signal and the atrial premature beat ECG signal in

is limited to the sum of two subsets, and the value of is limited to the sum of the

and

the value of

and ; the values of are all limited to the sum of the two subsets. As shown in Figure 7, the two-dimensional combination maps also put the results of the variant of the normal ECG signal and the atrial premature beat ECG

to that diagram.

three subsets.

Figure 7.

68

4.2 Two-dimensional combination maps

Practical Applications of Electrocardiogram

one picture, and the four combinations in Figure 6 are

signal in a single graph. The 12 combinations in Figure 7 are

Two-dimensional combination maps of normal ECG data and atrial premature beat.

insets. At the top of each small map is the mapping mode corresponding

As shown in Figures 8–10, the three-dimensional combination maps are a combination of the normal ECG signal and the atrial premature beat ECG signal in the three-dimensional space. The mode of the (X, Y, Z) combination in Figure 8 is the combination of (X, Y, Z) in Figure 9 is and the combination of (X, Y, Z) in Figure 10 is ; the values of X and Y are both defined as the sum of the two subsets, and the values of Z are all limited to the sum of the three subsets.

Figure 9. Three-dimensional combination maps of normal ECG data and atrial premature beat.

#### 5. Results analysis

Through the display of two-dimensional integral maps, two-dimensional combination maps, and three-dimensional combination maps, we can observe that:

beat ECG signal appears as an irregular cone. As the mapping mode changes, the shape of the variant maps also change, but the normal and abnormal ECG signals

Three-dimensional combination maps of normal ECG data and atrial premature beat.

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

DOI: http://dx.doi.org/10.5772/intechopen.83551

The two-dimensional combination map puts the variant maps of the two types of ECG signals on one canvas, and the difference between the normal and abnormal variant obtained by the same mapping method is more clear on one canvas. The mapping method selected in this chapter is more comprehensive, so the obtained

The three-dimensional combination map is based on the two-dimensional combination maps subjoining the Z-axis to form a spatial distribution display of the

always exhibit different variant characteristics.

variant map results are also universal.

Figure 10.

71

The two-dimensional integral maps are to show the macro difference between the normal ECG signal and the atrial premature beat ECG signal through the variant experiment. From the two-dimensional whole figure, there are significant differences in the distribution shape and range between normal and abnormal ECG signals. The variant maps of the normal ECG signal show that the scattered points are disperse, even spreading the entire canvas, and the shape of the atrial premature

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps DOI: http://dx.doi.org/10.5772/intechopen.83551

Figure 10. Three-dimensional combination maps of normal ECG data and atrial premature beat.

beat ECG signal appears as an irregular cone. As the mapping mode changes, the shape of the variant maps also change, but the normal and abnormal ECG signals always exhibit different variant characteristics.

The two-dimensional combination map puts the variant maps of the two types of ECG signals on one canvas, and the difference between the normal and abnormal variant obtained by the same mapping method is more clear on one canvas. The mapping method selected in this chapter is more comprehensive, so the obtained variant map results are also universal.

The three-dimensional combination map is based on the two-dimensional combination maps subjoining the Z-axis to form a spatial distribution display of the

5. Results analysis

Practical Applications of Electrocardiogram

Figure 9.

70

Through the display of two-dimensional integral maps, two-dimensional combination maps, and three-dimensional combination maps, we can observe that: The two-dimensional integral maps are to show the macro difference between the normal ECG signal and the atrial premature beat ECG signal through the variant experiment. From the two-dimensional whole figure, there are significant differences in the distribution shape and range between normal and abnormal ECG signals. The variant maps of the normal ECG signal show that the scattered points are disperse, even spreading the entire canvas, and the shape of the atrial premature

Three-dimensional combination maps of normal ECG data and atrial premature beat.

variant maps. The (X, Y, Z) combination of the three-dimensional combination map selects , and and combines the two subsets and three subsets. The combination of the two is well integrated and is a more comprehensive illustration of the variant of normal and abnormal ECG signals. In the graphic display, five kinds of views are selected for each mapping method, which are (X, Y, Z), (Y, X, Z), (X, Z), (Y, Z), and (X, Y) as the screenshot of the main view. Through the results, we can see that there are also large differences in the three-dimensional spatial distribution of normal ECG signals and atrial premature beat ECG signals.

#### 6. Summary and outlook

In this chapter, the variant measurement model is used to perform the variant experiment on the acquired batch ECG data. Finally, the experimental results of the variant measurement are displayed through three visualization methods. It is found through experiments that the variant measurement model can be well applied to the classification of normal ECG signals and atrial premature beat ECG signals.

In the future, we hope to get more abundant ECG data and can cooperate with the hospital to implement the application of the variant measurement model in the classification of ECG signals, so that it can assist the traditional ECG application in the clinical field.

#### Acknowledgements

Thanks to the Xishan People's Hospital of Wuxi City of Jiangsu Province for ECG datasets, to First People's Hospital of Yunnan Province for calibrator of ECG data, and to the Key Project of Electric Information and Next Generation IT Technology of Yunnan (2018ZI002), National Science Foundation of China NSFC (61362014), and the Overseas Higher Level Scholar Project of Yunnan for financial supports of the project.

Author details

, Jeffery Zheng<sup>2</sup>

provided the original work is properly cited.

Yunnan Branch, Kunming, China

\* and Jing Zhang<sup>3</sup>

2 School of Software, Yunnan University, Kunming, China

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps

DOI: http://dx.doi.org/10.5772/intechopen.83551

\*Address all correspondence to: conjugatelogic@yahoo.com

1 Technology and Product Management Department, Agricultural Bank of China,

3 Department of Cadre Health, Yunnan First People's Hospital, Kunming, China

© 2019 The Author(s). Licensee IntechOpen. 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,

Lihua Leng<sup>1</sup>

73

Characteristics of Atrial Premature Beat ECG Signals on Variant Maps DOI: http://dx.doi.org/10.5772/intechopen.83551

#### Author details

variant maps. The (X, Y, Z) combination of the three-dimensional combination map selects , and and combines the two subsets and three subsets. The combination of the two is well integrated and is a more comprehensive illustration of the variant of normal and abnormal ECG signals. In the graphic display, five kinds of views are selected for each mapping method, which are (X, Y, Z), (Y, X, Z), (X, Z), (Y, Z), and (X, Y) as the screenshot of the main view. Through the results, we can see that there are also large differences in the three-dimensional spatial distribution of normal ECG signals and atrial

In this chapter, the variant measurement model is used to perform the variant experiment on the acquired batch ECG data. Finally, the experimental results of the variant measurement are displayed through three visualization methods. It is found through experiments that the variant measurement model can be well applied to the

In the future, we hope to get more abundant ECG data and can cooperate with the hospital to implement the application of the variant measurement model in the classification of ECG signals, so that it can assist the traditional ECG application in

Thanks to the Xishan People's Hospital of Wuxi City of Jiangsu Province for ECG datasets, to First People's Hospital of Yunnan Province for calibrator of ECG data, and to the Key Project of Electric Information and Next Generation IT Technology of Yunnan (2018ZI002), National Science Foundation of China NSFC (61362014), and the Overseas Higher Level Scholar Project of Yunnan for financial supports of

classification of normal ECG signals and atrial premature beat ECG signals.

premature beat ECG signals.

Practical Applications of Electrocardiogram

6. Summary and outlook

the clinical field.

the project.

72

Acknowledgements

Lihua Leng<sup>1</sup> , Jeffery Zheng<sup>2</sup> \* and Jing Zhang<sup>3</sup>

1 Technology and Product Management Department, Agricultural Bank of China, Yunnan Branch, Kunming, China

2 School of Software, Yunnan University, Kunming, China

3 Department of Cadre Health, Yunnan First People's Hospital, Kunming, China

\*Address all correspondence to: conjugatelogic@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. 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.

### References

[1] Thompson SC, Ting SA. Avoidance denial versus optimistic denial in reaction to the threat of future cardiovascular disease. Health Education & Behavior the Official Publication of the Society for Public Health Education. 2012;39(5):620

[2] Zheng J, Zheng C. Variant measures and visualized statistical distributions. Acta Photonica Sinica. 2011;40(9): 1397-1404

[3] Mitchell LB. Atrial Premature Beats. The ECG. Springer. 2004:239-335

[4] Wallmann D, Tüller D, Wustmann K, et al. Frequent atrial premature beats predict paroxysmal atrial fibrillation in stroke patients: An opportunity for a new diagnostic strategy. Stroke. 2007; 38(8):2292-2294

[5] Zheng J, Zheng C. A framework to express variant and invariant functional spaces for binary logic. Frontiers of Electrical and Electronic Engineering in China. 2010;5(2):163-172

[6] Zheng J, Zheng C, Kunii TL. A Framework of Variant Logic Construction for Cellular Automata, Cellular Automata—Innovative Modelling for Science and Engineering. Rijeka, Croatia: InTech Press; 2011

[7] Zheng J, Luo J, Zhou W. Pseudo DNA sequence generation of non-coding distributions using variant maps on cellular automata. Applied Mathematics. 2014;5(1):153-174

[8] Zheng J. Novel Pseudo Random Number Generation Using Varian Logic Framework. Australian Security Congress. 2011:100-104

[9] Heim DM, Heim O, Zeng PA, Zheng J. Successful creation of regular patterns in variant maps from bat echolocation

calls. Biological Systems: Open Access. 2016;5:166. DOI: 10.4172/2329-6577. 1000166

[10] Leng L, Zheng J. Mapping ECG signal sequences on variant maps. In: 2017 IEEE Trustcom/BigDataSE/ICESS; 2017. pp. 881-884. DOI: 10.1109/ Trustcom/BigDataSE/ICESS.2017.326

[11] Leng L, Zheng J. Visualization research of ECG sequence in sinus arrhythmia. Computer Science. 2016;43 (s2):183-185 (in Chinese)

[12] Zheng J. Variant Construction from Theoretical Foundation to Applications. Springer-Nature. 2019. DOI: 10.1007/ 978-981-13-2282-2

**75**

**Chapter 5**

Failure

*Hakan Altay*

**1. Introduction**

fibrillation [1].

condition related with VT and HF.

reduced ejection fraction (HFREF).

**Abstract**

Ventricular Tachycardia and Heart

Ventricular tachycardia (VT) is a common arrhythmia seen in patients with heart failure (HF) and is now seen more frequently as these patients survive longer with modern therapies. In patients with HF, half of the deaths are sudden due to life-threatening ventricular arrhythmias, including VT. Although disease modifying drugs, such as beta blockers, mineralocorticoid drugs, and angiotensin receptor neprilysin inhibitors, prevent the occurrence of VT to some extent, the mainstay of therapy is the antiarrhythmic drug therapy, implantable cardioverter-defibrillator (ICD) implantation, and traditional radiofrequency catheter ablation. Autonomic nerve system modulation and stereotactic body radiation therapy have emerged as novel techniques for the management of refractory VT cases. Patients with refractory VT and repetitive ICD shocks should be further evaluated regarding the

candidacy for left ventricular assist device and transplantation.

implantable-cardioverter defibrillator, ablation

**Keywords:** ventricular tachycardia, heart failure, antiarrhythmic therapy,

Ventricular tachycardia (VT) is common in patients with heart failure (HF). The presence and severity of VT increase as the severity of HF increases. Larger infarcts with greater left ventricle (LV) systolic dysfunction are more likely to be associated with VT. VT forms one of the most common electrical mechanisms responsible for sudden cardiac death (SCD) in HF. Patients with LV systolic dysfunction who develop VT are at increased risk of SCD from subsequent VT or ventricular

Patients with VT and HF may present either with cardiac arrest to the emergency department or with palpitations, syncope, chest pain, or ICD shocks to cardiology outpatient clinics, varying according to the hemodynamic stability of VT. Both non-sustained VT (VT duration < 30 sec) and sustained VT (VT duration > 30 sec) in patients with HF are associated with significant morbidity and mortality. VT storm (three or more separate episodes of sustained VT requiring intervention (such as ICD shock or ATP) within 24 hours) is the most troublesome

Although half of the patients with HF have preserved ejection fraction and SCD is also a common issue in these patients, there is no proved treatment either by ICD or drugs [2]. Because of this, VT and HF will be discussed in the context of HF with

#### **Chapter 5**

References

1397-1404

38(8):2292-2294

China. 2010;5(2):163-172

2014;5(1):153-174

74

[1] Thompson SC, Ting SA. Avoidance denial versus optimistic denial in reaction to the threat of future cardiovascular disease. Health Education & Behavior the Official Publication of the Society for Public Health Education. 2012;39(5):620

Practical Applications of Electrocardiogram

calls. Biological Systems: Open Access. 2016;5:166. DOI: 10.4172/2329-6577.

[10] Leng L, Zheng J. Mapping ECG signal sequences on variant maps. In: 2017 IEEE Trustcom/BigDataSE/ICESS; 2017. pp. 881-884. DOI: 10.1109/ Trustcom/BigDataSE/ICESS.2017.326

[11] Leng L, Zheng J. Visualization research of ECG sequence in sinus arrhythmia. Computer Science. 2016;43

[12] Zheng J. Variant Construction from Theoretical Foundation to Applications. Springer-Nature. 2019. DOI: 10.1007/

(s2):183-185 (in Chinese)

978-981-13-2282-2

1000166

[2] Zheng J, Zheng C. Variant measures and visualized statistical distributions. Acta Photonica Sinica. 2011;40(9):

[3] Mitchell LB. Atrial Premature Beats. The ECG. Springer. 2004:239-335

[4] Wallmann D, Tüller D, Wustmann K, et al. Frequent atrial premature beats predict paroxysmal atrial fibrillation in stroke patients: An opportunity for a new diagnostic strategy. Stroke. 2007;

[5] Zheng J, Zheng C. A framework to express variant and invariant functional spaces for binary logic. Frontiers of Electrical and Electronic Engineering in

[6] Zheng J, Zheng C, Kunii TL. A Framework of Variant Logic

Construction for Cellular Automata, Cellular Automata—Innovative

Modelling for Science and Engineering. Rijeka, Croatia: InTech Press; 2011

[7] Zheng J, Luo J, Zhou W. Pseudo DNA sequence generation of non-coding distributions using variant maps on cellular automata. Applied Mathematics.

[8] Zheng J. Novel Pseudo Random Number Generation Using Varian Logic

[9] Heim DM, Heim O, Zeng PA, Zheng J. Successful creation of regular patterns in variant maps from bat echolocation

Framework. Australian Security

Congress. 2011:100-104

## Ventricular Tachycardia and Heart Failure

*Hakan Altay*

#### **Abstract**

Ventricular tachycardia (VT) is a common arrhythmia seen in patients with heart failure (HF) and is now seen more frequently as these patients survive longer with modern therapies. In patients with HF, half of the deaths are sudden due to life-threatening ventricular arrhythmias, including VT. Although disease modifying drugs, such as beta blockers, mineralocorticoid drugs, and angiotensin receptor neprilysin inhibitors, prevent the occurrence of VT to some extent, the mainstay of therapy is the antiarrhythmic drug therapy, implantable cardioverter-defibrillator (ICD) implantation, and traditional radiofrequency catheter ablation. Autonomic nerve system modulation and stereotactic body radiation therapy have emerged as novel techniques for the management of refractory VT cases. Patients with refractory VT and repetitive ICD shocks should be further evaluated regarding the candidacy for left ventricular assist device and transplantation.

**Keywords:** ventricular tachycardia, heart failure, antiarrhythmic therapy, implantable-cardioverter defibrillator, ablation

#### **1. Introduction**

Ventricular tachycardia (VT) is common in patients with heart failure (HF). The presence and severity of VT increase as the severity of HF increases. Larger infarcts with greater left ventricle (LV) systolic dysfunction are more likely to be associated with VT. VT forms one of the most common electrical mechanisms responsible for sudden cardiac death (SCD) in HF. Patients with LV systolic dysfunction who develop VT are at increased risk of SCD from subsequent VT or ventricular fibrillation [1].

Patients with VT and HF may present either with cardiac arrest to the emergency department or with palpitations, syncope, chest pain, or ICD shocks to cardiology outpatient clinics, varying according to the hemodynamic stability of VT. Both non-sustained VT (VT duration < 30 sec) and sustained VT (VT duration > 30 sec) in patients with HF are associated with significant morbidity and mortality. VT storm (three or more separate episodes of sustained VT requiring intervention (such as ICD shock or ATP) within 24 hours) is the most troublesome condition related with VT and HF.

Although half of the patients with HF have preserved ejection fraction and SCD is also a common issue in these patients, there is no proved treatment either by ICD or drugs [2]. Because of this, VT and HF will be discussed in the context of HF with reduced ejection fraction (HFREF).

### **2. Epidemiology**

Ventricular tachycardia is common in patients with HF, with up to 20% of patients developing VT in 5 years after an ICD was placed [3]. In patients with HF, SCD occurs 6–9 times more often than the general population [4]. The most studied and proven predictor of ventricular tachyarrhythmia and SCD is left ventricle ejection fraction (LVEF) [5]. It has been shown that once the LVEF recovered, the incidence of ventricular tachyarrhythmia decreases [6].

The threshold of LVEF <35% represents an accepted threshold at which SCD risk is increased and primary prevention is indicated. Several other risk predictors of VT, such as non-sustained VT, programmed ventricular stimulation on electrophysiological study (EPS), microvolt T-wave alternans, late potentials on signalaveraged electrocardiogram, absence of heart rate variability, QT wave dispersion, baroreflex sensitivity, and heart rate turbulence have been proposed for patients with HF. However, none of these predictors has influenced the clinical practice.

#### **3. Pathophysiology**

There are multiple mechanisms that play a role in the occurrence of VT in patients with HF (**Table 1**). Adverse remodeling and progressive fibrosis occur in the ventricle following myocardial infarction (MI) or in association with nonischemic cardiomyopathy. These structural alterations as well as the ion channel changes form the essential substrate for the induction of VT [7].

The most common mechanism for VT is electrical reentry within and around patches of heterogenous myocardial fibrosis, most commonly occurring in areas of scar post-myocardial infarction or non-ischemic cardiomyopathy [8]. The scarrelated VT is typically monomorphic with single QRS morphology. Induction of monomorphic VT during EPS predicts patients who have the risk of spontaneous VT. Polymorphic VT is defined as a continually changing QRS morphology, often associated with acute ischemia, drugs which lead to QT prolongation or electrolyte imbalance.

Increased sympathetic nervous system (SNS) activation is another trigger for induction of VT. SNS activation, via beta-adrenoreceptors activates ryanodine receptor on the sarcoplasmic reticulum inside the cardiomyocytes leading to efflux of calcium and increase of intracellular concentration which is a trigger for VT. This is the rationale under the effect of beta blockers in suppressing VT, as well as SCD in HF patients.


**77**

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

clinical outcomes.

**4. Management**

antiarrhythmic treatment in this case [12].

VT occurring within 24–48 hours of acute MI is called primary VT, and acute ischemia is considered to be the transient or correctable cause of VT in this case. Revascularization is the primary management form of primary VT. VT occurring after 48 hours of acute MI is called secondary VT, which is associated with worse

Increased diastolic calcium levels, early and delayed after depolarizations, and some of the drugs also cause VT. Antiarrhythmic drugs are the foremost drugs causing VT. Digoxin that is commonly used in the management of HF is an arrhythmogenic drug. Dobutamine treatment for acute decompensated HF has also been associated with VT [9]. Because of this, patients should be continuously monitorized during treatment with dobutamine. VT can also present as a complication of left ventricular assist device in an advanced HF patient. Most of these types of VT occur perioperatively [10]. It is important to find out the definite mechanism of VT in order to implement the best effective treatment. In patients with sarcoidosis, for example, VT can occur as a result of inflammation, scar or both. If VT is thought to be due to inflammation, best treatment is antiarrhythmic drug and immunosuppressive, whereas if VT is of scar related, best treatment is antiarrhythmic drug and catheter ablation [11].

Management of VT in heart failure poses a great challenge to cardiologists since antiarrhythmic drugs are limited by incomplete efficacy and unfavorable adverse effect profile, ICD is complex and expensive and may affect the quality of life adversely because of inappropriate shocks, and invasive catheter ablation owns the risk of complication and recurrence. Therefore, multidisciplinary team approach including electrophysiologists, heart failure specialists, general cardiologists, intensivists, and cardiovascular surgeon should be used to tackle such a difficult disease. VT is a life-threatening condition and needs urgent management. Acute management of VT in HF patients depends on the hemodynamic stability of the patient. In hemodynamically unstable VT, the priority is electrical direct current cardioversion [12]. If the patient is hemodynamically stable, a trial of antiarrhythmic treatment should be applied. Intravenous amiodarone is the most effective and safe

Slow VT (<150 beats/minute) may be tolerated in the short term (**Figure 1**). However, slow VT in the presence of poor ventricular function may cause hemodynamic compromise in the long term. It is important to closely monitor the patient while administering antiarrhythmic therapy. If the antiarrhythmic therapy does not cardiovert the patient, shock should be applied as early as possible since sustained VT can compromise hemodynamic status of the patient with left ventricular dysfunction in due course. The initial approach to the management of VT should include evaluation for correctable causes of VT (e.g., electrolyte abnormalities and ischemia). Electrolyte abnormalities, particularly hypokalemia and hypomagnesemia which are known to facilitate VT in HF patients should be corrected. Potassium and magnesium levels should be kept >4 meq/l and > 2 meq/l, respectively. Agents,

for example, digoxin, that may induce arrhythmia should be withheld.

For chronic management of VT, optimization of guideline-directed medical treatment is very important especially in patients with HFREF. Until recently, these treatments consisted of angiotensin converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), beta blockers (BBs), and mineralocorticoid receptor antagonists (MRAs). Of these guideline-directed medical treatments, BB and MRA have been proved to prevent sudden cardiac death [13, 14]. These drugs have the ability to improve reverse modeling which reduces VT. BBs are the

#### **Table 1.**

*Mechanisms of VT occurrence in patients with heart failure.*

#### *Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

*Practical Applications of Electrocardiogram*

incidence of ventricular tachyarrhythmia decreases [6].

Ventricular tachycardia is common in patients with HF, with up to 20% of patients developing VT in 5 years after an ICD was placed [3]. In patients with HF, SCD occurs 6–9 times more often than the general population [4]. The most studied and proven predictor of ventricular tachyarrhythmia and SCD is left ventricle ejection fraction (LVEF) [5]. It has been shown that once the LVEF recovered, the

The threshold of LVEF <35% represents an accepted threshold at which SCD risk is increased and primary prevention is indicated. Several other risk predictors of VT, such as non-sustained VT, programmed ventricular stimulation on electrophysiological study (EPS), microvolt T-wave alternans, late potentials on signalaveraged electrocardiogram, absence of heart rate variability, QT wave dispersion, baroreflex sensitivity, and heart rate turbulence have been proposed for patients with HF. However, none of these predictors has influenced the clinical practice.

There are multiple mechanisms that play a role in the occurrence of VT in patients with HF (**Table 1**). Adverse remodeling and progressive fibrosis occur in the ventricle following myocardial infarction (MI) or in association with nonischemic cardiomyopathy. These structural alterations as well as the ion channel

The most common mechanism for VT is electrical reentry within and around patches of heterogenous myocardial fibrosis, most commonly occurring in areas of scar post-myocardial infarction or non-ischemic cardiomyopathy [8]. The scarrelated VT is typically monomorphic with single QRS morphology. Induction of monomorphic VT during EPS predicts patients who have the risk of spontaneous VT. Polymorphic VT is defined as a continually changing QRS morphology, often associated with acute ischemia, drugs which lead to QT prolongation or electrolyte

Increased sympathetic nervous system (SNS) activation is another trigger for induction of VT. SNS activation, via beta-adrenoreceptors activates ryanodine receptor on the sarcoplasmic reticulum inside the cardiomyocytes leading to efflux of calcium and increase of intracellular concentration which is a trigger for VT. This is the rationale under the effect of beta blockers in suppressing VT, as well as SCD in

changes form the essential substrate for the induction of VT [7].

**2. Epidemiology**

**3. Pathophysiology**

imbalance.

HF patients.

**Mechanisms**

Myocardial scar

Ischemia

Drugs

**Table 1.**

Positive remodeling and fibrosis

Electrolyte abnormalities Increased sympathetic tone

Abnormal calcium handling Delayed after depolarization

*Mechanisms of VT occurrence in patients with heart failure.*

**76**

VT occurring within 24–48 hours of acute MI is called primary VT, and acute ischemia is considered to be the transient or correctable cause of VT in this case. Revascularization is the primary management form of primary VT. VT occurring after 48 hours of acute MI is called secondary VT, which is associated with worse clinical outcomes.

Increased diastolic calcium levels, early and delayed after depolarizations, and some of the drugs also cause VT. Antiarrhythmic drugs are the foremost drugs causing VT. Digoxin that is commonly used in the management of HF is an arrhythmogenic drug. Dobutamine treatment for acute decompensated HF has also been associated with VT [9]. Because of this, patients should be continuously monitorized during treatment with dobutamine. VT can also present as a complication of left ventricular assist device in an advanced HF patient. Most of these types of VT occur perioperatively [10]. It is important to find out the definite mechanism of VT in order to implement the best effective treatment. In patients with sarcoidosis, for example, VT can occur as a result of inflammation, scar or both. If VT is thought to be due to inflammation, best treatment is antiarrhythmic drug and immunosuppressive, whereas if VT is of scar related, best treatment is antiarrhythmic drug and catheter ablation [11].

#### **4. Management**

Management of VT in heart failure poses a great challenge to cardiologists since antiarrhythmic drugs are limited by incomplete efficacy and unfavorable adverse effect profile, ICD is complex and expensive and may affect the quality of life adversely because of inappropriate shocks, and invasive catheter ablation owns the risk of complication and recurrence. Therefore, multidisciplinary team approach including electrophysiologists, heart failure specialists, general cardiologists, intensivists, and cardiovascular surgeon should be used to tackle such a difficult disease.

VT is a life-threatening condition and needs urgent management. Acute management of VT in HF patients depends on the hemodynamic stability of the patient. In hemodynamically unstable VT, the priority is electrical direct current cardioversion [12]. If the patient is hemodynamically stable, a trial of antiarrhythmic treatment should be applied. Intravenous amiodarone is the most effective and safe antiarrhythmic treatment in this case [12].

Slow VT (<150 beats/minute) may be tolerated in the short term (**Figure 1**). However, slow VT in the presence of poor ventricular function may cause hemodynamic compromise in the long term. It is important to closely monitor the patient while administering antiarrhythmic therapy. If the antiarrhythmic therapy does not cardiovert the patient, shock should be applied as early as possible since sustained VT can compromise hemodynamic status of the patient with left ventricular dysfunction in due course. The initial approach to the management of VT should include evaluation for correctable causes of VT (e.g., electrolyte abnormalities and ischemia). Electrolyte abnormalities, particularly hypokalemia and hypomagnesemia which are known to facilitate VT in HF patients should be corrected. Potassium and magnesium levels should be kept >4 meq/l and > 2 meq/l, respectively. Agents, for example, digoxin, that may induce arrhythmia should be withheld.

For chronic management of VT, optimization of guideline-directed medical treatment is very important especially in patients with HFREF. Until recently, these treatments consisted of angiotensin converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), beta blockers (BBs), and mineralocorticoid receptor antagonists (MRAs). Of these guideline-directed medical treatments, BB and MRA have been proved to prevent sudden cardiac death [13, 14]. These drugs have the ability to improve reverse modeling which reduces VT. BBs are the

**Figure 1.** *Slow VT at a rate of approximately 125/bpm in a patient on high dose of beta blocker and amiodarone.*

first-line therapy for the management of VT in HF patients. In MADIT-II trial (the Multicenter Automatic Defibrillator Implantation Trial II), patients with ICD treated with the highest dose of BB experienced less ICD treatment compared to patients not taking BB [15].

A meta-analysis compared medical treatment with ICD preventing SCD in patients with HF and left ventricular systolic dysfunction. MRAs were found to be the most effective drug when added to ACEi and BB, in preventing SCD [16]. Zannad et al. also showed that MRAs were equally effective in preventing SCD in patients with ICD as without ICD [17].

A newly emerged drug in HFREF, angiotensin receptor neprilysin inhibitor (ARNi), was compared with enalapril in PARADIGM-HF trial (prospective comparison of angiotensin neprilysin inhibitor (ARNI) with ACE-i to determine impact on global morbidity and mortality in heart failure) [18]. ARNi was shown to be superior in reducing cardiovascular death and hospitalization compared to enalapril. ARNi also reduced SCD by 20% compared to enalapril. European Society of Cardiology 2016 HF guideline has made a class 1 recommendation regarding the use of BB, MRA, and ARNi in patients with HFREF and VT [19].

Optimum use of guideline-directed medical treatment prevents development of VT to some extent. If the patient continues to be at risk of VT because of low ejection fraction, non-sustained or sustained VT, antiarrhythmic drugs, ICD implantation, and VT ablation are the subsequent treatment options for chronic management of VT. General use of antiarrhythmic drugs in HF is not recommended for VT since these drugs, except amiodarone, have been shown to increase mortality in patients with HF due to proarrhythmic or negative inotropic effects.

Notorious CAST trial (Cardiac Arrhythmia Suppression Trial) showed that class 1C agents, encainide, and flecainide increases mortality and non-fatal cardiac arrest when used to suppress VT post-myocardial infarction [20]. CAST trial was planned to answer the question of whether suppressing ventricular premature beats (VPB) also aid in reducing mortality. Patients who had myocardial infarction within the preceding 2 years and >6 VPBs on holter recording were enrolled. Those who had MI within 90 days were required to have EF < 55%, and those who had MI after this period were required to have EF < 40%. Patients were randomly assigned to class1C agents (encainide, flecainide, or moricizine). Patients whose PVBs were suppressed were allocated to the treatment with one of the class 1C agent or placebo. The trial was prematurely stopped based on the in-term analysis that showed that encainide and flecainide used to suppress VPBs increased the mortality by 2.5 times. It is likely that mortality excess can be attributed to the proarrhythmic effects of encainide and flecainide.

**79**

**Figure 2.**

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

amiodarone have been noted to be high [22].

assessed whether VT could be induced again [26].

amiodarone.

primary prevention.

Amiodarone is the sole agent that can be used safely for suppression of VT in HF patients. Amiodarone has been studied extensively in patients with left ventricular dysfunction. Its efficacy for decreasing mortality in patients with VT and LV dysfunction has not been shown in SCD-HeFT trial (the Sudden Cardiac Death in Heart Failure Trial) [21]. However, a meta-analysis including 8522 patients post-myocardial infarction or with systolic HF showed that amiodarone reduced SCD and cardiovascular mortality [22]. Its safety, unlike class 1 antiarrhythmic agents, has been confirmed in this patient population. In patients with more severe HF, amiodarone use is associated with adverse prognosis [21]. Amiodarone cannot be used for a long period of time because it is associated with multiple side effects, primarily affecting thyroid, lung, liver, skin, and eye [23]. Therefore, regular monitoring of lung, liver, and thyroid function is required. Due to these side effects, discontinuation rates of

Sotalol, a group III antiarrhythmic drug, with BB properties, is highly effective in suppressing VT but it is contraindicated in HF patients since increased mortality was demonstrated when D-sotalol was used in patients with left ventricular dysfunction after myocardial infarction in SWORD trial [24]. Dofetilide, another class III antiarrhythmic drug, failed to reduce arrhythmic death in patients with HF [25]. If VT occurs despite amiodarone therapy, mexiletine can be used as an adjunct to

Electrophysiologic study was once used for identification of successful antiarrhythmic therapy and also the patients who require other advanced therapies. Patients were given certain antiarrhythmic drugs after VT was induced at programmed stimulation. Patients on chronic oral antiarrhythmic drug were then

Of the therapies currently available to manage VT, ICD is by far the most effective one and has the best supported safety and efficacy data from the trials and registries. An ICD has two important components: an ICD generator and a lead for sensing, pacing, and shock delivery (**Figure 2**). ICD improves the survival of patients who had VT and syncope, patients who had VT and LVEF<40%, and hemodynamic compromise [27]. ICD has been shown to prevent sudden cardiac death prophylactically in patents with LVEF <35% resulting both from ischemic or non-ischemic cardiomyopathy [21, 28, 29]. The important issue in these primary prevention groups is that they should have already received guideline-directed medical treatment for at least 3 months before ICD implantation is planned. Electrophysiologic study is no longer a required procedure before planning ICD for

*A schematic representation of an intracardiac defibrillator implanted to right ventricle of heart failure patient.*

#### *Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

*Practical Applications of Electrocardiogram*

patients not taking BB [15].

**Figure 1.**

patients with ICD as without ICD [17].

first-line therapy for the management of VT in HF patients. In MADIT-II trial (the Multicenter Automatic Defibrillator Implantation Trial II), patients with ICD treated with the highest dose of BB experienced less ICD treatment compared to

*Slow VT at a rate of approximately 125/bpm in a patient on high dose of beta blocker and amiodarone.*

A meta-analysis compared medical treatment with ICD preventing SCD in patients with HF and left ventricular systolic dysfunction. MRAs were found to be the most effective drug when added to ACEi and BB, in preventing SCD [16]. Zannad et al. also showed that MRAs were equally effective in preventing SCD in

A newly emerged drug in HFREF, angiotensin receptor neprilysin inhibitor (ARNi), was compared with enalapril in PARADIGM-HF trial (prospective comparison of angiotensin neprilysin inhibitor (ARNI) with ACE-i to determine impact on global morbidity and mortality in heart failure) [18]. ARNi was shown to be superior in reducing cardiovascular death and hospitalization compared to enalapril. ARNi also reduced SCD by 20% compared to enalapril. European Society of Cardiology 2016 HF guideline has made a class 1 recommendation regarding the

Optimum use of guideline-directed medical treatment prevents development of VT to some extent. If the patient continues to be at risk of VT because of low ejection fraction, non-sustained or sustained VT, antiarrhythmic drugs, ICD implantation, and VT ablation are the subsequent treatment options for chronic management of VT. General use of antiarrhythmic drugs in HF is not recommended for VT since these drugs, except amiodarone, have been shown to increase mortality

Notorious CAST trial (Cardiac Arrhythmia Suppression Trial) showed that class 1C agents, encainide, and flecainide increases mortality and non-fatal cardiac arrest when used to suppress VT post-myocardial infarction [20]. CAST trial was planned to answer the question of whether suppressing ventricular premature beats (VPB) also aid in reducing mortality. Patients who had myocardial infarction within the preceding 2 years and >6 VPBs on holter recording were enrolled. Those who had MI within 90 days were required to have EF < 55%, and those who had MI after this period were required to have EF < 40%. Patients were randomly assigned to class1C agents (encainide, flecainide, or moricizine). Patients whose PVBs were suppressed were allocated to the treatment with one of the class 1C agent or placebo. The trial was prematurely stopped based on the in-term analysis that showed that encainide and flecainide used to suppress VPBs increased the mortality by 2.5 times. It is likely that mortality excess can be attributed to the proarrhythmic effects of encainide and flecainide.

use of BB, MRA, and ARNi in patients with HFREF and VT [19].

in patients with HF due to proarrhythmic or negative inotropic effects.

**78**

Amiodarone is the sole agent that can be used safely for suppression of VT in HF patients. Amiodarone has been studied extensively in patients with left ventricular dysfunction. Its efficacy for decreasing mortality in patients with VT and LV dysfunction has not been shown in SCD-HeFT trial (the Sudden Cardiac Death in Heart Failure Trial) [21]. However, a meta-analysis including 8522 patients post-myocardial infarction or with systolic HF showed that amiodarone reduced SCD and cardiovascular mortality [22]. Its safety, unlike class 1 antiarrhythmic agents, has been confirmed in this patient population. In patients with more severe HF, amiodarone use is associated with adverse prognosis [21]. Amiodarone cannot be used for a long period of time because it is associated with multiple side effects, primarily affecting thyroid, lung, liver, skin, and eye [23]. Therefore, regular monitoring of lung, liver, and thyroid function is required. Due to these side effects, discontinuation rates of amiodarone have been noted to be high [22].

Sotalol, a group III antiarrhythmic drug, with BB properties, is highly effective in suppressing VT but it is contraindicated in HF patients since increased mortality was demonstrated when D-sotalol was used in patients with left ventricular dysfunction after myocardial infarction in SWORD trial [24]. Dofetilide, another class III antiarrhythmic drug, failed to reduce arrhythmic death in patients with HF [25]. If VT occurs despite amiodarone therapy, mexiletine can be used as an adjunct to amiodarone.

Electrophysiologic study was once used for identification of successful antiarrhythmic therapy and also the patients who require other advanced therapies. Patients were given certain antiarrhythmic drugs after VT was induced at programmed stimulation. Patients on chronic oral antiarrhythmic drug were then assessed whether VT could be induced again [26].

Of the therapies currently available to manage VT, ICD is by far the most effective one and has the best supported safety and efficacy data from the trials and registries. An ICD has two important components: an ICD generator and a lead for sensing, pacing, and shock delivery (**Figure 2**). ICD improves the survival of patients who had VT and syncope, patients who had VT and LVEF<40%, and hemodynamic compromise [27]. ICD has been shown to prevent sudden cardiac death prophylactically in patents with LVEF <35% resulting both from ischemic or non-ischemic cardiomyopathy [21, 28, 29]. The important issue in these primary prevention groups is that they should have already received guideline-directed medical treatment for at least 3 months before ICD implantation is planned. Electrophysiologic study is no longer a required procedure before planning ICD for primary prevention.

#### **Figure 2.**

*A schematic representation of an intracardiac defibrillator implanted to right ventricle of heart failure patient.*

ICD has antitachycardia pacing (ATP) treatment in addition to defibrillator shock and also programs which can discriminate supraventricular tachycardia from VT which aids to minimize inappropriate shocks. ATP consists of one or more sequence of pacing stimuli, generally expressed as a percentage of tachycardia cycle length for a given RR interval. In case of burst ATP, pacing stimuli is delivered at constant coupling intervals, whereas ramp ATP consists of pacing stimuli with decrement coupling interval (**Figure 3**). Once VT is confirmed, first therapy in the form of ATP was given, and if ATP does not work, then shock is delivered. Generally ICD's VT detection zone is programmed to >167 beats/min and ventricular fibrillation detection zone to >185–200 beats/min. Antiarrhythmic drugs commonly prolong VT cycle length and hence cause slow VT, a condition which may require to lower the detection zone for VT (**Figure 1**). In secondary prevention patients with HF, the programming of detection zone depends on the cycle length of the VT occurred. Generally, the detection zone is programmed 20 bpm slower than the rate of the VT occurred before. ATP for faster VT (188–250 bpm) may also be programmed with the aim for reducing shocks. ICD shocks are related with poor prognosis and quality of life. For this reason, every effort should be made to reduce shocks. It was shown that reducing defibrillator shocks was associated with increased survival [30].

Cardiac resynchronization therapy (CRT) is also an important milestone in the management of moderate to severe HF patients with prolonged QRS duration (>150 msn and LBBB morphology). CRT without defibrillator (CRT-P) can prevent SCD by improving reverse remodeling. CARE-HF Trial (Cardiac Resynchronization—Heart Failure) showed that CRT-P prevents SCD by 46% in the long term follow-up [31]. Although CRT was shown to reduce new onset VT, it had no effect on recurrent VTs [32].

In patients with HF who are refractory to antiarrhythmic therapy, radiofrequency catheter ablation has emerged as an important therapeutic option. The success rate of this technique varies according to the type of cardiomyopathy. The American Heart Association(AHA)/the Heart Rhythm Society (HRS) recommends the use of VT ablation in patients with prior myocardial infarction and recurrent VT, unresponsive or intolerant to antiarrhythmic treatment [8]. Electrophysiologic study (EPS) with programmed electrical stimulation is recommended before ablation in case of sustained monomorphic VT in patients with prior MI [33]. Catheter ablation can be effective, but acute complications and long-term VT recurrence risk necessitating repeat ablation should be recognized. And worth notifying, procedure

#### **Figure 3.**

*Antitachycardia pacing (ATP) therapy of intracardiac defibrillator. (A) Burst ATP; pacing stimuli at lower than VT and constant coupling interval. (B) Ramp ATP; pacing stimuli starting with lower than VT cycle length and coupling intervals decreasing at each stimuli.*

**81**

for repetitive VTs [40].

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

operation [34].

of ablation lasts for long hours with extended recovery times. If VT remains refractory to catheter ablation, repeat ablation may be tried. If the first ablation was done by endocardial mapping, repeat ablations may be carried by epicardial mapping. Surgical ablation is indicated in patients with VT refractory to antiarrhythmic drugs whose catheter ablation has failed [12]. It was shown that surgical cryoablation guided by endocardial and epicardial mapping along with aneurysmectomy when indicated was a successful way of terminating VT in patients who underwent bypass

Due to multiple mechanisms of VT in idiopathic dilated cardiomyopathy, the success rate of catheter ablation is less than in ischemic cardiomyopathy. It has been shown that ablation in this type of cardiomyopathy results in higher recurrence rate of VT than ischemic cardiomyopathy [35]. Catheter ablation of VT in dilated cardiomyopathy should only be done in patients with clear mechanism of VT (e.g., bundle branch reentry) only in experienced centers. Despite these shortcomings, successful VT ablation in non-ischemic dilated cardiomyopathy has increased. Predictors of recurrence after VT ablation in non-ischemic dilated cardiomyopathy were found to be inducibility of sustained VT in the programmed stimulation study,

Worth mentioning, there are some types of VTs occurring in the structurally normal heart, termed idiopathic VT. Idiopathic VT is further categorized according to the anatomic location in the heart. Most of them originate from the right ventricular outflow tract (RVOT) and have left bundle branch block (LBBB) pattern on the electrocardiogram. The second most common idiopathic VT originating from the conduction system is termed as fascicular VT. The other idiopathic VT originates from the mitral or tricuspid annulus and termed as annular VT. The clinical course of idiopathic VT is usually benign; however, if they occur in the form of incessant VT, they may cause LV systolic dysfunction, termed as arrhythmia-induced cardiomyopathy (AIC). It is important to differentiate AIC from non-ischemic dilated cardiomyopathy because RF ablation is the first line treatment and curative in the former [8]. VT originating from left ventricular outflow tract (LVOT) is rare compared to VT originating from RVOT. Some form of VTs originating from LVOT cannot be ablated by using conventional approach. This unique type of VT with LBBB inferior axis and early precordial transition can successfully be ablated from the aortic root, using either the left or non-coronary aortic sinus of valsalva [37]. VTs can also originate from papillary muscle of left or right ventricle. Ablation of papillary muscle VT is difficult compared to other idiopathic VTs. However, there is a case report showing successful ablation of incessant VT originating from posterior papillary muscle of right ventricle [38]. EPS is highly recommended before ablation of VT in structurally normal hearts which are suspected to be originated from RVOT, LVOT, aortic cusps, and epicardial VT [33]. EPS has also a role in case of sustained monomorphic VT in patients with arrhythmogenic right ventricular dysplasia (ARVD). It was shown that inducibility of sustained monomorphic VT during EPS highly predicts SCD, heart transplantation, VT with hemodynamic

Another form of VT occurring in the structurally normal heart is catecholaminergic polymorphic VT. This type of VT should be suspected when syncope triggered by emotion or physical effort occurs in young patients with normal heart and QT interval. First line treatment is BBs. Hypertrophic cardiomyopathy (HCM), a common cause of SCD in young athletes, is a heterogenous group of cardiomyopathy with increased wall thickness. HCM with mid-ventricular obstruction and apical aneurysm is a rare form of HCM which is associated with frequent occurrence of VT. Prophylactic ICD is the main treatment, but RF ablation is required

poor systolic function (EF < 35%), and delayed intervention time [36].

compromise, or syncope in patients with ARVD [39].

#### *Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

*Practical Applications of Electrocardiogram*

increased survival [30].

no effect on recurrent VTs [32].

ICD has antitachycardia pacing (ATP) treatment in addition to defibrillator shock and also programs which can discriminate supraventricular tachycardia from VT which aids to minimize inappropriate shocks. ATP consists of one or more sequence of pacing stimuli, generally expressed as a percentage of tachycardia cycle length for a given RR interval. In case of burst ATP, pacing stimuli is delivered at constant coupling intervals, whereas ramp ATP consists of pacing stimuli with decrement coupling interval (**Figure 3**). Once VT is confirmed, first therapy in the form of ATP was given, and if ATP does not work, then shock is delivered. Generally ICD's VT detection zone is programmed to >167 beats/min and ventricular fibrillation detection zone to >185–200 beats/min. Antiarrhythmic drugs commonly prolong VT cycle length and hence cause slow VT, a condition which may require to lower the detection zone for VT (**Figure 1**). In secondary prevention patients with HF, the programming of detection zone depends on the cycle length of the VT occurred. Generally, the detection zone is programmed 20 bpm slower than the rate of the VT occurred before. ATP for faster VT (188–250 bpm) may also be programmed with the aim for reducing shocks. ICD shocks are related with poor prognosis and quality of life. For this reason, every effort should be made to reduce shocks. It was shown that reducing defibrillator shocks was associated with

Cardiac resynchronization therapy (CRT) is also an important milestone in the management of moderate to severe HF patients with prolonged QRS duration (>150 msn and LBBB morphology). CRT without defibrillator (CRT-P) can prevent SCD by improving reverse remodeling. CARE-HF Trial (Cardiac Resynchronization—Heart Failure) showed that CRT-P prevents SCD by 46% in the long term follow-up [31]. Although CRT was shown to reduce new onset VT, it had

In patients with HF who are refractory to antiarrhythmic therapy, radiofrequency catheter ablation has emerged as an important therapeutic option. The success rate of this technique varies according to the type of cardiomyopathy. The American Heart Association(AHA)/the Heart Rhythm Society (HRS) recommends the use of VT ablation in patients with prior myocardial infarction and recurrent VT, unresponsive or intolerant to antiarrhythmic treatment [8]. Electrophysiologic study (EPS) with programmed electrical stimulation is recommended before ablation in case of sustained monomorphic VT in patients with prior MI [33]. Catheter ablation can be effective, but acute complications and long-term VT recurrence risk necessitating repeat ablation should be recognized. And worth notifying, procedure

*Antitachycardia pacing (ATP) therapy of intracardiac defibrillator. (A) Burst ATP; pacing stimuli at lower than VT and constant coupling interval. (B) Ramp ATP; pacing stimuli starting with lower than VT cycle* 

**80**

**Figure 3.**

*length and coupling intervals decreasing at each stimuli.*

of ablation lasts for long hours with extended recovery times. If VT remains refractory to catheter ablation, repeat ablation may be tried. If the first ablation was done by endocardial mapping, repeat ablations may be carried by epicardial mapping. Surgical ablation is indicated in patients with VT refractory to antiarrhythmic drugs whose catheter ablation has failed [12]. It was shown that surgical cryoablation guided by endocardial and epicardial mapping along with aneurysmectomy when indicated was a successful way of terminating VT in patients who underwent bypass operation [34].

Due to multiple mechanisms of VT in idiopathic dilated cardiomyopathy, the success rate of catheter ablation is less than in ischemic cardiomyopathy. It has been shown that ablation in this type of cardiomyopathy results in higher recurrence rate of VT than ischemic cardiomyopathy [35]. Catheter ablation of VT in dilated cardiomyopathy should only be done in patients with clear mechanism of VT (e.g., bundle branch reentry) only in experienced centers. Despite these shortcomings, successful VT ablation in non-ischemic dilated cardiomyopathy has increased. Predictors of recurrence after VT ablation in non-ischemic dilated cardiomyopathy were found to be inducibility of sustained VT in the programmed stimulation study, poor systolic function (EF < 35%), and delayed intervention time [36].

Worth mentioning, there are some types of VTs occurring in the structurally normal heart, termed idiopathic VT. Idiopathic VT is further categorized according to the anatomic location in the heart. Most of them originate from the right ventricular outflow tract (RVOT) and have left bundle branch block (LBBB) pattern on the electrocardiogram. The second most common idiopathic VT originating from the conduction system is termed as fascicular VT. The other idiopathic VT originates from the mitral or tricuspid annulus and termed as annular VT. The clinical course of idiopathic VT is usually benign; however, if they occur in the form of incessant VT, they may cause LV systolic dysfunction, termed as arrhythmia-induced cardiomyopathy (AIC). It is important to differentiate AIC from non-ischemic dilated cardiomyopathy because RF ablation is the first line treatment and curative in the former [8]. VT originating from left ventricular outflow tract (LVOT) is rare compared to VT originating from RVOT. Some form of VTs originating from LVOT cannot be ablated by using conventional approach. This unique type of VT with LBBB inferior axis and early precordial transition can successfully be ablated from the aortic root, using either the left or non-coronary aortic sinus of valsalva [37]. VTs can also originate from papillary muscle of left or right ventricle. Ablation of papillary muscle VT is difficult compared to other idiopathic VTs. However, there is a case report showing successful ablation of incessant VT originating from posterior papillary muscle of right ventricle [38]. EPS is highly recommended before ablation of VT in structurally normal hearts which are suspected to be originated from RVOT, LVOT, aortic cusps, and epicardial VT [33]. EPS has also a role in case of sustained monomorphic VT in patients with arrhythmogenic right ventricular dysplasia (ARVD). It was shown that inducibility of sustained monomorphic VT during EPS highly predicts SCD, heart transplantation, VT with hemodynamic compromise, or syncope in patients with ARVD [39].

Another form of VT occurring in the structurally normal heart is catecholaminergic polymorphic VT. This type of VT should be suspected when syncope triggered by emotion or physical effort occurs in young patients with normal heart and QT interval. First line treatment is BBs. Hypertrophic cardiomyopathy (HCM), a common cause of SCD in young athletes, is a heterogenous group of cardiomyopathy with increased wall thickness. HCM with mid-ventricular obstruction and apical aneurysm is a rare form of HCM which is associated with frequent occurrence of VT. Prophylactic ICD is the main treatment, but RF ablation is required for repetitive VTs [40].

#### **5. Management of ICD repetitive shocks**

Despite ICD can effectively terminate ventricular tachycardia either by antitachycardia pacing or defibrillation shock, it cannot prevent VT recurrences. In patients with ICD, prevention of VT recurrence is required to minimize ICD shocks which can not only be quite uncomfortable for the patient leading to poor quality of life but also cause early battery depletion. Apart from these, recurrent shocks lead to HF progression, frequent hospitalization, and mortality. Use of antiarrhythmic drugs, particularly amiodarone can reduce ICD appropriate shocks by 34% [41]. In the OPTIC study (the Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients), beta blocker and amiodarone combination were shown to be superior in suppression of VT recurrence compared to BB alone or sotalol [42]. Drug discontinuation rate at 1 year was found to be 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for BB. Mexiletine, a class 1b antiarrhythmic drug, was shown to reduce VT recurrence as an adjunct to amiodarone in amiodarone-refractory VT in patients with ICD [43]. Ranolazine, a late Na channel inhibitor, was also shown to reduce VT burden and ICD shocks in patients with drug refractory VT and ICD [44].

Radiofrequency catheter ablation can be lifesaving in patients with ICD and repetitive shocks. In ischemic cardiomyopathy, some trials such as SMASH-VT (Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia), VTACH (Ventricular Tachycardia Ablation in Coronary Heart Disease), and VANISH trials have shown the superiority of ablation for reducing ICD shocks [45–47]. The SMASH-VT trial compared ICD implantation plus prophylactic ablation to ICD implantation alone in patients with recent VT. Ablation reduced ICD shocks significantly from 31 to 9% and reduced VT from 33 to 12%. The VTACH trial assessed the effect of catheter ablation in patients with ischemic cardiomyopathy and mappable VT. Ablation significantly prolonged time to recurrent VT. The VANISH trial compared catheter ablation to escalation of antiarrhythmic therapy on top of first-line antiarrhythmic therapy in patients with VT. Ablation significantly reduced composite outcome of death, appropriate ICD shocks, and VT storm. Repetitive ICD shocks should also warrant referral to an advanced heart failure unit, capable for left ventricular assist device (LVAD) implantation and transplantation [48]. Catheter ablation of VT has risk of complication like all other invasive procedures. Complications related to these procedures are cardiac perforation, systemic embolism including myocardial infarction/stroke, vascular complications, and mortality.

Autonomic modulation procedures may also be applied for VT refractory to ablation. It was shown that videoscopic surgical cardiac sympathetic denervation may reduce the number of ICD shocks in refractory cases [49]. The surgery involves removal of the lower half of the stellate ganglion and T2-T4 stellate ganglia. This technique is especially effective when sympathetic denervation was made bilaterally. Renal denervation was also shown to reduce VT recurrences [50].

Stereotactic body radiation therapy (SBRT) for VT in HF patients has recently emerged as a new way of suppression of VT. SBRT is a technique that delivers high dose of radiation (25 gray) to target tissues with reduced exposure to normal adjacent tissues. SBRT has been used for decades to target various cancers. First, Cuculich et al. showed a 99.9% reduction in VT burden with cardiac SBRT in a case series of five patients with a high burden of drug-refractory VT, who had been suffering through repeated ICD shocks [51]. And recently, ENCORE VT trial showed that SBRT reduced VT and premature ventricular contraction episodes 94% at 6 months among 18 patients with treatmentrefractory VT, over half of whom presented with VT storm [52].

**83**

**Figure 4.**

*taking blood from left ventricle and pumping it to aorta.*

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

may be applied in these patients.

In selected cases with recurrent VT which cannot be managed with the treatment recommendation given above, implantation of LVAD could temporarily stabilize patient hemodynamically, as well as improve reverse remodeling. LVAD is a battery-operated mechanical pump, which takes the blood from failed LV and pumps it to the aorta to be transmitted to the rest of the body (**Figure 4**). There are not many heart failure patients with LVAD. However, the management of VT in this patient population requires mention since it is somewhat different than HF patients without LVAD. LVAD may be able to continue maintaining cardiac output in spite of sustained VT, and most of the LVAD patients have ICD in place. When such patients present to the emergency department, first patient hemodynamic status should be assessed. If the blood pressure checked by Doppler ultrasonography is okay, it is reasonable to transfer the patient to a tertiary center where there is LVAD specialist and electrophysiologist. If there is hemodynamic compromise, then the patient should be immediately converted to normal sinus rhythm with electrical shock [53]. If the patient is a candidate neither for transplantation nor LVAD, end-of-life care should be applied for palliation. Shared decision making with the patient and relatives should be done, and discussion regarding measures such as ICD deactivation

*A schematic representation of a left ventricle assist device (LVAD) showing battery-operated mechanical pump* 

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

*Practical Applications of Electrocardiogram*

drug refractory VT and ICD [44].

vascular complications, and mortality.

presented with VT storm [52].

**5. Management of ICD repetitive shocks**

Despite ICD can effectively terminate ventricular tachycardia either by antitachycardia pacing or defibrillation shock, it cannot prevent VT recurrences. In patients with ICD, prevention of VT recurrence is required to minimize ICD shocks which can not only be quite uncomfortable for the patient leading to poor quality of life but also cause early battery depletion. Apart from these, recurrent shocks lead to HF progression, frequent hospitalization, and mortality. Use of antiarrhythmic drugs, particularly amiodarone can reduce ICD appropriate shocks by 34% [41]. In the OPTIC study (the Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients), beta blocker and amiodarone combination were shown to be superior in suppression of VT recurrence compared to BB alone or sotalol [42]. Drug discontinuation rate at 1 year was found to be 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for BB. Mexiletine, a class 1b antiarrhythmic drug, was shown to reduce VT recurrence as an adjunct to amiodarone in amiodarone-refractory VT in patients with ICD [43]. Ranolazine, a late Na channel inhibitor, was also shown to reduce VT burden and ICD shocks in patients with

Radiofrequency catheter ablation can be lifesaving in patients with ICD and repetitive shocks. In ischemic cardiomyopathy, some trials such as SMASH-VT

Autonomic modulation procedures may also be applied for VT refractory to ablation. It was shown that videoscopic surgical cardiac sympathetic denervation may reduce the number of ICD shocks in refractory cases [49]. The surgery involves removal of the lower half of the stellate ganglion and T2-T4 stellate ganglia. This technique is especially effective when sympathetic denervation was made bilater-

Stereotactic body radiation therapy (SBRT) for VT in HF patients has recently

emerged as a new way of suppression of VT. SBRT is a technique that delivers high dose of radiation (25 gray) to target tissues with reduced exposure to normal adjacent tissues. SBRT has been used for decades to target various cancers. First, Cuculich et al. showed a 99.9% reduction in VT burden with cardiac SBRT in a case series of five patients with a high burden of drug-refractory VT, who had been suffering through repeated ICD shocks [51]. And recently, ENCORE VT trial showed that SBRT reduced VT and premature ventricular contraction episodes 94% at 6 months among 18 patients with treatmentrefractory VT, over half of whom

ally. Renal denervation was also shown to reduce VT recurrences [50].

(Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia), VTACH (Ventricular Tachycardia Ablation in Coronary Heart Disease), and VANISH trials have shown the superiority of ablation for reducing ICD shocks [45–47]. The SMASH-VT trial compared ICD implantation plus prophylactic ablation to ICD implantation alone in patients with recent VT. Ablation reduced ICD shocks significantly from 31 to 9% and reduced VT from 33 to 12%. The VTACH trial assessed the effect of catheter ablation in patients with ischemic cardiomyopathy and mappable VT. Ablation significantly prolonged time to recurrent VT. The VANISH trial compared catheter ablation to escalation of antiarrhythmic therapy on top of first-line antiarrhythmic therapy in patients with VT. Ablation significantly reduced composite outcome of death, appropriate ICD shocks, and VT storm. Repetitive ICD shocks should also warrant referral to an advanced heart failure unit, capable for left ventricular assist device (LVAD) implantation and transplantation [48]. Catheter ablation of VT has risk of complication like all other invasive procedures. Complications related to these procedures are cardiac perforation, systemic embolism including myocardial infarction/stroke,

**82**

In selected cases with recurrent VT which cannot be managed with the treatment recommendation given above, implantation of LVAD could temporarily stabilize patient hemodynamically, as well as improve reverse remodeling. LVAD is a battery-operated mechanical pump, which takes the blood from failed LV and pumps it to the aorta to be transmitted to the rest of the body (**Figure 4**). There are not many heart failure patients with LVAD. However, the management of VT in this patient population requires mention since it is somewhat different than HF patients without LVAD. LVAD may be able to continue maintaining cardiac output in spite of sustained VT, and most of the LVAD patients have ICD in place. When such patients present to the emergency department, first patient hemodynamic status should be assessed. If the blood pressure checked by Doppler ultrasonography is okay, it is reasonable to transfer the patient to a tertiary center where there is LVAD specialist and electrophysiologist. If there is hemodynamic compromise, then the patient should be immediately converted to normal sinus rhythm with electrical shock [53]. If the patient is a candidate neither for transplantation nor LVAD, end-of-life care should be applied for palliation. Shared decision making with the patient and relatives should be done, and discussion regarding measures such as ICD deactivation may be applied in these patients.

#### **Figure 4.**

*A schematic representation of a left ventricle assist device (LVAD) showing battery-operated mechanical pump taking blood from left ventricle and pumping it to aorta.*

VT storm is a medical emergency requiring prompt intervention. Reversible causes of VT, such as hypokalemia, hypomagnesemia, ischemia, and hypoxia should be sought and corrected where applicable. Beta blocker dose should be uptitrated to decrease the sympathetic tone. Another intervention to reduce sympathetic drive is sedation. Radiofrequency catheter ablation has been shown to be effective in controlling VT storm [54].

#### **6. Conclusion**

Ventricular tachycardia is a frequent event in HF population and is one of the poor prognostic factors related with HF. Management of VT is important because it is associated with SCD which is the responsible cause of death in 50% of patients with HF. Optimization of guideline-directed treatment is the most important step to prevent occurrence of VT in these patients. ICD has resulted marked improvement in survival of patients with HF and VT. However, repetitive ICD shocks due to recurrent VT poses a great problem and decreases survival. Antiarrhythmic therapy and VT ablation generally offer a complementary treatment in patients with ICD. Patients with VT who have failed standard therapy (antiarrhythmic therapy and catheter ablation) have limited options, with one-year survival below 20%. Autonomic modulation procedures and stereotactic body radiation therapy could be applied in patients with refractory VT. Patients with recurrent VT despite all other measures should be referred to tertiary centers where they are evaluated in respect of indications for LVAD implantation and transplantation.

#### **Author details**

Hakan Altay Baskent University, Faculty of Medicine, Istanbul Hospital, Turkey

\*Address all correspondence to: sakaltay@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. 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.

**85**

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

[1] Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from nearfatal ventricular arrhythmias. NEJM.

prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;**15**(10):e190-e252. DOI: 10.1016/j. hrthm.2017.10.035. Epub 2017 Oct 30

[9] Tisdale JE, Patel R, Webb CR, Borzak S, Zarowitz BJ. Electrophysiologic and prodysrhythmic effects of intravenous inotropic agents. Progress in Cardiovascular Diseases.

[10] Nakahara S, Chien C, Gelow J, et al. Ventricular dysrhythmias after left ventricular assist device. Circulation: Arrhythmia and Electrophysiology.

[11] Yalagudri S, Zin Thu N, Devidutta S, Saggu D, Thachil A, Chennapragada S, et al. Tailored approach for management of ventricular tachycardia in cardiac sarcoidosis. Journal of Cardiovascular Electrophysiology. 2017;**28**(8):893-902.

[12] Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace. 2015;**17**(11):1601-1687. DOI: 10.1093/europace/euv319. Epub

1995;**38**:167-180

2013;**6**:648-654

DOI: 10.1111/jce.13228

2015 Aug 29

[2] Chan MM, Lam CS. How do patients with heart failure with preserved ejection fraction die? European Journal of Heart Failure. 2013;**15**:604-613

[4] Kunz R, Burnand B, Schünemann HJ, et al. Das GRADE-system. Der Internist.

[5] Klein L, Hsia H. Sudden cardiac death in heart failure. Cardiology

[6] Smer A, Saurav A, Azzouz MS, Salih M, Ayan M, Abuzaid A, et al. Meta-analysis of risk of ventricular arrhythmias after improvement in left ventricular ejection fraction during follow-up in patients with primary prevention implantable cardioverter defibrillators. The American Journal of Cardiology. 2017;**120**(2):279-286. DOI: 10.1016/j.amjcard.2017.04.020. Epub

[7] Baldinger SH, Stevenson WG, John RM. Ablation of ischemic ventricular tachycardia: Evidence, techniques, results, and future directions. Current Opinion in Cardiology. 2016;**31**:29-36

[8] Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the

[3] Moss AJ, Greenberg H, Case RB, et al. Long-term clinical course of patients after termination of ven-tricular tachyarrhythmia by an implanted defibrillator. Circulation.

2004;**110**(25):3760-3765

Clinics. 2014;**32**:135-144

2008;**49**:673-680

2017 Apr 27

1997;**337**:1576-1583

**References**

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

#### **References**

*Practical Applications of Electrocardiogram*

effective in controlling VT storm [54].

**6. Conclusion**

VT storm is a medical emergency requiring prompt intervention. Reversible causes of VT, such as hypokalemia, hypomagnesemia, ischemia, and hypoxia should be sought and corrected where applicable. Beta blocker dose should be uptitrated to decrease the sympathetic tone. Another intervention to reduce sympathetic drive is sedation. Radiofrequency catheter ablation has been shown to be

Ventricular tachycardia is a frequent event in HF population and is one of the poor prognostic factors related with HF. Management of VT is important because it is associated with SCD which is the responsible cause of death in 50% of patients with HF. Optimization of guideline-directed treatment is the most important step to prevent occurrence of VT in these patients. ICD has resulted marked improvement in survival of patients with HF and VT. However, repetitive ICD shocks due to recurrent VT poses a great problem and decreases survival. Antiarrhythmic therapy and VT ablation generally offer a complementary treatment in patients with ICD. Patients with VT who have failed standard therapy (antiarrhythmic therapy and catheter ablation) have limited options, with one-year survival below 20%. Autonomic modulation procedures and stereotactic body radiation therapy could be applied in patients with refractory VT. Patients with recurrent VT despite all other measures should be referred to tertiary centers where they are evaluated in respect

**84**

**Author details**

Hakan Altay

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. 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,

Baskent University, Faculty of Medicine, Istanbul Hospital, Turkey

\*Address all correspondence to: sakaltay@yahoo.com

of indications for LVAD implantation and transplantation.

[1] Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from nearfatal ventricular arrhythmias. NEJM. 1997;**337**:1576-1583

[2] Chan MM, Lam CS. How do patients with heart failure with preserved ejection fraction die? European Journal of Heart Failure. 2013;**15**:604-613

[3] Moss AJ, Greenberg H, Case RB, et al. Long-term clinical course of patients after termination of ven-tricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;**110**(25):3760-3765

[4] Kunz R, Burnand B, Schünemann HJ, et al. Das GRADE-system. Der Internist. 2008;**49**:673-680

[5] Klein L, Hsia H. Sudden cardiac death in heart failure. Cardiology Clinics. 2014;**32**:135-144

[6] Smer A, Saurav A, Azzouz MS, Salih M, Ayan M, Abuzaid A, et al. Meta-analysis of risk of ventricular arrhythmias after improvement in left ventricular ejection fraction during follow-up in patients with primary prevention implantable cardioverter defibrillators. The American Journal of Cardiology. 2017;**120**(2):279-286. DOI: 10.1016/j.amjcard.2017.04.020. Epub 2017 Apr 27

[7] Baldinger SH, Stevenson WG, John RM. Ablation of ischemic ventricular tachycardia: Evidence, techniques, results, and future directions. Current Opinion in Cardiology. 2016;**31**:29-36

[8] Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the

prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;**15**(10):e190-e252. DOI: 10.1016/j. hrthm.2017.10.035. Epub 2017 Oct 30

[9] Tisdale JE, Patel R, Webb CR, Borzak S, Zarowitz BJ. Electrophysiologic and prodysrhythmic effects of intravenous inotropic agents. Progress in Cardiovascular Diseases. 1995;**38**:167-180

[10] Nakahara S, Chien C, Gelow J, et al. Ventricular dysrhythmias after left ventricular assist device. Circulation: Arrhythmia and Electrophysiology. 2013;**6**:648-654

[11] Yalagudri S, Zin Thu N, Devidutta S, Saggu D, Thachil A, Chennapragada S, et al. Tailored approach for management of ventricular tachycardia in cardiac sarcoidosis. Journal of Cardiovascular Electrophysiology. 2017;**28**(8):893-902. DOI: 10.1111/jce.13228

[12] Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace. 2015;**17**(11):1601-1687. DOI: 10.1093/europace/euv319. Epub 2015 Aug 29

[13] Al-Gobari M, El Khatib C, Pillon F, Gueyffier F. β-Blockers for the prevention of sudden cardiac death in heart failure patients: a meta-analysis of randomized controlled trials. BMC Cardiovascular Disorders. 2013;**13**(52):1-9. DOI: 10.1186/1471-2261-13-52

[14] Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Epub 2003 Mar 31. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The New England Journal of Medicine. 2003;**348**(14):1309-1321

[15] Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. The New England Journal of Medicine. 2002;**346**:877-883

[16] Peck KY, Lim YZ, Hopper I, Krum H. Medical therapy versus implantable cardioverter-defibrillator in preventing sudden cardiac death in patients with left ventricular systolic dysfunction and heart failure: A meta-analysis of >35,000 patients. International Journal of Cardiology. 2014;**173**(2):197-203. DOI: 10.1016/j.ijcard.2014.02.014. Epub 2014 Feb 22

[17] Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. The New England Journal of Medicine. 2011;**364**:11-21

[18] McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England Journal of Medicine. 2014;**371**:993-1004

[19] Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.

Authors/task force members; document reviewers.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure. 2016;**18**(8):891-975. DOI: 10.1002/ejhf.592. Epub 2016 May 20

[20] Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The New England Journal of Medicine. 1989;**321**:406-412

[21] Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Sudden cardiac death in heart failure trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. The New England Journal of Medicine. 2005;**352**:225-237. DOI: 10.1056/ NEJMoa043399

[22] Piccini JP, Berger JS, O'Connor CM. Amiodarone for the prevention of sudden cardiac death: a meta-analysis of randomized controlled trials. European Heart Journal. 2009;**30**:1245-1253

[23] Bokhari F, Newman D, Greene M, Ko-rley V, Mangat I, Dorian P. Longterm comparison of the implantable cardioverter defibrillator versus amiodarone: Eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS). Circulation. 2004;**110**:112-116

[24] Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD

**87**

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

Investigators. Survival With Oral d-Sotalol. Lancet. 1996;**348**:7-12

[26] Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation.

[27] Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiar-rhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. European Heart Journal. 2000;**21**: 2071-2078. DOI: 10.1053/euhj.2000.2476

[28] Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Multicenter automatic defibrillator implantation trial II investigators. Prophylactic implantation of a

NEJMoa013474

defibrillator in patients with myocardial infarction and reduced ejection fraction. The New England Journal of Medicine. 2002;**346**:877-883. DOI: 10.1056/

[29] Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, et al. Defibrillators in non-ischemic cardiomy-opathy treatment evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated. NEJM.

2004;**350**(21):2151-2158

[30] Sweeney MO, Sherfesee L, DeGroot PJ, Wathen MS, Wilkoff

2000;**356**:2052-2058

1978;**58**(6):986-997

[25] Kober L, Bloch Thomsen PE, Moller M, Torp-Pedersen C, Carlsen J, Sandoe E, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: A randomised trial. Lancet.

BL. Differences in effects of

arrhythmias on mortality in

electrical therapy type for ventricular

implantable cardioverter-defibrillator patients. Heart Rhythm. 2010;**7**:353- 360. DOI: 10.1016/j. hrthm.2009.11.027

[31] Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger

L, et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial ex- tension phase]. European Heart Journal.

[32] Sapp JL, Parkash R, Wells GA, Yetisir E, Gardner MJ, Healey JS, et al. Cardiac resynchronization therapy reduces ven-tricular arrhythmias in primary but not secondary prophylactic implantable cardioverter defibrillator patients: Insight from the resynchronization in ambulatory heart failure trial. Circulation. Arrhythmia and Electrophysiology. 2017;**10**. pii:

[33] Muresan L, Cismaru G, Martins RP, Bataglia A, Rosu R, Puiu M, et al. Recommendations for the use of electrophysiological study: Update 2018. Hellenic Journal of Cardiology. 2018S;**1109- 9666**(18)30352-X:1-19. DOI: 10.1016/j.

[34] Pagé PL, Cardinal R, Shenasa M, Kaltenbrunner W, Cossette R, Nadeau R. Surgical treatment of ventricular tachycardia. Regional cryoablation guided by computerized epicardial and endocardial mapping. Circulation.

[35] Dinov B, Fiedler L, Schönbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy in comparison to ischemic cardiomyopathy: Results from the Prospective HEart Centre of LeiPzig VT (HELP-VT) Study. Circulation. 2014;**129**:728-736

2006;**27**:1928-1932

004875

hjc.2018.09.002

1989;**80**(3 Pt 1):I124-I134

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

Investigators. Survival With Oral d-Sotalol. Lancet. 1996;**348**:7-12

*Practical Applications of Electrocardiogram*

Authors/task force members; document reviewers.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure. 2016;**18**(8):891-975. DOI: 10.1002/ejhf.592. Epub 2016 May 20

[20] Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary

flecainide on mortality in a randomized

[21] Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Sudden cardiac death in heart failure trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. The New England Journal of Medicine. 2005;**352**:225-237. DOI: 10.1056/

[22] Piccini JP, Berger JS, O'Connor CM. Amiodarone for the prevention of sudden cardiac death: a meta-analysis of randomized controlled trials. European Heart Journal. 2009;**30**:1245-1253

[23] Bokhari F, Newman D, Greene M, Ko-rley V, Mangat I, Dorian P. Longterm comparison of the implantable cardioverter defibrillator versus amiodarone: Eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS).

Circulation. 2004;**110**:112-116

[24] Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD

report: effect of encainide and

trial of arrhythmia suppression after myocardial infarction. The New England Journal of Medicine.

1989;**321**:406-412

NEJMoa043399

[13] Al-Gobari M, El Khatib C, Pillon F, Gueyffier F. β-Blockers for the prevention of sudden cardiac death in heart failure patients: a meta-analysis of randomized controlled trials. BMC Cardiovascular Disorders. 2013;**13**(52):1-9. DOI:

10.1186/1471-2261-13-52

[14] Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Epub 2003 Mar 31. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The New England Journal of Medicine. 2003;**348**(14):1309-1321

[15] Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. The New England Journal of Medicine.

[16] Peck KY, Lim YZ, Hopper I, Krum H. Medical therapy versus implantable cardioverter-defibrillator in preventing sudden cardiac death in patients with left ventricular systolic dysfunction and heart failure: A meta-analysis of >35,000 patients. International Journal of Cardiology. 2014;**173**(2):197-203. DOI: 10.1016/j.ijcard.2014.02.014. Epub

[17] Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. The New England Journal of

[18] McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England Journal of Medicine.

[19] Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.

Medicine. 2011;**364**:11-21

2014;**371**:993-1004

2002;**346**:877-883

2014 Feb 22

**86**

[25] Kober L, Bloch Thomsen PE, Moller M, Torp-Pedersen C, Carlsen J, Sandoe E, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: A randomised trial. Lancet. 2000;**356**:2052-2058

[26] Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation. 1978;**58**(6):986-997

[27] Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiar-rhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. European Heart Journal. 2000;**21**: 2071-2078. DOI: 10.1053/euhj.2000.2476

[28] Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Multicenter automatic defibrillator implantation trial II investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. The New England Journal of Medicine. 2002;**346**:877-883. DOI: 10.1056/ NEJMoa013474

[29] Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, et al. Defibrillators in non-ischemic cardiomy-opathy treatment evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated. NEJM. 2004;**350**(21):2151-2158

[30] Sweeney MO, Sherfesee L, DeGroot PJ, Wathen MS, Wilkoff BL. Differences in effects of electrical therapy type for ventricular arrhythmias on mortality in implantable cardioverter-defibrillator patients. Heart Rhythm. 2010;**7**:353- 360. DOI: 10.1016/j. hrthm.2009.11.027

[31] Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial ex- tension phase]. European Heart Journal. 2006;**27**:1928-1932

[32] Sapp JL, Parkash R, Wells GA, Yetisir E, Gardner MJ, Healey JS, et al. Cardiac resynchronization therapy reduces ven-tricular arrhythmias in primary but not secondary prophylactic implantable cardioverter defibrillator patients: Insight from the resynchronization in ambulatory heart failure trial. Circulation. Arrhythmia and Electrophysiology. 2017;**10**. pii: 004875

[33] Muresan L, Cismaru G, Martins RP, Bataglia A, Rosu R, Puiu M, et al. Recommendations for the use of electrophysiological study: Update 2018. Hellenic Journal of Cardiology. 2018S;**1109- 9666**(18)30352-X:1-19. DOI: 10.1016/j. hjc.2018.09.002

[34] Pagé PL, Cardinal R, Shenasa M, Kaltenbrunner W, Cossette R, Nadeau R. Surgical treatment of ventricular tachycardia. Regional cryoablation guided by computerized epicardial and endocardial mapping. Circulation. 1989;**80**(3 Pt 1):I124-I134

[35] Dinov B, Fiedler L, Schönbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy in comparison to ischemic cardiomyopathy: Results from the Prospective HEart Centre of LeiPzig VT (HELP-VT) Study. Circulation. 2014;**129**:728-736

[36] Della Bella P, Trevisi N. Catheter ablation of ventricular tachycardia in nonischemic dilated cardiomyopathy: A difficult field where we should focus our efforts. Circulation. Arrhythmia and Electrophysiology 2016;**9**(10). pii: e004649

[37] Kanagaratnam L, Tomassoni G, Schweikert R, Pavia S, Bash D, Beheiry S, et al. Ventricular tachycardias arising from the aortic sinus of valsalva: An under-recognized variant of left outflow tract ventricular tachycardia. Journal of the American College of Cardiology. 2001;**37**(5):1408-1414

[38] Fragakis N, Karamitsos TD, Vassilikos V. Successful catheter ablation of an incessant ventricular tachycardia originating from the posterior papillary muscle in a structurally normal right ventricle. Hellenic Journal of Cardiology. 2016;**57**:286-288

[39] Saguner AM, Medeiros-Domingo A, Schwyzer MA, On CJ, Haegeli LM, Wolber T, et al. Usefulness of inducible ventricular tachycardia to predict long-term adverse outcomes in arrhythmogenic right ventricular cardiomyopathy. The American Journal of Cardiology. 2013;**111**(2):250-257. DOI: 10.1016/j. amjcard.2012.09.025

[40] Lim KK, Maron BJ, Knight BP. Successful catheter ablation of hemodynamically unstable monomorphic ventricular tachycardia in a patient with hypertrophic cardiomyopathy and apical aneurysm. Journal of Cardiovascular Electrophysiology. 2009;**20**(4):445-447. DOI: 10.1111/j.1540-8167.2008.01366.x

[41] Antangeli P, Muser D, Maeda S, et al. Comparitive effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis

of randomized contolled trials. Heart Rhythm. 2016;**13**:1552-1559. DOI: 10.1016/j. hrthm.2016.03.004. PMID: 26961297

[42] Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: The optic study: A randomized trial. JAMA. 2006;**295**:165-171

[43] Gao D, Van Herendael H, Alshengeiti L, et al. Mexiletine as an adjunctive therapy to amiodarone reduces the frequency of ventricular tachyarrhythmia events in patients with an implantable defibrillator. Journal of Cardiovascular Pharmacology. 2013;**62**:199-204. DOI: 10.1097/ FJC.0b013e31829651fe. PMID: 23609328

[44] Bunch TJ, Mahapatra S, Murdock D, Molden J, Weiss JP, May HT, et al. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing and Clinical Electrophysiology. 2011;**34**:1600-1606

[45] Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. The New England Journal of Medicine. 2007;**357**:2657-2665. DOI: 10.1056/ NEJMoa065457. PMID: 18160685

[46] Kuck KH, Schaumann A, Eckhardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): A multicentre randomised controlled trial. Lancet. 2010;**375**:31-40. DOI: 10.1111/jce.12073. PMID: 23350967

[47] Sapp JL, Wells GA, Parkash R, Stevenson WG, Blier L, Sarrazin JF, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. The New England Journal of Medicine. 2016;**375**(2):111-121

**89**

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

[48] Yancy CW, Januzzi JL Jr, Allen LA, Butler J, Davis LL, Fonarow GC, et al. 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: Answers to 10 pivotal issues about heart failure with reduced ejection fraction: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. Journal of the American College of Cardiology. 2018;**71**(2): 201-230. DOI: 10.1016/j.jacc.2017.11.025. [54] Carbucicchio C, Santamaria M, Trevisi N, Maccabelli G, Giraldi F, Fassini G, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverterdefibrillators: Short and long-term outcomes in a prospective single-center study. Circulation. 2008;**117**:462-469

[49] Vaseghi M, Barwad P, Malavassi Corales FJ, et al. Cardiac sympathetic denervation for refractory ventricular arrhythmias. Journal of the American College of Cardiology. 2017;**69**: 3070-3080. DOI: 10.1016/j. jacc.2017.04.035. PMID: 28641796

[50] Bradfield JS, Ajijola OA, Vaseghi M, et al. Mechanisms and management of refractory ventricular arrhythmias in the age of autonomic modulation. Heart Rhythm. 2018;**15**:1252-1260. DOI: 10.1016/j.hrthm.2018.02.015. PMID:

[51] Cuculich PS, Schill MR, Kashaniand R, et al. Noninvasive cardiac radiation for ablation of ventricular tachycardia. The New England Journal of Medicine. 2017;**377**:2325-2336. (Abstract)

[52] Robinson CG, Samson PP, Moore KMS, Hugo GD, Knutson N, Mutic S, et al. Phase I/II trial of electrophysiology-guided

2019;**139**(3):313-321

2016;**50**(3):e135-e141

[53] Fitzgibbon J, Kman NE,

noninvasive cardiac radioablation for ventricular tachycardia. Circulation.

Gorgas D. Asymptomatic sustained polymorphic ventricular tachycardia in a patient with a left ventricular assist device: Case report and what the emergency physician should know. The Journal of Emergency Medicine.

Epub 2017 Dec 22

29454137

*Ventricular Tachycardia and Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.85256*

*Practical Applications of Electrocardiogram*

[36] Della Bella P, Trevisi N. Catheter ablation of ventricular tachycardia in nonischemic dilated cardiomyopathy: A difficult field where we should focus our efforts. Circulation. Arrhythmia and Electrophysiology 2016;**9**(10). pii:

of randomized contolled trials. Heart Rhythm. 2016;**13**:1552-1559. DOI: 10.1016/j. hrthm.2016.03.004. PMID:

[42] Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: The optic study: A randomized trial.

FJC.0b013e31829651fe. PMID: 23609328

[44] Bunch TJ, Mahapatra S, Murdock D, Molden J, Weiss JP, May HT, et al. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing and Clinical Electrophysiology. 2011;**34**:1600-1606

[45] Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. The New England Journal of Medicine. 2007;**357**:2657-2665. DOI: 10.1056/ NEJMoa065457. PMID: 18160685

[46] Kuck KH, Schaumann A, Eckhardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): A multicentre randomised controlled trial. Lancet. 2010;**375**:31-40. DOI: 10.1111/jce.12073. PMID: 23350967

[47] Sapp JL, Wells GA, Parkash R, Stevenson WG, Blier L, Sarrazin JF, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. The New England Journal of Medicine. 2016;**375**(2):111-121

JAMA. 2006;**295**:165-171

[43] Gao D, Van Herendael H, Alshengeiti L, et al. Mexiletine as an adjunctive therapy to amiodarone reduces the frequency of ventricular tachyarrhythmia events in patients with an implantable defibrillator. Journal of Cardiovascular Pharmacology. 2013;**62**:199-204. DOI: 10.1097/

26961297

[37] Kanagaratnam L, Tomassoni G, Schweikert R, Pavia S, Bash D, Beheiry S, et al. Ventricular tachycardias arising from the aortic sinus of valsalva: An under-recognized variant of left outflow tract ventricular tachycardia. Journal of the American College of Cardiology.

2001;**37**(5):1408-1414

amjcard.2012.09.025

[40] Lim KK, Maron BJ, Knight BP. Successful catheter ablation of hemodynamically unstable

in a patient with hypertrophic cardiomyopathy and apical

monomorphic ventricular tachycardia

aneurysm. Journal of Cardiovascular Electrophysiology. 2009;**20**(4):445-447. DOI: 10.1111/j.1540-8167.2008.01366.x

[41] Antangeli P, Muser D, Maeda S, et al. Comparitive effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis

[38] Fragakis N, Karamitsos TD,

muscle in a structurally normal right ventricle. Hellenic Journal of Cardiology. 2016;**57**:286-288

Vassilikos V. Successful catheter ablation of an incessant ventricular tachycardia originating from the posterior papillary

[39] Saguner AM, Medeiros-Domingo A, Schwyzer MA, On CJ, Haegeli LM, Wolber T, et al. Usefulness of inducible ventricular tachycardia to predict long-term adverse outcomes in arrhythmogenic right ventricular cardiomyopathy. The American Journal of Cardiology. 2013;**111**(2):250-257. DOI: 10.1016/j.

e004649

**88**

[48] Yancy CW, Januzzi JL Jr, Allen LA, Butler J, Davis LL, Fonarow GC, et al. 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: Answers to 10 pivotal issues about heart failure with reduced ejection fraction: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. Journal of the American College of Cardiology. 2018;**71**(2): 201-230. DOI: 10.1016/j.jacc.2017.11.025. Epub 2017 Dec 22

[49] Vaseghi M, Barwad P, Malavassi Corales FJ, et al. Cardiac sympathetic denervation for refractory ventricular arrhythmias. Journal of the American College of Cardiology. 2017;**69**: 3070-3080. DOI: 10.1016/j. jacc.2017.04.035. PMID: 28641796

[50] Bradfield JS, Ajijola OA, Vaseghi M, et al. Mechanisms and management of refractory ventricular arrhythmias in the age of autonomic modulation. Heart Rhythm. 2018;**15**:1252-1260. DOI: 10.1016/j.hrthm.2018.02.015. PMID: 29454137

[51] Cuculich PS, Schill MR, Kashaniand R, et al. Noninvasive cardiac radiation for ablation of ventricular tachycardia. The New England Journal of Medicine. 2017;**377**:2325-2336. (Abstract)

[52] Robinson CG, Samson PP, Moore KMS, Hugo GD, Knutson N, Mutic S, et al. Phase I/II trial of electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia. Circulation. 2019;**139**(3):313-321

[53] Fitzgibbon J, Kman NE, Gorgas D. Asymptomatic sustained polymorphic ventricular tachycardia in a patient with a left ventricular assist device: Case report and what the emergency physician should know. The Journal of Emergency Medicine. 2016;**50**(3):e135-e141

[54] Carbucicchio C, Santamaria M, Trevisi N, Maccabelli G, Giraldi F, Fassini G, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverterdefibrillators: Short and long-term outcomes in a prospective single-center study. Circulation. 2008;**117**:462-469

**91**

**Chapter 6**

**Abstract**

*Nevra Alkanli and Arzu Ay*

the diagnosis of the disease.

**1. Introduction**

Genetic Polymorphisms that

Playing Role in Development of

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a complex heart disease with various physiopathological, morphological, functional, and clinical features. In this disease, HCM is known to be an autosomal genetic disease in more than half of the cases. Mutations in sarcomeric genes are thought to play an important role in the pathogenesis of the disease. Modifying genes and environmental factors also together affect the phenotypic expression and severity of HCM. The phenotypic expression of HCM is determined by causal sarcomeric gene mutations and the regulatory genetic basis of genes. HCM, a multi-factorial disease, involves the effects of many environmental gene modifiers and the sarcomeric/cytoskeletal genes. The single nucleotide polymorphisms occurring in the human genome differ in terms of susceptibility to disease in various populations. Therefore, the determination of genetic polymorphisms involved in the development of HCM disease is very important for

**Keywords:** hypertrophic cardiomyopathy, gene polymorphisms, LVH, PCR

HCM is a complex cardiac disease with major clinical heterogeneity and diagnostic and prognostic effects specific to each mutation. At the same time, this disease has different physiopathological, morphological, functional, and clinical features. HCM, with left ventricular hypertrophy (LVH), is a primary cardiac disorder and occurs when there is no cardiac or systemic disease. Throughout life, it is known that it has a clinical course ranging from symptomatic patients to heart failure symptoms and sudden deaths. It is an autosomal dominant genetic disease in more than half of cases, but it still does not have a fully defined etiology [1]. Modifying genes and environmental factors play an important role in the pathogenesis of HCM. Phenotypic expression and the formation of cardiovascular events are affected by means of these factors [2]. The cardiac β-myosin heavy chain (MYHC) gene, cardiac troponin T (cTnT) gene, α-tropomyosin gene, myosinbinding protein C (MYBP-C) gene, cardiac troponin I gene, and regulatory and essential myosin light chain genes are found among genes encoding the proteins of sarcomere [1]. These genes encoding sarcomeric proteins are localized on different chromosomes. It is known that the first gene identified from these genes is the βMYHC gene encoding the major contractile protein. In HCM patients, due to

#### **Chapter 6**

## Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy

*Nevra Alkanli and Arzu Ay*

#### **Abstract**

Hypertrophic cardiomyopathy (HCM) is a complex heart disease with various physiopathological, morphological, functional, and clinical features. In this disease, HCM is known to be an autosomal genetic disease in more than half of the cases. Mutations in sarcomeric genes are thought to play an important role in the pathogenesis of the disease. Modifying genes and environmental factors also together affect the phenotypic expression and severity of HCM. The phenotypic expression of HCM is determined by causal sarcomeric gene mutations and the regulatory genetic basis of genes. HCM, a multi-factorial disease, involves the effects of many environmental gene modifiers and the sarcomeric/cytoskeletal genes. The single nucleotide polymorphisms occurring in the human genome differ in terms of susceptibility to disease in various populations. Therefore, the determination of genetic polymorphisms involved in the development of HCM disease is very important for the diagnosis of the disease.

**Keywords:** hypertrophic cardiomyopathy, gene polymorphisms, LVH, PCR

#### **1. Introduction**

HCM is a complex cardiac disease with major clinical heterogeneity and diagnostic and prognostic effects specific to each mutation. At the same time, this disease has different physiopathological, morphological, functional, and clinical features. HCM, with left ventricular hypertrophy (LVH), is a primary cardiac disorder and occurs when there is no cardiac or systemic disease. Throughout life, it is known that it has a clinical course ranging from symptomatic patients to heart failure symptoms and sudden deaths. It is an autosomal dominant genetic disease in more than half of cases, but it still does not have a fully defined etiology [1]. Modifying genes and environmental factors play an important role in the pathogenesis of HCM. Phenotypic expression and the formation of cardiovascular events are affected by means of these factors [2]. The cardiac β-myosin heavy chain (MYHC) gene, cardiac troponin T (cTnT) gene, α-tropomyosin gene, myosinbinding protein C (MYBP-C) gene, cardiac troponin I gene, and regulatory and essential myosin light chain genes are found among genes encoding the proteins of sarcomere [1]. These genes encoding sarcomeric proteins are localized on different chromosomes. It is known that the first gene identified from these genes is the βMYHC gene encoding the major contractile protein. In HCM patients, due to

defects in sarcomeric proteins, mutations such as MYBP-C, α-tropomyosin, cTnT, ventricular myosin essential and regulatory light chains, cardiac troponin I, and cardiac α-actin and titin have been described. This disease, known to be caused by the defects in sarcomeric proteins, is called sarcomere disease [3]. In addition to mutations in sarcomeric and non-sarcomeric genes, many other gene mutations also lead to metabolic disorders with similar phenotypes in HCM [4]. So far, more than 1400 mutations have been identified in many genes, and the most important genes of these mutations have been identified to encode the protein components of cardiac sarcomere that perform contractile, structural, and regulatory functions [5]. The purpose of this chapter, in addition to giving general information about HCM, is to summarize the studies that investigated the relationship between gene polymorphisms that play a role in the development of HCM and the risk of developing HCM.

#### **2. Hypertrophic cardiomyopathy**

HCM, a cardiac disease, is characterized by marked hypertrophy and genetic variability. It is known as a disease characterized by LVH which may cause primary or systemic hypertrophy when there is no other disease [6]. LVH, known as a physiological adaptation to increased workload of the heart, usually develops in clinical conditions such as hypertension, valvular disease, and myocardial infarction. In some patients, cardiac hypertrophy develops when there are no clinical conditions causing cardiac overload. This condition is considered to be the basic form of LVH, and it is thought that this form, which is frequently familial, is caused by mutations in sarcomeric genes. This form of the most common hereditary heart disease is defined as HCM [7]. HCM is one of the leading causes of sudden deaths in young people and athletes. One person in 500 people worldwide is affected by this disease [6]. HCM is a common heterogeneous disease with high morbidity and mortality in the elderly, and it is characterized by enlarged heart, abnormally thickened left ventricular walls, and reduced chamber capacity [8]. Histologically, in this disease, characterized by left ventricular thickness resulting from cardiomyocyte hypertrophy, cardiomyocytes lose their cleavage ability in the first week after birth. Thus, cardiomyocyte hypertrophy is effective instead of cardiomyocyte proliferation in postnatal growth of the heart. Postpartum cardiac growth is a physiological response of myocardium to stress signals as well as its role in cardiomyocyte hypertrophy. It is known that the response of cardiomyocytes to stress signals is characterized by reactivation of fetal gene program [4]. This disease is thought to be caused by contractile proteins encoding genes that cause contractile dysfunction and then hypertrophy. Familial HCM, defined as an autosomal dominant disorder, is usually disseminated by incomplete penetrance due to heterozygous pathogenic gene mutations [8]. HCM is a genetically transmitted, cardiovascular disease with heterogeneous clinical features. Sudden cardiac death in HCM occurs as a frequent complication of 2–3% per year. HCM can be seen form of autosomal dominant feature as a familial disorder; on the other, it can also occur as a sporadic disease that may develop due to novo mutations. These familial and sporadic forms represent different parts of the same spectrum. According to phenotypic models, HCM phenotypes, asymmetric septal hypertrophy (ASH), apical hypertrophy (AH), diffuse hypertrophy (DH), and left ventricular free wall hypertrophy (FH) are classified as. The etiology of the disease is multifactorial, and the majority of cases occur due to secondary mutations in sarcomere myofilament genes. The sarcomere myofilament genes are genes that contribute to heterogeneity in the phenotype of the disease. HCM has a

**93**

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

wide familial variability ranging from severe symptomatic individuals to asymptomatic individuals [4]. Cardiac phenotype and variability in clinical course not only depend on pathogenic genes but also depend on environmental factors [3]. Important information can be obtained in terms of prognosis and treatment of the disease through the identification of these environmental and genetic

Mutations in cardiac β-myosin encoded by the MYH7 gene and myosin-binding protein C sarcomere proteins encoded by MYBC3 gene have been associated with the development of HCM disease. Mutations in these genes are responsible for 50–70% of HCM's genetic cases. β-myosin is a large protein containing 1935 amino acids and is localized on chromosome 14 (14q11) in human. During muscle contraction 2q13 interacts with the thin filament, and this gene consists of 40 exons. The MYBP-C gene is also localized on chromosome 11 (11p.11.2), and 14 mutations have been identified in this gene so far. It has been reported that four of these mutations to be caused by nucleotide changes and eight of which by truncated mutations. The most important feature of these mutations is moderate hypertrophy and low penetration until a certain period of life. About 40 mutations have been identified in β-MYHC that may cause disease, and it is known that most of these mutations occur as a result of the translocation of DNA nucleotides. Displacement in nucleotides also causes amino acid changes in the protein sequence. This change is particularly observed in the familial form of HCM. Among these 40 mutations, there are mutations with high, medium, and low sudden death risks. Arg403Gln, Arg453Cys, and Arg719Gln mutations are known to be malignant. Arg403Gln-related phenotypes were observed in many families, and it is determined that these phenotypes were associated with high penetrance, high incidence of sudden death, and severe hypertrophy. Glu930Lys and Arg249Gln polymorphisms were associated with the middle risk of sudden death. However, Leu908Val, Gly256Glu, Val606Met, and Fhe513Cys polymorphisms have been reported to be associated with benign prognostic and normal survival. Myosin, a hexameric protein, consists of two heavy and two light chains. Light chains contain two light chains as the regulatory light chain (RLC) and the basic light chain (ELC). The myosin heavy chain is also divided into three parts as the lower part 1 (S1), the lower part 2 (S2), and the light meromyosin (LMM). Regulatory and essential myosin light chains were first found in 1996. The regulatory MYL2 gene is localized on chromosome 12 (12q23-q24.3). The essential gene is localized on chromosome 3 (3p) [1]. A large number of mutations have been identified in most S1 and S2 regions, which are associated with HCM in the MYH7 gene. The frequency of these mutations is variable and is known to be associated with marked hypertrophy. MYH7 and MYBPC3 genes are responsible for about 70% of genotyped HCM cases. Mutations in the MYH7 gene are missense mutations and localized at the head of globular myosin. The MYH7 gene is also known to be associated with dilated cardiomyopathy, and a large number of mutations have been identified in the rod region of the gene. There are many studies that demonstrate a relationship between mutations in the MYH7 gene and the family history of HCM. Studies to investigate MYH7 mutations have generally been limited by the analysis of regions encoding the head and neck domains of βMYHC. However, it is

*DOI: http://dx.doi.org/10.5772/intechopen.83473*

**3. Genetic polymorphisms**

**3.1 Sarcomeric gene polymorphisms**

*3.1.1 βMYHC versus MYBP-C gene polymorphisms*

factors [4].

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83473*

wide familial variability ranging from severe symptomatic individuals to asymptomatic individuals [4]. Cardiac phenotype and variability in clinical course not only depend on pathogenic genes but also depend on environmental factors [3]. Important information can be obtained in terms of prognosis and treatment of the disease through the identification of these environmental and genetic factors [4].

#### **3. Genetic polymorphisms**

*Practical Applications of Electrocardiogram*

**2. Hypertrophic cardiomyopathy**

ing HCM.

defects in sarcomeric proteins, mutations such as MYBP-C, α-tropomyosin, cTnT, ventricular myosin essential and regulatory light chains, cardiac troponin I, and cardiac α-actin and titin have been described. This disease, known to be caused by the defects in sarcomeric proteins, is called sarcomere disease [3]. In addition to mutations in sarcomeric and non-sarcomeric genes, many other gene mutations also lead to metabolic disorders with similar phenotypes in HCM [4]. So far, more than 1400 mutations have been identified in many genes, and the most important genes of these mutations have been identified to encode the protein components of cardiac sarcomere that perform contractile, structural, and regulatory functions [5]. The purpose of this chapter, in addition to giving general information about HCM, is to summarize the studies that investigated the relationship between gene polymorphisms that play a role in the development of HCM and the risk of develop-

HCM, a cardiac disease, is characterized by marked hypertrophy and genetic

variability. It is known as a disease characterized by LVH which may cause primary or systemic hypertrophy when there is no other disease [6]. LVH, known as a physiological adaptation to increased workload of the heart, usually develops in clinical conditions such as hypertension, valvular disease, and myocardial infarction. In some patients, cardiac hypertrophy develops when there are no clinical conditions causing cardiac overload. This condition is considered to be the basic form of LVH, and it is thought that this form, which is frequently familial, is caused by mutations in sarcomeric genes. This form of the most common hereditary heart disease is defined as HCM [7]. HCM is one of the leading causes of sudden deaths in young people and athletes. One person in 500 people worldwide is affected by this disease [6]. HCM is a common heterogeneous disease with high morbidity and mortality in the elderly, and it is characterized by enlarged heart, abnormally thickened left ventricular walls, and reduced chamber capacity [8]. Histologically, in this disease, characterized by left ventricular thickness resulting from cardiomyocyte hypertrophy, cardiomyocytes lose their cleavage ability in the first week after birth. Thus, cardiomyocyte hypertrophy is effective instead of cardiomyocyte proliferation in postnatal growth of the heart. Postpartum cardiac growth is a physiological response of myocardium to stress signals as well as its role in cardiomyocyte hypertrophy. It is known that the response of cardiomyocytes to stress signals is characterized by reactivation of fetal gene program [4]. This disease is thought to be caused by contractile proteins encoding genes that cause contractile dysfunction and then hypertrophy. Familial HCM, defined as an autosomal dominant disorder, is usually disseminated by incomplete penetrance due to heterozygous pathogenic gene mutations [8]. HCM is a genetically transmitted, cardiovascular disease with heterogeneous clinical features. Sudden cardiac death in HCM occurs as a frequent complication of 2–3% per year. HCM can be seen form of autosomal dominant feature as a familial disorder; on the other, it can also occur as a sporadic disease that may develop due to novo mutations. These familial and sporadic forms represent different parts of the same spectrum. According to phenotypic models, HCM phenotypes, asymmetric septal hypertrophy (ASH), apical hypertrophy (AH), diffuse hypertrophy (DH), and left ventricular free wall hypertrophy (FH) are classified as. The etiology of the disease is multifactorial, and the majority of cases occur due to secondary mutations in sarcomere myofilament genes. The sarcomere myofilament genes are genes that contribute to heterogeneity in the phenotype of the disease. HCM has a

**92**

#### **3.1 Sarcomeric gene polymorphisms**

#### *3.1.1 βMYHC versus MYBP-C gene polymorphisms*

Mutations in cardiac β-myosin encoded by the MYH7 gene and myosin-binding protein C sarcomere proteins encoded by MYBC3 gene have been associated with the development of HCM disease. Mutations in these genes are responsible for 50–70% of HCM's genetic cases. β-myosin is a large protein containing 1935 amino acids and is localized on chromosome 14 (14q11) in human. During muscle contraction 2q13 interacts with the thin filament, and this gene consists of 40 exons. The MYBP-C gene is also localized on chromosome 11 (11p.11.2), and 14 mutations have been identified in this gene so far. It has been reported that four of these mutations to be caused by nucleotide changes and eight of which by truncated mutations. The most important feature of these mutations is moderate hypertrophy and low penetration until a certain period of life. About 40 mutations have been identified in β-MYHC that may cause disease, and it is known that most of these mutations occur as a result of the translocation of DNA nucleotides. Displacement in nucleotides also causes amino acid changes in the protein sequence. This change is particularly observed in the familial form of HCM. Among these 40 mutations, there are mutations with high, medium, and low sudden death risks. Arg403Gln, Arg453Cys, and Arg719Gln mutations are known to be malignant. Arg403Gln-related phenotypes were observed in many families, and it is determined that these phenotypes were associated with high penetrance, high incidence of sudden death, and severe hypertrophy. Glu930Lys and Arg249Gln polymorphisms were associated with the middle risk of sudden death. However, Leu908Val, Gly256Glu, Val606Met, and Fhe513Cys polymorphisms have been reported to be associated with benign prognostic and normal survival. Myosin, a hexameric protein, consists of two heavy and two light chains. Light chains contain two light chains as the regulatory light chain (RLC) and the basic light chain (ELC). The myosin heavy chain is also divided into three parts as the lower part 1 (S1), the lower part 2 (S2), and the light meromyosin (LMM). Regulatory and essential myosin light chains were first found in 1996. The regulatory MYL2 gene is localized on chromosome 12 (12q23-q24.3). The essential gene is localized on chromosome 3 (3p) [1]. A large number of mutations have been identified in most S1 and S2 regions, which are associated with HCM in the MYH7 gene. The frequency of these mutations is variable and is known to be associated with marked hypertrophy. MYH7 and MYBPC3 genes are responsible for about 70% of genotyped HCM cases. Mutations in the MYH7 gene are missense mutations and localized at the head of globular myosin. The MYH7 gene is also known to be associated with dilated cardiomyopathy, and a large number of mutations have been identified in the rod region of the gene. There are many studies that demonstrate a relationship between mutations in the MYH7 gene and the family history of HCM. Studies to investigate MYH7 mutations have generally been limited by the analysis of regions encoding the head and neck domains of βMYHC. However, it is

determined that mutations in the tail region of the protein may be related to the risk of developing HCM. Mutations in the MYH7 gene are known as a cause of HCM, and sudden death was significantly higher in the family history and in patients with severe left ventricular hypertrophy. In a previous study, four new mutations are identified. In some of these mutations, the relationship between genotype and phenotype is constant. There are significant differences between phenotypes in other mutations [9]. In a study conducted with the Venezuelan population, no missense mutation identified in the MYH7 gene was found. In the same study, the frequency of mutation of MYH7 gene in adult HCM patients was found to be low. In another study performed by Ronkaratti et al., in the Italian population, it is found that the frequency of mutations determined in the MYH7 gene was found to be very low. Many factors, such as modifying genes, epigenetic factors, microRNAs, posttranslational protein modifications, and environmental factors, may affect the clinical course of HCM disease [1, 10]. Genetic studies are required to understand the clinical and prognostic heterogeneity of HCM. The obtained information of clinical and morphological characteristics of different mutation carriers is important in terms of clinical decision-making in their genetic studies [9].

#### *3.1.2 Cardiac troponin T gene polymorphisms*

The cardiac troponin T gene is localized on chromosome 1 (1q3), and so far eight mutations have been identified in this gene. The most important feature of these mutations is that they cause hypertrophy and high incidence of sudden death in younger patients under 30 years of age [1].

#### *3.1.3 Alpha tropomyosin gene polymorphisms*

Alpha tropomyosin gene is localized on chromosome 15 (15q2), and two mutations of this gene have been observed to date. It is observed in a low proportion of HCM cases and is known to be associated with normal survival [1].

#### **3.2 TLR4 gene polymorphisms**

Studies have shown that the immune system and multiple proinflammatory factors play an important role in the pathogenesis of HCM. Toll-like receptor 4 (TLR4), a member of the pattern recognition receptors, plays an important role as mediation in inflammatory response. TLR4 consists of three exons involved in immunoregulation and is localized in region 9q32-q33. It acts by suppressing T lymphocyte proliferation and regulating macrophage function. The lack of TLR4, which is known to play an important role in the development of cardiovascular diseases, has been reported to be associated with doxorubicin-induced cardiomyopathy in mice. A significant relationship between abnormal expression or genetic polymorphisms and cardiovascular remodeling, which is considered to be an important risk factor for metabolic syndrome, has been found. TLR4, which can trigger protein kinase signaling and innate immune response active with mitogen, leads to activation of proinflammatory cytokines and Chemokines. Common polymorphisms in the TLR4 gene are the rs4986791 and rs4986790 polymorphisms. In addition to these polymorphisms, new polymorphisms have been identified in the promoter region and in the 3′ untranslated region (3′-UTR) of TLR4. Even if the polymorphisms occurring in the promoter region do not alter the gene's coding sequence, the initiation of gene transcription is affected when these gene polymorphisms lead to pathogenicity. Cohort studies aimed at determining the relationship between cardiovascular diseases and TLR4 gene polymorphisms were performed, and inconsistent results were

**95**

**Table 1.**

−2081G > A 5′

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

obtained in these studies. In a study by Lindstrom et al., TLR4 gene polymorphisms were associated with decreased risk of prostate cancer. In another study by Castano et al., TLR4 was found to be associated with increased gastric cancer risk in the 3**′**- UTR region. In a study by Kiechl et al., it was concluded that TLR4 gene polymorphisms were associated with heart diseases such as atherogenesis. No large number of studies have been carried out to determine whether TLR4 gene polymorphisms are genetic risk factors for HCM. In a study conducted with the Han-China population, TLR4 gene polymorphisms were found to be genetic risk factors in the development of HCM. In this study, it was determined that rs11536865 and rs10983755 gene polymorphisms in the promoter region of the TLR4 gene are important risk factors for HCM development. In this study, the potential relationships of TLR4 gene polymorphisms with the sensitivity and prognosis of HCM have been revealed. It is determined that it is associated with decreased plasma TLR4 levels of the GG genotypes of −728G > C polymorphism and GG genotypes of −2081G > A polymorphism in HCM patients. However, the C allele of the −728G > C polymorphism and the A-allele of −2081G > A polymorphism were found to be related to the highest plasma TLR4 levels. Inflammation and innate immunity are also contributed to the development of cardiomyopathy. Accordingly, it is believed that TLR4 gene polymorphisms affect the progression of natural immunity or inflammation, thus altering the expression level of TLR4, which is involved in the development of HCM. When studies with larger populations are performed, different results are likely to occur [8]. Primer sequences for −728G > C and −2081G > A gene polymor-

Homeodomain only protein x (HOPX) is a homeodomain protein that regulates the serum response factor (SRF)-dependent gene expression. In addition, HOPX is thought to play a role as tumor suppressor gene in some tissues, and expression is silenced in human carcinomas such as choriocarcinoma, lung cancer, head and neck squamous carcinoma, and esophageal cancer during cardiac hypertrophy, SRF activity, which controls the transcription of genes, including cellular immediateearly genes, and cell skeletal and contractile proteins, is controlled by cofactors such as myocardium and compressors such as HOPX. The expression of the HOPX gene encoding a homeodomain protein is under the control of the two promoter regions. One of these promoters is regulated by the cardiac-specific transcription factor Nkx2–5. The HOPX gene plays a role as SRF antagonist, and it is effective in prenatal cardiomyocyte proliferation and postnatal cardiomyocyte hypertrophy. This antagonistic effect performed through by the take of histone deacetylase. In addition, HOPX is thought to play a role as tumor suppressor gene in some tissues, and expression is silenced in human carcinomas such as choriocarcinoma, lung cancer, head and neck squamous carcinoma, and esophageal cancer. HOPX has a role coactivator on SRF activity. Through this, it plays an active role in cardiac hypertrophy. HOPX gene expression is known to be downregulated in kalp insufficiency, but

**SNPs Forward primer (5′–3′) Reverse primer (5′–3′)**

*PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.*

*Primer sequences used in PCR for TLR4 gene polymorphisms.*

−728G > C 5′-TGATAGACCCCACAACTCCT-3′ 5′-TGATTTCCCCC- CATAGGATG-3′


*DOI: http://dx.doi.org/10.5772/intechopen.83473*

phisms are presented in **Table 1**.

**3.3 HOPX gene polymorphisms**

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83473*

obtained in these studies. In a study by Lindstrom et al., TLR4 gene polymorphisms were associated with decreased risk of prostate cancer. In another study by Castano et al., TLR4 was found to be associated with increased gastric cancer risk in the 3**′**- UTR region. In a study by Kiechl et al., it was concluded that TLR4 gene polymorphisms were associated with heart diseases such as atherogenesis. No large number of studies have been carried out to determine whether TLR4 gene polymorphisms are genetic risk factors for HCM. In a study conducted with the Han-China population, TLR4 gene polymorphisms were found to be genetic risk factors in the development of HCM. In this study, it was determined that rs11536865 and rs10983755 gene polymorphisms in the promoter region of the TLR4 gene are important risk factors for HCM development. In this study, the potential relationships of TLR4 gene polymorphisms with the sensitivity and prognosis of HCM have been revealed. It is determined that it is associated with decreased plasma TLR4 levels of the GG genotypes of −728G > C polymorphism and GG genotypes of −2081G > A polymorphism in HCM patients. However, the C allele of the −728G > C polymorphism and the A-allele of −2081G > A polymorphism were found to be related to the highest plasma TLR4 levels. Inflammation and innate immunity are also contributed to the development of cardiomyopathy. Accordingly, it is believed that TLR4 gene polymorphisms affect the progression of natural immunity or inflammation, thus altering the expression level of TLR4, which is involved in the development of HCM. When studies with larger populations are performed, different results are likely to occur [8]. Primer sequences for −728G > C and −2081G > A gene polymorphisms are presented in **Table 1**.

#### **3.3 HOPX gene polymorphisms**

*Practical Applications of Electrocardiogram*

clinical decision-making in their genetic studies [9].

*3.1.2 Cardiac troponin T gene polymorphisms*

younger patients under 30 years of age [1].

*3.1.3 Alpha tropomyosin gene polymorphisms*

**3.2 TLR4 gene polymorphisms**

determined that mutations in the tail region of the protein may be related to the risk of developing HCM. Mutations in the MYH7 gene are known as a cause of HCM, and sudden death was significantly higher in the family history and in patients with severe left ventricular hypertrophy. In a previous study, four new mutations are identified. In some of these mutations, the relationship between genotype and phenotype is constant. There are significant differences between phenotypes in other mutations [9]. In a study conducted with the Venezuelan population, no missense mutation identified in the MYH7 gene was found. In the same study, the frequency of mutation of MYH7 gene in adult HCM patients was found to be low. In another study performed by Ronkaratti et al., in the Italian population, it is found that the frequency of mutations determined in the MYH7 gene was found to be very low. Many factors, such as modifying genes, epigenetic factors, microRNAs, posttranslational protein modifications, and environmental factors, may affect the clinical course of HCM disease [1, 10]. Genetic studies are required to understand the clinical and prognostic heterogeneity of HCM. The obtained information of clinical and morphological characteristics of different mutation carriers is important in terms of

The cardiac troponin T gene is localized on chromosome 1 (1q3), and so far eight mutations have been identified in this gene. The most important feature of these mutations is that they cause hypertrophy and high incidence of sudden death in

Alpha tropomyosin gene is localized on chromosome 15 (15q2), and two mutations of this gene have been observed to date. It is observed in a low proportion of

Studies have shown that the immune system and multiple proinflammatory factors play an important role in the pathogenesis of HCM. Toll-like receptor 4 (TLR4), a member of the pattern recognition receptors, plays an important role as mediation in inflammatory response. TLR4 consists of three exons involved in immunoregulation and is localized in region 9q32-q33. It acts by suppressing T lymphocyte proliferation and regulating macrophage function. The lack of TLR4, which is known to play an important role in the development of cardiovascular diseases, has been reported to be associated with doxorubicin-induced cardiomyopathy in mice. A significant relationship between abnormal expression or genetic polymorphisms and cardiovascular remodeling, which is considered to be an important risk factor for metabolic syndrome, has been found. TLR4, which can trigger protein kinase signaling and innate immune response active with mitogen, leads to activation of proinflammatory cytokines and Chemokines. Common polymorphisms in the TLR4 gene are the rs4986791 and rs4986790 polymorphisms. In addition to these polymorphisms, new polymorphisms have been identified in the promoter region and in the 3′ untranslated region (3′-UTR) of TLR4. Even if the polymorphisms occurring in the promoter region do not alter the gene's coding sequence, the initiation of gene transcription is affected when these gene polymorphisms lead to pathogenicity. Cohort studies aimed at determining the relationship between cardiovascular diseases and TLR4 gene polymorphisms were performed, and inconsistent results were

HCM cases and is known to be associated with normal survival [1].

**94**

Homeodomain only protein x (HOPX) is a homeodomain protein that regulates the serum response factor (SRF)-dependent gene expression. In addition, HOPX is thought to play a role as tumor suppressor gene in some tissues, and expression is silenced in human carcinomas such as choriocarcinoma, lung cancer, head and neck squamous carcinoma, and esophageal cancer during cardiac hypertrophy, SRF activity, which controls the transcription of genes, including cellular immediateearly genes, and cell skeletal and contractile proteins, is controlled by cofactors such as myocardium and compressors such as HOPX. The expression of the HOPX gene encoding a homeodomain protein is under the control of the two promoter regions. One of these promoters is regulated by the cardiac-specific transcription factor Nkx2–5. The HOPX gene plays a role as SRF antagonist, and it is effective in prenatal cardiomyocyte proliferation and postnatal cardiomyocyte hypertrophy. This antagonistic effect performed through by the take of histone deacetylase. In addition, HOPX is thought to play a role as tumor suppressor gene in some tissues, and expression is silenced in human carcinomas such as choriocarcinoma, lung cancer, head and neck squamous carcinoma, and esophageal cancer. HOPX has a role coactivator on SRF activity. Through this, it plays an active role in cardiac hypertrophy. HOPX gene expression is known to be downregulated in kalp insufficiency, but


#### **Table 1.**

*Primer sequences used in PCR for TLR4 gene polymorphisms.*

the association between gene polymorphisms in the HOPX gene and heart disease such as heart failure or HCM has not been well established. HOPX protein is not a component of sarcomere and plays a role as a modifying gene. In a study investigating the relationship between HOPX gene polymorphism and SRF-dependent gene expression, it was determined that the expression decreased in heart muscles of mutant mice. Sequence variations in the HOPX gene in particular in the regulatory region have been shown to be associated with HCM. The relationship between HOPX and syncope in HCM is classified in two ways as dependent on SRF and independent on SRF. The HOPX gene plays a modifying role in HCM pathogenesis through SRF-dependent genes, and it is thought that the modifying effect may be more pronounced in patients with mutations in target genes. In a previous study performed in HCM patients, no mutation was detected in the coding sequence of the HOPX gene, but two noncoding polymorphisms associated with syncope were detected. In these polymorphisms, it is determined that homozygous states are protective against syncope and heterozygote cases are a genetic risk factor for syncope. The epigenetic status and genetic variations of the HOPX gene are important as modifying factors in HCM [4]. Primer sequences for HOPXe1, HOPXe2, and HOPXe3 gene polymorphisms are presented in **Table 2**.

#### **3.4 PRKHC gene polymorphisms**

The PRKCH gene is a susceptibility gene that plays an important role in atherosclerotic diseases such as cerebral infarction and is associated with the development and progression of atherosclerosis in humans. This gene encodes protein kinase C (PKC), and PKC is activated by diacylglycerol which calcium and secondary messenger. Protein kinase C (PKC) functions as an important signal transduction pathway in the development of cardiac hypertrophy, and studies performed with cell culture and animal models explain this function. It is serine-threonine kinase which is effective in regulating various important cellular functions including proliferation, differentiation, and apoptosis. Members of the PKC family which phosphorylate a wide variety of protein targets are associated with several signalization pathways. There are studies showing that PKC activation is important in the pathology of cardiovascular diseases. The PRKCH gene is located in the ATP-binding region of PKCη in exon 9. PKCη, expressed in the skin and heart tissues, is effective by the way of contributing to cellular processes such as proliferation, differentiation, secretion, and apoptosis. PKCη also plays an important role in immune functions such as regulation of TLR2 responses in macrophages, T-cell proliferation, and homeostasis. The 1425G/A (Val374Ie) polymorphism in the PRKCH gene localized on 14q22-q23 in human increases the kinase activity. In a study conducted by Centurione et al., PKCη has been reported to regulate hypertrophic and apoptotic events, NF-Kb signaling system, and intrinsic mitochondrial apoptotic pathway in rat neonatal heart. In a study conducted with a Chinese population, the PRKCH 1425G/A gene polymorphism was found to be a genetic risk factor in the development of hypertrophic obstructive cardiomyopathy (HOCM). In studies conducted with Chinese and


**97**

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

**SNPs Common primer (5′–3′) Allele-specific primer (A)**

Japanese populations, PRKCH 1425G/A gene polymorphism was found to be associated with increased ischemic stroke and the risk of cerebral hemorrhage. More studies should be performed related to molecular mechanisms to determine the relationship between the risk of developing PRKCH and HOCM [5]. Primer sequences for PRKCH

**Allele-specific primer (G)**

5′-CATAGGTGATGCTTGCAAGAA-3′ 5′-CATAGGTGATGC TTGCAAGAG-3′

The SCN10A gene encodes NaV1.8, a neuronal sodium channel isoform. NaV1.8 is an alpha subunit of sodium channels with voltage door. NaV1.8 localized in the peripheral nervous system is associated with chronic and neuropathic pain. With rapid and sustained stimulation, long-term action potential is observed and excitability is maintained. SCN10A identified in the human heart was found to be associated with changes in cardiac and atrioventricular conduction. Significant relationships were found between the PR interval, QRS duration, and SCN10A gene polymorphisms in recent genome-wide association studies. Starting from this, it is concluded that NaV1.8 plays an important role in cardiac electrophysiology. In a study by Chambers et al., rs6795970 gene polymorphism has been shown to result in the amino acid exchange A1073V in the IDII/III intracellular cycle of NaV1.8. In another study, it was determined that the A-allele of the rs6795970 gene polymorphism occurring in the SCN10A

gene may be related to the cardiac conduction abnormalities observed in HCM patients. In addition, significant correlations were found between the A-allele of the rs6795970 gene polymorphism and the increase in the risk of first-degree heart block,

Heat shock protein 70 (HSP 70) is localized on 6p21.3 and is located in the class III region of the major histocompatibility complex (MHC). This gene is expressed in response to heat shock and stress stimulators such as oxidative free radicals and toxic metal ions. Some of the HSPs play an important role in controlling protein folding, translocation, or degradation and are structurally expressed in non-stressed cells. There are three gene modifiers such as HSP 70-1, HSP 70-2, and HSP 70-Hom. HSP 70-1 and HSP 70-2 are those that encode an identical protein of the heat-inducible HSP 70. HSP 70-Hom is expressed at structurally low levels; it encodes a protein non-inducible with heat. There are studies showing that the overexpression of heat shock proteins has a cardioprotective role and that genetic variants of HSP 70 may reduce the ability of cells to protect against ischemia. The genetic polymorphisms in the HSP 70 gene have been found to play an important role in various diseases such as Parkinson's disease, schizophrenia, breast carcinoma, ischemic stroke, and coronary artery disease. The relationship between HSP 70 specific genotypes and hypertrophic cardiomyopathy has not been reported so far. In a previous study, the modifying role of HSP 70 has been described. In the study, it was found that HSP plays a regulatory role in HCM-related inflammatory

*DOI: http://dx.doi.org/10.5772/intechopen.83473*

TTCAG-3′

5′-GCAGAATCACGTCCTTC

*PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.*

*Primer sequences used in PCR for PRKCH gene polymorphism.*

PRKCH 1425G/A

**Table 3.**

1425G/A gene polymorphisms are presented in **Table 3**.

bundle brunch block, and bifascicular heart block [2].

**3.6 HSP 70 gene polymorphisms**

**3.5 SCN10A gene polymorphisms**

### **Table 2.**

*Primer sequences used in PCR for HOPX gene polymorphisms.*

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83473*


**Table 3.**

*Practical Applications of Electrocardiogram*

HOPXe3 gene polymorphisms are presented in **Table 2**.

**3.4 PRKHC gene polymorphisms**

the association between gene polymorphisms in the HOPX gene and heart disease such as heart failure or HCM has not been well established. HOPX protein is not a component of sarcomere and plays a role as a modifying gene. In a study investigating the relationship between HOPX gene polymorphism and SRF-dependent gene expression, it was determined that the expression decreased in heart muscles of mutant mice. Sequence variations in the HOPX gene in particular in the regulatory region have been shown to be associated with HCM. The relationship between HOPX and syncope in HCM is classified in two ways as dependent on SRF and independent on SRF. The HOPX gene plays a modifying role in HCM pathogenesis through SRF-dependent genes, and it is thought that the modifying effect may be more pronounced in patients with mutations in target genes. In a previous study performed in HCM patients, no mutation was detected in the coding sequence of the HOPX gene, but two noncoding polymorphisms associated with syncope were detected. In these polymorphisms, it is determined that homozygous states are protective against syncope and heterozygote cases are a genetic risk factor for syncope. The epigenetic status and genetic variations of the HOPX gene are important as modifying factors in HCM [4]. Primer sequences for HOPXe1, HOPXe2, and

The PRKCH gene is a susceptibility gene that plays an important role in atherosclerotic diseases such as cerebral infarction and is associated with the development and progression of atherosclerosis in humans. This gene encodes protein kinase C (PKC), and PKC is activated by diacylglycerol which calcium and secondary messenger. Protein kinase C (PKC) functions as an important signal transduction pathway in the development of cardiac hypertrophy, and studies performed with cell culture and animal models explain this function. It is serine-threonine kinase which is effective in regulating various important cellular functions including proliferation, differentiation, and apoptosis. Members of the PKC family which phosphorylate a wide variety of protein targets are associated with several signalization pathways. There are studies showing that PKC activation is important in the pathology of cardiovascular diseases. The PRKCH gene is located in the ATP-binding region of PKCη in exon 9. PKCη, expressed in the skin and heart tissues, is effective by the way of contributing to cellular processes such as proliferation, differentiation, secretion, and apoptosis. PKCη also plays an important role in immune functions such as regulation of TLR2 responses in macrophages, T-cell proliferation, and homeostasis. The 1425G/A (Val374Ie) polymorphism in the PRKCH gene localized on 14q22-q23 in human increases the kinase activity. In a study conducted by Centurione et al., PKCη has been reported to regulate hypertrophic and apoptotic events, NF-Kb signaling system, and intrinsic mitochondrial apoptotic pathway in rat neonatal heart. In a study conducted with a Chinese population, the PRKCH 1425G/A gene polymorphism was found to be a genetic risk factor in the development of hypertrophic obstructive cardiomyopathy (HOCM). In studies conducted with Chinese and

**SNPs Forward primer (5′–3′) Reverse primer (5′–3′)**

*PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.*

*Primer sequences used in PCR for HOPX gene polymorphisms.*

HOPXe1 5′-AACGTGCTATCAGCAGCCTG-3′ 5′-GACGAACAGGACCGCCCAGC-3′ HOPXe2 5′-CGACCGCCTTCCTTCGCTGC-3′ 5′-CCTTCATGGAGTGAAGCTGTC-3′ HOPXe3 5′-CTTGTGCCACAGAGGCTACC-3′ 5′-CCTTCATGGAGTGAAGCTGTC-3′

**96**

**Table 2.**

*Primer sequences used in PCR for PRKCH gene polymorphism.*

Japanese populations, PRKCH 1425G/A gene polymorphism was found to be associated with increased ischemic stroke and the risk of cerebral hemorrhage. More studies should be performed related to molecular mechanisms to determine the relationship between the risk of developing PRKCH and HOCM [5]. Primer sequences for PRKCH 1425G/A gene polymorphisms are presented in **Table 3**.

#### **3.5 SCN10A gene polymorphisms**

The SCN10A gene encodes NaV1.8, a neuronal sodium channel isoform. NaV1.8 is an alpha subunit of sodium channels with voltage door. NaV1.8 localized in the peripheral nervous system is associated with chronic and neuropathic pain. With rapid and sustained stimulation, long-term action potential is observed and excitability is maintained. SCN10A identified in the human heart was found to be associated with changes in cardiac and atrioventricular conduction. Significant relationships were found between the PR interval, QRS duration, and SCN10A gene polymorphisms in recent genome-wide association studies. Starting from this, it is concluded that NaV1.8 plays an important role in cardiac electrophysiology. In a study by Chambers et al., rs6795970 gene polymorphism has been shown to result in the amino acid exchange A1073V in the IDII/III intracellular cycle of NaV1.8. In another study, it was determined that the A-allele of the rs6795970 gene polymorphism occurring in the SCN10A gene may be related to the cardiac conduction abnormalities observed in HCM patients. In addition, significant correlations were found between the A-allele of the rs6795970 gene polymorphism and the increase in the risk of first-degree heart block, bundle brunch block, and bifascicular heart block [2].

#### **3.6 HSP 70 gene polymorphisms**

Heat shock protein 70 (HSP 70) is localized on 6p21.3 and is located in the class III region of the major histocompatibility complex (MHC). This gene is expressed in response to heat shock and stress stimulators such as oxidative free radicals and toxic metal ions. Some of the HSPs play an important role in controlling protein folding, translocation, or degradation and are structurally expressed in non-stressed cells. There are three gene modifiers such as HSP 70-1, HSP 70-2, and HSP 70-Hom. HSP 70-1 and HSP 70-2 are those that encode an identical protein of the heat-inducible HSP 70. HSP 70-Hom is expressed at structurally low levels; it encodes a protein non-inducible with heat. There are studies showing that the overexpression of heat shock proteins has a cardioprotective role and that genetic variants of HSP 70 may reduce the ability of cells to protect against ischemia. The genetic polymorphisms in the HSP 70 gene have been found to play an important role in various diseases such as Parkinson's disease, schizophrenia, breast carcinoma, ischemic stroke, and coronary artery disease. The relationship between HSP 70 specific genotypes and hypertrophic cardiomyopathy has not been reported so far. In a previous study, the modifying role of HSP 70 has been described. In the study, it was found that HSP plays a regulatory role in HCM-related inflammatory

responses and hemodynamic compensatory mechanisms. HSP genes are genes that encode a family of structurally produced proteins in the fulfillment of basic functions, which increase expression in response to various metabolic stimuli. One of the most important tasks of these genes is to facilitate the synthesis and folding of proteins within the cells. In addition HSP genes play an important role in protein binding, secretion, protein degradation, and in the regulation of protein kinases via transcription factors. Polymorphisms in the expression of HSP genes are controlled by a number of transcription factors, and these factors are called heat shock factors (HSF). As a result of the increase and accumulation of HSPs, the protection of the stressed cell is increased; thus the cell survival is maintained. Overexpression of HSP 70 elicits its cardioprotective property. As a result of the polymorphisms occurring in the HSP 70 gene, the synthesis of HSP 70 protein can be changed [11].

#### *3.6.1 HSP 70-1 (+190G/C) polymorphism*

The HSP 70-1 (+190G/C) polymorphism is a silent polymorphism of the initial domain translated in the 5**′**-UTR region of the gene. It has been reported to be a significant relationship between this polymorphism and various diseases such as Parkinson's disease, high-altitude illness, and diabetes mellitus. HSP 70 is known as a significant stress protein whose production is increased under stress [11].

#### *3.6.2 HSP 70-2 (+1267A/G) polymorphism*

The HSP 70-2 (1267A/G) polymorphism is a polymorphism located in the coding region of the gene. HSP 70-2 changes the expression of mRNA, and the relationship between this expression and the +1267A/G polymorphism is shown in several studies. In a study, G allele of HSP 70-2 (1267A/G) polymorphism was found to be an important risk factor in the development of HCM. In a study by Pociot et al., it was determined that the differences between individuals in HSP 70 expression may be related to different regulatory mechanisms than transcriptional regulation. In addition, the HSP 70 polymorphic region affects expression and enzyme activity of the synonymous gene polymorphism. As a result of changing the timing of co-translational folding, the secondary structure of mRNA, stability, substrate, or inhibitor binding sites of the brain vary. In a study, there was no change in the secondary structures of the A and G alleles of HSP 70-2 mRNA [11].

#### *3.6.3 HSP 70-Hom (+2437C/T) polymorphism*

The HSP 70-Hom (+ 2437C/T) polymorphism is characterized by the Met493Thr missense translocation, which affects the substrate specificity and chaperone activity of HSP 70-Hom. In a study conducted with a Mexican population, a significant relationship was found between the +2437 T allele and spondyloarthropathies of HSP 70-Hom (+ 2437C/T) gene polymorphism. It is known that nucleotide changes in the coding region may influence the peptide binding kinetics and the affinity of ATPase activity with HSP 70 proteins. Furthermore, as a result of the nucleotide changes that occur in the side regions, the inducibility, expression grade, and stability of mRNA can be affected. Overexpression of HSP 70 is a preservative against the damaging effects of ischemia. In consequence of excessive expression, the release of the creatine kinase of the heart, recovery of high-energy phosphate depots, and correction of metabolic acidosis are performed. Protective effects of HSP include protein folding, abnormal protein degradation, inhibition of apoptosis, preservation of the cell skeleton, and improved NO synthesis. Apoptosis, a programmed cell death involving the release of cytochrome c, is an important consequence of

**99**

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

5′-CGCCATGGAGACCAACACCC-3′ 5′-GCGGTTCCCTGCTCTCTGTC-3′

5′-CATCGACTTCTACACGTCCA-3′ 5′-CAAAGTCCTTGAGTCCCAAC-3′

5′-GTCCCTGGGGCTGGAGACG-3′ 5′-GATGATAGGGTTACACATCTGCT-3′

**SNPs Forward primer (5′–3′) Reverse primer (5′–3′)**

hypertrophy decompensation. HSP 70 expression and activation of procaspase 9, leading to cardiac hypertrophy, can inhibit caspase-mediated apoptosis activity. Hence, the expression of HSP proteins is affected by HSP 70 genes and polymorphisms in these genes. Thus, the ability to inhibit apoptosis resulting in HCM due to cardiac hypertrophy may be affected. In a previous study, the C allele of the HSP 70-1 gene polymorphism and the G allele of the HSP 70-2 gene polymorphism were found to be associated with increased risk of HCM [11]. Primer sequences for HSP-70-1 +190G/C, HSP-70-2 −1267A/G, and HSP-70-hom −2437T/C gene poly-

The renin-angiotensin-aldosterone system (RAAS) can cause ventricular hypertrophy through circulating angiotensin. RAAS plays an important role in cell proliferation, regulation, and the partial expression of heart hypertrophy, thereby developing LVH [3]. It is also known to play a regulatory role in cardiac function, blood pressure, and electrolyte homeostasis in the body. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II receptors of RAAS are found in the heart, and these components function more independently than circulating RAAS [7]. Angiotensin I is converted to angiotensin II through ACE, and angiotensin II is linked to type 1 receptor angiotensin II (AGTR1). Angiotensin II has an important role in supporting cell growth and hypertrophy. In addition, angiotensin II is converted to aldosterone by aldosterone synthase (CYP11B2), and aldosterone supports cardiac fibrosis. Aldosterone plays an important mediator role in HCM, among sarcomeric mutations and cardiac phenotypes [12]. RAAS activation or receptor function may increase as a result of genetic polymorphisms in genes encoding RAAS. In some studies, a significant relationship was found between RAAS gene polymorphisms and increased hypertrophic response against HCM. In some studies, RAAS gene polymorphisms have been found to be genetic risk factors in the development of LVH, but there are studies that have not confirmed this. Childhood HCM is an early onset HCM and it shows a rapid progress. Furthermore, a growing heart shows more dependence on RAAS than the adult heart. Therefore, it is thought that the growing heart may be more sensitive to RAAS gene polymorphisms. Although studies have shown that there is a relationship between RAAS and HCM, in some studies with different populations, the role of RAAS in the change of HCM phenotype is not well-known [7]. It is thought that modifier genes that regulate RAAS may alter the responses to drug therapies and hence may be effective in the prognosis of HCM patients. RAAS, which is known to be associated with hypertrophy in familial HCM, has been shown to be more effective in sporadic HCM. Early diagnosis of genetic risk factors such as RAAS gene polymorphisms in terms of risk classification and development

*DOI: http://dx.doi.org/10.5772/intechopen.83473*

*PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.*

*Primer sequences used in PCR for HSP 70 gene polymorphisms.*

HSP 70-1 +190G/C

HSP 70-2 −1267A/G

**Table 4.**

HSP 70-hom −2437T/C

morphisms are presented in **Table 4**.

**3.7 RAAS gene polymorphisms**

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83473*


#### **Table 4.**

*Practical Applications of Electrocardiogram*

*3.6.1 HSP 70-1 (+190G/C) polymorphism*

*3.6.2 HSP 70-2 (+1267A/G) polymorphism*

*3.6.3 HSP 70-Hom (+2437C/T) polymorphism*

responses and hemodynamic compensatory mechanisms. HSP genes are genes that encode a family of structurally produced proteins in the fulfillment of basic functions, which increase expression in response to various metabolic stimuli. One of the most important tasks of these genes is to facilitate the synthesis and folding of proteins within the cells. In addition HSP genes play an important role in protein binding, secretion, protein degradation, and in the regulation of protein kinases via transcription factors. Polymorphisms in the expression of HSP genes are controlled by a number of transcription factors, and these factors are called heat shock factors (HSF). As a result of the increase and accumulation of HSPs, the protection of the stressed cell is increased; thus the cell survival is maintained. Overexpression of HSP 70 elicits its cardioprotective property. As a result of the polymorphisms occurring in the HSP 70 gene, the synthesis of HSP 70 protein can be changed [11].

The HSP 70-1 (+190G/C) polymorphism is a silent polymorphism of the initial domain translated in the 5**′**-UTR region of the gene. It has been reported to be a significant relationship between this polymorphism and various diseases such as Parkinson's disease, high-altitude illness, and diabetes mellitus. HSP 70 is known as

The HSP 70-2 (1267A/G) polymorphism is a polymorphism located in the coding

The HSP 70-Hom (+ 2437C/T) polymorphism is characterized by the Met493Thr missense translocation, which affects the substrate specificity and chaperone activity of HSP 70-Hom. In a study conducted with a Mexican population, a significant relationship was found between the +2437 T allele and spondyloarthropathies of HSP 70-Hom (+ 2437C/T) gene polymorphism. It is known that nucleotide changes in the coding region may influence the peptide binding kinetics and the affinity of ATPase activity with HSP 70 proteins. Furthermore, as a result of the nucleotide changes that occur in the side regions, the inducibility, expression grade, and stability of mRNA can be affected. Overexpression of HSP 70 is a preservative against the damaging effects of ischemia. In consequence of excessive expression, the release of the creatine kinase of the heart, recovery of high-energy phosphate depots, and correction of metabolic acidosis are performed. Protective effects of HSP include protein folding, abnormal protein degradation, inhibition of apoptosis, preservation of the cell skeleton, and improved NO synthesis. Apoptosis, a programmed cell death involving the release of cytochrome c, is an important consequence of

region of the gene. HSP 70-2 changes the expression of mRNA, and the relationship between this expression and the +1267A/G polymorphism is shown in several studies. In a study, G allele of HSP 70-2 (1267A/G) polymorphism was found to be an important risk factor in the development of HCM. In a study by Pociot et al., it was determined that the differences between individuals in HSP 70 expression may be related to different regulatory mechanisms than transcriptional regulation. In addition, the HSP 70 polymorphic region affects expression and enzyme activity of the synonymous gene polymorphism. As a result of changing the timing of co-translational folding, the secondary structure of mRNA, stability, substrate, or inhibitor binding sites of the brain vary. In a study, there was no change in the

secondary structures of the A and G alleles of HSP 70-2 mRNA [11].

a significant stress protein whose production is increased under stress [11].

**98**

*Primer sequences used in PCR for HSP 70 gene polymorphisms.*

hypertrophy decompensation. HSP 70 expression and activation of procaspase 9, leading to cardiac hypertrophy, can inhibit caspase-mediated apoptosis activity. Hence, the expression of HSP proteins is affected by HSP 70 genes and polymorphisms in these genes. Thus, the ability to inhibit apoptosis resulting in HCM due to cardiac hypertrophy may be affected. In a previous study, the C allele of the HSP 70-1 gene polymorphism and the G allele of the HSP 70-2 gene polymorphism were found to be associated with increased risk of HCM [11]. Primer sequences for HSP-70-1 +190G/C, HSP-70-2 −1267A/G, and HSP-70-hom −2437T/C gene polymorphisms are presented in **Table 4**.

#### **3.7 RAAS gene polymorphisms**

The renin-angiotensin-aldosterone system (RAAS) can cause ventricular hypertrophy through circulating angiotensin. RAAS plays an important role in cell proliferation, regulation, and the partial expression of heart hypertrophy, thereby developing LVH [3]. It is also known to play a regulatory role in cardiac function, blood pressure, and electrolyte homeostasis in the body. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II receptors of RAAS are found in the heart, and these components function more independently than circulating RAAS [7]. Angiotensin I is converted to angiotensin II through ACE, and angiotensin II is linked to type 1 receptor angiotensin II (AGTR1). Angiotensin II has an important role in supporting cell growth and hypertrophy. In addition, angiotensin II is converted to aldosterone by aldosterone synthase (CYP11B2), and aldosterone supports cardiac fibrosis. Aldosterone plays an important mediator role in HCM, among sarcomeric mutations and cardiac phenotypes [12]. RAAS activation or receptor function may increase as a result of genetic polymorphisms in genes encoding RAAS. In some studies, a significant relationship was found between RAAS gene polymorphisms and increased hypertrophic response against HCM. In some studies, RAAS gene polymorphisms have been found to be genetic risk factors in the development of LVH, but there are studies that have not confirmed this. Childhood HCM is an early onset HCM and it shows a rapid progress. Furthermore, a growing heart shows more dependence on RAAS than the adult heart. Therefore, it is thought that the growing heart may be more sensitive to RAAS gene polymorphisms. Although studies have shown that there is a relationship between RAAS and HCM, in some studies with different populations, the role of RAAS in the change of HCM phenotype is not well-known [7]. It is thought that modifier genes that regulate RAAS may alter the responses to drug therapies and hence may be effective in the prognosis of HCM patients. RAAS, which is known to be associated with hypertrophy in familial HCM, has been shown to be more effective in sporadic HCM. Early diagnosis of genetic risk factors such as RAAS gene polymorphisms in terms of risk classification and development

of new strategies for interventions to individual according to this classification are very important [13].

#### *3.7.1 ACE gene polymorphisms*

ACE increases the synthesis of angiotensin II by inducing cell proliferation, migration, and hypertrophy. Angiotensin II develops the proinflammatory cytokines and matrix metalloproteinases. Therefore, overexpression of angiotensin II is thought to play an important role in cardiomyopathy. ACE, which converts angiotensin I to angiotensin II, functions as a growth factor for cardiac myocytes. It has been reported to induce the cardiac hypertrophy independent of hemodynamic and neurohumoral effects. The ACE gene is localized on chromosome 17 (17q23.3) in the human genome. The gene, which is 21 kilobase in length, consists of 26 exons. The ACE insertion/deletion (I/D) gene polymorphism corresponds to a repetitive sequence of 287 base pairs (Alu) in intron 16. DD genotype of ACE (I/D) gene polymorphism was found to be associated with increased ACE and angiotensin II levels. This causes increased hypertrophy and fibrosis. Phenotypic expression of HCM is also affected as a result of increase of angiotensin II levels. Previous studies have shown a significant relationship between ACE (I/D) gene polymorphisms and plasma angiotensin II levels. ACE (I/D) gene polymorphism has been shown to modulate the phenotype in HCM patients. In studies conducted with different populations, contradictory results were found in terms of the relationship between ACE (I/D) gene polymorphisms and the risk of developing HCM. In a study performed in Japanese population by Yamada et al., no significant relationship was found between ACE (I/D) gene polymorphism and HCM. In a study by Perkins et al., it was determined that the DD genotype of the ACE (I/D) gene polymorphism was important in the phenotypic expression of HCM and the ACE tissue levels were higher in patients with DD genotype. In another study carried out by Schunkert et al., a significant association was found between D allele of the ACE (I/D) gene polymorphism and increased LVH in HCM patients. In a study conducted by Rai et al., in the Indian population, ACE (I/D) gene polymorphism was found to be a genetic risk factor for HCM and dilated cardiomyopathy. In a metaanalysis study, D allele of ACE (I/D) gene polymorphism has been reported to be associated with increased risk of HCM. In patients with HCM that carry the DD genotype of the ACE (I/D) gene polymorphism, higher serum ACE levels, increased risk of sudden death, and higher severity of hypertrophy are observed than other genotypes. Angiotensin II, which shows trophic effects on the heart, also plays an important role in the development of myocardial hypertrophy. The AGTR1 antagonist has an important role in reducing myocardial hypertrophy, so it may be an important treatment option to prevent the sudden cardiac death in patients with HCM. It is thought that obtaining different results in the studies is due to differences in research design, environmental backgrounds, genetic structure, or sample selection criteria in studies. Further genome-wide relationship studies are needed to determine the relationship between the ACE gene and HCM [3, 7].

#### *3.7.2 AGTR1 and AGTR2 gene polymorphisms*

LVH is known to be variable in patients with HCM. Angiotensin II plays an important role in the change of LVH. AGTR1 A1166C and angiotensin II type 2 receptor (AGTR2). As a result of A3123C gene polymorphisms, phenotypic expression of hypertrophy in HCM is affected. The AGTR1 gene is localized on

**101**

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

chromosome 3q21. AGTR1 A1166C gene polymorphism is characterized by adenine (A)/cytosine (C) base translocation at position 1166 of the gene. Different results have been obtained in studies attempting to explain the relationship between these

It has been determined that aldosterone, which can be produced locally in the heart, is associated with sarcomeric mutations and cardiac phenotype. The CYP11B2 −344C/T gene polymorphism is characterized by C/T base displacement at the −344 position of the CYP11B2 gene localized on the 8q22 chromosome. The CYP11B2 gene polymorphism was found to be associated with left ventricular mass in human essential hypertension. In a previous study, aldosterone was found to modify the phenotypic expression of the mutated gene in HCM. A significant relationship between CYP11B2 genotype and cardiac hypertrophy has been shown in HCM. It has also been reported that the T allele of the CYP11B2 gene polymorphism in patients with essential hypertension has been identified as a genetic risk factor for left ventricular mass. In another study, a significant association was found between the CYP11B2 −344C/T gene polymorphism CC genotype and cardiac hypertrophy among healthy controls [14]. Several previous studies have reported that the T allele of the CYP11B2 gene polymorphism is associated with increased plasma aldosterone levels. Therefore,

it is thought to be a significant relationship between T allele of this gene

AGT released into the circulation is a glycoprotein produced by hepatocytes containing 485 amino acids. It is known that AGT is converted into angiotensin I by the renin enzyme. The rate in angiotensin production plays a role in the regulation of AGT concentration and angiotensin II production. In addition, AGT plays an important role in essential hypertension, renal tubular dysgenesis, non-familial structural atrial fibrillation, and in LVH via strong myotrophic effect. The AGT gene is known to regulate the expression of AGT. AGT M235T gene polymorphism is characterized by methionine/threonine base displacement in chromosome 1q42 of the AGT gene [14]. In studies conducted to

investigate the relationship between AGT M235T gene polymorphism and HCM, controversial results were found. Although in some studies significant relationships were determined, in some studies were not found. In a study conducted with the Japanese population by Kawaguchi et al., it was determined that TT genotype and T allele of the AGT M235T gene polymorphism were genetic risk factors for HCM. However, in the same study, no significant relationship was found between TT genotype and T allele of this gene polymorphism and familial form of HCM. A higher T allele frequency was found in patients with sporadic HCM. The TT genotype of the AGT M235T gene polymorphism is thought to be a genetic marker for LVH. It was also found to be significant relationship between this polymorphism and other cardiovascular diseases such as myocardial infarction, coronary atherosclerosis, and hypertension. In another study conducted with the South Indian population, the relationship between T704C gene polymorphism and HCM in exon 2 of the AGT gene was investigated. In this study, T allele of AGT T704C gene polymorphism was found to be associated with sporadic HCM. However, it was concluded that this allele is not a genetic risk factor for familial HCM. In conclusion, the T allele of the AGT

*DOI: http://dx.doi.org/10.5772/intechopen.83473*

*3.7.3 CYP11B2 gene polymorphisms*

gene polymorphisms and HCM development [12].

polymorphism and cardiac hypertrophy [12].

*3.7.4 AGT gene polymorphisms*

chromosome 3q21. AGTR1 A1166C gene polymorphism is characterized by adenine (A)/cytosine (C) base translocation at position 1166 of the gene. Different results have been obtained in studies attempting to explain the relationship between these gene polymorphisms and HCM development [12].

#### *3.7.3 CYP11B2 gene polymorphisms*

*Practical Applications of Electrocardiogram*

very important [13].

*3.7.1 ACE gene polymorphisms*

of new strategies for interventions to individual according to this classification are

ACE increases the synthesis of angiotensin II by inducing cell proliferation,

migration, and hypertrophy. Angiotensin II develops the proinflammatory cytokines and matrix metalloproteinases. Therefore, overexpression of angiotensin II is thought to play an important role in cardiomyopathy. ACE, which converts angiotensin I to angiotensin II, functions as a growth factor for cardiac myocytes. It has been reported to induce the cardiac hypertrophy independent of hemodynamic and neurohumoral effects. The ACE gene is localized on chromosome 17 (17q23.3) in the human genome. The gene, which is 21 kilobase in length, consists of 26 exons. The ACE insertion/deletion (I/D) gene polymorphism corresponds to a repetitive sequence of 287 base pairs (Alu) in intron 16. DD genotype of ACE (I/D) gene polymorphism was found to be associated with increased ACE and angiotensin II levels. This causes increased hypertrophy and fibrosis. Phenotypic expression of HCM is also affected as a result of increase of angiotensin II levels. Previous studies have shown a significant relationship between ACE (I/D) gene polymorphisms and plasma angiotensin II levels. ACE (I/D) gene polymorphism has been shown to modulate the phenotype in HCM patients. In studies conducted with different populations, contradictory results were found in terms of the relationship between ACE (I/D) gene polymorphisms and the risk of developing HCM. In a study performed in Japanese population by Yamada et al., no significant relationship was found between ACE (I/D) gene polymorphism and HCM. In a study by Perkins et al., it was determined that the DD genotype of the ACE (I/D) gene polymorphism was important in the phenotypic expression of HCM and the ACE tissue levels were higher in patients with DD genotype. In another study carried out by Schunkert et al., a significant association was found between D allele of the ACE (I/D) gene polymorphism and increased LVH in HCM patients. In a study conducted by Rai et al., in the Indian population, ACE (I/D) gene polymorphism was found to be a genetic risk factor for HCM and dilated cardiomyopathy. In a metaanalysis study, D allele of ACE (I/D) gene polymorphism has been reported to be associated with increased risk of HCM. In patients with HCM that carry the DD genotype of the ACE (I/D) gene polymorphism, higher serum ACE levels, increased risk of sudden death, and higher severity of hypertrophy are observed than other genotypes. Angiotensin II, which shows trophic effects on the heart, also plays an important role in the development of myocardial hypertrophy. The AGTR1 antagonist has an important role in reducing myocardial hypertrophy, so it may be an important treatment option to prevent the sudden cardiac death in patients with HCM. It is thought that obtaining different results in the studies is due to differences in research design, environmental backgrounds, genetic structure, or sample selection criteria in studies. Further genome-wide relationship studies are needed to determine the relationship between the ACE gene and

**100**

HCM [3, 7].

*3.7.2 AGTR1 and AGTR2 gene polymorphisms*

LVH is known to be variable in patients with HCM. Angiotensin II plays an important role in the change of LVH. AGTR1 A1166C and angiotensin II type 2 receptor (AGTR2). As a result of A3123C gene polymorphisms, phenotypic expression of hypertrophy in HCM is affected. The AGTR1 gene is localized on

It has been determined that aldosterone, which can be produced locally in the heart, is associated with sarcomeric mutations and cardiac phenotype. The CYP11B2 −344C/T gene polymorphism is characterized by C/T base displacement at the −344 position of the CYP11B2 gene localized on the 8q22 chromosome. The CYP11B2 gene polymorphism was found to be associated with left ventricular mass in human essential hypertension. In a previous study, aldosterone was found to modify the phenotypic expression of the mutated gene in HCM. A significant relationship between CYP11B2 genotype and cardiac hypertrophy has been shown in HCM. It has also been reported that the T allele of the CYP11B2 gene polymorphism in patients with essential hypertension has been identified as a genetic risk factor for left ventricular mass. In another study, a significant association was found between the CYP11B2 −344C/T gene polymorphism CC genotype and cardiac hypertrophy among healthy controls [14]. Several previous studies have reported that the T allele of the CYP11B2 gene polymorphism is associated with increased plasma aldosterone levels. Therefore, it is thought to be a significant relationship between T allele of this gene polymorphism and cardiac hypertrophy [12].

#### *3.7.4 AGT gene polymorphisms*

AGT released into the circulation is a glycoprotein produced by hepatocytes containing 485 amino acids. It is known that AGT is converted into angiotensin I by the renin enzyme. The rate in angiotensin production plays a role in the regulation of AGT concentration and angiotensin II production. In addition, AGT plays an important role in essential hypertension, renal tubular dysgenesis, non-familial structural atrial fibrillation, and in LVH via strong myotrophic effect. The AGT gene is known to regulate the expression of AGT. AGT M235T gene polymorphism is characterized by methionine/threonine base displacement in chromosome 1q42 of the AGT gene [14]. In studies conducted to investigate the relationship between AGT M235T gene polymorphism and HCM, controversial results were found. Although in some studies significant relationships were determined, in some studies were not found. In a study conducted with the Japanese population by Kawaguchi et al., it was determined that TT genotype and T allele of the AGT M235T gene polymorphism were genetic risk factors for HCM. However, in the same study, no significant relationship was found between TT genotype and T allele of this gene polymorphism and familial form of HCM. A higher T allele frequency was found in patients with sporadic HCM. The TT genotype of the AGT M235T gene polymorphism is thought to be a genetic marker for LVH. It was also found to be significant relationship between this polymorphism and other cardiovascular diseases such as myocardial infarction, coronary atherosclerosis, and hypertension. In another study conducted with the South Indian population, the relationship between T704C gene polymorphism and HCM in exon 2 of the AGT gene was investigated. In this study, T allele of AGT T704C gene polymorphism was found to be associated with sporadic HCM. However, it was concluded that this allele is not a genetic risk factor for familial HCM. In conclusion, the T allele of the AGT


#### **Table 5.**

*Primer sequences used in PCR for RAAS gene polymorphisms.*

T704C gene polymorphism has been reported to be associated with the development of sporadic HCM. A larger scale of cohort studies should be performed to confirm the relationship between T alleles and HCM development of these gene polymorphisms [3]. Primer sequences for RAAS gene polymorphisms are presented in **Table 5** [15, 16].

#### **4. Conclusions**

It is known that genetic and environmental factors play a role in the pathogenesis of HCM. Numerous studies have been conducted to investigate gene polymorphisms playing the role in HCM development. The differences in the results of these studies are thought to be stemmed from different race and population characteristics and different selection criteria of patient and control groups in the study. The identification of genes and the polymorphisms occurring in these genes that are effective in the development of HCM will enable us to have knowledge about disease-related mechanisms in HCM susceptibility and to develop new drug and treatment strategies in the prevention of HCM. Different results can be obtained in studies with different and larger populations.

#### **Acknowledgements**

This chapter was performed by Nevra Alkanli and Arzu Ay from the Department of Biophysics in Halic University Medical Faculty and in Trakya University Medical Faculty.

#### **Conflict of interest**

We declare that there is no conflict of interest with any financial organization regarding the material discussed in the chapter.

**103**

**Author details**

Nevra Alkanli1

Turkey

provided the original work is properly cited.

\* and Arzu Ay2

\*Address all correspondence to: nevraalkanli@halic.edu.tr

© 2019 The Author(s). Licensee IntechOpen. 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,

1 Department of Biophysics, Faculty of Medicine, Halic University, Istanbul, Turkey

2 Department of Biophysics, Faculty of Medicine, Trakya University, Edirne,

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

*DOI: http://dx.doi.org/10.5772/intechopen.83473*

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83473*

### **Author details**

*Practical Applications of Electrocardiogram*

presented in **Table 5** [15, 16].

*PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.*

*Primer sequences used in PCR for RAAS gene polymorphisms.*

**4. Conclusions**

AGTR1 A1166C

CYP11B2 −344C/T

AGT M235T

AGT T704C

**Table 5.**

populations.

Faculty.

**Acknowledgements**

**Conflict of interest**

regarding the material discussed in the chapter.

T704C gene polymorphism has been reported to be associated with the development of sporadic HCM. A larger scale of cohort studies should be performed to confirm the relationship between T alleles and HCM development of these gene polymorphisms [3]. Primer sequences for RAAS gene polymorphisms are

**SNPs Forward primer (5′–3′) Reverse primer (5′–3′)**

ACE (I/D) 5′-CTGGAGAGCCACTCCCATCCTTTCT-3′ 5′-GACGTGGCCATCACATTCGTCAGAT-3′

5′-GAAGCCTGCACCATGTTTTGA-3′ 5′-GGCTTTGCTTTGTCTTGTTG-3′

5′-CAGGAGGAGACCCCATGTGAC-3′ 5′-CCTCCACCCTGTTCAGCCC-3′

5′-CAGGGTGCTGTCCACACTGGACCCC-3′ 5′-CCGTTTGTGCAGGGCCTGGCTCTCT-3′

5′-CAGGGTGCTGTCCACACTGGACCCC-3′ 5′-CCGTTTGTGCAGGGCCTGGCTCTCT-3′

It is known that genetic and environmental factors play a role in the pathogenesis of HCM. Numerous studies have been conducted to investigate gene polymorphisms playing the role in HCM development. The differences in the results of these studies are thought to be stemmed from different race and population characteristics and different selection criteria of patient and control groups in the study. The identification of genes and the polymorphisms occurring in these genes that are effective in the development of HCM will enable us to have knowledge about disease-related mechanisms in HCM susceptibility and to develop new drug and treatment strategies in the prevention of HCM. Different results can be obtained in studies with different and larger

This chapter was performed by Nevra Alkanli and Arzu Ay from the Department of Biophysics in Halic University Medical Faculty and in Trakya University Medical

We declare that there is no conflict of interest with any financial organization

**102**

Nevra Alkanli1 \* and Arzu Ay2

1 Department of Biophysics, Faculty of Medicine, Halic University, Istanbul, Turkey

2 Department of Biophysics, Faculty of Medicine, Trakya University, Edirne, Turkey

\*Address all correspondence to: nevraalkanli@halic.edu.tr

© 2019 The Author(s). Licensee IntechOpen. 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.

#### **References**

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[2] Iio C, Akiyoshi O, Nagai T, et al. Association between genetic variation in the *SCN10A* gene and cardiac conduction abnormalities in patients with hypertrophic cardiomyopathy. International Heart Journal. 2015;**56**:421-427

[3] Manohar Rao PPK, Anjana M, Mullapudi R, et al. The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy. Journal of the Renin-Angiotensin-Aldosterone System. 2010;**12**(3):238-242. DOI: 10.1177/1470320310387955

[4] Güleç Ç, Abacı N, Bayrak F. Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic cardiomyopathy. Anadolu Kardiyoloji Dergisi. 2014;**14**:617-624. DOI: 10.5152/ akd.2014.4972

[5] Ji F, Liu Q, Feng Z, et al. Genetic association between 1425G/A SNP in PRKCH and hypertrophic cardiomyopathy in a Chinese population. Oncotarget. 2017;**8**(70):114839-114844

[6] Rodríguez R, Guerrero D, Rivas Y, et al. Genetic variations of β-MYH7 in Venezuelan patients with hypertrophic cardiomyopathy. Investigación Clínica. 2014;**55**(1):23-31

[7] Yuan Y, Meng L, Zhou Y, et al. Genetic polymorphism of angiotensinconverting enzyme and hypertrophic cardiomyopathy risk. A systematic review and meta-analysis. Medicine. 2017;**96**(e8639):48. DOI: 10.1097/ MD.0000000000008639

[8] Han K, Li Y-P. Prognostic predictive value of TLR4 polymorphisms in Han Chinese population with hypertrophic cardiomyopathy. Kaohsiung Journal of Medical Sciences. 2018;**34**:569-575

[9] Laredo R, Monserrat L, Hermida-Prieto M. Beta-myosin heavy Chain gene mutations in patients with hypertrophic cardiomyopathy. Revista Española de Cardiología. 2006;**59**(10):1008-1018

[10] Kraker J, Viswanathan SK, Knöll R. Recent advances in the molecular genetics of familial hypertrophic cardiomyopathy in South Asian descendants. Frontiers in Physiology. 2016;**7**(499):1-14

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[12] Chai W, Hoedemaekers Y, van Schaik RH, et al. Cardiac aldosterone in subjects with hypertrophic cardiomyopathy. Journal of the Renin-Angiotensin-Aldosterone System. 2006;**7**(4):225-230. DOI: 10.3317/ jraas.2006.042

[13] Kaufman BD, Auerbach S, Reddy S. RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy. Human Genetics. 2007;**122**:515-523. DOI: 10.1007/ s00439-007-0429-9

[14] Ortlepp JR, Vosberg HP, Reith S. Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the

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*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy*

*DOI: http://dx.doi.org/10.5772/intechopen.83473*

myosin binding protein C gene. Heart.

[16] Kaplan İ, Sancaktar E, Ece A. Gene polymorphisms of adducin GLY460TRP, ACE I/D, and AGT M235T in pediatric hypertension patients. Medical Science Monitor. 2014;**20**:1745-1750. DOI:

10.12659/MSM.892140

[15] Ramu P, Umamaheswaran G, Shewade DG, et al. Candidate gene polymorphisms of renin angiotensin system and essential hypertension in a South Indian Tamilian population. International Journal of Human Genetics. 2011;**11**(1):31-40

2002;**87**:270-275

*Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83473*

myosin binding protein C gene. Heart. 2002;**87**:270-275

[15] Ramu P, Umamaheswaran G, Shewade DG, et al. Candidate gene polymorphisms of renin angiotensin system and essential hypertension in a South Indian Tamilian population. International Journal of Human Genetics. 2011;**11**(1):31-40

[16] Kaplan İ, Sancaktar E, Ece A. Gene polymorphisms of adducin GLY460TRP, ACE I/D, and AGT M235T in pediatric hypertension patients. Medical Science Monitor. 2014;**20**:1745-1750. DOI: 10.12659/MSM.892140

**104**

*Practical Applications of Electrocardiogram*

[1] Tirone AP, Arteaga E. Familial hypertrophic cardiomyopathy. Genetic characterization. Arquivos [8] Han K, Li Y-P. Prognostic predictive value of TLR4 polymorphisms in Han Chinese population with hypertrophic cardiomyopathy. Kaohsiung Journal of Medical Sciences. 2018;**34**:569-575

[9] Laredo R, Monserrat L, Hermida-Prieto M. Beta-myosin heavy Chain gene mutations in patients with hypertrophic cardiomyopathy. Revista Española de Cardiología.

[10] Kraker J, Viswanathan SK, Knöll R. Recent advances in the molecular genetics of familial hypertrophic cardiomyopathy in South Asian descendants. Frontiers in Physiology.

[11] Rangaraju A, Satyanarayana ML, Ananthapur V, et al. Heat shock protein 70 polymorphism in hypertrophic cardiomyopathy of South Indian cohort. Journal of Indian College of Cardiology. 2013;**3**:9-15. DOI: 10.1016/j.

[12] Chai W, Hoedemaekers Y, van Schaik RH, et al. Cardiac aldosterone

cardiomyopathy. Journal of the Renin-Angiotensin-Aldosterone System. 2006;**7**(4):225-230. DOI: 10.3317/

[13] Kaufman BD, Auerbach S, Reddy S. RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy. Human Genetics. 2007;**122**:515-523. DOI: 10.1007/

[14] Ortlepp JR, Vosberg HP, Reith S. Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the

in subjects with hypertrophic

2006;**59**(10):1008-1018

2016;**7**(499):1-14

jicc.2012.12.007

jraas.2006.042

s00439-007-0429-9

[2] Iio C, Akiyoshi O, Nagai T, et al. Association between genetic variation in the *SCN10A* gene and cardiac conduction abnormalities in patients with hypertrophic cardiomyopathy.

Brasileiros de Cardiologia.

International Heart Journal.

10.1177/1470320310387955

[5] Ji F, Liu Q, Feng Z, et al. Genetic association between 1425G/A SNP in PRKCH and hypertrophic cardiomyopathy in a Chinese population. Oncotarget. 2017;**8**(70):114839-114844

[4] Güleç Ç, Abacı N, Bayrak F. Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic

cardiomyopathy. Anadolu Kardiyoloji Dergisi. 2014;**14**:617-624. DOI: 10.5152/

[6] Rodríguez R, Guerrero D, Rivas Y, et al. Genetic variations of β-MYH7 in Venezuelan patients with hypertrophic cardiomyopathy. Investigación Clínica.

[7] Yuan Y, Meng L, Zhou Y, et al. Genetic polymorphism of angiotensinconverting enzyme and hypertrophic cardiomyopathy risk. A systematic review and meta-analysis. Medicine. 2017;**96**(e8639):48. DOI: 10.1097/

MD.0000000000008639

[3] Manohar Rao PPK, Anjana M, Mullapudi R, et al. The M235T

polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy. Journal of the Renin-Angiotensin-Aldosterone System. 2010;**12**(3):238-242. DOI:

1999;**72**(4):520-522

2015;**56**:421-427

akd.2014.4972

2014;**55**(1):23-31

**References**

### *Edited by Umashankar Lakshmanadoss*

This book provides an excellent overview of the diagnosis of abnormal electrocardiograms (ECGs) through deep learning methods. These methods include optimal techniques that can link the processing and analysis of nonstationary ECG signals, the various statistical methods of converting ECG data into variant maps, and the application of various ways of identifying premature atrial beats, ECG characteristics of right and left ventricular tachyarrhythmia, and conditions producing left ventricular hypertrophy, including hypertrophic cardiomyopathy. This book is divided into two sections, including basic and practical applications of ECGs. We hope that it will serve as a reference for the techniques used to obtain and process electrical signals for ECGs. This book will also function as an excellent reference for atrial and ventricular tachyarrhythmia.

Published in London, UK © 2020 IntechOpen © Photodsotiroff / iStock

Practical Applications of Electrocardiogram

Practical Applications of

Electrocardiogram

*Edited by Umashankar Lakshmanadoss*