**4.4** *CYP11B2* **genotypic variants and hypertrophic cardiomyopathy**

Hypertrophic cardiomyopathy (HCM) is a clinical cardiac dysfunction characterized mainly by hypertrophy of left ventricle. HCM is an autosomal dominant disorder and its diagnosis needs to exclude other cardiac or systemic causes of increased ventricular wall thickening. HCM comprises different histological features as cardiomyocyte hypertrophy, myofibrillar disarray, and fibrosis. Several factors are involved in the pathogenesis of HCM, with the genetic element has an upper hand. Mutations and polymorphisms in genes encoding the sarcomere proteins and renin-angiotensin-aldosterone system (RAAS) seem to be related to the predisposition for left ventricular hypertrophy (LVH) and HCM [92].

Evidences suggested that aldosterone seems to play a major role in the progression of LVH and HCM as it is produced locally in the heart and *CYP11B2*

*The Recent Topics in Genetic Polymorphisms*

**4.2** *CYP11B2* **genotypic variants and atrial fibrillation**

with an 85% increased relative risk for AF [71].

RAAS [72].

phism and lone AF patients.

persistence of AF [80].

Atrial fibrillation (AF) is the most clinically prevalent type of cardiac arrhythmia which may be precipitated due to the presence of underlying heart disease such as valvular dysfunction, ventricular dysfunction, and hypertension. However, AF does not exist in some patients with one or more of these risk factors and presents in others without any risk factors. Accordingly, the genetic role had been emerged in the predisposition for AF. A positive family history of AF in at least one parent was suggested by a recent Framingham Heart study on 2243 participants to be associated

Taking together this genetic role, two types of AF have been identified regarding

the heredity characteristics as familial and non-familial AF. Recent studies have detected several candidate genes which were suggested to be associated with the familial AF type such as genes encoding for subunits of potassium or sodium channels, sarcolipin, connexin 40, endothelial nitric oxide synthase, interleukin 10, and

Association of genetic variants of renin angiotensin aldosterone system (RAAS) system with non-familial AF was suggested by Tsai et al. [73] using a risk-factor matched design. *CYP11B2* −344C/T polymorphism was reported to be associated with the susceptibility of AF by Amir et al. [74] in a cohort of 196 patients with symptomatic systolic heart failure. They found that the −344 CC genotype to be a strong independent predictor for AF (adjusted OR 2.35, 95% CI 1.57–3.51, *P* = 0.03). Therefore, *CYP11B2* −344C/T polymorphism may predispose to AF in patients with HF. Another study by Lu et al. [75] on 359 of Han and Kazak population with non-valvular AF and 527 non-AF patients as a control reported that −344C/T polymorphism of *CYP11B2* was associated with AF risk as the frequencies of TT genotype, and co-dominant model (CC + TT genotype) in Han population and of TT genotype, and dominant model (CT + TT genotype) in Kasak population were significantly higher in AF group than in the control group. Furthermore, a meta-analysis by Li et al. [76] involving 2758 subjects from six distinct studies reported that *CYP11B2* T−344C gene polymorphism was significantly associated with AF in all genetic models; allelic (OR: 1.26, *P* = 0.0002), recessive (OR: 1.99, *P* = 0.003), dominant (OR: 0.903, *P* = 0.036), and homozygous (OR: 1.356, 95% CI: 1.130–1.628, *P* = 0.001), and additive (OR: 1.153, *P* = 1.0 × 10<sup>−</sup>10). On the other hand, no significant association was detected by Zhang et al. [77] between different genotype and alleles of −344 T/C polymor-

The possible mechanisms for the association of *CYP11B2* polymorphism and AF are mainly related to increased aldosterone production. Aldosterone exerts its effect via direct and indirect ways. Indirect effect of aldosterone on the heart arise from its role on increasing blood volume, blood pressure, left ventricular pressure, left ventricular hypertrophy, left atrial pressure, and left atrial volume. However, aldosterone can directly act on the heart inducing cardiac hypertrophy and fibrosis [78, 79] via the proliferation and differentiation of myocardial cells, vascular smooth muscle cells, and fibroblasts, leading to a significant increase in collagen production. These effects lead to cardiac fibrosis and structural remodeling leading to heart rhythm disorders. Specifically, in the atrium, aldosterone may directly or indirectly cause atrial enlargement and fibrosis, leading to structural and electrical atrial remodeling resulting in atrial fibrillation. Based on these findings, aldosterone antagonists as angiotensin II receptor antagonists may be used clinically in the patients with AF to control and minimize the incidence and

**28**

mRNA levels show sevenfold increase in the cardiac tissue of HCM patients when compared normal cardiac tissue [93]. It exerts its action via stimulation of mineralocorticoid receptor resulting in enhancement of myocardial cell hypertrophy, progressive myocardial fibrosis leading to ventricular and septal remodeling, and hypertrophy, resulting in elevated ventricular mass observed in HCM patients [94, 95]. Therefore, genetic variations involving *CYP11B2* gene might influence the structure and function of the left ventricle via increasing aldosterone secretion [93].

Several polymorphisms in the *CYP11B2* had been described in the HCM with −344C>T and intron 2 conversion have significant associations with left ventricular size, mass, and function in different population studies. However, the −344C>T promoter polymorphism is a much better predictor of left ventricular size than is the intron 2 gene conversion [96]. The −344C>T polymorphism have proved to be associated with the risk for HCM progression in many previous studies [93, 94, 97–99], whereas no association has suggested by other studies [100, 101].This controversy extents to the risk allele, which may be the −344C in some studies [96, 98–100, 102, 103] or −344T in another study [97]. Moreover, the risk allele for increased ventricular size and thickness differs regarding gender as with a study by Chai et al., [97] in which the T allele carrier is associated with a significantly higher intra-ventricular septum thickness in males, whereas in females, CC genotype carriers had a higher risk for increased intra-ventricular mass thickness, left ventricular mass index, and Wigle score.

#### **4.5** *CYP11B2* **genotypic variants and heart failure**

Heart failure (HF) is a cardiac disorder characterized by cardiac remodeling with subsequent cardiac dysfunction [104]. It is a multifactorial disease, which is precipitated due to underlying cardiac disorders as hypertension, CAD, valvular dysfunction, arrhythmia, and cardiomyopathy. Integrated neuronal and hormonal elements are involved in the pathogenesis of HF including activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, and other mediators as endothelin, vascular endothelial growth factor, and inflammatory cytokines. Based on the previously described neurohormonal factors, therapeutic approaches for HF have developed to block these factors including angiotensinconverting enzyme inhibitors (ACEI), and aldosterone antagonists [105]. Several risk and prognostic factors have influenced the progression of chronic congestive heart failure (CHF) including age, New York Heart Association (NYHA) class, renal function, and comorbidities such as atrial fibrillation, diabetes mellitus, and ischemic heart disease [106]. However, genetic elements seem to affect the risk, severity, and therapeutic response of HF [107]. *CYP11B2* polymorphisms specifically −344C/T is among these genetic factors and has been associated with the susceptibility, therapeutic response, or prognosis of HF.

A study by McNamara et al. [108] was performed on a total of 354 subjects from A-HeFT (African American Heart Failure Trial). They detected a higher frequency of −344 TT genotypes carriers (61%) than CC genotypes carriers (6.2%) in African Americans. Also, the −344 C allele was associated with significantly poorer HF hospitalization-free survival and a higher rate of death. Moreover, the therapeutic influence of nitric oxide donor (isosorbide dinitrate and hydralazine) was augmented in the presence of the TT genotype.

Another study by Feola et al. [109] on 175 patients from the European continental ancestry congestive heart failure (CHF) population and revealed that no significant differences between −344 CC and −344 TT genotypes carriers regarding cardiac output, end-systolic or diastolic left ventricle diameter, left ventricular ejection fraction (LVEF), and pro-natriuretic peptide (BNP). Also, −344 C allele

**31**

*Aldosterone Synthase Gene (*CYP11B2*) Polymorphisms and Enhanced Cardiovascular Risk*

carriers have a higher degree of disability (Barthel Index), NYHA class, and a lower cardiac index. Moreover, the two groups showed a similar clinical outcomes either

In 107 Black South African patients with dilated cardiomyopathy in functional class II–III, Tiago et al. [110] detected that the −344C allele was associated with improvement of LVEF after traditional therapy despite it is not related to the baseline LVEF as well as left ventricular dimension. Also, the allele distribution has proven to be different among races as the C allele was significantly more frequent in non-African-American HF patients if compared with African-American patients and associated only in the African-American with a lower end-systolic left ventricular diameter at 1 year follow-up [111]. Moreover, the association of −344C allele was confirmed as a risk factor for the progression of AF in a cohort of 194 African-

*CYP11B2* gene polymorphism is associated with increased cardiovascular risk via enhancing aldosterone synthesis and production which acts either systemically or locally on the heart. There is a large number of polymorphisms has been identified for *CYP11B2*. Among them, **−**344C/T polymorphism was extensively studied in different ethnic groups and has proved to be associated either solely or synergistic with other *CYP11B2* polymorphisms in the risk for progression and susceptibility of several cardiovascular disorders as hypertension, AF, CAD, cardiomyopathy, and HF. Also, *CYP11B2* polymorphisms were confirmed as a predictor for survival and therapeutic response in some cardiovascular disorders as hypertension and HF. Moreover, gene-environment interactions of *CYP11B2* were suggested in several

First of all thanks to gracious ALLAH who guided me to the frank clear way. Second, I dedicate this work to my parents and my dear professor Murad Ahmad Murad for their encouragement and sustained support. And finally, I am grateful to

Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta,

© 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,

\*Address all correspondence to: mohammedtarek5514@yahoo.com

*DOI: http://dx.doi.org/10.5772/intechopen.89133*

American HF patients [112].

studies but still need to be confirmed.

my lovely niece, Marium.

Muhammad Tarek Abdel Ghafar

provided the original work is properly cited.

**Author details**

Egypt

**5. Conclusions**

**Thanks**

death or re-hospitalization after 4 years follow up period.

*Aldosterone Synthase Gene (*CYP11B2*) Polymorphisms and Enhanced Cardiovascular Risk DOI: http://dx.doi.org/10.5772/intechopen.89133*

carriers have a higher degree of disability (Barthel Index), NYHA class, and a lower cardiac index. Moreover, the two groups showed a similar clinical outcomes either death or re-hospitalization after 4 years follow up period.

In 107 Black South African patients with dilated cardiomyopathy in functional class II–III, Tiago et al. [110] detected that the −344C allele was associated with improvement of LVEF after traditional therapy despite it is not related to the baseline LVEF as well as left ventricular dimension. Also, the allele distribution has proven to be different among races as the C allele was significantly more frequent in non-African-American HF patients if compared with African-American patients and associated only in the African-American with a lower end-systolic left ventricular diameter at 1 year follow-up [111]. Moreover, the association of −344C allele was confirmed as a risk factor for the progression of AF in a cohort of 194 African-American HF patients [112].
