Arterial Stiffness Assessment in Children with Familial Hypercholesterolemia

*Dinara Sadykova, Liliia Galimova, Evgeniia Slastnikova, Zulfiia Khabibrakhmanova and Natalya Guseva*

### **Abstract**

Familial hypercholesterolemia (FH) is the genetic disease which characterized by an increase of level total cholesterol and low density lipoproteins since childhood. The aim of the study was to assess arterial stiffness in children with heterozygous FH by measuring the pulse wave velocity (PWV) in the aorta. The study involved 118 children, 60 healthy children in the control group and 58 children with heterozygous FH in the main group. Both groups were divided into 3 age subgroups: 5–7 years old, 8–12 years old and 13–17 years old. The diagnosis of FH was made using British criteria by Simon Broome. The lipid profile was determined for all children, blood pressure was monitored daily with an estimate of the minimum, mean and maximum PWV (PWVmin, mean PWV, PWVmax) in aorta using oscillometric method. Correlation analysis in patients with FH revealed direct correlation between PWVmin, mean PWV and PWVmax with total cholesterol (r = 0.46, r = 0.46 and r = 0.464, respectively, p < 0.001). The study demonstrates an increase in the PWV in the aorta in children with FH compared with healthy peers from 8–12 years of age and a progression of arterial stiffness most significant in the group of 13–17 years.

**Keywords:** familial hypercholesterolemia, arterial stiffness, pulse wave velocity, children

### **1. Introduction**

Familial hypercholesterolemia (FH) is a monogenic disease with a predominantly autosomal dominant mode of inheritance, accompanied by a significant increase of the low-density lipoprotein cholesterol (LDL-C) level in the blood [1]. Patients with FH have a high risk of early development of atherosclerosis [2, 3]. The incidence of FH in the general population is estimated at about 1 per 200 persons [3], in addition, the evidence exist that in patients with established coronary heart disease, the prevalence of potential FH is up to 8.3% in men and 11.1% in women [4]. However, despite this, there is a low level of diagnosis and treatment [5, 6]. In this regard, registers of patients with FH have recently been developed for assessing the level of diagnosis, treatment and improvement in results of therapy [7, 8]. In

#### *Management of Dyslipidemia*

more than 90% of cases, FH is caused by mutations in the gene encoding the LDL receptor, which reduce the cellular uptake of LDL and, therefore, significantly increase their plasma level [9]. Mutations in other genes leading to the same phenotype have also been identified: associated with apolipoprotein B, which affect the LDL-binding domain of apolipoprotein B as the most important apolipoprotein for uptake of LDL particles, and mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) [10, 11].

It is known that high plasma cholesterol level is a risk factor for the development of cardiovascular diseases [12] and may be the cause of early vascular damage. Currently, there are methods that allow registering pathological changes in blood vessels at preclinical stage. The detection of early changes in the walls of arteries by non-invasive methods, such as ultrasound duplex scanning, assessment of central aortic pressure and pulse wave velocity, has opened up new perspectives, helping to identify high-risk patients [13–17].

Several studies have shown that hypercholesterolemia can cause the loss of elasticity and increased stiffness of arterial vessels, leading to an increase in the pulse wave velocity due to its rapid spreading in stiff arteries [18, 19]. Arterial stiffness is considered to be a significant predictor of overall and cardiovascular mortality in patients with arterial hypertension [20–23], in patients with endstage renal failure [24, 25] and in the elderly patients [26]. In addition, it was noted that arterial stiffness is closely related to structural changes in the artery such as thickening of the intima-media complex [27]. Changes in the elastic properties of arteries may indicate a functional disorder long before the appearance of clinical symptoms. One of the indicators for assessing the stiffness of the arteries is the pulse wave velocity (PWV) measurement in aorta. It is the measurement of the speed of pulse pressure propagation along a segment of the arterial vessels [28]. It should be noted that the measurement of the arterial stiffness is quite widespread among adult patients [29, 30], while in pediatrics, despite its non-invasiveness and high informativeness, it is used much less frequently. This is probably due to the complexity of standardization, time costs and the need for additional equipment.

## **2. The aim of this study**

The aim of this study is to assess arterial stiffness in children with heterozygous familial hypercholesterolemia by measuring the pulse wave velocity in the aorta

## **3. Materials and methods**

The study involved 118 children. The control group consisted of 60 healthy children and 58 children with heterozygous familial hypercholesterolemia formed the main group (**Table 1**). The diagnosis of FHC was established in accordance with the British Simon Broome criteria [31]. The study included children with FH who were not taking statins. 15 patients from the main group underwent genetic testing in the Health in Code laboratory (Spain) for the detection of a monogenic mutation responsible for the development of familial hypercholesterolemia, and a positive DNA test was obtained. Exclusion criteria: secondary dyslipidemia, arterial hypertension, obesity. Written informed consent was obtained from all the participants of the study.

**99**

*Arterial Stiffness Assessment in Children with Familial Hypercholesterolemia*

Age, years (М ± σ) 11,53 ± 4,2 10,92 ± 4,1 Gender, m/f 40/20 37/21 Smoking, n/% 0(0) 0(0) Obesity, n/% 0(0) 0(0) Arterial hypertension, n/% 0(0) 0(0) Cutaneous xanthomas 0(0) 0(0) Corneal arch 0(0) 0(0) Thickening of the Achilles tendon 0(0) 0(0) TC, mmol/l (М ± σ) 3,5 ± 1,2 7,8 ± 2,3 LDL, mmol/l (М ± σ) 1,6 ± 0,8 6,1 ± 1,2 HDL, mmol/l (М ± σ) 0,9 ± 0,1 1,1 ± 0,3 TG, mmol/l (М ± σ) 0,8 ± 0.4 1,2 ± 0,3

**Control group, n = 60 Main group, n = 58**

Total cholesterol, triglycerides, LDL, and high-density lipoprotein cholesterol

(HDL) were measured using commercial kits (Beckman Coulter, USA) on an

*Abbreviations: TC - total cholesterol; LDL - low density lipoprotein; HDL - high density lipoprotein;* 

The clinical examination included a careful life history and family history taking, physical examination, and body mass index (BMI) assessment. All children underwent 24-hour blood pressure monitoring with an assessment of the pulse wave velocity in the aorta using the oscillometric method of the BPLab Vasotens

In the BPLab program for determining PWV in aorta the following ratio is used: PWVaorta = K × (2 × L) /RWTT, where PWVaorta is PWV in the aorta; K is the scale factor for standardizing the obtained value of the PWV; L is the length of the aortic trunk (in BPLab software, the distance from the upper edge of the sternum to the pubic bone is taken as the length of the aorta); RWTT (reflected

Statistical analysis was carried out using the IBM SPSS Statistics v.23 software

(developed by IBM Corporation, USA). The results were subjected to statistical processing using nonparametric methods in connection with the established absence of a normal distribution of quantitative indicators (testing for normal distribution was carried out using the Shapiro–Wilk test). Quantitative data were described using the values of the median (Me) and the lower and upper quartiles [Q1-Q3]. Comparison of quantitative indicators between two groups was carried out using the Mann–Whitney test, between the three groups using the Kruskal-Wallis test with an a posteriori Dunn test. Correlation analysis was carried out using the Spearman's rank correlation coefficient; the assessment of the tightness of correlation was carried out using the Chaddock scale. Differences in indicators and

identified relationships were considered statistically significant at p < 0.05.

automatic biochemical analyzer (Au5800 Beckman Coulter, USA).

*Clinical and laboratory characteristics of children of the main and control groups.*

system (Petr Telegin Ltd., Russia).

wave transit time) [32].

*TG - triglycerides.*

**Table 1.**

**4. Statistical analysis**

*DOI: http://dx.doi.org/10.5772/intechopen.96018*


#### *Arterial Stiffness Assessment in Children with Familial Hypercholesterolemia DOI: http://dx.doi.org/10.5772/intechopen.96018*

*Abbreviations: TC - total cholesterol; LDL - low density lipoprotein; HDL - high density lipoprotein; TG - triglycerides.*

#### **Table 1.**

*Management of Dyslipidemia*

type 9 (PCSK9) [10, 11].

additional equipment.

the aorta

**2. The aim of this study**

**3. Materials and methods**

identify high-risk patients [13–17].

more than 90% of cases, FH is caused by mutations in the gene encoding the LDL receptor, which reduce the cellular uptake of LDL and, therefore, significantly increase their plasma level [9]. Mutations in other genes leading to the same phenotype have also been identified: associated with apolipoprotein B, which affect the LDL-binding domain of apolipoprotein B as the most important apolipoprotein for uptake of LDL particles, and mutations in proprotein convertase subtilisin/kexin

It is known that high plasma cholesterol level is a risk factor for the development

Several studies have shown that hypercholesterolemia can cause the loss of elasticity and increased stiffness of arterial vessels, leading to an increase in the pulse wave velocity due to its rapid spreading in stiff arteries [18, 19]. Arterial stiffness is considered to be a significant predictor of overall and cardiovascular mortality in patients with arterial hypertension [20–23], in patients with endstage renal failure [24, 25] and in the elderly patients [26]. In addition, it was noted that arterial stiffness is closely related to structural changes in the artery such as thickening of the intima-media complex [27]. Changes in the elastic properties of arteries may indicate a functional disorder long before the appearance of clinical symptoms. One of the indicators for assessing the stiffness of the arteries is the pulse wave velocity (PWV) measurement in aorta. It is the measurement of the speed of pulse pressure propagation along a segment of the arterial vessels [28]. It should be noted that the measurement of the arterial stiffness is quite widespread among adult patients [29, 30], while in pediatrics, despite its non-invasiveness and high informativeness, it is used much less frequently. This is probably due to the complexity of standardization, time costs and the need for

The aim of this study is to assess arterial stiffness in children with heterozygous familial hypercholesterolemia by measuring the pulse wave velocity in

The study involved 118 children. The control group consisted of 60 healthy children and 58 children with heterozygous familial hypercholesterolemia formed the main group (**Table 1**). The diagnosis of FHC was established in accordance with the British Simon Broome criteria [31]. The study included children with FH who were not taking statins. 15 patients from the main group underwent genetic testing in the Health in Code laboratory (Spain) for the detection of a monogenic mutation responsible for the development of familial hypercholesterolemia, and a positive DNA test was obtained. Exclusion criteria: secondary dyslipidemia, arterial hypertension, obesity. Written informed consent was obtained from all the participants

of cardiovascular diseases [12] and may be the cause of early vascular damage. Currently, there are methods that allow registering pathological changes in blood vessels at preclinical stage. The detection of early changes in the walls of arteries by non-invasive methods, such as ultrasound duplex scanning, assessment of central aortic pressure and pulse wave velocity, has opened up new perspectives, helping to

**98**

of the study.

*Clinical and laboratory characteristics of children of the main and control groups.*

Total cholesterol, triglycerides, LDL, and high-density lipoprotein cholesterol (HDL) were measured using commercial kits (Beckman Coulter, USA) on an automatic biochemical analyzer (Au5800 Beckman Coulter, USA).

The clinical examination included a careful life history and family history taking, physical examination, and body mass index (BMI) assessment. All children underwent 24-hour blood pressure monitoring with an assessment of the pulse wave velocity in the aorta using the oscillometric method of the BPLab Vasotens system (Petr Telegin Ltd., Russia).

In the BPLab program for determining PWV in aorta the following ratio is used: PWVaorta = K × (2 × L) /RWTT, where PWVaorta is PWV in the aorta; K is the scale factor for standardizing the obtained value of the PWV; L is the length of the aortic trunk (in BPLab software, the distance from the upper edge of the sternum to the pubic bone is taken as the length of the aorta); RWTT (reflected wave transit time) [32].

### **4. Statistical analysis**

Statistical analysis was carried out using the IBM SPSS Statistics v.23 software (developed by IBM Corporation, USA). The results were subjected to statistical processing using nonparametric methods in connection with the established absence of a normal distribution of quantitative indicators (testing for normal distribution was carried out using the Shapiro–Wilk test). Quantitative data were described using the values of the median (Me) and the lower and upper quartiles [Q1-Q3]. Comparison of quantitative indicators between two groups was carried out using the Mann–Whitney test, between the three groups using the Kruskal-Wallis test with an a posteriori Dunn test. Correlation analysis was carried out using the Spearman's rank correlation coefficient; the assessment of the tightness of correlation was carried out using the Chaddock scale. Differences in indicators and identified relationships were considered statistically significant at p < 0.05.
