Background: Essential hypertension in adults may begin in childhood. The damages to the heart and blood vessels in children with essential hypertension are hidden and difficult to detect. We noninvasively examined changes in cardiovascular structure and function in children with hypertension at early stage using ultrasonography. Methods: All patients with essential hypertension admitted from March 2020 to May 2021 were classified into simple hypertension (group 1, n = 34) and hypertension co-existing with obesity (group 2, n = 11) isolation. Meanwhile 32 healthy children were detected as control heathly group (group 3). We used pulse-wave Doppler to measure carotid–femoral pulse wave velocity (cfPWV), intimal–medial thickness (cIMT) and distensibility of carotid artery (CD). Cardiac structure and function (left atrial diameter [LAD], left ventricular mass [LVM], LVM index [LVMI], relative wall thicknes [RWT], end-diastolic left ventricular internal diameter [LVIDd], diastolic interventricular septum thickness [IVSd], diastolic left ventricular posterior wall thickness [LVPWd], root diameter of aorta [AO], E peak, A peak, E' peak, A' peak, E/E' ratio, and E/A ratio) were measured by echocardiography. Results: The cfPWV of children in group 1 and group 2 were significantly higher than healthy children in group 3. Significant differences were observed in LVM, LVMI, RWT, LVIDd, IVSd, LVPWd, LAD, A peak, E' peak, A' peak, and E/E' among three groups. Conclusion: Children and adolescents with essential hypertension demonstrate target organ damages in the heart and blood vessels.
Keywords: Hypertension; Echocardiography; Cardiovascular damage; Children; Noninvasively
Wei Liu and Cui Hou these authors contributed equally to this work.
Essential hypertension (HTN) in adults may begin in childhood (the so-called trajectory phenomenon [[
The diagnostic criteria for HTN in children are not uniform and are generally considered higher than percentile values for blood pressure in this age group. In 2017, Jie Mi et al. [[
Over time, essential hypertension leads from structural changes in heart to systolic and diastolic dysfunctions eventually culminate in heart failure. Although heart failure is uncommon in children and adolescents with hypertension, it is important to assess the presence of early changes in diastolic and systolic function. Hypertension in adults is often associated with the heart and other target organs. However, studies on target organ damage in children with essential hypertension are lacking.
Hypertension can also lead to changes in vascular structure and function. There are multiple models available to assess vascular structure and function, which are divided into three categories: vascular structure, arterial stiffness, and endothelial function. Pulse wave velocity (PWV) is the most commonly measured non-imaging parameter to assess arterial stiffness. Carotid intimal–medial thickness (cIMT) is the primary index for measuring vascular structure.
This study aimed to noninvasively evaluate changes in cardiovascular structure and function in children with hypertension by ultrasonography to verified the target organ damages.
We continously retrospectively studied 45 children (34 simple hypertensive in group 1, 11 hypertensive co-existing with obesity in group 2) with newly diagnosed essential hypertension admitted in the cardiology department in the Children's Hospital of Soochow University from March 2020 to May 2021, and 32 healthy children matched with age and sex were recruited from the community-based population as the control healthy group 3. Clinical parameters (Table 1), including age, gender, body mass index (BMI; kg/m2), blood pressure (BP) and biochemical data on lipids were obtained in all children. Hypertension was diagnosed on systolic and/or diastolic pressure ≥ 95th percentile for sex, age, and height according to the reference value of the Chinese Child Blood Pressure References Collaborative Group
Table 1 The Clinical Characteristics of Children in Three Groups
variables Hypertensive (n = 34) hypertensive + obese (n = 11) Control (n = 32) Sex (male/female) 25/9 6/5 17/14 0.202 Age (years) 11.8 ± 2.6 11.5 ± 3.0 10.9 ± 2.5 0.365 Weight (kg) 59.5 ± 17.6 77.0 ± 22.1 43.0 ± 14.1 0.000 Height (cm) 160.2 ± 17.7 156.9 ± 17.2 152.2 ± 18.2 0.192 BMI (kg/m2) 22.4 ± 3.9 30.6 ± 4.9 18.0 ± 2.8 0.000 SBP(mmHg) 144.4 ± 16.3 144.6 ± 14.0 106.5 ± 11.3 0.000 DBP(mmHg) 85.6 ± 14.1 94.6 ± 13.8 65.9 ± 6.0 0.000 PP(mmHg) 58.8 ± 11.9 50.0 ± 15.4 40.9 ± 10.6 0.000 TG(mmol/L) 1.3 ± 0.7 1.6 ± 0.7 1.3 ± 0.5 0.361 TC(mmol/L) 4.3 ± 1.0 5.0 ± 0.8 4.2 ± 0.7 0.103 HDL(mmol/L) 1.2 ± 0.3 1.2 ± 0.1 1.4 ± 0.3 0.210 LDL(mmol/L) 2.6 ± 0.9 3.4 ± 0.6 2.8 ± 0.4 0.091 drug therapy for hypertension No drugs No drugs - -
Abbreviations: BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, PP Pulse pressure, TG Triglycerides, TC Total cholesterol, HDL High-density lipoprotein cholesterol, LDL Low-density lipoprotein cholesterol. * and
Among the 45 hypertension patients, 8 patients were admitted with obese and 5 children were admitted with dizziness and chest tightness as the chief complaint. 31 patients were admitted with high blood pressure on routine physical examination, and 1 patient was admitted to hospital for digestive tract foreign body. All the children were newly diagnosed with essential hypertension and had not been treated with drugs. They were excluded secondary hypertension, cardiomyopathy, and valvular heart disease at the time of admission to hospital, meanwhile subjects with hyperthyroidism or diabetes mellitus were also excluded.
Irritant drugs and food were not permitted before measurement. Patients were required to sit for 5–10 min in a quiet environment, with the cubital fossa and heart at the same level. A standard clinical cuff sphygmomanometer was used to measure blood pressure in the right upper arm. The chest part of the membrane stethoscope was placed on the medial side of the cubital fossa for brachial artery pulsation (2 cm above the elbow fossa). We took the K1 tone as the standard for systolic blood pressure and the K5 tone as the standard for diastolic blood pressure. We performed measurements twice continuously and averaged the two measurements. The interval between each measurement was 3 min. If the difference between the first two readings was > 5 mmHg, we used the average value after obtaining a third reading. The first diagnosis of hypertension was verified by a third examination.
Echocardiography was performed using a Philips EPIQ7C color Doppler ultrasound machine (Koninklijke Philips Ultrasound Inc., Netherland), equipped with S8-3, S5-1 and L12-5 probes ranging from low to high frequency (3–6 MHz, 1.6–3.2 MHz and 4.4–8.8 MHz, respectively). According to American Society of Echocardiography guidelines for pediatric echocardiogram from 2006 [[
The Doppler spectrum of the mitral valve pulse was recorded in an apical four-chamber view. The peak velocity of the filling peak in the early diastolic period (E) and the peak velocity of the filling peak in the late diastolic period (A) were measured, and the E/A ratio was calculated. Three cardiac cycles were measured, and the average value was used. We used the Tissue Doppler Imaging technique to measure the velocity of the mitral annulus (E') and calculated the E/E' value by combining this with the velocity of early diastolic blood flow (E) through the mitral valve orifice. This study defined left ventricular diastolic dysfunction as an E/E' > 15 or an E/A < 1.0.
The calculations of left ventricular mass (LVM), LVM index (LVMI), and relative wall thickness (RWT) were based on Devereux formulas:
Graph
Graph
Graph
Three cardiac cycles were measured, and the average value was taken. The criterion for left ventricular hypertrophy (LVH) was a LVMI > 38.6 g/m
Carotid–femoral PWV (cfPWV) was calculated as the ratio of the travel distance (D) to carotid–femoral pulse transit time (T). The path length of the direct carotid-femoral distance segment (D) was estimated based on the surface distance (Ds) from the carotid arteral measurement point to the femoral measuremental point using the formula: D = Ds × 0.8 (a correction of the distance for a fixed factor of 0.8 was applicated jn order to encount the simultaneously traveling of the pulse wave from aorta to carotid and to femoral arteries) [[
Graph: Fig. 1 The Measurement Method of Carotid-femoral PWV. A indicate the time measurement of carotid artery from the R wave of QRS to the foot of the waveform. B indicate the time measurement of femoral artery from the R wave of QRS to the foot of the waveform
Patients assumed a supine position to expose the neck. Ultrasonography of the carotid artery lumen was performed, and cIMT of the anterior and posterior walls was measured. At 1–2 cm below the bifurcation plane, the thickness of the internal–medial carotid membrane were automatically measured by the built-in software package.
Carotid distensibility (CD) can be measured by acquiring carotid artery diameter in end diastole and the systo-diastolic change also called distension or the diameter changes of carotid artery (∆D). The systolic and diastolic diameter of carotid artery were manually measured, then calculated ∆D. After that CD is calculated according to the reneman formula:
Graph
where Dd is the end diastolic diameter of the vessel, Ds is the systolic diameter of the carotid artery. PP is the central pulse pressure [[
We used SPSS 25.0 software (SPSS Inc., Chicago, IL) to perform statistical processing of the data. Measurement data are expressed as mean ± standard deviation. As we were primarily interested in comparing both disease groups (hypertension and hypertension + obesity) with the healthy control group, we performed one-way analysis of variance (ANOVA), where the disease groups were considered mutually exclusive. All results are presented from the one-way ANOVA. A P value of < 0.05 was considered statistically significant.
The clinical characteristics and biochemical parameters of hypertension and control groups are shown in Table 1. There was no significant difference in age, sex, height, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL) among the three groups (P > 0.05). There were significant differences in body weight, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) in group 1 and group 2 compared with group 3 (P < 0.05).
There were significant differences in LVM, LVMI, RWT, LVIDd, IVSd, LVPWd, LAD, A peak, E' peak, A' peak and E/E' among the three groups (P < 0.05). LVM, RWT, LVIDd, LVPWd, LAD and E/E' in group 1 and group 2 were significantly higher than the healthy control group. The two hypertension groups were not significantly different from each other. IVSd and LVMI were significantly different among the three groups by S–N-K test. A peak and A' peak were significantly higher in group 1 compared with group 2 and group 3 in a post-hoc analysis. Moreover, E' peak was significantly lower in group 2 compared with group 1 and group 3. However, there was no difference in AO, E peak and E/A ratio among the three groups (Table 2).
Table 2 Comparison of Cardiac Structure and Diastolic Function in Three Groups
variables Hypertensive (n = 34) Hypertensive + Obese (n = 11) Control (n = 32) LVM (g) 128.1 ± 37.8 142.9 ± 51.0 82.5 ± 28.1 0.000 LVMI (g/m2.7) 34.1 ± 7.0 43.3 ± 11.6 26.2 ± 6.1 0.000 RWT 0.36 ± 0.058 0.39 ± 0.057 0.30 ± 0.039 0.000 LVIDd (mm) 46.3 ± 4.6 46.1 ± 6.1 42.4 ± 4.7 0.006 IVSd (mm) 8.2 ± 1.6 9.3 ± 1.0 6.6 ± 1.1 0.000 LVPWd (mm) 8.1 ± 1.4 8.4 ± 1.9 6.3 ± 1.2 0.000 AO (mm) 22.7 ± 3.0 22.1 ± 2.5 20.1 ± 4.1 0.087 LAD (mm) 28.2 ± 3.8 28.2 ± 4.3 23.5 ± 3.4 0.000 E peak (m/s) 111.2 ± 16.1 103.9 ± 17.1 106.2 ± 17.1 0.352 A peak (m/s) 68.3 ± 20.6 55.6 ± 17.2 51.2 ± 11.9 0.001 E' peak (cm/s) 12.6 ± 2.1 10.5 ± 1.4 13.9 ± 1.8 0.000 A' peak (cm/s) 8.1 ± 1.7 6.4 ± 1.3 5.9 ± 1.5 0.000 E/E' 9.0 ± 1.6 10.0 ± 1.6 7.7 ± 1.1 0.000 E/A 1.7 ± 0.5 2.2 ± 1.1 2.2 ± 1.0 0.067
Abbreviations: LVM Left ventricular mass, LVMI Left ventricular mass index, RWT Relative wall thickness, LVIDd Left ventricular internal diameter at end-diastole, IVSd Diastolic interventricular septum thickness, LVPWd Diastolic left ventricular posterior wall thickness, AO diameter of aortic root, LAD Left atrial diameter, E peak E peak of mitral valve pulse by doppler spectrum, A peak A peak of mitral valve pulse by doppler spectrum, E' peak E' peak of mitral valve pulse by tissue doppler imaging, A' peak: A' peak of mitral valve pulse by tissue doppler imaging, E/E' E peak/E' peak, E/A E peak/A peak. * and
A 0.31 cut-off value of RWT had 85.7% sensitivity and 77.4% specificity for hypertension patients. A cut-off value of cfPWV is 4.55 m/s, and this value had 88.9% sensitivity and 53.6% specificity for hypertension patients. 2 of 11 children in HTN + Obese group were concentric hypertrophy (2/11, 18.1%), 2 children were eccentric hypertrophy (2/11, 18.1%) and 1 child were concentric remodeling (1/11, 9.0%), respectively. Of the 34 HTN patients, 2, 6 and 5 children had concentric hypertrophy(2/34, 5.9%), eccentric hypertrophy(6/34, 17.6%) and concentric remodeling(5/34, 14.7%), respectively.
There were significant differences in cfPWV among the three groups. cfPWV was significantly higher in both hypertension groups in comparison with the healthy control group (Fig. 2). There were no significant differences in cIMT, ∆D% and CD among three groups as shown in Table 3.
Graph: Fig. 2 The Differences of PWV in The Three Groups. Column bar graph shows the differences of PWV among the Healthy group, the Hypertensive group, and the Hypertensive and Obese group. * indicate P value < 0.01
Table 3 Vascular Structure and Function Difference in Three Groups
variables Hypertensive (n = 34) hypertensive + obese (n = 11) Control (n = 32) IMT (mm) 0.46 ± 0.05 0.46 ± 0.05 0.44 ± 0.05 0.355 PWV (m/s) 5.4 ± 1.0 5.7 ± 1.2 4.6 ± 0.7 0.001 ∆D% 16.8 ± 4.3 15.4 ± 3.7 16.1 ± 4.6 0.640 CD 9.6 ± 5.6 13.6 ± 7.3 12.0 ± 7.4 0.177
Abbreviations: IMT intima-media thickness, PWV carotid-femoral pulse wave velocity; ∆D%: Rates of diameter changes of carotid artery(%); CD: Carotid distensibility. *indicates there is statistical difference compared with the healthy group and P < 0.05
In 2017, with the blood pressure standards for Chinese children by sex and age, and height developed, hypertension in children and adolescents aroused great concern in pediatrics. It is the most widely used diagnostic criteria. Our definition of hypertension is based on this criterion, and our study found the structural changes in heart, cardiac diastolic dysfunction and vascular stiffiness.
There were significant differences in LVM, LVMI, RWT, LVIDd, IVSd, LVPWd, LAD in hypertensive children. An increase in afterload caused by high blood pressure leads to an increase in ventricular wall stress and eventually changes in myocardial structure, which is called left ventricular hypertrophy or remodeling. In patients with continuous hypertension in the systemic circulation, cardiac afterload increases, resulting in an increase in left ventricular end-systolic residual blood volume and diastolic volume. This in turn results in left ventricular compensatory hypertrophy, a decrease in myocardial elasticity, and an increase in left ventricular volume. Then an increasing in left atrial residual blood volume at the end of diastole and gradual left atrial enlargement maintain an atrioventricular pressure difference and excessive cardiac output [[
High blood pressure leads to an increase in myocardial mass, which is reflected by an increase in LVIDd, IVSd, LVPWd of cardic morphology and structure. An increase in LVM is a manifestation of left ventricular hypertrophy (LVH) and an independent risk factor for LVH [[
RWT is also an important indicator of cardiovascular remodeling in hypertension. Although the RWT of hypertensive groups were higher than that of the control group, their values were all within the normal range in our study. A 0.31 cut-off value had 85.7% sensitivity and 77.4% specificity for hypertension patients while a 0.41 cut-off value only had 21.4% sensitivity and 100% specificity. We should establish a new cut-off value for RWT in children with hypertension.
Among children with 45 hypertension, 12 (12/45, 26.7%) ones had LVH and 6 children(13.3%) had left ventricular remodeling. The incidence of LVH was consistent with the 27% reported by Sorof [[
Studies had shown a positive correlation between high blood pressure and obesity in children and adolescents [[
In addition to changes in left ventricular structure, changes in left atrial structure and function have been confirmed as early pathological changes in patients with hypertension [[
Previous study defined left ventricular diastolic dysfunction as an E/E' of > 15 or an E/A of < 1.0. We compared E/E' ratio between the three groups and found that although E/E' in children with hypertension was < 15, children in these groups had a significantly increased E/E' compared with the healthy group. This indicated that left ventricular diastolic function decreases in the groups with hypertension. We found that the E' peak of the ventricular septum in group 2 was significantly decreased, and A' peak of the ventricular septum and A peak of mitral valve were higher in group 1 than the other two groups. These results proved that increased left atrial pressure and impaired left atrial function were common in children with hypertension. There was no significant difference in E/A ratio between the three groups but the E/E' in children with hypertension whatever obese or not was significantly increased. E/A probably is less sensitive than E/E' as previously reported literatures [[
In addition to the above cardiac damage, hypertension can also cause changes in vascular structure and function. Arterial stiffness or arterial compliance can be measured as PWV which was the speed of pulse wave transmitted across the length of the arterial tree. A higher PWV indicates a stiffer blood vessel, contributing to increased afterload and subsequent cardiac remodeling [[
The predictors of PWV were age, SBP, heart rate, BMI, antihypertensive treatment and drug classes, not related to race, gender, smoking, dyslipidaemia, diabetes, kidney disease, or genetic factors. Two factors were identified as being responsible for accelerated progression of PWV after correction for HR: age and BP values [[
Doppler methods to assess cfPWV is feasible. It is not the preferred one compared to the automatic one using tonometey or pressure sensor, but it's a good replacement to assess cfPWV when you don't have the automatic machine. Although Doppler-PWV measurements determined more evaluation error than ones of applanation tonometry, piezoelectric mechano-transducer or cuff-based oscillometry, Doppler-PWV exactly showed close correlation with invasive assessment as well. Styczynski G. et al. [[
In our study, absolute cfPWV values in the three groups were much lower than the threshold for severe cardiovascular events in adults (10 m/s), but both HTN groups had significantly higher values than the healthy children. We found that 4.55 m/s cut-off value of cfPWV had 88.9% sensitivity and 53.6% specificity for hypertension patients. Although 10 m/s cut-off value had gained independent predictive value for fatal and nonfatal cardiovascular events in hypertensive adult patients, this threshold did not distinguish HTN let alone stratify them in child and adolescents. We need more studies of vascular PWV in children to further determine the cut-off value and reclassify intermediate risk patients into higher or lower target organ damage risk.
There were no significant difference in carotid IMT and CD between the three groups of children, probably because our sample size was too small to stratified analysis based on age, weight and height. Carotid ultrasound measurement of IMT is the most commonly used assessment of vascular structure, since it is considered to reflect overall atherosclerotic burden. Currently, many machines had built-in software that can automatically measure IMT to reduce manual measurement error. Kollias et al. [[
Carotid distensibility is probably the most standardized and used carotid arterial stiffness index. Measuring CD means quantify changes in arterial diameter in response to BP changes from diastole to systole. Like cIMT distensibility has also been related to all cause mortality, cardiovascular morbidity and mortality and the presence and severity of cardiovascular diseases in adults [[
There are some limitations of this study that should be noted. First, this was a retrospective study, thus selection bias was inevitable. Second, the sample size was small, and the regional distribution was uneven, and because of the small sample size of children with obesity, we did not evaluate the effects of obesity on cardiovascular structure and function alone. Finally, a coefficient of variation of the mean value of the intra-session within- and between-operator variability respectively was missing and there was no agreement data between the Doppler technique and tonometry or piezoelectric mechano-transducer technique, as well as intra- / inter- reproducibility for our center when assessing cfPWV. In view of these limitations, follow-up studies should expand the sample size and increase the analysis of cardiovascular effects in individuals with obesity. Our future research directions include longitudinal studies to assess changes in cfPWV over time in healthy children and children with hypertension and obesity. We can do further consistency study between ultrasonographic and automatic tonometey methods.
In conclusion, although essential hypertension has no obvious clinical symptoms, Doppler ultrasonography showed that the heart and blood vessels of children with hypertension undergo structural and functional changes. Our data provide fundamental support for the argument that hypertension is having an effect on target organ damage of cardiovascular system in adolescents and young adults.
Doppler ultrasonography shows that the heart and blood vessels of children with hypertension undergo structural and functional target organ damages.
Not applicable.
YYD, as the corresponding author, was the chief investigator. WL, CH, MH, QQX, HW, PPG, LS, and HTL were co-investigators. WL, CH, QQX, HW, and PPG collected and managed ultrasonography data. MH, LS, and HTL collected and analyzed clinical data. WL drafted the manuscript. HTL participated in data interpretation and manuscript drafting. All authors read and approved the final manuscript. WL and CH equally contribute to this study as first co-authors.
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81870365 and 81970436), Young Scientists Fund of the National Science Foundation of China (Nos. 81800437 and 81900450), and Jiangsu Provincial Medical Young Talents (QNRC2016764).
The data and material in the current study are available from the corresponding author on reasonable request.
This retrospective study was approved by the Ethics Committee of the Children's Hospital of Soochow University with a waiver for written informed consent obtained from each participant's legal guardian/next of kin.
Not applicable.
The authors declare that they have no competing interests.
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By Wei Liu; Cui Hou; Miao Hou; Qiu-Qin Xu; Hui Wang; Pei-Pei Gu; Ling Sun; Hai-Tao Lv and Yue-Yue Ding
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