Abstract
The aim of this study was to compare ambulatory blood pressure (BP) monitoring (ABPM) data and determine which hypertension type is a risk factor in target organ damage. A total of 82 children (47 boys) with suspected hypertension based on office BP measurements and considered hypertensive by ABPM were studied. Target organ damage included the following: 35.3% hypertensive retinopathy, 25.6% microalbuminuria, 15.8% increased left ventricular mass index, 29.2% increased carotid intima‐media thickness (cIMT), 24.3% high augmentation index (AIx), and 19.5% high pulse wave velocity (PWV). The association between BP load, PWV, and cIMT was statistically significant. There were significant correlations between daytime systolic BP load, PWV, AIx, and cIMT. A statistically significant difference was also detected between nighttime systolic BP load, PWV, and cIMT values and nighttime diastolic BP load levels and values of AIx and cIMT. There was also a statistically significant difference between the high level of nighttime diastolic BP load and cIMT. The authors found that target organ damage was seen more often in children with primary hypertension who had systolic loads.
Pediatric hypertension (HTN) is a significant risk factor for cardiovascular system disorders and cerebrovascular diseases that occur in adulthood. Accurate evaluation of HTN in pediatric patients is fundamental in the prevention of cardiovascular and renal diseases.1
Ambulatory blood pressure (BP) monitoring (ABPM) has been shown to be a powerful tool in the evaluation and treatment of HTN in pediatric patients and adolescents.2, 3 Pediatric studies have demonstrated the relationship between ambulatory BP and target organ damage, which have established a close correlation between ambulatory BP with target organ damage and cardiovascular outcome.4 The aim of our study was to describe the earliest damage that occurs during early‐onset (pediatric) HTN.
ABPM is useful in the evaluation of hypertensive target organ damage, along with identifying white‐coat HTN (WCH), masked HTN, and nondipping BP pattern.5, 6
ABPM may be a better predictor of patients at the highest risk for target organ damage than office BP measurement. It is stated that ABPM is a determinant7 of cardiovascular risk in adults and is associated with target organ damage, particularly left ventricular hypertrophy (LVH) in children.8, 9, 10
Another parameter obtained from ABPM is the arterial stiffness index. Arterial stiffness index is associated with arterial stiffness (pulse wave velocity [PWV]) and predicts cardiovascular mortality in adults. Arterial stiffness index was found to be higher in children with HTN.3
This study aimed to compare ABPM data with those of target organ damage and determine which HTN type is a risk factor in target organ damage. Because we were uncertain that both diastolic load and dipping BP could be risk factors for target organ damage, we aimed to investigate the most common cause of target organ damage in HTN.
Materials and Methods
This study was carried out prospectively between the dates of February 2011 and April 2013 in the Department of Pediatric Nephrology, Faculty of Medicine, at Ege University. A total of 82 pediatric patients (aged 6–17, body height >120 cm) who were suspected of having HTN based on office BP measurements were referred to the HTN center for the evaluation of HTN and confirmed as hypertensive by ABPM. A total of 82 patients with HTN were included in the study and evaluated with regard to target organ damage. Secondary causes of HTN were excluded by history, physical examination, urinalysis, serum chemistries, renal ultrasonography, and other tests as indicated, according to guidelines from the Working Group on High Blood Pressure in Children and Adolescents.10 Patients with acute or chronic illness or on drug treatment that might affect BP levels (eg, nonsteroidal anti‐inflammatory drugs, corticosteroids, bronchodilators) in the past 15 days before study entry were excluded. Patients with obesity or secondary HTN and under medical treatment for HTN were excluded from the study. Patients' body mass index (BMI) was calculated as weight (kg)/height2 (m2). BMI percentile was determined for each patient according to the 2000 Centers for Disease Control and Prevention growth charts.11 Obesity was defined as a BMI ≥95th percentile for age and sex. The study was carried out in accordance with the regulation on patients' rights and ethical standards.
Office BP was measured using standard auscultatory technique by a physician with a stethoscope and a sphygmomanometer on at least three valid systolic readings and three valid diastolic readings. Multiple measurements were averaged when taken on one occasion. BP classification was made after all measurements at different occasions were averaged. Office HTN was determined when average systolic BP (SBP) or diastolic BP (DBP) levels were ≥95th percentile for age, sex, and height, as stipulated in the Report by the Second Task Force on Blood Pressure Control in Children.12
ABPM was performed in all patients and 24‐hour BP monitoring was performed in a clinical environment using a Spacelabs 90217 device (Spacelabs Healthcare, Redmond, WA). The BP cuff chosen was two thirds of the upper arm length and was attached to the nondominant arm of the patient. Measurements were performed every 20 minutes during waking hours and every 30 minutes during sleeping hours. After 24 hours of monitoring, they were transferred to a computer program. Successful monitoring was defined as at least one successful reading for each hour of the 24‐hour period. The patients were instructed to maintain their typical daily routines during the measurements and to note their activities and locations in a diary. According to participants' diary, the periods of daytime and nighttime were determined as the waking and sleeping times of the patient, respectively, and mean values of 24‐hour, daytime, and nighttime BPs were calculated. SBP and DBP load was calculated as the percentage of readings exceeding the 95th percentile for age, sex, and height percentile during each period.13 The readings were compared with established norms to determine associated BP load, defined as the percentage of valid ambulatory BP measures above the set 95th percentile of BP for age, sex, and height, which is also provided in the report for both day and night and over the entire 24 hours. ABPM also provides information on nocturnal dipping (ie, the normal reduction in BP that occurs with sleep) for both SBP and DBP. Nocturnal dipping was defined as the percent decrease in BP during nocturnal sleep and calculated as (daytime BP−nighttime BP)/daytime BP)×100%. Nondipping describes a pattern of a blunted sleep‐related fall in mean SBP or DBP (<10%). The smoothed age‐ and sex‐specific 95th percentiles of Wühl and colleagues,14 which were calculated from the original data from Soergel and colleagues,15 were the preferred reference data. Age‐ and sex‐specific estimates of the distribution median (M), coefficient of variation (S), and degree of skewness (L) were obtained by a maximum‐likelihood curve‐fitting technique. The estimates of L, M, and S can be used to normalize ABPM data to sex and age or height. According to ABPM results, the diagnosis of HTN was established following the guidelines of Lurbe and colleagues.16 BP load analyses were conducted using 25% as the cutoff value. In adults, the BP load is more predictive of hypertensive end‐organ injury than is mean BP, and normotension defined solely as mean 24‐hour BP <95th percentile may be insensitive to the risk of hypertensive end‐organ damage. BP loads in excess of 25% are typically considered elevated and loads in excess of 50% have been demonstrated to be predictive of LVH. Children with normal mean BP and elevated loads can be at risk for target organ damage and may need antihypertensive therapy, even if they do not fit into the proposed criteria for the diagnosis of ambulatory HTN.
Evaluation of Target Organ Damage
Microalbumin level was examined by collecting a 24‐hour urine sample from all patients. Participants were asked to provide a 24‐hour collection during the period starting from the second urine sample on the morning of the collection day and ending with the first urine sample from the following morning. They were instructed to report whether the 24‐hour collection was complete and whether the day of urine collection day was unusual for them. Urine microalbumin excretion was measured by immune turbid metric method. The presence of microalbuminuria was defined as a microalbumin level exceeding 20 µg/min.
Carotid‐femoral PWV and AIx were measured using a VICORDER device (SMT Medical, Wuerzburg, Germany). Results were obtained through automatic calculation by recording carotid‐femoral pulse waves using an oscillometric method.
The mean values of arterial stiffness index of healthy children, which were presented in a thesis study conducted by Riggio and colleagues,17 were obtained for the reference values of the AIx. Normal values of healthy children (aged 3–18 years) were used by Reusz and colleagues for the PWV values.18
Carotid Ultrasonography
Ultrasound examinations of both carotid arteries were performed using a high‐resolution Duplex scanner (model SSA‐390A; Toshiba, Tokyo, Japan) with the probe at a frequency of 7.5 MHz for the B‐scan. All measurements were performed by two experienced sonographers who were unaware of the patients' clinical data. The carotid arteries were carefully examined according to wall changes from different longitudinal and transverse views. The common carotid artery, the carotid bulb, and the internal and external carotid arteries were studied in all patients. Each ultrasound image was taken during the end‐diastolic phase. Normal values for age, height, and sex were used as a reference for normal levels of carotid intima‐media thickness (cIMT) in healthy children.19
Echocardiography
All measurements were performed by the same pediatric cardiologist using two‐dimensional M‐mode echocardiography with 3.5‐mHz transducer (HP SONOS 1000 System, Philips, Best, The Netherlands). Echocardiographic parameters were measured by two experienced investigators who were unaware of the patients' clinical data including office and ambulatory BP. Measurements consisted of interventricular septal thickness (IVSTd), posterior wall thickness (PWTd), left ventricular (LV) diameter at end‐diastole (LVDd), and LV diameter at end‐systole (LVDs). LV mass was calculated using the formula validated by Devereux and Reichek20: LV mass (g)=1.04×{(IVSTd+PWTd+LVDd)3+LVDd3}−13.6. LV mass was indexed for height2.7 to minimize the interference of age, sex, and obesity.17 LVH was defined as LV mass index (LVMI) ≥36.88 g/m2.7 in women and ≥39.36 g/m2.7 in men (sex‐specific 95th percentile for LVMI in normal children and adolescents).21
Eye‐ground evaluation was performed by the same ophthalmologist, who was blinded to patients' clinical data, using a direct ophthalmoscope after dilating the pupil with a cycloplegic drop in a dark room. Retinal lesions were classified according to Keith‐Wagener‐Barker staging described by Keith and colleagues in 1939.22 Detecting the findings of hypertensive retinopathy on funduscopic examination was considered as the presence of hypertensive retinopathy.
Target organ damage was defined as ocular, renal, or cardiac or presence of one or more target organs in one individual. Diagnosis of target organ damage was established in all children during the initial standardized diagnostic evaluation as mentioned above.16
The study was conducted in compliance with the regulation of patient rights and ethical rules. Local ethics committee approval was received.
Statistical Analysis
Statistical analyses were performed using SPSS 15.0 (IBM, Armonk, NY). Definitive analyses, mean, standard deviation, and frequency tables were described. Student t test was used for the variables that followed normal distribution in between‐group comparisons and in independent groups. Definitive statistics were expressed as mean±standard deviation. Significance test of the difference between rates was used for advanced statistical analysis (Fisher exact test, Ki kare), and P<.05 was considered significant on statistical evaluations. The correlations between variables were examined using Kruskal‐Wallis variance analysis and Pearson and Spearman rank correlation analysis based on the distribution of the quantitative data.
Results
A total of 82 patients were included in this study (47 boys, 35 girls). The age range of the patients was 6 to 17 years and the mean age was 13.3±4.1 years. The demographic features of the patients are shown in Table 1.
Table 1.
Demographic Features of Patients
| Male, No. (%) | 47 (57.3) |
| Female, No. (%) | 35 (6.42) |
| Age, y | 13.3±4.1 |
| Birth weight, g | 2979.6±723.7 |
| Body weight, kg | 64.1±24.9 |
| Height, cm | 147.8±20.1 |
| BMI, kg/m2 | 22.7±5.3 |
| Family history, % | |
| Mothers with HT | 19 (15.8) |
| Fathers with HT | 17 (14.1) |
| Triglycerides, mg/dL | 96.4±45.7 |
| Total cholesterol, mg/dL | 163.9±27.7 |
| HDL, mg/dL | 44.5±10.8 |
| LDL, mg/dL | 107.7±30.2 |
| Creatinine, mg/dL | 0.65±0.29 |
Abbreviations: BMI, body mass ındex; HDL, high‐density lipoprotein; HT, hypertension; LDL, low‐density lipoprotein. Values are expressed as means±standard deviations unless otherwise indicated.
Of all the patients, 64 (78.04%) had daytime SBP load >25% and 34 (41.1%) had >50% daytime SBP load, while 78 (95.1%) had nighttime SBP load >25% and 42 (51.2%) had >50%. A total of 30 patients (36.5%) had daytime DBP load >25%, 11 (13.4%) had >50% DBP load, while 54 (65.8%) had nighttime DBP load >25% and 24 (29.2%) had >50% nighttime DBP load (Table 2).
Table 2.
Mean ABPM Values of Patients
| Mean±SD | |
|---|---|
| Daytime systolic BP, mm Hg | 118.7±12.0 |
| Daytime diastolic BP, mm Hg | 70.6±11.2 |
| Nighttime systolic BP, mm Hg | 110.4±11.2 |
| Nighttime diastolic BP, mm Hg | 63.4±12.0 |
| Daytime systolic load, % | 32.9±28.8 |
| Daytime diastolic load, % | 19.5±22.5 |
| Nighttime systolic load, % | 38.2±29.7 |
| Nighttime diastolic load, % | 19.5±22.5 |
Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; SD, standard deviation.
A total of 51 patients had nighttime and/or daytime SBP load and/or DBP load >50% during ABPM.
It was determined that 59 of 82 patients found to have HTN by ABPM had nondipping and 23 had dipping HTN. In patients diagnosed as hypertensive with ABPM, nondipper HTN frequency was determined to be 71.9%, while dipper HTN frequency was 28.1%.
Target organ damage was detected in 63 of 82 patients included in the study. The frequency of target organ damage was determined as 76.8%. It was detected that 29 patients (35.3%) had hypertensive retinopathy, 21 (25.6%) had microalbuminuria, and 13 (15.8%) had increased LVMI (Table 3).
Table 3.
Evaluation of End‐Organ Involvement in Patients
| End‐Organ Involvement | No. (%) |
|---|---|
| Retinopathy | 29 (35.3) |
| Stage 1 | 11 |
| Stage 2 | 18 |
| Nephropathy | |
| Microalbuminuria | 21 (25.6) |
| Cardiopathy | |
| Increased left ventricular mass index | 13 (15.8) |
Sixty of 82 patients were detected to have vascular changes. The frequency of vascular involvement in HTN was determined as 73.1%. It was observed that 29 patients (29.2%) had increased cIMT, 20 (24.3%) had high AIx, and 16 (19.5%) had high PWV.
PWV and cIMT levels were found to be significantly higher when target organ damage values of patients who had BP load were >50% compared with <50%. The association between BP load, PWV, and cIMT was shown to be statistically significant. No statistically significant difference was found between BP load, LVMI, and microalbumin values (Table 4).
Table 4.
Comparison of BP Loads With Target Organ Damage Values
| BP Load <50% (n=51) | BP Load >50% (n=31) | P Value | |
|---|---|---|---|
| Microalbuminuria, µg/min | 12.480±16.3819 | 10.849±10.4022 | >.05 |
| AIx, % | 7.94±4.58 | 9.57±4.388 | .051 |
| PVW, m/s | 4.81±0.77 | 5.14±0.83 | .031 |
| cIMT, mm | 0.45±0.11 | 0.51±0.11 | .004 |
| LVMI, g/m2.7 | 18.30±5.38 | 18.75±5.63 | >.05 |
Abbreviations: AIx, augmentation index; BP, blood pressure; cIMT, carotid intima‐media thickness; LVMI, left ventricular mass index; PWV, pulse wave velocity. P value adjusted for effects of covariates. Bold values indicate significance.
Target organ damage was detected in 39 of 59 patients (66.1%) with nondipping HTN and in 14 of 23 patients (60.8%) with dipping HTN (P>.05).
BP loads were compared with target organ damage and there was a significant correlation between daytime SBP load, PWV, AIx, and cIMT. A statistically significant difference was detected between nighttime SBP load, PWV, and cIMT values. The correlation between SBP loads and target organ damage is shown in Table 5. A statistically significant difference was detected between nighttime DBP load levels and values of AIx and cIMT. There was a statistically significant difference between the high level of nighttime DBP load and cIMT. The correlation between DBP loads and target organ damage is shown in Table 6.
Table 5.
Correlation Between Systolic Blood Pressure Loads and Target Organ Damage
| BP Load, % | Daytime Systolic Load | Nighttime Systolic Load | |||
|---|---|---|---|---|---|
| Mean | P Value | Mean | P Value | ||
| Microalbuminuria, µg/min | <25 | 11.51±16.73 | >.05 | 12.5±14.82 | >.05 |
| >25 | 12.03±12.02 | >.05 | 11.43±13.91 | >.05 | |
| AIx, % | <25 | 7.71±4.33 | >.05 | 7.32±4.01 | >.05 |
| >25 | 9.41±4.62 | .037 | 9.34±4.75 | .021 | |
| PWV, m/s | <25 | 4.71±0.73 | >.05 | 4.76±0.65 | >.05 |
| >25 | 5.02±0.85 | .047 | 5.01±0.83 | >.05 | |
| LVMI, g/m2.7 | <25 | 17.93±4.64 | >.05 | 18.28±4.77 | >.05 |
| >25 | 18.93±6.03 | >.05 | 18.64±5.86 | >.05 | |
| cIMT, mm | <25 | 0.43±0.12 | >.05 | 0.42±0.15 | >.05 |
| >25 | 0.53±0.13 | .018 | 0.41±0.12 | .03 | |
Abbreviations: AIx, augmentation index; BP, blood pressure; cIMT, carotid intima‐media thickness; LVMI, left ventricular mass index; PWV, pulse wave velocity. P value adjusted for effects of covariates. Bold values indicate significance.
Table 6.
Correlation Between Diastolic Load and Indicators of Target Organ Damage
| Nighttime Diastolic Load | Daytime Diastolic Load | |||
|---|---|---|---|---|
| Mean | P Value | Mean | P Value | |
| Microalbuminuria, µg/min | ||||
| <25% | 10.36±13.55 | >0.05 | 12.62±16.60 | >0.05 |
| >25% | 16.14±15.55 | >0.05 | 10.73±10.25 | >0.05 |
| AIx, % | ||||
| <25% | 7.99±3.98 | >.05 | 8.35±4.27 | >.05 |
| >25% | 10.57±5.59 | .007 | 8.98±4.90 | >.05 |
| PWV, m/s | ||||
| <25% | 4.86±0.75 | >.05 | 4.82±0.73 | >.05 |
| >25% | 5.21±0.092 | >.05 | 5.10±0.87 | >.05 |
| LVMI, g/m2.7 | ||||
| <25% | 18.10±5.22 | >.05 | 18.06±5.39 | >.05 |
| >25% | 19.68±6.08 | >.05 | 19.02±5.57 | >.05 |
| cIMT, mm | ||||
| <25% | 0.46±0.11 | >.05 | 0.45±0.11 | >.05 |
| >25% | 0.52±0.101 | .007 | 0.52±0.10 | .001 |
Abbreviations: AIx, augmentation index; BP, blood pressure, cIMT, carotid intima‐media thickness; LVMI, left ventricular mass index; PWV, pulse wave velocity. P value adjusted for effects of covariates. Bold values indicate significance.
Discussion
Pediatric HTN, which is an important risk factor for the cardiovascular systemic diseases and cerebrovascular diseases seen in adulthood, has been found to be an etiologic factor for 50% of end‐stage renal failure in adults. The present study contributes to the literature by determining the frequency of pediatric HTN, the frequency of target organ damage in masked HTN, and the degree of functional changes in the cardiovascular system.
Diagnosis of HTN is one of the main indications for the implementation of ABPM in children and adolescents. ABPM is particularly useful in the evaluation of hypertensive target organ damage and in identifying WCH, masked HTN, and nondipping BP pattern. ABPM should also be performed in children and adolescents with suspected autonomic neuropathy.
In the present study, we provided information that HTN in children is related to target organ damage, suggesting an adverse effect on cardiac structure at early ages. To the best of our knowledge, this is the first study to evaluate the presence of target organ damage in children and adolescents who were diagnosed as hypertensive by ambulatory BP measurements. Long‐term observation of HTN in pediatric patients for cardiovascular morbidities including several practical issues regarding the length of follow‐up, association between BP levels, and the risk of future cardiovascular disease has not yet been established.23
There are sufficient data that show the close link between elevated BP levels in childhood and the risk for future target organ damage. Pooled data from longitudinal epidemiological studies of cardiovascular risk factors in youths from the International Childhood Cardiovascular Cohort (i3C) Consortium demonstrated that higher BP measured at as young as 12 years predicted increased adult cIMT.24 In our study, cIMT, considered an early indicator of cardiac involvement, was detected to have 29.2% frequency among other signs of target organ damage. A statistically significant difference was detected between cIMT and both daytime and nighttime SBP and DBP loads. In addition, there were significant correlations detected between the values of cIMT, PWV, AIx, and LVMI. Recent studies have demonstrated that increased cIMT is an indicator of subclinical atherosclerosis and manifests even in moderate‐risk groups. cIMT has been shown to be the most affected parameter during pediatric HTN and, therefore, it has to be examined for the evaluation of target organ damage.
It is well‐known that cardiovascular events occur frequently in the early morning when BP increases rapidly. Kario and colleagues25 have shown that the morning surge in BP is independently associated with silent and clinical cerebrovascular disease, and morning HTN is the strongest independent risk factor for stroke in elderly hypertensive patients. It is also reported that the morning rise in BP correlates with LVMI or LV hypertrophy in hypertensive patients,26 and high morning BP is associated with a loss of functional independence in elderly patients.27 Therefore, morning HTN seems to play a role in target organ damage and cardiovascular events.
ABPM BP loads were compared with target organ damage. There was a relationship detected between high level of daytime systolic and diastolic load, cIMT, and AIx. In addition, correlation between daytime diastolic load and cIMT was detected. It was found that the high level of daytime systolic load most often caused target organ damage. The correlation between high level of systolic load and target organ damage was demonstrated in our study. We believe that high level of daytime systolic load leads to vascular function disorders. PWV, AIx, and cIMT should be assessed particularly in the event of a high level of SBP load in children.
In our study, no significant correlation was found between daytime systolic load and LVMI. However, we found a strong correlation between daytime SBP load and PWV, AIx, and cIMT in children with primary HTN. There are limited data on the relationship between daytime SBP load of children and target organ damage. Some studies have suggested that there is a close link between ABPM parameters and nighttime SBP load and left ventricular hypertrophy in children.28
We found a strong correlation of daytime SBP load with PWV, AIx, and cIMT. To the best of our knowledge, our study serves as the first study conducted on this subject. There was a strong relationship found between nighttime BP load and target organ damage in a study of 3468 hypertensive adults.29 Several clinical studies carried out on adult HTN have reported a positive association between daytime SBP load and target organ.30, 31, 32 A strong correlation between daytime SBP load and target organ damage was demonstrated in pediatric primary HTN. The reason daytime SBP load has a strong association with target organ damage compared with nighttime SBP can be explained by daytime SBP variability caused by physical activities during the day.33, 34
A number of studies have demonstrated that nondipping pattern or high level of nighttime BP is associated with advanced organ damage and poor prognosis.23, 35, 36 Unlike our study, the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study suggested that the contribution of daytime BP to cardiovascular mortality was relatively weak compared with nighttime BP.37
SBP has been demonstrated to independently determine cIMT in both children38 and adolescents.39 Changes in vascular function also occur at higher levels of childhood BP, including reduced brachial artery distensibility,40, 41 higher PWV,42, 43 and increased AIx,44 all of which indicate increasing arterial stiffness. This is relevant to future cardiovascular disease, because increased vascular thickness45 and stiffness46 are associated with higher LVM in adolescents, a risk factor for future adult cardiovascular disease. BP loads in excess of 25% are typically considered elevated47 and loads in excess of 50% have been demonstrated to be predictive of LVH.7 Children with normal mean BP and elevated loads can be at risk for target organ damage and may need antihypertensive therapy, even if they do not fit into the proposed criteria for the diagnosis of ambulatory HTN.
If other studies carried out on this subject support the findings presented above, we believe that keeping daytime SBP load at low levels may prevent future target organ damage in children with primary HTN.
One possible limitation of our study is selection bias because our population was a referral and not a general population sample.
Conclusions
In this study, we examined our experience with the use of ABPM in the routine evaluation and management of childhood HTN. Children with primary HTN who had systolic load were most likely to have target organ damage. Daytime systolic HTN seems to have a strong association with target organ damage. It is important to identify and evaluate individuals with daytime systolic HTN and determine the appropriate treatment for each patient according to the cause of this condition.
Disclosures
The authors have no financial conflicts of interest.
J Clin Hypertens (Greenwich). 2015:760–766. DOI: 10.1111/jch.12608. © 2015 Wiley Periodicals, Inc.
[Correction added after initial online publication on July 3, 2015: The surname of the fourth author was changed from Bozovalı to Bozabalı.]
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