A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension.

BACKGROUND: Primary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the comorbid cardiovascular disease risk factors that confound studies in adults. METHODS: Youths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTS: VASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONS: The findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

Ambulatory Blood Pressure and Number of Subclinical Target Organ Injury Markers in Youth: The SHIP AHOY Study.

Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75 th percentile), mid- (75 th -90 th percentile) and high-risk (>90 th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers. Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.

Screening and Management of Pediatric High Blood Pressure-Challenges to Implementing the Clinical Practice Guideline.

PURPOSE OF REVIEW: Elevated blood pressure (BP) and hypertension in childhood convey risk for hypertension and cardiovascular events in adulthood. Early recognition of abnormal BPs is key to preventing or lessening this risk. However, the process for making the diagnosis of hypertension is complex, and overall adherence to the 2017 American Academy of Pediatrics Clinical Practice Guidelines (CPG) is poor. We will review obstacles to adherence to the CPG and approaches designed to improve the diagnosis and management of hypertension in children. RECENT FINDINGS: Baseline data from the multi-center quality improvement intervention, "Boosting Primary Care Awareness and Treatment of Hypertension" (BP-CATCH), demonstrate that childhood hypertension remains underdiagnosed. Other studies confirm a lack of compliance with the process outlined in the CPG. The provision of electronic prompts, coaching, and education results in modest improvements. The combination of embedded medical record tools and education seems to offer the most hope for improvement.

Association of Blood Pressure-Related Increase in Vascular Stiffness on Other Measures of Target Organ Damage in Youth.

BACKGROUND: Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)-related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. METHODS: Participants were stratified by systolic BP into low- (systolic BP <75th percentile, n=155), mid- (systolic BP ≥80th and <90th percentile, n=88), and high-risk BP categories (≥90th percentile, n=139), based on age-, sex- and height-specific pediatric BP cut points. Clinic BP, 24-hour ambulatory BP monitoring, anthropometrics, and laboratory data were obtained. Arterial stiffness measures included carotid-femoral pulse wave velocity and aortic stiffness. Left ventricular mass index, left ventricular systolic and diastolic function, and urine albumin/creatinine were collected. ANOVA with Bonferroni correction was used to evaluate differences in cardiovascular risk factors, pulse wave velocity, and cardiac function across groups. General linear models were used to examine factors associated with arterial stiffness and to determine whether arterial stiffness is associated with TOD after accounting for BP. RESULTS: Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. CONCLUSIONS: Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.

Cardiovascular Risk Factors and Target Organ Damage in Adolescents: The SHIP AHOY Study.

BACKGROUND: Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. METHODS: We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. RESULTS: The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). CONCLUSIONS: These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

White Coat Hypertension Persistence in Children and Adolescents: The Pediatric Nephrology Research Consortium Study.

OBJECTIVES: To determine whether youth with white coat hypertension on initial ambulatory blood pressure monitoring (ABPM) continue to demonstrate the same pattern on repeat ABPM. STUDY DESIGN: Retrospective longitudinal cohort study of patients referred for high blood pressure (BP) and diagnosed with white coat hypertension by ABPM who had follow-up ABPM 0.5-4.6 years later at 11 centers in the Pediatric Nephrology Research Consortium. We classified ABPM phenotype using the American Heart Association guidelines. At baseline, we classified those with hypertensive BP in the clinic as "stable white coat hypertension," and those with normal BP as "intermittent white coat hypertension." We used multivariable generalized linear mixed effect models to estimate the association of baseline characteristics with abnormal ABPM phenotype progression. RESULTS: Eighty-nine patients met the inclusion criteria (median age, 13.9 years; 78% male). Median interval time between ABPM measurements was 14 months. On follow-up ABPM, 61% progressed to an abnormal ABPM phenotype (23% ambulatory hypertension, 38% ambulatory prehypertension). Individuals age 12-17 years and those with stable white coat hypertension had greater proportions progressing to either prehypertension or ambulatory hypertension. In the multivariable models, baseline wake systolic BP index ≥0.9 was significantly associated with higher odds of progressing to ambulatory hypertension (OR 3.07, 95% CI 1.02-9.23). CONCLUSIONS: The majority of the patients with white coat hypertension progressed to an abnormal ABPM phenotype. This study supports the 2017 American Academy of Pediatrics Clinical Practice Guideline's recommendation for follow-up of ABPM in patients with white coat hypertension.

Salt sensitivity of blood pressure in childhood and adolescence.

Although moderation of sodium intake is recommended population-wide, it remains uncertain who benefits from salt restriction. Salt sensitivity refers to changes in blood pressure in response to sodium intake and may occur with or without hypertension. Unfortunately, there is no practical way to assess salt sensitivity in daily practice. Assessment of salt sensitivity even in research studies is challenging with varying protocols utilized which may contribute to differing results. Building on studies in animals and adults, risk factors and conditions associated with salt sensitivity have been identified in the pediatric and young adult populations. This review presents the limited evidence linking obesity, low birth weight, diabetes, chronic kidney disease, and race/ethnicity with salt sensitivity in children, adolescents, and young adults. The impact of stress on sodium handling is also reviewed. The influence of age on the timing of introduction of dietary salt restriction and the long-term influence of salt sensitivity on risk for hypertension are considered. Lastly, interventions other than salt restriction that may improve salt sensitivity and may inform recommendations to families are reviewed.

Influence of Blood Pressure Percentile Reporting on the Recognition of Elevated Blood Pressures.

OBJECTIVES: To explore the impact of displaying blood pressure (BP) percentiles with BP readings in the electronic health record (EHR) on the recognition of children with elevated blood pressures (EBPs). METHODS: This was a retrospective cohort study of children (ages 1-17), including inpatients and outpatients, with at least 1 EHR noninvasive BP recording. In phase 1, BP percentiles were calculated, stored, and not displayed to clinicians. In phase 2, percentiles were displayed adjacent to the EHR BP. Encounters with 1 BP ≥95th percentile were classified as elevated. EBP recognition required the presence of at least 1 EBP-related International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision code. We compared recognition frequencies across phases with logistic regression. RESULTS: In total, 45 504 patients in 115 060 encounters were included. Inpatient recognition was 4.1% (238 of 5572) in phase 1 and 5.5% (338 of 5839) in phase 2. The adjusted odds ratio (OR) associated with the intervention was 1.22 (95% confidence interval [CI]: 0.90-1.66). Outpatient recognition rates were 8.0% (1096 of 13 725 EBP encounters) in phase 1 and 9.7% (1442 of 14 811 encounters) in phase 2. The adjusted OR was 1.296 (95% CI: 0.999-1.681). Overall, recognition rates were higher in boys (outpatient OR: 1.51; 95% CI: 1.15-1.98) and older children (outpatient/inpatient OR: 1.08/1.08; 95% CI: 1.05-1.11/1.05-1.11) and lower for those on a surgical service (outpatient/inpatient: OR: 0.41/0.38; 95% CI: 0.30-0.58/0.27-0.52). CONCLUSIONS: Addition of BP percentiles to the EHR did not significantly change EBP recognition as measured by the addition of an EBP diagnosis code. Girls, younger children, and patients followed on a surgical service were less likely to have their EBP recognized by providers.

Pediatric and Adult Ambulatory Blood Pressure Thresholds and Blood Pressure Load as Predictors of Left Ventricular Hypertrophy in Adolescents.

[Figure: see text].

Ambulatory blood pressure monitoring in children undergoing polysomnography.

Ambulatory blood pressure monitoring (ABPM) is recommended for the diagnosis of hypertension in children at high risk, such as children with obesity or obstructive sleep apnea (OSA). Nocturnal hypertension is highly predictive of cardiovascular outcomes. ABPM allows for early detection of nocturnal hypertension in children. Although OSA is the most common sleep disorder associated with hypertension, studies have also shown an increase in cardiovascular risk in adult patients with other sleep disorders; therefore, there is an imperative need to provide early diagnosis in children at high risk. In the present study, we evaluated the feasibility of using ABPM during polysomnography (PSG) in children referred for sleep disordered breathing to the Seattle Children's Hospital Sleep Disorders Center. A total of 41 children aged 7-18 years were included in this study. The ABPM monitor was worn for a mean (SD) of 10.2 (1.5) hr. No significant changes were seen in PSG parameters when ABPM was co-performed with PSG, including sleep efficiency and arousals. In total, 12 of the 41 patients were identified as having nocturnal hypertension. Our study is important in that it shows that concomitant use of ABPM during PSG can aid in the early identification of nocturnal hypertension in this population.

Use of Automated Office Blood Pressure Measurement in the Evaluation of Elevated Blood Pressures in Children and Adolescents.

OBJECTIVES: To determine the level of agreement between automated office blood pressures (AOBP), auscultated or manual office BP (manual office blood pressure), and 24-hour ABPM, and to explore the ability of AOBP and manual office blood pressure to correctly identify daytime ambulatory hypertension in children. STUDY DESIGN: We retrospectively compared BPs obtained by AOBP and manual office blood pressure to predict daytime hypertension on ABPM. Six BPs were taken by AOBP followed by manual office blood pressure. Office hypertension was defined by BPs ≥95th percentile for sex and height percentiles for those <13 years of age and a BP of ≥130/80 mm Hg for ages ≥13 years. Daytime ambulatory hypertension was diagnosed if mean wake BPs were ≥95th percentile and BP loads were ≥25%. Application of adult ABPM thresholds for daytime hypertension (130/80 mm Hg) was assessed in ages ≥13 years. Sensitivity and specificity were calculated considering ABPM as the reference. RESULTS: Complete data were available for 187 patient encounters. Overall, the best agreement was found if both AOBP and manual office blood pressure showed hypertension, but owing to low sensitivity up to 49% of children with hypertension would be misclassified. The use of adult thresholds for ABPM did not improve agreement. CONCLUSIONS: Neither AOBP nor manual office blood pressure confirm or exclude daytime ambulatory hypertension with confidence. These results suggest an ongoing role for ABPM in evaluation of hypertension in children.

Subclinical Systolic and Diastolic Dysfunction Is Evident in Youth With Elevated Blood Pressure.

Hypertension is associated with cardiovascular events in adults. Subclinical changes to left ventricular strain and diastolic function have been found before development of decreased left ventricular ejection fraction and cardiovascular events. Our objective was to study effects of blood pressure (BP) on ventricular function in youth across the BP spectrum. Vital signs and labs were obtained in 346 participants aged 11 to 19 years who had BP categorized as low-risk (N=144; systolic BP <75th percentile), mid-risk (N=83; systolic BP ≥80th and <90th percentile), and high-risk (N=119; systolic BP ≥90th percentile). Echocardiography was performed to assess left ventricular strain and diastolic function. Differences between groups were analyzed by ANOVA. General linear models were constructed to determine independent predictors of systolic and diastolic function. Mid-risk and high-risk participants had greater adiposity and more adverse metabolic labs (lower HDL [high-density lipoprotein], higher glucose, and higher insulin) than the low-risk group. Mid-risk and high-risk participants had significantly lower left ventricular ejection fraction and peak global longitudinal strain than the low-risk group (both P≤0.05). The E/e' ratio was higher in the high-risk group versus the low-risk and mid-risk groups, and the e'/a' ratio was lower in the high-risk versus the low-risk group (both P≤0.05). BP and adiposity were statistically significant determinants of left ventricular systolic and diastolic function. Subclinical changes in left ventricular systolic and diastolic function can be detected even at BP levels below the hypertensive range as currently defined.

Changes in Ambulatory Blood Pressure Phenotype over Time in Children and Adolescents with Elevated Blood Pressures.

OBJECTIVE: To determine the stability of ambulatory blood pressure monitoring (ABPM) over time in children referred for evaluation of elevated BPs and assess for factors predicting change. STUDY DESIGN: This retrospective chart review conducted at Seattle Children's Hospital and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh identified 124 children referred for elevated BPs with 2 ABPM studies at least 6 months apart. All subjects received lifestyle counseling. Subjects with secondary hypertension (HTN) or on antihypertensive medication were excluded. ABPM phenotype was classified using American Heart Association guidelines as showing normal BP, prehypertension, and HTN. Generalized linear mixed effect regression models were used to regress stable, improving, or worsening HTN outcomes at study follow-up on baseline BP index and load variables. RESULTS: The median age of patients was 14.1 years (73% males) and the median interval between studies was 18 months. ABPM phenotype changed in 58 of 124 children, with 16% worsening and 31% improving. Older age was associated with persistence of HTN. Although not significant, decrease in body mass index z-score tracked with sustained normal ambulatory BPs. CONCLUSIONS: Although the sample size is small, our study suggests ABPM phenotype shows variability over time. Further study is required to identify factors supporting risk for progression of ABPM phenotype over time.

Risk Behaviors in Teens with Chronic Kidney Disease: A Study from the Midwest Pediatric Nephrology Consortium.

INTRODUCTION: There is a paucity of information about risk behaviors in adolescents with chronic kidney disease (CKD). We designed this study to assess the prevalence of risk behaviors among teens with CKD in the United States and to investigate any associations between risk behavior and patient or disease characteristics. METHODS: After informed consent, adolescents with CKD completed an anonymous, confidential, electronic web-based questionnaire to measure risk behaviors within five domains: sex, teen driving, alcohol and tobacco consumption, illicit drug use, and depression-related risk behavior. The reference group was composed of age-, gender-, and race-matched US high school students. RESULTS: When compared with controls, teens with CKD showed significantly lower prevalence of risk behaviors, except for similar use of alcohol or illicit substances during sex (22.5% vs. 20.8%, p=0.71), feeling depressed for ≥2 weeks (24.3% vs. 29.1%, p=0.07), and suicide attempt resulting in injury needing medical attention (36.4% vs. 32.5%, p=0.78). Furthermore, the CKD group had low risk perception of cigarettes (28%), alcohol (34%), marijuana (50%), and illicit prescription drug (28%). Use of two or more substances was significantly associated with depression and suicidal attempts (p < 0.05) among teens with CKD. CONCLUSIONS: Teens with CKD showed significantly lower prevalence of risk behaviors than controls. Certain patient characteristics were associated with increased risk behaviors among the CKD group. These data are somewhat reassuring, but children with CKD still need routine assessment of and counselling about risk behaviors.

Association of Blood Pressure Level With Left Ventricular Mass in Adolescents.

Hypertension is associated with left ventricular hypertrophy (LVH), a risk factor for cardiovascular events. Since cardiovascular events in youth are rare, hypertension has historically been defined by the 95th percentile of the normal blood pressure (BP) distribution in healthy children. The optimal BP percentile associated with LVH in youth is unknown. We aimed to determine the association of systolic BP (SBP) percentile, independent of obesity, on left ventricular mass index (LVMI), and to estimate which SBP percentile best predicts LVH in youth. We evaluated SBP, anthropometrics, and echocardiogram in 303 adolescents (mean age 15.6 years, 63% white, 55% male) classified by SBP as low-risk (L=141, <80th percentile), mid-risk (M=71, 80-<90th percentile), or high-risk (H=91, ≥90th percentile) using the mean of 6 measurements at 2 visits according to the 2017 guidelines. Logistic regression was used to determine the sensitivity and specificity of various SBP percentiles associated with LVH. Results: BP groups did not differ by age or demographics but differed slightly by body mass index. Mean BP, LVMI, and prevalence of LVH increased across groups (BP: L=111/75, M=125/82, and H=133/92 mm Hg; LVMI: L=31.2, M=34.2, and H=34.9 g/m2.7; LVH: L=13%, M=21%, H=27%, all P<0.03). SBP percentile remained a significant determinant of LVMI after adjusting for covariates. The 90th percentile for SBP resulted in the best balance between sensitivity and specificity for predicting LVH (LVMI≥38.6 g/m2.7). Abnormalities in cardiac structure in youth can be found at BP levels below those used to define hypertension.

Angiotensin II receptor blocker attenuates stress pressor response in young adult African Americans.

African Americans (AAs) are susceptible to hypertension (HTN) and its associated organ damage leading to adverse cardiovascular (CV) outcomes. Psychological stress is proposed to contribute to the development of HTN; however, the potential role of the renin-angiotensin system (RAS) in stress-related HTN in AAs is largely unknown. In this study, we tested the hypothesis that activation of RAS is a potential contributing factor for altered CV responses to stress, and suppression of angiotensin II (Ang II) activity will improve hemodynamic responses to a prolonged mental stressor in healthy young AAs. Utilizing a double-blind, randomized, crossover study design, 132 normotensive AAs (25 ± 7 years) were treated with either a placebo (PLC) or 150 mg/d irbesartan (an Ang II type 1 receptor blocker; ARB) for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before, during and after a 45 minute-mental stress. The magnitude of stress-induced increase in blood pressure with ARB was blunted and delayed compared to PLC. Systolic blood pressure at the end of recovery on ARB was significantly lower compared to either PLC (110 ± 13 vs 117 ± 12 mm Hg respectively; P < 0.001) or the prestress level on ARB (P = 0.02). ARB treatment reduced overall vasoconstriction and improved poststress UNaV. ARB attenuated blood pressure responses to mental stress and improved the poststress BP recovery process which were partly linked to reduced overall vasoconstriction and improved stress-induced UNaV in young adult AAs prior to the development of disease conditions. These results suggest that treatment approaches that inhibit RAS action could have significant relevance to potentially lower susceptibility to stress responses and eventually the premature development of HTN in AAs.

Evaluation and Management of Elevated Blood Pressure in Children and Adolescents with Attention Deficit Hyperactivity Disorder.

PURPOSE OF REVIEW: To understand the impact of attention deficit hyperactivity disorder (ADHD) and its medications on blood pressure (BP) in children and adolescents and provide recommendations for management of elevated BP in children and adolescents with ADHD. RECENT FINDINGS: ADHD medications have cardiovascular effects including elevated BP. However, the bulk of the evidence indicates that stimulants and other ADHD medications are safe and do not cause severe cardiovascular diseases. BP should be assessed carefully at the time of ADHD diagnosis, because some behavioral changes similar to ADHD may be associated with hypertension. ADHD medications appear to be safe. However, their long-term impact on the cardiovascular system is not clearly understood and needs further investigation. BP should be monitored regularly during ADHD pharmacotherapy in order to optimize the management of both conditions.

Ambulatory blood pressure monitoring tolerability and blood pressure status in adolescents: the SHIP AHOY study.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) provides a more precise assessment of blood pressure (BP) status than clinic BP and is currently recommended in the evaluation of elevated BP in children and adolescents. Yet, ABPM can be uncomfortable for patients and cumbersome to perform. OBJECTIVE: Evaluation of the tolerability to ABPM in 232 adolescent participants (median age: 15.7 years, 64% white, 16% Hispanic, 53% male) in the Study of Hypertension In Pediatrics Adult Hypertension Onset in Youth and its potential effects on ABPM results. PARTICIPANTS AND METHODS: Ambulatory BP status (normal vs. hypertension) was determined by sex and height-specific pediatric cut-points. Participants were asked to rank their wake and sleep tolerability to ABPM from 1 (most tolerant) to 10 (least tolerant); those with tolerability score of at least 8 were considered ABPM intolerant. RESULTS: Forty-three (19%) participants had wake ambulatory hypertension (HTN), 42 (18%) had sleep ambulatory HTN, and 64 (28%) had overall (wake and/or sleep) ambulatory HTN. Forty (17%) participants were intolerant to ABPM during wake hours and 58 (25%) were intolerant during sleep. ABPM intolerance during wake (but not sleep) hours was independently associated with wake (odds ratio: 2.34, 95% confidence interval: 1.01-5.39) and overall (odds ratio: 2.94, 95% confidence interval: 1.21-7.18) ambulatory HTN. CONCLUSION: Poor tolerability to ABPM is associated with a higher prevalence of ambulatory HTN in adolescents, and should be taken into consideration at time of ABPM interpretation.