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P E D I AT R I C H Y P E R T E N S I O N
RECENT TRENDS IN PEDIATRIC HYPERTENSION RESEARCH
http://www.lebanesemedicaljournal.org/articles/58-3/doc12.pdf
Van Anthony M. VILLAR, Tianbing LIU, Pedro A. JOSE
Villar VAM, Liu T, Jose PA. Recent trends in pediatric
hypertension research. J Med Liban 2010 ; 58 (3) : 179184.
Villar VAM, Liu T, Jose PA. Tendances récentes de la
recherche en matière d’hypertension pédiatrique. J Med Liban
2010 ; 58 (3) : 179-184.
ABSTRACT • Hypertension in the young is increasingly being recognized as an emerging critical healthcare
problem, not only because of its increasing prevalence
in recent years but also of its significant impact on the
health and well-being of children and adolescents and
tracking into adult life. A wealth of epidemiological
studies has allowed the formulation of guidelines and
recommendations on the diagnosis and classification of
hypertension in the pediatric group based on normative data. Significant advances in the field of medicine
and genetics have paved the way for the identification
and demonstration of recent trends in hypertension
research in children and adults. This article highlights
both established and emerging concepts in order to
provide a quick yet panoramic view of the current
understanding on pediatric hypertension.
INTRODUCTION
RÉSUMÉ • L’hypertension chez les jeunes est de plus en
plus reconnue comme étant un problème de santé émergent et critique non seulement du fait de sa prévalence
croissante au cours de ces dernières années et de l’impact considérable qu’elle a sur la santé et le bien-être des
enfants et des adolescents mais aussi à cause dudit phénomène de tracking vers l’âge adulte. Une profusion
d’études épidémiologiques a permis la mise en place de
directives et de recommandations relatives au diagnostic
et à la classification de l’hypertension pédiatrique, sur
base de données normatives. Les progrès considérables
réalisés dans les domaines de la médecine et de la génétique ont permis de paver le chemin pour l’identification et la démonstration des tendances récentes de la
recherche en matière d’hypertension pédiatrique et
adulte. Cet article met en relief les concepts établis et les
concepts émergents, afin de fournir un aperçu rapide et
néanmoins panoramique de l’hypertension pédiatrique
telle qu’elle est comprise aujourd’hui.
Hypertension (HT) and its sequelae remain as one of the
most pressing healthcare problems globally, affecting
developed and developing countries alike. It afflicts close
to a billion people worldwide and the cost of health services, notwithstanding the economic burden borne from
preventing complications and managing disabilities, runs
in billions of dollars annually. Hypertension is the most
common primary diagnosis in the United States, accounting for more than 37 million clinic visits [1]. It poses a
major risk for cardiovascular, renal and neurological diseases, including stroke, for millions of people around the
globe. The relationship between an individual’s average
blood pressure (BP) and the development of cardiovascular disease is linear, continuous, consistent and independent of other risk factors such as smoking, obesity,
hypercholesterolemia, and diabetes mellitus [2]. Cardiovascular disease risk, which begins at approximately
115/75 mmHg, doubles for each 20/10 mmHg increase.
In spite of rigorous patient education and concerted
efforts to prevent and control the disease and its various
complications, there is evidence that the problem is only
getting worse. There are 43 million people with HT in the
United States alone, which comprises 29% of the middleaged population. Globally, the number of adults with HT
in 2025 is predicted to increase by about 60% to a total of
1.56 billion [3].
Essential HT has been long recognized as an insidious
adult-onset disorder. It was not until the last three decades that the disease has been reported to occur in the
young and that early predictors of HT have been identified among young children. It is estimated that up to 2%
of term and preterm neonates receiving care in modern
neonatal intensive care units have HT. Among older children, the prevalence of essential HT ranges between
1-2% and appears to have steadily increased over the
years, primarily attributable to the increase in the prevalence of obesity. We discuss here the issues that constitute
recent trends in pediatric HT research.
Center for Molecular Physiology Research, Children’s Research
Institute, Children National Medical Center, Washington DC,
USA.
Correspondance to: Van Anthony M. Villar, MD. Center for
Molecular Physiology Research. Children’s National Medical
Center. 111 Michigan Avenue NW. Washington DC 20010. USA.
e-mail: [email protected]
CLASSIFICATION OF PEDIATRIC HYPERTENSION
In the adult population, the relationship between systemic
BP and morbidity is quantitative rather than qualitative,
thus a classification system for individuals 18 years and
older was established for making judicious decisions on
Lebanese Medical Journal 2010 • Volume 58 (3) 179
the aggressiveness of treatment and other therapeutic interventions. Pursuant to the guidelines in “The Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure”, or JNC VII [2], the diagnosis of HT is made when
the average of multiple seated diastolic BP measurements
on at least two subsequent clinical visits is 90 mmHg or
higher, and/or when the average of multiple seated systolic
BP measurements is consistently 140 mmHg or more. A
new category, prehypertension, has been added to emphasize the risk of an individual having BP measurements previously considered normal to develop frank HT; prehypertensives are at twice the risk to develop HT than those with
lower values. Increased education and awareness is needed to prevent the onset of HT in the general population.
Due to the paucity of available risk information, the
current definition of HT in children is based on normative
data culled from previous epidemiologic database and the
recent 1999-2000 National Health and Nutrition Examination Survey (NHANES). The Fourth Report on the
Diagnosis, Evaluation, and Treatment of High Blood
Pressure in Children and Adolescents (WGR4) by the
National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and
Adolescents (NHBPEP) provides an updated normative
data for BP classification of children aged 1 to 17 according to age, gender, and height for the 50th, 90th, 95th, and
99th percentiles. Blood pressure values are based on auscultatory measurements, pursuant to recommended protocols. The dependence on statistical data to define HT in
the young has disadvantages including the difference
in BP indices for various populations, variability of BP
determinants in a given population over time, and the
inclusion of single BP measurements in the database.
Normal BP in the pediatric age group is defined as systolic and diastolic BP that are below the 90th percentile,
while HT is defined as the average systolic or diastolic BP
that is ≥ 95th percentile on more than two occasions [4].
Analogous to JNC VII, a new category, prehypertension,
has been included and is defined as an average systolic or
diastolic BP between the 90th and 95th percentiles, or if the
BP exceeds 120/80 mmHg regardless of the normative
score [4], and is an indication for lifestyle modifications.
Moreover, Stage 1 HT is defined as persistent systolic or
diastolic BP that is between the 95th and 99th percentiles,
while Stage 2 HT is when the average systolic or diastolic
BP exceeds the 99th percentile [4]. These stages of HT are
intended to facilitate the appropriate and timely management of the affected child.
Despite the detailed instructions on proper BP measurement and guidelines on appropriate diagnostic and
therapeutic interventions, recent data showed that these
recommended strategies are not adhered to in clinical
practice [5]. A recent cohort study revealed that HT and
pre-HT are under-diagnosed among children and adolescents [6]. Of the subjects that had HT, only 26% were
appropriately diagnosed, while only 11% of prehypertensive subjects were correctly diagnosed. Although the
180 Lebanese Medical Journal 2010 • Volume 58 (3)
exact reasons for these findings are still unclear, it is possible that unfamiliarity of the diagnostic cut-off scores for
HT in the young and the clustering of HT and obesity and
lack of confidence on the BP readings obtained in the
clinics may contribute to the problem [5].
TARGET-ORGAN DAMAGE
The clinical significance of HT among children and adolescents is difficult to evaluate because of the considerable time interval between the diagnosis of HT and the
manifestation of a clinical crisis. However, numerous
reports have shown that HT in the young is invariably
accompanied by findings of early target organ damage
[5, 7]. Left ventricular hypertrophy (LVH), an important
predictor of cardiovascular morbidity and mortality in
adults, is the most commonly identified measurable cardiac abnormality, occurring in more than a third of children with HT [8-9]. The correlation of BP elevation with
the occurrence of LVH has been reported by several
groups [8-9], but not by others [10]. The exact mechanism underlying the development of LVH remains to be
defined, although abnormalities in diastolic function and
cardiac ischemia due to increased oxygen consumption
have been postulated [7].
Another consequence of sustained HT is vascular damage, such as increased carotid intima-media thickness
(cIMT), a marker of atherosclerosis and a strong predictor of cardiovascular morbidity and mortality in adults.
Studies have shown that there is increased incidence of
cIMT in several childhood diseases that increase cardiovascular risk like diabetes, hypercholesterolemia and
end-stage renal disease [11]. The usefulness in using
cIMT as a marker of hypertensive vascular damage has
been demonstrated in a recent matched controlled study
that showed increased cIMT in hypertensive children
independent of obesity – another risk factor for increased
cIMT – and that higher cIMT correlated with more severe
HT [12]. Lower levels of high density cholesterol are also
associated with cIMT in children [13]. The occurrence of
hypertensive retinopathy, another marker of hypertensive
vascular damage in adults, has also been reported in 50%
of affected infants studied, although the retinal abnormalities resolved with the normalization of the BP [14].
Other clinical sequelae of HT in the young include
impaired cognitive function [15] and renal damage. More
recently, French-Canadian boys with elevated systolic BP
were found to have lower scores on a spatial learning and
memory factor score relative to boys with lower BP that
could not be related to differences in socioeconomic status [16]. Although it is frequently seen in children with
chronic kidney disease and undoubtedly contributes to the
progression of disease, HT is rarely the cause of the disease in children [17]. Microalbuminuria accompanies
more than half of hypertensive adolescents, occurring
more in those with Stage 2 HT compared to Stage 1 [18];
however, microalbuminuria correlates more with LVH
than with renal damage [18-19].
V.A.M. VILLAR et al. – Recent trends in pediatric hypertension research
AMBULATORY BLOOD PRESSURE MONITORING
BLOOD PRESSURE TRACKING IN CHILDREN
Measurable target organ damage has been documented to
occur even in children with unconventional forms of HT
such as white-coat and masked HT.
White-coat HT is defined as a condition in which a
patient has an average BP reading ≥ 95th percentile when
measured in a clinical setting but falls below the 90th percentile elsewhere. This form of HT is more prevalent
among obese subjects [20], appears to be relatively common in children with Stage 1 compared to those with
Stage 2 HT [5], and is accompanied by left ventricular
mass indices that are intermediate between those of normotensive and hypertensive subjects [5] and characterized by decreased performance on exercise testing [21].
Masked, or isolated ambulatory HT, on the other hand,
is defined as a condition in which patients have normal
BP in the clinic but are hypertensive in their regular environment [4]. This condition is more prevalent in nonobese subjects [20] and is associated with greater-thannormal prevalence of organ damage, such as increased
prevalence of metabolic risk factors, left ventricular mass
index, cIMT, and impaired large artery distensibility [22],
all important indices of cardiovascular disease. In children and adolescents, increased BMI is a predictor of
masked HT [23].
Thus, ambulatory BP monitoring, a well established
technique that involves the recording of BP at 20-minute
intervals throughout a 24-hour duration, has been endorsed by WGR4 primarily for the identification of unconventional forms of HT and for the prediction of targetorgan damage [5, 23]. Since the BP of an individual is
dynamic and oscillates with his Circadian pattern, physical activity and level of stress – BP is higher during the
day and falls by 10% during sleep – ambulatory BP monitoring provides not only a better reflection of the variability of the subject’s actual BP and an objective BP in his
normal environment but also allows a better prognostication for end-organ damage compared to regular BP measurement [7]. Several studies have been performed to
establish normal values for ambulatory BP monitoring in
children and young adults and to compare and contrast
these values with those obtained by regular BP measurements. These studies revealed that the diastolic ambulatory BP is independent of height and that the subjects have
higher daytime diastolic and systolic ambulatory BP values, especially in the shorter groups. The reasons for these
disparities are still not fully understood. Furthermore,
ambulatory BP monitoring can be used to distinguish
between primary and secondary forms of HT; secondary
HT is characterized by daytime diastolic BP and nocturnal
systolic BP elevations [24].
Indications for the use of ambulatory BP monitoring
include Stage 1 HT, obesity not accompanied by HT, a
strong family history of HT, or an early cardiovascular
event. It can also prove useful for the assessment of
refractory HT or drug-induced hypotension [22].
Several studies have shown that precursors of adult cardiovascular diseases such as obesity and dyslipidemias
begin early during childhood, although abnormal levels of
risk factors by adult criteria are not evident in children and
only appear in young adults. For instance, data gleaned
from autopsy reports demonstrate the presence of fatty
streaks and plaque formation in children and young adults
with cardiovascular disease risk factors years before the
development of frank disease.
Blood pressure tracking, or the predictability of adult
BP based on BP measurements early in an individual’s
life, has been demonstrated by several large longitudinal
studies [25]. Hypertension during childhood has been
shown to more likely follow patients into adulthood [26].
Adult BP correlates with childhood BP and BMI. Blood
pressure tracking has important clinical implications as it
is tied to the development of atherosclerosis and the progression of metabolic syndrome in the young adults [27].
Moreover, data on BP tracking provide insights into the
efficacy of various therapeutic approaches to manage HT
in the young and could help determine the extent of influence of genetics vs. environment on BP control [5]. An
inadequate compensatory increase in urinary sodium excretion in response to a stress-induced BP increase could
lead to the premature development of essential HT and
has recently been suggested as a new intermediate phenotype to study the etiology of HT [28]. Moreover, cardiovascular reactivity to stress may be a predictor of BP.
V.A.M. VILLAR et al. – Recent trends in pediatric hypertension research
FETAL PROGRAMMING OF HYPERTENSION
Fetal programming or imprinting refers to the cogent
association between adverse prenatal environmental
events and altered fetal growth and development with persistent, abnormal pathophysiology and frank disease later
in life. Based on observations that factors found in utero
may be involved in the development of cardiovascular
disease, Barker and colleagues hypothesized that fetal
influences that retard fetal growth could program and permanently result in alterations of the body’s structure and
physiology and thus set the stage for the development of
cardiovascular disease in adults [29]. Numerous epidemiological studies support the inverse relationship between
low birth weight and HT. Fetal growth and development
are governed by several determinants including the fetal
genetic endowment, maternal health and placental capacity to supply oxygen and nutrients to the fetus [30]. Suboptimal fetal conditions and other insults during crucial
windows of growth and development, which may coincide with periods of rapid cell proliferation, may result in
adaptive changes in the structure and function of vulnerable tissues, which conceivably are antecedents of HT.
Alterations to genetic pattern during fetal development
may be influenced by the nature, timing, duration and
severity of the insult.
Studies on humans reveal two distinct mechanisms
Lebanese Medical Journal 2010 • Volume 58 (3) 181
that link low birth weight with HT. First, birth weight has
been shown to be a strong predictor of nephron number
and mean glomerular volume [31]. In fact, retarded intrauterine growth often results in significant reduction in
nephron number, which translates to reduced filtration
surface area. This consequently leads to progressive renal
insufficiency and systemic adult HT. Fetal programming
regulates nephrogenesis up to 34-36 weeks of gestational
age, hence intrauterine growth retardation or prenatal or
postnatal insults in preterm infants may result in reduced
nephron number [32]. Second, low birth weight individuals exhibit impaired endothelial function, probably due to
perturbation of angiogenesis and vascular function during
fetal development [33]. The altered vascular physiology
related to low birth weight is invariably irreversible.
Smaller birth weight is also associated with chronic lowgrade inflammation in children and adolescents [34], further supporting the observation that low birth weight is
related to increased risk of coronary heart disease in adults
and to the pathogenesis of atherosclerosis in later life.
Glucocorticoids are potent regulators of fetal growth,
development and morphogenesis. The placenta is highly
enriched with the enzyme 11-ß-hydroxycorticosteroid
dehydrogenase that inactivates maternally derived glucocorticoids, and thus keeps the circulating levels of fetal
glucocorticoids low under normal conditions [30]. Numerous studies, in both humans and animals, have shown
that antenatal exposure to exogenous or increased endogenous glucocorticoids results in low birth weight, HT,
impaired sugar metabolism, and alterations in behavior
and neuroendocrine responses throughout the lifespan,
possibly through various mechanisms that include
changes in the “set point” of the hypothalamic-pituitaryadrenal axis and tissue glucocorticoid receptor expression
[35]. Preterm babies who received a single course of
maternal betamethasone do not have long-term metabolic
risks other than decreased GFR, indicating impaired
nephrogenesis [36].
Utero-placental insufficiency may also lead to HT, as
shown in several animal models [37]. Uterine artery ligation during the early phase of gestation results in growth
retardation and elevations in BP [38]. Interestingly, the
initiating event in pregnancy-induced HT has been postulated to involve reduced utero-placental perfusion, which
leads to impaired maternal vascular endothelial function
[39].
GENETICS OF BLOOD PRESSURE AND HYPERTENSION
Hypertension is a multifactorial, polygenic complex trait.
It was estimated through twin and family studies that about
30% of BP variations is due to variations in genes. Recent
genome-wide association studies have shown genetic loci
that account for about 2% of genetic factors that influence
BP level [40]. The kidney was shown to be the major organ
where the inherited tendency of HT predominantly resides
in through transplantation studies [41]. Genetics of HT is
the topic of a separate paper in this issue of the LMJ.
182 Lebanese Medical Journal 2010 • Volume 58 (3)
ASSOCIATION WITH THE METABOLIC SYNDROME
Hypertension is frequently associated with other anthropometric and metabolic abnormalities such as visceral
obesity, dyslipidemia, glucose intolerance, insulin resistance, and hyperuricemia, which are collectively called
the metabolic syndrome [42]. The metabolic syndrome is
more prevalent among patients with HT than in the general population and is more prevalent in women than in
men. The prevalence of obesity now approaches 20% in
children 4-11 years of age [5], and is highest in American
Indian/Native Alaskan, Hispanic and non-Hispanic blacks
and lowest in non-Hispanic whites and Asians [43]. In
children, as in adults, the prevalence of HT is increased
with obesity, and may be as high as 10% in overweight
adolescents [44]. The incidence of prehypertension in
adolescents, which is about 12%, and 60% in adults, is
greater in the obese than in the non-obese [4].
OBESITY, INFLAMMATION AND
REACTIVE OXYGEN SPECIES (ROS)
A common link to the abnormalities in metabolic syndrome is subclinical inflammation which, along with
insulin resistance and adiposity, is implicated in the
development of type 2 diabetes and cardiovascular disease [45]. Elevated markers of subclinical systemic inflammation (e.g., C-reactive protein, coagulopathy) are
present in cardiovascular disease, including atherosclerosis and HT in adults and children [46]. Reactive oxygen
species (ROS) is important in the pathogenesis of HT
[47]. As stated above, children born small for gestational
age have increased incidence of HT and increased oxidative stress. Obesity is associated with increased secretion
of proinflammatory cytokines, and decreased secretion of
anti-inflammatory cytokines by adipocytes [48]. Inflammation contributes to increased insulin resistance [49].
Weight loss secondary to diet, exercise, and/or surgery
results in a decrease in circulating inflammatory cytokines [50] and increase in insulin sensitivity [51].
LIFESTYLE MODIFICATION
AND PREVENTION OF HYPERTENSION
Dietary modification is recommended as a first-line
approach for pediatric patients with elevated BP. Promising research in adults supports the use of a diet high in
fruits, vegetables, and low-fat dairy foods, the so-called
DASH diet, to normalize BP among hypertensive individuals. Modest reduction of dietary salt for a short duration
has a significant effect on BP control in both individuals
with normal and elevated BP, however, dietary sodium
restriction may not be beneficial to all, and some have
suggested that chloride rather than sodium should be
restricted. Salt depletion may promote insulin resistance,
one of the criteria used to define the metabolic syndrome.
A low salt diet may also have a paradoxical effect on BP.
Preterm infants (33 weeks gestation or less) who are not
V.A.M. VILLAR et al. – Recent trends in pediatric hypertension research
provided with a diet containing 4-5 mmol NaCl/day may
be predisposed to poor neurodevelopmental outcome in
the second decade of life. Indeed, salt restriction can decrease cognitive function in adult salt-sensitive rats.
Underlying genetic models of salt-sensitive, low-renin,
and possibly other subclasses of hypertension are variable
[47].
In children, waist circumference has been associated
with systolic HT while high total fat intake was related to
diastolic HT. The amount of dietary omega-3 polyunsaturated fatty acid intake is inversely associated with cardiovascular disease mortality and morbidity in several populations. The protective effect may arise from their ability
to promote vasodilatory and anti-inflammatory eicosanoid
generation, reduce angiotensin-converting enzyme activity, enhance endothelial nitric oxide production, and activate the parasympathetic activity. Preliminary clinical trials showed that omega-3 polyunsaturated fatty acids are
able to slightly improve arterial HT [52].
Sedentary lifestyle has been shown to markedly increase the risk for cardiovascular disease [53]. Sedentary
behavior, such as TV viewing and screen time, but not
computer use, were positively associated with both systolic and diastolic BP as well as obesity in children [54].
A TV in the child’s bedroom is an even stronger marker of
increased risk of being overweight [55]. This topic has
been discussed in detail elsewhere in this issue of the LMJ.
SUMMARY
Essential HT is increasingly recognized in children.
Hypertension in the young may already be associated
with target-organ damage. Blood pressure levels and HT
during childhood track into adulthood. There is fetal programming of BP; low birth weight is associated with HT
later in life. High BP may also be caused by genetic factors. A healthy diet, maintenance of normal body weight
and waist circumference, and active lifestyle are important in the treatment and prevention of HT. Whether or not
these beneficial effects carry throughout adult life remain
to be determined by long-term longitudinal studies.
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