08 Hypertensionaha 120 14592
08 Hypertensionaha 120 14592
08 Hypertensionaha 120 14592
REVIEW
ABSTRACT: The intent of this review is to critically consider the data that support the concept of programming and its
implications. Birth weight and growth trajectories during childhood are associated with cardiometabolic disease in adult life.
Both extremes, low and high birth weight coupled with postnatal growth increase the early presence of cardiometabolic risk
factors and vascular imprinting, crucial elements of this framework. Data coming from epigenetics, proteomics, metabolomics,
and microbiota added relevant information and contribute to better understanding of mechanisms as well as development of
biomarkers helping to move forward to take actions. Research has reached a stage in which sufficiently robust data calls for
new initiatives focused on early life. Prevention starting early in life is likely to have a very large impact on reducing disease
incidence and its associated effects at the personal, economic, and social levels.
Correspondence to: Empar Lurbe, Department of Pediatrics, Consorcio Hospital General, University of Valencia, Avda. Tres Cruces s/n, 46014 Valencia, Spain. Email
[email protected]
For Sources of Funding and Disclosures, see page 315.
© 2020 American Heart Association, Inc.
Hypertension is available at www.ahajournals.org/journal/hyp
Review
AGA appropriate for gestational age become recognized.
AT1b angiotensin type 1b receptor Data in children from the National Health and Nutri-
AT2 angiotensin type 2 receptor tion Examination Survey from 1999 through 2014, which
BMI body mass index included 28 153 subjects from birth to 15 years, were
CVD cardiovascular disease divided into 5 BW categories (<2.5, 2.5–3.0, 3.0–3.5, 3.5–
4.2, and ≥4.2 kg), with <2.5 kg as the LBW group (8.2%)
DOHaD developmental origins of health and
disease and ≥4.2 kg as the HBW group (10.4%).18 Over the entire
population, with an increasing BW, the results showed a
HBW high birth weight
significant rising trend for the risk of general and central
IMT intima-media thickness
obesity. In contrast, BW was significantly and inversely
LBW low birth weight
associated with high systolic blood pressure, high glycated
miRNA microRNA hemoglobin, and low high-density lipoprotein cholesterol,
SGA small for gestational age independent of current body size. The relation between
BW and childhood cardiometabolic risk factors showed
different patterns, depending on ethnic background.18
how to manage them in children and adolescents. Birth
While reports consistently note that upon reaching
weight, growth trajectories during childhood, and the
adult life there is an association between BW and type
cardiometabolic risk factors themselves are crucial ele-
2 diabetes,15–17 the link with CVD has been inconsis-
ments of this framework.
tent.19–23 Both of these issues were evaluated in a meta-
analysis of almost 8 million participants from 135 studies
The Importance of Birth Weight stratified into 6 BW groups from <2.5 kg to >4.5 kg.24
The findings suggested that BW is associated with the
Birth weight is a sentinel marker of fetal health, reflect-
risk of type 2 diabetes and CV disease in a J-shaped
ing both intrauterine growth and length of gestation. The
trend with increments of risk at both extremes. In con-
World Health Organization defines LBW as <2.5 kg, with
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whom there was information on BW and gestational age, childhood, that does not necessarily connote childhood
together with longitudinal data on cardiovascular risk obesity, also increases the risk, which underscores the
markers from age 3 to 18 years in 1980 to age 34 to 49 importance of regular growth monitoring.
years in 2011, the authors observed increased BP lev-
Review
The Role of Postnatal Growth longitudinal studies has been the association with later
Early childhood growth trajectories and rapid catch-up obesity. New findings on the predictors of obesity from
growth have also been shown to independently influence the Family Life Project, assessing longitudinal patterns of
the development of risk factors and the incidence of obesity, were that by age 6 stable obesity was associated
chronic disease. In a study of the Helsinki Birth Cohort by with both LBW and HBW.33 Repeating BMI measure-
Barker et al,3 adults with a coronary event were noted to ments, from childhood into adolescence, the UK Mille-
be relatively small at birth and thin at 2 years of age and nium Cohort Study showed that rapid weight gain in early
thereafter gained weight rapidly. This pattern of growth life was associated with higher BMI at 5 years and more
during childhood was associated with insulin resistance rapid BMI gain subsequently from 5 to 14 years, espe-
in later life. Furthermore, the risk of coronary events was cially in those large for gestational age at birth.34 Further
more related to the pace of childhood BMI gain than to follow-up of these cohorts will be needed to examine if
the BMI achieved at any particular age.3 the increased risk of obesity associated with HBW and
The impact of BW and postnatal growth on the pres- LBW is accompanied by obesity-related markers of dis-
ence of overweight or obesity, BP values, metabolic ease such as insulin resistance or high BP.
parameters, and diseases such as hypertension and type A prospective study went a step further, reaching
2 diabetes, was the topic of a systematic review that the end of the first decade of life and analyzing car-
included children, adolescents, and adults.30 While some diometabolic risk factors.35,36 Healthy, full-term infants
studies reviewed had a significant association with BW of uncomplicated pregnancies were stratified as SGA,
and postnatal growth, in others no association was found. AGA, or large for gestational age. At age 5 years, fast-
The most frequent association was seen with BP values ing insulin levels were higher in all children who had
and fasting insulin. Furthermore, the greatest adverse become heavy by that time, and the levels were high-
levels of cardiometabolic risk factors in children were est among the SGA group. Even the SGA infants who
consistently present in those who started life as LBW remained small at 5 years of age had measures of insulin
newborns but then became relatively heavy.30 It is worth resistance comparable to those who became heavy at
noting that the use of obesity criteria to detect children at 5 years, suggesting metabolic programming in the SGA
risk of future cardiometabolic risk will miss many at risk group.35 Among participants reexamined at 10 years of
persons. An upward crossing of BMI percentiles during age, children with fasting insulin levels >15 U/L had a
clustering of cardiometabolic risk factors: higher office pediatric normative data, this method remains a research
systolic blood pressure, higher plasma triglyceride and tool rather than a predictor in pediatrics.
uric acid levels, and lower high-density lipoprotein cho-
lesterol.36 Such findings are especially relevant, consid-
Review
ering that insulin resistance does not resolve in youth MOLECULAR TECHNIQUES AND THEIR
who are entering puberty, which may result in increased CONTRIBUTION TO UNDERSTANDING OF
cardiometabolic risk. Notably, puberty is associated with
PROGRAMMING
a marked decrease in insulin sensitivity. Little is known
about the underlying pathophysiology of insulin resis- The molecular era brought the capacity to perform rapid
tance in puberty, and how it might contribute to increased nucleic acid sequencing and microarray studies, as well
disease risk (eg, type 2 diabetes).37 as other molecular techniques and has provided the
potential for far more understanding of DOHaD. Molec-
ular and proteomic techniques have made it feasible to
Vascular Imprinting investigate the mechanisms underlying both epidemio-
Using the life course perspective concept of the con- logical data and experimental studies that have been
tinuum of aging, new elements need to be considered. heretofore phenomenological. Ultimately, such studies
There is a constant debate over whether the assess- may be able to define causality for developmental ori-
ment of arterial wall function and structure can add gins. For example, one of the most logical explanations
relevant information for further lowering the cardio- for programming presently lies in the many observa-
vascular risk beyond that from assessing conventional tions that epigenetic mechanisms play an important role
risk factors. Though there are an increasing number in DOHaD.45
of methods currently available to evaluate arterial wall An early molecular approach involved seeking variants
function and structure, those used the most in pedi- (mutations) induced by perinatal stressors. Indeed, some
atrics are arterial stiffness, intima-media thickness toxins may lead to mutations. However, finding germ-
(IMT), and endothelial function. However, information line mutations or somatic mutations in promoter regions
that links early life programming to arterial function and of genes, or in coding or noncoding areas and relating
structure is still scarce. these to DOHaD has not resulted in cogent explanations.
Arterial stiffness is a dynamic parameter that depends Much of the data that suggest that other changes,
on the arterial wall, its function and concomitant BP val- termed epigenetic changes, which do not alter DNA
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ues. An increment in arterial stiffness may be an early sequence, but, rather, accessibility to genes, in con-
marker of higher cardiovascular risk. Considered as a trast, may play a substantial role in both maternal and
core component in the concept of early vascular aging, paternal influences on the fetus. Such alterations may
it has been associated with early life factors, BW, and persist and exert not only effects on offspring but on
postnatal growth patterns.38,39 future generations.
Arterial IMT is an acknowledged marker of subclini- Epigenetics as a concept (and term) was coined by
cal vascular damage in both adults and children. Even Waddington nearly 80 years ago (1942) and was envi-
though carotid IMT has been the most frequently ana- sioned broadly.45–48 It has evolved as a field with mul-
lyzed as a target, previous studies have suggested that tiple dimensions with potential application to the area
aortic IMT may be a more discriminating measure in of DOHaD.46–48 The known manner in which epigenetic
childhood.40,41 Aortic wall thickening is increased in SGA changes occur include DNA methylation, histone modifi-
neonates compared with that of healthy newborns.40,41 cations, and changes through noncoding RNAs such as
A recent study found increased IMT both at the carotid microRNAs (miRNAs), IncRNAs, and piRNAs—which are
and thoracic aorta in 6- to -8-year-old children born SGA small, noncoding RNAs that contribute greatly to tissue-
as compared to that for those born AGA, somewhat not specific phenotype and function. Beyond that, other phe-
explained by differences in body size.42 nomena are considered epigenetic as well.
A few studies that have tested the impact of BW on Within the cell (and there are over 200 cell types in
endothelial function, measured by flow-mediated vaso- mammals), chromatin stores the DNA—packaged either
dilation induced by ischemia, indicated that children with as heterochromatin, which is closed and tightly wound,
a history of LBW show impaired endothelial function.43 and euchromatin, which is relatively open. Studies in
More recently, LBW has been associated with a decrease the 1970s showed that DNA lies within nucleosomes,
in the circulating/functional capacity of endothelial pro- where it is wrapped around dimers of histone (classified
genitor cells among healthy children 7 to 11 years of age, as H2A, H2B, H3, and H4; histone H1 does not form
independent of traditional cardiovascular risk factors.44 dimers).49 The structure of chromatin changes substan-
There are still many unanswered questions regarding the tially both during development and cell differentiation.
effect of BW on endothelial function. Indeed, because Further, processes such as acetylation (which is the
of the time requirements and the absence of reliable most extensively studied), methylation, ubiquitylation, as
well as by ribosylation, phosphorylation, citrullination, and and hydrophobic properties of DNA. Methylation gener-
sumoylation all modify histone.45–48 ally impacts gene expression—hypermethylation lowers
Both maternal and paternal epigenetic changes expression, while hypomethylation increases it. Within
impact the fetus—the mother, through changes from the body of a gene, methylation generally increases tran-
Review
the inception of fertilization to birth (and beyond in scription by changing how compact chromatin is through
breast fed infants) and via epigenetic changes in sperm attracting proteins that complex with the methyl group
that fertilize the egg. The exposures in the environ- and, then, the DNA, silencing or enhancing transcription
ment reported to affect male germ cells include stress, factors.53 Further, modifications of histones can alter the
heavy metals, bisphenols, and endocrine disruptors, as N-terminal region of histones, which affects the conden-
well as some foods, and more, shown directly in animal sation of chromatin.
models (Figure 1). The genome’s methylation profile undergoes changes
There is now a growing literature concerning the early in embryogenesis with demethylation in the pater-
role of epigenetics in DOHaD, the majority of which has nal genome (except for paternally imprinted genes), and
been performed in experimental models, particularly in remethylation occurs.54–56 Most animal studies of epi-
rodents.50,51 There are, however, some epidemiological genetics have focused on changes in maternal protein-
data, as well as epigenome-wide association studies. calorie intake during gestation.
Taken together, such investigation is presently consid-
ered highly relevant to the observational data amassed
over the past decades.52
Methylation and Perinatal Programming of
Methylation (and demethylation) of cytosine nucleo- Hypertension
tides within the promoter region in a gene alters gene In a low protein model of induced programming Bogda-
expression. The most commonly methylated cytosines are rina et al,57 found that the angiotensin type 1b receptor
adjacent to guanosine and the event impacts hydrophilic promoter was undermethylated in the adrenal, which they
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took as a link between fetal insults and epigenetic modi- state of the microbiome influences BP and salt-sen-
fication. The investigators hypothesized that low protein sitive hypertension. Increasingly, the concept that the
diet might decrease methyl donors, but, more plausibly, microbiome may play a role in DOHaD with respect
that stress would influence glucocorticoid production to hypertension seems appealing.74 While a number
Review
and release, affecting methylation. Goyal et al,58 using a of animal studies hint that the microbiome may play a
murine model, also found evidence that maternal protein role in the development of hypertension, such data in
deprivation led to changes in the methylation in genes humans are lacking.
of the renin-angiotensin system in the brain. They found
that CpG islands in the ACE-1 (angiotensin-converting
enzyme 1) promoter were hypomethylated, and, further
Proteomics and Perinatal Programming
found that miRNAs that influence ACE-1 mRNA trans- The structure and function of the large number of pro-
lation (mmu-mir-27a and -27b) were hypomethylated, teins within cells, organs, and whole beings is elucidated
along with decreased levels of a miRNA that regulates by proteomics; in human beings there are over 100 000
AT2 (angiotensin type 2 receptor) translation (miRNA known proteins, and presently, the use of high through-
mmu-mir-330). put techniques makes it possible to examine differen-
A number of studies that may be related to metabolic tial expression of proteins, which are emblematic of
syndrome are reviewed in Bianco-Miotto et al,59 none of physiology, pathophysiology, and treatment. Proteomic
which related to directly to the programming of hyperten- techniques are time intensive and difficult to perform in
sion per se. The degree of adiposity in adult life has been large numbers of patients, rendering widespread clinical
correlated with changes in methylation of DNA at birth or applications difficult. These techniques involve 2-dimen-
early in life, suggesting that epigenetic markers might be sional gel electrophoresis, or 2-dimensional dimensional
sought as a predictor.60–64 difference gel electrophoresis, the use of Western blots,
Payton et al65 studied miRNA in the placenta and and surface-enhanced laser desorption/ionization time-
related that to BW using placental samples from the of-flight mass spectrometry.75
Extremely Low Gestational Age Newborns cohort. They While the promise of finding biomarkers or a mean-
observed that mRNA was upregulated for particular ingful signature of protein changes that signify risk of
pathways, especially glycoprotein VI, as well as hepa- later disease in possibly at risk persons seems worthy,
tocyte growth factor and human growth factors. Using there have not been many studies of proteomics with
respect to perinatal programming.
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Again, examining protein-calorie malnutrition models a metabolomic platform kit that quantified 163 metabo-
and growth-restricted kidneys Guo et al78 examined pro- lites that included free carnitine, 40 acylcarnitines, 14
files of ion channel and transporter proteins. They looked amino acids (13 proteinogenic+ornithine), hexoses
at 367 proteins that were differentially expressed and (sum of hexoses—about 90%–95% glucose), 92 glyc-
Review
then used Ingenuity Pathway Analysis. These investiga- erophospholipids (15 lysophosphatidylcholines and 77
tors found that in the kidneys of growth-restricted fetuses, phosphatidylcholines), and 15 sphingolipids. In another
a number of carriers were differentially expressed, and, study, Horgan et al88 found that the metabolic profile
they hypothesized, dysregulated. In analyzing the data, during pregnancy led to a potential phenotypic signa-
they noted 22 differentially expressed proteins that are ture for fetuses who would become SGA neonates.
known to be involved with transporters and ion channels. Such studies hint that there may be value in metabo-
They took the results to indicated that such dysregulation lomic studies that could ultimately hone down the rea-
may be involved with changes in kidney function in fetal sons for programming of hypertension; however, these
growth-restricted offspring. presently constitute, at best, pilot data.
Overall, a variety of noncoding events impact the
future health of offspring. Some of the presently known
Metabolomics and Programming factors are epigenetics, proteomics, metabolomics, the
The examination of low molecular weight compounds in microbiome and other impactful events (Figure 2).
a given biological sample to attain a picture of the com-
plete metabolites is called metabolomics.79 The involved
methodology, which requires high-resolution techniques THE AT RISK CHILD AND A
such as mass spectrometry, nuclear magnetic resonance PERSONALIZED MEDICINE APPROACH-
studies, and Fourier transform infrared spectrometry
are time and funding intensive.79 As the metabolome
FEASIBILITY
changes quickly (within seconds to minutes), the choice Presently, the phenotype of LBW for gestational age
of sampling is crucial. With respect to DOHaD, metab- and prematurity (with either LBW for gestational age,
olomic profiling has been performed in some animal birth weight appropriate for age, or high for gestational
metabolome studies and on clinical samples from reposi- age) are easily determined. The data linking individual
tories.80 Such studies have the potential to contribute a children to future risk, however, are lacking.84 However,
physiological signature to changes that may contribute to a common-sense approach is feasible, as suggested
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Review
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