Article
Though vascular disease in children is a growing concern due to
sedentary lifestyle, poor diet and obesity, it remains a rarity. Small
size, continued development of the body, and vascular conduit durability
pose unique challenges regarding treatment of pediatric vascular
conditions. These include trauma, tumor invasion of major abdominal
vessels, aortoiliac aneurysm, acute or chronic arterial occlusion, and
renovascular hypertension.2 From an evolutionary
medicine perspective, recognizing rare diseases that are unique to
particular populations or subpopulations can spark interesting
discussions that may elucidate otherwise hidden risk factors and
maximize timely diagnosis. Pediatric renovascular hypertension might be
one such condition.
When considering pediatric hypertension, one may question if there are
any unique contributors pertinent to a younger population susceptible to
developing high blood pressure. The most common cause of secondary
hypertension is renal artery stenosis (RAS). As opposed to
atherosclerosis in adults, etiologies of pediatric RAS appear to vary by
geography and disease process; fibromuscular dysplasia (FMD) contributes
to most cases in North America and Europe while Takayasu arteritis (TA)
prompts renovascular lesions largely in Asian and South African
youth.3 FMD is a rare, idiopathic vascular disease
that causes non-inflammatory, non-atherosclerotic disease mostly in
renal and carotid arteries; it appears to be most common in Caucasians
and women.4,5 TA is a granulomatous large vessel
vasculitis involving mostly the aorta and its proximal branches,
affecting mostly young, Asian females.6 In
approximately 10% of hypertensive children, renovascular lesions prompt
increased renin secretion, eventual systemic hypertension, and
potentially myocardial infarction or stroke should treatment be delayed
or ineffective.3,7 Discussing why there is geographic
variation of disease processes causing pediatric RAS may yield important
points for future investigators interested in developing preventative or
targeted therapies.
A general breakdown of the proximate mechanisms contributing to RAS
provides some necessary background for the forthcoming discussion of
potential ultimate causes. First described by Goldblatt et
al.,8 the pathophysiology of renovascular hypertension
(RVH) consists of several mechanisms that arise subsequent to ischemia
of the kidneys. Secretion of renin by the juxtaglomerular apparatus is
triggered by either renal baroreceptors responsible for detecting
reduced perfusion, macula densa sensing of low sodium levels, or
activation of beta-adrenergic receptors. Renin is then secreted into the
blood and cleaves angiotensinogen produced by the liver into angiotensin
I (ang I) which is transformed into angiotensin II (ang II) by
angiotensin converting enzyme (ACE) produced by the lung and kidney. Ang
II induced vasoconstriction of vascular smooth muscle, aldosterone
release, and fibrotic vessel wall thickening all contribute, if
prolonged, to eventual hypertensive injury which may result in decreased
blood flow.9 In addition to isolated RAS, RVH can be
concomitantly or separately caused by midaortic syndrome (MAS). MAS is
characterized by segmental narrowing of the distal descending thoracic
or abdominal aorta, in which concomitant RAS is observed in 60% of
these children.10
The discussion now takes on a more evolutionary tone. Though the
etiologies of RAS/RVH vary with age and are perhaps narrower in scope
compared with essential hypertension overall, attempting to understand
the increased hypertension prevalence observed in African American
adults and other populations can yield valuable insights regarding the
impact geography can have on hypertension etiology. One proposed
hypothesis associated with this topic involves natural selection for
sodium-conserving genotypes that protected ancestral populations from
dehydration in hot climates. Some studies have identified several
allelic variants that contribute to heat adaptation via sodium
conservation, such as the −6A allele of the promoter of the
angiotensinogen (AGT) gene, the 825T allele of the GNB3 gene, the −946G
allele of the epithelial sodium channel α-subunit gene, and the 47A and
79C alleles of the β2-adrenergic receptor gene. These ancestral variants
exhibit latitude dependency, in which they are much more prevalent in
African populations residing near the equator and less so in areas
farther away from the imaginary planetary line.11 In
extreme temperatures sodium conservation was advantageous given that
increased fluid retention slowed dehydration. However, salt-rich
environments, such as those present in the United States, have
negatively affected descendants given that retention becomes maladaptive
in lower temperatures. This latitude-dependent phenomenon may even occur
in lower risk groups, such as Asians. Nguyen et al. found, despite low
mean body mass indices, in their study that the prevalence of
hypertension in Chinese, Indonesian, and Vietnamese men were 22.9%,
24.8%, and 14.4% and 16.6%, 26.9%, and 11.7% in women
respectively.12 It is important to note, however, that
a subsequent literature search revealed little data supporting a
latitude dependency that could explain the geographic variation
associated with pediatric RAS.
No causative genes or distinct pathogenic factors associated with FMD
have been determined to date.13 However, a study
conducted by Bofinger et al. found that the ACE insertion/deletion (ACE
I/D) polymorphism presents at a higher frequency in renal FMD patients
compared with controls. The ACE I allele correlates with lower
circulating ACE levels and potentially lower ang I levels. Given that
ang II modulates growth of smooth muscle, ACE I may increase
susceptibility of arterial media remodeling and subsequent development
of multifocal renal arterial FMD. This differs from the arterial intima
thickening observed in atherosclerotic RAS which is associated with the
ACE D allele.14 Interestingly, an earlier study
conducted by Bloem et al. found in their cohort that white children and
adolescents homozygous for D alleles exhibit a higher level of ACE
activity compared with the D/I genotype or those homozygous for I
alleles.15 It should be noted that this study did not
disclose any subjects with FMD, suggesting that whites homozygous for
ACE I might have a lower risk of essential hypertension but increased
risk of FMD-induced hypertension which manifests at a young age. If this
is confirmed by future studies, could there be a tradeoff benefit in a
subset of white ancestors that increased FMD susceptibility in
descendants? The literature reports that increased endurance is
associated with lower resting blood pressure.16-18Though understanding the association between the ACE I/D polymorphism
and race is complex and largely inconclusive, it has been
well-documented that the ACE I allele is associated with increased
endurance in Europeans.19-22 It has been proposed that
endurance may have played a role in helping hominin scavengers
outcompete other terrestrial vertebrate scavengers for
carcasses.22 Setting chance aside for sake of
exploration, it appears plausible that possessing the ACE I allele
maximized endurance for scavengers but in turn predisposed some
descendants to increased FMD susceptibility. However, it is unclear as
to why a benefit that perhaps emerged as early as 4.4 million years ago
poses this particular disadvantage mostly in whites today.
Shifting focus to the connection between TA and pediatric RAS in Asians,
a meta-analysis by Lee et al. found an association between the ACE I/D
polymorphism and susceptibility to several forms of vasculitis,
including Bechet Disease and Henoch-Schonlein
purpura.23 Though they only compiled 12 studies and
did not discuss TA, their findings suggest that there might be a common
pathway involved in FMD and TA manifestation. In contrast to the
European population, several studies have found that ACE I/D
polymorphisms in the Japanese exhibit an opposite pattern regarding
endurance.24,25,26 The ID and DD genotype of the ACE
I/D polymorphism in the Japanese population is associated with greater
endurance. The etiology of TA is not well understood, but the strongest
connection concerns the Japanese population and the HLA-B52 serotype. It
is important to note that this serotype is present in some other
populations. However, it appears that Japanese who are HLA-B52 positive
carry the worst prognosis.27 Given the lack of
understanding of the genes responsible for TA manifestation, it would
perhaps be useful for studies to clarify whether any association exists
between the ACE I/D polymorphism and HLA-B52 serotype in TA patients.
Might the aforementioned scavenging benefit apply here as well, in which
a different pattern of genes be responsible for increased TA, as opposed
to FMD, susceptibility in the Japanese population?
Though it is currently unclear what fitness advantage greater endurance
offered ancestors of each discussed population, possessing the ACE-I
allele is a trait that may be part of an evolutionary tradeoff where the
benefit of endurance is offset by increased risk of FMD development or
TA. If both groups required greater endurance to scavenge, why were a
different pattern of genes required? Could this be due to environmental
differences that shaped two different diseases processes involved in a
similar tradeoff? It is debatable whether questions like these will
yield clinically relevant answers. However, should the geographic
variation associated with FMD or TA-mediated RAS in the pediatric
population not be due to chance, further discussion of potential
ultimate causes may eventually lead to studies dedicated to identifying
the gene patterns responsible for this observation and perhaps lead to
earlier treatment.