Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension

doi:10.1016/S0140-6736(96)10508-0

The Lancet

Volume 350, Issue 9082, 27 September 1997, Pages 953-955

https://doi.org/10.1016/S0140-6736(96)10508-0 Get rights and content

Summary

There is much evidence that people who had low birthweight tend to have higher blood pressure in later life. However, the mechanisms that mediate this relation are unknown. We argue that, in fetuses whose growth is impaired, synthesis of elastin in the walls of the aorta and large arteries may be deficient, and that this deficiency would lead to permanent changes in the mechanical properties of these vessels. Over a lifetime, such changes could predispose an individual to higher blood pressure, increased left-ventricular mass, and cardiovascular disease.

Section snippets

Molecular basis of aortic compliance

The aorta's elastic properties depend largely on the presence of a long-lived scleroprotein—elastin–in the vessel wall. Elastin accounts for 4–50% of the dry weight of the tissue in the thoracic aorta, and is a major component in the abdominal aorta and carotid arteries.⁴ Aortic elastin is arranged in multiple concentric lamellae, interspersed with smooth muscle and collagen. The number of elastic lamellae is greatest in the proximal part of the aorta. They begin to develop early in fetal life,

Effects of ageing

By middle age, the human aorta has undergone about two billion cycles of expansion and contraction. The effect of cyclic mechanical stress on any material is gradually to reorganise its molecular structure, and to cause its fracture at a load it could previously bear. In the aorta, the fatiguing effects of cyclic stress lead to fracture of elastin fibres and transfer of stress to collagen fibres.¹² This process is visible on microscopy as a fragmentation and loss of regularity in the elastic

Regulation of vascular elastogenesis during development

Experiments in animals have shown that synthesis of elastin in the tunica media of developing arteries is influenced by local haemodynamic conditions. For example, at birth, in rabbits, when pulmonary and systemic pressures are similar, the ratios of elastin to collagen in the pulmonary artery and the aorta are the same. 2 months after birth, by which time pulmonary pressure has decreased from 40 mm Hg to 15 mm Hg, and systemic pressure increased to 80 mm Hg, the ratio of elastin to collagen in

Hypothesis

A 1996 systematic review of 34 studies, based on more than 66 000 people, found that in both adults and prepubertal children, there was a consistent negative relation between birthweight and current blood pressure.²⁷ One mechanism that might underlie this association is impairment in elastin synthesis in fetuses of retarded growth during a critical period of blood-vessel development. This impairment may result from haemodynamic changes in the fetal circulation that accompany intrauterine growth

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The MEDLINE, Embase, Scopus, CINAHL, and Allied and Complementary Medicine databases were searched from inception to July 2021. Eligibility criteria included observational controlled studies in youths aged <20 years with risk factors/exposures during the first 1000 days and aIMT measurements (unadjusted mean ± SD). Outcome data were pooled using a random-effects meta-analysis. Meta-regression was used to investigate confounders.
A total of 8657 articles were identified, of which 34 were included in our meta-analysis. The age of participants ranged from 22.9 weeks gestation in utero to 10.9 years. In the meta-analysis (n = 1220 cases, n = 1997 controls), the following factors were associated with greater aIMT: small for gestational age (SGA) status (14 studies, mean difference, 0.082 mm; 95% CI, 0.051-0.112; P < .001; I² = 97%), intrauterine growth restriction (6 studies; mean difference, 0.198 mm, 95% CI, 0.088-0.309; P < .001; I² = 97%), preeclampsia (2 studies; mean difference, 0.038 mm; 95% CI, 0.024-0.051; P < .001; I² = 38%), and large for gestational age (LGA) status (3 studies; mean difference, 0.089 mm; 95% CI, 0.043-0.0136; P < .001; I² = 93%). In meta-regression, older age (P < .001), higher prevalence of maternal smoking (P = .04), and SGA (P < .001) were associated with greater difference in aIMT in preterm participants compared with controls. Limitations included the high heterogeneity present in most meta-analyses and the scope of our meta-regression.
Adverse early life exposures are associated with greater aIMT in youths, consistent with an increased risk for CVD later in life. Further research is needed to determine whether intervention and preventive strategies deliver clinical benefits to improve future cardiovascular health.
Early life determinants of arterial stiffness in neonates, infants, children and adolescents: A systematic review and meta-analysis
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Certain exposures and risk factors during the first 1,000 days of life are known to influence future cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a measure of arterial stiffness and a recognised surrogate marker of CVD. We performed a systematic review and meta-analyses to investigate whether early life exposures were associated with increased PWV compared with controls in youth.
Databases AMED, MEDLINE, EMBASE, CINAHL and Scopus were searched from inception until February 2022. Eligibility criteria: observational controlled studies in youth aged <20 years with risk factors/exposure during the first 1,000 days and PWV measurement. This review is registered with PROSPERO (CRD42019137559). Outcome data were pooled using random-effects meta-analysis. Meta-regression was used to investigate potential confounders.
We identified 24 eligible studies. Age of participants ranged from 1-day to 19-years at time of PWV assessment. Exposures included pre-term birth, small for gestational age (SGA), maternal diabetes and assisted reproductive technologies, none of which were significantly associated with PWV in meta-analysis. Sub-group analysis by age demonstrated increased PWV in childhood and adolescence in those exposed to maternal diabetes or born SGA. In meta-regression of pre-term studies, higher prevalence of SGA was associated with increased PWV compared with controls (p = 0.034, R² = 1).
We found limited evidence that youth exposed to maternal diabetes or born SGA have increased PWV, consistent with increased future CVD risk. These changes in PWV appear to manifest in later childhood and adolescence. Further research is required to better understand the observed relationships.
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A strong body of evidence demonstrates that inflammation plays an important role in arterial stiffening. This chapter explores the relationship between inflammation and arterial stiffness by looking at cross-sectional, prospective, and experimental data as well as reviewing the most recent data on arterial stiffness in chronic inflammatory conditions. The possible mechanisms by which inflammation could lead to arterial stiffening are discussed and studies investigating the effect of antiinflammatory drugs for arterial stiffness reduction are summarized.
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Vascular aging (VA) is a reflection of biological aging in general and subject to many influences during the life course. It involves all aspects of the cardiovascular system but is most visible in the age-related increased arterial stiffness of large elastic arteries, such as the aorta. It is possible to measure this process by pulse wave velocity (PWV). Several studies have now documented that increased PWV is an independent risk marker for both cardiovascular and noncardiovascular events, as well as total mortality, in a range of population-based cohorts as well as in groups of patients, for example, with end-stage renal disease or inflammatory conditions. In some individuals, this process is taking a more rapid course, so called early vascular aging (EVA), with increased aortic PWV, even adjusted for other age, sex, and other hemodynamic variables as well as cardiovascular risk factors. However, in other more fortunate individuals, the vascular tree seems to be remarkably protected from such aging phenomena, even under the same risk factor burden—a variant of more healthy VA or even supernormal vascular aging (SUPERNOVA). This chapter focuses on the epidemiological, mechanistic, and treatment aspects of EVA and what can be learned about protective factors associated with SUPERNOVA. Ongoing studies try to test drugs that may favorably influence EVA and whether a treatment strategy based on addressing arterial stiffness could be more beneficial than conventional treatment based on blood pressure levels. Interesting aspects of genetics and epigenetics, as well as mechanotransduction and early life influences of VA will be further discussed.
Ethnic differences in arterial stiffness and central aortic hemodynamics
2022, Textbook of Arterial Stiffness and Pulsatile Hemodynamics in Health and Disease
Studying ethnic contrasts in arterial function throws light on potential etiology, pathophysiology, and opportunities to improve treatment in often neglected groups. In this chapter, we review the impact of ethnicity on arterial stiffness. We do not focus on “race” which is not biologically defined and whenever possible avoid skin “color.” We take a life-course approach (intrauterine, childhood, adolescence, and youth), with most data in middle-aged and older adults. Available evidence supports the presence of an important influence of race/ethnicity on large artery stiffening and cardiovascular risk. Ethnic differences in arterial indices are clearest where obesity, socioeconomic and psychosocial factors are most marked, with intergenerational transmission. Few studies have examined what mechanisms beyond standard risk factors contribute to disparities. Genetic effects are not obvious; studies of maternal risk and between generations are yet rare. It seems self-evident that mounting simple, large, randomized trials (RCTs) with large artery stiffness as the target and events as the primary outcome may provide evidence for the implementation of novel preventive and therapeutic approaches to reducing cardiovascular risk, particularly in ethnic minorities.
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HypothesisImpaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension

Summary

Section snippets

Molecular basis of aortic compliance

Effects of ageing

Regulation of vascular elastogenesis during development

Hypothesis

Risk factors for changes in aorto-iliac arterial compliance in healthy men

Atherosclerosis

Arterial distensibility and left ventricular hypertrophy in patients with sustained essential hypertension

Am Heart J

Pulse wave velocity as a marker of vascular disease

Lancet

Structure and metabolism of arterial elastin

Int Rev Exp Pathol

Elastic lamina growth in the developing mouse aorta

J Histochem Cytochem

Rapid accumulation of elastin and collagen in the aortas of sheep in the immediate perinatal period

Circ Res

Nucleic acid and scleroprotein content of the developing human aorta

J Pathol

Aorta elastin turnover in normal and hypercholesterolemic Japanese quail

Biochim Biophys Acta

Marked longevity of human lung parenchymal elastic fibres deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon

J Clin Invest

An alteration in the chemical structure of the aortic wall induced by a finite period of growth inhibition

J Anat

Aging, high blood pressure and disease in humans

A new in vitro system for studying cell response to mechanical stimulation: different effects of cyclic stretching and agitation on smooth muscle cell biosynthesis

Exp Cell Res

Structure and function of the arteries in hypertension

Am Heart J

Hypothesis
Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension