(Hypertension. 1995;26:34-37.)
© 1995 American Heart Association, Inc.
Articles |
Genetic and Environmental Factors in the Function and Structure of the Arterial Wall
From the Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Australia.
Correspondence to Dr A. Avolio, Graduate School of Biomedical Engineering, University of New South Wales, Sydney 2052, Australia. E-mail a.avolio@unsw.edu.au.
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Abstract |
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 Top Abstract IntroductionPulsatile Arterial Function and...DiscussionReferences |
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Abstract In large arteries the structure of the arterial wall determines pulsatile hemodynamics of pressure and flow. Mechanical wall stiffness, wall thickness, and elastin and collagen content vary along the arterial tree. The contribution of genetic and environmental factors to such structural properties is not yet known, but some data are available on possible functional correlates. In hypertensive rats diastolic and pulse pressure have been shown to be linked to two different genes on separate chromosomes. Although a genetic component contributes to intimal calcification, medial hypertrophy is not associated with genetic factors. A study of French West Indies families showed a preferential genetic determinant for pulse pressure in contrast to systolic or diastolic pressure. Environmental and geographic factors are associated with markedly different prevalences of hypertension and age-related increases in arterial stiffening in urban and rural communities in China. Salt consumption has also been implicated in modifications of pulse wave velocity. Recent data on structural parameters of the aortic trunk in oriental (Chinese) and occidental (American and Australian) subjects have shown that the ascending aorta in oriental subjects is of a relatively larger diameter and thinner media. This suggests that in this population a relatively higher primary pressure pulse would be generated because of increased stiffness of the proximal aorta. This suggests that factors other than arterial pressure are responsible for structural differences in the aortic wall and that oriental populations may have a predisposition to increased arterial pressure based on structural factors that affect the interaction between ventricular ejection and arterial load.
Key Words: population • aorta • atherosclerosis • blood pressure • sodium, dietary
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Introduction |
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TopAbstractIntroductionPulsatile Arterial Function and...DiscussionReferences |
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Studies of genetic and environmental determinants of many cardiovascular disorders abound, especially with the recent advances in the science of molecular biology. Hypertension has traditionally been at the forefront of the controversy of whether its causes are predominantly genetic, whether an increase in arterial pressure is an inherent outcome of the aging process, and whether there is significant modification of arterial pressure by external environment such as dietary salt and lifestyle patterns.1 2 3 Such issues are addressed by epidemiological studies in human populations4 5 or laboratory studies in animal models of hypertension, mainly in spontaneously hypertensive rats (SHR).6 7 Although arterial pressure is a pulsatile phenomenon, the approach has been to consider aspects of the circulation that relate to steady or nonoscillatory factors such as fluid volume, peripheral resistance, or cardiac output to gain insight into the determinants of hypertension.8 With respect to structural arterial modification, high arterial pressure is known to be associated with altered vascular changes, mainly increases in the wall thickness of resistance vessels.9 The question still remains, however, as to whether the trigger is a functional alteration, causing increased intravascular pressure and so producing adaptive structural vascular changes, or whether the arterial vasculature itself is predisposed to vascular changes that precipitate and result in altered arterial pressure. What is common to both points of view is that arterial pressure is developed in the aorta because of the oscillatory nature of ventricular ejection. That is, both the pulsatile function of the heart and arterial system and the structure of the large arteries become relevant factors in gaining an insight into the mechanisms responsible for development of high arterial pressure. The modification of the structure and function of large arteries by genetic and environmental factors thus becomes an issue of importance equal to that of peripheral resistance vessels in understanding underlying mechanisms of arterial disorders and hypertension.
These issues will be addressed against a background of the limited information available on both epidemiological and laboratory evidence of the effects of genetic and environmental factors, specifically on the structure and function of large arteries. With increasing awareness of the importance of pulsatile function of large arteries with respect to the heart (in relation to ventricular hypertrophy) and blood vessels (in relation to arterial pressure) and its modification by new classes of pharmacological agents (such as calcium antagonists and angiotensin-converting enzyme inhibitors), some recent studies have attempted to produce evidence of genetic and environmental associations with pulsatile parameters such as pulse pressure, arterial compliance, and arterial pulse wave velocity.
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Pulsatile Arterial Function and Wall Structure |
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TopAbstractIntroductionPulsatile Arterial Function and...DiscussionReferences |
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Genetic Factors
Studies relating genetic factors specifically to pulsatile hemodynamic parameters are scarce. A recent study on genetic determinants of arterial pressure in hypertensive rats addressed the problem of genetic heterogeneity by considering different hemodynamic variables as subphenotypes of blood pressure.10 In the Lyon hypertensive rat strain, the study reports two independent loci for diastolic and pulse pressures. A statistical linkage was found between a marker of the renin gene on chromosome 13 and diastolic pressure and between the carboxypeptidase B gene on chromosome 2 and pulse pressure. Both of these genes also show a statistical linkage to systolic pressure. The authors conclude that the two different genes related to the steady and pulsatile components of blood pressure may therefore be related to corresponding properties of the arterial vasculature and structure of the arterial wall. These are interesting speculations, but it is not yet known whether similar linkages are found with structural components of the arterial wall such as elastin, collagen, and smooth muscle in large arteries and resistance vessels.
Some studies aimed at associating genetic factors with specific events in wall morphology have highlighted the difference between medial and intimal structure. In jejunal arteries cross-transplanted between normotensive Wistar-Kyoto rats (WKY) and SHR, it was shown that medial hypertrophy only occurred in the SHR hosts, that is, independent of genetic factors.11 In contrast, calcification of aortic atheromatous lesions was found to be genetically determined in inbred mouse strains.12
Morphological studies in hypertensive and normotensive rats have shown that the arterial wall structure may be specifically modified by long-term treatment with angiotensin-converting inhibitors, leading to functional increase in arterial compliance.13 14 It has also been shown that angiotensin II has a pressure-independent effect on smooth muscle hypertrophy15 and is a major stimulant for collagen synthesis in vitro.16
An epidemiological study to demonstrate a genetic association with pulse pressure in preference to either systolic or diastolic pressure was performed in a group of 151 nuclear families that constituted 80% of the total population of the French West Indies island of La Désirade.17 The results of this study, however, do not agree with those of other studies involving twins or relatives of hypertensive subjects who show some degree of genetic linkage with systolic pressure even among normotensive subjects.18 Without further supporting evidence, it is difficult to interpret these results in relation to structural aspects of large arteries. Furthermore, conclusions drawn on pulse pressure alone do not necessarily pertain to pulsatile arterial function alone but pertain also to a combined effect of pulsatile arterial hemodynamic and ventricular ejection.19
Several investigators measured structural and functional parameters of the aorta and large arteries in families with hereditary connective tissue disorders. Although alteration of arterial wall structure in certain monogenic syndromes such as Ehlers-Danlos or Marfan's is different from that which occurs with age or hypertension, changes in functional arterial parameters relate to changes in basic properties of load-bearing components. Pulse wave velocity in the upper limb and aortic trunk and lower limb is markedly reduced in families with ecchymotic Ehlers-Danlos syndrome, a condition associated with a collagen type III deficiency.20 Although this genetic factor is involved in improved arterial distensibility, it is at the expense of a serious structural disorder of the arterial wall, which predisposes it to rupture because of the generally weakened structural collagenous support. Specific aortic structural changes have also been described for other connective tissue disorders. Aortic root dilatation and increased wall stiffness occur in the hereditary conditions of osteogenesis imperfecta and Marfan's syndrome.21 22 These conditions are associated with an increased frequency of hypertension.23
Environmental Factors: Population Studies, Pulse Wave Velocity,
Arterial Pressure, and Dietary Salt
The contribution of environmental factors to the structure
and function of large arteries has been extensively studied in the
attempt to uncover the mechanisms responsible for the development of
hypertension. Whereas many early studies confirmed the age-related
increase in arterial pressure24 and increased
arterial stiffness of the aortic wall, others showed that
these phenomena are present in different degrees in different
populations. In highland populations of New Guinea, the aortic caliber
increased with age in males and females to the same degree, whereas
pulse pressure decreased in males and increased in
females.5 Overall, this population did not exhibit the
age-related increase in arterial pressure seen in other
Western populations. Urban and rural Chinese communities exhibit
markedly different increases in arterial pressure and pulse
wave velocity with age.25 26 The same value of aortic
pulse wave velocity in a Southern Guangzhou rural community occurred 30
years of age later compared with that of a Northern Beijing urban
community. This difference in increase in pulse wave velocity with age
was similar to the prevalence of hypertension in the two communities.
The main factor that was implicated to explain the large difference
between the two communities was the consumption of dietary salt (7.3
g/d in Guangzhou; 13.3 g/d in Beijing).
While the association between salt consumption and arterial pressure has been subjected to exhaustive investigation, the specific association of salt with properties of the arterial wall has been studied to a lesser degree. Cross-sectional studies of pulse wave velocity in salt-free subjects indicate that wall stiffness is significantly reduced compared with that in age-matched control subjects.27 Decreased arterial compliance has also been found in the carotid, brachial, and femoral arteries of salt-sensitive subjects with borderline hypertension.28 In terms of genetic influences in different racial groups, salt sensitivity is higher in black populations compared with white populations, and this is associated with a higher prevalence of hypertension in blacks.29 30 Saline infusion also has been shown to reduce regional brachial artery compliance.31 This suggests possible modifications of viscoelastic properties of large arteries in this group of subjects, although confirmation of this would require specific measurements of mechanical properties together with morphological quantification of structural changes. Environmental factors such as aerobic exercise also have been demonstrated to improve arterial pulse wave velocity and wall stiffness32 and total systemic compliance.33
Aortic Structure
The geometric structure of the aorta in oriental and
occidental populations has been examined in a recent study involving
postmortem perfusion-fixed aortic specimens of American, Chinese, and
Australian subjects.34 35 The American and Australian
subjects were combined to form the occidental group and were compared
with the Chinese (oriental) group. Population data and causes of death
are given in Table 1. Compared with the occidental
population, the Chinese population was slightly older, had a lower
average body weight, and was of a smaller stature. Mortality was lower
for cardiovascular causes but much greater for
cancer-related causes.
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Outer circumference, medial thickness, intimal thickness, and degree of intimal atheroma were measured at four separate locations along the aortic trunk (ascending aorta, upper descending thoracic aorta at the level of T6, suprarenal abdominal aorta, and lower abdominal aorta) in subjects ranging from 18 to 103 years of age (n=521). The effects of shrinkage due to tissue processing were previously determined.35 Fixation caused an average retraction in length of 5.8% and in circumference of 6.5%. Embedding caused an average reduction of circumference of 18.9%. Since all specimens were processed in a similar manner, it was deemed unnecessary to correct for these effects when comparing similar age groups.
Comparison of the oriental with the occidental population showed a substantial difference in age-related change of aortic morphology along the aortic trunk. The Chinese showed a relatively lower average intimal thickness throughout the aorta, with a significant difference in the abdominal aorta (Table 2, top). This correlated with a lower atherosclerosis score in this location (Table 2, bottom) and is consistent with the usually accepted fact that oriental populations have a lower prevalence of atherosclerosis than occidental populations.35
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The most striking result from this study was the marked difference in the ratio of radius to medial thickness (R/h). Since the aortas were all fixed at the same pressure (100 mm Hg), R/h is proportional to wall stress (S) from Laplace's law: S=P · (R/h). When corrected for the effects of age, height, and weight, the ratio R/h was significantly higher in the Chinese ascending aorta (16%; P<.001), with little variation along the aortic trunk (Figure). Although the Chinese population was of relatively smaller body size, the ascending aorta was larger and the wall thinner. Thus, it is subjected to a relatively higher wall stress. One outcome of this is that the structure of the wall undergoes adaptive changes by increasing the stiffness to compensate for the higher stress. That is, the left ventricle of an oriental subject ejects into a relatively stiffer ascending aorta; thus a similar stroke volume would generate a higher primary pulse pressure. Since the profile of wall stress along the aortic trunk is different, relative stiffness would also be different, thereby affecting the secondary phenomenon of pressure augmentation due to wave reflection. Hence, simply on structural parameters alone, the aortas of oriental subjects would generate a higher pulse pressure compared with the aortas of occidental subjects. On this basis alone, one would conclude that oriental populations are subjected to a higher probability of developing hypertension.
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Discussion |
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TopAbstractIntroductionPulsatile Arterial Function and...DiscussionReferences |
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The effects of genetic and environmental factors on the structure and function of large arteries are relevant to the understanding of the pathophysiology of hypertension and arterial disorders. There is some preliminary indirect evidence that genetic factors are linked to pulsatile pressure, but no conclusive evidence of whether this is related to specific structural aspects of large arteries has been found. Geographic and environmental factors such as dietary salt consumption and exercise have been shown to be related to indexes of arterial wall stiffness such as pulse wave velocity and regional arterial compliance. Structural attributes of the ascending aortic wall may provide an explanation for the difference in prevalence of hypertension among different populations independent of other factors. It is not known, however, whether these attributes are due to genetic factors or other modifying environmental influences in different racial groups.
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References |
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TopAbstractIntroductionPulsatile Arterial Function and...DiscussionReferences |
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