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Gender Differences in Large Artery Stiffness Pre- and Post Puberty

Alfred and Baker Medical Unit, Baker Heart Research Institute, Melbourne, Victoria, 8008 Australia

Address all correspondence and requests for reprints to: Dr. Bronwyn Kingwell, Alfred and Baker Medical Unit, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria, 8008 Australia. E-mail: b.kingwell{at}alfred.org.au.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Age-related large artery stiffening is more pronounced in women compared with men and is an important cause of isolated systolic hypertension. This study aimed to investigate whether such gender differences are inherent or the result of sex steroid influences. Healthy children prepuberty [26 female (10.3 ± 0.1 yr), 32 male (10.3 ± 0.1 yr), mean age ± SD] and post puberty [30 female (15.9 ± 0.2 yr), 22 male (15.9 ± 0.4 yr)] were studied. Large artery stiffness was assessed globally via systemic arterial compliance and regionally via pulse wave velocity. Prepubertal males and females did not differ in body size, cardiac output, or heart rate. Prepubertal females had stiffer large arteries and higher pulse pressure than age-matched males (P < 0.05). Postpubertal males were taller and heavier and had a greater cardiac output and lower heart rate compared with similarly aged females. In relation to pubertal status, females developed more distensible large arteries post puberty whereas males developed stiffer large vessels (P < 0.05). These changes where such that central large artery stiffness was similar between genders in the postpubertal group. Together these data suggest that large artery stiffness varies intrinsically between genders but is also modulated by both male and female sex steroids.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE INCIDENCE OF cardiovascular disease is lower in women at all ages compared with men but increases disproportionately in women after the menopause when secretion of ovarian sex steroids is low (1, 2). Ovarian hormones are known to have multiple effects on the cardiovascular system including lipid profile (3) and important effects on blood vessel wall physiology (4, 5, 6). The large arteries have become a recent focus with regard to cardiovascular risk, and the properties of these vessels may be influenced by sex steroids.

Large artery stiffness has been recognized as an independent risk factor for cardiovascular disease (7, 8). It is the principal determinant of pulse pressure (PP) and increases with age in both men and women. However, women exhibit a greater age-related rise in arterial stiffness such that, post menopause, their large arteries are stiffer than those of similarly aged men (9). Furthermore, women have lower brachial systolic blood pressure (SBP) than men premenopausally, but a greater age-related rise is evident in many populations, such that women have higher systolic and PP than men after the seventh decade (10, 11).

Gender differences in arterial stiffness may be both intrinsic and influenced by sex steroids. Changes in the sex steroid profile associated with menopause have been linked with higher arterial stiffness in postmenopausal women (9). Furthermore, in both cross-sectional (12, 13) and longitudinal studies (14), estrogen-containing hormonal therapy has been associated with lower arterial stiffness in postmenopausal women. Together these data indicate that female sex steroids modulate large artery stiffness; however, little is known regarding the role of male sex steroids. Furthermore the fact that women have stiffer large arteries than men in the postmenopausal years when sex steroid levels are relatively low also suggests that intrinsic gender differences may exist. Specifically these data suggest that women have intrinsically stiffer large arteries than men. To further investigate the origin of gender differences in artery properties, the current study has examined large artery stiffness in pre- and postpubescent children. We hypothesized that prepubescent females would have stiffer large arteries than age-matched males and that such differences would be minimized post puberty.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study population

Children (recruited from a local school) and their guardians gave written informed consent for the project, which was approved by the Ethics Committee of the Alfred Healthcare Group and carried out in accordance with the Declaration of Helsinki (2000). The study population consisted of 110 children of whom 58 were prepubescent (26 female, 32 male) and 52 were postpubescent (30 female, 22 male). Pubertal status was confirmed using salivary hormone assays.

Resting blood pressure

Supine brachial blood pressure and heart rate were determined using an automated oscillometric blood pressure monitor (Dinamap Vital Signs Monitor 18465X, Criticon, Tampa, FL) after 5 min of quiet rest. The mean of three measurements made at 2-min intervals was recorded.

Arterial stiffness

Large artery properties were assessed globally through measurement of systemic arterial compliance (SAC) and regionally via pulse wave velocity (PWV). Arterial compliance (SAC) measures the change in volume for a given change in contained pressure and is determined by the interaction of arterial mechanical properties and vessel geometry. In general, arterial compliance may be expected to relate to body size. Distensibility is a measure of the relative change in volume with respect to pressure and is thus independent of body size. PWV is inversely related to distensibility and estimates the underlying mechanical properties of the artery being assessed. PWV is thus a geometry-independent measure of arterial stiffness.

SAC. SAC was determined noninvasively using a two-element Windkessel model of the arterial system as described previously (15, 16, 17). The method involves measurements of ascending aortic blood flow and simultaneous driving pressure in the ascending aorta to derive compliance over the systemic arterial tree (15, 16, 17). Ascending aortic blood flow velocity was measured with a 3.5-MHz transducer (Multi-Dopplex MD1; Huntleigh Technology, Luton, UK) placed at the suprasternal notch. The product of aortic flow velocity and left ventricular outflow tract area measured by two-dimensional echocardiography (Hewlett-Packard Sonos 1500; Hewlett-Packard, Andover, MA) was used to calculate aortic volumetric flow. Aortic root driving pressure was estimated via applanation tonometry of the right carotid artery, using a Millar Micro-Tip pressure transducer (SPT-301, Millar Instruments, Houston, TX). Brachial artery blood pressure was simultaneously measured (Dinamap Vital Signs Monitor 18465X) and used to calibrate the carotid arterial pressure contour using mean and diastolic blood pressure. This method has been validated against invasive pressure recordings (18, 19).

PWV. PWV is related directly to arterial stiffness and was measured centrally (between the right carotid and femoral arteries) and peripherally (between the right femoral and dorsal pedis arteries) by simultaneous applanation tonometry (SPT-301, Millar Instruments) (20).

Biochemical analyses

Pubertal status was confirmed by measuring salivary sex steroid levels. All children provided a 2-ml saliva sample in a sterile container during the morning. No cotton or polyester swabs or chewing gum were used to increase flow rate. Samples were centrifuged (at 1500 rpm for 8 min) to remove particulate matter. The supernatant was frozen at -70 C for subsequent analysis. Testosterone concentrations were assessed in males (SPECTRIA testosterone-coated tube RIA, Orion Diagnostica, Espoo, Finland), and 17ß-estradiol (CLIA 17ß-estradiol; Assay Designs, Inc., Ann Arbor, MI) and progesterone (SPECTRIA progesterone-coated tube RIA, Orion Diagnostica, Espoo, Finland) concentrations were determined in females. These assays have been previously validated and relate closely to plasma levels (21, 22, 23).

Plasma total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and triglycerides were determined using a bench-top analyzer (Cholestech LDX, Hayward, CA).

Statistical analysis

Gender comparisons between the pre- and postpubertal groups were made by unpaired t tests. All other data were compared using ANOVA incorporating the between-subject factors of gender and pubertal status. Individual means were compared using the Fisher’s least significant difference test. All analyses were performed using SPSS (Version 10.0 SPSS Inc., Chicago, IL). Results are expressed as mean ± SEM. The level of significance employed was P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Salivary sex steroid levels confirmed pubertal status with complete stratification of the pre- and postpubescent groups achieved based on gender-specific sex steroid levels (Fig. 1). Specifically estradiol (Fig. 1, upper panel) and progesterone (Fig. 1, center panel) were higher in all postpubescent males compared with prepubescent females. Similarly, testosterone levels were higher in all postpubescent males compared with prepubescent males (Fig. 1, lower panel).

View larger version (9K): [in this window] [in a new window]   FIG. 1. 17ß-Estradiol (upper panel) and progesterone levels (center panel) of pre- and postpubertal females and testosterone levels (lower panel) of pre- and postpubertal males. Individual data are shown as open circles; solid circles are mean data ± SEM. Note that there is no overlap between pre- and postpubertal values.

Males and females in the prepubertal group were of similar age, height, weight, body mass index, cardiac output, and left ventricular outflow tract area (Table 1). LDL cholesterol was higher in females (Table 1). No significant differences were present between prepubertal males and females in brachial diastolic, mean arterial blood pressure and heart rate, although females were characterized by higher brachial systolic and PP and higher carotid PP (Table 1 and Fig. 2).

View larger version (18K): [in this window] [in a new window]   FIG. 2. Brachial PP (upper panel) and central PP (lower panel) in females (filled bars) and males (open bars) prepuberty and post puberty. Data are presented as mean ± SEM; *, P < 0.05.

View larger version (18K): [in this window] [in a new window]   FIG. 3. Mean values of SAC (upper panel), central and peripheral PWV (center and lower panels) in females and males pre- and post puberty. Data are presented as mean ± SEM; *, P < 0.05.

Table 2 shows the characteristics of the postpubertal males and females. Groups were of similar age, although postpubertal males were taller and heavier and had greater cardiac output and left ventricular outflow track area than females. Heart rate was lower in males (Table 2). LDL cholesterol did not change with pubertal status in males but was reduced post puberty in females such that females had lower levels than males in the older age group (Table 2). HDL cholesterol was not different between gender post puberty (Table 2). Although mean arterial pressure did not differ with gender in the postpubertal group, males had significantly higher brachial and carotid PP (Table 2 and Fig. 2). This was due to both higher systolic pressure and lower diastolic pressure (Table 2).

Age-related changes in arterial stiffness and PP

SAC represents the capacitance of the entire arterial system and incorporates a measure of vessel geometry. The capacitance of the arterial system (SAC) would be expected to increase with growth (increased aortic length and diameter), and thus SAC was higher in both gender post puberty compared with prepuberty (Fig. 3, upper panel). PWV provides a geometry-independent measure of vessel stiffness. Both central and peripheral PWV increased in males with age, consistent with large vessel stiffening (Fig. 3, center and lower panels). The reverse was true in females where central PWV was lower post puberty compared with prepuberty suggesting that the large vessels were more distensible post puberty (Fig. 3, center panel). Peripheral PWV did not change with pubertal status in females (Fig. 3, lower panel).

Although large artery stiffness is an important determinant of PP, cardiac output, which increases with age, is also an important factor. Both central and brachial PP increased with age in males but not in females (Fig. 2, lower panel). The increase in males is likely caused by greater size-related increases in cardiac output as well as arterial stiffening (Fig. 3, upper panel).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study demonstrates that central and peripheral large arteries are stiffer in prepubertal females compared with males and that gender differences in large artery stiffness are eliminated post puberty. Although both genders experienced an increase in the capacitance of their large arteries post puberty, females developed more distensible large arteries whereas males developed stiffer large vessels. Together these data suggest that gender differences in large artery stiffness are intrinsic but are modulated by both male and female sex steroids. Intrinsic gender differences observed in the prepubertal group when sex steroid secretion is low may provide insight into gender differences observed post menopause. Because large artery stiffness is an important determinant of both systolic and PP, these findings have relevance to gender differences with respect to isolated systolic hypertension. Thus the stiffer large arteries and higher PP observed in prepubertal females suggest that intrinsic gender differences may underlie the greater prevalence of isolated systolic hypertension in postmenopausal women.

Prepubertal arterial properties

Lower SAC and higher central and peripheral PWV provided evidence of stiffer large arteries in prepubertal females compared with males. Because there were no gender differences in potential confounding factors including mean pressure, these results suggest that young females have intrinsically stiffer large vessels compared with males. The origin of such differences is likely to be genetic and may have multiple origins. It is interesting to note that LDL cholesterol was higher in prepubescent females compared with males and could potentially contribute to large artery stiffening. There has been substantial controversy surrounding the role of cholesterol in modulation of large artery stiffness with both positive and negative relationships demonstrated (24). In the current study, however, LDL did not contribute to gender differences in large artery stiffness in multivariate analysis.

Because there were no gender differences with respect to body size or cardiac output in the prepubertal group, large artery stiffness was the main factor contributing to the higher PP in prepubertal females.

Postpubertal arterial properties

SAC increased post puberty indicating an increase in vessel capacitance in both genders. The increase was greater for females such that there were no longer gender differences in SAC in the postpubertal group. The increase in capacitance in both genders would be expected to relate in part to growth-associated increases in vessel length and diameter that occur during the pubertal years. Such changes allow accommodation of the concurrent increase in cardiac output without substantial PP elevation.

The central PWV data also indicate that sex steroid and growth-associated pubertal changes eliminated the prepubertal differences in large vessel properties between gender. This occurred through reduction in arterial stiffness in females post puberty whereas the reverse was true for males. In the periphery, pubertal status did not affect leg PWV in females, but there was a substantial increase in males to levels significantly higher than females. Together these data suggest that female sex steroids may exert their actions primarily in the large vessels to reduce stiffness whereas male sex steroids have more widespread actions and increase stiffness. Sex hormones may exert their influence on arterial stiffness through a variety of genomic and nongenomic mechanisms. These include modulation of vascular tone and structure through effects on the vasa vasorum, vascular smooth muscle cell growth, extracellular matrix composition, cardiovascular risk factors, and atherosclerotic progression.

Hormonal mechanisms

Estrogen (25) and progesterone (26) receptors have been demonstrated in human aorta, but their relative density in proximal and distal regions has not been studied. A greater effect of female sex steroids in the proximal aorta is consistent with the localization of the vasa vasorum, which through modulation of blood flow influences large artery stiffness (27). Estrogen increases blood flow through both endothelium-dependent (28) and -independent mechanisms (29). The effect of progestagens on vascular tone is more varied and controversial (30) suggesting that estrogen may be more important in relation to postpubertal reduction in arterial stiffness in females. Estrogen also has other well-documented antiatherogenic effects that could reduce arterial stiffness including inhibition of smooth muscle cell proliferation (31) and modulation of extracellular matrix composition (32, 33). Finally, estrogen is well known to improve lipid profile (34); however, LDL cholesterol was not a predictor of arterial stiffness indices in multivariate analyses.

In contrast to female hormones, male sex steroids appear to have more widespread actions that promote vessel stiffening in both central and peripheral regions. Androgen receptors have been identified in vascular tissues in experimental animals and cell culture (35, 36, 37, 38) but are less well studied than female sex steroid receptors. There are no reports with regard to androgen receptor localization in human vascular tissues. Androgen deprivation has, however, been shown to enhance endothelium-dependent vasodilation in adult men (39). An elevation in androgen levels associated with puberty would thus increase arterial tone and may contribute to stiffening in the large vessels. Androgens also increase smooth muscle cell proliferation (40) and monocyte adhesion to endothelial cells (41), atherogenic effects that also promote arterial stiffening.

Pulse pressure

Arterial stiffness and cardiac output are the main determinants of PP. In females, it is evident that cardiac output and arterial stiffness changed in a reciprocal manner during puberty such that PP was not different in pre- and postpuberty females. Males, however, experienced an increase in both cardiac output and arterial stiffness during puberty such that PP increased dramatically. Thus, whereas males had lower PP than females prepuberty, this was reversed post puberty. In contrast to females, the mechanical properties of the large arteries did not adapt to the increase in cardiac output associated with puberty in males.

Clinical relevance

The observed influence of pubertal status on arterial mechanical properties has relevance to the mechanisms underlying the higher incidence of isolated systolic hypertension in postmenopausal women compared with men (10, 11). The greater arterial stiffness and systolic and PP occurring in the absence of significant levels of ovarian hormones in prepubertal females is analogous to observations in postmenopausal women (9). Our data suggest that the greater arterial stiffness and PP in postmenopausal women is not therefore just a result of declining levels of ovarian steroids but also due to intrinsic gender differences. Early menopause is a known risk factor for cardiovascular disease (42, 43). Our findings suggest that this effect may be mediated in part through the higher levels of arterial stiffness evident in females when ovarian hormone levels are low. With regard to males, androgens appear to contribute to arterial stiffening and higher blood pressures compared with females during the reproductive years.

Conclusion

Prepubertal females have stiffer large arteries compared with age-matched males, indicating that intrinsic, genetic gender differences exist. Such gender differences were eliminated post puberty, suggesting that both female and male sex steroids modulate large artery stiffness. Indeed, in relation to pubertal status, females develop more distensible large arteries post puberty whereas males develop stiffer large vessels. These finding suggest that both genetic and hormonal influences contribute to stiffer large vessels in postmenopausal women and thus to the greater incidence of isolated systolic hypertension in elderly women. Therefore, a gender-specific approach is warranted in the diagnosis and treatment of systolic hypertension, and therapy targeting the large arteries would be particularly beneficial in postmenopausal females.

	Acknowledgments

 
We are grateful for the assistance of Jenny Starr, Marcus Somerville, and the staff and students of Wesley College.

	Footnotes

 
This work was supported by grants from the National Health and Medical Research Council of Australia and from The National Heart Foundation of Australia.

Abbreviations: HDL, High-density lipoprotein; LDL, low-density lipoprotein; PP, pulse pressure; PWV, pulse wave velocity; SAC, systemic arterial compliance; SBP, systolic blood pressure.

Received April 30, 2003.

Accepted July 28, 2003.

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