Hemodynamics of Increased Pulse Pressure in Older Women in the Community-Based Age, Gene/Environment Susceptibility–Reykjavik Study
Pulse pressure increases with advancing age particularly in women. As a result, women have a higher pulse pressure than men from midlife onward. Higher pulse pressure in older women as compared to men is often attributed to increased aortic wall stiffness and premature wave reflection. To evaluate this hypothesis, we measured central aortic input impedance, pulse wave velocity, and wave reflection in 408 older men and women (age range, 69 to 94 yr, mean 75 yr) participating in the community-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik). Women as compared to men had higher pulse pressure (75.8±18.7 versus 69.5±16.8 mm Hg, P<0.001) and smaller aortic diameters (2.74±0.24 versus 2.97±0.28 cm, P<0.001). Augmentation index (AI) was higher (11.0±15.9 versus 7.9±12.9%, P=0.032) in women whereas proximal aortic elastance-wall thickness product (Eh) did not differ (P=0.61). In a stepwise model for pulse pressure that included age and sex and offered aortic diameter, Eh, mean pressure, AI, pulse wave velocity, height, weight, and body surface area as additional covariates, higher pulse pressure was associated with increased wall stiffness, smaller aortic diameter, higher mean pressure, and increased AI (Model R2=0.59, P<0.001). The sex difference in pulse pressure (6.6±1.7 mm Hg, P<0.001) persisted after Eh entered the model (6.9±1.5 mm Hg, P<0.001) but not after aortic diameter entered the model (−0.4±1.4 mm Hg, P=0.75). Thus, reduced aortic diameter and impaired matching between diameter and flow accounts for the sex difference in pulse pressure in an unselected community-based cohort of older people.
Pulse pressure increases with advancing age, particularly in women. Before 50 years of age, relative to men, women have lower pulse pressure and carotid-femoral pulse wave velocity (CFPWV). After 60 years of age, pulse pressure is higher in women than men.1,2 Accelerated aortic wall stiffening could potentially contribute to higher pulse pressure in women. However, the observation that CFPWV, which is a good measure of aortic wall stiffness, remains comparable or lower in older women as compared to men suggests that factors other than aortic wall stiffness may contribute to higher pulse pressure in women.2 Premature wave reflection because of shorter stature has been suggested as an additional contributor to higher pulse pressure in women. One study suggested that reduced arterial diameter may contribute to higher pulse pressure in women, although this hypothesis was not tested.3 A recent study demonstrated that reduced aortic diameter and mismatch between aortic flow and diameter, leading to elevated forward pressure wave amplitude, was associated with increase pulse pressure in middle-age and older people with systolic hypertension.4,5 In the present study, we evaluated the relative contribution of aortic wall stiffness, diameter, and wave reflection to increased pulse pressure in women as compared to men in a community-based sample of older people.
The rationale and design of the Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik) have been presented in detail.6 AGES-Reykjavik originates from the Reykjavik Study, a community-based cohort established in 1967 to prospectively study cardiovascular disease in Iceland. Between 2002 and 2006, a total of 5764 men and women participated in detailed evaluations of cardiovascular, neurocognitive, musculoskeletal, and metabolic phenotypes. AGES-Reykjavik was approved by the National Bioethics Committee in Iceland, which acts as the institutional review board for the Icelandic Heart Association (approval number VSN-00-063), and by the National Institute on Aging Intramural Institutional Review Board. All participants gave written informed consent.
Arterial tonometry was added to the study protocol for all participants beginning January 12, 2005, and continuing through to the end of the examination cycle. In addition, tonometry was combined with a limited echocardiographic study to assess aortic input impedance in a random subset of approximately 50% of the tonometry cohort. Tonometry was attempted in 1083 participants and was accompanied by limited echocardiography in 566 participants. After exclusions for data quality and missing covariates, usable aortic input impedance, aortic diameter, and covariate data were available in 408 participants, who represent the sample for this analysis.
Hemodynamic Data Acquisition
The hemodynamic protocol has been described.4 In brief, after 15 to 20 min of supine posture, auscultatory blood pressure was assessed by using a computer-controlled device that automatically inflated the cuff to a user preset maximum pressure and then precisely controlled deflation at 2 mm Hg/sec. This device digitized and recorded mean and oscillometric cuff pressure and ECG (1000 Hz) and a cuff microphone channel (12 kHz) throughout the inflation and deflation sequence so that all blood pressure measurements could be overread by the core laboratory (Cardiovascular Engineering Inc). Arterial tonometry with ECG was obtained from the brachial, radial, femoral, and carotid arteries using a custom transducer (Cardiovascular Engineering Inc). Next, 2-dimensional echocardiographic images of the left ventricular outflow tract and proximal aortic root were obtained from a parasternal long axis view, followed by acquisition of tonometry of the carotid artery and pulsed Doppler of the left ventricular outflow tract from an apical 5-chamber view. Body surface measurements from suprasternal notch to pulse recording sites were obtained by using a fiberglass tape measure for carotid, brachial, and radial sites and a caliper for the femoral site.
Tonometry waveforms were signal-averaged using the ECG as fiducial point. Average systolic and diastolic cuff pressures were used to calibrate peak and trough of the signal-averaged brachial waveform. Diastolic and mean brachial pressures were then used to calibrate carotid, radial, and femoral waveforms.7 CFPWV was calculated as previously described.8 Characteristic impedance of the aorta (Zc) was computed in the time domain.9 Augmentation index (AI) was assessed from the carotid pressure waveform.10 Aortic annulus diameter was measured just proximal to the aortic leaflets, and aortic root diameter was measured just distal to the sinuses of Valsalva. At each location, the largest (systolic) diameter was identified visually from a 5-second loop and measured on-screen from the original digital images. The left ventricular outflow tract Doppler flow velocity waveform was multiplied by aortic annulus area to compute aortic volume flow for impedance measurements and was multiplied by the ratio of aortic annulus area to aortic root area to compute aortic flow velocity. Aortic root flow velocity (V) was converted to local shear stress (τ) using the following equation: τ=8 x μ×V/D, where μ is viscosity of blood, which was assumed to be 0.035 dyne×s/cm2, and D is aortic root diameter. The water hammer equation was used to calculate the proximal aortic PWV, co=(Zc×A)/ρ, where Zc is characteristic impedance, A is aortic root cross-sectional area, and the density of blood, ρ, was assumed fixed at 1.06 g/cm3. The aortic elastance-wall thickness product (Eh), a measure of wall stiffness, was computed by rearranging the Moens-Korteweg equation to give: Eh=co2×ρD, where co is central aortic PWV and D is measured aortic root diameter.
Sample characteristics and hemodynamic variables were tabulated separately by sex and compared using an unpaired t test. Differences in hemodynamic variables between women and men adjusted for body surface area were assessed by using a general linear model. Stepwise multivariable regression analysis was used to assess relations between brachial pulse pressure and potential covariates including age, sex, height, weight, body surface area, aortic diameter and Eh, CFPWV, AI, and mean arterial pressure (MAP). Eh and AI were ln transformed and CFPWV was inverted (1/x) to normalize variance before regression analysis. Values are presented as mean±SD except as noted. A 2-sided P<0.05 was considered significant.
Sample characteristics are presented by sex in Table 1. Age and body mass index were similar in men and women, whereas heart rate and systolic blood pressure were higher in women despite a higher prevalence of antihypertensive drug administration (Table 1).
Central and peripheral pulse pressure and MAP were higher in women (Table 2). Zc was higher, aortic PWV was comparable, and CFPWV was lower in women as compared to men (Table 2). Aortic diameter was smaller in women and was associated with elevated aortic flow velocity and shear stress (Figure). In contrast, aortic wall tension was lower in women. Smaller diameter in association with increased resting flow velocity and shear stress indicates mismatch between aortic diameter and cardiac output in these older women as compared to the men. To test whether body size contributed to sex differences in aortic properties and flow, aortic variables were adjusted for body surface area (Table 3). Adjusted cardiac output and aortic wall tension did not differ between men and women. In contrast, aortic diameter remained lower and Zc, aortic flow velocity and shear stress remained higher in women after adjusting for body size (Table 3).
We next evaluated correlates of brachial pulse pressure in a multivariable model that included sex and age and offered height, weight, body surface area, MAP, aortic Eh, aortic diameter, CFPWV, and AI (Table 4) as additional covariates. In Model 1, pulse pressure was 6.6 mm Hg higher in women (Table 4). When aortic wall stiffness (Eh) entered (Model 2), R2 increased considerably but the difference in pulse pressure between women and men persisted. When aortic diameter entered (Model 3), model R2 again increased substantially and the difference between women and men was eliminated (Table 4). The effect of sex remained nonsignificant as MAP and AI entered the model (Models 4 and 5, respectively; Table 4). In the final model, a 1 SD increase in aortic wall stiffness (Eh) was associated with an 11-mm Hg increase in pulse pressure whereas a 1 SD decrease in aortic diameter was associated with a 9-mm Hg increase in pulse pressure (Table 4).
We tested for effect modification by repeating stepwise models including only hypertensive individuals (184 women, 130 men) and then including only treated hypertensive individuals (143 women, 95 men) with results that were substantially similar to those observed in the full sample. We also ran the model including only those individuals without coronary heart disease and not treated for hypertension (78 women, 80 men) and obtained similar results. To evaluate potential effects of hypertension duration on the relation between aortic diameter and pulse pressure, we determined hypertension status at a midlife visit (average age, 53.0±5.8 yr). At that time, 41% of the women and 45% of the men were hypertensive (blood pressure ≥140/90 or treated). We repeated the pulse pressure model including only those who were and then only those who were not hypertensive at the midlife visit, with comparable results in each case. Thus, there is no evidence that duration of hypertension significantly influenced our observations.
This study evaluated hemodynamic correlates of pulse pressure in a community-based sample of older men and women. In contrast to findings in younger adults, systolic and pulse pressures were higher in women as compared to men in this older sample. Proximal aortic wall stiffness was similar in women and men whereas proximal aortic diameter was smaller in women even after adjusting for body size. Smaller aortic diameter in women was associated with higher resting aortic flow velocity and shear stress, suggesting mismatch between aortic diameter and cardiac output in older women as compared to men. This mismatch between aortic diameter and flow was sufficient to account fully for the difference in pulse pressure between women and men.
Increased aortic stiffness and elevated pulse pressure are associated with increased risk for various major adverse events, including coronary artery disease,11–14 heart failure,15 stroke,16 and kidney disease.17 Cardiovascular disease and stroke become markedly more prevalent in women after 55 yr of age, becoming more prevalent in women than men.18 Similarly, pulse pressure in women meets then exceeds pulse pressure in men at approximately the same age,1 suggesting that abnormal aortic function may contribute to the excess age-related increase in prevalence of these debilitating disorders in women. For example, prior work has shown that heart failure with preserved systolic function is more common in women and is associated with an accentuated, parallel increase in effective arterial elastance and ventricular elastance with advancing age in women.19
A greater age-related increase in pulse pressure in older women as compared to men often is attributed axiomatically to excessive stiffening of the wall of the aorta. Higher PWV, which is sensitive to aortic wall stiffness, and early wave reflection are often invoked as possible mechanisms for increased pulse pressure. We found that pulse pressure was closely related to proximal aortic wall stiffness in this older community-based sample; however, proximal aortic wall stiffness did not differ between women and men in our study. Furthermore, CFPWV, which assesses average wall stiffness of the descending thoracic and abdominal aorta, iliac, and femoral arteries, was actually lower in women. Higher pulse pressure in the women in our sample was fully explained by smaller proximal aortic diameter, which could not be explained by differences in body size alone. Furthermore, smaller diameter was associated with increased mean flow velocity and shear stress in the proximal aorta in women as compared to men, indicating mismatch between aortic diameter and flow, suggesting that modulation of aortic diameter was either impaired in women or enhanced in men in our community-based sample of older people. Because Zc of the aorta, as compared to PWV, is more highly (inversely) sensitive to aortic diameter, smaller aortic diameter would be expected to increase pulse pressure primarily through an increase in Zc and forward pressure wave amplitude, as was evident in our study.
The basis for impaired matching between aortic diameter and flow in older women remains speculative. Active modulation of aortic diameter in response to alterations in hemodynamic load and estrogen levels is known to occur in young women. For example, aortic diameter increases during normal pregnancy, when estrogen levels and resting cardiac output are both elevated.20 In animal models, aortic remodeling during pregnancy is associated with increased activity of matrix metalloproteinases that are known to be involved in vascular remodeling.21 In postmenopausal women, acute estrogen administration increases diameter and decreases stiffness of the proximal aorta, suggesting that dynamic modulation of aortic diameter may be possible even in older women.22 Thus physiological and pharmacological elevations of estrogen levels are associated with increased diameter and reduced functional stiffness of the proximal aorta in women. Conversely, the reduction in estrogen levels after menopause may impair matching between flow and aortic diameter and may thus contribute to increased pulse pressure in women.
Recent studies suggest that aortic diameter may be involved in modulation of pulse pressure throughout life. A prior analysis in the Asklepios cohort demonstrated that Zc remains unchanged in women and actually falls in men between 35 and 55 yr of age whereas CFPWV increases in women and men.2 An observation of discordant change in Zc and CFPWV suggests an alteration in aortic diameter.4 The pattern of change in Zc and CFPWV in Asklepios suggests a blunted midlife increase in aortic diameter with advancing age in women, possibly indicating the early onset of impaired aortic diameter compensation for wall stiffening in women. In the Asklepios cohort, estimated aortic enlargement in women between 35 and 55 yr of age was found to be about half that in men, leading to relatively higher Zc in women.2 Thus modest aortic enlargement with advancing age may be compensatory rather than pathological, serving to attenuate the increase in pulse pressure that would otherwise occur as the aortic wall stiffens.23 Studies in animal models have demonstrated the importance of endothelial function as a modulator of aortic diameter, wall viscosity, and pulse pressure.24–28 Loss of endothelial function and NO bioavailability in the aorta with advancing age could interfere with matching between flow and diameter, preventing compensatory enlargement and manifesting as elevated pulse pressure. The extent of compensatory diameter matching to flow may differ by sex in older individuals, leading to our observation of a relatively smaller aortic diameter, higher flow velocity, and higher pulse pressure in older women as compared to men of comparable age and body size.
Potential limitations and strengths of our study should be considered. We measured aortic diameter by using transthoracic echocardiography. Using this approach, we were able to obtain a reproducible estimate of aortic root diameter but could not assess wall thickness. Newer imaging modalities such as transesophageal echocardiography (TEE) or MRI may provide more robust estimates of diameter and wall thickness and may help better define the pathophysiology of aortic diameter mismatch in older women.
Higher pulse pressure in older women as compared to men could represent selective survival, wherein men with higher pulse pressure died earlier than women. However, an association between diameter and pulse pressure that affects survival would be more likely to obscure rather than create an association between diameter and pulse pressure. Instead we found that pulse pressure was inversely related to aortic diameter in men as well as women in this community-based sample. However, women had lower aortic diameters, which were not explained by body size alone, together with higher flow velocities and higher pulse pressures, suggesting that impaired matching between aortic diameter and flow was more common in women and accounted for the sex difference in pulse pressure.
Women in our sample were more likely to have hypertension and were more likely to be taking antihypertensive drugs. Prior studies in animals have shown that antihypertensive drugs may have an effect on pulse pressure through their effect on matching between aortic diameter and flow.29 However, our observations persisted when treated individuals were excluded from the analyses, making it unlikely that adverse effects of antihypertensive drugs explain the relations between aortic diameter and pulse pressure that we observed.
Major strengths of our study are the cross-sectional, community-based nature of the sample, and routine assessment of hemodynamics using a comprehensive protocol with careful attention to quality control measures.
Excessive arterial pressure pulsatility is associated with microvascular damage in the heart, brain, and kidneys and increased risk for major adverse clinical events involving these organ systems. Pulse pressure is lower in women than men before menopause, but subsequently rises to levels that are considerably higher than those found in men. This accentuated rise in pressure pulsatility is paralleled by an increase in cardiovascular disease events in older women and may contribute to the higher prevalence of cardiovascular disease in older women as compared to men. Aortic diameter, an important determinant of pulsatile hemodynamic load, is a dynamic variable that may be amenable to change through lifestyle or pharmacological modification. Thus, interventions aimed at modulating aortic diameter may limit or reverse age-related increases in pulse pressure, particularly in women.
Sources of Funding
This study was funded by National Institutes of Health contract N01-AG-12100, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).
G.F.M. is owner of Cardiovascular Engineering Inc, a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical trials that evaluate the effects of diseases and interventions on vascular stiffness. The remaining authors report no conflicts.
- Received December 3, 2007.
- Revision received December 30, 2007.
- Accepted January 9, 2008.
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