Smaller Aortic Dimensions Do Not Fully Account for the Greater Pulse Pressure in Elderly Female Hypertensives
This study examined the importance of aortic dimensions in determining pulse pressure in elderly hypertensives participating in the 2nd Australian National Blood Pressure Study, including a substantial number not previously receiving blood pressure lowering medication. Aortic dimensions were determined by ultrasound at the transverse arch and at the insertion of the aortic valve. Unadjusted data showed negative (P<0.001) correlations between central (carotid) and (brachial) peripheral pulse pressure and both arch (−0.200, −0.181) and outflow tract (−0.238, −0.238) diameters. Correlations were similar in those previously treated with blood pressure lowering medication and in the treatment naïve. Central pulse pressure (84±26 versus 75±28 mm Hg, P<0.001) was higher and aortic dimensions (transverse arch 2.56±0.31 versus 2.88±0.35 mm, P<0.001) smaller in women than men. Women had greater aortic stiffness (beta index 29.4±36.1 versus 22.1±21.3, P<0.03). Other bivariate correlates of central pulse pressure were age, mean arterial pressure, height, heart rate, augmentation index, aortic stiffness (all P<0.001), and weight (P=0.027). In multivariate analyses gender remained a predictor of central pulse pressure (P<0.001) even with inclusion of aortic dimensions (P=0.013) height and weight. Other significant terms were age, heart rate, mean blood pressure, and aortic stiffness (all P<0.001). These findings demonstrate an independent inverse relation between aortic size and pulse pressure in older hypertensive subjects. Differences in aortic dimensions and stiffness between genders do not fully account for the observed blood pressure differences, suggesting that a contributory factor to gender differences in pulse pressure is an increased age-related mismatch in ventricular function and aortic stiffness in women compared with men.
Pulse pressure (PP) has been recognized as a major determinant of blood pressure related end organ damage and cardiovascular clinical events.1 Central PP is determined by the interaction between cardiac left ventricular ejection and the mechanical properties of the recipient arterial circulation determined by intrinsic stiffness and geometry.2 Pulse pressure increases with age and, at least in hypertensive men, age-related changes in stroke volume contribute during early adulthood but less so at older ages.3 Large artery stiffness increases with age in both genders and is believed to be a major determinant of the increase in pulse pressure at older ages. Although in young adults blood pressure is lower in women than men, with age there is a more rapid increase in systolic and PP in women.4 It has previously been suggested that large (and not only small) arterial properties modulate the gender difference in the level of blood pressure.5,6
Aortic root dimensions have been related to diastolic blood pressure and in some but not all studies to the presence of hypertension7–10 though none of these studies included measurement of aortic dimensions at other sites. Recent data has led to the inference that there is also an inverse relation between aortic dimensions and PP such that elevated PP is found in subjects with smaller, rather then larger, aortic areas.6 Although this influence has been proposed as more significant than increased pressure reflection in determining PP, the inference was based on data which did not include actual aortic dimension measurements. Previous data from Framingham, however, suggested that in this population the influence of PP, measured at the brachial artery, on aortic root dimensions was minimal.7
Aortic dimensions are different between men and women, raising the possibility that if they substantially determine central PP this may explain the documented difference in PP between genders. Previous studies from the 2nd Australian National Blood Pressure Study11 (ANBP2) cohort have implicated gender related differences in aortic stiffness as being involved in systolic hypertension,12 and a comparison in men and women of similar height showed gender dependant differences in timing of ventricular ejection as well as pressure wave reflection.13 In the present study we have specifically examined the influence of aortic dimensions on central and peripheral PP in the ANBP2 cohort of elderly hypertensives. In addition, as the effect of long-term treatment of blood pressure on aortic dimensions and PP is not known we compared relationships in treated hypertensives with treatment naive subjects.
Subjects were recruited from participants in the Australian Comparative Outcome Trial of Angiotensin-Converting Enzyme Inhibitor- and Diuretic-Based Treatment of Hypertension in the Elderly (ANBP2).14 This was a comparative outcome trial using a prospective, randomized, open-label design with blinding of end point assessments. Subjects in ANBP2 were recruited through general practices. They were seen by a study nurse 3 times at least 1 week apart to assess eligibility for the trial. Eligibility required an age between 65 and 84 yr, an untreated systolic blood pressure of ≥160 mm Hg or diastolic pressure ≥90 mm Hg (if systolic pressure ≥140 mm Hg), no stroke or myocardial infarction within the previous 6 months, serum creatinine <2.5 mg/dL, no cardiac failure, dementia, or serious comorbidity. After ascertaining eligibility, but before randomization, participants recruited in the greater Melbourne area were asked to participate in a substudy on left ventricular and arterial properties, independent of their enrolment in the main trial, and informed consent was obtained.15 Previous separate ethics approval for the substudy and use of trial data were obtained from the ethics committee of the Royal Australian College of General Practitioners in accordance with the declaration of Helsinki. The main ANBP2 trial was approved by the same body.11,16
Results reported here are from all subjects in the substudy who had carotid blood pressure waveform recordings and adequate ultrasound images for assessment of aortic outflow and transverse aortic arch measurements.
Subjects were placed in the recumbent position in a quiet air-conditioned room. After at least 10 min of rest 3 measurements of brachial mean, systolic, and diastolic pressures (Dinamap 1846 SXP; Critikon) were made with the average of the last 2 used in further calculation. 2D-guided M-mode echocardiography of the aortic root and transverse aortic arch (suprasternal, long axis) was performed as previously described using Hewlett-Packard Sonos 500 equipment and recorded on videotape.12 Left ventricular dimensions at end diastole and during systole were determined by 2D guided M mode echocardiography using leading edge to leading edge measurements.
From the videotape recordings a single operator (YLL) measured minimal (diastole) and maximal (systole) internal dimensions of the transverse aortic arch in up to 5 representative cardiac cycles. The left ventricular outflow tract diameter was determined as the maximum diameter between the insertion points of the aortic valve. Patients with significant aortic valve disease were excluded.
Central PP was determined by applanation tonometry of the right carotid artery as previously described.17 The beta index, a stiffness index that is pressure independent, was calculated as beta=(ln (systolic)−ln(diastolic blood pressure))×diastolic diameter/(systolic−diastolic diameter).18,19
Results are reported in Table 1 as mean±SD and otherwise as mean±SEM. Comparisons between means were evaluated by unpaired t. Bivariate correlation between continuous variables was by linear regression techniques (method of least squares). Multiple regression used a method of stepped entry and removal with P to enter set at <0.05 and P to remove at <0.10. All statistics were calculated using SPSS for Windows version 15.1 (SPSS Inc).
Data were available from 691 (384 female, 307 male) subjects. Baseline characteristics are shown in Table 1. As noted previously, brachial systolic and diastolic blood pressures measured at the time of the ultrasound examination were significantly lower than those obtained at the time of randomisation.16 Mean brachial PP was 79 mm Hg (Table 1) and was significantly (P<0.001) higher in females (83.0±0.9 mm Hg) than males (73.9±0.9 mm Hg). Central (carotid) PP was also higher in females (Table 1; Figure 1). Mean transverse aortic arch measurements were significantly greater (P<0.001) during systole (2.80±0.01 cm) than diastole (2.70±0.01 cm). Diastolic arch diameters (Figure 2) were smaller (P<0.001) in women (2.56±0.01 cm) than men (2.88±0.02 cm). The systolic expansion was 3.7±0.1% for both men and women, but the beta index of arterial stiffness was significantly higher (P<0.001) in women than men (Table 1).
There was a significant bivariate inverse relation (r= −0.132, P<0.001) between central PP and the diameter of the transverse aortic arch during diastole. In other bivariate analyses (P<0.001 for all, unless otherwise stated) central PP was positively associated with augmentation index (r=0.260), age (r=0.203), age2 (r=0.201), mean arterial pressure (r=0.661), beta index (r=0.226) and negatively with height (r=−0.151), heart rate (r=−0.17), and weight (r=−0.084, P=0.027). In multivariate analysis the independent predictors of PP were mean arterial pressure, age, gender, beta index, heart rate, and aortic arch diameter at the level of the transverse aortic arch (Table 2).
The left ventricular outflow tract diameter, measured as the diameter of the aortic valve, was less in women than men (Table 1, Figure 3) and was also inversely related to central PP (−0.181, P<0.001). In multivariate analyses (Table 3) significance was limited to age, gender, mean arterial pressure, beta index, heart rate, and aortic outflow diameter.
Similar results were found if brachial, rather than central, PP was used in the analysis. Thus bivariate correlations between brachial PP and aortic arch and valve diameters were r=−0.204 and r=−0.238 respectively (P<0.001 for both) and r=0.274 (P<0.001) for augmentation index (heart rate not related). In multivariate analyses including aortic arch diameter significant terms were age (P<0.001), mean arterial pressure (P<0.001), gender (P<0.001), aortic arch diameter (P=0.012), and augmentation index (P=0.001) whereas beta index almost achieved significance (P=0.054). When aortic valve diameter was substituted for arch diameter in the multiple regression, significance was limited to mean arterial pressure (P<0.001), gender (P=0.001), age (P<0.001), augmentation index (P=0.002), and valve diameter (P=0.003). Negative correlations between aortic dimensions and PP were found in subjects who had previously received blood pressure medication as well as in the treatment naïve. For central PP correlations with valve and arch diameters were r=−0.169, −0.139, −0.202, and −0.104 for previously treated and treatment naïve, respectively, whereas for brachial pressures they were r=−0.241, −0.212, −0.261, and −0.190 (P<0.05 for all). Inclusion of previous blood pressure treatment status did not achieve significance when added to the various multiple regression analyses.
There was a positive correlation (r=0.367, P<0.0001) between the aortic valve diameter and the diameter of the transverse aortic arch during diastole. Positive correlations were also observed between both outflow tract and arch diameters and left ventricular diameters during systole and diastole. For arch diameters the correlations (all P<0.001) were r=0.307 for LVIDd and r=0.233 for LVIDs, whereas for outflow tract the respective values were r=0.451 and r=0.335.
In the elderly and in those with hypertension or cardiovascular disease the usual physiological difference between central and peripheral PP is decreased and brachial BP more closely matches central aortic pressures, as seen in the ANBP2 population of elderly hypertensives.16 The principal finding from the present study is that the diameter of the proximal aorta, independent of stiffness and gender, is a significant determinant of central and therefore brachial PP in elderly hypertensive subjects; with elevated PP found in those with smaller proximal aortas. This inverse correlation was evident for aortic size measured at the level of both the transverse aortic arch as well as at the left ventricular outflow tract. The correlations remained significant when examined in multivariate analyses in which age, gender, mean arterial pressure, and intrinsic aortic root stiffness were other significant determinants.
Mitchell et al have previously suggested that increased PP in systolic hypertension is primarily attributable to a decrease in “effective” aortic diameter as calculated from the water-hammer equation.6 These investigators found PP to be more closely related to effective aortic diameter and characteristic impedance than to the effect of PWV and pressure wave reflection. Our results are consistent with this, but with the additional benefit of directly measured aortic diameters; an important additional finding was that the greater PP observed in women is not solely related to their lower proximal aortic diameter and increased stiffness. In our study we were able to use measured aortic and out-flow tract diameters to directly investigate the association between aortic size, aortic stiffness, and central PP and thus provide the first demonstration of this relationship using direct measures of aortic size in elderly patients with hypertension.
Despite this association and the presence of smaller aortic dimensions in women than in men, gender remained significant in multiple regression analyses suggesting that neither aortic cross sectional area, aortic stiffness, nor aortic length (associated with height) differences between men and women were able to adequately account for all the difference in PP apparent between men and women in our group.
Central PP is determined by the interaction between stroke volume and the properties of the arterial inflow system, particularly of the proximal aorta,20 and brachial PP will depend on the developed central pressure and changes attributable to pressure propagation. Thus in the presence of a given systemic arterial system, an increase in stroke volume would be accompanied by an increased central and peripheral PP. There are several potential ways in which changes to the aortic inflow system could affect pulse pressure. A stiffer, less compliant, aorta, such as found in postmenopausal women,21,22 would lead to a greater rise in systolic and PP for any given stroke volume. A smaller aorta, for any given stiffness and stroke volume, would also lead to greater systolic and pulse pressure because of both a reduced buffering capacity as well as an enhanced pulse wave velocity which is inversely related to vessel diameter. The earlier return of the reflected wave would increase summation between forward and reverse traveling pressure waves and thus amplify systolic and pulse pressure. It is of note here that, likely because of the strong inverse relationship between these parameters heart rate, not augmentation index, remained in the multivariate model predicting central PP. Also noteworthy is the observation that inclusion of heart rate did not remove gender as a significant determinant of PP (a priori this may be expected given that women have both a higher heart rate and a higher pulse pressure).
The presence of such a relation as we have demonstrated between gender and PP would imply that differences in aortic size were not accompanied by proportional changes in cardiac and stroke volumes, despite the expected correlation between cardiac and aortic dimensions. Increasing central PP in our group therefore implies a mismatch in stroke volume, aortic diameter, or pulse wave velocity (PWV).
Pulse pressure has recently received considerable attention as a determinant of both target organ damage and clinical events,23 in many studies proving a superior predictor to other blood pressure indices,24,25 including left ventricular hypertrophy. Previous indirect evidence has suggested the inverse relation reported in the present study.6 Direct evidence relating blood pressure variables to aortic dimensions has been limited to aortic root dimensions, predominantly in somewhat younger subjects, and to brachial blood pressures. The most consistent finding of such studies has been to relate such diameters positively to diastolic blood pressure, though studies on the Framingham cohort did report a small negative association with contemporary brachial pulse pressure.7,8 An important additional finding from the present study was that the relationships between aortic dimensions, gender, and pulse pressure were similar between previously treated and untreated subjects.
In summary, the present findings demonstrate an independent, inverse relation between aortic size, determined by cross-sectional diameter, and pulse pressure in older subjects with hypertension. Although aortic dimensions were smaller and pulse pressures higher in the women than the men, the differences in aortic dimensions and stiffness were not enough to fully account for the observed blood pressure differences. Taken together with previous findings, the present data suggest that a contributory factor to the gender differences in pulse pressure is an increased age-related mismatch in ventricular function and aortic stiffness in women compared with men.
Pulse pressure has been increasingly recognized as a predictor of adverse cardiovascular outcomes, and thus identifying its determinants is of considerable relevance. In older subjects the stiffness of the large arterial circulation has long been recognized as a major factor and in this study was again identified as a significant contributor to the variation in pulse pressure across the cohort. Other determinants such as age, mean blood pressure, and heart rate (inversely) were again consistent with previous data. More recently, and in some cases indirectly, the cross sectional dimensions of the aorta have also been identified as a determinant of pulse pressure, and this has been confirmed in the present study. It is likely that the relevance of this factor becomes more important in the presence of a stiff and incompliant large artery circulation such as occurs at older age and in the presence of hypertension. At older ages pulse pressure is higher in women than men. Although neither anthropometric features (ie, length and diameter of the aorta) nor the presence of increased aortic stiffness fully account for this gender difference in older hypertensive subjects, it is likely that these factors contribute to the elevated pulse pressure found in women. This study has not elucidated the other pathophysiological factors which must be contributing to the remaining gender difference which would require more sophisticated investigations of ventricular-vascular coupling. Knowledge of differences between the genders in the age-related ventriculo-vascular mismatch associated with increased pulse pressure may potentially provide guidance in selection of therapies. Similarly, knowledge of mechanisms of hypertension in the elderly may enable appropriate and selective use of new modalities including therapeutic agents directly targeting the aorta.
Sources of Funding
Professor Dart and Associate Professor Kingwell are both in receipt of research fellowships from the NHMRC. The ANBP2 study was supported by the Australian Commonwealth Department of Health and Aging; the National Health and Medical Research Council of Australia (NHMRC); and Merck Sharp and Dohme Pty Ltd, Australia.
- Received November 29, 2007.
- Revision received December 17, 2007.
- Accepted January 11, 2008.
Alfie J, Waisman GD, Galarza CR, Camera MI. Contribution of stroke volume to the change in pulse pressure pattern with age. Hypertension. 1999; 34 [part 2]: 808–812.
Franklin SS, Gustin WT, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997; 96: 308–315.
Mitchell GF, Lacourciere Y, Ouellet JP, Izzo JL Jr, Neutel J, Kerwin LJ, Block AJ, Pfeffer MA. Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure-flow relationship. Circulation. 2003; 108: 1592–1598.
Vasan RS, Larson MG, Levy D. Determinants of echocardiographic aortic root size. The Framingham Heart Study. Circulation. 1995; 91: 734–740.
Palmieri V, Bella JN, Arnett DK, Roman MJ, Oberman A, Kitzman DW, Hopkins PN, Paranicus M, Rao DC, Devereux RB. Aortic root dilatation a sinus of valsalva and aortic regurgitation in hypertensive and normotensive subjects. The Hypertension Genetic Epidemiology Network Study. Hypertension. 2001; 37: 1229–1235.
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Eng J Med. 2003; 348: 583–592.
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Marley JE, Morgan TO, Shaw J, Steven ID, West MJ. Second Australian National Blood Pressure Study (ANBP2). Australian Comparative Outcome Trial of ACE inhibitor- and diuretic-based treatment of hypertension in the elderly. Management Committee on Behalf of the High Blood Pressure Research Council of Australia. Clin Exp Hypertens. 1997; 19: 779–791.
Dart AM, Gatzka CD, Cameron JD, Kingwell BA, Liang YL, Berry KL, Reid CM, Jennings GL. Large artery stiffness is not related to plasma cholesterol in older subjects with hypertension. Arterioscler Thromb Vasc Biol. 2004; 24: 962–968.
Dart AM, Gatzka CD, Kingwell B, Wilson K, Cameron JD, Liang Y-L, Berry KL, Wing LM, Reid CM, Ryan P, Beilin LJ, Jennings GL, Johnston CI, McNeil JJ, MacDonald GJ, Morgan TO, West MJ. Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives. Hypertension. 2006; 47 (4): 785–790.
Hirai T, Sasayama S, Kawasaki T, Yagi S. Stiffness of systemic arteries in patients with myocardial infarction. A noninvasive method to predict severity of coronary atherosclerosis [published erratum appears in Circulation 1989 Dec;80(6):1946]. Circulation. 1989; 80: 78–86.
Dart A, Silagy C, Dewar E, Jennings G, McNeil J. Aortic distensibility and left ventricular structure and function in isolated systolic hypertension. Eur Heart J. 1993; 14: 1465–1470.
Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening. A Community-Based Study. Circulation. 2005;: 2254–2262.
Asmar R, Rudnichi A, Blacher J, London GM, Safar ME. Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens. 2001; 14: 91–97.
Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. Circulation. 1999; 100: 354–360.