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(Circulation. 2003;108:1592.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

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

Gary F. Mitchell, MD; Yves Lacourcière, MD; Jean-Pascal Ouellet, MD; Joseph L. Izzo, Jr, MD; Joel Neutel, MD; Linda J. Kerwin, MS; Alan J. Block, PhD; Marc A. Pfeffer, MD, PhD

From Cardiovascular Engineering, Inc, Holliston, Mass (G.F.M.); Centre hospitalier de l’Universite Laval, Ste Foy, Quebec, Canada (Y.L.); Q&T Research, Inc, Sherbrooke, Quebec, Canada (J.-P.O.); State University of New York at Buffalo, Buffalo, NY (J.L.I.); Orange County Research Center, Orange, Calif (J.N.); Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ (L.J.K., A.J.B.); and Brigham and Women’s Hospital, Boston, Mass (M.A.P.).

Correspondence to Gary F. Mitchell, MD, Cardiovascular Engineering, Inc, 327 Fiske St, Holliston, MA 01746. E-mail garyfmitchell{at}mindspring.com

Received December 11, 2002; de novo received May 9, 2003; revision received June 12, 2003; accepted June 13, 2003.

	Abstract

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Background— Elevated pulse pressure (PP) is associated with increased cardiovascular risk and is thought to be secondary to elastin fragmentation with secondary collagen deposition and stiffening of the aortic wall, leading to a dilated, noncompliant vasculature.

Methods and Results— By use of calibrated tonometry and pulsed Doppler, arterial stiffness and pulsatile hemodynamics were assessed in 128 subjects with uncomplicated systolic hypertension (supine systolic pressure 140 mm Hg off medication) and 30 normotensive control subjects of comparable age and gender. Pulse-wave velocity was assessed from tonometry and body surface measurements. Characteristic impedance (Z_c) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Effective aortic diameter was assessed by use of the water hammer equation. Hypertensives were heavier (P<0.001) and had higher PP (P<0.001), which was attributable primarily to higher Z_c (P<0.001), especially in women. Pulse-wave velocity was higher in hypertensives (P=0.001); however, this difference was not significant after adjustment for differences in mean arterial pressure (MAP) (P>0.153), whereas increased Z_c remained highly significant (P<0.001). Increased Z_c in women and in hypertensive men was attributable to decreased effective aortic diameter, with no difference in wall stiffness at comparable MAP and body weight.

Conclusions— Elevated PP in systolic hypertension was independent of MAP and was attributable primarily to elevated Z_c and reduced effective diameter of the proximal aorta. These findings are not consistent with the hypothesis of secondary aortic degeneration, dilation, and wall stiffening but rather suggest that aortic function may play an active role in the pathophysiology of systolic hypertension.

Key Words: hypertension • aorta • impedance • pressure • stiffness

	Introduction

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Pulse pressure (PP), an indirect indicator of arterial stiffness, has recently emerged as a strong independent predictor of cardiovascular events in patients with hypertension.^1–4 Increased PP and premature timing of the reflected pressure wave add to load on the left ventricle and arteries and may trigger ventricular and vascular hypertrophy and fibrosis.^5,6 Vascular stiffening is associated with abnormalities in central aortic flow that can activate endothelium.⁷ Activation of the endothelium and increased pulsatile stress on the arterial wall may promote atherogenesis.⁸ These adverse consequences of abnormal ventricular–vascular interaction may culminate in myocardial or cerebral infarction or congestive heart failure and may therefore explain the observed association between higher PP and increased clinical events.

Abnormal aortic function in hypertension is generally attributed to accelerated breakdown of elastin in the aorta, leading to dilatation of the lumen and stiffening of the wall as elastin is replaced with stiffer collagen.⁹ However, the status of "arterial stiffness" and the genesis of increased PP in hypertension remain controversial. The primary hemodynamic measures of aortic stiffness are pulse-wave velocity (PWV) and local or characteristic impedance (Z_c). PWV affects the timing of wave reflection and has been shown to predict adverse events in hypertensives¹⁰ and the elderly.¹¹ Both central (carotid–femoral) and peripheral (carotid–brachial, carotid–radial) vessels can be assessed by use of this approach. Z_c, which has been less well studied in hypertension, is an indicator of the pressure generated by a given flow waveform in the proximal aorta during early systole, before return of the reflected pressure wave. These related measures of arterial stiffness have important differences. Each has a square root dependence on the product of wall elastance and thickness. However, PWV is relatively insensitive to changes in lumen diameter (inverse square root), whereas Z_c has an amplified sensitivity to diameter.¹² This fundamentally important role of geometry is apparent from the water hammer equation, Z_c=4xPWVx/D², where is density of blood and D is vessel diameter. If the paradigm of accelerated aortic elastin breakdown, wall stiffening, and lumen dilatation is correct, one would expect a far greater abnormality in PWV than Z_c in hypertensives compared with normotensives, because the increase in diameter should attenuate the effects of increased wall stiffness on Z_c. As a result, conclusions regarding aortic stiffness may differ depending on whether PWV or Z_c was assessed.

Several studies have demonstrated increased stiffness of central arteries in hypertensives,^13–15 whereas others have demonstrated normal or even reduced stiffness in peripheral arteries.^16,17 One possible explanation for this divergence of findings lies in the structural and functional diversity of central elastic and peripheral muscular vessels. For example, with normal aging, stiffness of the central arteries increases,¹⁸ whereas stiffness of peripheral arteries remains unchanged or decreases.¹⁹ This divergent change in peripheral vessel properties may moderate the abnormalities in total arterial compliance (TAC) and pulse-wave transmission that would otherwise result from deterioration in aortic properties. A similar pattern of differential alterations in peripheral and central vessel stiffness was recently reported in patients with congestive heart failure.²⁰ Thus, conclusions regarding vessel stiffness in hypertension may also differ depending on the vascular territory studied.

In addition to these technical issues, the possibility remains that abnormalities in vascular stiffness may be a consequence of associated conditions, such as diabetes, smoking-related disease, or atherosclerosis. Therefore, we designed this study to evaluate changes in central and peripheral PWV and central Z_c in otherwise healthy adults with uncomplicated systolic hypertension.

	Methods

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Study Subjects
Male or female subjects 40 to 75 years of age with a history of hypertension were included if they were in sinus rhythm and had systolic or mixed systolic–diastolic hypertension. Patients were eligible for inclusion if their qualifying seated systolic blood pressure (SBP) was 160 mm Hg and <200 mm Hg and diastolic BP (DBP) 110 mm Hg and if their supine SBP was 140 mm Hg at the time of the hemodynamic study after withdrawal of all antihypertensive medications for at least 1 week. Patients with known or suspected secondary forms of hypertension were excluded. Patients with a history of diabetes, coronary artery disease, or peripheral vascular disease and current smokers were excluded. Control subjects had no known history of cardiovascular disease, diabetes, lipid disorder that was treated or that warranted treatment, malignancy (aside from skin cancer requiring only local therapy), or other medical condition that required pharmacotherapy, other than hormone replacement therapy. They were in sinus rhythm and had a supine SBP <140 mm Hg and a DBP <90 mm Hg at the time of the hemodynamic study. They were recruited by each clinical center in proportion to the number of hypertensive patients studied at that center, and their recruitment was stratified by median age and gender on the basis of demographics of the overall hypertensive cohort. The study protocol was approved by an institutional review board at each clinical center, and each patient gave written informed consent before enrollment.

Hemodynamic Data Acquisition
Subjects were studied in the supine position after 10 minutes of rest. With a semiautomated computer-controlled device, auscultatory BP was obtained 3 to 5 times at 2-minute intervals with a goal of obtaining 3 sequential readings that agreed to within 5 mm Hg for SBP and DBP. Arterial tonometry and ECG were obtained from the brachial, radial, femoral, and carotid arteries with a custom transducer. Next, subjects were placed in the left lateral decubitus position to image the left ventricular outflow tract in a parasternal long-axis view. This was followed by duplicate acquisitions of simultaneous tonometry of the carotid artery and pulsed Doppler of the left ventricular outflow tract from an apical 5-chamber view. Finally, body surface measurements were assessed from suprasternal notch to brachial, radial, femoral, and carotid recording sites. All data were digitized during the primary acquisition (ECG and tonometry pressures at 1000 Hz, audio at 12 kHz, and video at 30 frames/s), transferred to CD-ROM, and shipped to the Core Laboratory at Cardiovascular Engineering, Inc, for analysis.

Data Analysis
Tonometry waveforms were signal-averaged with the ECG used as a fiducial point.²¹ BPs were overread by 2 reviewers in the core laboratory. Average systolic and diastolic cuff pressures were used to calibrate the peak and trough of the signal-averaged brachial pressure waveform. Diastolic and integrated mean brachial pressures were then used to calibrate carotid, radial, and femoral pressure tracings.²² Carotid-brachial, carotid-radial, and carotid-femoral PWVs were calculated from tonometry waveforms, and body surface measurements were corrected for parallel transmission as described previously.²³ Systolic ejection period was measured from the foot of the carotid pressure waveform to the dicrotic notch. Augmentation index was calculated as described previously.²⁴ True peripheral amplification was calculated by taking the difference in amplitude of the central primary wave and peripheral PP (PPP) and expressing this difference as a percentage of the central primary wave. Apparent amplification, which is reduced by the presence of pressure augmentation in the central aorta, was calculated by taking the difference in PPP and central PP (CPP) and expressing this difference as a percentage of CPP.²⁵ The central primary wave was defined as the difference between DBP and pressure at the first systolic inflection point or peak. Z_c was estimated in the time domain as described previously.^20,26,27 Pressure waveforms were decomposed into forward (P_f) and backward (P_b) waves in the time domain²⁸; the ratio of their amplitudes was taken as an index of global reflection, and the extent of their temporal overlap, expressed as a percentage of systolic ejection period, was taken as an index of abnormal reflected wave timing. Proximal aortic compliance per unit length was calculated as described previously.¹²

Statistical Analysis
Baseline characteristics were tabulated and compared by use of a ² statistic for dichotomous variables and ANOVA for continuous variables. By use of a general linear model, comparisons were adjusted for differences in relevant covariates, which were identified by correlation analysis. The hemodynamic correlates of PP were assessed by forward stepwise linear regression. Variance inflation factors were evaluated at each step in these models and were confirmed to be well below 10. The contribution of each predictor variable to the observed difference in PP between control and hypertensive subjects was estimated by multiplying the raw regression coefficient for predictor variables that entered the model by the observed difference in predictor variable between groups. All models included a gender term or were evaluated separately by gender. Reproducibility for impedance variables, such as Z_c, obtained by use of a noninvasive approach is high, as we²⁰ and others²² have shown previously. Values are presented as the mean±SD except as noted. A 2-sided value of P<0.05 was considered significant.

	Results

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Characteristics of the study participants are presented in Table 1. By design, hypertensive and control subjects were evenly distributed by age and gender. Hypertension was associated with increased weight and body mass index in both genders. Higher SBP was associated with higher mean arterial pressure (MAP) and PP in hypertensives of either gender (Table 2). PP was disproportionately elevated in hypertensive women, as indicated by the significant interaction term. Cardiac output, peak aortic flow, and heart rate did not differ by BP status, although peak flow was reduced in hypertensives (P=0.021) when adjusted for weight. Gender differences in cardiac output were not significant (P=0.384) when adjusted for weight, whereas differences in peak flow (P<0.001) and stroke volume (P=0.004) persisted, indicating that cardiac output was successfully maintained by higher heart rate in women. Proximal aortic stiffness (Z_c) was increased and TAC was reduced in women compared with men and in hypertensives compared with normotensives (Table 2). Carotid-brachial, carotid-radial, and especially carotid-femoral PWVs were all elevated in hypertensive subjects at ambient pressures (Table 2).

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Hemodynamic Data

Hypertension and female gender were associated with earlier return of the reflected pressure wave to the central aorta and with longer systolic ejection period, despite the higher heart rate in women, resulting in increased temporal overlap between forward and reflected pressure waves (Table 3). This excess overlap, coupled with increased global reflection coefficient (P_b/P_f) in hypertensives, resulted in increased augmentation index and delayed timing of peak pressure in hypertensives and women. True amplification was higher in hypertensives, consistent with the elevated peripheral resistance and global reflection coefficient, whereas apparent amplification did not differ significantly (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Waveform Morphology

Because vessel stiffness may be dependent on MAP and weight, which differed between BP groups, we performed correlation analyses adjusted for gender and BP status (Table 4). On the basis of these results, we evaluated general linear models that included terms for gender and BP group (all models) and a gender–hypertension interaction (PPP, CPP) and that adjusted further for MAP (regional PWVs), weight (Z_c, TAC), or both (PPP, CPP). Differences in PPP, CPP, Z_c, and TAC remained (all P<0.001), whereas differences in regional PWV were no longer significant (all P>0.191) (Figure). Because this was a multicenter study, we repeated these models and included a grouping variable for center number. Differences in PPP, CPP, Z_c, and TAC remained significant. Because the relationship between MAP and vessel stiffness may be nonlinear, we repeated those models with a MAP term (CPP, PPP, regional PWVs) and included a MAP² term as well. Differences in regional PWV remained not significant (P>0.500), whereas differences in CPP and PPP remained highly significant (P<0.001).

View this table: [in this window] [in a new window]   TABLE 4. Correlations Between MAP, Weight, and Stiffness Measures

View larger version (19K): [in this window] [in a new window]   CPP adjusted for MAP and weight and Zc adjusted for weight in normotensive and hypertensive women and men. Values shown correspond to MAP=112 mm Hg and weight=84 kg. Values are mean±SEM.

A predominant increase in Z_c with a lesser increase in carotid-femoral PWV in hypertensives implied abnormal aortic geometry as a contributing factor, because changes in wall stiffness or thickness have equal impact on Z_c and PWV.¹² To assess this hypothesis, effective aortic diameter and the aortic elastance–wall thickness product (Eh) were calculated as described previously.¹² Eh was natural log transformed (lnEh) to normalize variance between groups. At ambient pressure, hypertensive patients had comparable diameter and increased lnEh. Correlation analysis of diameter and lnEH with MAP and weight, adjusted for hypertension and gender, demonstrated significant relations of diameter with MAP (R=0.21, P=0.007) and weight (R=0.26, P=0.001) and of lnEh with MAP (R=0.19, P=0.019). In male subjects, a general linear model that included hypertension, MAP, a MAP-hypertension interaction term, and weight demonstrated reduced aortic diameter (P=0.048) and reduced the slope of the relationship between MAP and diameter (P=0.037) in hypertensives. At the overall average MAP (112 mm Hg) and weight (88.8 kg), estimated diameter was significantly lower in hypertensive versus normotensive men (mean±SEM, 2.87±0.06 versus 3.78±0.38 cm, respectively; P=0.020). A similar model did not reveal a significant difference in diameter between hypertensive and normotensive women (mean±SEM, 2.48±0.08 versus 2.72±0.48, respectively; P=0.621), although effective diameter adjusted for weight and MAP remained significantly lower in women compared with men (mean±SEM, 2.70±0.07 versus 2.94±0.06, respectively; P<0.001). In models for lnEh that included MAP, hypertension, and an interaction term, neither hypertension nor the interaction term was significant in men or women (all P>0.500), indicating that at comparable pressure, lnEh did not differ in normotensive and hypertensive subjects of either gender.

Hemodynamic correlates of PPP and CPP were assessed separately for men and women by stepwise forward linear regression analysis. Candidate predictor variables included measures of central pressure-flow (Z_c, peak aortic flow, time to peak flow) and pressure-volume (TAC, stroke volume) interactions, wave propagation (carotid-brachial, carotid-radial, carotid-femoral PWVs), wave reflection (augmentation index, wave amplification, global reflection coefficient, systolic ejection period), steady-flow load (peripheral resistance), and heart rate. Augmentation index was used in the model for CPP, whereas true waveform amplification was used in the model for PPP. The final models and the contribution of each predictor variable to the observed difference in PP between control and hypertensive subjects are presented in Table 5. These analyses demonstrated that Z_c accounted for a substantial component of the difference in PP between normal and hypertensive subjects, especially in women. Indices of wave amplification and reflection (women) and TAC (men) accounted for much of the remainder of the PP difference (Table 5).

View this table: [in this window] [in a new window]   TABLE 5. Correlates of Increased PP and Their Contribution to Differences in PP Between Hypertensive and Control Subjects

	Discussion

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This study evaluated abnormalities in CPP and PPP and arterial stiffness in subjects with uncomplicated systolic hypertension compared with normotensive subjects of comparable age and gender. We demonstrated that CPP and PPP were elevated out of proportion to the increase in MAP in subjects with hypertension. Increased PP was associated with a marked increase in Z_c, which was independent of MAP, along with increases in central (carotid-femoral) and peripheral (carotid-brachial, carotid-radial) PWV, which were not independent of MAP. This pattern of elevation of Z_c out of proportion to elevation of PWV at comparable MAP was suggestive of reduced aortic diameter in hypertensives, which was confirmed by analysis of effective diameter calculated from the water hammer equation. In contrast, aortic wall stiffness (Eh) did not differ from control when evaluated at comparable MAP. Abnormal Z_c accounted for much of the difference in PP between hypertensive and normotensive subjects, especially in women, with TAC in men and measures of wave reflection in women emerging as the next largest contributor. These data suggest that an abnormality in proximal aortic diameter, rather than a difference in the material properties of the aortic wall, may be responsible for the abnormal aortic pressure-flow relationship and increased CPP and PPP in subjects with systolic hypertension.

A number of previous studies have used invasive methods to evaluate aortic input impedance in hypertensive patients undergoing cardiac catheterization and have presented conflicting results,^14,29–33 possibly because subjects differed considerably among studies. Subjects in the studies by Ting et al^32,33 were ethnic Chinese and were relatively young (mean age, 32 years). Like many previous studies, elevated DBP was required, thus systematically eliminating subjects with widest PP and presumably stiffest aortas. This may explain the low value for Z_c that was reported for hypertensives. Merillon et al²⁹ studied a younger group of hypertensives (group mean ages, 38 and 32 years for normotensive versus hypertensive) and found no difference in Z_c; however, a later study in slightly older subjects (mean ages, 42 and 46 years, respectively) revealed increased Z_c in hypertensives.³⁰ The study by Nichols et al,¹⁴ which more closely parallels ours in terms of patient characteristics (although their subjects were still a decade younger), found increased Z_c in the hypertensive subjects. Using a noninvasive approach, we have extended the foregoing observations to a cohort of relatively healthy normotensive and hypertensive subjects with no evidence of atherosclerosis and no indication for cardiac catheterization. Consistent with the current emphasis on use of SBP to diagnose and stage hypertension,³⁴ we did not specify a minimum entry criterion for DBP in the hypertensive group. Using this approach, we found a marked elevation of Z_c in hypertensives. Furthermore, by analyzing differential changes in PWV and Z_c, we showed that aortic geometry rather than wall properties may be involved in the abnormal pulsatile hemodynamics of hypertension.

Consistent with previous observations,^15–17 after adjusting for differences in mean arterial pressure, we found no differences in the stiffness of peripheral (brachial or radial) arteries in hypertensives and control subjects. There was a disproportionate contribution of wave reflection to CPP and PPP in women, which may be a manifestation of shorter stature.³⁵ Early systolic loading caused by increased Z_c may explain reduced peak flow and stroke volume and increased heart rate in women, which may in turn account for the reduced dependence of PP on TAC.

Several hypotheses have been proposed to explain increased central aortic stiffness in patients with hypertension. In animal models of hypertension, increased deposition of collagen and elastin has been observed in the aortic wall,³⁶ suggesting that changes in wall stiffness may provide the basis for abnormal vessel properties. However, our analysis of the pattern of change of Z_c and PWV (ie, MAP-adjusted abnormality in Z_c exceeds abnormality in PWV) suggests that reduced vessel diameter may play an important role in the genesis of increased functional stiffness of the aorta. Although our estimate of diameter is based on a functional rather than an image-based assessment, our mean values, if converted to areas, are comparable to those previously reported by several groups,^{29,31,33,37,38} most of whom also found no difference in proximal aortic dimension at ambient pressure despite much higher MAP in the hypertensive group. An evaluation of determinants of aortic root diameter in participants in the Framingham Heart Study provides additional strong evidence that aortic diameter may be abnormally small in patients with systolic hypertension. These investigators demonstrated that aortic root diameter, when evaluated as a continuous variable, was inversely related to SBP and brachial PP.³⁹ Furthermore, aortic root dilatation, when assessed as a categorical variable (>95th percentile), was also inversely related to SBP and PP. Women had lower aortic root diameter than men after body size had been accounted for in that study, which is consistent with our finding of reduced effective diameter, higher Z_c, and higher PP despite lower peak flow in normotensive and hypertensive women. Thus, image-based methods used in previous studies and physiological measures used in our study both indicate that aortic diameter is reduced rather than increased in patients with hypertension.

The basis for abnormal pressure-flow and pressure-diameter relationships in our hypertensive subjects remains speculative. Arterial diameter is influenced by the interaction of local and systemic forces. Increased aortic tone or myocyte hypertrophy in the setting of hyperactivity of the sympathetic nervous system or in response to elevated MAP (myogenic tone) may contribute. Alternatively, abnormal endothelial function may be involved in the functional imbalance between aortic flow and diameter that we have described. It is well accepted that the endothelium is capable of modulating smooth muscle mass and tone and therefore diameter in large and small blood vessels; this modulation may be impaired in the aorta of hypertensives. Finally, a primary abnormality in aortic diameter or resting smooth muscle tone may be involved.

Z_c has a strong dependence on vessel diameter (to a power of 2.5), whereas PWV has a square root dependence.²⁰ Changes in vessel tone therefore have an amplified effect on Z_c and PP and a moderated effect on PWV, resulting in an expected 5-fold greater change in Z_c than PWV with modest changes in vessel diameter, which is comparable to what has been observed experimentally.⁴⁰ Even minor alterations in the regulation of vascular tone can thus have a major effect on Z_c^41,42 and PP. These observations, coupled with findings from our recent study, which demonstrated that aortic properties can be favorably modified after a relatively short (12-week) intervention,²³ are consistent with the hypothesis that at least a component of abnormalities in large artery function is dynamic and reversible rather than structural and irreversible. These findings suggest that an earlier hypothesis that aortic stiffness in hypertension is attributable to accelerated fragmentation of elastin, leading to a dilated aorta with a stiffer wall, should be critically reevaluated.⁹ Instead, our study indicates that reduced aortic diameter with unchanged wall properties contributes to elevated PP and may represent a mechanism rather than a result of systolic hypertension.

The limitations of our study should be underscored. We excluded patients with clinical evidence of atherosclerosis, although we did not perform a cardiac catheterization on each patient. Therefore, we cannot exclude the possibility of subclinical atherosclerotic disease. Furthermore, although we had well-defined criteria for inclusion of normal control subjects with respect to the presence of classic risk factors (glucose, lipids), we did not measure these values in the context of the present study. Therefore, we cannot exclude the possibility that intranormal variation in glucose or lipid levels contributed to the observed differences in vessel stiffness.

In summary, we have shown that PP is elevated out of proportion to the increase in mean arterial pressure in patients with systolic hypertension because of increased Z_c and reduced effective aortic diameter. Elevated Z_c accounted for nearly half of the excess PP in men and more than two thirds of the excess PP in women with hypertension. Because elevated PP is an important risk factor for cardiovascular end points, central aortic stiffness represents an attractive new target in the treatment of systolic hypertension.

	Acknowledgments

 
This study was funded by a grant from Bristol-Myers Squibb Pharmaceutical Research Institute.

	Footnotes

 
Drs Mitchell, Lacourcière, Ouellet, Izzo, Neutel, and Pfeffer have received grants from Bristol-Myers Squibb; Drs Kerwin and Block are employees of Bristol-Myers Squibb. Dr Mitchell is owner of Cardiovascular Engineering, Inc, a company that makes devices that measure vessel stiffness.

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