Association Between Local Pulse Pressure, Mean Blood Pressure, and Large-Artery Remodeling
Background—The aim of the present study was to determine the respective influences of local pulse pressure and mean blood pressure on arterial remodeling in humans at 2 arterial sites: a central, predominantly elastic artery (the common carotid artery) and a peripheral muscular artery (the radial artery).
Methods and Results—Forty-three healthy subjects and 124 never-treated hypertensive patients were included in the study. Intima-media thickness and internal diameter of the carotid and radial arteries were noninvasively determined with high-definition echo-tracking devices. Pulse pressure was measured locally with applanation tonometry. Multivariate regression models including mean blood pressure and local pulse pressure were established in the whole population. Carotid internal diameter and intima-media thickness were strongly influenced (P<0.0001) by carotid pulse pressure but not by mean blood pressure or brachial pulse pressure, independently of age and sex. Radial artery internal diameter was correlated with age but not with mean blood pressure or radial pulse pressure. Radial artery intima-media thickness was correlated with mean blood pressure (P<0.001) but not with radial pulse pressure.
Conclusions—Carotid pulse pressure was a strong independent determinant of carotid artery enlargement and wall thickening, whereas mean blood pressure and brachial pulse pressure were not, indicating the prominent influence of local pulsatile mechanical load on arterial remodeling. These relationships were observed at the site of an elastic artery but not at the site of a muscular artery, suggesting the contribution of cyclic stretching to the pulse pressure–induced arterial remodeling.
Large-artery damage is a major factor in cardiovascular morbidity and mortality. Increased arterial stiffness with aging and hypertension contributes to a further rise in pulse pressure (PP) and systolic blood pressure (SBP) at any given value of mean arterial pressure.1 2 Independently of mean blood pressure (MBP), PP is a strong determinant of cardiovascular events, including coronary heart disease and stroke.3 4 5 Various mechanisms have been suggested, including reduced coronary perfusion and a remodeling of large arteries in response to the chronic increase in circumferential wall stress.1 2 3 4 5 During essential hypertension, large-artery remodeling is characterized mainly by an increase in intima-media thickness (IMT) aimed at maintaining circumferential wall stress, lumen enlargement of proximal elastic arteries, and no change in the lumen diameter of distal muscular arteries.1 6 Wall thickening may facilitate the development of atherosclerotic lesions.1 6 7 8 The association between carotid intima-media thickening and coronary heart disease7 8 might thus involve a common mechanical factor, such as PP. However, the precise links between local mechanical factors and large-artery remodeling remain to be determined.
Although a growing body of work led to the conclusion that cyclic strain is a major determinant of the phenotype and growth of vascular smooth muscle cells in vitro,9 10 11 the effect of pulsatile circumferential wall stress on large-artery remodeling has been little studied. In humans, brachial PP was associated with increased wall thickness at the site of the common carotid artery (CCA),7 8 12 but few studies showed that this relationship was independent of MBP and age.12 In addition, in these studies7 8 12 as well as in the above-mentioned epidemiological studies,3 4 5 PP was calculated from brachial SBP and diastolic BP (DBP) and was not measured at the precise site of the wall thickness measurement, preventing any definitive conclusion as to a causal association. Because of the physiological pulse-pressure amplification between central and peripheral arteries,1 13 brachial PP is a poor estimate of the local pressure regimen that acts on the arterial wall. To determine the relationship between cyclic stress and arterial remodeling, it is necessary to measure PP locally, at the site of the arterial segment whose geometry is studied.
Thus, the main objective of the present study was to determine the respective influences of pulsatile and steady mechanical loads on arterial geometry in humans. We also hypothesized that the effect of pulsatile mechanical load on arterial remodeling could be more easily detected at the site of an elastic artery (the CCA), which undergoes high stroke changes in diameter, than at the site of a muscular artery (the radial artery [RA]), in which stroke changes in diameter are much lower.
Patients and Subjects
One hundred sixty-seven subjects were included in the study: 124 never-treated ambulatory hypertensive patients from 24 to 70 years of age, referred to the hypertension unit of Broussais Hospital, and 43 normal subjects from 23 to 76 years old. Essential hypertension was defined by the presence of a sustained increase in blood pressure (BP), ie, as casual sitting BP ≥140 mm Hg (SBP) or ≥90 mm Hg (DBP) measured by sphygmomanometer and auscultatory methods (phase I and V of Korotkoff sounds), and the absence of clinical or laboratory evidence suggestive of secondary forms of hypertension. Only 9 patients among the 124 referred for hypertension proved to have normal BP values on assessment for the study. They were included in the multivariate analysis because it took into account BP as a continuous variable. None of the patients had atherosclerotic plaque on the CCA, and only 5 had a plaque on the carotid bifurcation or the internal carotid. Normotensive control subjects were derived from medical personnel and their family members with supine SBP <140 mm Hg and DBP <90 mm Hg. All subjects were free of clinical evidence of coronary artery or cerebrovascular disease. No patients with valvular heart disease, arrhythmia, or renal disease were included.
The study was approved by the institutional review committee of Broussais Hospital, and the subjects gave informed consent.
The noninvasive investigation was performed in a controlled environment kept at 22±1°C after subjects had reclined at rest for 15 minutes. A senior technician (B.L.) and physician (P.B.), trained and certified in vascular echography, performed BP and arterial measurements.
Brachial BP was measured with a mercury sphygmomanometer at the start of the investigation, with the subject in the sitting position. Supine BP was then monitored every 3 minutes by an oscillometric method (Dinamap model 845, Critikon) during the entire investigation. Brachial artery pressure values (SBP, DBP, MBP, and PP) used in further calculations were the averages of 5 measurements performed during 3 successive 15-minute periods, corresponding to baseline BP measurements, then to carotid and radial measurements.
CCA and RA Pressures and Pressure Waveforms
CCA and RA pressure waveforms were recorded noninvasively with a pencil-type probe incorporating a high-fidelity strain gauge transducer (SPT-301, Millar Instruments), as previously described by our group14 and others.15 The transducer has a small pressure-sensitive area (0.5×1.0 mm) with a frequency response >2 kHz that is coplanar with a larger area (7 mm diameter) of flat surface that is in contact with the skin overlying the pulse. The accuracy of the probe has been validated in humans.14 15 Noninvasively measured carotid pulse contours and invasively measured ascending aortic pulses have been shown to have close similarities in both time and frequency domains.15
We validated local PP measurement through 3 steps. First, we checked the internal calibration of the tonometer with a mercury manometer. The agreement of the 2 methods was excellent, with a mean absolute difference of 1.2 mm Hg. Second, we checked whether the geometric and mechanical patterns of the tube could influence the value of PP, measured through the applanation principle, using 2 silicon rubber tubes with opposite geometric and mechanical patterns. The distensible tube had a 2.5-fold larger diameter and a 14.5-fold lower elastic modulus than the stiff tube. The agreement between internal and external PPs was good, with a 10.4±0.5% underestimation with tonometer in the distensible tube and 7.3±0.2% overestimation in the stiff tube and with mean absolute differences of 0.20 mm Hg and 0.24 mm Hg, respectively. Finally, in 16 patients undergoing cardiac catheterization for suspected coronary artery disease, we14 previously reported good agreement between PP measured at the site of the carotid artery (PPcar) with applanation tonometry and PP measured invasively at the level of the aortic arch (PPao): PPcar=(0.98±0.11)×PPao+(0.13±8.14); r=0.96; mean difference=10 mm Hg.
Arterial Internal Diameter and Wall Thickness
Carotid internal diameter and wall thickness were measured on the right CCA and 2 cm beneath the carotid bifurcation with a 7.5-MHz pulsed ultrasound echo-tracking system (Wall Track System, Neurodata) that analyzed the radiofrequency signal originating from an M line perpendicular to the longitudinal and transversal axes of the artery, selected on the 2D B-mode image (Sigma 44 Kontron). This system has been validated and described in detail16 and used for various clinical studies.14 17
Measurements of RA internal diameter and wall thickness were obtained on the right arm with a 10-MHz ultrasound system that analyzed the radiofrequency signal (NIUS 02; SMH), previously described and validated18 and used in clinical studies.17 The repeatability of carotid and radial measurements has been reported previously.17
Mean circumferential wall stress (ςθ, in kPa) was calculated according to Lamé’s equation as ςθ=MBP×Di/2h, where Di is mean internal diameter and h is wall thickness.
Data are expressed as mean±SD. Quantitative variables were compared by means of an unpaired Student t test and categorical variables by means of a χ2 test. Correlation matrixes for CCA and RA parameters were done by Spearman rank test. Multivariate regression models19 were constructed for the entire population and systematically included MBP. The other variables included in the model were chosen by a multivariate variable selection procedure among the following variables: age, sex, body surface area, carotid or radial PP, brachial PP, and heart rate. The algorithm allows the selection of a set of variables among all possible pertinent ones on the basis of the maximization of R2. Up to 5 variables were kept until R2 reached a plateau. Once the set of variables was determined for the parameter of interest, a robust multiple stepwise regression analysis was performed. This procedure has been shown to be more robust to the marginal violation of normality assumption and to the presence of outliers than classic parametric regression. The resulting model depends more on the body of data than on the excessive weight of some observations. A value of P<0.05 was considered significant. The statistical analysis was performed with NCSS 6.0 software (J.L. Hintze, Kaysville, Utah).
Baseline characteristics of normotensives and hypertensives did not differ significantly (Table 1⇓). By definition, hypertensives presented higher levels of SBP, MBP, DBP, and PP than normotensives. However, age, sex ratio, tobacco use, fasting glucose level, and lipid levels did not differ between the 2 populations.
Hypertensives had larger and thicker carotid arteries than normotensives (Table 2⇓). Therefore, carotid wall cross-sectional area was markedly increased. No difference in wall-to-lumen ratio was observed. Thus, circumferential wall stress was higher in hypertensives. Carotid PP was higher in hypertensives than in normotensives (Table 2⇓), like brachial and radial PP (Tables 1⇑ and 3⇓). In multivariate analysis of the entire population, the brachial/carotid PP ratio, an index of the PP amplification phenomenon, was attenuated by aging (P<0.001) and potentiated by MBP (P<0.05).
In univariate analysis of the entire population, carotid internal diameter was significantly related to carotid PP (r=0.33; P<0.0001) but not to brachial PP (r=0.09; P=NS) (Table 4⇓ and Figure 1⇓); carotid IMT was significantly related to carotid PP (r=0.42; P<0.0001) and to brachial PP (r=0.27; P<0.001) (Table 4⇓ and Figure 2⇓). Despite significant interrelations between variables of interest (Table 4⇓), multivariate models (Tables 5⇓ and 6⇓) provided useful information. Indeed, 47% of the variance of carotid diameter was explained by the model that included sex, carotid PP, heart rate, and age in the population as a whole (Table 5⇓). Carotid PP was strongly and independently associated with internal diameter (Table 5⇓) and IMT (Table 6⇓), whereas MBP was not. After similar adjustments, a significant correlation was observed between carotid PP and wall cross-sectional area (P<0.0001; data not shown). Thus, in addition to age, carotid PP was the strongest predictor of dilatation of the carotid artery and of wall hypertrophy, explaining as much as 18% and 12% of the variance (R2 increment) of internal diameter and IMT, respectively (Tables 5⇓ and 6⇓). It is noteworthy that none of the other factors classically associated with IMT increase (eg, cholesterol level or smoking) influenced the model in this sample of subjects and patients.
When brachial PP, measured with a Dinamap monitor, was introduced into the multivariate model instead of carotid PP, no significant correlation was observed with internal diameter (Table 5⇑), IMT (Table 6⇑), or wall cross-sectional area. Correla-tions between brachial PP measured with Dinamap and carotid artery parameters (as well as RA parameters; see below) were not significantly modified when sphygmomanometer brachial PP was used instead of Dinamap brachial PP.
The RA of hypertensives was thicker than that of normotensives and not dilated (Table 3⇑). Subsequently, wall cross-sectional area and wall-to-lumen ratio were markedly increased in hypertensives, which normalized circumferential wall stress. Radial PP was increased in hypertensives and was of the same magnitude as brachial PP.
In normotensives and hypertensives considered as a whole, RA PP was not correlated with internal diameter (Table 5⇑) or IMT (Table 6⇑). MBP significantly influenced RA IMT (Table 5⇑) independently of age and sex. Brachial PP did not influence RA diameter (Table 5⇑) or IMT (Table 6⇑).
To the best of our knowledge, the present study is the first to determine the respective influences of local pulsatile and steady pressures on large-artery remodeling in normotensive subjects and never-treated hypertensive patients. The 2 new findings are as follows: (1) local PP is a strong independent determinant of CCA enlargement and wall thickening, whereas brachial PP and MBP are not; and (2) the predominant role of pulsatile mechanical load on arterial remodeling is observed at the site of a central elastic artery, the CCA, but not at the site of a distal muscular artery, the RA.
Enlargement of the large arteries with aging and MBP has been extensively described1 14 and is generally attributed to fracture of the load-bearing elastin fibers in response to the fatiguing effect of tensile stress. The present study, which shows that local PP is a strong independent determinant of carotid artery enlargement whereas MBP is not, suggests that pulsatile stress plays a more important role than steady stress. According to engineering principles,20 the fatiguing effect of cyclic stress is dependent on both the number of cycles (duration times frequency) and the amplitude of each cycle. Interestingly, in the present study, carotid diameter was significantly influenced by its clinical equivalents: age, heart rate, and carotid PP. Carotid artery diameter enlargement might explain why circumferential wall stress was not normalized in hypertensives despite wall thickening, in contrast to the RA.
Carotid wall thickening was related to brachial PP in some studies in essential hypertensive patients7 12 but not to carotid PP locally measured with applanation tonometry. To determine the relationship between cyclic stress and arterial remodeling, it is necessary to measure PP locally, at the site of the arterial segment whose geometry is studied, because of the physiological PP amplification between central and peripheral arteries.1 13 14 15 In older subjects, the augmentation of central PP can cancel out the normally present higher peripheral arterial PP seen in young subjects,1 13 14 15 and PP tends to be similar in both central and peripheral arteries. This is well illustrated by 2 findings of the present study: (1) the brachial/carotid PP ratio, an index of the PP amplification phenomenon, was significantly attenuated by aging and potentiated by MBP; and (2) carotid PP was a strong determinant of carotid artery internal diameter and IMT, whereas brachial PP was not.
Local PP was related to carotid IMT but not to radial IMT, suggesting that the amplitude of stroke change in diameter, 10-fold higher at the site of the CCA than at the site of the RA, could be a mechanism by which PP influences IMT. This finding is in accordance with numerous in vitro studies showing that cyclic stretching exerts a greater influence than static load on phenotype and growth of vascular smooth muscle cells (including synthesis of DNA, smooth muscle myosin, and collagen).9 10 11
The present study has some limitations. First, in addition to mechanical factors, neurohumoral and genetic factors should be considered, because they can directly influence the remodeling not only of conduit arteries but also of arterioles, leading to an earlier return of wave reflections and an increase in PP. Second, the time-dependent relation between increased PP and arterial remodeling could not be determined in the present study because of its cross-sectional design. Third, we cannot exclude that the strength of the correlation might depend more on the accuracy of the measurement than on the physiology involved (for instance, that carotid tonometric PP, measured by a trained investigator, could simply be more accurate than Dinamap MBP or PP). Fourth, ultrasound imaging cannot discriminate between the intimal and medial layers of the vessel wall to distinguish true arteriosclerosis (ie, the adaptive response of the medial layer to changes in tensile stress) from atherosclerosis (which is viewed as a disorder restricted to the intimal layer).6 7 8 However, the CCA is usually spared of atherosclerosis, in contrast to the carotid bifurcation and proximal internal carotid.
In conclusion, carotid PP was a strong independent determinant of carotid artery remodeling, whereas MBP and brachial PP were not. The predominant role of pulsatile mechanical load on arterial remodeling was observed at the site of an elastic artery but not at the site of a muscular artery. Pulsatile circumferential wall stress, which may exert a fatiguing effect on elastic fibers and a growth effect on smooth muscle cells, should be taken into account when large-artery remodeling is studied.
This study was performed with grants from Institut National de la Santé et de la Recherche Médicale (INSERM grant 35 494014), as well as a grant (BIOMED) from the European Community.
Reprint requests to Professeur Stéphane Laurent, Service de Pharmacologie, Assistance Publique-Hôpitaux de Paris, Hôpital Broussais, 96, rue Didot, 75674 Paris Cedex 14, France.
- Received April 12, 1999.
- Revision received June 14, 1999.
- Accepted June 17, 1999.
- Copyright © 1999 by American Heart Association
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