Effects of Blood Pressure, Smoking, and Their Interaction on Carotid Artery Structure and Function
Abstract—In the present study, we examined the relationships among carotid blood pressure, arterial geometry, and wall stress and determined the impact of hypertension, smoking status, and their interaction on these relationships. The study involved 679 subjects aged 49 to 82 years: 372 smokers (190 men and 182 women) and 307 nonsmokers (110 men and 197 women). Blood samples were taken to determine total cholesterol levels. Central pulse pressure was derived from measured brachial artery pressure with a linear regression equation from data obtained in a subgroup of 276 subjects that related brachial and carotid pulse pressures; the latter was measured with applanation tonometry. Carotid intima-media thickness (IMT), lumen diameter (D), and stiffness index (SI) were determined with high-resolution B-mode ultrasound. Mean and pulsatile circumferential stress (ςC) was calculated according to the Laplace relationship. Indexes of arterial geometry and function were adjusted for age, height, and heart rate. Hypertension (treated and/or screening blood pressure of >140/90 mm Hg) was present in 71 nonsmokers and 186 smokers. Nonsmokers and smokers did not differ in blood pressure and cholesterol levels. Hypertension and smoking individually and interactively significantly increased adjusted IMT, D, and SI. The radius-to–wall thickness ratio (R/IMT) (where R=D/2) and ςC were increased in hypertensives. SI was correlated with IMT (r=0.56, P<0.001); radius-to–wall thickness ratio was inversely correlated with central pulse pressure (r=−0.38, P<0.001). Smoking did not influence these relationships. In conclusion, carotid artery wall remodeling appears to follow Laplace’s law but is insufficient to prevent an increase in circumferential stress in hypertensive subjects. Unlike hypertension, smoking does not influence the lumen-to-wall ratio but has a significant effect on wall stiffness.
It is well known from experimental and clinical studies that hypertension causes left ventricular and resistance arterial remodeling consistent with Laplace’s law for cylindrical structures with finite wall thickness.1 2 3 The common carotid artery is an elastic artery, of which the wall thickness increases with cardiovascular risk factors such as age and hypertension.4 5 6 Whether the Laplace relationship, which generally holds for cardiac wall and resistance artery wall remodeling, can describe changes in large conduit arteries like the carotid artery remains unclear.
Few studies have examined, in the same subjects, the structure-function relationships in large arteries. In a 4-year longitudinal study, Zureik et al7 showed that elevated brachial artery pulse pressure (PPbrachial) was associated with increasing common carotid artery intimal-medial wall thickness (IMT). Smoking increases age-related arterial wall thickness and arterial stiffness.8 9 10 The extent to which an increase in IMT in hypertension is due to vascular remodeling of the common carotid artery in response to high central blood pressure or is a marker of atherosclerosis or a combination of the 2 has not been defined. Moreover, the potential interactions between key cardiovascular risk factors such as smoking and hypertension in structure-function relationships have not been evaluated.
The aim of the present study, which included a large group of older subjects, was to examine the relationships among central blood pressure, carotid arterial geometry, and wall stress and to determine the impact of hypertension, smoking, and their interaction on these relationships.
Six hundred seventy-nine subjects were studied. Subjects were aged 49 to 82 years (mean 62.6 years) and were recruited through advertisement from an urban population in Melbourne, Australia. Exclusion criteria were serious illness such as cancer or organ failure, stenosis of >80% of either carotid artery, myocardial infarction, or stroke within the previous 6 months. All women were postmenopausal, and none were taking hormone replacement therapy. The study procedure was undertaken in a quiet, air-conditioned room. Subjects were advised not to consume coffee in the 8 hours before the study. Nonfasting blood samples were taken for analysis of total cholesterol.
Carotid IMT, Lumen Diameter, and Stiffness Index
An imaging study of the right common carotid artery was performed with a high-resolution ultrasound machine (Diasonics DRF-400) and a hand-held transducer with 7.5-MHz central frequency mechanical sector transducer as previously reported.5 6 Three B-mode and M-mode images in different directions (anterior, lateral, and medial) were recorded. The images were digitized and saved on computer via a customized computer program. The right common carotid artery IMT and lumen diameter (D) measurements were analyzed using methods previously described.5 6 Lumen radius (R) was calculated as carotid lumen diameter divided by 2. Carotid stiffness was determined in terms of the stiffness index (SI); this index is given as SI=Ln(Ps/Pd)/[(Ds−Dd)/Dd].11 Ps and Pd indicate systolic and diastolic pressures, and Ds and Dd indicate systolic and diastolic diameters.
Definition of Arterial Circumferential Stress
Circumferential stress (ςC) is generated in the artery wall in response to transmural pressure and can be calculated from the law of Laplace (in units of force per unit area) as ςC=P · r/w, where P is central transmural pressure, r is the lumen radius of the carotid artery (R), and w is the carotid wall thickness (here taken as IMT). If the thin wall approximation is accepted, the transmural pressure is theoretically equal to the difference between instantaneous contained blood pressure and local interstitial pressure (usually approximated to zero). Also relevant is the concept of critical opening pressure, the blood pressure at which the artery is patent but where ςC=0. Inability to obtain a valid estimate at either true transmural pressure or critical opening pressure necessitates further assumptions concerning the calculation of ςC. In the present study, we calculated mean circumferential stress ςC(MAP) as P*r/w and pulsatile wall stress (assuming ΔR≪R) as ςC(PP)=ΔP*r/w.12
Determination of Central Pulse Pressure
A Dinamap device (CRITIKON 1846 SX) was used for brachial blood pressure measurements recorded at 5-minute intervals throughout the study (30 to 40 minutes) in all 679 subjects. The first Dinamap blood pressure recording was excluded, and all subsequent blood pressure measurements were averaged. Central blood pressure was measured through applanation tonometry of the right common carotid artery with a noninvasive pressure transducer (Millar Mikro-tip; Millar Instruments) in 276 subjects. In this subgroup, carotid artery pressure waveforms, obtained simultaneously with the brachial artery Dinamap pressure recordings, were analyzed to obtain central PP (PPcen) measurements through linear interpolation with the oscillometrically obtained brachial mean and diastolic blood pressures (MAP and DBP, respectively). There was a close relationship between PPcen and measured PPbrachial (PPcen=0.86×PPbrachial−3.82; r=0.81, P<0.001). The 95% CIs for slope and intercept were 0.78 to 0.94 and −1.3 to 8.0, respectively. Multiple regression analysis showed that this relationship was not significantly influenced by gender, age, or heart rate (HR). This expression was then applied to the entire study population to derive PPcen from PPbrachial.
Statistical analysis was performed using Microsoft Excel 97 and SPSS version 8. Data are reported as mean±SD. All main parameters and indices were adjusted by age, height, and HR with the formula Yo=yi+b(xi−¯x), where xi and yi are a part of the data points in a linear regression with slope b; x̄ is the mean value for variable x; and Yo is the adjusted value for variable y.13 This was done because age, height, and HR are major factors known to affect arterial structure and function.4 5 14 15 Hypertension was defined as systolic blood pressure (SBP) of ≥140 mm Hg and/or DBP of ≥90 mm Hg or the current use of antihypertensive medications. Student’s unpaired t test was used to determine the significance of differences between subgroups (normotensive nonsmokers [NTNS], hypertensive nonsmokers [HTNS], normotensive smokers [NTS], and hypertensive smokers [HTS]). Differences were considered significant at P<0.05. Univariate, bivariate, and linear regression analyses were used to determine the relationships between various indexes.
Table 1⇓ summarizes the characteristics of the study population. There were 372 smokers (190 men and 182 women) and 307 nonsmokers (110 men and 197 women). Smokers had being smoking for ≥8 years (range 8 to 70.7 years), and average use was 21.3 cigarettes/d (range 5 to 82). The mean±SD pack/y of smoking was 42.2±20.6. Hypertension was present in 257 subjects (38%). For the entire population, PPbrachial was significantly higher than PPcen (58±13 versus 46±11 mm Hg, P<0.001). Hypercholesterolemia (total cholesterol >5.5 mmol/L) and/or the use of cholesterol-lowering drug therapy was present in 174 subject (25.6%). Physical activity score was similar in both genders and in all 4 subgroups. Eighty-five percent of subjects drank <2 and none drank >4.5 standard drinks/d.
Bivariate correlation analysis showed that for the whole group, age was a key determinant of all indexes except for DBP. IMT (r=0.37, P<0.001), LD (r=0.25, P<0.001), SI (r=0.33, P<0.001), PPcen (r=0.22, P<0.001), SBPcen (r=0.18, P<0.001), MAP (r=0.09, P<0.05), and both ςC(MAP) and ςC(PP) (r=0.09, P<0.05; r=0.10, P<0.05) were all related to age. In the age group of 49 to 59 years, DBP correlated positively with age (r=0.13, P<0.05), whereas in those >60 years old, DBP correlated negatively with age (r=−0.10, P<0.05).
Indexes of carotid arterial geometry and function, adjusted by age, height, and HR, are shown in Table 2⇓. As expected, all blood pressure measurements (SBP, DBP, MAP, and PP) differed significantly between normotensive and hypertensive groups. PPcen was greater in normotensive smokers than in nonsmokers but similar in the 2 hypertensive groups. IMT, D, and SI were increased in hypertensives and in smokers compared with corresponding normotensive and nonsmoker groups. The radius-to-wall thickness (R/IMT) ratio differed significantly between normotensive and hypertensive groups (NTNS versus HTNS P<0.05, NTS versus HTS P=0.05) but not between smoker and nonsmoker groups. ANOVA revealed significant interactions between smoking and blood pressure for IMT (F=31.2, P<0.001), LD (F=46.3, P<0.001), and SI (F=34.6, P<0.001), but not for R/IMT (F=2.6, P=NS). Carotid ςC(PP) differed significantly between the normotensive and hypertensive groups and between normotensive smokers and nonsmokers. For ςC(MAP), only the difference between normotensive and hypertensive smokers reached significance (Table 2⇓).
Multiple regression analysis showed strong interrelationships between indexes of arterial geometry and function adjusted for age, height, and HR and PPcen. Adjusted IMT and D were positively correlated with PPcen (r=0.59, P<0.001; r=0.34, P<0.001), and R/IMT was negatively correlated with PPcen (r=−0.38, P<0.001). The relationship between R/IMT and PPcen was not affected by smoking status (Figure 1⇓). These relationships persisted when data from smokers and users of antihypertensive medication were excluded (IMT versus PPcen r=0.65, P<0.001; D versus PPcen r=0.34, P<0.005; R/IMT versus PPcen r=−0.42, P<0.001). Although IMT and LD both correlated with MAP (r=0.28 and 0.36, both P<0.001), there was no significant relationship between R/IMT and MAP (Figure 1⇓). SI correlated with IMT in the whole group (r=0.56, P<0.001) and in both nonsmoking (r=0.60, P<0.001) and smoking (r=0.46, P<0.001) subgroups. SI was strongly related to PPcen (r=0.71, P<0.001).
Adjusted IMT (r=0.19, P<0.001), SI (r=0.20, P<0.001), D (r=0.16 P<0.05), and MAP (r=0.17, P<0.05) were significantly correlated with pack-years of smoking, but ςC(MAP), ςC(PP), and PPcen did not relate to smoking status. As shown in Figure 2⇓, there was a dose-dependent effect of smoking on both adjusted IMT and SI. Figure 3⇓ shows modeled pressure-versus-strain characteristics, using the values from the smoking and nonsmoking groups. Arterial stiffness is represented by the slope of the line at any point. Hypertension tended to move the operating point up the curve, whereas the relationship in smokers had a steeper gradient than the curve for nonsmokers.
There was no significant difference in mean total cholesterol in the 4 groups (NTNS 5.86±0.96, HTNS 5.98±0.90, NTS 5.94±1.36, HTS 5.95±1.33). None of the measurements of arterial blood pressure nor any of the indexes of arterial structure or function were correlated with total cholesterol levels.
The present study in older subjects has confirmed the importance of age as a determinant of arterial structure and function as shown by the significant relationships between age and PPcen, IMT, LD, and SI. With advancing age, there is an increase in large artery stiffness caused by intrinsic structural abnormalities.1 The pathological processes of increased collagen and calcium deposition and thinning, fragmentation, and eventual fracturing of elastin in the large arteries are likely explanations. Moreover, as shown in Figure 4⇓, it is likely that an increase in PPcen with advancing age is a key factor that contributes to an increase in IMT and a fall in R/IMT in accordance with Laplace’s law.
PPcen, Carotid Arterial Geometry, and Laplace’s Law
Circumferential stress, defined in accordance with Laplace’s law, is likely to be the major contributing factor in the remodeling effects of hypertension on the left ventricular wall and small resistance arterioles.1 2 3 In accordance with Laplace’s law, to resist changes in ςC the relationship between blood pressure and R/IMT would have to be maintained. Wall structural components and/or their relative proportions in larger arteries are quite different from those of resistance vessels; the more proximal the large artery, the less smooth muscle and more elastin fibers are found. Thus, central arterial remodeling is likely to be less obvious than that demonstrated in smaller resistance arterioles. Even small change in smooth muscle content, however, may cause a significant change in collagen/elastin interaction and in stress carriage within elastic arteries. A number of studies have shown an important influence of raised blood pressure on IMT and/or carotid arterial diameter.2 7 16 In particular, PP has been identified as a key factor that determines cardiovascular geometry.7 12 17 The strength of the relationships of carotid IMT and R/IMT to PPcen shown in the present study provides compelling evidence for operation of Laplace’s law in vivo in the carotid artery in response to change in contained pressure. Our results are consistent with those of Boutouyrie et al,18 who examined carotid and radial artery characteristics in 43 normotensive and 124 hypertensive subjects. They reported the local PP was an independent determinant of diameter and wall thickness in the carotid but not the radial artery. Moreover, in both their study and the current one, MAP was not a determinant of carotid arterial wall remodeling, suggesting that it is the cyclical stretching that is important.
Carotid IMT is generally recognized to be a composite measure of intima and medial wall thickness, although it may well be a measure of total wall thickness.19 During recent years, IMT has emerged as a strong risk factor of cardiovascular disease and is generally regarded as a marker of atherosclerosis, yet the importance of the contribution of the smooth muscle layer in the arterial media to this measurement has been largely overlooked. The carotid arterial pressure-structure-function relationships described in the present study suggest that changes in this layer contribute significantly to changes in IMT in response to hypertension. Smoking and hypercholesterolemia are important risk factors that have been associated with an increased IMT. However, after correction for age, smoking status, and cholesterol level, PPcen remained an important determinant of IMT.
Smoking Status, Arterial Geometry, and Function
Smoking is a key risk factor for cardiovascular disease and leads to increased arterial stiffness and wall thickness.8 9 10 In the present study, adjusted IMT was 9.2% thicker, D was 8.1% larger, and SI was 25.3% greater in normotensive smokers than in nonsmokers. Moreover, as shown in Figure 3⇑, these appear to be dose-dependent effects of smoking on IMT and SI. Smoking status had no apparent effect on the negative relationship between R/IMT and PPcen. It has been suggested that atherosclerosis, a major complication of smoking, may not result in increase stiffness of the arterial wall until there in significant plaque development.20 The results of the present study, with a more direct method of assessing arterial wall stiffness than the method used by the Atherosclerosis Risk in Communities (ARIC) investigators, are not consistent with that hypothesis, because SI was increased in the smokers, most of whom did not have any significant plaque in the common carotid artery as defined by an IMT of >1 mm. On the other hand, as shown in a recent review by Safar et al,21 arterial wall stiffness is not dependent on structural changes alone but is significantly influenced by endothelium-dependent vasomotor changes.
As shown in Figure 3⇑, our results suggest that smoking increases carotid stiffness independent of PP. This finding is consistent with smokers operating on a steeper pressure-strain characteristic. In this model, hypertension would move the operating point up the curve (point A→B in the case of nonsmokers; point C→D in the case of smokers), whereas smoking causes additional functional/structural changes that move the entire operating characteristic to the left. Our data also showed that smoking and hypertension were interacting risk factors that influenced IMT, LD, and SI but not R/IMT. Results similar to those described with SI were found when the mechanical characteristics of the carotid artery were described with a different index of stiffness, namely, the distensibility coefficient, as described by Gamble et al.19 Results that show dissociation of the effect of HT and smoking were also recently reported from the ARIC Study.22 In these noninvasive studies, actual structure cannot be determined, and we can only hypothesize as to what the underlying changes may be. Our results, however, are consistent with smoking initially causing a decreased ability of the carotid artery to contain pressure with a corresponding increase in diameter, accompanied by wall changes that cause increased stiffness. Endothelium-dependent functional changes are also likely to contribute to the increased stiffness, given the adverse effects smoking on endothelial function.21
Circumferential stress was significantly greater in hypertensive subjects. This is consistent with the results reported by Ferrara et al23 and Boutouyrie et al.18 In hypertension, although remodeling occurs, the circumferential stress remains at a high level. It appears, therefore, that an increased transmural pressure in the carotid artery in hypertension is not adequately compensated for by increased IMT and that lumen diameter actually increases.
Figure 4⇑ is a representation of the ways in which different risk factors may affect the carotid arterial wall. It is suggested that compensatory changes in the medial smooth muscle layer in response to increased PP are the major factor that causes increased IMT and arterial stiffness. The impact of smoking and probably other risk factors is likely to be due to wall damage secondary to intimal damage, with a breakdown in pressure opposing elements in the arterial wall leading to dilatation and increased stiffness because of rearrangement and loss of elastic fibers and sclerosis.
In the present study of older subjects, carotid arterial wall remodeling in response to pressure was consistent with Laplace’s law. Hypertension, most likely working through PPcen, was associated with increases in carotid IMT and LD, with wall remodeling, and with a reduction in R/IMT, but this adaptation was insufficient to prevent an increase in ςC. Smoking was associated with similar proportional increases in carotid IMT and LD, with no change in R/IMT. Both hypertension and smoking were interactive in their effects on IMT, LD, and arterial wall stiffness. Thus, different cardiovascular risk factors appeared to influence the relationship among arterial geometry, wall stress, and stiffness in different ways.
This study was supported by grants-in aid from the National Health and Medical Research Council of Australia (904862), the National Heart Foundation of Australia (G95 M4418), and Monash University Postgraduate Publications Award. We thank Prof Anthony Dart for help with the statistical analysis.
- Received May 12, 2000.
- Revision received May 26, 2000.
- Accepted July 24, 2000.
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