Journal of Human Hypertension (2007) 21, 141–148 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh
ORIGINAL ARTICLE
Relationship between blood pressure parameters and pulse wave velocity in normotensive and hypertensive subjects: invasive study EJ Kim1, CG Park1, JS Park1, SY Suh1, CU Choi1, JW Kim1, SH Kim2, HE Lim1, SW Rha1, HS Seo1 and DJ Oh1 1
Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital, Guro-gu, Seoul, Republic of Korea and 2Division of Cardiology, Department of Internal Medicine, Hallym University Medical Center, Youngdeungpo-dong, Seoul, Republic of Korea
Blood pressure (BP) is one of the most important contributing factors to pulse wave velocity (PWV), a classic measure of arterial stiffness. Although there have been many non-invasive studies to show the relation between arterial stiffness and BP, the results are controversial. The aim of this study is to evaluate the role of BP as an influencing factor on PWV using invasive method. We observed 174 normotensive and untreated hypertensive subjects using coronary angiography. Arterial stiffness was assessed through aorto-femoral PWV by foot-to-foot velocity method using fluid-filled system. And BP was measured by pressure wave at the right common femoral artery. From univariate analysis, age, diabetes mellitus (DM), hypertension, waist, waist-to-hip ratio, total cholesterol-tohigh-density lipoprotein cholesterol ratio, systolic BP (SBP), pulse pressure (PP) and mean arterial pressure
(MAP) showed significant association with PWV. To avoid multiple colinearity among SBP, PP and MAP, we performed multiple regression analysis predicting PWV thrice. Age, DM and each BP were significantly and consistently correlated to PWV. In the first and third modules, compared to age, SBP and MAP were less strong predictors, respectively. However, PP was the stronger predictor than age and DM in the second module. Lastly, we simultaneously forced MAP and PP with other variables in the fourth multivariate analysis. Age, DM and PP remained significantly correlated with PWV, but the significance of MAP was lost. This is the first invasive study to suggest that PP has the strongest correlation with PWV among a variety of BP parameters. Journal of Human Hypertension (2007) 21, 141–148. doi:10.1038/sj.jhh.1002120; published online 30 November 2006
Keywords: pulse wave velocity; pulse pressure; large artery stiffness
Introduction 1
Arterial stiffening increases with age and is associated with generalized atherosclerotic vascular disease.2–4 In population-based studies, aortic stiffness is an independent predictor of cardiovascular outcomes after adjustment for traditional cardiovascular risk factors.4–7 Arterial stiffness has been shown to predict coronary artery disease8–11 and cardiovascular mortality in patients with essential hypertension,12 end-stage renal disease13,14 and impaired glucose tolerance and diabetes mellitus (DM).15 Although there are many measures to Correspondence: Professor Dr CG Park, Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital, 80 Guro-dong, Guro-gu, Seoul 152-703, Korea. E-mail:
[email protected] Received 29 May 2006; revised 9 October 2006; accepted 11 October 2006; published online 30 November 2006
quantify stiffness, none of them is a gold standard, but approximations.16,17 It is believed that the most reliable (and still probably the best) measure of arterial stiffness is pulse wave velocity (PWV).16 PWV is known to be associated with age, gender, blood pressure (BP), heart rate, salt intake, genetic factors and others. Although BP is one of the strongest factors influencing PWV, varying correlation coefficients have been reported between the various PWV (aorta-leg-arm) and BP (systolic, diastolic, mean, pulse) using non-invasive methods.5,18–24 This variation may be attributable, at least in part, to the inherent variability of both PWV and BP within and across individual subjects and also to the method of BP25 and PWV measurements. The aim of this study is to elucidate the relationship between the various BP and aortic PWV through direct measurement of BP wave in the artery using invasive method.
Pulse wave velocity and pulse pressure EJ Kim et al 142
Materials and methods Study subjects
Investigations were carried out in the cardiology department at the Korea University Guro Hospital, Seoul, Korea, between March 2002 and July 2003. To obtain BP and aortic PWV through a direct pressure wave in the artery using invasive method, we selected the study population from those who underwent coronary angiography owing to chest symptoms or preoperative evaluation. Of the 435 subjects who gave written informed consents for PWV measurement, 227 were receiving antihypertensive drug therapy and 17 were not clear of their medical history and, therefore, were excluded from the study. Additional 17 patients were excluded owing to one or more of the exclusion criteria; acute myocardial infarction, cardiomyopathy, more than mild valvular disease, post-cardiac surgery, atrial fibrillation, aortic dissection and chronic renal failure. Thus, 174 normotensive and untreated hypertensive subjects (101 women; 73 men) were observed. Their median age was 59.0712.03 years (71s.d.). The study was approved by the local ethics committee. Hypertension was characterized with repeated measurements of X140 mm Hg systolic BP (SBP) or X90 mm Hg diastolic BP (DBP). DM was defined as a fasting blood glucose concentration X126 mg/dl or antihyperglycaemic drug treatment. Current smoking was defined as having smoked the last cigarette less than 1 month before coronary angiography.
Measurement of haemodynamic variables
Haemodynamic measurements were obtained from patients in supine position. PWV was measured along the descending thoraco-abdominal aorta using the foot-to-foot velocity method. Briefly, waveforms were obtained using a fluid-filled system (5Fr right Judkin’s catheter) at the descending aorta, just below the origin of left subclavian artery and the right common femoral artery (Figure 1). At each site, the pressure waves were simultaneously recorded with the electrocardiography using polygraph at the speed of 100 mm/s. We defined T1 as the time interval from the starting point of QRS complex to the foot of pressure wave in the descending aorta and T2 as the time interval from the starting point of QRS complex to the foot of pressure wave in the right common femoral artery. We measured T1 and T2 from three different QRS complexes and pressure waves, and computed the mean value to minimize the error. The time delay (T) was calculated as T2T1 and the distance (D) was obtained by the length of the catheter between the two recording sites. PWV was calculated by PWV ¼ D (m)/T (s). We measured SBP, DBP and pulse pressure (PP) by pressure tracing method in the right common femoral artery. Mean arterial pressure (MAP) was obtained by the formula MAP ¼ DBP þ PP/3. Statistical analysis
Values were expressed as mean7one standard deviation (s.d.). Differences in the mean value of PWV between the two groups were compared using
Figure 1 The measurement of PWV. Catheter was located on the descending aorta just distal to left subclavian artery (upper left panel), and surface ECG and arterial pressure wave were recorded on a paper with speed 100 mm/s and T1 transit time was measured (upper right panel). Introducing sheath was located on the right common femoral artery (lower left panel) and T2 transit time was measured (lower right panel). Journal of Human Hypertension
Pulse wave velocity and pulse pressure EJ Kim et al 143
a Student’s t-test for a parametric statistical test and Mann–Whitney’s test for a non-parametric analysis. A Po0.05 was considered significant. Correlations between each of the measured variables and PWV were assessed by Pearson’s correlation coefficient. The effects of traditional cardiovascular risk factors and haemodynamic variables on PWV were analysed by multivariate regression analysis. With the variables selected from univariate analyses, we performed the analysis thrice to avoid multiple colinearity among SBP, PP and MAP. Variables included in the first module were common ones, such as age, DM, waist-to-hip ratio, total cholesterolto-high-density lipoprotein cholesterol (HDL-C) ratio and SBP. The second and third modules included common variables along with PP and MAP. We also performed the fourth multiple regression analysis including the same non-haemodynamic variables, PP and MAP with a test of variance influence factor. Statistical analyses were performed using the SPSS 10.0 software package (SPSS Inc., Chicago, IL, USA).
Results
three modules also included SBP, PP and MAP, separately. The results indicated that age and DM were significantly and consistently correlated to PWV. And within each analysis, SBP, PP and MAP also showed significant association with PWV. The first and third module showed that age was the strongest predictor among 3 significant correlating factors (age, DM, SBP or MAP). In the second module, on the other hand, PP was the stronger predictor than age or DM (for age, b ¼ 0.233, P ¼ 0.001; for DM, b ¼ 0.201, P ¼ 0.005; for PP, b ¼ 0.255, Po0.001). When we used age as an index variable for comparison, this result indirectly demonstrated that PP was the only stronger predictor for PWV compared to age among BP parameters. That is, PP showed the most potent correlation with PWV over a variety of BP parameters. Lastly, we included both MAP and PP with other common independent variables in the fourth multiple regression model (Table 4). Considering continuous characteristic of MAP and pulsatile characteristic of PP, we tried to determine whether
Table 1 Baseline clinical characteristics of study subjects
The baseline clinical characteristics of the study population are presented in Table 1. Table 2 shows the results of the independent-samples t-test for comparison of the PWV mean value between the two groups according to gender, hypertension, DM and smoking status. Compared with subjects who did not have hypertension or DM, subjects who had hypertension or DM showed significantly higher PWV mean value (for hypertension, 13.276.2 vs 10.373.5 m/s, Po0.001; for DM, 15.678.6 vs 11.174.3 m/s, P ¼ 0.003). However, the differences of PWV between men and women, or smoker and non-smoker were not prominent. In bivariate analysis (Table 3), age, waist-to-hip ratio, total cholesterolto-HDL-C ratio, SBP, PP and MAP were positively correlated with PWV. The relations of PWV to age, SBP, PP and MAP were displayed in Figures 2–5, respectively. To avoid multiple colinearity among SBP, PP and MAP, we performed multiple regression analysis predicting PWV three times with variables selected from univariate analyses (Table 4). In every multiple regression analysis, age, waist-to-hip ratio, DM and total cholesterol-to-HDL-C ratio were used as common independent variables and each of the
n ¼ 174
Parameters Age (year) Gender (male) Hypertension Diabetes Smoker BMI (kg/m2) Height (cm) Waist/hip
59.0712.03 73 (42.0%) 82 (47.1%) 21 (12.1%) 38 (21.8%) 24.473.4 161.078.2 0.970.07
Total cholesterol (mg/dl) HDL-C TG LDL-C Heart rate (b.p.m.)
185.9743.8 46.4712.0 132.4770.0 111.4738.5 74.5713.8
Blood pressure (mm Hg) Systolic Diastolic Pulse Mean Pulse wave velocity (m/s)
146.8725.3 78.9713.1 67.9719.0 101.5715.8 11.675.2
Abbreviations: BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.Continuous variables are expressed as mean7s.d. except age, which is expressed as median7s.d.
Table 2 Independent-samples t-test results for pulse wave velocity Gender Men (n ¼ 73) PWV (m/s) P
Women (n ¼ 101)
12.176.0
11.374.5 0.321
Hypertension Yes (n ¼ 92)
No (n ¼ 82)
13.276.2 10.373.5 o0.001
Diabetes Yes (n ¼ 21) 15.678.6
No (n ¼ 153)
11.174.3 0.003
Smoking Yes (n ¼ 38) 12.375.2
No (n ¼ 136)
11.475.2 0.370
Abbreviation: PWV, pulse wave velocity. Journal of Human Hypertension
Pulse wave velocity and pulse pressure EJ Kim et al 144
Table 3 Pearson’s correlation coefficient between pulse wave
30
Age BMI Height Waist/hip TC HDL-C TG LDL-C TC/HDL-C Heart rate Systolic BP Diastolic BP Pulse pressure Mean BP
r
P
0.357 0.105 0.048 0.178 0.080 0.129 0.058 0.152 0.159 0.018 0.330 0.110 0.363 0.238
o0.001 0.175 0.536 0.021 0.314 0.111 0.473 0.061 0.048 0.820 o0.001 0.150 o0.001 0.002
Pulse Wave Velocity (m/s)
velocity and clinical parameters
20
10
0 20
Abbreviations: BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.
40
60 80 100 Pulse Pressure (mmHg)
120
140
Figure 4 Relation between aortic PWV and PP (r ¼ 0.363, Po0.001).
30
Pulse Wave Velocity (m/s)
Pulse Wave Velocity (m/s)
30
20
10
20
10
0 10
20
30
40 50 60 Age (years)
70
80
90 0 40
Figure 2 Relation between aortic PWV and age (r ¼ 0.357, Po0.001).
Pulse Wave Velocity (m/s)
30
20
10
0 80
100
120 140 160 180 200 Systolic Blood Pressure (mmHg)
220
240
Figure 3 Relation between aortic PWV and SBP (r ¼ 0.330, Po0.001). Journal of Human Hypertension
60
80 100 120 140 Mean Arterial Pressure (mmHg)
160
Figure 5 Relation between aortic PWV and MAP (r ¼ 0.238, P ¼ 0.002).
PP remained significantly correlated with PWV after other factors including MAP were forced in the model. In the analysis, age (b ¼ 0.356, Po0.001), DM (b ¼ 0.161, P ¼ 0.028) and PP (b ¼ 0.221, P ¼ 0.023) remained significantly correlated with PWV, but MAP lost the significance of correlation with PWV (b ¼ 0.129, P ¼ 0.154). The variance influence factors for all independent variables were less than 2, thereby the multiple colinearity was not prominent. The analysis was also performed adding SBP as an independent variable (data not shown). However, the result was the same as the fourth module except automatic exclusion of SBP from the analysis because its multi colinearity was over the limit. In our cross-sectional study, it is suggested that the pulsatile BP had more effect on PWV than the continuous part of BP.
Pulse wave velocity and pulse pressure EJ Kim et al 145
Table 4 Multiple linear regression analysis predicting PWV: relationships between PWV and clinical parameters 1st module b Age Waist/hip Diabetes TC/HDL-C Systolic BP PP MAP
0.286 0.003 0.219 0.114 0.283 — —
2nd module P
b
o0.001 0.961 0.002 0.092 o0.001
0.233 0.018 0.201 0.130
P 0.001 0.803 0.005 0.059 —
0.255
3rd module b
P
b
P
VIF
0.333 0.006 0.241 0.099
o0.001 0.933 0.001 0.145
0.356 0.014 0.161 0.138
1.30 1.12 1.12 1.07
o0.001
0.221 0.129
o0.001 0.848 0.028 0.054 — 0.023 0.154
— —
o0.001
—
4th module
0.268
1.98 1.73
Abbreviations: BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse wave velocity; TC, total cholesterol; VIF, variance influence factor.
Discussion The key finding of our study was that in normotensive and untreated hypertensive middle-aged and elderly subjects (median age of 59.0712.03 years) PP showed the strongest correlation with aortic PWV over other haemodynamic BP parameters. PWV measured along the aortic and aorto-femoral pathways has been known to be the most clinically relevant because the aorta and its first branches are responsible for most of the pathophysiological effects of arterial stiffness. Although non-invasive technique showed acceptable reproducibility, the length of arterial segment was usually estimated by direct superficial measurement of the distance between two transducers. Therefore aortic PWV by non-invasive method would be underestimated because arteries become longer and more tortuous with age. In vivo measurement of the travel distance was calculated by subtracting (i) the known sheath length and (ii) the external catheter length behind the sheath, from the known length of the total catheter and obtained more accurate PWV. Also, we minimized the error of BP measurement by using intra-arterial pressure wave. Arterial stiffness has been known to be related to BP; however, there are controversial results in the literature regarding the relation between PWV and each BP (SBP, DBP, PP and MAP). Ngim et al.19 reported that carotid-femoral PWV was correlated with SBP and also MAP, but not with DBP in untreated hypertensive and normotensive middleaged Malay men. Stompor et al.24 also found out that aortic PWV was correlated significantly with SBP, MAP and PP, but not with DBP in peritoneal dialysis patients. Those findings are consistent with our results. In some studies, PWV was only correlated with SBP,20,21 but in others with both SBP and DBP.22 Sa Cunha et al.23 suggested gender difference; SBP showed correlation with PWV in both genders, whereas DBP was correlated with PWV only in women. In contrast to the previous studies, Nurnberger et al.18 reported that DBP was an only important haemodynamic determinant of PWV in young healthy males.
The causes of controversial results may be different demographic characteristics such as age range, gender distribution and body size. Whether the subjects were on antihypertensive agents and the kinds of drugs, if used, might also affect the results.26 Also, the different methods of BP measurement (e.g. 24-h ambulatory BP monitoring, casual BP measurement, automatic BP monitoring for 30 min) could attribute to the results.27 In particular, as indirect measurement of DBP by cuff-mercury sphygmomanometer tends to be overestimated, the true intra-arterial PP might be underestimated, which could also affect the results.28 In terms of PWV measurement, different methods and locations were used in the studies, and most non-invasive methods basically had a limitation mentioned above, therefore, showed controversial results. Because this study used invasive method for the measurement of BP and aortic PWV excluding subjects on antihypertensive agents, our findings reflect the effect of BP on aortic PWV more clearly. In population-based studies, aortic PWV has been known to be a superior independent predictor of cardiovascular outcome even after adjusting the traditional cardiovascular risk factors5,7 and elevated PP also has been known to be an independent risk factor of cardiovascular disease.29–31 Haemodynamic patterns of age-related changes in BP was shown in the Framingham heart study.32 After age 50–60 years, DBP declined, PP rose steeply and MAP reached a plateau. The changes were mainly attributed to the age-related large artery stiffness. The effect of ageing on the prognostic significance of BP was reported in hypertensive subjects33 and Framingham population.34 By ambulatory intraarterial BP monitoring, DBP parameters provided the best prognostic value for cardiovascular outcomes in the middle aged (o60 years), whereas PP parameters were the most predictive in the elderly (X60 years) individuals.33 With increasing age, the relative prognostic value of BP for coronary heart disease was gradually shifted from DBP to SBP and then to PP in the Framingham heart study.34 In subjects aged o50 years, DBP was the strongest predictor. Age 50–59 years was a transition period when SBP, DBP and PP Journal of Human Hypertension
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were similar predictors, whereas from age 60 years and over, DBP was negatively related to the risk of coronary events so that PP became a better predictor than SBP. We suggest that as the median age of our subjects is 59 years, these age-related trends of the Framingham heart study could be similarly applied to our research, which demonstrates PP as the strongest determinant of aortic PWV. Because our results also showed prognostic significance of SBP and MAP for aortic PWV and no correlation of DBP with PWV, the findings were in agreement with the previous data.32–34 Interestingly, Nurnberger et al.18 reported a contrary result. They showed DBP was the only important determinant of PWV among all BP parameters. But, the study population included only young (23–35 years old) healthy males, in whom DBP has been known to be the strongest predictor of coronary heart disease in the Framingham heart study. Although the results of the present study and Nurnberger’s report are different, together they might reflect the age-related different relation between BP parameters and PWV. It is suggested that aortic PWV and BP are strongly influenced by age, and the role of BP parameters as a predictor of PWV could be different according to the age range of the population studied. Elastic properties of the arterial wall are highly pressure dependent. At low levels of arterial pressure, wall stress is supported by compliant elastin fibres, whereas at higher levels of pressure, wall stress is supported by much stiffer collagen fibres. An increase in elastic artery stiffness is related to arterial wall composition and occurs over a long period, for example, with advancing age, hypertension and arteriosclerosis. Acute changes can occur in elastic arteries with changes in distending MAP, but these are passive. For example, during vasodilation, both pressure and diameter decrease in elastic arteries, causing a passive decrease in wall stiffness and a decrease in PWV.35 As it was cross-sectional and because there was no BP manipulation, our study reveals chronic changes of elastic arteries well. It was further supported by the fourth module of multiple regression analysis (Table 4). MAP, which is more related to acute BP influence on PWV, lost the significance of correlation with PWV when it was adjusted for other factors. However, age, DM and PP remained significantly correlated with PWV in the analysis. In terms of the relationship between PWV and two important BP characteristics, continuous and pulsatile, the result also suggested that the pulsatile BP had more impact on aortic PWV than the continuous part of BP. We found no significant relationship of PWV with total cholesterol, triglycerides, low-density lipoprotein cholesterol or HDL-C. Although positive and negative associations of aortic stiffness with cholesterol have been reported using different methods, most studies using PWV have shown no Journal of Human Hypertension
correlation with total cholesterol.5,25 The present findings are in agreement with a recent large population-based study by Amar et al.5 These investigators found no significant relationship between PWV and total cholesterol and the various components of the metabolic syndrome, including body mass index, fasting glucose, insulin, triglycerides and HDL-C. The lack of correlation of PWV with smoking in the present study is also consistent with previous reports.5,36–38 The effect of heart rate on arterial stiffness is somewhat a controversial issue. In a recent observational study, Sa Cunha et al.23 showed that high heart rate was strongly associated with elevated PWV even after adjustment for age and BP. The increase in heart rate by isoproterenol and pacing was associated with an increase in PWV.39 Our result, however, demonstrated no significant correlation and is in agreement with other previous studies.40–42 There was also a contradictory study showing reduced aortic stiffness and increased distensibility during incremental pacing.43 Therefore, in order to clarify the relationship between arterial distensibility and heart rate, and its pathophysiology, further specific studies are necessary. Several aspects of validity need to be discussed. There was a potential limitation in PWV measurement method, as we could not obtain pressure wave at two recording sites at the same time. However, we think that there were no significant haemodynamic variations between the two assessments obtained from two different sites because it took less than 3 s to disconnect the catheter from the manifolder, remove it and connect the side arm of the introducer sheath to the manifolder. That is, there was a time interval of less than 3 s between the aortic pressure wave and the right common femoral arterial pressure wave. Nevertheless, we could not affirm whether there was a variation of BP between the two assessments, because the patient’s real-time BP was being monitored and was obtained through the catheter at each recording site in the arterial system. However, in terms of heart rate, no significant variation between the two assessments was affirmed by paired t-test (heart rate in femoral artery, 74.57 13.8 b.p.m. vs heart rate in aorta, 74.4713.6 b.p.m., P ¼ 0.49). In addition, we measured T1 and T2 by electrocardiography gating and averaged the values from three measurements at each site (mean T1 ¼ 108.0 ms, mean s.d. ¼ 4.9 ms (0.6– 13.2 ms); mean T2 ¼ 149.3 ms, mean s.d. ¼ 4.4 ms (1.2–13.0 ms)). One other potential problem of our study is the confinement to symptomatic patients referred for coronary angiography. Thus, our findings might not be applicable to the general population. In terms of the relation between BP parameters and aortic PWV, we think, however, the subjects studied matter little to the results. Moreover, it is unlikely that confounding explains our results because we were able to adjust for many important potential confounders.
Pulse wave velocity and pulse pressure EJ Kim et al 147
In conclusion, PP showed the strongest correlation with aortic PWV among a variety of BP parameters in the normotensive and untreated hypertensive middle aged and elderly subjects, and it was first confirmed by an invasive method. In combination with the previous studies,18,32–34 the present study also suggests that the role of BP parameters as a predictor of PWV could be different according to the age range of the population studied. Further large population-based studies are needed to characterize the age-related changes in the impact of BP on large artery stiffness. What is known about the topic K BP is one of the most important determinants of PWV, a classical measure of arterial stiffness. K Although there have been many non-invasive studies to show the relation between PWV and BP, the results are controversial. K Haemodynamic patterns of age-related changes in BP and the effect of aging on the prognostic significance of BP were shown in the Framingham heart study.32,34 What this study adds K Because this study used invasive method for the measurement of BP and aortic PWV and excluded subjects on the antihypertensive agents, our findings more clearly reflect the effect of BP on aortic PWV. K In normotensive and untreated hypertensive middle-aged and elderly subjects, pulse pressure showed the strongest correlation with aortic PWV over other BP parameters. 18,32–34 K In combination with the previous studies, our findings also suggest that the role of BP parameters as a predictor of PWV could be different according to the age range of the population studied. Abbreviations: BP, blood pressure; PWV, pulse wave velocity.
Acknowledgements This work was partially supported by a grant from the Seoul R LBD program, Republic of Korea (10528).
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35 36 37 38 39
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