Original Article
Arterial stiffness and hypertension in a large population of untreated individuals: the Rotterdam Study Germaine C. Verwoert a,b, Oscar H. Franco a, Arnold P.G. Hoeks c, Robert S. Reneman d, Albert Hofman a, Cornelia M. v Duijn a, Eric J.G. Sijbrands b, Jacqueline C.M. Witteman a, and Francesco U.S. Mattace-Raso a,b
Objective: We studied whether arterial stiffness measured as aortic pulse wave velocity (aPWV) and carotid distensibility was associated with different subtypes of hypertension in a large population of untreated middleaged and elderly men and women. Methods: The study was conducted within the framework of the population-based Rotterdam Study. We included 4088 individuals with information on aPWV, with 3554 individuals with carotid distensibility measurements without use of antihypertensive medication. Isolated systolic hypertension (ISH) was defined as SBP at least 140 mmHg and DBP less than 90 mmHg. Combined systolic and diastolic hypertension (Sys/Dia hypertension) was defined as SBP at least 140 mmHg and DBP at least 90 mmHg. Analysis of covariance was used to compare means of arterial stiffness for the different subtypes of hypertension. Multinomial logistic regression analysis was performed to investigate the association of arterial stiffness and the subtypes of hypertension in models adjusted for age, sex, mean arterial pressure, heart rate and cardiovascular risk factors. Results: The mean age of the individuals was 68 years: 45.3% were men, 1597 individuals had ISH and 441 individuals had Sys/Dia hypertension. aPWV was higher (13.2 vs. 12.9 m/s; P ¼ 0.008) in individuals with ISH compared to those with Sys/Dia hypertension. Multivariate odds ratios and corresponding 95% confidence interval of aPWV for ISH were 1.53 (1.38–1.71) and 1.28 (1.09– 1.53) for Sys/Dia hypertension. Corresponding odds ratios associated with carotid distensibility were 0.84 (0.75–0.94) and 0.66 (0.54–0.81), respectively. Age significantly modified the association of aPWV with subtypes of hypertension (P < 0.001). Conclusion: In a large untreated population, we found significant associations of both aPWV and carotid distensibility with ISH and Sys/Dia hypertension. individuals with ISH had higher values of aortic stiffness when compared to individuals with Sys/Dia hypertension, a difference that was most pronounced at older age. The results suggest that aortic stiffness contributes to ISH in older individuals without treatment for hypertension.
Keywords: ageing, arterial stiffness, combined systolic and diastolic hypertension, isolated systolic hypertension, population-based study Abbreviations: DD, the absolute stroke change in diameter during systole; DD/D, the relative stroke change in diameter; aPWV, aortic pulse wave velocity; CHD, coronary heart disease; CI, confidence interval; D, enddiastolic diameter; HDL, high-density lipoprotein; ISH, isolated systolic hypertension; MI, myocardial infarction; MMP, matrix metalloproteinase; OR, odds ratio; RS-I, original Rotterdam Study started in 1990; RS-II, extension of the Rotterdam Study in 1999; Sys/Dia hypertension, combined systolic and diastolic hypertension
INTRODUCTION
H
ypertension is a common and well established risk factor for cardiovascular disease [1]. The prevalence of hypertension increases with advancing age. Isolated systolic hypertension (ISH) is the most frequent type of hypertension in the elderly [2]. This is due to the continuous increase in SBP with advancing age, whereas DBP tends to remain constant or declines with advancing age, indicating a patent regulation of mean arterial pressure [3]. The most likely explanation for the age-related rise in SBP and fall in DBP is large artery stiffening [3]. Indeed, several studies have shown that a specific measure of arterial stiffness, that is, aortic pulse wave velocity (aPWV), is increased in individuals with
Journal of Hypertension 2014, 32:1606–1612 a Department of Epidemiology, bDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, cDepartment of Biomedical Engineering and dDepartment of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Correspondence to Germaine Verwoert, MD, MSc, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Tel: +31 107035979; fax: +31 107034768; e-mail: g.verwoert@eras musmc.nl Received 18 November 2013 Revised 1 April 2014 Accepted 1 April 2014 J Hypertens 32:1606–1612 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000237
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Arterial stiffness and hypertension
ISH compared to controls [4,5], whereas carotid distensibility shows a decline. This relation has been confirmed in young adults [6] and elderly women [7]. Furthermore, aPWV has been shown to be an independent predictor of the longitudinal increase in SBP [8] and is associated with subsequent cardiovascular morbidity and mortality [9,10]. Previous studies included relatively small groups of individuals and there is limited information on the relation of arterial stiffness with ISH in different age categories of healthy untreated individuals. Furthermore, the relation of arterial stiffness with the different types of hypertension, including ISH and combined systolic and diastolic hypertension (Sys/Dia hypertension), has not been fully elucidated. Therefore, we studied whether two measures of arterial stiffness, aPWV and carotid distensibility, were associated with ISH and Sys/Dia hypertension in a large population of untreated individuals. We additionally investigated whether the association was different in categories for age.
METHODS Study population The present study was performed within the framework of the Rotterdam Study, a large population-based prospective cohort study. From 1990 to 1993, 7983 individuals aged 55 and over living in Ommoord, a suburb of Rotterdam, the Netherlands, participated in the Rotterdam Study (RS-1). In 1999, inhabitants who turned 55 years of age or moved into the study district since the start of the study were invited to participate in an extension of the Rotterdam Study (RS-II) of whom 3011 participated. The overall aim of the Rotterdam Study is to access the occurrence of risk factors for chronic diseases in the elderly. The study design and objectives of the Rotterdam Study are described elsewhere [11]. The Medical Ethics Committee of Erasmus Medical Center approved the study and written consent was obtained from all participants.
Measures of arterial stiffness Aortic pulse wave velocity The aPWV was obtained with individuals in supine position. Before the aPWV measurement, blood pressure was measured twice with a sphygmomanometer after 5 min of rest and the mean was taken. The aPWV was assessed with an automatic device (Complior Artech Medical, Pantin, France) [12] that measures the time delay between the rapid early upstroke of the pulse pressure (PP) waves recorded simultaneously in the carotid artery and the femoral artery. The distance between the recording sites in the carotid and the femoral artery was measured with a tape over the surface of the body. The aPWV was calculated as the ratio between distance and the foot–foot time delay and was expressed in meter per second. Carotid distensibility Common carotid distensibility was assessed with the individuals in supine position, with the head tilted slightly to the contralateral side for the measurement in the common carotid artery. The vessel wall motion of the right common Journal of Hypertension
carotid artery was measured by means of a duplex scanner (ATL Ultramark IV, operating frequency 7.5 MHz) connected to a vessel wall movement detector system. The details of this technique have been described elsewhere [13]. After 5 min of rest, a region at 1.5 cm proximal to the origin of the bulb of the carotid artery was identified with the use of B-mode ultrasound, where after the system was switched to M-mode. The displacement of the arterial walls was obtained by processing the radiofrequency signals originating from two selected sample volumes positioned over the anterior and posterior walls. The end-diastolic diameter (D), the absolute stroke change in diameter during systole (DD), and the relative stroke change in diameter (DD/D) were computed as the mean of four cardiac cycles of three successive recordings. The cross-sectional arterial wall distensibility coefficient, expressed in per MPa, was calculated according to the following equation: distensibility coefficient ¼ 2DD/(D PP) [14], with PP defined as the difference between SBP and DBP. In a reproducibility study performed among 47 individuals, the intraclass correlation coefficient was 0.80 for both the aPWV and the carotid distensibility coefficient [15].
Blood pressure measurements Two blood pressure measurements were obtained at the right brachial artery with a random zero sphygmomanometer after the individual had been seated for at least 5 min. SBP, first Korotkoff phase, and DBP, fifth Korotkoff phase, were obtained and the mean of the two blood pressure values was used in the analyses. Normotensive was defined as SBP below 140 mmHg and DBP below 90 mmHg. ISH was defined as SBP at least 140 mmHg and DBP 90 mmHg or less [16]. Sys/Dia hypertension was defined as SBP at least 140 mmHg and DBP at least 90 mmHg. Mean arterial pressure was estimated as MAP ¼ DBP þ PP/3.
Cardiovascular risk factors Information on medical history, smoking habits and medication use was obtained during a home interview. Smoking was divided into three categories: current, former and never smokers. During the research center visit, height and weight were measured, and the BMI was computed (kg/ m2). Diabetes mellitus was defined as a history of diabetes mellitus and/or the use of blood glucose-lowering medication and/or a fasting serum glucose level at least 7.0 mmol/l [17]. Serum total cholesterol and high-density lipoproteins (HDL)-cholesterol values were determined by an automated enzymatic procedure (Boehringer Mannheim System, Mannheim, Germany) [18].
Prevalent coronary heart disease A history of coronary heart disease (CHD) was obtained through direct questioning and was considered positive when confirmed according to hospital discharge date or written information from the individual’s general practitioner, as described previously [19]. CHD was defined myocardial infarction (MI), a percutaneous transluminal coronary angioplasty, a coronary artery bypass graft. A history of MI was considered present in case of self-report of MI confirmed by electrocardiogram or additional clinical www.jhypertension.com
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Verwoert et al.
information or the presence of an electrocardiogram characteristic of prior MI.
Population for analysis During the third examination phase of RS-I (1997–1999) and during the first examination phase of RS-II (2000– 2001), a computerized questionnaire was completed and cardiovascular risk factors and arterial stiffness were assessed. In total, 6938 individuals visited the research center. Measures of both blood pressure levels and aPWV were obtained in 5773 individuals, and among these, 4640 individuals had a measurement for carotid distensibility. We excluded individuals with use of antihypertensive medication (n ¼ 1309) and those with missing covariate information (n ¼ 376), resulting in 4088 individuals for analyses with aPWV. Among these, 3554 individuals were available for carotid distensibility analyses. Missing information was primarily due to logistic reasons.
Statistical analysis Mean values of systolic, diastolic, mean arterial and PP, aPWV and carotid distensibility in different age categories were plotted in figures. Analysis of covariance (ANCOVA) was used to compare age, sex, aPWV and carotid distensibility between subtypes of hypertension categories, that is, normotensive, ISH and Sys/Dia hypertension. Multinomial logistic regression models were performed to investigate the association of standardized cardiovascular risk factors and standardized values of aPWV and carotid distensibility with subtypes of hypertension. Standardized values were obtained by dividing each measure by its SD. The models were adjusted for age, sex, cohort, BMI, total cholesterol, high-density cholesterol, smoking, diabetes mellitus, and for mean arterial pressure and heart rate, when appropriate. We tested for interaction by age, sex, diabetes mellitus and prevalent cardiovascular disease. If the interaction term was significant, we performed stratified analyses. ANCOVA was used to compare means of arterial stiffness in subtypes of hypertension by age categories, adjusted for age, sex, cohort, mean arterial pressure, heart rate and cardiovascular risk factors, when appropriate. For descriptive purposes, we generated figures with mean values of measures of arterial stiffness in the age categories for individuals in the different hypertension categories. P-values less than 0.05 were considered statistically significant. All analyses were performed using SPSS 15.0 statistical package for Windows 2003 (SPSS, Inc., Chicago, Illinois, USA).
RESULTS The baseline characteristics of the study population are shown in Table 1. The mean age of the study population was 68.1 years and the percentage of men was 45.3%. With increasing age, there is an increase in SBP and PP, a decrease in DBP and no change in mean arterial pressure (Fig. 1a). There is an increase in aPWV and decrease in carotid distensibility with age (Fig. 1b). Of the 4088 individuals in this study, 1597 (39.1%) individuals had ISH and 414 (10.1%) had Sys/Dia hypertension. Individuals with ISH were older compared to normotensive individuals and individuals with Sys/Dia hypertension (P < 0.001). 1608
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Of the traditional cardiovascular risk factors, age [per SD, odds ratio (OR) 1.78, 95% confidence interval (CI) 1.64– 1.94], BMI (per SD, OR 1.26, 95% CI 1.17–1.35) and diabetes mellitus (OR 1.54, 95% CI 1.23–1.93) were strongly associated with ISH. Male sex (OR 1.68, 95% CI 1.33–2.13), BMI (per SD, OR 1.45, 95% CI 1.30–1.61) and diabetes mellitus (OR 1.53, 95% CI 1.10–2.14) were strongly associated with Sys/Dia hypertension. Age was only weakly associated with Sys/Dia hypertension (per SD, OR 1.14, 95% CI 0.99–1.30) (Table 2). Aortic PWV and carotid distensibility were strongly associated with both ISH and Sys/Dia hypertension. ORs and corresponding 95% CIs of aPWV, after adjustment for cardiovascular risk factors, were 1.53 (1.38–1.71) for ISH and 1.28 (1.09–1.53) for Sys/Dia hypertension. ORs for carotid distensibility were 0.84 (0.75–0.94) for ISH and 0.66 (0.54–0.81) for Sys/Dia hypertension (Table 2). After adjustment for age, sex, mean arterial pressure and heart rate, individuals with ISH had higher aPWV values, compared to normotensive individuals (P < 0.001) and individuals with Sys/Dia hypertension (P ¼ 0.008). Subsequently, we had individuals with ISH lower carotid distensibility values compared to normotensive individuals, but compared to individuals with Sys/Dia hypertension there was no significant difference (P ¼ 0.071) (Table 3). Age significantly modified the relation between aPWV and subtypes of hypertension (P ¼ 0.001); this was not the case for the relation between carotid distensibility and subtypes of hypertension (Table 4). Aortic PWV increased with increasing age for all subtypes of hypertension (Fig. 2); this increase was stronger among normotensive individuals and among individuals with ISH compared to those with Sys/Dia hypertension, resulting in higher mean values in individuals with ISH compared to those with Sys/Dia hypertension. There was no significant interaction between arterial stiffness and subtypes of hypertension according to categories of sex, diabetes mellitus and previous CHD. TABLE 1. Baseline characteristics of the study participants in untreated individuals (n ¼ 4088) Characteristics Age (years) Men (%) SBP (mmHg) DBP (mmHg) Mean arterial pressure (mmHg) Pulse pressure (mmHg) Heart rate (b.p.m.) BMI (kg/m2) Total cholesterol (mmol/l) High-density lipoprotein cholesterol (mmol/l) Current smokers (%) Diabetes mellitus (%) Aortic pulse wave velocity (m/s) Carotid distensibility coefficient (/MPa)a Prevalent CHD (%)
Total (n ¼ 4088) mean SD or percentage 68.1 8.1 45.3 141 20 76 11 98 12 65 17 74 13 26.5 3.8 5.83 1.00 1.41 0.39 18.7 11.1 12.8 3.0 12.0 4.8 8.9
CHD, coronary heart disease; n, number. a Available for 3554 individuals.
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Arterial stiffness and hypertension (a) 155
80
SBP
76
145
74
mmHg
mmHg
DBP
78
150
140 135
72 70
130
68
0 55–65
65–75
75–85
0
>85
55–65
Age categories 80
105
PP
>85
MAP
100
70
mmHg
mmHg
75–85
Age categories
75
65 60
95 90 85
55 0
65–75
55–65
65–75
75–85
0
>85
55–65
Age categories
65–75
75–85
>85
Age categories
(b) PWV
17 16 14
MPa
m/s
15 13 12 11 0 55-65
65-75
75-85
15 14 13 12 11 10 9 8 7 6 0
>85
DC
55-65
Age categories
65-75
75-85
>85
Age categories
FIGURE 1 (a) Blood pressure components in age categories. (b) Pulse wave velocity and carotid distensibility in categories of age. DC, carotid distensibility coefficient; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse wave velocity.
DISCUSSION In the present study performed in a large middle-aged and elderly untreated population, we found significant associations of both aPWV and carotid distensibility with ISH and Sys/Dia hypertension. Individuals with ISH had higher
values of aortic stiffness when compared to those with Sys/Dia hypertension. The difference was largest among older individuals. The main finding of this study was that individuals with ISH have a stiffer aorta, as measure with aPWV, than those
TABLE 2. Odds ratios for isolated systolic hypertension and combined systolic and diastolic hypertension associated with cardiovascular risk factors and measures of arterial stiffness (per 1 SD) Odds ratio [95% CI ISH (n ¼ 1597)] Age Male sex BMI Total cholesterol High-density cholesterol Current smoking Diabetes mellitus Aortic pulse wave velocitya Carotid distensibilitya
1.78 1.11 1.26 1.06 0.97 0.82 1.54 1.53 0.84
(1.64–1.94) (0.96–1.30) (1.17–1.35) (0.98–1.13) (0.90–1.05) (0.69–0.98) (1.23–1.93) (1.38–1.71) (0.75–0.94)
Odds ratio [95% CI Sys/Dia HT (n ¼ 414)] 1.14 1.68 1.45 1.04 1.03 0.72 1.53 1.28 0.66
(0.99–1.30) (1.33–2.13) (1.30–1.61) (0.93–1.17) (0.91–1.16) (0.54–0.97) (1.10–2.14) (1.09–1.53) (0.54–0.81)
Multinomial logistic regression with normotensives as reference outcome category. All models are adjusted for age, sex, cohort, BMI, total cholesterol, high-density cholesterol, smoking and diabetes mellitus, when appropriate. CI, confidence interval; ISH, isolated systolic hypertension; Sys/Dia HT, combined systolic and diastolic hypertension. a Additionally adjusted for mean arterial pressure and heart rate.
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Verwoert et al. TABLE 3. Measures of arterial stiffness in subtypes of hypertension Normotensive
ISH
Sys/Dia HT
2077 (50.8) 66.6 43.6 12.5 12.4
1597 (39.1) 70.5a,c 45.1c 13.2a,c 11.8a
414 (10.1) 66.7 54.6a 12.9b 11.3a
N (%) Age (years) Male sex (%) aPWV (m/s) DC (1/MPa)
Models are adjusted for age, sex, mean arterial pressure and heart rate, when appropriate. aPWV, aortic pulse wave velocity; DC, carotid distensibility coefficient; ISH, isolated systolic hypertension; Sys/Dia HT, combined systolic and diastolic hypertension. a Significantly different from normotensive at P less than 0.001. b Significantly different from normotensive at P less than 0.05. c Significantly different from Sys/Dia hypertension at P less than 0.05.
with Sys/Dia hypertension. Franklin et al. [3] showed already two decades ago that there is a reduction of DBP after age 60 and an increase in SBP, resulting in a steep increase of PP. The most likely explanation is the agerelated stiffening of the aorta. This has been confirmed in several cross-sectional studies, showing that individuals with ISH have higher values of arterial stiffness compared to normotensive individuals [4,5] and has also been confirmed in young adults and elderly women [7]. Furthermore, it is traditionally believed that arterial stiffening is accelerated by higher mean and SBPs because of structural and functional alterations in the walls of the central elastic arteries in response to the chronically elevated distending pressures [20]. Recently, the Baltimore Longitudinal Study of Aging (BLSA) showed prospectively that arterial stiffening precedes and predisposes to accelerated longitudinal increases in SBP and to future hypertension, suggesting that arterial stiffening is an underlying pathophysiological cause of the increase in pressure [8]. Interestingly, we found a higher value of carotid distensibility in individuals with ISH than compared with those with Sys/Dia hypertension, indicating more elastic carotid arteries in individuals with ISH compared to those with Sys/ Dia hypertension. You might speculate about this difference in carotid stiffness compared to aortic stiffness. The arterial tree is not a homogenous system and there are differences in the structure and function of various arteries. Carotid distensibility is a local measure of carotid stiffness, whereas aPWV is a more regional measure of arterial stiffness, combining the central elastic aorta and more muscular illiaca and femoral arteries [21]. Although carotid femoral pulse wave velocity and carotid stiffness provide similar information on the impact of aging on large artery stiffness in normal individuals, this is not the case for individuals with cardiovascular risk factors, such as hypertension and diabetes mellitus. The influence of hypertension on the
different parts of the arterial tree has been shown in a study by Laurent et al. [22] in which there is a reduced distensibility in the proximal large arteries compared to the medium-sized distal arteries. In individuals with type 1 diabetes mellitus, there is an alteration of aortic distensibility earlier in disease process, compared to carotid distensibility [23]. In addition, it has been shown that the correlation between aortic stiffness and carotid stiffness becomes weaker as the number of cardiovascular risk factors increase. The discrepancies between aortic stiffness and carotid stiffness result from different influences of cardiovascular risk factors on both parameters [24]. We confirmed previous observations that with increasing age, there is a rise of SBP and PP, and a reduction of DBP, implying that ISH is the most prevalent form of hypertension in the elderly [3]. Increasing age is also associated with increased arterial stiffness even in healthy normotensive individuals, confirming previous observations that ISH is primarily associated with stiffening of the central arteries [4,5,7]. The association remained after correction for mean arterial pressure, suggesting an increase in isobaric stiffness rather than a passive rise because of an increase in mean pressure [25,26]. Proposed mechanisms underlying arterial stiffening include degeneration of elastin, endothelial wall dysfunction and calcium deposition in the vascular wall [27]. Enzymes degrading elastin, including matrix metalloproteinase (MMP)-9, MMP-2 and various serine proteases, were all correlated with aortic stiffness [28], suggesting that extracellular matrix remodeling contributes to stiffening of the aorta. Wallace et al. [4] showed that endothelial function was independently associated with aortic stiffness and several studies have shown that calcification was correlated with stiffer central arteries [29,30]. We found an age-dependency of the relation of aortic stiffness with ISH and Sys/Dia hypertension. We found a stronger age-related increase of aortic stiffness in
TABLE 4. Mean values of aortic pulse wave velocity and carotid distensibility in subtypes of hypertension according to age Normotensive
Age (years) 70
a
ISH
Sys/Dia HT a
a
Normotensive a
ISH a
Sys/Dia HT
n
aPWV
aPWV
aPWV
n
DC
DC
DCa
422/186/84 1035/601/203 620/810/127
11.0 0.10 11.9 0.07 14.0 0.12
11.7 0.14b 12.6 0.09b 14.7 0.10b
11.8 0.24b 12.3 0.16 14.2 0.26
369/161/76 927/508/173 552/676/112
15.4 0.24 13.2 0.13 9.9 0.13
14.5 0.34b 13.0 0.17 9.2 0.12b
13.8 0.57b 12.5 0.31 9.2 0.29b
aPWV, aortic pulse wave velocity; DC, carotid distensibility coefficient; ISH, isolated systolic hypertension; n, number of individuals, normotensive individuals, individuals with ISH, individuals with Sys/Dia hypertension, respectively, per age categories; Sys/Dia HT, combined systolic and diastolic hypertension. a Adjusted mean standard error. Model is adjusted for age, sex, cohort, BMI, total cholesterol, high-density cholesterol, smoking and diabetes mellitus. b Significantly different from normotensive at P less than 0.05.
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Arterial stiffness and hypertension 15
NT Sys/Dia HT
14,5
ISH
PWV (m/s)
14 13,5 13 12,5 12
distensibility with ISH and Sys/Dia hypertension. individuals with ISH had higher values of aortic stiffness when compared with individuals with Sys/Dia hypertension, which was primarily present in older individuals without treatment for hypertension.
ACKNOWLEDGEMENTS
11,5 11
Conflicts of interest
10,5 70
Age categories
FIGURE 2 Pulse wave velocity by age in different subtypes of hypertension. ISH, isolated systolic hypertension; NT, normotension; PWV, pulse wave velocity; Sys/ Dia HT, combined systolic and diastolic hypertension.
individuals with ISH when compared with those with Sys/ Dia hypertension. Interestingly, the aorta of the very old individuals with Sys/Dia hypertension was as stiff as the aorta of normotensive individuals. The main physiological abnormality in the Sys/Dia hypertension is an increased MAP concomitant with a higher peripheral vascular resistance. Although previous studies have shown that central ‘elastic’ arteries are also stiffer in individuals with Sys/Dia hypertension [31,32], it is less clear whether this increased aortic stiffness is simply due to the higher operating pressure of hypertensive arteries. Studies, in which mean pressure was reduced, showed a normalization of aortic stiffness values, suggesting that isobaric stiffness was normal in hypertensive individuals [33,34]. The finding of this study reinforces the hypothesis that Sys/Dia hypertension is not a pathophysiological result of stiff arteries. Several issues regarding the methods of the present study need to be discussed. First, the measures of stiffness were not available for all the participants; it might be that information was missing mostly in those individuals with a higher cardiovascular risk load, though missing information was mostly due to logistic reasons and therefore mostly random. Second, the measurements of aortic and carotid stiffness were performed only once; it is likely that the use of multiple measurements would have improved accuracy and precision. Third, in computing the carotid distensibility coefficient, we used the brachial PP rather than the carotid PP. Information on comparisons between carotid and brachial PPs indicates that the difference between these pressures is 8 mmHg in a presumed healthy population and 2.6 mmHg in individuals with severe coronary artery disease [35]. These findings indicate that using brachial artery PP instead of carotid artery PP may have led to an underestimation of the distensibility, different in individuals with and without cardiovascular disease. This may lead to an underestimation of the association with disease. It has been suggested to derive carotid artery PP using brachial artery PP [36]. However, to perform this procedure, brachial mean pressure should be directly measured, whereas in our study, this was computed from blood pressure components. Fourth, we conducted an observational crosssectional study; therefore, we cannot determine the direction of the observed associations. Finally, the present results are obtained in a Caucasian population and therefore cannot be extrapolated to other populations. In summary, in this population of untreated individuals, we found significant associations of both aPWV and carotid Journal of Hypertension
R.S.R. reports having served as a consultant for ESAOTE till January 2011. The remaining authors report no conflict of interest.
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The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105–1187. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183–1197. Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Vasc Biol 1998; 18:185–192. Leening MJG, Kavousi M, Heeringa J, van Rooij FJA, Verkroost-van Heemst J, Deckers JW, et al. Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study. Eur J Epidemiol 2012; 27:173–185. O’Rourke MF, Nichols WW. Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension 2005; 45:652–658. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27:2588–2605. Laurent S, Hayoz D, Trazzi S, Boutouyrie P, Waeber B, Omboni S, et al. Isobaric compliance of the radial artery is increased in patients with essential hypertension. J Hypertens 1993; 11:89–98. Giannattasio C, Failla M, Grappiolo A, Gamba PL, Paleari F, Mancia G. Progression of large artery structural and functional alterations in type I diabetes. Diabetologia 2001; 44:203–208. Paini A, Boutouyrie P, Calvet D, Tropeano AI, Laloux B, Laurent S. Carotid and aortic stiffness: determinants of discrepancies. Hypertension 2006; 47:371–376. Nichols WW, Nicolini FA, Pepine CJ. Determinants of isolated systolic hypertension in the elderly. J Hypertens Suppl 1992; 10:S73–S77. Meaney E, Soltero E, Samaniego V, Alva F, Moguel R, Vela A, et al. Vascular dynamics in isolated systolic arterial hypertension. Clin Cardiol 1995; 18:721–725.
Reviewers’ Summary Evaluations Reviewer 1 A strength of the study is the fact that - in contrast to previous publications on arterial stiffness - it is population-based and includes normotensives as well as untreated patients with hypertension. For the calculation of the carotid artery distensibility coefficient, the blood pressure measured in the brachial artery was used. This is a weakness of the study, since brachial artery blood pressure is not identical with the pressure measured in the carotid artery.
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27. McEniery CM, Wilkinson IB, Avolio AP. Age, hypertension and arterial function. Clin Exp Pharmacol Physiol 2007; 34:665–671. 28. Yasmin. McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005; 25:372. 29. Odink AE, Mattace-Raso FU, van der Lugt A, Hofman A, Hunink MG, Breteler MM, et al. The association of arterial stiffness and arterial calcification: the Rotterdam study. J Hum Hypertens 2008; 22:205– 207. 30. McEniery CM, McDonnell BJ, So A, Aitken S, Bolton CE, Munnery M, et al. Aortic calcification is associated with aortic stiffness and isolated systolic hypertension in healthy individuals. Hypertension 2009; 53:524–531. 31. Asmar R, Benetos A, London G, Hugue C, Weiss Y, Topouchian J, et al. Aortic distensibility in normotensive, untreated and treated hypertensive patients. Blood Press 1995; 4:48–54. 32. Safar ME, Laurent S. Behaviour of conduit arteries in hypertension. Clin Exp Hypertens 1993; 15:1033–1045. 33. Ting CT, Brin KP, Lin SJ, Wang SP, Chang MS, Chiang BN, et al. Arterial hemodynamics in human hypertension. J Clin Investig 1986; 78:1462– 1471. 34. Merillon JP, Fontenier GJ, Lerallut JF, Jaffrin MY, Motte GA, Genain CP, et al. Aortic input impedance in normal man and arterial hypertension: its modification during changes in aortic pressure. Cardiovasc Res 1982; 16:646–656. 35. Waddell TK, Dart AM, Medley TL, Cameron JD, Kingwell BA. Carotid pressure is a better predictor of coronary artery disease severity than brachial pressure. Hypertension 2001; 38:927–931. 36. Van Bortel LM, Balkestein EJ, van der Heijden-Spek JJ, Vanmolkot FH, Staessen JA, Kragten JA, et al. Noninvasive assessment of local arterial pulse pressure: comparison of applanation tonometry and echo-tracking. J Hypertens 2001; 19:1037–1044.
Reviewer 2 In this paper the authors studied whether arterial stiffness, measured as aortic pulse wave velocity (aPWV) and carotid distensibility, was associated with different subtypes of hypertension in a large population of untreated middleaged and elderly subjects. The limitations of the study are: the use of brachial pulse pressure for calculating arterial distensibility and the absence of an ambulatory blood pressure monitoring to certify the real blood pressure burden along the day. The principal strengths are the large population and the absence of any treatment, possibly influencing arterial properties.
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Arterial stiffness and hypertension in a large population of untreated individuals: the Rotterdam Study Germaine C. Verwoert a,b, Oscar H. Franco a, Arnold P.G. Hoeks c, Robert S. Reneman d, Albert Hofman a, Cornelia M. v Duijn a, Eric J.G. Sijbrands b, Jacqueline C.M. Witteman a, and Francesco U.S. Mattace-Raso a,b
Objective: We studied whether arterial stiffness measured as aortic pulse wave velocity (aPWV) and carotid distensibility was associated with different subtypes of hypertension in a large population of untreated middleaged and elderly men and women. Methods: The study was conducted within the framework of the population-based Rotterdam Study. We included 4088 individuals with information on aPWV, with 3554 individuals with carotid distensibility measurements without use of antihypertensive medication. Isolated systolic hypertension (ISH) was defined as SBP at least 140 mmHg and DBP less than 90 mmHg. Combined systolic and diastolic hypertension (Sys/Dia hypertension) was defined as SBP at least 140 mmHg and DBP at least 90 mmHg. Analysis of covariance was used to compare means of arterial stiffness for the different subtypes of hypertension. Multinomial logistic regression analysis was performed to investigate the association of arterial stiffness and the subtypes of hypertension in models adjusted for age, sex, mean arterial pressure, heart rate and cardiovascular risk factors. Results: The mean age of the individuals was 68 years: 45.3% were men, 1597 individuals had ISH and 441 individuals had Sys/Dia hypertension. aPWV was higher (13.2 vs. 12.9 m/s; P ¼ 0.008) in individuals with ISH compared to those with Sys/Dia hypertension. Multivariate odds ratios and corresponding 95% confidence interval of aPWV for ISH were 1.53 (1.38–1.71) and 1.28 (1.09– 1.53) for Sys/Dia hypertension. Corresponding odds ratios associated with carotid distensibility were 0.84 (0.75–0.94) and 0.66 (0.54–0.81), respectively. Age significantly modified the association of aPWV with subtypes of hypertension (P < 0.001). Conclusion: In a large untreated population, we found significant associations of both aPWV and carotid distensibility with ISH and Sys/Dia hypertension. individuals with ISH had higher values of aortic stiffness when compared to individuals with Sys/Dia hypertension, a difference that was most pronounced at older age. The results suggest that aortic stiffness contributes to ISH in older individuals without treatment for hypertension.
Keywords: ageing, arterial stiffness, combined systolic and diastolic hypertension, isolated systolic hypertension, population-based study Abbreviations: DD, the absolute stroke change in diameter during systole; DD/D, the relative stroke change in diameter; aPWV, aortic pulse wave velocity; CHD, coronary heart disease; CI, confidence interval; D, enddiastolic diameter; HDL, high-density lipoprotein; ISH, isolated systolic hypertension; MI, myocardial infarction; MMP, matrix metalloproteinase; OR, odds ratio; RS-I, original Rotterdam Study started in 1990; RS-II, extension of the Rotterdam Study in 1999; Sys/Dia hypertension, combined systolic and diastolic hypertension
INTRODUCTION
H
ypertension is a common and well established risk factor for cardiovascular disease [1]. The prevalence of hypertension increases with advancing age. Isolated systolic hypertension (ISH) is the most frequent type of hypertension in the elderly [2]. This is due to the continuous increase in SBP with advancing age, whereas DBP tends to remain constant or declines with advancing age, indicating a patent regulation of mean arterial pressure [3]. The most likely explanation for the age-related rise in SBP and fall in DBP is large artery stiffening [3]. Indeed, several studies have shown that a specific measure of arterial stiffness, that is, aortic pulse wave velocity (aPWV), is increased in individuals with
Journal of Hypertension 2014, 32:1606–1612 a Department of Epidemiology, bDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, cDepartment of Biomedical Engineering and dDepartment of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Correspondence to Germaine Verwoert, MD, MSc, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Tel: +31 107035979; fax: +31 107034768; e-mail: g.verwoert@eras musmc.nl Received 18 November 2013 Revised 1 April 2014 Accepted 1 April 2014 J Hypertens 32:1606–1612 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000237
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Arterial stiffness and hypertension
ISH compared to controls [4,5], whereas carotid distensibility shows a decline. This relation has been confirmed in young adults [6] and elderly women [7]. Furthermore, aPWV has been shown to be an independent predictor of the longitudinal increase in SBP [8] and is associated with subsequent cardiovascular morbidity and mortality [9,10]. Previous studies included relatively small groups of individuals and there is limited information on the relation of arterial stiffness with ISH in different age categories of healthy untreated individuals. Furthermore, the relation of arterial stiffness with the different types of hypertension, including ISH and combined systolic and diastolic hypertension (Sys/Dia hypertension), has not been fully elucidated. Therefore, we studied whether two measures of arterial stiffness, aPWV and carotid distensibility, were associated with ISH and Sys/Dia hypertension in a large population of untreated individuals. We additionally investigated whether the association was different in categories for age.
METHODS Study population The present study was performed within the framework of the Rotterdam Study, a large population-based prospective cohort study. From 1990 to 1993, 7983 individuals aged 55 and over living in Ommoord, a suburb of Rotterdam, the Netherlands, participated in the Rotterdam Study (RS-1). In 1999, inhabitants who turned 55 years of age or moved into the study district since the start of the study were invited to participate in an extension of the Rotterdam Study (RS-II) of whom 3011 participated. The overall aim of the Rotterdam Study is to access the occurrence of risk factors for chronic diseases in the elderly. The study design and objectives of the Rotterdam Study are described elsewhere [11]. The Medical Ethics Committee of Erasmus Medical Center approved the study and written consent was obtained from all participants.
Measures of arterial stiffness Aortic pulse wave velocity The aPWV was obtained with individuals in supine position. Before the aPWV measurement, blood pressure was measured twice with a sphygmomanometer after 5 min of rest and the mean was taken. The aPWV was assessed with an automatic device (Complior Artech Medical, Pantin, France) [12] that measures the time delay between the rapid early upstroke of the pulse pressure (PP) waves recorded simultaneously in the carotid artery and the femoral artery. The distance between the recording sites in the carotid and the femoral artery was measured with a tape over the surface of the body. The aPWV was calculated as the ratio between distance and the foot–foot time delay and was expressed in meter per second. Carotid distensibility Common carotid distensibility was assessed with the individuals in supine position, with the head tilted slightly to the contralateral side for the measurement in the common carotid artery. The vessel wall motion of the right common Journal of Hypertension
carotid artery was measured by means of a duplex scanner (ATL Ultramark IV, operating frequency 7.5 MHz) connected to a vessel wall movement detector system. The details of this technique have been described elsewhere [13]. After 5 min of rest, a region at 1.5 cm proximal to the origin of the bulb of the carotid artery was identified with the use of B-mode ultrasound, where after the system was switched to M-mode. The displacement of the arterial walls was obtained by processing the radiofrequency signals originating from two selected sample volumes positioned over the anterior and posterior walls. The end-diastolic diameter (D), the absolute stroke change in diameter during systole (DD), and the relative stroke change in diameter (DD/D) were computed as the mean of four cardiac cycles of three successive recordings. The cross-sectional arterial wall distensibility coefficient, expressed in per MPa, was calculated according to the following equation: distensibility coefficient ¼ 2DD/(D PP) [14], with PP defined as the difference between SBP and DBP. In a reproducibility study performed among 47 individuals, the intraclass correlation coefficient was 0.80 for both the aPWV and the carotid distensibility coefficient [15].
Blood pressure measurements Two blood pressure measurements were obtained at the right brachial artery with a random zero sphygmomanometer after the individual had been seated for at least 5 min. SBP, first Korotkoff phase, and DBP, fifth Korotkoff phase, were obtained and the mean of the two blood pressure values was used in the analyses. Normotensive was defined as SBP below 140 mmHg and DBP below 90 mmHg. ISH was defined as SBP at least 140 mmHg and DBP 90 mmHg or less [16]. Sys/Dia hypertension was defined as SBP at least 140 mmHg and DBP at least 90 mmHg. Mean arterial pressure was estimated as MAP ¼ DBP þ PP/3.
Cardiovascular risk factors Information on medical history, smoking habits and medication use was obtained during a home interview. Smoking was divided into three categories: current, former and never smokers. During the research center visit, height and weight were measured, and the BMI was computed (kg/ m2). Diabetes mellitus was defined as a history of diabetes mellitus and/or the use of blood glucose-lowering medication and/or a fasting serum glucose level at least 7.0 mmol/l [17]. Serum total cholesterol and high-density lipoproteins (HDL)-cholesterol values were determined by an automated enzymatic procedure (Boehringer Mannheim System, Mannheim, Germany) [18].
Prevalent coronary heart disease A history of coronary heart disease (CHD) was obtained through direct questioning and was considered positive when confirmed according to hospital discharge date or written information from the individual’s general practitioner, as described previously [19]. CHD was defined myocardial infarction (MI), a percutaneous transluminal coronary angioplasty, a coronary artery bypass graft. A history of MI was considered present in case of self-report of MI confirmed by electrocardiogram or additional clinical www.jhypertension.com
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Verwoert et al.
information or the presence of an electrocardiogram characteristic of prior MI.
Population for analysis During the third examination phase of RS-I (1997–1999) and during the first examination phase of RS-II (2000– 2001), a computerized questionnaire was completed and cardiovascular risk factors and arterial stiffness were assessed. In total, 6938 individuals visited the research center. Measures of both blood pressure levels and aPWV were obtained in 5773 individuals, and among these, 4640 individuals had a measurement for carotid distensibility. We excluded individuals with use of antihypertensive medication (n ¼ 1309) and those with missing covariate information (n ¼ 376), resulting in 4088 individuals for analyses with aPWV. Among these, 3554 individuals were available for carotid distensibility analyses. Missing information was primarily due to logistic reasons.
Statistical analysis Mean values of systolic, diastolic, mean arterial and PP, aPWV and carotid distensibility in different age categories were plotted in figures. Analysis of covariance (ANCOVA) was used to compare age, sex, aPWV and carotid distensibility between subtypes of hypertension categories, that is, normotensive, ISH and Sys/Dia hypertension. Multinomial logistic regression models were performed to investigate the association of standardized cardiovascular risk factors and standardized values of aPWV and carotid distensibility with subtypes of hypertension. Standardized values were obtained by dividing each measure by its SD. The models were adjusted for age, sex, cohort, BMI, total cholesterol, high-density cholesterol, smoking, diabetes mellitus, and for mean arterial pressure and heart rate, when appropriate. We tested for interaction by age, sex, diabetes mellitus and prevalent cardiovascular disease. If the interaction term was significant, we performed stratified analyses. ANCOVA was used to compare means of arterial stiffness in subtypes of hypertension by age categories, adjusted for age, sex, cohort, mean arterial pressure, heart rate and cardiovascular risk factors, when appropriate. For descriptive purposes, we generated figures with mean values of measures of arterial stiffness in the age categories for individuals in the different hypertension categories. P-values less than 0.05 were considered statistically significant. All analyses were performed using SPSS 15.0 statistical package for Windows 2003 (SPSS, Inc., Chicago, Illinois, USA).
RESULTS The baseline characteristics of the study population are shown in Table 1. The mean age of the study population was 68.1 years and the percentage of men was 45.3%. With increasing age, there is an increase in SBP and PP, a decrease in DBP and no change in mean arterial pressure (Fig. 1a). There is an increase in aPWV and decrease in carotid distensibility with age (Fig. 1b). Of the 4088 individuals in this study, 1597 (39.1%) individuals had ISH and 414 (10.1%) had Sys/Dia hypertension. Individuals with ISH were older compared to normotensive individuals and individuals with Sys/Dia hypertension (P < 0.001). 1608
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Of the traditional cardiovascular risk factors, age [per SD, odds ratio (OR) 1.78, 95% confidence interval (CI) 1.64– 1.94], BMI (per SD, OR 1.26, 95% CI 1.17–1.35) and diabetes mellitus (OR 1.54, 95% CI 1.23–1.93) were strongly associated with ISH. Male sex (OR 1.68, 95% CI 1.33–2.13), BMI (per SD, OR 1.45, 95% CI 1.30–1.61) and diabetes mellitus (OR 1.53, 95% CI 1.10–2.14) were strongly associated with Sys/Dia hypertension. Age was only weakly associated with Sys/Dia hypertension (per SD, OR 1.14, 95% CI 0.99–1.30) (Table 2). Aortic PWV and carotid distensibility were strongly associated with both ISH and Sys/Dia hypertension. ORs and corresponding 95% CIs of aPWV, after adjustment for cardiovascular risk factors, were 1.53 (1.38–1.71) for ISH and 1.28 (1.09–1.53) for Sys/Dia hypertension. ORs for carotid distensibility were 0.84 (0.75–0.94) for ISH and 0.66 (0.54–0.81) for Sys/Dia hypertension (Table 2). After adjustment for age, sex, mean arterial pressure and heart rate, individuals with ISH had higher aPWV values, compared to normotensive individuals (P < 0.001) and individuals with Sys/Dia hypertension (P ¼ 0.008). Subsequently, we had individuals with ISH lower carotid distensibility values compared to normotensive individuals, but compared to individuals with Sys/Dia hypertension there was no significant difference (P ¼ 0.071) (Table 3). Age significantly modified the relation between aPWV and subtypes of hypertension (P ¼ 0.001); this was not the case for the relation between carotid distensibility and subtypes of hypertension (Table 4). Aortic PWV increased with increasing age for all subtypes of hypertension (Fig. 2); this increase was stronger among normotensive individuals and among individuals with ISH compared to those with Sys/Dia hypertension, resulting in higher mean values in individuals with ISH compared to those with Sys/Dia hypertension. There was no significant interaction between arterial stiffness and subtypes of hypertension according to categories of sex, diabetes mellitus and previous CHD. TABLE 1. Baseline characteristics of the study participants in untreated individuals (n ¼ 4088) Characteristics Age (years) Men (%) SBP (mmHg) DBP (mmHg) Mean arterial pressure (mmHg) Pulse pressure (mmHg) Heart rate (b.p.m.) BMI (kg/m2) Total cholesterol (mmol/l) High-density lipoprotein cholesterol (mmol/l) Current smokers (%) Diabetes mellitus (%) Aortic pulse wave velocity (m/s) Carotid distensibility coefficient (/MPa)a Prevalent CHD (%)
Total (n ¼ 4088) mean SD or percentage 68.1 8.1 45.3 141 20 76 11 98 12 65 17 74 13 26.5 3.8 5.83 1.00 1.41 0.39 18.7 11.1 12.8 3.0 12.0 4.8 8.9
CHD, coronary heart disease; n, number. a Available for 3554 individuals.
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Arterial stiffness and hypertension (a) 155
80
SBP
76
145
74
mmHg
mmHg
DBP
78
150
140 135
72 70
130
68
0 55–65
65–75
75–85
0
>85
55–65
Age categories 80
105
PP
>85
MAP
100
70
mmHg
mmHg
75–85
Age categories
75
65 60
95 90 85
55 0
65–75
55–65
65–75
75–85
0
>85
55–65
Age categories
65–75
75–85
>85
Age categories
(b) PWV
17 16 14
MPa
m/s
15 13 12 11 0 55-65
65-75
75-85
15 14 13 12 11 10 9 8 7 6 0
>85
DC
55-65
Age categories
65-75
75-85
>85
Age categories
FIGURE 1 (a) Blood pressure components in age categories. (b) Pulse wave velocity and carotid distensibility in categories of age. DC, carotid distensibility coefficient; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse wave velocity.
DISCUSSION In the present study performed in a large middle-aged and elderly untreated population, we found significant associations of both aPWV and carotid distensibility with ISH and Sys/Dia hypertension. Individuals with ISH had higher
values of aortic stiffness when compared to those with Sys/Dia hypertension. The difference was largest among older individuals. The main finding of this study was that individuals with ISH have a stiffer aorta, as measure with aPWV, than those
TABLE 2. Odds ratios for isolated systolic hypertension and combined systolic and diastolic hypertension associated with cardiovascular risk factors and measures of arterial stiffness (per 1 SD) Odds ratio [95% CI ISH (n ¼ 1597)] Age Male sex BMI Total cholesterol High-density cholesterol Current smoking Diabetes mellitus Aortic pulse wave velocitya Carotid distensibilitya
1.78 1.11 1.26 1.06 0.97 0.82 1.54 1.53 0.84
(1.64–1.94) (0.96–1.30) (1.17–1.35) (0.98–1.13) (0.90–1.05) (0.69–0.98) (1.23–1.93) (1.38–1.71) (0.75–0.94)
Odds ratio [95% CI Sys/Dia HT (n ¼ 414)] 1.14 1.68 1.45 1.04 1.03 0.72 1.53 1.28 0.66
(0.99–1.30) (1.33–2.13) (1.30–1.61) (0.93–1.17) (0.91–1.16) (0.54–0.97) (1.10–2.14) (1.09–1.53) (0.54–0.81)
Multinomial logistic regression with normotensives as reference outcome category. All models are adjusted for age, sex, cohort, BMI, total cholesterol, high-density cholesterol, smoking and diabetes mellitus, when appropriate. CI, confidence interval; ISH, isolated systolic hypertension; Sys/Dia HT, combined systolic and diastolic hypertension. a Additionally adjusted for mean arterial pressure and heart rate.
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Verwoert et al. TABLE 3. Measures of arterial stiffness in subtypes of hypertension Normotensive
ISH
Sys/Dia HT
2077 (50.8) 66.6 43.6 12.5 12.4
1597 (39.1) 70.5a,c 45.1c 13.2a,c 11.8a
414 (10.1) 66.7 54.6a 12.9b 11.3a
N (%) Age (years) Male sex (%) aPWV (m/s) DC (1/MPa)
Models are adjusted for age, sex, mean arterial pressure and heart rate, when appropriate. aPWV, aortic pulse wave velocity; DC, carotid distensibility coefficient; ISH, isolated systolic hypertension; Sys/Dia HT, combined systolic and diastolic hypertension. a Significantly different from normotensive at P less than 0.001. b Significantly different from normotensive at P less than 0.05. c Significantly different from Sys/Dia hypertension at P less than 0.05.
with Sys/Dia hypertension. Franklin et al. [3] showed already two decades ago that there is a reduction of DBP after age 60 and an increase in SBP, resulting in a steep increase of PP. The most likely explanation is the agerelated stiffening of the aorta. This has been confirmed in several cross-sectional studies, showing that individuals with ISH have higher values of arterial stiffness compared to normotensive individuals [4,5] and has also been confirmed in young adults and elderly women [7]. Furthermore, it is traditionally believed that arterial stiffening is accelerated by higher mean and SBPs because of structural and functional alterations in the walls of the central elastic arteries in response to the chronically elevated distending pressures [20]. Recently, the Baltimore Longitudinal Study of Aging (BLSA) showed prospectively that arterial stiffening precedes and predisposes to accelerated longitudinal increases in SBP and to future hypertension, suggesting that arterial stiffening is an underlying pathophysiological cause of the increase in pressure [8]. Interestingly, we found a higher value of carotid distensibility in individuals with ISH than compared with those with Sys/Dia hypertension, indicating more elastic carotid arteries in individuals with ISH compared to those with Sys/ Dia hypertension. You might speculate about this difference in carotid stiffness compared to aortic stiffness. The arterial tree is not a homogenous system and there are differences in the structure and function of various arteries. Carotid distensibility is a local measure of carotid stiffness, whereas aPWV is a more regional measure of arterial stiffness, combining the central elastic aorta and more muscular illiaca and femoral arteries [21]. Although carotid femoral pulse wave velocity and carotid stiffness provide similar information on the impact of aging on large artery stiffness in normal individuals, this is not the case for individuals with cardiovascular risk factors, such as hypertension and diabetes mellitus. The influence of hypertension on the
different parts of the arterial tree has been shown in a study by Laurent et al. [22] in which there is a reduced distensibility in the proximal large arteries compared to the medium-sized distal arteries. In individuals with type 1 diabetes mellitus, there is an alteration of aortic distensibility earlier in disease process, compared to carotid distensibility [23]. In addition, it has been shown that the correlation between aortic stiffness and carotid stiffness becomes weaker as the number of cardiovascular risk factors increase. The discrepancies between aortic stiffness and carotid stiffness result from different influences of cardiovascular risk factors on both parameters [24]. We confirmed previous observations that with increasing age, there is a rise of SBP and PP, and a reduction of DBP, implying that ISH is the most prevalent form of hypertension in the elderly [3]. Increasing age is also associated with increased arterial stiffness even in healthy normotensive individuals, confirming previous observations that ISH is primarily associated with stiffening of the central arteries [4,5,7]. The association remained after correction for mean arterial pressure, suggesting an increase in isobaric stiffness rather than a passive rise because of an increase in mean pressure [25,26]. Proposed mechanisms underlying arterial stiffening include degeneration of elastin, endothelial wall dysfunction and calcium deposition in the vascular wall [27]. Enzymes degrading elastin, including matrix metalloproteinase (MMP)-9, MMP-2 and various serine proteases, were all correlated with aortic stiffness [28], suggesting that extracellular matrix remodeling contributes to stiffening of the aorta. Wallace et al. [4] showed that endothelial function was independently associated with aortic stiffness and several studies have shown that calcification was correlated with stiffer central arteries [29,30]. We found an age-dependency of the relation of aortic stiffness with ISH and Sys/Dia hypertension. We found a stronger age-related increase of aortic stiffness in
TABLE 4. Mean values of aortic pulse wave velocity and carotid distensibility in subtypes of hypertension according to age Normotensive
Age (years) 70
a
ISH
Sys/Dia HT a
a
Normotensive a
ISH a
Sys/Dia HT
n
aPWV
aPWV
aPWV
n
DC
DC
DCa
422/186/84 1035/601/203 620/810/127
11.0 0.10 11.9 0.07 14.0 0.12
11.7 0.14b 12.6 0.09b 14.7 0.10b
11.8 0.24b 12.3 0.16 14.2 0.26
369/161/76 927/508/173 552/676/112
15.4 0.24 13.2 0.13 9.9 0.13
14.5 0.34b 13.0 0.17 9.2 0.12b
13.8 0.57b 12.5 0.31 9.2 0.29b
aPWV, aortic pulse wave velocity; DC, carotid distensibility coefficient; ISH, isolated systolic hypertension; n, number of individuals, normotensive individuals, individuals with ISH, individuals with Sys/Dia hypertension, respectively, per age categories; Sys/Dia HT, combined systolic and diastolic hypertension. a Adjusted mean standard error. Model is adjusted for age, sex, cohort, BMI, total cholesterol, high-density cholesterol, smoking and diabetes mellitus. b Significantly different from normotensive at P less than 0.05.
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Arterial stiffness and hypertension 15
NT Sys/Dia HT
14,5
ISH
PWV (m/s)
14 13,5 13 12,5 12
distensibility with ISH and Sys/Dia hypertension. individuals with ISH had higher values of aortic stiffness when compared with individuals with Sys/Dia hypertension, which was primarily present in older individuals without treatment for hypertension.
ACKNOWLEDGEMENTS
11,5 11
Conflicts of interest
10,5 70
Age categories
FIGURE 2 Pulse wave velocity by age in different subtypes of hypertension. ISH, isolated systolic hypertension; NT, normotension; PWV, pulse wave velocity; Sys/ Dia HT, combined systolic and diastolic hypertension.
individuals with ISH when compared with those with Sys/ Dia hypertension. Interestingly, the aorta of the very old individuals with Sys/Dia hypertension was as stiff as the aorta of normotensive individuals. The main physiological abnormality in the Sys/Dia hypertension is an increased MAP concomitant with a higher peripheral vascular resistance. Although previous studies have shown that central ‘elastic’ arteries are also stiffer in individuals with Sys/Dia hypertension [31,32], it is less clear whether this increased aortic stiffness is simply due to the higher operating pressure of hypertensive arteries. Studies, in which mean pressure was reduced, showed a normalization of aortic stiffness values, suggesting that isobaric stiffness was normal in hypertensive individuals [33,34]. The finding of this study reinforces the hypothesis that Sys/Dia hypertension is not a pathophysiological result of stiff arteries. Several issues regarding the methods of the present study need to be discussed. First, the measures of stiffness were not available for all the participants; it might be that information was missing mostly in those individuals with a higher cardiovascular risk load, though missing information was mostly due to logistic reasons and therefore mostly random. Second, the measurements of aortic and carotid stiffness were performed only once; it is likely that the use of multiple measurements would have improved accuracy and precision. Third, in computing the carotid distensibility coefficient, we used the brachial PP rather than the carotid PP. Information on comparisons between carotid and brachial PPs indicates that the difference between these pressures is 8 mmHg in a presumed healthy population and 2.6 mmHg in individuals with severe coronary artery disease [35]. These findings indicate that using brachial artery PP instead of carotid artery PP may have led to an underestimation of the distensibility, different in individuals with and without cardiovascular disease. This may lead to an underestimation of the association with disease. It has been suggested to derive carotid artery PP using brachial artery PP [36]. However, to perform this procedure, brachial mean pressure should be directly measured, whereas in our study, this was computed from blood pressure components. Fourth, we conducted an observational crosssectional study; therefore, we cannot determine the direction of the observed associations. Finally, the present results are obtained in a Caucasian population and therefore cannot be extrapolated to other populations. In summary, in this population of untreated individuals, we found significant associations of both aPWV and carotid Journal of Hypertension
R.S.R. reports having served as a consultant for ESAOTE till January 2011. The remaining authors report no conflict of interest.
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Reviewers’ Summary Evaluations Reviewer 1 A strength of the study is the fact that - in contrast to previous publications on arterial stiffness - it is population-based and includes normotensives as well as untreated patients with hypertension. For the calculation of the carotid artery distensibility coefficient, the blood pressure measured in the brachial artery was used. This is a weakness of the study, since brachial artery blood pressure is not identical with the pressure measured in the carotid artery.
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Reviewer 2 In this paper the authors studied whether arterial stiffness, measured as aortic pulse wave velocity (aPWV) and carotid distensibility, was associated with different subtypes of hypertension in a large population of untreated middleaged and elderly subjects. The limitations of the study are: the use of brachial pulse pressure for calculating arterial distensibility and the absence of an ambulatory blood pressure monitoring to certify the real blood pressure burden along the day. The principal strengths are the large population and the absence of any treatment, possibly influencing arterial properties.
Volume 32 Number 8 August 2014
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