Differences in Effects of Age and Blood Pressure on Augmentation Index

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1 Original Article Differences in Effects of Age and Blood Pressure on Augmentation Index Hirofumi Tomiyama, 1 Mari Odaira, 1 Kazutaka Kimura, 1 Chisa Matsumoto, 1 Kazuki Shiina, 1 Kazuo Eguchi, 2 Hiroshi Miyashita, 2 Kazuyuki Shimada, 2 and Akira Yamashina 1 background The effect of age on the augmentation index (AI) differs between young adults and the elderly, and the AI reaches a plateau after the age of 60 years. We examined whether the effects of age and an elevation in blood pressure on the AI differ between young adults and the elderly, between subjects with and without high blood pressure, or between subjects with and without a high AI. methods The radial AI was measured in 10,190 subjects who were either healthy or had hypertension (n = 5,477 men and 4,743 women). results In both sexes, a phased increase in the radial AI with age could only be confirmed up to an age of 60 years. A phased increase in the radial AI with the systolic blood pressure (SBP) could be confirmed up to an SBP Abnormal central hemodynamics is an independent risk for cardiovascular disease, 1 and the augmentation index (AI) and central blood pressure are markers of the central hemodynamics. 2,3 The AI reflects the ratio of the forward pressure wave and the reflected pressure wave and can be used to estimate the central blood pressure. 1 3 Recently, peripheral AI, such as the radial AI, has been used as a surrogate marker of central hemodynamics because it is closely correlated with central AI. 4 7 Among the risks for cardiovascular disease, age is an important factor influencing the AI. The effect of age on the AI differs between young adults and the elderly, and the AI reaches a plateau over the age of 60 years. 5,7,8 Accordingly, the AI is thought to predict cardiovascular outcome more effectively among young adults than among the elderly. 6 Although the underlying mechanisms of this AI plateau have not been fully clarified, plausible mechanisms include (i) impedance mismatching between the conduit elastic and the peripheral muscular arteries 8,9 and (ii) difficulty in identifying the shoulder of the waveform. 9 On the other hand, blood pressure is also an important factor influencing the AI. 4,5 The ACCT III study demonstrated that the effect of blood pressure on the AI is more of >170 mm Hg. Among subjects categorized within the highest age tertile, the highest SBP tertile, or the highest radial AI tertile, stepwise multivariable analyses demonstrated that SBP, but not age, was a significant independent factor influencing the radial AI. conclusions The effect of age and blood pressure on AI differ not only between young adults and the elderly but also between those with and those without high blood pressure or between those with and those without a high AI. The effect of an elevation in blood pressure, but not aging, on the AI is significant in the elderly, in subjects with high blood pressure, or in those with a high AI. Keywords: age; augmentation index; blood pressure; hypertension. doi: /ajh/hpu082 marked among young adults than among the elderly. 4 Conduit arterial stiffness and peripheral reflectance are major determinants of the AI. 2,3 It might be possible that high blood pressure also causes impedance mismatching in arterial tree. 8,9 On the other hand, age and blood pressure are known to be independently associated with the AI. 4,5,7 When hypertension is treated, the reduction of the blood pressure improves the AI without changing the pulse wave velocity, a marker of conduit arterial stiffness. 10,11 These findings suggest that the effect of elevated blood pressure on the AI is significant even in patients with a high blood pressure. However, these issues remain to be clearly elucidated. Furthermore, although increase of the conduit elastic arterial stiffness is also observed in patients with a high AI, 2,3 it has not been clarified whether the effects of age and elevated blood pressure on the AI are significant in patients with a high AI. This study was conducted using a cohort of the Antihypertensives and Blood Pressure of Central Artery Study in Japan (ABC-J study; i.e., subjects with hypertension) 12 and a cohort from a health screening center (i.e., mostly healthy subjects) 5 to clarify whether the effects of age and an elevation in blood pressure on the AI differ between Correspondence: Hirofumi Tomiyama (tomiyama@tokyo-med.ac.jp). Initially submitted December 15, 2013; date of first revision January 9, 2014; accepted for publication March 28, 2014; online publication May 12, Second Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan; 2 Jichi Medical University, Tochigi, Japan. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com American Journal of Hypertension 27(12) December

2 Tomiyama et al. young adults and the elderly, between subjects with and without high blood pressure, and between subjects with and without a high AI. METHODS Study cohort The study subjects consisted of two cohorts. The first cohort consisted of subjects who visited the Health Screening Center of Tokyo Medical University, and the second cohort consisted of subjects from the ABC-J study. The clinical characteristics of both cohorts have been described elsewhere 5,12 and are briefly summarized below. Health screening cohort. This study cohort (n = 8,595) consisted of subjects who underwent a health screening examination at the Health Care Center of Tokyo Medical University between June 2006 and November In this cohort, in addition to a routine health checkup that included an evaluation of cardiovascular risk factors, the radial AI was also measured. Written informed consent was obtained from all participants before these measurements. The study was conducted with the approval of the Ethical Guidelines Committee of Tokyo Medical University. ABC-J study cohort. Japanese patients with essential hypertension who had been receiving a stable dosage of antihypertensive medication for at least 3 months and for whom the required medical data, including radial artery tonometry derived parameters relating to central blood pressure, were available were asked to participate in the ABC-J study (n = 4,077). 12 The study protocol was approved by the institutional review board of each ABC-J center. All participants were informed of this study procedure and consented to the use of their medical data. Measurements Augmentation index. Measurements of the blood pressure and radial AI were conducted after the subjects had rested for 5 minutes in a sitting position. The blood pressure was determined in the right upper arm using the oscillometric method (HEM-907; Omron Healthcare, Kyoto, Japan). Immediately after this measurement, the left radial arterial waveform was recorded using an arterial applanation tonometry probe incorporating an array of 40 micropiezo-resistive transducers (HEM-9010AI; Omron Healthcare). The HEM-9010AI device was programmed to automatically determine the pressure of the radial artery to yield the optimal radial arterial waveform. 5,12,13 Then, the first and second peaks of the peripheral systolic pressure (SP1 and SP2) and peripheral diastolic pressure (DBP) were automatically detected using the fourth derivatives for each radial arterial waveform, and averaged. The radial AI was calculated as follows: (SP2 DBP)/(SP1 DBP) 100 (%). 5,12,13 We previously reported a good reproducibility of the radial AI between visit 1 and visit 2 (Pearson s correlation coefficient = 0.95; P < 0.01; coefficient of variation = 3.2%) American Journal of Hypertension 27(12) December 2014 Laboratory measurements. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, and serum creatinine levels were measured using enzymatic methods. All blood samples were obtained in the morning after the patients had fasted overnight. Statistical analysis Data were expressed as the means ± SDs. Univariable linear regression analyses were used to assess the correlations between the radial AI and other variables. A general linear model univariable linear regression analysis was applied to assess the independency and interaction of the correlations. In addition, a step-wise multivariable linear regression analysis was conducted to identify the strength of the significance of the relationship of risk factors for cardiovascular disease with the AI. The mean radial AI for each age group (increments of every 10 years) or blood pressure group (increments of every 10 mm Hg) was compared with that of those at the previous level using a general linear model univariable analysis. All analyses were conducted using IBM/SPSS software for Windows, version 18.0J (IBM/SPSS, Chicago, IL). P < 0.05 was considered statistically significant. RESULTS Among 12,672 total subjects (health screening cohort: n = 8,595; ABC-J study cohort: n = 4,077), 1,288 subjects were excluded because of heart disease (n = 1,066) and/or cerebrovascular disease (n = 298). In addition, smoking history was not available in 771 subjects, and blood chemical data were not available in 423 subjects. Finally, the analysis was conducted in 10,190 subjects. Changes in the radial augmentation index and changes in the relative number of the values of radial AI with an increase in age (10-year increments) or with an increase in systolic blood pressure (SBP; 10 mm Hg increments) are depicted in men (Figure 1) and women (Figure 2). The relative number of the values of radial AI was calculated as the value of the radial AI minus the standard (the standard was the mean value of the radial augmentation index in subjects aged <40 years or in subjects whose systolic blood pressure was <130 mm Hg). Among the men, when the age was expressed in 10-year increments, a phased increase in the radial AI with age and an increase in the relative number of the values of radial AI with age could only be confirmed up until the age of 60 years; no further increase in these variables was observed with further increases of age beyond 60 years (Figure 1). On the other hand, when the SBP values were expressed in 10 mm Hg increments, a phased increase in the radial AI with the SBP and an increase in the relative number of the values of radial AI with SBP could be confirmed up to an SBP of >170 mm Hg (Figure 1). Thus, the increase in the radial AI with the SBP did not reach a plateau. Similar findings were observed in women (Figure 2). Table 1 shows the clinical characteristics of the study subjects. The radial AI differed according to sex (data not shown); therefore, the analyses were conducted in both sexes

3 Age, Blood Pressure, and Augmentation Index Men Radial AI (%) Rela ve number of the value of radial AI (%) Age separately. In univariable linear regression analyses, age and the mean blood pressure were significantly correlated with the radial AI in both sexes (age of men: beta = 0.382, P < 0.001; SBP of men: beta = 0.251, P < 0.001; age of women: beta = 0.422, P < 0.001; SBP of women: beta = 0.361, P < 0.001). The general linear model multivariable analysis demonstrated that age and SBP were independently associated with the radial AI after adjustments for confounding variables, and these associations exhibited a significant interaction in both sexes (Table 2). Age, SBP, and radial AI were divided into tertile ranges in both sexes (age of men: 20 45, 46 56, years; SBP of men: , , mm Hg; radial AI of men: 31% 71%, 72% 82%, 83% 128%; age of women: 20 42, 43 56, years; SBP of women: , , mm Hg; radial AI of women: 32% 79%, 80% 90%, 91% 147%). The results of stepwise multivariable linear regression analyses to assess the relationship of age and SBP with the radial AI in subjects categorized into high, middle, SBP (mm Hg) Figure 1. Changes in the radial augmentation index (AI) and those in the relative number of values of the radial augmentation index with an increase in age (10-year increments) or an increase in systolic blood pressure (SBP; 10 mm Hg increments) in men. The equations used to calculate the relative number of the value of the radial AI are described in the Results section. P < 0.05 vs. the value in the previous age or systolic blood pressure group (as assessed using a general linear model univariable analysis with a repeated contrast method). and low tertile ranges of age, SBP, or radial AI are shown in Table 3. Stepwise multivariable analyses demonstrated that age and SBP were significantly independent variables for radial AI among subjects categorized in the middle or low tertile ranges of age, among those categorized in the middle or low tertile ranges of SBP, and among those categorized in the middle or low tertile ranges of radial AI in both sexes (Table 3). On the other hand, among the subjects categorized into the high tertile range of age, the high tertile range of SBP, or the high tertile range of radial AI, SBP was a significantly independent variable for radial AI in both sexes. However, age was not a significant variable affecting the radial AI among subjects categorized into the high tertile range of age or among those categorized into the high tertile range of radial AI in men. In women, age was not a significant variable associated with the radial AI among subjects categorized into the high tertile range of age or among those categorized into the high tertile range of SBP (Table 3). American Journal of Hypertension 27(12) December

4 Tomiyama et al. Women Radial AI (%) Rela ve number of the value of radial AI (%) Discussion This cross-sectional study demonstrated that an elevation in blood pressure was significantly associated with an increase in the AI in not only the elderly but also subjects with high blood pressure or subjects with a high AI. Several studies have demonstrated that, among the risk factors for cardiovascular disease, age and blood pressure are major factors associated with an increase in the AI, and these studies have also demonstrated a plateau in the AI beyond the age of 60 years. 5,7,8 O Rourke described that the changes in the pressure waveform in patients with hypertension are similar to those seen with aging in his review. 9 On the other hand, the ACCT III study reported that age and blood pressure have an interactive effect on the AI, and the effect of the blood pressure on the AI is more marked in subjects aged <50 years of age than in those aged 50 years. 4 Even so, blood pressure had a significant effect on the AI in subjects aged 50 years in the ACCT III study. 4 However, the significance of the effect of blood pressure on the AI in subjects with high blood pressure has not been fully clarified. In addition, although the AI is increased along with aging or an Age SBP (mm Hg) Figure 2. Changes in the radial augmentation index (AI) and those in the relative number of values of the radial augmentation index with an increase in age (10-year increments) or an increase in systolic blood pressure (SBP; 10 mm Hg increments) in women. elevation in blood pressure, no study has examined the difference in the effects of age and those of blood pressure on the AI between subjects with and without a high AI. In addition to cardiac performance, the travelling speed of the pressure wave on the conduit arterial wall and the pressure wave reflectance of the peripheral arteries are major determinants of the AI. 2,3 Impedance mismatching between the conduit elastic and peripheral muscular arteries is thought to be one of the underlying mechanisms responsible for the plateau in the AI at ages >60 years. 8,9 In our study, the effect of age on the AI was also small (mostly not significant) in subjects with high blood pressure or in those with a high AI. Although our study did not measure the pulse wave velocity, a marker reflecting conduit arterial stiffness, the stiffness of the conduit elastic artery is increased not only in subjects with elevated blood pressure but also in those with a high AI. Therefore, the results of our study suggested that the effect of age on AI is attenuated even in patients with increased conduit elastic arterial stiffness caused by several factors other than aging. On the other hand, the effect of the elevation in blood pressure on the AI was significant even in patients with high blood pressure or those with a high AI American Journal of Hypertension 27(12) December 2014

5 Age, Blood Pressure, and Augmentation Index Table 1. Subject characteristics Age, y 51 ± 13 Sex, men/women (%) 5,447/4,743 (54) BMI, kg/m ± 3.5 Smoking history, not/current (%) 2,201/7,989 (29) SBP, mm Hg 122 ± 19 DBP, mm Hg 73 ± 12 HR, beats/min 68 ± 10 SP 2, mm Hg 110 ± 19 radial AI, % 81 ± 14 TC, mg/dl 210 ± 35 HDL, mg/dl 63 ± 16 TG, mg/dl 117 ± 91 FPG, mg/dl 100 ± 20 Crnn, mg/dl 0.7 ± 0.2 Medication, no. (%) MedHBP 2,665 (26) MedDLIP 1,239 (12) MedDM 613 (6) Data are mean ± SD unless otherwise noted. Abbreviations: AI, radial augmentation index; BMI, body mass index; Crnn, serum creatinine levels; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, serum high-density lipoprotein cholesterol; HR, heart rate; MedDLIP, medication for dyslipidemia; MedDM, medication for diabetes mellitus; MedHBP, medication for hypertension; SBP, systolic blood pressure; SP 2, second peak of the radial pressure waveform; TC, serum total cholesterol; TG, serum triglycerides. Table 2. Results of a general linear model analysis to assess the independency and interactions between the association of age and that of systolic blood pressure with the radial augmentation index B (SE) P value Men Age (0.150) <0.001 SBP (0.073) <0.001 Interaction (0.033) <0.001 Women Age (0.138) <0.001 SBP (0.069) <0.001 Interaction (0.029) <0.001 Covariables were height, body mass index, smoking, heart rate, serum total cholesterol, high-density lipoprotein cholesterol; serum trigylcerides, serum creatinine levels, fasting plasma glucose, medicination for dyslipidemia, medicination for diabetes mellitus, and medication for hypertension. Abbreviations: AI, arterial index; B, nonstandardized coefficient; SBP, systolic blood pressure; SE, standard error. Thus, as compared with the mechanisms responsible for the increase in the AI related to aging, not only increased conduit elastic arterial stiffness through an elevation in blood pressure but also increased pressure wave reflectance of the peripheral artery may be a significant determinant for the increase in AI related to an elevation in blood pressure. The plateau in the AI at ages >60 years might support the concept that the AI is thought to predict cardiovascular outcomes more effectively in young adults than in the elderly. 6 On the other hand, in our study, the effect of blood pressure on the AI was significant even in the elderly, in subjects with high blood pressure, and in those with a high AI. Therefore, these results suggest that blood pressure control is important to improve the abnormal central hemodynamics in these subjects. Furthermore, Mitchell et al. reported that arterial stiffness, as assessed using pulse wave velocity rather than central blood pressure, was associated with an increased risk for a first cardiovascular event in the Framingham Heart Study. 14 However, the mean age of the study subjects in the Framingham Heart Study was 63 years, and only 32% of the subjects were being treated for hypertension. Thus, the effect of elevated blood pressure on the risk of cardiovascular disease, which is related to an increased AI, could not be fully clarified. Therefore, further study is needed to determine whether markers of central hemodynamics estimated using the radial pressure waveform are associated with an increased risk for cardiovascular events in subjects with hypertension. The large arterial stiffness or amplitude of the reflected pressure wave was not measured in this study; therefore, it is difficult to elucidate the mechanisms underlying the differences in the effects of age and blood pressure on the AI based on the findings of this study. Furthermore, although radial pressure waveform analysis is an accepted method for estimating the central hemodynamics, 1,4 7 we did not measure the central hemodynamics directly. Chirinos et al. demonstrated ethnic differences of the AI (i.e., lower values of central/radial AI in Asians than those in Africans and Hispanics matched for age), 6 and Thomas et al. suggested that other factors, such as environmental factors (including socioeconomic factors), geography, and/or climate, may also affect the central AI. 15 Thus, further study is proposed to examine whether the effect of elevated blood pressure on the AI may be significant in other ethnicities and/or other countries. In 762 of the10,190 subjects in this study (7.5%), the value of the radial AI was >100%. The probable technical problems arising from the present approach of measuring the radial AI when the inflection between the SP1 and SP2 cannot be identified and/or the SP2 is greater than the SP1 (i.e., a radial AI >100%) have been considered. However, Sugawara et al. reported that the radial AI was significantly correlated with the carotid AI even in patients with a radial AI >100%. 16 Takenaka et al. reported that a radial AI of >100% was a risk factor for left ventricular hypertrophy. 17 Accordingly, in our study, age and pulse pressure were higher in the subjects with a radial AI 100% (n = 762) than in those with a radial AI <100% but 90% (n = 1,862; 59 ± 11 vs. 56 ± 12 years, P < 0.01; 57 ± 15 mm Hg vs. 52 ± 13 mm Hg, P < 0.01). Even after adjustments for age, the pulse pressure was higher in American Journal of Hypertension 27(12) December

6 Tomiyama et al. Table 3. Results of stepwise multivariable linear regression analyses conducted to assess the relationships of age and systolic blood pressure with the radial augmentation index in subjects categorized into high, middle, and low tertile ranges of age, systolic blood pressure, and radial augmentation index Variable ChR 2 B (SE) Beta P value ChR 2 B (SE) Beta P value ChR 2 B (SE) Beta P value In men (n = 5,477) High tertile of age ( 57 y) (n = 1,924) Total R 2 = Middle tertile of age (46 to <57 y) (n = 1,837) Total R 2 = Low tertile of age (<46 y) (n = 1,686) Total R 2 = Age (0.015) < (0.058) <0.001 SBP (0.013) < (0.073) < (0.021) <0.001 In men (n = 5,477) High tertile of SBP ( 131 mm Hg) (n = 1,929) Total R 2 = Middle tertile of SBP (118 to <131 mm Hg) (n = 1,711) Total R 2 = Low tertile of SBP (<118 mm Hg) (n = 1,807) Total R 2 = Age (0.025) < (0.027) < (0.027) <0.001 SBP (0.019) < (0.067) < (0.042) <0.001 In men (n = 5,477) High tertile of rai ( 83%) (n = 1,875) Total R 2 = Middle tertile of rai (72% to <83%) (n = 1,706) Total R 2 = Low tertile of rai (< 72%) (n = 1,866) Total R 2 = Age (0.009) < (0.018) <0.001 SBP (0.009) < (0.005) < (0.013) <0.001 In women (n = 4,743) High tertile of age (aged 57 y) (n = 1,581) Total R 2 = Middle tertile of age (aged 43 years to <57 y) (n = 1,574) Total R 2 = Lower tertile of age (aged < 43 y) (n = 1,588) Total R 2 = Age (0.060) < (0.044) <0.001 SBP (0.014) < (0.015) < (0.025) <0.001 In women (n = 4,743) High tertile of SBP ( 123 mm Hg) (n = 1,637) Total R 2 = Middle tertile of SBP (106 to <123 mm Hg) (n = 1,542) Total R 2 = Low tertile of SBP (<106 mm Hg) (n = 1,564) Total R 2 = Age (0.026) < (0.027) <0.001 SBP (0.018) < (0.054) < (0.050) In women (n = 4,743) High tertile of rai ( 91%) (n = 1,578) Total R 2 = Middle tertile of rai (80% to <91%) (n = 1,560) Total R 2 = Low tertile of rai (<80%) (n = 1,605) Total R 2 = Age (0.016) < (0.008) (0.018) <0.001 SBP (0.009) < (0.005) < (0.015) <0.001 Covariates: Height, BMI, Smoke, HR, TC, HDL, TG, Crnn, FBG, MedHBP, MedDM, and MedDLIP Covariables were height, body mass index, smoking, heart rate, serum total cholesterol, high-density lipoprotein cholesterol, serum trigylcerides, serum creatinine levels, fasting plasma glucose, medicination for dyslipidemia, medicination for diabetes mellitus, and medication for hypertension. Abbreviations: B, nonstandardized coefficient; beta, standardized coefficient; ChR 2, changes of R 2 in stepwise analysis; rai, radial arterial index; SBP, systolic blood pressure; SE, standard error American Journal of Hypertension 27(12) December 2014

7 Age, Blood Pressure, and Augmentation Index the former group than in the latter group. Thus, the radial AI, even if its value is >100%, may reflect some pathophysiological abnormalities related to vascular damages. The effects of age and blood pressure on the AI are different not only between young adults and the elderly but also between those with and without high blood pressure and between those with and without a high AI. Although the effect of age on the AI is not significant in the elderly, in subjects with high blood pressure, or in those with a high AI, an elevation in blood pressure is significantly associated with a high AI in those subjects. ACKNOWLEDGMENT This work was partially supported by a grant from OMRON Health Care (Kyoto, Japan). DISCLOSURE The authors declared no conflict of interest. References 1. Vlachopoulos C, Aznaouridis K, O Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 2010; 31: O Rourke MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol 2007; 50: Tomiyama H, Yamashina A. Non-invasive vascular function tests: their pathophysiological background and clinical application. Circ J 2010; 74: McEniery CM, Yasmin, Maki-Petaja KM, McDonnell BJ, Munnery M, Hickson SS, Franklin SS, Cockcroft JR, Wilkinson IB; Anglo-Cardiff Collaboration Trial Investigators. The impact of cardiovascular risk factors on aortic stiffness and wave reflections depends on age: the Anglo- Cardiff Collaborative Trial (ACCT III). Hypertension 2010; 56: Tomiyama H, Yamazaki M, Sagawa Y, Teraoka K, Shirota T, Miyawaki Y, Yamashina A. Synergistic effect of smoking and blood pressure on augmentation index in men, but not in women. Hypertens Res 2009; 32: Chirinos JA, Kips JG, Roman MJ, Medina-Lezama J, Li Y, Woodiwiss AJ, Norton GR, Yasmin, Van Bortel L, Wang JG, Cockcroft JR, Devereux RB, Wilkinson IB, Segers P, McEniery CM. Ethnic differences in arterial wave reflections and normative equations for augmentation index. Hypertension 2011; 57: McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR; ACCT Investigators. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 2005; 46: Vyas M, Izzo JL Jr, Lacourcière Y, Arnold JM, Dunlap ME, Amato JL, Pfeffer MA, Mitchell GF. Augmentation index and central aortic stiffness in middle-aged to elderly individuals. Am J Hypertens 2007; 20: O Rourke MF. Time domain analysis of the arterial pulse in clinical medicine. Med Biol Eng Comput 2009; 47: Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens 2008; 26: Asmar RG, London GM, O Rourke ME, Safar ME; REASON Project Coordinators and Investigators. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/ indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001; 38: Miyashita H, Aizawa A, Hashimoto J, Hirooka Y, Imai Y, Kawano Y, Kohara K, Sunagawa K, Suzuki H, Tabara Y, Takazawa K, Takenaka T, Yasuda H, Shimada K. Cross-sectional characterization of all classes of antihypertensives in terms of central blood pressure in Japanese hypertensive patients. Am J Hypertens 2010; 23: Melenovsky V, Borlaug BA, Fetics B, Kessler K, Shively L, Kass DA. Estimation of central pressure augmentation using automated radial artery tonometry. J Hypertens 2007; 25: Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the framingham heart study. Circulation 2010; 121: Thomas F, Pannier B, Safar ME. Impact of country of birth on progression of steady and pulsatile hemodynamic parameters in normotensive and hypertensive subjects. J Am Soc Hypertens 2013; 7: Sugawara J, Komine H, Hayashi K, Maeda S, Matsuda M. Relationship between augmentation index obtained from carotid and radial artery pressure waveforms. J Hypertens 2007; 25: Takenaka T, Mimura T, Kanno Y, Suzuki H. Qualification of arterial stiffness as a risk factor to the progression of chronic kidney diseases. Am J Nephrol 2005; 25: American Journal of Hypertension 27(12) December