The Diurnal Profile of Central Hemodynamics in a General Uruguayan Population

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1 Original Article The Diurnal Profile of Central Hemodynamics in a General Uruguayan Population José Boggia, 1,2,3 Leonella Luzardo, 1,2,3 Inés Lujambio, 1,2 Mariana Sottolano, 1,2,3 Sebastián Robaina, 1,2 Lutgarde Thijs, 4 Alicia Olascoaga, 5 Oscar Noboa, 1,3 Harry A. Struijker-Boudier, 6 Michel E. Safar, 7 and Jan A. Staessen 4,8 BACKGROUND No previous population study assessed the diurnal profile of central arterial properties. METHODS In 167 participants (mean age, 56.1 years; 63.5% women), randomly recruited in Montevideo, Uruguay, we used the oscillometric Mobil- O-Graph 24-h PWA monitor to measure peripheral and central systolic (SBP), diastolic (DBP), and pulse (PP) pressures and central hemodynamics standardized to a heart rate of 75 bpm, including aortic pulse wave velocity, systolic augmentation (first/second peak 100), and pressure amplification (peripheral PP/central PP). RESULTS Over 24 hours, day and night, peripheral minus central differences in SBP/ DBP and in PP averaged 12.2/ 1.1, 14.0/ 0.7, and 9.7/0.2 mm Hg and 12.6, 14.7, and 9.5 mm Hg, respectively (P < except for nighttime DBP (P = 0.38)). The central-to-peripheral ratios of SBP, DBP, and PP were 0.89, 1.00, and 0.70 unadjusted, but after accounting for anthropometric characteristics decreased to 0.74, 0.97, and 0.63, respectively, with strong influence of height for SBP and DBP and of sex for PP. From day (10 20 h) to nighttime (0 6 h), peripheral ( 10.4/ 10.5 mm Hg) and central ( 6.0/ 11.3 mm Hg) SBP/DBP, pulse wave velocity ( 0.7 m/s) and pressure amplification ( 0.05) decreased (P < 0.001), whereas central PP (+5.3 mm Hg) and systolic augmentation (+2.3%) increased (P < 0.001). CONCLUSIONS The diurnal rhythm of central pressure runs in parallel with that of peripheral pressure, but the nocturnal fall in SBP is smaller centrally than peripherally. pulse wave velocity, systolic augmentation, and pressure amplification loop through the day with high pulse wave velocity and pressure amplification but low systolic augmentation in the evening and opposite trends in the morning. Keywords: aortic pulse wave velocity; arterial stiffness; blood pressure monitoring; central blood pressure; hypertension; population science. doi: /ajh/hpv169 Arterial stiffness predicts cardiovascular complications over and beyond traditional risk factors. 1,2 From the classical view, the arterial pressure wave consists of a forward component generated by the heart and reflected waves returning to the central aorta from peripheral sites. 3 As arteries stiffen, for instance with advancing age, 4 the reflected waves return faster, reach the proximal aorta during systole, and augment late systolic blood pressure. 3 The youngest approach of wave intensity analysis points that wave reflection is not the sole contributor to central blood pressure waveform. 5,6 Experts consider aortic pulse wave velocity as the gold standard in the assessment of arterial stiffness, 7 whereas systolic augmentation is also influenced by other factors, including cardiac output, stroke volume, left ventricular ejection time, 8 identification of the inflection point, age, height, and gender. 6 Ambulatory blood pressure monitoring provides information not only on the blood pressure level but also on the diurnal blood pressure profile. The Mobil-O-Graph 24-h PWA monitor (I.E.M. GmbH, Stolberg, Germany) is a portable monitor validated for the recording of brachial blood pressure. 9 It includes the ARCSolver software, 10 which allows pulse wave analysis to estimate central blood pressure Correspondence: José Boggia (jboggia@hc.edu.uy). Initially submitted April 7, 2015; date of first revision August 22, 2015; accepted for publication September 26, 2015; online publication October 16, Unidad de Hipertensión Arterial, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay; 2 Departamento de Fisiopatología, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay; 3 Centro de Nefrología, Universidad de la República, Montevideo, Uruguay; 4 Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; 5 Departamento de Laboratorio Clínico, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay; 6 Department of Pharmacology, Maastricht University, Maastricht, The Netherlands; 7 Faculty of Medicine, Hôtel- Dieu Hospital, Paris-Descartes University, Paris, France; 8 R & D VitaK Group, Maastricht University, Maastricht, The Netherlands. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com American Journal of Hypertension 29(6) June

2 Boggia et al. and aortic pulse wave velocity. We 11 and other researchers 12 validated the central hemodynamic measurements in resting conditions against a tonometric 11 or invasive standard. 12,13 This monitor therefore combines 2 worlds, allowing the simultaneous assessment of 24-h blood pressure and central arterial properties, 2 major cardiovascular risk factors. 1 To our knowledge no previous population study assessed the diurnal profile of central arterial characteristics. We addressed this issue in a randomly recruited Uruguayan population sample enrolled in the GEnotipo, Fenotipo y Ambiente de la HiperTensión Arterial en UruguaY (GEFA- HT-UY) study. 14 METHODS Study population GEFA-HT-UY complies with the Helsinki Declaration for investigation in human subjects. The Ethics Committee of the Hospital de Clínicas approved the GEFA-HT-UY study. A detailed protocol has been published elsewhere. 14 In short, we recruited a random sample of nuclear families living in a geographically defined neighborhood of Montevideo, the Juana de América housing estate. To be eligible families had to include 2 parents with at least 1 offspring or 1 parent with 2 offspring. The minimum age for participation was 18 years with no upper age limit. All participants gave informed written consent. At the time of writing of this manuscript, 332 family members had been invited for an enrollment home visit, of whom 238 (71.7%) participated. Of those, we excluded 55 from the present analysis, because they withdrew consent (n = 36) or because they had declined (n = 10) or had not yet undergone (n = 9) ambulatory blood pressure measurement. Finally we excluded 16 participants, because they did not meet the quality standards for the 24-h ambulatory assessment of the central hemodynamics (see below). Thus, the number of participants available for statistical analysis totaled 167. Clinical measurements Participants were asked to refrain from heavy exercise, smoking, and intake of alcohol and caffeine-containing beverages for at least 2 hours prior to the examination at the local study center. Trained nurses measured the participants anthropometric characteristics and office blood pressure and administered a questionnaire to collect information about each individual s medical history. Plasma glucose and serum cholesterol and creatinine were measured on venous blood samples obtained after 8 hours of fasting. Methods used for office blood pressure measurement, definitions of hypertension, diabetes, body mass index, and glomerular filtration rate are described in detail in the Supplementary Material (pages, S2 S3). Ambulatory measurements We programmed oscillometric Mobil-O-Graph 24-h PWA monitors (I.E.M. GmbH, Stolberg, Germany), 9 fitted with the same cuff size as for the office blood pressure measurements, to obtain readings with an interval of 20 minutes from 7:00 until 23:00 hours and every 30 minutes from 23:00 until 7:00 hours. For analysis, daytime was the interval from 10:00 to 20:00 hours, while nighttime ranged from midnight to 6:00 hours. These fixed intervals eliminate the transition periods in the morning and evening when blood pressure changes rapidly, resulting in daytime and nighttime blood pressure levels that are within 1 2 mm Hg of the awake and asleep levels. 15 Except for 2 participants, all day and night periods corresponded with awake and sleep periods in participants diary registry. If the ambulatory recordings were longer than 1 day, only the first 24 hours were analyzed. Intra-individual means of the ambulatory measurements were weighted by the time interval between successive readings. 16 The ARCSolver algorithm, as implemented in Mobil-O- Graph 24-h PWA monitor, reconstructs the central pulse wave by applying a transfer function. 10 Recordings of the central hemodynamics are carried out at the diastolic blood pressure level (±5 mm Hg) for approximately 10 seconds, using a high-fidelity pressure sensor (MPX5050, Freescale, Tempe, AZ). The central blood pressure was calibrated to brachial mean and diastolic blood pressure. 17 The transfer function implemented in the ARCSolver software includes an algorithm for checking quality of the signal on a scale from 1 to 4. Results of excellent or good quality are labeled 1 and 2 and include respectively more than 80% or over 50% of the cardiac cycles during signal acquisition. Grade 3 results are estimated from <50% of the recorded cycles and are of poor quality. Grade 4 indicates missing results because of insufficient signal quality. We included central hemodynamic measurements in the analyses only if graded 1 or 2. Moreover, the ARCSolver software excludes central hemodynamic measurements obtained at a cuff pressure that is not within 5 mm Hg of diastolic blood pressure. More information on ambulatory measurements using the ARCSolver software is detailed in the Supplementary Material (pages, S2 S3). The augmentation ratio and index are quotients of the second over the first peak of the central blood pressure wave and of the absolute difference between the second and first peak over central pulse pressure, both expressed as a percentage (Supplementary Figure S1). Pressure amplification is the ratio of peripheral to central pressure. We standardized the hemodynamic variables (systolic augmentation, pressure amplification, and aortic pulse wave velocity) to a heart rate of 75 beats per minute. Statistical analysis For statistical analysis and database management, we used SAS software, version 9.3 (SAS Institute, Cary, NC). We compared means and proportions, using a t-test for paired or unpaired observations, as appropriate, and the χ 2 -statistic, respectively. Our statistical methods also included single and multiple linear regression. Statistical significance was an α-level of To investigate the effects of sex and age, we generated descriptive statistics of the ambulatory measurements in women and men and in 2 age groups (<60 and 60 years). 738 American Journal of Hypertension 29(6) June 2016

3 Diurnal Profile of Central Hemodynamics Next, we plotted the 2-hourly averages of the ambulatory measurements of blood pressure level and the central hemodynamic measurements over 24 hours. Criteria to differentiate a significant diurnal rhythm from random variability consisted of the differences between daytime and nighttime values in all participants and of the runs test with a 1-sided probability set at 5% in individual participants. 18 Using twelve 2-hourly means in mixed models with individual participants entered as a random effect, we expressed central systolic pressure as function of peripheral systolic pressure, first unadjusted and next stepwise and cumulatively adjusted for sex, age, height, weight, smoking, drinking, serum cholesterol, serum creatinine, and history of cardiovascular disease. In sensitivity analyses, we excluded participants on antihypertensive drug treatment. RESULTS Characteristics of participants The 167 participants had an average (SD) age of 56.1 ± 17.1 years (5th to 95th percentile interval, ; range, 18 95). Table 1 lists the main characteristics of the participants by sex. Women compared with men, less frequently reported drinking alcohol, included more smokers, had lower waist-to-hip ratio and lower serum creatinine, but higher pulse rate, and serum cholesterol. The other characteristics were similar among women and men (P 0.15). In current smokers of either sex, median tobacco use was 9 cigarettes/day (5th to 95th percentile interval, 2 20). In participants reporting alcohol intake, median consumption was 5 grams per day (5th to 95th percentile interval, 1 11) among women and 8 grams per day (5th to 95th percentile interval, 2 32) among men. Supplementary Table S1 lists the characteristics of participants by age groups (<60 vs. 60 years). Peripheral and central ambulatory blood pressure Number of measurements. For brachial blood pressure, the median number of readings averaged to estimate mean levels of 24-h, daytime and nighttime blood pressure were 53 (5th 95th percentile interval, 36 64; range, 23 68), 26 (5th 95th percentile interval, 13 33; range, 10 34), and 12 (5th 95th percentile interval, 7 14; range, 5 18), respectively. For central blood pressure, the corresponding numbers were 37 Table 1. Characteristics of participants by sex Variable Women (N = 106) Men (N = 61) All (N = 167) Number (%) with characteristic Age 60 years 60 (57) 27 (44) 87 (52) Current smoking 20 (19) 5 (8) * 25 (15) Drinking alcohol 26 (25) 31 (51) 57 (34) Hypertension 53 (50) 31 (51) 84 (50) On antihypertensive treatment 40 (37) 21 (34) 61 (37) Diabetes mellitus 20 (19) 6 (10) 26 (16) History of cardiovascular disease 22 (21) 11 (18) 33 (20) Mean (SD) characteristic Age (year) 58 ± ± ± 17 Height (m) 1.58 ± ± ± 0.10 Weight (kg) 74.6 ± ± ± 17.5 Body mass index (kg/m 2 ) 29.9 ± ± ± 6.5 Waist-to-hip ratio 0.86 ± ± ± 0.08 Office blood pressure Systolic pressure (mm Hg) 129 ± ± ± 21 Diastolic pressure (mm Hg) 81 ± ± ± 12 Heart rate (beats per minute) 73 ± 9 69 ± 12 * 71 ± 11 Fasting plasma glucose (mg/dl) 98 ± ± ± 15 Serum cholesterol (mg/dl) 213 ± ± ± 41 Serum creatinine (mg/dl) 0.72 ± ± ± 0.22 egfr (ml/min/1.73 m 2 ) 91 ± ± ± 21 Hypertension was a blood pressure (mean of 5 consecutive readings) of at least 140 mm Hg systolic or 90 mm Hg diastolic, or use of antihypertensive drugs. Diabetes mellitus was a self-reported diagnosis, a fasting plasma glucose of 126 mg/dl or higher, or use of antidiabetic drugs. Estimated glomerular filtration rate (egfr) was derived from serum creatinine, using the Chronic Kidney Disease Epidemiology Collaboration equation. Significance of the sex difference: * P 0.05; P 0.01; P American Journal of Hypertension 29(6) June

4 Boggia et al. (5th 95th percentile interval, 18 56; range, 15 62), 17 (5th 95th percentile interval, 6 28; range, 2 30), and 9 (5th 95th percentile interval, 2 13; range, 1 16). Daytime vs. nighttime. Peripheral blood pressure (Table 2) decreased from day to night by 10.4 mm Hg systolic (95% confidence interval (CI), 8.7 to 12.0; P < ) and 10.5 mm Hg diastolic (CI, 9.2 to 11.7; P < ), whereas peripheral pulse pressure did not change (0.1 mm Hg; CI, 0.9 to 1.2; P = 0.84). Compared with daytime (Table 2 and Figure 1), at night, central blood pressure decreased by 6.0 mm Hg systolic (CI, 4.6 to 7.5; P < ) and 11.3 mm Hg diastolic (CI, 10.0 to 12.6; P < ), whereas central pulse pressure increased by 5.3 mm Hg (CI, 4.3 to 6.3; P < ). Sensitivity analyses stratified by sex (Supplementary Table S2) or from which participants treated for hypertension were excluded (Supplementary Figure S2) were confirmatory. The average (±SD) mean blood pressures were 88.9 ± 8.8, 92.1 ± 9.6 and 81.8 ± 10.1 for 24 hours, daytime and nighttime periods, respectively. The nocturnal decrease in systolic blood pressure was 4.3 mm Hg (CI, 3.3 to 5.2; P < ) greater peripherally than centrally (10.4 vs. 6.0 mm Hg). In contrast, the nocturnal decrease in diastolic blood pressure was 0.8 mm Hg (CI, 0.5 to 1.7; P < 0.01) less peripherally than centrally (10.5 vs mm Hg). Consequently, the nocturnal change in pulse pressure was 5.2 mm Hg less (CI, 4.3 to 6.1 mm Hg; P < ) peripherally than centrally (0.1 vs. 5.3 mm Hg). Among 167 participants, the runs test applied to individual readings of the central blood pressure over 24 hours indicated a significant (P < 0.05) diurnal rhythm in 73 (43.7%) for systolic blood pressure, in 95 (56.9%) for diastolic blood pressure, in 65 (38.9%) for pulse pressure, and in 118 (70.7%) for pulse rate. Central vs. peripheral levels. Central systolic blood pressure and central pulse pressure were lower (P < 0.001) than the peripheral levels (Table 2). The 24-h and daytime diastolic pressures (P < 0.001), but not nighttime diastolic pressure (P = 0.38), were higher as estimated centrally than as measured peripherally (Table 2). The differences of peripheral minus central systolic blood pressure averaged 12.2 mm Hg (CI, 11.5 to 12.7) over 24 hours, 14.0 mm Hg (CI, 13.3 to 14.7) during daytime, and 9.7 mm Hg (CI, 8.7 to 10.7) at night. For pulse pressure, the corresponding estimates were 12.6 mm Hg (CI, 12.0 to 13.2), 14.7 mm Hg (CI, 14.0 to 15.4), and 9.4 mm Hg (CI, 8.6 to 10.4). The average differences of peripheral minus central diastolic blood pressure amounted to 0.5 mm Hg (CI, 0.8 to 0.2) over 24 hours, 0.7 mm Hg (CI, 1.1 to 0.3) during daytime and 0.2 (CI, 0.3 to 0.8) at night. All aforementioned differences were significant Table 2. Level of peripheral and central blood pressure and central hemodynamics in 167 participants Blood pressure level and heart rate Central hemodynamic measurements Systolic blood pressure 740 American Journal of Hypertension 29(6) June 2016 Peripheral Central Crude Standardized Systolic augmentation ratio 24-h (mm Hg) 119 ± ± h (%) 110 ± ± 5 Daytime (mm Hg) 122 ± ± 11 Daytime (%) 108 ± ± 4 Nighttime (mm Hg) 112 ± ± 13 Nighttime (%) 114 ± ± 7 Diastolic blood pressure Systolic augmentation index 24-h (mm Hg) 74 ± 9 75 ± 9 24-h (%) 28 ± 8 28 ± 8 Daytime (mm Hg) 78 ± ± 10 Daytime (%) 28 ± 8 26 ± 7 Nighttime (mm Hg) 67 ± ± 10 Nighttime (%) 28 ± ± 12 Pulse pressure Pressure amplification 24-h (mm Hg) 45 ± 8 32 ± 8 24-h 1.4 ± ± 0.1 Daytime (mm Hg) 45 ± 9 30 ± 8 Daytime 1.5 ± ± 0.1 Nighttime (mm Hg) 45 ± 9 35 ± 9 Nighttime 1.3 ± ± 0.1 Heart rate Aortic pulse wave velocity 24-h (beats per minute) 76 ± h (m/s) 8.0 ± ± 2.2 Daytime (beats per minute) 82 ± 12 Daytime (m/s) 8.1 ± ± 2.2 Nighttime (beats per minute) 68 ± 11 Nighttime (m/s) 7.8 ± ± 2.3 Values are mean ± SD. The augmentation ratio and index are quotients of the second over the first peak of the central blood pressure wave and of the absolute difference between the second and first peak over central pulse pressure, both expressed as a percentage. Pressure amplification was the ratio of peripheral to central pulse pressure. Crude and standardized refer to the central hemodynamic measurements (systolic augmentation, systolic augmentation index, peripheral-to-central pulse pressure ratio, and aortic pulse wave velocity) not standardized or standardized to a heart rate of 75 beats per minute. Differences between peripheral and central blood pressure levels were significant (P < 0.001) with the exception of nighttime diastolic blood pressure (P = 0.38). Crude and heart-rate standardized hemodynamic measurements were significantly different (P < ) during daytime and nighttime, but not over 24 hours (P 0.23). All differences between day and night were significant (P < 0.001) with the exception of peripheral pulse pressure (P = 0.87) and the crude augmentation index (P = 0.74).

5 Diurnal Profile of Central Hemodynamics Figure 1. Diurnal profiles in 167 participants of central systolic (A) and diastolic blood pressures (B), pulse pressure (C), and heart rate (D). Plotted values are 2-hourly mean with 95% confidence interval. P-values are for the comparison between daytime (10:00 20:00 hours) and nighttime (00:00 06:00 hours) means. (P < 0.001) except for nighttime diastolic blood pressure (P = 0.38). Figure 2 shows the influence of anthropometric measurements and cardiovascular risk factors on estimates of central systolic and diastolic pressure and central pulse pressure expressed as a percentage of the corresponding peripheral measurement with individuals modeled as a random effect. The initial estimates after just introducing the peripheral blood pressure were 0.89 for systolic pressure, 1.00 for diastolic pressure, and 0.70 for pulse pressure. These estimates reflect the mean values of the central estimates as a fraction of the peripheral measurements, as reported in Table 2. Cumulatively accounting for covariables showed a major effect of body height on the estimates of central systolic and diastolic blood pressure and a major effect of sex on the estimate of central pulse pressure (Figure 2). Among 61 participants on antihypertensive drug treatment (Supplementary Table S3), there were no differences (P 0.18) in the drug classes used or in the prevalence of monotherapy and combination therapy according to the median amplification pressure (1.41 mm Hg). Central hemodynamics Crude and heart-rate standardized hemodynamic measurements (Table 2) were significantly different (P < ) during daytime and nighttime, but not over 24 hours (P 0.23). Within-subject analyses of the correlates of the hemodynamic measurements. We determined the within-subject coefficients of determination (r 2 ) for the relation of the central hemodynamic measurements with peripheral systolic pressure. The 5th to 95th intervals ranged from <0.001 to 0.25 for the augmentation ratio, from <0.01 to 0.33 for the augmentation index, from <0.01 to 0.47 for pressure amplification, and from 0.56 to 0.97 for pulse wave velocity. If we replaced peripheral by central systolic pressure, these ranges encompassed <0.001 to 0.31, <0.001 to 0.24, <0.001 to 0.32, and 0.73 to Between-subject analyses of the correlates of the central hemodynamic measurements. Next, we determined the between-person coefficients of determination (r 2 ) for the relation of the central hemodynamic measurements with age; r 2 was 0.28 for the augmentation ratio, 0.27 for the augmentation index, 0.07 for pressure amplification, and 0.93 for pulse wave velocity. With peripheral systolic pressure, sex, height and weight, total cholesterol, serum creatinine, and history of cardiovascular disease added to the models already including age, the coefficients of multiple determination (R 2 ) were 0.42, 0.65, 0.14, and 0.95, respectively. If in these models peripheral systolic pressure was replaced by central systolic pressure, R 2 values were 0.47, 0.63, 0.16, and 0.96, respectively. Daytime vs. nighttime. In all participants combined (Table 2), differences between day and night in the central hemodynamics were significant (P 0.01) with the exception of the crude augmentation index (P = 0.74). Considering the heart-rate standardized hemodynamic measurements, from daytime to nighttime (Figure 3), the augmentation ratio and index increased by 2.3% (CI, 1.5 to 3.2; P < ) and 2.0% American Journal of Hypertension 29(6) June

6 Boggia et al. (CI, 0.6 to 3.4; P < 0.01), respectively. In contrast, pressure amplification and pulse wave velocity decreased by 0.05 (CI, 0.02 to 0.07; P < ) and 0.7 m/s (CI, 0.6 to 0.8; P < ). Excluding participants on treatment for hypertension produced confirmatory results (Supplementary Figure S3). Relation between systolic augmentation and pulse wave velocity. Figure 4 shows the relation of systolic augmentation, the systolic augmentation index, and the peripheral to central pulse pressure ratio with pulse wave velocity throughout the day. These associations describe a loop with the high values of pulse wave velocity in the evening between 20:00 hours and midnight coinciding with the diurnal minimal values of the systolic augmentation ratio and index, but high pressure amplification. Conversely, the lowest values of pulse wave velocity occur from 04:00 to 08:00 hours and coincide with high values of the systolic augmentation ratio and index and the diurnal minimum of pressure amplification. Limiting the analyses to untreated participants were confirmatory (Supplementary Figure S4). DISCUSSION Figure 2. Influence of anthropometric measurements and cardiovascular risk factors on estimates of central systolic (A) and diastolic (B) blood pressures and central pulse pressure (C) expressed as a percentage of the corresponding peripheral measurement. The factors listed along the horizontal axis were consecutively and cumulatively entered in the mixed models with individuals modeled as a random effect. Abbreviations: PSBP, peripheral systolic pressure; PDBP, peripheral diastolic pressure; PPP, peripheral pulse pressure; HR, heart rate; CHOL, serum cholesterol; CRT, serum creatinine; CVD, cardiovascular disease. Our current findings rely on the ARCSolver software. The key findings of our current population study can be summarized as follows: (i) the ARCSolver software allows computing central blood pressure and central hemodynamic variables over the whole day; (ii) central systolic and diastolic blood pressure and pressure amplification decreased at night with a concomitant increase in central pulse pressure, the systolic augmentation ratio and index, and pulse wave velocity; (iii) pulse wave velocity, systolic augmentation, and pressure amplification loop through the day with high pulse wave velocity and pressure amplification but low systolic augmentation in the evening with opposite trends in the morning; (iv) the major determinants of the central-to-peripheral blood pressure ratios were height for systolic and diastolic blood pressure and sex for pulse pressure; and (v) estimates of pulse wave velocity obtained with the ARCSolver software are strongly dependent on age and systolic blood pressure. To the best of our knowledge, no previous populationbased study described the diurnal rhythm of central blood pressure and central hemodynamics, including aortic pulse wave velocity, systolic augmentation, and pressure amplification. The Ambulatory Central Aortic Pressure (AmCAP) study described the diurnal patterns of simultaneously measured 24-h ambulatory brachial and central blood pressures in 171 participants with hypertension enrolled into the ASSERTIVE trial. 19 The brachial and central pressures were measured by an oscillometric and tonometric approach, using the SpaceLabs monitor (Spacelabs Healthcare, Snoqualmie, WA) and the BPro wrist device (HealthSTATS International, Singapore), respectively. The simultaneously measured 24-h ambulatory systolic pressure was lower centrally than as measured at the brachial artery. In line with our current findings, the nocturnal fall in the central systolic blood pressure was smaller (P < 0001) than the corresponding fall in brachial systolic blood pressure, when expressed 742 American Journal of Hypertension 29(6) June 2016

7 Diurnal Profile of Central Hemodynamics Figure 3. Diurnal profiles in 167 study participants of the augmentation ratio (A) and index (B), pressure amplification (C), and aortic pulse wave velocity (D). The augmentation ratio and index are quotients of the second over the first peak of the central blood pressure wave and of the absolute difference between the second and first peak over central pulse pressure, both expressed as a percentage. Pressure amplification was the ratio of peripheral to central pulse pressure. Plotted values are 2-hourly mean with 95% confidence interval, standardized to a heart rate of 75 beats per minute. P-values are for the comparison between daytime (10:00 20:00 hours) and nighttime (00:00 06:00 hours) means. either as an absolute nocturnal fall (9.7 vs mm Hg) or as a percentage dip from the daytime pressure average (6.9 vs. 8.2%). AmCAP investigators did not report on the diurnal differences between the peripherally and centrally measured diastolic blood pressure or pulse pressure nor on other central hemodynamic measurements. Oscillometric and tonometric assessment of pulse wave velocity, as respectively implemented in the ARCSolver algorithm and the SphygmoCor software (SphygmCor software, AtCor Medical, West Ryde, New South Wales, Australia), differ in that the oscillometric approach does not necessitate measurement of travel distance and provides aortic rather than carotid-femoral pulse wave velocity. A detailed discussion of this issue is available in the Supplementary Material (page S3). The ARCSolver software computes aortic pulse wave velocity from age, central pressure, and aortic characteristic impedance. 20 This explains why in our current study the correlations of aortic pulse wave velocity with systolic blood pressure within subjects and with age across subjects were extremely high with r 2 values ranging from 0.73 to Along similar lines Nunan and coworkers reported that aortic pulse wave velocity, as assessed by the ARCSolver software, was correlated with age and blood pressure category with r values of 0.98 and 0.63, respectively. 20 Because age and blood pressure are required input, aortic pulse wave velocity as reported by the ARCSolver software cannot be used to study correlations with these 2 covariables. We demonstrated that the central-to-peripheral ratios of systolic diastolic and pulse pressure drop after accounting for anthropometric characteristics and inter-individual variability in a mixed model (Figure 2). Height was the main determinant explaining the drop-off for systolic and diastolic blood pressure and sex for pulse pressure. Because people of short stature necessarily have correspondingly short arterial trees, their reflection sites in the lower part of the body are closer to the heart. 21 A short body height is associated with a faster heart rate, increased systolic augmentation, faster aortic pulse wave velocity, and a smaller diastolic-to-systolic pressure time index. 22 Besides, in a recent population study, central systolic BP, augmentation index at 75 bpm and aortic pulse wave timing were independently associated with height in both sexes. 23 Furthermore, women compared with men have a higher systolic augmentation ratio (standardized to heart rate), a decreased brachial-to-central pulse pressure ratio, and an increased reflection magnitude (the ratio of the backward to forward pressure amplitude) and amplitude of the backward pressure wave. 24 Shorter body height in women also results in less peripheral systolic amplification with lower peripheral but not central systolic blood pressure. 25 The relationship between central and peripheral blood pressures is still not fully understood. During nighttime, systolic and diastolic blood pressure level decreased both centrally and peripherally. However, the nocturnal decrease in the systolic blood pressure was larger peripherally while the diastolic blood pressure fall was slightly predominant at the central level. Therefore, during nighttime, the central pulse pressure increased while the brachial pulse pressure remains stable. Consequently, pulse amplification as determined by the peripheral-to-central pulse pressure ratio decreased during nighttime. Aortic pulse wave velocity, systolic augmentation, and pressure amplification loop through the day (Figure 4) with high values of pulse wave velocity and pressure amplification but low systolic augmentation in the evening (20:00 hours to midnight) with opposite trends in the morning (4:00 to 8:00 hours). We also noticed a significant diurnal rhythm in systolic augmentation with low values in the evening (20:00 American Journal of Hypertension 29(6) June

8 Boggia et al. Figure 4. Relation in 167 study participants of the augmentation ratio (A) and index (B) and pressure amplification (C) with aortic pulse wave velocity throughout the day. Data points represent mean values of 2-hour time intervals. Numbers indicate the time of day. hours to midnight) and greater values in the morning (4:00 to 8:00 hours). Besides, systolic augmentation and central pulse pressure were higher during nighttime than during the day (Figure 3). In addition to the circadian rhythm set by the internal biologic clock, body position probably plays an overriding role in explaining these diurnal changes. Indeed, during a passive head-up tilt in normal volunteers, diastolic blood pressure (+5.2%), heart rate (+27.6%), and vascular resistance (+12.5%) increased, whereas aortic pulse pressure ( 23.3%), the systolic augmentation index ( 11.6%), aortic reflection time ( 7.0%), and cardiac output ( 5.0%) decreased. 26 The diurnal curves of central systolic and diastolic blood pressure, pressure amplification and to a lesser extent pulse wave velocity showed a dip in the afternoon corresponding with siesta time. The diurnal association of systolic augmentation and pressure amplification showed a small extra loop from 14:00 to 18:00 hours. This observation supports the hypothesis that resting in the supine position both during the siesta and while sleeping might substantially contribute to the diurnal profile of the central hemodynamics. The hemodynamic profile of the postprandial pooling of blood does not fit our current observations. 27 Finally, the diurnal curves showing inverse changes of augmentation and pulse wave velocity supports the results from wave intensity analysis where wave reflection is not the sole contributor to central augmentation. 5,6 Sensitivity analyses from which we excluded hypertensive patients on blood pressure lowering medications were confirmatory (Supplementary Material). Our study has to be interpreted within the context of its limitations. First, the sample size was relatively small. On the other hand, the initial participation rate was 71.7%. Second, participants compared with nonparticipants were more frequently female (63.5% vs. 41.3%) and older (mean age, 56.1 vs years). Third, we did not apply actigraphy to document physical activity or sleep. However, the fixed clock-time intervals that we applied to define daytime and nighttime result in daytime and nighttime blood pressure levels that are within 1 2 mm Hg of the awake and asleep levels. 15 Finally, our findings in Uruguayans, predominantly of European descent, are not necessarily generalizable to other ethnic group or people with a different life style or living in different climatological conditions. 28 Our current study demonstrates that recording the diurnal profile of central hemodynamic variables is possible. We and others demonstrated acceptable reproducibility within 11 and between 29 sessions. Nevertheless, important issues remain to be resolved. There is worldwide consensus on the procedures for validation of automated devices measuring brachial blood pressure. 30 In contrast, a standardized process for validating portable monitors that estimate central blood pressure and hemodynamic variables does not exist. The Mobil-O-Graph 24-h PWA Monitor implements high-sensitivity cuff oscillometry and generates an ensemble waveform during a period of constant cuff pressure around diastolic blood pressure, which is analyzed by a transfer function or fit to other circulatory models. 10,12 Other portable devices estimate central hemodynamics from the interval between the onset of ventricular electrical excitation and the arrival of the pulse wave at a peripheral site and the brachial systolic blood pressure 31 or apply a n-point moving average, a mathematical low-pass filter that can smooth peaked noninvasively acquired radial pressure waveforms American Journal of Hypertension 29(6) June 2016

9 Diurnal Profile of Central Hemodynamics Whether central blood pressure is closely related to target organ damage or is a better predictor of adverse health outcomes remains a matter of debate. 33,34 Our current observations highlight that in this debate the time of day at which central hemodynamics are measured might be an important confounder. Furthermore, the scientific community should reach consensus on validation of devices recording central hemodynamics independent from the manufacturers. Ultimately, the technique of ambulatory monitoring of central blood pressure and hemodynamics awaits its final validation in demonstrating association of the recorded measurements with adverse health outcomes. In our view, there is still a long way to go. SUPPLEMENTARY MATERIAL Supplementary materials are available at American Journal of Hypertension ( ACKNOWLEDGMENTS The Comisión Sectorial de Investigación Científica, Universidad de la República (grant I+D 2010), and the Agencia Nacional de Investigación e Innovación (grant FMV ) gave support to the GEFA-HT-UY. IEM, Stolberg, Germany kindly provided 6 Mobil-O-Graph 24-h PWA monitors for use in the study. The European Union (grants HEALTH EU-MASCARA, HEALTH-F HOMAGE and the European Research Council Advanced Researcher Grant EPLORE) and the Ministry of the Flemish Community, Brussels, Belgium (grants G and G N) supported the Studies Coordinating Centre, Leuven, Belgium. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H, Jeppesen J. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. 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