DIV (18/05/23 10:17), document.doc & ABP.RMD,

Journal of Human Hypertension

Ambulatory Blood Pressure Monitoring for Risk Stratification in Obese and Non-Obese Subjects from 10 Populations

Short title: Risk Stratification by BMI and ABP

Tine W. Hansen, MD, PhD; Lutgarde Thijs, MSc; Yan Li, MD, PhD; José Boggia, MD, PhD;

Yanping Liu, MD; Kei Asayama, MD, PhD; Masahiro Kikuya MD, PhD; Kristina Björklund-Bodegård, MD, PhD;

Takayoshi Ohkubo, MD, PhD; Jørgen Jeppesen, MD, PhD; Christian Torp-Pedersen, MD, PhD; Eamon Dolan,

MD, PhD; Tatiana Kuznetsova, MD, PhD; Katarzyna Stolarz-Skrzypek, MD, PhD; Valérie Tikhonoff, MD, PhD;

Sofia Malyutina, MD, PhD; Edoardo Casiglia MD, PhD; Yuri Nikitin, MD, PhD; Lars Lind, MD, PhD;

Edgardo Sandoya, MD, PhD; Kalina Kawecka-Jaszcz, MD, PhD; Jan Filipovský, MD, PhD;

Yutaka Imai, MD, PhD; Jiguang Wang, MD, PhD; Eoin O’Brien, MD, PhD;

Jan A. Staessen, MD, PhD; on behalf of the International Database on Ambulatory blood pressure

in relation to Cardiovascular Outcomes (IDACO) Investigators

Word Counts: Manuscript 0, Body of Manuscript, 3529, Abstract 200

Number: Tables 3, Figures 3

Correspondence and requests for reprints to: Jan A. Staessen, MD, PhD, Studies Coordinating Centre, Laboratory of Hypertension, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Block D, Box 7001, BE-3000 Leuven, Belgium

Telephone: +32-16-34-7104 (office) +32-15-41-1747 (home) +32-47-632-4928 (mobile)

Facsimile: +32-16-34-7106 (office) +32-15-41-4542 (home)

email: jan.staessen@med.kuleuven.be jan.staessen@maastrichtuniversity.nl

Risk Stratification by BMI and ABP -2-

Authors Affiliations: Steno Diabetes Centre, Gentofte and Research Centre for Prevention and

Health, Glostrup, Denmark (Dr Hansen); Studies Coordinating Centre, Division of Hypertension and

Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of Leuven, Belgium

(Drs Thijs, Liu, Asayama, Kuznetsova, and Staessen); Tohoku University Graduate School of Phar-

maceutical Science and Medicine, Sendai, Japan (Drs Asayama, Kikuya, and Imai); Center for Epi-

demiological Studies and Clinical Trials (Drs Li and Wang) and Center for Vascular Evaluation (Dr Li),

Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Centro de Nefrol-

ogía and Departamento de Fisiopatología, Hospital de Clínicas, Universidad de la República, Montev-

ideo, Uruguay (Dr Boggia); Section of Geriatrics, Department of Public Health and Caring Sciences,

Uppsala University, Uppsala, Sweden (Drs Björklund-Bodegård and Lind ); Department of Health Sci-

ences, Shiga University of Medical Sciences, Otsu, Japan (Dr Ohkubo); Copenhagen University Hos-

pital, Copenhagen, Denmark (Drs. Jeppesen and Torp-Pedersen); Cambridge University Hospitals,

Addenbrook’s Hospital, Cambridge, United Kingdom (Dr Dolan); First Department of Cardiology and

Hypertension, Jagiellonian University Medical College, Kra-ków, Poland (Drs Stolarz-Skrzypek and

Kawecka-Jaszcz); Department of Clinical and Experimental Medicine, University of Padova, Padova,

Italy (Drs Tikhonoff and Casiglia); Insti-tute of Internal Medicine, Novosibirsk, Russian Federation (Drs

Malyutina and Nikitin); the Asociación Española Primera de Socorros Mutuos, Montevideo, Uruguay

(Dr Sandoya); Faculty of Medicine, Charles University, Pilsen, Czech Republic (Dr Filipovský); the

Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

(Dr O’Brien); and the Department of Epidemiology, Maastricht University, Maastricht, The Netherlands

(Dr Staessen). The IDACO investigators are listed in reference 16.

Corresponding Author: Jan A. Staessen, MD, PhD, Studies Coordinating Centre, Division of Hyper-

tension and Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of Leu-

ven, Campus Sint Rafaël, Kapucijnenvoer 35, Block D, Box 7001, BE-3000 Leuven, Belgium.

E-mail: jan.staessen@med.kuleuven.be.

Risk Stratification by BMI and ABP -3-

Expanded Methods

Study population

As described in detail elsewhere (1), we constructed the International Database on Am-

bulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO). Stud-

ies were eligible for inclusion, if they involved a random population sample, if baseline infor-

mation on the ambulatory BP and cardiovascular risk factors was available, and if the sub-

sequent follow-up included both fatal and nonfatal outcomes. Baseline information for each

cohort are shown in Table S1. All studies received ethical approval and have been reported

in peer-reviewed publications.

Analyzed participants were 2,142 residents from Copenhagen, Denmark (2); 1,317 in-

habitants from Ohasama, Japan (3); 1,096 subjects from Noorderkempen, Belgium (4);

1,098 older men from Uppsala, Sweden (5); 1,438 subjects from Montevideo, Uruguay (6);

349 villagers from the JingNing county, China (7); 244 subjects from Novosibirsk, the Rus-

sian Federation (8); 165 from Pilsen, Czech Republic (9); 310 from Padova, Italy (9); and

308 from Kraków, Poland (9). All participants gave informed written consent. Subjects re-

cruited in Kraków, Novosibirsk, Pilsen, and Padova took part in the European Project on

Genes in Hypertension (EPOGH) (9). All participants gave informed written consent.

BP measurement

Conventional BP was measured by trained observers with a mercury sphygmomanome-

ter (7;9;10), with validated auscultatory (3) (USM-700F, UEDA Electronic Works, Tokyo,

Risk Stratification by BMI and ABP -4-

Japan) or oscillometric (6) (OMRON HEM-705CP, Omron Corporation, Tokyo, Japan) de-

vices, using the appropriate cuff size, with participants in the sitting (3;4;6-10) or supine (5)

position. Conventional BP was the average of 2 consecutive readings obtained either at

the person’s home (4;6-9) or at an examination center (3;5;10). We programmed portable

monitors to obtain ambulatory BP readings at 30 minute intervals throughout the whole day

(3), or at intervals ranging from 15 (10) to 30 (5) minutes during daytime and from 30 (10) to

60 (5) minutes at night. The devices implemented an auscultatory algorithm (Accutracker II)

in Uppsala (5) or an oscillometric technique (SpaceLabs 90202 and 90207, Nippon Colin,

and ABPM 630) in the other cohorts (3-9).

The same SAS macro processed all ambulatory recordings, which generally stayed

unedited. The Ohasama recordings were edited sparsely according to previously published

criteria (11). Within individual subjects, we weighted the means of the ambulatory BP by

the interval between readings. When accounting for the daily pattern of activities of the par-

ticipants, we defined daytime as the interval ranging from 10:00 h to 20:00 h in people from

Europe (4;5;8-10) and South America (6), and from 08:00 h to 18:00 h in those from Asia

(3;7). The corresponding night-time intervals ranged from midnight to 06:00 h (4-6;8-10)

and from 22:00 h to 04:00 h (3;7). These fixed intervals eliminate the transition periods in

the morning and evening when BP changes rapidly, resulting in daytime and night-time BP

levels that are within 1–2 mm Hg of the awake and asleep levels (7;12).

In line with current guidelines (13;14), we defined conventional hypertension as a BP

equal to or exceeding 140 mm Hg systolic or 90 mm Hg diastolic. The corresponding

thresholds for daytime ambulatory hypertension were 135 mm Hg systolic and 85 mm Hg di-

astolic. Patients on antihypertensive drug treatment were classified according to the

achieved BP. Normotension and sustained hypertension were a consistently normal or con-

Risk Stratification by BMI and ABP -5-

sistently elevated BP on conventional and ambulatory measurement(13;14). White-coat hy-

pertension was a raised conventional BP in the presence of a normal daytime BP (13;14).

Masked hypertension was an elevated ambulatory BP with normal conventional BP (13;14).

Irregular heart rate was defined as an average real variability of 24-h heart rate

(ARV24) in the highest decile (≥12.05). The ARV averages the absolute differences

of consecutive measurements and accounts in this manner for the order in which the

measurements are obtained. It is calculated by the following formula:

where k ranges from 1 to N-1 and wk is the time interval between HRk and HRk+1.

N is the number of heart rate readings (15).

Risk Stratification by BMI and ABP -6-

References

(1) Thijs L, Hansen TW, Kikuya M, Björklund-Bodegård K, Li Y, Dolan E, et al. The Inter-

national Database of Ambulatory blood pressure in relation to Cardiovascular Out-

come (IDACO) : protocol and research perspectives. Blood Press Monit

2007;12:255-62.

(2) Hansen TW, Jeppesen J, Rasmussen F, Ibsen H, Torp-Pedersen C. Ambulatory

blood pressure monitoring and mortality : a population-based study. Hypertension

2005;45:499-504.

(3) Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, Michimata M, et al. Prog-

nostic significance of the nocturnal decline in blood pressure in individuals with and

without high 24-h blood pressure : the Ohasama study. J Hypertens 2002;20:2183-

9.

(4) Staessen JA, Bieniaszewski L, O'Brien ET, Imai Y, Fagard R. An epidemiological ap-

proach to ambulatory blood pressure monitoring : the Belgian population study.

Blood Press Monit 1996;1:13-26.

(5) Ingelsson E, Björklund K, Lind L, Ärnlöv J, Sundström J. Diurnal blood pressure pat-

tern and risk of congestive heart failure. JAMA 2006;295:2859-66.

(6) Schettini C, Bianchi M, Nieto F, Sandoya E, Senra H, Hypertension Working Group.

Ambulatory blood pressure. Normality and comparison with other measurements.

Hypertension 1999;34 (part 2):818-25.

Risk Stratification by BMI and ABP -7-

(7) Li Y, Wang JG, Gao HF, Nawrot T, Wang GL, Qian YS, et al. Are published charac-

teristics of the ambulatory blood pressure generalizable to rural Chinese? The

JingNing population study. Blood Press Monit 2005;10:125-34.

(8) Kuznetsova T, Malyutina S, Pello E, Thijs L, Nikitin Y, Staessen JA. Ambulatory

blood pressure of adults in Novosibirsk, Russia : interim report on a population

study. Blood Press Monit 2000;5:291-6.

(9) Kuznetsova T, Staessen JA, Kawecka-Jaszcz K, Babeanu S, Casiglia E, Filipovský

J, et al. Quality control of the blood pressure phenotype in the European Project on

Genes in Hypertension. Blood Press Monit 2002;7:215-24.

(10) Hansen TW, Jeppesen J, Rasmussen S, Ibsen H, Torp-Pedersen C. Ambulatory

blood pressure monitoring and risk of cardiovascular disease: a population based

study. Am J Hypertens 2006;19:243-50.

(11) Ohkubo T, Imai Y, Tsuji I, Nagai K, Ito S, Satoh H, et al. Reference values for 24-

hour ambulatory blood pressure monitoring based on a prognositic criterion. The

Ohasama Study. Hypertension 1998;32:255-9.

(12) Fagard R, Brguljan J, Thijs L, Staessen J. Prediction of the actual awake and asleep

blood pressures by various methods of 24 h pressure analysis. J Hypertens

1996;14:557-63.

(13) O'Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, et al. Practice guide-

lines of the European Society of Hypertension for clinic, ambulatory and self blood

pressure measurement. J Hypertens 2005;23:697-701.

Risk Stratification by BMI and ABP -8-

(14) Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., et al.

Seventh report of the Joint National Committee on Prevention, Detection, Evalua-

tion, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.

15) Mena L, Pintos S, Queipo NV, Aizpúrua JA, Maestre G, Sulbarán T. A reliable index

for the prognostic significance of blood pressure variability. J Hypertens.

2003;23:505-511.

Risk Stratification by BMI and ABP -9-

Table S1. Baseline information for each cohortCohortreference

Period of recruitment

Invited Participated Eligible for in-clusion in IDACO*

Excluded from the present analyses**

Included in the present analy-

sisCopenhagen Hansen TW. Am J Hypertens. 2006; 19(3): 243-59

1993-94 3,794 2,656 (70.0%) 2,311 169 (7.3%) 2,142

Ohasama Ohkubo T. J Hyperten. 2002; 20(11): 2183-9

1987-91 1,989 1,542 (77.5%) 1,535 218 (14.2%) 1,317

NoorderkempenLi Y. Hypertension. 2007; 49(6): 1291-7

1985-2005 4,277 3,338 (78.0%) 2,904 1,808 (62.3%) 1,096

UppsalaIngelsson E. JAMA. 2006; 295(24): 2859-66

1991-95 1,681 1,221 (72.6%) 1,143 45 (3.9%) 1,098

MontevideoSchettini C. Hypertension. 1999; 34 (4 pt 2): 818-25

1995-98 2,650 2,070 (78.1%) 1,859 421 (22.6%) 1,438

JingNingLi Y. Blood Press Monit. 2005; 10(3): 125-34

2003-05 839 509 (60.7%) 360 11 (3.1%) 349

EPOGHStolarz-Skrzypek K. JAMA. 2011; 305(17): 1777-85

1999-2001 1,721 1,187 (68.9%) 1,055 28 (2.6%) 1,027

EPOGH (European Project on Genes in Hypertension) includes participants recruited at Kraków, Novosibirsk, Padova and Pilsen. * Having ambulatory blood pressure and covariables measured at baseline and having information on fatal and nonfatal outcomes.** Excluded because they were younger than 18 years, because their conventional blood pressure had not been measured, or because they had fewer than 10 daytime or 5 nighttime blood pressure readings.

Risk Stratification by BMI and ABP -10-

Table S2. Adjusted hazard ratios according to the cross-classification of participants by conventional and daytime

ambulatory blood pressureQuartiles of BMI

Limits, kg/m2 ≤22.6 >22.6 to ≤25.1 >25.1 to ≤27.9 >27.9 P

Total mortality

White-coat hypertension 1.34 (0.93, 1.94) 0.92 (0.62, 1.38) 1.18 (0.82, 1.72) 1.04 (0.70, 1.55) 0.87

Masked hypertension 1.66 (1.17, 2.36)† 1.46 (1.03, 2.06)* 1.04 (0.70, 1.54) 0.76 (0.50, 1.15) 0.015

Sustained hypertension 1.66 (1.23, 2.24)‡ 1.26 (0.95, 1.68) 1.21 (0.89, 1.63) 1.13 (0.83, 1.53) 0.21

All cardiovascular endpoints

White-coat hypertension 0.92 (0.56, 1.52) 0.90 (0.57, 1.43) 1.45 (0.97, 2.16) 1.48 (0.93, 2.36) 0.23

Masked hypertension 1.83 (1.21, 2.77)† 1.95 (1.32, 2.89)§ 1.44 (0.97, 2.15) 1.21 (0.78, 1.89) 0.29

Sustained hypertension 2.18 (1.54, 3.09)‡ 1.92 (1.34, 2.68)§ 1.72 (1.25, 2.37)‡ 1.93 (1.37, 2.75)‡ 0.37

The definition of the BP categories is given in the eMethods. White-coat, masked and sustained hypertension had a prevalence of 7.9%, 12.2% and 13.6% in the low BMI quartile, 8.5%, 14.0% and 21.2% in the medium-low quartile, 11.7%, 15.5% and 29.6% in the medium-high quartile and 12.8%, 14.0% and 39.9% in the high quartile. Hazard ratios (95% confidence intervals) express the risk of white-coat hypertension, masked hypertension and sustained hy-pertension vs. normotension in quartiles of BMI. The hazard ratios were stratified for cohort and adjusted for sex, age, smoking and drinking, serum cholesterol, history of cardiovascular disease, diabetes, and treatment with antihypertensive drugs. Significance of the hazard ratios: *≤0.05; †≤0.01; ‡≤0.001. The P-values are for the linear trend in the hazard ratios across the BMI categories.

Risk Stratification by BMI and ABP -11-Table S3. Hazard ratios for total mortality in relation to BMI category and 24-h systolic BP

Subgroup analyzed

(n° of deaths/n) at risk

Quartiles of BMI

Low Medium-low Medium-high High Pcon Pint

Europeans and South Americans (980/6,801)

BMI 1.20 (1.07, 1.35)† 0.96 (0.86, 1.07) 0.88 (0.79, 0.98)* 0.99 (0.89, 1.10) 0.010 0.97

Systolic BP 1.10 (0.97, 1.26) 1.16 (1.02, 1.32)* 1.23 (1.08, 1.40)† 1.11 (0.99, 1.26)

European and Asians (1,175/7,029)

BMI 1.21 (1.08, 1.35)‡ 1.02 (0.92, 1.13) 0.83 (0.75, 0.92)‡ 0.98 (0.88, 1.09) <0.0001 0.80

Systolic BP 1.12 (0.99, 1.25) 1.22 (1.08, 1.37)‡ 1.27 (1.13, 1.44)‡ 1.11 (0.89, 1.23)

Nonsmokers (831/6,037)

BMI 1.18 (1.03, 1.35)* 0.96 (0.85, 1.09) 0.91 (0.85, 1.09) 0.97 (0.86, 1.10) 0.11 0.39

Systolic BP 1.19 (1.02, 1.38)* 1.22 (1.06, 1.42)† 1.10 (0.94, 1.28) 1.20 (1.04, 1.38)*

Not treated for hypertension (774/6,648)

BMI 1.10 (0.95, 1.26) 1.05 (0.93, 1.18) 0.91 (0.80, 1.03) 0.96 (0.85, 1.09) 0.32 0.50

Systolic BP 1.10 (0.95, 1.27) 1.25 (1.09, 1.43)† 1.22 (1.06, 1.41)† 1.09 (0.95, 1.24)

Subjects with regular 24-h heart rate rhythm (1,131/7,621)

BMI 1.17 (1.09, 1.26)‡ 0.99 (0.92, 1.06) 0.89 (0.83, 0.96)† 1.01 (0.94, 1.08) 0.44 0.93

Systolic BP 1.15 (1.02, 1.29)* 1.20 (1.06, 1.36)† 1.17 (1.03, 1.33)* 1.14 (1.02, 1.28)*

Women (396/3,978)

BMI 1.18 (0.98, 1.42) 1.13 (0.96, 1.34) 0.91 (0.79, 1.09) 0.82 (0.69, 0.98)* 0.049 0.77

Systolic BP 1.17 (0.95, 1.45) 1.34 (1.10, 1.64)‡ 1.23 (0.98, 1.55) 1.20 (0.97, 1.50)

Men (875/4,489)

BMI 1.16 (1.02, 1.31)* 0.93 (0.83, 1.05) 0.85 (0.76, 0.96)* 1.08 (0.96 ,1.22) 0.0084 0.89

Systolic BP 1.10 (0.98, 1.25) 1.13 (0.99, 1.30) 1.22 (1.05, 1.40)† 1.08 (0.96, 1.22)

Hazard ratios (95% confidence intervals) express the risk of death associated with categories of BMI (vs. the average risk in the analyzed population) or for a 1- SD in-crease in the 24-h BP (~15.0 mm Hg). Hazard ratios were stratified for cohort. In addition to BMI and 24-h BP, all models included sex, age, smoking and drinking, serum cholesterol, history of cardiovascular disease, diabetes, and treatment with antihypertensive drugs (where appropriate). Significance of the hazard ratios: * ≤0.05; † ≤0.01; and ‡ ≤0.001. PCon denotes the significance of the likelihood ratio testing the contribution of BMI quartiles to the prediction of death over and beyond BP and Pint ex-presses the significance of the interaction between BP and BMI

Risk Stratification by BMI and ABP -12-

Figure S1. Incidence of death (A) or of a composite cardiovascular endpoint (B) by cross-classification of BMI and conventional systolic BP

categorized into quartiles. The incidence rates were standardized for cohort, sex and age (<60 and ≥60 years).

Risk Stratification by BMI and ABP -13-

Figure S2. Absolute 10-year risk of death (A) or a composite cardiovascular endpoint (B) in relation to conventional systolic BP in classes

of body mass. For clarity, the second and third quartile of BMI were combined, because the risk functions were coincident. Risk estimates

were stratified for cohort and adjusted for sex, age, serum cholesterol, smoking and drinking, history of cardiovascular disease, diabetes,

and antihypertensive drug treatment. P values are for the independent contributions to risk of BMI and conventional systolic BP.