Prognosis in Relation to Blood Pressure Variability

Abstract

HomeHypertensionVol. 65, No. 6Prognosis in Relation to Blood Pressure Variability Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBPrognosis in Relation to Blood Pressure VariabilityCon Side of the Argument Kei Asayama, Fang-Fei Wei, Azusa Hara, Tine W. Hansen, Yan Li and Jan A. Staessen Kei AsayamaKei Asayama From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.-F.W., A.H., J.A.S.); Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (K.A.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A.); the Steno Diabetes Center, Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L.); and VitaK Research and Development, Maastricht University, Maastricht, The Netherlands (J.A.S.). Search for more papers by this author , Fang-Fei WeiFang-Fei Wei From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.-F.W., A.H., J.A.S.); Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (K.A.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A.); the Steno Diabetes Center, Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L.); and VitaK Research and Development, Maastricht University, Maastricht, The Netherlands (J.A.S.). Search for more papers by this author , Azusa HaraAzusa Hara From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.-F.W., A.H., J.A.S.); Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (K.A.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A.); the Steno Diabetes Center, Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L.); and VitaK Research and Development, Maastricht University, Maastricht, The Netherlands (J.A.S.). Search for more papers by this author , Tine W. HansenTine W. Hansen From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.-F.W., A.H., J.A.S.); Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (K.A.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A.); the Steno Diabetes Center, Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L.); and VitaK Research and Development, Maastricht University, Maastricht, The Netherlands (J.A.S.). Search for more papers by this author , Yan LiYan Li From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.-F.W., A.H., J.A.S.); Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (K.A.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A.); the Steno Diabetes Center, Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L.); and VitaK Research and Development, Maastricht University, Maastricht, The Netherlands (J.A.S.). Search for more papers by this author and Jan A. StaessenJan A. Staessen From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.-F.W., A.H., J.A.S.); Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (K.A.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A.); the Steno Diabetes Center, Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L.); and VitaK Research and Development, Maastricht University, Maastricht, The Netherlands (J.A.S.). Search for more papers by this author Originally published27 Apr 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.04808Hypertension. 2015;65:1170–1179Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Blood pressure variability includes short-term, circadian, and long-term components. Assessment of blood pressure variability requires multiple readings obtained within a single or several visits, by home or 24-hour ambulatory blood pressure monitoring, or by beat-to-beat recordings. Factors that affect visit-to-visit and diurnal blood pressure variability, as reviewed elsewhere1–6 include ethnicity,1 sex,2,3 age,2,3 hypertension,3 body mass index,2,3 use of β-blockers,3,4 a history of cardiovascular disease,2,5 renal dysfunction,5 diabetes mellitus,2 a sedentary lifestyle,5 and socioeconomic position.6The prognostic significance of blood pressure variability remains controversial. Some studies reported association of end-organ damage,7–9 cardiovascular events,4,10–15 or mortality5 with blood pressure variability, whereas others failed to do so or found variability to be inferior to the level of blood pressure.3,16,17 Several publications proposing that the magnitude of the morning blood pressure surge predicted stroke,18 in particular cerebral hemorrhage,19 or cardiovascular endpoints20 remained unconfirmed in recently published large-scale observational studies.21–23 This review will address the current controversy on the morning blood pressure surge, highlight the methodological problems in capturing blood pressure variability, and illustrate how large international population studies and a clinical trial do not support blood pressure variability as target in the management of hypertension.Methodological IssuesCurrent indexes of blood pressure variability raise methodological issues related to their poor reproducibility, their interdependence, and their association with the level of blood pressure.Morning Surge—Inconsistent Definitions and Poor ReproducibilityWe will use the morning surge in blood pressure as a showcase to highlight how inconsistent definitions and poor reproducibility limit the clinical applicability of indexes of blood pressure variability. In 2003, Kario et al18 introduced 2 definitions of the morning surge in blood pressure (Figure 1A). The sleep-through morning surge is the difference between the morning pressure (the average blood pressure during the 2 hours after awaking) and the lowest nighttime blood pressure (the average of the lowest pressure and the readings immediately preceding and following the lowest value). The preawaking morning surge is the difference between the morning blood pressure (the average blood pressure during the 2 hours after waking up) and the preawakening blood pressure (the average blood pressure during the 2 hours before waking up). Other investigators redefined the preawakening morning surge because the blood pressure differences >1-hour interval prior and after awakening or the blood pressure difference between all readings during sleep and those obtained >2 hours after awakening.24 Several investigators reported that an exaggerated morning surge predicted outcome.18–20 However, using a variety of definitions of a single index of blood pressure variability induces confusion and raises the suspicion that definitions were revised to serve the hypothesis to be proven.Download figureDownload PowerPointFigure 1. Derivation of the morning blood pressure surge (A) and ARV24 (B) from 24-hour ambulatory blood pressure recordings. The sleep-through morning surge is the difference between the morning pressure and the lowest nighttime blood pressure. The preawakening morning surge is the difference between the morning blood pressure and the preawakening blood pressure (see text for more details). The ARV24 averages the absolute differences between consecutive readings and thereby accounts for the order of the blood pressure readings. For distinct blood pressure signals, SD can be the same, whereas ARV24 is not. ARV24 indicates average real variability over 24 hours. Reprinted from Kario et al18 and Hansen et al.17In 2008, we analyzed the substudy25 on ambulatory blood pressure monitoring to the Systolic Hypertension in Europe (Syst-Eur) trial.26 Patients underwent 24-hour ambulatory blood pressure monitoring twice before randomization at a 1-month interval and once 10 months after randomization to double-blind placebo.25 In 173 patients with repeat recordings within 33 days (median), the short-term repeatability coefficients, expressed as percentages of maximal variation, ranged from 35% to 41% for the daytime and nighttime blood pressure, but from 52% to 75% for the sleep-through and the preawakening morning surge, higher values representing worse reproducibility. In 219 patients with repeat recordings within 10 months (median), the corresponding long-term estimates ranged from 45% to 64% and from 76% to 83%, respectively. In categorical analyses of the short-term repeatability of the sleep-through morning surge and the preawakening morning surge, using the 75th percentile as arbitrary cutoff, surging status changed in 28.0% and 26.8% of patients (κ-statistic, ≤0.33). In the long-term, these proportions were 32.0% and 32.0%, respectively (κ-statistic, ≤0.20). The κ-statistic indicating moderate reproducibility is 0.4. Stergiou et al24 confirmed the poor intraindividual reproducibility of the blood pressure surge in the morning after sleep and in the evening after the siesta.24 Using the 4 definitions described above,18 the κ-statistics were consistently <0.20.24The poor reproducibility of the morning surge and per extension blood pressure variability in general can be ascribed to several factors. Within individuals, blood pressure levels differ between rapid eye movement sleep and non–rapid eye movement sleep. Rapid eye movement sleep is accompanied by neural sympathetic and electroencephalographic activity similar to that when awake, with distinct cardiovascular effects. In contrast, non–rapid eye movement sleep is characterized by a suppression in neural sympathetic activity, resulting in a decrease in blood pressure.27 Ambient temperature and season influence blood pressure levels during sleep and during daytime. Cold conditions result in higher morning blood pressure surge and in later sleep stage transition and delayed sympathetic activation.28 The position of the cuff relative to the heart level introduces variability, in particular during sleep, when subjects cannot consciously control body position. Getting up methods, such as using an alarm clock, being waked up, or natural awakening, affect blood pressure rising at awakening. For patients on antihypertensive drugs, the times of dosing (eg, morning versus evening) and the duration of action of the drugs administered influence blood pressure level and the diurnal blood pressure variability, including the magnitude of the morning surge.Blood Pressure Variability—Association with Blood Pressure LevelA major problem in many reports is that they assessed target organ damage or the incidence of events as a function of blood pressure variability indexes that are highly dependent on blood pressure level. In the early 1970s, Clement et al29 assessed blood pressure variability from the SD and the coefficient of variation of blood pressure measurements obtained every 5 minutes for 3 hours in 70 untreated hypertensive patients. Sympathetic activity correlated with the level and the SD of blood pressure, but not with the coefficient of variability, a measure of variability that is less dependent on level than the SD.29 In the 1980s, Mancia et al30, by analyzing continuous 24-hour intra-arterial recordings replicated the observation that SD, but not coefficient of variation, is highly dependent on the blood pressure level. Nevertheless, until today, investigators continue using the SD to capture blood pressure variability.Other measures of variability, such as the weighted SD,31 the difference between the maximum minus minimum blood pressure level (MMD) and average real variability (ARV)32 remains highly dependent on blood pressure level. The weighted SD is the mean of day and night SD values weighted for the number of hours covered by these 2 periods during ambulatory monitoring. ARV is the average of the absolute differences between consecutive readings, weighted for the between-reading time intervals and accounting for the order of the blood pressure readings (Figure 1B). More recently, Rothwell et al4,11 proposed blood pressure variability independent of the mean (VIM) as a new index. VIM4,11 is the within-subject SD divided by the within-subject mean blood pressure level to the power x and multiplied by the population mean blood pressure level to the power x. The power x is obtained by fitting a curve through a plot of SD against mean blood pressure level, using the model SD=a×meanx, where x is derived by nonlinear regression. The correlation of VIM with the other indexes of blood pressure variability is high,33 but VIM does not correlate with the blood pressure level.4,11 VIM therefore allows assessing association of outcome with blood pressure variability with little confounding by blood pressure level.4,11Morning Blood Pressure SurgeInitial StudiesKario et al18 studied stroke prognosis in 519 patients with hypertension on office measurement (63.6% women; mean age, 72.5 years). They assessed silent cerebral infarction by MRI. For analysis, patients were dichotomized according to the 90th percentile of the sleep-through distribution (≥55 mm Hg). During an average follow-up of 41 months (range, 1–68 months), 44 patients experienced a stroke, of whom 2 had a silent stroke. The 53 patients in the top 10th of the sleep-through morning surge distribution, compared with the 466 remaining patients, had a higher baseline prevalence of multiple infarcts (57% versus 33%; P=0.001) and a higher stroke incidence (19% versus 7.3%, P=0.004) than the 466 remaining patients.18 The top 10 patients were also older (77 versus 72 years), had higher office (171 versus 163 mm Hg) and 24-hour (143 versus 138 mm Hg) systolic blood pressures, and were followed up for a longer period (41 versus 37 months).18 Because of these disparities, Kario et al matched 46 patients with exaggerated morning surge with 145 control patients for age and 24-hour systolic blood pressure. After matching, the relative risk of stroke in the morning surge compared with the control group was 2.71 (95% confidence interval [CI], 1.05–7.21; P=0.047).18Studies published shortly after Kario’s seminal report18 were not confirmatory.19,20 Among 1430 Japanese recruited in the framework of the Ohasama population study, the preawakening morning surge in systolic blood pressure marginally predicted cerebral hemorrhage (hazard ratio [HR] per 1-SD increase [+13.8 mm Hg], 1.34; CI, 0.95–1.89), whereas the prognostic value for ischemic stroke was far from significant (HR, 0.97; CI, 0.79–1.19). Gosse et al20 recorded 31 cardiovascular events among 507 white hypertensive patients with a mean follow-up of 92 months.20 With adjustments applied for age and 24-hour systolic blood pressure, the risk of cardiovascular events was not associated with the preawakening systolic blood pressure, calculated as the difference of the first systolic blood pressure after standing up minus the last supine systolic blood pressure at awakening. For each 1-mm Hg increase, the estimate of relative risk amounted to 3.3% (95% CI, 0.8–5.8%).20Recent EvidenceVerdecchia et al22 investigated the relation between the day-to-night blood pressure dip and the early morning surge in a cohort of 3012 initially untreated subjects with essential hypertension.22 The day-to-night reduction in systolic blood pressure showed a direct association (P<0.0001) with the sleep-through (r=0.56) and the preawakening (r=0.55) morning surge in systolic blood pressure.22 During a mean follow-up period of 8.4 years, 220 patients died and 268 experienced a cardiovascular event. A blunted sleep-through (≤19.5 mm Hg; the lowest quartile) and preawakening (≤9.5 mm Hg) blood pressure surge were both associated with an excess risk of events (HRs, 1.66 [CI, 1.14–2.42] and 1.71 [CI, 1.12–2.71], respectively). However, neither patients with a high sleep-through (>36.0 mm Hg; the highest quartile) nor those with a high preawakening (>27.5 mm Hg) systolic blood pressure had an increased risk of death or a cardiovascular complication.We21 analyzed the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO). This resource included 12 randomly recruited population cohorts with follow-up of both fatal and nonfatal outcomes. During a median follow-up of 11.4 years, 785 deaths and 611 fatal and nonfatal cardiovascular events occurred in 5645 IDACO participants (mean age, 53.0 years; 54.0% women).21 Although accounting for covariables and the night:day ratio of systolic blood pressure, the HR expressing the risk of all-cause mortality in the top 10th of the sleep-through morning surge distribution (≥37.0 mm Hg) compared with the remainder of the study population was 1.32 (CI, 1.09–1.59; Figure 2). For cardiovascular and noncardiovascular mortality, the corresponding HRs were 1.18 (CI, 0.87–1.61) and 1.42 (CI, 1.11–1.80); for all cardiovascular, cardiac, coronary, and cerebrovascular events, the HRs amounted to 1.30 (CI, 1.06–1.60; Figure 2), 1.52 (CI, 1.15–2.00), 1.45 (CI, 1.04–2.03), and 0.95 (CI, 0.68–1.32), respectively. Analyses of the risk associated with the top 10th of the distribution of the preawakening systolic morning surge (≥28.0 mm Hg) generated similar results (Figure 2). Furthermore, the risk of death or a major cardiovascular event in the 50th percentile group of the sleep-through morning surge was over 35% lower (P<0.01) than the average risk in the whole study population.21Download figureDownload PowerPointFigure 2. Multivariable-adjusted hazard ratios (95% confidence intervals [CIs]) for all-cause mortality (A and C) and for all fatal combined with nonfatal cardiovascular events (B and D) by ethnic- and sex-specific deciles of the sleep-through (A and B) and the preawakening (C and D) morning surge in systolic blood pressure in 5645 participants. The hazard ratios express the risk in deciles compared with the average risk in the whole study population and were adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, diabetes mellitus, antihypertensive drug treatment, 24-hour systolic blood pressure, and the systolic night:day blood pressure ratio. The number of events and incidence rates (events per 1000 person-years) are also given for each decile. Reprinted from Li Y et al.21In the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, Bombelli et al23 analyzed ambulatory blood pressure data of 2011 people. Cardiovascular mortality showed a positive relation with the sleep-through morning surge in unadjusted analyses (HR, 1.3; CI, 1.1–1.6), which disappeared after adjustment for covariables (HR, 0.9; CI, 0.7–1.1). Cardiovascular mortality, irrespective of adjustment, was unrelated to the preawakening morning surge (P≥0.12). Along similar lines, in this Italian population study,23 there were no differences in the risks of total and cardiovascular mortality when the bottom and top tenths of the distributions of the sleep-through and preawakening morning surge were compared (P≥0.39).Blood Pressure VariabilityIn addition to the morning surge, diurnal blood pressure variability encompasses the day-to-night changes in the blood pressure level and reading-to-reading blood pressure variability in 24-hour ambulatory blood pressure recordings. Beat-to-beat recordings allow capturing blood pressure variability, even during short-time intervals.34Diurnal Blood Pressure VariabilityIn 1988, O’Brien et al35 reported for the first time that an abnormal circadian blood pressure profile with decreased nighttime dipping had a more frequent history of stroke. Subsequent studies of populations36–39 and hypertensive cohorts40–46 usually corroborated that an elevated nocturnal blood pressure is a harbinger of an unfavorable outcome. In spite of the apparent concordance between these previously published large-scale outcome studies,36–46 several potential limitations required further clarification of the prognostic accuracy of the daytime versus the nighttime ambulatory blood pressure. Many studies considered only fatal outcomes36,37,44,45 or did not have the power to study cause-specific cardiovascular end points.36,37,39,43 Investigators dichotomized the night:day blood pressure ratio or applied widely different definitions of dipping status or of the daytime and nighttime intervals.The IDACO consortium therefore assessed the prognostic accuracy of day versus night ambulatory blood pressure in 7458 people enrolled in prospective population studies in Europe, China, and Uruguay.47 Median follow-up was 9.6 years. Adjusted for daytime blood pressure, confounders, and cardiovascular risk factors, nighttime blood pressure predicted (P<0.01) total (n=983), cardiovascular (n=387), and noncardiovascular (n=560) mortality.47 Conversely, adjusted for nighttime blood pressure and other covariables, daytime blood pressure predicted only noncardiovascular mortality (P<0.05), with lower blood pressure levels being associated with increased risk. Both daytime and nighttime blood pressure consistently predicted (P<0.05) all cardiovascular events (n=943) and stroke (n=420).47 Adjusted for nighttime blood pressure, daytime blood pressure lost prognostic significance for cardiac events (n=525; P≥0.07). Adjusted for the 24-hour blood pressure, the night:day blood pressure ratio predicted mortality, but not fatal combined with nonfatal events. Participants with a systolic night:day blood pressure ratio value of ≥1 were older, at higher risk of death, and died at an older age than those whose night:day ratio was normal (≥0.80 to <0.90).47In contrast to commonly held views, the IDACO analysis showed that daytime blood pressure adjusted for nighttime blood pressure predicted fatal combined with nonfatal cardiovascular events, except in treated patients, in whom antihypertensive drugs probably reduced blood pressure during the day, but not at night.47 The increased mortality in patients with higher nighttime than daytime blood pressure probably indicated reverse causality. The IDACO findings confirmed that both daytime and nighttime blood pressure hold valuable prognostic information.47 They supported the conclusion that recording blood pressure during the whole day should be the standard in clinical practice. A 2014 IDACO publication48 highlighted that identification of truly low-risk white-coat hypertension requires setting thresholds simultaneously to 24-hour, daytime, and nighttime blood pressures. In line with the 2007 report,47 we also demonstrated that isolated nocturnal hypertension predicted cardiovascular outcome even in patients who are normotensive on office or on ambulatory daytime blood pressure measurement.49Reading-to-Reading Blood Pressure VariabilityWe also assessed blood pressure variability from the SD and ARV (Figure 3) in 24-hour ambulatory recordings in the IDACO population.17 Higher diastolic ARV in 24-hour ambulatory blood pressure recordings predicted (P≤0.03) total (HR, 1.13; CI, 1.07–1.19) and cardiovascular (HR, 1.21; CI, 1.12–1.31) mortality and all types of fatal combined with nonfatal end points (HR, ≥1.07), with the exception of cardiac and coronary events (HR, ≤1.02; P≥0.58). Similarly, higher systolic ARV in 24-hour ambulatory recordings predicted (P<0.05) total (HR, 1.11; CI, 1.04–1.18) and cardiovascular (HR, 1.17; CI, 1.07–1.28) mortality and all fatal combined with nonfatal end points (HR, ≥1.07), with the exception of cardiac and coronary events (HR, ≤1.03; P≥0.54). SD predicted only total and cardiovascular mortality. The incremental cardiovascular risk explained by adding ARV to models already including 24-hour ambulatory blood pressure level and other covariables was <1%. Our report established that reading-to-reading blood pressure variability is an independent risk factor, significant in a statistical but not in a clinically meaningful manner. It highlighted that the level of the 24-hour blood pressure remains the primary blood pressure–related risk factor to account for in clinical practice.17Download figureDownload PowerPointFigure 3. Ten-year absolute risk of combined cardiovascular events in relation to 24-hour blood pressure (A and B) at different levels of systolic and diastolic ARV24 and in relation to ARV24 (C and D) at different levels of 24-hour systolic and diastolic blood pressure. The analyses were standardized to the distributions (mean or ratio) of cohort, sex, age, 24-hour heart rate, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. A and B, The risk functions span the 5th to 95th percentile interval of the 24-hour blood pressure and correspond to the 5th, 25th, 50th, 75th, and 95th percentiles of ARV24. C and D, The risk functions span the 5th to 95th percentile interval of ARV24 and correspond to the 5th, 25th, 50th, 75th, and 95th percentiles of the 24-hour blood pressure. P values are for the independent effect of ARV24 (Parv) and 24-hour blood pressure (Pbp). np and ne indicate the number of participants at risk and the number of events. ARV24 indicates average real variability over 24 hours; and CV, coefficient of variation. Reprinted from Hansen et al.17Within-Visit and Between-Visit Blood Pressure Variability in a Prospective StudyIn a randomly recruited Flemish population sample (n=2944; mean age, 44.9 years; 50.7% women), highly trained observers measured blood pressure 5× consecutively at each of 2 home visits and recorded the incidence of adverse health outcomes in relation to the variability of systolic blood pressure at enrolment.3 We computed VIM, MMD, and ARV for within-visit variability (WVV) and for within-visit combined with between-visit variability. We captured between-visit variability from VIM and MMD. During a median follow-up of 12 years, 401 deaths occurred and 311 participants experienced a fatal or nonfatal cardiovascular event. Overall (10 readings >2 visits), systolic blood pressure variability averaged (SD) 5.45 (2.82) units for VIM, 15.9 (8.4) mm Hg for MMD, and 4.08 (2.05) mm Hg for ARV. In multivariable-adjusted analyses, overall and within- and between-visit blood pressure variability did not predict total or cardiovascular mortality or the composite of any fatal plus nonfatal cardiovascular end point. For instance, the HRs for all cardiovascular events combined in relation to overall variability as captured by VIM, MMD, and ARV were 1.05 (CI, 0.96–1.15), 1.06 (CI, 0.96–1.16), and 1.08 (CI, 0.98–1.19), respectively. By contrast, mean systolic blood pressure level was a significant predictor of all end points under study, independent of blood pressure variability.3 These findings suggest that, in the general population, within-subject blood pressure variability does not have any prognostic signific