Prognosis in Relation to Blood Pressure Variability

Hypertension is the most powerful risk factor for the cardiovascular diseases, including stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic and peripheral arterial diseases. There is a significant variability in BP level among hypertensives; however, the diagnosis of hypertension and the therapeutic target of BP are based on the average of each BP measured. There is marked diurnal variation in the onset time of cardiovascular events, with the peak being exhibited in early morning. Blood pressure (BP) also exhibits a similar diurnal variation, with a decrease during sleep and a surge in the morning.1,2 In addition to the persistent pressor stress (averaged throughout a 24-hour period), dynamic diurnal variation in pressor stress from the nadir to the peak in the morning, that is, the morning surge in BP, would be expected to progress target organ damage and trigger cardiovascular events, particularly those occurring in the morning.3,4 Because my group first demonstrated that exaggerated morning surge in BP constitutes a risk for stroke independent of 24-hour BP,5 there has been a steady increase in cross-sectional and prospective evidence supporting the idea that morning BP surge is an independent risk factor for cardiovascular disease. Here I review the recent evidence and the remaining unresolved issues on this topic. ### Prospective Findings on Cardiovascular Events Normal morning BP surge is a physiological phenomenon, but an exaggerated morning BP surge is a cardiovascular risk. Thus, the association between the degree of morning BP surge and cardiovascular risk is not linear but rather has a threshold. There have been 6 prospective studies demonstrating that the morning surge in BP is a risk for cardiovascular events (Table 1).5–10 These studies have used 3 different definitions of the morning BP surge as follows (Figure 1): (1) a sleep-trough surge defined as the morning BP (2-hour …

Ambulatory Blood Pressure in Chronic Kidney Disease: Ready for Prime Time?

Variations in Levels of Blood Pressure: Of Prognostic Value or Not?

ome days it just doesn't pay to get out of bed.As long recognized, there is an increased risk for heart attack, stroke, and sudden death in the first few hours of the morning. 1,2In this issue of Circulation, Kario and colleagues have shown that, as for strokes, this risk is associated with a morning surge in blood pressure. 3Among the 519 elderly hypertensives in this study, the risk of stroke identified by brain MRI was 2.7-fold greater among the 55 who were in the top decile of the degree of morning surge of systolic blood pressure compared with the remaining subjects.

Morning blood pressure surge and the risk of stroke.

Morning Surge in Blood Pressure and Stroke Events in a Large Modern Ambulatory Blood Pressure Monitoring Cohort: Results of the JAMP Study.

To define the influence of morning physical activity levels on the magnitude of the morning surge in blood pressure and heart rate. Blood pressure and physical activity were simultaneously recorded in 420 patients by 24-h monitor and actigraphy. The morning surge was defined as the difference between mean blood pressure and heart rate values in the 4-h periods before and after waking; the trough-to-peak surge in blood pressure was also calculated. These values were regressed on the difference in mean (log transformed) physical activity for the same two periods. The analysis was adjusted for covariates, including age, sex, clinic blood pressure and use of antihypertensive medication, in a multiple linear regression. The mean morning surges in blood pressure and heart rate were 23/15(+/- 13/10) mmHg and 17(+/- 10) beats/min, respectively. The geometric mean increase in physical activity after waking was 33(+/- 1.5) units. The magnitudes of the morning surge in systolic blood pressure, diastolic blood pressure and heart rate were all significantly and positively correlated with the difference in mean physical activity before and after waking (P < 0.005). Greater clinic blood pressure was significantly associated with a greater morning surge in blood pressure on physical activity (P < 0.0005). The magnitude of the morning surge is significantly associated with the level of physical activity in the hours after waking. Physical activity should be taken into account when the results of ambulatory blood pressure monitoring are interpreted.

Hypertension Editors' Picks: Hypertension and Sleep.

The morning blood pressure surge

New guidelines for the management of hypertension were recently released by the European Society of Hypertension/European Society of Cardiology (the 2018 ESH/ESC guidelines) and the American College of Cardiology/American Heart Association (the 2017 ACC/AHA guidelines).1, 2 These guidelines stress the importance of out-of-office blood pressure (BP) values over that of office BP values. In Japan and other Asian countries, we have highlighted the use of the out-of-office BP-guided management of hypertension.3-5 Ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM) are the two standard measurements of out-of-office BP. Their use can detect masked (uncontrolled) hypertension (normotension in office BP and hypertension in out-of-office BP) in individuals at the highest risk of cardiovascular events.6-8 There are three clinical phenotypes of masked hypertension: morning hypertension, daytime hypertension, and nocturnal hypertension.9 Ambulatory BP monitoring has traditionally been considered the gold standard to detect the risk of high BP throughout the 24-hour day, and its use can detect all three types of masked hypertension. Toward the achievement of the goal of "zero" cardiovascular events, three components are needed for "perfect 24-hour BP control": (a) lowering the 24-hour BP level, (b) maintaining an adequate circadian rhythm, and (c) avoiding excessive BP variability including the morning BP surge.10 All three of these components can be assessed by ABPM. Extremely disrupted patterns of circadian rhythm of nighttime BP and exaggerated morning BP surge such as the riser pattern (higher nighttime BP than daytime BP) and the extreme-dipper pattern (excessive nighttime BP falls) are reported to be associated with cardiovascular risk.11-13 Home BP monitoring is frequently used in clinical practice and to identify masked hypertension defined by self-measured home BP. The use of HBPM can detect the risk of morning hypertension.14-18 The recently developed "nighttime HBPM" automatically obtains and records BP values at fixed intervals while an individual is sleeping, and it can be used as an alternative to ABPM for the assessment of nighttime BP.13 Two additional modalities have been developed to detect the risk of hypertension during sleep (especially in patients with obstructive sleep apnea): (a) "trigger nighttime HBPM" with a hypoxic episode-trigger function and a heart rate-trigger function and (b) beat-by-beat continuous surge BP monitoring.13, 19 Home BP monitoring can thus detect the risk of morning hypertension and that of nocturnal hypertension. However, HBPM would underestimate the risk of daytime hypertension, because HBPM measures an individual's blood pressure in the less stressful resting condition at home. A patient's behavior, surrounding environment, and various triggering factors affect his or her daytime ambulatory BP changes. Masked daytime hypertension (ie, normotension in office BP and hypertension in daytime BP) induced by physical activity or work- or home-related psychological stress can be detected only by ABPM. We recently developed a device that provides information/communication technology (ICT)-based multi-sensor ABPM (IMS-ABPM), which can store all of the waveforms of intra-cuff pressures during oscillometric BP measurement.20 One of the limitations of the original ABPM is the accuracy of "real" daytime BP measurements, because the daytime movement of the ABPM device wearer's upper arm may modify the intra-cuff pressure and produce BP reading artifacts. By excluding the abnormal BP values with abnormal waveforms as artifacts, we can evaluate the "real" daytime BP measurements more accurately. In addition, based on the IMS-ABPM's stored waveforms and its function of detecting an irregular heartbeat (IHB),21 the device can be used for the screening of atrial fibrillation (AF). The IMS-ABPM device is equipped with a thermosensor, a highly sensitive actigraph, and an atmospheric pressure sensor to simultaneously assess the triggers of BP surge (a pressor component of BP variability).20 By determining the association between many subjects' BP measurements and these triggers, new BP sensitivity indexes could be calculated; for example, the slope of the ambulatory BP values against specific triggers such as temperature (thermosensitivity evaluation), physical activity (actisensitivity), atmospheric pressure (atmospheric sensitivity), humidity (humidity sensitivity), and more. Based on these new indicators, we could classify the characteristics of hypertension with excessive BP sensitivity to specific triggers such as thermosensitive hypertension, actisensitive hypertension, atmospheric hypertension, and humidity-sensitive hypertension. These sensitivities might overlap and augment each other. In fact, the actisensitivity of BP (the slope of daytime BP change against physical activity change during a 5-minute period before the BP measurement) is augmented in the cold winter season compared to the warm summer in the same patients.22 This may partly explain the winter increase in the rate of cardiovascular events. The IMS-ABPM device can specifically detect masked daytime hypertension with a physical activity-induced BP surge. As an example: a 72-year-old woman developed B-type aortic dissection during the daytime. Although she had been treated with amlodipine, candesartan, and hydrochlorothiazide, the IMS-ABPM device detected abnormal 24-hour BP profiles during the year prior to the onset of aortic dissection. The riser pattern was detected in the summer (8 months before the onset), and an excessive morning surge was detected in the autumn (4 months before the onset) (Figure 1A). The patient's simultaneously calculated actisensitivity was also disrupted. The actisensitivity was within the normal range in autumn; however, the inverse actisensitivity (physical activity reduced the ambulatory BP) was found in summer (Figure 1B). The disrupted BP regulation against physical activity, which is modified by environmental (eg, seasonal) conditions, might produce the excessive BP surge that triggers cardiovascular events. Based on recent technology developments, it has been suggested that the use of ICT-based devices and a real-time feedback IoT (Internet of Things)-based system could facilitate a novel approach to patient management.22, 23 In the ImPACT program (IMpulsing PAradigm Change through disruptive Technologies program of the Cabinet Office, Government of Japan), we have successfully developed an integrated system that collects both biologic and environmental data, with the hybrid Wi-SUN/Wi-Fi transmission system (Figure 2). Environmental sensors introduced in a patient's home continuously monitor the temperature, humidity, and illumination in different rooms with different conditions throughout 24-hour periods. An ICT-based wrist-type pulse wave monitoring device (wearable monitoring) which we also developed in the ImPACT program continuously monitors the wearer's pulse rate, pulse wave, and activity. With the combination of these biological sensor devices, environmental sensors, and the hybrid Wi-SUN/Wi-Fi transmission system, the environmental determinants of BP surges (ie, the pressor component of BP variability) with different time phases could be used to identify the riskiest places and times at which an individual's maximum BP surge is exaggerated at home throughout the year (Figure 3). Health information technology (HIT) solutions like this are increasingly being recognized as an important component of the advances in health care, and the latest version of the ACC/AHA hypertension guidelines highlight the importance and emerging roles of HIT.1 Using these new technologies, it is hoped that the occurrence of cardiovascular events could be anticipated based on data obtained by these novel approaches to out-of-office patient monitoring, with the ultimate goal of eliminating the occurrence of cardiovascular events in patients with hypertension. Such an approach is referred to as "anticipation medicine" for zero cardiovascular events, within which BP variability is a key biomarker.10, 19, 20, 22 The self-monitoring of blood pressure using HBPM, particularly when combined with telemonitoring, has recently been shown to facilitate the titration of antihypertensive therapy in subjects with poorly controlled hypertension in general practice, without increasing the general practitioner's workload.24, 25 This highlights the potential for ICT-based out-of-office BP measurement solutions in clinical practice. There is a gap between the guideline-initiated general management of hypertension and the individualized optimal management of hypertension. An increase in the number of out-of-office BP measurements could increase the sensitivity and specificity of the average BP-based diagnosis of hypertension (as guideline-based medicine), and this increase in data could also detect the various specific trigger-induced BP surges, that is, diurnal, day-by-day, and seasonal BP surges (as individualized medicine) (Figure 4). The resonance hypothesis holds that the exaggerated pathological surge BP generated by the resonance of different BP surges with different time phases would trigger cardiovascular events.26 The times and places at which the surge BP is generated would be the most risky times/places for an individual's cardiovascular event onset. Even among well-controlled hypertensive patients, the morning BP surge remains significant in the winter.27 Anticipation medicine for cardiovascular diseases—which both anticipates pathological surge BP based on the previous time series of individual BP data and avoids the generation of surge BP—is an ideal future practical direction to take in order to decrease the gap between the guidelines and individualized medicine in the era of ICT-based "real-world" big data analysis and feedback systems. This paper was supported in part by the IMpulsing PAradigm Change through disruptive Technologies (ImPACT) program of the Cabinet Office, Government of Japan. We thank Makoto Kato, Hiroko Masaki, Tomohide Sato, Satoshi Hoshide, Tomoyuki Kabutoya, Kimiyo Saito, and Tomoko Shiga for their support. We also thank Shinobu Ozaki, Yoshiteru Nozoe, Shinichi Takahashi, and Takahiro Fujiwara from A&D Co. for developing IMS-ABPM, wearable wrist pulse monitoring, and the ICT-based data collecting system, and Takeya Shigezumi, Terumi Sata, and Takashi Naiki from Rohm Co. for developing multi-sensors and the real-time and hybrid Wi-SUN/Wi-Fi transmission system. This paper was supported in part by the IMpulsing PAradigm Change through disruptive Technologies (ImPACT) program of the Cabinet Office, Government of Japan. Nobuhiko Yasui is an employee of A&D Co. Other authors report no conflicts of interest to disclose.

ObjectivesThe exaggerated surge in morning blood pressure (BP) that many patients experience upon awakening may be closely related to target organ damage and may be a predictor of cardiovascular complications....

The ability of the arterial baroreflex to regulate blood pressure may influence the magnitude of the morning surge in blood pressure (MSBP). The aim was to investigate the relationships between sympathetic and cardiac baroreflex sensitivity (BRS) and the morning surge. Twenty-four hour ambulatory blood pressure was recorded in 14 young individuals. The morning surge was defined via the pre-awakening method, which is calculated as the difference between mean blood pressure values 2 h before and 2 h after rising from sleep. The mean systolic morning surge, diastolic morning surge, and morning surge in mean arterial pressures were 15 ± 2, 13 ± 1, and 11 ± 1 mmHg, respectively. During the laboratory protocol, continuous measurements of blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were made over a 10-min period of rest. Sympathetic BRS was quantified by plotting MSNA burst incidence against diastolic pressure (sympathetic BRSinc), and by plotting total MSNA against diastolic pressure (sympathetic BRStotal). Cardiac BRS was quantified using the sequence method. The mean values for sympathetic BRSinc, sympathetic BRStotal and cardiac BRS were −1.26 ± 0.26 bursts/100 hb/mmHg, −1.60 ± 0.37 AU/beat/mmHg, and 13.1 ± 1.5 ms/mmHg respectively. Significant relationships were identified between sympathetic BRSinc and the diastolic morning surge (r = 0.62, p = 0.02) and the morning surge in mean arterial pressure (r = 0.57, p = 0.03). Low sympathetic BRS was associated with a larger morning surge in mean arterial and diastolic blood pressure. Trends for relationships were identified between sympathetic BRStotal and the diastolic morning surge (r = 0.52, p = 0.066) and the morning surge in mean arterial pressure (r = 0.48, p = 0.095) but these did not reach significance. There were no significant relationships between cardiac BRS and the morning surge. These findings indicate that the ability of the baroreflex to buffer increases in blood pressure via reflexive changes in MSNA may play a role in determining the magnitude of the MSBP.

Blood Pressure, Heart Rate Variability, and Renal Function in Nonsmoker and Smoker Hypertensive Patients.

In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted (P<or=0.03) total (HR: 1.14) and cardiovascular (HR: 1.21) mortality and all types of fatal combined with nonfatal end points (HR: >or=1.07) with the exception of cardiac and coronary events (HR: <or=1.02; P>or=0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted (P<0.05) total (HR: 1.11) and cardiovascular (HR: 1.16) mortality and all fatal combined with nonfatal end points (HR: >or=1.07), with the exception of cardiac and coronary events (HR: <or=1.03; P>or=0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added <1% to the prediction of a cardiovascular event. Sensitivity analyses considering ethnicity, sex, age, previous cardiovascular disease, antihypertensive treatment, number of BP readings per recording, or the night:day BP ratio were confirmatory. In conclusion, in a large population cohort, which provided sufficient statistical power, BP variability assessed from 24-hour ambulatory recordings did not contribute much to risk stratification over and beyond 24-hour BP.

The Need to Reduce Variability in the Study of Blood Pressure Variability