COMMENTARY Hemodynamic Biomarker-Initiated Anticipation Medicine in the Future Management of Hypertension Kazuomi Kario1,2 Hypertension, defined by the increased average of systolic and/or diastolic blood pressure (BP) values, is a well-established risk factor for cardiovascular disease. Accumulating evidence indicates that independently of an individual’s average BP levels, increased BP variability presents risks of both cardiovascular events and organ damage.1–9 There are various types of BP variability with time phases that range from the shortest beat-by-beat variability to orthostatic, psychological, or physical stress-induced, diurnal, day-byday, office or clinic visit-to-visit, seasonal changes, and the longest yearly variability,8 and some of these can be examined by methods such as office, home, and ambulatory BP measurements. Nearly all of the phenotypes of BP variability correlate with each other to some degree, and nearly all have been reported to be cardiovascular risk factors. BP variability is both a sensor of cardiovascular dysregulation that is affected by an individual’s characteristics, medication status, and the many daily stressors of environmental conditions and psychobehavioral factors, and a modifiable risk factor for cardiovascular disease and organ damage. BP variability is thus considered a “master biomarker” in the healthcare field.1 The components of different types of BP variability may be generated by different mechanisms and may have different clinical impacts on cardiovascular disease. A long-term increase in the average of BP values would be considered a chronic risk factor for advancing endothelial dysfunction and subsequent atherosclerosis, whereas relatively short-term exaggerated BP variability (e.g., the BP surge) would be considered an acute risk factor that triggers an atherothrombotic cardiovascular event by a mechanical stress-induced plaque rupture. These different roles of the risks presented by BP variability are similar to the risks of heart failure, i.e., chronically progressing left ventricular hypertrophy and the triggering of acute heart failure by afterload mismatch due to an abrupt increase in systolic BP. We recently published the “resonance hypothesis” of BP variability, which postulates that when various BP surges with different time phases are synchronized by resonance, dynamic BP surges are generated, triggering the abovedescribed cardiovascular events.10 BP is a vertical mechanical force to the arterial wall, and the BP waveform during one systole is the shortest BP variability. In this issue of the American Journal of Hypertension, Dr H.C. Chen’s research group demonstrates an independent association between the BP waveform assessed by tonometry once in the laboratory and BP variability assessed by ambulatory BP monitoring (ABPM). In their study, among the hemodynamic variables, backward wave reflection calculated based on the carotid BP waveform11,12 was an independent and potent determinant of relatively short-term (24 hour) ambulatory BP variability. The magnitude of backward reflection wave but not the arterial stiffness evaluated by the carotid-femoral pulse wave velocity was independently associated with the read-to-read average real variability.13 It is interesting that the magnitude of the reflection wave assessed even just one time in steadystate laboratory conditions was a major determinant of the dynamic ambulatory BP variability during active daily life. Clinically, an assessment of the BP reflection wave even once in a clinic or doctor’s office may be useful to identify high-risk patients with exaggerated BP variability in ambulatory situations. Since 24-hour ambulatory BP variability is affected by various factors including the individual’s behavior, physical activity, and psychological stress as well as environmental conditions such as temperature and atmospheric pressure, the BP magnitude of the reflection wave that can be assessed in the office may be a better hemodynamic biomarker than conventional ABPM-derived BP variability as the therapeutic target. As the next step, it is important to validate more effective reductions in BP variability by antihypertensive medications targeting the reflection wave, in comparisons with conventional medications in hypertensive patients with higher reflection wave magnitudes. Vasodilators such as calcium antagonists are good candidates to reduce reflection wave and BP variability.14,15 Correspondence: Kazuomi Kario (firstname.lastname@example.org). 1Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan; 2Jichi Medical University Center of Excellence, Cardiovascular Research and Development (JCARD), Tochigi, Japan. Initially submitted November 18, 2016; accepted for publication November 30, 2016; online publication January 7, 2017. doi:10.1093/ajh/hpw160 © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: email@example.com 226 American Journal of Hypertension 30(3) March 2017 Commentary Arterial wave reflections arise mainly from the distal arterial tree, and the reflected component calculated from the carotid pressure waveform is the summation of each wave from the different distal reflection points. Thus, the magnitude of the reflection wave may be one of the new integrated cardiovascular biomarkers that reflect the functional and structural vascular properties of each peripheral artery at the different reflection sites, such as vascular tonus, arteriosclerosis, atherosclerosis (at more proximal sites), small artery remodeling, etc. In fact, previous studies demonstrated that the magnitude of the reflection wave is a predictor of cardiovascular events including heart failure.16,17 In addition, the higher magnitude of the reflection wave of the carotid waveform may reflect the functional synchronization of each reflection wave from the different sites. Increased central sympathetic tonus may synchronize each reflection wave from the different peripheral reflection sites, resulting in a greater total magnitude of the reflection wave calculated using the carotid waveform. This may explain why the relatively short-term ambulatory BP variability, which is closely influenced by sympathetic nervous activity, was more closely associated with the reflection wave than the carotidfemoral pulse wave velocity, which is a measure of vascular stiffness of the central artery. The assessment of forward and backward (reflection) waves calculated from BP waveforms obtained by 24-hour ABPM and/or home BP monitoring in relation to the assessment of stressors such as individual physical activity and environmental conditions (e.g., temperature, atmospheric pressure) would be helpful to estimate the physiological and pathological generations of BP variability on an individual basis. To detect the effects of different stressors on individual hemodynamic properties, we developed a new information communication technology (ICT)-based home and ABPM device equipped with (i) high-sensitive actigraphy that can detect the wearer’s fine-scale physical movements in 3 directions, (ii) a thermometer, and (iii) a barometer (i.e., ICTbased multisensor ABPM [IMS-ABPM], A&D Co, Tokyo). This device can be used for both ABPM and home BP monitoring, and it stores the data of intra-cuff pressure and each waveform. The device can then send the data to a data center by ICT. Using this device, we can examine the following 3 hemodynamic properties under resting-home and active-ambulatory conditions (Figure 1): (i) the cardiac ejection wave and vascular reflection wave form, by a waveform analysis, (ii) various types of BP variability such as day-by-day home BP variability, disrupted circadian BP variability, and morning ambulatory BP surges, by a variability analysis, and (iii) BP reactivity based on the slope of the ambulatory BP increase against activity just before the BP measurement (actisensitivity), based on the slope of temperature (thermosensitivity)1,2,7 or that of atmospheric pressure (atmospheric sensitivity). Using these indices, we have introduced the concepts of “trigger-induced BP reactivity index” to identify specific high-risk patients as those with “thermosensitive hypertension,” “actisensitive hypertension,” or “atmospheric hypertension,” respectively. These forms of situational BP reactivity may interact with each other as well as with sleep quality and salt sensitivity. The assessment of individual hemodynamic profiles will contribute to precision medicine for cardiovascular disease. Combined with the reduction of the average of BP levels, real-time ICT-based hemodynamic biomarker-initiated anticipation medicine1 that can predict BP changes based on individual hemodynamic profiles and provide early intervention by an ICT-based real-time feedback system could prevent or combat the onset, recurrence, and severity of cardiovascular events, resulting in healthy lives and increased longevity. Figure 1. Home and ambulatory blood pressure monitoring for assessing 3 hemodynamic properties. Abbreviations: ABPM, ambulatory BP monitoring; BP, blood pressure; BPV, BP variability; CVD, cardiovascular disease. American Journal of Hypertension 30(3) March 2017 227 Commentary DISCLOSURE Dr Kario has received research grants from Teijin Pharma Ltd, Shionogi Pharma K.K., Mochida Pharmaceutical Co Ltd, Omron Healthcare Co Ltd, and Fukuda Denshi and honoraria from Takeda Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd. REFERENCES 1. Kario K. Evidence and perspectives on the 24-hour management of hypertension: hemodynamic biomarker-initiated ‘anticipation medicine’ for zero cardiovascular event. Prog Cardiovasc Dis 2016; 59: 262–281. 2. Kario K. Essential Manual of 24-hour Blood Pressure Management from Morning to Nocturnal Hypertension, Wiley-Blackwell, London, UK, 2015, pp 1–138. 3. Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol 2013; 10:143–155. 4.Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, Sever PS, Poulter NR. 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