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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
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 (
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.
© American Journal of Hypertension, Ltd 2017. All rights reserved.
For Permissions, please email:
226 American Journal of Hypertension 30(3) March 2017
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
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
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.
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