Preface

Toward a chronomically interpreted home ABPM
The desire prevails in current everyday medical practice for the fiction of a stable, "true"
blood pressure measurement, that is of "the average pressure over long periods of time"1-6. It is
mistakenly assumed that, in a long record, blood pressure is time-invariant, yet variations aboveand below ﬁxed threshold (such as 140/90 or 135/85 mm Hg) are commonly seen from one day
to another, from one week to another, from one month or even longer spans to the next span ofsimilar duration, even for the 24-hour rhythm-adjusted mean value (MESOR). For instance, inthe light of chronobiologic reference values, half-yearly summaries of half-hourly around-theclock measurements, in a case studied for decades, changed from MESOR-hypertensive in one
span to normotensive in the next such span. This fact and very many others7-9 question a diagnosis
based on ofﬁce measurements with one or a few 24-hour ambulatory blood pressure monitorings(ABPM), the current false platinum standard1-6. The ofﬁcially recommended goal of current WHOor national guidelines remains today to estimate a "true ﬁxed" (yet imaginary!) pressure and tocompare it with a ﬁxed (gender-, age- and time-invariant) threshold as a reference standard. The
consequence is that false negative and false positive diagnoses abound and calling them whitecoat hypertension or masked hypertension does not alter the number of misdiagnoses and hence of
mistreatments or of failures to treat when this is indicated.
The foregoing status quo ignores the predictable variability due to the many cycles in andaround us, apparent to the unaided eye in any around-the-clock and along-the-years record.
Measurements are usually lower by night than by day; they vary further, not only with the seasons,but often more so with frequencies found in the solar wind, shorter than a half-year (cis-halfyears
or quinmensals) or longer than a calendar year, near- and far-transyears) and further with one
cycle in one, two or more than three decades. Even the location along the 24-hour scale of highand low values can change as a function of time, not only in shift-workers or after transcontinental
ﬂights but also in severe depression.
A clearly lengthened circadian period is seen in the (acro)phase domain in row 3 of Figure
1 during half-yearly recurring depressions lasting 2-3 months (often coexisting in this casewith a 24-hour component, not seen in the ﬁgure), characterizing blood pressure and heart rateof a 61-year-old woman (JF) who experiences a circadian vascular, endocrine and behavioral
ecfrequentia during her downtimes7). Section IV of Figure 2 7) visualizes this vascular variability
anomaly, VVA, or in the case of Figure 1, where it recurs, a vascular variability disorder, VVD.
VVAs and VVDs are defined only abstractly in Figure 2, but they are actually diagnosed byreference to data from gender- and age-matched peers 8;cf.7). For the same case of JF, Figure 3
shows that if the values during sleep are omitted, the diagnosis of ecfrequentia cannot be made 9):
the diagonal delaying course of acrophases in row 3 is no longer seen on the right where, for the
analysis, values during sleep are omitted.

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Figure 1 Chronobiologic serial section ofsystolic blood pressure of JF, a 61-yearold woman at start of monitoring. Dashedhorizontal lines at 0˚ and 360˚ indicate midnightin row 3. Numbers on abscissa are full moons.
Acrophases − peaks in the best-ﬁtting 24-hourcosine function − in row 3 show a horizontal
time course in the first 2 months indicating
24-hour synchronization; they occur at about thesame time in the afternoon. They start delaying
after the second full moon and run diagonallywith a period longer than 24 hours, scanning thislength for the next 3 months. These acrophases
are resynchronized after full moon 5, only todesynchronize again after full moon 8.
© Halberg

Figure 2 Abstract visualization of vascularvariability anomalies, VVAs, found in 7-day
around-the-clock records. If replicated several
times, VVAs can be called vascular variability
disorders, VVDs.
© Halberg* Validated by chronobiologic analysis ef
around-the-clock 7 day/24-hour records ofmeasurements at 1-hour or shorter intervals,
interpreted in the light of time-specified
reference standards qualiﬁed by gender andage.
** E c f r e q u e n t i a : s h o r t f o r f r e q u e n c y ( f )alteration (e.g., desynchronization) that canbe Dysfrequentia when associated withsymptoms and/or persisting in repeatedconsecutive 7-day records.

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Figure 3
JF's data during sleep as wellas waking are required for the diagnosisof circadian ecfrequentia (left, row 3). The
diagonal, systematically changing time course ismissed when data during sleep are removed.
© Halberg

One's view changes further when one has found trans (= beyond)- tridecadal cycles (ofabout 35 years) in sets of around-the-clock series covering decades. One set of about 6 daily
measurements extends from 20 to beyond 60 years, an entire clinically healthy adulthood; anotherbegins with an acceptable blood pressure, to arrive, after two decades, at a high average bloodpressure (MESOR-hypertension). The MESOR, estimated by curve fitting, is usually moreaccurate and more precise than the arithmetic mean. In several other long series covering decades,
one finds a mostly acceptable MESOR of blood pressure under treatment yet with occasional
VVAs if not VVDs, all findings that must be detected to be corrected, if a high risk of severe
cardiovascular disease associated with VVDs is to be avoided.
Thus, previously mysterious non-photic, unseen features of human life become readily
apparent under the virtual telescope of chronomics, the study of interactions among time structures(chronomes) in and around us, approached with glocality in time as in space. Glocality in space10)
means that globally valid approaches can be applied to ﬁnd differences locally geographically, as
Prof. Otsuka does for health surveillance in cities in Hokkaido and Kochi, as well as within the
Arctic Circle and at high altitudes in the Indian subcontinent 11-15).
For a methodologic temporal glocality, we can prospectively as well as retrospectively lookglobally at ever longer cycles with repeated passes over the same data until we dispose of an entire
4-decade-long time series for assessing any transtridecadal cycle, while the same data for bloodpressure and heart rate are also analyzed in weekly and longer sections of the time series as-onegoes, locally in time for their circadian and infradian characteristics. The sections may serve the3individual for severe disease prevention, while the same blood pressures and heart rates are further
pooled and aligned with time series of terrestrial and extraterrestrial weather to ﬁnd, e.g., an about
35-year cycle, off and on, in rainfall and environmental temperature, important in human affairs,
bearing on problems of global warming, economics and military-politics. Further nonphotic cycles
include those of about (~) a week, ~ a month, 5, 6 or 16 months, as well as decadal, didecadal ortranstridecadal cycles. Quinmensals, semiannuals and transannual cycles, along with circadiansand circannuals, can all be monitored, e.g., by systolic blood pressure as are mental functions, tostudy mechanisms, e.g., of terrorism on a population basis, Figures 4 and 5 16), while initially thesame data served, as noted, for the detection and personalized treatment of VVAs in 7-day aroundthe-clock records as a start. These 7-day proﬁles are to be repeated once an abnormality is found,and, if a VVD is conﬁrmed, continuous, e.g., half-hourly monitoring is advocated, that may serve
everybody anyhow, once affordable, cuff-free unobtrusive instrumentation becomes available for
automatic transfer into a multilingual also automatic website that does on a large scale what isbeing done by a project BIOCOS for all comers free of charge.

Figure 4 Weather in space, that is the speed of the solar wind, and terrestrial magnetism, may trigger
terrorism at a transannual frequency, at which terrorism, as a population phenomenon, may continue toresonate after the environmental stimuli can no longer be detected.
© Halberg* Seen by bracketing dots (delineating 95% conﬁdence intervals of the acrophase, a measure of thetiming of overall high values recurring in each cycle, obtained by the ﬁt of a 16.27-month cosine curveby chronobiologic serial section, using an 8-year interval displaced by 1 month throughout the timeseries.
** Solar wind speed data from the omniweb (http://omniweb.gsfc.nasa.gov/), aa index from NOAA
(ftp://ftp.ngdc.noaa.gov/STP/GEOMAGNETIC_DATA/AASTAR) and number of terrorist acts (N/day,assessed monthly) from the Terrorism Knowledge Base (httpz//www.tkb.org/) from the Memorial
Institute for the Prevention of Terrorism (MIPT).

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Figure 5 Some inferentially statistically validated congruences of human somatic and mental functions
with the environment, gauged by the antipodal geomagnetic disturbance value (aa) (top) and solar windspeed (SWS) (bottom). While limited to a single clinically healthy case, RBS, a man aging during thestudy from 20 to 60 years of age, discussed in detail elsewhere, the number of congruences found for theestimation of 1-minute and for mood in the spectral range investigated (from one cycle in 2.5 years to 3
cycles per year) more than equals that of the known association of helio- and geomagnetism, commented
upon in 1852 by Gen. Sir Edward Sabine (on the basis of too few data) -- "... it is certainly a most striking
coincidence, that the period, and the epochs of minima and maxima, which M. SCHWABE has assigned
to the variation of the solar spots, are absolutely identical with those which have here been assigned tothe magnetic variations". When congruence is assessed by means of the odds ratio based on the noncentral hypergeometric distribution, mental functions show higher congruence than somatic functions;among the latter, SBP is responsive, perhaps constituting a seemingly acceptable approximation for themental functions.
© Halberg

Against the background of these thoughts, it is a pleasure to introduce a book on bloodpressure by Prof. Kuniaki Otsuka. We do this with deep personal affection and continue tolearn from him, ﬁrst from 297 cases that served to deﬁne and compare ﬁve of the major VVAs,
including MESOR-hypertension and a circadian overswing or circadian hyper-amplitude-tension,
CHAT. In Asians, if several of these VVDs persist and coexist, they raise cardiovascular diseaserisk within 6 years to nearly 100%, Figure 6 17). Second, we owe Prof. Otsuka the original
introduction of a glocal approach that is global and local in space10-15) and can be glocal in time.
For the practitioner of medicine and the educated lay person, the late Thomas G. Pickering,recipient of the prestigious Franz Volhard Award, asked in 2008 rightly 1;cf.2-6): "Should doctors
still measure blood pressure?" 1). Pickering also advocated, as do we, an international data base of
ABPM studies. His father, Sir George White Pickering, Regius Professor of Medicine at Oxford
University18), had delivered the ﬁrst Volhard lecture in 1972. Concern about blood pressure was5Figure 6
Prof. Kuniaki Otsuka's major original contribution: the incidence of VVDs was assessedin a clinic population of 297 patients. Blood pressure (BP) and heart rate (HR) of each subject weremonitored around the clock for two days at 15-minute intervals at the start of study. Each record wasanalyzed chronobiologically and results interpreted in the light of time-speciﬁed reference limits qualiﬁed
by gender and age. On this basis, MESOR-hypertension (MH, diagnosed in 176 patients), excessive
pulse pressure (EPP), CHAT (a circadian overswing), and a deﬁcient heart rate variability (DHRV) wereidentified and their incidence related to outcomes (cerebral ischemic attack, coronary artery disease,nephropathy, and/or retinopathy). Outcomes, absent at the start of study in these non-diabetic patients,
were checked every six months for six years, to estimate the relative risk associated with each VVD
alone (primary diagnosis, PD) or in combination with 1, 2, or 3 additional VVDs. Earlier work showed that
CHAT was associated with a risk of cerebral ischemic event and of nephropathy higher than MH, andthat the risks of CHAT, EPP, and DHRV were mostly independent and additive. It thus seemed important
to determine the incidence of each VVD, present alone or in combination with one or more additional
VVDs. The 176 patients with MH were broken down into 103 (34.7% of the population of 297 patients)
with uncomplicated MH, 55 (18.5%) with MH complicated by one additional VVD, 15 (5.1%) and 3 (1.0%)
with MH complicated by two or three additional VVDs. In the last group, all three patients had a morbid
outcome within six years of the BP monitoring. Ambulatory BP monitoring over only 48 hours, used for
diagnosis, is much better than a diagnosis based on casual clinic measurements, yet its results apply
only to groups. With this qualiﬁcation, of the 176 patients with MH, 73 (42.2%) had additional VVDs thatfurther increase their vascular disease risk, and that are not considered in the treatment plan of thesepatients since current practice does not assess these VVDs. This proportion may be smaller when VVDs
are diagnosed on the basis of a 7-day record (available for CHAT). Results related to EPP (bottom
left), CHAT (upper right), and DHRV (bottom right) illustrate that these conditions can be present in theabsence of MH in as many as 12 (4.0%) of the 297 subjects. Since they do not have MH, it is unlikelythat these subjects would be treated from a conventional viewpoint, even though their vascular diseaserisk can be as high as or even higher than MH. Evidence suggests that treating these conditions may
translate into reducing morbidity and/or mortality from vascular disease. Another lesson is that aroundthe-clock monitoring of BP and HR interpreted chronobiologically is needed, even in the absence of MH,
to detect vascular disease risk associated with VVDs such as CHAT and DHRV, that cannot be assessedon the basis of casual clinic measurements, so that non-pharmacologic and/or pharmacologic intervention
can be instituted in a timely fashion before the occurrence of adverse outcomes. Once implemented
across the board rather than in selected patient populations, vascular disease could be curbed to a muchlarger extent at relatively low cost if the monitoring is offered directly to the public and care providers
become involved only after detection of a VVD. A website has to be built to educate, interest and serve
many people and to provide cost-free analyses in exchange for the deidentiﬁed data, that as a pool areused for monitoring solar effects upon the biosphere. On a small scale, these services are now provided
worldwide by the world-wide BIOCOS project (corne001@umn.edu). This ongoing personalized yet alsosocietally oriented approach is an alternative to a polypill that as yet ﬂies blind in the sense that it neither
detects nor treats VVDs and VVSs.
© Halberg* Results stem from 207 patients, among which only 34.7 % had uncomplicated MESOR-hypertension(upper left, N=0) and 40.7 % were MESOR-normotensive, including 2.4 % and 1.7 % with only CHAT
or DHRV, respectively (right top and bottom, N=0). For complementary results on 1,177 untreatedpatients, see Hypertension 2007; 49; 237-239.

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Figure 7 Top: With the relatively small sample sizes of 6 patients with a moderately elevated fasting
glucose and a slightly abnormal glucose tolerance versus 6 healthy controls, all undergoing 7-day/24hour ambulatory BP and HR monitoring, analyses indicate that a chronobiological approach works whena classiﬁcation in terms of "dipping" based on the day-night ratio (DNR) fails. Indeed, no abnormality
was detected in the light of time-speciﬁed reference standards qualiﬁed by gender and age among the 6controls, but 4 of the 6 pre-diabetic patients showed one or more VVDs (P<0.001). By contrast, in bothgroups, there were two patients with a DNR > 20% ("excessive dipping") and one patient with a DNR< 10% ("non-dipping"). It was thus impossible to discriminate the patients with pre-diabetes from thehealthy controls in terms of "dipping", when a chronobiological interpretation worked 20).
Middle and bottom: Circadian parameters and day-night ratios (DNRs) of systolic blood pressure(SBP) are compared between groups of presumably healthy MESOR-normotensive subjects and prehypertensive subjects with incipient signs of minimal change hypertensive retinopathy. Minimal retinal
alterations, presumably reflecting an increased vascular disease risk, are associated with a higher
MESOR and a larger circadian amplitude of SBP (P<0.01). A classiﬁcation in terms of dipping, based on
the DNR of SBP, however, is misleading, as the pre-hypertensive patients as a group are "dippers" with a
DNR between 10% and 20%, but the MESOR-normotensive controls as a group are non-dippers, with a© Halberg
DNR of SBP below 10% 22).

in the Pickering family time structure (chronome1-6,18)), if not in their genome. (The Volhards −Jakob, the father [a chemist] who synthesized creatinine, and Franz, the son [a clinician], who
preceded Goldblatt in focusing scholars of blood pressure on the kidney − had the kidney intheir chronomes.) As clinicians, both Sir George and Tom Pickering eventually (Tom was a fastlearner1 vs. 2-6)) helped focus attention on the indispensability of ABPM, and Tom also on modern
data bases. Hence this book is dedicated to their memories.
Pressure is being monitored continuously in the tires of modern cars to avoid accidents, and insmall animals to develop drugs. If there is a popular demand stemming from those who read Prof.
Otsuka's book, affordable, unobtrusive technology will become available to continuously monitor
the individual's pressure, to allow one to know oneself, to learn from VVA analysis what one
likes and dislikes, a problem as yet unsolved 19), and further to treat VVAs, preferably before they
become VVDs and VVSs, as well as when these latter conditions already prevail. A classiﬁcation
by dipping, its positive aspects on large groups notwithstanding, is no substitute; it may mislead,
Figure 7 20-22).

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Figure 8 Currently, a project on The BIOsphere and the COSmos (at corne001@umn.edu) provides
analyses multilingually, in English, French and German (and as soon as possible in Arabic andSpanish) to all comers worldwide, in exchange for the data. These analyses serve multiple purposestransdisciplinarily: for the person monitored, the analyses diagnose any VVD and guide treatment via
consultation by a care provider for lifelong self-help in continuously monitored sphygmochrons, datasummaries in the light of gender, age and other temporal norms. The data in turn also serve for eventually
improving reference standards (after lifetime records from disease-free subjects become available) andto look for novel harbingers in records from individuals with hard events. Furthermore, the data can beused with illustrations to educate the public and care professionals. Finally, analyses of the data ﬂow
can monitor solar activity with signatures in blood pressure and heart rate and in archived hard events.
The Phoenix Project of volunteering members of the Twin Cities chapter of the Institute of Electrical andElectronics Engineers (http://www.phoenix.tc-ieee.org) is planning on developing an inexpensive, cufﬂess
automatic monitor of BP and on implementing the concept of a website (www.sphygmochron.org) fora service providing automatic analyses in exchange for the data that in turn are to be used for reﬁning
methods and for monitoring psychophysiological effects of space weather.
© Halberg

We need not fly blind 23): the conventional blood pressure cuff must be removed from thephysician's ofﬁce; instead, home ABPM can be interpreted chronomically (C-ABPM) today by
BIOCOS (corne001@umn.edu) and eventually by an automatic multilingual website, Figure 8;
it is immediately feasible for a personalized health care, e.g., for stroke prevention and further forproviding data for monitoring the cosmos and eventually for the development of rational methods
to prevent social diseases such as crime and terrorism. What is good for cars' tires and drug
development is recommended for those who drive the cars and who may wish to avoid the needfor drugs by early prevention as well as for those who wish to use these drugs with monitoring of
the treatment of VVDs, as needed.

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1988 年，東京女子医大東医療センターを訪れ，時間医学とは何かについて講義をするハルバーグ教授（67 歳）

Franz Halberg, M.D., Dr. h.c. (mult.):- Montpellier- Ferrara- Tyumen- Brno- L'Aquila- Moscow (People's Friendship University of Russia)
Professor of Laboratory Medicine and Pathology,
Physiology, Biology, Bioengineering and Oral Medicine
Co-director, Halberg Chronobiology Center
University of Minnesota
US MAIL: Campus Mail Code 8609 - MMC 609
OFFICE: 715 Mayo Memorial Building
420 Delaware St. S.E.
Minneapolis, MN 55455, USA
PHONE +1 (612) 624.6976, 624.3144 OR 626.5404
FAX +1 (612) 624.9989
HOME PHONE +1 (651) 454.6334 (mornings)
E-MAILhalbe001@umn.edu
URLhttp://www.msi.umn.edu/~halberg/,http://www.franz-halberg.wosco.org

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Japan Society of Neurovegetative Research. Tokyo, November 1-3, 2006. p. 32.
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7. Halberg F, Cornélissen G, Cegielski N, Hillman D, Halberg Francine, Schwartzkopff O, McCraty R, Finley
J, Thomas F, Kino T, Chrousos G, Sonkowsky RP, El-Khoury M, Ilyia E. Circadian dysfrequentia ofcortisol, melatonin, DHEA, testosterone and estradiol. In: Halberg F, Kenner T, Fiser B, Siegelova J, editors.
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RB, BIOCOS project. Extended consensus on need and means to detect vascular variability disorders (VVDs)
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9. Hillman D, Finley J, Halberg F, Cornélissen G, Thomas F, Ilyia E, McCraty R, Singh RB, Kino T, Chrousos G.
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10. Otsuka K, Cornélissen G, Norboo T, Takasugi E, Halberg F. Chronomics and "glocal" (combined global andlocal) assessment of human life. Invited presentation, Nishinomiya-Yukawa International & Interdisciplinary
Symposium 2007, What is Life? The Next 100 Years of Yukawa's Dream, Yukawa Institute for Theoretical
Physics, Kyoto University, October 15-20, 2007. Progress of Theoretical Physics 2008; Suppl 173: 134-52.
11. Otsuka K, Oinuma S, Cornélissen G, Weydahl A, Ichimaru Y, Kobayashi M, Yano S, Holmeslet B, Hansen
TL, Mitsutake G, Engebretson MJ, Schwartzkopff O, Halberg F. Alternating-light-darkness-influenced
human electrocardiographic magnetoreception in association with geomagnetic pulsations. Biomedicine &Pharmacotherapy 2001; 55 Suppl 1: s63-s75.
12. Otsuka K, Cornélissen G, Schwartzkopff O, Bakken EE, Halberg F, Burioka N, Katinas GS, Kane R, Regal PJ,
Schaffer E, Sonkowsky R, Patterson R, Engebretson M, Brockway B, Wang ZR, Delmore P, Halpin C, Sarkozy
S, Wall D, Halberg J. Clinical chronobiology and chronome-geriatrics: At variance with recommendations ofsubsequent guidelines, yet focusing indeed on pre-hypertension in the physiological range. Biomedicine &Pharmacotherapy 2003; 57 Suppl 1: 164-198.
13. Otsuka K, Yamanaka G, Shinagawa M, Murakami S, Yamanaka T, Shibata K, Yano S, Ishizuka S, Singh
RB, Cornélissen G, Halberg F. Chronomic community screening reveals about 31% depression, elevatedblood pressure and infradian vascular rhythm alteration. Biomedicine & Pharmacotherapy 2004; 58 Suppl 1:
S48-S55.
14. Otsuka K, Cornélissen G, Weydahl A, Holmeslet B, Hansen TL, Shinagawa M, Kubo Y, Nishimura Y, Omori
K, Yano S, Halberg F. Geomagnetic disturbance associated with decrease in heart rate variability in a subarctic
area. Biomedicine and Pharmacotherapy 2001; 55: 51-56.
15. Otsuka K, Norboo T, Otsuka Y, Higuchi H, Hayajiri M, Narushima C, Sato Y, Tsugoshi T, Murakami S, Wada T,
Ishine M, Okumiya K, Matsubayashi K, Yano S, Chogyal T, Angchuk D, Ichihara K, Cornélissen G, Halberg F.
Effect of aging on blood pressure in Leh, Ladakh, a high-altitude (3524 m) community, by comparison with aJapanese town. Biomedicine & Pharmacotherapy 2005; 59 Suppl 1: S54-S57.
16. Halberg F, Cornélissen G, Sothern RB, Katinas GS, Schwartzkopff O, Otsuka K. Cycles tipping thescale between death and survival (= "life"). Invited presentation, Nishinomiya-Yukawa International &Interdisciplinary Symposium 2007, What is Life? The Next 100 Years of Yukawa's Dream, Yukawa Institutefor Theoretical Physics, Kyoto University, October 15-20, 2007. Progress of Theoretical Physics 2008; Suppl
173: 153-181.

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17. Otsuka K, Cornélissen G, Halberg F. Predictive value of blood pressure dipping and swinging with regard tovascular disease risk. Clinical Drug Investigation 1996; 11: 20-31.
18. Richardson DW, Honour AJ, Fenton GW, Stott FH, Pickering GW. Variation in arterial pressure throughout the
day and night. Clin Sci 1964; 26: 445-460.
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20. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with abnormal circadian
blood pressure variability. J Human Hypertension 2008; 22(9): 627-633. doi:10:1038/jhh.2008.32.
21. Cugini P, Cruciani F, Turri M, Regine F, Gherardi F, Petrangeli CM, Gabrieli CB. 'Minimal-change
hypertensive retinopathy' and 'arterial pre-hypertension', illustrated via ambulatory blood-pressure monitoringin putatively normotensive subjects. International Ophthalmology 1999; 22(3): 145-149.
22. Cornélissen G, Halberg F, Beaty L, Kumagai Y, Halberg E, Halberg J, Lee J, Schwartzkopff O, Otsuka K.
Cugini's syndrome in statu nascendi: Oratio contra morem prevalentem et pro chronobiologica ratione adpressione sanguinis curandam. La Clinica Terapeutica 2009; 160 (2): e13-e24.
23. Fossel M. Editor's Note (Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka K, Watanabe Y,
Kumagai Y, Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff O. Circadian Hyper-AmplitudeTension, CHAT: a disease risk syndrome of anti-aging medicine. J Anti-Aging Med 1998; 1: 239-59). J AntiAging Med 1998; 1: 239.

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