Franz Halberg’s research while affiliated with University of Minnesota Medical Center, Fairview and other places

Hypertension is associated with high morbidity and mortality. Blood pressure (BP) levels vary widely due to predictable biological rhythms and unpredictable environmental factors. Daily (circadian) rhythm characteristics are considered essential parameters for recognizing and treating increased risks in BP. Franz Halberg spent most of his academic career in cardiovascular research, focused on ambulatory monitoring and developing chronobiological methods for clinical application. To compare BP Variability (BPV), automatically monitored ambulatory BP around the clock at 30-60 min intervals in 20 human subjects was compared with telemetered circadian BP in rats after one-cell homozygous embryo-transfer into spontaneously hypertensive (SHR, pup:shr) or normotensive (WKY, pup:wky) rats' oviducts (embryos: s,w; oviduct-uterus: S,W) and cross-suckled at birth (nurses S,W). The circadian response peaked in the late afternoon hours in most human subjects and early morning hours in rats. Human circadian double amplitudes (2A) varied from 8 to 26 mm Hg with higher 2A in elder adults, and 3-8 mm Hg in rats with significantly higher fluctuations in SHR groups (7.5±0.7 for sSS, 8.3±0.6 for sSW vs. 4.7±0.3 mm Hg for wWW). The circaseptan 2A in the adolescents were 10±1 for SBP and 12±3 mm Hg for DBP, and sharp increased winter 2A (SBP 54; HR 48, both P<0.0001) were observed. In rats, mostly clustered peaks around the light-on hours, while sWS and wSS groups showed peak-hour variations (19:18 to 08:06 and 02:58 to 09:10 hrs, respectively). The peak-hour in shr strains was shifted to earlier or delayed in the WKY uterus (sWW and sWS groups) with large deviations as compared to the wWW group. Hypertensive-prone shr strains showed significantly lowered BPs in WKY uterine and/or WKY nursing environments indicating that environment can strongly modify genetic influence, yet the lowered shr MESORs by the WKY environments remained above the MESORs encountered in wky donors. Thus, the maternal environment may be a major factor that affects the offspring’s BP and BPV later in life. Chronomes broader than circadian BPs are considered as a gauge of vascular disease status. Abnormal BP/BPV modifications may lead to novel implications in preventive and therapeutic strategies in CVD.

Blood pressure (BP) fluctuates due to complex interactions between genetic factors and environmental stimulation. BP variability (BPV) is a physiological phenomenon, as a measure of hemodynamic conditions reflected in the autonomic nervous system. Daily (circadian) rhythms as biological time structures are considered essential parameters for recognizing and treating BP risk factors. Thus, ambulatory BP and heart rate (HR) were monitored (ABPM) in 11 normotensive (NT) in a free living, and 13 borderline hypertensive (BH) adults with Na and weight (WT, Kg) interventions in a freely moving lab environments, around the clock at 30-minute to hourly intervals. In the intervention study, circadian BP, HR, urinary aldosterone (Aldo, μg/h), creatinine (Cr), Na, K in mEq/h and Na/K ratio were compared. Data was analyzed by the linear least square rhythmometry method. All subjects showed significant circadian fluctuations in BP (mm Hg) and HR (beats/min). The circadian response peaked in the noon to late afternoon hours in the NT and in the reference stage of the intervention study. In NT, SBP: 111±2 with variability 14.6% and peak hr at 16:00; DBP: 74.0±1 with variability 16.0% and peak hr at 15:40; and HR: 64.3±2 with peak hr at 16:96 (-254°). In the intervention study with reference (I), Na restriction (II) and weight (WT) reduction (III) stages, SBP: 130±3.7; 130±1.7; 116±1.7 with variability (SBPV), 27.5, 31.4, and 25.4%; peak hrs at 16:26, 13:52; 12:24, respectively; DBP: 85±2.3; 83±2.2; 77±1.9 with variability (DBPV), 21.1, 26.4, 33.5%; peak hrs at 16:15, 18:29, 07:52, respectively; and HR: 64±2.1; 61±2.1; 66±2.3 with HRV, 30.2, 34.6, 28.3%; peak hrs at 15:07; 14:64, 14:55, respectively. Circadian UAldo: 0.63, 0.73, 0.58; UNa: 6.3, 2.9, 3.5; UK: 3.1, 3.1, 2.9; and WT: 89.9, 87.8, 83.2 in I, II, and III study stages, respectively. Thus, BP and HR, and their variabilities are the factors readjusted in the Na and WT reductions, and the peak shifted to earlier hours in the intervention. The variability, in the reference stage already higher than the NT levels, was not favorably changed with Na and WT interventions, although BP was normalized, especially following the WT reduction. Increased or shallow amplitudes may be predictive risk factors of vascular disease.

There is a strong connection between space weather and fluctuations in technological systems. Some studies also suggest a statistical connection between space weather and subsequent fluctuations in the physiology of living creatures. This connection, however, has remained controversial and difficult to demonstrate. Here we present support for a response of human physiology to forcing from the explosive onset of the largest of space weather events—space storms. We consider a case study with over 16 years of high temporal resolution measurements of human blood pressure (systolic, diastolic) and heart rate variability to search for associations with space weather. We find no statistically significant change in human blood pressure but a statistically significant drop in heart rate during the main phase of space storms. Our empirical findings shed light on how human physiology may respond to exogenous space weather forcing.

Communicable and non‐communicable diseases show coperiodisms (shared cycles) with the sun's and earth's magnetism. About 11‐year cycles and components with periods a few weeks or a few months longer than one year (near‐ and far‐transyears, respectively) are the cases in point. Published data on the incidence of malaria in Burundi, Papua New Guinea, and Thailand are analysed by the linear‐nonlinear cosinor to assess the relative prominence of transyears versus the calendar year. An about 2.3‐year component characterizes malaria incidence in Burundi and Papua New Guinea (Thailand data were only sampled yearly). Long‐term trends cannot be distinguished from the presence of an about 11‐year cycle found in a 100‐year long record from Chizhevsky on mortality from cholera in Russia, albeit its second harmonic is statistically significant in Burundi’s data. Whereas far‐ and near‐transyears characterize malaria incidence in Burundi more prominently than the calendar year, only a candidate near‐transyear of small amplitude is barely detected in Papua New Guinea, where the calendar year is most prominently expressed. Both regions are located near the equator. Selectively‐assorted geographic differences such as these, observed herein for a communicable disease, have been previously observed for non‐communicable conditions, such as sudden cardiac death.

Adversity with erythropoietin (Epo) treatment (Epo-Rx) is grim in the cardio-cerebrovascular system. Because circadian rhythmic variability is an important aspect of cardiovascular function, we evaluated circadian blood pressure (BP), hematocrit (Hct), body and spleen weight (BW, SW) variability immediately before and after 4-week, twice-weekly course of Epo-Rx (50 U/kg) along with physiological saline (control), pure human Epo-receptor protein (Epo-bp) and anti-Epo-bp antibody (αEpo-bp) groups at midnight, 4 AM, 8 AM, noon, 4 PM and 8 PM in Sprague-Dawley rats. In our earlier report, Epo-Rx increased BP, Hct and SW markedly overall compared with saline, Epo-bp, and αEpo-bp groups (Hypertension 2007;50:439-45). In this current report, variability (%) of BP, Hct, BW and SW are compared. Epo-bp treated BP Variability (BPV) was lower than others (9.5 vs. 15.5 control and others in similar values). Phase changes were noticed when exposed to Epo (daytime peaks in Epo, Epo+Epo-bp and Epo+αEpo-bp). Hct variability (HctV) in Epo and Epo-bp treated groups shows somewhat lower than in control group (18.3 in C vs. 13.3, 12.9, and 19.4 in Epo, Epo-bp and αEpo-bp, respectively). However, Epo effect was additive to HctV when Epo was added to Epo-bp or αEpo-bp (32.0 and 30.4, respectively). All 5-study groups showed phase changes, although Epo-exposed groups had a much greater magnitude with markedly increased Hct (peak at 19:00 in control and 5 study groups during the daytime through noon-hour peaks). BW variability is similar in each group (except lower BW in the Epo-group) with various peak hours but SW variability (SWV) showed a similar pattern as shown in HctV. Best treatment times for Epo, Epo+Epo-bp and Epo+αEpo-bp were estimated: BP at 4 PM, 4 AM and 4 AM, respectively; Hct at 4 AM and both at midnight, respectively; SW at midnight, 8 PM and noon, respectively. Thus, significantly increased BPV, HctV and SWV in Epo-Rx than those of other groups and extremely increased Hct resulted in splenomegaly.

This chapter sketches some of the highlights of chronobiology. In a nutshell, considering time as the fourth dimension in biology amounts to changing variability from foe to friend. Akin to the splitting of the “indivisible” atom, chronobiology indeed splits the otherwise neglected seemingly indivisible range into rhythms and other predictable changes, such as trends and chaotic behavior.

In this chapter, we introduce case presentations of the circadian and circaseptan (i.e., about 7 day) profiles of blood pressure (BP), including “ambulatory BP (ABP) normotension,” “white-coat hypertension,” “BP morning surge,” and “Monday BP surge,” from a viewpoint of 7-day/24-hour ABP monitoring.

Franz Halberg (1919–2013) developed chronobiology and founded the field of chronomedicine including chronomics, chronoastrobiology, and chronobioethics. His work is summarized in his over 3,600 scientific publications, in cooperation with colleagues from around the world. Progress in chronomedicine depends on how his research developed. Several international meetings have revealed an accumulating body of reference values for well-established about-daily and about-yearly rhythms of photic origin. Evidence was also provided for about-7-day, about-27-day, about-half-yearly, about-10.5 and about-21-yearly, and even about-50-yearly rhythmicities in us as well as around us, as invisible nonphotic heliogeophysical signatures possibly built into individuals and/or populations. In time series, biological or other, the characteristics of rhythms, chaos, and trends can all be quantified as elements of structures, called chronomes. Chronome mapping with outcomes could eventually serve an individualized optimization of lifestyle, for chronoprevention and chronotherapy as well as for inquiries into the evolution and future of life. The historical path of Franz Halberg’s research leading to chronomedicine is presented herein.

In this chapter, we introduce case presentations of vascular variability anomalies, including the Midline-Estimating Statistics Of Rhythm (i.e., MESOR)-hypertension and circadian hyper-amplitude-tension (i.e., CHAT), BP ecphasia, excessive pulse pressure, and “vascular variability syndrome,” from a viewpoint of 7-day/24-hour ABP monitoring.