Factors that must be considered while solving the problem of adequate control of blood pressure

«One reading (measurement) can only tell you that you are still alive» (Franz Halberg#)

#This statement belongs to the scientist and physician who probably knew about the dynamics of blood pressure more than anyone who ever lived – for more than 40 years, notably since the appearance of the first stationary and then – ambulatory monitors, he scrupulously studied ultradian, circadian, short-term and long-term variability, continuously inventing more and more sophisticated strategies to investigate and interpret observations of blood pressure measured by all existing methods. Monitoring data from around the world flocked to his worldwide famous chronobiology laboratory, including records from tens of thousands of people, and unique long-term, even decade-long databases. Each of the hundreds of scientists who visited Halberg’s lab was required to wear a monitor. He himself, with short interruptions, wore a monitor for over 25 years; his data figured prominently among those demonstrating their role in health surveillance as well as in studying the effect of space weather on human physiology. With colleagues around the world, he derived chronobiologic reference standards in health qualified by gender and age, which he used to identify abnormal patterns of blood pressure and heart rate variability, the so-called «Vascular Variability Disorders (VVDs)» shown in multiple outcome studies to be predictive e development of telemedicine technologies and the concept of hypertension, circadian rhythm, diagnosis, chronotherapy, of adverse cardiovascular events, ischemic cerebral events in particular.

Many physicians still believe that single blood pressure (BP) measurements provide reliable information for diagnostic purposes and treatment decisions. However, already 40 years ago, long before ambulatory BP monitoring became available, it was recognized that such strategy is nearly equal to flipping a coin and may end up in over 40% of false diagnostic conclusions (Management Committee, Australian National Blood Pressure Study, 1980). Today we know much more about BP variability (BPV). Plenty of factors heavily influence BP (irrespective of the device doctors or patients are using to measure BP). Not only are BP values influenced at the time of measurement, BPV and circadian characteristics of BP have also been shown to be affected.

«Googling» the now classic term «circadian» will find almost 10.5 million references. One may find interesting a story behind how Franz Halberg coined this term back in 1950s (Halberg et al., 2003a). Franz also taught us that there are many more important rhythmic functions reflecting cycling processes within and outside us, in the near and far environment that may affect our physiology but are much less well understood as yet and await the uncovering of their underlying mechanisms.

Why are single measurements of blood pressure uninformative and misleading?

«NORMAL» BLOOD PRESSURE – PHYSIOLOGICAL VARIABLE THAT LARGELY DEPENDS ON MANY FACTORS:

Relatively stable (linear) personal modifiers:

Sex – In men, BP is higher on average, due to hormonal characteristics; however, hormonal concentrations change dynamically, exhibiting consistent ultradian and circadian rhythms* (Cappuccio et al, 2007; Cifkova et al, 2008; Gubin et al, 2017, 2019; Li et al, 2019).

Height – BP grows almost linearly depending on height (Evans et al, 2017; Hosseini et al, 2015).

Body weight, body area surface, body mass index (BMI) – BP is much dependent on the body surface area and increases even within the normal BMI range (Evans et al, 2017).

Age – with increasing age, BP tends to increase primarily due to increase in peripheral vascular resistance (Poiseuille’s formula) (Gubin, 2000; Gubin et al, 1997, 2013) – SBP peaks around 80 years and DBP around 50 years; the circadian waveform also changes with age. With age, the structure of BP variability also changes significantly – the decrease in night BP becomes less pronounced, the 12-hour component increases, which is accompanied by a more pronounced postprandial nadir (which, however, is not due to any dinner meal (lunch BP decrease in the elderly is the smallest among all meals (Vloet et al., 2003), nor siesta (Cornelissen et al., 2008; Gubin et al., 2013, 2016). In addition, BP variability becomes less predictable with more prominent «jumps’ which are not related to activity and rest, but are observed without obvious reasons, which is a manifestation of extra-circadian dissemination (Agajanyan and Gubin, 2004; Gubin, 2012; Gubin et al, 2001, 2013, 2016).

Ethnic characteristics / personal genetic polymorphisms – due to individual genetic polymorphism of multilevel factors of BP control (Lackland, 2014; Brown, 2006).

Features of the microbiome – chemicals that are produced by intestinal and other microbiota may indirectly affect BP, including influence that may act via circadian BP control (Al Khodor et al, 2017; Yan et al, 2017).

Dynamic (nonlinear) modifiers:

Sleep – lowers BP, and diastolic, DBP, to a greater extent than systolic, SBP (Gubin et al, 2017; 2018). Both deficiency (shortened sleep duration) and excess (lengthened sleep duration) correlate with increased risk of hypertension (Grandner et al, 2018; Capuccio et al, 2007; Knutson et al, 2009; Makarem et al, 2019).

Time of day (circadian rhythm), CR * – the best model of the normal circadian pattern of BP is neither a single sinusoidal, nor a step U (Russian letter П) -shaped curve. However, the latter is currently most often used in the clinic to categorize simplified dipper / non-dipper / night-peaker profiles. The classical BP 24-hour pattern is a bimodal (two-peak curve) with morning rise, afternoon nadir and the second evening peak. Moreover, it is the evening peak that reflects the structure of the en- dogenous circadian rhythm of BP. Morning rise is a stress element accompanying the sympathoadrenal mechanism of preparation for awakening and transition from sleep to wakefulness. Its size and time of occurrence depend on a sleep mode or need to wake up on an alarm clock. Of note, some studies indicate that adding more harmonic terms (i.e., 8-hour and 6-hour components) may yield an improved approximation of the BP raw data (Gubin et al, 2000).

Physical activity* – affects SBP more prominently than DBP during daytime hours (Gubin et al., 2017). The same exercise-related physical activity has a different effect on SBP, DBP or heart rate, and the degree of change has a sinusoidal character, confirmed by Cosinor analysis, but the phase position of the daily rhythm of this dependence is almost opposite for SBP and DBP (Singh et al, 2013).

Food (Diet) * – the effect of this factor on BP requires further targeted research and may, like salt, depend on individual genetic characteristics (Stewart et al, 2019), age (Westenend et al, 1985; Stewart et al, 2019), amount and composition of food (Ahuja et al, 2009; Ndanuko et al, 2016; Fekete et al, 2018), in particular, its glucose content (Murai et al, 2017), protein content (Altorf-van der Kuil et al., 2010), salt content, as well as timing of meals (Vloet et al. (2003), duration after the last meal (Fekete et al., 2018), and frequency of daily meals (Kim et al., 2014). Contrary to popular belief that eating always lowers BP (Murai et al., 2017), this feature may depend on the initial age-dependent BP (Westenend et al, 1985). Immediately after a meal, the most typical can be a short-term rise in BP (Otsuka et al, 1990; Fekete et al, 2018), which after 30 minutes can be followed by a more pronounced decrease in BP (Fekete et al, 2018). The degree BP change in isocaloric nutrition may be different at different times. Managing only the diet can normalize BP in the long term (Ndanuko et al, 2016; Sutton et al, 2018; Cornelissen et al, 2019).

Water supply * – modulates short-term BP through plasma volume and blood flow; depends in the long term on renal physiology and kidney circadian clock status (Stow and Gumz, 2011; Ohashi et al, 2017).

Salt consumed * – increased BP response to consumed salt, however, occurs only among the carriers of a certain set of genes (Sanada et al, 2011; Elijovich et al, 2016; Hachiya et al, 2018; Choi et al, 2015). Moreover, depending not only on the habitual quantity (Graudal, et al, 2014), but also on the time, salt may exert different effects, and, accordingly, reduced salt consumption can produce unequal-to-opposite outcomes, including even reduction of BP when the amount of salt consumed is increased (Cornelissen et al, 2014).

Ambient light * – modulates BP depending on the time and nature of exposure (through the skin or through the organ of vision): BP decreases if whole body is exposed to ultraviolet light and sunlight in the daytime through modulation of NO (Stern et al, 2018; Johnson et al, 2016), or vitamin D (Rostand et al, 2016); BP increases when exposed to blue light through the organ of vision (eye) during the nocturnal phase (Gubin et al, 2017; 2018), proba- bly due to inhibition of endogenous melatonin production (Gubin et al, 2019).

Darkness (chemically mediated by melatonin) * – exposure to low light intensity (<10 lx) reduces SBP even when sleep is deprived (Gubin et al, 2017; 2018). Melatonin has a significant hypotensive effect (Scheer et al, 2004, Cagnacci et al, 2005) that depends on circadian phase timing (Gubin et al, 2013; 2016; 2018).

Ambient temperature * – modulates BP due to principles of adaptation to low and high temperatures: low temperatures usually have a pressor effect, thus elevating BP (Wang et al, 2017; Huang et al, 2019). Seasonal changes in temperature can have a more significant effect on the amplitude of the circadian phenotype of BP than on its mean value (Watanabe et al, 2017).

Emotions * – modulate BP depending on their nature and personal perception (James et al, 1986; Herrmann-Lingen et al, 2018). The importance of psychological and emotional factors deserves a focused and in-depth study: according to ABPM data, this factor’s impact on BP may exceed the action of most other factors (Halberg et al, 2010).

Sound (noise) * – modulates BP depending on the time of day and the nature of the impact (Rizk et al, 2016; Basinou et al, 2017), notably, music: «subjectively perceived harmonic sound» has BP-lowering effect in contrast to noise (do Amaral et al, 2016). In addition, influence of music on BP varies significantly depending on the time of day and circadian phase (Cornelissen et al, 2012).

Density of receptors in the heart and blood vessels (i.e., adrenergic) * – persons with high density respond via BP increase on stressing factors quickly and prominently (Ayada et al, 2015; Yiallouris et al, 2019), probably constituting a main category of the «white-coat phenome-non» (Cengiz et al, 2015).

Electromagnetic, solar and cosmic factors * – modulate BP depending on their nature and timing (Braune et al, 1998; Halberg et al, 2004, 2012).

All marked * factors will have an unequal effect on BP depending on the circadian rhythm phase (timing). Some factors will also affect the circadian rhythm characteristics (amplitude and/or acrophase). For instance, the circadian amplitude of BP can differ to a larger extent than the MESOR between summer and winter.

In addition to the above, there are complex internal physiological and biochemical factors coordinating the daily dynamics of BP (Gubin et al, 2000; Smolensky et al, 2007).

Finally, circadian (24-hour) (Otsuka et al, 1997; Cornelissen et al, 2005, 2007, 2019; Halberg et al, 2013; Her-mida et al, 2013, 2017, 2018), or circaseptan (near-weekly) (Gubin et al, 1997; Gubin, 2000, 2002), or lower frequency (longer period) (Halberg et al, 2003b; 2004) BP variability is important for predicting the risks of cardiovascular accidents.

Fundamentally important «paradoxes»:

• 1.    Abnormal circadian pattern of BP is a risk factor for cardiovascular accidents, even in the absence of an elevated average BP, determined by ABPM or by scarce

  office or self-measurements (Otsuka et al, 1997; Cornelissen et al, 2007; Halberg et al, 2012, 2013, Hermi-da et al, 2013, 2017, 2018);

• 2.    High average daily and episodic increases in daytime BP values may not reflect the risk of adverse outcomes, and, in fact, may even not necessarily be considered a pathology (Garrison et al, 2017; Hermida et al, 2018), while BP during sleep (not to be confused with «night-time» BP) is probably the most valuable and sensitive among all currently known criteria for analysis of BP (Hermida et al, 2018) in assessing the risk of catastrophic events (however, it is only if just one criterion is selected). Halberg and his team used the cumulative sum, CUSUM, approach to ascertain the efficacy of treatment. These findings surely await further big-data multi-centre clinical investigations on different populations to validate its high potential value for both prevention and intervention (Hristova et al, 2015).

Conclusions and practical prospects. For an appropriate understanding of the «norm» and «pathology», while interpreting results of BP monitoring, or in projects aimed at self-observation of BP, as well as in telemedicine projects, it is necessary to consider all the above factors, paying special attention to their structured variability (i.e., circadian, ultradian and infradian components).