, Germaine Cornelissen2 and Franz Halberg2
(1)
Department of Chronomics & Gerontology, Tokyo Women’s Medical University Medical Center East, Arakawa-ku, Tokyo, Japan
(2)
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
Abstract
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.
Keywords
Ambulatory blood pressure normotensionChronodesmCircadian period of systolic BPMaximum Entropy Method (MEM)Least-squares analysisWhite-coat hypertension syndrome18.1 A Case Report of “Ambulatory BP Normotension”
An example of “ambulatory blood pressure (ABP) normotension” based on 7-day/24-hour ambulatory blood pressure (ABP) monitoring is this 39-year-old non-obese (BMI = 20.4 kg/m2) woman (ID number: Tosa0195). She usually goes to bed around 00:00 and gets up around 07:35. She feels like she sleeps well on most days and wakes up well rested in the morning. She does not have a depressive mood and shows a null score on the two-item Patient Health Questionnaire (PHQ-2).
Her office BP was 126/86 mmHg, and her home BP measurements averaged over 30 days were 117.0/77.0 mmHg (morning) and 122.6/80.5 mmHg (evening). Time series of systolic BP (SBP), diastolic BP (DBP), and pulse (HR) are shown in Fig. 18.1. A model consisting of cosine curves with periods of 24 and 12 hours was fitted by least squares to her data [1]. The MESOR (midline estimating statistic of rhythm) estimates of SBP, DBP, and HR from the 7-day/24-hour ABP record were 109.7 mmHg, 70.0 mmHg, and 76.0 bpm, respectively.
Fig. 18.1
An example of normotension. Time plots of the 7-day/24-hour record of a 39-year normotensive woman: SBP (thick continuous line), DBP (thin continuous line), and HR (dashed line). These variables fluctuate somewhat predictably, following a circadian rhythm, suggesting a regular rest-activity schedule
Average circadian profiles of SBP and HR are shown in Fig. 18.2. Each time-specified point, shown as a closed square, represents the average of measurements at that time of day during the 7 days of monitoring. The depicted line graphs in Fig. 18.2 thus illustrate averaged circadian profiles of SBP (left) and HR (right).
Fig. 18.2
Circadian profiles of systolic BP (left) and heart rate (HR) (right). 24-hour patterns of systolic BP (left) and heart rate (HR) (right) of a normotensive woman, averaged over the 7 days of monitoring (polygonal line graph with closed squares), are shown along with corresponding time-specified 90 % prediction limits (continuous thin lines). Both variables vary in the middle portion of the respective chronodesms
Time-specified reference limits, chronodesms, have been computed for each variable in each group as 90 % prediction limits, derived from ABP monitoring of a non-hypertensive reference population. Thus, Fig. 18.2 depicts not only circadian profiles of the 39-year-old normotensive woman but also the 90 % prediction limits (i.e., upper and lower thresholds) derived from data provided by clinically healthy women of her age group, shown as the two continuous curves. It can be seen that the circadian profiles of SBP and HR of this subject are completely located within the reference limits, drawn in the central portion of the reference range for most of the 24-hour cycle.
Parameters of circadian profiles were calculated by the chronobiological method are. Her double 24-hour amplitudes of SBP and DBP were 24.39 and 17.51 mmHg, respectively, both within acceptable limits. Circadian acrophases of SBP and DBP were 15:23 and 15:28, respectively, both also within the 90 % prediction limits (between ~12:00 and ~16:00).
The circadian period of SBP was estimated by the Maximum Entropy Method (MEM), using the MemCalc software (GMS Co., Tokyo) [2], which requires the data to be equidistant. Outliers were first deleted from the original SBP time series (middle section of Fig. 18.3). Data were then made equidistant by averaging and linear interpolation (bottom section of Fig. 18.3).
Fig. 18.3
Three versions of the time series of systolic BP. Upper: original data of systolic BP. Middle: edited data after mathematically excluding outliers. Lower: equidistantly arranged (averaged and linearly interpolated) data for analysis by the Maximum Entropy Method, using the MemCalc software (GMS Co., Tokyo)
The MEM spectrum is shown on the middle left of Fig. 18.4, which shows a prominent circadian component with a period of 1.0033 day, together with two smaller peaks at periods of 7.5994 and 0.5081 days. Periods extracted by the MEM analysis in the range up to 2.5 cycles/day are shown in the right upper side of this figure. Ten components are listed here, and that with a period of 1.0033 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 18.4
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 1.0033 day (left middle part). Data are shown with a 5-component model fitted by least squares and consisting of the components with the five largest amplitudes (right lower part)
On the bottom left of Fig. 18.4, the edited data are fitted by least squares with a 5-component model consisting of the five cosine curves with the largest amplitudes, with corresponding periods of 7.599, 1.249, 1.003, 0.715, and 0.508 days.
Least-squares amplitude and power spectra of the raw and edited (equidistant) data are shown in Fig. 18.5. In addition to a weak circaseptan component, a prominent circadian rhythm is readily apparent, three additional harmonic terms (with periods of 12, 8, and 6 hours) contributing to its waveform. These results are very similar to those of the MEM analysis, accounting for the fact that the least-squares spectra were computed using a fundamental period of 7 days rather than the exact length of the record.
Fig. 18.5
Least-squares amplitude (left) and power (right) spectra of the original (top) and edited (bottom) SBP data. Note similarity of results with those of the MEM analysis
Figure 18.6 shows that the results do not differ greatly between the analysis of the original (raw) data and the edited record where outliers were deleted and data linearly interpolated to render the time series equidistant. Only small differences in the relative prominence of the 12-hour and 6-hour components are observed in the least-squares spectra of the raw and edited data. As seen from Fig. 18.7, models consisting of the 7-day variation and the circadian rhythm, including the first three harmonic terms, describing the raw and edited data are also very similar, differing only slightly, notably during the night when data needed to be interpolated because of the change in sampling rate.
Fig. 18.6
Comparison of least-squares amplitude (top, left) and power (bottom, left) spectra from raw and edited SBP data shows only small differences. Signals are reconstructed on the basis of the five largest components (with periods of 7 days, 24, 12, 8, and 6 hours) for the raw (top, right) and edited (bottom, right) data
Fig. 18.7
Comparison of 5-component models obtained for the original and edited data shows only small differences, notably during the night when data had to be interpolated because of the change in sampling rate
These results illustrate two complementary approaches to analyze blood pressure records for an assessment of anticipated components such as the circadian and circaseptan variations. The MEM analysis yields a more refined spectral view than the least-squares spectrum. Model building based on MEM results may provide a better fit for the data over the available record. The least-squares spectrum performed while accounting for the anticipated presence of a 24-hour synchronized circadian rhythm and a 7-day synchronized biological week, in turn, provides estimates that may apply also outside the observation span. By further fixing the model to be fitted to the data, it becomes possible to derive reference values from which screening for abnormal circadian patterns identifies vascular variability disorders. These diagnoses, validated in several outcome studies, represent useful guidelines for primary prevention as well as for treatment optimization by timing (chronotherapy).
18.2 Case Report 1 of “White-Coat Hypertension”
In this chapter, we introduce four cases of “white-coat hypertension” from the viewpoint of 7-day/24-hour ambulatory blood pressure (ABP) monitoring.
18.2.1 Case Report 1 of “White-Coat Hypertension”
The first example of “white-coat hypertension” is a 40-year-old non-obese (BMI = 22.6 kg/m2) man (ID number: Tosa0282). His weight was 64.5 kg and height 169 cm. He goes to bed usually around 23:30 and gets up around 06:40. He falls asleep within 10 min and believes he sleeps well most days. Whereas he does not wake up at night and has no disturbances of waking too early, he does not feel rested upon awakening. He does not smoke and usually does not drink alcohol, but his intake of meat is frequent and he seldom eats fish. His intake of vegetables is somewhat below average. He eats eggs regularly every day, but does not drink milk. Once or twice a week, he eats something within 2 hours of going to bed.
He feels healthy now, but does not take care of his health. He does not have a depressive mood and has something to live for. Scores on the Geriatric Depression Score 15 (GDS-15) and PHQ-2 were 5 and 0, respectively. Subjective quality of life (QOL) was 85 % (health) and 65 % (happiness).
This subject does not take any antihypertensive medications. His office BP was 155/94 mmHg and his home BP measurements averaged over 30 days were 113.4/70.8 mmHg (morning) and 105.7/58.5 mmHg (evening). Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 18.8. A model consisting of cosine curves with periods of 24 and 12 hours was fitted by least squares to his data [1]. The MESOR (midline estimating statistic of rhythm) estimates of SBP, DBP, and HR from the 7-day/24-hour ABP record were 114.6 mmHg, 71.4 mmHg, and 74.1 bpm, respectively.
Fig. 18.8
An example of white-coat hypertension. Time plots of the 7-day/24-hour records of SBP (thick continuous line), DBP (thin continuous line), and HR (dashed line) of a 40-year-old man with white-coat hypertension. When the 7-day/24-hour ABP monitoring session was started at 11:00 in front of a doctor on January 31, 2013, his blood pressure and pulse were 155/94 mmHg and 71 bpm, suggesting mild hypertension, but measurements dropped thereafter within the normal range, where they fluctuated periodically, following a circadian rhythm, suggesting a regular rest-activity schedule. High systolic BP on the first day of monitoring can readily be seen
Average circadian profiles of SBP and HR of this subject are shown in Fig. 18.9. They are well within the reference limits despite the episodic BP elevation (white-coat effect) on the first day.
Fig. 18.9
Circadian profiles of systolic BP (left) and heart rate (HR) (right). 24-hour patterns of systolic BP (left) and heart rate (HR) (right) of this subject with white-coat hypertension, averaged over the 7 days of monitoring (polygonal line graph with closed squares), are shown along with time-specified 90 % prediction limits (continuous thin lines). Both variables vary in the middle portion of their respective chronodesms
The circadian profiles are characterized by their double 24-hour amplitudes of 30.55 mmHg (SBP) and 25.16 mmHg (DBP), both within acceptable limits, and by their 24-hour acrophases of 14:26 (SBP) and 14:32 (DBP), also within acceptable limits (between ~12:00 and ~16:00).
The circadian period of SBP was estimated by the Maximum Entropy Method (MEM), using the MemCalc software (GMS Co., Tokyo), which requires the data to be equidistant. Outliers were deleted from the original SBP time series (middle section of Fig. 18.10). Data were then made equidistant (bottom section of Fig. 18.10).
Fig. 18.10
Three versions of the time series of systolic BP. Upper: original data of systolic BP. Middle: edited data after mathematically excluding outliers. Lower: equidistantly arranged time series for analysis by the Maximum Entropy Method, using the MemCalc software (GMS Co., Tokyo)
The MEM spectrum is shown on the middle left of Fig. 18.11, which shows a prominent circadian component with a period of 1.0213 day, together with three smaller peaks at periods of 5.9442, 3.8640, and 0.4761 days. Periods extracted by the MEM analysis in the range up to 2.5 cycles/day are shown in the right upper side of this figure. Ten components are listed here, and that with a period of 1.0213 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 18.11
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 1.0213 day (left middle part). Data are shown with a 5-component model fitted by least squares to the data, consisting of cosine curves with the five largest amplitudes (right lower part)
18.2.2 Case Report 2 of “White-Coat Hypertension”
Another example of “white-coat hypertension” concerns a 76-year-old man (ID number: KOts078). He goes to bed usually around 21:30 and gets up around 05:00. Hypertension was suspected at the annual health check when he visited our hospital. He takes no antihypertensive medication.
His office BP was 185/110 mmHg. Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 18.12. When his 7-day/24-hour ABP monitoring started at 15:13 in front of a doctor on September 19, 2001, his blood pressure and pulse were 203/111 mmHg and 76 bpm.
Fig. 18.12
An example of white-coat hypertension syndrome. Time plots of the 7-day/24-hour records of SBP (thick continuous line), DBP (thin continuous line), and HR (dashed line) of a 76-year-old man with white-coat hypertension. When the 7-day/24-hour ABP monitoring session was started at 15:13 in front of a doctor, his blood pressure and pulse were 203/111 mmHg and 76 bpm, coinciding with grade 3 hypertension, but these values decreased thereafter, getting close to the normal range where they fluctuate rhythmically as a function of his rest-activity cycle. Nocturnal rise is observed on Friday night, and a non-dipping pattern is seen on Tuesday night (SBP and DBP day-night ratios: −20.6 % and 1.5 %, respectively). A low day-night ratio also prevails for the entire profile, suggesting the presence of “masked non-dipping”
A model consisting of cosine curves with periods of 24 and 12 hours was fitted by least squares to the 7-day data series. The MESOR (midline estimating statistic of rhythm) of SBP, DBP, and HR was estimated as 135.1 mmHg, 90.1 mmHg, and 70.3 bpm, respectively. In accordance with the guidelines for the management of high blood pressure in Japan, published in 2014 [3], hypertension is defined for 24-hour ABP as ≧130 (SBP) and/or ≧80 mmHg (DBP). Thus, hypertension is diagnosed in this case. However, the circadian profiles of SBP and HR of this subject are located within the 90 % chronodesmic limits most of the time, as depicted in Fig. 18.13 along the 24-hour scale. Thus, this case should be diagnosed as white-coat hypertension syndrome [4].
Fig. 18.13
Circadian profiles of systolic BP (left) and heart rate (HR) (right). 24-hour patterns of systolic BP (left) and heart rate (HR) (right) of this subject with white-coat hypertension, averaged over the 7 days of monitoring (polygonal line graph with closed squares), are shown along with time-specified 90 % prediction limits (continuous thin lines). Although both patterns are located well within the acceptable limits, the SBP profile is biased toward the upper part of the chronodesm, and a mild morning surge is also observed. This subject’s BP is particularly high at night, close to the upper limit of the chronodesm, in keeping with a non-dipping pattern
The double amplitudes of SBP and DBP estimated from the fitted model are 14.34 and 14.88 mmHg, respectively, both within acceptable limits. The corresponding circadian acrophases of SBP and DBP were 11:12 and 12:19, respectively, suggesting a slight degree of phase advance in SBP along with an aging effect [5].
The circadian period of SBP was estimated by the Maximum Entropy Method (MEM), using the MemCalc software (GMS Co., Tokyo), which requires the data to be equidistant. Outliers were deleted from the original SBP time series (middle section of Fig. 18.14). Data were then made equidistant (bottom section of Fig. 18.14).
Fig. 18.14
Three versions of the time series of systolic BP. Upper: original data of systolic BP. Middle: edited data after mathematically excluding the outliers. Lower: equidistantly arranged time series for analysis by the Maximum Entropy Method, using the MemCalc software (GMS Co., Tokyo)
The MEM spectrum is shown on the middle left of Fig. 18.15, which shows a prominent circasemidian component with a period of 0.5133 day, together with three smaller peaks at periods of 2.4326, 0.9963, and 0.8223 days. Periods extracted by the MEM analysis in the range up to 2.5 cycles/day are shown in the right upper side of this figure. Twelve components are listed here, and that with a period of 0.5133 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 18.15
Period analysis of the circadian rhythm of systolic BP. MEM analysis shows a weak circadian component for systolic BP with a period of 0.9963 day (left middle part). Data are shown with a 5-component model fitted by least squares to the data, consisting of cosine curves with the five largest amplitudes (right lower part)
On the bottom left of Fig. 18.4, the edited data are fitted by least squares with a 5-component model consisting of the five cosine curves with the five largest amplitudes, with corresponding periods of 4.604, 2.433, 0.996, 0.822, and 0.513 days (right lower part of Fig. 18.15). The most prominent component with a period of 0.513 day cannot be readily seen in the fitted mode, contrasting with results from the MEM spectral analysis.
In conclusion, the clinical diagnosis derived from the 7-day/24-hour ABP monitoring consists of (1) a prominent white-coat effect, (2) a mild ABP hypertension, (3) a “masked non-dipping” hypertension, and (4) a circadian disruption of systolic BP. Accordingly, we started to treat by antihypertensive medicine with a calcium channel blocker (CCB) (benidipine, 4 mg, once daily), together with guidance regarding lifestyle, focusing especially on an erratic sleeping habit.
18.2.3 Case Report 3 of “White-Coat Hypertension”
The third example of “white-coat hypertension” is a 77-year-old non-obese (BMI = 23.0 kg/m2) man (ID number: KOts063). He goes to bed usually around 22:00 and gets up around 07:00. He takes benidipine (4 mg daily) as antihypertensive medication at about 08:00 after breakfast. He does not have a depressive mood, his scores on the GDS-15 and PHQ-2 scales being 5 and 0 points, respectively. His subjective quality of life (QOL) of health was fairly low, however, at 35 %, and his subjective QOL of happiness was 65 %.
His office BP was 148/94 mmHg. Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 18.16. When starting his 7-day/24-hour ABP monitoring at 13:00 in front of a doctor on March 30, 2001, his blood pressure and pulse were 183/93 mmHg and 53 bpm. At the time of his 7-day/24-hour ABP monitoring, he attended the Shogi game at his town on Sunday and won his game 4 days, from Sunday to Wednesday, but lost the championship on Thursday after a close competition. Thus, this time series includes not only a white-coat phenomenon on the first day but also mental stress related to the close competition lasting for 5 days.
Fig. 18.16
Another example of white-coat hypertension syndrome complicated by circadian over-swinging hypertension. Time plots of the 7-day/24-hour records of SBP (thick continuous line), DBP (thin continuous line), and HR (dashed line) in a 77-year-old man. When the 7-day/24-hour ABP monitoring was started at 13:00 in front of a doctor on March 30, 2001, his blood pressure and pulse were 183/93 mmHg and 53 bpm, suggesting grade 3 hypertension. Values were lower the next day, within the acceptable range. Differences of BPs between day and night are large from the 4th to 7th day. Data fluctuate rhythmically, following mostly his rest-activity cycle
The circadian profiles of SBP and HR of this subject are shown in Fig. 18.17. SBP differs greatly between day and night, exceeding the normal range for the double 24-hour amplitude. The MESOR, estimated from the 2-component model fitted to the 7-day/24-hour ABP record, of SBP, DBP and HR was 116.8 mmHg, 71.5 mmHg, and 56.2 bpm, respectively. The circadian acrophase of SBP and DBP was 13:13 and 13:34, respectively. All parameters were within acceptable limits. The double amplitude of SBP and DBP, however, was excessive, reaching 44.92 and 30.19 mmHg, respectively. Such an over-swinging circadian pattern, characterized by an excessive amplitude, is called circadian hyper-amplitude-tension (CHAT).
Fig. 18.17
Circadian profiles of systolic BP (left) and heart rate (HR) (right). 24-hour patterns of systolic BP (left) and heart rate (HR) (right) of this subject with white-coat hypertension, averaged over the 7 days of monitoring (polygonal line graph with closed squares), are shown along with time-specified 90 % prediction limits (continuous thin lines). Within the chronodesms, SBP swings greatly and HR varies only a little
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