An example of “masked ABP hypertension” is this 41-year-old nonobese (BMI = 23.8 kg/m²) man (ID number: KOts100). He visited us for a health check. He goes to bed regularly at 23:30 and gets up at 07:30, but he does not sleep well. His office BP was 129/99 mmHg and pulse was 71 betas per minute (bpm). He has a history of cerebellum bleeding when he worked in China 3 years ago and takes three antihypertensive medications, including CCB and ARB.

Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 20.1. From Saturday to Friday, the 24-hour average of SBP assumes values of 111.6 mmHg (Saturday; NT), 115.9 mmHg (Sunday; NT), 121.3 mmHg (Monday; NT), 116.8 mmHg (Tuesday; NT), 130.2 mmHg (Wednesday; hypertension), 131.9 mmHg (Thursday; hypertension), and 115.5 mmHg (Friday; NT). The 24-hour mean of SBP was above 130 mmHg on Wednesday and Thursday, indicating the presence of masked ABP hypertension. The corresponding 24-hour averages of DBP were 82.6 mmHg (Saturday), 81.3 mmHg (Sunday), 85.7 mmHg (Monday), 84.4 mmHg (Tuesday), 90.4 mmHg (Wednesday), 92.3 mmHg (Thursday), and 83.2 mmHg (Friday), indicating persistent DBP hypertension.

Based on the model fitted to the 7-day/24-hour ABP monitoring record, MESOR estimates of SBP, DBP, and HR were 118.0 mmHg, 83.7 mmHg, and 79.9 bpm, respectively, indicating DBP MESOR-hypertension. The double 24-hour amplitudes of SBP, DBP, and HR were 13.23 mmHg, 9.68 mmHg, and 13.39 bpm, respectively, and corresponding circadian acrophases were 13:36, 13:00, and 15:27, all within acceptable limits.

The circadian profiles of SBP and HR are shown in Fig. 20.2. Both SBP and HR vary well within the chronodesmic limits, but their circadian pattern is somewhat unusual with evening values of SBP much lower and HR values much higher than those found at other circadian stages.

The circadian period of SBP was estimated by the Maximum Entropy Method (MEM), which requires the data to be equidistant. Outliers were deleted from the original SBP time series (middle section of Fig. 20.3). Data were then made equidistant (bottom section of Fig. 20.3).

The MEM spectrum is shown on the middle left of Fig. 20.4, which shows a clear but weak circadian component with a period of 1.0358 day, together with two other peaks at periods of 0.8853 and 0.5017 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. Eleven components are listed here, and that with a “period” of 1.0358 day has the second largest spectral power, as assessed by the “area” covered by the spectral peak, the most prominent component having a period of 0.5017 day.

On the bottom left of Fig. 20.4, the edited data are fitted by least squares with a five-component model consisting of the five cosine curves with the five largest amplitudes, with corresponding periods of 5.891, 2.486, 1.036, 0.885, and 0.502 days (right lower part of Fig. 20.4). None of these components has an amplitude larger than 10 mmHg.

In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) masked ABP hypertension; (2) DBP MESOR-hypertension; (3) persistent DBP hypertension; (4) masked dipping pattern, changing from non-dipping or reverse dipping to dipping from one day to another; and (5) weak circadian rhythm of SBP. Accordingly, we recommended that him to strictly improve his lifestyle, focusing on salt intake. Under this treatment plan, he now seems to be in good health.

The first example of “masked ABP normotension” is a 75-year-old nonobese (BMI = 22.9 kg/m²) woman (ID number: Ura0256). Her office BP was 144/97 mmHg while on two antihypertensive medications, CCB and ARB.

Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR), covering 6 days, are shown in Fig. 20.5. From Thursday to Tuesday, 24-hour averages of SBP assumed values of 140.8 mmHg (Thursday; HT), 148.3 mmHg (Friday; HT), 143.7 mmHg (Saturday; HT), 137.7 mmHg (Sunday; HT), 126.6 mmHg (Monday; normotension), and 125.7 mmHg (Tuesday; normotension). The 24-hour mean of SBP was below 130 mmHg on Monday and Tuesday, indicating masked ABP normotension. The corresponding 24-hour means of DBP also showed masked normotension, assuming values of 87.6 mmHg (Thursday; HT), 89.2 mmHg (Friday; HT), 88.3 mmHg (Saturday; HT), 83.4 mmHg (Sunday; HT), 78.3 mmHg (Monday; normotension), and 77.8 mmHg (Tuesday; normotension), the 24-hour mean of DBP dropping below 80 mmHg on Monday and Tuesday.

Based on the model fitted to the 6-day/24-hour ABP monitoring record, MESOR estimates of SBP, DBP, and HR were 134.3 mmHg, 82.5 mmHg, and 70.0 bpm, respectively. As shown in Fig. 20.5, the 24-hour means of SBP/DBP vary from 1 day to another, assuming values of 144.0/88.0 mmHg (Thursday; both SBP and DBP MESOR-HT), 146.3/90.0 mmHg (Friday; both SBP and DBP MESOR-HT), 135.9/82.3 mmHg (Saturday; normotension), 127.4/79.0 mmHg (Sunday; normotension), 126.6/77.3 mmHg (Monday; normotension), and 126.1/78.2 mmHg (Tuesday; normotension), indicating SBP and DBP MESOR-HT with masked normotension.

The double 24-hour amplitudes of SBP, DBP, and HR were 29.47 mmHg, 20.56 mmHg, and 18.21 bpm, respectively, all within acceptable limits. Gender- and age-matched limits for the circadian amplitude of SBP in health are 3.41–34.0 mmHg. The circadian amplitude of SBP is acceptable on some days but excessive (CHAT) on others, assuming values from 1 day to another of 51.43 mmHg (Thursday; CHAT), 35.74 mmHg (Friday; CHAT), 36.80 mmHg (Saturday; CHAT), 14.65 mmHg (Sunday; acceptable), 13.94 mmHg (Monday; acceptable), and 29.69 mmHg (Tuesday; acceptable), indicating intermittent CHAT.

She goes to bed regularly at 21:30 and gets up at 05:00, but her circadian acrophases of SBP, DBP, and HR were 10:51, 11:10, and 11:47, respectively, slightly earlier than usually found in clinical healthy women of her age group. The circadian profiles of SBP and HR are shown in Fig. 20.6. SBP varies mostly within the chronodesmic limits, peaking slightly earlier than in other clinically healthy women her age. HR varies well within the chronodesmic limits.

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. 20.7). Data were then made equidistant (bottom section of Fig. 20.7).

The MEM spectrum is shown on the middle left of Fig. 20.8, which shows a circadian component with a period of 0.9631 day, together with a prominent peak at a period of 10.5764 days and a weaker peak at a period of 0.4998 day. 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. Nine components are listed here, and that with a “period” of 10.58 days has the largest spectral power, as assessed by the “area” covered by the spectral peak.

On the bottom left of Fig. 20.8, the edited data are fitted by least squares with a five-component model consisting of the five cosine curves with the five largest amplitudes, with corresponding periods of 10.576, 0.963, 0.714, 0.500, and 0.338 days (lower right of Fig. 20.8).

In conclusion, the clinical diagnosis based on the chronobiologically interpreted 6-day/24-hour ABP monitoring consists of (1) masked ABP normotension, (2) intermittent CHAT, (3) masked non-dipping pattern, and (4) a small circadian phase advance of SBP. Accordingly, we increased the dose of the calcium channel blocker (CCB) and made lifestyle recommendations to her, focusing on salt intake. Under this treatment plan, she now seems to be in good health.

The second example of “masked ABP normotension” is a 66-year-old nonobese (BMI = 24.5 kg/m²) man (ID number: Tosa0131). His weight was 70.5 kg and height 170 cm. His office BP was 171/111 mmHg and home BP measurements averaged over 30 days were 149.4/96.9 mmHg in the morning and 145.3/94.0 mmHg in the evening. He was not yet on antihypertensive treatment.

He has a regular rest-activity cycle, usually going to bed around 21:30 and getting up at 06:30. He falls asleep within 10 min and claims to sleep well most days. He does not snore and wakes up rested. He says he prefers light seasoning but has two cups of miso soup every morning and eats pickled salted vegetables at least twice a day. He does not smoke but usually drinks more than 2 go (360 ml) of “Japanese sake” every evening. Not rarely he ends up drinking too much.

He does not have a depressive mood, and his scores on the GDS-15 and PHQ-2 scales were 1 and 0, respectively. He maintains that he usually takes care of his health and has something to live for. His subjective QOL indices of health, mood, family relationships, relationships with friends, financial satisfaction, life satisfaction, and happiness, assessed by visual analog scale (VAS), were 96 %, 100 %, 99 %, 99 %, 84 %, 95 %, and 96 %, respectively.

Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) covering 7 days are shown in Fig. 20.9. From Thursday to Wednesday, the 24-hour average of SBP assumed values of 151.7 mmHg (Thursday; hypertension), 141.0 mmHg (Friday; hypertension), 115.3 mmHg (Saturday; normotension), 142.7 mmHg (Sunday; hypertension), 146.3 mmHg (Monday; hypertension), 152.6 mmHg (Tuesday; hypertension), and 154.9 mmHg (Wednesday; hypertension). The 24-hour mean of SBP was below 130 mmHg on Saturday, indicating masked ABP normotension.

The sphygmochron is shown in Fig. 20.10. This two-barreled approach includes the least-squares fit of a model consisting of cosine curves with periods of 24 and 12 hours (results of the 24-hour component are listed with the MESOR for each of the three variables), and the computer comparison of the subject’s data stacked over an idealized 24-hour day with time-specified reference values qualified by gender and age. The MESOR and the circadian amplitude and acrophase are further evaluated in the light of 90 % prediction limits derived from clinically healthy subjects of the same gender and age group as the subject. As seen in Fig. 20.10, the MESOR of DBP is above the upper 95 % prediction limit in health. Accordingly, diastolic MESOR-hypertension is diagnosed. Similarly, CHAT is diagnosed as the double amplitude of both SBP and DBP is above the upper limit of acceptability.

The MESOR (rhythm-adjusted mean), interpreted in the light of gender- and age-matched reference limits, varies between 113.5 and 141.6 mmHg, assuming values of 146.7 mmHg (Thursday; MESOR-hypertension), 133.0 mmHg (Friday; MESOR-normotension), 113.5 mmHg (Saturday; MESOR-normotension), 141.4 mmHg (Sunday; MESOR-normotension), 137.9 mmHg (Monday; MESOR-normotension), 149.8 mmHg (Tuesday; MESOR-hypertension), and 150.3 mmHg (Wednesday; MESOR-hypertension), indicating masked MESOR-normotension. The day-to-day change in the SBP MESOR is illustrated in Fig. 20.11.

The circadian profiles of SBP and HR are shown in Fig. 20.12. SBP swings excessively (extreme dipping by night and overshooting above the time-varying threshold by day) (Fig. 20.12, left). HR shows a normal circadian swing, but varies in the upper portion of the chronodesm (Fig. 20.12, right). Figure 20.13 illustrates the fit of a 24-hour cosine curve (left) and of a composite model consisting of cosine curves with periods of 24 and 12 hours (right) to the stacked SBP data. Corresponding results for DBP are shown in Fig. 20.14.

Based on the model fitted to the 7-day/24-hour ABP monitoring record, MESOR estimates of SBP, DBP, and HR were 138.8 mmHg, 91.4 mmHg, and 87.0 bpm, respectively, indicating DBP MESOR-hypertension. The circadian acrophases of SBP, DBP, and HR were 14:09, 13:23, and 15:29, respectively, all within acceptable limits. The double 24-hour amplitudes of SBP and DBP were 47.70 and 29.20 mmHg, both exceeding the upper acceptable limit, indicating the presence of SBP CHAT and DBP CHAT. From Thursday to Wednesday, the SBP double amplitude (BP-2A) changed from 1 day to another, assuming values of 59.50 mmHg (Thursday; CHAT), 79.79 mmHg (Friday; CHAT), 41.50 mmHg (Saturday; CHAT), 24.33 mmHg (Sunday; acceptable), 67.46 mmHg (Monday; CHAT), 37.77 mmHg (Tuesday; CHAT), and 52.89 mmHg (Wednesday; CHAT). Except for Sunday, BP-2A exceeds the upper 95 % prediction limit of clinically healthy peers matched by gender and age (34.00 mmHg in this case). Day-to-day changes in the circadian amplitude of SBP are visualized in Figs. 20.11 and 20.15.

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. 20.16). Data were then made equidistant (bottom section of Fig. 20.16).

The MEM spectrum is shown in the middle part of Fig. 20.17 (left), which shows a prominent peak corresponding to the circadian component with a period of 0.9926 day, together with another prominent peak at a period of 0.5071 day and a smaller peak at a period of 6.6592 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. Eleven components are listed here, and that with a “period” of 0.9926 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.

On the bottom left of Fig. 20.17, the edited data are fitted by least squares with a five-component model consisting of the five cosine curves with the five largest amplitudes, with corresponding periods of 6.659, 3.024, 2.520, 0.993, and 0.507 days (lower right of Fig. 20.17).

In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) masked ABP normotension (or masked MESOR-normotension), showing a much lower 24-hour average of ABPs on Saturday, with a usual timing of the circadian BP rhythm; (2) masked non-dipping pattern on Sunday night; (3) both SBP and DBP CHAT; (4) persistent SBP CHAT, except for Sunday; and (5) DBP MESOR-hypertension. We have reported that CHAT complicated by MESOR-hypertension is associated with a very high risk of ischemic stroke and other catastrophic diseases. This subject also has a masked non-dipping pattern with great between-day variability of circadian BP profiles.

Accordingly, we immediately started antihypertensive treatment with a combination of CCB and ARB. In addition, we recommended that he strictly improve his lifestyle, especially focusing on salt intake and drinking habit. Under this treatment plan, he fortunately seems to keep himself healthy.

The first example of “masked non-dipping” is a 61-year-old nonobese (BMI = 24.9 kg/m²) woman (ID number: Tosa0251). Her weight is 56.0 kg and height 150 cm. Although she has cervical spondylosis and knee joint pain, she feels healthy and has an easy time every day. She does housework for 4 hours and walks to do her shopping for 2 hours daily. She does not smoke and usually does not drink alcohol. She rarely eats meat but frequently eats fish and vegetables. She prefers her food lightly seasoned.

She does not have a depressive mood and has something to live for. Her scores on the GDS-15 and PHQ-2 scales were 2 and 1, respectively. Her subjective QOL of health, mood, family relationships, relationships with friends, financial satisfaction, and happiness were 95 %, 85 %, 85 %, 85 %, 70 %, 90 %, and 95 %, respectively. She has a family history of hypertension (parents) and stroke (parents and elderly brother).

She does not take any antihypertensive medication. Her office BP was 135/80 mmHg and her home BP measurements averaged over 30 days were 120.4/80.6 mmHg in the morning and 126.8/83.4 mmHg in the evening. Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 20.18. A model consisting of cosine curves with periods of 24 and 12 hours was fitted by least squares to the data to estimate the MESOR (Midline-Estimating Statistics Of Rhythm) and the amplitude and acrophase (time of predicted maximum) of each component.

MESOR estimates of SBP, DBP, and HR, estimated from the 7-day/24-hour ABP measurements, were 117.8 mmHg, 73.5 mmHg, and 80.9 bpm, respectively. In accordance with the guidelines for management of high blood pressure, in the case of 24-hour ABP, in Japan, published in 2014, she is diagnosed as being normotensive, as her 24-hour SBP and DBP averages were below 130 mmHg and 80 mmHg, respectively.

However, day-to-day analyses showed “masked ABP hypertension,” as the 24-hour average of SBP changed from one day to another, assuming values of 124.7 (Thursday; normotension), 118.1 (Friday; normotension), 136.2 (Saturday; hypertension), 125.3 (Sunday; normotension), 111.3 (Monday; normotension), 117.5 (Tuesday; normotension), and 113.7 mmHg (Wednesday; normotension).

Variation in the day-night ratio of SBP during the weeklong record indicated the presence of “masked non-dipping,” the dipping pattern varying from 1 day to another (from extreme dipping to dipping and non-dipping), and the day-night ratio assuming values of 35.4 % (Thursday night; extreme dipping), 14.4 % (Friday night; dipping), 7.3 % (Saturday night; non-dipping), 25.9 % (Sunday night; extreme dipping), 12.4 % (Monday night; dipping), 25.6 % (Tuesday night; extreme dipping), and 12.3 % (Wednesday night; dipping).

From this 7-day/24-hour ABP monitoring, we can see an evident BP increase in the evening, reaching particularly high values on the 3rd and 4th day (Saturday and Sunday). A non-dipping pattern is observed on Saturday night. After talking to her, we understood why her BP increased during the 2 days. Usually, she has a regular sleep-wake cycle, going to bed around midnight and getting up at 07:00. She usually falls asleep within 10 min and feels like she sleeps well most days. However, on January 29 (Saturday) and 30 (Sunday), she took a brief 2-day trip to a neighboring city and had an outdoor bath in a hot spring, even though it was a cold night and snow had fallen.

The circadian profiles of SBP and HR are shown in Fig. 20.19. Based on the fitted model, the double 24-hour amplitudes of SBP, DBP, and HR were 32.37 mmHg, 23.50 mmHg, and 12.27 bpm, respectively, and corresponding circadian acrophases were 16:56, 16:19, and 16:46, all almost within acceptable limits.

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. 20.20). Data were then made equidistant (bottom section of Fig. 20.20).

The MEM spectrum is shown on the middle left of Fig. 20.21, which shows a prominent circadian period of 1.0137 day, together with several peaks corresponding to periods of 6.1118, 2.6474, and 0.4954 days, among others. 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 1.0137 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.

On the bottom left of Fig. 20.21, the edited data are fitted by least squares with a five-component model consisting of the five cosine curves with the five largest amplitudes, with corresponding periods of 6.112, 2.647, 1.263, 1.014, and 0.495 days (right lower part of Fig. 20.21).

In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) masked non-dipping and (2) masked ABP hypertension. These diagnoses, however, depend in part on environmental factors, as evidenced by effects observed in association with the brief winter trip outdoor including the hot-spring bath on a wintery night when snow was falling. Accordingly, we made lifestyle recommendations, focusing on environmental conditions and salt intake. She remains in good health despite not taking antihypertensive medication.