, 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 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.
Keywords
MESOR (Midline-Estimating Statistics Of Rhythm)-hypertensionCircadian hyper-amplitude-tensionEcphasiaExcessive pulse pressureVascular variability syndrome19.1 MESOR-Hypertension
In this chapter, we introduce three cases of “Midline-Estimating Statistics Of Rhythm (MESOR) hypertension” based on 7-day/24-hour ambulatory blood pressure (ABP) monitoring. The MESOR is a rhythm-adjusted mean that takes into consideration the rhythmic variation in the data, approximated by cosine curve(s) (left, Fig. 19.1). MESOR-hypertension is a chronobiologically validated elevation in BP (right, Fig. 19.1).
Fig. 19.1
MESOR-hypertension. MESOR-hypertension (MH) is a chronobiologically validated elevation in BP (right, Fig. 19.1), which can be systolic (S-MH), diastolic (D-MH), or both (SD-MH), or mean arterial (MA-MH), demonstrated parametrically. Although this graph is demonstrated with a single component model, the data are usually fitted with a two-component model consisting of cosine curves with periods of 24 and 12 hours. Acceptable limits for the MESOR have been derived as 90 % prediction limits (PI) from ABP obtained from clinically healthy peers matched by gender and age. “MESOR-hypertension” (MH) is used only if the diagnosis is based on the MESOR obtained by the least squares fit of cosine curves with anticipated (24- and 12-hour) periods, for comparison with ranges (90 % P!s) of acceptable MESORs characterizing data from clinically healthy peers matched by gender and age. The minimal time series length is a 24-hour/7-day record of data collected automatically at hourly or shorter intervals, analyzed both daily and for the week as a whole. It serves to rule out MH if negative when analyzed parametrically for the weeklong record as a whole, but data collection is continued when abnormality is found. MH is a condition where the BP-M is above the upper 95 % prediction limit of BP-Ms from clinically healthy peers matched by gender and age. BP elevation is noted when the hyperbaric index (extent of excess during 24 hours) exceeds the threshold of 50 mmHg x hour during 24 hours. MH can be the sole vascular variability disorder (VVD) or it can coexist and/or alternate with other VVDs to constitute a vascular variability syndrome (VVS)
19.1.1 Case Report 1 of “MESOR-Hypertension”
The first example of “MESOR-hypertension” is a 56-year-old woman (ID number: KOts098). Her office BP and HR were 160/93 mmHg and 75 bpm, but she does not take any antihypertensive medication. Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 19.2. A model consisting of cosine curves with periods of 24 and 12 hours fitted by least squares to the data was used to estimate the MESOR and the amplitude and acrophase (time of predicted maximum) of each component. The MESORs of SBP, DBP, and HR, estimated from the 7-day/24-hour ABP measurements, were 152.9 mmHg, 82.2 mmHg, and 70.0 bpm, respectively. Thus, she is diagnosed as having SBP MESOR-hypertension. The difference between the MESORs of SBP and DBP was 70.7 mmHg. As it is above 60 mmHg, she is also diagnosed as having an excessive pulse pressure (EPP), another vascular variability disorder (VVD).
Fig. 19.2
An example of SBP MESOR-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 56-year-old woman. SBP MESOR-hypertension is complicated by excessive pulse pressure (EPP) and masked dipping-type hypertension (nocturnal BP displays a non-dipping pattern on the 1st day, but a dipping pattern prevails during the subsequent 6 days)
The 24-hour double amplitudes of SBP, DBP, and HR were 28.42 mmHg, 13.00 mmHg, and 19.82 bpm, respectively, all within acceptable limits. The circadian acrophases of SBP, DBP, and HR were 13:12, 12:18, and 15:58, respectively, all within acceptable limits (between ~12:00 and ~16:00).
The 24-hour SBP pattern, as shown in the left side of Fig. 19.3, exceeds the upper limit of the chronodesm during most of the time along the 24-hour scale. On the average over 7 days, SBP remains above 130 mmHg, indicative of persistent 24-hour ABP hypertension. By contrast, HR is located well within the chronodesmic limits. The BP day-night ratio is low the first day (5.8 %), corresponding to a non-dipping pattern, but the day-night ratio is above 10 % on the other 6 days. This type of day-to-day alteration in the day-night ratio of BP is defined as “masked dipping-type hypertension” from the viewpoint of 7-day/24-hour ABP monitoring.
Fig. 19.3
Circadian profiles of systolic BP (left) and heart rate (HR) (right) plotted in the light of circadian chronodesms (thin lines). The average 24-hour SBP pattern is elevated during most of the time, exceeding the upper chronodesmic limit
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. 19.4). Data were then made equidistant (bottom section of Fig. 19.4).
Fig. 19.4
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. 19.5, which shows a prominent circadian period of 1.0061 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. Thirteen components are listed here, and that with a period of 1.0061 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 19.5
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 1.0061 day (left middle part). Data are shown with a five-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. 19.5, 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 1.006, 0.517, 0.410, 0.231, and 0.188 days (right lower part of Fig. 19.5).
In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) SBP MESOR-hypertension (152.9 mmHg), (2) excessive pulse pressure (70.7 mmHg), (3) persistent 24-hour ABP hypertension, and (4) “masked dipping”-type hypertension. This patient thus has moderate to severe hypertension. Accordingly, we immediately started treatment with a long-acting CCB (benidipine, 8 mg twice daily).
19.1.2 Case Report 2 of “MESOR-Hypertension”
The second example of “MESOR-hypertension” is a 48-year-old non-obese (BMI = 21.2 kg/m2) woman (ID number: KOts051). She is treated with a long-acting calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) once daily, but her office BP and HR still were 176/110 mmHg and 75 bpm. She takes care of her health and has something to live for, but she has a depressive mood; her PHQ-2 score was 2 points. Her subjective quality of life (QOL) of health was 75 %, and her subjective QOL of happiness was 70 %. On average, she sleeps 8 hours and 50 min, perhaps a little too long.
Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 19.6. During all 7 days, the 24-hour average of SBP is invariably above 130 mmHg, indicative of persistent ABP hypertension. Her day-night ratio of BP varies from day to day, however. On the first day, it is 9.8 % (non-dipping), and on days 2–7, it changes to 18.2 % (dipping), 14.7 % (dipping), 20.9 % (extreme dipping), 18.9 % (dipping), 20.4 % (extreme dipping), and 18.9 % (dipping). Her “masked dipping-type hypertension” includes not only non-dipping and dipping but also extreme-dipping patterns.
Fig. 19.6
An example of both SBP and DBP MESOR-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 48-year-old woman. MESOR-hypertension is complicated by “masked dipping”-type hypertension (non-dipping on the 1st day, but dipping or extreme dipping on subsequent days)
A model consisting of cosine curves with periods of 24 and 12 hours was fitted by least squares to the data, yielding estimates of the MESOR, and of the amplitude and acrophase (time of predicted maximum) of each component. MESORs of SBP, DBP, and HR, estimated from the 7-day/24-hour ABP measurements, were 153.9 mmHg, 98.5 mmHg, and 71.4 bpm, respectively. She is thus diagnosed as having both systolic and diastolic MESOR-hypertension.
The 24-hour SBP pattern, as shown on the left side of Fig. 19.7, lies mostly above the upper limit of the chronodesm. By contrast, HR varies well within the acceptable limits. The circadian acrophases of SBP, DBP, and HR were 16:40, 16:32, and 16:06, respectively, slightly phase-delayed with respect to acrophases of clinically healthy peers (between ~12:00 and ~16:00). The 24-hour double amplitudes of SBP, DBP, and HR were 36.39 mmHg, 21.92 mmHg, and 10.97 bpm, respectively, all within acceptable limits.
Fig. 19.7
Circadian profiles of systolic BP (left) and heart rate (HR) (right) plotted in the light of circadian chronodesms. The average 24-hour SBP pattern is elevated above the upper chronodesmic limit almost during the entire 24-hour period
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. 19.8). Data were then made equidistant (bottom section of Fig. 19.8).
Fig. 19.8
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. 19.9, which shows a prominent circadian period of 0.9925 day, together with two other clear peaks corresponding to periods of 9.7226 and 0.5648 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 the one with a period of 0.9925 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 19.9
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 0.9925 day (left middle part). Data are shown with a five-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. 19.9, 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 9.723, 2.136, 0.992, 0.565, and 0.250 days (right lower part of Fig. 19.9).
In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) both SBP and DBP MESOR-hypertension (153.9/98.5 mmHg), (2) delayed phase of the circadian SBP rhythm, (3) persistent ABP hypertension, and (4) “masked dipping”-type hypertension, including non-dipping, dipping, and extreme-dipping patterns on different days. Results suggest that this subject has a moderate hypertensive condition. Accordingly, we reiterated lifestyle recommendations focusing on an improvement of her depressive mood. This treatment seems to work well and she appears to be in good health now.
19.1.3 Case Report 3 of “MESOR-Hypertension”
The third example of “MESOR-hypertension” is a 36-year-old mildly obese (BMI = 26.7 kg/m2) woman (ID number: KOts058). She has a regular rest-activity cycle and goes to bed usually at about 23:00 and gets up around 06:00. She is treated with a three-drug combination, a long-acting calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), and a β-blocker, taken once daily at about 08:00 after breakfast. Nevertheless, her office BP and HR were 145/96 mmHg and 96 bpm. She takes care of her health and has something to live for. She does not have a mild depressive mood, and her PHQ-2 score was 1 point. Her subjective quality of life (QOL) was low: her QOL of health was 65 %, and her QOL of happiness was 50 %. She does not have diabetes; her fasting glucose and hemoglobin A1c were 90 mg/dl and 4.6 %, respectively. She has a mild dyslipidemia, her blood total cholesterol, triglyceride, and HDL-cholesterol being 183, 150, and 68 mg/dl, respectively.
Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 19.10. During the 7 days of monitoring, the 24-hour average of SBP is invariably above 130 mmHg, indicating persistent ABP hypertension. Her BP day-night ratio varies from day to day, however. On the first day, it is 21.3 % (extreme dipping), but on days 2–7, it changes to 8.6 % (non-dipping), 26.6 % (extreme dipping), 13.3 % (dipping), 21.9 % (extreme dipping), 19.3 % (dipping), and 21.0 % (extreme dipping). She shows a “masked non-dipping-type hypertension,” including not only non-dipping but also dipping and extreme-dipping patterns on different days.
Fig. 19.10
An example of both SBP and DBP MESOR-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 36-year-old woman. MESOR-hypertension is complicated by “masked non-dipping”-type hypertension (extreme-dipping on the 1st day, but non-dipping pattern on the 2nd day)
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 and the amplitude and acrophase (time of predicted maximum) of each component. MESOR estimates of SBP, DBP, and HR, calculated based on the 7-day/24-hour ABP measurements, were 142.0 mmHg, 91.3 mmHg, and 84.3 bpm, respectively. She is thus diagnosed as having both systolic and diastolic MESOR-hypertension.
The 24-hour SBP pattern, as shown in the left side of Fig. 19.11, exceeds the upper limit of the chronodesm during most of the time along the 24-hour scale. By contrast, HR is located well within the chronodesmic limits. The circadian acrophase of SBP, DBP, and HR was 15:28, 14:13, and 16:13, respectively. Acrophases of systolic and diastolic BP were within acceptable limits (between ~12:00 and ~16:00). The 24-hour double amplitudes of SBP and DBP were 30.52 and 17.01 mmHg, respectively, both within acceptable limits.
Fig. 19.11
Circadian profiles of systolic BP (left) and heart rate (HR) (right) plotted in the light of circadian chronodesms (thin lines). The average 24-hour SBP pattern is elevated during most of the time, exceeding the upper chronodesmic limit. The circadian profile of HR, however, is located within the chronodesmic limits
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 and the amplitude and acrophase (time of predicted maximum) of each component. The MESORs of SBP, DBP, and HR, based on the 7-day/24-hour ABP measurements, were 153.9 mmHg, 98.5 mmHg, and 71.4 bpm, respectively. This subject is thus diagnosed as having both systolic and diastolic MESOR-hypertension.
The 24-hour SBP pattern, as shown in the left side of Fig. 19.11, exceeds the upper limit of the chronodesm during most of the time along the 24-hour scale. By contrast, HR is located well within the chronodesmic limits. The circadian acrophase of SBP, DBP, and HR was 15:28, 14:13, and 16:13, respectively, mostly within acceptable limits (between ~12:00 and ~16:00). The 24-hour double amplitude of SBP, DBP, and HR was 36.39 mmHg, 21.92 mmHg, and 10.97 bpm, respectively, all 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. 19.12). Data were then made equidistant (bottom section of Fig. 19.12).
Fig. 19.12
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. 19.13, which shows a prominent circadian period of 0.9869 day, together with three other clear peaks corresponding to periods of 10.4674, 3.3828, and 0.4970 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 0.9925 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 19.13
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 0.9869 day (left middle part). Data are shown with a five-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. 19.13, 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 10.467, 3.383, 2.079, 0.987, and 0.497 days (right lower part of Fig. 19.13).
In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) both SBP and DBP MESOR-hypertension (142.0/91.3 mmHg), (2) persistent ABP hypertension, and (3) “masked non-dipping”-type hypertension, including extreme-dipping, dipping, and non-dipping patterns on different days. This subject is still moderately hypertensive despite being on three antihypertensive medications. Accordingly, we reiterated recommendations for improving her lifestyle, focusing on salt intake and on improving her mood. The treatment seems to be working well and she is now healthy and normotensive.
19.2 Blood Pressure Circadian Hyper-Amplitude-Tension (CHAT)
In this chapter, we introduce three cases of “circadian hyper-amplitude-tension (CHAT)” from the viewpoint of 7-day/24-hour ambulatory blood pressure (ABP) monitoring. CHAT is a circadian overswing (excessive BP swing), a condition characterized by a double 24-hour amplitude of BP (BP-2A), derived from a 24-hour/7-day record, exceeding the upper 95 % prediction limit of BP-2A estimates from clinically healthy peers matched by gender and age (Fig. 19.14).
Fig. 19.14
CHAT (circadian hyper-amplitude-tension). CHAT means circadian over-swinging (excessive BP swing), which is a condition characterized by a double amplitude of BP exceeding the upper 95 % prediction limit of double amplitudes of BP from clinically healthy peers matched by gender and age
CHAT can occur alone in MESOR-normotension and with a usual timing of the circadian BP rhythm, or it can coexist and/or alternate with other vascular variability disorders (VVDs), such as complicating MESOR-hypertension.
19.2.1 Case Report 1 of “CHAT”
The first example of “CHAT” is a 61-year-old non-obese (BMI = 21.6 kg/m2) woman (ID number: Tosa0275). Her weight was 52.5 kg and height 156 cm. She goes to bed usually around 23:30 and gets up at 07:20. She falls asleep within 10 min and feels that she sleeps well most days. She does not smoke and usually does not drink alcohol. She eats meat only rarely, but frequently eats fish with an average intake of vegetables. She prefers light seasoning.
She feels healthy and takes care of her health. She has something to live for and has no depressive mood. Her scores on the GDS-15 and PHQ-2 scales were 6 and 0 points, respectively. Her subjective quality of life (QOL) of health, assessed by a visual analog scale (VAS), was 85 %, but her subjective QOL of happiness was a little low (65 %).
She does not take any antihypertensive medication. Her office BP was 127/83 mmHg, and her home BP measurements averaged over 30 days were 130.9/81.6 mmHg in the morning and 120.4/76.9 mmHg in the evening. Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 19.15. 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 Statistic 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 125.1 mmHg, 77.6 mmHg, and 73.1 bpm, respectively. In accordance with the guidelines for management of high blood pressure based on ABP in Japan published in 2014, she is normotensive; her 24-hour SBP and 24-hour DBP averages are lower than 130 mmHg and 80 mmHg, respectively.
Fig. 19.15
Both SBP CHAT and DBP CHAT occur in masked ABP normotension with a usual timing of the circadian BP rhythm. Time plots of the 7-day/24-hour records of SBP (thick continuous line), DBP (thin continuous line) and HR (dashed line) of a 61-year-old woman. The 24-hour average of her SBP (in mmHg) varies from day to day, as follows: 132.7 (Thursday; hypertensive), 135.3 (Friday, hypertensive), 119.7 (Saturday; normotensive), 126.3 (Sunday; normotensive), 137.6 (Monday; hypertensive), 130.4 (Tuesday; hypertensive), and 127.4 (Wednesday; normotensive)
The circadian profile of SBP shows an excessive BP swing, that is, extreme dipping at night and overshooting above a time-varying threshold in the daytime (Fig. 19.16, left). The circadian profile of HR is mostly located in the center of the chronodesmic limits (Fig. 19.16, right).
Fig. 19.16
Circadian profiles of systolic BP (left) and heart rate (HR) (right). 24-hour systolic BP (left) and heart rate (HR) (right) patterns of a woman with CHAT, averaged over the 7 days of monitoring (polygonal line graph with closed squares), are shown along with time-specified prediction limits (continuous thin lines)
Based on the fitted model, the circadian acrophases of SBP, DBP, and HR were 15:28, 14:42, and 14:59, respectively, within acceptable limits (between ~12:00 and ~16:00). The double circadian amplitudes of SBP and DBP were 60.23 and 32.40 mmHg, both exceeding the upper 95 % prediction limit in health. Daily estimates of her SBP double amplitude (BP-2A) changed from Thursday to Wednesday, assuming values of 49.48, more than 100, 37.15, 48.29, 60.61, 48.52, and 75.73 mmHg, respectively, all exceeding the upper 95 % prediction limit of BP-2A (34.00 mmHg in this case, estimated from clinically healthy women of her age group).
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. 19.17). Data were then made equidistant (bottom section of Fig. 19.17).
Fig. 19.17
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. 19.18, which shows a prominent circadian period of 0.9882 day, together with two clear peaks with periods of 1.7225 and 0.4982 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 0.9882 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 19.18
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 0.9882 day (left middle part). Data are shown with a five-component model fitted by least squares to the data, consisting of cosine curves with the five largest amplitudes, the 0.988 day being the most prominent (lower right part)
On the bottom left of Fig. 19.18, 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 3.910, 2.766, 1.723, 0.988, and 0.498 days (right lower part of Fig. 19.18).
In conclusion, the clinical diagnosis based on the chronobiologically interpreted 7-day/24-hour ABP monitoring consists of (1) both SBP and DBP CHAT, (2) persistent SBP CHAT, and (3) masked ABP normotension, with a usual timing of the circadian BP rhythm. We have reported that CHAT is associated with a very high risk of ischemic stroke and other catastrophic disease. This subject also had dyslipidemia; her blood LDL-cholesterol and HDL-cholesterol were 159 and 51 mg/dl, respectively (LDL/HDL ratio = 3.12), although she did not have diabetes. Her ECG and CAVI were normal. After giving her lifestyle recommendations, focusing notably on salt intake, and providing her with guidance regarding her sleep-wake cycle and how to improve her dyslipidemia, she is now in good health.
19.2.2 Case Report 2 of “Circadian Hyper-Amplitude-Tension (CHAT)”
Another example of “CHAT” is a 63-year-old non-obese (BMI = 22.2 kg/m2) man (ID number: Tosa0292). His weight was 59.0 kg and height 163 cm. He goes to bed usually at about midnight and gets up at 07:30. He falls asleep within 15 min and feels that he sleeps well most days. He has diabetes and a history of effort angina, which was treated by coronary aorta bypass grafting surgery when he was 58 years old. He stopped smoking and his occasional alcohol consumption. He frequently eats fish and his intake of vegetables is average, as is his seasoning.
His diabetes and dyslipidemia are now well treated, and his hemoglobin A1c and LDL-/HDL-cholesterol were 6.7 % and 115/79 mg/dl, respectively. Serum uric acid was 4.5 mg/dl. He has no atrial fibrillation and no left ventricular hypertrophy on ECG, and his CAVI was 8.0 m/s, suggesting normal arterial stiffness.
He feels healthy and takes care of his health. He has something to live for and has no depressive mood. Both scores on the GDS-15 and PHQ-2 scales were null. His subjective quality of life (QOL) of happiness, however, assessed by a visual analog scale (VAS), was low (47 %), while his subjective QOL of health was 85 %.
Coronary artery disease and hypertension are treated by angiotensin II receptor blocker (ARB) once daily. Nevertheless, his office BP remains high at 153/95 mmHg, and his home BP measurements averaged over 30 days were 137.8/85.0 mmHg in the morning and 116.9/74.1 mmHg in the evening.
Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 19.19. MESOR estimates of SBP, DBP, and HR, estimated from the 6-day/24-hour ABP measurements, were 126.8 mmHg, 79.8 mmHg, and 64.8 bpm, respectively. In accordance with the guidelines for management of high blood pressure based on ABP in Japan, published in 2014, he is normotensive (24-hour SBP and DBP averages are lower than 130 mmHg and 80 mmHg, respectively). However, day-to-day analyses indicated “masked ABP normotension,” as the 24-hour average of SBP changed from day to day: 141.5 (Saturday; hypertensive), 135.0 (Sunday; hypertensive), 125.8 (Monday; normotensive), 144.9 (Tuesday; hypertensive), 125.1 (Wednesday; normotensive), and 124.5 mmHg (Thursday; normotensive).
Fig. 19.19
Both SBP CHAT and DBP CHAT complicated by “masked ABP normotension.” Time plots of the 6-day/24-hour records of SBP (thick continuous line), DBP (thin continuous line), and HR (dashed line) of a 63-year-old man. His 24-hour average of SBP changed from day to day between 124.5 and 144.9 mmHg. Day-to-day analyses also showed that his double 24-hour amplitude (BP-2A) of SBP varied greatly: 67.98 (Saturday), 78.08 (Sunday), 72.25 (Monday), 66.45 (Tuesday), 82.14 (Wednesday), and 44.25 mmHg (Thursday), all exceeding the upper 95 % prediction limit of BP-2A in healthy peers matched by gender and age. His SBP day-night ratio indicates extreme dipping every day (from Saturday to Thursday: 24.9 %,41.1 %,37.5 %,33.5 %,46.4 %, and 31.9 %)
The circadian profile of SBP shows an overswing, with extreme dipping at night and overshooting above a time-varying threshold in the daytime (Figs. 19.19 and 19.20, left). The circadian profile of HR is normal, however, as shown on the right side of Fig. 19.20.
Fig. 19.20
Circadian profiles of systolic BP (left) and heart rate (HR) (right). 24-hour systolic BP (left) and heart rate (HR) (right) patterns of a man with CHAT, averaged over the 6 days of monitoring (polygonal line graph with closed squares), are shown along with time-specified prediction limits (continuous thin lines)
The circadian acrophases of SBP, DBP, and HR were 13:08, 13:28, and 13:42, respectively, all within acceptable limits, but the double amplitudes of SBP and DBP were 66.23 and 35.43 mmHg, both exceeding the upper limit of acceptability. Day-to-day analyses yielded estimates of the double amplitude of SBP (SBP-2A) which varied from Saturday to Thursday: 67.98, 78.08, 72.25, 66.45, 82.14, and 44.25 mmHg, respectively, all exceeding the upper 95 % prediction limit of BP-2A estimated from clinically healthy peers matched by gender and age (34.00 mmHg in this case).
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. 19.21). Data were then made equidistant (bottom section of Fig. 19.21).
Fig. 19.21
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. 19.22, which shows a prominent circadian period of 1.0375 day, together with two clear peaks with periods of 3.2436 and 0.5016 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 1.0375 day has the largest spectral power, as assessed by the “area” covered by the spectral peak.
Fig. 19.22
Period analysis of the circadian rhythm of systolic BP. MEM analysis estimates the circadian period of systolic BP to be 1.0375 day (left middle part). Data are shown with a five-component model fitted by least squares to the data, consisting of cosine curves with the five largest amplitudes, the 1.038 day being the most prominent one (right lower part)
On the bottom left of Fig. 19.22, 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 6.620, 3.244, 1.038, 0.502, and 0.388 days (right lower part of Fig. 19.22).
In conclusion, the clinical diagnosis based on the chronobiologically interpreted 6-day/24-hour ABP monitoring consists of (1) both SBP and DBP CHAT, (2) persistent SBP CHAT, and (3) masked ABP normotension, with a usual timing of the circadian BP rhythm. We have reported that CHAT is associated with a very high risk of ischemic stroke and other catastrophic disease. In addition, this subject had office hypertension and morning hypertension, assessed by home BP monitoring. Accordingly, we reviewed his lifestyle and made recommendations, focusing on salt intake, sleep-wake cycle, and how to improve the management of his diabetes. In addition, after starting a combination therapy for his hypertension and CAD with a CCB (benidipine, 4 mg/day), he now seems to be in good health.
19.2.3 Case Report 3 of “Circadian Hyper-Amplitude-Tension (CHAT)”
The third example of “CHAT” is a 61-year-old non-obese (BMI = 21.8 kg/m2) woman (ID number: Tosa0206). She has a regular rest-activity cycle and goes to bed usually at about 23:30 and gets up at 06:40. She is treated with 3-drug combination regimen, a long-acting calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), and a β-blocker, once daily at about 08:00 after breakfast. Nevertheless, her office BP and HR were 138/96 mmHg and 95 bpm. Home BP measurements averaged over 30 days were 144.0/90.4 mmHg in the morning and 127.4/79.7 mmHg in the evening, indicating morning hypertension.
Time series of systolic BP (SBP), diastolic BP (DBP), and heart rate measured by pulse (HR) are shown in Fig. 19.23. MESOR estimates of SBP, DBP, and HR, estimated from the 7-day/24-hour ABP measurements, were 127.1 mmHg, 81.6 mmHg, and 71.0 bpm, respectively. In accordance with the guidelines for management of high blood pressure based on ABP in Japan, published in 2014, she has mild diastolic hypertension. However, 7-day/24-hour ABP monitoring showed “masked SBP normotension,” as her 24-hour average of SBP varied from day to day, assuming values of 132.3 (Thursday; hypertension), 132.2 (Friday; hypertension), 123.6 (Saturday; normotension), 127.9 (Sunday; normotension), 134.7 (Monday; hypertension), 132.0 (Tuesday; hypertension), and 134.2 mmHg (Wednesday; hypertension). Her circadian profile of SBP shows an excessive BP swing with respect to the time-varying thresholds (Fig. 19.24, left), while her circadian HR profile is within acceptable limits (Fig. 19.24, right).
