Published online before print October 30, 2006, doi: 10.1161/01.HYP.0000250392.51418.64
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(Hypertension. 2007;49:237.)
© 2007 American Heart Association, Inc.
Letters to the Editor |
Chronobiology Predicts Actual and Proxy Outcomes when Dipping Fails
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minn
Tokyo Women’s Medical University, Medical Center East, Tokyo, Japan
Halberg Hospital and Research Institute, Moradabad, India
National Yang-Ming University, Taipei Taiwan
As a gauge of variability, dipping, based on day-night ratios of blood pressure, is much discussed,1 with 2194 hits in a search of the literature on the Internet. But, as compared with dipping, a classification based on chronobiological end points (such as the circadian amplitude and phase) interpreted in the light of reference values specified by gender and age offers superior discrimination in our data. Abnormality in the normal range can occur as (1) a (circadian) blood pressure overswing or circadian hyper-amplitude-tension (CHAT) gauged by a circadian amplitude exceeding the upper prediction limit of presumably clinically healthy peers of the same gender, age group, and ethnicity; (2) an excessive pulse pressure gauged by a persisting excessive difference between systolic pressure, when the heart contracts, and diastolic pressure, when the heart relaxes, measured around-the-clock; (3) circadian ecphasia, an odd timing of the daily blood pressure swing in the absence of an oddly timed daily heart rate pattern to rule out effects of work and sleep schedule shifts that may affect the timing of both blood pressure and heart rate rhythms; or (4) too little heart rate jitter, gauged by a reduced around-the-clock standard deviation of heart rate.
In a 6-year prospective study of 297 patients with no initial history of morbid cardiovascular event undergoing 48-hour ambulatory blood pressure monitoring,2 a circadian amplitude above the upper 95% prediction limit of clinically healthy peers matched by gender and age had a relative risk of 4.27 (95% CI: 2.43, 7.51; P<0.001), whereas nondipping was not discriminatory (RR=1.37; 95% CI: 0.75, 2.51; P>0.05). Analyses of 1179 untreated patients3 indicate that the concomitantly assessed left ventricular mass index (LVMI) of patients with an abnormal circadian pattern of diastolic blood pressure (DBP) is greatly elevated (Fisher statistic from 1-way ANOVA: F=15.959, P<0.001), contrasting with the LVMI of reverse dippers, nondippers, dippers, or extreme dippers (F=1.605, P=0.186) (Figure).
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Much larger LVMI values, considered as a surrogate outcome measure available from all 1179 patients, are observed in the presence of abnormal circadian patterns of DBP, whether the phase occurs at an odd time (ecphasia) or whether the amplitude is excessive (CHAT). Comparable elevations in LVMI are not seen for patients with an abnormal day-night ratio. A similar comparison based on systolic blood pressure (not shown) also favors a classification based on cosinor-derived circadian characteristics, whether considering all patients (All) or only women (F) or men (M), as does broader evidence in the Table. In populations of presumably healthy subjects and untreated or treated hypertensive patients, usually with no prior cardiovascular morbidity, a classification in terms of dipping based on the day-night ratio, routinely assessed in our analyses, has not contributed risk information beyond prediction achieved by means of chronobiological end points.
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To detect variability disorders, we need to replace the single office measurement of blood pressure by a 7-day profile of 3-hourly (self-) or denser (eg, half-hourly) automatic measurements analyzed chronobiologically, because there can be large day-to-day variability in circadian characteristics.4,5 We may find a midline estimating statistic of rhythm (MESOR)-hypertensive patient, whose overall blood pressure is seemingly well treated by drugs, with acceptable measurements during office hours, but who may still have much too high or much too low values during the night: high DBP around 120 mm Hg values each night because the medication no longer works (patient DJ), or low DBP values <30 mm Hg because it works too well (patient BLB). In both cases, such nightly readings present a danger in themselves and because they are associated with the occurrence of CHAT that can also happen when most or all values are within the acceptable range.
In MESOR-normotensive patients, the single blood pressure measurement in the provider’s office may be acceptable, but if CHAT is present, their risk of stroke and other severe vascular diseases may be greater than that associated with MESOR-hypertension (high blood pressure), all chronobiological diagnoses relying on a reference database preferably adjusted for gender, age, and ethnicity for all variability disorders. Whereas, on the average, blood pressure may not be too high or too low, variability in blood pressure, heart rate, or both may be abnormal. CHAT can thus be traded for a seemingly acceptable average, an undesirable outcome. Treatment of variability disorders can reduce the risk of severe morbid events,6 even among seemingly normotensive patients who, rather than relying on office spotchecks, monitor for 1 week for a chronome (time structure) analysis.
The long-proposed assessment of circadian rhythmicity4,5 as part of a much broader time structure can now be obtained cost effectively, with automatic monitors available with an 80% price reduction and free chronobiologic analysis (corne001@umn. edu) until a Phoenix Project (http://www.phoenix.tc-ieee.org/) will enable all users to analyze their data themselves by cosinor. With actual outcomes based on sample sizes larger than the 297 cases in Reference 2 or other studies listed in the Table, it seems desirable to compare in other already available databases the relative merits of a classification based on dipping (which in the study herein had no statistically significant predictive value) with one based on a chronobiological assessment of the data, and to apply chronobiological principles to individually optimize the timed prophylactic or palliative treatment of patients diagnosed with prehypertension or MESOR-hypertension, respectively.4–6 Fixed demarcations used for the day–night ratio do not account for the fact that the circadian blood pressure pattern is influenced by more than sleep-wake and activity and that it also changes with age. To further compare the relative merits of the circadian parameters and of dipping in all populations, cosinor analyses of ABPM data from existing outcome studies are offered at the Halberg Chronobiology Center.
Human monitoring around-the-clock for decades has also proved its heuristic value and provides a vast perspective beyond dipping classification.4,5 It awaits clinical scrutiny as a mechanism of inhibitions and exacerbations of disease, including sudden cardiac death, quite apart from an attempt at tighter control of blood pressure disorders akin to benefits of dense glucose monitoring already documented for the treatment of diabetes.
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Acknowledgments |
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Source of Funding
This work was funded by US Public Health Service (GM-13981; to F.H.).
Disclosures
None.
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References |
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