Prevention
A similar finding was made for non-pregnant women, suggesting that pressures which are seemingly acceptable by current standards may be a cause for concern. Reference limits (chronodesms) that are specified as a function of the circadian scale are accumulating from newborns, children and adults of all ages, including pregnant women at different gestational ages (Figure 17/IB). Chronobiometry provides reference limits not only for the interpretation of single values, but also for that of rhythm parameters (Figure 17/IC). The systolic blood pressure profile of this pregnant woman in her 20th gestational week showed an excessive amplitude: whereas the 90% prediction limits for the double amplitude of the circadian systolic blood pressure rhythm of clinically healthy women extend from 1.7 to 30.9 mm Hg, hers was 38.6 mm Hg. It was hence flagged as being too large. The warning from this excessive circadian amplitude was disregarded, in view of a seemingly acceptable blood pressure mean. Action may have prevented convulsions 8 weeks later and the subsequent delivery of a very premature boy who was hospitalized on and off for the first 26 months of life and whose care during the first 13 (cost-accounted) months of life cost U.S. $615,000.
A form for the interpretation of blood pressure (and heart rate) profiles over 24 or 48 hours or preferably longer, called a sphygmochron (Figure 17/II), is illustrated for systolic blood pressure. It presents a comparison of a patient's profile with peer group limits, using a parametric and a non-parametric approach. Parametrically, estimates of the MESOR, double amplitude and acrophase of the circadian rhythm are listed along with 90% prediction limits derived from similar data obtained from healthy peers of the same gender and of a similar age. Nonparametrically, the patient's profile is compared by computer to the time-specified reference limits (chronodesms). When the patient's profile exceeds these limits upward and/or downward, blood pressure excess and/or deficit is recognized. The results are integrated over a full 24-hour cycle to assess a) the percentage time elevation (PTE), b) the timing when most of the excess occurs within 24 hours and c) the extent of the excess, measured in mm Hg x h during 24 h and defined as the area delineated by the upper limit of the chronodesmic band and the patient's profile whenever it exceeds that limit, the hyperbaric index (HBI). On the basis of the parametric and non-parametric results, a recommendation is made regarding the need for any further follow-up or intervention.
The information listed in the sphygmochron can be utilized for timing treatment as secondary prevention (Figure 17/III). Profiles from two patients are shown (Figure 17/IIIA). Whereas both patients have a similar percentage time elevation (PTE = 84% and 75%), the severity of their blood pressure excess differs (HBI=231 vs. 764 mm Hg x h during 24 h). By examining the distribution in time of the blood pressure excess, it is possible to determine when most of the excess occurs (Figure 17/IIIB and C) and to time the administration of treatment accordingly, when it is needed. The merit of this approach is shown for the case of propranolol (Figure 17/IIID). As compared to once-traditional treatment 3 times a day, chronotherapy was applied by giving the drug 1.5 to 2 hours before the daily blood pressure peak, determined by around-the-clock measurements for the preceding 3 days. While less drug is needed, blood pressure is lowered more and faster with chronotherapy as compared to traditional therapy, and is accompanied by fewer complications and less overdosage (Figure 17/IIID). Similar results are obtained for certain other anti-hypertensive drugs as well (Figure 18).
Results noted earlier on a small sample of women suggest, with statistical significance, not only that low doses of aspirin affect prostaglandin and adrenergic pathways, but also that such effects vary as a function of the circadian stage at which the aspirin is taken. Six clinically healthy women, 20-30 years of age, volunteered to participate in a randomized pilot study consisting of a reference stage (lasting 2 days, starting after a 5-day adjustment to hospital conditions) followed by a 7-day span during which aspirin (100 mg/day) was administered at one of 6 different circadian stages: upon awakening, 3, 6, 9 or 12 hours after awakening, or at bedtime. During the reference stage and during the last 2 days of the low-dose aspirin test span, venous blood samples were collected every 4 hours for the determination of, among others, lipoperoxide concentration in platelet-rich plasma (LP) and the affinity of lymphocyte beta-2-adrenergic receptors (B-R) for 3H-dihydroalprenolol.
The circadian variation in lipoperoxide concentration in platelet-rich plasma before (upper curve) and on days 6 and 7 of prophylactic treatment with low doses of aspirin (100 mg/day for one week; lower curve) is shown in Figure 4/IVB. Each profile spans 2 days as shown on the horizontal scale. Whereas lipoperoxides are invariably depressed by aspirin, the extent of this effect varies as a function of the circadian stage of its administration. Aspirin use upon awakening (top row left in Figure 4/IVB) is associated with a clear (desired) inhibition.
Inhibition is also seen when aspirin is taken 3 hours after awakening (top row center in Figure 4/IVB). By comparison, the effect is very greatly reduced if aspirin is taken 12 hours after awakening (bottom row center in Figure 4/IVB).
The circadian variation in beta-2-adrenergic receptors on lymphocytes is shown in Figure 19. These receptors are said to counteract platelet aggregation. Again, the desired increase is seen when aspirin is taken each day on awakening or 3 hours after awakening, but not when it is used 12 hours later. The effect of daily low doses of aspirin for one week on B-R is reproduced as a vertical bar at the bottom of Figure 19 representing the extent of enhancement of B-R by low doses of aspirin. The extent of inhibition of LP by low doses of aspirin as a function of the circadian stage when aspirin is taken is shown in Figure 4/IVC. The differences in mean value between the low-dose aspirin test span and the reference stage computed for each subject were assigned to the circadian stage of treatment administration and fitted by least squares with a 24-hour cosine curve to assess the response (rhythm) to aspirin. When taken on awakening or 3 hours thereafter, aspirin depressed LP (perhaps by inhibiting thromboxane synthesis) and enhanced B-R: these effects were much smaller when the drug was taken 6 or 9 hours after awakening and were not demonstrated 12 hours after awakening. The circadian stage dependence of the effect is statistically significant (LP: P=0.012; B-R: P=0.003).
A test of the clinical signification of timing (according to circadian and other chronome components) of drugs proposed or used for the case of vascular disease prophylaxis seems mandatory. Chronobiologic pilot studies are best initiated in all biologic tests or procedures, whether nutritional, hygienic, or involving exercise, drugs or prosthetic devices, prophylaxis and disease risk lowering or for treating overt illness. Such phase zero tests are best implemented to explore the role of all chronome components, not only the circadians but also those with periods of about a week, a month, and a year. At times specified by these phase zero studies, trials on larger groups can then be implemented to determine outcomes and thus the statistical signification of an intervention, in the best-tolerated dose (phase I trials), for the most effective dose (phase II trials), and as compared to the best current procedure (phase III trials). Pilot studies can suggest no more, yet may be cost-savers in providing the way to detect, sooner and with smaller sample sizes, desired or undesired effects that may otherwise be missed.