S. Ohkawa

Impact of circadian amplitude and chronotherapy: relevance to prevention and treatment of stroke

The long-acting calcium antagonist nifedipine reduces the incidence of stroke in Eastern Asia, as shown by the Shanghai Trial Of Nifedipine in the Elderly (STONE) and the Systolic Hypertension in China (Syst-China) trials. Recent trials in Japan have shown that benidipine may be more efficient than the former drug in preventing strokes in the elderly. Benidipine, commonly prescribed in Japan for a definite depressor effect, reportedly without causing remarkable fluctuations in blood pressure (BP), is investigated herein from a chronobiological viewpoint. Eighteen subjects (nine women and nine men, 39 to 87 years of age) with essential hypertension (office and ambulatory systolic, S/diastolic, D BP values above 160/95 mm Hg and 130/80 mm Hg, respectively) were enrolled in this investigation. Ambulatory BP was monitored at 30-min intervals for at least 24 h (ABPM-630, Colin Medical) before and after 4 weeks of crossover treatment with nifedipine tablets (twice daily, 20 mg/d) and benidipine (once daily, 4 mg/d, in the morning). The results indicate that: 1) benidipine and nifedipine reduce 24-h daytime (10:00-20:00) and nighttime (00:00-06:00) averages of SBP and DBP (P < 0.001); 2) the circadian double amplitude of BP is decreased after treatment with benidipine (from 28.6 to 21.1 mm Hg SBP and from 19.7 to 15.2 mm Hg DBP; P< 0.05), while the day-night difference in SBP is increased after treatment with nifedipine (18.6 vs 27.9 mm Hg, P< 0.01); and 3) the increase in the day-night difference of heart rate (HR) is significant after treatment with benidipine (13.6 vs 18.8 beats per minute, bpm; P< 0.05), but not with nifedipine. We have previously evaluated the usefulness of the circadian amplitude of BP as a prognostic tool of cardiovascular outcome, and found that an excessive circadian SBP or DBP amplitude was associated with an increased risk of vascular disease. The fact that benidipine reduces the circadian BP amplitude may be one reason for the superiority of this treatment over nifedipine in preventing an adverse outcome. A reduced heart rate variability (HRV) also predicts adverse cardiovascular outcomes in patients with overt cardiovascular disease and in hypertensive subjects. The fact that benidipine increases the day-night difference in HR may be another reason for the positive effects of this treatment.

Associations by signatures and coherences between the human circulation and helio- and geomagnetic activity.

Helio-geomagnetic influences on the human circulation are investigated on the basis of an 11-year-long record from a clinically healthy cardiologist, 35 years of age at the start of monitoring. He measured his blood pressure and heart rate around the clock with an ambulatory monitor programmed to inflate an arm cuff, mostly at intervals of 15-30 minutes, with only few interruptions, starting in August 1987. While monitoring is continuing, data collected up to July 1998 are analyzed herein by cosinor rhythmometry and cross-spectral coherence with matching records of solar activity, gauged by Wolf numbers (WN) and of the geomagnetic disturbance index, Kp. A direct association between heart rate (HR) and WN is found to be solar cycle stage-dependent, whereas an inverse relationship between heart rate variability (HRV) and WN is found consistently. An inverse relation is also observed between WN and the variability in systolic blood pressure (SBP), and to a lesser extent, diastolic blood pressure (DBP). Moreover, HR is cross-spectrally coherent with WN at a frequency of one cycle in about 7.33 months. The results support previously reported associations on morbidity and mortality statistics, extending their scope to human physiology monitored longitudinally.

Graded response of heart rate variability, associated with an alteration of geomagnetic activity in a subarctic area

It is becoming recognized that geomagnetic activity may influence biological processes, including the incidence of various human diseases. There is evidence that heart rate variability (HRV) may serve not only as an index of autonomic coordination of the circulation, but also as a powerful predictor of risk in apparently healthy subjects. This study focuses on the effects of geomagnetic disturbance on HRV, by comparing different indices of HRV of young, healthy men living in a subarctic area on days of low (Ap; 0-7), middle (Ap; 7-20), and high (Ap; 20-45) geomagnetic activity. The effect of geomagnetic disturbance on HRV is examined on the basis of 7-day records by Holter ECG, obtained longitudinally on 5 clinically healthy men, 21-31 years of age, in Alta, Norway (70 degree N). Frequency- and time-domain measures of HRV were analyzed for each subject on separate 24-hour spans. A graded alteration of HRV endpoints was found in association with increased geomagnetic activity. As time-domain measures of HRV, SDNNIDX and the 90% length of the Lorenz plot decreased statistically significantly on days with increased geomagnetic disturbance (p = 0.0144 and p = 0.0102, respectively). A graded decrease in frequency-domain HRV measures was also validated statistically for the total spectral power (decrease of 18.1% and 31.6% on days when 7 < Ap < 20 and 20 < Ap < 45 versus days when Ap < 7; p = 0.0013). The decrease in spectral power was mainly found at frequencies below 0.04 Hz, in the ultra-low-frequency (0.0001-0.003 Hz; 18.1% and 27.5% decrease, respectively; p = 0.0102) and very-low-frequency (0.003-0.04 Hz; 12.9% and 28.6% decrease, respectively; p = 0.0209) regions of the spectrum. The decrease in spectral power was much less pronounced around 10.5 sec (low frequency; N.S.) and around 3.6 sec (high frequency; N.S.). Evidence is provided here that HRV decreases on magnetically disturbed days, and that it does so in a dose-dependent fashion, HRV being depressed more on days when 20 < Ap < 45 than on days when 7 < Ap < 20, by comparison with days when Ap < 7. This graded response of HRV to geomagnetic activity should encourage us to search for human magnetoreceptors and for a better understanding of putative mechanisms of magnetoreception.

Effect of H2 blockers on the circadian rhythm of intragastric acidity

Most patients with peptic ulcer or gastro-oesophageal reflux disease develop nocturnal pain (epigastric and retrosternal pain from midnight to early morning), which often disappears before breakfast. Such pain may be related to a disturbance of the circadian rhythm of gastric acid secretion. Helicobacter pylori is a known aetiological agent of peptic ulcer disease and patients with gastritis or ulcers now undergo infection eradication therapy. However, this can result in the onset or exacerbation of gastro-oesophageal reflux disease. There has been a marked increase in the number of patients with oesophagitis rather than peptic ulcer and because most are negative for H. pylori, attention has centred on the status of their gastric acid secretion. Some patients with oesophagitis complain of nocturnal pain despite treatment with a proton pump inhibitor, and in those cases a short course of an H2 blocker can be very effective. We used a portable pH meter to study, in a cross-over fashion, the changes in the circadian rhythm of gastric acid secretion caused by two H2 blockers, laftidine and famotidine, in 10 H. pylori-negative subjects. There was a significant difference in the rhythm between baseline (no treatment) and when laftidine or famotidine were administered, with mean values for amplitude of 28.1, 13.80 and 10.82, respectively; for the midline estimating statistic of rhythm (MESOR), 22.7, 10.80, and 11.54; and for acrophase, 324.0. 312.3, and 274.5 (p < 0.001). The H2 blockers suppressed the normal circadian rhythm of intragastric acidity, which rises in the evening until the middle of the night and then drops in the morning.

Positive impact of social intervention on disturbed neurobehavioral function in an elderly community-dwelling population: Longitudinal investigation for longevity and aging in Hokkaido county (LILAC)

Several kinds of health consultation and rehabilitation for functional disorders aimed at stroke prevention and maintenance of cognitive function in an elderly population in Hokkaido county, Japan. Changes in cardiovascular and neurobehavioral endpoints between 2000 and 2002 were assessed in 72 of 115 subjects over 75 years of age. Direct social intervention, including lifestyle modification can have a positive impact, notably on subjects with cardiovascular disorders.