Toward a personalized chronotherapy of blood pressure

Fig. 1. Average response of systolic (left) and diastolic (right) blood pressure of 7–13 hypertensive patients to one of five different anti-hypertensive agents. In addition to different extents of blood pressure lowering effect, atenolol and long-acting carteolol are also associated with a reduction of the 24-h amplitude of blood pressure, and long-acting carteolol is associated with a 1-h advance in the 24-h acrophase of blood pressure. Considering how the 12-h component modifies the circadian waveform of blood pressure, predicted maxima shifted considerably from morning to evening (atenolol) or from evening to morning (long-acting carteolol).

Fig. 2. Average 24-h profiles of systolic and diastolic blood pressure of a 66-year old hypertensive man. He provided around-the-clock measurements at 30-min intervals for 7 days after taking losartan/hydrochlorothiazide for at least one month on each of six different occasions when treatment was taken daily either upon awakening (top left), 3 (top, center), 6 (top, right), 9 (bottom, left), 12 (bottom, center), or 15 (bottom, right) hours after awakening. While he used the same dose of the same treatment in each case, the average SBP achieved on treatment ranged from 108.6 to 127.1 mmHg and the average DBP ranged from 71.6 to 80.1 mmHg. Corresponding estimated 24-h amplitudes also varied greatly depending on the timing of treatment, namely from 10.6 to 24.4 (SBP) and from 7.1 to 16.0 mmHg (DBP). The timing of overall high values recurring each day varied from around 10:00 a.m. when the patient took the medication in the evening to 6–8 h later when he took the same dose of the same medication 3–12 h after awakening. Deciding on the optimal treatment time for this patient needs balancing all aspects of his 24-h variation in blood pressure.

Fig. 3. Average 24-h profiles of systolic and diastolic blood pressure of a 60-year old hypertensive man computed from 7-day/24-h ABPM records of measurements at 30-min intervals obtained after taking losartan/hydrochlorothiazide daily for at least one month either 3 (left) or 12 (right) hours after awakening. In the absence of a difference in MESOR, the 24-h amplitude of both SBP and DBP more than doubles when he takes losartan/hydrochlorothiazide daily later in the day, suggesting that this treatment time may be preferred for this patient.

Fig. 4. Need to personalize the optimization of treatment timing. Average 24-h profiles of systolic and diastolic blood pressure of a 62-year old hypertensive woman (top) and of a 73-year old hypertensive man (bottom) computed from 7-day/24-h ABPM records of measurements at 30-min intervals. They were treated daily with losartan/hydrochlorothiazide for at least one month either in the morning upon awakening (left) or in the evening, 15 h after awakening (right). Whereas treatment achieved a desired nocturnal blood pressure decrease with evening dosing but not with morning dosing for one patient (top), morning rather than evening dosing is the preferred treatment time for the other patient (bottom). These results illustrate the need to personalize the optimization of treatment timing. A fixed 2-component model is considered herein to fit the data for capturing the circadian variation in blood pressure. In order to characterize variations with periods shorter than 12 h (and reduce the models' lack of fit), higher-order harmonic terms need to be incorporated in the model. Their addition to the model, however, will not change the conclusion that a more pronounced circadian variation is…