Toward a Personalized Chronotherapy of High Blood Pressure and a Circadian Overswing

Abstract

Timing can greatly affect the response to a stimulus, including antihypertensive medications. Herein, we assess the response of 30 patients to losartan/hydrochlorothiazide (L/H), administered for at least 1 month at a given circadian stage to each patient, this stage being changed during consecutive spans to cover six treatment times from awakening to bedtime at approximately 3-hour intervals. At the end of each stage, each patient underwent a 7-day around-the-clock ambulatory blood pressure (BP) profile, analyzed chronobiologically. A larger reduction of the midline estimating statistic of rhythm (MESOR; a rhythm-adjusted mean) of diastolic BP was achieved by L/H administration in the early morning for more patients (P < .05), while treatment upon awakening was the best choice for most patients to reduce the circadian amplitude of BP the most (P < .01). The optimal treatment time varied considerably among patients, however. Special attention should be given to the effect on the circadian amplitude since treatment can increase it above a threshold, beyond which there is a marked increase in cardiovascular disease risk. The results indicate the desirability to individualize the optimization of the antihypertensive effect of L/H by timing along the circadian scale.

Chronobiology of Aging: A Mini-Review

“…Deviation from the norm by 1 or 2 additional features of blood pressure or heart rate variability raised 6-year morbidity from 9 to 29 and 53%, respectively [19] . Recognizing that different patients present with differently altered circadian profiles of blood pressure (chronodiagnosis), chronotherapy is best adjusted to the chronodiagnosis (chronotheranostics) [43] via truly personalized medicine, since the optimal treatment time differs from one patient to another, as demonstrated in a study by Watanabe et al [48] .…”

Diagnosing vascular variability anomalies, not only MESOR-hypertension

“…With notable exceptions (12,13,39,41,68), it is generally believed that changing the timing of administration of 24-h formulations should only have minor effects. This is far from the truth.…”

“…In the same 30 series, the 2A of HR was higher on Sundays and Saturdays than on other days of the week (P Ͻ 0.05). during the last week on that schedule (68). Underlying our recommendation to individualize the optimization by timing of the daily administration of antihypertensive medication is the concept of chronotheranostics, where the timed treatment is adjusted to the chronodiagnosis (14): if a patient has CHAT, treating at a circadian stage when the circadian amplitude of blood pressure is increased even further is likely to be harmful, even if the 24-h average pressure is lowered to a larger extent.…”

“…Furthermore, personalization of treatment time can change harm (such as CHAT induction or enhancement) into benefit (reducing or eliminating CHAT), while also lowering the MESOR of blood pressure. Most importantly, the optimal time of gaining benefit rather than doing harm is shown to differ among patients (68). No shoe fits all.…”

Personalized Hypertension Management in Practice

“…Altering the timing of medication administration, or chronotherapy, is also showing promise in improving the response to medication, for example, dosing with an ARB at night time [89], though these findings need further validation. As diurnal variation is itself genetic, with variable individual metabolic variation, it is not surprising that the timing of antihypertensive medication can itself be personalized [90].…”