Chronobiologic analyses assess abnormal circadian patterns of variability in blood pressure (BP) and heart rate (HR). These so-called Vascular Variability Disorders (VVDs) are independently associated with increases in cardiovascular disease risk. As compared to blood pressure elevation uncomplicated by other VVDs, their additional presence markedly increases cardiovascular disease risk, as documented in several outcome studies.
Current use of ABPM consists of automatically measuring BP and HR around the clock for about 24 hours, to compute daytime, night-time, and 24-hour mean values from which a day-night ratio is determined for a classification in terms of "dipping" instead of assessing the circadian characteristics, as done to identify VVDs. Threshold values defining dipping categories are fixed instead of being gender- and age-specified as reference values are to identify VVDs. Results indicate that BP variability assessed in terms of the circadian amplitude and phase is more reproducible than the conventional assessment based on "dipping" classified by the day-night ratio.
Analyses of longitudinal records of around-the-clock BP measurements covering years are proceeding to determine the extent of generality of the group's observation of a marked modulation of the circadian amplitude of BP by the about-yearly rhythm. The fact that the circadian amplitude of BP can be much larger in winter than in summer has implications for the correct diagnosis of an abnormal BP variability, and hence of its bearing on the correct assessment of cardiovascular disease risk.
Ongoing work examines the predictive value of the circadian amplitude of BP in at-risk versus clinically healthy populations to determine differences related to secondary versus primary prevention. For instance, the circadian characteristics of BP and HR are altered in obese asymptomatic adults and in patients with type 2 diabetes. The researchers have also documented differential effects of different anti-hypertensive medications on the circadian variation of BP. They are pursuing their investigation of the need to adjust the kind and scheduling of treatment to the chronodiagnosis, a procedure leading to the concept of chronotheranostics. The same dose of the same drug administered to the same patient can either induce or eliminate certain VVDs when administered at one or another circadian stage (6 test times, 3 hours apart from awakening to bedtime, each tested for at least one month). This protocol, originally tested on the anti-hypertensive drug combination Hyzaar, is ongoing with other drug combinations. Results suggest that more than 50% of treated patients may benefit from such personalized chronotherapy.
Analyses of longitudinal records of around-the-clock BP measurements covering years are proceeding to determine the extent of generality of the group's observation of a marked modulation of the circadian amplitude of BP by an about-yearly rhythm. The fact that the circadian amplitude of BP can be much larger in winter than in summer has implications for the correct diagnosis of an abnormal BP variability, and hence of its bearing on the correct assessment of cardiovascular disease risk.
VVDs rely on the availability of reference values from clinically healthy peers of both genders and different age groups. They are screened for on the basis of records longer than a single 24-hour day in view of the large day-to-day variability in circadian characteristics found in most people. The group's results indicate marked differences in BP mean and 24-hour amplitude between untreated men and women as well as trends as a function of age. The gender differences, however, are no longer detected in patients treated with anti-hypertensive medication, suggesting that current treatment does not account for gender differences.
A chronobiologic approach is also applied to the analysis of ECG records, notably of data collected on astronauts on the ISS to assess effects of microgravity on the cardiovascular system. Newly obtained results suggest that astronauts may slowly adapt to the space environment, and that adaptation to microgravity may involve circadian and ultradian rhythms, and may be influenced by fluctuations in the magnetic field. Two of this group's publications are highlighted in NASA annual reports.
Beyond serving to improve screening, diagnosis, and treatment, worldwide monitoring and analyses of BP and HR records also serve basic science, notably to assess how environmental factors affect human physiology. For instance, BP and HR show shared periodicities with space weather. The systematic assessment of these “coperiodisms” is being documented in a repository or “atlas” of chronomes (broad time structures) in us and around us.
A project has been initiated to explore the longitudinal analysis of vital signs recorded in wearables such as the Apple watch. Progress is being made to extract and convert the data to be analyzed on a day-to-day basis for associations with lifestyle factors such as sleep and exercise.
This group's pursuit of these goals is greatly facilitated by access to the supercomputer to:
- Analyze long and dense data series
- Organize data into databases
- Automatically update reference standards as added data accumulate
- Detect the earliest risk by means of chronome alterations
- Follow up at-risk individuals longitudinally by means of control charts
- Explore large parameter spaces in nonlinear analyses not requiring the specification of initial values
Artificial intelligence is also being considered as a complementary approach to analyze beat-to-beat blood pressure waveforms.
This research was featured on the MSI website in October 2020: Desynchronization of Circadian Rhythms in ICU Patients.