Analysis of 24-h Blood Pressure Dysregulations Using Population-Based and Clinical Cohorts Data - PROJECT SUMMARY High variability in blood pressure (BP) over 24-hour (24-h) is associated with target organ damage and increases the risk of most common age-related diseases including glaucoma, stroke, Alzheimer’s disease-related disorders, and cardiovascular complications. While the exact mechanisms remain unclear, evidence suggests that organs may experience periods of unstable blood flow and supply when BP excessively varies. This mechanism has been studied by estimating averaged BP variability or categorizing nocturnal BP dipping. However, these metrics do not fully capture hypotensive episodes and rather simplify BP circadian rhythms. As a result, the contribution of 24-h BP variability for the risk-stratification of outcomes remains poor, hampered by limited reproducibility and inconsistent significant associations. We urgently need innovative metrics and methods to change the paradigm of studying BP variability as absolute values. 24-h ambulatory BP monitoring (ABPM) provides a set of time-series BP points from which specific BP could be generated. However, we are not aware of studies examining 24-h BP dysregulation beyond mean absolute values and current evidence lacks whether diseases correlate with specific 24-h BP patterns. Our overall hypothesis is that 24-h BP dysregulation is a syndrome characterized by 1) hypotensive states and 2) abnormal patterns in BP that correlate with the presence and development of health outcomes. By leveraging and analyzing 24-h BP data from three large population-based studies (~4000 participants aged ≥40y), this project aims 1) to examine the relationship of 24-h hypotensive states with age-related ophthalmic (glaucoma- related damage), neurological (Alzheimer’s disease-related disorders), and cardiovascular outcomes; 2) to study whether these outcomes exhibit specific 24-h BP patterns; and 3) to correlate 24-h BP patterns with hypotensive states and conventional metrics of BP. In Aim 1, we will evaluate 24-h hypotensive states by providing a new conceptual framework that considers magnitude, frequency, and time. Ho: drastic, sporadic, and prolonged drops in BP over 24-h are associated with worse outcomes (burden and progression). In Aim 2, we will construct BP signals into a three-dimensional space and cluster patterns based on the BP signals’ distance. Ho: patterns of 24-h BP are specific to age-related complications. In Aim 3, we will correlate metrics derived from Aim 1 as well as 24-h BP level and variability with the generated patterns of 24-h BP waveforms. We will additionally use longitudinal ABPM to test whether patterns of 24-h BP change over time and whether greater BP variability and more 24-h hypotensive states accompany such longitudinal changes. The paradigm presented here proposes to study 24-h BP dysregulation as a syndrome characterized by 24-h hypotensive states and abnormal patterns associated with specific diseases. The approach we propose would address unmet needs for biomarkers of abnormal BP circadian rhythms in clinical and research settings.
