The National Heart, Lung, and Blood Institute (NHLBI) virtually convened a workshop of multidisciplinary experts in the fields of hypertension, circadian biology, and sleep science on October 27-29, 2021. The goals of this workshop were: (i) to review the current state of science and knowledge about circadian rhythm in blood pressure regulation and chronotherapy for hypertension and (ii) to identify research gaps and opportunities which are inhibiting progress in understanding these two important connections.
The working group is responsive to NHLBI Strategic Vision Objectives 1-5.
There is great hope that collecting and coupling human genomic data and other omics data can help precision medicine. In order to pave the way toward precision medicine in hypertension, we need to remove multiple roadblocks that currently exist to hinder this progress. One of the most critical roadblocks (as identified by a recent NHLBI Workshop on “Hypertension: Barriers to Translation” –published in Hypertension, 2020) is our limited understanding in gene-environment and gene-gene interactions in blood pressure regulation. Many environmental and behavioral factors (i.e., temperature, diet, meal timing, stress, exercise, sleep habits, etc.) can affect blood pressure via various mechanisms, including altered circadian rhythms in our body. Normally, blood pressure displays a variation over a 24-hour period with higher blood pressure during the wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes. Sleep-wake cycles (i.e., sleep patterns), hormone release, eating habits, digestion, body temperature, renal and cardiovascular function and other important bodily functions exhibit circadian rhythms and can influence circadian rhythms of blood pressure. Potential benefits of non-pharmacologic and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications have recently been described in some studies. However, the effectiveness of chronotherapy in hypertension, and the mechanisms underlying circadian rhythm-mediated blood pressure regulation remain unclear.
The co-chairs and planning committee identified 31 national and international academic experts in basic, translational, clinical, and population science of hypertension, circadian biology, and sleep research. The speakers and moderators were selected from diverse areas of research in order to facilitate cross-cutting discussion to spark innovative ideas for future research pathways and to identify major areas of gaps and barriers in circadian biology of hypertension research and its clinical application.
Five plenary sessions were followed by small group sessions on the last day. Five session topics included: (i) Phenotypic Manifestations of Circadian Rhythm of Blood Pressure; (ii) Abnormal Circadian Rhythm of Blood Pressure, Target Organ Damage, and Disease; (iii) Mechanisms Influencing Circadian Rhythm of Blood Pressure; (iv) Additional Factors Associated with Circadian Rhythm of Blood Pressure; and (v) Interventions. During small group sessions, invited speakers and moderators attended one of two virtual rooms: basic/translational science room or population/clinical science room. Each small group was charged with identifying (1) high priority research questions, (2) gaps and barriers to addressing these questions, and (3) research opportunities on removing barriers. A final plenary session was held to share the summary of both small group discussions.
Research Gaps, Barriers and Opportunities
The workshop participants identified the following research gaps and barriers as well as opportunities for future research.
Gaps and Barriers
- The role of circadian rhythms on blood pressure has been documented in humans via association studies and in rodents via association studies and gene deletion models. To address gaps in knowledge, it is necessary to move from association studies to cause-and-effect relationship studies.
- Both circadian clock and non-clock mechanisms need to be examined in connection with the following three factors: endogenous factors, environmental factors, and host-microbial interactive factors.
- Examples of endogenous factors include genetics, epigenetics, metabolites, transgenerational effects, sex, metabolism, immune system, cells/tissue-specific mechanisms, and interorgan cross talks.
- Examples of environmental factors include diet (composition and timing), ambient temperature, stress, sleep, and light.
- Examples of host-microbial interactive factors include microbial profiles in response to various environmental factors/anti-hypertensive medications and microbial metabolites.
- Time of day and night (awake/asleep) is a key biological variable. However, time of day and night is not routinely reported in the literature, impairing efforts toward rigor and reproducibility.
- Sex differences and health disparities are both important factors affecting circadian rhythm of blood pressure. Studies should be sufficiently powered for differences between sexes and racial and ethnic subpopulations to be analyzed.
- Standardized “circadian” definitions, nomenclature, and methods across studies (e.g., day versus night, active versus inactive, awake versus asleep, circadian misalignment) are needed to avoid confusion. In particular, these definitions impact translation given that humans are diurnal and rodents are nocturnal.
- Scalable biomarkers and measurements are needed to provide cost-effective phenotyping of human circadian rhythms at scale.
- Ambulatory Blood Pressure Monitoring (ABPM) is a useful tool for assessing the diurnal blood pressure variation in humans but has limitations. Novel blood pressure monitoring methods are emerging but not ready for widespread use.
- Limited public databases are available that contain blood pressure, sleep times, and circadian rhythm data (including raw telemetry data) since most large cohort studies do not assess 24-hour blood pressure or circadian processes.
Opportunities For Future Research
- Emphasize the following priority research areas:
- Diverse animal models for circadian rhythms as well as for chronotherapy
- High quality randomized clinical trials of antihypertensive chronotherapy
- Time restricted feeding and meal timing studies
- Sleep targeted intervention studies
- Gut microbiome targeted studies
- Implication of blood pressure pattern and level on health outcomes
- Interplay of sleep dimensions, circadian rhythm, and blood pressure
- Genetic assessments of circadian timing and chronotype
- Scalable biomarkers for circadian biology
- Develop a reliable, low-burdensome assessment method or device to monitor 24-hour blood pressure over days in populations
- Leverage wearables and artificial intelligence (AI) to scale and improve evaluation of blood pressure, circadian rhythm, sleep and their inter-relationships
- Develop standardized approaches for annotating sleep timing in clinical and population studies
- Encourage team science including sleep, circadian biology, and vascular disease and break down barriers to interaction across disciplines
- Support sufficiently powered prospective studies and strategic ancillary studies
- Move circadian medicine into the clinic
The workshop participants plan to prepare a manuscript for publication in a peer-reviewed journal.
Young S Oh, PhD, Division of Cardiovascular Sciences (DCVS), NHLBI
Workshop Invited Participants
Michelle L Gumz, PhD, University of Florida
Daichi Shimbo, MD, Columbia University Irving Medical Center
Speakers and Moderators
- Marwah Abdalla, MD, Columbia University Irving Medical Center
- Christian Benedict, PhD, Uppsala University, Sweden
- Mercedes Carnethon, PhD, Northwestern University
- Yabing Chen, PhD, University of Alabama at Birmingham
- David J Ernest, PhD, Texas A&M University
- Karen L Gamble, PhD, University of Alabama at Birmingham
- Scott R Garrison, MD, PhD, University of Alberta, Canada
- Ming C Gong, MD, PhD, University of Kentucky
- John B Hogenesch, PhD, University of Cincinnati
- Jessica R Ivy, PhD, University of Edinburgh, UK
- Bina Joe, PhD, University of Toledo
- Mingyu Liang, PhD, Medical College of Wisconsin
- Eric J MacLaughlin, PharmD, Texas Tech University
- Tami A Martino, PhD, University of Guelph, Canada
- Paul Muntner, PhD, University of Alabama at Birmingham
- David M Pollock, PhD, University of Alabama at Birmingham
- Jennifer S Pollock, PhD, University of Alabama at Birmingham
- Mahboob Rahman, MD, Case Western Reserve University
- Susan Redline, MD, MPH, Harvard University
- Amy Rogers, MD, University of Dundee, UK
- Dan Rudic, PhD, Augusta University
- Eva Schernhammer, MD, DrPH, Harvard University
- Steven A Shea, PhD, Oregon Health & Science University
- David W Stepp, PhD, Augusta University
- George S Stergiou, MD, FRCP, Athens University, Greece
- Marie-Pierre St-Onge, PhD, Columbia University Irving Medical Center
- Joseph S Takahashi, PhD, University of Texas Southwestern Medical Center
- Xiaoling Wang, MD, PhD, Augusta University
- Phyllis C Zee, MD, PhD, Northwestern University
NHLBI Workshop Planning Committee
- Ravi Balijepalli, PhD, Heart Failure and Arrhythmias Branch, DCVS, NHLBI
- Yuling Hong, MD, PhD, Epidemiology Branch, DCVS, NHLBI
- Aaron Laposky, PhD, National Center on Sleep Disorders Research, DLD, NHLBI
- Young Oh, PhD, Vascular Biology and Hypertension Branch, DCVS, NHLBI
- Jacqueline Wright, DrPH, Epidemiology Branch, DCVS, NHLBI
Welcoming Remarks and Meeting Overview
Introduction – Dr.Young Oh, Meeting Organizer, DCVS, NHLBI
Welcome – Dr.David Goff, Director, DCVS, NHLBI
Goals and Sessions Overview – Meeting Co-Chairs: Dr. Michelle Gumz (University of Florida) and Dr. Daichi Shimbo (Columbia University)
SESSION 1: Phenotypic Manifestations of Circadian Rhythm of Blood Pressure
Moderator: Dr. David Pollock (University of Alabama at Birmingham)
12:25 – 12:40 p.m. Molecular Architecture of the Mammalian Circadian Clock – Dr. Joseph Takahashi (University of Texas Southwestern)
12:40 – 12:55 p.m. Human: Behavioral and Endogenous Circadian Factors Interact to Produce a Day/Night Pattern of Blood Pressure – Dr. Steven A. Shea (Oregon Health & Science University)
12:55 – 1:10 p.m. Human: Measurement Approaches to Circadian Rhythm of Blood Pressure – Dr. George Stergiou (University of Athens, Greece)
1:10 – 1:25 p.m. Animal: Circadian Rhythm of Blood Pressure in Rodent Models – Dr. Michelle Gumz (University of Florida)
1:25 – 1:40 p.m. Animal: Data Analysis for Circadian Rhythm of Blood Pressure – Dr. Jessica R. Ivy (University of Edinburgh, UK)
1:40 – 2:00 p.m. Panel Discussion with All Session Speakers – Moderator: Dr. David Pollock (University of Alabama at Birmingham)
2:00 – 2:15 p.m. Break
2:15 - 4:05 p.m.
SESSION 2: Abnormal Circadian Rhythm: Blood Pressure, Target Organ Damage, and Disease
Moderator: Dr. Bina Joe (University of Toledo)
2:15 – 2:30 p.m. Human: Cardiovascular –Dr. Paul Muntner (University of Alabama at Birmingham)
2:30 – 2:45 p.m. Human: Kidney – Dr. Mahboob Rahman (Case Western Reserve University)
2:45 – 3:00 p.m. Human: Brain, Cognition, and Dementia – Dr. Christian Benedict (University of Uppsala, Sweden)
3:00 – 3:15 p.m. Human: Night Shift – Dr. Eva Schernhammer (Harvard)
3:15 – 3:30 p.m. Animal: Shift Work, Sex Differences, and Stroke – Dr. David J. Earnest (Texas A&M University)
3:30 – 3:45 p.m. Animal: Vasculature – Dr. Yabing Chen (University of Alabama at Birmingham)
3:45 – 4:05 p.m. Panel Discussion with All Session Speakers – Moderator: Dr. Bina Joe (University of Toledo)
4:05 p.m. Adjourn
12:00 - 12:10 p.m.
Welcome and Sessions Overview
12:10 - 2:15 p.m.
SESSION 3: Mechanisms Influencing Circadian Rhythm of Blood Pressure
Moderator: Dr. David Stepp (Augusta University)
12:10 - 12:25 p.m. Circadian Clock Gene Networks in Animals and Human – Dr. John B. Hogenesch (University of Cincinnati)
12:25 – 12:40 p.m. Human: GWAS, Genes, and Genetics – Dr. Xiaoling Wang (Augusta University)
12:40 – 12:55 p.m. Human: Epigenetics – Dr. Mingyu Liang (Medical College of Wisconsin)
12:55 – 1:10 p.m. Human: Sleep Disturbances and Disorders – Dr. Marwah Abdalla (Columbia University)
1:10 – 1:25 p.m. Animal: Food Intake Timing in Diabetic Animal Model – Dr. Ming Gong (University of Kentucky)
1:25 – 1:40 p.m. Animal: Food Intake Timing in Animal Model – Dr. David Pollock (University of Alabama at Birmingham)
1:40 – 2:00 p.m. Panel Discussion with All Session Speakers – Moderator: Dr. David Stepp (Augusta University)
2:00 – 2:15 p.m. Break
2:15 - 4:05 p.m.
SESSION 4: Additional Factors Associated with Circadian Rhythm of Blood Pressure
Moderator: Dr. Susan Redline (Harvard University)
2:15 - 2:30 p.m. Human: Aging, Sex, and Sleep – Dr. Phyllis C. Zee (Northwestern University)
2:30 – 2:45 p.m. Human: Health Disparities – Dr. Mercedes Carnethon (Northwestern University)
2:45 – 3:00 p.m. Animal: Obesity – Dr. David Stepp (Augusta University)
3:00 – 3:15 p.m. Animal: Salt – Dr. Jennifer Pollock (University of Alabama at Birmingham)
3:15 – 3:30 p.m. Animal: Aging – Dr. Dan Rudic (Augusta University)
3:30 – 3:45 p.m. Animal: Microbiome – Dr. Bina Joe (University of Toledo)
3:45 – 4:05 p.m. Panel Discussion with All Session Speakers – Moderator: Dr. Susan Redline (Harvard University)
4:05 p.m. Adjourn
12:00 - 12:10 p.m.
Welcome and Sessions Overview
12:10 - 2:20 p.m.
SESSION 5: Interventions
Moderator: Dr. Tami Martino (University of Guelph, Canada)
12:10 – 12:20 p.m. Introduction: Chronotherapy for Hypertension – Dr. Daichi Shimbo (Columbia University)
12:20 – 12:35 p.m. Human: Non-Pharmacologic (Sleep Duration & Timing) – Dr. Marie-Pierre St-Onge (Columbia University)
12:35 – 12:50 p.m. Animal: Non-Pharmacologic (Time Restricted Feeding) – Dr. Karen Gamble (University of Alabama at Birmingham)
12:50 – 1:05 p.m. Pharmacologic (HYGIA Trial) – Dr. Eric J. MacLaughlin (Texas Tech University)
1:05 – 1:20 p.m. Pharmacologic (TIME Trial) – Dr. Amy Rogers (University of Dundee, UK)
1:20 – 1:35 p.m. Pharmacologic (BedMed and BedMed-Frail Trials) – Dr. Scott R. Garrison (University of Alberta, Canada)
1:35 – 1:50 p.m. Gaps and Future Directions on Chronotherapy Interventions: Translation from Animals to Humans – Dr. Tami Martino (University of Guelph, Canada)
1:50 – 2:10 p.m. Panel Discussion with All Session Speakers – Moderator: Dr. Tami Martino (University of Guelph, Canada)
2:10 – 2:20 p.m. Break
2:20 - 4:00 p.m.
SESSION 6: Breakout Sessions
SESSION 6: Breakout Sessions
Breakout Room Moderators
(i) Basic/Translational Science: Dr. David Pollock (University of Alabama at Birmingham), Dr. Bina Joe (University of Toledo), and Dr. David Stepp (Augusta University)
(ii) Population/Clinical Science: Dr. Susan Redline (Harvard University) and Dr.Tami Martino (University of Guelph, Canada)
Main Room Moderators – Dr. Michelle Gumz (University of Florida) and Dr. Daichi Shimbo (Columbia University)
2:20 – 3:00 p.m. Breakout Sessions (For Invited Speakers Only; Break for Other Participants)
Two break out rooms (Invited Speakers Only – a separate zoom link will be provided):
(i) basic/translational science and (ii) population/clinical science.
Each room will identify (1) high priority research questions, (2) barriers to addressing these gaps and questions, and (3) recommendations on removing barriers.
3:00 – 4:00 p.m. Breakout Session Summary and Discussion
Return to main room. Spokespersons for basic/translational science room and population/clinical science room will each report on the summary of the discussion. Moderated discussion will occur after presentations.
4:00 p.m. Closing Including Next Steps – Dr. Young Oh (DCVS, NHLBI)