Description
The National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health, hosted a two-day virtual workshop titled "Sleep Health and Dysfunction Across the Spectrum of Pulmonary Vascular Disease" on August 30-31, 2023. The workshop was a multidisciplinary initiative that brought together leading clinical researchers, pulmonologists, sleep medicine specialists, cardiologists, data scientists, and other key stakeholders from the fields of sleep disorders and pulmonary vascular diseases (PVD). The goal of the workshop was to bridge the gap between clinical observational studies and hypothesis-driven basic research, focusing on the complex relationship between sleep health and PVD. Through a series of expert presentations and interactive sessions, the workshop aimed to identify testable hypotheses, pinpoint future research directions, and explore appropriate experimental systems and tools. The ultimate objective was to formulate a collaborative research agenda to advance our understanding of the link between sleep dysfunction and PVD, thereby setting the stage for innovative diagnostic and therapeutic strategies.
Background
Sleep and circadian disorders encompass a range of conditions, such as sleep apnea, insomnia, restless leg syndrome, and shift work disorders, all of which have significant ramifications for public health. For instance, obstructive sleep apnea, characterized by repeated episodes of partial or complete airway occlusion and intermittent hypoxemia, is not only associated with poor sleep quality, but also increases risk for developing atrial fibrillation, stroke, heart failure, coronary heart disease, and hypertension. Insomnia, defined by difficulty in falling and/or staying asleep with subsequent daytime impairment, can increase risk for mental health issues like depression and anxiety, as well as cardiovascular disease and premature mortality.
PVD similarly encompass a group of conditions. These disorders are characterized by pathologies affecting the pulmonary arteries and veins and manifest most commonly as an increase in pulmonary vascular pressure which can ultimately cause right heart failure (RHF). Pulmonary hypertension (PH) can be due to isolated pulmonary arterial remodeling (pulmonary arterial hypertension, or PAH) or secondary to other diseases such as chronic clots, parenchymal lung disease resulting in hypoxia, and left atrial hypertension. PH has been shown to have potential interactions with sleep disorders like sleep apnea and obesity hypoventilation syndrome, where disrupted breathing leads to significant oxygen desaturation, which may drive elevations in pulmonary arterial pressure. While less studied, sleep and circadian disorders, such as insomnia, restless legs syndrome, and circadian rhythm disorders also may increase PH risk through the effects of sleep fragmentation, insufficient sleep, and disrupted circadian rhythms on inflammation and/or iron metabolism.
There are numerous knowledge gaps concerning the intersection of sleep disorders and PVD. Much remains to be discovered about underlying mechanisms and therapeutic approaches and outcomes to sleep-related breathing disorders and PVD. Sleep disorders such as sleep apnea exhibit a strong correlation with cardiovascular diseases; however, individual susceptibility to cardiovascular disease varies considerably. This variation is partially attributable to differences in physiological stressors, such as the extent of hypoxemia, sleep fragmentation, and disturbances in the autonomic nervous system that affect individuals with similar diagnoses differently. Causal and bi-directional pathways relating sleep disorders and PH are not well understood. For example, while intermittent hypoxemia secondary to sleep-related breathing disturbances can increase pulmonary arterial pressures, complications of PH, including RHF and medication use, can exacerbate sleep-related symptoms and may impact quality of life and potentially worsen outcomes. Genetic and other risk factors that influence systemic and pulmonary inflammation, as well as vascular biology, may represent shared mechanisms that increase risk for both sleep disorders and PVD. The distinct demographic trends of sleep disorders and PVD add complexity to the study of their interrelationship. For example, sleep apnea is more prevalent in men; while insomnia, restless legs syndrome, and PH are more common in women. Given the nuanced and potential bidirectional relationship between sleep disorders and PVD, a more comprehensive understanding is needed to identify diagnostic markers, decode underlying mechanisms, and develop effective treatment strategies that consider both conditions and appropriately targets individuals most likely to benefit.
Identifying Research Opportunities:
- Phenotypic Complexity
- The first notable research opportunity is the need for data to inform which specific sleep disorders (and potential subtypes) will be highest yield for the field to focus on, for interventions, and target identification. There is substantial mechanistic and physiological heterogeneity in both sleep disorders and pulmonary vascular disease. This creates a challenge to a reductionist approach to detection of intersecting mechanisms.
- Divergent Effects of Hypoxia
- While experimental data indicates that hypoxia has markedly divergent effects related to dose and severity, as well as duration and chronicity in sleep-related breathing disorders, such differences have not been fully elucidated in studies linking sleep-related breathing disorders to pulmonary vascular disease. Moreover, genetic and other factors that modify responses to hypoxia are poorly understood.
- Measurement
- Given the variation in sleep disorder subtypes, there is uncertainty on how to utilize various existing and emerging testing methodologies most effectively, like full polysomnography (PSG), home sleep apnea studies, and commercial wearables when studying the association of sleep disorders and PVD. Moreover, scalable and precise tests are yet to be developed, indicating a research opportunity in diagnostic methods.
- Data and Analytics
- Despite the presence of electronic health records (EHR), sleep data are poorly represented. Registries have been developed for PVD, but it is unclear whether they include relevant sleep disorder data. Sleep repositories likewise include limited PVD data.
- Ethical Challenges
- There are concerns among some in the field about randomizing patients with chronic hypoxia and PH to placebo or an intervention that may improve hypoxia. These ethical considerations pose potential challenges to implementing certain randomized clinical trials, requiring careful consideration of issues related to equipoise.
- Treatment Specificity
- The current “one-size-fits-all” approach to treatment was noted as insufficient. There is a research opportunity in tailoring treatments based on individual genetics, phenotypes, and other factors like age and gender. The emergence of alternative treatments for obstructive sleep apnea and insomnia (for example, new pharmacological agents, novel devices, and behavioral interventions) also provides opportunities to apply a precision medicine approach for directing specific sleep interventions to patients with PH most likely to benefit from such intervention(s).
- Animal Models
- The capacity of experimental data from animal models to aid in understanding how specific sleep disorders and their related physiological stressors may interact with and potentially cause PVD remains a subject of debate, underscoring the need to explicate a clear rationale for model selection, including how a given model will achieve the stated objectives.
Recommended Research Opportunities:
- Mechanistic studies to understand the complex, potentially bidirectional, relationship, between sleep disorders and pulmonary vascular disease. These studies will facilitate new understanding of how pulmonary hypertension may be linked to sleep disorders and may include animal models or human studies. Understanding how distinct sleep disorders, e.g., those that are associated with hypoxia vs. those that do not cause hypoxia but that cause sleep insufficiency, sleep fragmentation, or circadian disruption affect the pulmonary vasculature is a priority. Such studies may explore a potential dose-response relationship between sleep-related hypoxia or other sleep disorder severity and pulmonary vascular disease severity to lend support to a mechanistic relationship and to identify potential non-linear associations between hypoxia (and/or other sleep-related stressors) and health outcomes. Studies that include multi-omics data and/or are focused on the genetic or early-life exposure risk for co-development of sleep disorders and pulmonary vascular disease may also offer novel mechanistic insight into this complex relationship.
- Defining patient subgroups with specific PVD and sleep subtypes most likely to benefit from targeted co-management strategies. Given that there are multiple sleep disorders and PVD subtypes, each with distinct mechanisms and outcomes, there is a need to generate data to allow refinement of which subtypes of sleep and PVD are related by causal, bi-directional, or common risk factors. An additional opportunity is to understand whether composite summaries of global (multi-dimensional) sleep health associates with, and influences, PVD subtypes. Expanding and exploiting large data sets with sufficiently phenotyped individuals, in conjunction with data from multi-omics, biomarkers (e.g., of circadian phase, inflammation, autonomic dysfunction, etc.) and health outcomes, along with powerful analytical tools including Mendelian Randomization and network analytics, could clarify which subtypes aggregate together and identify potential mechanistic links, pleiotropy, and causal associations. Strategies include expanding existing data registries and biobanks with additional or deeper pulmonary vascular or sleep phenotypes and molecular markers; improving tools for extracting data from electronic medical records; and optimizing data extraction on relevant sleep, circadian, and vascular phenotypes from routinely used clinical monitors and emerging commercial wearables and nearables. The ultimate goal of such investigations would be to facilitate data-informed interventions to improve sleep health, PVD, or both.
Workshop chairs
- Anna Hemnes, MD – Vanderbilt University
- Susan Redline, MD, PhD – Brigham and Women’s Hospital
Workshop participants
- Steve Abman, MD – University of Colorado
- Suzanne M. Bertisch, MD – Brigham and Women’s Hospital
- Andrew Bryant, MD – University of Florida
- Daniel Buysse, MD – University of Pittsburgh
- Brian Cade, PhD – Brigham and Women’s Hospital
- Stephen Chan, MD, PhD – University of Pittsburgh
- Vinicio de Jesus Perez, MD, PhD – Stanford University
- Alex Gileles-Hillel, MD – The Wohl Institute for Translational Medicine
- Kara Goss, MD – University of Texas Southwestern
- Syed Moin Hassan, MD – Brigham and Women’s Hospital
- Nicholas S. Hill, MD – Tufts University
- Daniel Katz, MD – Stanford University
- Jane Leopold, M.D. – Brigham and Women’s Hospital
- Eldrin F. Lewis, MD– Stanford University
- Katherine Liao, MD – Brigham and Women’s Hospital
- Steve Mathai, MD – Johns Hopkins University
- Reena Mehra, MD, MS – Cleveland Clinic
- Omar Mesarwi, MD – University of California San Diego
- Jasleen Minhas, MD – University of Pennsylvania
- Babak Mokhlesi, MD – Rush University
- Ankit Parekh, PhD – Mount Sinai Icahn School of Medicine
- Sairam Parthasarathy, MD – University of Arizona
- Naresh Punjabi, MD, PhD – University of Miami
- Franz Rischard, DO – University of Arizona
- Christopher Schmickl, MD, PhD – University of California San Diego
- Neomi Shah, MD, MS – Mount Sinai Icahn School of Medicine
- Tamar Sofer, PhD – Beth Israel Deaconess Hospital
- Andrew Sweatt, MD – Stanford University
NHLBI staff
- Alfonso Alfini, PhD – Division of Lung Diseases
- J. Matt Craig, PhD – Division of Lung Diseases
- James Kiley, PhD – Division of Lung Diseases
- Roy Sutliff, PhD – Division of Lung Diseases
- Lei Xiao, MD, PhD – Division of Lung Diseases