The National Heart, Lung, and Blood Institute (NHLBI), in partnership with the National Institutes of Health (NIH) Office of the Director (OD), convened a workshop on “Autonomic Neural Mechanisms of Cardiopulmonary Regulation.” The workshop brought together both national and international multi-disciplinary experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders, and representatives of academic institutions, federal agencies, and other organizations. The workshop provided a forum for discussing the latest advances, cutting-edge approaches, and methodologies to identify the highest priority research gaps and opportunities to advance the field. The workshop objectives were to:
View the Workshop Agenda
Neural circuitry and control of the cardiopulmonary systems are central to life, with profound physiological linking and interplay. The nervous system modulates almost all known physiological aspects of cardiac organ physiology (i.e., heart rate, heart rhythm/signal conduction, contraction, relaxation, sensations, and response to injury). Afferent neural signals originating in the myocardium and the lung are ‘processed’ at various levels of the neuroaxis - intrinsic cardiac neurons (the ‘little brain’ of the heart), lung afferents, extracardiac-intrathoracic ganglia (stellate ganglia), spinal cord, brain stem, and higher centers, and are required for the fine efferent cardiomotor and airway control via the sympathetic and parasympathetic nerves. Following cardiac injury, the alterations in this system characterized by sympathetic over-excitation and parasympathetic withdrawal contribute to progression of heart disease, including heart failure and arrhythmias. The pathologic sequence begins with short-term adaptations to cardiac injury followed by a profound maladaptation eventually resulting in adverse outcomes, including structural and functional remodeling of the neural structures that control the heart. Respiratory diseases also profoundly alter afferent signals to the higher levels of the neuroaxis resulting in sympathetic output changes with deleterious clinical consequences. Neuromodulation therapies targeting these cardiopulmonary circuits (e.g., vagal nerve stimulation and surgical stellate ganglionectomy) show great promise for improving related morbidity and mortality.
Recent advances in cardiopulmonary neuromodulation can be attributed in part to NIH’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) program. The program builds on the scientific foundation of peripheral neural control of organ function to create and advance the next generation of therapeutic neuromodulation devices and protocols. This includes novel neuroanatomical techniques spanning across the autonomic nervous system, new footholds established in larger animal models suitable for device development, and strategies to mature from proof-of-principle studies to targeting specific organs. While SPARC focuses on mapping the innervation of healthy organs, understanding impaired circuitry and function in heart and lung disease is crucial in establishing effective cardiopulmonary neuromodulation therapies.
Workshop participants summarized the current state of knowledge in the basic and clinical sciences related to neural control of cardiac and lung physiology and pathophysiology. Advances in ANS research in recent years have led to numerous discoveries that have initiated a return of this classic discipline back to the center stage of health and disease. At the same time, a number of challenges and knowledge gaps had to be addressed to clarify the role of ANS in cardiopulmonary diseases and to harness the power of ANS science for human therapy. Important gaps in knowledge were identified, as were proposed novel approaches to advance basic, translational, and clinical/population sciences. The workshop participants identified a spectrum of opportunities and prioritizing schema to address these questions for future research in the near, intermediate, and long term periods. The workshop was structured to address the following six topic areas:
There was appreciation for the critical need to determine fundamental mechanisms of neural control of the nerve-organ interface (heart and lung) and identify key regulatory circuits that can be targeted for therapies. Challenges to exploring these questions relate to lack of roadmaps, limitations of tools and technologies for animal, tissue, and cellular models, and limited mechanistic studies in humans to inform the design and implementation of clinical trials. To overcome these research challenges, greater emphasis on experimental rigor and methodological transparency is needed to control for and assess the influence of neural signaling in cardiopulmonary physiology. Many published animal studies have not rigorously accounted for the complexity of neural circuit readouts or biological variables. Human studies often do not consider circadian rhythms and environmental influences and are limited by the absence of reliable biomarkers of neural remodeling. Improved knowledge of neural control-related variables in populations has high potential for development of specific interventions and novel preventive strategies.
In synergy with the scientific discussion, noteworthy foundational statements from the workshop participants include:
Key domains and priority research knowledge gaps within ANS science were identified across basic science, translational/applied and clinical investigative categories. Salient cross-cutting pathophysiologic domains emerged across these categories, and given the nascent stage of understanding of many of the research opportunities emanating from the knowledge gaps, immediate, intermediate, and long-terms goals are outlined. Therefore, workshop participants were mindful of the following cross-cutting domains identifying the gaps and opportunities:
The following scientific gaps in knowledge and research priorities were identified:
I. Basic research:
Target areas included:
a. Gap: Limited knowledge on cellular electrophysiology and biophysics within intact peripheral autonomic ganglia, integrative reflex control, and reflex remodeling in health and cardiopulmonary disease.
b. Gap: Lack of understanding of the pathobiology of intra-ganglionic inflammation, immune-mediated mechanisms, and distinguishing effects driven by systemic inflammation from intra-ganglionic inflammation.
c. Gap: Uncertainty regarding the cross-talk between cardiopulmonary afferent stimulation and sympathetic modulation in multiple visceral organs and responses to neuromodulation.
d. Gap: Need for research on baroreflex mechanisms in cardiopulmonary disease.
II. Translational and applied research:
Target areas included new research collaborative mechanisms focused on ANS and its therapies, optimization of cardiopulmonary circulation and cardiac conduction performance in health and ANS states of perturbation.
a. Gap: Lack of ANS mechanistic biomarkers reflective of cardiopulmonary pathobiology, predictors of outcome risk, and targets for novel therapeutics.
b. Gap: Limited computational multi-layered integrative methods to elucidate ANS pathophysiology and pathobiology
c. Gap: Underappreciated role of neuromodulation therapy in cardiopulmonary disease with the need to identify appropriate indication, personalized strategies, predictors of responsiveness, inflammation, and neural remodeling to be used in a variety of diseases with common mechanisms inclusive of devices, biomolecules, or drugs.
d. Gap: Lack of understanding of cardiac transplant de-centralization/reinnervation and influences in cardiopulmonary disease.
III. Clinical evaluative research:
Target areas included integrating data from all large-scale cohorts with data on cardiopulmonary disease, ANS function and -omics data, using the already available infrastructures from the two existing large consortia in this field.
a. Gap: Limited availability of population-based neuro-cardiopulmonary physiologic data to shed insight on ANS mechanisms and outcomes of ANS dysfunction
b. Gap: Lack of novel interventions to target ANS dysfunction and inform clinical trials
A white paper is in preparation that will expand on workshop deliberations and detailed research opportunities.
National Heart, Lung, and Blood Institute:
Olga Tjurmina, PhD, Heart Failure and Arrhythmias Branch, Division of Cardiovascular Sciences
George Sopko, MD, MPH, Heart Failure and Arrhythmias Branch, Division of Cardiovascular Sciences
Aaron Laposky, PhD, National Center on Sleep Disorders Research, Division of Lung Diseases
Josh Fessel, MD PhD, Lung Biology and Disease Branch, Division of Lung Diseases
Mike Twery, PhD, National Center on Sleep Disorders Research, Division of Lung Diseases
Office of Strategic Coordination, Office of the NIH Director:
Gene Civillico, PhD, SPARC Program, Division of Program Coordination, Planning, and Strategic Initiatives
Felicia Qashu, PhD, SPARC Program, Division of Program Coordination, Planning, and Strategic Initiatives
Kristina Faulk, SPARC Program, Division of Program Coordination, Planning, and Strategic Initiatives
Kalyanam Shivkumar, MD, PhD, David Geffen School of Medicine at UCLA
Reena Mehra, MD, MS, Cleveland Clinic, Case Western Reserve University
Olujimi A. Ajijola, MD, PhD, David Geffen School of Medicine at UCLA
Rishi Arora, MD, Feinberg School of Medicine at Northwestern University
Donald C. Bolser, PhD, University of Florida
Mark W Chapleau, PhD, University of Iowa Carver College of Medicine
Peng-Sheng Chen, MD, Cedars-Sinai Medical Center
Colleen E. Clancy, PhD, University of California Davis
Brian P. Delisle, PhD, University of Kentucky
Michael R Gold, MD, PhD, Medical University of South Carolina
Jeffrey J. Goldberger, MD, MBA, University of Miami Miller School of Medicine
David S. Goldstein, MD, PhD, National Institute of Neurological Disorders and Stroke, NIH
Beth A. Habecker, PhD, Oregon Health and Science University School of Medicine
M. Louis Handoko, MD, PhD, VU University Medical Center Amsterdam, Netherlands
Robert Harvey, PhD, University of Nevada Reno
James P. Hummel, MD, Yale University School of Medicine
Thomas Hund, PhD, Ohio State University
Christian Meyer, MD, MA, University of Düsseldorf, Germany
Susan Redline, MD MPH, Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center
Crystal Ripplinger, PhD, University of California Davis School of Medicine
Marc A. Simon, MD, MS, University of Pittsburgh Medical Center
Virend K. Somers, MD, PhD, Mayo Clinic
Stavros Stavrakis, MD, PhD, University of Oklahoma Health Sciences Center
Thomas Taylor-Clark, PhD, University of South Florida
Bradley Joel Undem, PhD, Johns Hopkins University
Richard L. Verrier, PhD, Beth Israel Deaconess Medical Center, Harvard Medical School
Irving H. Zucker, PhD, University of Nebraska Medical Center
The NHLBI and OD organizers wish to thank the National Institute of Neurological Disorders and Stroke for help in advertising this workshop.