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:

• Critically evaluate the current state of knowledge of the roles that the autonomic neural system (ANS) plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, and breathing disorders.
• Identify approaches to further develop predictive markers of ANS dysfunction and to precisely target these mechanisms with neural-based antiarrhythmic, heart failure, pulmonary, and sleep disorders therapies, including novel approaches to both subclinical and clinical heart failure and arrhythmia prevention.
• Identify opportunities related to non-pharmacological neuromodulation and device-based therapies.
• Provide a concise list of research opportunities based on identified gaps in the field and public health impact.

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Background

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.

Discussion

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:

1. Fundamental mechanisms of neural signaling in development and progression of cardiopulmonary diseases
2. ANS-related pathophysiology of heart failure
3. Neuro-electrophysiologic contributions to atrial arrhythmias
4. Neuro-electrophysiologic aspects of ventricular arrhythmias
5. ANS alterations in cardiopulmonary related sleep disorders
6. Neurophysiologic mechanisms in pulmonary diseases and interaction with cardiac function

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:

1. Recognition of ANS science as a multi-system, multi-disciplinary, and “syndromic” area
2. Recognition of SPARC as a highly valuable facilitative resource data ecosystem providing ready access to a data portal, offering opportunities to develop innovative approaches, new tools, and high-impact resources to enhance the pipeline of ANS science and as a training vehicle for junior scientists
3. Need for standardization in use of experimental models, approaches, and reporting
4. Importance of addressing temporal and circadian dynamics, scale, and time across basic, animal, and human ANS scientific endeavors

Knowledge Gaps and Research Opportunities 

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:

1. Biologic system (i.e., cardiac, pulmonary, sleep/circadian)
2. Sex as a biologic variable
3. Behavioral states (wake, sleep cycles) and circadian rhythm
4. Inflammation and immunity
5. Neuromodulation and neurostimulation

The following scientific gaps in knowledge and research priorities were identified:

I. Basic research:

Target areas included:

• Develop novel basic science and molecular genetic approaches that promote better understanding of specific mechanisms by which ANS function and dysfunction affect different cells of the cardiovascular and pulmonary system in both health and disease.
• Evaluate the impact of sex as a biological variable in autonomic control of the cardiopulmonary and sleep/circadian rhythm systems, in intra-ganglionic inflammation and immune mechanisms, as well as in neuromodulation and neurostimulation of cellular, tissue, and organ-level responses.

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.

Research Opportunities

• Execute cellular and biophysics studies focused on:
  • Isolated role of i) peripheral autonomic ganglia (e.g., labeling to distinguish cardiac and non-cardiac neurons, efferent, and afferent pathways), ii) integrative reflex control and remodeling, and iii) sleep state and circadian influences in health and cardiopulmonary disease
  • Cellular signaling processes and gene expression variations regulating ANS as a model of contractile, conduction, and cardiopulmonary regulation
  • Role of ANS in cardiopulmonary functional and structural integrity in protection from cardiovascular diseases (CVD) or lung disease or facilitating these diseases
  • Role of parasympathetic and sympathetic signaling in the emergence and maintenance of cardiopulmonary disease
• Dissect how changes to nerve structure and function (e.g., newly identified co-transmitters) impact cardiac signaling, ion channel function, action potentials, and calcium transients in both acute and chronic settings in vitro
• Integrate information from cellular gene expression, electrophysiology, morphology, and neurochemistry to identify and clarify interacting substrates

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.

Research Opportunities:  

• Identify key cell types involved in intra-ganglionic inflammation and actions of peripheral and local pro- and anti-inflammatory cytokines on neurons and glia, including electrophysiological and neurochemical remodeling
• Identify inflammation and immune-specific targets for therapies and role of pathways of altered inflammation, immunity in neuromodulation, and immunomodulation in cardiopulmonary disease while delineating sleep state and circadian influences

c. Gap: Uncertainty regarding the cross-talk between cardiopulmonary afferent stimulation and sympathetic modulation in multiple visceral organs and responses to neuromodulation.

Research Opportunities:

• Investigate cross-talk across organs/systems and integrative reflex control with a focus on reflex interactions between cardiac and pulmonary afferent stimulation
• Investigate the impact of cardiopulmonary disease and inflammation on cardiopulmonary afferent-modulated reflexes
• Investigate neuromodulation and neurostimulation of cellular, tissue, and organ-level responses in electrophysiology and vascular pressure in cardiopulmonary disease while delineating sleep state and circadian influences
• Conduct experimental studies to bridge the gap between cellular and organ-level electrophysiological function to assess the role of cell-cell coupling, cellular synchronization, and heterogeneity contributing to cardiopulmonary disease

d. Gap: Need for research on baroreflex mechanisms in cardiopulmonary disease.

Research Opportunities: 

• Investigate interactions of the baroreflex with excitatory reflexes leveraging application of new technologies (e.g., chemo- and optogenetics, RNA sequencing, inducible neuron-specific knockouts, tissue clearing, multiplexed electrode arrays)
• Broaden investigation of baroreceptor/baroreflex phenotypes in heart failure, particularly with preserved ejection fraction (HFpEF) (e.g., single-fiber recordings from afferents, arterial/cardiac compliance, baroreflex control of venous compliance and blood pressure buffering capacity)

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.

Research Opportunities: 

• Develop and validate blood-borne biomarkers to assess behavioral, central, and peripheral autonomic rhythms and assess correlations with disease risk
• Investigate novel mechanistic biomarkers, such as neuropeptide Y, in animal models and patients with HFpEF and reduced ejection fraction heart failure (HFrEF)
• Assess role of biomarkers of adrenoceptors and intracellular catecholamines in Takotsubo cardiopathy, stroke-related cardiac necrosis, and other forms of acute cardiac pathophysiology 
• Identify temporal biomarkers that predict increased likelihood of life-threatening events
• Characterize biomarkers underlying airway hyperresponsiveness in asthma 
• Enhance understanding of potential novel therapeutic targets such as cardiac glial cells
• Identify biomarkers to facilitate patient selection for indication for and response to neurotherapeutics in cardiopulmonary disease
• Improve electrocardiogram (ECG) markers of baroreceptor function and autonomic tone 

b. Gap: Limited computational multi-layered integrative methods to elucidate ANS pathophysiology and pathobiology

Research Opportunities: 

• Develop new animal and computational models for basic and preclinical studies to reveal fundamental mechanisms and translate findings across scales and species
• Develop multi-layered computational models, which integrate the role of sensory feedback in controlling the excitability of the autonomic control system and influence on dynamic networks 
• Develop computational modeling of stress, negative feedback, feed-forward regulation, allostatic load and positive feedback loops
• Integrate individual characteristics, GWAS, whole exome/genome sequencing data, epigenetics, mRNA expression, metabolomics and functional (e.g., ECG) data to generate an ANS-cardiopulmonary prediction model to prevent cardiopulmonary complications by personalizing treatment of ANS dysfunction 

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.

Research Opportunities: 

• Investigate targeted modulation, optimal stimulation parameters, and patient-specific differences of the parasympathetic and/or sympathetic nervous system in the atrium, with the goal of attenuating electrical remodeling in atrial fibrillation, mitigating heart failure progression, and addressing ventricular cardiac arrhythmia and sudden cardiac death
• Test vagal nerve stimulation for pulmonary artery hypertension as a promising therapy 
• Assess role of neural ablation/modulation in asthma and chronic obstructive pulmonary disease 
• Elucidate chronotherapeutics and behaviors such as exercise, meal ingestion, sleep, social interactions in the etiology, pathophysiology, and treatment response of cardiopulmonary diseases
• Foster innovations in bioengineering approaches, including developing methods for inducing neuromodulation, new mechanical devices, biosensors for detection of critical ANS dysfunction, methods for neuromodulation/regeneration, and gene product sensors
• Identify subgroups most responsive to neuromodulatory interventions and understand interplay of pharmacologics on outcomes
• Improve understanding of currently used and newly proposed pharmacologic agents:
  • Selective and nonselective beta receptor blockade provides an immediate opportunity to inform clinical approaches including the importance of chronotherapeutics
  • Repurposing of existing drugs (e.g., pyridostigmine) poses an immediate opportunity
  • Comparing propranolol and metoprolol in long term management of ventricular arrhythmias in patients with heart failure.

d. Gap: Lack of understanding of cardiac transplant de-centralization/reinnervation and influences in cardiopulmonary disease.

Research Opportunities: 

• Learn from cardiac transplant de-centralization/reinnervation and apply to other cardiopulmonary disease states
• Examine physiologic substrate via state-of-the-art imaging and physiologic mechanisms, such as beta receptor density/norepinephrine transport
•  Understand influences on clinical outcomes such as survival and exercise capacity
• Assess the effects of other transplant factors, including rejection/inflammation, variations in immunomodulation therapy, and cardiac allograft vasculopathy

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

Research Opportunities: 

• Create or leverage established large-scale human datasets via collaboratives and networks that include autonomic measures combined with cardiopulmonary outcomes
• Facilitate development of wearable sensors enabling long-term, continuous measurements of blood pressure, heart rate, and other cardiovascular signals as well as oxygen saturation, sleep, and circadian rhythm physiology during daily activities
• Develop tools for optimal accurate assessment of ANS physiology in population-based studies of health and disease
• Advance signal processing approaches to analyze data from noninvasive multi-day/night physiological monitoring and optimize precision to identify subgroups at risk for abnormal ANS control and CVD
• Develop big data/machine learning/artificial intelligence approaches to detect autonomic dysfunction
• Examine the influence of co-existent disease states like sleep apnea on onset, progression, and therapy of atrial and ventricular cardiac arrhythmia and heart failure
• Address temporal dynamics and time specificity (date/time stamp specimens) during monitoring, e.g., skin-based neural activity, overnight polysomnography, multi-day monitoring
• Conduct genetic studies with a strong focus on the ANS axis to allow more integrative analyses of CVD, ANS function, and genetic vulnerability

b.  Gap: Lack of novel interventions to target ANS dysfunction and inform clinical trials

Research Opportunities: 

• Test optimal strategies for management of subclinical ANS dysfunction in patients with and without pre-existing cardiovascular and pulmonary disease
•  Develop and test circadian-informed therapeutics (chronotherapy) for modulating ANS function to optimize cardiovascular, lung, and sleep health and include assessing dynamics of ANS to inform clinical trials
• Identify appropriate surrogate (intermediate) endpoints for smaller randomized controlled trials (RCTs) to help plan large RCTs
• Study or identify roles of alternative treatments for sleep apnea on intermediate disease mechanisms (ventilatory oscillations, sympathetic nervous activation) and clinical outcomes in CVD (incident heart disease, recurrent atrial fibrillation, etc.) with consideration of pragmatism, scale, and feasibility
• Test/explore modulation of carotid body and other sensory afferent output (e.g., supplemental oxygen, neuromodulation) as a target for stabilization of breathing and improvement in sympathetic activation and secondarily, heart disease. 

Publication Plans

A white paper is in preparation that will expand on workshop deliberations and detailed research opportunities.

NIH Staff Workshop Organizers

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

Workshop Chairs:

Kalyanam Shivkumar, MD, PhD, David Geffen School of Medicine at UCLA 
Reena Mehra, MD, MS, Cleveland Clinic, Case Western Reserve University

Workshop Members:

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.