Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation

Highlights • The ANS is a key regulator of cardiopulmonary health and disease and sleep/circadian pathophysiology.• Understanding cardiopulmonary sympathetic and parasympathetic nerve structure/function over disease time-course and cell type interactions is essential.• In vitro autonomic nervous system and experimental and computational integrative studies are necessary.• Clarifying sex-and race-specific cardiopulmonary and sleep/circadian influence on autonomic nerve function in response to neurotherapeutic interventions is critical to inform personalized strategies.


SUMMARY
This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed. however, they are invasive, expensive, and also associated with side effects (2). Furthermore, there are limitations with human model systems including heart rate, heart rate variability (HRV), plasma catecholamines, and noradrenaline spillover that can have limitations in terms of largescale implementation, can be confounded in certain states such as heart failure (HF), and have age-and sex-specific influences that need to be considered (3). The overarching conceptual framework of opportunities presented in this report is characterized by a better The premise of the workshop is based upon a need to articulate gaps and research priorities specific to the ANS-responsible for regulation of cardiac, vascular, and pulmonary physiology via maintaining a balance of sympathetic and parasympathetic outputs to the heart, vasculature, and lungs in response to stimuli. The ANS plays a key role in the development and progression of cardiopulmonary disease and in sleep and circadian rhythm pathophysiology. Aff ¼ afferent; ANS ¼ autonomic nervous system; DRG ¼ dorsal root ganglia; HR ¼ heart rate; ParaSNA ¼ parasympathetic nerve activity; SNA ¼ sympathetic nerve activity.
gaps and opportunities to accelerate key discoveries in neural science and neurotherapeutics in cardiopulmonary and sleep and circadian rhythm disorders.
Importantly, targeting the ANS is a major therapeutic opportunity, and therefore, key to this is understanding the neurobiology of end-organ function in normal and disease states. This report presents a summary of cross-cutting themes, challenges, opportunities, and available resources discussed at the workshop. function. Sensory afferent fibers innervating the heart, vasculature, and lungs include mechanosensitive nerves that detect changes in cardiac stretch, lung stretch, blood pressure, and blood volume, and chemosensitive fibers that are normally quiescent, but are activated by stimuli such as ischemia and inflammation (7). Information transmitted to the brainstem (8,9)   Normal cardiopulmonary reflexes are disrupted in disease, leading to increased sympathetic and decreased parasympathetic transmission.
Injury activates afferent nerves that mediate sympathoexcitatory-positive feedback reflexes that contribute to myocardial and/or lung injury.
We do not adequately understand (clockwise from top) the electrophysiological and biophysical properties of autonomic ganglia; the impact of sex as a biological variable; how to distinguish the roles of ganglionic versus systemic inflammation in neural remodeling; the mechanisms that drive afferent and efferent remodeling during disease; how to integrate clinical data from a variety of sources, scales, and modalities to guide therapy for specific patients; and the nature of interactions between cardiac and pulmonary nerves. neuropeptides. Release of norepinephrine (NE) has positive chronotropic, dromotropic, and inotropic effects (11), but sympathetic activation has a limited effect on airway smooth muscle or mucus secretion (although circulating epinephrine causes bronchodilation). Parasympathetic transmission predominates in healthy humans, and decreased cardiac parasympathetic tone or the ratio of sympathetic to parasympathetic tone are powerful predictors of susceptibility to arrhythmia and death.
Normal cardiopulmonary reflexes are disrupted in disease states, for example, ischemia, hypertension, and chronic HF, leading to increased sympathetic and decreased parasympathetic transmission ( Figure 1). In some instances, ischemia or mechanical changes activate afferents that mediate sympathoexcitatory, positive feedback reflexes in a nonhomeostatic way (12,13). Excessive sympathetic transmission contributes to cardiac hypertrophy and fibrosis, and can trigger arrhythmias (14). This pathologic increase in sympathetic outflow can be blunted by selective destruction of cardiac spinal afferents using resiniferatoxin (14,15 (27,28). The coordination of NE synthesis, release, and removal becomes disrupted, with elevated release and suppressed reuptake leading to high extracellular NE that is detrimental to the heart (29).
As the disease progresses, acetylcholine (Ach) replaces NE in some sympathetic neurons, and NPY synthesis and release increase, potentially contributing to pathology (30,31). It is now recognized that neural remodeling occurs throughout the nervous system in HF. In addition to neurochemical plasticity, morphologic changes include remodeling of axon arbors in the heart-both degeneration and regrowthas well as increased size of cell bodies and dendritic arbors within stellate and intracardiac ganglia (27,28).
Electrical remodeling includes enhanced excitability in stellate ganglia (32), altered firing frequencies of sensory afferents (33) and parasympathetic efferents, as well as remodeling of connections within intracardiac ganglia (34). These neural changes influence the heart, causing down-regulation of b1, upregulation of b2 adrenergic receptors, and modulating cardiac electrophysiology (35). A recent clinical trial showed that propranolol, which blocks both b1 and b2 receptors, is much more effective than metoprolol in managing patients with electrical storm (36).   adapted from Goldstein (201) shows a concept diagram relating stress to chronic disorders such as heart failure that involve autonomic effectors. Stress is a condition in which a homeostatic comparator senses a discrepancy between afferent information to the brain about a monitored variable and a set point or other instructions for responding. The error signal drives effectors including components of the autonomic nervous system in a manner that reduces the discrepancy. Cumulative wear and tear (allostatic load) decreases effector efficiency, eventually precipitating dyshomeostatic vicious cycles. Feed-forward anticipatory processes shift input-output curves determined by the "Regulator." The right panel shows major types of sensory afferent nerves and the corresponding abnormalities in autonomic reflexes observed in heart failure are illustrated. Sympathoexcitatory afferents are shown in green; sympathoinhibitory afferents in blue. Examples of underlying mechanisms acting at sensory, central, efferent, and effector organ sites that contribute to the reflex cardiovascular/respiratory dysregulation are noted. Aff ¼ afferent; DRG ¼ dorsal root ganglia; HR ¼ heart rate; ParaSNA ¼ parasympathetic nerve activity; SNA ¼ sympathetic nerve activity.        Other sleep disturbances also can trigger the ANS and contribute to CVD. Periodic limb movements can trigger large sympathetic and blood pressure surges, and in the long term, are associated with increased risk for daytime hypertension and CVD (172,173). Insomnia and other disorders characterized by sleep fragmentation also lead to SNSA and are associated with CVD (174). However, the roles of treating these disorders as a strategy for CVD risk reduction or for treating associated AD have not been systematically assessed.
A summary of the ANS alterations association with sleep and circadian processes and the related knowledge gaps and research priorities are depicted in Figure 5.   Airway hyper-responsiveness is a hallmark of asthma (and some forms of chronic obstructive pulmonary disease [COPD]) that is defined as increased sensitivity to bronchospastic agents ( Figure 6).  Figure 6). Consequences include perturbations of resting cardiac physiology (increased heart rate, loss of HRV, increased nocturnal blood pressure) as well as exercise physiology (diminished maximal heart rate, slower heart rate increase and recovery, decreased contractility, decreased functional capacity) (188). Over the course of years after transplantation, there can be a process of reinnervation (which may improve functional capacity and outcomes) (189,190), but this is highly variable and not well-understood.
Pulmonary parasympathetic activity is enhanced in COPD and may play a critical role in the airway obstruction, airway hyper-responsiveness, and increased mucus production characteristic of this condition (184,191). Inhaled anticholinergic therapies have thus been the mainstay of COPD treatment (192,193). Similarly, disruption of pulmonary parasympathetic nerves in patients with COPD has the potential to provide long-lasting anticholinergic effects with reduction of symptoms and exacerbations.
Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts the afferent and efferent pulmonary branches of the vagus nerve along the outside of the main stem bronchi using radiofrequency ablation ( Figure 6). Initial studies have demonstrated the safety and feasibility of TLD and have shown trends toward improvements in symptoms and exacerbations (194,195); its efficacy is currently being assessed in the pivotal AIRFLOW-3 (Evaluation of the Safety and Efficacy of TLD in Patients With COPD) trial (196). Determining the appropriate radiofrequency ablation parameters in TLD is challenging because there are few direct assessments of afferent/efferent function. Because TLD also targets lung afferents, evaluation of cardiopulmonary reflexes such as respiratory sinus arrhythmia pre-and post-treatment may have the potential to assess the extent of pulmonary vagal denervation achieved with this approach (197,198).
1. There are critical gaps in our understanding of the contribution of specific afferent and efferent nerve subsets (199,200)