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Research Opportunities in the Autonomic Neural Mechanisms of Cardiopulmonary Regulation

03.05.22 06:18 PM Comment(s) By Sol

This blog is a summary of some of the findings reached during a workshop organized by the National Heart, Lung, and Blood Institute (September 2020). The topics to be discussed were the still unknown aspects about the autonomous neural mechanisms of cardiopulmonary regulation. The objective was to bring together an international multidisciplinary group to define the role of the Autonomic Nervous System in cardiopulmonary diseases, as well asto demonstrate its importance in diseases related to sleep. This is a selection of highlights from such a workshop.

Circadian physiology: influences on the heart and functions of the Autonomic Nervous System

The circadian system (which comprises a master central clock located in the suprachiasmatic nucleus of the hypothalamus as well as peripheral clocks located in multiple tissues) governs a series of physiological oscillations that occur over 24-hour periods. The negative feedback loops that occur in the central clock at the level of transcription/translation activity (CLOCK, BMAL1, PERIOD, CRYPTOCHROME) result in rhythmic oscillations in both gene expression, ion channel function, and neurohumoral signaling (including autonomic function), which in turn, influences multiple other physiological systems.


Events and disorders that affect circadian alignment can increase the risk of cardiovasculardiseases.  Environmentalstimuli (such as light and temperature), internal signals (diet, exercise, and sleep), social conditions (shift work), and health conditions (obesity, diabetes) modulate circadian expression through neural humoralsignaling. Therefore, unwelcome light, unhealthy habits, work-related stressors, and metabolic disorders, can lead to circadian mismatch, contributing to cardiovascular disease.


Since circadian signaling is mediated, at least partially, by the Autonomic Nervous System, disorders that affect it can affect cardiovascular health by altering circadian rhythms.

Changes in normal autonomic function during sleep

Sleep is generally considered to be a protected period, in which the cardiovascular system benefits from the restorative influences of the sleeping brain. However, the dynamics of cardiovascular control during sleep can test the capacity of the diseased coronary circulation and myocardium with increased autonomic activity related to sleep status and alterations in airway function and Autonomic Nervous System regulation; thus, sleep could be conceived as an autonomic stress test for the heart.


Sleep disorders also disturb the normal function of the Autonomic Nervous System during sleep, enhancing this autonomic cardiac stress test, which has relevance in a wide variety of conditions, including in cardiacinsufficiency, with risk of decompensation and atrial and ventricular arrhythmias; in channelopathies, including prolonged QT3 and Brugada; and in epilepsy, with an increased risk of sudden unexpected death in patients with epilepsy.


To understand the role of the Autonomic Nervous System in both the etiology of sleep-related respiratorydisorder and its impact on heart disease, it is necessary to improve the understanding of the different physiological phenotypes of the condition. That is, to subtype patients according to their autonomic response to apnea, as well as the mechanisms that predominate in the generation of the syndrome: loop gain (the tendency of a feedback-controlled system to generate unstable behavior), excitation threshold, circulatory delay, and neuromuscular collapse. For example, a recent study showed that the heart rate response to apneas and hypopneas predicts cardiovascular morbidity and mortality more than the apnea-hypopnea index and other traditional metrics used in the evaluation of respiratorydisordersduring sleep.


Periodic limb movement can trigger large sympathetic and blood pressure oscillations that, in the long term, are associated with an increased risk of diurnal hypertension andcardiovasculardisease. Insomnia and other disorders characterized by sleep fragmentation lead to an increase in the activity of the Sympathetic System and are also associated with cardiovascular disease. However, the possibility of treating these disorders as a strategy to reduce the risk of cardiovascular disease or to treat associated arterialdisease has not been systematically evaluated.

Challenges for researchers

To understand the importance of the Autonomic Nervous System in cardiopulmonary diseases, it isnecessary to learn the role it plays, both in the etiology of the expiratorydisorderrelated to sleep, and its impact on heart disease, and to use this knowledge to better characterize the phenotypes of the disease. In other words, it is necessaryto:


A)   Specifying which phenotypes reflect underlying arterial disease (AD) and predisposition to heart disease.

B) Specifying the phenotypes that reflect the predisposition to AD and the mediation of heart disease.

C) Takeadvantage of improved methods of typifying phenotypes that can be expanded and validated; for example, using signals from long-standing devices, wearable devices, and polysomnography (i.e., subtyping patients according to their autonomic response to apneas, and according to their predominant mechanisms in affectation: loop gain, excitation threshold, circulatory delay, and neuromuscular collapsibility).


D) It is necessary to identify the role of intermittent hypoxemia and/or hypercapnia in the function of the Autonomic Nervous System and heart disease, and to understand the mechanisms by which intermittent hypoxemia and hypercapnia lead to an increase in the Activity of the Sympathetic System and a possible modulation of the central and peripheral chemoreceptors.


E) It is also necessary to understand the impact of sleep apnea on susceptibility to Atrial Fibrillation and the implications for the treatment of apnea in the context of atrial fibrillation ablation.


Participants in this workshop expressed confidence that this current landscape of autonomic control of cardiopulmonary diseases and sleep and circadian dysfunction will be a starting point to encourage others to do more research on the subject.


Translated and commented by Claudio Lopez Bruzual, MD.


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