Cough As a Cause and Consequence of Heart Dysfunction - Current State of Art
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Physiol. Res. 69 (Suppl. 1): S105-S121, 2020 https://doi.org/10.33549/physiolres.934408 REVIEW Cough as a Cause and Consequence of Heart Dysfunction - Current State of Art Elzbieta M. GRABCZAK1, Sebastian STEC2, Marta DABROWSKA1, Jana PLEVKOVA3, Rafal KRENKE1 1Department of Internal Medicine, Pulmonary Diseases and Allergy, University Clinical Centre, Medical University of Warsaw, Poland, 2MediNice Research and Development Centre, Krosno, Poland, 3Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, Martin, Slovak Republic Received October 5, 2019 Accepted November 25, 2019 Summary diseases. Even though cough is triggered exclusively by The cough reflex is an airway defensive process that can be vagal reflex and is aimed at the airway defence, it can be modulated by afferent inputs from organs located also out of the elicited and modulated by afferent inputs from respiratory system. A bidirectional relationship between cough extrapulmonary organs, e.g. esophagus or external and heart dysfunctions are presented in the article, with the auditory canal (Canning et al. 2014, Widdicombe 1995), special insights into an arrhythmia-triggered cough. Albeit rare, because the cough is related to stimulation of vagal cough induced by cardiac pathologies (mainly arrhythmias) afferents, irrespective of the organ localization seems to be an interesting and underestimated phenomenon. (Widdicombe 1995). Although the vagal nerve plays This condition is usually associated with the presence of a fundamental role in cough, the significance of abnormal heart rhythms and ceases with successful treatment of convergence of other than vagal afferent inputs to the arrhythmia either by pharmacotherapy or by radiofrequency neuronal clusters in the brainstem - known as the cough ablation of arrhythmogenic substrate. The two main hypotheses pattern generator - cannot be ignored. These neuronal on cough-heart relationships – reflex and hemodynamic - are circuits are subjects of neuronal plasticity, where simple discussed in the review, including the authors’ perspective based neuronal interaction or more complex neuroplastic on the experiences with an arrhythmia-triggered cough. relationships between vagal and other than vagal (e.g. trigeminal, glossopharyngeal) nerves modulate the final Key words cough motor pattern (Canning et al. 2014). Cough Cardiopulmonary reflexes Arrhythmia Strong physiological interactions between respiration and heart function have been well described, Corresponding author including e.g. the alterations in sinus heart rhythm during Sebastian M. Stec, MediNice Research and Development Centre, breathing and the hypoxemia causing the increase in ul. Korczynska 31, 38-400 Krosno, Poland. E-mail: [email protected] blood pressure and supraventricular arrhythmias in obstructive sleep apnea (Shepherd 1981, Shivkumar et al. Introduction 2016). Also, the impact of cough on heart hemodynamics associated with the robust changes of intraabdominal and Cough is a defensive mechanism of the airways intrathoracic pressure, influencing preload or afterload, is evoked by stimulation of nerve endings localized in well known (Sharpey-Schafer 1953, Lo Mauro and larynx, trachea and main bronchi (Canning et al. 2014). It Aliverti 2018). However, there is a number of case is also a common symptom of various pulmonary reports documenting an opposite relation, e.g. heart PHYSIOLOGICAL RESEARCH • ISSN 1802-9973 (online) 2020 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres S106 Grabczak et al. Vol. 69 diseases, mainly arrhythmias, being a trigger of cough Airway chemosensitive afferents (both C- and (Hargreaves and Channon 1994, Odeh and Oliven 1996, A-delta fiber subtypes) originate from the nodose and Niimi et al. 2005, Stec et al. 2007, Brandon 2008, Stec et jugular ganglia and they are broadly distributed all over al. 2009, Patberg et al. 2012, Hasdemir et al. 2013, the airways and lungs. Airway chemosensors are Ozturk and Yetkin 2016). Although the prevalence of activated by different endogenous and exogenous arrhythmia-related cough seems to be rather low, the chemicals such as inflammatory mediators, oxidizing mutual interactions have been recently recognized by substances or air-born irritants (Canning and Chou, national and international cough guidelines (Kardos et al. 2009). The unmyelinated C-fibers show low conducting 2010, Irwin et al. 2018, Lai et al. 2018). Nonetheless, the velocity (0.5-2.0 m/s). They comprise the majority of the mechanisms of heart disorder-related cough still remain afferent fibers innervating lungs. These include not completely elucidated. Therefore, the main objective pulmonary C-fibers (with the endings located in the lungs of this review is to discuss the available data on possible and airways receiving blood perfusion from the heart-cough relations. Both directions of the heart-cough pulmonary circulation) and bronchial C-fibers (with interactions are reviewed. First, the effect of cough on endings located in the larger bronchi receiving blood heart function is presented and then, the mechanisms of supply from bronchial arteries) (Lee and Pisarri 2001, “cardiac cough” or "cough triggered by heart function Kollarik et al. 2010). C-fibers are rather inactive during disorders" are discussed. the normal breathing cycle, but their activity increases significantly after exposure to noxious stimuli (Kollarik Physiology of cough et al. 2010). C-fiber terminals are located between the epithelial cells covering the airways, close to the airway Cough induced from airways lumen. This arrangement allows the detection of irritants There is indisputable evidence on the close entering the airways and makes the C-fibers the perfect relationship between cough and vagal nerve function. The candidates for “cough-related afferents” (Canning et al. vagotomy or vagal nerve cooling in animals completely 2006). It has been demonstrated that activation of airway abolishes cough (Canning et al. 2006). The bodies of the chemosensors is necessary for conscious perception of neurons innervating airways are located in the nodose and airway irritation, which mediates behavioral cough jugular ganglia of the vagal nerve (Mazzone 2005). response (Davenport 2009). A-delta (Aδ) fibers are Airway afferents relevant for cough are classified into myelinated afferents that exhibit both chemosensitive and mechano- and chemosensitive terminals depending on mechanosensitive properties. They are extrapulmonary, their activation profile. Airway mechanosensors are low threshold and rapidly adapting fibers that conduct derived from the nodose ganglion and terminate in impulses faster than unmyelinated C-fibers, but slower airways and lungs. These fibers have relatively fast than other A fiber subtypes. Aδ-fibers are sensitive conduction speed (10-20 m/s) and their endings are mainly to the rapid decrease of pH. As documented in classified as rapidly or slowly adapting receptors (RARs animal studies, both C- and Aδ-fibers function and SARs, respectively) based on the adaptation pattern synergistically to regulate cough (Canning 2010). to the lung inflation. The main stimuli for these receptors There is compelling evidence that cough reflex include lung volume changes, contraction of airway can be initiated from the larynx, trachea and the main smooth muscles and the airway wall edema. These fibers bronchi. In contrast, there is no sufficient data on the participate in the regulation of breathing pattern, presence of “cough receptors” in the peripheral airways. bronchomotor response and other reflex responses in the Therefore, the relationship between different conditions respiratory tract (Mazzone 2005, Widdicombe 1995). affecting the peripheral bronchi and alveoli and the cough They are not sensitive to chemicals, unless these is unclear (Widdicombe 1995). It has been documented substances cause airway edema, increase mucus secretion that the pulmonary C-fibers (called juxta-pulmonary or induce the changes in airway muscle tone. The role of receptors or J receptors) are activated consistently by RARs and SARs, as a structural elements of the cough pulmonary congestion and edema, being sensitive to an reflex, is rather limited, they probably regulate the increase in interstitial fluid volume, the elevated pressure duration and magnitude of the inspiratory and expiratory in the lung or an increase in the fluid filtration across the phases of coughing but do not usually initiate the reflex capillary wall (Lee and Pisarri 2001). Noteworthy is the itself (Canning et al. 2014). fact, that intravenous injection of lobeline (the substance 2020 Heart-Cough Interactions S107 believed to stimulate J receptors) in a higher dose resulted the observations that patients with gastroesophageal in “transient sensations involving the throat, larynx and reflux-related cough rarely report typical symptoms like upper chest”, but also in cough (Raj et al. 1995, Gandevia heartburn, which are mediated by spinal pathways et al. 1998). However, the conditions affecting mainly (Kollarik and Brozmanova 2009). Infusion of acid into peripheral airways and vessels, such as pulmonary distal esophagus was associated with increased capsaicin embolism, pneumothorax and pulmonary congestion are cough sensitivity (Javorkova et al. 2008). Therefore, associated with dyspnea and chest tightness rather than among two types of vagal nerve endings