Autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD)
Review Article
Autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD)
Arnoldus JR van Gestel1,2,5, Joerg Steier3,4
1Department of Pneumology, University Hospital Ruhrlandklinik, Essen, Germany; 2Pulmonary Division, University Hospital of Zurich, Zurich, Switzerland; 3Kings College London School of Medicine, London, United Kingdom; 4Royal Brompton Hospital, London, United Kingdom; 5Zurich University of Applied Sciences, Winterthur, Switzerland
Correspondence: Arnoldus JR van Gestel, MScPT. Zurich University of Applied Sciences, Technikumstrasse 71, CH-8401 Winterthur, Switzerland. Phone: +41-58 934 6328; Fax: +41-58 935 6314. E-mail: vrns@zhaw.ch.
Abstract
It has been recognized that chronic obstructive pulmonary disease (COPD) is a systemic disease which has been shown to negatively affect the cardiovascular and autonomic nerve system. The complexity of the physiologic basis by which autonomic dysfunction occurs in patients with COPD is considerable and the knowledge in this field remains elementary. The purpose of this review is to provide an overview of important potential mechanisms which might affect the autonomic nervous system in patients with COPD. This review aims to summarize the basic research in the field of autonomic dysfunction in patients with COPD. In COPD patients the activity of sympathetic nerves may be affected by recurrent hypoxemia, hypercapnia, increased intrathoracic pressure swings due to airway obstruction, increased respiratory effort, systemic inflammation and the use of betasympathomimetics. Furthermore, experimental findings suggest that autonomic dysfunction characterized by a predominance of sympathetic activity can significantly modulate further inflammatory reactions. The exact relationship between autonomic dysfunction and health status in COPD remains to be elucidated. Treatment aimed to restore the sympathovagal balance towards a reduction of resting sympathetic activity may modulate the inflammatory state, and possibly contributes to improved health status in COPD.
Key words
COPD; cardiac autonomic dysfunction; hypoxemia; hypercapnia; increased intrathoracic pressure swings; increased respiratory effort; systemic inflammation; betasympathomimetics
J Thorac Dis 2010;2:215-222. DOI: 10.3978/j.issn.2072-1439.2010.02.04.5
Introduction
The autonomic nervous system (ANS) regulates multiple physiological processes. Amongst other factors it is responsible adjusting heart rate, blood pressure, gastrointestinal secretion, temperature regulation, vagally mediated reflex constriction of airway smooth muscle, secretion from submucosal glands, capillary permeability and blood flow in the bronchial circulation, cardiovascular responses to exercise and release of mediators from the mast cells and other inflammatory cells. Dysfunctions of the autonomic nervous system are recognized by the symptoms that result from failure of the sympathetic or parasympathetic components. Disruption of autonomic reflexes with increased sympathetic tone, loss of parasympathetic tone and altered baroreceptor sensitivity (BRS) have been shown to be major risk factors for cardiac morbidity and mortality (1-3).
Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory response of the lungs to chronic inhalational of noxious inhaled gases or particles causing obstruction of the airways which is often irreversible. There is increasing evidence, indicating that COPD is more complex and not only involving airflow obstruction. It has been recognized that COPD is a systemic disease which has been shown to negatively affect the cardiovascular and autonomic nerve system (4, 5).
The complexity of the physiologic basis by which autonomic dysfunction occurs in patients with COPD is considerable and the knowledge in this field remains elementary. The insight into sympathovagal imbalance as a pathological phenomenon in COPD may be important in understanding the pathophysiology of COPD and may have a potential clinically importance for improving risk stratification and treatment of patients with COPD. Therefore, the purpose of this review is to provide an overview of important potential mechanisms which might affect the autonomic nervous system in patients with COPD.
Cardiac autonomic dysfunction in COPD
Patients with COPD have functional alterations of cardiac autonomic modulation as reflected in elevated resting heart rate, reduced baroreflex sensitivity, reduced heart rate variability (HRV) (6, 7), reduced respiratory sinus arrhythmia (RSA) (8), a direct increase in muscle sympathetic nerve activity (9, 10) and abnormal heart rate recovery (HRR) following exercise (11). This phenomenon suggests that COPD patients have enhanced sympathetic tone at rest and are less able to respond to sympathetic and parasympathetic stimuli, in comparison with healthy persons. In addition, resting muscle sympathetic nerve activity is significantly higher in patients with COPD as compared to age- and sex-matched healthy control subjects (9). Enhanced sympathetic tone at rest and disruption of autonomic reflexes give rise to a self-perpetuating cycle that contributes to the pathogenesis of COPD and possibly play an important role regarding the mortality in these patients (1, 2).
Sensory receptors
COPD seems to induce a generalized attenuation of excitatory pathways regulating respiratory, cardiac autonomic and cardiovascular systems. In this context, mutual interference of these systems is likely to occur in response to alterations affecting only single parts, because these systems share identical control mechanisms (12). The abnormality of autonomic function in patients with COPD may affect stimulus reception, afferent nerve conduction, central processing, efferent nerve conduction, and neuromuscular response. The sensory receptors that might play a significant role in autonomic dysfunction in patients with COPD are arterial and cardiac baroreceptors, metabolic and pulmonary stretch receptors, bronchopulmonary C-fibres and arterial chemoreceptors.
Arterial chemoreceptors
Type II respiratory failure in COPD is defined by co-existing hypoxemia and hypercapnia. It is likely that these two conditions have different effects on the autonomic nervous system; hypoxia is acting mainly on peripheral chemoreceptors while hypercapnia is mainly stimulating central chemoreceptors. It has been demonstrated that acute hypoxemia increases sympathetic nerve activity by stimulation of arterial chemoreceptors in healthy humans (13, 14). Saito et al have demonstrated that the degree of hypoxia correlates with the degree of sympathetic muscle nerve activity (15). Furthermore, it has been demonstrated that short-term oxygen supplementation significantly and favorably improves cardiac autonomic modulation underlining the predominant role of hypoxemia in COPD patients with mild hypoxemia (16).
However, the overall role of hypoxia may be overestimated as impaired or altered autonomic regulation was observed in both hypoxemic and normoxemic patients with COPD (4, 6-7, 17), and daytime blood gases do not correlate with sympathetic activation (9). The effect of chronic hypoxemia on autonomic dysfunction however, is difficult to predict as the sensitivity of arterial chemoreceptors may change over time. Furthermore, an interaction between arterial baroreceptors and the chemoreceptor reflex has been demonstrated; an increase in baroreceptor activation causes an inhibition of the chemoreceptor reflex (22).
Conflicting evidence exists regarding the role of hypercapnia on autonomic dysfunction in patients with COPD. Several studies have suggested that hypercapnia leads to increased sympathetic tone (23) and that combined hypercapnia and hypoxia synergistically increase sympathetic activity through impaired baroreceptor-cardiac reflex control in healthy humans (22, 24). On the contrary, in other studies hypercapnia and respiratory acidosis were found to increase the parasympathetic modulation of HRV in healthy humans (25, 26).
Arterial and cardiac baroreceptors
Peripheral baroreceptors are located in the carotid and aortic vessels and are responsive to changes in systemic blood pressure. Under normal conditions, arterial blood pressure fluctuates throughout the respiratory cycle, falling with inspiration and rising with expiration. Large intrathoracic pressure changes, as occurring in chronic obstructive pulmonary disease, are transmitted to the heart and great vessels and can influence both peripheral baroreceptors and cardiac performance. Large pressure changes may cause fluctuations in cardiac performance, and therefore, in systemic blood pressure provoking finely modulated compensatory changes of the heart rate mediated by separate outputs of both intra- and extrathoracic baroreceptors (27). Furthermore, intrathoracic baroreceptors can be influenced high aortic transmural pressure gradients induced by abnormal breathing (28). Even in healthy subjects, resistive load breathing stimulates aortic baroreceptors and consecutively impacts on the autonomic nerve system (29, 30).
Furthermore, mechanical mechanisms linked to respiratory fluctuations in cardiac transmural pressure, atrial stretching and venous return sensed by cardiac baroreceptors may also determine autonomic dysfunction in COPD (31, 32).
Patients with COPD have reduced baroreflex sensitivity to transient rise of blood pressure (BRS) (6, 7). It has been demonstrated, that impaired baroreflex sensitivity leads to an increase in sympathetic activity through inhibitory afferents (21, 18). Besides mechanical influences, other factors are discussed as possible causes of the reduced baroreflex sensitivity in patients with COPD. There is considerable evidence of interactions between peripheral chemoreceptor and arterial baroreceptor reflexes (19). Hypoxia, but not hypercapnia, alters the baroreflex sensitivity (20). Furthermore it has been demonstrated, that elevated pulmonary arterial pressure alters baroreflex sensitivity in patients with COPD (33).
Fig 1 Overview of peripheral baroreceptors (tensiosensoren) located in the carotid and aortic vessels. Large intrathoracic pressure changes, as occurring in chronic obstructive pulmonary disease, are transmitted to the peripheral baroreceptors and may play a predominant role in autonomic dysfunction in these patients.
Breathing pattern
Eckhart and colleagues found evidence that the respiratory pattern influences autonomic output by inhibiting the ability of baroreceptor inputs to modulate the activity of autonomic motoneurons (34). The influence of the respiratory pattern on cardiac autonomic modulation is well known: the magnitude of parasympathetic induced heart rate variability has been shown to depend on both the lung hyperinflation (tidal volume VT) and respiratory rate (FR) (35, 36). One would expect different patterns of activity of cardiac autonomic modulation influenced by the extent to which lung hyperinflation (tidal volume VT) and respiratory rate (FR) change in patients with COPD. Slow breathing reduces sympathetic activity quickly, tends to increase baroreflex sensitivity and reduces chemoreflex sensitivity (37, 18) in COPD patients (90). Higher respiratory rate (FR) above a characteristic frequency causes sympathetic activation and vagal withdrawal (21, 38). However, it should be stressed, that breathing at lower respiratory rates does not lead to a normalization of baroreflexes and sympathetic activity in patients with COPD (21). Furthermore, no causal link has been found between breathing pattern, altered baroreflexes and heightened sympathetic activity in COPD (21). Instead, it is reasonable to suggest that a number of other synergistic mechanisms, including lung inflation reflexes, contribute to sympathetic activation in COPD. It may be postulated, that the development of a rapid shallow breathing pattern during an exacerbation or exercise probably is a contributor to autonomic dysfunction in patients with COPD.
Fig 2 Internal thoracic cave with diaphragm and thoracic blood vessels. Overview of important sensory receptors which might affect the autonomic nervous system in patients with COPD.
Metaboreceptors
The increased work of breathing due to severe obstructive and restrictive breathing in patients with chronic lung disease could lead to sympathetic activation through stimulation of local metaboreceptors. Oxygen radicals and products of ischemic metabolism generated during muscular contraction (e.g., isometric exercise) have been shown to stimulate local receptors and cause increases in heart rate, arterial pressure, and sympathetic activity (39, 40). In healthy humans, repeated contractions of respiratory muscles inducing fatigue have also been shown to increase metaboreflex-mediated sympathetic excitation (41, 12).
The role of local metaboreceptors on cardiac autonomic dysfunction in patients with COPD has not yet been investigated. As diaphragm remodeling (42) and even injury of the diaphragm (43) has been observed, it is reasonable to believe that stimulation of local metaboreceptors occurs in patients with COPD.
Pulmonary stretch receptors
Lung inflation reflexes mediated by pulmonary vagal afferents may also contribute to sympathetic activity in patients with COPD (41). It was hypothesized that pulmonary stretch receptors may play a role in the regulation of systemic vascular tone and cardiac autonomic modulation in healthy humans (69). Pulmonary stretch receptors can be divided in two types: slowly adapting (tonic) and rapidly adapting (phasic) receptors. Slowly adapting receptors (SAR) convey information about the level of inflation of the lung while rapidly adapting receptors (RAR) fire in response to transient changes in lung volume. When the lungs are adequately inflated, pulmonary stretch receptor excitation terminates inspiration, initiates expiration and decreases parasympathetic output (Hering-Breuer reflex, HBR) (44, 45). However, the exact explanation of how mechanical energy of pulmonary tissue distention is transduced to neural activation in pulmonary stretch receptors is unknown. A potential contribution may be that breathing at a state of hyperinflation increases the activity of the SAR fibers (44, 46). If the respiratory rate increases, a corresponding increase in activity of RAR fibers may follow (44). Due to chronic hyperinflation of the lungs, SAR fibers may be permanently active and therefore diminish their responses to other stimuli. As a result the activity of mechanosensitive afferent nerves is grossly altered (44) and HBR is diminished (45), which could eventually lead to the alteration in vagal nerve activity in these patients.
Bronchopulmonary C-fibers
The lungs, both bronchi and parenchyma, are innervated by thin nonmyelinated fibers, afferents capable of signaling local mechanical and chemical properties. Pulmonary C-fibers (J-receptors), and nociceptive C-fibers in general, are designed to respond to tissue inflammation (44), local edema and a variety of chemicals that may accumulate in COPD. Pulmonary C-fibers are capable of triggering ventilatory, bronchomotor, and cardiovascular effects. Numerous inflammatory mediators, a decrease in pH in the interstitial fluid, hypoxemia and nicotine can effectively activate bronchopulmonary C-fibers in patients with COPD. Furthermore, in several animal studies it has been shown that transient hypercapnia (47) and decreased lung compliance (48) markedly increase the responses of bronchopulmonary C-fiber afferents to various chemical stimulants.Use of betasympathomimetics increases the sympathetic nervous activity of COPD patients (57). Inhalation of therapeutic doses of betasympathomimetics in healthy subjects results in significant haemodynamic changes and a shift of sympathovagal balance towards increased sympathetic tone (58). Silke et al have demonstrated that inhaled betasympathomimetics increase sympathetic activity, as measured by heart rate variability analysis, in healthy persons, however, these agents do not change the parasympathetic (HF) cardiac modulation (59, 60). In patients with COPD the use of betasympathomimetics is associated with significant increases in heart rate, and it has also been associated to be related to increase in cardiovascular morbidity and mortality (61). may directly trigger sympathetic activation. There is growing evidence that persistent low-grade systemic inflammation is present in COPD (53) and it may be postulated that this may contribute to the pathogenesis of cardiac autonomic dysfunction among COPD. The exact interaction between systemic inflammation and the autonomic nervous system is complex. The effects of systemic inflammation range from cytokine--induced priming of peripheral leukocytes, to muscle wasting induced by cytokines such as tumour necrosis factor-alpha (49). Accordingly, recent clinical studies have found a significant association between autonomic dysfunction and increased markers of inflammation in several populations, including apparently healthy subjects (50, 51), and patients with congestive heart failure (52). In patients with COPD, enhanced systemic inflammation is linked to profound neurohumoral activation (53). Furthermore it may be postulated, that an imbalance of the autonomous nervous system activity, characterized by a predominance of sympathetic activity, may favour the inflammatory state (54, 55).
Pulmonary hypertension
Pulmonary hypertension due to pulmonary arterial vasoconstriction causes right ventricular wall stress and has been shown to play a role in the attenuation of baroreflex responses in COPD patients (56). It has been demonstrated, that attenuation of baroreflex responses leads to an increase in sympathetic activity through inhibitory afferents (21, 18).
Sympathoexcitatory medication
Use of betasympathomimetics increases the sympathetic nervous activity of COPD patients (57). Inhalation of therapeutic doses of betasympathomimetics in healthy subjects results in significant haemodynamic changes and a shift of sympathovagal balance towards increased sympathetic tone (58). Silke et al have demonstrated that inhaled betasympathomimetics increase sympathetic activity, as measured by heart rate variability analysis, in healthy persons, however, these agents do not change the parasympathetic (HF) cardiac modulation (59, 60). In patients with COPD the use of betasympathomimetics is associated with significant increases in heart rate, and it has also been associated to be related to increase in cardiovascular morbidity and mortality (61).
Dyspnoea
Although dyspnea is a frequently encountered clinical symptom in patients with COPD, the impact of breathlessness on autonomic dysfunction remains uncertain. Acute dyspnea is often associated with anxiety and emotions. Specifically the perception of respiratory discomfort is represented in the sensorimotor integration area of the limbic system that governs autonomic control, (62) and central respiratory motor drive is linked with central sympathetic output in the brainstem (63). Increased endogenous release of catecholamines influences objectively ventilation and subjectively breathlessness in healthy persons (64).
Summary
Expiratory flow limitation in patients with chronic obstructive pulmonary disease (COPD) results from progressive airway inflammation causing parenchymal destruction, mucosal oedema, airway remodelling, mucoid impaction and increased cholinergic airway smooth muscle tone (65). Increasing evidence indicates that COPD is a complex disease resulting from more than airflow obstruction. It has been recognized that COPD is a systemic disease which has been shown to negatively affect the cardiovascular and autonomic nervous system (4, 5). In COPD patients the activity of sympathetic nerves may be affected by recurrent hypoxemia, hypercapnia, increased intrathoracic pressure swings due to airway obstruction, increased respiratory effort, systemic inflammation and the use of betasympathomimetics. Autonomic dysfunction is another important factor of the pathophysiological mechanism of COPD because of the multiple parameters that are under control of the autonomic nervous system. Furthermore, experimental findings suggest that autonomic dysfunction characterized by a predominance of sympathetic activity can significantly modulate inflammatory reactions. Cardiac autonomic dysfunction encompasses various and multiple disorders and might be associated with increased incidence of cardiovascular diseases in patients with COPD (66). Although several studies have demonstrated that the ventilatory response to exercise performance is limited in patients with COPD (67, 68), the role of autonomic dysfunction on exercise intolerance is mostly unknown. In patients with chronic heart failure, increased sympathetic activity is related to muscular wasting and impaired exercise tolerance (69).
The exact relationship between autonomic dysfunction and health status in COPD remains to be elucidated. Treatment aimed to restore the sympathovagal balance towards a reduction of resting sympathetic activity may modulate the inflammatory state, and possibly contributes to improved health status in COPD.
References
  • Bigger JT Jr, Kleiger RE, Fleiss JL. Components of heart rate variability measured during healing of acute myocardial infarction. Am J Cardiol 1988;61:208-15.[LinkOut]
  • Billman GE, Hoskins RS. Time-series analysis of heart rate variability during submaximal exercise: evidence for reduced cardiac vagal tone in animals susceptible to ventricular fibrillation. Circulation 1989;80:146-57.[LinkOut]
  • Bilmann GE, Schwartz PJ, Stone HL. Baro-receptor reflex control of heart rate: a predictor of sudden cardiac death. Circulation 1982;66:874-80.[LinkOut]
  • Stein PK, Nelson P, Rottman JN, Howard D, Ward SM, Kleiger RE, et al. Heart rate variability reflects severity of COPD in PiZ α1-antitrypsin deficiency. Chest 1998;113:327-33.[LinkOut]
  • Stewart AG, Waterhouse JC, Howard P. Cardiovascular autonomic nerve function in patients with hypoxaemic chronic obstructive pulmonary disease. Eur Respir J 1991;4:1207-14.[LinkOut]
  • Volterrani M, Scalvini S, Mazzuero G. Decreased heart rate variability in patients with chronic obstructive pulmonary disease. Chest 1994;106:1432-7.[LinkOut]
  • Steward RI, Lewis M. Cardiac output during exercise in patients with COPD. Chest 1986;89:199-205.[LinkOut]
  • Patakas D, Louridas G, Kakavelas E. Reduced baroreceptor sensitivity in patients with chronic obstructive pulmonary disease. Thorax 1982;37:292-5.[LinkOut]
  • Heindl S, Lehnert M, Criée CP. Marked sympathetic activation in patients with chronic respiratory failure. Am J Respir Crit Care Med 2001;164:597-601.[LinkOut]
  • Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 2004;110:1308-12.[LinkOut]
  • Poirier P, Lacasse Y, Marquis K, Jobin J, LeBlanc P. Post-exercise heart rate recovery and mortality in chronic obstructive pulmonary disease. Respiratory Medicine 2005;99:877-86.[LinkOut]
  • Derchak PA, Sheel AW, Morgan BJ, Dempsey JA. Effects of expiratory muscle work on muscle sympathetic nerve activity. J Appl Physiol 2002;92:1539-52.[LinkOut]
  • Hardy JC, Gray K, Whisler S, Leuenberger U. Sympathetic and blood pressure responses to voluntary apnea are augmented by hypoxemia. J Appl Physiol 1994;77:2360-5.[LinkOut]
  • Leuenberger U, Gleeson K, Wroblewski K, Prophet S, Zelis R, Zwillich C, et al. Norepinephrine clearance is increased during acute hypoxemia in humans. Am J Physiol 1991;261:1659-64.[LinkOut]
  • Saito M, Mano T, Abe H. Responses in muscle sympathetic activity to acute hypoxia in humans. J Appl Physiol 1986;55:493-8.[LinkOut]
  • Bartels M, Gonzalez J, Kim W, De Meersman R. Oxygen supplementation and cardiac-autonomic modulation in COPD. Chest 2000;118:691-6.[LinkOut]
  • Scalvini S, Porta R, Zanelli E. Effects of oxygen on autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease. Eur Respir J 1999;13:119-24.[LinkOut]
  • Bernardi L, Porta C, Spicuzza L. Slow breathing increases arterial baroreflex sensitivity in patients with chronic heart failure. Circulation 2002;105:143-5.[LinkOut]
  • Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 1991;87:1953-7.[LinkOut]
  • Cooper VL, Pearson SB, Bowker CM, Elliott MW, Hainsworth R. Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia - a mechanism for promoting hypertension in obstructive sleep apnoea. J Physiol 2005;568:677-87.[LinkOut]
  • Raupach T, Bahr F, Herrmann P, LüthjeL, Hasenfuß G, Andreas S. Slow breathing reduces sympathoexcitation in COPD. Eur Respir J 2008;32:387-92.[LinkOut]
  • Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 1988;11;608-12.[LinkOut]
  • Somers VK, Mark AL, Zavala DC. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol 1989;67:2095-100.[LinkOut]
  • Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia: implications for sleep apnea. Clin Exp Hypertens 1988;10:413-22.[LinkOut]
  • Brown SJ, Howden R. The Effects of a Respiratory Acidosis on Human Heart Rate Variability. Adv Exp Med Biol 2008;605:361-65.[LinkOut]
  • Sasano N, Vesely A, Hayano J, Sasano H, Somogyi R, Preiss D, et al. Direct effect of PaCO2 on respiratory sinus arrhythmia in conscious humans. Am J Physiol Heart Circ Physiol 2002;282:973-6.[LinkOut]
  • Buda AJ, Pinsky MR, Ingles NB, Daugter GT, Stinson EB. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979:301:453-9.[LinkOut]
  • Cournand A, Motley HL, Werko L, Richards DW. Physiological studies of the effects of intermittent positive pressure breathing on cardiac output in man. Am J Physiol 1948;152:162-74.[LinkOut]
  • Calabrese P, Perrault H, Dinh TP, Eberhard A, Benchetrit G. Cardiovascular interactions during resistive load breathing. Am J Physiol Regul Intergr Comp Physiol 2000;279:2208-13.[LinkOut]
  • Peters J, Kindred MK, Robotham JL. Transient analysis of cardiopulmonary interactions. I. Diastolic events. J Appl Physiol 1988;64:1506-17.[LinkOut]
  • Ranieri VM, Dambrosio M, Brienza N. Intrinsic PEEP and cardiopulmonary interaction in patients with COPD and acute ventilatroy failure. Eur Respir J 1996;9:1283-92.[LinkOut]
  • Pinsky MR. Cardiovascular Issues in respiratory care. Chest 2005;128:592-7.[LinkOut]
  • Dempsey JA, Sheel AW, St Croix CM, Morgan BJ. Respiratory influences on sympathetic vasomotor outflow in humans. Respir Physiol Neurobiol 2002;130:3-20.[LinkOut]
  • Eckberg DL, Orshan CR. Respiratory and baroreceptor reflex interactions in man. J Clin Invest 1977;59:780-5.[LinkOut]
  • Giardino ND, Chan L, Borson S. Combined heart rate variability and pulse oximetry biofeedback for chronic obstructive pulmonary disease: preliminary findings. Appl Psychophysiol Biofeedback 2004;29:121-33.[LinkOut]
  • Brown TE, Beightol LA, Koh J, Eckberg DL. Important influence of respiration on human R-R interval power spectra is largely ignored. J Appl Physiol 1993;75:2310-231.[LinkOut]
  • Goso Y, Asanoi H, Ishise H. Respiratory modulation of muscle sympathetic nerve activity in patients with chronic heart failure. Circulation 2001;104:418-23.[LinkOut]
  • Hirsch JA, Bishop B. Respiratory sinus arrhythmia in humans: how breathing pattern modulates heart rate. Am J Physiol Heart Circ Physiol 1981;241:620-9.[LinkOut]
  • Mark AL, Victor RG, Nerhed C, Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res 1985;57:461-9.[LinkOut]
  • Mitchell JH, Schmidt RF. Cardiovascular reflex control by afferent fibers from skeletal muscle receptors. In: Shepherd JT, Abboud FM, editors. Handbook of physiology. The cardiovascular system. New York: Oxford University Press; 1983. p. 623-58.
  • Dempsey JA, Sheel AW, St Croix CM. Respiratory influences on sympathetic vasomotor outflow in humans. Respir Physiol Neurobiol 2002;130:3-20.[LinkOut]
  • Levine S, Nguyen T, Kaiser LR. Human diaphragm remodeling associated with chronic obstructive pulmonary disease: clinical implications. Am J Respir Crit Care Med 2003;168:706-13.[LinkOut]
  • Orozco-Levi M, Lloreta J, Minguella J. Injury of the human diaphragm associated with exertion and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1734-9.[LinkOut]
  • Undem BJ, Kollarik M. The Role of Vagal Afferent Nerves in Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc 2005;2:355-60.[LinkOut]
  • Tryphon S, Kontakiotis Th, Mavrofridis Eu, Patakas D. Hering-Breuer Reflex in Normal Adults and in COPD Patients. Respiration 2001;68:140-4.[LinkOut]
  • Schelegle ES, Green JF. An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors. Respiration Physiology 2001;125:17-31.[LinkOut]
  • Gu Q, Lee LY. Alveolar hypercapnia augments pulmonary C-fiber responses to chemical stimulants: role of hydrogen ion. J Appl Physiol 2002;93:181-8.[LinkOut]
  • Ma A, Bravo M, Kappagoda CT. Responses of bronchial C-fiber afferents of the rabbit to changes in lung compliance. Respir Physiol Neurobiol 2003;138:155-63.[LinkOut]
  • Oudijk EJD, Lammers JWJ, Koenderman J. Systemic inflammation in chronic obstructive pulmonary disease. Eur Respir J 2003;22:5-13.[LinkOut]
  • Jensen-Urstad M, Jensen-Urstad K, Ericson M, Johansson J. Heart rate variability is related to leucocyte count in men and to blood lipoproteins in women in a healthy population of 35-year-old subjects. J Intern Med 1998;243:33-40.[LinkOut]
  • Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J 2004;25:363-70.[LinkOut]
  • Anker SD, Coats AJ. Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation. Chest 1999;115:836-47.[LinkOut]
  • Andreas S, Anker SD, Paul D, Scanlon PD, Virend K, Somers VK. Neurohumoral activation as a link to systemic manifestations of chronic lung disease. Chest 2005;128;3618-24.[LinkOut]
  • Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458-62.[LinkOut]
  • Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384-8.[LinkOut]
  • Bhattachaya J, Cunningham DJC, Howson MG. The effects of mild hypoxia with constant PACO2 and ventilation on the setting and sensitivity of the baroreceptor-cardiacdepressor reflex in man. J Physiol 1973;234:112-4.[LinkOut]
  • Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a ß2-receptor agonist: a human in vivo study. Circulation 1999;99:2402-7.[LinkOut]
  • Cekici L, Valipour A, Kohansal R, Burghuber OC. Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study. Br J Clin Pharmacol 2009l;67:394-402.[LinkOut]
  • Silke B, Hanratty CG, Riddell JG. Heart-rate variability effects of beta-adrenoceptor agonists (xamoterol, prenalterol, and salbutamol) assessed nonlinearly with scatterplots and sequence methods. J Cardiovasc Pharmacol 1999;33:859-67.[LinkOut]
  • Hanratty CG, Silke B, Riddell JG. Evaluation of the effect on heart rate variability of a beta2-adrenoceptor agonist and antagonist using non-linear scatterplot and sequence methods. Br J Clin Pharmacol 1999;47:157-66.[LinkOut]
  • Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest 2004;125:2309-21.[LinkOut]
  • Hardy JC, Gray K, Whisler S, Leuenberger U. Sympathetic and blood pressure responses to voluntary apnea are augmented by hypoxemia. J Appl Physiol 1994;77:2360-5.[LinkOut]
  • Leuenberger U, Gleeson K, Wroblewski K, Prophet S, Zelis R, Zwillich C, et al. Norepinephrine clearance is increased during acute hypoxemia in humans. Am J Physiol 1991;261:1659-64.[LinkOut]
  • Bartels MN, Jelic S, Ngai P, Basner RC, DeMeersman RE. High-frequency modulation of heart rate variability during exercise in patients with COPD. Chest 2003;124:863-9.[LinkOut]
  • O’Donell DE, Lavenesiana P. Physiology and consequences of lung hyperinflation in COPD. Eur Respir Rev 2006;100:61-7.[LinkOut]
  • Engström G, Gerhardsson de Verdier M, Dahlbäck M, Janson C, Lars Lind L. BP variability and cardiovascular autonomic function in relation to forced expiratory volume: a population-based study. Chest 2009;136:177-83.[LinkOut]
  • Bauerle O, Chrusch CA, Younes M. Mechanisms by which COPD affects exercise tolerance. Am J Respir Crit Care Med 1998;157:57-68.[LinkOut]
  • West JB, Wagner PD, Neder JA, Scano GL, Jones NL, Zakynthinos SG, et al. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles vs. lower limb muscle dysfunction vs. dynamic hyperinflation. J Appl Physiol 2008;105:758-62.[LinkOut]
  • Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 1997;96:526-34.[LinkOut]
Cite this article as: van Gestel AJR, Steier J. Autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD). J Thorac Dis 2010;2(4):215-222. doi: 10.3978/j.issn.2072-1439.2010.02.04.5