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).

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.

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.

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.

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 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).

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).

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).