Cardiac autonomic modulation (CAM) is essential for the preservation of heart function according to metabolic needs, contributing to the maintenance of internal stable conditions.1^,2 Time variation between heart beats is considered normal and is related to greater or lesser activation of sympathetic and parasympathetic systems in response to central and peripheral stimuli.3^-5

Among the events that may interfere with the physiological oscillations of the heart rate (HR), the most prominent are those originating from respiration.6^,7 Therefore, any disease that may impair breathing in some way, such as chronic obstructive pulmonary disease (COPD), tend to interfere with cardiovascular mechanisms8^-10 by affecting the RR intervals (RRi) of the cardiac cycle and, consequently, the CAM.5^,8^,11^,12

Changes in the CAM can be detected and quantified by analysis of the heart rate variability (HRV). In studies on spontaneous breathing in patients with COPD, however, HRV analysis has yielded conflicting results.11^-13 Part of this controversy may be due to the use of certain drugs that cannot be withdrawn from patients during data collection, and the inclusion of patients with different disease severity and, consequently, different cardiovascular conditions.

Other methods to assess the CAM consist of standardized autonomic functional tests, including controlled breathing (CB) techniques, which promote the increase of respiratory sinus arrhythmia frequently employed as an index of cardiac parasympathetic control. During CB, the oscillatory components present in the high frequency band (0.15 to 0.4 Hz) of HRV, related to cardiac parasympathetic activity, are generally potentiated1^,14^-16 and sensitive changes in the RRi are documented.

Considering these assumptions, the objective of the present study was to evaluate and compare the CAM in COPD patients with CAM in healthy people, subjected to spontaneous breathing (SB) and CB trials, to identify the presence of cardiac dysautonomia in COPD and how much the CB may interfere with cardiac modulation of these patients.

Cross-sectional observational study approved by the Ethics Committee in Research Involving Human Beings of the Pontifical Catholic University of Campinas (PUC Campinas - approval number 393.938), São Paulo state, Brazil.

There was no significant difference in anthropometric data between the CG and the COPD group (Table 1). The COPD group showed significantly higher BP values and lower SpO₂ compared with controls.

During SB, in the TD parameters, statistical differences were found in SD RRi and RMSSD index, which were reduced in individuals with COPD (Table 2). In the FD, TP and HF were statistically lower in the COPD group, confirming the reduction of both parasympathetic and sympathetic cardiac tones in COPD.

During CB, the COPD group showed significantly lower values of SD RRi, RMSSD and pNN50 (Table 3). For the HRV indexes in FD, significant differences were found in PT, LF (ms²) and HF (ms²), which were reduced in the COPD group.

Figure 1 depicts the values of median TP during SB and CB, showing a great difference (p < 0.0001) between the groups, with higher values for the CG.

Figure 1

Table 4 shows the medications used by the patients during data collection. It is noteworthy that, at the request of the ethics committee, the researchers did not interfere with patients’ usual medications during data collection.

The main finding of the present study was that COPD patients showed changes in CAM, characterized by lower sympathetic and parasympathetic modulation during SB and CB. In addition to this, other relevant results are discussed below.

First, it is worth pointing out that all factors that could be sources of bias in the analyses were controlled during patients’ selection and before and during data collection. These factors included age, body weight, functional capacity acquired through physical training, caffeine intake, sleep hours, room temperature and circadian rhythm of HR.19^,21

In addition, medications used by the patients may have influenced the results. However, one of the objectives of this investigation was to know how patients with COPD would react when they were submitted to SB and CB trials at the same conditions of their daily lives, which included their usual medications. Also, despite our concern about the influence of medications on HRV measurements, it is worth mentioning that there are studies that have concluded that anticholinergic or β-agonist drugs do not interfere with these measures.

The only variable related to anthropometric data that may draw attention would be age, particularly due to the high standard deviation in the CG. However, no significant difference between the groups was found according to the p-value (Table 1).

With respect to clinical data, although COPD patients showed higher BP values than controls, these values were within normal range and probably had no effect on autonomic modulation.21^,22 Similarly, despite lower in COPD than controls, SpO₂ values were also within normal standards. According to Schettino et al.,23 and Dourado et al.,24 significant falls in SpO₂ may occur even in the resting state; however, these changes are documented only in advanced stages of the disease.

In a previous study by our group published in 2002,11 which included analysis of HRV in COPD, we already showed that patients with COPD had lower values of SD RRi than healthy individuals, corroborating other works.20^,25^,26 A reduction in SD RRi can be associated with the time a disease affects the cardiovascular system, disease severity and the use of some drugs. The SD RRi is also influenced by respiratory, vasomotor and thermoregulatory stimuli, among others.27

Another result obtained by us in 200211 and confirmed in the present study was that COPD patients had lower TP values during SB. In the present study, besides the fact that TP values in COPD were decreased during SB, they were also lower than CG group during CB. These results lead us to suggest that the investigation of the TP index is fundamental when the aim is to evaluate the presence of cardiac dysautonomia in COPD patients (Figure 1).

Therefore, we have one index of TD (SD RRi) and one index of FD (TP) that confirm the reduction in HRV in the COPD group. Maybe the most important problem that causes changes in the indexes of total variability is related to characteristics of the respiratory system in COPD. The less compliant thoracic-pulmonary system does not allow great changes in tidal volume, regardless of the form of breathing interfering with the venous return to the heart.

This lower complacency decreases the volume of blood directed to the right atrium during the inspiratory phase and the lower venous return tends to decrease HRV at rest, and thereby is one of the important factors involved in the reduction of the autonomic modulation of the heart of these patients.

The impaired blood flow from the right ventricle to the lungs may also contribute to these HRV changes. Patients with COPD have greater resistance to blood circulation in the heart-lung circuit, which requires more force from the heart. This may result in increased sympathetic tone and decreased vagal tone.11^,21

Other aspects to be considered in HRV reduction, according to Van Gestel and Steier,28 are recurrent hypoxemia, hypercapnia, increased intrathoracic pressure due to airway obstruction, increased respiratory effort, and asystemic inflammation.

Our results suggest that the tendency of increase in sympathetic tone to overcome altered pressure in the heart-lung circuit of COPD, has interfered with the absolute and relative index values of the LF component - LF (ms²) and LF (un) - during the SB, so that they did not differ from the values presented by the CG. Also, during SB, TP values in COPD patients were only 7.1% of those shown by the CG. However, in CB, TP increased by 27.0% in the COPD group compared to that obtained during SB and was 13.8% of that presented by the CG.

These findings reveal that in COPD, even with its limitations related to complacency of the thoracic-pulmonary system, the TP is increased by almost 100% during deeper, oriented breathing. Despite this, COPD patients still showed significantly lower values of TP (p < 0.0001) than the CG. Therefore, we suggest that, during diaphragmatic breathing, COPD patients experience positive changes in CAM,14 despite significantly lower values of PT compared with controls.

Considering the analysis of HRV through TD variables, it is known that the lower the frequencies of the ventilatory cycles, as performed during the CB trial, the higher the values of TD indexes in HRV.14 However, the COPD group showed similar pNN50 and RMSSD values during both CB and SB, differently from what was observed with the CG, which showed elevation of the two parameters during CB.

Similar results were reported by Gunduz et al.,26 in COPD patients during SB, with lower RMSSD (25.0 ± 10.0 ms vs 60.0 ± 35.0 ms) and pNN50 values (11.8 ± 9.4 vs 15.7 ± 8.1%) compared with healthy individuals. Reis et al.,12 reported RMSSD values of 17.7 ± 6.1 ms and 18.3 ± 15.6 ms during CB and SB, respectively in COPD patients. These values were lower than those observed in controls, and lower than those presented by our volunteers with COPD. The authors, however, did not evaluate pNN50 in these patients.

Although many clinicians believe that patients with COPD tend to have elevated cardiac sympathetic tone, the present study and other studies have shown that both the LF index (considered mainly as a sympathetic component) and the LF/HF ratio (considered mainly as a sympathetic component when greater than 1) in these patients are not different from those in healthy subjects (Tables 2 and 3).12^,28^,29

In the present study, the absolute values found in the LF band (LFms²) were lower in the COPD group than in CG. However, when these data were analyzed in standardized units (LFun), the percentage of sympathetic contribution to the autonomic modulation of the heart was not different between COPD patients and the CG. In other words, when ULF and VLF values were excluded from the analysis, the percentage of the LF band in COPD was similar to that presented by the CG.

Our results are similar to those of Incalzi et al.29 who also reported that sympathetic modulation decreases according to the severity of COPD. They also confirm the statement by Carvalho et al.5 who reported reductions in HRV indexes that reflect not only parasympathetic modulation alone but also sympathetic and parasympathetic modulation together in COPD patients.

In relation to the absolute index of HF, COPD patients showed lower values as compared with the CG. This is in accordance with that observed by Pantoni et al.,9 who found lower values of the HF components in absolute units in these patients. This suggests that this parameter of the HRV analysis is decreased in COPD patients, and hence should be carefully observed when dealing with this group of patients.

The lower values of HF in COPD were more significant during CB than SB, which agrees with the data reported by Reis et al.,12 According to these authors, during CB, there is an increase in tidal volume and in respiratory rate in healthy individuals. Therefore, the respiratory pattern performed during the CB protocol could affect lung compliance and pulmonary stretch receptors, and consequently increase the values of LF, HF and TP indexes of HRV. On the other hand, in COPD patients, changes in chest expansion and pulmonary volume are less evident. The elevated and unchanged intrapulmonary pressure reduces venous return, resulting in lower RRi oscillations and changes in cardiocirculatory adjustments promoted by the autonomic nervous system.

As a study limitation, we could not determine the exact volume of air mobilized during the breaths, which would allow the establishment of the relationship between the volume of air during breathing and respective changes in HRV measurements.

The study showed a reduction in cardiac sympathetic and parasympathetic modulation in patients with COPD during both SB and CB. These changes, together with the findings on TP, were the main contributions to the literature. These changes reinforce the need for the analysis of CAM as part of the evaluation of these patients aiming at early detection and treatment of possible cardiac dysautonomia.