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Abstract

Objective

Cardiac autonomic function predicts cardiovascular disease risk. The aim of this study was to investigate the relationship between sensitization to dust allergens and cardiac autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD), and to provide new ideas for the prevention of cardiovascular complications in these patients.

Methods

Immunoassays for sensitization to cats/dogs, cockroaches and dust mites were performed in 840 patients with COPD. Indicators of heart rate variability in these patients were used to assess cardiac autonomic function, including standard deviation of normal-to-normal intervals (SDNN), root-mean square of successive differences between normal-to-normal intervals (RMSSD), low-frequency power (LF), high-frequency power (HF), and LF/HF ratios, which were obtained based on ambulatory electrocardiographic monitoring data. The relationship between sensitization to these dust allergens and heart rate variability was explored using multivariate logistic regression.

Findings

The multivariate analyses showed that sensitization to total allergens was associated with reduced levels of SDNN, RMSSD, LF and HF and with increased levels of the LF/HF ratio in the patients with COPD (p < .05).

Conclusion

Dust allergen sensitization may be associated with cardiac autonomic dysfunction in patients with COPD. Whether desensitization can prevent cardiovascular complications in these patients should be further explored.

Keywords

Cardiac autonomic function cardiovascular complications chronic obstructive pulmonary disease dust allergen sensitization heart rate variablity

Introduction

Cardiovascular complications are one of the leading causes of death in patients with chronic obstructive pulmonary disease (COPD).^1,2 Therefore, identifying and intervening in risk factors for cardiovascular complications is important to effectively improve patient prognosis.

Previous studies have shown that outdoor and indoor air pollution increases the risk of cardiovascular and respiratory diseases and worsens the prognosis of these patients.^3–5 Cardiac autonomic dysfunction may be one of the mechanisms in this process. On the one hand, severe air pollution leads to impaired heart rate variability (HRV), which is an important indicator of cardiac autonomic function. On the other hand, HRV is strongly associated with the risk and prognosis of myocardial infarction, heart failure and chronic obstructive pulmonary disease.^6–8

In addition, allergic factors have been associated with air pollution, cardiac autonomic dysfunction and COPD. First, dust allergen exposure is an important aspect of air pollution and may contribute to the deterioration of lung function in the public population.^9,10 Second, certain allergen tests can cause dynamic changes in HRV.¹¹ Third, a proportion of patients with COPD have features of asthma, such as elevated eosinophil counts.^12,13 More than 1/3 of patients with COPD are affected by allergies.^14,15 However, it remains unclear whether dust allergen sensitization is associated with cardiac autonomic dysfunction in these patients and, in turn, is a potential risk factor for cardiovascular complications in these patients.

Therefore, the present study recruited 840 patients with COPD and explored the relationship between sensitization to four dust allergens (including cats/dogs, cockroaches, and dust mites) and HRV, which could help to refine strategies for the prevention of cardiovascular complications in this patient population.

Materials and methods

Ethical requirements

The study was approved by the Ethics Committee of Longyan First Affiliated Hospital of Fujian Medical University and was conducted in accordance with the Declaration of Helsinki. All subjects agreed to participate in this study and signed a written informed consent.

Subjects

From 1 January 2013 to 10 December 2021, 840 consecutive patients with COPD were enrolled from the Department of General Practice in Longyan First Affiliated Hospital of Fujian Medical University.

The inclusion criteria were as follows: First, all subjects were local residents with no history of out-of-town residence (>7 days). Second, the subjects stayed mainly at home every day and did not regularly go out or participate in regular physical activity. Third, all subjects were current or former smokers. Fourth, all subjects had chronic cough, sputum, chest tightness and shortness of breath. Fifth, the ratio of the forced expiratory volume in the first one second to the forced vital capacity of the lungs (FEV1/FVC) after the use of bronchodilators, obtained by pulmonary function testing, was less than 0.7 in each subject.¹⁶

The exclusion criteria were as follows: First, the subjects with asthma, bronchiectasis or interstitial pulmonary fibrosis were excluded from the study. Second, the subjects with acute myocardial infarction, acute/chronic heart failure, acute cerebrovascular disease, diabetic ketoacidosis or hypertensive crisis were excluded from the study. However, the subjects with stable coronary artery disease, diabetes mellitus, or hypertension may participate in this study. Third, the subjects with acute infections or malignant tumours were excluded from the study.

Data collection

Two trained researchers were responsible for data collection. They first collected data from the subjects’ medical records and then used face-to-face interviews to identify information that was not in the medical records. These data included basic information (including age, sex, race, education, income, smoking, height, weight, and seasons included), history of disease (including hyperlipidaemia, type 2 diabetes mellitus, hypertension, stroke, allergy, coronary artery disease), family history of disease (including COPD and allergy), history of medication use (including glucocorticoids, anticholinergics, beta-agonists, and β-blockers), serological markers (including eosinophil count and IgE), cardiac markers (including left ventricular ejection fraction and heart rate), pulmonary function markers (including FEV1% predicted), a clinical score of COPD, and outcomes of COPD in the last 180 days.

Current smokers were defined as those who had smoked regularly for at least 6 months prior to study entry. Former smokers were defined as those who had smoked regularly for more than a year in their lifetime but had not smoked in the 6 months prior to joining the study. For both current and former smokers, smoking level was assessed by “pack-years smoked.”

The history of disease was determined by final diagnosis or treatment measures in the medical record. The clinical score for COPD described above was the modified Medical Research Council dyspnoea scores (mMRCs), which is one of the most commonly used scores for patients with COPD, assessing the degree of dyspnoea on a scale of 0 to 4, with a score of 0 indicating the least severe symptoms and a score of 4 indicating the most severe.¹⁷

The medication history of COPD involved the use of various bronchodilators and hormones, including long-acting beta-agonists (LABA), long-acting anticholinergic drugs (LAMA), short-acting beta-agonists (SABA), short-acting anticholinergic drugs (SAMA), and inhaled corticosteroids (ICS).

The outcome for COPD in the last 180 days was defined as an exacerbation or severe exacerbation during this period. An exacerbation was defined as a change in medication regimen or a visit to a community physician or specialist. A change in medication regimen was defined as meeting any of the following criteria: (1) an increase in the dose of ICS; (2) initiation of a combination of medications; and (3) use of oral glucocorticoids. Severe exacerbation was defined as hospitalisation for COPD.

Sensitization assessment

On admission, a venous blood sample was collected from each subject to test for sensitization to four common indoor allergens using the ImmunoCAP (Phadia, ThermoFisher), which is widely regarded as the gold standard for quantitative in vitro testing of specific IgE.¹⁸ The allergens included cats/dogs, cockroaches, and dust mites, of which the dust mite was Dermatophagoides farinae or D. pteronyssinus. The threshold of sensitization for each allergen was greater than 0.1 kU/L to be considered positive.

Heart rate variability assessment

On admission, R-R interval data were collected for at least 5 min from each subject using a continuous ECG monitoring device (H12B-plus/H12B ECG system, Huaqing Xinyi, Shenzhen, China). During this process, the subject must remain in the prone position, avoid exercise, and maintain a normal respiratory rhythm, while the investigators continuously monitored the ECG through the screen to ensure that the incidence of artefacts or arrhythmias was less than 5%, i.e., the number of R-R intervals (during a period of at least 5 min) that were significantly affected by artefacts or arrhythmias was approximately less than 15 to 25. If the data did not meet these requirements, the subject would be asked to repeat the recording process.

Raw data were exported from the ECG monitoring device, and the R-R intervals were processed and artefact-corrected using the RHRV package in the R software to select 256 consecutive R-R intervals free of significant artefacts and arrhythmias.¹⁹ Previous studies had shown that 256 R-R intervals (or 5 min) was a suitable signal duration window for assessing HRV.²⁰

Subsequently, the present study used the above data to analyse HRV in both the time and frequency domains. In the time-domain analysis, the standard deviation of normal-to-normal intervals (SDNN) and root-mean square of successive differences between normal-to-normal intervals (RMSSD) were used. From the values of these two indicators and their relationship with HRV, the greater the SDNN and RMSSD, the greater the HRV.²¹

Under physiological conditions, parasympathetic nerves slow the heart rate during expiration and this effect is diminished during inspiration. This is the respiratory sinus arrhythmia that affects HRV. Frequency-domain analysis can quantify the effect of parasympathetic and sympathetic nervous systems on HRV using power spectral density.²¹ Briefly, the high-frequency band (0.15–0.40 Hz) reflects respiratory sinus arrhythmia produced by parasympathetic stimulation, the low-frequency band (0.04–0.15 Hz) measures rhythm information during inspiratory parasympathetic inhibition, and the ratio of the low-frequency to the high-frequency band indicates the proportion of parasympathetic inhibition relative to parasympathetic stimulation.²¹ Therefore, low-frequency power (LF), high-frequency power (HF), and the LF/HF ratio were used for the analysis of HRV in this study. In addition, LF and HF were normalized to express their relative contribution to the spectral components, i.e., LF% = LF/(LF + HF) and HF% = HF/(LF + HF). The above analyses were also conducted using the RHRV package in the R software.¹⁹

Statistical analysis

Continuous variables were expressed as mean ± standard deviation (SD) and differences between two variables were compared using the independent samples t test. Categorical variables were expressed as frequencies (component ratios), and differences between two variables were compared using the chi-square test. Correlations between peripheral IgE levels and HRV indicators were assessed by Pearson linear regression. In the above analyses, a p-value of less than 0.05 indicated a statistically significant difference or correlation. The correlations between sensitization to dust allergens and HRV indicators were assessed by multivariate logistic regression, adjusting for several confounders (including age, sex, race, education, income, smoking, body mass index, seasons included, history of disease, and history of medication use), and odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. A 95% CI excluding the value one indicated that the correlation was statistically significant. The predictive significance of HRV indicators for dust allergen sensitization was assessed by receiver operating characteristic curve analysis. A p-value of less than 0.05 indicated the correlation was statistically significant. An AUC value of between 0.5 and 0.7 indicated a low predictive value, and an AUC value of greater than 0.9 indicated a high predictive value. All statistical analyses were performed using SPSS 23.0.

Results

Basic characteristics of the subjects

In Table 1, 147 subjects were assigned to the sensitive group and they were sensitive to at least one common indoor allergen. Specifically, 81 subjects were sensitive to cats/dogs, 66 subjects were sensitive to cockroaches, and 72 subjects were sensitive to dust mites. The remaining 693 subjects were not sensitive to any of the above allergens and were categorised as the non-sensitive group.

Table 1.

Basic characteristics of subjects in the sensitive and non-sensitive groups.

Variables^a	Sensitive group	Non-sensitive group	p Value^b
Total, n (%)	147 (100.0)	693 (100.0)	—
Age, years	64.3 ± 7.8	65.6 ± 9.9	0.127
Male, n (%)	69 (46.9)	384 (55.4)	0.061
Han Chinese, n (%)	135 (91.8)	660 (95.2)	0.096
More than 9 years of education, n (%)	87 (59.2)	378 (54.5)	0.304
Annual household income per Person, yuan	5457.8 ± 899.1	5544.0 ± 949.3	0.313
Pack-years smoked	52.7±27.1	59.4 ± 29.1	0.010
Current smokers, n (%)	51 (34.7)	221 (31.9)	0.509
Former smokers, n (%)	96 (65.3)	472 (68.1)
Body mass index, kg/m²	23.0 ± 3.1	22.5 ± 3.3	0.100
History of hyperlipidaemia, n (%)	69 (46.9)	363 (52.4)	0.230
History of type 2 diabetes, n (%)	33 (22.4)	135 (19.5)	0.414
History of hypertension, n (%)	78 (53.1)	393 (56.7)	0.418
History of stroke, n (%)	24 (16.3)	81 (11.7)	0.122
Seasons included, n (%)
Spring	27 (18.4)	171 (24.7)	0.102
Summer	21 (14.3)	126 (18.2)	0.259
Autumn	36 (24.5)	154 (22.2)	0.551
Winter	63 (42.9)	242 (34.9)	0.069
Eosinophil count, cells/μl	217.1 ± 110.0	198.9 ± 115.4	0.081
IgE, IU/ml	438.6 ± 253.3	99.1 ± 58.3	;0.001
Family history of allergy, n (%)	21 (14.3)	30 (4.3)	;0.001
Sensitive to cats/dogs, n (%)	81 (55.1)	—	—
Sensitive to cockroaches, n (%)	66 (44.9)	—	—
Sensitive to dust mites, n (%)	72 (49.0)	—	—

^aContinuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as frequency (constituent ratio).

^bDifference of two continuous variables were compared with independent sample t test, and difference of two categorical variables were compared using Chi-square test. A p-value less than 0.05 indicated statistical significance.

The distribution of most demographic indicators and disease history was comparable between the above two groups (p > .05). And, the subjects in the non-sensitive group had a higher level of pack-years smoked compared to the sensitive group (p = .010). Compared to the non-sensitive group, peripheral IgE levels were significantly higher and family history of allergy was more common in the sensitive group (p < .001, p < .001).

Characteristics of COPD in the subjects

In Table 2, there were no differences between the sensitive and non-sensitive groups in the mMRC levels, family history of COPD, use of ICS, LABA, or LAMA, and daily use of SABA or SAMA (p > .05). And, compared with the non-sensitive group, the FEV1% predicted level was significantly lower in the sensitive group (p = .012), and exacerbations and severe exacerbations were also more common in this group (p = .001, p < .001).

Table 2.

Characteristics of chronic obstructive pulmonary disease in the sensitive and non-sensitive groups.

Variables^a,b	Sensitive group	Non-sensitive group	p Value^c
Total, n (%)	147 (100.0)	693 (100.0)	—
FEV1% predicted	49.5 ± 14.4	52.8 ± 14.7	0.012
mMRC	2.1 ± 1.2	2.0 ± 1.3	0.539
Exacerbations, n (%)	48 (32.7)	141 (20.3)	0.001
Severe exacerbations, n (%)	30 (20.4)	66 (9.5)	;0.001
Family history of COPD, n (%)	18 (12.2)	57 (8.2)	0.121
Use of ICS, LABA or LAMA, n (%)	126 (85.7)	603 (87.0)	0.673
Daily use of SABA or SAMA, n (%)	78 (53.1)	414 (59.7)	0.135

^aContinuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as frequency (constituent ratio).

^bFEV1 = Forced expiratory volume in the first second, mMRC = modified Medical Research Council dyspnea score, COPD = Chronic obstructive pulmonary disease, ICS = Inhaled corticosteroids, LABA = Long-acting beta-agonists, LAMA = Long-acting anticholinergic drugs; SABA = Short-acting beta-agonists, SAMA = Short-acting anticholinergic drugs.

^cDifference of two continuous variables were compared with independent sample t test, and difference of two categorical variables were compared using Chi-square test. A p-value less than 0.05 indicated statistical significance.

Cardiac characteristics of the subjects

In Table 3, there were no differences in heart rate, left ventricular ejection fraction, history of coronary artery disease, history of myocardial infarction, history of angina, and use of β-blocker between the sensitive and non-sensitive groups (p > .05). And, compared with the non-sensitive group, the levels of SDNN, RMSSD, LF, HF, and HF% were significantly lower in the sensitive group (p = .002, p < .001, p = .024, p < .001, p = .007), and the levels of LF% and LF/HF ratio were significantly higher in this group (p = .007, p = .011).

Table 3.

Cardiac characteristics of subjects in the sensitive and non-sensitive groups.

Variables^a,b	Sensitive group	Non-sensitive group	p Value^c
Total, n (%)	147 (100.0)	693 (100.0)	—
Heart rate (bpm)	77.2 ± 12.4	75.7 ± 12.2	0.163
SDNN (ms)	110.7 ± 38.7	122.6 ± 42.1	0.002
RMSSD (ms)	22.1 ± 9.2	24.9 ± 11.9	;0.001
LF (ms²)	798.7 ± 332.6	869.8 ± 350.1	0.024
HF (ms²)	415.8 ± 186.0	478.4 ± 189.2	;0.001
LF% (nu)	65.4 ± 6.8	63.7 ± 7.1	0.007
HF% (nu)	34.6 ± 6.8	36.3 ± 7.1	0.007
LF/HF ratio	2.0 ± 0.7	1.9 ± 0.6	0.011
Left ventricular ejection fraction (%)	57.9 ± 8.5	58.6 ± 8.6	0.390
History of coronary heart disease, n (%)	35 (23.8)	171 (24.7)	0.825
History of myocardial infarction, n (%)	6 (4.1)	15 (2.2)	0.176
History of angina, n (%)	24 (16.3)	141 (20.3)	0.265
Use of beta blocker, n (%)	18 (12.2)	120 (17.3)	0.132

^aContinuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as frequency (constituent ratio).

^bSDNN = Standard deviation of normal-to-normal interval, RMSSD = Root-mean square of successive differences between normal-to-normal interval; HF = High frequency power; LF = Low frequency power.

Dust allergen sensitization and heart rate variability in the subjects

In Table 4, the multivariate analyses revealed that the sensitization to total dust allergen was associated with the lower levels of SDNN, RMSSD, LF, HF, and HF% (OR = 0.935, 95%CI = 0.894∼0.976, p = .002; OR = 0.804, 95%CI = 0.689∼0.939, p = .006; OR = 0.943, 95%CI = 0.896∼0.994, p = .028; OR = 0.830, 95%CI = 0.748∼0.920, p ;.001; OR = 0.789, 95%CI = 0.626∼0.995, p = .044); and the sensitization to total dust allergen was also associated with the higher levels of LF% and LF/HF ratio (OR = 1.304, 95%CI = 1.033∼1.645, p = .026; OR = 1.375, 95%CI = 1.101∼1.715, p = .005). In addition, the multivariate analyses still reported that the sensitization to total dust allergen was related to the exacerbations and severe exacerbations in the subjects (OR = 1.899, 95%CI = 1.284∼2.808, p = .001; OR = 2.437, 95%CI = 1.517∼3.916, p;.001).

Table 4.

Association of dust allergen sensitization with disease outcome and heart rate variability in the study.

Variable^a	Univariate analysis		Multivariate analysis^b
Variable^a	p Value	OR (95%CI)	p Value	Or (95%CI)
Exacerbations	0.001	1.898 (1.284 ∼ 2.807)	0.001	1.899 (1.284 ∼ 2.808)
Severe exacerbations	;0.001	2.436 (1.516 ∼ 3.915)	;0.001	2.437 (1.517 ∼ 3.916)
SDNN	0.002	0.934 (0.894 ∼ 0.975)	0.002	0.935 (0.894 ∼ 0.976)
RMSSD	0.006	0.804 (0.688 ∼ 0.939)	0.006	0.804 (0.689 ∼ 0.939)
LF	0.027	0.943 (0.896 ∼ 0.993)	0.028	0.943 (0.896 ∼ 0.994)
HF	;0.001	0.829 (0.748 ∼ 0.919)	;0.001	0.830 (0.748 ∼ 0.920)
LF%	0.026	1.303 (1.033 ∼ 1.644)	0.026	1.304 (1.033 ∼ 1.645)
HF%	0.044	0.788 (0.625 ∼ 0.994)	0.044	0.789 (0.626 ∼ 0.995)
LF/HF ratio	0.005	1.374 (1.100 ∼ 1.715)	0.005	1.375 (1.101 ∼ 1.715)

^aSDNN = Standard deviation of normal-to-normal interval, RMSSD = Root-mean square of successive differences between normal-to-normal interval; HF = High frequency power; LF = Low frequency power, OR = Odds ratio, 95%CI = 95% confidence interval.

^bMultivariate logistic regression was adopted to assess the relationship, and these analyses were adjusted for age, sex, race, education, income, smoking, body mass index, season included, history of disease and history of medication use. A 95% confidence interval excluding 1 indicated that it was statistically significant.

In Table 5, the subjects in the sensitive group were divided into three subgroups according the dust allergens, and the multivariate analyses were performed again. Then, the analyses reported that the sensitization to cats/dogs was associated with the severe exacerbations in the subjects (OR = 2.715, 95%CI = 1.542∼4.778, p = .001). The analyses reported that the sensitization to cockroaches was associated with the lower levels of HF and HF% (OR = 0.835, 95%CI = 0.720∼0.967, p = .015; OR = 0.608, 95%CI = 0.440∼0.842, p = .003), and was associated with the higher levels of LF% and LF/HF ratio (OR = 1.720, 95%CI = 1.240∼2.383, p = .001; OR = 1.702, 95%CI = 1.261∼2.297, p = .001). The analyses also reported that the sensitization to dust mites was associated with the exacerbations and severe exacerbations in the subjects (OR = 1.960, 95%CI = 1.172∼3.279, p = .011; OR = 2.458, 95%CI = 1.346∼4.487, p = .003), and was associated with the lower levels of SDNN, LF and HF (OR = 0.930, 95%CI = 0.877∼0.987, p = .015; OR = 0.929, 95%CI = 0.865∼0.997, p = .039; OR = 0.809, 95%CI = 0.701∼0.934, p = .004).

Table 5.

Association of single allergen sensitization with disease outcome and heart rate variability in the study.

Variable^a	Univariate analysis		Multivariate analysis^b
Variable^a	p Value	OR (95%CI)	p Value	Or (95%CI)
Sensitization to cats/dogs
Exacerbations	0.060	1.620 (0.980 ∼ 2.676)	0.060	1.621 (0.981 ∼ 2.677)
Severe exacerbations	0.001	2.714 (1.542 ∼ 4.777)	0.001	2.715 (1.542 ∼ 4.778)
SDNN	0.404	0.977 (0.925 ∼ 1.032)	0.405	0.978 (0.925 ∼ 1.033)
RMSSD	0.184	0.875 (0.718 ∼ 1.066)	0.185	0.875 (0.719 ∼ 1.066)
LF	0.353	0.969 (0.907 ∼ 1.036)	0.354	0.969 (0.907 ∼ 1.037)
HF	0.165	0.915 (0.807 ∼ 1.037)	0.166	0.915 (0.807 ∼ 1.038)
LF%	0.206	1.212 (0.900 ∼ 1.633)	0.207	1.213 (0.901 ∼ 1.634)
HF%	0.225	0.832 (0.618 ∼ 1.120)	0.226	0.832 (0.618 ∼ 1.121)
LF/HF ratio	0.105	1.265 (0.952 ∼ 1.679)	0.106	1.265 (0.952 ∼ 1.680)
Sensitization to cockroaches
Exacerbations	0.335	1.322 (0.750 ∼ 2.333)	0.336	1.322 (0.750 ∼ 2.334)
Severe exacerbations	0.076	1.825 (0.939 ∼ 3.550)	0.076	1.826 (0.939 ∼ 3.551)
SDNN	0.099	0.950 (0.894 ∼ 1.010)	0.099	0.951 (0.894 ∼ 1.011)
RMSSD	0.058	0.809 (0.649 ∼ 1.007)	0.058	0.810 (0.649 ∼ 1.008)
LF	0.461	0.973 (0.905 ∼ 1.046)	0.462	0.974 (0.906 ∼ 1.046)
HF	0.015	0.834 (0.720 ∼ 0.966)	0.015	0.835 (0.720 ∼ 0.967)
LF%	0.001	1.719 (1.240 ∼ 2.382)	0.001	1.720 (1.240 ∼ 2.383)
HF%	0.003	0.607 (0.439 ∼ 0.841)	0.003	0.608 (0.440 ∼ 0.842)
LF/HF ratio	0.001	1.701 (1.261 ∼ 2.296)	0.001	1.702 (1.261 ∼ 2.297)
Sensitization to dust mites
Exacerbations	0.010	1.959 (1.171 ∼ 3.279)	0.011	1.960 (1.172 ∼ 3.279)
Severe exacerbations	0.003	2.457 (1.346 ∼ 4.486)	0.003	2.458 (1.346 ∼ 4.487)
SDNN	0.015	0.929 (0.876 ∼ 0.986)	0.015	0.930 (0.877 ∼ 0.987)
RMSSD	0.111	0.843 (0.684 ∼ 1.040)	0.111	0.844 (0.684 ∼ 1.041)
LF	0.039	0.928 (0.865 ∼ 0.996)	0.039	0.929 (0.865 ∼ 0.997)
HF	0.004	0.808 (0.700 ∼ 0.933)	0.004	0.809 (0.701 ∼ 0.934)
LF%	0.331	1.169 (0.853 ∼ 1.601)	0.331	1.170 (0.853 ∼ 1.602)
HF%	0.561	0.911 (0.665 ∼ 1.248)	0.561	0.912 (0.665 ∼ 1.249)
LF/HF ratio	0.167	1.235 (0.915 ∼ 1.666)	0.167	1.236 (0.915 ∼ 1.667)

In Supplemental Table 1, the receiver operating characteristic curve analyses confirmed the association of the sensitization to total dust allergen with the levels of SDNN, RMSSD, LF, HF, LF%, HF% and LF/HF ratio (p = .002, p = .009, p = .026, p;.001, p = .012, p = .012, p = .012). However, these HRV indicators were of low value in predicting the sensitization to total dust allergen, with their AUC values ranging from 0.5 to 0.7.

Peripheral IgE levels and heart rate variability in the subjects

In Table 6, the linear regression analyses did not find any association of peripheral IgE levels with SDNN, RMSSD, LF, HF, LF%, HF% and LF/HF ratio (p > .05).

Table 6.

Association of serum IgE level with heart rate variability in the study.

Cardiac autonomic function^a	r value	p Value^b
SDNN	0.088	0.288
RMSSD	0.010	0.900
LF	0.132	0.111
HF	0.066	0.430
LF%	0.084	0.313
HF%	−0.084	0.313
LF/HF ratio	0.062	0.458

^aSDNN = Standard deviation of normal-to-normal interval, RMSSD = Root-mean square of successive differences between normal-to-normal interval; HF = High frequency power; LF = Low frequency power.

^bPearson linear regression was adopted to assess the relationships. A p-value less than 0.05 indicated statistical significance.

Discussion

It is well known that patients with COPD spend more time in indoor environments and have more exposure to indoor dust allergens than healthy individuals.²² Therefore, it is necessary to explore the effect of dust allergen on COPD and its complications. In this study, we used a cross-sectional design and found a correlation between dust allergen sensitization and cardiac autonomic dysfunction. Since cardiac autonomic function plays an important role in the development of cardiovascular disease, this study implied that there might be a potential correlation between dust allergen sensitization and cardiovascular complications of COPD. If this correlation can be conclusively confirmed, these findings may help refine strategies for the prevention and control of COPD and contribute to improving the prognosis of the patients.

The multivariate analyses indicated that the total allergen sensitization may be associated with a 15% to 20% decrease in the levels of SDNN, RMSSD, LF and HF, and may be associated with an increase in the LF/HF ratio by about 30% to 40%. It is worth mentioning that the levels of SDNN, RMSSD, LF and HF in the study decreased to varying degrees compared to normal reference values of these indicators. Considering the physiological significance of them, the parasympathetic function was significantly reduced in the patients with COPD, and the dust allergen sensitization may reduce the function further. In addition, a lower stimulatory than inhibitory effect of the parasympathetic nerves led to an elevated LF/HF ratio.

The subgroup analyses exploring the correlation between the sensitization to a single allergen and HRV reported a series of positive results consistent with the results of the total analyses described above, whereas some other negative results reported may had been due to a reduced sample size. The correlation between sensitization to dust allergens and HRV was also confirmed by the receiver operating characteristic curve analyses, but the predictive value of the indicators was low. The interpretation of these results was that the dust allergen sensitization may be related to HRV or that the dust allergen sensitization may be involved in the mechanism of cardiac autonomic dysfunction, but the correlation between them may not be at the level of a predictive or diagnostic indicator.

The study also explored the potential linear relationship between peripheral IgE levels and these HRV indicators in the sensitized patients, but none of them was statistically significant. The explanation for these results was that the mechanism of the correlation between the sensitization to allergens and HRV may be complex and not a one-to-one relationship. The multivariate prognostic analyses also reported that the sensitization to dust allergens was related to the exacerbations of COPD. These results were consistent with a recent study in which the exposure to dust allergens was associated with multiple adverse prognoses in COPD.⁹ These results also supported the main findings of this study.

Asthma was more closely related to sensitization than COPD. Some studies had even explored the use of allergen immunotherapy to control asthma.²³ A correlation between asthma and HRV had also been revealed. One study suggested that children with asthma may develop cardiac autonomic imbalance, which was related to parasympathetic overexcitation.²⁴ Another study showed that circadian rhythm disturbances in HRV and increased parasympathetic tone in the early morning coincided, at least temporally, with increased asthma symptoms in the early morning .²⁵ These studies demonstrated the relationship between sensitization and cardiac autonomic function in other diseases, indirectly supporting the results of the present study.

In this study, there was no difference in the composition ratio of current and former smokers between the sensitive and non-sensitive groups. However, when comparing the smoking levels of these subjects during their respective smoking periods, we found that the non-sensitive group had significantly higher smoking levels than the sensitive group. Previous studies had shown that smoking was an important factor affecting cardiac autonomic function.^26,27 Therefore, it was possible that the difference in smoking levels between the two groups may have an impact on the results of this study. Therefore, this variable was adjusted in this study using multivariate analysis, and the results still confirmed the correlation between dust allergen sensitization and HRV.

It was noteworthy that although peripheral IgE levels were significantly higher in the sensitive group than in the non-sensitive group, peripheral eosinophil counts did not differ between the two groups. These results seemed contradictory but were consistent with the findings of a recent study from COPDGene.²⁸ In those studies, allergic disease could affect peripheral IgE levels compared to controls, but could not significantly alter peripheral eosinophil count levels.²⁸ This suggested that peripheral blood IgE and eosinophil counts were not fully synchronised, and the reason for this might be that the two indicators represented different pathways of allergic or inflammatory responses, respectively.

The mechanism underlying the correlation between the sensitization to dust allergens and HRV may be closely related to inflammation and immunity.²⁹ Previous studies had revealed a novel regulatory mechanism, the pulmonary parasympathetic inflammatory reflex. When the lungs were challenged with pathogens, this regulatory pathway may connect the lungs, immune system, and nervous system, and play an important role in fighting infection. Based on these findings, the present study speculated that a similar autonomic regulatory pathway may also be activated when the body was exposed to allergens, resulting in HRV abnormalities.

There were several limitations in this study. First, the majority of the included subjects were Han Chinese. But, allergic reactions may vary across ethnic groups, so it was possible that the findings of this study may not be applicable to other ethnic groups. However, as the Han Chinese population was over 1 billion, this study was still of significant medical and social value. Second, this study was a cross-sectional study, which could lead to causal inversion or recall bias. However, the majority of the data in this study were obtained from their medical records. Common medical knowledge suggested that allergies clearly preceded the onset of COPD and its cardiovascular complications. So, we thought that this deficiency may not affect the results of this study. Third, this study only tested the subjects for sensitization to cats/dogs, cockroaches and dust mites, but did not test if these allergens were also present in their homes. This was mainly due to the fact that most of the subjects did not agree to be sampled and tested in their homes. Further studies would be conducted to remedy this limitation.

In conclusion, the study suggested that the sensitization to cats/dogs, cockroaches, and dust mites, which were considered to be the most common indoor dust allergens, was associated with the cardiac autonomic dysfunction in the patients with COPD. If these correlations can be shown to be causal in the future, it will help us to refine the preventive and control strategies of COPD and alleviate the cardiovascular complications.

Supplemental Material

Supplemental Material - Relationship between dust allergen sensitization and cardiac autonomic function in patients with chronic obstructive pulmonary disease

Supplemental Material for Relationship between dust allergen sensitization and cardiac autonomic function in patients with chronic obstructive pulmonary disease by Meie Zeng, Shuifen Ye, Wanling Huang, Weiwei Deng, Simin Zou, Chunmei Huang and Hanzhong Qiu in Chronic Respiratory Disease

Footnotes

Authors’ contributions

Meie Zeng conducted the study design. Meie Zeng and Shuifen Ye performed the literature research and manuscript preparation. All authors carried out the blood sample collection and allergy-related testing, all authors contributed to the electrocardiogram monitoring and assessment of heart rate variability, and all authors conducted the collection of other data and final data analysis.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Meie Zeng

Data Availability Statement

The data can not be shared because this is an ongoing study. All data will be made public as soon as the study is fully completed.

Supplemental Material

Supplemental material for this article is available online.

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