Alteration of the irisin–brain-derived neurotrophic factor axis contributes to disturbance of mood in COPD patients

Figures & data

Table 1 Main characteristics of the whole COPD cohort (n=74)

Parameters	Data
Age (years)	62.15±9.70
Gender (female/male)	27/47
Smoker	25/74 (33.8%)
Smoking (pack-years)	20.00 (5.25–33.75)
Smoking (years)	10.00 (0.00–33.00)
Diabetes present	13/74 (17.6%)
Dyslipidemia present	26/74 (35.1%)
Hypertension present	43/74 (58.1%)
Disease duration (years)	5.00 (3.00–10.00)
Waist (cm)	101.99±14.31
Weight (kg)	79.71±17.12
Height (m)	1.68±0.094
BMI (kg/m^2)	28.19±5.09
Irisin (ng/mL)	7.22 (6.63–8.10)
BDNF (ng/mL)	345.6 (294.20–387.90)
CK (U/L)	101.00 (74.00–139.00)
LDH (U/L)	208.62±34.98
Glucose (mmol/L)	5.00 (4.20–5.80)
Insulin (mU/L)	8.95 (5.55–16.50)
HgA1C (%)	5.70 (5.50–6.10)
HOMA index	2.14 (1.14–4.67)
Cholesterol (mmol/L)	5.30 (4.00–6.30)
LDL-C (mmol/L)	3.10 (2.60–3.70)
HDL-C (mmol/L)	1.40 (1.20–1.80)
Triglyceride (mmol/L)	1.35 (1.00–2.00)
CRP (mg/L)	2.00 (1.21–4.00)
Fibrinogen (g/L)	3.67 (3.25–4.00)
Procalcitonin (µg/L)	0.00 (0.00–0.00)
SGRQ Symptoms score	32.66 (13.64–58.28)
SGRQ Impacts score	29.64 (15.44–49.79)
SGRQ Activity score	57.32 (47.24–72.08)
SGRQ Total score	41.08±20.99
FEV1 (L/s)	1.86±0.72
FEV1 % pred	66.54±20.29
FEF25%–75% (L/s)	1.18 (0.65–1.81)
FEF25%–75% % pred	35.50 (24.00–55.00)
RV/TLC	54.45±10.08
RV/TLC% pred	139.97±21.27
FVC (L)	2.75 (2.23–3.39)
FVC% pred	82.54±17.44
Raw (kPa⋅s/L)	0.27 (0.22–0.42)

Note: Data are presented as mean ± SD or median (interquartile range) unless otherwise stated.

Abbreviations: BDNF, brain-derived neurotrophic factor; BMI, body mass index; CK, creatine kinase; CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HDL, high-density lipoprotein; HOMA, homeostatic model assessment; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; RV, residual volume; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire; TLC, total lung capacity.

Table 2 Main characteristics of two groups of the COPD cohort dichotomized according to mood disturbances indicated by the Impacts score

Parameters	Lower Impacts score	Higher Impacts score	P-value
Age (years)	62.75±9.15	61.44±10.40	0.567
Gender (female/male)	12/28	15/19	0.209
Smoker	13/40 (32.5%)	12/34 (35.3%)	0.800
Smoking (pack-years)	19 (2.25–33)	20 (8.8–37.5)	0.227
Smoking (years)	5.50 (0.00–30.00)	12.50 (0.00–38.00)	0.460
Diabetes present	5/40 (12.5%)	8/34 (23.5%)	0.214
Dyslipidemia present	9/40 (22.5%)	17/34 (50.0%)	0.017
Hypertension present	18/40 (45.0%)	25/34 (73.5%)	0.013
RR systolic (mmHg)	135.45±15.34	137.70±16.60	0.545
RR diastolic (mmHg)	83.00±14.62	81.65±13.60	0.683
Prior AMI	4/40 (10.0%)	5/34 (14.7%)	0.538
Prior stroke (n/y)	0/40 (0%)	1/34 (2.9%)	0.275
Disease duration (years)	5.00 (3.00–8.00)	6.00 (3.00–10.00)	0.301
Waist (cm)	101.11±13.04	103.02±15.81	0.570
Weight (kg)	78.77±15.41	80.81±19.13	0.617
Height (m)	1.70±0.94	1.65±0.10	0.110
BMI (kg/m^2)	27.29±4.25	29.25±5.82	0.103
Irisin (ng/mL)	7.37 (6.99–8.12)	6.85 (6.49–7.99)	0.030
BDNF (ng/mL)	347.55 (316.10–413.60)	343.15 (292.00–377.90)	0.400
Urea (mmol/L)	5.31±1.30	5.31±1.47	0.995
Creatinine (µmol/L)	69.50 (57.50–81.50)	72.00 (61.00–80.00)	0.840
GFR (mL/min/1.73 m^2)	90.00 (81.50–91.00)	91.00 (80.00–91.00)	0.920
GOT (U/L)	20.00 (16.00–24.00)	19.00 (15.00–22.00)	0.384
GPT (U/L)	20.50 (14.50–29.50)	1.00 (13.00–21.00)	0.102
γGT (U/L)	32.50 (19.50–49.00)	32.50 (20.00–47.00)	0.724
CK (U/L)	101.50 (77.50–138.50)	93.50 (73.00–147.00)	0.640
LDH (U/L)	207.55±36.08	209.88±34.12	0.780
Glucose (mmol/L)	4.08 (4.00–5.50)	5.30 (4.70–6.60)	0.015
Insulin (mU/L)	7.50 (5.30–13.50)	9.45 (5.90–22.40)	0.243
HgA1c (%)	5.70 (5.45–6.00)	5.70 (5.50–6.20)	0.550
HOMA index	1.48 (1.00–3.38)	2.35 (1.46–5.92)	0.092
Cholesterol (mmol/L)	5.70 (4.00–6.30)	5.00 (4.00–5.80)	0.112
LDL-C (mmol/L)	3.25 (2.65–4.00)	2.80 (2.40–3.30)	0.030
HDL-C (mmol/L)	1.45 (1.20–1.80)	1.35 (1.00–1.80)	0.570
Triglyceride (mmol/L)	1.35 (0.95–1.95)	1.35 (1.00–2.00)	0.691
CRP (mg/L)	1.90 (0.85–3.65)	2.60 (1.50–7.00)	0.060
Fibrinogen (g/L)	3.63 (3.13–4.00)	3.69 (3.33–4.00)	0.543
Procalcitonin (µg/L)	0.00 (0.00–0.00)	0.00 (0.00–0.00)	0.360
sTSH (mU/L)	1.36 (0.84–2.00)	1.12 (0.78–1.43)	0.216
FEV1 % pred	71.37±19.26	60.85±20.25	0.025
FVC% pred	86.3±16.92	78.12±17.25	0.043

Notes: Patients in the lower and higher Impacts score groups had smaller and higher (or equal) Impacts score than (or to) 32.65%, respectively, with 32.65% being the mean Impacts score of the whole cohort. Data are presented as mean ± SD or median (interquartile range), unless otherwise stated. Differences between the two groups were considered significant at P<0.05 (indicated in bold).

Abbreviations: AMI, acute myocardial infarction; BDNF, brain-derived neurotrophic factor; BMI, body mass index; CK, creatine kinase; CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GFR, glomerular filtration rate; GOT, glutamate-oxaloacetate transaminase; GPT, glutamate-pyruvate transaminase; HDL, high-density lipoprotein; HOMA, homeostatic model assessment; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; RR, blood pressure measured according to Riva-Rocci; sTSH, thyroid-stimulating hormone-sensitive; γGT, gamma-glutamyltransferase.

Figure 1 Correlation of mood disturbance (characterized by the Impacts score of SGRQ) and reciprocal of serum irisin concentration in the whole data set (n=74).

Notes: The x-axis shows the reciprocal of serum irisin level (in ng/mL), whereas the y-axis denotes the Impacts score of SGRQ. The blue line shows the fitted line to the data points (represented by the green dots), whereas the grey zone indicates the 95% CI.
Abbreviations: CI, confidence interval; SGRQ, St George’s Respiratory Questionnaire.

Table 3 Significant predictors of reciprocal of serum irisin level and Impacts score of SGRQ determined with simple linear regression for the whole COPD cohort (n=74)

Parameter	Coefficient (95% CI)	P-value
Simple linear regression of reciprocal of irisin
Waist circumference	0.00045 (0.00015, 0.00075)	0.004
Weight	0.00027 (0.00002, 0.00052)	0.036
Reciprocal of glucose square	−0.31 (−0.56, −0.06)	0.014
Log HgA1c	0.043 (0.008, 0.077)	0.016
Urea	0.0035 (0.00027, 0.0068)	0.034
LDH	−0.00014 (−0.00026, −9.94∙10^−6)	0.035
Log triglyceride	0.011 (0.0033, 0.019)	0.006
Log HDL cholesterol	−0.022 (−0.035, −0.008)	0.002
FVC	0.0061 (0.00084, 0.011)	0.024
FEV1	0.0068 (0.0006, 0.013)	0.032
RV/TLC% pred	−0.0023 (−0.00043, −0.00002)	0.03
Simple linear regression of Impacts score
Height	−57.86 (−109.01, −6.65)	0.027
Sqrt of disease duration	5.52 (0.89, 9.58)	0.019
Reciprocal of glucose square	−369.63 (−635.69, −103.58)	0.007
Log HgA1c	44.97 (7.58, 82.37)	0.019
CRP	0.95 (0.19, 1.72)	0.015
Log cholesterol	−21.41 (−39.21, −3.61)	0.019
Log LDL cholesterol	−15.56 (−28.7, −2.42)	0.021
Log HOMA index	5.82 (1.29, 10.56)	0.012
BMI	1.16 (0.23, 2.1)	0.016
Log sTSH	−9.89 (−17.35, −2.43)	0.01
FVC	−10.04 (−15.36, −4.73)	<0.001
FVC% pred	−0.39 (−0.66, −0.12)	0.005
FEV1	−12.24 (−18.5, −5.99)	<0.001
FEV1 % pred	−0.38 (−0.61, −0.15)	0.001
FEF25%–75%	−7.01 (−12.96, −1.06)	0.022
Log FEF25%–75% % pred	−9.45 (−17.91, −1)	0.029
RV/TLC	0.62 (0.15, 1.08)	0.01
RV/TLC% pred	0.34 (0.12, 0.55)	0.03

Note: Regression coefficient values are presented with their 95% CI.

Abbreviations: BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HDL, high-density lipoprotein; HOMA, homeostatic model assessment; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; RV, residual volume; SGRQ, St George’s Respiratory Questionnaire; SQRT, square root; TLC, total lung capacity; sTSH, thyroid-stimulating hormone-sensitive.

Table 4 Multiple linear regression model for the SGRQ’s Impacts score of the whole COPD cohort and its strata with respect to the median BDNF level

Parameter	Coefficient (95% CI)	P-value
Whole cohort
Reciprocal of irisin	419.97 (204.31, 635.63)	0.000
Age	−0.42 (−0.85, 0.01)	0.053
Gender	0.45 (−9.92, 10.83)	0.931
FEV1 % pred	−0.52 (−0.71, −0.32)	0.000
BMI	3.68 (2.01, 5.34)	0.000
Log triglyceride	−8.70 (−16.38, −1.02)	0.027
Weight	−0.78 (−1.31, −0.25)	0.004
Lower BDNF stratum
Reciprocal of irisin	434.11 (166.17, 702.05)	0.002
Age	−0.39 (−0.94, 0.16)	0.160
Gender	−3.87 (−23.46, 15.72)	0.689
FEV1 % pred	−0.50 (−0.76, −0.23)	0.001
BMI	3.45 (0.49, 6.42)	0.024
Log triglyceride	−11.91 (−22.31, −1.50)	0.026
Weight	−0.58 (−1.60, 0.43)	0.250
Higher BDNF stratum
Reciprocal of irisin	373.49 (−74.91, 821.88)	0.099
Age	−0.49 (−1.38, 0.40)	0.269
Gender	1.19 (−15.55, 17.94)	0.885
FEV1 % pred	−0.56 (−0.93, −0.19)	0.004
BMI	3.70 (1.25, 6.15)	0.005
Log triglyceride	−4.62 (−18.32, 9.07)	0.494
Weight	−0.83 (−1.59, −0.07)	0.033

Notes: Regression coefficient values are presented with their 95% CI. The initial model for the multiple linear regression analysis consisted of the significant parameters provided by the simple linear regression and the relevant a priori identified parameters (age, gender). P-values <0.05 are indicated in bold.

Abbreviations: BDNF, brain-derived neurotrophic factor; BMI, body mass index; CI, confidence intervals; FEV₁, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire.

Table 5 ANOVA tables describing the final model for the whole cohort (Panel A), lower BDNF stratum (Panel B), and higher BDNF stratum (Panel C)

Panel	SS	df	MS
A
Model	15,192.92	7	2,170.42	N=72
Residual	15,875.15	64	248.05	F (7, 64) =8.75
Total	31,068.07	71	437.58	P<0.001
				R^2=0.489
				Adj R^2=0.433
				Root MSE =15.75
B
Model	7,877.75	7	1,125.39	N=37
Residual	6,880.71	29	237.27	F (7, 29) =4.74
Total	14,758.46	36	409.96	P=0.0012
				R^2=0.534
				Adj R^2=0.421
				Root MSE =15.40
C
Model	7,576.25	7	1,082.32	N=35
Residual	8,545.32	27	316.49	F (7, 29) =3.42
Total	16,121.57	34	474.16	P=0.0095
				R^2=0.4699
				Adj R^2=0.3325
				Root MSE =17.79

Note: Data regarding the weight of two patients were missing; thus, they were not included in the analysis.

Abbreviations: ANOVA, analysis of variance; BDNF, brain-derived neurotrophic factor; df, degree of freedom; MS, mean of the sum of squares; MSE, mean squares of error; SS, sum of squares.

Figure 2 The model describing the correlation between the Impacts score of SGRQ and reciprocal of serum irisin concentration in the whole data set (n=74).

Notes: The x-axis shows the reciprocal of serum irisin concentration (in ng/mL), whereas the y-axis denotes the Impacts score of SGRQ. The blue and red dots indicate the raw and fitted values obtained by multiple linear regression, respectively. The green and orange lines indicate the curves fitted to the raw data and to data provided by multiple linear regression. Fitting was done by locally weighted scatterplot smoothing (lowess).
Abbreviation: SGRQ, St George’s Respiratory Questionnaire.