Positive correlation of airway resistance and serum asymmetric dimethylarginine level in COPD patients with systemic markers of low-grade inflammation

Figures & data

Figure 1 The influence of ADMA on the NOS and arginase pathways in COPD.

Notes: Green arrows denote activation and enhancement. Red lines denote inhibition. Black arrows denote transformation or metabolic connection.
Abbreviations: ADMA, asymmetric dimethylarginine; NOS, nitric oxide synthase; L-arg, L-arginine; NOHA, N-hydroxy-L-arginine; NO, nitric oxide; ONOO⁻, peroxynitrite anion; PRMT, protein methyltransferase; DDAH, dimethylarginine dimethylaminohydrolase (or dimethylargininase); eNOS, endothelial NOS; iNOS, inducible NOS.

Table 1 Characteristics of the whole population of COPD patients (n=74) and of its two groups containing patients with lower (n=34) and higher (n=40) R_aw values

Parameters	Whole population	Lower Raw	Higher Raw	P-value
Age (years)	62.15±9.70	59.53±7.92	64.38±10.58	0.031
Gender (female/male)	27/47	12/22	15/25	0.844
Smoker (no/yes)	49/25	23/11	26/14	0.810
Smoking (pack-years)	20.00 (5.25–33.75)	17.50 (2.25–25.00)	26.68 (8.38–39.40)	0.035
Smoking (years)	10.00 (0.00–33.00)	0.50 (0.00–20.00)	20.00 (0.00–40.00)	0.031
Diabetes (no/yes)	61/13	29/5	32/8	0.551
Dyslipidemia (no/yes)	48/26	23/11	25/15	0.644
RR systolic (mmHg)	136.49±15.85	134.18±14.65	138.45±16.74	0.251
RR diastolic (mmHg)	82.38±14.06	80.85±15.24	83.68±13.04	0.393
Hypertension (no/yes)	31/43	18/16	13/27	0.076
AMI (no/yes)	65/9	29/5	36/4	0.537
Stroke (no/yes)	73/1	33/1	40/0	0.275
Disease duration (years)	5.00 (3.00–10.00)	5.50 (3.00–10.00)	5.00 (3.00–9.00)	0.798
Waist (cm)	101.99±14.31	102.25±14.01	101.78±14.74	0.888
Weight (kg)	79.71±17.12	81.55±17.44	78.15±16.92	0.406
Height (m)	1.68±0.094	1.71±0.086	1.65±0.091	0.003
BMI (kg/m^2)	28.19±5.09	27.61±4.94	28.68±5.23	0.380
ADMA (μmol/L)	0.58 (0.44–0.67)	0.58 (0.43–0.64)	0.58 (0.46–0.70)	0.354
SDMA (μmol/L)	0.48 (0.42–0.58)	0.49 (0.42–0.57)	0.48 (0.41–0.62)	0.425
L-Arginine (μmol/L)	104.20±28.81	107.70±28.71	101.23±28.92	0.339
B12 (pmol/L)	302.40 (237.70–348.50)	308.00 (243.10–347.30)	288.75 (224.35–348.65)	0.498
Folate (nmol/L)	17.85 (13.74–23.47)	18.49 (14.91–23.86)	16.92 (12.71–22.84)	0.293
Urea (mmol/L)	5.31±1.37	5.37±1.35	5.26±1.40	0.731
Creatinine (μmol/L)	71.00 (61.00–81.00)	70.50 (58.00–90.00)	73.50 (61.00–79.00)	0.576
GFR (mL/min/1.73 m^2)	91.00 (80.00–91.00)	88.50 (80.00–91.00)	91.00 (80.50–91.00)	0.677
GOT (U/L)	19.50 (15.00–23.00)	20.50 (16.00–23.00)	19.00 (14.00–23.00)	0.254
GPT (U/L)	18.00 (14.00–24.00)	20.00 (13.00–26.00)	18.00 (15.00–24.00)	0.490
γGT (U/L)	32.50 (20.00–49.00)	31.00 (20.00–49.00)	33.00 (19.50–47.00)	0.991
CK (U/L)	101.00 (74.00–139.00)	106.00 (74.00–165.00)	99.00 (76.00–135.50)	0.591
LDH (U/L)	208.62±34.98	204.15±36.82	212.43±33.32	0.314
Glucose (mmol/L)	5.00 (4.20–5.80)	5.00 (4.00–5.60)	5.10 (4.60–6.25)	0.462
Insulin (mU/L)	8.95 (5.55–16.50)	10.15 (5.65–15.35)	7.80 (5.25–19.85)	0.892
HgA1c (%)	5.70 (5.50–6.10)	5.60 (5.40–6.10)	5.80 (5.50–6.20)	0.295
HOMA	2.14 (1.14–4.67)	2.14 (1.23–3.64)	2.15 (1.05–5.21)	0.910
Cholesterol (mmol/L)	5.30 (4.00–6.30)	5.60 (5.00–6.30)	5.00 (4.00–6.15)	0.159
LDL-C (mmol/L)	3.10 (2.60–3.70)	3.20 (2.60–3.80)	2.85 (2.4–3.65)	0.116
HDL-C (mmol/L)	1.40 (1.20–1.80)	1.45 (1.20–1.80)	1.40 (1.10–1.80)	0.752
ApoA1 (g/L)	1.55 (1.38–1.80)	1.61 (1.47–1.76)	1.52 (1.33–1.85)	0.365
ApoB (g/L)	1.00 (0.85–1.28)	1.00 (0.91–1.28)	0.95 (0.83–1.19)	0.219
Lp(a) (mg/L)	129.50 (58.00–455.00)	136.00 (38.00–568.00)	106.50 (59.50–363.50)	0.991
TG (mmol/L)	1.35 (1.00–2.00)	1.70 (1.00–2.00)	1.20 (0.90–1.85)	0.256
CRP (mg/L)	2.00 (1.210–4.00)	1.85 (1.210–3.10)	2.80 (1.25–6.65)	0.052
CRP (normal/high)	58/16	31/3	27/13	0.014
Fibrinogen (g/L)	3.67 (3.25–4.00)	3.56 (3.12–4.03)	3.77 (3.35–4.00)	0.282
Procalcitonin (μg/L)	0.00 (0.00–0.00)	0.00 (0.00–0.00)	0.00 (0.00–0.00)	0.278
sTSH (mU/L)	1.26 (0.84–1.93)	1.30 (0.76–2.16)	1.21 (0.84–1.67)	0.558
SGRQ Symptoms score	32.66 (13.64–58.28)	25.55 (8.28–36.98)	40.46 (21.54–68.19)	0.004
SGRQ Impacts score	29.64 (15.44–49.79)	20.85 (11.00–38.70)	36.58 (22.20–52.67)	0.011
SGRQ Activity score	57.32 (47.24–72.08)	53.25 (23.41–66.09)	65.39 (53.57–72.91)	0.008
SGRQ Total score	41.08±20.99	33.82±21.46	47.07±18.81	0.006

Notes: Patients with R_aw<0.27 kPa⋅s/L formed the lower R_aw group, while patients with R_aw≥0.27 kPa·s/L were put in the higher R_aw group (0.27 kPa·s/L was the median R_aw 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). Clinically meaningful differences of SGRQ results are underlined.

Abbreviations: R_aw, airway resistance; RR, blood pressure (measured according to Riva-Rocci); AMI, acute myocardial infarction; BMI, body mass index; ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; GFR, glomerular filtration rate; GOT, glutamate–oxaloacetate transaminase; GPT, glutamate–pyruvate transaminase; γGT, gamma-glutamyltransferase; CK, creatinine kinase; LDH, lactate dehydrogenase; HgA1c, hemoglobin A1c; HOMA, homeostatic model assessment; LDL-C, low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol; ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; Lp(a), lipoprotein(a); TG, triglyceride; CRP, C-reactive protein; sTSH, thyroid-stimulating hormone-sensitive; SGRQ, St George’s Respiratory Questionnaire; SD, standard deviation.

Table 2 Main characteristics of the whole population of COPD patients (having complete SGRQ data; n=73) and of its better-controlled (n=37) and worse-controlled (n=36) groups

Parameters	Whole population	Better-controlled	Worse-controlled	P-value
Demographic and anthropometric parameters
Age (years)	62.01±9.70	61.32±8.35	62.72±10.99	0.542
Gender (female/male)	27/46	13/24	14/22	0.740
Height (m)	1.68±0.09	1.70±0.10	1.66±0.08	0.083
Weight (kg)	79.61±17.22	82.36±18.65	76.77±15.37	0.173
Lung function test parameters
FVC% pred	82.30±17.44	87.46±16.58	77.00±16.90	0.009
IVC% pred	87.00 (74.00–100.00)	89.00 (78.00–100.00)	85.00 (70.00–99.50)	0.166
TLC% pred	113.00 (103.00–127.00)	108.00 (101.00–120.00)	121.50 (106.50–130.00)	0.086
TGV% pred	140.00 (123.00–167.00)	135.00 (116.00–155.00)	157.00 (126.50–178.50)	0.025
RV% pred	172.03±47.23	157.14±35.80	187.33±52.87	0.006
RV/TLC% pred	140.47±20.99	132.00±16.71	149.17±21.57	<0.001
FEV1% pred	66.08±20.04	74.19±16.98	57.75±19.71	<0.001
PEF% pred	52.00 (39.00–73.00)	58.00 (50.00–77.00)	41.50 (29.50–59.50)	<0.001
FEF25–75%% pred	35.00 (24.00–53.00)	42.00 (29.00–60.00)	28.50 (18.50–46.50)	0.006
MEF50%% pred	37.00 (20.00–58.00)	43.00 (32.00–63.00)	24.50 (16.00–49.00)	<0.001
FEV1/IVC% pred	76.11±16.36	82.19±13.36	69.86±16.96	<0.001
FEV1/FVC	0.65 (0.54–0.74)	0.68 (0.64–0.76)	0.59 (0.48–0.71)	0.007
Raw (kPa⋅s/L)	0.27 (0.22–0.42)	0.25 (0.20–0.31)	0.33 (0.26–0.53)	0.008
Gaw (L/kPa⋅s)	3.67 (2.36–4.64)	3.96 (3.27–4.96)	3.07 (1.90–3.86)	0.007
SGRQ
Symptoms score	32.66 (13.64–58.28)	13.64 (5.20–25.55)	60.02 (43.24–76.70)	<0.001
Impacts score	29.66 (17.09–49.79)	18.51 (10.10–29.66)	47.01 (31.34–54.40)	<0.001
Activity score	59.45 (47.63–72.08)	52.14 (24.62–59.45)	66.41 (57.32–82.57)	<0.001
Total score	41.08±20.99	27.61±15.94	54.93±15.98	<0.001

Notes: Patients in the better-controlled group had a Symptoms score smaller than the median Symptoms score (for the whole cohort), while Symptoms score of patients in the worse-controlled group reached or exceeded this median value (32.66 was the median SGRQ Symptoms 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). Clinically meaningful differences of SGRQ results are underlined. It should be noted that only 73 patients had complete SGRQ results.

Abbreviations: SGRQ, St George’s Respiratory Questionnaire; FVC, forced vital capacity; IVC, inspiratory vital capacity; TLC, total lung capacity; TGV, thoracic gas volume; RV, residual volume; FEV₁, forced expiratory volume in 1 s; PEF, peak expiratory flow; FEF_25–75%, forced expiratory flow between 25% and 75% of FVC; MEF, maximal expiratory flow; R_aw, airway resistance; G_aw, airway conductance; SD, standard deviation.

Figure 2 Correlation of (log transformed values of) R_aw and serum concentration of ADMA in the whole data set (n=74).

Notes: The x-axis shows the common logarithm of serum ADMA concentration (in μmol/L), while the y-axis denotes the common logarithm of R_aw (in kPa·s/L). The blue line shows the fitted values of log ADMA and log R_aw data pairs (represented by the green dots), while the gray zone indicates the 95% CI.
Abbreviations: R_aw, airway resistance; ADMA, asymmetric dimethylarginine; CI, confidence interval.

Table 3 Significant predictors of ADMA serum level and R_aw determined with simple and multiple (for R_aw only) linear regression for the whole population of COPD patients (n=74)

Parameters	Coefficient (95% CI)	P-value
Simple linear regression of ADMA (log transformed)
Smoker	0.13 (0.006, 0.26)	0.039
Log SDMA	1.28 (0.93, 1.63)	<0.001
Fibrinogen	0.11 (0.034, 0.19)	0.006
Log Raw	0.13 (0.012, 0.24)	0.030
Simple linear regression of Raw (log transformed)
Age	0.019 (0.0076, 0.031)	0.002
Height	−1.72 (−2.97, −0.47)	0.008
Uric acid	0.0017 (0.00050, 0.0029)	0.006
Fibrinogen	0.18 (0.014, 0.34)	0.034
CRP (normal/high)	0.61 (0.35, 0.87)	<0.001
Log ADMA	0.51 (0.049, 0.96)	0.030
SDMA	0.94 (0.032, 1.85)	0.043
FVC	−0.32 (−0.44, −0.19)	<0.001
FVC% pred	−0.0087 (−0.015, −0.0020)	0.012
FEV1	−0.42 (−0.56, −0.28)	<0.001
FEV1 % pred	−0.011 (−0.016, −0.0051)	<0.001
FEV1/FVC	−0.015 (−0.024, −0.0059)	0.002
FEF25–75%	−0.38 (−0.50, −0.25)	<0.001
Log FEF25–75% % pred	−0.49 (−0.68, −0.31)	<0.001
RV/TLC%	0.024 (0.013, 0.035)	<0.001
RV/TLC% pred	0.0080 (0.0025, 0.013)	0.005
IC/TLC	−2.22 (−3.45, −0.98)	0.001
Corticosteroid use	0.31 (0.023, 0.60)	0.035
SGRQ Symptoms score	0.0042 (−0.000083, 0.0086)	0.054
SGRQ Activity score	0.0063 (0.0014, 0.011)	0.012
SGRQ Impacts score	0.0055 (−0.00023, 0.011)	0.060
SGRQ Total score	0.0060 (0.00033, 0.012)	0.038
Multiple linear regression of Raw (log transformed)
Log ADMA	0.42 (0.062–0.771)	0.022
Log FEF25–75% % pred	−0.336 (−0.517, −0.154)	<0.001
CRP (normal/high)	0.489 (0.266, 0.713)	<0.001

Notes: The Symptoms and Impacts scores are also included, although these are on the verge of significance. Regression coefficient values are presented with their 95% CIs. The initial model for the multiple regression analysis consisted of the significant parameters provided by the simple regression and the relevant a priori identified parameters (the latter ones were omitted from the present table as they did not contribute significantly to the final model). Bold represents statistically significant values.

Abbreviations: ADMA, asymmetric dimethylarginine; R_aw, airway resistance; CI, confidence interval; SDMA, symmetric dimethylarginine; CRP, C-reactive protein; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 s; FEF_25–75%, forced expiratory flow between 25% and 75% of FVC; RV, residual volume; TLC, total lung capacity; IC, inspiratory capacity; SGRQ, St George’s Respiratory Questionnaire.

Figure 3 The model describing the correlation between (log transformed values of) R_aw and serum concentration of ADMA in the whole data set (n=74).

Notes: The x-axis shows the common logarithm of serum ADMA concentration (in μmol/L), while the y-axis denotes the common logarithm of R_aw (in kPa·s/L). The blue and red dots indicate the raw (ie, original) values 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).
Abbreviations: R_aw, airway resistance; ADMA, asymmetric dimethylarginine.