Association Between Systemic and Pulmonary Vascular Dysfunction in COPD

Figures & data

Table 1 Characteristics of the Study Subjects

	Non-Smoking Controls (n=27)	Smoking Controls (n=20)	COPD without PVD (n=46)	COPD with PVD (n=15)
Age, years	56 ± 8	54 ± 8	62 ± 7 ^ab	64 ± 6 ^ab
Male gender, n (%)	12 (44%)	9 (45%)	38 (83%) ^ab	13 (87%) ^ab
Smoking status
Current smokers, n (%)	0 (0%)	20 (100%)	14 (30%)	2 (13%)
Ex-smokers, n (%)	9 (33%)	0 (0%)	32 (70%)	13 (87%)
Pack-years smoking	4 ± 8	30 ± 24	62 ± 29 ^ab	69 ± 29 ^ab
GOLD stage 1-2-3-4, n	NA	NA	3–16-13-14	0-1-5-9
FEV1, % ref	107 ± 12	103 ± 10	48 ± 20 ^ab	30 ± 10 ^abc
FVC, % ref	106 ± 11	104 ± 12	84 ± 19 ^ab	65 ± 13 ^abc
FEV1/FVC, %	79 ± 5	77 ± 5	43 ± 14	34 ± 9
TLC, % ref	106 ± 8	106 ± 9	116 ± 19 ^a	113 ± 21
RV, % ref	108 ± 18	110 ± 23	181 ± 57 ^ab	197 ± 62 ^ab
DLCO, % ref	92 ± 15	85 ± 9	57 ± 20 ^ab	39 ± 12 ^abc
PaO2, mmHg	NA	NA	73 ± 9	63 ± 10^c
Systemic arterial hypertension, n (%)	5 (19%)	3 (15%)	21 (46%) ^ab	10 (67%) ^abc
Dyslipidemia, n (%)	7 (26%)	7 (35%)	14 (30%)	6 (40%)
Diabetes mellitus, n (%)	1 (4%)	0 (0%)	2 (4%)	5 (33%) ^abc
Framingham score, points	4.9 ± 5.1	7.00 ± 6.0	10.2 ± 5.8 ^a	12.1 ± 6.8 ^ab
Systolic pulmonary artery pressure, mmHg	27 ± 4	27 ± 3	31 ± 3	43 ± 10 ^abc
Mean pulmonary artery pressure, mmHg *	NA	NA	21.2 ± 1.9	29.9 ± 5.9 ^abc
Cardiac index, L/min/m^Citation2 *	NA	NA	2.24 ± 0.89	2.77 ± 0.47 ^abc
Pulmonary artery wedge pressure, mmHg *	NA	NA	8.3 ± 3.1	9.30 ± 4.1
Pulmonary vascular resistance, dyn·s·cm−^Citation5 *	NA	NA	247 ± 40	328 ± 113
Left ventricular ejection fraction, %	64 ± 3	64 ± 3	62 ± 5	60 ± 6
Systolic blood pressure, mmHg	124 ± 18	123 ± 16	130 ± 20	135 ± 19

Notes: Results are expressed in mean±standard deviation. ^a p<0.05 compared with non-smokers; ^b p<0.05 compared with smokers; ^c p<0.05 compared with COPD without PVD; * Right heart catheterization was performed in 5 patients of the COPD without PVD group and in 10 patients of the COPD with PVD group.

Abbreviations: COPD, chronic obstructive pulmonary disease; PVD, pulmonary vascular disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; FEV₁, forced expiratory volume in 1st second; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DL_CO, diffusing capacity for carbon monoxide; PaO2, partial pressure of arterial oxygen; NA, not available.

Table 2 Vascular Function in Systemic Arteries

	Non-Smoking Controls (n = 26)	Smoking Controls (n = 20)	COPD without PVD (n = 45)	COPD with PVD (n = 15)
Flow-mediated dilation, % change from baseline diameter	10.10 (6.15–14.30)	6.60 (4.58–9.50)	5.40 (3.13–7.30) ^a	2.70 (0.78–4.70) ^ab
Flow-mediated dilation/Baseline brachial artery diameter, %/mm	2.50 (1.48–3.82)	1.34 (0.80–2.04)	1.16 (0.49–1.65) ^a	0.49 (0.18–1.02) ^ab
Augmentation index, %	25.0 (19.3–35.3)	33.0 (20.0–43.0)	25.0 (17.3–30.0)	27.0 (17.3–34.0)
Augmentation index 75, %	23.5 (17.0–29.3)	26.0 (20.0–40.0)	27.0 (16.8–31.0)	26.0 (19.5–31.8)
Pulse wave velocity, m/s	8.3 (6.6–9.7)	7.6 (6.6–8.9)	9.8 (8.4–11.8) ^ab	11.4 (10.4–13.2) ^abc

Notes: Results are expressed as median (percentile 25-percentile 75). Non-adjusted comparisons: ^ap<0.05 compared with non-smokers; ^b p<0.05 compared with smokers; ^c p<0.05 compared with COPD without PVD.

Abbreviations: COPD, chronic obstructive pulmonary disease; PVD, pulmonary vascular disease.

Figure 1 Results of (A) endothelial function, assessed with flow-mediated dilation, and (B) arterial stiffness, assessed with pulse wave velocity, in non-smoking controls, smoking controls, chronic obstructive pulmonary disease (COPD) without pulmonary vascular disease (PVD) [COPD PVD(-)] and COPD with PVD [COPD PVD(+)]. Boxplots show median and 25–75 percentiles, whiskers show 5 and 95 percentiles, points show values out of this range. Between-group differences were analyzed with unadjusted ANOVA using Tukey as post-hoc test; *p<0.05.

Figure 2 Correlation between flow-mediated dilation (left column) and pulse wave velocity (right column) with forced expiratory volume during the first second (FEV₁), diffusing capacity for carbon monoxide (DLCO) and systolic pulmonary artery pressure (PAPs; estimated by doppler echocardiography in patients with tricuspid regurgitation and thus a measurable PAPs or measured at right heart catheterization). Patients are grouped as non-smoking controls, smoking controls, chronic obstructive pulmonary disease (COPD) without pulmonary vascular disease (PVD) [COPD PVD(-)] and COPD with PVD [COPD PVD(+)].

Table 3 Vascular and Systemic Inflammatory Markers

	Non-Smoking Controls (n=27)	Smoking Controls (n=20)	COPD without PVD (n=46)	COPD with PVD (n=15)
hsCRP, mg/dL	0.15 (0.05–0.24)	0.09 (0.05–0.33)	0.40 (0.12–0.87)	0.27 (0.20–0.80)
BNP, pg/mL	13.7 (4.1–23.4)	12.0 (7.6–28.1)	13.5 (7.7–24.9)	21.2 (8.4–40.5)
Fibrinogen, g/L	3.40 (3.00–3.70)	3.30 (2.90–3.78)	3.80 (3.10–5.05)^ab	4.00 (3.60–4.50)
Glycemia, mg/dL	92 (85–99)	92 (83–99)	96 (87–109)	112 (94–138)
VEGF, detectable %	12 (44.4)	12 (60)	22 (47.8)	7 (46.7)
VEGF, pg/mL	47.0 (20.8–87.3)	13.3 (8.9–40.1)	9.5 (4.6–39.5)	20.7 (16.8–30.0)
TGF-β, ng/mL	2.31 (1.42–3.43)	2.08 (1.39–5.70)	3.00 (2.06–3.65)	2.18 (1.83–3.29)
IL-6, pg/mL	1.74 (0.96–5.23)	2.55 (0.88–8.00)	1.84 (0.87–3.26)	1.12 (0.54–2.07)
HGF, pg/mL	274 (220–437)	257 (218–365)	336 (309–407)	338 (309–448)
Leptin. ng/mL	11.0 (8.8–16.9)	13.9 (6.6–17.4)	11.5 (8.2–22.5)	16.6 (9.5–20.5)
Angiopoietin-2, pg/mL	776 (593–939)	942 (599–1319)	923 (746–1172)	1244 (844–1551)
cGMP, nmol/mL	2.52 (2.02–3.18)	2.19 (1.82–3.00)	2.23 (1.81–3.10)	2.58 (2.20–3.09)
sTNF-αRI, pg/mL	1039 (706–1348)	897 (691–1159)	1050 (878–1359)	1303 (1207–1659) ^ab
sICAM-1, ng/mL	77.1 (59.0–94.5)	85.8 (67.0–144.8)	96.0 (80.7–190.5)	92.6 (82.8–212.4)
Adiponectin, ng/mL	1046 (795–1494)	1118 (859–1628)	927 (691–1223)	815 (717–996)
sAxl, pg/mL	38.3 (15.8–70.9)	42.4 (20.8–69.3)	38.8 (23.0–57.7)	31.9 (20.3–72.7)

Notes: Results are expressed in median (percentile 25-percentile 75). ^a p<0.05 compared with non-smokers; ^b p<0.05 compared with smokers.

Abbreviations: hsCRP, high sensitivity C-reactive protein; BNP, brain natriuretic peptide; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor; IL-6, Interleukin-6; HGF, hepatocyte growth factor; cGMP, cyclic guanosine monophosphate; sTNF-αRI, soluble receptor of tumor necrosis factor-alpha; sICAM-1, soluble intercellular adhesion molecule-1; sAxl, adiponectin, soluble tyrosine kinase receptor Axl. COPD, chronic obstructive pulmonary disease; PVD, pulmonary vascular disease.

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