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      Association Between Systemic and Pulmonary Vascular Dysfunction in COPD

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          In chronic obstructive pulmonary disease (COPD), endothelial dysfunction and stiffness of systemic arteries may contribute to increased cardiovascular risk. Pulmonary vascular disease (PVD) is frequent in COPD. The association between PVD and systemic vascular dysfunction has not been thoroughly evaluated in COPD.


          A total of 108 subjects were allocated into four groups (non-smoking controls, smoking controls, COPD without PVD and COPD with PVD). In systemic arteries, endothelial dysfunction was assessed by flow-mediated dilation (FMD) and arterial stiffness by pulse wave analysis (PWA) and pulse wave velocity (PWV). PVD was defined by a mean pulmonary artery pressure (PAP) ≥25 mmHg at right heart catheterization or by a tricuspid regurgitation velocity >2.8 m/s at doppler echocardiography. Biomarkers of inflammation and endothelial damage were assessed in peripheral blood.


          FMD was lower in COPD patients, with or without PVD, compared to non-smoking controls; and in patients with COPD and PVD compared to smoking controls. PWV was higher in COPD with PVD patients compared to both non-smoking and smoking controls in a model adjusted by age and the Framingham score; PWV was also higher in patients with COPD and PVD compared to COPD without PVD patients in the non-adjusted analysis. FMD and PWV correlated significantly with forced expiratory volume in the first second (FEV 1), diffusing capacity for carbon monoxide (DL CO) and systolic PAP. FMD and PWV were correlated in all subjects.


          We conclude that endothelial dysfunction of systemic arteries is common in COPD, irrespective if they have PVD or not. COPD patients with PVD show increased stiffness and greater impairment of endothelial function in systemic arteries. These findings suggest the association of vascular impairment in both pulmonary and systemic territories in a subset of COPD patients.

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          Most cited references 35

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          The influence of heart rate on augmentation index and central arterial pressure in humans.

          Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. Twenty-two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non-invasively, during incremental pacing (from 60 to 110 beats min-1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non-invasively from the brachial artery. There was a significant, inverse, linear relationship between AIx and heart rate (r = -0.76; P < 0.001). For a 10 beats min-1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r = -0. 51; P < 0.001). Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.
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            Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.

            Cigarette smoking is the most important modifiable risk factor for atherosclerosis. Endothelial dysfunction is an early event in atherogenesis, and we hypothesized that smoking might be associated with endothelial damage in the systemic arteries of otherwise healthy young adults. We studied noninvasively the brachial arteries of 200 subjects aged 15 to 57 years, all normotensive, nondiabetic with cholesterol level < or = 240 mg/dL and no family history of premature vascular disease: 80 control subjects aged 16 to 56 years (mean, 35), 80 current smokers aged 15 to 55 years (mean, 33), and 40 former smokers aged 25 to 57 years (mean, 38). Total lifetime amount smoked varied from 1 to 75 pack years in the smokers. Using high-resolution ultrasound, vessel diameter was measured at rest, during reactive hyperemia (with flow increase causing endothelium-dependent dilation), and after sublingual glyceryl trinitrate (GTN, an endothelium-independent vasodilator). Flow-mediated dilation (FMD) was observed in all the control subjects (10 +/- 3.3%; range, 4% to 22%) but was impaired or absent in the smokers (4 +/- 3.9%; range, 0% to 17%; P < .0001). FMD in the smokers was inversely related to lifetime dose smoked (6.6 +/- 4.0% in very light smokers, 4.0 +/- 3.1% in light smokers, 3.2 +/- 3.2% in moderate smokers, and 2.6 +/- 1.2% in heavy smokers; P < .01). FMD for the former smokers was 5.1 +/- 4.1% (range, 0% to 15%). In a multivariate model adjusting for age, sex, cholesterol, smoking history, and vessel size, former smoking was associated with a higher FMD than current smoking (P = .07); when only male former and current smokers were considered, the higher FMD was significant (P = .0001) but not for female smokers (P = .24). GTN caused dilation in all subjects (control subjects, 20 +/- 5.2%; smokers, 17 +/- 5.8%; former smokers, 17.4 +/- 5.4%). Vessel diameter, baseline flow, and degree of reactive hyperemia (Doppler estimated) were similar in all groups. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent arterial dilation in asymptomatic young adults, consistent with endothelial dysfunction.
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              Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study.

              Chronic obstructive pulmonary disease (COPD) is considered an inflammatory pulmonary disorder with systemic inflammatory manifestations. The aim of this study was to assess the systemic levels of six inflammatory mediators in a large cohort of COPD patients and controls. 409 COPD patients and 231 healthy subjects, aged 40-75 yrs, were included from the first phase of the Bergen COPD Cohort Study. All COPD patients were clinically diagnosed by a physician, and had a forced expiratory volume in 1 s/forced vital capacity ratio less than 0.7 and a smoking history of >10 pack-yrs. The plasma levels of C-reactive protein (CRP), soluble tumour necrosis factor receptor (sTNFR)-1, osteoprotegrin, neutrophil activating peptide-2, CXCL16 and monocyte chemoattractant protein-4 were determined by ELISA. After adjustment for all known confounders, COPD patients had significantly lower levels of osteoprotegrin than subjects without COPD (p<0.05), and higher levels of CRP (p<0.01). Among COPD patients, CRP was elevated in patients with frequent exacerbations (p<0.05). sTNFR-1 and osteoprotegrin were both related to Global Initiative for Chronic Obstructive Lung Disease stage and frequency of exacerbations in the last 12 months (p<0.05). In addition, sTNFR-1 was significantly associated with important comorbidities such as hypertension and depression (p<0.05). The present study confirms that certain circulating inflammatory mediators are an important phenotypic feature of COPD.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                26 August 2020
                : 15
                : 2037-2047
                [1 ]Department of Pulmonary Medicine, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona , Barcelona, Spain
                [2 ]Biomedical Research Networking Centre on Respiratory Diseases (CIBERES) , Madrid, Spain
                [3 ]Department of Cardiology, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona , Barcelona, Spain
                [4 ]Biomedical Research Networking Centre on Cardiovascular Diseases (CIBERCV) , Madrid, Spain
                Author notes
                Correspondence: Joan Albert Barberà Department of Pulmonary Medicine, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona , Villarroel 170, Barcelona08036, SpainTel +34 932275779 Email
                © 2020 Piccari et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 2, Tables: 8, References: 49, Pages: 11
                Funded by: Instituto de Salud Carlos III (ISCiii);
                The present study was supported by grants PS090536, PI12/00510 and PI13/00836 from the Instituto de Salud Carlos III (ISCiii), 197/2015 from the Spanish Society of Respiratory Medicine (SEPAR), Catalan Society of Pulmonology (SOCAP) and Fundación Contra la Hipertensión Pulmonar (FCHP).
                Original Research


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