European Journal of Internal Medicine 25 (2014) 370–373
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Vascular responsiveness in patients with chronic obstructive pulmonary disease (COPD) Arnon Blum ⁎, Claudia Simsolo, Rizak Sirchan Department of Medicine, Baruch Padeh Poria Hospital, Lower Galilee 15208, Israel
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Article history: Received 22 November 2012 Received in revised form 15 March 2013 Accepted 26 March 2013 Available online 24 April 2013 Keywords: Endothelial function COPD ABI
a b s t r a c t Background: Ischemic heart disease and peripheral vascular diseases are prevalent in COPD and it is estimated that any 10% decrease in forced expiratory volume in 1 second (FEV1) is associated with 30% increased cardiovascular risk of death. Endothelial dysfunction may be one of the mechanistic pathways that link between COPD and cardiovascular mortality. Our aim was to study the vascular reactivity of patients with stable COPD and to try to correlate endothelial dysfunction, vascular reactivity and functional capacity of these patients that eventually may lead to cardiovascular mortality. Methods: This was a prospective study. Twenty-three consecutive ambulatory COPD patients were enrolled. All were smoking men, aged 64.4 ± 8.4 years. Twenty-two healthy volunteers aged 44.7 ± 11.7 years, BMI of 25.2 ± 4.2, height of 172 ± 8 cm served as the control group. Vascular studies included endothelial function and ankle brachial index. Results: Baseline diameter of the brachial artery was larger in COPD patients compared with controls. The absolute change in diameter post hyperemia was signiﬁcantly less in patients (0.004 ± 0.02 cm vs. 0.05 ± 0.02 cm, p b 0.001) and COPD patients responded to hyperemia by constriction instead of dilatation (FMD% was −0.6 ± 6.3% in patients vs. 15.6 ± 7.6% in controls, p b 0.001). There was no difference in ABI in patients and controls (0.95 ± 0.26 vs. 1.06 ± 0.16, p = 0.07). Discussion: We found that patients with COPD have dilated arteries, have impaired ability to respond to high shear stress that triggers nitric oxide dependent ﬂow mediated dilatation, and have also impaired ability to function — represented by the poor 6 minute walk test. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Chronic obstructive pulmonary disease (COPD) is a leading chronic disease worldwide and one of the leading causes of mortality, expected to be the 3rd leading cause of death by 2020 . Ischemic heart disease and peripheral vascular diseases are prevalent in COPD and it is estimated that any 10% decrease in forced expiratory volume in 1 second (FEV1) is associated with 30% increased cardiovascular risk of death [2,3]. There are some common pathways that may link chronic lung disease and cardiovascular disease — such as chronic inﬂammation with increased levels of TNF-α, interleukin 6 and 8, and C reactive protein [4,5]. Endothelial dysfunction may be one of the mechanistic pathways that link between COPD and cardiovascular mortality. Our aim was to study the vascular reactivity of patients with stable COPD and to try to correlate endothelial dysfunction, vascular reactivity and functional capacity of these patients that eventually may lead to cardiovascular mortality.
This was a prospective double blind controlled study that was approved by the internal review board of the hospital. All patients signed a consent form before enrollment. Inclusion criteria included patients with COPD who had GOLD  criteria of COPD (FEV1%/ FVC b 0.7) with no age or gender limitation, who did not suffer from any other debilitating diseases like cancer or an autoimmune disease and did not have any neurological or orthopedic limitations in movement and walking. Exclusion criteria included patients with debilitating cardiovascular disease, heart failure, autoimmune disease, renal failure, neurological deﬁcit or any orthopedic disorder that could limit their walking ability.
⁎ Corresponding author at: Interdisciplinary Stem Cell Institute, University of Miami Florida 33136, USA. E-mail addresses: [email protected]
, [email protected]
2.1. Study group Twenty-three consecutive ambulatory patients were enrolled. All were in stable COPD (no exacerbation in the last month) and their average saturation was 93.8 ± 3% (post 6 minute walk saturation was 92.7 ± 4%). All were men, aged 64.4 ± 8.4 years, BMI of 26.3 ± 4.5, height of 170 ± 6 cm. All were smoking, 6 had coronary artery disease, 15 had hypertension, and 7 had diabetes mellitus type II (non insulin dependent).
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.03.017
A. Blum et al. / European Journal of Internal Medicine 25 (2014) 370–373
2.2. Control group Twenty-two employees of the hospital were enrolled. All were healthy, aged 44.7 ± 11.7 years, BMI of 25.2 ± 4.2, height of 172 ± 8 cm. 2.3. Respiratory function tests Spirometry was performed using a water-sealed bell spirometer (Biomedin Srl, Padova, Italy) and the best of 3 acceptable maneuvers was selected. Spirometric performance had to meet the 2005 ATS/ERS criteria of acceptability and reproducibility of the curves . 2.4. Vascular measurements 2.4.1. Endothelial function measurements The percent change in the brachial artery ﬂow mediated diameter (FMD %) was measured according to the guidelines [8–11]. Measurements were done in all patients between 8 and 9 AM in a quiet temperature controlled room (22–24 °C). All patients and healthy volunteers were studied after overnight fast, and smokers were refrained from smoking and vasoactive medications were discontinued in the 12 hours preceding the study. The subjects lied in a supine position and the right brachial artery was imaged along a longitudinal section 5–10 cm above the antecubital fossa. In each examination, recording of vessel images were followed by inﬂation of a cuff to supra-systolic pressure (40 to 50 mmHg above systolic pressure) for 5 minutes. Then the cuff was deﬂated and the brachial artery diameter was imaged and recorded for 3 minutes. FMD% more than 10% is considered a normal response. Lower than 10% FMD% reﬂects endothelial dysfunction, which means a high likelihood to develop cardiovascular events in the future. Subjects with negative FMD% results (the artery is constricted after stress and not dilated as was expected) have the worst prognosis. 2.4.2. Ankle-brachial index (ABI) An ABI was performed while the patient was supine and measurement of the systolic blood pressure in all four extremities was done. To measure an ankle systolic pressure, a standard adult blood pressure cuff was placed around the ankle just above the malleoli. While using the Doppler ﬂow-meter to monitor the signal from the posterior of the anterior tibial artery, distal to the cuff, the cuff was inﬂated to a pressure approximately 30 mm Hg above the systolic pressure to occlude ﬂow temporarily. As the cuff was slowly deﬂated (2 to 5 mm Hg/s), the pressure at which the Doppler ﬂow signal was ﬁrst heard and recorded was the ankle systolic pressure. An ABI was calculated by dividing the ankle systolic blood pressure by the greater of the two systolic upper extremity systolic blood pressures. An ABI of >1.0 was normal. An ABI of 0.5 to 0.9 was indicative of injury to a single arterial segment. An ABI of b 0.5 was indicative of severe arterial injury or injury to multiple arterial segments. 2.4.3. Statistical analysis Students' T test was used for comparison between patients and controls. We compared age, gender, height, smoking rate, CAD, HTN, DM type II, and vascular characteristics (baseline brachial artery diameter, ﬂow mediated diameter percent change, and ABI). Besides we compared FEV1% and FEV1/FVC of our patients to the published known data in the literature for elderly healthy subjects [12–14] and the 6 minute walk of our patients to the known data in the literature for healthy elderly subjects [15,16]. 3. Results We studied 23 patients with stable COPD and 22 healthy volunteers. As can be seen in Table 1 patients were older (64.4 ± 8.4 years old vs. 44.77 ± 11.7 years old, p b 0.001), and only men served in the
Table 1 Clinical characteristics.
Number Gender [men (%)] Age (years) BMI Height (cm) Smoking CAD HTN DM type II
23 23 (100%) 64.4 ± 8.4 26.3 ± 4.5 170 ± 6 23 (100%) 6 (26%) 15 (65%) 7 (30%)
22 12 (54%) 44.7 ± 11.7 25.2 ± 4.2 172 ± 8 0 (0%) 0 (0%) 0 (0%) 0 (0%)
NS b0.001 b0.001 0.41 NS b0.001 b0.05 b0.05 b0.05
CAD — coronary artery disease. HTN — hypertension. DM type II — Diabetes Mellitus type II.
patients' group while half of the controls were women. There was no difference in BMI (p = 0.41) and height (NS). Only patients were smokers (100%), had coronary artery disease (26%), hypertension (65%) and diabetes mellitus type II (30%); (Table 1). When vascular responsiveness was studied (Table 2), a novel ﬁnding was discovered, that the baseline diameter of the brachial artery was larger in COPD patients compared with controls (0.41 ± 0.06 cm vs. 0.35 ± 0.06 cm, p = 0.003). The absolute change in diameter post hyperemia was signiﬁcantly less in patients (0.004 ± 0.02 cm vs. 0.05 ± 0.02 cm, p b 0.001) and we found that COPD patients responded to the hyperemic trigger by constriction instead of dilatation (FMD% was −0.6 ± 6.3% in patients vs. 15.6 ± 7.6% in controls, p b 0.001) (Table 2). Even though the baseline diameter was larger in patients, there was no difference in ABI both in patients and controls (0.95 ± 0.26 vs. 1.06 ± 0.16, p = 0.07) (Table 2). Lung function tests (Table 3) were compared between the patients and large groups of healthy subjects published in previous papers. The average FEV1% in our patients was 45 ± 14, while in 37 healthy males (aged 66–68 years old) it was 99.99 ± 20.42 (10). The FEV1/FVC in our patients was 0.59 ± 0.10 and in the age-sex matched healthy volunteers it was 0.79 ± 0.07 . In order to study the functional capacity of our patients a 6 minute walk test was done and found that the patients' average distance achieved was 343 ± 87 meters. When this test was compared with 70 healthy Caucasian subjects (33 men) aged 55–75 years old, the average 6 minute walk test was 659 ± 62 meters, and men managed to walk 59 ± 13 meters further than females . It means that our COPD patients managed to walk half the average distance of their age-sex matched controls. 4. Discussion We found that patients with COPD had severe endothelial dysfunction manifested as impairment in the ability to dilate the brachial artery (they responded to the hyperemic trigger by constriction)
Table 2 Vascular characteristics.
Diameter of the brachial Baseline Post hyperemia Delta FMD% ABI
artery (cm) 0.41 ± 0.06 0.41 ± 0.05 0.004 ± 0.02 −0.6 ± 6.3 0.95 ± 0.26
0.35 ± 0.06 0.40 ± 0.06 0.05 ± 0.02 +15.6 ± 7.6 1.06 ± 0.16
0.003 NS b0.001 b0.001 NS (0.07)
FMD% — ﬂow mediated dilatation percent change. ABI — ankle brachial index.
A. Blum et al. / European Journal of Internal Medicine 25 (2014) 370–373
5. Study limitations
Table 3 Lung capacity and general functional capacity. COPD patients
Age matched controls (Refs.  and )
45 ± 14 0.59 ± 0.10
99.99 ± 20.42 0.79 ± 0.07
following hyperemia. We also found that these patients had dilated arteries at baseline, an unknown phenomenon. We also documented impaired functional capacity, manifested as an impaired 6 minute walk compared to age sex matched healthy subjects. Few studies were done that investigated the vascular responsiveness of patients with lung disease. However, among the few studies done, it is quite clear that there is impaired vascular responsiveness among patients with COPD. A clinical trial that compared 44 COPD patients with well controlled disease to 48 healthy controls found that COPD patients had worse mean FMD% that was inversely related with FEV1/ VC ratio, and these effects were veriﬁed after correction for potential confounders in a multiple linear regression model . Another clinical study found that acute exacerbation of COPD was associated with low FMD% that improved to normal FMD% values after recovery from the acute attack . A recent study showed that patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inﬂammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial–coagulative system during acute exacerbations. In 30 COPD subjects interleukin-6 (IL-6) and von-Willebrand study factor (vWF) were elevated during exacerbation and decreased signiﬁcantly at clinical stability (IL-6, p = 0.005; vWF, p b 0.001). Elevation of IL-6 and vWF levels during COPD exacerbations implies a strict association between acute inﬂammation, endothelial activation and clotting initiation . Erectile dysfunction was found to be common in COPD patients, estimated as 57% of the COPD patients compared with only 20% of the aged-matched control group . Erectile dysfunction is known to be one of the earliest signs of endothelial dysfunction, and it represents the chronic vascular inﬂammation affecting patients with COPD, leading eventually to develop atherosclerosis and its complications. The mechanism for this impairment is related with chronic inﬂammation, and indeed it was found that patients with COPD have high levels of markers of inﬂammation, that increase further (altogether with vascular endothelial growth factor [VEGF]) during acute exacerbations . Another possible mechanism could be related with impaired endothelial progenitor cell mobilization and colony forming capacity. Patients with COPD had impaired mobilization of endothelial progenitor stem cells after surgery and they could not produce endothelial progenitor cellscolony forming units as a response to the surgical trigger, unlike patients without COPD who responded intensely to that trigger . Another study found that bone marrow derived progenitors were greatly reduced in patients with severe COPD who also had low body mass index . Another clinical observation was that patients with COPD have more dilated arteries at baseline compared with healthy volunteers. This phenomenon has not been reported before, and one possibility could be related with hydraulic load of the right and left ventricles in patients with COPD. It has been demonstrated before that patients with cor pulmonale had higher vascular load in the right ventricle, and the characteristic impedance was not increased in cor pulmonale patients — a phenomenon that was related to the dilated pulmonary artery . These phenomena could be paralleled to our observations that patients with COPD have dilated vessels (part of the hydraulic overload) with poor vascular dilatation in response to the hyperemic trigger.
The small sample size and the fact that all patients were men and smoking affect the ability to predict clinical implication and validity for other populations; it could be that the differences observed in arterial diameters and response to hyperemia were inﬂuenced by the fact that volunteers were younger and were not smoking but we could not ﬁnd smoking volunteers without pulmonary disease that agreed to participate in the study. 6. In summary We found that patients with COPD have dilated arteries, have impaired ability to respond to high shear stress that triggers nitric oxide dependent ﬂow mediated dilatation, and performed a poor 6 minute walk test. Learning points • COPD is associated with endothelial dysfunction that may explain the high cardiovascular morbidity and mortality among patients with COPD. Conﬂict of Interests There is no conﬂict of interest to any of the authors. References  Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997;349:1498–504.  Ferrer M, Alonso J, Morera J, Marrades RM, Khalaf A, Aquar MC, et al. Chronic obstructive pulmonary disease stage and health-related quality of life. The Quality of Life of Chronic Obstructive Pulmonary Disease Study Group. Ann Intern Med 1997;127:1072–9.  Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: ﬁndings from the Renfrew and Paisley prospective population study. BMJ 1996;313:711–5.  Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inﬂammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–9.  Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inﬂammation: a systemic review and a metaanalysis. Thorax 2004;59:574–80.  Mannino DM. Chronic obstructive pulmonary disease: epidemiology and evaluation. Hosp Physician 2001:22–31.  ATS/ERS recommendations for standardized procedures for the online and ofﬂine measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J Respir Crit Care Med 2005;171:912–30.  Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004;109:III27–32.  Behrendt D, Ganz P. Endothelial function. From vascular biology to clinical applications. Am J Cardiol 2002;90:40L–8L.  Raitakari OT, Celermajer DS. Flow mediated dilatation. Br J Pharmacol 2000;50: 397–404.  Corretti MC, Anderson TJ, Benjamin EJ, Celemajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent ﬂow mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–65.  de Bisschop C, Marty ML, Tessier JF, Barberger-Gateau P, Dartigues JF, Guenard H. Expiratory ﬂow limitation and obstruction in the elderly. Eur Respir J 2005;26: 594–601.  Szanto O, Montnemery P, Elmstahl S. Prevalence of airway obstruction in the elderly: results from a cross-sectional spirometric study of nine age cohorts between the ages of 60 and 93 years. Prim Care Respir J 2010;19:231–6.  Medbo A, Melbye H. Lung function testing in the elderly — can we still use FEV1/FVC b70% as a criterion of COPD? Respir Med 2007;101:1097–105.  Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S. Six minute walk distance in healthy subjects aged 55–75 years. Respir Med 2006;100:658–65.  Trooster T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J 1999;14:270–4.  Ozben B, Eryuksel E, Tanrikulu AM, Papila-Topal N, Celikel T, Basaran Y. Acute exacerbation impairs endothelial function in patients with chronic obstructive pulmonary disease. Arch Turk Soc Cardiol 2010;38:1–7.  Polosa R, Malerba M, Cacciola RR, Morjaria JB, Maugeri C, Prosperini G, et al. Effect of acute exacerbations on circulating endothelial, clotting and ﬁbrinolytic markers in
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