original article Wien Klin Wochenschr (2014) 126:106–112 DOI 10.1007/s00508-013-0478-0
Insulin resistance may contribute to vascular dysfunction in patients with chronic obstructive pulmonary disease Matthias Helmut Urban · Leyla Ay · Georg-Christian Funk · Otto Chris Burghuber · Philipp Eickhoff · Michael Wolzt · Arschang Valipour
Received: 5 March 2013 / Accepted: 19 November 2013 / Published online: 17 December 2013 © Springer-Verlag Wien 2013
Summary Background Patients with chronic obstructive pulmonary disease (COPD) are at an increased cardiovascular risk; however, the underlying mechanisms for this relationship are ill defined. Altered glucose metabolism may increase cardiovascular risk via impaired endothelial function. Methods We conducted a longitudinal pilot study to assess the interrelationship between systemic vascular function, glucose metabolism, and lung function in patients with COPD. Eighteen non-smoking patients with stable moderate-to-severe COPD [67 % male; median (first to third quartiles) Forced Expiratory Volume in 1 second (FEV1) % predicted: 38 % (28–55 %); body mass index: 26 kg/m2 (24–28 kg/m2)] free from cardiovascular risk factors were evaluated. Systemic vascular function was assessed by means of flow-mediated dilation technique of the brachial artery. Laboratory measurements included fasting blood glucose levels, circulating con-
Ass. Prof. A. Valipour, MD, FCCP () · M. H. Urban, MD · Ass. Prof. G.-C. Funk · Prof. O. C. Burghuber Department of Respiratory and Critical Care Medicine, Ludwig Boltzmann Institute for COPD, Otto Wagner Hospital, Sanatoriumstrasse 2, 1140 Vienna, Austria e-mail: [email protected] L. Ay, MD 1st Department of Internal Medicine, Rudolfstiftung, Juchgasse 25, 1030 Vienna, Austria P. Eickhoff, MD St. Anna Childrens Hospital, Kinderspitalgasse 6, 1090 Vienna, Austria Prof. M. Wolzt Department of Clinical Pharmacology, Medical University Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
centrations of insulin, C-reactive protein, and fibrinogen. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined. Measurements were performed at baseline and were repeated after 12 months. Results Flow-mediated dilation significantly decreased from 13.5 % (11–15 %) at baseline to 9.8 % (6–12 %; p = 0.002) at the follow-up visit, whereas both fasting blood glucose concentrations and HOMA-IR increased from 94 mg/dl (86–103 mg/dl) to 102 mg/dl (94–111 mg/dl; p = 0.027) and from 1.2 (0.8–2.1) to 1.7 (1.2–3.0; p = 0.023), respectively. There was a significant relationship between changes in endothelial function and changes in fasting serum glucose (r = − 0.483, p = 0.009), HOMA-IR (r = − 0.441, p = 0.019), and FEV1 (r = 0.336, p = 0.05). Conclusion Altered glucose metabolism may be associated with progression of endothelial dysfunction in patients with COPD. Keywords Cardiovascular diseases · Chronic obstructive pulmonary disease · Insulin resistance · Lung function · Vasodilation
Insulinresistenz bei Patienten mit COPD möglicherweise an vaskulärer Dysfunktion beteiligt Zusammenfassung Grundlagen Patienten mit Chronisch Obstruktiver Lungenerkrankung (COPD) sind einem erhöhten kardiovaskulären Risiko ausgesetzt; die zugrundeliegenden Mechanismen für diesen Zusammenhang sind jedoch nicht gänzlich bekannt. Ein gestörter Glukosemetabolismus könnte via endothelialer Dysfunktion das kardiovaskuläre Risiko erhöhen. Methodik Wir führten eine prospektive Pilotstudie durch, um die Zusammenhänge zwischen systemischer Gefäßfunktion, Glukosemetabolismus, und Lun-
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genfunktion bei Patienten mit COPD zu untersuchen. Achtzehn Patienten mit stabiler moderat-schwerer COPD (Nichtraucher, 67 % Männer; medianer (1. bis 3. Quartile) FEV1 % Soll 38 % (28–55 %); Body mass index 26 kg/m2 (24–28 kg/m2)) ohne relevante kardiovaskuläre Risikofaktoren wurden untersucht. Die systemische Gefäßfunktion wurde anhand der Fluss-mediierten Dilatation der Arteria brachialis determiniert. Die erhobenen Laborparameter umfassten die Bestimmung des Nüchternblutzuckerspiegel, zirkulierende Insulinkonzentrationen, C-reaktives Protein, und Fibrinogen. Der Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index wurde errechnet. Alle Untersuchungen wurden zum Zeitpunkt der Erstuntersuchung durchgeführt und nach 12 Monaten wiederholt. Ergebnisse Die Fluss-mediierte Dilatation der Arteria brachialis nahm von 13,5 % (11–15 %) zum Zeitpunkt der Erstuntersuchung auf 9,8 % (6–12 %) (p = 0,002) nach 12 Monaten ab, der Nüchternblutzuckerspiegel hingegen stieg im gleichen Zeitraum von 94 mg/dl (86–103 mg/ dl) auf 102 mg/dl (94–111 mg/dl) (p = 0,027) und der HOMA-IR Index von 1.2 (0,8–2,1) auf 1,7 (1,2–3,0) (p = 0,023) an. Es zeigt sich ein statistisch signifikanter Zusammenhang zwischen den Veränderungen der endothelialen Dysfunktion und dem Nüchternblutzuckerspiegel (r = − 0,483, p = 0,009), HOMA-IR (r = − 0,441, p = 0,019), und FEV1 (r = 0.336, p = 0.05). Schlussfolgerung Ein veränderter Glukosemetabolismus scheint mit einer Progression der endothelialen Dysfunktion bei Patienten verbunden zu sein. Schlüsselwörter Kardiovaskuläre Erkrankungen · Chronisch Obstruktive Lungenerkrankungen · Insulinresistenz · Lungenfunktion · Vasodilatation
Introduction Chronic obstructive pulmonary disease (COPD) is defined as a chronic inflammatory disease of the lungs; however, it is associated with a variety of cardiovascular co-morbidities [1]. Patients with COPD are at a fourfold increased risk of cardiovascular death within 3 years compared with matched controls [2]. Using data from the NHANES I cohort, Sin et al. [3] similarly demonstrated an increased cardiovascular mortality risk for patients with mild COPD. Importantly, these observations were independent of classic cardiovascular risk factors such as smoking, cholesterol, and/or high blood pressure [4, 5]. The mechanisms for the relationship between COPD and cardiovascular disease remain poorly understood. Recent data suggest early evidence of systemic vascular dysfunction in patients with COPD [5–10]. Endothelial function is a major determinant of systemic vascular function. It can be quantified by means of flow-mediated vasodilation of the brachial artery [11]. We have recently demonstrated evidence of impaired flow-mediated dilation (FMD) in patients with COPD compared with controls in a cross-sectional study [5]. Endothelial dys-
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function was related to airflow obstruction, blood glucose levels, and markers of systemic inflammation in that report. Both systemic inflammation and altered glucose metabolism have the potential to reduce vascular nitric oxide bioavailability and thus systemic vascular dysfunction in COPD [12, 13]. Altered glucose metabolism is frequently preceded by insulin resistance [14], an independent predictor of cardiovascular morbidity and mortality [15]. Previous reports have shown a relationship between insulin resistance and endothelial dysfunction in other chronic inflammatory disease conditions, such as polycystic ovarian syndrome [16] or rheumatoid arthritis [17]. The existence of such an association in patients with COPD remains unknown. Thus, the current study attempts to determine longitudinal relationships between lung function, systemic vascular function, circulating inflammatory markers, and insulin resistance in patients with stable COPD free from traditional cardiovascular risk factors. We hypothesized that a worsening of insulin resistance would be associated with worsening endothelial function in COPD.
Methods The study received approval by the Ethics Committee of the Vienna City Council, and participants gave written informed consent. The reporting of this observational study is in accordance with the “Strengthening the Reporting of Observational Studies in Epidemiology” Statement [18].
Study population The study sample comprised 40 patients with stable moderate-to-severe COPD from our outpatient clinic. Inclusion criteria were age between 40 and 75 years, a smoking history of 20 pack-years or more, evidence of airflow obstruction on spirometry (FEV1/Forced Vital Capacity (FVC) ratio less than 70 %), and a body mass index less than 30 kg/m2. The recruitment of these patients at baseline has been previously described [5]; however, the current analysis is completely novel. Stable COPD was characterized as absence of acute exacerbations within the previous 4 months, defined as any episode with systemic corticosteroid and/or antibiotic use because of disease worsening. Exclusion criteria included a diagnosis of or medication for any conditions potentially affecting measurements of vascular function such as autoimmune diseases, cerebrovascular disease, angina, coronary heart disease, congestive heart failure, anemia (hemoglobin 1.5 mg/dl), diabetes (fasting blood glucose ≥ 7.0 mmol/l or 126 mg/dl) and/or hemoglobin A1c greater than 6.5 %, hypertension, liver disease, lung diseases (other than COPD), lung volume reduction, lung transplantation, malignancy within the past 5 years, isch-
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emic heart disease, obstructive sleep apnea, oral corticosteroid use, peripheral artery occlusive disease, stroke, acute pulmonary embolism or revascularization within 24 months, and rheumatoid diseases. We, furthermore, excluded current smokers at either visit. Abstinence from smoking for at least 3 months was confirmed by measuring exhaled carbon monoxide with a cutoff level less than 10 ppm or by carboxyhemoglobin levels less than 2.0 % [19]. Furthermore, we excluded patients with regular use of oral corticosteroids, cardiovascular medication, and/ or antidiabetic medication.
Measurements All participants underwent physical examination, arterial blood gas analysis, and lung function testing both at baseline and follow-up after 12 months; medical history was also taken at these visits. Fasting blood samples were taken for complete blood count and lipid, blood glucose, insulin, and C-reactive protein level determination. Fasting plasma insulin levels were measured via chemiluminescence assay (Monobind Lake Forest, CA). Based on the quantification of insulin and blood glucose levels, the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated [20]. Spirometry was performed according to international recommendations [21]. Arterial blood gas analyses was performed with the patient breathing room air. Using ultrasonography, both endothelium-dependent FMD and endothelium-independent nitroglycerinemediated dilation of the brachial artery were measured in accordance with published recommendations [11]. Briefly, changes in lumen diameter of the brachial artery following reactive hyperemia after release of suprasystolic compression (flow-mediated) or after a single 0.8-mg dose of sublingual nitroglycerine were quantified as the percentage change during hyperemia compared with baseline arterial diameter. The maximum diameters for both FMD and nitroglycerine-mediated dilation were taken as the average of three consecutive measurements. Individuals were instructed not to eat or drink after 8 p. m. the previous evening, except water or decaffeinated black coffee or tea. Subjects had to refrain from strenuous exercise for at least 12 h before the measurements. Measurements were always performed at the same time of the day and at least 4 h after a light meal. The ultrasound examinations were carried out in a quiet, semi-darkened room, always by the same investigators (Leyla Ay, Philipp Eickhoff ) who were blinded to clinical data.
laboratory markers, and spirometric and cardiovascular parameters. The threshold for statistical significance was defined as two-sided p-value less than 0.05. Biometric analyses were calculated with Statistical Package for the Social Sciences (Version 15.0, IL, USA).
Results Study sample and clinical characteristics Of the 40 patients with COPD, 18 (45 %) were eligible for final analysis. Figure 1 outlines reasons for dropout. Baseline characteristics showed no significant differences between patients included and those not included (data not shown). Clinical characteristics and spirometric and cardiovascular parameters at baseline and follow-up are listed in Table 1. Patients included were predominantly male (67 %), with a median (IQR) age of 67 (65–69.5) years at baseline, and evidence of moderate-to-severe COPD [FEV1 % predicted: 38.5 % (28–54 %)]. All subjects received inhaled long-acting beta agonists, and most (72 %) were receiving inhaled corticosteroids. We observed no statistically significant changes in body mass index, parameters of lung function, arterial blood gas analysis, hemodynamic measurements, or medication between baseline and follow-up.
Patients with stable COPD from a previous cohort n = 40
Loss to follow-up n=7 n = 33 Deceased n=3 n = 30 Exclusion criteria n=6 n = 24 Refused n=6
Data analysis Data are presented as medians and first to third quartiles [interquartile range (IQR)]. Data from baseline and follow-up were compared using the Wilcoxon’s matched pairs test. Kendall’s Tau was calculated to determine relations between changes in FMD, clinical characteristics,
Available for analysis n = 18
Fig. 1 Selection flow chart for patients with stable chronic obstructive pulmonary disease
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Table 1 Clinical characteristics, lung function results, arterial blood gas analysis, and cardiovascular measurements of the study population Baseline
Follow-up
n = 18
n = 18
26.6 (24.2–27.5)
26.1 (23.3–28.4)
p-value
Clinical characteristics Body mass index, kg/m2
0480
Table 2 Hemodynamic parameters in the study population Baseline
Follow-up
n = 18
n = 18
Systolic blood pressure, mmHg
127.5 (120.0–140.0)
125.0 (110.0–131.3)
0.348
Diastolic blood pressure, mmHg
80.0 (73.8–80.0)
80.0 (71.5–90.0)
0.314
Mean blood pressure, mmHg
94.2 (90.8–100.0)
93.3 (87.1–103.3)
0.962
Heart rate, bpm
84.5 (74.8–94.3)
83.5 (75.0–96.3)
0.556
Flow-mediated dilation, %
13.5 (10.5–14.9)
9.8 (6.4–11.8)
0.002
Lung function FVC, % predicted
84.0 (73.3–93.8)
85.5 (72.8–92.0)
0.760
FEV1, % predicted
38.5 (27.8–54.5)
38.5 (29.0–55.3)
0.845
FEV1/FVC ratio
39.5 (31.8–57.0)
47.0 (38.3–60.5)
0.138
Arterial blood gas analysis
p-value
Arterial pO2, mmHg
67.5 (61.8–72.3)
65.0 (62.3–70.8)
0.586
Nitroglycerine-mediated dilation, %
22.1 (19.9–28.0)
19.9 (16.0–25.0)
0.133
Arterial pCO2, mmHg
39.0 (37.8–41.0)
40.5 (37.0–43.3)
0.185
Flow-mediated dilation index
0.55 (0.51–0.65)
0.49 (0.46–0.59)
0.043
Hemodynamic measurements Systolic blood pressure, mmHg
127.5 (120.0– 140.0)
125.0 (110.0– 131.3)
0.348
Baseline brachial artery diameter, mm
3.5 (3.0–4.23)
3.7 (3.2–4.2)
0.236
Diastolic blood pressure, mmHg
80.0 (73.8–80.0)
80.0 (71.5–90.0)
0.314
Baseline blood flow, m/s
0.80 (0.64–0.87)
0.79 (0.70–0.88)
0.977
Mean blood pressure, mmHg
94.2 (90.8–100.0)
93.3 (87.1–103.3)
0.962
Hyperemic blood flow, m/s
1.8 (1.4–1.9)
1.7 (1.4–1.9)
0.972
Nitrogen induced flow, m/s 84.5 (74.8–94.3)
0.82 (0.61–1.0)
0.510
Heart rate, bpm
0.82 (0.62–0.90)
83.5 (75.0–96.3)
0.556
Values are shown as median (first to third quartiles) and compared by Wilcoxon’s matched pairs test FVC Forced Vital Capacity FEV1 Forced Expiratory Volume in 1 second
Brachial artery vasomotor function and laboratory markers (Table 2) Ultrasound measurements were well tolerated; there was no evidence of atherosclerotic plaques in the brachial artery. Baseline brachial artery diameter showed no significant differences between baseline and followup in our sample [3.5 (3.0–4.2) versus 3.7 (3.2–4.2) mm, p = 0.236]. Similarly, there were no significant changes from baseline to follow-up measurements in brachial artery blood flow velocity at rest (baseline flow), following reactive hyperemia, or following nitroglycerine appli-
Values are shown as median (first to third quartiles) and compared by Wilcoxon’s matched pairs test
cation, indicating an equivalent stimulus between the two tests for FMD and nitroglycerine-mediated dilation. Endothelium-dependent FMD expressed as a percentage of change of the baseline diameter, however, was significantly lower at follow-up when compared with baseline measurements [9.8 % FMD (6.4–11.8 %) versus 13.5 % (11–15 %), p = 0.002]. In contrast, there was no significant difference in percentage of endotheliumindependent nitroglycerine-mediated dilation between baseline and follow-up in the study population [22 % (20–28 %) versus 20 % (16–25 %), p = 0.133]. Consequently, there was a significant decrease in the ratio of FMD and nitroglycerine-mediated dilation (FMD index) from 0.55 (0.51–0.65) to 0.49 (0.46–0.59; p = 0.043; Fig. 2).
Fig. 2 a Flow-mediated dilation (FMD) response in patients with stable chronic obstructive pulmonary disease at baseline and follow-up visit. b Flow-mediated dilation (FMD) index in patients with stable chronic obstructive pulmonary disease at baseline and follow-up visit
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Table 3 Laboratory markers of cardiovascular risk in the study population Baseline
Follow-up
n = 18
n = 18
p-value
Table 4 Correlation (Kendall’s tau, τK) between changes in endothelial function (FMD response expressed as percentage change of baseline diameter) and changes in clinical characteristics, spirometry, and cardiovascular and laboratory measurements
Traditional cardiovascular risk factors
Correlation coefficient
p-value
0.014
0.938
FVC, % predicted
− 0.092
0.595
1.00
FEV1, % predicted
0.336
0.053
0.222
FEV1 / FVC ratio, % predicted
0.296
0.088
Arterial pO2, mmHg
0.192
0.271
Arterial pCO2, mmHg
− 0.289
0.101
Total cholesterol, mg/dl
196.0 (183.5– 205.5)
196.0 (185.0–230.0)
0.535
Triglycerides, mg/dl
109.0 (70.0–127.0)
100.0 (60.5–144.0)
0.513
Systemic inflammatory markers Leukocytes, × 103/ml C-reactive protein, mg/l
8.2 (6.8–9.4) 3.0 (1.0–5.3)
7.6 (6.7–9.0) 2.5 (1.0–3.0)
Clinical characteristics Body mass index, kg/m2 Lung function
Arterial blood gas analysis
Markers of glucose metabolism Blood glucose, mg/dl
94.0 (86.0– 102.5)
102.0 (93.5–110.5)
0.027
Insulin, μU/ml
5.3 (3.4–9.5)
6.9 (5.3–10.4)
0.179
Cardiovascular parameters
HOMA-IR
1.2 (0.8–2.1)
1.7 (1.2–3.0)
0.023
Systolic blood pressure, mmHg
− 0.055
0.759
Diastolic blood pressure, mmHg
− 0.295
0.099
Mean blood pressure, mmHg
− 0.192
0.270
Heart rate, bpm
0.296
0.088
Leukocyte count, g/l
− 0.117
0.528
C-reactive protein, mg/l
− 0.070
0.715
Interleukin-6, pg/ml
− 0.21
0.225
Cholesterol, mg/dl
0.303
0.104
Triglycerides, mg/dl
− 0.042
0.822
Glucose, mg/dl
− 0.483
0.009
Insulin, μU/ml
− 0.376
0.035
HOMA-IR
− 0.441
0.019
Values are shown as median (first to third quartiles) and compared by Wilcoxon’s matched pairs test HOMA-IR homeostatic model assessment for insulin resistance
Laboratory markers There was no significant difference in most of the traditional cardiovascular risk factors between the baseline and follow-up visit (Table 3). We observed, however, a significant increase in both fasting serum glucose levels [94 (86–102) to 102 (93–110) mg/dl, p = 0.027) and insulin resistance [HOMA-IR 1.2 (0.8–2.1) to 1.7 (1.2–3.0), p = 0.023] over 12 months.
Relationships between endothelial function, spirometry, and insulin resistance Associations between changes in FMD and clinical characteristics, spirometric and cardiovascular parameters, arterial blood gas analysis, and laboratory markers are presented in Table 4. The deterioration in endothelial function expressed as a change in FMD over 12 months (ΔFMD) showed a statistically significant inverse relationship with changes in fasting blood glucose levels (r = − 0.483, p = 0.009) and HOMA-IR (r = − 0.441, p = 0.019; Fig. 3). Finally, we observed a borderline significant correlation between ΔFMD and changes in FEV1 (r = 0.336, p = 0.053).
Discussion This study has evaluated longitudinal changes in systemic vascular function and glucose metabolism in a small, but otherwise well-characterized, patient group with moderate-to-severe COPD without diabetes or clinically apparent cardiovascular disease. We observed a significant deterioration in endothelium-dependent vascular reactivity and altered glucose metabolism over
Laboratory markers
Correlation was quantified by Kendall’s tau test FMD flow-mediated dilation, HOMA-IR homeostatic model assessment for insulin resistance FVC Forced Vital Capacity FEV1 Forced Expiratory Volume in 1 second
a 12-month period in patients with stable COPD. The observed changes in endothelial function were related to changes in FEV1 and insulin resistance. A variety of pathophysiological mechanisms may contribute to the excess cardiovascular risk in COPD, including sympathetic nervous system hyperactivity, tissue hypoxia, oxidative stress, systemic inflammation, arterial stiffness, and/or endothelial dysfunction [1]. Endothelial dysfunction is considered a precursor of atherosclerotic abnormalities and an independent predictor of cardiovascular events [22–24]. We recently demonstrated impaired FMD in patients with stable COPD compared with smoking and non-smoking controls [5]. The current findings extend these observations by verifying a further decline in endothelium-dependent systemic vascular function in the absence of traditional cardiovascular risk factors in patients with moderate-to-severe COPD. Worsening of endothelial function was associated with a decrease in FEV1 and an increase in insulin resistance in the presence of blood glucose levels within the limits of physiologic concentrations.
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Fig. 3 a Correlation (Kendall’s tau, τK) between changes in flow-mediated dilation (FMD) response and changes in blood glucose concentrations in patients with chronic obstructive pulmonary disease. b Correlation (Kendall’s tau, τK) be-
tween changes in flow-mediated dilation (FMD) response and changes in homeostatic model assessment for insulin resistance (HOMA-IR) in patients with chronic obstructive pulmonary disease
Insulin resistance refers to a decreased ability of insulin to promote glucose uptake in target tissues (i.e., adipose tissue and skeletal muscle) and impaired hepatic glucose delivery, resulting in reactive hyperinsulinemia to maintain physiological blood glucose levels. Insulin resistance may lead to endothelial dysfunction via exaggerated (oxidative stress induced) degradation of endothelial-derived nitric oxide [25], as well as diminished nitric oxide bioavailability following insufficient activation of endothelial nitric oxide synthase [26]. Hyperinsulinemia, furthermore, increases endothelin-1 secretion and activity, which in turn deteriorates vascular function through increased vasoconstrictor tone [27]. Experimental [12] as well as clinical [16] studies confirmed a significant association between endothelial dysfunction and hyperinsulinemia. Endothelial dysfunction, in turn, may worsen insulin resistance by altering transcapillary insulin permeation into peripheral tissues, establishing a vicious circle that results in accelerated atheroslerosis [26, 28]. Thus, the coexistence of systemic vascular dysfunction and insulin resistance may result in a mutual aggravation of pro-atherogenic effects with a consecutive increase of cardiovascular events. Engström et al. [29], using data from a population-based cohort study, observed a significantly increased number of cardiovascular events only in those subjects with impaired lung function who developed insulin resistance during follow-up. The link between insulin resistance and vascular dysfunction in COPD may be further driven by body composition and exercise limitation. Minet et al. [30] recently studied 44 patients with COPD and identified both walking distance and fat-free mass index as independent contributors of post-ischemic reactive hyperemia.
group and the small sample size, which prevented us from conducting multivariate statistical analysis. The latter is the result of a careful selection process, which was intended to investigate the influence of disease-specific mechanisms on systemic vascular function. Thus, the findings in the present study may not be applicable to a clinical COPD sample with frequent cardiovascular comorbidities. The present approach, in turn, can largely rule out the potential impact of traditional cardiovascular risk factors or frequently prescribed medications known to influence systemic vascular function or insulin resistance, such as corticosteroids, statins, and/or beta-blockers.
Potential limitations
Conflict of interest Otto C. Burghuber has been serving on advisory board meetings for Boehringer Ingelheim RCV Austria and Nycomed Austria. He has received honorary and consultancy fees from Boehringer Ingelheim, Glaxo-SmithKline, Nycomed, and Astra Zeneca not exceeding the
We have to acknowledge the hypothesis-generating nature of this study; the results represent associations but allow no inferences about causality. Other limitations include the lack of longitudinal data from a control
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Conclusion In conclusion, the relationship between endothelial dysfunction and insulin resistance in stable COPD emphasizes the complex interaction of risk factors in the development of systemic abnormalities associated with the disease. Activity monitors as well as measures of body composition should be used in future studies to assess the true impact of interventions aimed at modifying insulin resistance and subsequent cardiovascular risk in patients with COPD. Acknowledgments The authors thank the laboratory staff from the Otto Wagner Hospital and the Department of Clinical Pharmacology (Medical University Vienna) for their help in analyzing the blood samples. This research was supported by the Ludwig Boltzmann Institute for COPD, Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna, Austria.
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amount of $ 5,000 per year. Dr. Burghuber further received unrestricted research support grants from Boehringer-Ingelheim and Astra Zeneca over the past years. Arschang Valipour has been serving on advisory board meetings for Boehringer Ingelheim RCV Austria. He has received honorary and consultancy fees from Boehringer Ingelheim and Astra Zeneca not exceeding the amount of $ 5,000 per year. The other authors declare that they have no competing interests. Matthias Urban, Leyla Ay, Georg-Christian Funk, Philipp Eickhoff, and Michael Wolzt have no conflicts of interest to disclose.
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112 Insulin resistance may contribute to vascular dysfunction in patients with chronic obstructive pulmonary disease
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Insulin resistance may contribute to vascular dysfunction in patients with chronic obstructive pulmonary disease Matthias Helmut Urban · Leyla Ay · Georg-Christian Funk · Otto Chris Burghuber · Philipp Eickhoff · Michael Wolzt · Arschang Valipour
Received: 5 March 2013 / Accepted: 19 November 2013 / Published online: 17 December 2013 © Springer-Verlag Wien 2013
Summary Background Patients with chronic obstructive pulmonary disease (COPD) are at an increased cardiovascular risk; however, the underlying mechanisms for this relationship are ill defined. Altered glucose metabolism may increase cardiovascular risk via impaired endothelial function. Methods We conducted a longitudinal pilot study to assess the interrelationship between systemic vascular function, glucose metabolism, and lung function in patients with COPD. Eighteen non-smoking patients with stable moderate-to-severe COPD [67 % male; median (first to third quartiles) Forced Expiratory Volume in 1 second (FEV1) % predicted: 38 % (28–55 %); body mass index: 26 kg/m2 (24–28 kg/m2)] free from cardiovascular risk factors were evaluated. Systemic vascular function was assessed by means of flow-mediated dilation technique of the brachial artery. Laboratory measurements included fasting blood glucose levels, circulating con-
Ass. Prof. A. Valipour, MD, FCCP () · M. H. Urban, MD · Ass. Prof. G.-C. Funk · Prof. O. C. Burghuber Department of Respiratory and Critical Care Medicine, Ludwig Boltzmann Institute for COPD, Otto Wagner Hospital, Sanatoriumstrasse 2, 1140 Vienna, Austria e-mail: [email protected] L. Ay, MD 1st Department of Internal Medicine, Rudolfstiftung, Juchgasse 25, 1030 Vienna, Austria P. Eickhoff, MD St. Anna Childrens Hospital, Kinderspitalgasse 6, 1090 Vienna, Austria Prof. M. Wolzt Department of Clinical Pharmacology, Medical University Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
centrations of insulin, C-reactive protein, and fibrinogen. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined. Measurements were performed at baseline and were repeated after 12 months. Results Flow-mediated dilation significantly decreased from 13.5 % (11–15 %) at baseline to 9.8 % (6–12 %; p = 0.002) at the follow-up visit, whereas both fasting blood glucose concentrations and HOMA-IR increased from 94 mg/dl (86–103 mg/dl) to 102 mg/dl (94–111 mg/dl; p = 0.027) and from 1.2 (0.8–2.1) to 1.7 (1.2–3.0; p = 0.023), respectively. There was a significant relationship between changes in endothelial function and changes in fasting serum glucose (r = − 0.483, p = 0.009), HOMA-IR (r = − 0.441, p = 0.019), and FEV1 (r = 0.336, p = 0.05). Conclusion Altered glucose metabolism may be associated with progression of endothelial dysfunction in patients with COPD. Keywords Cardiovascular diseases · Chronic obstructive pulmonary disease · Insulin resistance · Lung function · Vasodilation
Insulinresistenz bei Patienten mit COPD möglicherweise an vaskulärer Dysfunktion beteiligt Zusammenfassung Grundlagen Patienten mit Chronisch Obstruktiver Lungenerkrankung (COPD) sind einem erhöhten kardiovaskulären Risiko ausgesetzt; die zugrundeliegenden Mechanismen für diesen Zusammenhang sind jedoch nicht gänzlich bekannt. Ein gestörter Glukosemetabolismus könnte via endothelialer Dysfunktion das kardiovaskuläre Risiko erhöhen. Methodik Wir führten eine prospektive Pilotstudie durch, um die Zusammenhänge zwischen systemischer Gefäßfunktion, Glukosemetabolismus, und Lun-
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genfunktion bei Patienten mit COPD zu untersuchen. Achtzehn Patienten mit stabiler moderat-schwerer COPD (Nichtraucher, 67 % Männer; medianer (1. bis 3. Quartile) FEV1 % Soll 38 % (28–55 %); Body mass index 26 kg/m2 (24–28 kg/m2)) ohne relevante kardiovaskuläre Risikofaktoren wurden untersucht. Die systemische Gefäßfunktion wurde anhand der Fluss-mediierten Dilatation der Arteria brachialis determiniert. Die erhobenen Laborparameter umfassten die Bestimmung des Nüchternblutzuckerspiegel, zirkulierende Insulinkonzentrationen, C-reaktives Protein, und Fibrinogen. Der Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index wurde errechnet. Alle Untersuchungen wurden zum Zeitpunkt der Erstuntersuchung durchgeführt und nach 12 Monaten wiederholt. Ergebnisse Die Fluss-mediierte Dilatation der Arteria brachialis nahm von 13,5 % (11–15 %) zum Zeitpunkt der Erstuntersuchung auf 9,8 % (6–12 %) (p = 0,002) nach 12 Monaten ab, der Nüchternblutzuckerspiegel hingegen stieg im gleichen Zeitraum von 94 mg/dl (86–103 mg/ dl) auf 102 mg/dl (94–111 mg/dl) (p = 0,027) und der HOMA-IR Index von 1.2 (0,8–2,1) auf 1,7 (1,2–3,0) (p = 0,023) an. Es zeigt sich ein statistisch signifikanter Zusammenhang zwischen den Veränderungen der endothelialen Dysfunktion und dem Nüchternblutzuckerspiegel (r = − 0,483, p = 0,009), HOMA-IR (r = − 0,441, p = 0,019), und FEV1 (r = 0.336, p = 0.05). Schlussfolgerung Ein veränderter Glukosemetabolismus scheint mit einer Progression der endothelialen Dysfunktion bei Patienten verbunden zu sein. Schlüsselwörter Kardiovaskuläre Erkrankungen · Chronisch Obstruktive Lungenerkrankungen · Insulinresistenz · Lungenfunktion · Vasodilatation
Introduction Chronic obstructive pulmonary disease (COPD) is defined as a chronic inflammatory disease of the lungs; however, it is associated with a variety of cardiovascular co-morbidities [1]. Patients with COPD are at a fourfold increased risk of cardiovascular death within 3 years compared with matched controls [2]. Using data from the NHANES I cohort, Sin et al. [3] similarly demonstrated an increased cardiovascular mortality risk for patients with mild COPD. Importantly, these observations were independent of classic cardiovascular risk factors such as smoking, cholesterol, and/or high blood pressure [4, 5]. The mechanisms for the relationship between COPD and cardiovascular disease remain poorly understood. Recent data suggest early evidence of systemic vascular dysfunction in patients with COPD [5–10]. Endothelial function is a major determinant of systemic vascular function. It can be quantified by means of flow-mediated vasodilation of the brachial artery [11]. We have recently demonstrated evidence of impaired flow-mediated dilation (FMD) in patients with COPD compared with controls in a cross-sectional study [5]. Endothelial dys-
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function was related to airflow obstruction, blood glucose levels, and markers of systemic inflammation in that report. Both systemic inflammation and altered glucose metabolism have the potential to reduce vascular nitric oxide bioavailability and thus systemic vascular dysfunction in COPD [12, 13]. Altered glucose metabolism is frequently preceded by insulin resistance [14], an independent predictor of cardiovascular morbidity and mortality [15]. Previous reports have shown a relationship between insulin resistance and endothelial dysfunction in other chronic inflammatory disease conditions, such as polycystic ovarian syndrome [16] or rheumatoid arthritis [17]. The existence of such an association in patients with COPD remains unknown. Thus, the current study attempts to determine longitudinal relationships between lung function, systemic vascular function, circulating inflammatory markers, and insulin resistance in patients with stable COPD free from traditional cardiovascular risk factors. We hypothesized that a worsening of insulin resistance would be associated with worsening endothelial function in COPD.
Methods The study received approval by the Ethics Committee of the Vienna City Council, and participants gave written informed consent. The reporting of this observational study is in accordance with the “Strengthening the Reporting of Observational Studies in Epidemiology” Statement [18].
Study population The study sample comprised 40 patients with stable moderate-to-severe COPD from our outpatient clinic. Inclusion criteria were age between 40 and 75 years, a smoking history of 20 pack-years or more, evidence of airflow obstruction on spirometry (FEV1/Forced Vital Capacity (FVC) ratio less than 70 %), and a body mass index less than 30 kg/m2. The recruitment of these patients at baseline has been previously described [5]; however, the current analysis is completely novel. Stable COPD was characterized as absence of acute exacerbations within the previous 4 months, defined as any episode with systemic corticosteroid and/or antibiotic use because of disease worsening. Exclusion criteria included a diagnosis of or medication for any conditions potentially affecting measurements of vascular function such as autoimmune diseases, cerebrovascular disease, angina, coronary heart disease, congestive heart failure, anemia (hemoglobin 1.5 mg/dl), diabetes (fasting blood glucose ≥ 7.0 mmol/l or 126 mg/dl) and/or hemoglobin A1c greater than 6.5 %, hypertension, liver disease, lung diseases (other than COPD), lung volume reduction, lung transplantation, malignancy within the past 5 years, isch-
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emic heart disease, obstructive sleep apnea, oral corticosteroid use, peripheral artery occlusive disease, stroke, acute pulmonary embolism or revascularization within 24 months, and rheumatoid diseases. We, furthermore, excluded current smokers at either visit. Abstinence from smoking for at least 3 months was confirmed by measuring exhaled carbon monoxide with a cutoff level less than 10 ppm or by carboxyhemoglobin levels less than 2.0 % [19]. Furthermore, we excluded patients with regular use of oral corticosteroids, cardiovascular medication, and/ or antidiabetic medication.
Measurements All participants underwent physical examination, arterial blood gas analysis, and lung function testing both at baseline and follow-up after 12 months; medical history was also taken at these visits. Fasting blood samples were taken for complete blood count and lipid, blood glucose, insulin, and C-reactive protein level determination. Fasting plasma insulin levels were measured via chemiluminescence assay (Monobind Lake Forest, CA). Based on the quantification of insulin and blood glucose levels, the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated [20]. Spirometry was performed according to international recommendations [21]. Arterial blood gas analyses was performed with the patient breathing room air. Using ultrasonography, both endothelium-dependent FMD and endothelium-independent nitroglycerinemediated dilation of the brachial artery were measured in accordance with published recommendations [11]. Briefly, changes in lumen diameter of the brachial artery following reactive hyperemia after release of suprasystolic compression (flow-mediated) or after a single 0.8-mg dose of sublingual nitroglycerine were quantified as the percentage change during hyperemia compared with baseline arterial diameter. The maximum diameters for both FMD and nitroglycerine-mediated dilation were taken as the average of three consecutive measurements. Individuals were instructed not to eat or drink after 8 p. m. the previous evening, except water or decaffeinated black coffee or tea. Subjects had to refrain from strenuous exercise for at least 12 h before the measurements. Measurements were always performed at the same time of the day and at least 4 h after a light meal. The ultrasound examinations were carried out in a quiet, semi-darkened room, always by the same investigators (Leyla Ay, Philipp Eickhoff ) who were blinded to clinical data.
laboratory markers, and spirometric and cardiovascular parameters. The threshold for statistical significance was defined as two-sided p-value less than 0.05. Biometric analyses were calculated with Statistical Package for the Social Sciences (Version 15.0, IL, USA).
Results Study sample and clinical characteristics Of the 40 patients with COPD, 18 (45 %) were eligible for final analysis. Figure 1 outlines reasons for dropout. Baseline characteristics showed no significant differences between patients included and those not included (data not shown). Clinical characteristics and spirometric and cardiovascular parameters at baseline and follow-up are listed in Table 1. Patients included were predominantly male (67 %), with a median (IQR) age of 67 (65–69.5) years at baseline, and evidence of moderate-to-severe COPD [FEV1 % predicted: 38.5 % (28–54 %)]. All subjects received inhaled long-acting beta agonists, and most (72 %) were receiving inhaled corticosteroids. We observed no statistically significant changes in body mass index, parameters of lung function, arterial blood gas analysis, hemodynamic measurements, or medication between baseline and follow-up.
Patients with stable COPD from a previous cohort n = 40
Loss to follow-up n=7 n = 33 Deceased n=3 n = 30 Exclusion criteria n=6 n = 24 Refused n=6
Data analysis Data are presented as medians and first to third quartiles [interquartile range (IQR)]. Data from baseline and follow-up were compared using the Wilcoxon’s matched pairs test. Kendall’s Tau was calculated to determine relations between changes in FMD, clinical characteristics,
Available for analysis n = 18
Fig. 1 Selection flow chart for patients with stable chronic obstructive pulmonary disease
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Table 1 Clinical characteristics, lung function results, arterial blood gas analysis, and cardiovascular measurements of the study population Baseline
Follow-up
n = 18
n = 18
26.6 (24.2–27.5)
26.1 (23.3–28.4)
p-value
Clinical characteristics Body mass index, kg/m2
0480
Table 2 Hemodynamic parameters in the study population Baseline
Follow-up
n = 18
n = 18
Systolic blood pressure, mmHg
127.5 (120.0–140.0)
125.0 (110.0–131.3)
0.348
Diastolic blood pressure, mmHg
80.0 (73.8–80.0)
80.0 (71.5–90.0)
0.314
Mean blood pressure, mmHg
94.2 (90.8–100.0)
93.3 (87.1–103.3)
0.962
Heart rate, bpm
84.5 (74.8–94.3)
83.5 (75.0–96.3)
0.556
Flow-mediated dilation, %
13.5 (10.5–14.9)
9.8 (6.4–11.8)
0.002
Lung function FVC, % predicted
84.0 (73.3–93.8)
85.5 (72.8–92.0)
0.760
FEV1, % predicted
38.5 (27.8–54.5)
38.5 (29.0–55.3)
0.845
FEV1/FVC ratio
39.5 (31.8–57.0)
47.0 (38.3–60.5)
0.138
Arterial blood gas analysis
p-value
Arterial pO2, mmHg
67.5 (61.8–72.3)
65.0 (62.3–70.8)
0.586
Nitroglycerine-mediated dilation, %
22.1 (19.9–28.0)
19.9 (16.0–25.0)
0.133
Arterial pCO2, mmHg
39.0 (37.8–41.0)
40.5 (37.0–43.3)
0.185
Flow-mediated dilation index
0.55 (0.51–0.65)
0.49 (0.46–0.59)
0.043
Hemodynamic measurements Systolic blood pressure, mmHg
127.5 (120.0– 140.0)
125.0 (110.0– 131.3)
0.348
Baseline brachial artery diameter, mm
3.5 (3.0–4.23)
3.7 (3.2–4.2)
0.236
Diastolic blood pressure, mmHg
80.0 (73.8–80.0)
80.0 (71.5–90.0)
0.314
Baseline blood flow, m/s
0.80 (0.64–0.87)
0.79 (0.70–0.88)
0.977
Mean blood pressure, mmHg
94.2 (90.8–100.0)
93.3 (87.1–103.3)
0.962
Hyperemic blood flow, m/s
1.8 (1.4–1.9)
1.7 (1.4–1.9)
0.972
Nitrogen induced flow, m/s 84.5 (74.8–94.3)
0.82 (0.61–1.0)
0.510
Heart rate, bpm
0.82 (0.62–0.90)
83.5 (75.0–96.3)
0.556
Values are shown as median (first to third quartiles) and compared by Wilcoxon’s matched pairs test FVC Forced Vital Capacity FEV1 Forced Expiratory Volume in 1 second
Brachial artery vasomotor function and laboratory markers (Table 2) Ultrasound measurements were well tolerated; there was no evidence of atherosclerotic plaques in the brachial artery. Baseline brachial artery diameter showed no significant differences between baseline and followup in our sample [3.5 (3.0–4.2) versus 3.7 (3.2–4.2) mm, p = 0.236]. Similarly, there were no significant changes from baseline to follow-up measurements in brachial artery blood flow velocity at rest (baseline flow), following reactive hyperemia, or following nitroglycerine appli-
Values are shown as median (first to third quartiles) and compared by Wilcoxon’s matched pairs test
cation, indicating an equivalent stimulus between the two tests for FMD and nitroglycerine-mediated dilation. Endothelium-dependent FMD expressed as a percentage of change of the baseline diameter, however, was significantly lower at follow-up when compared with baseline measurements [9.8 % FMD (6.4–11.8 %) versus 13.5 % (11–15 %), p = 0.002]. In contrast, there was no significant difference in percentage of endotheliumindependent nitroglycerine-mediated dilation between baseline and follow-up in the study population [22 % (20–28 %) versus 20 % (16–25 %), p = 0.133]. Consequently, there was a significant decrease in the ratio of FMD and nitroglycerine-mediated dilation (FMD index) from 0.55 (0.51–0.65) to 0.49 (0.46–0.59; p = 0.043; Fig. 2).
Fig. 2 a Flow-mediated dilation (FMD) response in patients with stable chronic obstructive pulmonary disease at baseline and follow-up visit. b Flow-mediated dilation (FMD) index in patients with stable chronic obstructive pulmonary disease at baseline and follow-up visit
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Table 3 Laboratory markers of cardiovascular risk in the study population Baseline
Follow-up
n = 18
n = 18
p-value
Table 4 Correlation (Kendall’s tau, τK) between changes in endothelial function (FMD response expressed as percentage change of baseline diameter) and changes in clinical characteristics, spirometry, and cardiovascular and laboratory measurements
Traditional cardiovascular risk factors
Correlation coefficient
p-value
0.014
0.938
FVC, % predicted
− 0.092
0.595
1.00
FEV1, % predicted
0.336
0.053
0.222
FEV1 / FVC ratio, % predicted
0.296
0.088
Arterial pO2, mmHg
0.192
0.271
Arterial pCO2, mmHg
− 0.289
0.101
Total cholesterol, mg/dl
196.0 (183.5– 205.5)
196.0 (185.0–230.0)
0.535
Triglycerides, mg/dl
109.0 (70.0–127.0)
100.0 (60.5–144.0)
0.513
Systemic inflammatory markers Leukocytes, × 103/ml C-reactive protein, mg/l
8.2 (6.8–9.4) 3.0 (1.0–5.3)
7.6 (6.7–9.0) 2.5 (1.0–3.0)
Clinical characteristics Body mass index, kg/m2 Lung function
Arterial blood gas analysis
Markers of glucose metabolism Blood glucose, mg/dl
94.0 (86.0– 102.5)
102.0 (93.5–110.5)
0.027
Insulin, μU/ml
5.3 (3.4–9.5)
6.9 (5.3–10.4)
0.179
Cardiovascular parameters
HOMA-IR
1.2 (0.8–2.1)
1.7 (1.2–3.0)
0.023
Systolic blood pressure, mmHg
− 0.055
0.759
Diastolic blood pressure, mmHg
− 0.295
0.099
Mean blood pressure, mmHg
− 0.192
0.270
Heart rate, bpm
0.296
0.088
Leukocyte count, g/l
− 0.117
0.528
C-reactive protein, mg/l
− 0.070
0.715
Interleukin-6, pg/ml
− 0.21
0.225
Cholesterol, mg/dl
0.303
0.104
Triglycerides, mg/dl
− 0.042
0.822
Glucose, mg/dl
− 0.483
0.009
Insulin, μU/ml
− 0.376
0.035
HOMA-IR
− 0.441
0.019
Values are shown as median (first to third quartiles) and compared by Wilcoxon’s matched pairs test HOMA-IR homeostatic model assessment for insulin resistance
Laboratory markers There was no significant difference in most of the traditional cardiovascular risk factors between the baseline and follow-up visit (Table 3). We observed, however, a significant increase in both fasting serum glucose levels [94 (86–102) to 102 (93–110) mg/dl, p = 0.027) and insulin resistance [HOMA-IR 1.2 (0.8–2.1) to 1.7 (1.2–3.0), p = 0.023] over 12 months.
Relationships between endothelial function, spirometry, and insulin resistance Associations between changes in FMD and clinical characteristics, spirometric and cardiovascular parameters, arterial blood gas analysis, and laboratory markers are presented in Table 4. The deterioration in endothelial function expressed as a change in FMD over 12 months (ΔFMD) showed a statistically significant inverse relationship with changes in fasting blood glucose levels (r = − 0.483, p = 0.009) and HOMA-IR (r = − 0.441, p = 0.019; Fig. 3). Finally, we observed a borderline significant correlation between ΔFMD and changes in FEV1 (r = 0.336, p = 0.053).
Discussion This study has evaluated longitudinal changes in systemic vascular function and glucose metabolism in a small, but otherwise well-characterized, patient group with moderate-to-severe COPD without diabetes or clinically apparent cardiovascular disease. We observed a significant deterioration in endothelium-dependent vascular reactivity and altered glucose metabolism over
Laboratory markers
Correlation was quantified by Kendall’s tau test FMD flow-mediated dilation, HOMA-IR homeostatic model assessment for insulin resistance FVC Forced Vital Capacity FEV1 Forced Expiratory Volume in 1 second
a 12-month period in patients with stable COPD. The observed changes in endothelial function were related to changes in FEV1 and insulin resistance. A variety of pathophysiological mechanisms may contribute to the excess cardiovascular risk in COPD, including sympathetic nervous system hyperactivity, tissue hypoxia, oxidative stress, systemic inflammation, arterial stiffness, and/or endothelial dysfunction [1]. Endothelial dysfunction is considered a precursor of atherosclerotic abnormalities and an independent predictor of cardiovascular events [22–24]. We recently demonstrated impaired FMD in patients with stable COPD compared with smoking and non-smoking controls [5]. The current findings extend these observations by verifying a further decline in endothelium-dependent systemic vascular function in the absence of traditional cardiovascular risk factors in patients with moderate-to-severe COPD. Worsening of endothelial function was associated with a decrease in FEV1 and an increase in insulin resistance in the presence of blood glucose levels within the limits of physiologic concentrations.
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Fig. 3 a Correlation (Kendall’s tau, τK) between changes in flow-mediated dilation (FMD) response and changes in blood glucose concentrations in patients with chronic obstructive pulmonary disease. b Correlation (Kendall’s tau, τK) be-
tween changes in flow-mediated dilation (FMD) response and changes in homeostatic model assessment for insulin resistance (HOMA-IR) in patients with chronic obstructive pulmonary disease
Insulin resistance refers to a decreased ability of insulin to promote glucose uptake in target tissues (i.e., adipose tissue and skeletal muscle) and impaired hepatic glucose delivery, resulting in reactive hyperinsulinemia to maintain physiological blood glucose levels. Insulin resistance may lead to endothelial dysfunction via exaggerated (oxidative stress induced) degradation of endothelial-derived nitric oxide [25], as well as diminished nitric oxide bioavailability following insufficient activation of endothelial nitric oxide synthase [26]. Hyperinsulinemia, furthermore, increases endothelin-1 secretion and activity, which in turn deteriorates vascular function through increased vasoconstrictor tone [27]. Experimental [12] as well as clinical [16] studies confirmed a significant association between endothelial dysfunction and hyperinsulinemia. Endothelial dysfunction, in turn, may worsen insulin resistance by altering transcapillary insulin permeation into peripheral tissues, establishing a vicious circle that results in accelerated atheroslerosis [26, 28]. Thus, the coexistence of systemic vascular dysfunction and insulin resistance may result in a mutual aggravation of pro-atherogenic effects with a consecutive increase of cardiovascular events. Engström et al. [29], using data from a population-based cohort study, observed a significantly increased number of cardiovascular events only in those subjects with impaired lung function who developed insulin resistance during follow-up. The link between insulin resistance and vascular dysfunction in COPD may be further driven by body composition and exercise limitation. Minet et al. [30] recently studied 44 patients with COPD and identified both walking distance and fat-free mass index as independent contributors of post-ischemic reactive hyperemia.
group and the small sample size, which prevented us from conducting multivariate statistical analysis. The latter is the result of a careful selection process, which was intended to investigate the influence of disease-specific mechanisms on systemic vascular function. Thus, the findings in the present study may not be applicable to a clinical COPD sample with frequent cardiovascular comorbidities. The present approach, in turn, can largely rule out the potential impact of traditional cardiovascular risk factors or frequently prescribed medications known to influence systemic vascular function or insulin resistance, such as corticosteroids, statins, and/or beta-blockers.
Potential limitations
Conflict of interest Otto C. Burghuber has been serving on advisory board meetings for Boehringer Ingelheim RCV Austria and Nycomed Austria. He has received honorary and consultancy fees from Boehringer Ingelheim, Glaxo-SmithKline, Nycomed, and Astra Zeneca not exceeding the
We have to acknowledge the hypothesis-generating nature of this study; the results represent associations but allow no inferences about causality. Other limitations include the lack of longitudinal data from a control
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Conclusion In conclusion, the relationship between endothelial dysfunction and insulin resistance in stable COPD emphasizes the complex interaction of risk factors in the development of systemic abnormalities associated with the disease. Activity monitors as well as measures of body composition should be used in future studies to assess the true impact of interventions aimed at modifying insulin resistance and subsequent cardiovascular risk in patients with COPD. Acknowledgments The authors thank the laboratory staff from the Otto Wagner Hospital and the Department of Clinical Pharmacology (Medical University Vienna) for their help in analyzing the blood samples. This research was supported by the Ludwig Boltzmann Institute for COPD, Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna, Austria.
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original article
amount of $ 5,000 per year. Dr. Burghuber further received unrestricted research support grants from Boehringer-Ingelheim and Astra Zeneca over the past years. Arschang Valipour has been serving on advisory board meetings for Boehringer Ingelheim RCV Austria. He has received honorary and consultancy fees from Boehringer Ingelheim and Astra Zeneca not exceeding the amount of $ 5,000 per year. The other authors declare that they have no competing interests. Matthias Urban, Leyla Ay, Georg-Christian Funk, Philipp Eickhoff, and Michael Wolzt have no conflicts of interest to disclose.
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