Michelle John

Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality. pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic–femoral pulse wave velocity. pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=−0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05). In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD. Elastin degradation is a hallmark of emphysema and may have a role in the pathogenesis of atherosclerosis with COPD http://ow.ly/Y9GsC

Cardiovascular and inflammatory effects of simvastatin therapy in patients with COPD: a randomized controlled trial

Background There is excess cardiovascular mortality in patients with chronic obstructive pulmonary disease. Aortic stiffness, an independent predictor of cardiovascular risk, and systemic and airway inflammation are increased in patients with the disease. Statins modulate aortic stiffness and have anti-inflammatory properties. A proof-of-principle, double-blind, randomized trial determined if 6 weeks of simvastatin 20 mg once daily reduced aortic stiffness and systemic and airway inflammation in patients with chronic obstructive pulmonary disease. Methods Stable patients (n=70) were randomized to simvastatin (active) or placebo. Pre-treatment and post-treatment aortic stiffness, blood pressure, spirometry, and circulating and airway inflammatory mediators and lipids were measured. A predefined subgroup analysis was performed where baseline aortic pulse wave velocity (PWV) was >10 m/sec. Results Total cholesterol dropped in the active group. There was no significant change in aortic PWV between the active group and the placebo group (−0.7 m/sec, P=0.24). In those with aortic stiffness >10 m/sec (n=22), aortic PWV improved in the active group compared with the placebo group (−2.8 m/sec, P=0.03). Neither systemic nor airway inflammatory markers changed. Conclusion There was a nonsignificant improvement in aortic PWV in those taking simvastatin 20 mg compared with placebo, but in those with higher baseline aortic stiffness (a higher risk group) a significant and clinically relevant reduction in PWV was shown.

Target renal damage: the microvascular associations of increased aortic stiffness in patients with COPD

BackgroundAlthough renal impairment has been described in COPD, there is opportunity to evaluate further to determine nature and consider optimal management. Increased aortic stiffness, as seen in COPD, leads to reduced buffering of pulsatile flow. We hypothesised that urinary albumin creatinine ratio (UACR) would reflect glomerular damage related to aortic stiffness.MethodsPatients with COPD and controls underwent spirometry, blood pressure, arterial stiffness - aortic pulse wave velocity (PWV) and provided a spot urine sample for UACR, with other renal biomarkers measured.ResultsThe UACR was increased in patients (n = 52): 0.80 mg/mmol compared to controls (n = 34): 0.46 mg/mmol, p < 0.05. Aortic PWV was related to log10 UACR in all subjects (r = 0.426, p < 0.001) and COPD patients alone. Aortic PWV was a significant variable for UACR with oxygen saturations, after accounting for potential confounders. Eight subjects (7 patients) reached a defined clinical microalbuminuria threshold, with aortic PWV greater in these patients compared to those patients without, although albuminuria is a continuum. Proximal tubular damage biomarkers, unlike the glomerular marker, were not different between patients and controls.ConclusionsThere is glomerular damage in patients with COPD evidenced by increased UACR, related to increased aortic stiffness. Besides the macrovascular prognostic implications of increased aortic stiffness, the microvascular state in COPD management should be considered.

Multiple Circulating Cytokines Are Coelevated in Chronic Obstructive Pulmonary Disease.

Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal. To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum. Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1–3). Certain individual circulating cytokines (particularly TNFα and IL-1β) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation. However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease.

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Background Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. Objective To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. Methods 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. Results Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7). Conclusions This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Traditional and emerging indicators of cardiovascular risk in chronic obstructive pulmonary disease

With the increased cardiovascular (CV) morbidity and mortality in subjects with chronic obstructive pulmonary disease (COPD), there is a priority to identify those patients at increased risk of cardiovascular disease. Stable patients with COPD (n = 185) and controls with a smoking history (n = 106) underwent aortic pulse wave velocity (PWV), blood pressure (BP) and skin autofluorescence (AF) at clinical stability. Blood was sent for fasting lipids, soluble receptor for advanced glycation end products (sRAGE) and CV risk prediction scores were calculated. More patients (18%) had a self-reported history of CV disease than controls (8%), p = 0.02, whilst diabetes was similar (14% and 10%), p = 0.44. Mean (SD) skin AF was greater in patients: 3.1 (0.5) AU than controls 2.8 (0.6) AU, p < 0.001. Aortic PWV was greater in patients: 10.2 (2.3) m/s than controls: 9.6 (2.0) m/s, p = 0.02 despite similar BP. The CV risk prediction scores did not differentiate between patients and controls nor were the individual components of the scores different. The sRAGE levels were not statistically different. We present different indicators of CV risk alongside each other in well-defined subjects with and without COPD. Two non-invasive biomarkers associated with future CV burden: skin AF and aortic PWV are both significantly greater in patients with COPD compared to the controls. The traditional CV prediction scores used in the general population were not statistically different. We provide new data to suggest that alternative approaches for optimal CV risk detection should be employed in COPD management.

Role of the Timed Up and Go Test in Patients With Chronic Obstructive Pulmonary Disease.

PURPOSE: The Timed Up and Go (TUG) test is a measure of functional mobility. It is a short test and requires minimal space. We determined the potential role of TUG test as a measure of function in patients with chronic obstructive pulmonary disease (COPD) and compared with controls. Furthermore, we wanted to determine the association and reliability of TUG test time to fall history. METHODS: Patients with COPD (n = 119) and controls with a smoking history (n = 58) were recruited. The TUG test, 6-minute walk distance and subsequent BODE score, spirometry, and history of falls were assessed. The TUG test was measured across observers and on separate days within the same individual. RESULTS: The TUG test time was greater in patients, 11.9 ± 3.7 seconds, than controls, 9.5 ± 1.8 seconds (P < .001). The TUG test was inversely related to 6-minute walk distance in patients (r =−0.74) and controls (r =−0.71); P < .001. In patients, TUG test was related to BODE score (r = 0.53; P < .001) but not spirometry measurements. A receiver operator curve analysis of 0.77 in patients indicated reasonable ability for TUG test to indicate those who had fallen in the past year. A TUG of ≥12 seconds had 74% sensitivity and specificity for a history of a fall in the past year. Inter- and intraobserver values indicated minimal differences between measurements. CONCLUSION: These results support a potential role for the TUG test to be incorporated into community COPD assessment to stratify patients functionally, particularly where time and space are limited. Future studies are required to assess impact of interventions on TUG test and determine the predictive ability to identify future falls.

S27 The effects of statin therapy on inflammatory markers in patients with copd: a double blind randomised controlled trial

Background Systemic and airway inflammation are recognised in COPDand reducing inflammation has been postulated to alter disease course1. Statins have pleiotropic effects including anti-inflammatory properties2. A study in asthma showed that statins reduced sputum macrophage levels3. We hypothesised that statins would reduce systemic (hs-CRP) and airway (exhaled nitric oxide: FeNO, sputum neutrophils and macrophages) inflammation in patients with COPD. Methods Clinically stable patients with confirmed COPD were recruited and randomised to either simvastatin 20mg od (active) or placebo for 6 weeks in a double blinded parallel group randomised controlled trial. Circulating hs-CRP and fasting lipids were measured in all subjects’ pre- and post- treatment. 5-flow FeNO and induced sputum were performed in consenting patients where possible pre- and post-treatment. Primary analysis compared the six week change in each inflammatory marker between active and placebo groups. Results Patients were matched for age, sex, smoking and lung function; active: n = 33, placebo: n = 37. Compliance was good and the active group achieved total cholesterol reduction: between arms mean (95% CI): -1.1 (-1.3, -0.8)mmol/L, p < 0.001. Baseline median (IQR) hs-CRP was 3.09 (1.3–7.4)mg/l but there was no significant change after treatment between active and placebo: between arms mean (95% CI) 0.5(-3.2, 4.1)mg/l. Baseline sputum samples were obtained in n = 27 and 22/27 had neutrophilic sputum. Paired samples were obtained in 20 patients: active n = 8 and placebo n = 12 with no significant difference in change between treatment arms for sputum neutrophils or macrophages. FeNO was measured in 36 patients: active n = 17, placebo n = 19 with no significant difference in change between arms. Conclusions In this pilot RCT, despite significant lipid lowering, there was no demonstrable systemic or airway anti-inflammatory effect over 6 weeks with simvastatin 20mg od in patients with COPD. Baseline results showed a majority had neutrophilic sputum however only a small proportion had airway inflammation evaluation. Trial reference: NCT01151306 Supported by NIHR RfPB grant References Sin, DD, et al. AJRCCM 2004;170:760–765 Walsh, G. M Expert Review of Respiratory Medicine 2008;2(3):329–335 Hothersall, EJ, et al., Thorax 2008;63(12):1070–5

P128 Cardiovascular Effects of Statin Therapy on Arterial Stiffness in Patients with COPD: A Double Blind Randomised Controlled Trial

Background As cardiovascular disease is a comorbidity and major cause of death in patients with COPD, primary preventative strategies are required. Arterial stiffness, as measured by aortic pulse wave velocity (PWV) is increased in patients with COPD1, and is an independent predictor of cardiovascular risk2, which is modifiable over the short term. We hypothesised that aortic PWV, would be reduced by six weeks treatment of simvastatin 20mg once daily compared to placebo in selected patients with COPD without concurrent heart disease, diabetes or hypercholesterolemia. Methods Clinically stable patients with confirmed COPD were recruited and randomised to either simvastatin 20mg od (active) or placebo in double blinded fashion. Aortic PWV, blood pressure, spirometry, six minute walking distance, and lipids were measured pre- and post- 6 weeks treatment. Primary analysis compared PWV between groups. A predefined subgroup analysis compared those with a baseline PWV≥10m/s. Results The patients were well matched for age, sex, smoking and lung function; active, n = 33 and placebo, n = 37. The recruitment target was met. Compliance was high with the active group achieving significantly lower total cholesterol - between arms mean (95% CI): -1.1 (-1.3, -0.8)mmol/L, p < 0.001. There was no significant change in aortic PWV after treatment in the active compared to placebo group: -0.7 (-1.8, 0.5)m/s, p = 0.24, In the subgroup with aortic PWV≥10m/s, n = 22, aortic PWV improved in the active arm compared to placebo: -2.8 (-5.2, -0.3)m/s, p = 0.03. This latter difference remained statistically significant after adjusting for age and sex. Blood pressure, lung function and six minute walking distance did not change. Conclusions In this pilot study, despite a significant reduction in total cholesterol there was no improvement in aortic PWV in patients with COPD taking simvastatin 20mg compared to placebo over 6 weeks. The positive findings in the subgroup with a higher baseline aortic PWV warrants further studies in high risk patients to confirm the impact of statin use on the cardiovascular outcome of COPD. Trial reference: NCT01151306 Supported by NIHR RfPB grant References Sabit, R., et al., Am J Respir Crit Care Med, 200;175:1259–65 Laurent, S., et al., Eur Heart J, 2006; 27:2588–605

P40 Increased advanced glycation end products in patients with chronic obstructive pulmonary disease (COPD)

Introduction Advanced glycation endproducts (AGE) are markers of glycaemic and oxidative stress, pro-inflammatory and alter structure through collagen cross-linking, formed through the Maillard reaction. There has been recent interest in AGE and its receptor: RAGE in airways1 and circulating2 in subjects with COPD as well as in a GWAS of lung function.3 Skin autofluoresence permits non-invasive measurement of skin AGE, validated against biopsies. Skin levels reflect accumulation, unlike circulating levels which are more variable. We hypothesised that skin AGE was increased in subjects with COPD and related to lung function. Methods Subjects >40 years, with and without COPD, all with >10 smoking pack years, were recruited. All subjects were assessed at clinical stability. Control never smokers were also recruited. Detailed history, post-bronchodilator spirometry and skin AGE were determined. Circulating AGE and soluble RAGE were measured by ELISA. Results There were 49 COPD subjects; 18 current/ex-smokers without COPD; 16 never smokers, Abstract P40 table 1. The mean skin AGE was greatest in subjects with COPD compared to both control groups, p<0.05, ANOVA, Abstract P40 table 1. There was an indirect relationship between FEV1 % predicted and skin AGE, r=−0.46, p<0.01. A stepwise multiple regression was performed, with skin AGE as the dependent, and FEV1 % predicted, smoking pack years, age, BMI and gender entered into the model. FEV1 % predicted and smoking pack years were independent variables, p<0.01. There was no significant difference in serum AGE between groups. Mean soluble RAGE was lowest in the COPD subjects and significantly lower than control never smokers, p<0.05, ANOVA, Abstract P40 table 1.Abstract P40 Table 1 Mean (SD) Control never smoker (n=16) Control current/ex smoker (n=18) COPD (n=49) Age (years) 56 (7) 55 (10) 67 (10)* † Men, n (%) 8 (50%) 5 (28%) 28 (57%) BMI (kg/m2) 24.5 (3.4) 27.0 (4.6) 27.9 (5.5) Smoking pack years 0 27 (18) 52 (30)* † Oxygen saturations (%) 97 (1) 96 (1) 95 (2) FEV1 (L) 3.11 (0.75) 2.64 (0.70) 1.52 (0.60)* † FEV1 % predicted 103 (14) 99 (15) 58 (15)* † Skin AGE (AU) 2.2 (0.4) 2.5 (0.6) 2.9 (0.5)* † Serum AGE‡ (pg/ml) 3863.7 (2.3) 2691.5 (1.8) 3388.4 (1.9) Serum soluble RAGE‡ (pg/ml) 81.3 (1.9) 41.4 (2.2) 33.8 (3.3)** p<0.05 compared to control never smoker.† p<0.05 compared to control smoker.‡ =arithmetic mean (SD). Conclusions People with COPD have increased skin AGE compared to subjects with a smoking history and control never smokers. Subjects with COPD also have decreased serum soluble RAGE levels compared to never smokers. The FEV1 % was an independent variable of skin AGE. Further research should explore the potential role of AGE in the co-morbidities of COPD.