| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:1514.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Department of Medicine, Pulmonary Division (D.D.S., S.F.P.M.), University of Alberta, Edmonton, Alberta, Canada, and The Institute of Health Economics (D.D.S.), Edmonton, Alberta, Canada.
Correspondence and reprint requests to Dr Don D. Sin, 2E4.29 Walter C. Mackenzie Centre, University of Alberta, Edmonton, AB, Canada T6G 2B7. E-mail don.sin{at}ualberta.ca
| Abstract |
|---|
|
|
|---|
Methods and Results We analyzed data from participants,
50 years of age, of the Third National Health and Nutrition Examination Survey (n=6629) to determine whether C-reactive protein (CRP) and other systemic inflammatory markers are present in participants with chronic airflow obstruction and are associated with cardiac injury. Participants with severe airflow obstruction had circulating leukocyte, platelet, and fibrinogen levels that were 460/µL (95% confidence interval [CI], 30 to 890/µL), 39 510/µL (95% CI, 21 730 to 57 290/µL), and 41.63 mg/dL (95% CI, 19.87 to 63.39 mg/dL) higher, respectively, than in those without airflow obstruction. They were also 2.18 times (95% CI, 1.46 to 3.27) more likely to have an elevated circulating CRP level. Moderate airflow obstruction was associated with smaller but still significant increases in these levels. Moderate and severe airflow obstruction was associated with increased occurrence of ischemic changes on electrocardiograms of participants. In the presence of both highly elevated CRP and moderate or severe airflow obstruction, the Cardiac Infarction Injury Score was 2.68 and 5.88 U higher, respectively, than in those without airflow obstruction and with low CRP, which suggests an additive effect of CRP and COPD on the risk of cardiac injury.
Conclusion Low-grade systemic inflammation was present in participants with moderate to severe airflow obstruction and was associated with increased risk of cardiac injury. This may in part explain the high rates of cardiovascular complications in COPD.
Key Words: chronic obstructive pulmonary disease inflammation, systemic C-reactive protein epidemiology
| Introduction |
|---|
|
|
|---|
Although the pathogenesis of atherothrombosis is complex and multifactorial, persistent low-grade systemic inflammation is believed to be one of the centerpieces in effecting clot formation.6 Compelling epidemiological data link systemic inflammation to atherosclerosis, ischemic heart disease, strokes, and coronary deaths.7,8 These observations have been strongly supported by biomedical experiments that show the direct effects of certain inflammatory markers, such as C-reactive protein (CRP), on the pathogenesis of plaque formation.9,10
We used population-based data from the Third National Health and Nutrition Examination Survey (NHANES III) to determine (1) whether COPD is associated with increased circulating levels of CRP and other inflammatory markers; (2) whether the intensity of the systemic inflammation is associated with the severity of airflow obstruction; and (3) whether systemic inflammation and COPD are associated with cardiac injury.
| Methods |
|---|
|
|
|---|
50 years of age who performed spirometry that met acceptability and reliability criteria of the American Thoracic Society (n=6629).12 We chose this age cutoff in order to improve the diagnostic accuracy of using airflow obstruction as a marker of COPD.13
Spirometry and Electrocardiography
Spirometry was performed with equipment that met the American Thoracic Society performance criteria.12 To adjust for height, age, sex, and race, we used published prediction equations for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).14 We used a FEV1FVC ratio of <0.70 to define airflow obstruction.13 Mild, moderate, and severe airflow obstruction were defined as FEV1 of >80% of predicted (equivalent to Stage 1 of the National Heart, Lung, and Blood Institute/World Health Organization Global initiative for chronic Obstructive Lung Disease [GOLD] classification),13 50% to 80% of predicted (Stage 2a),13 and <50% of predicted (Stages 2b and 3),13 respectively.
The NHANES cohort received a resting 12-lead ECG with a Marquette MAC 12 U.15 An ECG coding scheme was then applied to the data to calculate a Cardiac Infarction Injury Score (CIIS) for each participant.16 We used these scores to estimate the participants risk of underlying ischemic heart disease. A CIIS of
15.0 denoted "possible or probable infarction."17 NOVACODE ECG classification procedures were used to estimate left ventricular mass index of study participants.17 Left ventricular mass indexes of >150 g/m2 for men and >120 g/m2 for women were used as cutoff points to define left ventricular hypertrophy.15
Laboratory Measurements
The CRP level was measured by using latex-enhanced nephelometry.18 Because most participants had CRP values below the lowest detectable level (0.22 mg/dL), for analytic purposes, CRP was treated as a categorical rather than a continuous variable. CRP levels
0.22 mg/dL were considered "elevated," whereas levels >1.00 mg/dL were categorized as "highly elevated."19 We determined serum fibrinogen; leukocyte and platelet counts; and levels of total serum cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride, and apolipoproteins AI and B.18
Covariates
We classified age (in years) into 4 strata: 50 to 59, 60 to 69, 70 to 79, and
80. Race was divided into 3 categories: white, black, and other. Smoking status was divided into 3 strata: current, former, and never smokers. For current and former smokers, we estimated total cigarette consumption by using pack-year equivalents. We divided body mass index (BMI; in kg/m2) into quartiles:
23.7, 23.8 to 26.6, 26.7 to 30.1, and
30.2. Presence of comorbidities was determined by participants responses to the question: "Has the doctor ever told you had diabetes (congestive heart failure, chronic bronchitis, etc)?" Participants were deemed to have rheumatoid arthritis or a related inflammatory disorder if they had a significantly elevated titer of rheumatoid factor (
1:40) on a serum dilution latex fixation test.20
Statistical Analyses
The baseline characteristics of the study participants with mild, moderate, or severe airflow obstruction were compared with controls (ie, those without any airflow obstruction) with a
2 test for binary variables and a t test for continuous variables. To assess whether there was a gradient in various baseline demographic and clinical factors across the lung function categories, we used a Mantel-Haenszel test for trend.21 For Tables 2 and 5, we performed a weighted multiple linear regression analysis, with one degree of freedom, as a test for trend.22 In Table 3, we used multiple linear regression techniques to estimate the independent impact of airflow obstruction on circulating levels of leukocytes, platelets, and fibrinogen.21 We used a multiple logistic modeling technique to determine whether airflow obstruction was associated with elevations in CRP levels (Table 4). 21 In all these models, we forced in age, sex, BMI, smoking status (including pack-years), race, and various comorbidities as covariates to adjust for their potential effects on lung function and/or systematic inflammation. All tests were 2-tailed in nature. SAS version 8.1 (Cary, NC) and SUDAAN Release 8.0 (Research Triangle Institute, Research Triangle Park, NC) were used to incorporate population weights for NHANES III. Continuous variables are shown as mean±SEM, unless otherwise indicated.
|
|
|
|
| Results |
|---|
|
|
|---|
|
The circulating levels of leukocytes, platelets, fibrinogen, and CRP were higher in participants with than in those without airflow obstruction. The highest levels for all of these inflammatory markers were observed in the group with severe airflow obstruction (Table 2). Adjustments for confounders made little difference to the overall results (Tables 3 and 4). We observed that participants with severe airflow obstruction had leukocyte, platelet, and fibrinogen levels that were on average 460/µL, 39 510/µL, and 41.63 mg/dL higher, respectively, than those of the controls. In an analysis that excluded those on oral corticosteroids, we found that leukocyte, platelet, and fibrinogen levels were on average 400/µL, 37 590/µL, and 40.39 mg/dL higher, respectively, than those of the controls. The increases in leukocyte count among those with severe airflow obstruction were driven largely by the neutrophilic subpopulation of cells (Table 2). Participants with severe airflow obstruction were also 2.18 and 2.74 times more likely to have elevated and highly elevated circulating CRP levels than the controls (Table 4). Participants with moderate airflow obstruction had smaller increases in circulating leukocyte, fibrinogen, and CRP levels. Mild airflow obstruction was not associated with elevations in any of these measurements.
Lipid profiles among the 4 groups are shown in Table 2. There were no significant differences in the LDL, apolipoprotein B, or HDL concentrations among the groups. Participants with severe airflow obstruction had slightly lower serum concentrations of triglycerides and a slightly raised apolipoprotein AI levels.
There were important differences in ECG findings among the 4 lung function groups (Table 5). Compared with the control group, mild, moderate, and severe airflow obstruction were associated with an increase in CIIS of 0.38±0.48 (P=0.437), 2.38±0.53 (P=0.001), and 3.62±0.76 (P=0.001) U, respectively. Compared with controls, those with severe airflow obstruction were 2.1 times more likely to have ECG evidence of probable or possible (prior) myocardial infarction (adjusted odds ratio [OR] 2.12; 95% CI, 1.37 to 3.29). This risk was also elevated among those with moderate airflow obstruction (adjusted OR, 1.38; 95% CI, 1.04 to 1.82) but not in those with mild airflow obstruction (adjusted OR, 1.28; 95% CI, 0.95 to 1.72).
Because CIIS may be confounded by a variety of factors, including presence of pulmonary hypertension and digitalis use, we performed a series of subgroup analyses that excluded participants with these characteristics. First, we excluded participants with ECG evidence of right ventricular hypertrophy (defined as R amplitude greater than S amplitude in V1 or V2) or right-axis deviation (defined as QRS or P axis of >90°). In this subgroup analysis, we found that compared with controls, mild, moderate, and severe airflow obstruction were associated with an increase in CIIS of 0.81±0.59 (P=0.174), 2.51±0.61 (P=0.001), and 3.55±1.05 (P=0.001) U, respectively. In an analysis that excluded participants with a history of current cardiac glycoside use, mild, moderate, and severe airflow obstruction were associated with an increase in CIIS of 0.38±0.48 (P=0.437), 2.38±0.53 (P=0.001), and 3.62±0.76 (P=0.001) U, respectively.
There was a significant correlation between CRP and CIIS. Individuals with highly elevated CRP levels had CIIS values that were 1.25±0.56 (P=0.029) U higher than those with low CRP levels. We observed an additive effect of airflow obstruction and CRP on CIIS. Individuals with severe airflow obstruction and highly elevated CRP levels had CIIS that were, on average, 5.88±1.61 U higher than those of participants with no airflow obstruction and with low CRP levels (Figure, A). A similar interaction was observed for moderate airflow obstruction and highly elevated CRP (increase of 2.68±8.59 U; Figure, B).
|
| Discussion |
|---|
|
|
|---|
Second, although prior studies have shown systemic inflammation in severe COPD,2326 none of these studies have established a link between systemic inflammation in COPD and cardiac injury. Our findings indicate that airflow obstruction is an important risk factor for cardiac injury. In the presence of elevated CRP, the risk increases almost 2-fold, which suggests an important interplay of systemic inflammation with airflow obstruction in the development of ischemic heart disease (see Figure, A and B).
Our observations are similar to those of Cirillo et al,27 who showed an inverse association between FEV1 and serum CRP. Unlike our study, however, they included all adult NHANES participants (increasing the risk of confounding by age). They also did not use a prediction equation for FEV1 to adjust for differences in age, sex, height, and race of study participants, which could have led to residual confounding by these variables.17 More importantly, the study by Cirillo et al27 did not evaluate the role of airflow obstruction (or its severity) on systemic inflammation. We have extended the findings of Cirillo et al27 and have shown that moderate to severe (but not mild) COPD is strongly associated with systemic low-grade inflammation and ECG evidence of ischemic heart disease.
We have concentrated on CRP in the present study because it has been shown to upregulate the production of proinflammatory cytokines and tissue factors by monocytes, increase the uptake of LDL by macrophages, and directly induce expression of adhesion molecules by human endothelial cells.28 Additionally, CRP may deposit directly into the arterial wall during atherogenesis, interacting with other inflammatory mediators to create foam cells, which serve as building blocks of atherosclerotic plaques.10 Serum fibrinogen may promote atherosclerosis by increasing blood viscosity and acting as a cofactor for platelet aggregation.29 Leucocytosis and thrombocytosisalso promote plaque formation but likely through different pathways.29 Because neutrophilic inflammation may destabilize atherosclerotic plaques, leading to their rupture, our finding of increased circulating neutrophils among participants with severe airflow obstruction also may be relevant.30
Several limitations of this study should be emphasized. First, we do not know whether the reduction of proinflammatory markers would improve prognosis in COPD. Future studies are needed to determine if certain therapies that reduce the burden of systemic inflammation can lead to improved cardiovascular outcomes in COPD. Second, there may be alternate mechanistic pathways that may be responsible for cardiovascular complications in COPD. Among our study cohort, severe airflow obstruction was associated with elevated resting systolic blood pressure. Although the differences in blood pressure were slight and not associated with increased left ventricular mass, the possibility exists that the blood pressure increases represent excess sympathetic nervous activity in severe COPD.31 Future work is needed to determine what role (if any) the autonomic nervous system plays in the pathogenesis of adverse cardiovascular events in COPD. Third, medication effects on circulating CRP and other inflammatory markers should also be considered. Systemic corticosteroids, for instance, may decrease CRP levels32 while slightly increasing circulating levels of leukocytes and platelets.33 Exclusion of individuals who were taking oral corticosteroids made no difference to the overall findings, which suggests that this medication was not an important confounder in the analysis.
Over the next 20 years, nations across the world will experience a dramatic rise in COPD-related morbidity and mortality.13 Data from the present study confer a plausible mechanism to explain the strong relationship between COPD and cardiovascular diseases. More importantly, they extend the current concept of COPD as a systemic inflammatory disorder (and not just an inflammatory disorder of the pulmonary system) and provide potential new therapeutic targets to reduce cardiovascular complication rates in COPD.
| Acknowledgments |
|---|
Received November 21, 2002; accepted December 5, 2002.
| References |
|---|
|
|
|---|
2. Bang KM, Gergen PJ, Kramer R, et al. The effect of pulmonary impairment on all-cause mortality in a national cohort. Chest. 1993; 103: 536540.
3. Hole DJ, Watt GC, Davey-Smith G, et al. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ. 1996; 313: 711715.
4. Friedman GD, Klatsky AL, Siegelaub AB. Lung function and risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1976; 294: 10711075.[Abstract]
5. Engstrom G, Lind P, Hedblad B, et al. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation. 2002; 106: 25552560.
6. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115126.
7. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000; 321: 199204.
8. Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med. 1999; 130: 933937.
9. Lagrand WK, Visser CA, Hermens WT. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999; 100: 96102.
10. Zwaka TP, Hombach V, Torzewski J. C-reactive proteinmediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103: 11941197.
11. National Center for Health Statistics. Plan and Operation of the Third National Health And Nutrition Examination Survey, 198894. Hyattsville, Md: US Dept of Health and Human Services; 1994. Publication No. (PHS)941308.
12. American Thoracic Society. Standardization of spirometry: 1987 update. Am Rev Respir Dis. 1987; 136: 12851298.[Medline] [Order article via Infotrieve]
13. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001; 163: 12561276.
14. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999; 159: 179187.
15. US Department of Health and Human Services (DHHS), National Center for Health Statistics. Third National Health and Nutrition Examination Survey, 19881994: NHANES III Second Laboratory Data File [CD-ROM, Series 11, No. 2A]. Hyattsville, Md: Centers for Disease Control and Prevention; 1998.
16. Rautaharju PM, Warren JW, Jain U, et al. Cardiac infarction injury score: an electrocardiographic coding scheme for ischemic heart disease. Circulation. 1981; 64: 249256.
17. Rautaharju PM, MacInnis PJ, Warren JW, et al. Methodology of ECG interpretation in the Dalhousie program: NOVACODE ECG classification procedures for clinical trials and population health surveys. Methods Inf Med. 1990; 29: 362374.[Medline] [Order article via Infotrieve]
18. Gunter EW, Lewis BG, Koncikowski. Laboratory Procedures Used for the Third National Health and Nutrition Examination Survey (NHANES III), 198894. Hyattsville, Md: National Center for Health Statistics; 1996.
19. Visser M, Bouter LM, McQuillan GM, et al. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999; 282: 21312135.
20. Wener MH, Mannik M. Rheumatoid factors. In: Rose NR, Conway de Macario E, Fahey JL, et al, eds. Manual of Clinical Laboratory Immunology. 5th ed. Washington, DC: American Society for Microbiology; 1997.
21. Schlesselman S. Case-Control Studies. New York, NY: Oxford; 1982: 203206.
22. Leuraud K, Benichou J. A comparison of several methods to test for the existence of a monotonic dose-response relationship in clinical and epidemiological studies. Stat Med. 2001; 20: 33353351.[CrossRef][Medline] [Order article via Infotrieve]
23. Schols AM, Creutzberg EC, Buurman WA, et al. Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999; 160: 12201226.
24. Takabatake N, Nakamura H, Abe S, et al. The relationship between chronic hypoxemia and activation of the tumor necrosis factoralpha system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000; 161: 11791184.
25. Eid AA, Ionescu AA, Nixon LS, et al. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001; 164: 14141418.
26. Schols AM, Buurman WA, Staal van den Brekel AJ, et al. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax. 1996; 51: 819824.
27. Cirillo DJ, Agrawal Y, Cassano PA. Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2002; 155: 842848.
28. Pasceri V, Willerson JT, Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 21652168.
29. Danesh J, Collins R, Appleby P, et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998; 279: 14771482.
30. Buffon A, Biasucci LM, Liuzzo G, et al. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002; 347: 512.
31. Heindl S, Lehnert M, Criee C, et al. Marked sympathetic activation in patients with chronic respiratory failure. Am J Respir Crit Care Med. 2001; 164: 597601.
32. Volk T, Schmutzler M, Engelhardt L, et al. Influence of aminosteroid and glucocorticoid treatment on inflammation and immune function during cardiopulmonary bypass. Crit Care Med. 2001; 29: 21372142.[CrossRef][Medline] [Order article via Infotrieve]
33. Laakko T, Fraker P. Rapid changes in the lymphopoietic and granulopoietic compartments of the marrow caused by stress levels of corticosterone. Immunology. 2002; 105: 111119.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
![]() |
W. T. McNicholas Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea: Overlaps in Pathophysiology, Systemic Inflammation, and Cardiovascular Disease Am. J. Respir. Crit. Care Med., October 15, 2009; 180(8): 692 - 700. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. D. Maclay, D. A. McAllister, N. L. Mills, F. P. Paterson, C. A. Ludlam, E. M. Drost, D. E. Newby, and W. MacNee Vascular Dysfunction in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., September 15, 2009; 180(6): 513 - 520. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. R. B. M. van Gestel, M. Chonchol, S. E. Hoeks, G. M. J. M. Welten, H. Stam, F. W. Mertens, R. T. van Domburg, and D. Poldermans Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients Nephrol. Dial. Transplant., September 1, 2009; 24(9): 2763 - 2767. [Abstract] [Full Text] [PDF] |
||||
![]() |
P-O. Bridevaux, M. W. Gerbase, C. Schindler, D. Felber Dietrich, I. Curjuric, J. Dratva, U. Ackermann-Liebrich, N. M. Probst-Hensch, J-M. Gaspoz, and T. Rochat Sex-specific effect of body weight gain on systemic inflammation in subjects with COPD: results from the SAPALDIA cohort study 2 Eur. Respir. J., August 1, 2009; 34(2): 332 - 339. [Abstract] [Full Text] [PDF] |
||||
![]() |
R P Young, R Hopkins, and T E Eaton Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence Postgrad. Med. J., August 1, 2009; 85(1006): 414 - 421. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. A. Ngan, S. V. Vickerman, D. J. Granville, S. F. P. Man, and D. D. Sin The possible role of granzyme B in the pathogenesis of chronic obstructive pulmonary disease Therapeutic Advances in Respiratory Disease, June 1, 2009; 3(3): 113 - 129. [Abstract] [PDF] |
||||
![]() |
D-W. Perng, C-W. Tao, K-C. Su, C-C. Tsai, L-Y. Liu, and Y-C. Lee Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD Eur. Respir. J., April 1, 2009; 33(4): 778 - 784. [Abstract] [Full Text] [PDF] |
||||
![]() |
S.F. P. Man, Xuekui Zhang, R. Vessey, T. Walker, K. Lee, D. Park, and D. D. Sin The effects of inhaled and oral corticosteroids on serum inflammatory biomarkers in COPD: an exploratory study Therapeutic Advances in Respiratory Disease, April 1, 2009; 3(2): 73 - 80. [Abstract] [PDF] |
||||
![]() |
N. Leone, D. Courbon, F. Thomas, K. Bean, B. Jego, B. Leynaert, L. Guize, and M. Zureik Lung Function Impairment and Metabolic Syndrome: The Critical Role of Abdominal Obesity Am. J. Respir. Crit. Care Med., March 15, 2009; 179(6): 509 - 516. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. M. Hawkins, Z. Huang, K. S. Pieper, S. D. Solomon, L. Kober, E. J. Velazquez, K. Swedberg, M. A. Pfeffer, J. J.V. McMurray, A. P. Maggioni, et al. Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) Eur J Heart Fail, March 1, 2009; 11(3): 292 - 298. [Abstract] [Full Text] [PDF] |
||||
![]() |
G Engstrom, N Segelstorm, M Ekberg-Aronsson, P M Nilsson, F Lindgarde, and C-G Lofdahl Plasma markers of inflammation and incidence of hospitalisations for COPD: results from a population-based cohort study Thorax, March 1, 2009; 64(3): 211 - 215. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. M. Hawkins, M. C. Petrie, P. S. Jhund, G. W. Chalmers, F. G. Dunn, and J. J.V. McMurray Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology Eur J Heart Fail, February 1, 2009; 11(2): 130 - 139. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. S. Braman Chronic Obstructive Pulmonary Disease ACCP Pulmonary Med Brd Rev, January 1, 2009; 25(0): 153 - 186. [Full Text] [PDF] |
||||
![]() |
H. Iwamoto, A. Yokoyama, Y. Kitahara, N. Ishikawa, Y. Haruta, K. Yamane, N. Hattori, H. Hara, and N. Kohno Airflow Limitation in Smokers Is Associated with Subclinical Atherosclerosis Am. J. Respir. Crit. Care Med., January 1, 2009; 179(1): 35 - 40. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Eickhoff, A. Valipour, D. Kiss, M. Schreder, L. Cekici, K. Geyer, R. Kohansal, and O. C. Burghuber Determinants of Systemic Vascular Function in Patients with Stable Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., December 15, 2008; 178(12): 1211 - 1218. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Gerhardsson de Verdier The Big Three Concept: A Way to Tackle the Health Care Crisis? Proceedings of the ATS, December 1, 2008; 5(8): 800 - 805. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. MacNee, J. Maclay, and D. McAllister Cardiovascular Injury and Repair in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, December 1, 2008; 5(8): 824 - 833. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. I. Rennard Lessons from Multidisciplinary Cross-Fertilization: Chronic Obstructive Pulmonary Disease, Lung Cancer, and Heart Disease Proceedings of the ATS, December 1, 2008; 5(8): 865 - 868. [Abstract] [Full Text] [PDF] |
||||
![]() |
F M E Franssen, D E O'Donnell, G H Goossens, E E Blaak, and A M W J Schols Obesity and the lung: 5 {middle dot} Obesity and COPD Thorax, December 1, 2008; 63(12): 1110 - 1117. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Singh, Y. K. Loke, and C. D. Furberg Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients With Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis JAMA, September 24, 2008; 300(12): 1439 - 1450. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. S. Gilmartin, R. Tamisier, M. Curley, and J. W. Weiss Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H778 - H785. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Sunyer, R. Pistelli, E. Plana, M. Andreani, F. Baldari, M. Kolz, W. Koenig, J. Pekkanen, A. Peters, and F. Forastiere Systemic inflammation, genetic susceptibility and lung function Eur. Respir. J., July 1, 2008; 32(1): 92 - 97. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Moro, C. Pedone, S. Scarlata, V. Malafarina, F. Fimognari, and R. Antonelli-Incalzi Endothelial Dysfunction in Chronic Obstructive Pulmonary Disease Angiology, July 1, 2008; 59(3): 357 - 364. [Abstract] [PDF] |
||||
![]() |
A K Johnston, D M Mannino, G W Hagan, K J Davis, and V A Kiri Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort Thorax, July 1, 2008; 63(7): 599 - 605. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. C. Todd, R. A. McIvor, S. O. Pugsley, and G. Cox Approach to chronic obstructive pulmonary disease in primary care Can Fam Physician, May 1, 2008; 54(5): 706 - 711. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. A. Falk, S. Kadiev, G. J. Criner, S. M. Scharf, O. A. Minai, and P. Diaz Cardiac Disease in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, May 1, 2008; 5(4): 543 - 548. [Abstract] [Full Text] [PDF] |
||||
![]() |
N L Mills, J J Miller, A Anand, S D Robinson, G A Frazer, D Anderson, L Breen, I B Wilkinson, C M McEniery, K Donaldson, et al. Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk Thorax, April 1, 2008; 63(4): 306 - 311. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. H. Brekke, T. Omland, S. H. Holmedal, P. Smith, and V. Soyseth Troponin T elevation and long-term mortality after chronic obstructive pulmonary disease exacerbation Eur. Respir. J., March 1, 2008; 31(3): 563 - 570. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Cazzola, W. MacNee, F. J. Martinez, K. F. Rabe, L. G. Franciosi, P. J. Barnes, V. Brusasco, P. S. Burge, P. M. A. Calverley, B. R. Celli, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur. Respir. J., February 1, 2008; 31(2): 416 - 469. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Poulain, M. Doucet, V. Drapeau, G. Fournier, A. Tremblay, P. Poirier, and F. Maltais Metabolic and inflammatory profile in obese patients with chronic obstructive pulmonary disease Chronic Respiratory Disease, February 1, 2008; 5(1): 35 - 41. [Abstract] [PDF] |
||||
![]() |
S. Bozinovski, A. Hutchinson, M. Thompson, L. MacGregor, J. Black, E. Giannakis, A.-S. Karlsson, R. Silvestrini, D. Smallwood, R. Vlahos, et al. Serum Amyloid A Is a Biomarker of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 1, 2008; 177(3): 269 - 278. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. D. Sin and S. F. P. Man Interleukin-6: A Red Herring or a Real Catch in COPD? Chest, January 1, 2008; 133(1): 4 - 6. [Full Text] [PDF] |
||||
![]() |
R. E. Walter, J. B. Wilk, M. G. Larson, R. S. Vasan, J. F. Keaney Jr, I. Lipinska, G. T. O'Connor, and E. J. Benjamin Systemic Inflammation and COPD: The Framingham Heart Study Chest, January 1, 2008; 133(1): 19 - 25. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. K. Han, V. V. McLaughlin, G. J. Criner, and F. J. Martinez Pulmonary Diseases and the Heart Circulation, December 18, 2007; 116(25): 2992 - 3005. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. A. McAllister, J. D. Maclay, N. L. Mills, G. Mair, J. Miller, D. Anderson, D. E. Newby, J. T. Murchison, and W. MacNee Arterial Stiffness Is Independently Associated with Emphysema Severity in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., December 15, 2007; 176(12): 1208 - 1214. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Tamisier, B. E. Hunt, G. S. Gilmartin, M. Curley, A. Anand, and J. W. Weiss Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3027 - H3035. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Tkac, S. F. P. Man, and D. D. Sin Review: Systemic consequences of COPD Therapeutic Advances in Respiratory Disease, October 1, 2007; 1(1): 47 - 59. [Abstract] [PDF] |
||||
![]() |
A. Agusti Systemic Effects of Chronic Obstructive Pulmonary Disease: What We Know and What We Don't Know (but Should) Proceedings of the ATS, October 1, 2007; 4(7): 522 - 525. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. I. Rennard Inflammation in COPD: a link to systemic comorbidities Eur. Respir. Rev., September 1, 2007; 16(105): 91 - 97. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Brusasco, E. Crimi, and R. Pellegrino Airway Inflammation in COPD: Friend or Foe? Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 425 - 426. [Full Text] [PDF] |
||||
![]() |
F. L. Fimognari, P. Pasqualetti, L. Moro, A. Franco, G. Piccirillo, R. Pastorelli, P. M. Rossini, and R. A. Incalzi The Association Between Metabolic Syndrome and Restrictive Ventilatory Dysfunction in Older Persons J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2007; 62(7): 760 - 765. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Tomoda, M. Yoshikawa, T. Itoh, S. Tamaki, A. Fukuoka, K. Komeda, and H. Kimura Elevated Circulating Plasma Adiponectin in Underweight Patients With COPD Chest, July 1, 2007; 132(1): 135 - 140. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Vestbo Systemic inflammation and progression of COPD Thorax, June 1, 2007; 62(6): 469 - 470. [Full Text] [PDF] |
||||
![]() |
D. Stolz, M. Christ-Crain, N. G. Morgenthaler, J. Leuppi, D. Miedinger, R. Bingisser, C. Muller, J. Struck, B. Muller, and M. Tamm Copeptin, C-Reactive Protein, and Procalcitonin as Prognostic Biomarkers in Acute Exacerbation of COPD Chest, April 1, 2007; 131(4): 1058 - 1067. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Agusti and J. B. Soriano Dynamic hyperinflation and pulmonary inflammation: a potentially relevant relationship? Eur. Respir. Rev., December 1, 2006; 15(100): 68 - 71. [Abstract] [Full Text] [PDF] |
||||
![]() |
D D Sin Inhaled corticosteroids and mortality in COPD. Thorax, October 1, 2006; 61(10): 918 - 918. [Full Text] [PDF] |
||||
![]() |
S F P Man, J E Connett, N R Anthonisen, R A Wise, D P Tashkin, and D D Sin C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease Thorax, October 1, 2006; 61(10): 849 - 853. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Aronson, I. Roterman, M. Yigla, A. Kerner, O. Avizohar, R. Sella, P. Bartha, Y. Levy, and W. Markiewicz Inverse Association between Pulmonary Function and C-Reactive Protein in Apparently Healthy Subjects Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 626 - 632. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. D. Sin and S.F. P. Man Cooling the Fire Within: Inhaled Corticosteroids and Cardiovascular Mortality in COPD. Chest, September 1, 2006; 130(3): 629 - 631. [Full Text] [PDF] |
||||
![]() |
D. D. Sin and S. F. P. Man Pharmacotherapy for Mortality Reduction in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, September 1, 2006; 3(7): 624 - 629. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Agusti Thomas A. Neff Lecture. Chronic Obstructive Pulmonary Disease: A Systemic Disease Proceedings of the ATS, August 1, 2006; 3(6): 478 - 481. [Full Text] [PDF] |
||||
![]() |
W. MacNee Conference Summary Proceedings of the ATS, August 1, 2006; 3(6): 539 - 542. [Full Text] [PDF] |
||||
![]() |
B. Thyagarajan, D. R Jacobs, G. G Apostol, L. J Smith, C. E Lewis, and O D. Williams Plasma fibrinogen and lung function: the CARDIA Study Int. J. Epidemiol., August 1, 2006; 35(4): 1001 - 1008. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. D Sin and S. P. Man Commentary: Fuelling the fire--systemic inflammation and development of lung disease in the general community Int. J. Epidemiol., August 1, 2006; 35(4): 1008 - 1010. [Full Text] [PDF] |
||||
![]() |
G.B. J. Mancini, M. Etminan, B. Zhang, L. E. Levesque, J. M. FitzGerald, and J. M. Brophy Reduction of Morbidity and Mortality by Statins, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin Receptor Blockers in Patients With Chronic Obstructive Pulmonary Disease J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2554 - 2560. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. F. M. Wouters The systemic face of airway diseases: the role of C-reactive protein. Eur. Respir. J., May 1, 2006; 27(5): 877 - 879. [Full Text] [PDF] |
||||
![]() |
E. F. M. Wouters Approaches to Improving Health Status in Chronic Obstructive Pulmonary Disease: One or Several? Proceedings of the ATS, May 1, 2006; 3(3): 262 - 269. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. I. Rennard Chronic Obstructive Pulmonary Disease: Linking Outcomes and Pathobiology of Disease Modification Proceedings of the ATS, May 1, 2006; 3(3): 276 - 280. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. P. de Torres, E. Cordoba-Lanus, C. Lopez-Aguilar, M. Muros de Fuentes, A. Montejo de Garcini, A. Aguirre-Jaime, B. R. Celli, and C. Casanova C-reactive protein levels and clinically important predictive outcomes in stable COPD patients Eur. Respir. J., May 1, 2006; 27(5): 902 - 907. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Poulain, M. Doucet, G. C. Major, V. Drapeau, F. Series, L.-P. Boulet, A. Tremblay, and F. Maltais The effect of obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies. Can. Med. Assoc. J., April 25, 2006; 174(9): 1293 - 1299. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. M. Ochs-Balcom, B. J.B. Grant, P. Muti, C. T. Sempos, J. L. Freudenheim, M. Trevisan, P. A. Cassano, L. Iacoviello, and H. J. Schunemann Pulmonary function and abdominal adiposity in the general population. Chest, April 1, 2006; 129(4): 853 - 862. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. M. Mannino, G. Watt, D. Hole, C. Gillis, C. Hart, A. McConnachie, G. Davey Smith, M. Upton, V. Hawthorne, D. D. Sin, et al. The natural history of chronic obstructive pulmonary disease. Eur. Respir. J., March 1, 2006; 27(3): 627 - 643. [Full Text] [PDF] |
||||
![]() |
R Broekhuizen, E F M Wouters, E C Creutzberg, and A M W J Schols Raised CRP levels mark metabolic and functional impairment in advanced COPD Thorax, January 1, 2006; 61(1): 17 - 22. [Abstract] [Full Text] [PDF] |
||||
![]() |
V M Pinto-Plata, H Mullerova, J F Toso, M Feudjo-Tepie, J B Soriano, R S Vessey, and B R Celli C-reactive protein in patients with COPD, control smokers and non-smokers Thorax, January 1, 2006; 61(1): 23 - 28. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. G. N. Agusti Systemic Effects of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 367 - 370. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. I. Rennard and J. A. Stoner Challenges and Opportunities for Combination Therapy in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 391 - 393. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Andreas, S. D. Anker, P. D. Scanlon, and V. K. Somers Neurohumoral Activation as a Link to Systemic Manifestations of Chronic Lung Disease Chest, November 1, 2005; 128(5): 3618 - 3624. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. C. Donaldson, T. A. R. Seemungal, I. S. Patel, A. Bhowmik, T. M. A. Wilkinson, J. R. Hurst, P. K. MacCallum, and J. A. Wedzicha Airway and Systemic Inflammation and Decline in Lung Function in Patients With COPD Chest, October 1, 2005; 128(4): 1995 - 2004. [Abstract] [Full Text] [PDF] |
||||
![]() |
F L Fimognari, L Moro, R Antonelli Incalzi, D D Sin, W Q Gan, S F P Man, and A Senthilselvan COPD, restrictive syndrome and inflammation Thorax, July 1, 2005; 60(7): 612 - 613. [Full Text] [PDF] |
||||
![]() |
D. D. Sin, L. Wu, and S. F. P. Man The Relationship Between Reduced Lung Function and Cardiovascular Mortality: A Population-Based Study and a Systematic Review of the Literature Chest, June 1, 2005; 127(6): 1952 - 1959. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Sunyer and C. S. Ulrik Level of FEV1 as a predictor of all-cause and cardiovascular mortality: an effect beyond smoking and physical fitness? Eur. Respir. J., April 1, 2005; 25(4): 587 - 588. [Full Text] [PDF] |
||||
![]() |
D. D. Sin and S. F. P. Man Chronic Obstructive Pulmonary Disease as a Risk Factor for Cardiovascular Morbidity and Mortality Proceedings of the ATS, April 1, 2005; 2(1): 8 - 11. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. B. Hunninghake Cardiovascular Disease in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 44 - 49. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. MacNee Pulmonary and Systemic Oxidant/Antioxidant Imbalance in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 50 - 60. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. F. P. Man and D. D. Sin Effects of Corticosteroids on Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 78 - 82. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Buhl and S. G. Farmer Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 83 - 93. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. I. Rennard Clinical Approach to Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease Proceedings of the ATS, April 1, 2005; 2(1): 94 - 100. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. Q. Gan, S.F. P. Man, and D. D. Sin The Interactions Between Cigarette Smoking and Reduced Lung Function on Systemic Inflammation Chest, February 1, 2005; 127(2): 558 - 564. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. D. Sin, P. Lacy, E. York, and S. F. P. Man Effects of Fluticasone on Systemic Markers of Inflammation in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 760 - 765. [Abstract] [Full Text] [PDF] |
||||
![]() |
W Q Gan, S F P Man, A Senthilselvan, and D D Sin Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis Thorax, July 1, 2004; 59(7): 574 - 580. [Abstract] [Full Text] [PDF] |
||||
![]() |
N.R. Anthonisen The British hypothesis revisited Eur. Respir. J., May 1, 2004; 23(5): 657 - 658. [Full Text] [PDF] |
||||
![]() |
D. D. Sin, F. A. McAlister, S. F. P. Man, and N. R. Anthonisen Contemporary Management of Chronic Obstructive Pulmonary Disease: Scientific Review JAMA, November 5, 2003; 290(17): 2301 - 2312. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. D. Sin Sleep-Disordered Breathing: A Heart-Changing Experience? Chest, September 1, 2003; 124(3): 778 - 780. [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |