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Diagnosis and Assessment of Comorbidities
Claus Vogelmeier
Department of Respiratory
Medicine, Philipps-University of
Marburg, Germany
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
COPD and Body Composition
Background
• BMI < 21kg/m2 associated with RR 7.11 for COPD-related
deaths1
• In pts. with normal weight loss of fat-free mass (FFM)
associated with increased mortality2
• FFM indirect measure of muscle mass3
• Loss of skeletal muscle mass main cause of weight loss4
• FFM strong predictor of muscle function5, exercise capacity6,
health status7
1C
Landbo et al., AJRCCM 160:1856, 1999, 2J Vestbo et al., AJRCCM 173:79, 2006,
3MA Vermeeren et al., Respir Med 100:1349, 2006, 4AM Schols, Curr Opin Pulm Med 6:110, 2000, 5MP Engelen et
al., Am J Clin Nutr 71:733, 2000, 6EM Baarends et al., Eur Respir J 10:2807, 1997, 7R Mostert et al., Respir Med
94:859, 2000
COPD and Body Composition
Potential Procedures
• BMI measurement
• FFMI measurement
– single frequency bioelectrical impedance analysis (50Hz)
– under fasting conditions
– following 10 min. resting time in supine position1,2
1M
Cazzola et al., Eur Respir J 31:416, 2008, 2UG Kyle et al, Clinical Nutrition 23:1226, 2004
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
Methods to determine exercise capacity
and/or activity in COPD
Measure
Field tests for exercise
capacity
6 min walk test
Laboratory tests for
exercise capacity
Bicycle ergometer
Assessment of activity
accelerometer
Shuttle walk test
Treadmill
T Glaab, C Vogelmeier, R Buhl, Respir Res 2010, 11:79
Exercise
capacity

Physical
activity
R Casaburi, Lund 12/10
Evaluation of Physical Activity
Multisensor Armband
Sensewear Pro Armband
1st study in COPD: H Watz et al., AJRCCM 177:743-751, 2008
Physical activity in COPD: steps per
day vs. GOLD stage
10000
8000
6000
4000
2000
0
CB
I
II
III
IV
GOLD stage
H Watz et al. Eur Respir J 33:262-72, 2009
Physical activity and mortality in COPD
Outpatients stable COPD (N=170, FEV1=56% pred)
•
•
•
•
•
•
•
•
•
Body plethysmography
Activity level (Sensewear)
6MWD
Echocardiography
Ankle-brachial index
NT-proBNP
BMI, FFMI
Biomarkers
Dyspnea, depressive symptoms
Follow-up 48 (10-53) months
• All-cause mortality=15.4%
• Best predictor – physical activity
B Washki et al. Chest 2011, epub ahead of print
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
Osteoporosis in COPD
Potential Risk Factors
 Smoking
  Vitamin D
 Genetic factors
 Treatment with Steroids
  skeletal mass and strength
  BMI and FFMI
 Hypogonadism
  Insulin like growth factors
 Systemic inflammation
AA Ionescu and E Schoon, 22: 64S-75S, 2003
COPD and Osteoporosis
Background
•
•
•
•
•
1F
Up to 4 fold risk increase in COPD pts.1,2,3
Hip fractures increase mortality in COPD4
Vertebral fractures may impact on lung function5,6
ICS possibly an independent risk factor7
Up to 86% of pts. treated with systemic steroids
develop osteoporosis3,8
Iqbal et al., Chest 116:1616, 1999, 2CE Bolton et al., AJRCCM 170:1286, 2004,
3NR Jorgensen et al., Respir Med 101:177, 2007, 4C de Luise et al., Eur J Epidem 2007,
5RA Harrison et al., J Bone Miner Res 22:447, 2007, 6HL Yang et al., J Spinal Disord Tech 20:221, 2007,
7R Hubbard et al., Chest 130:1082, 2006, 8DM Bioskobing, Chest 121:609, 2002
Vitamin D serum levels vs. GOLD stage
• (Ex)smokers > 50
yrs (N=414)
• Spirometry
• 25-OH Vitamin D
serum levels
• GOLD stage
• 25-OHD
W Janssens et al., Thorax 65:215-220, 2010
Effects of vitamin D with potential
importance for COPD
W Janssens et al.,
AJRCCM 179:630-636,
2009
COPD and Osteoporosis
Recommended Procedures
• Assessment of major risk factors (evidence level)
–
–
–
–
–
–
–
Prevalent fragility fractures (A)
Osteoporotic fractures in parents (B)
Multiple falls (A)
Smoking (A)
Immobility (A)
BMI < 20 kg/m2 (A)
Chronic use of steroids
According to German Osteoporosis Guidelines (www.dv.osteologie.de)
COPD and Osteoporosis
Recommended Procedures
• Baseline diagnostics
– History
– Clin. examination
– Lab tests (Hb, CRP, alkaline phospatase, Ca,
Phosphate, Creatinine, Gamma-GT, TSH,
electrophoresis)
• Bone density measurement (if clinically
indicated)(C)
– DXA
According to German Osteoporosis Guidelines (www.dv.osteologie.de)
COPD and Osteoporosis
DXA
•
•
•
•
•
DXA = Dual energy X-ray absorptiometry
Two X-ray beams with differing energy levels
Aimed at bones
Soft tissue absorption subtracted
BMD determined from the absorption of each beam
by bone
• Most widely used and most thoroughly studied bone
density measurement technology
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
COPD and Cardiovascular Disease
Background
• FEV1 independent risk factor for coronary artery disease1
and cardiovascular mortality2
• Presence of COPD - 2-fold increase of mortality in pts.
undergoing coronary intervention3
• In COPD studies significant mortality attributable to
cardiovascular system4
• Acute exacerbations
– increased Troponin T associated with increased mortality5
– ß-blocker use associated with decreased mortality6
1DJ
Hole et al., BMJ 313:711, 1996, 2DD Sin et al., Chest 127:1952, 2005,
3JS Berger et al., Am J Cardiol 94:649,2004, 4LP McGarvey et al., Thorax 62:411, 2007,
5PH Brekke et al., Eur Respir J 31:563, 2008,6MT Dransfield et al., Thorax 63:301, 2008
Emphysema, Airflow Obstruction and
Impaired Left Ventricular Filling
• Indiv without clinical
cardiovascular disease
(N=2816, 45-84 yrs,
FEV1=96% )
LV end-diastolic volume vs.
emphysema
• Cardiac MRI
• Cardiac CT
• LV end-diastolic
volume vs.
– Emphysema
– FEV1/FVC
RG Barr et al., NEJM 362: 217-227, 2010
COPD: Cardiac chamber size and associated heart
dysfunction: the role of hyperinflation
Watz H et al Chest 2010; 138: 32 - 38
COPD and Cardiovascular System
Potential Procedures
• EKG at rest (Cardiac infarction injury score1)
• Echo at rest – standard protocol + assessment of right heart
(TAPSE, PAPsyst)2
• [6-min. walk test3]
• Ankle-Arm Index (RR taken blood at ankle and arm, indicator
of peripheral artery disease)4
1Rautaharju
et al., Circulation 64:249, 1981, 2American Society of Echocardiography
www.asecho.org/Guidelines.php), 3ATS Statement. AJRCCM 166:111, 2002, 4AB Newman et al.,
Circulation 88:837, 1993,
COPD and Cardiovascular System
Potential Procedures
• Carotid artery intima-media thickness (risk factor for
myocardial infarction and stroke)5
• Brachial flow mediated vasodilation (measure for coronary
endothelial function)6
• Pulse wave velocity (measure of art. stiffness)7
• Lab tests (lipids, troponine T, NT-proBNP, hsCRP)
5O´Leary
et al., New Engl J Med 340:14, 1999, 6DM Herrington et al., J Cardiovasc
Risk 8:319, 2001, 7SS Najjar et al., J Am Coll Cardiol 51:1377, 2008
Flow-mediated Dilution (FMD)
• Measure of coronary endothelial
function
• Predictor of cardiac risk
• Noninvasive
• High-resolution ultrasonography
• Brachial artery
• Blood flow increase in response
to reactive hyperemia
Arterial Stiffness
• predicts cardiovascular outcomes
• measured by aortic pulse wave velocity (PWV)
• PWV
– considered the most clinically relevant measure of
arterial stiffness and
– independently predicts cardiovascular risk
Cardiomyocyte: Synthesis and Secretion
of B-Type Natriuretic Peptide (BNP)
preproBNP (134 A.a.)
proBNP (108 A.a.)
signal peptide (26 A.a.)
cell membrane
NT-proBNP (1-76)
BNP (77-108)
Ch Mueller & P Buser. Swiss Med Wkly 132:618, 2002
BNP in Pts. with Acute Dyspnea
BNP for Acute Shortness of Breath
Evaluation (BASEL)
BNP (pg/mL)
Diagnosis/Therapy
< 100
Ø left heart failure
100-500
Additional tests
> 500
TX left heart failure
C. Mueller et al., NEJM 2004;350:647
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
COPD – mortality risk vs. BMI
Mortality risk
Never smokers
Ex-smokers
Smokers
KF Adams et al., N Engl J Med 2006; 355: 763-78
Frequency of the metabolic syndrome
vs. GOLD stage
Frequency (%)
70
60
50
40
30
20
10
0
CB
I
II
III
IV
GOLD stage
H Watz et al Chest 136:1039-46, 2009
The International Diabetes Federation
definition of the metabolic syndrome
Obligatory factor
central obesity
waist circumference ≥ 94cm for men
and ≥ 80cm for women
Plus any two of the following four factors
raised triglyceride
level
≥ 150 mg/dL (1.7 mmol/L)*
reduced HDL
cholesterol
< 40 mg/dL in males and < 50 mg/dL in females*
raised blood
pressure
systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg*
raised fasting
plasma glucose
≥ 100 mg/dL (5.6 mmol/L)*
* or specific treatment for this abnormality
http://www.idf.org/webdata/docs/MetS_def_update2006.pdf
COPD and OSA (Overlap Syndrom)
COPD (N=651)
PSG
+ OSA
+ CPAP
(N=228)
- OSA
(N=210)
- CPAP
(N=213)
9.4 (3.3-12.7) yrs
 Mortality
 Hospitalisation for
COPD exacerbation
COPD: FEV1/FVC<0.70; OSA: AHI ≥5
Marin-JM, AJRCCM 2010;182:325-31
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
COPD and Depression/Anxiety
Background
• Varying prevalence
– Depression 2-57%
– Anxiety 2-50%1
• More common in females2
• No correlation between prevalence and COPD
severity3
• Severe impact on
– SGRQ3
– Hospitalisation rate4
1RL
Mikkelson et al., Nord J Psychiatry 58:65, 2004, 2F di Marco et al., Respir Med 100:1767, 2000, 3G
Gudmundsson. Respir Med 2006, 4G Gudmundsson. Eur Respir J 26:414, 2005
COPD - Depression and Anxiety
Impact on Exacerbations/Hospitalisations
Stable COPD [N=491,
FEV1=47 %]
Depression and
anxiety [Hospital
Anxiety and
Depression Scale =
HADS]
12 months
• Exacerbations
• Hospitalisations
Depression
No
Yes
P
Symptom based 59.9 70.5 0.04
exac. (%)
Event based
44.1 57.1 0.003
exac. (%)
W Xu et al., AJRCCM 178:913-920, 2008
COPD and Depression/Anxiety
Potential Procedures
• Depression - PHQ-9
– 9 item depression scale of the Patient Health Questionnaire
– powerful tool for diagnosing depression and
– selecting and monitoring treatment
– assessing symptoms and functional impairment to
• make a depression diagnosis and
• derive a severity score1
1K Kroenke
K, RL Spitzer. Psychiatric Annals 32: 509, 2002,
COPD and Depression/Anxiety
Potential Procedures
• Anxiety
– Hamilton Anxiety and Depression Scale
• 14 item test to measure
• severity of anxiety (and depression) symptoms2
– Hospital Anxiety and Depression Scale
• 14 item test to assess
• presence and severity of anxiety and depression
• in non-psychiatric hospital settings3
2M
Hamilton. British Journal of Medical Psychology 32:55, 1959, 3AS Zigmond, RP Snaith. Acta Psychiatrica Scandinavica
67:361, 1983
COPD – systemic consequences/comorbidities
• Cachexia/weight loss
Airway
obstruction
Mucociliary
dysfunction
Structural
changes
• Muscle
 atrophy
 weakness
• Osteoporosis
Airflow
limitation
Inflammation
• Cardiovascular dis.
Systemic
effects
• Metabolic syndrome
• CNS
• Cancer
Mod. after A. Agusti
Cause and effect(s)
Images in Clinical Medicine, NEJM 2006
COPD and lung cancer
Potential procedures for screening
• 4 trials - screening with chest radiography ± sputum
cytology – no effect on lung cancer mortality1-9
• Conducted in an era with predominant squamous
cell histology10
• Currently adenocarcinoma most prevalent – tends
to be more peripherally located11
1BJ
Flehinger et al. Am Rev Respir Dis 130:555-560, 1984; 2MR Melamed Cancer 89(suppl):2356-62, 2000; 3JK Frost et al
Am Rev Respir Dis 130:549-55, 1984; 4MS Trockman Chest 89(suppl):324S-25S, 1986; 5RS Fontana et al. Am Rev Respir
Dis 130:561-65, 1984; 6BS Fontana et al. Cancer 67(suppl):1155-64, 1991; 7PM Marcus et al J Natl Cancer Inst 92:1308-16,
2000; 8A Kubik & J Polák Cancer 57:2427-37, 1986; 9AK Kubik et al Cancer 89(suppl):2363-68, 2000; 10EL Wynder & JE
Muscat. Environ Health Perspect 103(suppl) 143-8, 1995; 11National Cancer Institute http://cancer.gov/csr/1975_2005
COPD and lung cancer
Potential procedures for screening
• Multidetector helical CT
– Reduces problem of overlying structures
– Inherent contrast in lung parenchyma substantially greater
– Low dose CT – radiation exposure 20-25% of diagnostic CT
(1.5mSv)
– Potential problems
• Lead time bias
• Length bias
• Overdiagnosis bias
National Lung Screening Trial Research Team. Radiology 258:243-253, 2011
The National Lung Screening Trial
Overview and Study design
N=53.456, 55-74 yrs, ≥ 30 pack-yrs, active and ex-smokers
Low dose
helical CT
Chest X-ray
Baseline + 2 annual
screenings = 3 yrs
• Primary endpoint: lung cancer mortality
• Secondary endpoints:
–
–
–
–
–
–
Overall mortality
Incidence
Screening and treatment-related morbidity
Screening findings
Diagostic and predictive accuracy
National Lung Screening Trial Research
….
Team. Radiology 258:243-253, 2011
The National Lung Screening Trial
Press release November 4, 2010
N=53.456, 55-74 yrs, ≥ 30 pack-yrs, active and ex-smokers
Lung cancer deaths
•
•
•
•
Low dose
helical CT
Chest X-ray
N=354
N=442
„…20% fewer lung cancer deaths…
...all cause mortality was 7% lower…
…25% of deaths…due to lung cancer…
…other factors such as cardiovascular disease…“
National Cancer Institute, online
COPD – Diagnosis and Assessment of
Comorbidities
Summary
• Many potential parameters
Airway
obstruction
• Feasibility?
• Relative importance?
• Causal relationship?
• Independent variables?
Mucociliary
dysfunction
Structural
changes
Inflammation
Systemic
effects
Mortality in COPD Pts Discharged from Hospital
Role of Comorbidity
Pts. hospitalized for
exacerbation [N=416]
SGRQ total score ≤ 60
24 months follow-up
29.3 % died
Comorbidities =
diagnosis by treating
physician
G Gudmundsson et a., Respir Res 7:109, 2006
SGRQ total score > 60
Mortality in COPD Pts Discharged from Hospital
Role of Comorbidity
Diabetes
Pts. hospitalized for
exacerbation [N=416]
24 months follow-up
29.3 % died
Comorbidities =
diagnosis by treating
physician
G Gudmundsson et a., Respir Res 7:109, 2006
Clinical Consequences of Osteoporosis
• Acute and chronic
pain
• Kyphosis
• Bulging abdomen, reflux and other GI
symptoms
• Breathing difficulties
• Loss of height
• Loss of mobility (1/2)
• Depression
• Loss of independance (1/3)
Osteoporosis in Severe COPD
Severe COPD
[N=179, FEV1=26%,
prednisone 45%]
Dual energy X-ray
absorptiometry (DEXA)
lumbar spine + hip
GOLD stadium vs.
osteoporosis
L Li et al., AJRCCM 2007;175:A598
GOLD stage Osteop.
(%)
 Rate
(%)
2 (N=7)
57
0
3 (N=46)
54
20
4 (N=126)
68
14
COPD Exacerbations
Hospitalisations and Muscle Function
COPD [N=101,
FEV1=45%]
Hospitalized
Not
1
Hospitalized
Respiratory muscle
and quadriceps force
PImax
(cmH2O)
-7
+5
2 yrs
PEmax
(cmH2O)
-40
-9
Quad. force
(Nm)
-25
-6
Hospitalisation for
COPD exacerbation
D Testelmans et al., AJRCCM 2007;175:A137
Endothelial Dysfunction in COPD
Link Between Systemic Inflammation
and Cardiovascular Comorbidity
Ultrasound Art.
brachialis
Endothelial-Dependent
Flow-mediated Dilution
(FMD)
P EIckhoff et al., AJRCCM 178:1211, 2008
(%)
• COPD [N=15, FEV1=33% pred.]
20
• Healthy Smokers=HS [N=6]
• Healthy Nonsmokers=HNS [N=10]
P<0.001
P<0.001
10
0
COPD
HS
HNS
COPD - Depression and Anxiety
Impact on Exacerbations/Hospitalisations
Stable COPD [N=491,
FEV1=47 %]
Depression and
anxiety [Hospital
Anxiety and
Depression Scale =
HADS]
12 months
• Exacerbations
• Hospitalisations
Depression
No
Yes
P
Hospitalisations 80.2 70.5 0.03
(%)
Anxiety
No Yes
P
Hospitalisations 78.4 74.5 0.11
(%)
W Xu et al., AJRCCM 178:913-920, 2008
Risk of Death Following Clinical Fractures
Fracture Intervention Trial (FIT)
Any Symptomatic
Non-spine
6.7
Hip
Spine
8.6
Forearm
Other
0.0
1.0
2.0
5.0
10.0 16.0
Age-Adjusted Relative Risk (95% CI)
Cauley JA, et al. Osteoporosis Int. 2000;11:556-561.
Exercise: anti-inflammatory properties
on the molecular level (PGC-1)
Transcriptional
coactivator
Handschin and Spiegelman Nature 454:463-69, 2008
Exercise: the muscle as an endocrine organ
BK Pedersen and MA Febbraio Physiol Rev 88:1379-1406, 2008
Heart Dimensions in Pts with Severe
Emphysema
Control
• COPD (N=13, FEV1
15-30%)
• Controls (N=11)
COPD
Diastole
Heart MRI
 Dimensions
LV and RV
Systole
K Jörgensen et al., Chest 131:1050-1057, 2007
Prevalence of Osteoporosis in COPD
L Graat-Verboom
et al., ERJ 34:209218, 2009
LS+hip
Forearm
Hip
Sabit 2007
Dimai 2001
Karadag 2003
LS+hip
LS
Bolton 2004
Karadag 2003
Prevalence of Osteoporosis in COPD VS:
Other Respiratory Disorders
L Graat-Verboom
et al., ERJ 34:209218, 2009
LS+hip
LS+hip
Forli 2008
Tschopp 2002
LS
LS+hip+TB
Katsura 2002
Aris 1996
Lung Cancer in COPD
PJ Barnes and BR Celli, ERJ 33:1165-1185, 2009
COPD und OSA (Overlap Syndrom) mit
und ohne CPAP
651 Pat. mit COPD
PSG
+ OSA
mit CPAP
(n=228)
- OSA
(n=210)
ohne CPAP
(n=213)
Verlauf 9,4 (3,3,-12,7) Jahre
 Mortalität
 Hospitalisierung
bei COPD Exazerbation
COPD: FEV1/FVC<0,70; OSA: AHI ≥5
Marin-JM, AJRCCM 2010;182:325-31
COPD und OSA (Overlap Syndrom) mit
und ohne CPAP
651 Pat. mit COPD
PSG
+ OSA
mit CPAP
(n=228)
- OSA
(n=210)
ohne CPAP
(n=213)
Verlauf 9,4 (3,3,-12,7) Jahre
 Mortalität
 Hospitalisierung
bei COPD Exazerbation
COPD: FEV1/FVC<0,70; OSA: AHI ≥5
Marin-JM, AJRCCM 2010;182:325-31
COPD and lung cancer
Potential procedures for screening
• 4 trials - screening with chest radiography ± sputum
cytology – no effect on lung cancer mortality1-9
• Conducted in an era with predominant squamous
cell histology10
• Currently adenocarcinoma most prevalent – tends
to be more peripherally located11
1BJ
Flehinger et al. Am Rev Respir Dis 130:555-560, 1984; 2MR Melamed Cancer 89(suppl):2356-62, 2000; 3JK Frost et al
Am Rev Respir Dis 130:549-55, 1984; 4MS Trockman Chest 89(suppl):324S-25S, 1986; 5RS Fontana et al. Am Rev Respir
Dis 130:561-65, 1984; 6BS Fontana et al. Cancer 67(suppl):1155-64, 1991; 7PM Marcus et al J Natl Cancer Inst 92:1308-16,
2000; 8A Kubik & J Polák Cancer 57:2427-37, 1986; 9AK Kubik et al Cancer 89(suppl):2363-68, 2000; 10EL Wynder & JE
Muscat. Environ Health Perspect 103(suppl) 143-8, 1995; 11National Cancer Institute http://cancer.gov/csr/1975_2005
COPD and lung cancer
Potential procedures for screening
• Multidetector helical CT
– Reduces problem of overlying structures
– Inherent contrast in lung parenchyma substantially greater
– Low dose CT – radiation exposure 20-25% of diagnostic CT
(1.5mSv)
– Potential problems
• Lead time bias
• Length bias
• Overdiagnosis bias
National Lung Screening Trial Research Team. Radiology 258:243-253, 2011
Relationship between COPD and
Comorbidities
Factors Adding Complexity
Smoking
Aging
Medication interactions
Inaccuracy of diagnosis coding
Lack of specific case definitions for comorbidities
WM Chatila et al., PATS 5:549-555, 2008
Inactivity, obesity, systemic inflammation and
chronic diseases
Handschin and Spiegelman Nature 454:463-69, 2008
A Healthy Skeleton Depends on a
Balanced RANK Ligand/OPG Ratio
RANKL
OPG
No Bone Loss
Neveen A.T. Hamdy, 2007
Osteoporosis
Osteoprotegerin (OPG) - a natural RANK Ligand
antagonist
Osteoclast Formation, Function and
Survival Inhibited by OPG
OPG
RANK Ligand
RANK
CFU-M
Pre-fusion
Osteoclast
Growth Factors
Hormones
Cytokines
Multinucleated
Osteoclast
Mature
Osteoclast
Bone
Adapted from Boyle WJ et al. Nature 2003; 423: 337
Emphysema, Airflow Obstruction and
Impaired Left Ventricular Filling
• Indiv without clinical
cardiovascular disease
(N=2816, 45-84 yrs,
FEV1=96% )
LV end-diastolic volume vs.
FEV1/FVC
• Cardiac MRI
• Cardiac CT
• LV end-diastolic
volume vs.
– Emphysema
– FEV1/FVC
RG Barr et al., NEJM 362: 217-227, 2010
COPD - Exacerbation
Troponin T and Long-term Mortality
Hospital database COPD exacerbations
[N=396]
Troponin T
Troponin T (µg/L)
<0.01
0.01-0.03
Follow-up median
1.9 yrs
≥0.04
All-cause mortality vs.
Troponin T during exac.
P-H Brekke et al., Eur Respir J 31:563-570, 2008
COPD and ß-blockers
Risk of Death During Acute Exacerbations
COPD exacerbations
admitted to
University of
Alabama Hosp.
[N=825]
ß-blocker use
In-hospital mortality (5.2%)
vs. ß-blocker use
Adjusted 95 %
OR for
CI
death
ß-blocker
use
0.39
P
0.14- 0.049
0.99
MT Dransfield et al., Thorax 63:301-305, 2008
COPD Exacerbations
Brain Natriuretic Peptide (BNP) Levels
COPD exac. [N=58,
FEV1=0.71L ]
Day 1
6 weeks
• NT-BNP
S Bourne & J Fingleton 401s, ERS 2008
LV-dysfunction and severe COPDExacerbation – NT-proBNP
P<0.001
5000
+
-
4000
P<0.001
NT-proBNP
[pg/ml]
Right heart
failure
3000
2000
Modif. after F
Abroug et al.,
AJRCCM 2006
Epub
1000
0
LV-dysfunction
unlikely
definitive/possible
Endothelial Dysfunction in COPD Exacerbations
Link Between Systemic Inflammation and
Cardiovascular Comorbidity
• COPD exacerbation [N=21, FEV1=0.63L]
• Follow-up  Mo [N=8]
• Healthy Nonsmokers=HNS [N=9]
P<0.003
10
P=0.026
(%)
Ultrasound Art.
brachialis
Endothelial-Dependent
Flow-mediated Dilution
(FMD)
AD Crookshank et al., AJRCCM 2007;175:A514
5
0
Exacerb. Follow-up
HNS
Arterial Stiffness and Osteoporosis in
COPD
• COPD (N=75)
• Controls (Smokers or ex-smokers)(N=42)
Spirometry, PWV,
DXA, inflammatory
mediators (blood)
Arterial stiffness
Osteoporosis
R Sabit et al., AJRCCM 2007 epub ahead of print
Arterial Stiffness and Osteoporosis in COPD
PWV vs. FEV1
R Sabit et al., AJRCCM 2007 epub ahead of print
Arterial Stiffness and Osteoporosis in COPD
PWV vs. Osteoporosis
R Sabit et al., AJRCCM 2007 epub ahead of print
COPD - Depression and Anxiety
Impact on Exacerbations/Hospitalisations
Stable COPD [N=491,
FEV1=47 %]
Depression and
anxiety [Hospital
Anxiety and
Depression Scale =
HADS]
12 months
• Exacerbations
• Hospitalisations
Anxiety
No
Yes
P
No symptom 38.1 34.0 0.003
based exac. (%)
No event based 54.0 42.6 0.35
exac. (%)
W Xu et al., AJRCCM 178:913-920, 2008
Exercise Capacity Limitation and
Depression in COPD
COPD [N=106,
FEV1=52 %]
Depression scales
[CES-D, BASDEC]
• 6 MWD
K Al-Shair et al. 587s, ERS 2008
6MWD
 350m < 350m
P
CES-D
6
12
0.001
BASDEC
2
4.3
0.002
COPD Prevalence in Lung Cancer
• Lung cancer (N=446,
nonsmokers >>)
• Controls (N=654, ≥10
packyrs)
Pre-BD
spirometry
COPD
GOLD
RP Young et al., ERJ 2009 epub
COPD Prevalence in Lung Cancer
• Lung cancer (N=446,
nonsmokers >>)
• Controls (N=654, ≥10
packyrs)
Pre-BD
spirometry
RP Young et al., ERJ 2009 epub