Dennis Shale Co-morbidities and COPD - Systemic effects in COPD by dfsdf224s

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									Thinking differently – about
          COPD

            Dennis Shale

  David Davies Chair of Respiratory
    and Communicable Diseases
         School of Medicine
          Cardiff University
                  Clinical features

  Airway                                Structural   Muco-ciliary
              Inflammation
obstruction                             changes      dysfunction




                         Airflow limitation




Systemic              Declining lung function
                             Symptoms
component                  Exacerbations
                     Deteriorating health status
Time course of systemic effects?

                         Extra
                         pulmonary

                         Lung
Impact




             Time
Reported systemic effects
•   Weight loss / cachexia
•   Loss of skeletal muscle mass / function
•   Osteoporosis
•   Insulin resistance / Diabetes mellitus
•   Aortic / brachial artery stiffness
•   Ischaemic heart disease / stroke
•   Chronic heart failure
Questions
• Cause(s) ~ COPD?

• Are they linked?

• Role of systemic inflammation?

• Do they represent premature aging?
           Areas for review
• Changes in body composition

• Bone demineralisation

• Cardiovascular risk

• Other disorders
COPD related mortality




                         Landbo, AJRCCM 1999
Body composition and systemic inflammation




     1   2   3
1. Normal muscle mass
2. Underweight and low muscle mass     Eid, AJRCCM 2001
3. Normal weight and low muscle mass
                                    Systemic inflammation is present in COPD
                                      – CRP
                                      – IL-6
                                      – TNF-α sr I and II




                         0.35




                                                                                        Increased insulin
                          0.3



                         0.25
log insulin resistance




                          0.2
                                                                        Patient
                                                                                              resistance
                         0.15



                          0.1



                         0.05

                                             Healthy
                           0
                                0      0.1     0.2       0.3      0.4     0.5     0.6

                                                       log IL-6
       Bone thinning and FEV1
                                                                                                                                           osteoporosis
                                                                                                                                13
                                                                                                                                           osteopenia
                                                   100%
                                                                                                                                           normal
P e rc e n ta g e o f th e s u b je c t g ro u p




                                                                   41                          20                         13
                                                   90%
                                                                                                                          32
                                                   80%

                                                   70%
                                                                                               49

                                                   60%
                                                                   48
                                                   50%                                                                     55

                                                   40%

                                                   30%
                                                                                               31
                                                   20%

                                                   10%             11
                                                    0%
                                                            FEV1<50% pred (n=46)       FEV1>50% pred (n=35)       Healthy subject (n=38)

                                                                                         Subject Group
                                                          The figures on the graph represent the percentage of each goup with each bone status
Bone thinning and FFMI
                                                                                                  osteoporosis
                                                                                                  osteopenia
                               100%                                                               no bone loss
                                                                         18            13
                                          50             41



                               80%                                                     32
 Percentage of subject group




                                                                        50
                               60%




                               40%                       47
                                                                                       55
                                          50



                                                                        32
                               20%



                                                        12

                                0%
                                      low BMI-low     normal BMI-   normal BMI-      Healthy
                                       FFMI n=16    low FFMI n=17   normal FFMI   subjects n=38
                                                                       n=44
Airways obstruction and BMD at hip and lumbar spine

                                                                         Healthy

                                                                         FEV>50%
                                                                         pred
                                                                         FEV <50%
                                                                         pred



         hip                                               *
                                                       *




                                                                           *
lumbar spine

                                                                     *


               0   0.2   0.4       0.6       0.8   1           1.2
                                         2
                               BMD (g/cm )
                                                     Bone Mineral Density
P e rc e nta ge of S ubje c t G r oup
                                        100%                              7
                                                17
                                        80%                              33

                                        60%                                       Osteoporosis
                                                57
                                                                                  Osteopenia
                                        40%
                                                                         60       Normal BMD
                                        20%
                                                27
                                         0%
                                               COPD                     Control
                                                        Subject Group


74% of corticosteroid naïve males with COPD have evidence of loss of BMD
Bone resorption/ production
Schulz et al 2004
Aortic Stiffening and Early Wave
             Reflection
        Young compliant arteries : Normal PW velocity

    Diastole
    Systole
         Elderly stiff arteries with ISH : Increased PW velocity

    Systole
(1) Ventricular-vascular mismatch
(2) The reflected wave increases /“augments” central SBP in late systole:


•   Increases flow turbulence, endothelial dysfunction and atherogenesis
•   Increases in pulsatile strain and chance of plaque rupture
•   All recognized by a wide brachial artery pulse pressure in the elderly
Techniques for Pulse Wave
        Analysis
Aortic PWV and severity of COPD

                          18
                                                          p<0.01
                          16
                                          p<0.01
                          14
  Mean aortic PWV (m/s)




                          12

                          10

                           8

                           6

                           4

                           2

                           0
                               Controls            FEV1>50%        FEV1<50%



                                                                     Sabit et al 2006
Aortic PWV across age groups

                         25
 Mean aortic PWV (m/s)




                         20

                         15
                                                                                 Control
                                                                                 COPD
                         10

                         5

                         0
                              40-49   50-59     60-69      70-79   80-89
                                         Age Category (years)


                                                                    Sabit et al 2006
Inflammation and Aortic PWV
                   P<0.001




                 Yasmin et al. ATVB 2004;24:969
Log IL-6 and Aortic PWV
                               30


  M ean aortic P W V (m /s )



                               20




                               10




                                                                                           r=0.31, p<0.01

                                0                                                          r=0.51, p<0.01
                                    -.6   -.4   -.2   -.0   .2        .4   .6   .8   1.0


                                                        Log 10 IL-6
Schulz et al 2004
Bone disease and aortic PWV
B
  Causes of Death in COPD
Pulmonary disease 30-35%

Cardiovascular 30%

Cancer 20%

Other causes 20%
• Cardiovascular disease increased in
  COPD

• Over and above smoking risk ~ 2-3x

• 4.5 fold excess risk of chronic heart
  failure

• >30% of patients with COPD die of
  cardiovascular disease
     The impact of frequent exacerbations on
                     survival

                                                                                       Exacerbations in index year:
                                        1.0                                            Group A: no exacerbations
                                                                                       Group B: 1–2 exacerbations
                                                                                       Group C: ≥3 exacerbations
                                        0.8
                 Survival probability



                                                                                 A
                                                                            p<0.0002
                                        0.6
                                                                                B          p<0.0001
                                        0.4                                 p=0.069

                                                                                C
                                        0.2
                                                                                           n=304
                                        0
                                              0   10   20   30   40    50     60
                                                       Time (months)
   Prospective cohort study, exacerbations studied in an index year with subsequent 5-year follow-up

Soler-Cataluna JJ, et al. Thorax 2005;60:925–931
  What happens to myocardial
structure and function in COPD?
     COPD

   Systemic
 Inflammation
      ?
Arterial Stiffness




Cardiovascular
   Disease
              TDE parameters

•   Peak systolic velocity (PSV)
•   Real time annular peak velocity   Systolic
•   Strain                            Function
•   Strain rate

• IVRT – diastolic dysfunction
All p<0.05
LV diastolic function and severity of COPD


                                    p<0.01
                   140


                   120


                   100
  Mean IVRT (ms)




                    80


                    60


                    40


                    20


                     0
                         Controls            Mild COPD   Severe COPD
Global RV function and severity of COPD
                  0.25


                                                     p<0.05
                   0.2



                                    p<0.05
 Mean Tei index




                  0.15



                   0.1



                  0.05



                    0
                         Controls            Mild COPD        Severe COPD
Global RV function and fat free mass status
                     .20
                                      p<0.05

                     .18



                     .16
                                                             p<0.01
    Mean Tei index




                     .14



                     .12



                     .10



                     .08


                     .06
                           Low FFMI            Normal FFMI       Control subjects
  Multiple Regression Analysis
Dependent variable   Predictor     R2     Significance


      IVRT           Aortic PWV   0.215     P<0.01


    Tei index          FEV1       0.25      P<0.01


     RV IVRT           FEV1       0.17      P<0.01


Tricuspid velocity      IL-6      0.14      P<0.05
PET scan in COPD, metabolic syndrome and controls


              2.5


               2       *                                                              *
  m ean TBR




              1.5


               1


              0.5


               0
                    Ascending            Arch               Descending              Abdo
                                             Aortic Artery Territory

                           Control Average     COPD Average            Metabolic Average
Summary
• Patients with COPD have increased arterial stiffness,
  sub-clinical LV and RV systolic and diastolic
  dysfunction ~ arterial-ventricular stiffening

• Such changes are present in mild disease

• It may represent premature vascular ageing

• Cardiovascular changes are related to bone thinning,
  systemic inflammation, loss of FFM and protein
  catabolism

• Such changes may underlie the excess risk of
  cardiovascular mortality in this group
Summary
Systemic co-morbidities add to impact of
COPD
Origins early in the lung disease process
Sub-clinical for long periods
Related to inflammatory –catabolic
processes
Interrelated to exacerbations
Appropriate pharmacotherapy may modify
their development
                      The Team
•   Respiratory Medicine             •   Medical Physics
     – Charlotte Bolton                   – Wil Evans
     – Ramsey Sabit                       – Rebecca Pettit
     – James Duckers
                                     •   Bone Research Unit
•   Wales Heart Research Institute        – Michael Stone
     – John Cockcroft
     – Barry McDonnell               •   Child Health
     – Maggie Munnery                     – Bronwen Evans
     – Alan Fraser
     – James Coulson

•   Cambridge University
     – Ian Wilkinson
     – Carmel McEniery

•   Physiotherapy
     – Stephanie Enright
     – Nichola Gale

								
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