R Rodriguez-Roisin UNIVERSITAT DE BARCELONA ANOMALÍAS VASCULARES PULMONARES EN LA EPOC MUY SEVERA (TRANSEPOC)

Presentación del tema: "R Rodriguez-Roisin UNIVERSITAT DE BARCELONA ANOMALÍAS VASCULARES PULMONARES EN LA EPOC MUY SEVERA (TRANSEPOC)"— Transcripción de la presentación:

1 R Rodriguez-Roisin UNIVERSITAT DE BARCELONA ANOMALÍAS VASCULARES PULMONARES EN LA EPOC MUY SEVERA (TRANSEPOC)

2  Antecedentes  Bio- y Fisiopatología  Datos (TRANSEPOC) Contenido

3  Antecedentes  Bio- y Fisiopatología  Datos (TRANSEPOC) Contenido

4 ...in patients with mild COPD the enlargement of the intimal layer in pulmonary muscular arteries is associated with a higher degree of V A /Q inequality, and that intimal thickening in small arteries seems to reduce the response of the pulmonary circulation to different oxygen concentrations. Barberà JA et al. AJRCCM 1994;149:423-9

5 COPD: Bronchiolar & Pulmonary Vascular Abnormalities Intimal area (% total area) 60 50 40 30 20 10 0 0 203040 Bronchiolar inflammation score r = 0.65 p< 0.001

6 Intimal area, % total 0 10 20 30 40 NSm Sm COPD * COPD: Pulmonary Arteries Morphometry * Peinado VI et al. AJP 1998;274:L908-13

7 COPD: Endothelial Vascular Relaxation Adenosine Diphosphate, log [M] -10- 9- 8- 7- 6 -5- 4 -100 -80 -60 -40 -20 0 Never-Smokers Smokers COPD * Peinado VI et al. AJP 1998;274:L908-13 Maximal Relaxation (% Contraction to LP)

8 Intimal area (% total area) 182124273033 50 60 70 80 90 NSm Sm GOLD 1 & GOLD 2 Maximal relaxation to ADP (% Contraction to PE) COPD: Endothelium-Dependent Relaxation Peinado VI et al. AJP 1998;274:L908-13

9 COPD: Lymphocytic Infiltrate in Pulmonary Arteries NSmSm COPD 0 100 200 300 400 Cells/mm 2 CD8 + * * Peinado VI et al. AJRCCM 1999;159:1605-11 0 100 200 300 400 Cells/mm 2 CD4 + NSmSm COPD 0 0.5 1.0 1.5 2.0 2.5 CD4/CD8 ratio CD4 + /CD8 + * NSmSm COPD *

10 Leukocytes, cells/mm 2 02004006008001000 Maximal relaxation to ADP, % 20 40 60 80 100 120 r = - 0.38 p < 0.05 Peinado VI et al. AJRCCM 1999;159:1605-11 COPD: Lymphocytic Infiltrate in Pulmonary Arteries

11 Band intensity 0 30 60 90 120 150 Sm COPD: eNOS Expression in Pulmonary Arteries NSm Barberà JA et al. AJRCCM 2001;164:709-13 COPD  132 Kd *

12 COPD Never-Smoker Severe Emphysema Santos S et al. AJRCCM 2003;167:1250-6 COPD: VEGF Expression in Pulmonary Arteries

13 Non-SmokersSmokers COPD PULMONARY VASCULAR REACTIVITY INTIMAL THICKENING LYMPHOCYTIC INFILTRATE DECREASED eNOS & INCREASED VEGF COPD: Spectrum of Pulmonary Vascular Abnormalities

14  Antecedentes  Bio- y Fisiopatología  Datos (TRANSEPOC) Contenido

15 0 0.30 0.50 0.70 0.90 1.10 1.30 1.50 Grades 1234 LOG SDQ & LOG SDV Rodríguez-Roisin R et al. JAP 2009;106:1902-8 GOLD: Ventilation-Perfusion Imbalance n, 150

16 Never-SmokerGOLD-4 Estépar RSJ et al. AJRCCM 2013;188:231-9

17 CIGARETTE SMOKE INFLAMMATION Pulmonary Artery CELL PROLIFERATION ENDOTHELIAL DYSFUNCTION COPD: Pulmonary Vascular Abnormalities PULMONARY HYPERTENSION HYPOXEMIA Peinado VI et al. Chest 2008;134:308-14 VASCULAR REMODELLING INTIMAL THICKENING  Vascular Tone

18 Non-SmokersSmokers COPD PULMONARY VASCULAR REACTIVITY INTIMAL THICKENING LYMPHOCYTIC INFILTRATE DECREASED eNOS & INCREASED VEGF COPD: Spectrum of Pulmonary Vascular Abnormalities What About GOLD-3 & GOLD-4?

19  Antecedentes  Bio- y Fisiopatología  Datos (TRANSEPOC) Contenido

20 TRANSEPOC: General Characteristics Characteristics n, 17 Mean±SDRange Age, yrs56±4(49-63) Pack-years44±28(10-90) BMI, kg.m -2 26±4(18-34) 6MWT, m322±96(151-520) mMRC4±1(3-4) BODE Index (0 –10)7±2(5-10) Peinado VI et al. JHLT 2013;32:1262–69

21 VARIABLESMean±SDRange FEV 1 (% predicted)23±6(13-34) FEV 1 /FVC0.29±0.08(0.19-0.48) FRC (% predicted)210±73(151-436) RV (% predicted)281±81(172-470) TLC (% predicted)131±28(94-220) IC/TLC ratio0.20±0.06(0.09-0.33) RV/TLC (%)71±6(63-85) DL CO (% predicted)37±15(13-73) TRANSEPOC: Lung Function Tests Peinado VI et al. JHLT 2013;32:1262–69

22 AMBIENT AIR100% O 2 p values PaO 2, mmHg59±9 539±69 <0.001 PaCO 2, mmHg46±751±10 <0.001 Log SDQ (≤ 0.60)0.9±0.21.1±0.2 <0.001 Log SDV (≤ 0.65)1.1±0.21.1±0.2NS Dead Space, %35±1039±7<0.05 TRANSEPOC: Pulmonary Gas Exchange Peinado VI et al. JHLT 2013;32:1262–69

23 ΔLog SDQ TRANSCOPD 0.20 ± 0.10 HEALTHY Individuals (n, 5) 0.17 ± 0.15 Reactive COPD -1 & -2 (> 0.41) (n, 11) 0.57 ± 0.13 Non-Reactive COPD -1 & -2 (≤ 0.41) (n, 9) 0.25 ± 0.12 TRANSEPOC: Ventilation-Perfusion Response to 100% Oxygen Peinado VI et al. JHLT 2013;32:1262–69

24 AMBIENT AIR100% OXYGENp values Q T, L.min -1 4.8±0.84.5±0.6<0.01 PAP, mmHg23±519±5<0.01 PVR, mmHg.L -1.min -1 301±96251±85<0.001 TRANSEPOC: Pulmonary Hemodynamics Peinado VI et al. JHLT 2013;32:1262–69

25 TRANSEPOC: Emphysema Subjective Score (76 ± 17%; 47-95%)

26 TRANSEPOC: Lung Morphometry TOTAL PATHOLOGICAL Score 76 ± 27 EMPHYSEMA Score 62 ± 17 Mean Linear Intercept 0.36 ± 0.09 Peinado VI et al. JHLT 2013;32:1262–69

27 Endothelial Dysfunction Intimal Thickening (Remodelling) PAP CIGARETTE SMOKE eNOS SMCs Proliferation INFLAMMATION PRODUCTS HPV EC V A /Q Mismatch INFLAMMATION VEGF HYPOXEMIA Shear Stress COPD: Pulmonary Vascular Abnormalities Peinado VI et al. Chest 2008;134:308-14

28 Peinado VI et al. JHLT 2013;32:1262–69

29 CHEST 2012; 142:1654-8

30 Intima area, % total 0 10 20 30 40 NSm Sm * TRANSEPOC: Pulmonary Arteries Morphometry * COPD LT Peinado VI et al. JHLT 2013;32:1262–69

31 TRANSEPOC: Lymphocytic Infiltrate in Pulmonary Arteries NSmSm 0 100 200 300 400 Cells/mm 2 CD8 + * * 0 0.5 1.0 1.5 2.0 2.5 CD4/CD8 ratio CD4 + /CD8 + * NSmSmCOPD * LT * * Peinado VI et al. JHLT 2013;32:1262–69

32 Contraction to Hypoxia, % KCl 0 5 10 15 20 Sm COPD * * LT TRANSEPOC: Pulmonary Vascular Reactivity Peinado VI et al. JHLT 2013;32:1262–69

33 0510152025 100 200 300 400 500 600 PVR, dyn.s.cm -5 TRANSEPOC: PVR & Hypoxic Vascular Reactivity RESPONSE TO HYPOXIA, % KCl r = 0.60 p < 0.02 Peinado VI et al. JHLT 2013;32:1262–69

34 0510152025 PAP Changes, mmHg 2 0 -2 -4 -6 -8 -10 -12 r = 0.54 p < 0.04 TRANSEPOC: Oxygen-Induced Changes in PAP & Hypoxic Vascular Reactivity RESPONSE TO HYPOXIA, % KCl

35  El enfisema pulmonar es severo pero la hipertensión pulmonar (HP) es discreta  La morfometría vascular pulmonar está relativamente bien conservada  La reactividad vascular hipóxica y la relajación endotelial arterial son discretas  Hay un intenso infiltrado inflamatorio en la adventicia vascular Hallazgos principales

36  Es probable que el enfisema pulmonar constituya el mayor determinante de la HP (discreta) de estos pacientes con EPOC muy severa  Sorprenden las mínimas diferencias en las anomalías vasculares pulmonares entre estos pacientes con EPOC muy severa y las observadas previamente en no fumadores con espirometría normal, en contraste con las diferencias muy superiores observadas entre no fumadores y fumadores con espirometría normal o pacientes con EPOC leve-moderada Conclusiones

37 GOLD 2 GOLD 3 GOLD 4 DISEASE PROGRESSION IN COPD Decramer M & Cooper C. Thorax 2010;65:837-41 50 ml/yr 30 ml/yr 35 ± 1 ml/yr 25 ± 2 ml/yr 33 ± 1 ml/yr Vestbo J et al. NEJM 2011;365:1184-92