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

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

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

...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

COPD: Bronchiolar & Pulmonary Vascular Abnormalities Intimal area (% total area) Bronchiolar inflammation score r = 0.65 p< 0.001

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

COPD: Endothelial Vascular Relaxation Adenosine Diphosphate, log [M] Never-Smokers Smokers COPD * Peinado VI et al. AJP 1998;274:L Maximal Relaxation (% Contraction to LP)

Intimal area (% total area) 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

COPD: Lymphocytic Infiltrate in Pulmonary Arteries NSmSm COPD Cells/mm 2 CD8 + * * Peinado VI et al. AJRCCM 1999;159: Cells/mm 2 CD4 + NSmSm COPD CD4/CD8 ratio CD4 + /CD8 + * NSmSm COPD *

Leukocytes, cells/mm Maximal relaxation to ADP, % r = p < 0.05 Peinado VI et al. AJRCCM 1999;159: COPD: Lymphocytic Infiltrate in Pulmonary Arteries

Band intensity Sm COPD: eNOS Expression in Pulmonary Arteries NSm Barberà JA et al. AJRCCM 2001;164: COPD  132 Kd *

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

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

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

Grades 1234 LOG SDQ & LOG SDV Rodríguez-Roisin R et al. JAP 2009;106: GOLD: Ventilation-Perfusion Imbalance n, 150

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

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

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?

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

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( ) mMRC4±1(3-4) BODE Index (0 –10)7±2(5-10) Peinado VI et al. JHLT 2013;32:1262–69

VARIABLESMean±SDRange FEV 1 (% predicted)23±6(13-34) FEV 1 /FVC0.29±0.08( ) FRC (% predicted)210±73( ) RV (% predicted)281±81( ) TLC (% predicted)131±28(94-220) IC/TLC ratio0.20±0.06( ) 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

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

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

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

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

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

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

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

CHEST 2012; 142:1654-8

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

TRANSEPOC: Lymphocytic Infiltrate in Pulmonary Arteries NSmSm Cells/mm 2 CD8 + * * CD4/CD8 ratio CD4 + /CD8 + * NSmSmCOPD * LT * * Peinado VI et al. JHLT 2013;32:1262–69

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

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

PAP Changes, mmHg r = 0.54 p < 0.04 TRANSEPOC: Oxygen-Induced Changes in PAP & Hypoxic Vascular Reactivity RESPONSE TO HYPOXIA, % KCl

 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

 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

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