Η παθοφυσιολογία και η κλινική ταξινόμηση. της πνευμονικής υπέρτασης

Η παθοφυσιολογία και η κλινική ταξινόμηση της πνευμονικής υπέρτασης Ηρακλής Τσαγκάρης Πνευμονολόγος Εντατικολόγος Λέκτορας, 2 η Κλινική Εντατικής Θεραπείας και Ιατρείο Πνευμονικής Υπέρτασης Αττικό Νοσοκομείο

Outline Oρισμοί Παθοφυσιολογία Κλινική ταξινόμηση

Ορισμοί

Ορισμός PAH (2004) Φυσιολογικές τιμές Μέση PAP> 25 mmhg (10 15) (> 30 mmhg during exercise) PCWP<15 mmhg (2 12) PVR > 3 Wood units (2 3)

Old definition problems 1) the old definition did not take into account other forms of PH; 2) the threshold of pa >25 mmhg at rest does not reflect the upper limit of normal; 3) clinically relevant PH can be present, despite the P pa being <25 mmhg at rest; 4) the cut off value of 30 mmhg during exercise was arbitrarily chosen and not supported by published data 5) PH is often present in conjunction with elevated P pcw levels. Hoeper, ERJ, 2009

Etiologic classification of pulmonary hypertension MPA PCWP = CO * PVR MPA = CO * PVR + PCWP

Pulmonary Hypertension: Define Lesion Post-Capillary PH (PCWP>15 mmhg; ; PVR nl) Respiratory Diseases VC RA RV PA PC PV LA LV LVEDP Ao Pre-capillary PH PCWP<15 PVR > 3 Wu 15 mmhg

Outline Oρισμοί Παθοφυσιολογία Κλινική ταξινόμηση

Progression of vascular disease

Endothelial Cell Dysfunction in PAH ET-1NO PGI 2 ET-1 1 is elevated (+) Vasoconstriction Cell proliferation / Hypertrophy NO and PGI 2 are reduced (-)( Vasodilation Anti-proliferation Anti-inflammation inflammation Spieker LE et al. J Am Coll Cardiol. 2001;37:1493-1505. Luscher TF and Barton M. Circulation. 2000;102:2434-2440. Albrecht EW et al. J Pathol. 2003;199:8-17. Hankins SR and Horn EM. Curr Cardiol Rep. 2000;2:244-251.

McLaughlin & McGoon Circulation 2006, 114:1417-1431

Pathways in the pathogenesis of PH

Mechanisms of Inflammation Mediated Remodeling

At first examination, pulmonary arterial hypertension is not cancer. The vascular lesions of severe pulmonary arterial hypertension exhibit only some of the classic characteristics of malignancy. As cancer like processes, these lesions are angiogenic, apoptotic cells are rarely found, and antiapoptotic proteins are overexpressed. However, some major characteristics of cancer are missing, most importantly tissue invasion and metastasis.

As stated by the authors, the lesions characteristic of pulmonary arterial hypertension are not cancerous in the true meaning of word, but they show many features of neoplastic proliferation in that there is a process of abnormal and uncontrolled cell growth. Humbert and Hoeper Am J Respir Crit Care Med Vol 178. pp 551 557, 2008

Παθοφυσιολογία: Nέες οδοί??? Platelet derived growth factor (PDGF) Soluble guanylcyclase Serotonin

Platelet derived growth factor (PDGF) PDGF is synthesized by many different cell types, including smooth muscle cells (SMCs), endothelial cells, and macrophages. PDGF has the ability to induce the proliferation and migration of SMCs and fibroblasts, and it has been proposed as a key mediator in the progression of several fibroproliferative disorders such as atherosclerosis, lung fibrosis, and pulmonary hypertension.

Expression of PDGF and PDGF receptors is increased in the pulmonary arteries of patients with pulmonary arterial hypertension. PDGF induces proliferation and migration of human pulmonary artery smooth muscle cells, which is inhibited by imatinib, a PDGF receptor inhibitor. AJRCCM 2008; 78: 81-88

Imatinib Ghiofrani, NEJM, 2005;353:13 Phase II trial 59 pts 6 mo of imatinib 400mg/d or placebo Inclusion: Pts with PAH failing to treatment with ERA, prostanoids, sildenafil Primary outcome: safety tolerability 6MWT

Soluble GuanylCyclase Soluble GualylCyclase Platelet Aggregation Inhibition Soluble GualylCyclase The binding of NO to sgc results in activation and synthesis of the second messenger cyclic guanosinemonophosphate (cgmp). Further more, cgmp activates cgmp dependent protein kinases (protein kinase G) leading to reduction in cytosolic Ca2+ concentration and desensitisation of the actin myosin contractile system.

Evgenov, Nat Rev Drug Discov, 2006

Vascular muscularisation and soluble guanalate cyclase (sgc) expression in lungs and pulmonary arterial smooth muscle cells from healthy donors and IPAH patients

The receptor for NO, sgc, is highly expressed in vascular smooth muscle cells of small pulmonary arteries from patients with IPAH. Schermuly, ERJ 2008;32:881 891

Positive Phase II Findings Reported at European Respiratory Society Meeting / Phase III Studies to Begin in 2008 Berlin, Germany, October 6, 2008 Based on positive Phase II trial findings, Bayer Schering Pharma will move into Phase III trials with its oral agent riociguat (BAY 63 2521). Riociguat is the first member of a new class of vasodilating agents called soluble guanylate cyclase (sgc) stimulators. It is being investigated as a new approach for the treatment of different forms of pulmonary hypertension.

New therapies: Reverse remodelling

Outline Oρισμοί Παθοφυσιολογία Κλινική ταξινόμηση

History of the Diagnostic Classification PPH- World Symposium 1973 Primary pulmonary hypertension Secondary pulmonary hypertension PPH- World Symposium 1998 Evian Classification 1. Pulmonary arterial Hypertension 2. Pulmonary venous Hypertension 3. PH with respiratory diseases or hypoxia 4. PH due to chronic thrombotic and/ or embolic disease 5. PH with disorders directly affecting pulmonary vasculature

Classification of PHT (Venice, 2003) 1. Pulmonary arterial hypertension 2. Pulmonary hypertension with left heart failure 3. PHT with lung diseases and/or hypoxemia 4. PHT due to chronic thrombotic and/or embolic diseases 5. Miscellaneous 1.Sarcoidosis, histiocytosis X, tumors, lymphangiomatosis etc. 4.1. Proximal CTEPH 4.2. Distal CTEPH 1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. Associated (APAH) 2.1. Left sided atrial or ventricular heart disease 2.2. Left sided valvular heart disease 4.3. Non-thrombotic pulmonary embolism 1.4. Associated with significant venous or capillary involvement } 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep disordered breething 3.4. Alveolar hypoventilation disorders 3.5. High altitude Primary pulmonary hypertension 3.6. Developmental disorders Simonneau G et al. J Am Coll Cardiol 2004; 43: 5S 12S

Familial Heritable The distinction between patients with a family history or idiopathic PAH with germline mutation is artificial. All these patients have heritable disease In sporadic cases Mutation can be transmitted or de novo Family history can be ignored Classification does not mandate genetic testing

Connective tissue disease Collagen vascular disease is not considered useful by rheumatologists It does not reflect the important autoimmune and inflammatory aspects of the disease and may cause confusion, as it is sometimes applied to inherited conditions such as Marfan and Ehler Danlos syndrome. The usual term is autoimmune rheumatic disease or connective tissue disease.

Schistostomiasis 2004 Group (4)>PAH subcategory Thought to be embolic Histology is similar to PAH including plexiform lesions Multifactorial Eggs impaction (10%) Portal hypertension due to periportal fibrosis Local vascular inflammation

Hemoglobinopathies chronic hemolytic anemia Sickle cell disease, thalassemia, spherocytosis, stomatocytosis, and microangiopathic hemolytic anemia. PAH with plexiform lesions Mechanisms Disruption of red cell membrane, increased NO reaction with Hb, SMC guanylate cyclase is not activated, vasodilation is impaired Release of erythrocyte arginase, L arginine the substrate for NO synthesis, is converted to ornithine Functional or surgical asplenia

PVOD PCH as group 1 PVOD and PCH frequently associated and clinically indistiguishable Same risk factors as PAH Systemic sclerosis, familial case, BMPR2 mutation, HIV infection, anorexigens Close to PAH, but distinct Worse prognosis Risk of pulmonary edema on PAH therapy

PH due to left heart disease Venice 2004 Dana Point 2008

Proximal vs distal CTEPH No consensus among experts about the definition of proximal and distal CTEPH No attempt to distinguish between proximal and distal forms Strong recommendation that patients with suspected or confirmed CTEPH be referred to a center with expertise in the management of this disease to consider the feasibility of performing PEA, currently the only curative treatment.

Venice, 2004

Clinical classification:advantages Day to day practice To communicate about individual patients Guidelines To standardize diagnosis and treatment Clinical trials and labeling of new drugs To conduct trials with homogeneous groups of patients Basic research To analyze novel pathobiological abnormalities in well characterized patient populations

Clinical classification:limitations PAH is not the only cause of PH in Systemic sclerosis Interstitial lung disease Left heart stystolic/diastolic dysfunction Portopulmonary hypertension Hyperdynamic heart Fluid overload or diastolic dysfunction (high wedge) Schistostimiasis Post capillary hypertension Sickle cell disease Left heart disease Hyperkinetic state

Clinical classification:limitations How to deal with combined etiologies? How to classify disproportionate PH from groups 2 and 3? Individual patients 77 y.o. man with a history of coronary disease, mean PAP 47mmHg, wedge 12 after NO and fluid challenge; Is it PAH? 60 y.o. man with normal lung volumes and chest X ray, but a diffusion capacity of 26% and mean PAP of 54; Is it PAH?

Clinical classification:limitations Too many revisions of the classification (Evian 1998, Venice 2003, Dana Point 2008) Confusion for non experts Confusion for epidemiologists and health authorities International Statistical Classification of Diseases (ICD 9) not updated