1	PULMONARY HYPERTENSION Prof M Kramer Rabin Medical Center
2	Pulmonary Arterial Hypertension Pulmonary arterial hypertension (PAH) is a devastating illness with progressive morbidity and mortality There has been a rapid introduction of novel therapies in the past 10 years making this a treatable chronic disease
3	Pulmonary Hemodynamics
4	Normal vs Abnormal Pulmonary Vasculature
5	Pulmonary Hypertension Normal pulmonary pressures: 20/10; mean 14 Pulmonary hypertension: mean pressure >25mm Hg at rest OR > 30mmHg on exercise.
6	PHT-Classification (Wood)
7	Thromboembolic PHT
8	WHO classification of Pulmonary Hypertension 1. Pulmonary arterial hypertension 2. Pulmonary venous hypertension 3. PHT associated with respiratory disorders/hypoxemia 4. Chronic thrombo-embolic PH 5. PH due to disorders directly affecting the pulmonary vasculature
9	Evian clinical classification 1. Primary Arterial Hypertension Primary Pulmonary hypertension Sporadic Familial Related to : Collagen Vascular disease Congenital systemic to pulmonary shunts Portal Hypertension HIV infection Drugs / Toxins : anorexigens, other Persistent PH of the Newborn 2. Pulmonary Venous Hypertension Left-sided atrial of ventricular heart disease Left-sided valvular heart disease Extrinsic compression of central pulmonary veins Fibrosing mediastinitis Adenopathy / tumors Pulmonary veno-occlusive disease 3. PH associated with disorders of the respiratory system and/or hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Sleep disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Neonatal lung disease Alveolar-capillary dysplasia 4. PH due to chronic thromboembolic disease Thromboembolic obstruction of proximal PA Obstruction of distal pulmonary arteries PE (thrombus, tumor, OVA and/or parasites, foreign material) In-situ thrombosis Sickle cell disease 5. PH due to disorders directly affecting the pulmonary vasculature Inflammatory : schistosomiasis, sarcoidosis Pulmonary capillary hemangiomatosis
10	Pulmonary arterial hypertension Primary pulmonary hypertension (PPH) Sporadic Familial Secondary pulmonary hypertension (SPH) related to: Collagen vascular disease (CVD) Congenital heart disease/shunts (CHD) Portal HTN HIV Drugs/Toxins (anorexigens) Persistent PH of the newborn Other
11	Imbalance of Vascular Growth in Pulmonary Hypertension
12	Pathophysiology Increased Thromboxane A2 Increased Fibrinopeptide Increased endothelin-1 Decreased prostacyclin Decreased Nitric Oxide Impaired K+- ion channel
13	Primary Pulmonary Hypertension- Pathology Vasocostriction In-situ thrombosis. Intimal and medial thickening with obliteration. Plexiform lesions
14	Pulmonary Hypertension
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16	PPH- Clinical Young females 1-2/ million/ yr. Familial in 6-10% (chromosome 2q 31-32) Immune features (ANF+ in 20-30%) DELAYED DIAGNOSIS
17	Primary Pulmonary Hypertension- Symptoms Dyspnea on exertion Chest pain Syncope Right heart failure hemoptysis, palpitations.
18	Cor Pulmonale Hypertrophy and/ or dilatation of the right ventricle secondary to respiratory disease. Invariably associated with pulmonary hypertension. Right ventricular failure is a late consequence of chronic pulmonary hypertension.
19	Primary pulmonary hypertension-Signs Loud pulmonary second heart sound (P2), often with fixed splitting. Right ventricular heave Tricuspid insufficiency Third or fourth heart sound. Right sided cardiac failure: elevated JVP, hepatomegally, peripheral edema. Clear lungs Seldom clubbing
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21	Primary Pulmonary Hypertension- Diagnosis Low diffusion capacity, normal lung volumes Echocardiography. Right heart catheterization. Exclude other causes: vasculitis, pulmonary emboli, cardiac shunt, pulmonary parenchymal disease.
22	PHT-Diagnosis Rule our all other diagnosis Collagen-serology Eisenmenger’s-echo PE-V/Q, spiral CT Lung disease- Lung function
23	Spiral CT Highly diagnostic of clots in large vessels Non-diagnostic in small sub segmental arteries
24	The PPH gene! 6% of PPH are familial Linkage analysis localized the PPH gene to chromosome 2q33. Autosomal dominant; low penetrance.
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26	Molecular Pathways Involved in PAH Bone morphogenetic protein receptor mutation Induction of angiopoetin-1 Serotonin transporter activation
27	Familial Primary Pulmonary Hypertension (Gene PPH1) is Caused by Mutations in the Bone Morphogenetic Protein Receptor II Gene BMPs are members of TGF-beta superfamily Induce apoptosis in PA smooth muscle cells. Necessary for normal fetal growth and development of the pulmonary circulation Mutation is autosomal dominant 20% of carriers will develop PPH
28	BMPR-II 72% of PPH families have an identified BMPR2 mutation or show linkage to this locus. Mutations of the BMPR2 gene are present in at least 26% of patient with sporadic PPH.
29	PAH Etiology:HS-8 Association between herpes simplex and pulmonary hypertension and Castelman disease 11/16 patients with PAH positive for HS-8
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31	Pulmonary Hypertension and Serotonin Pts with PPH have increased circulating 5-HT levels Herve P, Am J Med 1995 PA smooth muscle cells from pts with PPH grow faster when exposed to 5-HT than normals Eddahibi S, J Clin Invest 2001 5-HTT expression is increased in pts with PPH 5-HTT expression is genetically controlled L/L genotype found in 70-80% PPH pts L/L genotype found in 20-30% controls
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33	PPH- Prognosis Poor : median survival 2.5 years . Poor predictors of survival: high mean PAP, high RAP, low CO, low diffusion capacity. Responders to vasodilators do well! Continuous intravenous epoprostanol prolongs survival.
34	Therapeutic Choices for Treating Pulmonary Hypertension Anticoagulants Calcium channel blockers Endothelin receptor antagonists Phosphodiesterase inhibitors Prostacyclins
35	Spectrum of Therapeutic Efficacy of PAH
36	Effects of Anticoagulation on Survival in PPH
37	Anticoagulation for Pulmonary Hypertension recommended for patients with pulmonary arterial hypertension may prolong survival by preventing thrombin induced vascular proliferation not likely to affect symptoms suggested INR 2.0-3.0
38	Acute Effects of Inhaled Nitric Oxide in PPH
39	Effect of High-Dose CCBs on Survival in PPH According to Response Status
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43	Sitaxsentan STRIDE Trial - multicenter, placebo controlled, 12 week clinical trial (180 patients) ET-A selective blocker Improved exercise tolerance (34 meters) Improved hemodynamics (modest) Elevated LFTs (5%-21%)
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45	Potential of Sildenafil as a Treatment for Pulmonary Hypertension Phosphodiesterase-5 located in pulmonary circulation PDE-5 responsible for cGMP hydrolysis in the lung cGMP appears to regulate pulmonary vascular tone and growth Sildenafil, a potent PDE-5 inhibitor, raises cGMP levels
46	Sildenafil in PAH
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48	First large multicenter randomized trail of PGI₂ in PPH Barst R, Rubin L, Long W et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med (1996) 334: 296- 301.
49	Survival in PPH
50	Eisenmenger’s syndrome and prostacyclin
51	Epoprostenol would be the Ideal Treatment for Pulmonary Arterial Hypertension Improves symptoms Improves exercise tolerance Improves hemodynamics Improves survival Works on appropriate biologic pathways if it were not for...
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53	Prostacyclin Analogues and Novel Delivery Systems Treprostinil (Remodulin): subcutaneous Iloprost: inhaled Beraprost: oral
54	Treprostinil Delivery System
55	Prostacyclin analogues Treprostinil (Remodulin) improvements in 6 min walk, symptoms and hemodynamics improvements related to dose of treprostinil treatment effect more impressive in NYHa 3 and 4 site pain
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57	Inhaled Iloprost Clinical Trials (Europe) inhaled iloprost will lower PA pressure and pulmonary resistance acutely patients taking the medication had better exercise tolerance and hemodynamics after 3 months effectiveness less than that seen with Flolan no serious problems arose from the treatment
58	Prostacyclin analogues: iloprost
59	Prostacyclin analogues: beraprost
60	Spectrum of Therapeutic Efficacy of PAH
61	Treatment of Pulmonary Arterial Hypertension current state of the art PPH/PAH is no longer a uniformly fatal disease Anticoagulants improve survival in most patients High doses of calcium blockers can markedly improve survival in select patients Endothelin receptor antagonists improve exercise tolerance in many patients PDE-5 inhibitors appear quite effective but need more study
62	Treatment of Primary Pulmonary Hypertension current state of the art Prostacyclins improve symptoms and survival in patients refractory to other therapies New generation prostacyclins hold great promise Lung transplantation improves survival in patients with very advanced disease Early diagnosis remains a major challenge
63	Conclusions: Pulmonary hypertension is more common than once thought Diagnosis should be suspected and looked for as early as possible There are multiple etiologies for this condition Without therapy prognosis is poor
64	PHT-Therapy