Pulmonary Hypertension Essentials. PD Dr. med. Silvia Ulrich Somaini University Hospital of Zurich
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1 Pulmonary Hypertension Essentials PD Dr. med. Silvia Ulrich Somaini University Hospital of Zurich
2 Agenda Basics and Presentation Classification Diagnosis Pathogenesis Diagnosis Treatment
3 Pathogenesis and Presentation The systemic circulation: pressures 120/80 mmhg The pulmonary circulation: pressures 20/8 mmhg Definition PH = mean pulmonary artery pressure (mpap) 25mmHg
4 Most common causes of PH: Hypoxic Parenchymal Lung Diseases Left Heart Diseases postcapillary PH or Pulmonary Venous Hypertension PCOP 15mmHg
5 Diseases of the pulmonary circulation precapillary PH : PCOP 15mmHg Intrinsic narrowing of pulmonary vessels = Pulmonary Arterial Hypertension PAH Chronic occlusion of pulmonary vessels = Chronic Thromboem bolic PH CTEPH
6 Classification of PH
7 Three steps in the diagnosis of Pulmonary Hypertension 1. Suspect 2. Detect 3. Characterize
8 Diagnosis of Pulmonary Hypertension: Suspect, detect and characterize Symptom Evaluation Screening Incidental Finding Suspected PH Detection Physical Examination Chest X-ray Electrocardiogram Echocardiogram PH Detected
9 Symptoms of PH: Pulmonary circulatory failure: Backward failure: - fluid retention - edema - weight gain - liver enlargement - decreased appetite Forward failure: - fatigue - exercise capacity - exhaustion - arrhythmia - syncope - depression Exertional dyspnea, cough, hoarseness
10 Clinical Examination
11 ECG in PH Bondermann ERJ 2010: ECG in combination with BNP Bassone et al Chest
12 ECG in PH The ECG lacks sufficient sensitivity to serve as an effective screening tool for PH However, it is abnormal in 90% of cases Right axis deviation Right ventricular hypertrophy Right atrial enlargement Bondermann ERJ 2010: ECG in combination with BNP Bassone et al Chest
13 Chest-XR Initially low sensitivity Important for DD: parenchymal lung disease? Kerley-B-lines? Hili? Sarcoidosis?...
14 Blood Tests Antinuclear Antibodies Liver Function HIV-Test BNP Clotting Studies
15 Pulmonary Function Testing Spirometry Airflow Lung Volumes Lung size Diffusion Capacity Gas exchange Low diffusion capacity often first and only pathologic result! Be aware!
16 Doppler Echocardiography in Pulmonary Hypertension Differential diagnosis: exclusion of mitral and/or aortic valvulopathy, LV systolic/diastolic failure Measurement of pressures: maximum velocity of tricuspid regurgitation, acceleration time of pulmonary flow Evaluation of right ventricular function: cardiac output, right heart volumes (surface areas), septal displacement (eccentricity index), pericardial effusion, inferior vena cava dimensions and collapsibility, Tei index, TAPSE Echo important as first confirmatory tool if PH is suspected
17 Measurement of systolic pulmonary artery pressure from tricuspid regurgitation Bernoulli-equation Delta P = 4 x v 2 Syst Ppa = Delta P + Pra m/s Ppa 21/9 mmhg Ppa 74/20 mmhg Naeije and Torbicki, Eur Respir J 1995; 8:
18 Transthoracic echocardiography (TTE): PAP estimate from tricuspid regurgitation High correlation between TTE and RHC measurements of spap ( ) 1 Moderate agreement Tricuspid gradient (mmhg) 100 R 2 = mpap (mmhg) at RHC Barst RJ, et al. J Am Coll Cardiol 2004; 43:40S-47S. Mukerjee D, et al. Rheumatology 2004; 43:461-6.
19 Diagnosis of Pulmonary Hypertension: Suspect, detect and characterize Essential Testing Pulmonary Function Testing V/Q Lung Scan Blood Tests - CTD Screen -HIV - LFTs Right Heart Cath with Acute Vasodilator Trial Characterization Further Testing TEE Spiral CT/EBCT/HRCT/MRI Pulmonary Angiography Blood tests - Clotting study -SaO 2, uric acid -BNP Sleep Study Lung Biopsy PH Detected and Characterized
20 Right heart catheterization: the gold standard for the diagnosis of PH Pulmonary hypertension is defined by a mean pulmonary artery pressure of > 25 mmhg at rest - Limits of normal of resting mean Ppa 8-20 mmhg - Upper limit of normal of exercise mean Ppa ~40 mmhg (systolic ~65 mmhg) Naeije R. Pulmonary vascular function. In: Pulmonary Circulation. AJ Peacock and LJ Rubin eds, 2 nd ed, Arnold, 2004, chap 1, pp 3-13,
21 Zeroing and referencing Do not forget!!!
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23
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25 Pressure, mmhg Pra Prv Ppa Ppao 20 0
26 Pulmonary arterial occlusion pressure Wedge-pressure LVEDP CAVE: not allways the case: Think!
27 Acute vasoreactivity testing In all patients with suspected PAH NO (inhaled) ppm, measure after 5-10 Iloprost (inhaled) 10 ug for 5, measure after 30 Sildenafil (oral) 50mg oral, measure after 60 Alle ähnlich wirksam und sicher Jolliet et al., Thorax 97; Leuchte et al., Chest 04, eigene Daten NO Ilo Sild MPAP 10mmHg and 40mmHg
28 Ventilation-Perfusion Scan Up to the year 2010: CT scans are NOT enough!!!!
29 Pulmonary Angiograpy Golden Standard for CTEPH Indication for pulmonary Endarterectomy To be performed in a specialized center!
30 Thoracic CT scan Central pulmonary artery- > 29mm (Sens 84%, Spez 75%) Arterial- / Bronchial- 1 in min. 3 segments (Sens 65%, Spez 78%) Up to the year 2010: CT scans are NOT enough for CTEPH!!!! Are important for DD
31 Diagnostic algorhythm I ERS/ECS Guidelines ERJ 2009
32 Diagnostic algorhythm II ERS/ECS Guidelines ERJ 2009 SGIM 2010 Diagnosis and Treatment for PH PD Dr. med. Silvia Ulrich Somaini
33 Classification of PH Essentials in Pulmonary Hypertension Core Curriculum Cardiology, Zurich PD Dr. med. Silvia Ulrich Somaini
34 Pulmonary HIV arterial SLE hypertension idiopathic (PAH) Myeloproliferative disease Rheumatoid arthritis Pulmonary hypertension associated with chronic hypoxemia Pulmonary venous hypertension in left heart disease Different disorders may lead to pulmonary hypertension Scleroderma different therapies may be Sleep disordered Congenital heart breathing disease Chronic thromboembolic pulmonary Liver hypertension cirrhosis (CTEPH) warranted
35 Time Course of Pulmonary Hypertension I Preclinical/ No Symptoms II Symptomatic / Stable III-IV IV Progression / Declining Pulm. pressure RV function Level Cardiac output Therapeutic window Years Months
36 Therapeutic options in PH Conventional Therapy Specific therapy for pulmonary arterial hypertension Prostanoids Endothelin-Receptor Antagonist Phosphodiesterase Inhibitors Combination therapy Chronic thromboembolic PH (CTEPH) Emerging therapies
37 Conventional therapy Oral anticoagulation (INR +2) Three non-randomized prospective cohort studies demonstrated survival benefits Oral anticoagulation indicated for all patients with chronic thromboembolic and patients with idiopathic & familial pulmonary arterial hypertension less clear indication for PH associated with connective tissue diseases, hypoxemia, others.. aspirin & other inhibitors of platelet aggregation no therapeutic trials available
38 Conventional therapy Diuretics Indicated for therapy for right heart failure Calcium Channel Blockers Indicated for PAH with positive acute vasodilator response defined as: MPAP 10mmHg and 40mmHg Close follow up of patients, sustained response < 50% Angiotensin converting enzyme inhibitors benefit for pulmonary venous hypertension
39 Conventional therapy Digoxin? No clinical trials available in PAH, may be beneficial for some selected patients Beta-Blockers Contraindicated in PAH and CTEPH Continuous nasal oxygen indicated for all patients with PH and hypoxemia (PaO2 8.0 kpa)
40 Specific therapies for pulmonary hypertension Humbert et al NEJM 04
41 Prostanoids for PH Vasodilators, antiproliferative, inhibitive for platelet-aggregation Efficacy in severe PAH documented in randomized controlled trials (RCT) for: intravenous epoprostenol/iloprost inhaled iloprost subcutaneous or intravenous treprostinil
42 Specific therapies for pulmonary hypertension Humbert et al NEJM 04
43 Endothelin receptor antagonists Vasodilators, antiproliferative Efficacy in moderate to severe PAH documented in RCT for: bosentan (ET A & ET B blocker) ambrisentan (ET A blocker)
44 Specific therapies for pulmonary hypertension Humbert et al NEJM 04
45 Phosphodiesterase-(5)- inhibitors Vasodilators, antiproliferative Efficacy in PAH documented in RCT for: Sildenafil Tadalafil Considerable differences between agents pulmonary selectivity: tadalafil & sildenafil improvement of arterial oxygenation: sildenafil May cause hypoxemia: vardenafil
46
47 If inadequate clinical response Sequential combination therapy Lung transplantation (balloon atrial septostomy)
48 Chronic thromboembolic pulmonary hypertension (CTEPH) Surgical pulmonary endarterectomy Extremely difficult operation (mortality in very experienced teams ~ 5-10%) Some patients persistent or relapsing PH despite optimal procedure (~ 15%) Careful indication through specialized team
49 Chest X-ray before PEA after PEA
50 MRI-angiography before PEA after PEA
51 Chronic thromboembolic pulmonary hypertension (CTEPH) medical therapy for CTEPH: uncontrolled trials show a benefit for Bosentan (Ulrich SMW 2006) Sildenafil (Reichenberger ERJ 2007) Prostanoide (Bresser ERJ 2004) One RCT: bosentan improved pulmonary hemodynamics but not 6MWD and quality of life
52 Advances in the pathogenetic understanding of PH New therapeutic modalities warranted!
53 Advances in the pathogenetic understanding of PH Pulmonary vascular wall remodeling??? Endothelial? dysfunction Inflammation In situ thrombosis?? Formation of plexiform lesions? Genetic background?
54 Emerging therapies: Imatinib 31 Glivec 28 Placebo Ghofrani AJRCCM 2010;epub
55 Imatinib: Zurich experience BL, baseline; 6M, results after 6 months of therapy with imatinib; B, Bosentan; S, Sildenafil; IH, inhaled iloprost; IV, intravenous iloprost; NYHA, NYHA/WHO functional class; 6MWD, 6- minute walking distance; ND, CAMPHOR assessment not done because of linguistic reasons; mpap, mean pulmonary artery pressure in mmhg; CI, cardiac index in L/min/m2; PVR, pulmonary vascular resistance in dyn*sec*cm-5, SvO2, mixed venous oxygen saturation
56 Imatinib: Zurich experience Imatinib improves hemodynamics, functional class and quality of life in patients with PAH. On the long-term it further improves right ventricular function. For patients suffering from PAH who are not eligible for clinical trials of antiproliferative agents, the off-label use of imatinib may be a potential therapeutic option.
57 Riociguat: sgc stimulator Oral stimulator of soluble guanylate cyclase (sgc) Acts independently of nitric oxide (NO) Targets reduced form of sgc Enhances the sensitivity of sgc to low levels of bioavailable NO Efficacy and anti-remodeling properties in experimental models of PH Efficacy and favorable safety profile in healthy volunteers (phase 1) and patients with PH (proof-of-concept) Stasch JP et al. Nature 2001;410:212 15; Evgenov OV et al. Circulation 2004;110:2253 9; Dumitrascu R et al. Circulation 2006;113:286 95; Evgenov OV et al. Nat Rev Drug Discov 2006;5:755 68; Schermuly et al. Eur Respir J 2008 Jun 11; Frey et al. J Clin Pharmacol 2008;48:926 34
58 Six-minute walking distance: all patients PAH CTEPH n = 31 n = 41 All n = 72 Change in 6-minute walking distance (m) Baseline Duration of treatment (weeks) Titration phase Baseline values PAH: ; CTEPH: ; All: RCTs on the way, Zurich participates Ghofrani, ERJ 2010;36:792.
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