ΣΥΝΟΠΤΙΚΗ ΔΙΑΓΝΩΣΤΙΚΗ ΚΑΙ ΘΕΡΑΠΕΥΤΙΚΗ ΠΡΟΣΕΓΓΙΣΗ ΚΑΡΔΙΑΓΕΙΑΚΩΝ ΠΑΘΗΣΕΩΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ

Περιφερικό Καρδιολογικό Συνέδριο ΕΚΕ Κοζάνη 2012 ΣΥΝΟΠΤΙΚΗ ΔΙΑΓΝΩΣΤΙΚΗ ΚΑΙ ΘΕΡΑΠΕΥΤΙΚΗ ΠΡΟΣΕΓΓΙΣΗ ΚΑΡΔΙΑΓΕΙΑΚΩΝ ΠΑΘΗΣΕΩΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ George Giannakoulas, MD Pulmonary Hypertension Clinic AHEPA University Hospital

Available on www.escardio.org/guidelines

What is Pulmonary Hypertension? An haemodynamic definition Pressure Mean PAP > 25 mmhg (rest) or > 30 mmhg (exercise) Extensive literature search* found N=14+2.3 mmhg upper limit 20+2 mmhg mpap < 20 mmhg Normal mpap 21-24 mmhg Borderline mpap > 25 mmhg Pulmonary hypertension * Olschewski et al. 4th World Congress on PAH, Dana Point Ca, Feb 2008

Updated clinical classification of pulmonary hypertension (Dana Point 2008)

PH diagnosis

Referral to Specialist centre London Royal Free Hammersmith Royal Brompton Great Ormond Street Glasgow Sheffield Cambridgeshire Republic of Ireland Newcastle Upon Tyne

Class NYHA Functional Class Pa6ent Symptoms Class I (Mild) No limita1on of physical ac1vity. Ordinary physical ac1vity does not cause undue symptoms Class II (Mild) Slight limita1on of physical ac1vity. Comfortable at rest, ordinary physical ac1vity results in symptoms. Class III (Moderate) Marked limita1on of physical ac1vity. Comfortable at rest, but less than ordinary ac1vity causes symptoms. Class IV (Severe) Symptoms of cardiac insufficiency at rest. If any physical ac1vity is undertaken, discomfort is increased.

Increased awareness of PAH may lead to earlier patient diagnosis Patients (%) 100 90 80 70 60 50 40 30 20 10 0 French registry (2002 2003): 75% of patients diagnosed in late-stage disease 1 1 24 63 12 Patients (%) 100 90 80 70 60 50 40 30 20 10 0 More recent findings from the REVEAL registry (2006 2007) suggest that increased disease awareness is leading to earlier patient referral in the symptomatic stages of the disease 2 8 38 49 66 FC I FC II FC III FC IV FC I FC II FC III FC IV FC = functional class; PAH = pulmonary arterial hypertension; REVEAL = Registry to Evaluate Early and Long-term PAH Disease Management 1. Humbert M, et al. Am J Respir Crit Care Med 2006;173:1023 30; 2. Badesch DB, et al. Chest 2007;132 (Suppl):473.

PH etiology 3,5% 10% 1,5% 78% 7% Adapted from Galiè N. ESC 2009 Gabbay et al. ATS 2007

Differential diagnosis of PH Diagnosis is based on echocardiographic suspicion and initial exclusion of the most common causes of PH Galiè et al. Eur Heart J 2009

Doppler echocadiography-based criteria for Pulmonary Hypertension Level of suspicion TR max Velocity Estimated RVSP (mmhg) Other DE findings Class/ Level Unlikely < 2.8 m/s < 36 mmhg No I/B Possible < 2.8 m/s < 36 mmhg Yes IIa/C 2.9 3.4 m/s 37 50 mmhg No Likely > 3.4 m/s > 50 mmhg Yes/No I/B Galiè et al. Eur Heart J 2009

When to proceed to RHC? Level of probability DE criteria Symptoms Risk factors RHC Class/ Level Low Unlikely No No No I/C Yes Yes No Yes No Yes Intermediate Possible No No No I/C No Yes Yes Yes? Yes IIb/C IIb/C High Likely Yes Y/N Yes I/C No Yes IIa/C RHC indicated in high and intermediate probability with symptoms and risk factors for PAH Galiè et al. Eur Heart J 2009

Favorable vasodilator response Drop in mean PAP of 10 mm Hg to a value <40 mm Hg with an unchanged or increased cardiac output

Vasoreactivity testing Base NO 20 ppm mpap 45 mmhg mpap 28 mmhg

Other imaging modalities Echocardiographic Measurements Male Age 25 Years mpap = 56 mmhg Female Age 24 Years mpap = 53 mmhg

Echocardiographic Measurements Male Age 25 Years mpap = 56 mmhg Female Age 24 Years mpap = 53 mmhg SV = 90 ml, 6MWD = 500 m SV = 30 ml, 6MWD = 300 m

PH treatment

Percentage Surviving 100 IPAH/FPAH (PPH): Progressive disorder associated with high mortality rate best! 40 20 PAH Survival-NIH registry data 1980 s 80 The earliest the 60 68% 50% mortality at 2.5 years if left untreated Time from sx to dx: 2.5 yrs Median: 2.8 yrs 50% survival at 2.5 yrs 48% 34% 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years of Followup D Alonzo GE, Barst RJ, Ayres SM. Survival in patients with PPH: Results from a National Prospective Registry. Ann Internal Med. 1991; 115: 343-349

BREATHE-1:Time to Clinical Worsening Event-Free (%) 100 75 50 25 0 95% 89% p = 0.003875% p = 0.0015 63% Bosentan (n = 144) Bosentan (n = 35) Placebo (n = 69) Placebo (n = 13) 0 4 8 12 16 20 24 28 Time (weeks) * Time to clinical worsening = Shortest time to either death, premature withdrawal or hospitalization due to PHT worsening, or initiation of epoprostenol therapy

ARIES Study ARIES-E: Long term effects of ambrisentan Improvement Change in 6MWD (m) 70 60 50 40 30 20 10 0-10 Years 5 mg, n = 186 10 mg, n = 96-20 0.0 0.25 0.5 1.0 1.5 2.0 Change from baseline data presented Mean ± 95% confidence interval Last observation carried forward for missing data Data on File Presentation by Ron Oudiz CHEST 2008

Sildenafil: Outcomes

I.V. Flolan

Advanced therapies for PAH Survival benefits Overall RR 0.57, 95% CI 0.35, 0.93 Reduce in mortality by 43%, p = 0.023 BUT Advanced therapies have improved survival Mortality remains high We need further progress Galiè N, et al. Eur Heart J 2009; 30:394-403.

Group 2

PDE- 5 Inhibi6on to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure: the RELAX trial A large NIH- funded, randomized, placebo- controlled trial that is currently ongoing in pa1ents with HF and preserved LV func1on. Preliminary results show: - Increase in exercise capacity - Improvement in arterial s1ffness - Improvement in arterioventricular coupling in the sildenafil group

Group 3

Group 4

Thank you

Targets for Therapy in PAH mbert et al. New Engl J Med 2004

Some RV actions of Current Stimulate s Therapies ETRA PDE5i Inhibits PDE5i PGI 2 ETRA PGI 2 PDE5i? ETRA? PGI 2 PDE5i PDE5i ETRA

Time-course of 25 published randomized controlled studies (identified by acronyms, if any, or drug and year of publication) in pulmonary arterial hypertension as of May 2010. Galiè N et al. Eur Heart J 2010;31:2080-2086

Prostacyclin Analogues: Intravenous, Subcutaneous, or Inhaled Epoprostenol (Flolan ) Treprostinil (Remodulin ) Treprostinil (Remodulin ) Iloprost (Ventavis )

Effects of the Combina6on of Bosentan and Sildenafil Versus Sildenafil Monotherapy on PAH the Compass 2 trial This study will investigate the effects of the combination of bosentan and sildenafil. Patients with symptomatic PAH treated with a stable dose of sildenafil equal to or greater tha 20 mg t.i.d. for at least 12 weeks will be randomized to placebo or bosentan 125 mg b.i.d. All randomized patients will be treated with study drug until the predefined target number of morbidity/mortality events is reached Estimated Enrollment: 250 Study Start Date: April 2006 Estimated Study Completion Date: June 2012 Estimated Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

A Study of First- Line Ambrisentan and Tadalafil Combina6on Therapy in Subjects With PAH the AMBITION trial The purpose of this study is to compare the two treatment strategies; first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in subjects with PAH. This will be assessed by time to the first clinical failure event. Estimated Enrollment: 352 Study Start Date: October 2010

Meta-analysis of PAH trials by pump function Handoko ML, et al. Eur Resp Rev 2010

Prevention of pulmonary vascular remodeling with losartan Rondelet B. Am J Physiol Heart Circ Physiol 2005

RV pacing Handoko ML. Am J Physiol Heart Circ Physiol 2009

IPAH patients are particularly susceptible to amiodarone-induced thyroid dysfunction, with potentially life-threatening consequences Prolonged exposure increases the risk

There has been progress The disease has remained incurable and median survival is still limited to,5 6 yrs, with insufficient functional improvement in many of the survivors

Γεώργιος Γιαννακούλας, MD, PhD, FESC Ιατρείο Συγγενών Καρδιοπαθειών και Πνευμονικής Υπέρτασης Α Καρδιολογική Κλινική ΑΧΕΠΑ

Diagnosis and assessment of PAH Patients are likely best assessed in a specialised referral centre An organised approach to the diagnostic evaluation is necessary To monitor patients status and response to management, using multiple assessment techniques is probably preferred over any single test. Such an evaluation should include assessment of: History and physical examination Exercise capacity (6MWT, CPET) Non-invasive imaging (ECHO, MRI, etc) Hemodynamics

Signs and symptoms of PAH Dyspnoea on exertion* Fatigue* Weakness* Syncope/pre-syncope* Chest pain* Abdominal bloating Cough Haemoptysis Raynaud's phenomenon Poor appetite Nausea Peripheral oedema Hoarseness *Typical early symptoms PAH = pulmonary arterial hypertension 1. McGoon M, et al. Chest 2004;126 (Suppl 1):14 34; 2. Rich S, et al. Ann Intern Med 1987;107:216 23; 3. Rubin LJ. Chest 2004;126 (Suppl 1):7 10.

PAH: physical examination Loud pulmonary valve closure sound (P2)* Early systolic pulmonary valve ejection click* Midsystolic pulmonary ejection murmur* Prominent jugular a wave* Left parasternal lift* Tachycardia: right ventricular S4 gallop* right ventricular S3 gallop Tachypnoea Diaphoresis Pallor/acrocyanosis/cyanosis Elevated jugular venous pressure Systolic murmur (TR) Diastolic murmur (PI) Hepatomegaly, frequently pulsatile Oedema Ascites Failure to thrive *Typical early signs P2 = pulmonic valve closure; PAH = pulmonary arterial hypertension; PI = pulmonary insufficiency; TR = tricuspid regurgitation 1. Bossone E, et al. Chest 2007;131:339 41; 2. McGoon M, et al. Chest 2004;126 (Suppl 1):14 34; 3. Rich S, et al. Ann Intern Med 1987;107:216 23.

PAH ASD

mpap 50 mmhg CI 2.4 l/sec/m² PVR 8.9 WU

When things are obvious!

But not always

Cardiopulmonary Haemodynamics CO = (LVOTd) 2. VTI LVOT. HR

Cardiopulmonary Haemodynamics 4 CO 3 2 1 0-1 -2-3 -4 0 2 4 6 8 10 12 Adapted from: Fisher MR et al. AJRCCM 2009; 179:615-621

Factors associated with a higher probability of PH due to LHD Clinical features Echocardiography Interim evaluation Age > 65 Elevated systolic BP Elevated pulse pressure Obesity, metabolic syndrome Coronary artery disease Diabetes mellitus Atrial fibrillation Left atrial enlargement Concentric remodelling of the LV Echocardiographic indicators of elevated LV filling pressure Symptomatic response to diuretics Exaggerated increase in BP during exercise Chest X-ray consistent with HF Galiè et al. Eur Heart J 2009

Out of proportion PH: TPG (mean PAP mean PWP) >12 mmhg or mpap >35-40mmHg Introduction of the concept of «out of proportion PH» Exclusion or confirmation of CTEPH Galiè et al. Eur Heart J 2009

Galiè et al. Eur Heart J 2009

Typical features of CTEPH Fedullo et al. N Engl J Med 2001 Hoeper M. Circulation 2006

High probability V/Q scan in Pulmonary Venoocclusive disease Bailey C et al. Am J Respir Crit Care Med Vol 162. pp 1974 1978, 2000

Galiè et al. Eur Heart J 2009

Why do we need RHC?

Bernoulli mod. equation RV-RA ΔP = 4. (TRV) 2 RV pressure = 4. (TRV) 2 + RAP RV pressure = Systolic PAP Yock PG, Popp RL. Circulation 1984;70:657-62 Sensitivity: 0.79-1.00 Specificity: 0.6-0.98 Diameter Collapse RAP < 2 50% 0-5 < cm2 < 50% mmhg 6-10 cm2 50% mmhg 10-15 cm2 0% mmhg >15

Pulmonary Pressures PAPs 29% (9%) 48% 23% (15%) Good Doppler signals Poor Doppler signals (31%) Adapted from: Fisher MR et al. AJRCCM 2009; 179:615-621

Pulmonary Pressures RAP RCH measurement 25 20 15 10 5 0 34% 0 5 10 15 20 Echocardiographic Estimate 39% Adapted from: Fisher MR et al. AJRCCM 2009; 179:615-621

Right heart catheterization RV, PA, PCWP, and LV pressures be measured at end expiration (esp in obese and pts with lung disease) For the measurement of cardiac output, both thermodilution and Fick methods are reliable in PAH patients, except severe TR and cardiogenic shock. The Fick method is mandatory in the presence of an intracardiac shunt. Vasodilator challenges with inhaled NO or intravenous epoprostenol or adenosine are encouraged in most patients

Exercise RHC An increase in PCWP to >15 mm Hg in response to exercise or fluid challenge suggests the presence of pulmonary venous hypertension Johns Hopkins University protocol for exercise RHC

Novel Techniques PVR is a simple measure of the opposition to the mean component of flow Pulmonary circulation is pulsatile with multiple bifurcations, and wave reflection is an inevitable consequence Impedance, the opposition to blood flow by the pulmonary circulation, is frequency dependent on and modulated by heart rate, vessel dimensions, vessel stiffness, and wave reflections Champion et al. Circulation 2009

Champion et al. Circulation 2009

RV-pulmonary circulation unit Champion et al. Circulation 2009

The effect of PH on the RV

RV is more sensitive to afterload changes Right Ventricle Stroke volume Left Ventricle -100 0 +100 % change in vascular resistance

MRI Gold standard for RV size and function Pulmonary angiography

Effect of advanced therapies

novel uses of MRI Using standard 1.5- T machines, pulses, and a single gadolinium injection as low as 2 to 5 cm 3 images were obtained without a breath hold

CT Normal

PET imaging

ESC/ERS 2009 PAH guidelines Galie N et al, Eur Heart J 2009

Mortality of PAH-SSc is elevated 1.0 Cumulative survival 0.8 0.6 0.4 0.2 Isolated PAH (n=259) 0.0 P=0.02 Respiratory disease (n=56) 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Years from diagnosis In the UK registry, 3-y survival of PAH-SScl = 47% Condliffe R et al. Am J Respir Crit Care Med 2009

Outcome of PAH-SSc is worse than IPAH % survival 100 75 50 25 Logrank p-value=0.002 0 IPAH (n=41) PAH-SScl (n=50) 0 1 2 3 4 Time (years) despite a less severe state of disease @ diagnosis, (Ppa 46 vs 54 mmhg) Fisher M et al. ARTHRITIS & RHEUMATISM 2006; 54: 3043 3050

SSc Other CTD (ie SLE) Asymptomatic or Decline in DLCO Echocardiography (yearly in asymptomatic SSc) Symptomatic TRV < 2.8 m/sec No other sign of PH TRV 2.8-3.4 m/s TRV > 3.4m/s With or without signs of PH No other sign of PH Other signs of PH PH unlikely PH possible PH likely PH highly likely - Biomarkers NI workup + Perform non invasive workup (Biomarker, V/Q scan, HRCT ) to exclude non PAH PH Consider Follow up echo (3-6 mo) In symptomatic patients RHC indicated For PAH diagnosis Vachiery JL, Coghlan G Eur Respir Review 2009

Which prognostic indicators? Clinical assessment Symptoms Clinical Signs Rate of progression NYHA/WHO FC Signs of RV failure Distance walked Peak VO 2 VE/VCO 2 slope Exercise capacity 6 minute walking test CP exercise test Evaluation of RV (dys)function Biomarkers Echocardiographic variables Invasive haemodynamics both @ baseline and follow up Changes in BP BNP/NT-ProBNP Troponin Uric acid Others (NA, Hb) TAPSE Tei index Pericardial effusion RAP Cardiac index

Problems and controversies The degree of PH (PAP) does not strongly correlate with symptoms or survival, whereas RV size and right atrial pressure reflect functional status and are strong predictors of survival Μeasurement of PAP is not necessarily a sensitive index of the condition of the pulmonary vasculature. PAP might drop as the RV function deteriorates The interobserver variability in interpreting a PCWP waveform is extremely large, with variations of as much as 23 mm Hg

Take home messages PAH should be considered in the differential diagnosis of exertional dyspnoea, syncope, angina, and/or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms or signs of common cardiovascular and respiratory disorders Special awareness should be directed towards patients with associated conditions and/or risk factors for development of PAH, such as family history, CTD, CHD, HIV infection, portal hypertension, haemolytic anaemia, or a history of intake of drugs and toxins known to induce PAH Echocardiography is a first line noninvasive tool and should always be performed in the case of suspected PH. However, decisions on initiating treatment or risk stratification should be based on multiple diagnostic tests, especially RHC

Thank you for your attention

PAH in CHD

1 HIV 6.2% ipah 39.2% PoHT 10.4% CHD 11.3% CTD 15.3% Anorex 9.5% FPAH 3.9% 52.6% PPH 4.3% had at least 2 coexisting factors Minimal incidence 2.4/million (n=121) Minimal prevalence 15/million (n=553) Large regional differences up to 25/million 1. Humbert AJRCCM 2006;173:1023

All hospital activities captured 1986 2001 Based on the Scottish Morbidity Record Scheme 16 65 years with ipah, PAH-CHD or PAH-CTD Scottish Pulmonary Vascular Unit 1997-2006 UK referral centre for Scotland Equivalent to french national reference centre Prevalence (cases/m) SMR 52 7.1 SPVU 26 7.6 Incidence (cases/m/year)

American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association, et al. J Am Coll Cardiol 2009;0:j.jacc.2009.01.004v2-14493

Inherited PAH Περιλαµβάνονται ασθενείς µε οικογενειακό ιστορικό ή ασθενείς µε IPAH και αναγνωρισµένες µεταλλάξεις Γονιδιακός έλεγχος δεν είναι απαραίτητος

Απώλεια της ανασταλτικής δράσης της ΒΜP στον πολ/σµό ΛΜΙ Προαγωγή της απόπτωσης του ενδοθηλίου

Mitral E/Em=7.8

LV Eccentricity index D2 D1 LVEI = D2/D1

RV systolic function

RV systolic function RV function Cut-off value = 10.5 cm. S -1 Sensitivity : 90% Specificity : 85% Meluzin J et al. Eur Heart J 2001; 22:340-48

RV systolic function RV systolic function Normal value: 0.28 ± 0.04 a b

RV systolic function RV systolic function c a b Adapted from Huez S. Index = (a + c)/b Harada K et al. Am J Card 2002; 90: 566-9

Noninvasive echo measurements mean PAP=90 (0.45 x PAAT) valid when PAAT<120ms Dabestani A et al. Am J Cardiol. 1987 PVR = TRV/TVI RVOT x 10 + 0.16 PVR ECHO =(3.64/6.5)x10+0.16 =5.76 WU PVR CATH= 6.0 WU Abbas AE et al. JACC 2003

Progression of PAH role of haemodynamics Asymptomatic Symptomatic/ Stable Progressive/ Declining Level RV function Cardiac output at exercise Cardiac output at rest Mean PAP Increasing PVR Time Adapted from Rich et al. In: Harrison s Principles of Internal Medicine. 15th ed. 2001: 1506-1507

Definition of inadequate response to PAH treatments Inadequate clinical response for patients who were initially in WHO-FC II or III: Resulting clinical status defined as stable and not satisfactory. Resulting clinical status defined as unstable and deteriorating. Inadequate clinical response for patients who were initially in WHO- FC IV: No rapid improvement to WHO-FC III or better. Resulting clinical status defined as stable and not satisfactory.

Risk assessment

PAH follow up

Αναδροµική µελέτη σε πληθυσµό 557 ασθενών µε IPAH Responders :12.6% (n=70) Μακροπρόθεσµη ανταπόκριση στους CCB: παραµονή σε στάδιο NYHA I/II µε παράλληλη βελτίωση των αιµοδυναµικών µετρήσεων, σε σχεδόν φυσιολογικές τιµές, υπό µονοθεραπεία µε CCB για τουλάχιστον 1 έτος Μακροπρόθεσµη ανταπόκριση: <10% ασθενών µε IPAH Circulation 2005;111:3105-3111

ERAs J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84

ΕΝΔΟΦΛΕΒΙΑ ΕΠΟΠΡΟΣΤΕΝΟΛΗ Χρόνος ηµίσειας ζωής <6min, ασταθές σε θερµοκρασία δωµατίου συνεχής ενδοφλέβια έγχυση µε µόνιµο καθετήρα Ανεπιθύµητες ενέργειες κεφαλαλγία, πόνος στη γνάθο, έξαψη, ναυτία, διάρροια, µυοσκελετικά άλγη σχετιζόµενες µε τον καθετήρα: λοίµωξη /σήψη, θρόµβωση διακοπή της λειτουργίας της αντλίας Αντενδείξεις Αριστερή καρδιακή ανεπάρκεια Πνευµονική φλεβοαποφρακτική νόσος Υψηλό κόστος

ΥΠΟΔΟΡΙΑ ΤΡΕΠΡΟΣΤΙΝΙΛΗ (sc TREPROSTINIL) Σταθερό ανάλογο προστακυκλίνης µε χρόνο ηµίσειας ζωής 4.5 ώρες Συνεχής υποδόρια έγχυση µε ειδική αντλία Ανεπιθύµητες δράσεις συστηµατικές πόνος στο σηµείο της έγχυσης τοπική αντίδραση Υψηλό κόστος Simonneau G,Barst RJ,Galie N et al. Am J Respir Crit Care Med 2002

Επίπτωση της θεραπείας πρώτηςγραμμής με προστακυκλίνη στην επιβίωση ασθενών με ΙΠΑΥ 100 89% 90 80 65% Survival in IPAH (%) 70 60 50 40 30 20 10 Sc Treprostinil (Lang et al. CHEST 2006) Expected (after D Alonzo et al. Ann Intern Med 1991) IV epoprostenol (Mc Laughlin et al. Circulation 2002) At risk (n) 0 0 13 26 39 52 65 78 91 104 117 130 143 156 169 182 195 208 32 30 21 16 9 Time (weeks)

ΕΙΣΠΝΕΟΜΕΝΗ ΙΛΟΠΡΟΣΤΗ (ILOPROST) PPH-CTD-CTEPH N = 203 NYHA : III-IV Iloprost = 2.5 or 5 µg 6-9/d Combined primary end-point (NYHA FC + 6MWT) Olschewski H, Simonneau G,Galie N et al. AIR study N Engl J Med 2002 Εκλεκτική αγγειοδιαστολή της πνευµονικής κυκλοφορίας Ανεπιθύµητες δράσεις ξηρός βήχας ήπιες συστηµατικές Χρήση ειδικού νεφελοποιητή Βραχεία διάρκεια δράσης 6-9 (- 12) εισπνοές /ηµέρα Διακοπή κατά τη διάρκεια της νύχτας

ΑΝΤΑΓΩΝΙΣΤΕΣ ΥΠΟΔΟΧΕΩΝ ΕΝΔΟΘΗΛΙΝΗΣ ERAs Ambrisentan Bosentan Sitaxentan Εκλεκτικότητα ΕΤ Α :ΕΤ Β 30:1 6500:1 4000:1 Δοσολογία 125-250mg 100mg 5-10mg Αλληλεπιδράσεις sildenafil αντιπηκτικά κυκλοσπορίνη Α Ανεπιθύμητες ενέργειες γλιβενκλαμίδη κυκλοσπορίνη Α, αντισυλληπτικά Ηπατοτοξικότητα (ALT/AST>3φορές) 0.8-3% κυκλοσπορίνη Α 11% 3-5% Περιφερικό οίδημα 4.7% 9%

IV sildenafil 10 mg (12.5ml) = 20 mg oral dose European Heart Journal (2004) 25, 431 436

Effect of Tadalafil* on 6MWD (PHIRST) Change in 6MWD (m) 70 60 50 40 30 20 10 Placebo Tadalafil 2.5 mg Tadalafil 10 mg Tadalafil 20 mg Tadalafil 40 mg p<0.001 p<0.05 p<0.05 0 0 4 8 12 16 Weeks *Adcirca Galiè N et al. Circulation. 2009;119;2894-2903.

Ευεργετικά αποτελέσµατα των νεότερων θεραπειών της ΠΑΥ

Chest 1987;92;330-334 D Alonzo et al. Ann Intern Med 1991;115:343-9 NIH Registry : Επιβίωση 1 yr 3 yr 5 yr 68% 48% 34%

NYHA I,II NYHA III NYHA IV

Συνδυασμοί φαρμάκων Προστανοειδή (iv, sc,inh) Ανταγωνιστές υποδοχέων ενδοθηλίνης Αναστολείς φωσφοδιεστεράσης-5 BREATHE 2 STEP PACES-1 TRIUMPH PHIRST IV epoprostenol + bosentan (as 1 st line Tx) Bosentan + inhaled iloprost IV epoprostenol + sildenafil Bosentan or sildenafil + inhaled treprostinil Bosentan + tadalafil

Dromparis P, Sutendra G, Michelakis ED. J Mol Med. 2010 Aug 24.

Michelakis ED, Sutendra G, Dromparis P, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010 ;2:31ra34 McMurtry MS, Bonnet S, Wu X, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004;95:830 840

ΣΧΟΛΙΑ - ΣΥΜΠΕΡΑΣΜΑΤΑ Η πρόγνωση των ασθενών µε ΠΑΥ βελτιώνεται Η θνητότητα παραµένει υψηλή Η βέλτιστη αντιµετώπιση των ασθενών απαιτεί: Συνεργασία µε εξειδικευµένο κέντρο Στενή παρακολούθηση των ασθενών Λογική χρήση των φαρµάκων και των συνδυασµών αυτών

ERAs J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84

Metaanalysis of randomised controlled trials in PAH (Galie N. et al. Eur Heart J Feb 2009)

Strategies to Prevent and Treat Right Heart Failure Reduce RV wall stress ( MVO 2, ischemia) Reduce RV afterload Pulmonary vasodilators (O 2, CCB, ERA s, prostanoids, nitric oxide) Anticoagulation to prevent thrombosis Reduce RV preload and TR (diuretics: loop, aldosterone antagonists) Improve RV inotropy Chronically: digoxin Acutely: IV epoprostenol, IV treprostinil low dose IV dobutamine or dopamine at 1-2 mcg/kg/

Invasive Treatment of Advanced RV Failure Atrial septostomy +/- ECMO Improve LV filling and systemic cardiac output Transplantation - lung / heart-lung Reserved for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy 1 year survival - 65-70% 5 year survival - 40-50%