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1

Clinical Challenges in Pulmonary Hypertension

Nattapong Jaimchariyatam, MD, MS, FCCPAssociate Professpr of Medicine, Pulmonary Vascular and Transplantation,

Faculty of Medicine, Chulalongkorn University

Case 1

• ผู้ ป่วยเดก็หญิงไทยอาย ุ14 ปี

• 4 wks มีอาการเหนื�อยหลงัจากไปประเทศจีน ไปที�คนุหมงิ ต้าลี� ลี�เจียง แล้วสดุท้ายที� Shangri La

• เริ�มเหนื�อยเวียนศีรษะระหว่างการเดนิทางจาก ต้าลี� ไป ลี�เจียง (FCII -> IV) ที� Shangri La นอนราบไม่ได้ ไอ ไม่มีไข้ ตาบวม ขาบวม ไม่ได้ไปโรงพยาบาลทานยาจากคนที�ไปด้วย (ยา?) และ O2 supplement นอนพกั 2 คืน เดนิทางกลบั เหนื�อยดีขึ �น

• กลบัถึงเมืองไทยยงัเหนื�อย FCII ขาไม่บวมแล้ว นอนราบได้มากขึ �น

Shangri La

Heaven on Earth

4350 m above sea level

คุนหมิง

ต้าลี�2 คนื

ลี�เจยีง2 คนื

แชงกรีลา2 คนื

1891 m elevation

2007 m elevation

2560 m elevation

4350 m elevation

เริ�มเหนื�อย

นอนราบไม่ได้ คนื

แรก

เหนื�อยมาก บวม ได้

O2 ยา

Case 1

• เคยผ่าตดัตบัตั �งแตเ่ดก็ (ทอ่นํ �าดีอดุตนั) หลงัจากนั �นสบายดี (FCI) ขาดการตดิตามมาหลายปี

• ไม่สบูบหุรี� ไม่ดื�มสรุา ไม่ได้ใช้ยาอะไรเป็นประจํา

• ROS: ยงัเหนื�อยง่าย ไม่บวมแล้ว นอนใช้หมอนหนึ�งใบ ปัสสาวะอจุจาระปกต ิไม่ซีดไม่เหลือง

Physical Examination

• BT 36.5 PR 88/min RR 28/min BP 120/75

• Not pale, No jaundice

• No central cyanosis (O2sat 92% RA)

• Normal lung examination

• RV heaving and accentuated P2 present

• No liver stigmata

• No limb edema

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2

Problem lists

• Persistent dyspnea after high altitude climbing

• History of bile duct obstruction s/p surgery (3 month of age)

Annals of Internal Medicine 2004; 141: 789-800.

High Altitude related Medical Conditions

• High altitude illness/conditions– Acute mountain sickness (AMS)

– High-altitude pulmonary edema (HAPE)

– High-altitude cerebral edema (HACE)

– Periodic breathing

– Pulmonary hypertension

• Medical conditions exacerbated by high altitude

– Pulmonary hypertension, COPD, OSA

Lancet 2003; 361: 1967–74.

Risk Factors

• Physical exertion

• Age less than 50 years

• Residence at an altitude less than 900-1500 m

• Rapid rate of ascent

• Obesity (AMS??)

• Underlying cardiopulmonary disease

Lancet 2003; 361: 1967–74.

High Altitude Pulmonary Edema

• The 2nd night at a new altitude, rarely occurs after 4 d

• Risk factors: children, Hx of recurrent HAPE, rate of ascent, altitude reached, cold, exertion

• 50% have AMS, 14% have HACE

• Fever is common

Lancet 2003; 361: 1967–74.Ann Intern Med 2004; 141:789

High Altitude Pulmonary Edema

• Prevention:

– Slow ascent

– Nifedipine SR 20 mg BID (60 mg/d) prior to ascent and continue for 5 d at altitude

– Sidenafil 50 mg tid

• PH or intracardiac/pulmonary Shunt, VHD– consider when occurs at altitude < 8250 ft (2500 m)

Lancet 2003; 361: 1967–74Ann Intern Med 2004; 141:789N Engl J Med 2002 ; 346: 1606

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Problems list

• Disproportionate high altitude Pulmonary Edema

• Persistent dyspnea after high altitude climbing

Underlying Cardiopulmonary diseases ?

Prominent central PAEnlarged rt descending PA

Peripheral hypovascularity

RV Enlargement

RA Enlargement

Diagnostic dilemma

Confirmation of PH

Identification of PH classIdentification of PH class

Evaluation of severityEvaluation of severity

Hx, PE, CXR, EKG, Echo, ± RHC

V/Q scan, CTPA, HRCTSerology, LFT, PFT, Genetic assessment

BNPWHO-FC6MWTCPET

Echo criteria for estimation of PH

ESC guideline 2015. EHJ 2015.

RVSP

Complete RHC

(+/- LHC)

การตรวจ echocardiogram เพื�อ ให้วินิจฉัยแยกโรคเช่น left sided heart disease, congenital heart disease, AV fistula, thrombus ใน atrium หรือ pulmonary

artery เป็นต้น ก่อนจงึจะพิจารณาใช้ค่า RVSP

RVSP 36- 50 mmHgRVSP < 36 mmHg RVSP ≥ 50 mmHg

No PAH

Diagnosis PAH

- E/e’ < 8 and

- LA Vol index ≤ 28 ml/m2

- mPAP ≥ 25 mmHg

- PVR ≥ 3 WU

- E/e’ < 8 and

- LA Vol index ≤ 28 ml/m2

yesNot sure

Thai PH Guideline 2013

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4

Echocardiography

• D-shaped LV, LVEF 65%, LA 28 mm, Mitral e/e’ 8

• Dilated RV (44 mm), PA (41 mm), TAPSE 15 mm

• TRV 4.31, est RA 15, RVSP 89.3

• No intracardiac shunt

1. Pulmonary arterial hypertension1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/orpulmonary capillary haemangiomatosis

1’’ Persistent PH of the newborn (PPHN)

2. PH due to LHD2.1 LV systolic dysfunction

2.2 LV diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia3.1 COPD

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. CTEPH and PA obstruction

5. PH with unclear multifactorial mechanisms5.1 Haematological disorders: chronic haemolytic anaemia,

myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

5th World Symposium and 2015 ESC Guideline on PH :

Modified classification of PH

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41ESC guideline 2015. EHJ 2015.

COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension; LHD: left heart disease; LV: left ventricular

VC RA RV PA PVPC

LA LV Ao

Post-Capillary PH (PCWP>15 mmHg; PVR nl)

Systemic HTNAoV Disease

Myocardial DiseaseDilated CMP-ischemic/non-isch.

Hypertrophic CMPRestrictive/infiltrative CMP

Obesity and others

Atrial MyxomaCor Triatriatum

PV compression

PVOD

PAHRespiratory

DiseasesPE

Pulmonary Hypertension: Define Lesion

MV Disease

LVEDP

Mixed PHPre-capillary

PH(PCWP<15 mmHg

PVR > 3 Wu) 23; 6 April 2014

Characteristic features of PH associated with LV diastolic dysfunction

Factors favouring diagnosis of LV diastolic dysfunction in the presence of PH as assessed by Doppler echocardiography

1. Clinical featuresAge > 65 yearsElevated systolic BPElevated pulse pressureObesity, metabolic syndromeHypertensionCoronary artery diseaseDiabetes mellitusAtrial fibrillation

2. EchocardiographyLA enlargementConcentric remodelling of the LV (relative wall thickness > 0.45)LV hypertrophyPresence of echocardiographic indicators of elevated LV filing pressure

3. Interim evaluation (after echocardiography)Symptomatic response to diureticsExaggerated increase in systolic BP with exerciseRe-evaluation of chest radiograph consistent with HF

Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.ESC guideline 2015. EHJ 2015

BP: blood pressure; HF: heart failure; LA: left atrium; LV: left ventricle/ventricular

5th World Symposium and 2015 ESC Guideline on PH: New proposed definition and classification of PH-LHD

Terminology PAWP Diastolic PAP – PAWP

Isolated post-capillary PH > 15 mmHg < 7 mmHg

Combined post-capillary and pre-capillary PH

> 15 mmHg ≥ 7 mmHg

2 types of PH-LHD have been proposed on the basis of the level of the diastolic pressure difference

The term “out-of-proportion” PH should be abandoned

LHD: left heart disease; PAP: pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure

Vachiéry JL, et al. J Am Coll Cardiol 2013; 62:D100-8.ESC guideline 2015. EHJ 2015

Yes Yes

5th World Symposium and 2015 ESC Guideline on PH : Diagnosis of PH

Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.ESC guideline 2015. EHJ 2015

Symptoms, signs, history suggestive of PH

Consider most common causes of PH (i.e, left heart disease, lung disease)

Echocardiography compatible with PH?

PH unlikely

History, signs, risk factors, ECG, X-ray, pulmonary function test incl. DLCO,

consider blood gas analysis, HR-CT

Consider other causes or recheck

Diagnosis of heart disease or lung disease confirmed?

No signs of severe PH/RV dysfunction

Signs of severe PH/RV dysfunction

V/Q scintigraphyUnmatched perfusion defects?

Treat underlying disease Refer to PH expert centre

CTEPH likelyCT angiography, RHC plus PA

(PEA expert centre)

RHCmPAP ≥ 25 mmHg, PAWP

≤ 15 mmHg, PVR > 3 Wood units

PAH likelySpecific diagnostic tests

Consider other causes

Yes No

No

Yes No

Yes No

CTEPH: chronic thromboembolic pulmonary hypertension; DLCO: carbon monoxide diffusing capacity; ECG: electrocardiogram; HR-CT: high resolution CT; mPAP: mean pulmonary arterial pressure; PA: pulmonary angiography; PAWP: pulmonary artery wedge pressure; PEA: pulmonary endarterectomy; PVR: pulmonary vascular resistance; RHC: right heart catheterisation; RV: right ventricular; V/Q: ventilation/perfusion

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CO = 4.52Qp:Qs = 1PVR = 902

55

4

6

5

HVPG = 17-7= 10 mmHg

CO = 4.52Qp:Qs = 1PVR = 902

55

4

6

5

Lab

• CBC: Hct 39 WBC 4800 (N59 L31) Plt 84000

• BUN/Cr 8/06

• Na 138 K 4 Cl 110 CO2 21

• LFT: Alb 4 Glob 2.3 TB/DB 1.78/1.39 AST/ALT 129/136 AP 374 GGT 252

• INR 1.2

• ANA neg AntiHIV neg

5th World Symposium and 2015 ESC Guideline on PH: Drug and Toxin-induced PAH

Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.ESC guideline 2015. EHJ 2015

04/03/60

6

Ultrasonography

• Liver: small size with nodular surface

• Small bowel at CBD

–post Kasai operation? (BA)

• No ascites

• Normal KUB

CirrhosisCirrhosis Cardiac cirrhosis ? Cardiac cirrhosis ?

Provisional Diagnosis

• Pulmonary hypertension (likely precap-PH)

• Cirrhosis (BA post Kasai operation OR Cardiac cirrhosis)

Pulmonary Hemodynamics Associated with Liver Disease

mPAP PVR CO PCWP

Hyperdynamiccirculatory state

Excess volume

Portopulmonaryhypertension

Final Diagnosis

HAPE in patient with POPH (?)

BA with cirrhosis s/p Kasai operation

Portopulmonary hypertension exacerbated by high altitude

Portopulmonary hypertension

• 6-9% of OLT candidate

• Neither severity of liver disease or degree of portal HT predict POPH

• Female gender, autoimmune hepatitis: independent risk factors

• Less severely impaired hemodynamics compared to IPAH (lower PVR, higher CO)

Fritz JS, et al. Am J Respir Crit Care Med 2013;187:133-43

Portopulmonary hypertension

• Diagnostic criteria

–Clinical portal hypertension

–mPAP > 25 mmHg

–PCWP < 15 mmHg (TPG > 12 mmHg)

–PVR > 240 dyn s cm-5

Roisin RR, et al. Eur Respir J 2004;24:861-80

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Survival from time of diagnostic RHC

Benza RL, et al. Chest 2012;142(2):448-56.

REVEAL study

Pavec JL, et al. Am J Respir Crit Care Med 2008;178:637-43

NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE

Pathogenesis of PAH

Dilated RV- Intact pericardium RAP

Intrapericardial pressure (IPP)

LV transmural filling pressure

LVEDP-IPP+

Shift of IV septum toward LV

LV preload and LV distensibility

Systemic Cardiac Output

Pulmpnary hypertension

Pressure overload

RV hypertrophyDec. wall stress

RV failureRV ischemiaTVRInc. wall stressPre&afterload mismatchDecrease LV compliance

Compensatory phaseNormal CO, RAP

Decompensatory phaseCO, RAP, PcWP

Hypoxia, AcidosisArrhythmias

Pathophysiology

43; 6 April 2014

RV anatomy: Normal versus PAH

Normal PAH

Chin KM, et al. Coron Artery Dis 2005; 16:13-8.

LV120 mmHg

RV LV PRV

Thickness

Stress

Coronary perfusion pressure + O2 demand = Supply/Demand

RV distension & LV filling = Cardiac output20 mmHg

LV: left ventricle/ventricular; RV: right ventricle/ventricular

Minai OA, et al. Cleveland Clincal J Med 2007;74:737-47

Asymptomatic compensated

Symptomatic decompensating

Advanced decompensated

Subtle Overt

S&S None SOB, Fatigue SOB, edema RVF, syncope, death

FC I II III IV

Hemodynamic trends

Pathologic appearance

CO

PAP PVR

RAP

PAH: Clinical course and progressionPAH: Clinical course and progression

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PAH is a malignant disease

0 1 2 3 4 5 6

Advanced lung cancer

WHO Class IV PAH

Advanced colorectal cancer

Advanced breast cancer

Advanced prostate cancer

WHO Class III PAH

Median survival (years) compared to advanced cancers

D’Alonzo GE, et al. Annals of Internal Medicine; 1991; 115(5): 343-9Kato I, et al. Cancer; 2001; 92: 2211-9

POPH: Management

• B-blocker and TIPS may be harmful

• Pulmonary vasodilators

– Prostacyclins

– Endothelin receptor antagonists

– Phosphodiesterase inhibitors

Fritz JS, et al. Am J Respir Crit Care Med 2013;187:133-43

Therapeutic Targets in Pulmonary Hypertension

Humbert M, et al. N Engl J Med 2004; 351:1425-36.

Mechanisms of action of prostacyclin

• Relax vss. smooth muscle

• Inhibit Platelet aggregation

• Inhibit vss. cell migration and proliferation

• Improve clearance of endothelin-1

• Reverse remodeling of pulmonary vascular changes

• Improve peripheral O2 use by skeletal M.

49; 6 April 2014

Epoprostenol I.V. (Flolan®)Subcutaneous Treprostinil (Remodulin®)

•SQ administration•Longer half-life than epoprostenol•Pre-mixed•Stable at room temperature

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Ventavis® (iloprost) Inhalation Solution: Dosage and Administration

Indicated for inhalation via • Indicated for inhalation via the Prodose® AAD® system only

• 2.5 mcg initial dose– increase to 5 mcg if 2.5 mcg

dose is tolerated

– maintain at maximum tolerable dose (2.5 mcg or 5 mcg)

• 6-9 inhalations daily during waking hours; 8-10 minutes each

Beraprost (Dorner® ; Procyclin®)

• First stable Prostacyclin Analog (oral)

• Approval for PPH and SPH (Japan+Korea)

• RCT (NYHA II +III, 3 mon (ALPHABET) (Galie, N. et al. JACC 2002)

– 6-min walk improvement : 25 m (only PPH)

– Dose limitation due to side effects (pain, nausea)

• RCT (1 yr, NYHA II), USA, 12 months, negative (Barst et al. JACC, 2003)

• Approved for PAH in Japan, Korea, Thai

Endothelin Signal Transduction

ET-1

Vasoconstriction Vasodilatation

NO, PGI1

Endothelial cellETB

ETBETA

& Proliferation

Recommended Laboratory Monitoring with Bosentan

Liver function testing

• Prior to initiation of treatment

• Monthly

Hemoglobin

• Prior to initiation of treatment

• After 1 month, then every 3 months

HCG

• Prior to initiation of treatment

• Monthly

ETA Specific Endothelin-Receptor-Antagonists

ETA Specific Endothelin-Receptor-Antagonists

• Sitaxsentan– Pilotstudie I, Barst et al; Chest 2002

• OL, 20 PAH-Patienten

– Pilotstudie II, Barst et al; AJRCCM 2003

• RPCT, 178 PAH-Patienten

– STRIDE-1,-2

– 100 mg/day, less hepatitis

– Drug interaction with coumadin

• Ambrisentan

– Pilotstudie Galie et al. JACC 2005

• RCT (multiple Dosen), 64 PAH-Patienten

– iPAH, HIV,CTD

– 5-10 mg/day

– ARIES-1, ARIES-2Olschewski et al. ERS 2005

Barst et al. 2004

56; 6 April 2014

cAMP

cGMP

5´-AMP

PDE 1 2 3 4 5

5´-GMP

PKG

PKA

Vasodilatation

Prostanoids

Olschewski H. et al. J Lab Clin Med, 2001

cGMP

PKG

cAMP

PKA

Vasodilatation

Sildenafil

PCI2

NOOlschewski H. et al. J Lab Clin Med, 2001

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RCTs in PAH approved: Oral drugs

Drugs Study Background Primary endpoint

2nd

endpointDuration No. of

subjects

Bosentan Study-351BREATHE-1Early

BREATHE-5

NoNoNoSildenafil (16%)No

6 MWD6 MWDPVR, 6 MWD

SaO2, PVR

TTCWTTCWTTCW

-

12 wks16 wks24 wks

12 wks

32213185

54

Ambrisentan ARIES-1ARIES-2

NoNo

6 MWD6 MWD

-TTCW

12 wks12 wks

202192

Sildenafil SUPER-1SastryPACES

NoNoEpoprostenol

6 MWDTTCW6 MWD

--TTCW

12 wks12 wks16 wks

27722264

Tadalafil PHIRST NoBosentan (54%)

6 MWD TTCW 16 wks 405

Beraprost ALPHABETBarst

NoNo

6 MWDCW

--

12 wks52 wks

130116

Channick RN, et al. Lancet 2001; Badesch D, et al. Curr Ther Res 2002; Rubin LJ, et al. N Engl J Med 2002; Galiè N, et al. Circulation 2006; Galiè N, et al. Lancet 2008; Galiè N, et al. Circulation 2008; Oudiz R, et al. Chest 2006; Oudiz RJ, et al. J Am Coll Cardiol 2009; Galiè N, et al.

N Engl J Med 2005; Simonneau G, et al. Ann Intern Med 2008; Galiè N, et al. Circulation 2009.

RCTs in PAH approved: Oral+Non-oral drugs

Drugs Study Background Primary endpoint

2nd

endpointDuration No. of

subjects

Epoprostenol RubinBarstBadesch

NoNoNo

6 MWD6 MWD6 MWD

-Survival-

12 wks12 wks12 wks

2381111

Treprostinil SC SimonneauInh TRIUMPH

PO Freedoom MPO Freedoom C1

PO Freedoom C1

NoBosentan/SildenafilNoBosentanand/orSildenafilBosentanand/orSildenafil

6 MWD6 MWD

6 MWD6 MWD (-)

6 MWD (-)

--

--

-

12 wks12 wks

16 wks16 wks

16 wks

470235

185354

310

Iloprost AIRSTEPCOMBI

NoBosentanBosentan

6 MWD&FC6 MWD 6 MWD (-)

12 wks12 wks12 wks

2036740

Rubin LJ, et al. Ann Intern Med 1990; Barst RJ, et al. N Engl J Med 1996; Badesch DB, et al. Ann Intern Med 2000;Simonneau G, et al. Am J Respir Crit Care Med 2002; McLaughlin VV, et al. J Am Coll Cardiol 2010; Olschewski H, et al. N Engl J Med 2002;

McLaughlin VV, et al. Am J Respir Crit Care Med 2006.

Oral drugs Recent RCTs in PAH approved: Oral drugs

Drugs Study Background Primary endpoint

2nd

endpointDuration No. of

subjects

Macitentan SERAPHIN NoPDEVI or Inhiloprost

TTCW Safety 100 wks 742

Riociguat PATENT NoBosentan or Prostanoid

6 MWD TTCW 12 wks 462

Pulido T, et al. N Engl J Med 2013;369:809-18; Ghofani HA, et al. N Engl J Med 2013;369:330-40; Ghofani HA, et al. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7;

Hoeper MM , et al. Circulation 2013 Mar 12;127(10):1128-38. 60; 6 April 2014

Approval of PAH therapies

Bosentan(Tracleer) 2001 – US2002 – Europe

Epoprostenoli.v.(Flolan)1995 – US

2001 – Europe

Treprostinil i.v. or s.c. (Remodulin)2002 – US2005 – Europe

Iloprost inhaled (Ventavis)2004 – US2003 – Europe

Iloprost i.v.(Ilomedin) only approved in New Zealand

2010 201520051995 2000

Sildenafil(Revatio) 2005

Beraprost(Careload†) 2007

Ambrisentan (Letairis –US; Volibris – EU/Canada)2007 – US 2008 – Europe

Epoprostenol i.v.(Veletri – US and Europe; Caripul – Canada and Italy; Epoprostenol ACT – Japan)2012 – US, Switzerland* & Canada2013 – Japan

2009Treprostinilinhaled† (Tyvaso)

Tadalafil (Adcirca)

2013Macitentan†

(Opsumit)

Treprostiniloral† (Orenitram)US

Riociguat†

(Adempas)

*Approval in other European countries is ongoing†Approval of these therapies varies by country, and thus might not be approved in the indications mentioned in your country. Please refer to your local full SmPC before prescribing

61; 6 April 2014

Initial Use of Ambrisentan plus Tadalafilin Pulmonary Arterial Hypertension

Galiè N, et al. N Engl J Med 2015;373:834-44.

Supervised exercise training (IIa-B)Psycho-social support (I-C)Avoid strenuous physical activity (III-C)Avoid pregnancy (I-C)Influenza and pneumococcal immunisation (I-C)

General measures and supportive therapy

Oral anticoagulants:• IPAH, heritable PAH and PAH due to anorexigens (IIb-C)

•APAH (IIb-C)Diuretics (I-C)Oxygen (I-C)Digoxin (IIb-C)Expert referral (I-C)

Acute vasoreactivity test(I-C for IPAH, HPAH, DPAH)

(IIb-C for APAH)

Initial therapy with PAH-approved drugs

Non-vasoreactiveFC I-III

CCB (I-C)Sustained response

(FC I-II)

Continue CCB No

Vasoreactive

Yes

5th World Symposium and 2015 ESC Guideline on PH: Evidence-based treatment algorithm

General measures and supportive therapy

Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.ESC guideline 2015. EHJ 2015.

APAH: associated PAH; CCB: calcium channel blockers; FC: functional class; IPAH: idiopathic PAH

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Mean PAP reached during acute vasodilator testing

0

10

20

30

40

50

60

70

80

90

Baseline Acutetesting

Baseline Acutetesting

mPA

P(m

mH

g)

Long-term CCB responders

Long-term CCB failure

33 / 38 long-term CCB responders had a mPAP < 40 mmHg with

normal or elevated CO during acute testing

O. Sitbon et al. Circulation 2005

Acute Responders: By diagnosis

13.5%

11.8%

10.1%

12.2%

1.6%

1.3%

0 5 10 15 20 25

Idiopathic PAH

Anorexigens-PAH

CTD-PAH

PVOD / PCH

HIV-PAH

Po-PH

Familial PAH and CHD-PAH: 0 %

(%)

O. Sitbon et al. Circulation 2005

6.8% long term responders

<1% long term responders

5th World Symposium and 2015 ESC Guideline on PH: Evidence-based treatment algorithm

Initial therapy with PAH approved drugsRecommendation(Evidence*)

FC II FC III FC IV

I (A or B) Ambrisentan BosentanMacitentanRiociguat†

Sildenafil

TadalafilSelexipagInitial combination therapy (Amb+Tad)

Ambrisentan, Bosentan,Epoprostenol i.v. ,Iloprost inhaled, Macitentan

Riociguat†, Sildenafil,Tadalafil,Treprostinil s.c., inhaled†

Selexipag, Initial combination therapy (amb+Tad)

Epoprostenol i.v.

IIa (C) Initial combination therapy (ERA+PDE5i)

Iloprost i.v.†

Treprostinil i.v.Initial combination therapy (ERA+PDE5i)

Initial combination therapy (+EpoIV)

IIb (B) Vadenafil Vadenafil, Treprostinil oralBeraprost†

IIb (C) Ambrisentan, Bosentan,Iloprost inhaled and i.v.†

Macitentan, Riociguat†, Sildenafil, Tadalafil, VadenafilTreprostinil s.c., i.v., inhInitial combination therapy (oral)

Inadequate clinical response

Sequential combination therapy (I-B to IIb-C)

ERAs

ProstanoidsPDE-5i

or sGCS

+

+

Initial therapy with PAH approved drugs

+

Referral forLUNG TRANSPLANTATION

(I-C; FCIII-IV)

Consider eligibility forlung transplantation

BAS (IIb-C; FCIII-IV)

Inadequate clinical response on

maximal therapy

BAS: balloon atrial septostomy; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase-5 inhibitor; sGCS: soluble guanylate cyclase stimulator

5th World Symposium and 2015 ESC Guideline on PH: Evidence-based treatment algorithm

Combination therapy and interventional procedures

Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.ESC guideline 2015. EHJ 2015

67; 6 April 2014

5th World Symposium and 2015 ESC Guideline on PH:

Goals of Therapy

• I or II, no syncopeFunctional Class

• Normalization of RV function (RAP < 8, CI > 2.5, SVO2>65%)Hemodynamics

• RA area<18 cm2, no pericardial effusionECHO/MRI

• BNP<50, NT-pro BNP<300 ng/l BNP level

• >440 m, may not be aggressive enough (young)6-minute walk

• Peak VO2 > 15 and VE/VCO2slope< 36CPET

McLaughlin VV, et al. J Am Coll Cardiol 2013; 62:D73-81.ESC guideline 2015. EHJ 2015

68; 6 April 2014

Heart Rate Recovery Predicts Clinical Worsening in Patients with PAH?

• 75 patients

• HRR 1 defined as the difference in HR at the end of 6MW

and at 1 minute after completion

– HRR≤16 more likely to show clinical worsening

– Report HRR<16 and mPAP as the best predictors via multivariate

analysis

– Compared with 6MWD, HRR1 < 16 a better predictor of CW and

TCW

– The addition of HRR1 to 6 MWD increases the capacity of 6MWD

to predict clinical worsening and TCW in patients with PAHMinai OA et al. AJRCCM 2012;185:400

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69; 6 April 2014

Atrial septostomy as a bridge to transplant

• Creation of inter-atrial right-to-left shunt can:– Decompress right heart chambers

– Increase left ventricle pre-load

– Increase cardiac output

• A pre-procedural risk assessment reduces mortality

• Atrial septostomy should be avoided in end-stage patients with:– Baseline mean right atrial pressure > 20 mmHg

– O2 saturation at rest of < 85% on room air

Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72. 70; 6 April 2014

Survival rates for lung transplant recipients have improved significantly

ISHLT registry data showing adult lung transplant recipients Kaplan-Meier survival by era (transplants January 1988-June 2011)

0

20

40

60

80

100

Surv

ival

(%)

Years0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

1988-1995 (n = 5953; number at risk = 518)

1996-2003 (n = 12654; number at risk = 169)

2004-6/2011 (n = 21256; number at risk = 924)

All pairwise comparisons were significant at p < 0.001

ISHLT: International Society for Heart and Lung Transplantation

Yusen RD, et al. J Heart Lung Transplant 2013; 32: 965-78.

Long-term outcomes are improved in the modern treatment era

1. Humbert M, et al. Eur Respir J 2010; 36:549–555.2. Benza RL, et al. Chest 2012;142(2):448-56.

100

80

60

40

00 1 2 3 4 5 6 7

Surv

ival

(%

)

Time from diagnosis (years)

No. at risk: 279 377 390 388 328 240 153 88

90.5 ± 2.2

74.5 ± 2.5

64.5 ± 2.558.9 ± 2.7

68.2

46.9

35.6 32.0

**

*

20 *REVEAL unweighted NIH cohort 2

Predicted survival by NIH equation 2

French Registry1

Ghofrani HA, et al. AJRCCM 2010;182:1171-7

Recent RCTs in PAH drug

Drugs Study Background Primary endpoint

2nd

endpointDuration No. of

subjects

Imatinib PHASE 2

IMPRES

Bosentanand/or Sildenafil and/or ProstanoidBosentanand/or Sildenafil and/or Prostanoid

6 MWD (-)

6 MWD

-

TTCW (-)

24 wks

24 wks

59

202

Pulido T, et al. N Engl J Med 2013;369:809-18; Ghofani HA, et al. N Engl J Med 2013;369:330-40; Ghofani HA, et al. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7;

Hoeper MM , et al. Circulation 2013 Mar 12;127(10):1128-38.

Current and Emerging Rx for PAH

O’Callaghan D, et al. Nat Rev Cardiol 2011;8:526–38.

04/03/60

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Anti-TNF alpha Prevents Pulmonary Vascular Remodeling in CIH-PH Rat Model

Jaimchariyatam N, et al, 2014 76; 6 April 2014

Potential Targets for PAH treatment

PDGF ET-1 NO PCI2

ACE2/Ang(1-7)/Mas Beta adrenergic SphK1/S1PLeptin TNF-alpha/NF-kB

Medications N Comments

Endothelin receptor antagonists

Hoeper, et al (bosentan) 18 1-and3-year survivals 94% and 89%, respectively

Cartin-Cebaetal (ambrisentan) 13 At 1 y, MPAP and PVR improved in 8/8; PVR normalized in 5

Savale, et al. (bosentan) 34 At 5 mo 31% reduction in PVR, 39% increase in CI

Phosphodiesterase inhibitors

Reichenberger, et al (sildena l) 12 Improvement at 3 mo; not sustained at 1y

Goughand White (sildena l) 11 PVR decreased in all at rst RHC follow-up

Hemmesand Robbins (sildena l) 10 At 1-year MPAP and PVR decreased in 3/5 patients

Prostacyclins

Kuo, et al (IV epoprostenol) 4 MPAP and PVR improved

Krowka, et al (IV epoprostenol) 15 MPAP and PVR improved

Ashfaq, et al (IV epoprostenol) 16 Successful LT in 11 patients; 5-year survival 67%

Fix, et al (IV epoprostenol) 19 PVR improved in 14/14; MPAP improved in 11/14

Sussman, et al (IV epoprostenol) 8 MPAP and PVR improved in 6/7

Sakai, et al (IV treprostinil) 3 Successful LT in two patients (moderate POPH)

Hoeper, et al (inhaled iloprost) 13 1-and 3-year survivals 77% and 46%, respectively

Melgosa, et al (inhaled iloprost) 21 Acute, but no long-term hemodynamic improvement

Case 1

• 6MWT– 6MWD 520 m, O2 sat 92%->88%

– Borg 4->6 – BP 133/72 -> 115/82

• ได้รับการรักษาด้วย Sildenafil 20 mg tid, Beraprost 60 mcg/d

• สง่ปรึกษา GI เพื�อประเมิน

–ภาวะ biliary cirrhosis ?

– Liver transplantation

3 months later

• 6MWT

– 6MWD 620 m, O2 sat 98%->96%

– Borg 2->4

– BP 123/72 -> 149/82

• Note form GI: “Can liver transplantation be done safely in this patient?”

POPH and Liver Transplantation

Stage mPAP(mmHg)

Operative mortality

Mild 25-34 0

Moderate 35-44 50

Severe ≥45 100

Rodriguez-Roisin, et al.Eur Respir J 2004;24:861–80.Krowka MJ, et al. Liver Transpl 2000;6:443–50.

Delcroix M. Eur Respir Mon 2006;34:129–38.

04/03/60

14

POPHPOPH

mPAP <35mPAP <35 mPAP 35-50mPAP 35-50 mPAP > 50mPAP > 50

Proceed to liver Tx

PVR≤250PVR≤250 PVR>250PVR>250

Proceed to liver Tx

Response to PAH Rx

No response To PAH Rx

Noliver Tx

Porres-Aguilar M, et al. Eur Respir Rev 2012;21:223-33

2nd Echocardiography

• Normal LV size (1st: D-shape), LVEF 85%, LA 28 mm, Mitral e/e’ 12

• Dilated RV (44 mm), PA (30 mm), TAPSE 24 mm (1st: 15)

• TRV 3.9, est RA 10, RVSP 70.84 (1st: 89)

• No intracardiac shunt

Case 1

• She was scheduled for RHC

• She refused to undergo OLT and thus, RHC was cancelled.

• 1 y later: significant improvement (FCI, 6MWD 650 m)

–Discontinued beraprost

Case 2

• ผู้ป่วยชายไทยอายุ 59 ปี รบัราชการ

• มานอนโรงพยาบาลด้วยอาการเหนื�อยง่ายมากขึ�น 6 เดือนก่อนมาโรงพยาบาล เป็นมากขณะออกกาํลงั (FCIII) ครั �งนี� เหนื�อยมากขึ�นแม้ขณะพกัในช่วงสองสามสปัดาห์

• ประวติัอดีตเป็นถงุลมโป่งพอง มา 3 ปี เคยนอนโรงพยาบาลด้วย COPD acute exacerbation เมื�อ 3 ปีก่อนหลงัจากนั�นไม่ได้มานอนโรงพยาบาลอีก

• สูบบหุรี� 30 packs-year หยุดสูบมาสามปี

Case 2

• BT 36.7, HR 120 /min, RR 26/min, BP 120/85 mmHg

• O2 saturation 88% on room air

• Auscultation revealed a grade III systolic murmur along LLPSB with an accentuated P2

• Prolonged expiration without any wheezes or rhonchi was noted

• Mild liver enlargement and mild pitting edema noted

04/03/60

15

Estimated RAP = 10 mmHg

• Echocardiogram:

– LA and LV are normal, LAVI 20, e/e’ 9

– LVEF 55%

– RA and RV are markedly dilated (RV 4.4 cm at mid part, RA 21.4 cm2, L=51 mm)

– Severely impaired RV systolic function (TAPSE =1.0 cm, lateral TDI = 7 cm/sec)

– Normal MV with mild MR

– TRV 4.7 m/s, estimated RAP 10 mmHg, RVSP 98.4

Investigation to confirm diagnosis

• No step-up oxygen saturation

• Mean PAP = 74 mmHg

• PAWP = 10 mmHg

• Mean RAP = 16 mmHg

• CO = 3.92 L/min (thermodilution), CI = 1.97

• Not respond to vasodilator agent (inhaled Iloprost)

Right cardiac catheterization

• FVC 2.56 L (64.9% of predicted value)

• FEV1 1.56 L (68.98% of predicted value)

• FEV1/FVC ratio 61%

• Residual volume 2.81 L (171.3% of predicted value)

• Carbonmonoxide diffusion capacity (DLCO) 31.0% of predicted value

Pulmonary Function Test

92; 6 April 2014

PH in chronic lung disease

04/03/60

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93; 6 April 2014

PH in chronic lung disease: Differential diagnosis between groups 1 and 3

Seeger W, et al. J Am Coll Cardiol 2013; 62:D109-16.ESC guideline 2015. EHJ 2015

Criteria favouring group 1 (PAH) Parameter Criteria favouring group 3 (PH due to lung disease)

Normal or mildly impairment:• FEV1 > 60% predicted (COPD)• FVC > 70% predicted (IPF)

Ventilatory function

Moderate to very severe impairment:• FEV1 < 60% predicted (COPD)• FVC < 70% predicted (IPF)

Absence of or only modest airway or parenchymal abnormalities

High-resolution CT

scan

Characteristic airway and/or parenchymal abnormalities

Features of exhausted circulatory reserve:• Preserved breathing reserve• Reduced oxygen pulse• Low CO/VO2 slope• Mixed venous oxygen saturation at lower

limit• No change or decrease in PaCO2 during

exercise

Features of exhausted ventilator reserve:• Reduced breathing reserve• Normal oxygen pulse• Normal CO/VO2 slope • Mixed venous oxygen saturation above

lower limit• Increase in PaCO2 during exercise

CO: cardiac output; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity;IPF: idiopathic pulmonary fibrosis; PaCO2: partial pressure ofcarbon dioxide in arterial blood; VO2: oxygen consumption 94; 6 April 2014

Management of PH in chronic lung disease setting

Underlying lungdisease

mPAP < 25 mmHg at rest

mPAP ≥ 25 mmHg and < 35 mmHg at rest

mPAP ≥ 35 mmHg at rest

COPD with FEV1 ≥ 60% of predicted

IPF with FVC ≥ 70% of predicted

CT: absence of or only very modest airway or parenchymal abnormalities

No PH

No PAH treatment recommended

PH classification uncertain

No data currently support treatment with PAH-approved drugs

PH classification uncertain: discrimination between PAH (group 1) with concomitant lung disease or PH caused by lung disease (group 3)

Refer to a centre with expertise in both PH and chronic lung disease

COPD with FEV1 < 60% of predicted

IPF with FVC < 70% of predicted

Combined pulmonary fibrosis and emphysema on CT

No PH

No PAH treatment recommended

PH-COPD, PH-IPF, PH-CPFE

No data currently support treatment with PAH-approved drugs

Severe PH-COPD, severe PH-IPF, severe PH-CPFE

Refer to a centre with expertise in both PH and chronic lung disease for individualised patient care because of poor prognosis; RCTs required

Seeger W, et al. J Am Coll Cardiol 2013; 62:D109-16.ESC guideline 2015. EHJ 2015

• The elevated PAPs do not correlate with the severity of COPD

• Mean PAP > 40 mmHg (severe PH with mPAP > 40 mmHg occurs in only 0.8% to 3.7% of COPD patients)

• More severe hypoxemia, and hypocapnia

• Very low DLCO (not explained by severity of COPD)

Disproportionate PH in COPD

Minai OA, et al. Chest 2010;137:39S-51SChaouat A, et al. Am J Respir Crit Care Med 2005;172:189-194,2005

Stevens D, et al. Ann Transplant 2000;5:8-12

• Disproportionate pulmonary hypertension in COPD, likely due to pulmonary arterial hypertension

–COPD plus

–IPAH

Final Diagnosis

Hypoxic VasoconstrictionHypoxic pulmonary vasoconstriction

PAO2 decrease

Improve V/Q matching

Increase BF to ventilated alveoli

Sildenafil

Hypoxic VasoconstrictionHypoxic pulmonary vasoconstriction

PAO2 decrease

Decrease BF to ventilated alveoli

Sildenafil

Increase BF to Non-ventilated alveoli

04/03/60

17

Inhaled Iloprost

100;6 April 2014

PAH and congenital heart disease

• A 22 y/o male suspected PH, FC III

• Echocardiogram:

– ASD secundum (1.5 x 1.5 cm) with bi-directional

shunt

– TR, RVSP 55 mmHg

• RHC and LHC

– mPAP 58 mmHg, PCWP 5 mmHg, PVR 11 WUs

– CI 3.2, SVR 13 WUs

– No vasodilator response

Case 35th World Symposium & 2015 ESC Guideline on PH :

Updated clinical classification of PAH-CHD

Clinical classification of PAH-CHD

Eisenmenger syndromeIncludes large intra- and extra-cardiac defects which begin as systemic-to-pulmonary shunts and progress with time to severe elevation of PVR and reversal (pulmonary-to-systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis and multiple organ involvement are usually present

Left-to-right shunts• Correctable*• NoncorrectableIncludes moderate to large defects; PVR is mildly to moderately increased; systemic-to-pulmonary shunting is still prevalent, whereas cyanosis is not a feature

PAH with coincidental CHDMarked elevation in PVR in the presence of small cardiac defects, which themselves do not account for development of elevated PVR; clinical picture very similar to IPAH. Defect closure is contra-indicated

Post-operative PAHCHD is repaired but PAH either persists immediately after surgery or recurs/develops months or years after surgery in the absence of significant post-operative haemodynamic lesions. The clinical phenotype is often aggressive

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.ESC guideline 2015. EHJ 2015

*Correctable with surgery or intravascular non-surgical procedureCHD: congenital heart disease; IPAH: idiopathic PAH; PVR: pulmonary vascular resistance

QP:QS > 1.5:1, PVR < 8

PVR < 6-8 WU, resting O2 desaturation

Acute vasoreactivity test in CHD-PH

• Severe PAH with high PVR

• Predictor of candidacy for successful systemic-to-pulmonary shunt closure

Positive response Agent Recommendation

PVR reduce to < 6-8 WU any 1, ++

PVR:SVR reduce to < 0.42 O2 1, ++

PVR:SVR reduce to < 0.3 iNO or Iloprost

1, ++

PVR:SVR reduce to < 0.27 iNO+O2 1, ++

Thai PH Guideline 2013104;6 April 2014

Treatment of PAH-CHD

ESC guideline 2015. EHJ 2015

04/03/60

18

105;6 April 2014

RV adaptation in IPAH versus PAH-CHD

• Compared with IPAH, Eisenmenger’s syndrome patients have higher CI and lower mRAP (despite having a higher mPAP)1

1. Chin KM, et al. Coron Artery Dis 2005; 16:13-8.2. Bristow MR, et al. Chest 1998; 114:S101-6.

Elevated mPAP

PAH-CHDRV adaptation = Better prognosis

Compensation2:• Increased RV wall thickness• Mild RV dilation

IPAHRV inability to adapt = Worse prognosis

Decompensation2:• RV dilation• RV failure

CHD: congenital heart disease; CI: cardiac index; IPAH: idiopathic PAH; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; RV: right ventricle/ventricular

106;6 April 2014 Manes A, et al. Eur Heart J 2013; Epub ahead of print.

Survival rates of clinical subgroups of PAH-CHD

Survival rates in a predominantly adult population (n = 192) over a 20-year period

CD: cardiac defect correction; CHD: congenital heart disease; ES: Eisenmenger syndrome; SD: small defects; SP: systemic-to-pulmonary shunts

0.00

Follow-up (years)

Surv

ival

5 10 15 20

0.2

0.4

1.0

0.8

0.6

ES

PAH-SP

PAH-SD

PAH-CD

Log-rankp < 0.0001

ES 90 71 59 52 48PAH-SP 48 22 18 11 10PH-SD 10 4 4 2 0PAH-CD 44 22 12 4 3

Patients at risk:

ES

PAH-SP

PAH-SD

PAH-CD

107;6 April 2014

Treatment of PAH-CHD

ESC guideline 2015. EHJ 2015 108;6 April 2014

New insights into CTEPH management

109;6 April 2014Piazza G, et al. N Engl J Med 2011;364:351-60.

110;6 April 2014

Pulmonary Endarterectomy

04/03/60

19

111;6 April 2014

CTEPH registry: Survival is significantly improved following PEA

Operated Non-operated

PVR (dsc-5) 728 (97 - 2880) 676 (165 - 2800)

Simonneau G, et al. Am J Respir Crit Care Med 2013; 187:A5365.

88%79%

70%

93% 91% 89% Operated n = 404

Non-operated n = 275

1.00

0.80

0.60

0.40

0.20

0.00

Cu

mu

lati

ve s

urv

ival

0 6 12 18 24 30 36 42 48 54 60 66

Months from diagnosis

p ≤ 0.0001

Patients at risk at the end of the time period:404 382 374 366 361 355 336 244 158 62 3 0275 246 228 214 200 188 164 120 58 20 2 0

CTEPH: chronic thromboembolic pulmonary hypertension; PEA: pulmonary endarterectomy; PVR: pulmonary vascular resistance

112;6 April 2014

CTEPH: The potential role of medical therapy

When is medical therapy for CTEPH appropriate?

Patients with predominantly distal disease that is not

surgically accessible1

PEA contraindicated due to prognostically significant

comorbidity1

Patients with persistent or residual

PH post-PEA1,2

Patients who are ‘high-risk’ due to extremely poor

haemodynamics prior to PEA1

1. Hoeper MM, et al. J Am Coll Cardiol 2009; 54:S85-96.2. Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.

? ?

CTEPH: chronic thromboembolic pulmonary hypertension; PEA: pulmonary endarterectomy

113;6 April 2014

Short term RCTs of medical therapy in CTEPH have shown varying degrees of efficacy

Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.

Drug First author, year Studydesign

Duration n NYHAFC

6MWD* Effect PVR# Effect

Epoprostenol (i.v.) Cabrol, 2007 - 3 months 23 III-IV 280 ± 112 66 (T) 29 ± 7† -21%

Treprostinil (s.c.) Skoro-Sajer, 2007 - 6 months 25 III-IV 260 ± 111 59 924 ± 347 -13%

Iloprost (inh) Olschewski, 2002 RCT 3 months 57 III-IV NA NS NA NS

Sildenafil (PO) Ghofrani, 2003 - 6 months 12 NA 312 ± 30 54 1935 ± 228 -30%

Sildenafil (PO) Reichenberger, 2007 - 3 months 104 II-IV 310 ± 11 51 863 ± 38 -12%

Sildenafil (PO) Suntharalingam, 2008 RCT 3 months 19 II-III 339 ± 58 18 (NS) 734 ± 363 -27%

Bosentan (PO) Hoeper, 2005 - 3 months 19 II-IV 340 ± 102 73 914 ± 329 -33%

Bosentan (PO) Hughes, 2005 - 3 months 20 II-IV 262 ± 106 45 (T) 1165 ± 392 -21%

Bosentan (PO) Bonderman, 2005 - 6 months 16 II-IV 299 ± 131 92 712 ± 213 NA

Bosentan (PO) Seyfarth, 2007 - 6 months 12 III 319 ± 85 72 1008 ± 428 NA

Bosentan (PO) Jais, 2008 RCT 4 months 157 II-IV 342 ± 84 2 (NS) 783 (703-861) -24%

Riociguat (PO) Ghofrani, 2010 - 3 months 41 II-III 390 (330-441) 55 691 (533-844) -29%

Riociguat (PO) Ghofrani, 2013 RCT 4 months 261 II-IV 347 ± 80 46 787 ± 422 -31%

*Mean ± SD or median (interquartile range) in meters#PVR dyn·s/cm5 in †Woods unit, dyn·s/cm5/m2

6MWD: 6-minute walk distance; CTEPH: chronic thromboembolic pulmonary hypertension; NYHA FC: New York Heart Association functional class; RCT: randomised controlled trial; PO: per os; PVR: pulmonary vascular resistance

114;6 April 2014

Pulmonary endarterectomy

5th World Symposium & 2015 ESC Guideline on PH:CTEPH treatment algorithm

Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.ESC guideline 2015. EHJ 2015

CTEPH diagnosisContinue lifelong anticoagulation

Operability assessment by CTEPH team

Operable Non-operableNon-operable

Targeted medical therapy

Persistent symptomatic PH

Referral for lung

transplantation

Percutaneoustransluminal pulmonary

angioplasty?

Operable

CTEPH: chronic thromboembolic pulmonary hypertension

Persistent symptomatic PH