Lecture presented by Dr Medhat Abdel Khalek Soliman at the Egyptian African Critical Care Summit held at Cairo, Egypt.

1. 1; 6 April 2014
A New Horizonin PH Management
BY
Medhat A. Soliman
Chest Department
Cairo University

2. 5th World Symposium on PH:
Haemodynamic definitionof PAH
PAWP
≤ 15 mmHg
Mean PAP
≥ 25 mmHg
PVR > 3 Wood
units
PAP: pulmonary arterial pressure; PAWP: pulmonary artery
wedge pressure; PVR: pulmonary vascular resistance
Definition
of PH
Definition of
PAH
Mean PAP
≥ 25 mmHg
Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.

3. The three pathwaysin PAHpathogenesis
Humbert M, et al. N Engl J Med 2004; 351:1425-36.
cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate;
ERA: endothelin receptor antagonist; ET: endothelin; PDE-5: phosphodiesterase-5;
PDE-5i: phosphodiesterase-5 inhibitor; PGI2: prostacyclin; SMCs: smooth muscle cells

5. 5th World Symposium on PH:
Modified classification of PH
1. Pulmonary arterial hypertension
1.1 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/or
pulmonary capillary haemangiomatosis
1’’ Persistent PH of the newborn (PPHN)
2. PH due to LHD
2.1 LV systolic dysfunction
2.2 LV diastolic dysfunction
2.3 Valvulardisease
2.4 Congenital/acquiredleft heart
inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia
3.1 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
5. PH with unclear multifactorial mechanisms
5.1 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
Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.
COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension;
LHD: left heart disease; LV: left ventricular

8. Characterisationof pre- and post-capillaryPH
RV
LA
PAP
Atrial
pressure
Pre-capillary PH:
• Mean PAP ≥ 25 mmHg
• PAWP < 15 mmHg
• TPG is increased
Post-capillaryPH:
• Mean PAP ≥ 25 mmHg
• PAWP ≥ 15 mmHg
• TPG may/may not be increased
LA: left atrium; PAP: pulmonary arterial pressure;
PAWP: pulmonary artery wedge pressure; RV: right ventricle;
TPG: transpulmonary pressure gradient (mean PAP-PAWP)
Guazzi M, et al. Circulation 2012; 126:975-90.
Galiè N, et al. Eur Heart J 2009; 30:2493-537.

9. PH due to left heartdiseasecan be caused by multiple
disorders
Fang JC, et al. J Heart Lung Transplant 2012; 31:913-33.
PH due to LHD
• LV systolic dysfunction
• Heart failure with reduced ejection
fraction (HFrEF)
• LV diastolic dysfunction
• Heart failure with preserved ejection
fraction (HFpEF)
Valvularleft heart disease
• Mitral stenosis
• Mitral regurgitation
• Aortic stenosis
• Aortic regurgitation
LHD: left heart disease; LV: left ventricular

10. DifferentiatingbetweenPH-LHDand PAH
Hansdottir S, et al. Chest 2013; 144:638-50.
It is particularlychallengingto differentiate the subset of patients
with PH due to HFpEF from PAH patients
Diastolicdysfunction
Both groups of patientshave the following:
Normal EF
ElevatedPAP estimates
DistinguishingPH due to HFpEF from PAH is vital since the management
is significantlydifferent for the 2 conditions
EF: ejection fraction; HFpEF: heart failure with preserved ejection fraction;
LHD: left heart disease; PAP: pulmonary arterial pressure

11. Remodelling
HyperinflationHypoxemia Alveolair destruction
Pulmonary hypertensionPolycythemia
Hypercapnia
Fluid retention
Cor Pulmonale
Genotype
Smoking
Multiple Causes of pulmonaryhypertensionin COPD

12. Courtesy of Dr Gopalan.
PH Imaging Modalities
V/Q scan
ThromboembolicDisease IPAH

13. Courtesy of Dr Gopalan.
PH Imaging Modalities
CT Pulmonary Angiography

14. Courtesy of Dr Gopalan.
CT Pulmonary Angiography
Acute vs Chronic PE

15. Courtesy of Dr Gopalan.
CT Pulmonary Angiography
Proximalvs DistalCTEPH

16. PH Imaging Modalities
Catheter Pulmonary Angiography
Courtesy of Dr Gopalan.

21. 5th World Symposium on PH: Recommendations for PAH
screening
Recommendations on screening of high-risk populations for PAH
Annualscreening for PAH is recommended in asymptomaticpatientswith the SSc
spectrum of diseases
Screening should include a two-step approach using clinicalassessment in the initial
stage, followed by echocardiographyand considerationof RHC in patientswith
abnormalfindings*†
Screening programs forpatients with SSc should be part of a scientific protocol,or a registry, whenever possible
Patients with SSc and other CTDs with clinical signs and symptoms of PH should be evaluated by RHC
Adapted from Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.
*Coghlan JG, et al. Ann Rheum Dis 2013; Epub ahead of print.
*Based on the DETECT study
†There is a lack of data with DLCO > 60%
CTD: connective tissue disease;
DLCO: carbon monoxide diffusing capacity;
RHC: right heart catheterisation; SSc: systemic sclerosis

22. Impactof screening in PAH-SSc:
Improvedlong-term outcomes
100
90
80
70
60
50
40
30
20
10
0
Survivalrate(%)
1 year 3 years 5 years 8 years
Follow-up (years)
100%
75%
31%
25%
17%
81%
73%
64%
Routine
practice
PAH-SSc
(n = 16)
Screened
PAH-SSc
(n = 16)
p = 0.0037
HR = 4.15
(95% CI 1.47 - 11.71)
Humbert M, et al. Arthritis Rheum 2011; 63:3522-30.
CI: confidence interval; HR: hazard ratio; SSc: systemic sclerosis

24. Edward’sLife Science VIP Thermodilution Catheter
PA Distal
ProximalInjectate
RA infusion port
Thermistorport
Balloon inflation
port
The standardcatheter is 7.5 FR and 110 cm long. Maximal balloon volume 1.5cc

25. Once inserted balloon should remain DEFLATED and ONLY
reinflatedfor periodic measurementof PCWP. PAP waveform should be
displayed at all other times.
Distal tip
(Yellow)
Proximaltip
(Blue)
Right ventricular
Port (Gray)
Distal tip measuresPAP and PCWP
Proximaltip measuresRA and is site
for CO measurementand fluid
administration
Right ventricular
port site for
fluid
administration
RA
infusion
port
(white)

26. Summary of Pulmonary Artery Pressure Waveforms
Normal 2-6 mmHg Normal 20-30/0-5 Normal 20-30/8-14 Normal 8-14 mmHg
mmHg mmHg

32. The three pathwaysin PAHpathogenesis
Humbert M, et al. N Engl J Med 2004; 351:1425-36.
cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate;
ERA: endothelin receptor antagonist; ET: endothelin; PDE-5: phosphodiesterase-5;
PDE-5i: phosphodiesterase-5 inhibitor; PGI2: prostacyclin; SMCs: smooth muscle cells

35. Approval of PAH therapies
Bosentan
(Tracleer)
2001 – US
2002 – Europe
Epoprostenol
i.v.
(Flolan)
1995 – US
2001 – Europe
Treprostinil i.v. or s.c.
(Remodulin)
2002 – US
2005 – Europe
2013
Macitentan†
(Opsumit)
Treprostiniloral†
(Orenitram)
US
Riociguat†
(Adempas)
Iloprost inhaled
(Ventavis)
2004 – US
2003 – Europe
Iloprost i.v.
(Ilomedin)only
approved in New
Zealand
2010 201520051995 2000
2009
Treprostinil inhaled†
(Tyvaso)
Tadalafil (Adcirca)
Sildenafil
(Revatio)
2005
Beraprost
(Careload†
)
2007
*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
Ambrisentan (Letairis –
US; Volibris – EU/Canada)
2007 – US
2008 – Europe
Epoprostenoli.v.
(Veletri – US and Europe; Caripul – Canada
and Italy; EpoprostenolACT – Japan)
2012 – US, Switzerland* & Canada
2013 – Japan

36. 5th World Symposium on PH: Evidence-basedtreatment
algorithm
Generalmeasuresandsupportive therapy
Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.
Supervisedexercise training(I-A)
Psycho-social support (I-C)
Avoidstrenuous physical activity(I-C)
Avoidpregnancy (I-C)
Influenzaand pneumococcal
immunisation(I-C)
General measuresand
supportive therapy
Oral anticoagulants:
•IPAH, heritable PAH andPAH due
toanorexigens (IIa-C)
•APAH (IIb-C)
Diuretics (I-C)
Oxygen (I-C)
Digoxin (IIb-C)Expert referral (I-C)
Acute vasoreactivity test
(I-C for IPAH) (IIb-C for APAH)
Initial therapy with
PAH-approved drugs
Non-vasoreactive
FC I-III
CCB (I-C)
Sustainedresponse
(FC I-II)
Continue CCB No
Vasoreactive
Yes
APAH: associated PAH; CCB: calcium channel blockers;
FC: functional class; IPAH: idiopathic PAH

37. 5th World Symposium on PH: Evidence-based treatment
algorithm
Combinationtherapyandinterventionalprocedures
Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.
Inadequate clinical response
Sequential combination
therapy (I-A)
ERAs
Prostanoids
PDE-5i
or sGCS
+
+
Initial therapy with PAH approved drugs
+
Referral for
LUNG TRANSPLANTATION
(I-C)
Consider eligibility for
lung transplantation
BAS (IIa-C)
Inadequate clinical
response on
maximal therapy
BAS: balloon atrial septostomy; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase-5 inhibitor;
sGCS: soluble guanylate cyclase stimulator

45. • Central location PA
• 5-L/min blood flow
• Thin-walledvessel
• Dual circulation
Pulmonary Endarterectomy
Difficultiesto Overcome
Courtesy of Mr Jenkins.

46. • Median sternotomy incision, for approach to
both lungs
• Cardiopulmonary bypass, with cooling to
20o C (circulatory arrest for 20 minutes)
• Clearance of PA obstruction to reduce PVR
• Full distal dissection to every segmental
vessel
Pulmonary Endarterectomy
Technique Overview
Courtesy of Mr Jenkins.

47. 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