This document summarizes a presentation on pulmonary hypertension. It discusses: 1) Updates from recent pulmonary hypertension guidelines and clinical trials, including new approved drugs for PAH like riociguat, treprostinil, and selexipag. 2) Right ventricular remodeling patterns in PAH and their relationship to prognosis. 3) The distinction between pulmonary hypertension due to left heart disease versus other causes, and challenges in management. 4) The lack of evidence for using PAH therapies for pulmonary hypertension in the setting of lung diseases or hypoxemia. 5) A case presentation of a patient with hereditary hemorrhagic telangiectasia, liver masses, and signs of severe pulmonary

1. 1
Wael Berjaoui MD
Pulmonary,Critical care and Sleep medicine
SHMG.
4th Annual: Topics in pulmonary and critical
care medicine.
Progress in Pulmonary
Hypertension.

2. No present conflict of interest.

3. Talk Highlights:
•Brief review of PAH including classification, pathophysiology and Dg.
•Updates from the 5th World Symposium on PAH (Nice, France 2013) .
•New approved drugs and therapeutic strategies for G1 PAH.
•PH and LHD
•.PH and lung disease
•Case review of PH in a rare disease.

5. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Heart J 2016; 37 (1): 67-119

7. 7
ESC/ERS Guidelines for the diagnosis and treatment of
pulmonary hypertension. Eur Heart J 2016; 37 (1).

16. RV in PAH:
Adaptive remodeling: Concentric, High mass-volume ratio, preserved
systolic and diastolic function (usually seen in Eisenmenger;s syndrome)
Maladaptive remodeling: eccentric, reduced function, mostly seen in
CTD-PAH or IPAH.RV disynchrony ( RV free wall contracting while LV in
early diastole leading to late systolic septal movement), more R-L shunt
via PFO)
Less RV fibrosis with pressure overload thus better recovery after lung
transplant

19. Updates in PAH management
- New FDA approved medications include Riocigualt ( sGC) , oral
Treprostinil ( PCA), Selexipeg (selective IP agonist) and Macitentan (
ERA).
- Intital Combintaion therapy ( Ambition trial)
- Sequential combination therapy
- Goal targeted therapy

20. Therapy-General Tx
Avoid hypoxemia, high altitude
Low salt diet
Immunizations
Avoid pregnancy
Diuretics
OXYGEN
Exercise/ Rehab: Class 1 recommendation

22. Approved PAH Drugs
Prostacyclin analogues
■ Epoprostenol, IV
■ Treprostinil, IV, sq, inhaled, PO
■ Iloprost, inhaled
■ Beraprost, PO (Japan)
■ Selexipeg, PO
Endothelin Receptor Antagonists
■ Bosentan
■ Ambrisentan
■ Macitentan
PDE V Inhibitors
■ Sildenafil
■ Tadalafil
sGC Stimulators
■ Riociguat

25. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Heart J 2016; 37 (1): 67-119

28. Riociguat: Mode of action
Riociguat directly stimulates the
native sGC independently of NO
Riociguat increases the sensitivity of
native soluble guanylate cyclase
(sGC) to NO
Both actions lead to vasodilatation
(and anti-proliferation)
Effect of riociguat is not limited by low
NO levels (unlike PDE-5-I)
Constricted
Pressure
Flow rate
Relaxed
Pressure
Flow rate
sGC*Riociguat cGMP
* native (intact)
NO
PDE-5-I = phosphodiesterase-5-inhibitor
NO = mitroc oxide

30. Endothelin Receptor Antagonists
Macitentan (Opsumit):
Nonselective dual action Endothelin receptor antagonist.
Sustained receptor binding and enhanced tissue penetration.
Functional Class II, III, IV
Improves mortality, morbidity and 6 MWT

33. Prostacycline Pathway:
Oral treprostinil
FREEDOM M trial: improved 6-minute walk distance (6MWD) by 23
meters at 12 weeks in 349 treatment-naive PAH patients (95%
confidence interval 4 to 41 m, p = 0.0125). However, there was no
improvement in functional class or time to clinical worsening.
Kanwar, Manreet K. et al.Update in treatment options in pulmonary hypertension
The Journal of Heart and Lung Transplantation , Volume 35 , Issue 6 , 695 - 703

34. Selexipag:
Orally available, non-prostanoid, highly selective agonist of inositol
triphosphate (IP) receptor.
This selectivity allows for minimal side effects (nausea, vomiting,
diarrhea and jaw pain), better tolerability and successful dose escalation.

35. GRIPHON trial, which was a multicenter, double-blind, placebo-
controlled trial of 1,156 patients who were randomized in a 1:1 fashion to
selexipag or placebo.
The primary end-point was a composite of death, lung transplantation,
atrial septostomy, hospitalization for worsening PAH or worsening PAH.
It reduced the risk of primary end-point by 40% compared with placebo
(hazard ratio [HR] = 0.60; 99% confidence interval [CI] 0.46 to 0.78; p <
0.0001).

36. Initial Use of Ambrisentan plus Tadalafil in
Pulmonary Arterial Hypertension
Nazzareno Galiè, M.D., Joan A. Barberà, M.D., Adaani E. Frost, M.D., Hossein-
Ardeschir Ghofrani, M.D., Marius M. Hoeper, M.D., Vallerie V. McLaughlin, M.D.,
Andrew J. Peacock, M.D., Gérald Simonneau, M.D., Jean-Luc Vachiery, M.D.,
Ekkehard Grünig, M.D., Ronald J. Oudiz, M.D., Anton Vonk-Noordegraaf, M.D., R.
James White, M.D., Ph.D., Christiana Blair, M.S., Hunter Gillies, M.D., Karen L.
Miller, Ph.D., Julia H.N. Harris, M.A., Jonathan Langley, B.Sc., Lewis J. Rubin, M.D.,
for the AMBITION Investigators
N Engl J Med
Volume 373(9):834-844
August 27, 2015

37. Components and Definitions of the Primary End Point.
Galiè N et al. N Engl J Med 2015;373:834-844

38. Primary and Secondary Efficacy End Points.
Galiè N et al. N Engl J Med 2015;373:834-844

39. Kaplan–Meier Curves for the Probability of a First Adjudicated Primary End-Point Event.
Galiè N et al. N Engl J Med
2015;373:834-844

40. Study Overview
• Patients with previously untreated pulmonary arterial hypertension who
were randomly assigned to combination therapy with ambrisentan and
tadalafil had a significantly lower risk of a composite clinical failure
outcome at 20 months than did the pooled monotherapy group.

41. Conclusions
• Among participants with pulmonary arterial hypertension who had not
received previous treatment, initial combination therapy with ambrisentan
and tadalafil resulted in a significantly lower risk of clinical-failure events
than the risk with ambrisentan or tadalafil monotherapy.

42. Kanwar, Manreet K. et al.Update in treatment options in pulmonary hypertension
The Journal of Heart and Lung Transplantation , Volume 35 , Issue 6 , 695 - 703

43. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Heart J 2016; 37 (1): 67-119

44. Kanwar, Manreet K. et al.Update in treatment options in pulmonary hypertension
The Journal of Heart and Lung Transplantation , Volume 35 , Issue 6 , 695 - 703

46. Lung transplant

47. PH Due to Left Heart Disease
Accounts for ~ 80%
LV systolic dysfunction
■ severity of PH is not related as much to the degree of systolic dysfunction,
but is closer related to measures of diastolic dysfunction and MR, which in
turn really determine LA pressure; it is LA pressure that drives PH
Diastolic (HFpEF): up to 70%
Left sided valvular heart disease
Left atrial disease: myxoma

48. How to Define Left Heart Disease
PAWP > 15 mmHg
History: age, DM, HTN, CAD, CHF, OSA
Symptoms: orthopnea, PND
Chest x-ray: congestion, history
Echo: EF usually normal; LVH, enlarged LA, diastolic dysfunction
Volume challenge or exercise RHC
■ 500 ml NS over 5 min: PAWP > 15 *
■ Supine cycle: PAWP > 20 – 25 mmHg
Vachiery JL. JACC Supp 2013

50. PH in LHD
Confusing nomenclature: “out of proportion”, passive vs reactive PH
Out of proportion if TPG >12, PVR >3 ( only if PCWP <25)
PVR is a composite variable ( Mpap-pcwp /CO)
Diastolic pressure difference= DPAP- mean PCWP
DPAP less influenced by PCWP than SPAP or mPAP due to lower
sensitivity to vessel distensibility.
DPD appears a better reflection of Pulmonary vascular disease

51. PH in LHD

52. PH in LHDPH

53. Riociguat and LHD:
In a recent multicentre, placebo-controlled trial, 201 patients with PH
due to systolic heart failure were randomized in four arms comparing
three doses of riociguat (0.5, 1 and 2 mg t.i.d.) with placebo over 16
weeks.
No effect on the primary endpoint (a change in PAPm after 16 weeks)
was observed at any dose of riociguat compared with placebo.
Bonderman et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular
dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.
Circulation 2013;128:502–511.

54. PH in LHD
Consensus from 5th World Symposium:
Not enough data to recommend use of PAH targeted therapy in G2
PH.

55. WHO Group 3: PH due to lung disease and/or
hypoxia
COPD: typically mild – moderate
ILD: IPF, scleroderma, sarcoid
Combined Fibrosis/Emphysema: often severe PH
Hypoventilation (> 50% in OHS)
Sleep Apnea (Overlap syndrome)
High Altitude

56. When to Suspect PH in Lung Dz
DLCO , PaO2, symptoms “out of proportion” to radiographic and PFT
changes
Physical, x-ray findings of PH
Echo often inaccurate
BNP may be useful
Adversely impacts functional status, survival particularly with RV
dysfunction

57. Systemic PAH meds failed to show any improvement.
Risk of worsening mismatch and hypoxemia
Raghu, G., Behr, J., Brown, K.K. et al. Treatment of idiopathic pulmonary fibrosis with
ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013; 158: 641–649
King, T.E., Brown, K.K., Raghu, G. et al. BUILD-3: a randomized, controlled trial of
bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011; 184: 92–
99
Hoeper, M.M., Halank, M., Wilkens, H. et al. Riociguat for interstitial lung disease and
pulmonary hypertension: a pilot trial. Eur Respir J. 2013; 41: 853–860
Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil
in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010; 363: 620–628

58. Inhaled Therapies
Delivering vasodilator by inhalation appealing as directs the effect to
areas in the lung with best airflow
Minimizes systemic side effects
Favorable effects with acute dosing studies and small medium term trials

59. Inhaled Treprostinil Study (INCREASE
Trial)
Multi-center, randomized, double-blinded, placebo controlled
Idiopathic interstitial lung diseases
Significant pulmonary HTN confirmed by right heart catheterization
Evaluate change in 6 minute walk distance after 16 weeks
Open-label therapy after 16 wk

60. Case presentation:
63 y.o female
Few days of SOB and abd pain
CTA Chest: No PE., RLL consolidation, Dilated PA, large mass in the
right lobe of the liver measuring up to 8 cm in size.
History: Hereditary Hemorrhagic Telengectasia.

62. 2d ECHO
The left ventricular ejection fraction is 62%.
The left atrium is severely dilated.
The right ventricle is moderately dilated. Right ventricle function is
moderately to severely decreased. The right ventricular fractional area
change is 8%.
The estimated right ventricular systolic pressure is 79 mmHg.
The estimated RA pressure is 15 mm Hg (10-20 mm Hg).

63. HEMODYNAMICS:
Under rest condition: Pulmonary pressure equals 62/35, with a mean pulmonary artery pressure of 44
mmHg. Pulmonary capillary wedge pressure 12 mm mean. Estimated Fick cardiac output equals 8.1
L/minute, with a cardiac index of 4.5 L
Nitric oxide inhalation vasodilator challenge: the pulmonary artery pressure did decline to 46/20, with a
mean of 30 mmHg. The pulmonary capillary wedge pressure was unchanged at 10 mmHg mean.

64. MRI Cardiac Morph/Func W + W/O contrast –
Impression:1. Mild left ventricular chamber dilation with normal left ventricular
systolic function. LVEF 62%. Systolic and diastolic septal flattening is present,
consistent with right ventricular pressure and/or volume
3. Severe right ventricular chamber dilation with moderate to severely reduced
right ventricular systolic function. RVEF 35%.4.
4. There is no evidence for significant intracardiac shunt by MRI criteria; the
calculated Qp/Qs is 0.9.5.
5. Mild tricuspid and mitral regurgitation as detailed above.6. Trivial-small
circumferential pericardial effusion.7. Dilated main pulmonary artery.

65. PH in HHT
1. High CO due to shunt via Liver AVMs.
2. Heritable PAH

66. 2 months later after CCB started
Interpretation Summary
The left atrial volume is severely increased.
The right ventricular size, thickness, and function are normal. (Tricuspid
annular plane systolic excursion is 19 mm. Systolic excursion velocity is
18cm/s. The right ventricular fractional area change is 40%.).
The estimated right ventricular systolic pressure is 44 mmHg.

67. Progress in treating PH but we are not
there yet.