1. Pulmonary Hypertension
George Chandy MD MSc FRCP(C)
Assistant Professor of Medicine, University of Ottawa
Co-Director, University of Ottawa Heart Institute
Pulmonary Hypertension Clinic
April 6thth 2016

2. Disclosures Advisory Board/Talks: Actelion, Pfizer, Bayer
Institutional Research:
Bayer, Actelion

3. LEARNING OBJECTIVES:
Review the classification scheme of Pulmonary Hypertension (PH) and the updated definition
Discuss the Poor prognosis associated with pulmonary hypertension and the need for early diagnosis
Differentiate the three distinct pathophysiologic pathways targeted by novel PAH-specific therapies including a review of specific theraapies.

4. Topics to be Discussed Briefly review Focus on Group 1, 3, 4, 5 PH
Normal and Abnormal Pulmonary Vascular Function
Definition and Classification
Pathophysiology and Presentation of Common Types of PH
Approach to Diagnosis
Focus on Group 1, 3, 4, 5 PH
Vasospecific Therapy

5. Clinical Message Severe PAH: Is rare.. But.. However...
Symptoms are vague
Signs are difficult for non-specialist
Basic investigation often unhelpful
But..
Treatments are effective
However...
Early diagnosis essential
Management requires specialized centres

6. Pulmonary artery (normal)
High flow, low resistance vessel
PA maximally dilated
-unique vascular supply – PA are normally maximally dilated and are high flow low resistance vessels
-the low vascular resistance compared to SVR is due to the very large cross secional area of the pulmonary circulation

7. Pulmonary Artery Physiology
Pressures low
1/5 systemic
Resistance low
1/10 systemic
Pulmonary arterioles contribute minimally to total peripheral resistance (no medial layer)
Systemic
High pressures
High vascular resistance
Arterioles supply 75% of total peripheral resistance to blood flow
the low vascular resistance compared to SVR is due to the very large cross secional area of the pulmonary circulation

8. Left
Ventricle
Right
Compared to the LV – the RV is thin walled, more compliant and maintains a much more crescentic shape, the RV can be thought of as a volume pump an the LV as a pressure pump
-the

9. Right Ventricle Left Ventricle
-when subjected to volume overload – the RV will dilate, it will also hypertrophy when subjected to high PA pressures

10. Pulmonary Hypertension: Clinical definition
mPAP >25 mmHg at rest
Pressures > 20mmHg are considered borderline
Associated with adverse changes
Pulmonary vasculature (vasculopathy)
Right ventricle (hypertrophy)
The clinical definition of pulmonary hypertension involves a mean pulmonary arterial pressure of over 25 mmHg at rest or over 30 during exercise, with a normal pulmonary capillary wedge pressure.
These will be associated with marked vasculopathy in the pulmonary vasculature and hypertrophy of the right ventricle.
Gaine SP, et al. Lancet. 1998;352:719.

11. Normal Cardiopulmonary Circulation
“Heart Disease”; Ed Braunwald, 1992:

12. Pulmonary remodelling From healthy state to disease state
ET-1 induces processes that contribute to the remodelling of the pulmonary vasculature, i.e. intimal hyperplasia and medial hypertrophy adventitial fibrosis, fibrinoid necrosis and the development of plexiform lesions.
Increased thickening of the media due to hypertrophy and hyperplasia of SMCs and increased thickening of the intima due to proliferation/migration of myofibroblasts and fibrosis lead to severe lumen reduction.
Pathological vascular remodelling is a key contributor to the symptomology of PAH and pathological changes within the lung microcirculation are virtually identical across all PAH classifications.
Adapted from Galiè N, et al. Eur Heart J 2010; 31:
Confidential 12

13. Schematic Progression of PAH
Pre-symptomatic/ Compensated
Symptomatic/ Decompensating
Declining/ Decompensated CO
This slide represents a synthesis of human and animal models of PAH that shows a putative model of disease progression.
Pulmonary hypertension may be classified into 3 rough categories, pre-symptomatic/compensating, symptomatic/decompensating, and declining/decompensated.
In this hypothetical model, as the vascular pathology progresses (proliferation of intima, hyperplasia of the SMC, and adventicial fibrosis), PVR increases and pulmonary artery pressure rises in concert in order to maintain CO. As long as the RV is able to compensate for the resistance, pressure continues to increase as PVR increases.
The increased RV work-load causes the RV to hypertrophy and its efficiency falls, right heart failure ensues, and PAP will fall as the patient decompensates.
Failure to maintain CO leads to the symptoms of the disease and ultimately right heart dysfunction and death
CO- Cardiac Output
PAP- Pulmonary arterial pressure
PVR- Pulmonary vascular resistance
Symptom Threshold
PAP
Right Heart Dysfunction
PVR
CO=
PAP
PVR
Time
Adapted from Harrison’s Principles of Internal medicine , 14th ed.

14. Dana Point Classification of PH
Galiè N et al. Eur Heart J 2009; 30:
Galiè N et al. Eur Resp J 2009; 34: 14

15. Group 1 Idiopathic Incidence 1-2 cases per million
Ratio 1.7: 1 female to male
Typical age: years
Often a diagnosis of exclusion
May be familial
Poor prognosis
Abenhaim, NEJM 1996;335 Rich Ann Int Med, 1987; 107:216, Rubin NEJM ;111.

16. Present will classic pathologic findings discussed above – fibrosis, medial hypertohpy, intimal and adventitial hypertrophy and thrombosis

17. Group 1 Pulmonary HTN due to Congenital Heart Disease
Left to right shunting
Increases flow through pulmonary vasculature
Sheer forces disrupt vascular endothelium
Activate cellular mechanisms critical to pathogenesis of PAH
-pressure and volume loading on pulmonary circuit

18. Left to Right Shunts
In ASD patients – initially pulmonary vasculature able to accommodate increased flow by recruiting unperfused vessels
VSD – overload and shear force stress
-this can

19. Eisenmenger Syndrome
Severe pulmonary hypertension at systemic levels which leads to bidirectional or reversed shunt
Process is end-stage and usually irreversible
In patients with Eisenmenger's syndrome, there is initially substantial left-to-right shunting. As a result, morphologic alterations occur in the small pulmonary arteries and arterioles (inset), leading to pulmonary hypertension and the resultant reversal of the intracardiac shunt, ie right-to-left (arrow). In the small pulmonary arteries and arterioles, medial hypertrophy, intimal cellular proliferation, and fibrosis lead to narrowing or closure of the vessel lumen with sustained pulmonary arterial hypertension. Eisenmenger's syndrome may occur in association with a ventricular septal defect (as shown), but it also may occur in association with an atrial septal defect or patent ductus arteriosus. Reproduced with permission from: Brickner, ME, Hillis, LD, Lange, RE. N Engl J Med 2000; 342:334. Copyright © 2000 Massachusetts Medical Society.

20. Group 1
CTD
Scleroderma
Rheumatoid Arthritis
Lupus

21. Dana Point Classification of PH
Galiè N et al. Eur Heart J 2009; 30:
Galiè N et al. Eur Resp J 2009; 34: 21

22. Group 2 Pulmonary Venous Hypertension
All causes of left heart failure can result in PH
Ishchemic and nonischemic CM
Acute ischemia
Valvular disease
Diastolic dysfunction (HTN)
Increased pulmonary venous pressure
Increased pulmonary vascular smooth muscle tone
Proliferation of fibrous connective tissue around alveoli
Endothelial dysfunction
-also distention of pulmonary lymphatics – which clears transudation of fluid
-in most patients –increase smooth muscle tone may be reversible –due to decreased synthesis of nitric oxide , and decreased clearance of a vasoconstrictor - endothelin

23. Group 3 Lung Disease COPD and Emphysema
Interstitial Lung Disease (Pulmonary fibrosis)
Sleep Disordered Breathing

24. How does lung disease result in PH?
Obliteration of vascular bed (decreased flow)
Hypoxia induced vasoconstriction
-usually from emphysematous –overinflated airways

25. Cor Pulmonale Definition: Acute:
Acute right heart strain or overload resulting from pulmonary hypertension which usually follows a massive pulmonary embolus
Chronic:
Right ventricular hypertrophy and/or dilation secondary to pulmonary hypertension which is due to disease of the lung parenchyma or pulmonary vascular system

26. Pathogenesis of Cor Pulmonale
Adapted from “Heart Disease”; Ed Braunwald, 1992:

27. Prognosis of PH in patients with chronic lung disease
The relationship between baseline mean pulmonary artery pressure (from less than 25 to more than 45 mmHg) and survival in patients with chronic obstructive pulmonary disease. Increasing pulmonary artery pressure was associated with a progressive decline in survival. Redrawn from Bishop, JM, Prog Respir Res 1975; 5:9.

28. Dana Point Classification of PH
Galiè N et al. Eur Heart J 2009; 30:
Galiè N et al. Eur Resp J 2009; 34: 28

29. Chronic Thromboembolic PH
Presentation
Persistent SOB after PE
Recurrent PE
Occurs in 1% of PE survivors
Pathophysiology not certain
May be related to underlying hypercoaguable state
Predisposition to pulmonary arteriopathy

30. Multiple thombi/emboli
Can extend into multiple lobar and segmental branches
Vascular fibrosis and inflammation

31. Group 5 PH Galiè N et al. Eur Heart J 2009; 30:2493-537
Galiè N et al. Eur Resp J 2009; 34: 31

32. Diagnosis and Evaluation

33. Signs and symptoms of pulmonary arterial hypertension
Initial signs and symptoms
Dyspnea
Syncope
Dizziness
Fatigue
Edema
Chest pain
Non-specific nature of complaints can lead to:
Confusion with other conditions
Delayed diagnosis

34. Diagnosis is made late in disease
Mean duration from symptom onset to diagnosis of PAH is 2.5 years
Late diagnosis due to
Under-recognition
Non-specific symptoms
Confusion with other conditions
iPAH is a diagnosis of exclusion
PAH tends to be diagnosed late in the disease – generally due to patients being asymptomatic until late in disease, under-recognition, lack of screening of those at risk, and the non-specific nature of symptoms.
Early in the disease process, patients are generally asymptomatic, one of the reasons for late diagnosis.
Dyspnea on exertion is the most common presenting symptom, sometimes accompanied by fatigue, dizziness, palpitations Later, other non-specific symptoms may include chest pain (which may be indistinguishable from coronary artery disease), recurrent syncope, coughing.
The non specific nature of symptoms can lead to confusion with other conditions such as: Deconditioning Psychological problems (depression, anxiety) Biventricular heart failure Coronary artery disease Asthma, chronic obstructive airway disease
Late in the disease there are characteristic symptoms and signs of right heart failure including edema and ascites.
Diagnosis requires confirmation of PAH with RHC and evaluation of etiology.

35. Where is the sphygmomanometer for the pulmonary vasculature?
Invasive
Right heart catheterization
Noninvasive
Echocardiographic estimate of pulmonary artery systolic pressure based on tricuspid regurgitation flow
PAP = (4 x tricuspid velocity flow2) + RAP
sphygomometer

36. Diagnosis of PAH by right heart catheterization
Right heart catheterization is mandatory to establish a diagnosis of PAH and exclude other causes.
PAH is associated with a marked vasculopathy in the pulmonary vasculature, increased PVR and subsequent hypertrophy of the right ventricle.
The hemodynamic definition of PAH is shown in the slide. Important to note that PCWP is normal and in early disease, increase in mPAP is more pronounced during exercise.
In PAH, increased PVR is an important hemodynamic parameter, however, PVR can not be measured directly, but is derived from CI and mPAP.
PAH definition
mPAP >20 mmHg at rest with a normal PCWP
Gaine et al. Lancet 1998;352:719

37. Right Heart Catheterization Diagnostic Gold StandardCI
PCWP
Rule out left sided heart disease
PVR
RAP
mPAP
Prognostic (RAP, CI, mPAP)
Acute vasodilator study
Exclusion of shunt
Pulmonary angiography
Right heart catheterization is the diagnostic gold standard. This evaluation is necessary to sufficiently rule out secondary causes of disease and left sided heart disease. This evaluation is also necessary to obtain the critical measures of cardiac index and calculated PVR which have significant value prognostically.
Rich et al. WHO Symposium on PPH. Evian, France,1998.

38. Management of PAH Goals Reduce PVR ( PAP ,  CO ) Improve RV function
Prolong survival
Improve quality of life
 symptoms
 exercise tolerance
Minimal side effects

39. Principles of Therapy Management of underlying causes Supportive care
Vasodilator therapy
Anticoagulation
Oxygen
Diuretics
Prevent disease progression
IV prostacyclin
Phosphodiesterase inhibitors
Endothelin receptor antagonists
Lung transplant

40. Conventional therapy of PAH
General Measures
Avoid heavy physical activities
Avoid exposure to high altitude (1000m)
Pregnancy contra-indicated
Caution with surgery
Conventional therapy
Anticoagulants (INR )
Oxygen as needed
Diuretics as needed
Digoxin?

41. Survival on Conventional Therapy
Median Survival (mo)
FC I and II
58.6
FC III
31.5
FC IV
6.0
Median survival 2.8 years 20 40 60 80
100
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
Years of follow up
Percentage surviving
N = 194 patients
Survival at 1yr: 69%
3 yrs 48%,
5 yrs 34%
PAH is associated with a poor prognosis – both for iPAH and PAH related to underlying diseases (although prognosis does vary by etiology, prognosis is poor in all cases).
The data on this slide represent the NIH Registry which included a cohort of prospectively followed iPAH patients (n=194) treated with conventional therapy prior to the availability of epoprostenol and bosentan.
In these patients with iPAH (see slide), the median survival was reported in 1991 to be 2.8 years with survival rates of 68%, 48% and 34% at 1, 3 and 5 years, respectively.
D’Alonzo et al. Ann Internal Med 1991;115:343

42. -3 pathways of therapeutic targets in PAH
-increased endothelin production
Viagra inhibits the breakdown of cGMP – encourages vasodilation, also shown recently to reduce RVH and fibrosis
-prostacyclin is a natural vasodilator -
-impaired production of vasoactive mediators like nitric oxide and prostacyclin, increased with prostacyclin analogues and cGMP stimulators like NO, or inhibition of phosphodiesterase type 5 with slidenifil
Humbert,et al. N Engl J Med 2004; 351:

43. Prostacylin (Flolan®)
Pulmonary Vasodilation
-can only be administered by continuous infusion – half life of 3 minutes, and inactive in gastric pH
-via a tunneled catheter
-costly, complicated infusion, multiple side effects, needs to be kept on ice
-pump failure or dislocation of catheter can be life-threatening
-also has a price tag of about 60k candian a year

44. Long-term epoprostenol in IPAH
Cumulative survival
0.2
0.4
0.6
0.8 1 12 24 36 48 60 72 84 96
108
Time (months)
Baseline NYHA FC III (n = 120)
p = 0.001
Baseline NYHA FC IV (n = 58)
120 58 92 37 65 20 46 11 31 5 17 4 6 2
NYHA III
NYHA IV
No. at risk
-survival better when therapy initiaed in fc 3 rather than 4
-despite improvements approx one third of patients with PAH die w/n 3 years of diagnosis
-patients with worse RHF had worse survival, patients whose fc could be reclassified to class 1 or 2 had much better survival
-recommend that patients still FC 4 after 3 months be referred for lung tx
-improvements in multiple causes of PAH including congenital, portal HTN and HIV
Sitbon O, et al. J Am Coll Cardiol 2002; 40:780-8.

45. -3 pathways of therapeutic targets in PAH
-increased endothelin production
Viagra inhibits the breakdown of cGMP – encourages vasodilation, also shown recently to reduce RVH and fibrosis
-prostacyclin is a natural vasodilator -
-impaired production of vasoactive mediators like nitric oxide and prostacyclin, increased with prostacyclin analogues and cGMP stimulators like NO, or inhibition of phosphodiesterase type 5 with slidenifil
Humbert,et al. N Engl J Med 2004; 351:

46. Targeted Therapy Endothelin receptor antagonists
Bosenten, Ambrisentan, Macitentan
Important target of therapy
Reduce pulmonary pressures
Delay time to clinical worsening
Improve functional capacity
Improve quality of life
Phosphodiesterase Inhibitors
Sildenafil/Tadalafil
Decreases CGMP breakdown which increases smooth muscle relaxation and vasodilation
Reduces pulmonary pressures
Improves quality of life and functional capacity
Reduces right ventricular hypertrophy
Riociguat
Stimulates soluble guanylate cyclase

47. Previous Studies - Shortcomings
Short in Duration
Small with low event rates
Focus on “soft” outcomes
Lack of mortality /morbidity data
Lack of Combination therapy data

48. Macitentan Macitentan Optimised physicochemical properties2
Enhanced affinity for ET receptors, long-lasting receptor occupancy3
Superior pre-clinical in vivo efficacy compared with other ERAs4,5
No relevant interaction with BSEP6
The goal was to find a molecule with superior efficacy, optimal potential to correct the structural cardiovascular changes in PAH, and with a minimised risk of safety and tolerability issues such as liver enzyme abnormalities.
Macitentan was selected on the basis of the following characteristics:
Optimised physicochemical properties to facilitate penetration into the tissue.
Enhanced affinity for the ET receptors, long-lasting receptor occupancy, and sustained pharmacological activity.
Superior pre-clinical in vivo pharmacological efficacy compared with other ERAs.
No relevant interaction with bile acid transporters, resulting in improved hepatic safety.
No relevant interaction with hepatic organic anion transporting polypeptides (OATP), resulting in reduced potential for drug-drug interactions.
No relevant interaction with hepatic OATP7
Bolli M, et al. J Med Chem 2012; 55:
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327: Gatfield J, et al. PloS One 2012; 7(10):e Iglarz M, et al. Am J Respir Crit Care Med 2011; 183:A Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s. 6. Raja SG. Curr Opin Investig Drugs 2010; 11: Bruderer S, et al. AAPS J 2012; 14:68-78.
BSEP: bile salt export pump
OATP: organic anion transporter polypeptide
Confidential 48

49. Selexipag Oral IP receptor Prostasyclin Agonist
More specific receptor activity is thought to result in fewer side effects
Previous oral formulations of Prostacyclin therapies limited by short prostacylcin half life
A titratable oral prostacyclin agent would revolutionalize PHTN therapy

50. 50 Galiè N et al. Eur Heart J 2009; 30:2493-537
Galiè N et al. Eur Resp J 2009; 34: 50

51. Summary Know the definition of PH
Understand the normal and abnormal physiology of the pulmonary vasculature
Recognize the common causes of pulmonary hypertension
Familiarity with the clinical presentation and diagnosis
Conventional and targeted treatment strategies