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

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

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.

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

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

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

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

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

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

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.

Normal Cardiopulmonary Circulation “Heart Disease”; Ed Braunwald, 1992:790-816

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; 31:2080-6. Confidential 12

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.

Dana Point Classification of PH Galiè N et al. Eur Heart J 2009; 30:2493-537 Galiè N et al. Eur Resp J 2009; 34:1219-63 14

Group 1 Idiopathic Incidence 1-2 cases per million Ratio 1.7: 1 female to male Typical age: 20-40 years Often a diagnosis of exclusion May be familial Poor prognosis Abenhaim, NEJM 1996;335 Rich Ann Int Med, 1987; 107:216, Rubin NEJM 1997 336;111.

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

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

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

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.

Group 1 CTD Scleroderma Rheumatoid Arthritis Lupus

Dana Point Classification of PH Galiè N et al. Eur Heart J 2009; 30:2493-537 Galiè N et al. Eur Resp J 2009; 34:1219-63 21

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

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

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

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

Pathogenesis of Cor Pulmonale Adapted from “Heart Disease”; Ed Braunwald, 1992:790-816

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.

Dana Point Classification of PH Galiè N et al. Eur Heart J 2009; 30:2493-537 Galiè N et al. Eur Resp J 2009; 34:1219-63 28

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

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

Group 5 PH Galiè N et al. Eur Heart J 2009; 30:2493-537 Galiè N et al. Eur Resp J 2009; 34:1219-63 31

Diagnosis and Evaluation

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

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.

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

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

Right Heart Catheterization Diagnostic Gold Standard CI 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.

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

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

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 1.5-2.5) Oxygen as needed Diuretics as needed Digoxin?

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

-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; 351:1425-36

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

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.

-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; 351:1425-36

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

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

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; 55:7849-61. Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45. 3. Gatfield J, et al. PloS One 2012; 7(10):e47662. 4. Iglarz M, et al. Am J Respir Crit Care Med 2011; 183:A6445. 5. Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s. 6. Raja SG. Curr Opin Investig Drugs 2010; 11:1066-73. 7. Bruderer S, et al. AAPS J 2012; 14:68-78. BSEP: bile salt export pump OATP: organic anion transporter polypeptide Confidential 48

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 Galiè N et al. Eur Heart J 2009; 30:2493-537 Galiè N et al. Eur Resp J 2009; 34:1219-63 50

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