Shilpa Johri, MD, MBBS, FCCP Pulmonary Associates of Richmond Pulmonary Hypertension: An Overview of Updated Classification, Diagnostic Algorithm and Treatment Options Shilpa Johri, MD, MBBS, FCCP Pulmonary Associates of Richmond

Objectives: Conflict of Interest Definition and updated classification of PH Clinical presentation in patients with PH Work up algorithm in suspected PH Identify predictors of increased morbidity and mortality Review management guidelines Clinical case examples Conflict of Interest Consultant and Advisory Board: Gilead Sciences Speaker’s Bureau: Gilead Sciences and Bayer Pharmaceuticals Research funding: Bellephoron Therapeutics and United Therapeutics

Definition of Pulmonary Hypertension General definition Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization Hemodynamic characterization of PAH Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units) PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance Several recommendations were published following the 5th world symposium on pulmonary hypertension. First, the general definition for pulmonary hypertension was agreed to be a mean PAP ≥ 25 mm Hg at rest as measured by right heart catheterization. Also, the hemodynamic characterization of PAH was determined to be a mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, and an elevated PVR (> 3 Wood Units). Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 3

Hemodynamic measurements Cardiac output: 5 L/min Systemic BP: 120/80 mmHg PAP: 25/10 mmHg PAWP: 10-12 mmHg Mean PAP : 15-20 mmHg (SPAP + 2x DPAP)/3 PVR : 0.5 – 2 WU Mean PAP- PAWP/ CO

Clinical Classification of Pulmonary Hypertension The next several slides focus on the subcategories of group 1 PAH. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 5

Clinical Classification of Pulmonary Hypertension- 5th World Symposium at Nice 1. Group I PAH Idiopathic BMPR2 ALK-1, ENG, SMAD9, CAV1, KCNK3 Unknown Heritable Drug- and toxin-induced Connective tissue disease (7-12% of patients with scleroderma) HIV infection (0.5% of patients with HIV) Portal hypertension (2-6% of patients with portal hypertension) Congenital heart disease (10% of the adults with CHD) Schistosomiasis (5% of affected patients) Associated with: BMPR2 = bone morphogenetic protein receptor type 2; ALK-1 = activin A receptor type II-like kinase-1; ENG = endoglin; CAV1 = caveolin-1 The types of PAH are listed on the slide. Idiopathic PAH is designated as 1.1. Heritable PAH is designated as 1.2 and includes patients with the following genetic mutations: BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3, and unknown. Drug and toxin induced PAH is designated as 1.3. Associated conditions are found under the last category of PAH (1.4) and include: connective tissue disease, HIV infection, portal hypertension, congenital heart disease, and Schistosomiasis. 1’ Pulmonary venoocclusive disease 1” Primary pulmonary hypertension of new born Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 6

Clinical Classification of Pulmonary Hypertension- 5th World Symposium at Nice 2. PH owing to left heart disease 2.1. Left ventricular systolic dysfunction 2.2. Left ventricular diastolic dysfunction 2.3. Valvular disease 2.4. Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cellhistiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH 3. PH owing to lung diseases and/or hypoxia 3.1. Chronic obstructive pulmonary disease 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 Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41

55 year old Caucasian female with history of HTN was referred for exertional dyspnea for 4 years Actively working with frequent travel- started finding it difficult to walk through airports with hand baggage Previous work up had included a negative stress test (3 years ago), negative left heart cath (2 years ago) and relatively unremarkable echo with PASP estimated at 35 one year ago, CTA negative for pulmonary emboli 2 years and 6 months ago. Was on treatment with beta blockers and benzodiazepines were added for dyspnea attributed to anxiety She worsened to a point where she had to stop several times before she could reach her seat in the 13th row during basketball games at UNC Accentuated P2 on exam, both previous CTA s showed dilated central PA

CT scan 2 years apart RHC: PAP 91/39, mean 60, PAWP 5, SvO2 79%, TDCO 6.97, PVR 7.89 Wood Units Sequential therapy, currently on 3 agents

PAH distribution Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41

Epidemiology of PAH Prevalence in the U.S.- 15-50 cases/million Only 1/3 to 1/2 of those are diagnosed and treated Historically: Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead” Modern day: Patient survival has dramatically improved as treatment options for PAH have increased Robin ED. The kingdom of the near-dead: the shortened unnatural life history of primary pulmonary hypertension. Chest. 1987;92:330-4. The prevalence of PAH is estimated at nearly 50,000 to 100,000, with only 15,000 to 25,000 patients diagnosed and treated. The disease course and prognosis for patients with PAH has dramatically improved over the last several decades. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. 11

Mechanisms of Pathology for PAH Endothelin pathway Prostacyclin pathway Nitric oxide pathway Endothelial cells L-arginine Preproendothelin Proendothelin Arachidonic acid Prostaglandin I2 NOS Nitric oxide Endothelin-1 Prostaglandin I2 sGC stimulator Endothelin-receptor A GTP Endothelin-receptor B The graphic shows three pathways that are believed to play a key role in the pathology of PAH: the endothelin pathway, nitric oxide pathway, and the prostacyclin pathway. The illustration also shows the sites and targets for common treatment options. Endothelin receptor antagonists act on the endothelin receptors in that pathway. The target for the phosphodiesterase-5 inhibitors, as well as the newly-approved agent riociguat, is the nitric oxide pathway. Meanwhile, the prostacyclin analogs target the prostacyclin pathway. Exogenous nitric oxide Prostacyclin analogues Endothelin-receptor antagonists cGMP cAMP Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436. 12

Mechanisms in PAH Increased pulmonary vascular resistance Sustained vasoconstriction Excessive pulmonary vascular remodeling In situ thrombosis Increased pulmonary vascular resistance is the hallmark of pulmonary hypertension. This increase is due to: sustained vasoconstriction, excessive pulmonary vascular remodeling, and in situ thrombosis. Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. 13

Pathology of PAH

Symptoms Suspect PH? Clinical symptoms Unexplained dyspnea on exertion Presyncope Syncope Signs of right ventricular dysfunction Other non-specific symptoms in patients with PAH Fatigue, weakness, angina, abdominal distension, edema In general, the clinical symptoms associated with PAH are rather non-specific, and may go unreported by patients or unrecognized by clinicians. Patients can present with one or more of the following symptoms: breathlessness, fatigue, weakness, angina, syncope, abdominal distension, and edema. Patients who present with unexplained dyspnea on exertion, presyncope, syncope, or signs of right ventricular dysfunction are candidates for additional diagnostic screening. Suspect PH? Galie, et al. Eur Heart J. 2009;30:2493-2537. Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 16

Diagnostic Algorithm for PAH RHC is MANDATORY to confirm the diagnosis of PAH V/Q = ventilation / perfusion lung scan; CTEPH = chronic thromboembolic pulmonary hypertension; RHC = right heart catheterization; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; WU = wood units A step-wise approach can be taken when evaluating patients for possible diagnosis of PAH. A diagnosis of PAH requires the exclusion of other causes of pulmonary hypertension. As such, heart and lung disease need to be ruled out. Also, chronic thromboembolic pulmonary hypertension (CTEPH) is ruled out by performing a V/Q scan and obtaining negative results. Right heart catheterization is mandatory for diagnostic confirmation. Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 17

Diagnostic Approach to PAH McLaughlin, V. V. et al. J Am Coll Cardiol 2009;53:1573-1619

Chest X-Ray and ECG in PAH McLaughlin, V. V. et al. J Am Coll Cardiol 2009;53:1573-1619

Echocardiography for PAH Evaluate left heart Evaluate valves Evaluate for structural lesions Evaluate right heart size Estimate right sided pressures Measure indices of RV function TAPSE Tei index Evaluate for pericardial effusion

6 Minute Walk Test Easy to perform Functional assessment during office visits Assess response to therapy Primary end point of clinical trials Performed according to stated ATS guidelines to ensure reproducibility

6 Minute Walk Test Correlation between RV function and cardiac output Correlation with prognosis 3 year survival in patients with 6MWD of < 332 m: 20% 3 year survival in patients with 6MWD of > 332 m: 92% Current goal directed therapy: aim for 380 m Miyamoto, S, Nagaya, N, Satoh, T . Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161(2 Pt 1):487–492.

RHC is more than just measuring pressures! Cardiac output: 5 L/min Cardiac index: 2.5-3.5 L/min/m2 PVR (mean PAP-PAWP/ CO): 0.6 to 2.5 WU Pulmonary artery saturation (PA sat): 70% Acute vasoreactivity test for PAH: Positive if decrease of >/= 10 in mPAP to < 40 without drop in cardiac output Agents: iNO, adenosine, epoprostenol Consider exercise, volume loading, LHC as indicated

Vasoreactive PAH Excellent prognosis ! 9/2011: 52 YO man at NYHA FC III (long distance runner, 10K 62 mins), was unable to run a soccer field lap with his son >> DOE with 1 flight of stairs >> DOE level ground. Stress echo: Resting RVSP 85-90 which rose to 110-120 mmHg post exercise. RHC – 10/2011 NYHA FC III PAP: 83/21 mPAP: 42 mPAWP: 11 TDCO: 6.27 PVR: 344 Post iNO Data PAP: 47/10 mPAP: 22 TDCO: 6.46 PVR: 86 RHC 5/2013 NYHA FC I 10K time of 56 mins!! Echo: enlarged RV PAP: 64/22 (36) TDCO: 6.83 mPAWP: 15 PVR: 245 Post iNO Data PAP 43/14 (23) PVR: 126 TDCO: 6.3 SBP:102/65, HR 62 Tadalafil 40 mg added 10 K off limits! Diltiazem 360 mg 8/2013- 3/2018 RVSP ~ 50- 60 Normal RV NYHA FC I 10K still off limits Vasoreactive PAH Excellent prognosis !

Survival In PAH- Depends On The Right Ventricle Patient 1 PASP 90 Normal RV size and function Patient 2 PASP 50 Dilated RV with reduced function