PH: Who Ya Gonna Call Pulm Consults Lana Melendres Pulm/CC Division Pulm Htn Program Director 4/24/13

Objectives Define pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) Identify the 5 different groups of PH When to call a lifeline (pulm consult) Review the workup for PH Making the diagnosis Therapeutic options

Case #1 35yo woman with PMHx significant for exercise induced asthma and anxiety presenting to the ED after “syncope”. Remembers trying to pick up her 2 year old daughter when the “curtains closed” and she “went down” SOB worsening despite use of inhalers

Case #2 29yo man with HIV presenting to the ED with 2 month h/o of worsening SOB on exertion that has dramatically worsened over the past week to the point that he is now having SOB at rest and feeling dizzy when standing not on any medications. Recently moved from California and has no information in our system.

Case #3 46yo morbidly obese woman with DM, htn, and presumed OSA/OHS presenting to the ED with fatigue and worsening lower ext edema. Recently established with a PCP and started on therapies for her DM, htn and was referred for a sleep study (will be seen in Oct 2013)

Case #4 65yo woman with little PMHx presenting with SOB and exhaustion. Has no medical problems that she knows of, just retired from teaching for the past 40years. Previously playing 18 holes of golf, now only able to walk 15ft before needing to stop and rest.

Case #5 47yo man with SOB that has been progressive for the past several months. Previously able to ride his bike 100-150 miles a week, now to sob to ride more than 5-10 miles at a time. No medical problems that he is aware of. Works as a nuclear engineer. Takes no medication. CT scan showed nodules, lymphadenopathy, and septal thickening. PVOD: CT findings with

Case #6 83yo woman has been healthy her whole life now presenting with worsening fatigue with exertion. Previously able to swim for 30 minutes a day and walk for 30min, now sob with much less. Unable to keep up with her friend. Experiencing palpitations and chest pressure intermittently.

Case #7 52yo man with ESRD on HD, htn, DM, CAD, cirrhosis from hep C and prior ETOH abuse and mild COPD, no longer smoking, admitted after missing two HD appointments with profound fluid overload. Also notes that he has had worsening SOB over the past year and fluid retention.

Normal Cardiac Hemodynamics

Diagnostic Definition: Pulmonary Hypertension Rest: - Mean PAP >25 mmHg PAH = above + PCWP or LVEDP <15 mmHg Associated with adverse changes - In the pulmonary vasculature (arteriopathy) - At the level of the right ventricle (hypertrophy) No longer part of the definition: Exercise: - Mean PAP > 30 mmHg Genevea convention in 2003 the diagnostic classification was mPAP of >25, included exercise >30 and wedge of <15mmHg with some mention of PVR needing to be >2 or 3 Woods units. At the Dana point conference in 2008 this definition was altered for a variety of reasons. The first was that when reviewing 47 studies on normal patients PAP, at rest the mean was 14 + 3 but with exercise there was a wide range especially respective to age (>50 could be as high as 47). Currently, it is felt that mPAP of 8-20 is normal; 21-24 is a gray zone with insufficient evidence; 25 or greater was PH. Plexogenic arteriopathy (the parent muscular artery shows medial and intimal thickening) due to inflammatory process from cytokines and chemokines undergoes shear stress which results in damage causing transmural destruction that is repaired by grnaulation tissue= plexiform lesion. Pleciform lesion= granulation tissue resulting from the parent muscular artery sustaining medial and intimal thickening that combined with shear stress at branch points Gaine et al. The Lancet, 1998.

New Proposed Classification of Pulmonary Hypertension (Dana Point, 2008) 1. Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable 1.2.1. BMPR2 1.2.2. ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia ) 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 diseases 1.4.5 Schistosomiasis 1.4.6 Chronic hemolytic anemia 1.5 Persistent pulmonary hypertension of the newborn 1’. Pulmonary veno-occlusive disease (PVO) and/or pulmonary capillary hemangiomatosis (PCH) 2. Pulmonary hypertension due to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3. Pulmonary hypertension due 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 abnormalities 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. PH with unclear multifactorial mechanisms 5.1 Hematologic disorders: myeloproliferative disorders splenectomy. 5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis.

Back to the Cases What do all the patients presented have in common? Each patient was found to have pulmonary arterial hypertension after full w/u and diagnosis by right heart catheterization.

Pulmonary Arterial Hypertension Case #1: IPAH Case #2: PAH associated with HIV

PAH Case #3: PAH assoc with drugs/toxins Case #4: PAH assoc with CTD

PAH Case #5: PVOD Case #6: PAH assoc with CHD Case #7: PAH assoc with portal htn

When to Call Pulmonary Definite Consult: Consider Consult: Patient with known PAH by RHC, on PAH specific therapies All patients followed by the PH clinic. Consider Consult: Patient with echo findings of elevated PASP: No known CTD, PASP >40mmHg Known CTD, PASP >35mmHg

Pulmonary Arterial Hypertension: Detection and Diagnosis Is there a reason to suspect PAH Clinical history (symptoms, risk factors, family Hs.), Exam, CXR, ECG yes no Is PAH likely? Echo Rationale TRV to measure RVSP; RVE; RAE; RV Dysfunction: No further evaluation for PAH no yes Is PAH due to LH disease? Echo yes Dx LV systolic, diastolic dysfunction; valvular disease: Appropriate treatment and further evaluation if necessary, including R&LHC no Dx abnormal morphology; shunt: Surgery. Medical treatment of PAH or evaluation for further definition or other contributing causes, including R&LHC if necessary Is PAH due to CHD? Echo with contrast yes no This detection and diagnosis algorithm was published in a recent Chest supplement focused on diagnosis and treatment of pulmonary hypertension. It provides a rigorous strategy to diagnose PH, and determine it’s cause which is key to determining the appropriate treatment approach. In some cases, medical history and/or the presence of risk factors will afford a re-order of this approach to initially hone in on and either confirm or eliminate the suspected cause. Dx Scleroderma, SLE, other CTD, HIV: Medical treatment of PAH and further evaluation for other contributing causes, including RHC Is PAH due to CTD, HIV? Serologies yes no Is chronic PE suspected? VQ scan McGoon et al. Chest 2004;126:14S-34S

Pulmonary Arterial Hypertension: Detection and Diagnosis Is chronic PE suspected? VQ scan yes Is chronic PE confirmed and operable? Pulmonary angiogram yes no VQ normal Anatomic definition (CT, MRI may provide additional useful but not definitive information): Thromboendarterectomy if appropriate or medical treatment; clotting evaluation; a/c Is PAH due to lung disease or hypoxemia? PFTs, arterial saturation no yes Dx parenchymal lung disease, hypoxemia, or sleep disorder: Medical treatment, oxygen, positive pressure breathing as appropriate, and further evaluation for other contributing causes, including RHC if necessary no Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/ response to treatment with serial reassessments What limitations are caused by the PAH? Functional class; 6-minute walk test ..... The final step in diagnosing PAH is right heart catheterization Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or uncertain), transpulmonary gradient CO, PVR, SvO2, response to vasodilators: Confirm PAH, or IPAH if no other cause identified Discuss genetic testing and counseling of IPAH What are the precise pulmonary hemodynamics? RHC McGoon et al. Chest 2004;126:14S-34S

NYHA Classification

Right Heart Catheterization is the Diagnostic Gold Standard Saturations Rule Out Shunts Intra-cardiac Intra-Pulmonary Hemodynamics RAP mPAP PCWP Rule out left sided heart disease CO/CI PVR Angiography Vessel properties CTEPH Vasodilator Response 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. RHC can also Prognosticate! Rich et al. WHO Symposium on PPH. Evian, France,1998.

Determinants of Disease Severity Determinants of risk Lower risk Higher risk Clinical evidence of RV failure No Yes Progression Gradual Rapid WHO functional class II, III IV 6MWD Longer (>400 m) Shorter (<300 m) BNP Minimally elevated Very elevated Echocardiographic findings Minimal RV dysfunction Significant RV dysfunction, pericardial effusion Hemodynamics Normal/near normal RAP and CI High RAP, low CI BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular. McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

Therapeutic Pathways

Therapies The only group that has been approved for the specialized medications for pulmonary hypertension are Group 1 (pulmonary arterial hypertension/PAH) The other groups require treatment of the underlying condition causing the elevated pressures.

Therapeutic Options for PAH Traditional therapies FDA approved for PAH Supplemental O2 Diuretics Oral vasodilators (CCB) Anticoagulants warfarin Inotropic agents Digitalis Prostanoids Epoprostenol (flolan/veletri) Treprostinil (IV/SQ/Inhaled) Inhaled Iloprost ERA’s Bosentan Ambrisentan PDE-5 Inhibitors Sildenafil Tadalafil

Natural History of PAH: NIH Registry1,2 69% 56% 46% Percent survival 38% Predicted survival Predicted survival* Years NIH = National Institutes of Health. Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension. 1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.

The Take Home Most crucial aspect: the patient’s history If concerned about PAH or have PAH, call the pulm consult service to help in management Timing of RHC is essential If on PAH specific therapy, Do Not Abruptly Stop

Questions?