Refining Views of Co-morbidities and Vascular Responsiveness in Pulmonary Arterial Hypertension

1. Refining Views of Co-morbidities and Vascular Responsiveness in Pulmonary Arterial Hypertension Roham T. Zamanian, MD, FCCP Assistant Professor of Medicine Director, Adult Pulmonary Hypertension Clinical Service Division of Pulmonary & Critical Care Medicine Stanford University School of Medicine

4. Disclosures: Personal Financial Relationships with Commercial interests relevant to medicine, within the past 3 years: Consultant: Gilead, United Therapeutics, Ikaria, Bayer, Actelion Industry-Sponsor Research: United Therapeutics, Gilead, Actelion Personal Financial Relationships with Non-Commercial interests relevant to medicine, within the past 3 years: Research Grants: - Vera Moulton Wall Center for Pulmonary Vascular Disease - NIH/NHLBI - NIH/NIAID Personal relationships with tobacco industry entities within the past 3 years: No relationships to disclose No “off-label” discussions in this presentation.

5. Pulmonary Hypertension - Diagnostic Definition: Diagnostic gold standard = hemodynamics Rest: • Mean PAP >25 mmHg (normal 10-15 mmHg) Exercise: • Mean PAP > 30 mmHg PAH = above + PCWP or LVEDP <15 mmHg (normal 8-10 mmHg) Associated with adverse changes • In the pulmonary vasculature (arteriopathy) • At the level of the right ventricle (hypertrophy) Courtesy Marlene Rabinovitch

6. Dana Point Classification of Pulmonary Hypertension • 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. 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 hemolyticanemia 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 Simonneau et al, JACC 2009

7. Outcomes in the Current Era: Stanford Adult & Pediatric Experience Zamanian et al 2011

8. REVEAL: Parameters Independently Associated With Survival (Cox Proportional Hazard Estimates) HR 1.59 3.60 2.17 1.90 2.18 0.42 1.41 3.13 1.39 1.67 0.58 1.68 0.50 1.97 1.35 0.59 1.46 1.79 4.08 p-value <0.001<0.0010.012 <0.001<0.001 0.0390.008<0.001 0.005<0.001 0.008<0.001 0.003<0.001 0.014 0.0310.018 0.043<0.001 APAH-CTDAPAH-PoPHFPAH Renal insufficiencyMales age ≥60 yrs IIIIIV Heart rate >92 bpmSystolic BP <110 mm Hg ≥440 m<165 m <50 pg/mL>180 pg/mL Pericardial effusion: any % predicted DLCO ≥80% predicted DLCO ≤32 mRAP >20 mm HgPVR >32 Wood Units WHO Group I PAH Subgroups Demographics and Comorbidities NYHA/WHO Functional Class Vitals 6MWD BNP ECHO DLCO RHC 1/8 1/4 1/2 1 2 4 8 Reduced risk Increased risk Hazard ratios and 95% CI Benza RL et al. Circulation. 2010; 122:164-172.

9. REVEAL: Observed 1-year Survival From Time of Enrollment According to Predicted Risk Strata 100 80 Risk strata Low Average Moderately high High Very high Survival (%) 60 40 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months from enrollment No. at risk: Low Average Mod. high High Very high 1368 659 277 293 100 1364 657 274 291 96 1359 653 269 284 89 1356 648 264 277 81 1352 647 263 270 74 1351 640 260 263 72 1346 628 259 255 69 1341 625 255 247 61 1336 618 254 241 59 1311 604 249 238 55 1304 602 244 233 52 1303 596 243 225 49 1374 665 280 295 102 Benza RL et al. Circulation. 2010;122:164-172.

10. What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Acute Vasoreactivity Testing Positive Negative Oral CCB No Sustained Response Yes Continue CCB McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

11. Therapeutic Options in USA for PAH – September 2012 • FDA Approved for PAH • Prostanoids • Epoprostenol • Treprostinil (IV/SQ/Inhaled) • Inhaled Iloprost • ERA’s • Bosentan • Ambrisentan • PDE-5 Inhibitors • Sildenafil • Tadalafil • Investigational Tx • Prostanoids • Oral Treprostinil • ERA’s • Actelion-1 • Tyrosine Kinase Inhib’s • Rho-Kinase Inhib’s • ElastaseInhib’s • Dicholoroacetate (DCA) • TetrahydroBiopterin • S. GuanylateCyclase Act’s • FK-506 • LTA4 Hydrolase Inhib’s • Stem Cell Tx Traditional Tx • Supplemental O2 • Diuretics • Oral vasodilators • (CCB) • Anticoagulants • warfarin • Inotropic agents • Digitalis

12. A Paradigm Shift in PAH Clinical Research • Although we realize that WHO Group I PAH has numerous etiologies, we have assumed to be “homogeneous” in its biology/physiology. • Over the last decade there has been an explosion of clinical research in PAH / PH focused on therapeutics. • A call for clinical-translational research • It is time for a Paradigm Shift: New Tools and Topics • Identification of Novel (modifiable?) Risk Factors / Co-morbidities • Refining our understanding of acute and chronic vascular responsiveness • Recognition of potentially novel therapeutics

13. Overview Pulmonary Vascular Responsiveness Acute Chronic Co-Morbidities Hemodynamics: Pulmonary Vascular Compliance Diffusing Capacity Carbon Monoxide Insulin Resistance

14. Insulin Resistance

15. Insulin Resistance in PAH: • Pulmonary Arterial Hypertension (PAH) is a vascular disease characterized by inflammation, proliferation, and vasoconstriction. • Multi-factorial & Complex • Unlikely that a single factor, pathway, mutation in etiology • Obesity, hyperlipidemia, and insulin resistance (IR) are known risk factors for systemic cardiovascular diseases (CVD). • Impact of obesity or IR in PAH instigation or progression have not been validated. • Several lines of evidence though, suggest a link between insulin resistance and PAH…..

16. IR in PAH: Suggestive Links • Obesity is associated with Insulin resistance • Obesity + Inactivity  IR • Obesity is common in PAH and maybe an overlooked risk factor. • Exercise intolerance is a feature of severe PAH • Insulin resistance has been linked to congestive heart failure and idiopathic cardiomyopathies • Elevation of “factors” and inflammatory cytokines which have been implicated in PAH are also involved in pathogenesis of IR • IL-6, ET-1, ADMA, MCP-1 Humbert el al. AJRCCM 1995 Ikeda et al. Am J Physiol Heart CircPhysiol2002 Stuhlinger et al. JAMA 2002 Yudkin el al. Lancet 2005 Abenhaim et al. NEJM 1996 Rich et al. Chest 2000 Taraseviciute et al. Eur J Med Res 2006

17. 6 6 5 4 PPARgActivation Reverses PAH in Insulin Resistant ApoE Deficient Mice IR Hansmann et al Circulation 2007

18. Hypothesis • Insulin resistance: • May be more prevalent in the PAH population • May be associated with disease severity • Modulation of insulin resistance may lead to improved outcomes in PAH

19. Design & Methods • Prospective screening of patients with pulmonary arterial hypertension at SUMC PH Clinic between 2004-2006. • The National Health and Nutrition Examination Survey (NHANES) as control population. • Identification of TG/HDL-C ratio as a surrogate marker for insulin resistance. • Excluded: Overt Diabetics, Secondary PH forms including those with pulmonary parenchymal disease and left heart failure • Data Collection (PAH): detailed demographic, functional, hemodynamics, and event-free survival.

20. Receiver-operating Characteristic Curves for Metabolic Markers of Insulin Resistance McLaughlin & Reaven et al. Ann Int Med. 2003

21. Higher Prevalence of IR in PAH Zamanian et al, ERJ 2009

22. Unlike Healthy Controls Insulin Resistance in PAH is NOT Associated with Age or BMI Zamanian et al, ERJ 2009

23. Zamanian et al, ERJ 2009

24. IR is a Predictor of Short-term Worse Outcomes 79% 58% Log-rank p = 0.043 Zamanian et al, ERJ 2009

25. Age & BMI Adjusted Univariate Analysis Zamanian et al, ERJ 2009

26. Right Ventricular Glucose Metabolism is Altered in IR PAH FIGURE 1: Representative FDG PET/CT images in (A) a healthy control and (B and C) 2 patients with PAH. (A) Fasting images in a healthy subject reveal nearly absent uptake in the right ventricle (RV) and minimal patchy FDG activity in the lateral wall of the left ventricle (LV) which is considered normal. (B) By comparison, abnormally intense FDG activity can be identified throughout the right ventricular myocardium in an insulin resistant (IR) patient with PAH. The activity appears significantly greater throughout the RV than in the LV. (C) Interestingly, even non-fasting, glucose challenged images in an insulin sensitive (IS) PAH patient demonstrate relatively normal RV FDG uptake highlighting the potential differences in RV myocardial metabolism between IS and IR PAH. RV LV Healthy RV LV IR PAH RV LV IS PAH

27. Impact of IR on RV Structure & Function: MESA-RV Study • The Multi-Ethnic Study of Atherosclerosis (MESA) performed interpretable cardiac MRIs on 5,004 participants without clinical cardiovascular disease at six field centers. • 4168 non-diabetic healthy controls were evaluated categorized as IR or IS and Cardiac MRI data analyzed. • IR in healthy cohort is associated with higher BMI, systolic and diastolic blood pressure, and higher CRP. Zamanian et al ATS 2012 A3453

28. Impact of IR on RV Function in PAH Skhiri et al ATS 2012 A3463

29. Early Experience with Pioglitazone in PAH Bosentan Pioglitazone

30. Interim Summary • Insulin resistance is more prevalent in women with PAH than the general female population. • Although obesity may be a link between IR and PAH, our results do not support the idea that obesity alone is the cause of insulin resistance in pulmonary arterial hypertension. • Though IR confers a poorer prognosis, Insulin resistance in PAH does not appear to correlate with functional class or disease severity. • IR may be linked to subtle changes in diastolic ventricular function and right ventricular metabolism.

31. Vascular Reactivity Acute & Chronic

32. Clinical Case Scenario • 35 yoFrench female (mother of 2) • Historically very active  3-5 sets of tennis daily • Over last year with profound dyspnea • Can’t garden • 1 episode of LOC picking up child

33. RPAP

34. RPCWP

35. NO

36. RPAP after 5 minutes NO @ 20 ppm

37. Vasoreactivity Traditionally Defined • Right Heart Catheterization: • Reduction in mPAP by at least 10 mmHg • Must reduce to a mPAP of <40 mmHg. • Cardiac output must be maintained or improved as a result. • Agents used: • Nitric Oxide • Adenosine • Epoprostenol • Standard of Care in 1st time RHC for iPAH.

38. French Registry:Response to Acute Vasodilator Challenge 10.3% 6.8% Response (%) 3.3% 2.6% 1.6% 0% 0% 0% Connective Tissue Portal Hypertension HIV Idiopathic Congenital Heart Anorexigens >2 Factors Familial N=649. Challenge with vasodilator at time of right heart catheterization. Humbert M, et al. Am J Respir Crit Care Med. 2006;173(9):1023-1030.

39. Survival in IPAH on Oral Calcium Channel Blocker Therapy 1.0 0.8 Responders 0.6 0.4 Failures Cumulative Survival 0.2 0 1 2 38 33 30 22 13 8 3 3 0 2 4 6 8 10 12 14 16 18 Years Responders Subjectsat Risk (n) Failures 0 19 12 7 4 (Long-term Calcium Channel Blocker Therapy) Survival endpoint included those who received transplants or were lost to follow-up. Acute response defined as defined by a fall in both mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) >20%. Sitbon O, et al. Circulation. 2005;111(23):3105-3111.

40. Thinking of the Right Ventricle – PA Compliance • Pulmonary arterial compliance (SV/Ps-Pd) is being recognized as an important contributor to right ventricular afterload and has been shown to be a strong predictor of survival. • Vasoreactivity or milder degrees of vascular responsiveness have not yet been correlated with pulmonary vascular compliance. Lankhaar J-W et al. European Heart Journal (2008)29,1688-1695

41. Hypotheses 1. Vasoreactivity is found not only in IPAH but also other forms of PAH and can change over time. 2. Even a mild degree of vasoresponsiveness is of prognostic value. 3. Correlating changes in PVR, mPAP and PAC during vasoreactivity testing could help identify additional patients with a reactive vascular bed.

42. Methods • Retrospective study (220 patients PAH Group 1) presented to Stanford Medical Center between 2000 - 2010. • Diagnosed at the time of RHC with vasodilator testing with 20ppm NO • Demographics, functional status, medication as well as hemodynamic parameters were evaluated. • A positive vasoreactivity was defined by a reduction in pulmonary artery mean pressure (PAPm)  10 mmHg to reach an absolute value of PAPm ≤ 40mmHg with an increased or unchanged cardiac output after challenge with NO (20 PPM) • Previous definitions of actuevasoreactivity (as defined by changes in pulmonary vascular resistance (PVR) or PAPm by > 20%) was also evaluated Spiekerkoetter et al, ATS 2011

43. Overall Demographics and Clinical Characteristics * 27% on CCB held for VR testing, 28 (12%) on multiple therapies Spiekerkoetter et al, ATS 2011

44. Clinical Characteristics Based on VR Status Spiekerkoetter et al, ATS 2011

45. Spiekerkoetter et al, ATS 2011

47. Acute Vasoreactivity isn’t “the” determinant to outcomes in PAH Spiekerkoetter et al, ATS 2011

48. 2009 2007 Arterial Phase CHRONIC VASCULAR REACTIVITY VASCULAR REMODELING? Capillary Blush

49. Diffusing Capacity for Carbon Monoxide as a Surrogate of Chronic Vaso-reactivity (remodeling?) • Diffusing capacity of the lung for carbon monoxide (DLCO) is a relatively simple, standardized, inexpensive, and widely available pulmonary function test. • DLCO is recognized as a measure of pulmonary gas exchange efficiency across the alveolar capillary interface. Decreased DLCO is associated with conditions such as parenchymal (e.g. interstitial lung diseases, emphysema) and pulmonary vascular diseases. • The decrease in DLCO in pulmonary hypertension has been thought to be due to pulmonary arterial remodeling and subsequent reduction in perfused pulmonary capillary bed. • Furthermore, reduction in DLCO has been related to the degree of functional capillary surface area loss in scleroderma associated pulmonary arterial hypertension (PAH), suggesting that DLCO is also a marker of endothelial cell function.

50. DLCO Cont • Numerous recent studies have demonstrated the clinical utility of DLCO in PAH. Baseline DLCO can predict long-term survival in PAH. • Decreasing DLCO over time can also predict the development of pulmonary hypertension in patients at risk, such as ones with limited scleroderma. • While changes in DLCO overtime have been demonstrated to be more powerful in predicting prognosis in idiopathic pulmonary fibrosis than single-point DLCO measurement, there are currently no studies evaluating the extent and utility of delta DLCO in pulmonary hypertension.