4/20/2018 Precision medicine and personalizing Proteomics and Biomarkers in the therapy in pulmonary hypertension Analysis of Pulmonary Hypertension and Precision Medicine Approaches Allen D. Everett, MD Professor of Pediatrics/Cardiology Director Pediatric Proteome Center Savale L. Eur Respir Rev 2018; 27:180004 April 20, 2018 2 Circulating proteins provide precision of PH measures individual physiological and pathological status. • Cardiac function – Invasive-RAP, MPAP, PVR, CO – Noninvasive-TR jet, septal flattening, TAPSE Static Dynamic Gene Protein Metabolite • Functional measures Dynamic Static Prognostic ++ + - – 6MWD – NYAHA/WHO functional class - +++ ++ Diagnostic • Circulating Biomarkers? Therapeutic +/- ++ +++ – Objective monitoring – Easily repeatable – What do they mean?
4/20/2018 Proteomics and Circulating Heart Failure Biomarkers for PH Protein Biomarkers Monitoring BNP • Relationship of NTproBNP, ST2 and • Indicator of cardiac stretch • Origin-atria and ventricles Galectin 3 to PAH hemodynamics and • Developmentally regulated functional outcomes in children and ST2 adults. Do multiple markers add • Circulating scavenger receptor for IL33 • IL33 necessary for cardiac function precision? • Origin: ubiquitous • Developmental regulation: none (2-17y) • Discovery of carbonic anhydrase 2 as a Galectin 3 new potential PAH therapeutic target. • Lectin protein regulated by aldosterone • Linked to cardiac fibrosis • Origin: ubiquitous • KO inhibits PH in animals • Developmental regulation: none (2-17y) April 20, 2018 5 Performance of Heart Failure Performance of Heart Failure Biomarkers in Adult PAH Biomarkers in Pediatric PAH NTproBNP ST2 Galectin 3 R (P) R (P) R (P) NTproBNP ST2 Galectin 3 • Cohort: NHLBI PAHBiobank • Cohort: NHLBI PAHBiobank *0.423 (3.61E-11) 0.127 (0.056) *0.328 (4.71E- Age R (P) R (P) R (P) • N=225 07) (N=50) and U. Colorado Age *-0.27 (0.04) 0.09 (0.39) 0.16 (0.22) BSA -0.041 (0.5516) 0.099 (0.155) 0.048 (0.486) • RHC < 6months of enrollment (DD. Ivy, N=61) BSA -0.09 (0.36) 0.12 (0.23) 0.15 (0.25) Heart Rate 0.121 (0.1396) 0.153 (0.062) 0.123 (0.135) • IPAH/APAH-CTD: 87/88 • N=111 CO *-0.23 (0.02) -0.02 (0.88) 0.12 (0.36) CO *-0.233 (0.0004) -0.088 (0.192) 0.021 (0.758) • Age: 57 (22-88) • RHC <12 months of enrollment PVRI 0.15 (0.25) *0.30 (0.02) 0.18 (0.17) CI *-0.227 (0.0010) -0.112 (0.109) 0.017 (0.803) • Female (%): 79 • % APAH-CHD: 60% (WU*m2) *0.258 (9.55E-05) 0.125 (0.062) -0.036 (0.592) PVR (WU) Mean PAP 0.07 (0.48) *0.19 (0.046) 0.15 (0.26) • FC I-II vs III-IV: 58 vs 94 • Age: 6 (0.083-20.64) Mean PAP *0.153 (0.021) 0.103 (0.125) -0.023 (0.732) Mean RAP 0.14 (0.18) 0.09 (0.37) 0.08 (0.55) • Female (%): 60 Mean RAP *0.304 (4.11E-06) *0.321 (1.09E-06) *0.136 (0.044) Mean PCWP 0.035 (0.72) -0.04 (0.69) 0.02 (0.89) Mean -0.070 (0.297) -0.027 (0.691) 0.017 (0.804) 6MWD (M) *-0.43 (0.03) *-0.50 (0.01) -0.02 (0.98) PCWP Mortality NA NA NA 6MWD (M) -0.005 (0.959) *-0.358 (0.001) *-0.317 (0.001) Mortality* *0.001 *0.0000 *0.015
4/20/2018 Heart Failure Biomarkers in PAH: Mass Spectrometry Discovery of What does it mean? Circulating PAH Biomarkers • NTproBNP- Marker of cardiac hemodynamics (RAP, PAP, CO, PVR) Number of proteins Discovery • ST2 and possibly Galectin 3-Marker of functional identified Cohort outcomes (6MWD, Mortality) 10 IPAH – Chida A, et al. Circ J 2014. 60 children “elevated ST2 had Questions: significantly worse prognosis with eleveated NTproBNP” 1. If NTproBNP falls (improvement in hemodynamics) – Zheng YG, et al. Clin Cardiol 2014. 40 adults “ST2 10 Normal with therapy, does ST2/Galectin 3 also decline correlated with severity and predicted clinical worsening” (improved functional outcome, decreased risk of 480 hours of MS time mortality)? 2. If NTproBNP falls, but ST2/Galectin 3 doesn’t, should we escalate treatment? Plasma PH Discovery-Mass Carbonic Anhydrase 2 Spectrometry • CA2 is member of a large family of 13 carbonic Unsupervised Hierarchical MS Spectral anhydrase isoenzymes, which catalyzes reversible Clustering Counts hydration of carbon dioxide. • CA2 is a cytoplasmic isoform of carbonic anhydrase and expressed in lung Type 1 and Type 2 alveolar epithelial cells and capillary endothelial cells. • Acetazolamide, a sulfonamide diuretic, is a Univariant Volcano Plot Analysis pharmacologic CA inhibitor and used clinically for the treatment of glaucoma and high altitude pulmonary edema. • In the lungs, acetazolamide lowers normoxic pulmonary artery pressure and markedly inhibits hypoxic pulmonary vasoconstriction in animals and humans.
4/20/2018 CA2 in Adult PAH versus Controls CA2 in Adult PAH versus Controls Discovery Spectral Counts ELISA AUROC ELISA AUROC 0.85, P < 0.0001 Conclusions Precision profiling using the NHLBI PAHBiobank (N=3000) • FDA approved Heart Failure Biomarkers NTproBNP Sensitive diagnostic and PAH ST2 for screening – NTproBNP with ST2 and Galectin 3 may be more informative for monitoring hemodynamic Gal3 PH Type and functional outcomes HDGF Severity/Survival • CA2 Gene defect IL6 – CA2 is a sensitive and specific new biomarker Endostatin for PAH Age Response to Therapy CA2 – Biologically, CA2 could be a novel drug target for PAH. + 5 other Treatment proteins Design of trial based on Biomarkers As of last week, >13,000 assays (7 analytes) April 20, 2018 16
4/20/2018 Acknowledgements Pediatric Proteome Center JHU Pulmonary and Critical Care Dr. Allen Everett (Director) Dr. Rachel Damico Dr. Melanie Nies NHLBI PAHBiobank Dr. Jun Yang Dr. Bill Nichols Dr. Zongming Fu Stephanie Brandal Vanderbilt University Jie Zhu Dr. Eric Austin University of Colorado Funding: NHLBI R01HL135114, Dr. Dunbar Ivy RC1HL099786, R03HL110830, CMREF, TEDCO April 20, 2018 17
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