Pulmonary Arterial Hypertension: Biomarkers and Treatment
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1 Pulmonary Arterial Hypertension: Biomarkers and Treatment Demos Papamatheakis, MD Assistant Clinical Professor Division of Pulmonary, Critical Care and Sleep Medicine UC San Diego Health
2 Definition EHJ 2016;37: PVR>3 WU No exercise PH definition used currently
3 Classification WHO Group Etiology 1 Idiopathic, heritable, drugs and toxins, associated (CTD, HIV, liver disease, CHD, Schistosomiasis) 2 Left heart disease 3 Lung disease or hypoxia 4 Chronic thromboembolic 5 Other (CKD, Sarcoid, hematologic or metabolic disorders, etc.) EHJ 2016;37:67-119
4 Epidemiology PH TYPES BY ECHO CTEPH 2% Unknown or Miscellenaous 18% PAH 3% Respiratory Disease 9% Left Heart Disease 68% Strange et. al. heart 2012;98:1805
5 PAH: Pathophysiology PAH = Group 1 PVR>3; mpap>25; PAOP<15 NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE Smooth Muscle Hypertrophy Etiology: Idiopathic, heritable, drugs & toxins, associated (CTD, HIV, liver disease, CHD, Schistosomiasis) Adventitial, Intimal Proliferation Plexiform Lesions CO PAP PVR WHO FC I II III IV Adapted from Gaine S. JAMA. 2000;284: Time
6 PH Diagnosis High index of suspicion! WNL PH Echo (to screen) Supportive tests to assess etiology PFT CXR or CT chest Polysomnogram VQ scan RHC (to confirm diagnosis)
7 RHC REQUIRED PAH specific Rx should not be initiated without a RHC Eur Respir Rev 2015; 24: 642 Detailed oriented RHC is important: consider doing at expert center Diagnostic (mpap, PAOP) and prognostic (RAP, CO/CI) Need to assess vasoreactivity (ino, etc.) for patient and insurance purposes Accurate PAOP measurement is very important Perform CO/CI via thermodilution & Fick methodologies Multiple technical details need to be addressed (zeroing, wedge tracing and endexpiratory measurement rather than mean, sat. run, etc.) EHJ 2016;37:67-119
8 PAH Management General measures Rehab/activity maintenance Avoiding pregnancy, surgeries Support groups, vaccinations, genetic counseling if heritable Supportive measures Diuretics Oxygen Anticoagulation Digoxin Pharmacotherapy for PAH
9 Therapy PAH specific medications Selexipag sgc activator + NEJM 2004;351:1425 sgc h metabolite h
10 PAH Management Multidimensional approach Looking at all the variables described above Risk stratification correlates with prognosis Make decisions on management/rx based on goals No Si/Sx of heart failure, no progression of Sx WHO FC I or II 6MWD > 440 m (other thresholds include 380m or 400m) Normal probnp or BNP Normalization of RV size and function on Echo/RHC RAP<8 mmhg and CI>2.5 l/min/m 2 CPET criteria
11 PAH biomarkers are based on PAH pathophysiology PAH Pathophysiology Myocyte insult Endothelial dysfunction Inflammation and Oxidative stress End-organ dysfunction Cellular proliferation Vascular remodeling Vasoconstriction Inflammation Thrombosis NT-prBNP * Nitric Oxide (NO) Osteopontin Hyponatrmiea BNP * Endothelin 1 Galectin-3 Total bilirubin Troponins I and T cgmp RDW Creatinine Uric acid Cellular and molecular pathways of above PAH therapy targets PAH biomarker targets Asymmetric dimethylarginine (ADMA) Interleukins (1B, 6, 8, 12p70) PaCO2 ANP C-reactive protein Cystatin C ST2 Growth differentiation factor 15 Soluble CD40 ligand TNF-a High-density lipoprotein cholesterol CXC chemokine ligand 10 PDGF
12 NT-proBNP and BNP Has significant prognostic impact (REVEAL registry Circulation 2010) BNP < 50 pg/ml or NT-proBNP <300 pg/ml increased survival BNP > 180 pg/ml or NT-proBNP >1500 pg/ml increased morbidity/mortality These cutoffs were incorporated in the 1 year mortality risk calculator generated by REVEAL Baseline BNP < 340 pg/ml strongly predicted 5 year survival (Frantz 2018) Change of BNP in 1 year, correlated with change in survival (Frantz 2018) BNP and NT-proBNP are used in every day practice Guidelines recommend regular follow up of these Escalation of therapy to normalized BNP/NT-proBNP values is recommended
13 NT-proBNP and BNP studies Multiple studies show promising results Lower values correlate with Improved survival (Nagaya, 2000) Better hemodynamics (Leuchte 2007) Improved exercise capacity (Leuchte 2004) Lower disease severity (Souza 2007) Positive response to treatment (Souza 2005) NT-proBNP vs. BNP More stable fragment in plasma Remains a prognostic indicator if renal dysfunction present (Fijalkowska 2006) BNP does not Loses correlation with hemodynamics Clinical trials looking at combination Rx for PAH show probnp improvements ATHENA-1, TRIUMPH, AMBITION, etc.
14 Other Biomarkers Uric Acid Increased levels correlate with worse prognosis and hemodynamics (Nagaya 1999) Troponin I (sensitive assay) Detectable levels correlated with worse prognosis and disease (Heresi 2012) Troponin T Similar results with lower survival if detectable levels are present (Torbicki 2003) Endothelin-1 and Endothelin-3 Higher ET-1 and ET-1/ET-3 levels correlate with worse hemodynamics/prognosis (Montani2007) ADMA (asymmetric dimethylarginine) NOS inhibitor Higher levels correlate with worse prognosis and hemodynamics in PAH (Pullamsetti 2005) and CTEPH (Kielstein 2005)
15 Other Biomarkers Soluble ST2 (circulating form of ST2, an IL-1 receptor family protein) Independent predictor of mortality in idiopathic PAH (Zheng 2014) Osteopontin (extracellular structural protein) Higher in PAH, correlateds with FC and moratliry predictor in PAH (Resenberg 2012) Cystatin C (mostly renal function biomarker) Higher in PAH, correlates with RVSP and RV volumes (Fenster 2014) Others? Serum camp or cgmp, exhaled NO, PCO 2, heart-type fatty acid-binding protein, HDL, urinary F(2)isoprostane, inflammatory markers (CRP, RDW), adrenomedullin, angiopoietin- 2, MMPs, PDGF
16 Micro-RNAs Small, non-coding RNAs that regulate gene expression posttranscriptionally Multiple are associated with PAH mirna-424(322) recently associated with HIF/BMPR path and PAH
17 Thank you! Demos Papamatheakis, MD Tel
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