The Year in Review: I have no financial relationships with a - PowerPoint PPT Presentation

3/9/2019 Conflict of Interest Disclosure Mary P. Mullen • I have no financial relationships with a The Year in Review: • I have no financial relationships with a commercial Clinical Science entity producing healthcare-related products or services • Site investigator for GSK, Bayer, Actelion and United Mary P. Mullen, M.D., Ph.D. Therapeutics sponsored PH studies Boston Children’s Hospital • Talk will include discussion of drugs which have not Harvard Medical School been FDA approved in pediatric age range Road map • WSHPH - lessons from Nice • Precision Medicine – New genes – Individualized monitoring • Predicting complications and mortality • Therapeutics • Burden of disease 1

3/9/2019 6 th World Symposium on Pulmonary Overview Hypertension – Nice, France • WSHPH - lessons from Nice • Precision Medicine • Pediatric Task force – January, 2018 – New genes • Consensus opinions – Feb 27-March 1, 2018 – Individualized monitoring of disease course and • Manuscript, Eur Resp J. 2019:53 progression • Predicting complications and mortality • Therapeutics • Burden of disease WSPH General Guidance for Key Takeaways operability in CHD-PAH • Adopted adult hemodynamic definition of PAH as > 20 mmHg with PVR > 3 WU as new Correctability / PVR index WU m2 PVR WU favourable long-term definition for pediatric PAH outcome • Standardization of AVT testing for children < 4 < 2.3 Yes 4 – 8 2.3 – 4.6 Individualize – Sitbon criteria for vasodilator testing advised for > 8 > 4.6 No use in acute vasodilator testing for determining response The long term impact of defect closure in the presence of PAH with increased PVR is –  mPAP by at least 10 mmHg to < 40 mmHg with unknown. sustained cardiac output Rosenzweig EB et al. Eur Respir J 2018 Rosenzweig EB et al. Eur Respir J 2018 2

3/9/2019 Updates in pediatric classification PPHN: Associated Disorders • Group 1.5 PAH Long term responders to CCBs • Group 1.3 Drug and toxin induced PAH – Diazoxide • Group 1.7 Persistent PH of the newborn syndrome – Multiple associated conditions Rosenzweig et al Eur Respir J 2019; 53:1-18. Classification Updates continued • Group 2.4 Congenital post-capillary obstructive lesions – Pulmonary vein stenosis – Cor triatriatum – Obstructed total anomalous pulmonary venous return – Mitral/aortic stenosis – Coarctation of the aorta • Group 3.5 Developmental lung disorders 3

3/9/2019 WSPH Summary Classification continued • Group 5.4 Complex CHD • Highlighted differences between children and • PH in this setting is difficult to define or adults classify • New findings in pediatric PH – Segmental pulmonary hypertension • Noted need for pediatric specific clinical trials – Single ventricle and clinical endpoints for children with PH – Scimitar syndrome • Need to understand how new definitions and • Down syndrome classifications affect diagnosis, clinical trials – Phenotype of DS related PH variable and our interpretation of previous data – Classified as Group 3 in the absence of CHD 2018- genetic causes of PAH • Novel genetic mutations reveal new heritable causes of idiopathic PAH • Sox 17 transcription factor involved in vascular development and remodeling – Identified in cohorts of adults and children with heritable, idiopathic and congenital heart disease PAH AS A GENETIC DISORDER associated PAH 4

3/9/2019 Rare SOX17 variants associated with GWAS suggests SOX17 enhancer PAH and congenital heart disease region associated with PAH risk PAH-CDH with: ASDs, VSDs, PDAs, ASD/VSD/AV canal defect Zhu N, et al. Genome Medicine 2018:10:56 Rhodes CJ, et al. Lancet Respir Med 2019;7:227-238 Frequency of Genetic Mutations in Loss of function mutations in ABCC8 encoding a Pediatric and Adult PAH regulatory subunit of the ATP sensitive potassium channel are associated with PAH Enrichment of variants in TBX4 but not other risk genes in pediatric onset Total: 21.5% Zhu N, et al. Circulation. Genomics and Precision Medicine 2018; April; 11 Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension, Volume: 11, Issue: 10, DOI: (10.1161/CIRCGEN.118.002087) 5

3/9/2019 Frequency of heritable PAH mutations Association of Lethal Lung Developmental Disorders with in adult and pediatric patients disruption of the TBX-FGF Pathway • Next Gen Sequencing on 268 PAH and PVOD/PCH Acinar dysplasia, patients ACD, pulmonary hypoplasia • Pathogenic mutations in 19.4% of sporadic PAH, and 54.5% of familial PAH • BMPR-2, TBX4 most common • BMP9 in 1.2% • BMP10 in two cases Karolak JA, et al. Am J Hum Gen 2019;104:213-228 Eyries M, et al. Eur Respir J 2018 (December) TBX4 Genetics: Implications • Guidelines for genetic testing in patients and families with PAH are needed • Classification schemes should evolve to reflect understanding of genetic causes of PAH • Outcomes and prospective clinical trials need to be defined for heritable / non-heritable cases • Underscores need for targeted therapeutics addressing molecular basis of disease Genetic Data Transforms Disease 6

3/9/2019 PH in Children with Down Syndrome PH in Children with DS (Colorado) • Association well recognized • Cohort of 1242 children with Down syndrome • Congenital heart disease/left to right shunt • Incidence of PH was 28% – Increases risk • Comorbid contributors: • Incidence of PPHN higher – OSA – Intermittent hypoxia • Underlying disease burden, role of specific co- – GERD morbidities, exacerbating factors – Chronic lung disease – Not completely understood – Chronic aspiration Bush Doug, et al. J Pediatric 2018:202:212-9 Focused approach to genetic PH in Children with Down Syndrome syndromes associated with PAH • Illustrates variability of PH in children with DS • CHD major risk factor • Multiple respiratory co-morbidities • Major disease burden in first year of life 86% first year of life • Ongoing need for respiratory evaluation after initial pulmonary hypertension management • Demonstrates challenges of diagnosis, therapies and compliance in this population Bush D, et al. J Pediatric 2018:202:212-9 Bush D, et al. J Pediatric 2018:202:212-9 7

3/9/2019 Individualized approach to monitoring Right Ventricular Stroke Work / EF Predicts Clinical Worsening in a Cohort of PAH patients (Stanford ) progression of disease • Novel MRI biomarkers Clinically Stable Clinically Worsening – Flow dynamics – RV performance • Specific predictors of outcome – RV ejection fraction, LV stroke volume index, RV volume • New research measures include assessment of ventricular-vascular coupling and RV stroke work Weiguang Yang; Alison L. Marsden; Michelle T. Ogawa; Charlotte Sakarovitch; Keeley K. Hall; Marlene Rabinovitch; Jeffrey A. Feinstein; Pulm Circ 2018; 8, 2045894018780534. D Precision therapeutics in Pediatric PH • Targeted approach to disease • Careful diagnosis and classification of each patient • Taking into account susceptibility to develop particular disease and disease recurrence • Focused treatment strategy PREDICTING COMPLICATIONS AND • Individualized monitoring of disease progress MORTALITY IN PEDIATRIC PAH 8

3/9/2019 Risk Factors for Major Early Adverse Events Related to Cardiac Impact Registry: Pediatric PAH (0-21 yrs) Catheterization in Children and Young Adults With Pulmonary Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital Treatment) Registry. • 88 hospitals • 8111 procedures in 7729 patients • Composite outcome of catheterization complications: death in 1-2 days, cardiac arrest, initiation of ECMO • Rate of catastrophic adverse event: 1.4% – Rate of death before discharge: 5.2% – Risk of major non-death AE: 5% • Predictors of adverse events: – Increased PA pressure – Increased PVRI – Decreased cardiac index – Fewer PAH cardiac catheterizations at center O’Byrne ML, et al. JAHA: J Am Heart Assoc 2018 O’Byrne ML, et al. JAHA: J Am Heart Assoc 2018 Perioperative events in children with PAH undergoing Perioperative events in children with PH non-cardiac procedures (Johns Hopkins) undergoing non-cardiac procedures • Single center retrospective cohort (JH) • 77 children with PH undergoing cardiac cath Major events - more frequent in or non-cardiac procedures severe PH • BPD (46.7%), CHD (29.9%), CDH (14.3%) • Major events – failed extubation (5.6%), postop arrest (4.7%), intraop arrest (2%), postop death (1.4%) Incidence associated with procedure type Bernier ML, et al. Pulmonary Circulation 2017 Bernier et al, Pulmonary Circulation 2017 9

3/9/2019 Mortality and morbidity associated Mortality and morbidity associated with PAH in PICU (UCSF) with PAH in PICU (UCSF) • Retrospective multicenter cohort study • 153 centers in Virtual PICU Systems database – 2009-2015 Younger Longer LOS Higher illness severity score More likely to receive - mechanical ventilation -CPR Balkin EM, et al. Pulmonary Circulation 2017 -ECMO Multivariate predictors of mortality in Mortality by admission type children with pulmonary hypertension Balkin EM, et al. Pulmonary Circulation 2017 Balkin EM, et al. Pulmonary Circulation 2017 10