Targeting the Right Ventricle Harm Jan Bogaard 3/9/2019 Its the - PowerPoint PPT Presentation

Disclosure Company Relationship Type Actelion Grant support UCSF Continuing Medical Education Therabel Grant support Glaxo Grant support Boehringer Ingelheim Grant support Targeting the Right Ventricle Harm Jan Bogaard 3/9/2019 It’s the RV! Hypothesis RV adaptation to load is main determinant of outcome in PAH RV adaptation can be improved, even when the afterload continues to be high Experimental models of RV pressure overload, although flawed, can give us directions for future RV specific treatment Van de Veerdonk et al. JACC 2011 San Francisco | March 2019 San Francisco | March 2019 1

CTR PAB CH+SU MCT RV Langendorff CTR PAB CH+SU MCT LV Langendorff Piao Circulation 2012 Haddad Circulation 2008 Cardiomyocyte stress Cardiomyocyte stress RV-LV interaction RV-LV interaction Neurohormones Neurohormonal Drive Ciarka, AJRCCM, 2010 Contractile dysfunction Contractile dysfunction Hypertrophy Hypertrophy Dilatation Dilatation - Betablockers • MHC switch • MHC switch • Ca 2+ handling • Ca 2+ handling • SNS overdrive worsens outcome Apoptosis • metabolism • metabolism Adrenergic receptor blockers • • loss of cells • loss of cells Veh Carvedilol effective in experimental PH • loss of structure • loss of structure • Clinical data is neutral at best, Bogaard, AJRCCM, 2010 Ischemia Ischemia possibly negative • Wrong concept, wrong drug, wrong ROS/RNS trial design? Dysequilibrium San Francisco | March 2019 Inflammation Inflammation ECM changes ECM changes Van Campen, ERJ, 2016 Bogaard, Chest 2010 San Francisco | March 2019 2

Neurohormonal Drive Neurohormonal Drive - Renal denervation - Renal denervation • Mitigates pulmonary vascular • RAAS inhibition in RV remodeling in the SuHx model Breaking the vicious circle • • Has some direct cardiac effect as well San Francisco | March 2019 San Francisco | March 2019 da Silva Gonçalves Bós JACC 2017 da Silva Gonçalves Bós JACC 2017 Neurohormonal Drive Neurohormonal Drive - Parasympathetic - Pyridostigmine withdrawal • Slower Heart rate recovery and local • Pyridostigmine restores changes in the cholinergic system in PAH parasympathetic function and improves experimental PH and associated RV failure San Francisco | March 2019 San Francisco | March 2019 da Silva Gonçalves Bós Circulation 2018 da Silva Gonçalves Bós Circulation 2018 3

Fibrosis Fibrosis Lai Int J Mol Sc 2018 - Evidence in Humans - Experimentally reversible • Delayed contrast enhancement • Inflammation, ischemia, EndoMT? Native T1 mapping Prostanoid receptor mediated? • • • Immunohistochemistry? • Reversible by neurohormonal blockade, nitrate, etc • Reversible by antifibrotic drugs Nintedanib and Perfenidone Rol Spruijt Int J Cardiovasc Imaging 2016 Cardiovasc Res 2018 San Francisco | March 2019 San Francisco | March 2019 Stiffness is more than Fibrosis related to fibrosis Inflammation? Neutrophils • Immune cell influx in SSc RV, not so Z-disk M-band Z-disk • Diastolic dysfunction is related to Sarcomere Actin Titin much in PAH RV Myosin RV fibrosis ánd titin Titin Actin • Neutrophils in acute PE Macrophages dephosphorylation • Inflammation probably more • Titin dephosphorylation may be due relevant via cardiosuppresive to lower PKA activity cytokines (IL-1, TNFs) or via anti- • Further linking stiffness to endothelial antibodies Lymphocytes sympathetic overdrive San Francisco | March 2019 San Francisco | March 2019 Overbeek Int J Rheum 2010 Rain Circulation 2013 & Circ Heart Fail 2016 4

O 2 Supply and Demand O 2 Supply and Demand imbalance imbalance • Levosimendan improves contractility Potus Circulation 2015 without increasing oxygen demand or • Planimetric evidence of capillary glucose uptake in the pulmonary trunk rarefaction banding rat model • Stereological counterattack • Recent history in LV failure curtail • Probably an issue during exercise enthusiasm • Direct intervention? Graham AJRCCM 2017 Hansen Pulm Circ 2017 San Francisco | March 2019 San Francisco | March 2019 O 2 Supply and Demand O 2 Supply and Demand imbalance imbalance • p38 MAPK inhibition reduces • p38 inhibition reduces fibrosis via hypertrophy after pulmonary trunk inhibition of myocardial fibroblasts banding in rats • Improvement in RV function Kojonazarov AJRCMB 2017 Kojonazarov AJRCMB 2017 San Francisco | March 2019 San Francisco | March 2019 5

50 RV efficiency (%) 40 30 20 O 2 Supply and Demand O 2 Supply and Demand 10 II III imbalance imbalance 0 0 20 40 60 80 RV ejection fraction (%) Wong Circulation HF 2011 • Ranolazine inhibits late inward sodium current of voltage-gated sodium • Increased RV work channels, reducing intracellular Excessive RV oxygen consumption • calcium and O 2 demand • Reduced efficiency • In MCT rat reduction of hypertrophy, • Oxidative metabolism of but also effect on PVR catecholamines by MAO-A? • Prevention of arrhythmia Liles J Pharmacol Exp Ther 2015 San Francisco | March 2019 San Francisco | March 2019 Peters, Unpublished It’s all about energy It’s all about energy Archer, Pulm Circ 2013 and mitochondria - Dichloroacetate Inhibitor of PDK, improves PDH • activity • Glucose oxidation ↓ , Glycolysis ↑ • Modest beneficial effects in • Fatty acid oxidation ↓ subgroup of PAH patients with • Impaired PGC-1 α mediated normal UCP2 and SIRT3 function mitochondrial biogenesis • Mediated by improved mitochondrial respiration San Francisco | March 2019 San Francisco | March 2019 Gomez-Arroyo, Circ Heart Fail, 2013 Michelakis Sci Transl Med 2017 6

Metabolism and Other mutations and BMPR2 mutations RV function • Hereditary PAH patients have • Loss of ion channel KCNK3 is early diminished RV adaptation hallmark of hypertrophy and Van der Bruggen, Circulation 2016 • May be related to accumulation of dysfunction of overloaded RV Oil red O staining lipids and lipotoxicity • Loss of KCNK3 function is associated • Unclear mechanism, but at minimum with hypertrophy, fibrosis and RV suggests that BMPR2 enhancing dysfunction (mediated by therapies may benefit RV tachycardia?) Lambert, Cardiovasc Res 2018 San Francisco | March 2019 San Francisco | March 2019 Hemnes, AJRCCM 2014 Moving forward on Areas in need of genetics of RV failure exploration Dawes, Radiol 2017 • MR imaging & Machine Learning • Gender differences in RV adaptation • Organ-on-a-chip • Direct RV effects of iron supplementation San Francisco | March 2019 San Francisco | March 2019 Courtesy of Frances de Man 7

Acknowledgements RV Failure – Mechanisms and Possible treatment Norbert Voelkel Anton Vonk Noordegraaf • The neglected ventricle has moved center stage Frances de Man • RV function in PH is not only dependent on RV load Aida Llucia-Valldeperas • Targeting neurohormonal activation remains of interest, but we need safe ways Robert Szulcek to intervene • Alternatives include metabolic modulators, but also antifibrotics, sex hormones Onno Spruijt Ingrid Schalij Denielli da Silva Gonçalves Bos and iron Michiel de Raaf Jose Gomez Arroyo Jasmijn van Campen Nina Rol Silvia Rain Eva Peters San Francisco | March 2019 San Francisco |March 2019 8