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

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3/9/2019

Harm Jan Bogaard

UCSF Continuing Medical Education

Targeting the Right Ventricle

Disclosure

Company Relationship Type Actelion Grant support Therabel Grant support Glaxo Grant support Boehringer Ingelheim Grant support

San Francisco | March 2019

It’s the RV!

Van de Veerdonk et al. JACC 2011

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

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Haddad Circulation 2008 RV Langendorff CTR MCT CTR MCT CH+SU PAB CH+SU PAB LV Langendorff Piao Circulation 2012

Cardiomyocyte stress Cardiomyocyte stress Contractile dysfunction

• MHC switch
• Ca2+ handling
• metabolism
• loss of cells
• loss of structure

Contractile dysfunction

• MHC switch
• Ca2+ handling
• metabolism
• loss of cells
• loss of structure

RV-LV interaction RV-LV interaction Inflammation Inflammation ECM changes ECM changes Ischemia Ischemia Hypertrophy Hypertrophy Dilatation Dilatation Neurohormones ROS/RNS Dysequilibrium Apoptosis

Bogaard, Chest 2010

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• SNS overdrive worsens outcome
• Adrenergic receptor blockers

effective in experimental PH

• Clinical data is neutral at best,

possibly negative

• Wrong concept, wrong drug, wrong

trial design?

Neurohormonal Drive

• Betablockers

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Ciarka, AJRCCM, 2010 Bogaard, AJRCCM, 2010 Veh Carvedilol Van Campen, ERJ, 2016

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• Mitigates pulmonary vascular

remodeling in the SuHx model

• Has some direct cardiac effect as well

Neurohormonal Drive

• Renal denervation

da Silva Gonçalves Bós JACC 2017

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• RAAS inhibition in RV
• Breaking the vicious circle

Neurohormonal Drive

• Renal denervation

da Silva Gonçalves Bós JACC 2017

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• Slower Heart rate recovery and local

changes in the cholinergic system in PAH

Neurohormonal Drive

• Parasympathetic

withdrawal

da Silva Gonçalves Bós Circulation 2018

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• Pyridostigmine restores

parasympathetic function and improves experimental PH and associated RV failure

Neurohormonal Drive

• Pyridostigmine

da Silva Gonçalves Bós Circulation 2018

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• Delayed contrast enhancement
• Native T1 mapping
• Immunohistochemistry?

Fibrosis

• Evidence in Humans

Spruijt Int J Cardiovasc Imaging 2016

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• Inflammation, ischemia, EndoMT?
• Prostanoid receptor mediated?
• Reversible by neurohormonal

blockade, nitrate, etc

• Reversible by antifibrotic drugs

Nintedanib and Perfenidone

Fibrosis

• Experimentally

reversible

Lai Int J Mol Sc 2018 Rol Cardiovasc Res 2018

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• Diastolic dysfunction is related to

RV fibrosis ánd titin dephosphorylation

• Titin dephosphorylation may be due

to lower PKA activity

• Further linking stiffness to

sympathetic overdrive

Stiffness is more than fibrosis

Myosin Actin Titin Titin Sarcomere Actin Z-disk M-band Z-disk

Rain Circulation 2013 & Circ Heart Fail 2016 San Francisco | March 2019

• Immune cell influx in SSc RV, not so

much in PAH RV

• Neutrophils in acute PE
• Inflammation probably more

relevant via cardiosuppresive cytokines (IL-1, TNFs) or via anti- endothelial antibodies

Fibrosis related to Inflammation?

Overbeek Int J Rheum 2010 Neutrophils Macrophages Lymphocytes San Francisco | March 2019

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• Planimetric evidence of capillary

rarefaction

• Stereological counterattack
• Probably an issue during exercise
• Direct intervention?

O2 Supply and Demand imbalance

Potus Circulation 2015 Graham AJRCCM 2017

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• Levosimendan improves contractility

without increasing oxygen demand or glucose uptake in the pulmonary trunk banding rat model

• Recent history in LV failure curtail

enthusiasm

O2 Supply and Demand imbalance

Hansen Pulm Circ 2017

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• p38 MAPK inhibition reduces

hypertrophy after pulmonary trunk banding in rats

• Improvement in RV function

O2 Supply and Demand imbalance

Kojonazarov AJRCMB 2017

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• p38 inhibition reduces fibrosis via

inhibition of myocardial fibroblasts

O2 Supply and Demand imbalance

Kojonazarov AJRCMB 2017

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• Ranolazine inhibits late inward sodium

current of voltage-gated sodium channels, reducing intracellular calcium and O2 demand

• In MCT rat reduction of hypertrophy,

but also effect on PVR

• Prevention of arrhythmia

O2 Supply and Demand imbalance

Liles J Pharmacol Exp Ther 2015

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• Increased RV work
• Excessive RV oxygen consumption
• Reduced efficiency
• Oxidative metabolism of

catecholamines by MAO-A?

O2 Supply and Demand imbalance

Wong Circulation HF 2011

20 40 60 80 10 20 30 40 50 II III RV ejection fraction (%)

RV efficiency (%) Peters, Unpublished

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It’s all about energy and mitochondria

• Glucose oxidation ↓, Glycolysis ↑
• Fatty acid oxidation ↓
• Impaired PGC-1α mediated

mitochondrial biogenesis

Archer, Pulm Circ 2013 Gomez-Arroyo, Circ Heart Fail, 2013

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It’s all about energy

• Dichloroacetate
• Inhibitor of PDK, improves PDH

activity

• Modest beneficial effects in

subgroup of PAH patients with normal UCP2 and SIRT3 function

• Mediated by improved

mitochondrial respiration

Michelakis Sci Transl Med 2017

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• Hereditary PAH patients have

diminished RV adaptation

• May be related to accumulation of

lipids and lipotoxicity

• Unclear mechanism, but at minimum

suggests that BMPR2 enhancing therapies may benefit RV

Metabolism and BMPR2 mutations

Van der Bruggen, Circulation 2016 Oil red O staining Hemnes, AJRCCM 2014

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• Loss of ion channel KCNK3 is early

hallmark of hypertrophy and dysfunction of overloaded RV

• Loss of KCNK3 function is associated

with hypertrophy, fibrosis and RV dysfunction (mediated by tachycardia?)

Other mutations and RV function

Lambert, Cardiovasc Res 2018

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• MR imaging & Machine Learning
• Organ-on-a-chip

Moving forward on genetics of RV failure

Dawes, Radiol 2017 Courtesy of Frances de Man

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• Gender differences in RV adaptation
• Direct RV effects of iron

supplementation

Areas in need of exploration

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• The neglected ventricle has moved center stage
• RV function in PH is not only dependent on RV load
• Targeting neurohormonal activation remains of interest, but we need safe ways

to intervene

• Alternatives include metabolic modulators, but also antifibrotics, sex hormones

and iron

RV Failure – Mechanisms and Possible treatment

San Francisco |March 2019

Norbert Voelkel Anton Vonk Noordegraaf Frances de Man Aida Llucia-Valldeperas Robert Szulcek Onno Spruijt Ingrid Schalij Denielli da Silva Gonçalves Bos Michiel de Raaf Jose Gomez Arroyo Jasmijn van Campen Nina Rol Silvia Rain Eva Peters

Acknowledgements

San Francisco | March 2019