Associate Professor Peter Molenaar - Phosphodiesterase control of β1- and β2-adrenoceptor mediated contractile responses in failing human ventricle

Speaker

Associate Professor Peter Molenaar (QUT)

Abstract

Cardio-vascular Molecular & Therapeutics Translation Research Group
Northside Clinical School of Medicine, The University of Queensland
School of Biomedical Sciences, QUT

We used explanted human hearts from patients with advanced heart failure undergoing heart transplantation at The Prince Charles Hospital to study contractility and arrhythmias. Heart failure (HF) is a global health issue with rising prevalence, affecting around 26 million people worldwide. In Australia, the prevalence of HF is 1.0-2.0% of the population, increasing to over 10% in patients 75 years or older. Despite advances in medications, mortality and readmission rates have remained largely unchanged with survival rates of ≤ 40% at 5 years from diagnosis. Sudden cardiac death (SCD) from ventricular arrhythmias (VA) is the leading mode of death (45-50%). Activation of the sympathetic nervous system contributes to the genesis of dangerous ventricular arrhythmias. Ventricular trabeculae were dissected and set up on tissue electrode blocks to contract and relax. Activation of both β₁-adrenoceptor (β₁AR) and β₂ARs caused arrhythmic contractions, increased diastolic RyR2 channel opening and phosphorylation, which correlated with altered levels of RyR2 phosphorylation at Ser-2808 and Ser-2814. Phosphodiesterases (PDEs) metabolize cyclicAMP increased by β₁AR and β₂AR activation. β₁AR and β₂AR mediated increases in contractility and arrhythmias were controlled by PDE3.

The βAR signalling pathway and RyR2 channel provide important therapeutic targets for prevention of sudden death in heart failure patients.

Speaker Bio

Peter Molenaar is an Associate Professor in the School of Biomedical Sciences at QUT and is an Honorary Associate Professor in the Northside Clinical School of Medicine at The University of Queensland, based at The Prince Charles Hospital. He is head of the in vitro human heart laboratory and co-head of the Cardio-vascular Molecular & Therapeutics Translational Research Group together with heart failure and electrophysiology researchers and clinicians.

Peter is a registered pharmacist with B Pharm and M Pharm degrees from the Victorian College of Pharmacy (now MIPS). His PhD was with Roger Summers in the Dept of Pharmacology, University of Melbourne. He then became an NHMRC RD Wright Fellow, Research Fellow and Senior Research Fellow before taking up an academic position at QUT.

Peter’s research has studied G-protein coupled receptor mechanisms in human heart, focussing mostly on β-adrenoceptor signalling mechanisms. Current research is directed towards understanding dangerous ventricular arrhythmias in heart failure patients which cause sudden death towards identifying therapeutic targets.