Cardiac ElectrophysiologyLaboratory

“To reduce sudden cardiac death in the young”

- Professor Jamie Vandenberg

Professor Jamie Vandenberg

Co-Deputy Director and Head, Cardiac Electrophysiology Laboratory

Research Overview

Key Research Areas

  • Electrical activity in the heart
  • Inherited arrhythmia syndromes
  • Cardiac arrest
  • Structural basis of cardiac ion channel function

Research Overview

The rhythm of the heartbeat is controlled by a high-fidelity electrical communication system. Disturbances to the rhythm of the heart can result in unexpected sudden cardiac arrest, which accounts for approximately one in ten deaths in Australia. Rates of sudden cardiac death have declined in the older age groups but reducing the incidence of sudden death in those under 50 has not been as successful.

The Cardiac Electrophysiology Laboratory is investigating the molecular mechanisms underlying abnormal electrical signals in the heart, with a long-term aim of developing better methods for assessing risk and thereby reducing the impact of sudden cardiac death, especially in the young.

research projects

There are 4 key projects underway in the Cardiac Electrophysiology Laboratory, led by Professor Jamie Vandenberg;

1. From sequence to consequence: Improving pathogenicity predictions in inherited long QT syndrome type 2

Long QT syndrome, the most common primary arrhythmia syndrome, is a particularly devastating disorder as it typically results in sudden death in young people who are otherwise fit and healthy. Establishing a genetic diagnosis can be invaluable for managing patients and their families. However, to realise the promise of genome sequencing, there is an urgent need for robust methods to establish a causative link between genetic variants and clinical phenotype. We are developing high throughput in vitro phenotyping assays that will enable us to prospectively characterise every possible missense variant in all the major cardiac ion channel genes. We will integrate all of this information using in silico models to enable development of population level risk predictions for every gene mutation associated with long QT syndrome.

2. Development of novel ECG biomarkers for stratifying risk of Sudden Death

The surface electrocardiogram provides an extraordinarily rich source of information about the electrical activity of the heart. Until recently, most of this information was not readily accessible. However, improvements in signal processing technology, the advent of high performance computers and sophisticated algorithms for the analysis of “big data” has opened up the possibility of exploiting this century old technology to develop novel biomarkers to help stratify risk for cardiac arrhythmias and reduce the impact of sudden cardiac death. We will also use this information to calibrate our populations of in silico models with the aim of developing a digital twin for every individual with Long QT syndrome. These digital twins will facilitate development of in silico clinical trials and personalisation of arrhythmia management.

3. Structural basis of gating and drug binding to hERG K+ channels

One of the most important ion channels in the heart is the human ether-a-go-go-related gene (hERG) K+ channel (official name: Kv11.1). Malfunction of hERG K+ channels due to inherited mutations results in long QT syndrome type 2. The hERG channel is also of great pharmaceutical importance as it is the molecular target for the vast majority of drugs that have the unwanted side effect of causing drug-induced cardiac arrhythmias and sudden death. Spectacular developments in the field of cryo electron microscopy (cryoEM) has opened up a new era of membrane protein structure determination. We are taking a multi-disciplinary approach encompassing molecular and cell biology, pharmacology, electrophysiology, mathematical modelling and molecular dynamics simulations along with cryo-EM to study the structural basis of how HERG K+ channels work. The main questions we wish to answer are (i) why do hERG K+ channels have such unusual gating properties? and (ii) why are these channels so promiscuous with respect to drug binding?

4. Single cell heterogeneity and cardiac electrical signalling: implications for abnormal heart rhythms

The aetiopathogenesis of cardiac arrhythmias is complex and clearly not yet fully understood, which explains why despite decades of research, we still do not have any effective anti-arrhythmic drugs. We are using the latest single cell RNA Seq and high throughput phenotyping platforms combined with in silico modelling to quantify the heterogeneity of molecular and cellular electrical properties in the heart and its impact on normal cardiac electrical signalling. We are also testing the hypotheses that (i) there are modules of co-expressed ion channel genes that ameliorate the impact of cellular heterogeneity and (ii) that reduced intercellular coupling, as for example occurs in dilated atria and post-infarct ventricles, exacerbates the intrinsic heterogeneity of heart cells to increase the risk of cardiac arrhythmias.

Laboratory Members & collaborators

Laboratory 

Andy Ng, Senior Staff Scientist

Carus Lau, Senior Postdoctoral Scientist

Jordan Thorpe, Post doctoral-Scientist

Matt Perry
, Senior Staff Scientist

Mark Hunter, Senior Research Officer

Nicholas Kerr, PhD Student

Joanne Ma, PhD Student

Justin Phan, PhD Student

Dan Tardo, Masters Student

Sanath Balasubramaniam, ILP Student

Jinmeng Zhou, Honours Student

Collaborators

Professor Toby Allen, RMIT University

A/Prof Rajesh Subbiah, St Vincent’s Hospital

A/Professor John Skinner, Children’s Hospital Westmead

Professor Christopher Semsarian, University of Sydney

Dr Jodie Ingles, Garvan Institute, Sydney

James Bouwer, University of Wollongong

Nathan Palpant, Institute of Molecular Bioscience, Brisbane

Professor Eduardo Perozo, University of Chicago

Dr Brett Kroncke, Vanderbilt Medical Centre

Professor Dan Roden, Vanderbilt Medical Centre

Professor Arthur Wilde, Amsterdam Medical Centre

Professor Wojciech Zareba, University of Rochester

Professor Jean-Philippe Couderc, University of Rochester

Publication highlights

1. Ballouz S et al. Co-expression of calcium and hERG potassium channels reduces the incidence of proarrhythmic events. Cardiovasc Res 2021;117(10):2216-2227 PMID: 33002116

2. Perry MD et al. Pharmacological activation of IKr in models of long QT Type 2 risks overcorrection of repolarization. Cardiovasc Res 2020;116(8):1434-1445 PMID: 31628797

3. Ng CA et al. High-throughput phenotyping of heteromeric human ether-à-go-go-related gene potassium channel variants can discriminate pathogenic from rare benign variants. Heart Rhythm 2020;17(3):492-500. PMID: 31557540

4. Vandenberg JI, Perozo E, Allen TW. Towards a Structural View of Drug Binding to hERG K(+) Channels. Trends Pharmacol Sci 2017 Oct;38(10):899-907. PMID: 28711156

5. Perry MD et al. Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations. J Physiol 2016 Jul 15;594(14):4031-49. PMID: 26958806

6. Mann SA et al. Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes. J Mol Cell Cardiol 2016 Nov;100:25-34. PMID: 27663173

7. Immanuel SA et al. T-wave morphology can distinguish healthy controls from LQTS patients. Physiol Meas 2016 Sep;37(9):1456-73. PMID: 27510854

8. Sadrieh A et al. Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2. Nat Commun 2014 Sep 25;5:5069. PMID: 25254353

9. Vandenberg JI et al. hERG K(+) channels: structure, function, and clinical significance. Physiol Rev 2012 Jul;92(3):1393-478. PMID: 22988594

10. Mann SA et al. R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy. J Am Coll Cardiol 2012 Oct 16;60(16):1566-73. PMID: 22999724

11. Mann SA et al. Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk. J Am Coll Cardiol 2012 Mar 13;59(11):1017-25. PMID: 2240207

12. Wang DT et al. Mapping the sequence of conformational changes underlying selectivity filter gating in the K(v)11.1 potassium channel. Nat Struct Mol Biol 2011 Jan;18(1):35-41. PMID: 21170050

13. Clarke OB et al. Domain reorientation and rotation of an intracellular assembly regulate conduction in Kir potassium channels. Cell 2010 Jun 11;141(6):1018-29. PMID: 20564790

14. Perrin MJ et al. Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-a-go-go-related gene channels. Mol Pharmacol 2008 Nov;74(5):1443-52. PMID: 18701618

Acknowledgement of Country

The Victor Chang Cardiac Research Institute acknowledges the traditional custodians of the land, the Gadigal of the Eora nation, on which we meet, work, and discover.
Our Western Australian laboratories pay their respect to the Whadjuk Noongar who remain as the spiritual and cultural custodians of their land.

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