Cardiac
Electrophysiology

"Before you can treat a patient,
you need to understand the disease
at a very fundamental level.
Only then can you discover a cure,"

- Professor Jamie Vandenberg

Professor Jamie Vandenberg

Head, Cardiac Electrophysiology Laboratory

Research Overview

Key Research Areas

  • Electrical activity in the heart
  • Inherited arrhythmia syndromes
  • 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 eight deaths in Australia.

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.

research projects

There are 3 key projects underway in the Cardiac Electrophysiology Laboratory, led by Professor Jamie Vandenberg;

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

Ion channels are integral membrane proteins that generate electrical signals in cells. 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, a potentially fatal disorder. 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. In recent years 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?

2. 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 very valuable for 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 investigating whether in vitro phenotyping of mutant hERG proteins can be used to improve algorithms for the differentiating between pathogenic and benign variants. We are also developing iPS cell and in silico models of mechanistic subtypes of long QT syndrome type 2 to allow us to examine the full range of phenotypes associated with pathogenic variants at the population level. 

3. 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.

Laboratory Members & collaborators

Laboratory 

Mark Hunter, Senior Research Officer 

Carus Lau, Postdoctoral Scientist  

Andy Ng, Senior Staff Scientist 

 Matt Perry, Senior Staff Scientist 


Collaborators 

Professor Eduardo Perozo, University of Chicago

Professor Tamir Gonen, Howard Hughes Medical Institute

Professor Toby Allen, Royal Melbourne Institute of Technology

Professor Glenn King, Institute for Molecular Bioscience

Professor Philip Kuchel, University of Sydney

A/Prof Rajesh Subbiah, St Vincent’s Hospital

A/Professor John Skinner, Starship Hospital

Professor Wojciech Zareba, University of Rochester

Professor Christopher Semsarian, University of Sydney

Dr Jodie Ingles, University of Sydney

A/Professor Mathias Baumert, University of Adelaide

Professor Jean-Philippe Couderc, University of Rochester

Publication highlights

1. 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

2. 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

3. 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

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

5. Hill AP et al. Kinetics of drug interaction with the Kv1.1 channel. Mol Pharm. 2014 May;85(5):769-76. PMID: 24586056

6. Perry MD, Ng CA, Vandenberg JI. Pore helices play a dynamic role as integrators of domain motion during Kv11.1 channel inactivation gating. J Biol Chem. 2013 Apr 19;288(16):11482-91. PMID: 23471968

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

8. 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

9. 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

10. 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

11. Ng CA et al. The N-terminal tail of hERG contains an amphipathic _-helix that regulates channel deactivation. PLoS One. 2011;6(1):e16191. PMID: 21249148

12. 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

13. Zhao JT et al. Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S, which has a dominant negative trafficking defect and a severe phenotype. J Cardiovasc Electrophysiol. 2009;20(8):923-30. PMID: 19490267

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

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