Jamie Vandenberg’s work focuses on the molecular basis of inherited and drug-induced arrhythmia syndromes. He has made major contributions to understanding of the molecular and structural basis of ion channel gatingandmechanisms underlyingdrug binding to hERG K+channels, the cause of the vast majority of cases of drug-induced arrhythmias. He has also made significant contributions to understanding the molecular basis of inherited arrhythmia syndromescaused by ion channel mutations. His work exemplifies how the combination of a deep understanding of basic biology combined with the study of clinically relevant problems can have significant translational benefits both in terms of the management of families with inherited heart rhythm disorders and in the industrial setting in terms of development of better assays to assess the pro-arrhythmic risk of drugs in the preclinical setting.

Molecular and structural basis of ion channel gating

Jamie was the intellectual driving force behind the discovery of the “Japanese Puzzle Box” model of inactivation gating in hERG K+ channels. His work characterising the kinetics of hERG K+ channel gating has also become accepted as the gold standard for the field and has been adopted by the Food and Drug Administration as the reference data set for establishing in silicomodels of hERG K+ channel gating.

Drug-induced arrhythmias

In addition to providing strong evidence for the state-dependence of drug binding to hERG K+ channels, in 2014 he reported the first direct measurements of the kinetics of binding and unbinding of drugs to hERG K+ channels. This work provides the groundwork for the development of molecularly accurate in silico models of hERG drug binding that can be used to predict the pro-arrhythmic risk of drugs from preclinical screening assays.

Molecular basis of inherited arrhythmia syndromes

Together with Andrew Grace and Bill Colledge we developed the first animal model of Brugada Syndrome. By adapting a clinical premature stimulation protocol we also demonstrated that the arrhythmia mechanism in the mouse was the same as that in humans. More recently, Jamie has had a very productive collaboration with Diane Fatkin’s molecular genetics group. Together, we demonstrated how gene-environment interactions contributed to the genesis of familial atrial fibrillation, developed novel computational tools to explain the epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk and identified a gene-guided therapy for a family with an inherited dilated cardiomyopathy.

Computational cardiology

Together with Adam Hill, Jamie has used computational modeling to complement their ion channel gating work for >10 years. Significant breakthroughs in recent years include the development of whole heart models based on graphical processor unit technology, which has enabled breakthrough discoveries in establishing causally cohesive links from genotype to whole organ phenotypes. His laboratory has also applied partial least square methods to permit the analysis of large populations of “genetically different” individuals to understand the variable penetrance of dominant molecular defects.

1. Molecular basis of gating in hERG K⁺ channels

• Wang DT, Hill AP, Mann SA, Tan PS, Vandenberg JI. 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.
• 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; 288(16): 11482-91
• Phan K, Ng CA, David E, Shishmarez D, Kuchel PW, Vandenberg JI, perry MD. The S1 helix critically regulates the finely-tuned gating of Kv11.1 channels. J Biol Chem (2017) In Press.

2. Genoptype-phenotype relationships in inherited arrhythmia syndromes

• Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, Stockhammer K, Thompson T, Playford D, Subbiah RN, Kuchar D, Aggarwal A, Vandenberg JI, Fatkin D. R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy J Am Coll Cardiol 2012; 60(16):1566-73
• Perry MD, Ng CA, Phan K, David E, Steer K, Hunter MJ, Mann SA, Imtiaz M, Hill AP, Ke Y, Vandenberg JI. Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations. J Physiol. 2016; 594(14): 4031-49

3. Development of ECG biomarkers for risk of sudden cardiac arrest

• Immanuel SA, Sadrieh A, Baumert M, Couderc JP, Zareba W, Hill AP, Vandenberg JI. T-wave morphology can distinguish healthy controls from LQTS patients. Physiol Meas. 2016; 37(9): 1456-73.

 4. Structural basis of hERG K⁺ channel function

• 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. 
• Ng CA, Hunter MJ, Perry MD, Mobli M, Ke Y, Kuchel PW, King GF, Stock D, Vandenberg JI. The N-Terminal Tail of hERG Contains an Amphipathic α-Helix That Regulates Channel Deactivation. PLoS One. 2011 Jan 13;6(1):e16191
• Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. hERG K+ channels: Structure, Function and Clinical Significance. Physiological Reviews 2012; 92(3):1393-1478