Andrew Grace

Cellular genetics of cardiac excitability.

The activity of the heart is genetically determined and is quantifiable to the extent that cardiac excitability provides an attractive model for defining the relationships between genetic makeup and cellular, tissue and whole organ behaviour. Furthermore disorders of cardiac excitability (arrhythmias) have significant impacts on public health that are unresolved. Atrial fibrillation is a major risk factor for stroke and ventricular fibrillation is responsible for sudden death. Our research has progressed from analysing the functional consequences of disruption of exemplar genes, identified as responsible for monogenic arrhythmogenic diseases studied in a range of model systems, to directly measuring cardiac excitation clinically in genetically complex disease. We have contributed to the development of powerful measurement and sampling tools that we are now employing strategically to address fundamental questions in cellular genetics.​

Research objectives

• What are the location-specific cellular genetic determinants of cardiac excitability in humans?

• How does the makeup of patients predisposed to arrhythmias differ from those with no such history?

• What are the cellular genetic characteristics of the location-specific drivers responsible for arrhythmias?

• Can those characteristics predisposing to arrhythmic phenotypes be rescued/corrected to provide an access for drug discovery/development?

Key publications

Papadatos GA, Wallerstein PM, Head CE, Ratcliff R, Brady PA, Benndorf K, Saumarez RC, Trezise AE, Huang CL, Vandenberg JI, Colledge WH, Grace AA (2002). Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. Proc. Natl. Acad. Sci. U.S.A., 99(9):6210-6215. doi: 10.1073/pnas.082121299

Saumarez RC, Pytkowski M, Sterlinski M, Bourke JP, Clague JR, Cobbe SM, Connelly DT, Griffith MJ, McKeown PP, McLeod K, Morgan JM, Sadoul N, Chojnowska L, Huang CL, Grace AA (2008). Paced ventricular electrogram fractionation predicts sudden cardiac death in hypertrophic cardiomyopathy. Eur. Heart J., 29(13):1653-1661. doi: 10.1093/eurheartj/ehn111

Dorn T, Kornherr J, Parrotta EI, Zawada D, Ayetey H, Santamaria G, Iop L, Mastantuono E, Sinnecker D, Goedel A, Dirschinger RJ, My I, Laue S, Bozoglu T, Baarlink C, Ziegler T, Graf E, Hinkel R, Cuda G, Kääb S, Grace AA, Grosse R, Kupatt C, Meitinger T, Smith AG, Laugwitz KL, Moretti A (2018). Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity. EMBO J., 37(12):e98133. doi: 10.15252/embj.201798133

Grace A, Willems S, Meyer C, Verma A, Heck P, Zhu M, Shi X, Chou D, Dang L, Scharf C, Scharf G, Beatty G (2019). High-resolution noncontact charge-density mapping of endocardial activation. JCI Insight, 4(6):126422. doi: 10.1172/jci.insight.126422

Willems S, Verma A, Betts TR, Murray S, Neuzil P, Ince H, Steven D, Sultan A, Heck PM, Hall MC, Tondo C, Pison L, Wong T, Boersma LV, Meyer C, Grace A (2019). Targeting nonpulmonary vein sources in persistent atrial fibrillation identified by noncontact charge density mapping. Circ. Arrhythm. Electrophysiol., 12(7):e007233. doi: 10.1161/CIRCEP.119.007233