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Professor Andrew Grace

Research themes

Experimental Medicine:

Research Interests

Andrew has strengths in strategic thinking and execution that have contributed significantly to developing new transformative treatments. His research impact has coincided with, and also significantly influenced, an era of enhanced awareness of the impact of arrhythmias on health with a research programme designed at its outset both to increase biological understanding and also provide real world benefit. Patient safety has been central with knowledge arising from his University-based lab work influencing practice most prominently through drug regulation across both the UK and Europe.

In addition to ‘soft’ impacts several of his innovations, developed through interdisciplinary collaboration, have already provided direct patient benefit. He has progressed from analysing mechanisms of cardiac Na+-dependent proton efflux, to describing functional consequences of the disruption of genes implicated in arrhythmogenesis (in model systems) to quantifying cardiac excitation in complex disease. Specific contributions leading to significant change include:

(i) Subcutaneous defibrillators (SICDs) - Andrew completed ‘proof of concept’ studies and then implanted the first devices in the UK, Netherlands, Germany and Saudi Arabia and is last-named author on the New England Journal of Medicine paper describing the advance. SICDs have been adopted into international guidelines, implanted in >90,000 patients, are the first leadless cardiac devices, and received the 2013 Prix Galien in New York for best Medtech product.

(ii) Pulmonary vein ablation catheters (PVAC) - he pioneered clinical work on ‘single-shot’ PVACs and is senior author on the first report (American College of Cardiology, New Orleans, 03.2007); the technology has been used to treat >60,000 patients and now provides the platform for electroporation-based pulsed field ablation recently trialled (01.2021).

(iii) Atrial-selective ion channel modulators - As Principal Scientific Advisor (2002-2016) to Cambridge-based VC- and Wellcome-backed Xention Ltd he played a leading role in developing atrial-selective Kv1.5 modulators shown to be effective in AF suppression in phase II clinical trials providing a template for the design of such trials.

(iv) Voltage-based cardiac mapping - Validated by his model-based work, he developed and then completed clinical trials of now patented (US 10,601,119) voltage-based activation mapping. The demonstration of capabilities in predicting VF occurrence refined ICD implant decisions and also prompts a re-evaluation of risk management strategies.

(v) Charge Density based cardiac mapping - he has shown most recently, through application of first principles in electrostatic field theory, that calculations of charge density (CD) greatly increase single-to-noise ratios compared to voltage and permit <2 mm localisation of cardiac electrical sources. Furthermore he provided evidence for enhanced ablation efficacy through CD-determined source ablation having completed two pivotal clinical trials via international collaboration. The combined data culminated in the manufacturer (Acutus Medical) completing the ‘most successful Medtech IPO in history’. Physically differentiated CD-based phenotyping not only guides ablation (>5000 patients to date) but also enables multisite endocardial sampling; when combined with single-cell assays e.g. scRNAseq it will facilitate resolution of relationships between genetic makeup and clinical cardiac electrical function.

The last few years have witnessed substantial advances in the arrhythmia field to which Andrew has made major contributions with his input achieving clear societal benefit. He has been recognized as providing a valuable skill set traversing the wide gap between fundamental science and industrial application in a previously underserved disease domain.

 


Keywords

genomics ; genetic variation ; cardiac mapping ; cardiac electrophysiology ; network modelling ; machine learning ; defibrillation ; single cell genomics ; Ion Channels ; drug discovery

Topics

  • Atrial fibrillation

Key Publications

1. Grace AA, Kirschenlohr HL, Smith GA, Metcalfe JC, Cragoe EJ, Weissberg PL, Vandenberg JI. (1993): Regulation of intracellular pH in the perfused heart by external HCO3- and Na+-H+ exchange.  American Journal of Physiology (Heart and Circulatory Physiology). 265:H289-298.

2. Vandenberg JI, Metcalfe JC, Grace AA. (1993): Mechanisms of proton efflux following total global ischemia in the perfused heart.  Circulation Research. 72:993-1003 (placed second American Heart Association Melvyn Marcus Awards 1992).

3. Papadatos GA, Wallerstein PM, Head CE, Ratcliff RR, Brady PA, Benndorf K, Saumarez RC, Trezise AE, Huang CL, Vandenberg JI, Colledge WH, Grace AA. (2002): Slowed conduction and ventricular tachycardia following targeted disruption of the cardiac sodium channel, Scn5aProceedings of the National Academy of Sciences, USA. 99:6210-5  (Highlighted Basic Science, Orlando AHA, 2001; PNAS – on the cover and Editorial).

4. Saumarez RC, Chojnowska L, Derksen R, Pytkowski M, Sterlinski M, Sadoul N, Hauer RWN, Ruzyllo W, Grace AA (2003): Sudden death in non-coronary disease is associated with delayed paced ventricular activation. Circulation. 107:2595-2600.

5. SaumarezRC, Pytkowski M, Chojnowska L, Sterlinski M, Sadoul N, Clague J, Connelly D, McLeod K,Morgan J, Cobbe SA, GriffithMJ, Bourke J, Huang C. L-H, Grace AA. (2008): Paced ventricular electrogram fractionation predicts sudden death in hypertrophic cardiomyopathy. European Heart Journal. 29:1653-1661.

6. Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L, Theuns D, Park RE, Wright DJ, Connelly DT, Fynn SP, Murgatroyd FD, Sperzel J, Neuzner J, Spitzer SG, Ardashev AV, Oduro A, Boersma L, Maas AH, Van Gelder IC, Wilde AA, van Dessel PF, Knops RE, Lupo P, Cappato R, Grace AA. (2010): The Subcutaneous only Implantable Cardioverter Defibrillator. New England Journal of Medicine. 363:36-44.

7. Matthews GD, Guzadhur L, Sabir IN, Grace AA, Huang CL (2013). Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a+/- hearts. Journal of Physiology 591:4167-88.

8. Dorn T, Haas J, Parrotta EI, Zawada D, Ayetey H, Santamaria G, Lop 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, Kaab S, Grace AA, Grosse R, Kupatt C, Meitinger T, Smith AG, Laugwitz K-L, Moretti A. (2018) Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocytic identity.  EMBO Journal.  Jun 15;37(12). pii: e98133. doi: 10.15252/embj.201798133.

9. Grace AA, Willems S, Meyer C, Verma A, Heck P, Dang L, Scharf G, Scharf C, Beatty G (2019). High Resolution Non-Contact Charge Density Source Mapping of Endocardial Activation. JCI Insight 4 (6): e126422.

10. Willems S, Verma A, Betts T, Murray S, Neuzil P, Ince H, Stevens D, Sultan A, Heck P, Hall M, Tondo C, Pison L, Wong T, Boersma L, Wong T, Meyer C, Grace AA. (2019). Targeting Non-Pulmonary Vein Sources in Persistent Atrial Fibrillation Identified by Non-Contact Charge Density Mapping: The UNCOVER AF trial. Circ Arrhythm Electrophysiol. Jul;12(7):e007233. doi: 10.1161/CIRCEP.119.007233. Epub 2019 Jun 27.

Selection of five invited reviews/commentaries:

1. Grace AA, Camm AJ. (1998): Quinidine. New England Journal of Medicine. 338:35-45

2. Grace AA, Roden DM. (2012): Systems Biology and Cardiac Arrhythmias. Lancet 380:1498-508

3. Grace AA. (2015): Prophylactic Implantable Defibrillators for Hypertrophic Cardiomyopathy: Disarray in the Era of Precision Medicine. Circ Arrhythm Electrophysiol. 8:763-6.

4. Grace AA, Matthews GDK (2018): Phenotypic landscape and risk management in Long QT Syndrome. Nudging forward. J Am Coll Cardiol. 71:1672-5

5. Grace AA (2019): Sudden Death in Hypertrophic Cardiomyopathy is Rare. Circulation. 2019;140:1717-1719.

Selection of Original Articles:

(>240 publications, Citations, 9373; h-index, 50; Orcid: https://orcid.org/0000-0002-0686-215X)

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