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Aim of the project
The goal of this project is to develop, refine and assess methods for the assessment of ventricular refractoriness in viable myocardium adjacent to scar that is critical to the development of reentrant ventricular arrhythmias (VA). Refractoriness is a property on which the development of reentry depends, however the profile of changes in refractoriness that occur in human ventricular tissue in which VA occur remain incompletely described. This represents an important knowledge gap in the contemporary understanding of the substrate for VA. Without a detailed understanding of the refractory properties of ventricular substrate, the ability to design accurate computational models that reflect physiological arrhythmias is limited. By using detailed clinical data and advanced computational modelling, the student will design and develop new metrics to define the refractoriness of ventricular tissue, which will be expected to enhance the ability of computational models to accurately reflect the physiological phenomenon of reentrant VA.
Project description
Sudden cardiac death is the mechanism of death in more than 50% of cardiovascular related deaths and is frequently due to ventricular arrhythmias (VA).1 The most common mechanism underlying VA is reentry, whereby one or more self-sustaining wavefronts of electrical activation result in extreme tachycardias associated with cardiac arrest. For reentry to occur, a wavefront of activation must continually encounter excitable tissue. This has been observed to occur most commonly in electrically excitable tissue in close proximity to pathological fibrosis in the heart, which has been described as the myocardial borderzone.2 The presence or absence of excitable tissue in the locus of a wavefront of activation determines whether reentry may be established.3 Therefore the refractory properties of ventricular myocardium, that is their recovery of excitability following activation, will be a critical determinant of the ability of tissue to sustain VA, and therefore the vulnerability of a heart to arrhythmias responsible for cardiac arrest. Changes in the heterogeneity of refractoriness in borderzone tissue is likely to be another important determinant of vulnerability to VA.4,5 Despite the fundamental importance of refractoriness in determining the vulnerability of a heart to reentry, the changes in this property that occur in myocardial tissue that is implicated in the development VA is poorly understood.
Action potential duration (APD) is a metric that reflects recovery of excitability at a cellular level, however requires voltage clamp experiments to measure.6 Activation-recovery interval (ARI) is a metric proposed as an in-vivo surrogate for APD and changes in ARI have been associated with an increased vulnerability to VA.7 A systematic assessment of the changes in refractoriness in regions adjacent to imaging defined fibrosis has not been carried out and therefore changes in the refractory properties of myocardial borderzone remain incompletely characterized. Our group have previously conducted an experimental analysis of the changes in refractory properties of borderzone in a porcine model of post-myocardial infarction VA.8
Hypotheses:
· The optimization of unipolar electrogram signal processing techniques will allow a reliable estimate of ARI to be derived from electrograms acquired during left ventricular endocardial ablation procedures
· Through the combination of high-resolution imaging and clinical electrogram data the electrical properties of human myocardial borderzone refractoriness may be assessed
· Novel metrics including maximum slope of the recovery phase of the unipolar electrogram reflect heterogeneity of repolarization which will be increased in the myocardial borderzone
· Knowledge of the changes in refractory properties of borderzone will allow the refinement of computational models of reenrant ventricular arrhythmia
In this project the student will develop pipelines to process unipolar electrograms acquired during clinical ablation procedures. Novel signal processing techniques will be developed to permit the automated calculation of both established and novel metrics of repolarization. The student will develop computational tissue models to test the hypothesis that observed changes in the slope of the recovery phase of unipolar electrograms is reflective of changes in the myocardial tissue composition as well as the heterogeneity of refractoriness in the field of view of the electrogram. The student will work with high-resolution cross-sectional magnetic resonance (MR) and computed tomography (CT) imaging to accurately classify the tissue from which the clinical electrograms are derived and test the hypothesis that pathological changes in refractoriness are common to regions of borderzone tissue. Finally, the student will generate computational whole-heart models from the clinical imaging, parameterized by the derived indices of refractoriness, in which the vulnerability to VA will be assessed and compared systematically with the clinically relevant arrhythmias which have been observed.
References:
1. Koplan, B. A. & Stevenson, W. G. SYMPOSIUM ON CARDIOVASCULAR DISEASES Ventricular Tachycardia and Sudden Cardiac Death. Mayo Clin Proc vol. 84 www.mayoclinicproceedings.com (2009).
2. Mehra, R., Zeiler, R. H., Gough, W. B. & El-Sherif, N. Reentrant Ventricular Arrhythmias in the Late Myocardial Infarction Period 9. Electrophysiologic-Anatomic Correlation of Reentrant Circuits. http://ahajournals.org.
3. Almendral, J., Caulier-Cisterna, R. & Rojo-Álvarez, J. L. Resetting and entrainment of reentrant arrhythmias: Part I: Concepts, recognition, and protocol for evaluation: Surface ECG versus intracardiac recordings. PACE - Pacing and Clinical Electrophysiology vol. 36 508–532 Preprint at https://doi.org/10.1111/pace.12064 (2013).
4. Fareh, S., Villemaire, C. & Nattel, S. Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused by Tachycardia-Induced Atrial Electrical Remodeling. http://www.circulationaha.org (1998).
5. Bishop, M. J., Connolly, A. & Plank, G. Structural heterogeneity modulates effective refractory period: A mechanism of focal arrhythmia initiation. PLoS One 9, (2014).
6. Trenor, B., Cardona, K., Saiz, J., Noble, D. & Giles, W. Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour. Journal of Physiology vol. 595 6599–6612 Preprint at https://doi.org/10.1113/JP273651 (2017).
7. Orini, M. et al. Evaluation of the reentry vulnerability index to predict ventricular tachycardia circuits using high-density contact mapping. Heart Rhythm 17, 576–583 (2020).
8. Mendonca Costa, C. et al. Determining anatomical and electrophysiological detail requirements for computational ventricular models of porcine myocardial infarction. Comput Biol Med 141, 105061 (2022).
9. Whitaker, J. et al. Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Assessment of Substrate for Ventricular Tachycardia With Hemodynamic Compromise. Front Cardiovasc Med 8, (2021).
Informal email enquiries from interested students to the supervisor are encouraged (contact details below).
Dr John Whitaker – john.whitaker@kcl.ac.uk
Dr Martin Bishop – martin.bishop@kcl.ac.uk
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