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SUMMARY:Emergent Behavior resulting from Incorporating Cellular Uncertaint
 y as Spatial Heterogeneity - Richard Gray (Food and Drug Administration)
DTSTART:20240604T135000Z
DTEND:20240604T141000Z
UID:TALK214570@talks.cam.ac.uk
DESCRIPTION:Background: Rigorous evaluation of computational cardiac elect
 rophysiological models is required for them be accepted for clinical use. 
 Such models typically represent the heart as millions of &lsquo\;cardiac c
 ells&rsquo\; that exhibit the same dynamics. Rigorous model evaluation inc
 ludes code verification\, model validation\, and uncertainty quantificatio
 n (UQ) of model parameters. Recently a cardiac cellular &lsquo\;action pot
 ential (AP)&rsquo\; model has been developed which includes comprehensive 
 data-driven UQ. Unfortunately\, when cellular-level UQ was propagated thro
 ugh the model\, the resulting APs exhibited not only the desired &lsquo\;n
 ormal repolarization&rsquo\; (NR) shape but also abnormal behavior such as
  repolarization oscillations (RO) and repolarization failure (RF). The fut
 ure of robust whole heart modeling for clinical use is not ensured because
  of the varied behavior of cellular APs resulting from incorporating measu
 red uncertainty into parameter values.\nMethods: A comprehensive model of 
 the rabbit action potential was developed by incorporating measured cellul
 ar uncertainty as parameter distributions (as done previously for the dog)
 . First\, cellular simulations were carried out to assess the behavior of 
 the resulting APs. Second\, this cellular uncertainty was imposed as a ran
 dom spatial field to investigate how such uncertainty would affect tissue-
 level phenomenon\, including propagation\, rate dependence\, and spiral wa
 ve dynamics.\nResults: Similar to our previous results in the dog model\, 
 the APs resulting from our new rabbit model exhibited a variety of behavio
 r with 67% exhibiting NR\; 27% displaying RO\; and 6% showing RF. However\
 , when these virtual cells were paced at the rate of the typical rabbit he
 art\, these percentages changed to: 94%: NR\; 0%: RO\; and 6%: RF. When th
 is cellular uncertainty was imposed as spatial heterogeneity\, the results
  were quite different. In 1-D and 2-D virtual tissues\, wave propagation w
 as uniform and 100% of sites exhibited normal repolarization at all pacing
  rates. In addition\, 100 instances of reentry simulations from the same i
 nitial conditions resulted in very similar and realistic behavior: &nbsp\;
 reentrant cycle length of 120&plusmn\;0.5 ms &nbsp\;and nearly identical p
 hase singularity trajectories\, albeit with variations in time before self
 -termination ranging from 3 to 12 beats.\nConclusion: Incorporating measur
 ed uncertainty into a model of the rabbit AP resulted in varied cellular b
 ehavior (which was rate dependent) with most cells exhibiting normal recov
 ery at the normal heart rate. Imposing cellular uncertainty as spatial het
 erogeneity revealed &lsquo\;emergent robustness&rsquo\; at the tissue leve
 l. Therefore\, incorporating cellular uncertainty as spatial heterogeneity
  into whole heart models might be a feasible approach to developing rigoro
 us models of clinically useful models of the electrical activity in the he
 art.
LOCATION:Seminar Room 1\, Newton Institute
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