Stretch of the papillary insertion triggers reentrant arrhythmia: an in silico patient study

Background The electrophysiological mechanism connecting mitral valve prolapse (MVP), premature ventricular complexes and life-threatening ventricular arrhythmia is unknown. A common hypothesis is that stretch activated channels (SACs) play a significant role. SACs can trigger depolarizations or shorten repolarization times in response to myocardial stretch. Through these mechanisms, pathological traction of the papillary muscle (PM), as has been observed in patients with MVP, may induce irregular electrical activity and result in reentrant arrhythmia. Methods Based on a patient with MVP and mitral annulus disjunction, we modeled the effect of excessive PM traction in a detailed medical image-derived ventricular model by activating SACs in the PM insertion region. By systematically varying the onset of SAC activation following sinus pacing, we identified vulnerability windows for reentry with 1 ms resolution. We explored how reentry was affected by the SAC reversal potential (ESAC) and the size of the region with simulated stretch (SAC region). Finally, the effect of global or focal fibrosis, modeled as reduction in tissue conductivity or mesh splitting (fibrotic microstructure), was investigated. Results In models with healthy tissue or fibrosis modeled solely as CV slowing, we observed two vulnerable periods of reentry: For ESAC of −10 and −30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For ESAC of −40 and −70 mV, SAC activated during the QRS complex could result in early repolarization of the SAC region and subsequent reentry. In models with fibrotic microstructure in the SAC region, we observed micro-reentries and a larger variability in which times of SAC activation triggered reentry. In these models, 86% of reentries were triggered during the QRS complex or T-wave. We only observed reentry for sufficiently large SAC regions ( >= 8 mm radius in models with healthy tissue). Conclusion Stretch of the PM insertion region following sinus activation may initiate ventricular reentry in patients with MVP, with or without fibrosis. Depending on the SAC reversal potential and timing of stretch, reentry may be triggered by ectopy due to SAC-induced depolarizations or by early repolarization within the SAC region.

Table S2.Parameter combinations for the supplementary models.For all listed combinations, we activated SAC for a duration of 50 ms, with a maximum conductance g SACtarget = 0.1 mS/ µF.The first column indicates the name used for referring to a type of model.Radius refers to the area with SAC activation.∆ APDs describes the global APD heterogeneity by referring to the minimum and maximum APD in the tissue, resulting from the selected set of I Ks scaling factors in the model.BCL refers to the duration between each sinus pacing.E SAC : resting potential of the SAC current (mV).BCL: basic cycle length

APD heterogeneity
In addition to the baseline APD gradient used in our main population of models, we ran simulations for two additional APD gradients in models with E SAC of -10 and -70 mV.This resulted in a total of three types of APD heterogeneities, the first which is described in the Materials and Methods section.
The second type of gradient was chosen based on previous work by [1] and [2].In accordance with these studies, we scaled the slow delayed rectifier K+ current (I Ks ) linearly by a factor of 1-1.5 in both the transmural and apicobasal direction.This resulted in a total scaling from 1 in the basal endocardium to 2.25 in the apical epicardium.The resulting APDs ranged from 290 ms in the basal endocardial cell to 241 ms in the apical epicardial cell.
For the third type of heterogeneity, we applied a global shortening of APDs.APD shortening reduces the wavelength for reentry and is known to affect arrhythmic vulnerability [3].APDs were shortened by adding a factor of 1.5 to all I Ks scaling factors from the second set of models, resulting in a final scaling from 2.5 in the basal endocardial cell to 5.5 in the apical epicardial cell.The APDs varied between 235 ms in the basal endocardial cell to 188 ms in the apical epicardial cell.

Varying APD gradient
. Grids illustrating the vulnerability to reentry for two example models with three different APD gradients.(A) In models with E SAC = -70 mV, timings for all three vulnerability windows overlap with the QRS complex.(B) For E SAC = -10 mV, reentry could not be induced in the model with the shortest APD gradient (APD 188−235 ), independent of when SAC was activated.Unsustained reentries are marked orange, while the sustained reentry is marked purple.

Effect of basic cycle length
For all E SAC , we explored how a change in BCL affected the reentry vulnerability windows.Figure S3 shows a vulnerability grid for models with a BCL of 1000 ms.Consistent with models with BCL of 500 ms, we observed two types of reentry: either caused by SAC-induced, early repolarization when SAC was activated during the QRS complex, or caused by SAC-induced depolarizations when SAC was activation during the T-wave.Like for BCL of 500 ms, we observed the first mechanism in models with E SAC of -70 to -40 mV, and the second mechanism in models with E SAC of -30 to -10 mV.However, in the population with BCL of 1000 ms, we observed one model with sustained reentry (E SAC = -10 mV) and one model with no reentry (E SAC = -20 mV).When changing the BCL from 500 ms to 1000 ms, the vulnerability windows were shifted to later time points.The shifts between the start of each vulnerability window were of 8, 11, 5, 7, 7 and 7 ms for E SAC of -10, -30, -40, -50, -60 and -70 mV, respectively.

Figure S1 .
Figure S1.Visualization of the coordinate (blue point) from where we recorded the extracellular potential.The point was determined by aligning our ventricular mesh (red) with torso mesh (grey) previously developed by Uv et al. (2022) [4].

Figure S3 .
Figure S3.Vulnerability windows for reentry across all levels of E SAC for models with APD 206−290 , 1000 ms BCL, healthy conductivities and a SAC region of 10 mm radius (models M26-M32, TableS2).The two time periods within which reentry occurred were during the T-wave (286-302, panel (A)) or during the QRS complex (64-70, panel (B)).(A) For E SAC of -10 to -40 mV, the first time of SAC onset which triggered ectopy (light orange bar) were 284, 285, 286 and 298 ms after sinus pacing.SAC activation at any time after these points (last point measured at 350 ms) always triggered full ventricular activation.Sustained reentry is marked purple, unsustained reentry is marked dark orange.BCL: basic cycle length.

Figure
Figure S4.(A) Activation map for a reentry triggered by SAC-induced depolarization in a model with fibrotic microstructure in the SAC region and E SAC = -10 mV.SAC was activated for 50 ms from 279 ms after the previous sinus pacing.t0 represents time of SAC onset.(B) Extracellular potential trace recorded from a single lead at the left shoulder.