Experimental verification that stretch-activated channels induce spiral-wave breakup in cardiac tissue at predicted mechano-electric thresholds

The 2007 reaction–diffusion–mechanics (RDM) study of Panfilov, Keldermann and Nash predicted that mechanical deformation of cardiac tissue, acting through stretch-activated ion channels (SACs), can break up an otherwise stable reentrant spiral wave of electrical excitation into fibrillation-like turbulence, with a breakup threshold on the SAC conductance that depends on the SAC reversal potential, and can also drift spiral waves through a resonance-like mechanism. Later work resolved the theoretical parts of the problem: a response-function theory (Dierckx et al. 2015) explained mechanically induced drift as a genuine resonance, and realistic-ionic-model, anisotropic, and three-dimensional anatomical simulations (2009–2019) reproduced the breakup. The surviving open core is experimental: whether SAC recruitment, at the conductances and reversal potentials actually measured in cardiac cells, induces spiral-wave breakup in real tissue; whether the predicted threshold locus matches measured cell parameters; and whether the predicted depolarization/sodium-inactivation/conduction-block mechanism operates as modeled.

Background

Rotating spiral waves of excitation organize wave patterns in many excitable media, from the Belousov–Zhabotinsky (BZ) oscillating chemical reaction to cardiac tissue, where reentrant rotating electrical waves underlie ventricular tachycardia and fibrillation — the chaotic electrical activity that stops coordinated pumping and is a leading cause of sudden cardiac death. Spiral-wave dynamics are usually modeled by reaction–diffusion (RD) equations, but in cardiac muscle the electrical wave triggers contraction, so wave rotation is accompanied by substantial deformation (local stretches of 10–15%) of the very medium in which the wave propagates. To capture this, Panfilov, Keldermann and Nash (2007) studied a reaction–diffusion–mechanics (RDM) system: a three-variable Fenton–Karma-type model — a simplified, low-dimensional ionic model of the cardiac action potential — coupled to finite-strain continuum elasticity equations, with feedback of deformation onto electrophysiology through stretch-activated ion channels (SACs). SACs are sarcolemmal ion channels (molecularly including Piezo and TRP family members) that open when the membrane is mechanically stretched and carry a largely depolarizing, roughly linear nonspecific cation current $I_s = G_s C (u - E_s)$, where $G_s$ is the maximal conductance, $E_s$ the reversal potential, $u$ the normalized transmembrane potential, and $C$ a local stretch measure. In this model they found two effects absent without mechanics. First, breakup: a stable spiral wave broke up into turbulence-like patterns, caused primarily by the SAC current, which produces diastolic depolarization that inactivates the fast inward (sodium) current and blocks propagation — an 'accommodation'-type mechanism; breakup occurred only above a conductance threshold, $G_{sTH} \approx 0.028$ in the model's dimensionless units, which increased when the reversal potential was lowered ($G_{sTH}=0.039$ at $E_s=0.75$ and $0.065$ at $E_s=0.5$). Second, drift: the spiral wave drifted through the deforming medium toward dynamical attractors, and the authors conjectured this was analogous to resonant drift — the drift of a spiral wave when the properties of the medium are modulated periodically in synchrony with the spiral's own rotation period, a phenomenon known from detailed ionic-model simulations and from BZ experiments. The authors noted that the breakup conclusion required confirmation 'both experimentally and by using modeling studies involving detailed ionic descriptions of cardiac tissue', that resonant drift had never been studied experimentally in cardiac tissue, and that the fibrous anisotropy (direction-dependent structure) of cardiac tissue had been neglected. A substantial computational and theoretical literature grew from this paper, so the open question is now its experimentally testable residue: whether SAC recruitment at physiological levels destabilizes reentrant waves in real tissue, as the RDM model predicts.

Problem Statement

The problem, as raised by Panfilov, Keldermann and Nash (2007) and left open after the subsequent computational and theoretical literature, is to verify the mechano-electric breakup prediction experimentally and quantitatively:

1. Determine, in real cardiac tissue, whether recruitment of stretch-activated ion channels can induce the breakup of an otherwise stable reentrant spiral (or scroll) wave into complex spatiotemporal patterns, as the reaction–diffusion–mechanics model predicts.
2. Measure or bound the breakup threshold as a function of the stretch-activated-channel parameters — the conductance $G_s$ and reversal potential $E_s$ of the stretch-activated current — and compare the predicted threshold locus $G_{sTH}(E_s)$ (in the 2007 model, $G_{sTH} \approx 0.028$ rising to $0.039$ and $0.065$ as $E_s$ is reduced to $0.75$ and $0.5$) with the conductances and reversal potentials measured in different cardiac cell types, establishing whether physiological SAC levels fall above or below the breakup threshold.
3. If item 1 is answered affirmatively, establish the mechanism experimentally: whether breakup proceeds through the predicted route — SAC-mediated diastolic depolarization, inactivation of the fast inward sodium current, and conduction block — rather than through other stretch-sensitive pathways.

Items 1 and 2, together with the isolation of the stretch-activated-channel contribution and the mapping of the dimensional SAC measurements onto the model's parameters, are jointly required to establish the prediction. Item 3 applies only if item 1 is answered affirmatively; if item 1 is negative, the item-2 above/below determination stands and no outcome-dependent mechanism test applies. The stretch-activated-channel contribution must be isolated from other mechanical effects with simultaneous electrical and mechanical observation of the reentrant wave, and the dimensional SAC measurements must be mapped onto the model's parameters. Optionally, experimental confirmation of mechanically induced spiral-wave drift in an excitable medium, and of its predicted resonance with the spiral rotation period, would additionally resolve the remaining part of the original conjecture; the drift mechanism itself has already been established theoretically and the confirmation is not required.

References

1. Panfilov AV, Keldermann RH, Nash MP (2007) Drift and breakup of spiral waves in reaction–diffusion–mechanics systems. Proceedings of the National Academy of Sciences 104(19):7922–7926. doi:10.1073/pnas.0701895104, https://doi.org/10.1073/pnas.0701895104
2. Dierckx H, Arens S, Li B-W, Weise LD, Panfilov AV (2015) A theory for spiral wave drift in reaction-diffusion-mechanics systems. New Journal of Physics 17:043055. doi:10.1088/1367-2630/17/4/043055, https://doi.org/10.1088/1367-2630/17/4/043055
3. Keldermann RH, Nash MP, Gelderblom H, Wang VY, Panfilov AV (2010) Electromechanical wavebreak in a model of the human left ventricle. American Journal of Physiology-Heart and Circulatory Physiology 299(1):H134–H143. doi:10.1152/ajpheart.00862.2009, https://doi.org/10.1152/ajpheart.00862.2009
4. Weise LD, Panfilov AV (2013) A discrete electromechanical model for human cardiac tissue: effects of stretch-activated currents and stretch conditions on restitution properties and spiral wave dynamics. PLoS ONE 8(3):e59317. doi:10.1371/journal.pone.0059317, https://doi.org/10.1371/journal.pone.0059317
5. Hu Y, Gurev V, Constantino J, Bayer J, Trayanova N (2013) Effects of mechano-electric feedback on scroll wave stability in human ventricular fibrillation. PLoS ONE 8(4):e60287. doi:10.1371/journal.pone.0060287, https://doi.org/10.1371/journal.pone.0060287
6. Nayak A, Pandit R (2014) Spiral-wave dynamics in ionically realistic mathematical models for human ventricular tissue: the effects of periodic deformation. Frontiers in Physiology 5:207. doi:10.3389/fphys.2014.00207, https://doi.org/10.3389/fphys.2014.00207
7. Jie X, Gurev V, Trayanova N (2010) Mechanisms of mechanically induced spontaneous arrhythmias in acute regional ischemia. Circulation Research 106(1):185–192. doi:10.1161/CIRCRESAHA.109.210864, https://doi.org/10.1161/CIRCRESAHA.109.210864
8. Weise LD, Panfilov AV (2011) New mechanism of spiral wave initiation in a reaction-diffusion-mechanics system. PLoS ONE 6(11):e27264. doi:10.1371/journal.pone.0027264, https://doi.org/10.1371/journal.pone.0027264
9. Weise LD, Panfilov AV (2012) Emergence of spiral wave activity in a mechanically heterogeneous reaction-diffusion-mechanics system. Physical Review Letters 108(22):228104. doi:10.1103/PhysRevLett.108.228104, https://doi.org/10.1103/PhysRevLett.108.228104
10. Christoph J, Chebbok M, Richter C, Schröder-Schetelig J, Bittihn P, Stein S, Uzelac I, Fenton FH, Hasenfuß G, Gilmour RF, Luther S (2018) Electromechanical vortex filaments during cardiac fibrillation. Nature 555(7698):667–672. doi:10.1038/nature26001, https://doi.org/10.1038/nature26001
11. Trayanova N, Constantino J, Gurev V (2010) Models of stretch-activated ventricular arrhythmias. Journal of Electrocardiology 43(6):479–485. doi:10.1016/j.jelectrocard.2010.05.014, https://doi.org/10.1016/j.jelectrocard.2010.05.014
12. Quinn TA, Kohl P (2021) Cardiac mechano-electric coupling: acute effects of mechanical stimulation on heart rate and rhythm. Physiological Reviews 101(1):37–92. doi:10.1152/physrev.00036.2019, https://doi.org/10.1152/physrev.00036.2019
13. Duong MT, Holz D, Alkassar M, Dittrich S, Leyendecker S (2019) Interaction of the mechano-electrical feedback with passive mechanical models on a 3D rat left ventricle: a computational study. Frontiers in Physiology 10:1041. doi:10.3389/fphys.2019.01041, https://doi.org/10.3389/fphys.2019.01041
14. Xu J, Wang F (2025) Cardiac mechano-electrical-fluid interaction: a brief review of recent advances. Eng 6(8):168. doi:10.3390/eng6080168, https://doi.org/10.3390/eng6080168