{"id":"f90c0a76-5e71-4700-918c-fc55e35a8c03","arxiv_id":"1908.05144","paper_version":1,"verdict":"CONDITIONAL","confidence":"MODERATE","novelty_score":7.0,"correctness_risk":"medium","formal_verification":"none","parameter_count":4,"one_line_summary":"In a computer model of human heart tissue, stretch-activated currents cause an instability where action potential duration grows beat by beat, leading to wave break and spiral wave meandering.","lead":"This computer simulation of heart tissue finds a new way electrical waves can go wrong: contraction stretches the tissue, stretch makes waves collide with their own tail, and each beat lasts longer until the wave breaks into spiral waves. This points to a mechanical trigger for dangerous heart rhythms, distinct from the usual short-long-short beat alternation.","discovery_kind":"extension","skeptic_critique":{"model":"deepseek-v4-flash","headline":"The 2D MEDI mechanism is inferred from a 1D moving-obstacle setup, and the local DI=T-APD feedback identity used to close the loop is not valid under strain-dependent CV; this transfer is the load-bearing assumption.","rationale":"The paper is a plausible and internally consistent computational study: MEDI is directly simulated in 2D, a parameter-space map is provided, and the 1D ICaL-block control supports the proposed biexcitability mechanism in that reduced setup. The reader's weakest assumption correctly identifies the transfer from the 1D moving-obstacle experiment to the full 2D model as the critical step. My stress-test sharpens this: the paper uses DI=T-APD to close the positive feedback loop, but at a collision site in a propagating wave the activation interval also depends on arrival-time differences, which are influenced by APD through strain-dependent CV. This makes the transfer assumption more fragile and explicitly deserves a direct test. I do not see an internal contradiction or a fatal flaw; the phenomenon is demonstrated, and the mechanism is plausible but under-supported in 2D. The appropriate verdict remains CONDITIONAL, as given by the reader, because the missing evidence is addressable. I mark agreement as partial because the reader did not explicitly name the invalid local restitution identity, although it falls under the same transfer concern. No code or data are provided, which further limits verification but is not itself the central scientific weakness.","tokens_in":6954,"tokens_out":5135,"duration_ms":57166,"concrete_test":"Repeat the Figure 1 protocol (Gs=50 S/F) in the full 2D model and record, at the site where APD grows (the white cross), the per-beat activation time, APD, DI, and the peak INa and ICaL during each upstroke. Also run the same 2D protocol with ICaL blocked. If the upstroke remains sodium-driven during APD growth, or if the inter-beat interval is not determined by APD through DI=T-APD, or if MEDI persists with ICaL blocked, then the 1D biexcitability mechanism does not transfer to 2D. A positive result would directly verify the mechanism and resolve the concern.","verdict_should_be":"UNCHANGED","load_bearing_attack":"The central claim that MEF causes MEDI through a positive feedback loop rests on the abnormal APD(DI) relation measured in a constantly stretched 1D cable with a moving obstacle (Figure 4). The paper does not directly measure this relation at the collision site in the full 2D electromechanical model (Figures 1 and 5), and the authors explicitly concede that 'in the full model it is more complex, as APD affects also the spatiotemporal strain distribution in the medium, and thus affects CV.' The missing step is not merely quantitative. The feedback argument uses DI=T-APD, which holds for periodic point stimulation, but at a propagating collision site the inter-beat interval is T plus the difference in arrival times from the stimulus site, and arrival times change as APD alters strain and CV. If the next activation arrives earlier or later than T-APD would predict, the alleged positive feedback can be weakened or even reversed. Thus the 2D simulations demonstrate APD growth and wave break, but they do not establish that the 1D biexcitability mechanism is the cause. The 1D ICaL-block control supports the mechanism in that reduced setup, but no equivalent control is reported in the 2D model, so the role of ICaL in the actual MEDI remains an extrapolation.","agreement_with_reader":"partial"},"referee_report":{"model":"deepseek-v4-flash","summary":"The manuscript reports a computational discovery of a 'mechano-electrical dynamical instability' (MEDI) in a two-dimensional electromechanical model of human cardiac tissue. The authors couple the Ten Tusscher-Panfilov epicardial ionic model to a discrete mechanical lattice with stretch-activated current Isac = Gs (λ-1)/(λmax-1) (V-Es), and simulate periodic pacing with a period of 300 ms after conditioning at 340 ms. They observe repeated wave front-back collisions, gradual local prolongation of APD, shortening of DI, and eventual wave break with formation of spiral waves. A parameter scan in (Gs, T) maps stable propagation, alternans, and MEDI regions. To explain the mechanism, the authors use a one-dimensional constantly stretched cable with a moving obstacle to force a controllable S1 conduction velocity, and show that during front-tail collisions short DI produces abnormally long APD, driven by a shift from sodium-dominated to ICaL-dominated upstroke ('biexcitability'); blocking ICaL abolishes MEDI in this 1D setup. They further show that in 2D, MEDI causes rapid spiral drift at larger Gs. The authors acknowledge that no analytical theory is provided and that the full 2D model is more complex because APD affects spatiotemporal strain and hence conduction velocity.","tokens_in":7221,"tokens_out":4944,"duration_ms":49437,"significance":"If the proposed mechanism is correct, MEDI is a genuinely new dynamical instability that is distinct from alternans and could contribute to wave break and spiral-wave hypermeander during cardiac arrhythmia. The paper has several concrete strengths: the simulation evidence is internally consistent; a useful negative control (blocking ICaL in the 1D setup) supports the role of biexcitability; the robustness scan over Gs and pacing period gives a predictive parameter range; and the spiral-drift results connect the instability to an observable arrhythmia-relevant phenotype. However, the significance of the central claim depends on whether the 1D reduced mechanism actually drives the 2D instability, which the manuscript does not yet establish.","major_comments":[{"comment":"The central conclusion that MEDI is caused by biexcitability-mediated abnormal APD(DI) restitution rests entirely on the 1D constantly stretched cable with a moving obstacle (Figures 3 and 4), in which electromechanical coupling is disabled by construction. At the 2D collision site the authors do not measure APD as a function of DI, nor do they identify the upstroke type (INa- vs ICaL-dominated) during the growing APD in Figure 1. The authors themselves state near the end of the paper that 'in the full model it is more complex, as APD affects also the spatiotemporal strain distribution in the medium, and thus affects CV'. Under strain-dependent CV, the inter-beat interval at a collision site is not T - APD, because arrival-time differences from the pacing site are themselves changing; the claimed positive feedback could therefore be weakened or reversed. A direct 2D measurement of APD(DI) at the collision site, or a 2D ICaL-block control, is needed to support the transfer.","section":"Mechanism explanation, Figures 3-4 and Figure 1"},{"comment":"The robustness diagram in Figure 2 is obtained by a dynamic protocol in which the pacing period is decreased by 2.5 ms after every ten beats, and the boundary between stable propagation and instability is identified during the ramp. The claim that MEDI occurs in a large parametric space (Gs between roughly 15 and 75 S/F and T between roughly 220 and 400 ms) would be stronger if the authors reported whether MEDI develops under constant pacing at the final period after many beats, and whether the onset depends on the ramp rate. This matters because the title and abstract present MEDI as an instability of a steady period, not of a particular sweep protocol.","section":"Figure 2 and protocol description"},{"comment":"The 1D 'constantly stretched cable' (λ = λmax) used to establish the mechanism has a uniform, time-independent stretch-activated current; it therefore cannot represent the dynamic strain feedback that the 2D model includes, where λ varies both in space and time as each wave triggers contraction. The agreement between Figure 3 and Figure 1 is qualitative and established by visual comparison, without a quantitative metric. Please provide at least one quantitative comparison (e.g., APD increase per beat or DI trajectory) and specify which features of the 2D instability are captured by the 1D model.","section":"Equation (2) and the 1D constantly stretched cable"}],"minor_comments":[{"comment":"There are several typographical errors and style inconsistencies: 'it's back' should be 'its back'; 'PloS One' appears in the bibliography instead of the journal's preferred 'PLoS ONE'; and the reference list contains inconsistent capitalization.","section":"Throughout"},{"comment":"The manuscript contains placeholder links such as [35], [36], [37], and [39] ('LINK TO SUPPLEMENTAL MOVIE', 'LINK TO SUPPLEMENTAL FIGURE', and 'LINK TO SI'); these should be resolved to actual URLs or removed before publication.","section":"Main text and figure captions"},{"comment":"The caption states 'Crosses: measurements' but the crosses are not explained in the main text; please clarify what measurements the crosses denote and how they were obtained.","section":"Figure 2 caption"},{"comment":"The definition of APD and DI recorded at -60 mV appears only in footnote [38]; this definition should be stated in the main text or methods, as it is essential for interpreting all quantitative claims.","section":"Methods, APD and DI definition"},{"comment":"The sentence 'To solve the mechanical model we assumed elastostatics, and used Verlet integration' seems contradictory; if a dynamic relaxation scheme is used, this should be stated explicitly, and the relation to elastostatics clarified.","section":"Mechanical model description"}],"recommendation":"major_revision","confidential_remarks":"The manuscript's main novelty hinges on transferring a mechanism from a reduced 1D setup to the full 2D electromechanical model, and the authors themselves concede the transfer is not straightforward. Given that the 2D ICaL-block control is absent and the APD(DI) relation is not measured in 2D, I recommend that the editor require at least one additional diagnostic as a condition of acceptance. There is no data or code availability statement, which limits reproducibility, but the request for code is not yet standard for this journal; the editor may wish to ask the authors to provide source code or simulation parameters as supplementary material."},"author_rebuttal":null,"desk_editor":{"model":"deepseek-v4-flash","letter":"The paper claims something new: a mechano-electrical dynamical instability (MEDI) in cardiac tissue, distinct from alternans, that can cause wave break and spiral hypermeander. The evidence is mostly simulation. The 2D electromechanical model shows APD at a collision site increasing beat to beat until break; the parameter map shows a large MEDI region; the 1D moving-obstacle setup shows that a calcium-driven upstroke at short DI produces long APDs; and blocking ICaL removes the instability in that setup. That is a solid chain of evidence for a plausible mechanism, and the authors are appropriately cautious about the limitations.\n\nThe main soft spot is the bridge between the 1D and 2D results. The positive-feedback argument rests on DI = T - APD at the collision site. That identity holds for periodic pacing at a fixed point with constant conduction delay, but in the full 2D model the local DI is the pacing interval plus any change in arrival time, and the authors concede that APD changes the strain distribution and hence CV. The 2D simulation shows the APD and DI traces, but does not directly measure the APD(DI) relationship at the collision site, and there is no ICaL-block control in 2D. So the causal claim that biexcitability drives the 2D instability is an extrapolation. It is a plausible one, and the paper identifies the right missing step, but it is not yet demonstrated.\n\nA second, smaller issue is that no code or data are provided. For a computational study this is an inconvenience, not a fatal flaw, because the model is specified and follows prior work. If this goes to review, I would ask for the 2D APD(DI) measurement and a 2D ICaL block, and encourage a deposition of the code.\n\nOverall this is a worthwhile paper. It identifies a genuinely new mechanism and gives a controlled 1D demonstration of the core idea. It will be of interest to people working on cardiac electromechanics, MEF, and spiral wave dynamics. The central finding is probably right, but the reviewer needs to decide whether the 2D evidence is sufficient. I would send it to peer review, with the expectation of moderate revision.","headline":"New and plausible computational mechanism for MEF-driven instability, but the 2D evidence leaves the causal chain from 1D biexcitability incomplete.","tokens_in":7754,"tokens_out":4275,"would_cite":true,"duration_ms":45057,"reading_group":"yes","serious_thinker":"yes","would_accept_peer_review":true},"rs_alignment":null,"lean_confirmation":null,"pith_extraction":{"msc":[],"pacs":[],"model":"deepseek-v4-flash","headline":"A new instability, MEDI, turns the heart's own contraction into a driver of spiral-wave arrhythmias.","keywords":["mechano-electrical feedback","stretch-activated channels","cardiac arrhythmia","spiral waves","biexcitability","action potential duration","wave break","calcium-driven upstroke"],"falsifier":"Record transmembrane voltage and calcium current at a collision site in a stretched cardiac tissue preparation while imposing a controlled front-tail interaction: if action potential duration still falls when diastolic interval shortens below the threshold at which the sodium upstroke fails, MEDI will not occur; if it rises as the upstroke becomes calcium-driven, the instability is confirmed.","tokens_in":6730,"feed_emoji":"💓","tokens_out":7516,"duration_ms":71355,"temperature":0.7,"pith_summary":"MEDI is a dynamical instability of excitation waves in cardiac tissue in which the tissue's own contraction feeds back into its electrical wave. The paper argues that stretch-activated currents accelerate the wave front until it collides with the tail of the preceding wave; at those collision sites a short diastolic interval does not shorten but lengthens the next action potential, because the upstroke switches from a sodium-driven to a calcium-driven form (biexcitability). This abnormal $\\mathrm{APD}(\\mathrm{DI})$ relation creates positive feedback — longer action potentials shorten the diastolic interval, which lengthens the next action potential — until the wave breaks and spiral waves form or hypermeander. If correct, MEDI provides a mechanical route to arrhythmia onset that operates at longer pacing periods than the classical alternans instability, and it identifies stretch-activated channels and L-type calcium current as control points.","feed_headline":"Heart stretch itself can trigger spiral-wave arrhythmias","feed_subtitle":"Computer model shows short pauses lengthening the next heartbeat until wavefronts break into spirals.","key_machinery":"The machinery that carries the argument is the electromechanical coupling chain: a reaction–diffusion equation for transmembrane voltage, a spring–mass mechanical model coupled to it, and a stretch-activated current $I_{sac}$ that adds a depolarizing conductance when local stretch $\\lambda>1$. To isolate the wave front–tail interaction, the authors use a moving obstacle in a one-dimensional cable that forces the first wave to propagate at a controlled speed, producing controlled collisions; varying the forced conduction velocity tunes $\\mathrm{DI}$ at the collision point and reveals the transition between a steep sodium-driven upstroke and a slow calcium-driven upstroke. Biexcitability — the coexistence of these two propagation modes in the same tissue — is the named phenomenon that converts short $\\mathrm{DI}$ into long $\\mathrm{APD}$, and blocking $I_{CaL}$ suppresses MEDI.","core_discovery":"The central discovery is that mechano-electrical feedback can create its own dynamical instability. In the authors' computational model of human cardiac tissue, stretch-activated current $I_{sac}=G_s(\\lambda-1)/(\\lambda_{\\max}-1)(V-E_s)$ accelerates the wave front, producing wave front–tail collisions. At the collision site, short $\\mathrm{DI}$ produces longer $\\mathrm{APD}$ (opposite to standard restitution) because the upstroke is no longer sodium-driven but is carried by L-type calcium current $I_{CaL}$; the longer $\\mathrm{APD}$ shortens the next $\\mathrm{DI}$, and this positive feedback grows beat to beat until the wave front blocks and curls into two counter-rotating spiral waves. The same mechanism makes spiral wave tips drift rapidly along the line of maximum $\\mathrm{APD}$, producing hypermeandering trajectories. The paper concludes that MEDI is a consequence of MEF and can cause both formation and hypermeandering of spiral waves.","pith_inferences":["If the same positive feedback transfers to three-dimensional hearts, MEDI would be a candidate driver of vortex filament breakup, a scenario the authors explicitly leave as an open next step.","A testable extension would be to apply localized stretch during pacing in a tissue preparation to reproduce controlled front-tail collisions and look for the abnormal $\\mathrm{APD}(\\mathrm{DI})$ slope at the collision site.","The same logic could apply to other excitable media with deformation-sensitive currents, such as smooth muscle, where mechanical state modulates excitability.","A practical consequence is that drugs or mutations that reduce $I_{CaL}$ availability may suppress MEDI even if stretch-activated channel conductance is unchanged, because the calcium-driven upstroke is the necessary switch."],"forward_implications":["MEDI offers a mechanism for wave break and spiral-wave formation that requires no anatomical heterogeneity and no alternans; it appears in the model for a broad range of stretch-activated conductances and pacing periods.","Because MEDI occurs at longer stimulation periods than classical $\\mathrm{APD}$ alternans, it could explain arrhythmia onset at heart rates where restitution-based predictions say the tissue should be stable.","In the spiral-wave simulations, MEDI causes rapid drift of the spiral core along the collision line, a hypermeandering motion the paper links to polymorphic ventricular tachycardia.","The dependence on $I_{CaL}$ means the instability is not a generic stretch effect but specifically requires the calcium-driven upstroke, giving a targeted point for intervention."],"supporting_citations":[{"why":"Supplies the moving-obstacle setup and the earlier finding that stretch-induced $I_{sac}$ accelerates wave fronts and produces wave front–tail collisions with biexcitability.","marker":"[24]"},{"why":"Provides the human epicardial ionic model whose sodium and calcium currents produce the upstroke transition central to MEDI.","marker":"[10]"},{"why":"Supplies the excitation–contraction coupling and stretch-activated current parameters adjusted to human cardiac tissue used in the simulations.","marker":"[14]"},{"why":"Provides the discrete mechanical model of cardiac tissue that couples deformation to the reaction–diffusion system.","marker":"[11]"},{"why":"Establishes the mechano-electrical feedback context and the reported range of stretch-activated conductances $G_s$ used in the parameter study.","marker":"[9]"},{"why":"Supports the claim that sodium channels are inactivated by accommodation at depolarized potentials, forcing the calcium-driven upstroke during collisions.","marker":"[27]"},{"why":"Documents the biexcitability phenomenon (coexistence of fast sodium-driven and slow calcium-driven propagation) in cardiac tissue.","marker":"[25]"},{"why":"Supplies resonant drift theory used to explain the onset of spiral meander under periodically varying excitability due to MEF.","marker":"[28]"}],"fun_headline_variants":["Stretch feedback twists heartbeats into spiral chaos","Heart muscle stretch spawns its own electrical storm","Mechano-electric loop turns beats into spiral waves","Stretch-induced APD lengthening curls waves into spirals","Biexcitability from stretch triggers spiral arrhythmias"],"cache_read_input_tokens":3200,"weakest_assumption_plain":"The load-bearing premise is that the abnormal one-dimensional relation — short diastolic interval produces longer action potential via the calcium-driven upstroke — also holds at the two-dimensional collision site in the full electromechanical model, where the paper does not directly measure it and where APD itself alters the strain distribution and conduction velocity.","fun_headline_variants_meta":{"raw":{"variants":["Stretch feedback twists heartbeats into spiral chaos","Heart muscle stretch spawns its own electrical storm","Mechano-electric loop turns beats into spiral waves","Stretch-induced APD lengthening curls waves into spirals","Biexcitability from stretch triggers spiral arrhythmias"]},"model":"deepseek-v4-flash","effort":"low","cost_usd":0.000483,"raw_usage":{"total_tokens":2316,"prompt_tokens":804,"completion_tokens":1512,"prompt_tokens_details":{"cached_tokens":384},"prompt_cache_hit_tokens":384,"prompt_cache_miss_tokens":420,"completion_tokens_details":{"reasoning_tokens":1434}},"tokens_in":420,"tokens_out":1512,"duration_ms":10472,"temperature":1.0,"reasoning_tokens":1434,"cache_read_input_tokens":384,"cache_creation_input_tokens":0},"cache_creation_input_tokens":0},"created_at":"2026-08-14T13:22:28.617253+00:00","model_set":{"reader":"deepseek-v4-flash"},"falsifier":"Record transmembrane voltage and calcium current at a collision site in a stretched cardiac tissue preparation while imposing a controlled front-tail interaction: if action potential duration still falls when diastolic interval shortens below the threshold at which the sodium upstroke fails, MEDI will not occur; if it rises as the upstroke becomes calcium-driven, the instability is confirmed.","supporting_citations":[{"cited_title":null,"cited_arxiv_id":null,"evidence_quote":"Supplies the moving-obstacle setup and the earlier finding that stretch-induced $I_{sac}$ accelerates wave fronts and produces wave front–tail collisions with biexcitability."},{"cited_title":"Ten Tusscher and A","cited_arxiv_id":null,"evidence_quote":"Provides the human epicardial ionic model whose sodium and calcium currents produce the upstroke transition central to MEDI."},{"cited_title":null,"cited_arxiv_id":null,"evidence_quote":"Supplies the excitation–contraction coupling and stretch-activated current parameters adjusted to human cardiac tissue used in the simulations."},{"cited_title":null,"cited_arxiv_id":null,"evidence_quote":"Provides the discrete mechanical model of cardiac tissue that couples deformation to the reaction–diffusion system."},{"cited_title":null,"cited_arxiv_id":null,"evidence_quote":"Establishes the mechano-electrical feedback context and the reported range of stretch-activated conductances $G_s$ used in the parameter study."},{"cited_title":"Qu and J","cited_arxiv_id":null,"evidence_quote":"Supports the claim that sodium channels are inactivated by accommodation at depolarized potentials, forcing the calcium-driven upstroke during collisions."},{"cited_title":"Vandersickel et al","cited_arxiv_id":null,"evidence_quote":"Documents the biexcitability phenomenon (coexistence of fast sodium-driven and slow calcium-driven propagation) in cardiac tissue."},{"cited_title":"Grill, V","cited_arxiv_id":null,"evidence_quote":"Supplies resonant drift theory used to explain the onset of spiral meander under periodically varying excitability due to MEF."}],"review_version":1}