Phase resetting in human stem cell derived cardiomyocytes explains complex cardiac arrhythmias

Q: What is the clinical evidence from this study?

Population: Premature ventricular complexes (PVCs) and parasystole (n=53). Intervention: Modulated parasystole modeling using optogenetically derived hiPSC-CM phase response curves. Primary outcome: Proportion of clinical multi-day Holter ECG recording inter-beat interval distributions reproduced by the modulated parasystole model (p=>0.05).

Khady Diagne; Thomas M. Bury; Morgan E Pettebone; Marc W. Deyell; Zachary Laksman; Alvin Shrier; Leon Glass; Gil Bub; Emilia Entcheva

doi:10.1371/journal.pcbi.1013935

February 4, 2026PLoS Computational BiologyOpen Access

Phase resetting in human stem cell derived cardiomyocytes explains complex cardiac arrhythmias

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Key result

Optogenetic human iPSC-CM parasystole models replicate up to ~95% of clinical PVC interval dynamics.

P>0.05
n=53

Key Points

To measure phase response curves in human stem cell-derived cardiomyocytes using optogenetic stimulation and determine whether phase resetting explains complex clinical arrhythmias.
Coupled spontaneously beating hiPSC-CM spheroids with light-responsive human embryonic kidney spheroids (N=6 pairs) and applied 10 ms periodic blue light pulses across multiple frequencies.
Recorded action potentials using the optical voltage sensor BeRST1 to generate experimental phase response curves and fit a piecewise-defined polynomial equation (RMSE = 0.056).
Modeled modulated parasystole by combining the experimental phase response curve with conduction delay (t_lag) and fit the equations to multi-day Holter ECG recordings from patients with frequent premature ventricular complexes (PVCs).
Across six hiPSC-CM pairs, spontaneous beating frequency ranged from 0.33 to 1.26 Hz and varied by about 18.5% over testing, with phase response curve discontinuities occurring between 0.38 and 0.71.
Light stimulation after the discontinuity produced cycle shortening characterized by a pronounced hook followed by a linear segment, confirming behavior consistent with a perturbed limit-cycle oscillator.
Adding a conduction delay to the phase response curve model reproduced the cycling coupling intervals and N:M locking ratios identified in 7 screened patients from a 53-patient PVC registry.

PICO

P

Population

53 patients with >5% premature ventricular complexes from the British Columbia PVC Registry (including 7 with parasystolic cycling coupling intervals) monitored via multi-day Holter ECG, alongside 6 in vitro hiPSC-CM spheroid pairs.

E

Exposure / Comparator

Modulated parasystole modeling using optogenetically derived hiPSC-CM phase response curves

O

Primary Outcome

Proportion of clinical multi-day Holter ECG recording inter-beat interval distributions reproduced by the modulated parasystole model, p=>0.05

Main Result

p-value: p=>0.05

Limitations

Spontaneous beating frequency across the six hiPSC-CM spheroid pairs varied by about 18.5% during the course of the experiment.
Small long-term effects of stimuli, measurement noise, and intrinsic biological noise caused spread around the fitted experimental PRC curve.
Ectopic beats are assumed in the model not to reset the sinus pacemaker due to refractory block at the AV node.
Reproducing rhythms across multi-day patient records required allowing model parameters to vary over time to account for non-stationary physiological fluctuations.

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Implication

Phase resetting elucidates cardiac arrhythmias in stem cell derived cardiomyocytes, suggesting therapy implications.

Abstract

Phase resetting of cardiac oscillators underlies some complex arrhythmias. Here we use optogenetic stimulation to construct phase response curves (PRC) for spheroids of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) and a computational cardiomyocyte model to identify ionic mechanisms shaping the PRC. The clinical utility of the human PRCs is demonstrated by adding a patient-based conduction delay to the same equations to explain complex multi-day Holter ECG dynamics and cardiac arrhythmias. Periodic stimulation of these patient-based models and the computational model of human iPSC-CM reveal similar bifurcation patterns and entrainment zones. Cell therapy by injecting iPSC-CM into diseased hearts can induce ectopic foci-based engraftment arrhythmias. The PRC analysis offers a potential strategy to entrain these foci in a parameter space that avoids such arrhythmias.

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Cite This Study

Diagne et al. (2026) studied Premature ventricular complexes (PVCs) and parasystole (n=53). Modulated parasystole modeling using optogenetically derived hiPSC-CM phase response curves was evaluated on Proportion of clinical multi-day Holter ECG recording inter-beat interval distributions reproduced by the modulated parasystole model (p=>0.05). Modulated parasystole models using optogenetically derived human iPSC-CM phase response curves reproduced 63.4% to 95.0% of inter-beat interval dynamics in patients with frequent PVCs (p>0.05).

synapsesocial.com/papers/698585db8f7c464f23009935 https://doi.org/10.1371/journal.pcbi.1013935

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Phase resetting in human stem cell derived cardiomyocytes explains complex cardiac arrhythmias

Key Points

PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Phase resetting in human stem cell derived cardiomyocytes explains complex cardiac arrhythmias

Key Points

PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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