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September 18, 2026Heart Rhythm O2Open Access

The long QT syndrome type 2-associated Kv11.1 R56Q+/- variant induces discordant alternans and premature activity in human stem cell-derived cardiomyocyte monolayers

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Population

CRISPR-edited human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers

Design

Preclinical

Key result

The hERG R56Q+/- variant introduces beat-to-beat heterogeneity in APD and spatially discordant alternans, increasing susceptibility to re-entrant arrhythmias without prolonging average steady-state APD.

Authors

PMPadmapriya MuralidharanDSDiya SehgalAAAlia Arslanova

Discussion

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Overview

May underlie arrhythmia risk in LQTS carriers without QT prolongation; hypothesis-generating in hiPSC models pending clinical validation.

Key Points

  • Investigate the cellular mechanisms underlying arrhythmogenesis driven by the hERG R56Q+/- variant of uncertain clinical significance in human cardiomyocyte monolayers.
  • Generated and evaluated CRISPR-edited human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers carrying the heterozygous hERG R56Q variant.
  • Measured steady-state beat-to-beat membrane voltage and cytoplasmic calcium dynamics under imposed rate pacing using multi-electrode array and optical mapping platforms.
  • The hERG R56Q+/- variant preserved average steady-state action potential duration (APD) but generated marked beat-to-beat APD heterogeneity.
  • Treated monolayers developed spatially discordant alternans, steeper electrical restitution curves, and elevated rates of premature electrical activity predisposing to re-entrant arrhythmias.

Structured PICO

P
Population
CRISPR-edited human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers
I
Intervention
hERG channel variant R56Q +/-
O
Outcome
Steady-state beat-to-beat membrane voltage and cytoplasmic calcium dynamics and their adaptations to imposed rate changessurrogate

The hERG R56Q+/- variant promotes arrhythmogenesis through beat-to-beat APD heterogeneity and spatially discordant alternans rather than average APD prolongation, providing a mechanism for sudden arrest risk in LQTS.

Cite This Study

Muralidharan et al. (2026) studied Long QT Syndrome (LQTS). hERG channel variant R56Q+/- was evaluated on Arrhythmia mechanisms (beat-to-beat heterogeneity in APD and spatially discordant alternans). The hERG R56Q+/- variant introduces beat-to-beat heterogeneity in APD and spatially discordant alternans, increasing susceptibility to re-entrant arrhythmias without prolonging average steady-state APD.

synapsesocial.com/papers/6aacf5ed0c46fbdff987dd36https://doi.org/10.1016/j.hroo.2026.09.003
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