Multichannel Dysfunction Associated With a Dominant-Negative KCNH2 Missense Variant, p.G604S, Results in Action Potential Duration Prolongation and Early Afterdepolarizations in a Patient-Specific, Reengineered Cardiomyocyte Model of Type 2 Long-QT Syndrome

Q: What are the key findings of this study?

The KCNH2-G604S variant severely prolonged action potential duration (765 vs 368 ms; P<0.005) in patient-specific iPSC-CMs through primary IKr loss-of-function and secondary persistent ICa,L.

Q: What is the clinical evidence from this study?

Population: Type 2 long-QT syndrome. Intervention: KCNH2-G604S variant vs. variant-corrected isogenic control iPSC-CMs. Primary outcome: action potential duration at 90% repolarization (APD90) (p=<0.005).

Q: What does this research mean for the field?

The KCNH2-G604S variant causes a severe type 2 long-QT syndrome phenotype through primary I_Kr loss-of-function synergistically amplified by secondary persistent L-type calcium current (I_Ca,L) gain-of-function. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To determine whether secondary inward-current remodeling amplifies electrophysiological dysfunction in patient-derived cardiomyocytes carrying the KCNH2-G604S variant of type 2 long-QT syndrome.

Trung Huynh; Dan Ye; Wei Zhou; David J. Tester; Ramin Garmany; John R. Giudicessi; Michael John Ackerman

doi:10.1161/circep.126.014919

October 12, 2026Circulation Arrhythmia and Electrophysiology

Multichannel Dysfunction Associated With a Dominant-Negative KCNH2 Missense Variant, p.G604S, Results in Action Potential Duration Prolongation and Early Afterdepolarizations in a Patient-Specific, Reengineered Cardiomyocyte Model of Type 2 Long-QT Syndrome

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Key result

KCNH2-G604S variant prolongs action potential duration ~2-fold in iPSC-CMs via IKr loss and persistent ICa,L.

P<0.005

Why the study?

The contribution of secondary inward-current dysfunction to the pathophysiology of type 2 long-QT syndrome caused by KCNH2 loss-of-function remains unclear.

Key Points

To determine whether secondary inward-current remodeling amplifies electrophysiological dysfunction in patient-derived cardiomyocytes carrying the KCNH2-G604S variant of type 2 long-QT syndrome.
Generated patient-specific KCNH2-G604S and CRISPR-corrected isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
Measured action potential duration (APD90), potassium current (IKr), late sodium current (INa,L), and L-type calcium current (ICa,L) via whole-cell patch-clamp, alongside calcium transient imaging.
Integrated experimental current data into a modified Kernik-Clancy computational model of iPSC-CMs to simulate single and combined ion channel defects.
The KCNH2-G604S variant reduced IKr by 72.5% and prolonged APD90 to 765±58 ms compared to 368±37 ms in isogenic controls (P<0.005), inducing early afterdepolarizations in 50% of variant cells.
G604S cells exhibited higher INa,L (0.60±0.1% vs 0.26±0.06%; P<0.01), increased persistent ICa,L (2.88±0.55% vs 1.26±0.35%; P<0.05), and delayed calcium transient decay (P<0.0001), all mitigated by calcium and sodium blockers.
In silico simulations showed IKr reduction alone extended APD90 to only 620 ms, whereas incorporating persistent ICa,L synergistically lengthened APD90 to 758 ms and disrupted intracellular calcium handling.

Structured PICO

P

Population

KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)

E

Exposure

KCNH2-G604S dominant-negative missense variant

C

Comparator

Variant-corrected isogenic control iPSC-CMs

O

Outcome

Action potential duration at 90% repolarization (APD90)surrogate

Main Result

Absolute Event Rate: 765% vs 368%

p-value: p=<0.005

In a patient-specific iPSC-CM model of Type 2 Long-QT syndrome, the KCNH2-G604S variant drives extreme action potential prolongation through both primary IKr loss-of-function and a secondary increase in persistent calcium current.

Implication

Secondary ICa,L remodeling may amplify LQT2 repolarization defects; hypothesis-generating for combined channel blockade in patient-derived models.

Abstract

BACKGROUND: Type 2 long-QT syndrome results from KCNH2 -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear. METHODS: We characterized sodium ( SCN5A , I Na ) and L-type calcium channel ( CACNA1C , I Ca ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I Kr ), sodium (I Na ), and calcium (I Ca, L ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I Na,L and I Ca,L fractions and simulated isolated and combined current defects. RESULTS: KCNH2-G604S caused severe I Kr loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765±58 ms) compared with isogenic controls (368±37 ms; P <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I Na,L (0.60±0.1% versus 0.26±0.06%; P <0.01), persistent I Ca,L (2.88±0.55% versus 1.26±0.35%; P <0.05), and calcium transient decay times ( P <0.0001) were greater in G604S iPSC-CMs. Increased persistent I Ca,L was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I Kr defect alone prolonged APD90 to only 620 ms. The addition of the observed I Na,L defect had a small additive effect (+20 ms); however, incorporating persistent I Ca,L synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca 2+ entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability. CONCLUSIONS: The KCNH2-G604S variant drives a severe multihit phenotype via primary I Kr loss-of-function and secondary state-dependent gain-of-function in persistent I Ca,L . These comprehensive validations demonstrate that the remodeled persistent I Ca,L acts as the essential amplifier driving extreme action potential duration prolongation and Ca 2+ mishandling.

Discussion

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Cite This Study

Huynh et al. (2026) studied Type 2 long-QT syndrome. KCNH2-G604S variant vs. variant-corrected isogenic control iPSC-CMs was evaluated on action potential duration at 90% repolarization (APD90) (p=<0.005). The KCNH2-G604S variant severely prolonged action potential duration (765 vs 368 ms; P<0.005) in patient-specific iPSC-CMs through primary IKr loss-of-function and secondary persistent ICa,L.

synapsesocial.com/papers/6ace6e0db52af824ab02bcf0 https://doi.org/10.1161/circep.126.014919

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Multichannel Dysfunction Associated With a Dominant-Negative KCNH2 Missense Variant, p.G604S, Results in Action Potential Duration Prolongation and Early Afterdepolarizations in a Patient-Specific, Reengineered Cardiomyocyte Model of Type 2 Long-QT Syndrome

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

Multichannel Dysfunction Associated With a Dominant-Negative KCNH2 Missense Variant, p.G604S, Results in Action Potential Duration Prolongation and Early Afterdepolarizations in a Patient-Specific, Reengineered Cardiomyocyte Model of Type 2 Long-QT Syndrome

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

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