May 28, 2026Circulation Research1 citations
Targeting Arrhythmogenic Late Sodium Current by FHF1 A -Derivative FixR in Heart Failure Cardiomyocytes
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Key Result
The FHF1A-derived peptide FixR significantly reduced pathological late Na+ current and attenuated proarrhythmogenic action potential changes in both HFrEF and HFpEF cardiomyocytes.
Key Points
- To investigate the role of FHF splice isoforms in modulating late sodium current (I Na,L) in heart failure cardiomyocytes.
- Used reverse-transcriptase quantitative polymerase chain reaction to analyze cardiac sodium channel and FHF isoforms in human and animal models of heart failure.
- Administered FixR to assess its effects on cardiomyocyte I Na,L and electrophysiological properties in rabbit and murine HFrEF models.
- Evaluated in vivo electrophysiology using adenoviral delivery in transgenic mice with CaMKIIδ C overexpression.
- Reduced expression of FHF long isoforms linked to enhanced I Na,L in failing hearts across species.
- FixR significantly reduced pathological I Na,L without affecting transient peak Na + current or major K + currents in rabbit myocytes.
- FixR showed antiarrhythmic effects, decreasing action potential duration and arrhythmia susceptibility in transgenic mice.
Structured PICO
Does FixR reduce pathological late Na+ current and proarrhythmogenic changes in heart failure cardiomyocytes?
P
Population
Human arrhythmogenic HFrEF samples, rabbit HFrEF models, murine HFrEF and HFpEF models, and transgenic mice with cardiomyocyte-specific overexpression of CaMKIIδC
I
Intervention
FixR (FHF inhibiting x region) cell-penetrating peptide (in vitro) and adenoviral delivery of FixR (in vivo)
C
Comparator
Untreated failing cardiomyocytes/mice
O
Outcome
Late Na+ current (INa,L) and proarrhythmogenic action potential changes (action potential duration, short-term variability, alternans susceptibility, delayed afterdepolarizations, QT prolongation, in vivo arrhythmia susceptibility)surrogate
FixR, an FHF1A-derived peptide, acts as a potent and selective late sodium current inhibitor with antiarrhythmic properties in preclinical models of heart failure.
Abstract
BACKGROUND: Enhanced late Na + current (I Na,L ) in heart failure (HF) contributes to cardiomyocyte proarrhythmia. In addition to CaMKII (Ca 2+ /calmodulin-dependent protein kinase II), FGF (fibroblast growth factor) homologous factors 1–4 (FHF1–4) also modulate I Na,L , and targeting these pathways may provide benefits in HF. METHODS: Reverse-transcriptase quantitative polymerase chain reaction analysis of cardiac Na + channel and FHF splice isoforms was performed in human arrhythmogenic HF with reduced ejection fraction (HFrEF) and in translational animal models of HFrEF and HF with preserved ejection fraction. We tested the effects of an FixR (FHF inhibiting x region) on cardiomyocyte I Na,L and electrophysiology in rabbit HFrEF and murine models of HFrEF and HF with preserved ejection fraction. We also tested the in vivo electrophysiological effects of FixR via adenoviral delivery in transgenic mice with cardiomyocyte-specific overexpression of CaMKIIδ C . RESULTS: Expression of key FHF long isoforms (FHF1 A in humans, FHF2 S in rabbits, and FHF2 VY in mice) that have inhibitory effects on I Na,L was reduced in human, rabbit, and murine failing hearts. I Na,L was markedly enhanced in both HFrEF and HF with preserved ejection fraction, and the FixR cell-penetrating peptide significantly reduced pathological I Na,L in both forms of HF. FixR had no effect on transient peak Na + current, L-type Ca 2+ current, or major K + currents in rabbit ventricular myocytes. FixR markedly attenuated proarrhythmogenic action potential changes (increased action potential duration, short-term variability, and alternans susceptibility) and delayed afterdepolarizations in both rabbit and murine failing cardiomyocytes. These cellular antiarrhythmic effects were mimicked by the selective I Na,L inhibitor GS967 and the CaMKII inhibitor AIP (autocamtide-2 inhibitory peptide). FixR also attenuated QT prolongation and in vivo arrhythmia susceptibility in transgenic mice with cardiomyocyte-specific overexpression of CaMKIIδ C . CONCLUSIONS: In HF, I Na,L is increased, and FHF splice isoform expression is altered, allowing a novel mechanism to therapeutically target I Na,L . FixR, an FHF1 A -derived peptide, is a potent and selective I Na,L inhibitor and has antiarrhythmic properties in both HFrEF and HF with preserved ejection fraction cardiomyocytes.
Cite This Study
Hegyi et al. (2026) studied Heart failure (HFrEF and HFpEF). FixR (FHF inhibiting x region) cell-penetrating peptide was evaluated on Late Na+ current (INa,L) and electrophysiological properties. The FHF1A-derived peptide FixR significantly reduced pathological late Na+ current and attenuated proarrhythmogenic action potential changes in both HFrEF and HFpEF cardiomyocytes.