Key result
FixR peptide selectively inhibits late sodium current and attenuates proarrhythmic triggers in failing cardiomyocytes.
Why the study?
Enhanced late Na+ current contributes to cardiomyocyte proarrhythmia in HF, and targeting FHF1-4 pathways modulating this current may provide benefits.
Does FixR prevent pathological late Na+ current and arrhythmogenic action potential changes in heart failure cardiomyocytes?
Does FixR prevent pathological late Na+ current and arrhythmogenic action potential changes in heart failure cardiomyocytes?
FixR, a novel FHF1A-derived peptide, potently and selectively inhibits pathological late sodium current, offering a promising antiarrhythmic strategy for both HFrEF and HFpEF.
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.
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Hegyi et al. (2026) studied Heart Failure. FixR (FHF1A-derived peptide) vs. Control (untreated or GFP-only vector) was evaluated on Late sodium current (INa,L) magnitude and arrhythmogenic action potential changes (p=<0.05). FixR, an FHF1A-derived peptide, potently and selectively inhibited pathogenic late sodium current and significantly attenuated proarrhythmogenic cellular mechanisms in failing cardiomyocytes.
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