Dataset DOI: 10.5061/dryad.83bk3jb7g

Description of the data and file structure

This dataset contains transcriptomic, electrophysiological (action potentials and ionic currents), morphometric, echocardiographic, and electrocardiographic (ECG) data in separate Excel sheets, with individual cell data and group statistics. The dataset is structured to follow the sequence of data presented in the Figures in the article entitled "Targeting arrhythmogenic late sodium current by FHF1_A-derivative FixR in heart failure cardiomyocytes" and to ease the navigation between the uploaded data files. For a full description of the materials and methods, including experimental procedures and instrumentation, please refer to the article on the Circulation Research journal website.

Files and variables

File: Fig1_data_FHF_expression.xlsx

Description: This file contains expression data of fibroblast growth factor homologous factor 1-4 (FHF1-4) splice isoforms and voltage-gated sodium channel subunits in human, rabbit, and mouse hearts. Sheet "Panel C" provides data for mRNA expression of FHF1-4 splice isoforms and voltage-gated Na⁺ channel subunits in non-failing control human, rabb^tand ^ouse h^arts relative to GAPDH. Sheet "Panel D" provides data on expression changes in human heart failure with reduced ejection fraction (HFrEF) normalized to non-failing control hearts.

Variables

• Fibroblast growth factor homologous factor 1-4 (FHF1-4) splice isoforms (FHF1A, FHF1B, FHF2S, FHF2U, FHF2V, FHF2Y, FHF2VY, FHF3, FHF4A, FHF4B)
• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
• Heart failure with reduced ejection fraction (HFrEF)
• Voltage-gated sodium channel subunits (NaV1.4, NaV1.5, NaV1.8, NaVβ, NaVβ4)

File: Fig2_data_FixR_HFrabbit_INaL.xlsx

Description: This file contains data on late sodium current (INa,L) regulation in rabbit heart failure with reduced ejection fraction (HFrEF) and age-matched control ventricles. Sheet “Panel A” provides morphometry data, including body weight (in kilograms), heart weight (in grams), heart weight to tibial length ratio (in grams per centimeter), lung weight (in grams), ejection fraction (EF, in %), left ventricular end-diastolic diameter (LV-EDD, in centimeters), and cardiomyocyte cell capacitance (in picofarads). Sheet “Panel B” provides mRNA expression data of FHF1-4 splice isoforms and voltage-gated sodium channel subunits in HFrEF rabbit hearts relative to age-matched controls. Sheet “Panel C” provides tetrodotoxin (TTX)-sensitivity data of INa, L under physiological action potential (AP)-clamp conditions in control and HFrEF ventricular cardiomyocytes. Sheet “Panel D” provides voltage-clamp INa, L density data normalized to cell capacitance at baseline and following fibroblast growth factor homologous factor 1A-mimicking peptide (FixR) treatment in control and HFrEF ventricular cardiomyocytes.

Variables

• Ejection fraction (EF), expressed in percentage
• Fibroblast growth factor homologous factor 1-4 (FHF1-4) splice isoforms (FHF1A, FHF1B, FHF2S, FHF2U, FHF2V, FHF2Y, FHF2VY, FHF3, FHF4A, FHF4B)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
• Heart failure with reduced ejection fraction (HFrEF)
• Late sodium current (INa, L, in amperes per farad)
• Left ventricular end-diastolic diameter (LV-EDD, in centimeters)
• Tetrodotoxin (TTX, in micromoles/liter)
• Voltage-gated sodium channel subunits (NaV1.4, NaV1.5, NaV1.8, NaVβ, NaVβ4)

File: Fig3_data_FixR_HFrabbit_AP.xlsx

Description: This file contains data on action potential (AP) remodeling in rabbit heart failure with reduced ejection fraction (HFrEF) and therapeutic efficacy of late sodium current inhibition by the FHF-inhibiting x region-mimicking synthetic peptide (FixR). Sheet “Panel A” provides AP duration at 90% repolarization (APD90, in milliseconds) data at baseline and following treatments with FixR, the selective late sodium current inhibitor GS967, and the selective Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide (AIP) at 1 Hz steady-state pacing frequency. Sheet “Panel B” provides short-term variability (STV, in milliseconds) of APD90 data at 1 Hz steady-state pacing frequency. Sheet “Panel C” provides frequency-dependence of APD90 and APD90 alternans data at 5 Hz steady-state pacing frequency. Sheet “Panel D” provides delayed afterdepolarizations (DADs) occurrence data following cessation of tachypacing.

Variables

• Action potential duration at 90% repolarization (APD90, in milliseconds)
• APD90 alternans magnitude (in milliseconds)
• Autocamtide-2-related inhibitory peptide (AIP)
• Delayed afterdepolarization (DAD)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart failure with reduced ejection fraction (HFrEF)
• Short-term variability of APD90 (STV, in milliseconds)

File: Fig4_data_FixR_HFmouse_INaL.xlsx

Description: This file contains data on late sodium current (INa,L) regulation in mouse heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Sheet “Panel A” provides morphometry data, including body weight (in grams), heart weight to tibial length ratio (in grams per centimeter), left ventricular mass (LV Mass, in grams), lung weight (wet to dry lung weight ratio), and ejection fraction (EF, in %). Sheet “Panel B” provides mRNA expression data of FHF1-4 splice isoforms and voltage-gated sodium channel subunits in HFrEF and HFpEF murine hearts relative to sham controls. Sheet “Panel D” provides data on voltage-clamp INa, L magnitude (in picoamperes) and INa, L density (in amperes per farad), when INa, L magnitude is normalized to cell capacitance (in picofarads) at baseline and following fibroblast growth factor homologous factor 1A-mimicking peptide (FixR) treatment in control, HFrEF, and HFpEF ventricular cardiomyocytes.

Variables

• Ejection fraction (EF), expressed in percentage
• Fibroblast growth factor homologous factor 1-4 (FHF1-4) splice isoforms (FHF1A, FHF1B, FHF2S, FHF2U, FHF2V, FHF2Y, FHF2VY, FHF3, FHF4A, FHF4B)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
• Heart failure with preserved ejection fraction (HFpEF)
• Heart failure with reduced ejection fraction (HFrEF)
• Late sodium current (INa, L)
• Voltage-gated sodium channel subunits (NaV1.4, NaV1.5, NaV1.8, NaVβ, NaVβ4)

File: Fig5_data_FixR_HFmouse_AP.xlsx

Description: This file contains data on action potential (AP) remodeling in mouse heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The therapeutic efficacy of late sodium current inhibition by the FHF-inhibiting x region-mimicking synthetic peptide (FixR) was studied. Sheet “Panel E” provides data on the frequency-dependence of AP duration at 90% repolarization (APD90, in milliseconds), APD90 at 1 Hz steady-state pacing frequency, and short-term variability of APD90 (STV, in milliseconds) in control and following FixR treatment. Sheet “Panel F” provides data on APD90 alternans magnitude (in milliseconds) at 10 Hz steady-state pacing frequency, and the frequency and occurrence of delayed afterdepolarizations (DADs) and spontaneous APs (sAPs) following cessation of tachypacing.

Variables

• Action potential duration at 90% repolarization (APD90, in milliseconds)
• APD90 alternans magnitude (in milliseconds)
• Delayed afterdepolarization (DAD)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart failure with preserved ejection fraction (HFpEF)
• Heart failure with reduced ejection fraction (HFrEF)
• Short-term variability of APD90 (STV, in milliseconds)
• Spontaneous action potential (sAP)

File: Fig6_data_FixR_CaMKII-TG_INaL-AP.xlsx

Description: This file contains data on late sodium current (INa, L) regulation and action potential (AP) alterations in mice with transgenic overexpression of CaMKII (CaMKII-TG). The therapeutic efficacy of INa, L inhibition by the FHF inhibiting x region-mimicking synthetic peptide (FixR) was studied. Sheet “Panel A” provides morphometry data, including body weight (in grams), heart weight (grams), heart weight to tibial length ratio (in grams per centimeter), lung weight (wet to dry lung weight ratio), and gastrocnemius and soleus muscle weight (in grams) in CaMKII-TG and wild-type (WT) littermate control mice. Sheet “Panel B” provides the Kaplan-Meier survival curve. Sheet “Panel C” provides mRNA expression data of CaMKII delta (CAMK2D), natriuretic peptide precursor A (NPPA), beta-myosin heavy chain (MYH7), FHF1-4 splice isoforms, and voltage-gated sodium channel subunits. Sheet “Panel E” provides data on cell capacitance (in picofarads) and INa, L density (in amperes per farad) in control and following fibroblast growth factor homologous factor 1A-mimicking peptide (FixR) treatment. Sheet “Panel G” provides data on AP duration at 90% repolarization (APD90, in milliseconds) and short-term variability of APD90 (STV, in milliseconds) at 1 Hz steady-state pacing frequency. Sheet “Panel I” provides data on APD90 alternans magnitude (in milliseconds) and the frequency of delayed afterdepolarization (DADs) and spontaneous APs (sAPs).

Variables

• Action potential duration at 90% repolarization (APD90, in milliseconds)
• APD90 alternans magnitude (in milliseconds)
• Beta-myosin heavy chain (MYH7)
• Ca/calmodulin-dependent protein kinase II (CaMKII)
• CaMKII delta gene (CAMK2D)
• CaMKII overexpressing transgenic mice (CaMKII-TG)
• Delayed afterdepolarization (DAD)
• Fibroblast growth factor homologous factor 1-4 (FHF1-4) splice isoforms (FHF1A, FHF1B, FHF2S, FHF2U, FHF2V, FHF2Y, FHF2VY, FHF3, FHF4A, FHF4B)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Late sodium current (INa, L)
• Natriuretic peptide precursor A (NPPA)
• Short-term variability of APD90 (STV, in milliseconds)
• Spontaneous action potential (sAP)
• Voltage-gated sodium channel subunits (NaV1.4, NaV1.5, NaV1.8, NaVβ, NaVβ4)

File: Fig7_data_FixR_CaMKII-TG_ECG.xlsx

Description: This file contains data on FixR in vivo application via retroorbital adeno-associated virus 9 (AAV9) delivery in mice with transgenic overexpression of CaMKII (CaMKII-TG). Sheet “Panel C” provides morphometry data, including heart weight to tibial length ratio (in grams per centimeter) and lung weight (wet to dry lung weight ratio) in CaMKII-TG and wild-type (WT) littermate control mice injected with FixR-AAV9 or GFP only. Sheet “Panel E” provides electrocardiogram (ECG) data on heart rate (in beats per minute) and QRS duration (in milliseconds). Sheet “Panel F” provides data on heart-rate corrected QT interval (QTc) and arrhythmia occurrence. Sheet “Panel G” provides data on heart rate (in beats per minute) and QRS duration (in milliseconds) in control and following isoproterenol (ISO) and caffeine (Caff) arrhythmia stress test. Sheet “Panel H” provides data on QTc interval and arrhythmogenic mortality during ISO + Caff arrhythmia stress test.

Variables

• Adeno-associated virus, isoform 9 (AAV9)
• Caffeine (Caff)
• Ca/calmodulin-dependent protein kinase II (CaMKII)
• CaMKII overexpressing transgenic mice (CaMKII-TG)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart rate (in beats per minute)
• Isoproterenol (ISO)
• QRS duration on electrocardiogram (in milliseconds)
• QT interval, heart rate-corrected (QTc, in milliseconds)

File: FigS1_data_FHF-NaV1.5_correlation.xlsx

Description: This file contains data on the correlation between key fibroblast growth factor homologous factor (FHF) isoforms and NaV1.5 expression in human, rabbit, and murine healthy control and failing hearts. Sheet “Panel A” provides data on the correlation between FHF1A and NaV1.5 as well as FHF1B and NaV1.5 in human non-failing and failing hearts. Sheet “Panel B” provides data on the correlation between FHF2S and NaV1.5, as well as FHF1B and NaV1.5 in rabbit control and failing hearts. Sheet “Panel C” provides data on the correlation between FHF2VY and NaV1.5 as well as FHF2Y and NaV1.5 in murine control, HFrEF, and HFpEF hearts.

Variables

• Fibroblast growth factor homologous factor (FHF) splice isoforms (FHF1A, FHF1B, FHF2S, FHF2Y, FHF2VY)
• Heart failure with preserved ejection fraction (HFpEF)
• Heart failure with reduced ejection fraction (HFrEF)
• Voltage-gated sodium channel NaV1.5

File: FigS2_data_FixR_INaT-ICaL.xlsx

Description: This file contains data on the FixR effect on the transient, fast sodium current (INa, T) and the L-type calcium current (ICa, L). Sheet “Panel A” provides data on the INa, T current-voltage (I-V) relationship, and the voltage-dependence of steady-state activation and inactivation in rabbit ventricular cardiomyocytes with and without FixR treatment. Sheet “Panel B” provides data on the ICa, L current-voltage (I-V) relationship, and the voltage-dependence of steady-state activation and inactivation in rabbit ventricular cardiomyocytes with and without FixR treatment.

Variables

• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• L-type calcium current (ICa, L, in amperes per farad)
• Transient, fast sodium current (INa, T, in amperes per farad)

File: FigS3_data_FixR_IK.xlsx

Description: This file contains data on the FixR effect on the major potassium currents in rabbit ventricular cardiomyocytes. Sheet “Panel A” provides data on the inward rectifier potassium current (IK1) measured under a voltage ramp protocol, and reports inward (at -150 mV) and outward (at -60 mV) IK1 densities (in amperes per farad). Sheet “Panel B” provides data on the transient outward potassium current (Ito) density (in amperes per farad) and voltage-dependence of Ito. Sheet “Panel C” provides data on the rapid delayed rectifier potassium current (IKr), and reports IKr tail current amplitude (in amperes per farad) and the voltage-dependence of IKr tail current. Sheet “Panel D” provides data on the slow delayed rectifier potassium current (IKs), and reports IKs tail current amplitude (in amperes per farad) and the voltage-dependence of IKs tail current.

Variables

• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Inward rectifier potassium current (IK1, in amperes per farad)
• Rapid delayed rectifier potassium current (IKr, in amperes per farad)
• Slow delayed rectifier potassium current (IKs, in amperes per farad)
• Transient outward potassium current (Ito, in amperes per farad)

File: FigS4_data_FixR_HFrabbit_ICaL-IK1.xlsx

Description: This file contains data on the FixR effect on the L-type calcium current (ICa, L) and the inward rectifier potassium current (IK1) in control and failing rabbit ventricular cardiomyocytes with and without FixR treatment. Sheet “Panel A” provides data on the ICa, L density (in amperes per farad) at +5 mV. Sheet “Panel B” provides data on the IK1 density (in amperes per farad) at -140 mV.

Variables

• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart failure with reduced ejection fraction (HFrEF)
• Inward rectifier potassium current (IK1, in amperes per farad)
• L-type calcium current (ICa, L, in amperes per farad)

File: FigS5_data_FIxR_HFrabbit_APparameters.xlsx

Description: This file contains data on the FixR effect on action potential (AP) parameters in control and failing rabbit ventricular cardiomyocytes with and without FixR treatment. Sheet “Panel A” provides data on AP duration at 20% and 50% repolarization (APD20 and APD50, respectively; both in milliseconds). Sheet “Panel B” provides data on maximal AP upstroke velocity (dV/dtmax, in volts per second) and resting membrane potential (RMP, in millivolts).

Variables

• Action potential duration at 20% repolarization (APD20, in milliseconds)
• Action potential duration at 50% repolarization (APD50, in milliseconds)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart failure with reduced ejection fraction (HFrEF)
• Maximal upstroke velocity (dV/dtmax, in volts per second)
• Resting membrane potential (RMP, in millivolts)

File: FigS6_data_FixR_APD90-BCL.xlsx

Description: This file contains data on the FixR effect on action potential (AP) duration at 90% repolarization (APD90, in milliseconds) measured at various steady-state basic pacing cycle length (BCL, in milliseconds). Sheet “Panel A” provides data on APD90 at each BCL in rabbit heart failure with reduced ejection fraction (HFrEF) and age-matched control ventricular myocytes with and without FixR treatment. Sheet “Panel B” provides data on APD90 at each BCL in mouse heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and sham controls.

Variables

• Action potential duration at 90% repolarization (APD90, in milliseconds)
• Basic pacing cycle length (BCL, in milliseconds)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart failure with preserved ejection fraction (HFpEF)
• Heart failure with reduced ejection fraction (HFrEF)

File: FigS7_data_FixR_HFmouse_APparameters.xlsx

Description: This file contains data on the FixR effect on action potential (AP) parameters in control, HFrEF, and HFpEF ventricular cardiomyocytes with and without FixR treatment. Sheet “Panel A” provides data on resting membrane potential (RMP, in millivolts), maximal AP upstroke velocity (dV/dtmax, in volts per second), and maximal repolarization velocity in phase 3 of the AP (-dV/dtmax, in volts per second). Sheet “Panel B” provides data on AP duration at 20%, 50%, and 75% repolarization (APD20, APD50, and APD75, respectively; all in milliseconds).

Variables

• Action potential duration at 20% repolarization (APD20, in milliseconds)
• Action potential duration at 50% repolarization (APD50, in milliseconds)
• Action potential duration at 75% repolarization (APD75, in milliseconds)
• FHF inhibiting x region-mimicking synthetic peptide (FixR)
• Heart failure with preserved ejection fraction (HFpEF)
• Heart failure with reduced ejection fraction (HFrEF)
• Maximal repolarization velocity in phase 3 (-dV/dtmax, in volts per second)
• Maximal upstroke velocity (dV/dtmax, in volts per second)
• Resting membrane potential (RMP, in millivolts)

Code/software

Microsoft Excel