Role of Galphaq signaling in heart failure-related atrial fibrillation - AHA dataset
Data files
Sep 14, 2026 version files 112.13 KB
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Activation_map_analysis_conduction_velocity_Gaq_scr_-_dryad.csv
1.57 KB
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Activation_map_analysis_inhomogeneity_index_Gaq_scr_-_dryad.csv
1.25 KB
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AF_duration_data_Gaq_Scr_-_dryad.csv
9.44 KB
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AF_inducibility_data_Gaq_Scr_-_dryad.csv
775 B
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Atrial_ERP_Gaq_Scr_-_dryad.csv
867 B
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Ca_imaging_demographics_-_dryad.csv
969 B
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clinical_HF_score.xlsx
9.48 KB
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HF_canine_atrial_myocyte_TCW_density_-_dryad.csv
39.44 KB
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HF_Gaq_scr_demographics_-_dryad.csv
2.24 KB
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HF_Gaq_scr_trichrome_quantification_-_dryad.csv
576 B
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normal_TCW_density_-_dryad.csv
37.03 KB
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README.md
8.48 KB
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia, and highly prevalent in patients suffering from heart failure. It is associated with significant morbidity and mortality, being a leading cause of stroke. AF is a multifactorial disease, with chronic insults leading to progressive changes in the myocardium with electrical, structural and autonomic remodeling. Endothelial dysfunction is a hallmark of most risk factors for AF including heart failure. While multiple studies showed an association between endothelial dysfunction and AF, the causal relationship remains unknown. Endothelin-1 (ET-1) and downstream protein Gαq are markedly upregulated in the atria of patients with heart failure. As ET-1-Gαq signaling was previously shown to affect both Ca2+ signaling and fibrosis, we hypothesize that ET-1-Gαq signaling contributes to AF in heart failure through a dual mechanism, by promoting both conduction inhomogeneity and arrhythmogenic triggered calcium waves. Our work showed that inhibition of Gαq signaling in a canine heart failure model could attenuate AF inducibility, and conduction inhomogeneity in vivo, predominantly in the posterior left atrium. This corresponded to an attenuation in interstitial fibrosis in the same region. In isolated myocytes, development of triggered calcium waves was favored by exposure to ET-1, which was attenuated by inhibition of Gαq signaling and downstream IP3R signaling. In conclusion, ET-1-Gαq-signaling promotes AF in HF through a dual mechanism, by increasing arrhythmogenic triggered calcium waves and promoting conduction inhomogeneity. Future optimization of gene therapy targeting ET-1 signaling may lead to novel, mechanism-guided treatments for AF in the context of HF. This repository contains two datasets related to AHA Career Development Award 941300: The first dataset includes animal demographics, atrial activation map analysis, atrial ERPs, AF inducibility, and Trichrome Masson quantification. The second dataset includes animal demographics, and triggered calcium wave quantification.
Dataset DOI: 10.5061/dryad.8sf7m0d5b
Description of the data and file structure
The goal of this project was to determine the role of ET-1-Gaq signaling in the development of HF-associated arrhythmogenic atrial remodeling.
For in vivo electrophysiology, plasmids expressingGq inhibitory peptides (Gq-ct) or scrambled sequence were injected and electroporated epicardially in the canine left atrium (n = 6 for Gq-ct and 15 for control). Heart failure was then induced by ventricular tachypacing (VTP) for 3 weeks. At terminal EP study, left atrial conduction vectors were recorded with high-density mapping, regional atrial effective refractory periods (ERPs) and AF inducibility were assessed. Atrial tissue was cryopreserved and fibrosis quantified by Masson Trichrome.
For in vitro electrophysiology, atrial myocytes were isolated from normal animals or after induction of heart failure by 3 weeks of VTP (n = 5 for normal, n = 6 for HF). Myocytes were treated with combinations of cell-permeable Gq-ct (cp-Gq-ct), cell-permeable scrambled peptide (cp-scr), ET-1, the IP3 receptor antagonist 2-APB, and/or DAG agonist PMA prior to confocal line-scan Ca2+ imaging with a Ca2+ sensitive dye and field stimulation at cycle lengths 1000ms to 200ms. We recorded the density of triggered calcium waves (TCW, 1/s) at cycle lengths 500 ms, 400 ms, 300 ms, and 200 ms.
Files and variables
File: clinical_HF_score.xlsx
Description: Metrics for the clinical HF score used in the files HF_Gaq_scr_demographics_-dryad and Ca_imaging_demographics-_dryad
Variables
- HF score metrics, associated score
File: HF_Gaq_scr_demographics_-_dryad.csv
Description: Demographics of animals used for gene injection of plasmids expressing the Gaq inhibitory peptide (Gaq-ct) or a scrambled sequence.
Variables
- name: animal identifier
- experimental group: heart failure (HF) Gaq-ct, or HF control (scrambled)
- DOB: date of birth
- weight: in kg
- sex (F): F = 1, M = 0
- age (years): age
- gene injection: date of gene injection
- start RVP: date of initiation of right ventricular pacing (RVP)
- terminal: terminal date
- pacing duration (days): pacing duration
- baseline LVEF (%): baseline left ventricular ejection fraction (%). If not performed, noted n.a.
- terminal LVEF (%): terminal left ventricular ejection fraction (%) If not performed, noted n.a.
- clinical HF score: clinical heart failure score, as detailed in separate file titled clinical_HF_score
- Conduction vectors (available): 1 = available, 0 = not available
- AF inducibility (available):1 = available, 0 = not available
- Atrial ERPs (available):1 = available, 0 = not available
- Tissue (available):1 = available, 0 = not available
File: Ca_imaging_demographics_-_dryad.csv
Description: Demographics of animals used for atrial cardiomyocyte cell isolation and single cell calcium imaging.
Variables
- Identifier: animal identifier
- experimental group: control (normal) or right ventricular pacing-induced heart failure
- DOB: date of birth
- weight: in kg
- sex (F): F = 1, M = 0
- age (years): age
- start RVP: date of initiation of right ventricular pacing. n.a. for control animals.
- terminal: terminal date.
- pacing duration (days): pacing duration. n.a. for control animals.
- baseline LVEF (%): baseline left ventricular ejection fraction (%). If not performed, noted n.a.
- terminal LVEF (%): terminal left ventricular ejection fraction (%). If not performed, noted n.a.
- clinical HF: clinical heart failure score, as detailed in separate file titled clinical_HF_score
File: AF_duration_data_Gaq_Scr_-_dryad.csv
Description: AF duration at EP terminal for animals described in "HF_Gaq_scr_demographics_-_dryad".
Variables
- Animal: identifier
- Experimental group: HF Gaq-ct or HF control
- AF duration (seconds): AF duration of each single episode
- censored (cardioverted): if data is censored, labeled as 1. If not censored (spontaneous termination), labeled as 0
File: AF_inducibility_data_Gaq_Scr_-_dryad.csv
Description: AF inducibility at EP terminal for animals described in "HF_Gaq_scr_demographics_-_dryad".
Variables
- Animal: identifier
- Experimental group: HF Gaq-ct or HF control
- Total # of AF episodes: total number of AF episodes, defined as any AF > 3 seconds
- Mean AF duration (sec): mean duration of any induced AF episode
- Pacing attempts: number of pacing attempts
- AF inducibility: number of AF episodes / number of pacing attempts
File: HF_Gaq_scr_trichrome_quantification_-_dryad.csv
Description: Left atrial interstitial fibrosis in animals described in "HF_Gaq_scr_demographics_-_dryad".
Variables
- Region: PLA = posterior left atrium; LAFW = left atrial free wall; LAA = left atrial appendage
- Experimental group: HF Gaq-ct or HF control
- PLA: interstitial fibrosis (%) in PLA
- LAFW: interstitial fibrosis (%) in LAFW
- LAA: interstitial fibrosis (%) in LAA
File: HF_canine_atrial_myocyte_TCW_density_-_dryad.csv
Description: Triggered calcium wave (TCW) density in single atrial cardiomyocytes of animals after VTP-induced heart failure described in "Ca_imaging_demographics_-_dryad".
Variables
- animal: identifier
- TCW density (1/s): triggered calcium wave density
- condition: experimental condition
- PCL (ms): paced cycle length
File: normal_TCW_density_-_dryad.csv
Description: Triggered calcium wave (TCW) density in single atrial cardiomyocytes of normal animals described in "Ca_imaging_demographics_-_dryad".
Variables
- animal: identifier
- TCW density (1/s): triggered calcium wave
- condition: experimental condition
- PCL (ms): paced cycle length
File: Activation_map_analysis_inhomogeneity_index_Gaq_scr_-_dryad.csv
Description: Left atrial inhomogeneity index during atrial pacing at terminal study of animals described in "HF_Gaq_scr_demographics_-_dryad".
Variables
- Region - PCL: PLA = posterior left atrium; LAFW = left atrial free wall; LAA = left atrial appendage; and paced cycle length (PCL) in ms
- Experimental group: HF Gaq-ct or HF control
- LAFW 400 ms: inhomogeneity index for left atrial free wall at PCL 400 ms
- LAFW 300 ms: inhomogeneity index for left atrial free wall at PCL 300 ms
- LAFW 200 ms: inhomogeneity index for left atrial free wall at PCL 200 ms
- PLA 400 ms: inhomogeneity index for posterior left atrium at PCL 400 ms
- PLA 300 ms: inhomogeneity index for posterior left atrium at PCL 300 ms
- PLA 200 ms: inhomogeneity index for posterior left atrium at PCL 200 ms
- LAA 400 ms: inhomogeneity index for left atrial appendage at PCL 400 ms
- LAA 300 ms: inhomogeneity index for left atrial appendage at PCL 300 ms
- LAA 200 ms: inhomogeneity index for left atrial appendage at PCL 200 ms
File: Activation_map_analysis_conduction_velocity_Gaq_scr_-_dryad.csv
Description: Left atrial conduction velocity (in m/s) during atrial pacing at terminal study of animals described in "HF_Gaq_scr_demographics_-_dryad".
Variables
- Region - PCL: PLA = posterior left atrium; LAFW = left atrial free wall; LAA = left atrial appendage; and paced cycle length (PCL) in ms
- Experimental group: HF Gaq-ct or HF control
- LAFW 400 ms: conduction velocity for left atrial free wall at PCL 400 ms
- LAFW 300 ms: conduction velocity for left atrial free wall at PCL 300 ms
- LAFW 200 ms: conduction velocity for left atrial free wall at PCL 200 ms
- PLA 400 ms: conduction velocity for posterior left atrium at PCL 400 ms
- PLA 300 ms: conduction velocity for posterior left atrium at PCL 300 ms
- PLA 200 ms: conduction velocity for posterior left atrium at PCL 200 ms
- LAA 400 ms: conduction velocity for left atrial appendage at PCL 400 ms
- LAA 300 ms: conduction velocity for left atrial appendage at PCL 300 ms
- LAA 200 ms: conduction velocity for left atrial appendage at PCL 200 ms
File: Atrial_ERP_Gaq_Scr_-_dryad.csv
Description: Left atrial effective refractory period (ERP) at terminal study of animals described in "HF_Gaq_scr_demographics_-_dryad".
Variables
- Animal: identifier
- Region: PLA = posterior left atrium; LAA = left atrial appendage
- ERP (ms) at BCL 400 ms: effective refractory period (ms) at basic cycle length 400 ms
For in vivo electrophysiology, plasmids expressing Gαq inhibitory peptides (Gαq-ct) or scrambled sequence were injected and electroporated epicardially in the canine left atrium (n = 6 for Gαq-ct and 15 for control). Heart failure was then induced by ventricular tachypacing (VTP) for 3 weeks. At terminal EP study, left atrial conduction vectors were recorded with high-density mapping, regional atrial effective refractory periods (ERPs) and AF inducibility were assessed. Atrial tissue was cryopreserved and fibrosis quantified by Masson Trichrome.
For in vitro electrophysiology, atrial myocytes were isolated from normal animals or after induction of heart failure by 3 weeks of VTP (n = 4 for each). Myocytes were treated with combinations of cell-permeable Gαq-ct (cp-Gαq-ct), cell-permeable scrambled peptide (cp-scr), ET-1, the IP3 receptor antagonist 2-APB, and/or DAG agonist PMA prior to confocal line-scan Ca2+ imaging with a Ca2+ sensitive dye and field stimulation at cycle lengths 1000ms to 200ms.