Misinterpretation of the mouse ECG: ‘musing the waves of <i>Mus musculus</i>’

Boukens, Bastiaan J.; Rivaud, Mathilde R.; Rentschler, Stacey; Coronel, Ruben

doi:10.1113/jphysiol.2014.279380

Cited by 114 publications

(127 citation statements)

References 89 publications

Supporting

Mentioning

116

Contrasting

Order By: Relevance

“…AP recordings in WT mice demonstrated a higher V max and APD in myocytes from subendocardium compared with subepicardium (P<0.05; Figure 4A and 4C). These transmural differences were diminished in Hey2 +/− mice (Figure 4B and 4D; P<0.05 interaction effect for V max and APD 90 ; P=0.1 and P=0.07 interaction effect for APD 20 and APD 50 , respectively) because of an increase in subepicardium in Hey2 +/− compared with WT mice (P<0.01 for V max , APD 20 , APD 50 , and APD 90 ; Online Table IV). Heterozygous loss of Hey2, thus, affects both depolarization and repolarization specifically in the subepicardium layer.…”

Section: Hey2 Affects Repolarization and Depolarization Specifically mentioning

confidence: 99%

“…Of note, this observation was consistent in both lead I and II ( Figure 3A), and the difference in J-wave derivative between WT and Hey2 +/− was independent of lead (2-way ANOVA). Because the murine J wave is an expression of early repolarization 20 ; this indicated that early repolarization may differ between the WT and Hey2 +/− animals. To further investigate this, we recorded APs from cardiomyocytes isolated from the subepicardium and subendocardium of the RV (implicated in the pathophysiology of BrS [21][22][23] ) from both WT and Hey2 +/− mice (Figure 4A and 4B; Online Table IV).…”

Section: Hey2 Affects Repolarization and Depolarization Specifically mentioning

confidence: 99%

“…APs were elicited at 4 Hz by 3 ms, 1.2× threshold current pulses. The following parameters were assessed: resting membrane potential, maximum upstroke velocity (V max ), AP amplitude, and AP duration (APD) at 20%, 50%, and 90% of repolarization (APD 20 , APD 50 , and APD 90 , respectively). Data from 10 consecutive APs were averaged.…”

Section: Ap Measurementsmentioning

confidence: 99%

See 2 more Smart Citations

The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity

Veerman

Podliesna

Tadros

et al. 2017

Circulation Research

Self Cite

View full text Add to dashboard Cite

Rationale: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2 ) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved. Objective: We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in Hey2 +/− ( Hey2 heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome. Methods and Results: We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for cis -expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (β=+0.159; P =0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2 , which uncovered KCNIP2 , encoding the β-subunit of the channel underlying the transient outward current ( I to ), as the transcript most robustly correlating with HEY2 expression (β=+1.47; P =2×10 −34 ). Transcript abundance of Hey2 and the I to subunits Kcnip2 and Kcnd2 , assessed by quantitative reverse transcription–polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2 +/− mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2 +/− mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower V max in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher I to and a lower sodium current ( I Na ) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2 +/− mice because of changes in subepicardial cardiomyocytes. Conclusions: This study uncovers a role of HEY2 in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a HEY2 -dependent alteration of ion channel expression across the cardiac ventricular wall.

show abstract

Section: Hey2 Affects Repolarization and Depolarization Specifically mentioning

confidence: 99%

Section: Hey2 Affects Repolarization and Depolarization Specifically mentioning

confidence: 99%

See 1 more Smart Citation

The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity

Veerman

Podliesna

Tadros

et al. 2017

Circulation Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cardiac activity is known to differ between humans and experimental animals. Beating rate and electrocardiogram results differ greatly between species, as do the molecular mechanisms of repolarization and expression of various genes and proteins (Boukens et al, 2014;Denning et al, 2016). These cause differences in each species' tolerance to chemical agents (Price et al, 2008), and might yield false-positive or -negative results when human toxicity is evaluated using experimental animals and cells.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac hazards, such as the threshold value for ventricular fibrillation, have been evaluated by magnetic or electrical stimulation of experimental animals (Elmas et al, 2012;Fozzard and Schoenberg, 1972;Mouchawar et al, 1989), and data from animal studies have been applied to humans after adjusting for body size (Geddes et al, 1973). However, theoretical models are limited in their ability to predict human responses, as it is known that many aspects of fundamental cardiac activity, such as beating rate and electrocardiogram results (Boukens et al, 2014;Denning et al, 2016), differ between species. Although some human studies have been reported, the strength of EMF exposure was sufficiently low to be safe (Cook et al, 1992;Korpinen et al, 1993;Graham et al, 1994;Korpinen and Partanen, 1994), and limited experimental data are available for direct evaluation of human effects.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the effects of power-frequency magnetic fields on the electrical activity of cardiomyocytes differentiated from human induced pluripotent stem cells

et al. 2017

View full text Add to dashboard Cite

-Although cardiac activity is known to differ between species in many respects, most evaluations of the cardiac effects of low-frequency electric and magnetic fields, which have a stimulant effect on electrically activated cells, have been performed in non-human experimental animals and cells, and the effects in humans have been assessed using theoretical models. In recent years, it has been verified that human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPS-CM) are useful for evaluating human responses to various cardioactive compounds. In this study, we applied hiPSCMs for the first time to evaluate the human cardiac effects of power-frequency magnetic fields (MFs). After preparation of hiPS-CMs, we subjected a hiPS-CM monolayer formed on a multi-electrode array to short-term exposure to a 50 Hz MF at 400 mT with recording of the extracellular field potentials. The field potential duration of the hiPS-CMs did not differ significantly pre-and post-exposure, indicating that under these conditions, exposure to a 50 Hz MF at 400 mT does not affect the electrical activity of hiPSCMs.

show abstract

Pericardial delta like non‐canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition

Jensen,

Johnsen,

Eskildsen

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundHeart failure due to myocardial infarction (MI) involves fibrosis driven by epicardium‐derived cells (EPDCs) and cardiac fibroblasts, but strategies to inhibit and provide cardio‐protection remains poor. The imprinted gene, non‐canonical NOTCH ligand 1 (Dlk1), has previously been shown to mediate fibrosis in the skin, lung and liver, but very little is known on its effect in the heart.MethodsHerein, human pericardial fluid/plasma and tissue biopsies were assessed for DLK1, whereas the spatiotemporal expression of Dlk1 was determined in mouse hearts. The Dlk1 heart phenotype in normal and MI hearts was assessed in transgenic mice either lacking or overexpressing Dlk1. Finally, in/ex vivo cell studies provided knowledge on the molecular mechanism.ResultsDlk1 was demonstrated in non‐myocytes of the developing human myocardium but exhibited a restricted pericardial expression in adulthood. Soluble DLK1 was twofold higher in pericardial fluid (median 45.7 [34.7 (IQR)) μg/L] from cardiovascular patients (n = 127) than in plasma (median 26.1 μg/L [11.1 (IQR)]. The spatial and temporal expression pattern of Dlk1 was recapitulated in mouse and rat hearts. Similar to humans lacking Dlk1, adult Dlk1−/− mice exhibited a relatively mild developmental, although consistent cardiac phenotype with some abnormalities in heart size, shape, thorax orientation and non‐myocyte number, but were functionally normal. However, after MI, scar size was substantially reduced in Dlk1−/− hearts as compared with Dlk1+/+ littermates. In line, high levels of Dlk1 in transgenic mice Dlk1fl/flxWT1GFPCre and Dlk1fl/flxαMHCCre/+Tam increased scar size following MI. Further mechanistic and cellular insight demonstrated that pericardial Dlk1 mediates cardiac fibrosis through epithelial to mesenchymal transition (EMT) of the EPDC lineage by maintaining Integrin β8 (Itgb8), a major activator of transforming growth factor β and EMT.ConclusionsOur results suggest that pericardial Dlk1 embraces a, so far, unnoticed role in the heart augmenting cardiac fibrosis through EMT. Monitoring DLK1 levels as well as targeting pericardial DLK1 may thus offer new venues for cardio‐protection.

show abstract

Misinterpretation of the mouse ECG: ‘musing the waves of Mus musculus’

Cited by 114 publications

References 89 publications

The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity

The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity

Evaluation of the effects of power-frequency magnetic fields on the electrical activity of cardiomyocytes differentiated from human induced pluripotent stem cells

Pericardial delta like non‐canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition

Contact Info

Product

Resources

About