Intracardiac electrophysiology to characterize susceptibility to ventricular arrhythmias in murine models

Introduction: Sudden cardiac death (SCD) and ventricular fibrillation are rare but severe complications of many cardiovascular diseases and represent a major health issue worldwide. Although the primary causes are often acute or chronic coronary diseases, genetic conditions, such as inherited channelopathies or non-ischemic cardiomyopathies are leading causes of SCD among the young. However, relevant experimental models to study the underlying mechanisms of arrhythmias and develop new therapies are still needed. The number of genetically engineered mouse models with cardiac phenotype is growing, making electrophysiological studies in mice essential tools to study arrhythmogenicity and arrhythmia mechanisms and to test novel treatments. Recently, intracardiac catheterization via the jugular vein was described to induce and record ventricular arrhythmias in living anesthetized mice. Several strategies have been reported, developed in healthy wild-type animals and based on aggressive right ventricular stimulation.Methods: Here, we report a protocol based on programmed electrical stimulation (PES) performed in clinical practice in patients with cardiac rhythm disorders, adapted to two transgenic mice models of arrhythmia - Brugada syndrome and cardiolaminopathy.Results: We show that this progressive protocol, based on a limited number of right ventricular extrastimuli, enables to reveal different rhythmic phenotypes between control and diseased mice. In this study, we provide detailed information on PES in mice, including catheter positioning, stimulation protocols, intracardiac and surface ECG interpretation and we reveal a higher susceptibility of two mouse lines to experience triggered ventricular arrhythmias, when compared to control mice.Discussion: Overall, this technique allows to characterize arrhythmias and provides results in phenotyping 2 arrhythmogenic-disease murine models

The nature of high [O iii ]88 μ m/[C ii ]158 μm galaxies in the epoch of reionization: Low carbon abundance and a top-heavy IMF?

International audienceABSTRACT ALMA observations of z > 6 galaxies have revealed abnormally high [O iii]88 $\mu$m/[C ii]158 $\mu$m ratios and [C ii]158 $\mu$m deficits compared to local galaxies. The origin of this behaviour is unknown. Numerous solutions have been proposed including differences in C and O abundance ratios, observational bias, and differences in ISM properties, including ionization parameter, gas density, or photodissociation region (PDR) covering fraction. In order to elucidate the underlying physics that drives this high-redshift phenomenon, we employ sphinx20, a state-of-the-art, cosmological radiation–hydrodynamics simulation, that resolves detailed ISM properties of thousands of galaxies in the epoch of reionization which has been post-processed with cloudy to predict emission lines. We find that the observed z > 6 [O iii]88 $\mu$m–SFR and [C ii]158 $\mu$m–SFR relations can only be reproduced when the C/O abundance ratio is ∼8 × lower than Solar and the total metal production is ∼4 × higher than that of a Kroupa IMF. This implies that high-redshift galaxies are potentially primarily enriched by low-metallicity core–collapse supernovae with a more top-heavy IMF. As AGB stars and type-Ia supernova begin to contribute to the galaxy metallicity, both the [C ii]158 $\mu$m–SFR and [C ii]158 $\mu$m luminosity functions are predicted to converge to observed values at z ∼ 4.5. While we demonstrate that ionization parameter, LyC escape fraction, ISM gas density, and CMB attenuation all drive galaxies towards higher [O iii]88 $\mu$m/[C ii]158 $\mu$m, observed values at z > 6 can only be reproduced with substantially lower C/O abundances compared to Solar. The combination of [C ii]158 $\mu$m and [O iii]88 $\mu$m can be used to predict the values of ionization parameter, ISM gas density, and LyC escape fraction and we provide estimates of these quantities for nine observed z > 6 galaxies. Finally, we demonstrate that [O i]63 $\mu$m can be used as a replacement for [C ii]158 $\mu$ m in high-redshift galaxies where [C ii]158 $\mu$ m is unobserved and argue that more observation time should be used to target [O i]63 $\mu$m at z > 6. Future simulations will be needed to self-consistently address the numerous uncertainties surrounding a varying IMF at high redshift and the associated metal returns

The Nature of High [OIII]88μm{\rm [OIII]}_{\rm 88\mu m}/[CII]158μm{\rm [CII]}_{\rm 158\mu m} Galaxies in the Epoch of Reionization: Low Carbon Abundance and a Top-Heavy IMF?

ALMA observations of $z>6$ galaxies have revealed abnormally high [OIII]$_{\rm 88\mu m}$/[CII]$_{\rm 158\mu m}$ ratios and [CII]$_{\rm 158\mu m}$ deficits compared to local galaxies. Numerous solutions have been proposed including differences in C and O abundance ratios, observational bias, and differences in ISM properties. In order to elucidate the underlying physics that drives this high-redshift phenomenon, we employ SPHINX$^{20}$, a state-of-the-art, cosmological radiation-hydrodynamics simulation, that resolves detailed ISM properties of thousands of galaxies in the epoch of reionization. We find that the observed $z>6$ [OIII]-SFR and [CII]-SFR relations can only be reproduced when the C/O abundance ratio is $\sim8\times$ lower than Solar and the total metal production is $\sim4\times$ higher than that of a Kroupa IMF. This implies that high-redshift galaxies are potentially primarily enriched by low-metallicity core-collapse supernovae with a more top-heavy IMF. As AGB stars and type-Ia supernova begin to contribute to the galaxy metallicity, both the [CII]-SFR and [CII] luminosity functions are predicted to converge to observed values at $z\sim4.5$. While we demonstrate that ionisation parameter, LyC escape fraction, ISM gas density, and CMB attenuation all drive galaxies towards higher [OIII]/[CII], observed values at $z>6$ can only be reproduced with substantially lower C/O abundances compared to Solar. The combination of [CII] and [OIII] can be used to predict the values of ionisation parameter, ISM gas density, and LyC escape fraction and we provide estimates of these quantities for nine observed $z>6$ galaxies. Finally, we demonstrate that [OI]$_{\rm 63\mu m}$ can be used as a replacement for [CII] in high-redshift galaxies where [CII] is unobserved and argue that more observation time should be used to target [OI] at $z>6$. (Abridged