Biology subjects

Sicard, P.

Publications and source records attributed to Sicard, P..

10 recordsLinked to original sources

bioRxiv2026

RyR2-Dependent Calcium Leak Drives the Acute Cardiovascular Manifestations of Ciguatera Poisoning: implications for an emerging climate-sensitive cardiotoxic disease

Background: Ciguatera is the most prevalent non-bacterial seafood poisoning worldwide. It results from the consumption of fish contaminated with ciguatoxins (CTXs). Cardiovascular manifestations are frequently reported in affected patients; however, the molecular mechanisms underlying CTX-induced cardiac dysfunction remain poorly understood. Methods: We investigated the effects of purified CTX-1B and CTX-3C on human induced pluripotent stem-cell-derived ventricular cardiomyocytes. Electrophysiology, intracellular calcium cycling and contractility, and cellular structure were assessed. The RyR2 channel activity was studied in planar lipid bilayers, and molecular docking was used to identify a potential CTX-1B interaction site. Consequences on cardiac function were assessed in rats using echocardiography and EKG. Findings: We found that ciguatoxin exposure rapidly increased diastolic intracellular calcium, with severe impacts on the cardiac excitation-contraction coupling, and caused sarcomeric disorganization in human cardiomyocytes. Single-channel recordings indicated that CTX-1B prolonged RyR2 openings at resting cytosolic calcium and altered ATP-dependent gating. These findings are consistent with a state-dependent remodeling of RyR2 gating rather than uniform potentiation. Docking placed CTX-1B within the RyR2 transmembrane region, near ATP-associated regulatory elements. In rats, CTX-1B caused premature atrial contractions, ventricular ectopy, and acute cardiac dysfunction, with impaired relaxation. Interpretation: These findings identify RyR2-dependent calcium leak as a plausible contributor to ciguatoxin cardiotoxicity and extend the established model based on sodium-channel activation and altered sarcolemmal ion handling. Combined disruption of membrane excitability and intracellular calcium release could explain the rapid electrical and mechanical abnormalities associated with ciguatera. As intensive international shipping traffic and the global dispersal of harmful microalgae via ballast water expand exposure risk alongside the international seafood trade, ciguatera should be considered an emerging global cardiovascular hazard.

physiology↗

bioRxiv2026

Ultrasound-Based Hemodynamic Force Trajectories in a Murine Model of Reversible Pressure Overload

Hemodynamic forces (HDF) quantify intraventricular pressure gradients as integrated vectors derived from myocardial motion and blood flow, providing a sensitive marker of left ventricular pump efficiency beyond conventional metrics such as ejection fraction or strain. Although HDF analysis has been clinically validated in heart failure, it remains underexplored in preclinical models. To determine whether HDF metrics derived from high-resolution murine echocardiography can sensitively track cardiac dysfunction and predict functional recovery, male mice (n = 8) underwent serial echocardiography at baseline, after transverse aortic constriction (TAC), and four weeks after aortic debanding (deTAC). Left ventricular function and interval-specific HDF components were quantified, including longitudinal and transverse forces over predefined systolic and diastolic windows. Longitudinal interval-based parameters emerged as sensitive, integrative markers of LV dysfunction after TAC and DeTAC. Notably, a novel systolic acceleration-to-relaxation longitudinal HDF ratio showed the strongest associations with pressure overload and subsequent functional recovery (baseline vs TAC: p < 0.001; TAC vs deTAC: p < 0.001; baseline vs deTAC: p = 0.043). In contrast, diastolic HDF indices, including the previously proposed longitudinal e-wave ratio, did not significantly differentiate between time points. Transverse HDF over the systolic impulse interval further demonstrated potential for predicting post-surgical recovery following unloading. These findings support systolic HDF metrics, particularly longitudinal and transverse interval-based parameters, as sensitive integrative markers of LV dysfunction and reverse remodeling in preclinical pressure-overload models, and highlight their translational relevance for echocardiography-based HDF analysis. Key pointsHemodynamic force (HDF) analysis evaluate intraventricular pressure gradients as integrated vectors of myocardial motion and blood flow, providing complementary markers of pump (in)efficiency beyond ejection fraction or strain. High-resolution murine echocardiography enables robust derivation of interval-specific HDF metrics. Systolic HDF metrics, particularly transverse components during impulse intervals showed potential for predicting recovery. Systolic HDF reflect key changes in force generation and intraventricular flow during pressure overload, allowing early detection of maladaptive remodeling and treatment response, with strong translational potential for non-invasive risk stratification in aortic stenosis patients.

physiology↗

bioRxiv2025

Abnormal autonomic regulation of heart rate underlies age-related and sexdependent cardiac dysfunction in the small primate Microcebus murinus.

Ageing is a major risk factor for cardiovascular disease associated with the decline of maximal heart rate (HR) and HR variability (HRV). Such a decline could reduce cardiac adaptability to physiological needs and increase susceptibility to arrhythmias. The small primate Grey Mouse Lemur (Microcebus murinus), is a valuable model of ageing because it spontaneously develops neurodegenerative diseases. Moreover, in a lifetime it generates about three billion heartbeats as humans. Thus, it could also represent a new effective model to study cardiac ageing. We investigated cardiac responses to handling stress in young (1-5 years) and aged (6-12 years) lemurs of both sexes by using a mini-Holter for electrocardiogram (ECG) recordings. Moreover, we measured urinary catecholamine, the effect of pharmacological blockade of the autonomic modulation and cardiac contractility. Aged lemurs, particularly aged males, displayed slower HR and abnormal HRV under stress, delayed recovery of cardiac rhythm following stress and a dissociation between HR and HRV metrics. They also exhibited reduced adrenaline levels, a blunted response to pharmacological vagal blockade and diastolic dysfunction with preserved ejection fraction. These findings indicate that ageing, especially in male lemurs, impairs cardiac adaptation and recovery from stress through disrupted autonomic balance and sympathetic incompetence.

physiology↗

bioRxiv2025

Non-Invasive Photoacoustic Imaging of Cerebral Oxygenation and Hemoglobin Content in Awake Mice

IntroductionInvestigating cerebral oxygen saturation dynamics in awake animal models remains technically challenging due to motion artifacts and anesthesia-related biases. Here, we introduce a novel high-resolution ultrasound-photoacoustic (PA) imaging approach enabling real-time, non-invasive monitoring of deep cerebrovascular oxygenation dynamics in awake mice with intact skulls. Materials and MethodsSwiss male and female mice (n = 5-6) were head-fixed using a customized holder adapted to the Neurotar Mobile HomeCage floating platform. High-resolution ultrasound combined with PA imaging (VevoLAZR-X, VisualSonics) was used to discriminate oxyhemoglobin, deoxyhemoglobin, and total hemoglobin in multiple brain regions. Cerebrovascular responses were assessed under three paradigms: (i) baseline awake state vs. 2% isoflurane anesthesia, and (ii) right whisker stimulation to probe sensory-driven hemodynamics. ResultsPA imaging successfully resolved deep-brain oxygenation in awake, intact-skull mice. Under isoflurane anesthesia, we observed a rapid and transient increase in cerebrovascular sO{square} (p < 0.01). During whisker stimulation, we detected robust, region-specific increases in total hemoglobin, reflecting localized neurovascular coupling in awake mice. ConclusionsThis study establishes high-resolution PA imaging as a powerful, non-invasive tool to monitor cerebrovascular oxygenation dynamics in awake mice. By integrating baseline, anesthetic, and sensory paradigms, we demonstrate its potential to dissect neurovascular physiology without the confounding effects of anesthesia. These findings provide new opportunities for preclinical neuroscience research and translational applications investigating cerebral oxygen metabolism.

neuroscience↗

bioRxiv2025

Simplified and refined murine model of reversible aortic constriction for characterizing cardiac functional recovery

BackgroundHeart failure with reduced ejection fraction (HFrEF) is a major clinical issue with a poor prognosis. Structural and functional recovery, known as "reverse remodeling (RR)," has been observed in subsets of patients who respond favorably to treatment. However, progress in understanding the mechanisms behind RR has been hindered by a lack of animal models that accurately replicate this complex process. ObjectivesWe introduced a convenient and reproducible modification to the widely used transaortic constriction (TAC) procedure that allows for refined, timed, and noninvasive aortic de-banding (de-TAC), and functional recovery. MethodsA modified and releasable knot was used for an initial aortic constriction. Suture ends were left accessible from underneath the skin layer following the TAC surgery. After three weeks, deTAC was performed by re-opening in the skin layer and pulling on the suture to release the constriction. We assessed cardiac function, strain, and geometry with 2D and 4D ultrasound at baseline, 3 weeks after TAC, 1 week- and 4 weeks after deTAC. Tissue remodeling and cellular infiltration was characterized by quantifying fibrosis and fibroblast numbers via immunofluorescence. ResultsUltrasound revealed that aortic de-banding was associated with both functional and mechanical recovery. Cardiac function and strain decreased due to pressure overload, exhibiting characteristics of systolic dysfunction, but recovered to near baseline values by 1 week after deTAC. However, left ventricular mass, fibrosis and fibroblast numbers remained elevated, despite functional recovery. ConclusionThis simplified and refined TAC-based model of RR significantly facilitates and enhances research on cardiac remodeling and recovery. CONDENSED ABSTRACTA subset of heart failure patients (HF) respond favorably to treatment, displaying functional recovery via a process known as reverse remodeling (RR). Developing RR models will be key to characterizing currently elusive mechanisms driving this process and ultimately identifying potential therapeutic targets. Transverse aortic constriction (TAC) in rodents increases the afterload on the LV and is a common model of heart failure due to pressure overload. Here, we report a convenient and reproducible method that allows for precisely timed and surgery-free removal of aortic constriction (de-TAC). When performed 3-weeks after TAC, de-TAC produced significant cardiac functional recovery, with normalization of ejection fraction and strain assessed by 2D and 4D echocardiography, respectively. However, signs of adverse myocardial remodeling persisted, including hypertrophy, fibrosis, and elevated fibroblast numbers. In the relatively young field of cardiac RR, our method could facilitate investigations of functional, structural, cellular, and molecular changes underlying recovery from HF. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/646758v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@7b0d62org.highwire.dtl.DTLVardef@abc428org.highwire.dtl.DTLVardef@db2fe0org.highwire.dtl.DTLVardef@243950_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIAdaptation to the widely used transverse aortic constriction (TAC) procedure allows for minimally invasive de-TAC for studying reverse remodeling. C_LIO_LIThis model increases feasibility and reproducibility, with no requirement for additional instruments or materials. C_LIO_LIState-of the art 4DUS assessment of cardiac function, mechanics, and geometry shows extensive left-ventricular remodeling and significant recovery of function following de-TAC. C_LIO_LICardiac fibrosis is persistent following functional recovery from heart failure with reduced ejection fraction (HFrEF). C_LI

pathology↗

bioRxiv2024

Left Atrial Strain as a Predictor of Cardiac Dysfunction in a Murine Model of Pressure Overload

AimLeft atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis. MethodsHigh resolution ultrasound was performed in a cohort of mice (n=16) to evaluate left atrial and left ventricular function at baseline and 2- and 4-weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n=10) with 3-days post TAC imaging. ResultsWe report an increase in LA max volume from 11.0 {+/-} 4.3{micro}L at baseline to 26.7 {+/-} 16.7{micro}L at 4 weeks (p=0.002) and a decrease in LA strain from 19.6 {+/-} 4.8% at baseline to 10.1 {+/-} 6.3% at 4 weeks (p=0.006). In the acute phase, LA strain dysfunction was present at 3-days (p<0.001) prior to alterations in LA volume (p=0.856) or left ventricular (LV) ejection fraction (p=0.120). LA strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r=0.563, p<0.001), longitudinal strain (r=-0.643, p<0.001) and strain rate (r=0.387, p=0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC=0.858, p<0.001), ejection fraction (AUC=0.901 p<0.001), and strain (AUC=0.878, p<0.001) all predicted LV dysfunction. ConclusionLA strain and function assessments provide a reliable, non-invasive method for early detection and prediction of cardiac dysfunction in a model of pressure overload.

physiology↗

bioRxiv2024

A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils

AL amyloidosis is one of the most common types of systemic amyloidosis, caused by the deposition in tissues of fibrillar aggregates of abnormal immunoglobulin (Ig) light chain (LC), leading to organ dysfunction. The most frequent and severe forms affect the kidneys and heart, the latter being associated with a poor prognosis. Despite extensive efforts to decipher the mechanisms of fibril formation and their toxicity, the lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic free LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits in the heart, vessels, spleen and, to a lesser extent, in the kidney and other visceral tissues. AL fibrils in mice contain both full length and fragmented LC with a fragmentation pattern highly superposable to that of human AL fibrils from the same LC subgroup (IGLV6-57). They also develop an early cardiac dysfunction closely resembling the human disease with increased NT-proBNP,and activation of pathways involved in the extracellular matrix remodeling and fibrosis. Overall, this transgenic AL model closely reproduces human cardiac AL amyloidosis and shares with humans the biochemical composition of the deposits, arguing for a conserved mechanism of amyloid fibrils formation. It also shows that a partial degradation of the LC is likely required to initiate amyloid fibril formations. This model offers a new avenue for research on AL amyloidosis and fills an important gap for the preclinical evaluation of new therapies.

pathology↗

bioRxiv2023

Opposing Strain Directions on Adjacent Left Ventricular Segments Predict Fibrotic Remodeling after Acute Myocardial Infarction

BackgroundDespite similar levels of coronary occlusion and standard of care management, the occurrence of scarring over adaptive heart repair following acute myocardial infarction (AMI) remains unpredictable. Recent studies indicate that mechanical cues may modulate the transcriptional programs involved in tissue repair, possibly explaining why ventricular mechanical dyssynchrony an independent predictor of post-infarction outcome. ObjectiveOur study aimed to investigate the relationship between mechanical cues and the outcome of post-myocardial infarction heart remodeling by live imaging. Specifically, we examined the impact of individual variability of myocardial dyssynchrony, characterized by a divergent direction of injured left ventricle wall movement next to live tissue, on the formation of a large scar, dilation of the left ventricle, and loss of pumping function. MethodsWe assessed the location and degree of regional systolic and diastolic dyssynchrony using transthoracic echocardiography coupled with speckle tracking imaging. Specifically, we measured the difference in absolute strain values between adjacent regions of the left ventricle at 5 days following the induction of a standard experimental infarction in female C57Bl6 mice. Three weeks later, transthoracic echocardiography was repeated to analyze the mass and global function of the left ventricle right before termination. We then examined the size of the scar in matched mid-sections of the left ventricle circumferential segments from each mouse using histomorphometry. Finally, we evaluated the potential impact on transcriptional tissue repair programs using spatial transcriptomic analysis on representative hearts with either adaptive or fibrotic post-infarction heart remodeling. ResultsWe analyzed all 96 systolic and diastolic strain-related parameters in the same 48 regions of the left ventricle in all mice, with echocardiographic and histological sections following the same orientation. Stepwise analysis of the live imaging data revealed that a combination of 8 regional strain parameters could predict fibrotic remodeling (Area under the ROC curve= 0.8290). We observed that scarring remodeling was associated with opposing trends of systolic and diastolic circumferential strain % delta values on adjacent regions at day 5, while adaptive remodeling at day 28 occurred when the trend followed the direction of control (sham) hearts. Cluster analysis of gene transcripts and speckle tracking assessment on representative hearts with adaptive or fibrotic post-infarction remodeling indicated a correlation between regional post-infarction dyssynchrony and the transcriptional program. Adrenergic receptors, including Adra1, Trpc3, and Myh7, were found to be linked to specific regional dyssynchrony values and scarring remodeling. ConclusionOur study demonstrates the potential of regional strain parameters obtained through live imaging in predicting fibrotic remodeling following myocardial infarction. Furthermore, our findings suggest a link between regional post-infarction dyssynchrony and the transcriptional program. These results highlight the potential applicability of our approach in clinical settings and provide insights for future personalization of therapeutic strategies.

physiology↗

bioRxiv2022

Crest maturation at the cardiomyocyte surface contributes to a new late postnatal development stage that controls the diastolic function of the adult heart

RATIONALEIn addition to its typical rod-shape, the mammalian adult cardiomyocyte (CM) harbors a unique lateral membrane surface architecture with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) the role of which is still unknown. OBJECTIVETo investigate the development and functional role of CM crests during the postnatal period. METHODS AND RESULTSElectron/confocal microscopy and western-blot of left ventricular tissues from rat hearts indicated a late CM surface crest maturation, between postnatal day 20 (P20) and P60, as shown by substantial SSM swelling and increased claudin-5 cell surface expression. The P20-P60 postnatal stage also correlates with an ultimate maturation of the T-Tubules and the intercalated disk. At the cellular level, we identified an atypical CM hypertrophy characterized by an increase in long- and short-axes without myofibril addition and with sarcomere lateral stretching, indicative of lateral stretch-based CM hypertrophy. We confirmed the P20-P60 hypertrophy at the organ level by echocardiography but also demonstrated a transcriptomic program after P20 targeting all the cardiac cell populations. At the functional level, using Doppler echocardiography, we found that the P20-P60 period is specifically dedicated to the improvement of relaxation. Mechanistically, using CM-specific knock-out mice, we identified ephrin-B1 as a determinant of CM crest maturation after P20 controlling lateral CM stretch-hypertrophy and relaxation. Interestingly, while young adult Efnb1CMspe-/- mice essentially show a relaxation impairment with exercise intolerance, they progressively switch toward heart failure with 100% KO mice dying after 13 months. CONCLUSIONSThis study highlights a new late P20-P60 postnatal developmental stage of the heart in rodents during which the CM surface crests mature through an ephrin-B1-dependant mechanism and regulate the diastolic function. Moreover, we demonstrate for the first time that the CM crest architecture is cardioprotective.

cell biology↗

bioRxiv2022

High-Resolution Ultrasound and Speckle Tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development

Gastrointestinal motor activity has been extensively studied in adults, conversely only few studies have investigated fetal motor skills. When the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development are not known. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos. We found that although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determinates the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allow visualizing and quantifying gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.

developmental biology↗