Background/Objectives: Visceral leishmaniasis remains a serious public health issue, with current antimonial therapies limited by systemic toxicity. Liposomal drug delivery systems offer a promising strategy to improve therapeutic outcomes. In this context, we previously demonstrated the antileishmanial efficacy of the liposomal formulation containing tartar emetic (Lip-TE) in reducing the parasite load in the spleen and liver of animals experimentally infected with Leishmania (Leishmania) infantum, this being an interesting alternative for the treatment of visceral leishmaniasis. In this study, we aimed to evaluate the physicochemical properties, biodistribution, pharmacokinetics, and cardiotoxicity of Lip-TE. Methods: Both Lip-Blank and Lip-TE exhibited monodisperse size distributions (PDI < 0.3), with Lip-TE having an increased particle size (205.1 ± 4.5 nm) compared to Lip-Blank (137.5 ± 0.8 nm). Both formulations demonstrated a positive zeta potential of about +17.0 mV. Biodistribution and cardiotoxicity studies were performed using female BALB/c mice, approximately 8 to 10 weeks old. Results: A significantly greater splenic, hepatic, and renal accumulation of Lip-TE was observed, particularly at 120 min post-injection, compared to Free TE treatment. The pharmacokinetic profile of the treatment with Lip-TE showed higher systemic exposure (AUC), extended half-life and mean residence time, and reduced clearance compared to Free TE treatment. Echocardiographic analysis revealed that treatment with Free TE significantly reduced the ejection fraction percentage and QRS complex prolongation after 10 days of treatment. These alterations persisted at 30 days, indicating progressive cardiotoxicity. In contrast, Lip-TE treatment preserved cardiac function, revealing the protective effect of the liposomal encapsulation. Conclusions: These findings highlight the potential of the Lip-TE treatment to enhance safety and efficacy.

Background/Objectives: Vascular aging is associated with increased arterial stiffness and changes in the wall structure, leading to a loss of elasticity. Silicon is abundant in arteries and plays a key role in the synthesis and stabilization of elastin fibers. In animal models of accelerated cardiovascular aging, a specific nutritional supplement based on silicon-enriched spirulina (SpSi) has been shown to have beneficial effects on vascular function. The present study, designed as a randomized, double-blind, placebo-controlled trial, aimed to evaluate the effectiveness of this SpSi supplement on aging-related changes in vascular function among healthy older adults. Methods: Here, 120 healthy volunteers aged 60-75 years were enrolled and randomly assigned to either the SpSi group (n = 60) or placebo group (n = 60). Over 6 months, the participants received either 3.5 g of specific 1% silicon-enriched spirulina (SpSi group) or placebo tablets daily. The primary outcome was the assessment of arterial wall pressure waveforms, which included blood pressure (BP) readings and the determination of the aortic pulse wave velocity (aPWV). Secondary outcomes included the vasomotor endothelial function through post-ischemic vasorelaxation, measured using the reactive hyperemia index (RHI), and carotid intima-media thickness. Results: When considering the entire sample, none of the studied parameters differed between the placebo and SpSi groups. However, when focusing on individuals with high-normal blood pressure (i.e., systolic BP between 130 and 150 mmHg) and aPWV levels above cutoff values (>10 m/s), the BP decreased by 8% (p < 0.001) and aPWV decreased by 13.5% (p < 0.0001) in subjects receiving SpSi. In individuals with BP and aPWV levels below the cutoff values, no effect was observed. Conclusions: In healthy elderly individuals, SpSi supplementation improved high-normal blood pressure and aortic pulse wave velocity, suggesting an enhanced vascular function.

Macroroughness ramps (e.g. with a rough bed and protruding blocks evenly distributed in staggered rows) are nature-like fishways offering a wide range of flow conditions and are expected to be very efficient tools to reduce the impact of weirs on the free movements of most life-stages of riverine fish species. However, their in situ efficiency has not been evaluated yet. Here, we used Radio Frequency Identification (RFID) telemetry to monitor during two years the displacement of eleven fish species, on such a macroroughness ramp located on a tributary of the Loire River in France. We (1) evaluated the migration rates of tagged fish species, poorly documented so far; (2) quantified macroroughness ramp attraction and efficiency; and (3) assessed the influence of fish species, fish length and environmental conditions (river discharge and temperature) on these efficiency estimates. All the species detected downstream of the weir successfully crossed the ramp, although at varying rates. Depending on the analytical approach (considering the whole study duration or taking into account different fish attempts), the ramp attraction efficiency ranged between 65.5% and 52.9%, the ramp passage efficiency between 81.8% and 77.0% and the overall efficiency between 53.6% and 41.6%. Fish between 70 and 451 mm in total length were detected crossing the ramp, usually within a short time. In comparison with the efficiency results available for other types of fishways, the macroroughness ramp studied here ranks among the most efficient devices for fish movement restoration.

Fish habitats and reproduction can be significantly altered downstream of hydroelectric power plants operated by hydropeaking and resulting in rapid and frequent changes in river hydrodynamic conditions. To mitigate the impacts, it is necessary to maintain the habitat quality through operational measures. The microhabitat method, coupling 1 D or 2 D hydraulic simulations to biological models, is a useful tool to assess the evolution of hydromorphological parameters and fish habitats and define these mitigation measures. Calibration of the hydraulic model must be carried out carefully because the model must accurately reproduce hydraulic conditions from low to high flows. The objective is therefore to evaluate the sensitivity of the habitat value as a function of the type of calibration and the friction law for shallow habitats. The analysis is performed by estimating the uncertainty in fish habitat values resulting from Strickler's law or Nikuradse's law. The study is carried out on a river in the French Pyrenees based on the modeling of 2 stations with different cross-sectional shapes, one with progressive overflow and the other without these phenomena. Thanks to field measurements at low and high flowrates, the calibration process showed that the friction coefficient can be multiplied by 2. Two dimensionnal simulations give similar results to those obtained with 1 D when the flow remains unidirectional but differ for areas with high overflows. Calibration and models can lead to different conclusions regarding the estimation of habitat modifications due to hydropeaking operation and the definition of base flow and maximum turbine discharge.

Methods and algorithms for measuring stream surface velocities have been continuously developed over the past five years to adapt to specific flow typologies. The free software ANDROMEDE allows easy use and comparison of these methods with image processing capabilities designed for measurements in natural environments and with unmanned aerial vehicles. Conventional particle tracking velocimetry, optical flow and particle image velocimetry algorithms, as well as filtering and statistical analysis methods, are available on a single platform. The code is written in Python, exploits available Python libraries, and allows accessible open-source code development. The validation of the integrated algorithms is presented on three case studies that represent the targeted applications: the study of currents for eco-hydraulics, the measurement of low water flows and the diagnosis of hydraulic structures. The field measurements are in very good agreement with the optical measurements and demonstrate the usefulness of the tool for rapid flow diagnosis for all the intended applications.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by the replacement of myocardium by fibro-fatty infiltration and cardiomyocyte loss. ACM predisposes to a high risk for ventricular arrhythmias. ACM has initially been defined as a desmosomal disease because most of the known variants causing the disease concern genes encoding desmosomal proteins. Studying this pathology is complex, in particular because human samples are rare and, when available, reflect the most advanced stages of the disease. Usual cellular and animal models cannot reproduce all the hallmarks of human pathology. In the last decade, human-induced pluripotent stem cells (hiPSC) have been proposed as an innovative human cellular model. The differentiation of hiPSCs into cardiomyocytes (hiPSC-CM) is now well-controlled and widely used in many laboratories. This hiPSC-CM model recapitulates critical features of the pathology and enables a cardiomyocyte-centered comprehensive approach to the disease and the screening of anti-arrhythmic drugs (AAD) prescribed sometimes empirically to the patient. In this regard, this model provides unique opportunities to explore and develop new therapeutic approaches. The use of hiPSC-CMs will undoubtedly help the development of precision medicine to better cure patients suffering from ACM. This review aims to summarize the recent advances allowing the use of hiPSCs in the ACM context.

AbstractAimsVentricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF.Methods and resultsThe MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis.ConclusionConnexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI.Clinical trial registrationClinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease associated with ventricular arrhythmias in patients. The occurrence of these arrhythmias is due to direct electrophysiological remodeling of the cardiomyocytes, namely a reduction in the action potential duration (APD) and a disturbance of Ca2+ homeostasis. Interestingly, spironolactone (SP), a mineralocorticoid receptor antagonist, is known to block K+ channels and may reduce arrhythmias. Here, we assess the direct effect of SP and its metabolite canrenoic acid (CA) in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) of a patient bearing a missense mutation (c.394C>T) in the DSC2 gene coding for desmocollin 2 and for the amino acid replacement of arginine by cysteine at position 132 (R132C). SP and CA corrected the APD in the muted cells (vs. the control) in linking to a normalization of the hERG and KCNQ1 K+ channel currents. In addition, SP and CA had a direct cellular effect on Ca2+ homeostasis. They reduced the amplitude and aberrant Ca2+ events. In conclusion, we show the direct beneficial effects of SP on the AP and Ca2+ homeostasis of DSC2-specific hiPSC-CMs. These results provide a rationale for a new therapeutical approach to tackle mechanical and electrical burdens in patients suffering from ACM.

AIM:Retrospective studies suggest that mild traumatic brain injury (mTBI) in pediatric patients may lead to an increased risk of cardiac events. However, the exact functional and temporal dynamics and the associations between heart and brain pathophysiological trajectories are not understood. METHODS:A single impact to the left somatosensory cortical area of the intact skull was performed on juvenile mice (17 days postnatal). Cerebral 3D photoacoustic imaging was used to measure the oxygen saturation (sO2 ) in the impacted area 4 h after mTBI followed by 2D and 4D echocardiography at days 7, 30, 90, and 190 post-impact. At 8 months, we performed a dobutamine stress test to evaluate cardiac function. Lastly, behavioral analyses were conducted 1 year after initial injury. RESULTS:We report a rapid and transient decrease in cerebrovascular sO2 and increased hemoglobin in the impacted left brain cortex. Cardiac analyses showed long-term diastolic dysfunction and a diminished systolic strain response under stress in the mTBI group. At the molecular level, cardiac T-p38MAPK and troponin I expression was pathologic modified post-mTBI. We found linear correlations between brain sO2 measured immediately post-mTBI and long-term cardiac strain after 8 months. We report that initial cerebrovascular hypoxia and chronic cardiac dysfunction correlated with long-term behavioral changes hinting at anxiety-like and memory maladaptation. CONCLUSION:Experimental juvenile mTBI induces time-dependent cardiac dysfunction that corresponds to the initial neurovascular sO2 dip and is associated with long-term behavioral modifications. These imaging biomarkers of the heart-brain axis could be applied to improve clinical pediatric mTBI management.

Acute heart failure (AHF) due to acute myocardial infarction (AMI) is likely to involve cardiogenic shock (CS), with neuro-hormonal activation. A relationship between AHF, CS and vasopressin response is suspected. This study aimed to investigate the implication of vasopressin on hemodynamic parameters and tissue perfusion at the early phase of CS complicating AMI. Experiments were performed on male Wistar rats submitted or not to left coronary artery ligation (AMI and Sham). Six groups were studied Sham and AMI treated or not with either a vasopressin antagonist SR-49059 (Sham-SR, AMI-SR) or agonist terlipressin (Sham-TLP, AMI-TLP). Animals were sacrificed one day after surgery (D1) and after hemodynamic parameters determination. Vascular responses to vasopressin were evaluated, ex vivo, on aorta. AHF was defined by a left ventricular ejection fraction below 40%. CS was defined by AHF plus tissue hypoperfusion evidenced by elevated serum lactate level or low mesenteric oxygen saturation (SmO2) at D1. Mortality rates were 40% in AMI, 0% in AMI-SR and 33% in AMI-TLP. Immediately after surgery, a sharp decrease in SmO2 was observed in all groups. At D1, SmO2 recovered in Sham and in SR-treated animals while it remained low in AMI and further decreased in TLP-treated groups. The incidence of CS among AHF animals was 72% in AMI or AMI-TLP while it was reduced to 25% in AMI-SR. Plasma copeptin level was increased by AMI. Maximal contractile response to vasopressin was decreased in AMI (32%) as in TLP- and SR- treated groups regardless of ligation. Increased vasopressin secretion occurring in the early phase of AMI may be responsible of mesenteric hypoperfusion resulting in tissue hypoxia. Treatment with a vasopressin antagonist enhanced mesenteric perfusion and improve survival. This could be an interesting therapeutic strategy to prevent progression to cardiogenic shock.

All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.

Hydropower production can cause migration delay and fish mortality, impeding the safe and timely downstream migration of diadromous fish, such as Atlantic salmon (Salmo salar) and silver eels (Anguilla anguilla). To date, only a few field performance tests, especially for eels, have evaluated the efficiency of fine-spaced angled racks associated to a surface bypass entrance to protect fish. Here, 115 salmon smolts and 65 silver eels were radio-tracked over a 2 yr period to assess passage efficiency and passage time at a hydropower intake (50 m3.s−1) retrofitted with a 20 mm rack associated to a surface bypass (2 m3.s−1). Results showed high impediment (89.6% and 96.9% for smolts and eels, respectively), and passage efficiency for the angled rack (89.1% and 93.3%), with short passage times (median, 3 and 7.5 min). However, our results highlighted a strong influence of hydrological conditions, in enhancing fish passage, especially through the bear-trap gate. We conclude that this fish passage solution, making use of existing spillways on the study site, is highly effective for both species. Special attention must, however, be paid to bar-rack design and its cleaning system to ensure fish guidance and prevent impingement or passage through the rack, especially for salmon smolts.

Downstream migrating fish can be strongly affected by hydroelectric facilities. To set up adapted mitigation measures, it is important to identify these impacts ( e.g. induced mortality rates). For Francis turbines, two mortality prediction formulas, developed in 1989 and updated in 2000, are currently used in France for salmonids according to turbine characteristics and fish size (Larinier and Dartiguelongue, 1989, updated by Bosc and Larinier, 2000). However, their use is limited when some parameters are unknown, such as turbine speed. Moreover, the updated version of can be criticized because of its unpublished development procedure and its unknown predictive power. The main purpose of this study is to update the existing formulae to meet the following objectives: (1) a transparent development procedure, (2) formulae simplification, (3) the use of simple (usually the best-known) turbine parameters, and (4) a maximization of the predictive power and an assessment of prediction errors. Based on data from 73 in situ mortality tests available in peer-reviewed and ‘grey’ literature, we developed two new formulae to estimate salmonid mortality rate in Francis turbines. The first one uses turbine peripheral speed, diameter and fish size (correlation between predicted and observed mortality rates r = 0.89, and root mean square error RMSE = 0.11). The second one is based on usually known parameters: turbine discharge, water head and fish size, to allow a broader applicability ( r = 0.89, RMSE = 0.10). This study comforts the validity of previous formulae and provides two new ones allowing a satisfactory precision in the estimations.

The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40-positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR' complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx25 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function.

The rod-shaped adult cardiomyocyte (CM) harbors a unique architecture of its lateral surface with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) with unknown role. Here, we investigated the development and functional role of CM crests during the postnatal period. We found in rodents that CM crest maturation occurs late between postnatal day 20 (P20) and P60 through both SSM biogenesis, swelling and crest-crest lateral interactions between adjacent CM, promoting tissue compaction. At the functional level, we showed that the P20-P60 period is dedicated to the improvement of relaxation. Interestingly, crest maturation specifically contributes to an atypical CM hypertrophy of its short axis, without myofibril addition, but relying on CM lateral stretching. Mechanistically, using constitutive and conditional CM-specific knock-out mice, we identified ephrin-B1, a lateral membrane stabilizer, as a molecular determinant of P20-P60 crest maturation, governing both the CM lateral stretch and the diastolic function, thus highly suggesting a link between crest maturity and diastole. Remarkably, while young adult CM-specific Efnb1 KO mice essentially exhibit an impairment of the ventricular diastole with preserved ejection fraction and exercise intolerance, they progressively switch toward systolic heart failure with 100% KO mice dying after 13 months, indicative of a critical role of CM-ephrin-B1 in the adult heart function. This study highlights the molecular determinants and the biological implication of a new late P20-P60 postnatal developmental stage of the heart in rodents during which, in part, ephrin-B1 specifically regulates the maturation of the CM surface crests and of the diastolic function.

Hydropower energy can contribute to achieve the carbon neutrality goals, but also needs to reach environmental sustainability. Hydropower plants (HPP) constitute barriers to fish migrations that are essential for accomplishing their complete biological cycle. Fish downstream passage solutions (FDPS) have to be implemented to maximize their survival, guiding them away from the turbine intakes towards a safe passage alternative. Recent telemetry studies confirmed the efficiency of 26° inclined low bar spacing (20 mm) rack associated to surface bypasses, installed upstream HPPs, to protect downstream migrating Atlantic salmon smolts. Here we tested the efficiency of such FDPS for eel protection using radiotelemetry at four successive HPPs (with intake capacities from 28 to 45 m 3 .s −1 ) in the Ariège River (southern France). Between 52 and 74 eels, longer than 550 mm, entered the HPP intakes and 100% of them were protected from turbine passage. All eels crossed the HPP water intake using the surface bypasses, and the great majority in few minutes from their first presentation in front of the rack. These results showed that in such rack configuration, it is not necessary to add a specific bottom bypass, usually recommended for eels. We also showed the importance of optimal hydraulic conditions, mainly tangential (parallel to the rack) velocity and bypass discharge, to efficiently guide the eels towards the surface bypasses, reducing their passage time. Overall, our study provided key elements to water managers for designing an efficient FDPS for eels.

Background Despite 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. Objective Our 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. Methods We 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. Results We 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. Conclusion Our 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.

RATIONALE In 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. OBJECTIVE To investigate the development and functional role of CM crests during the postnatal period. METHODS AND RESULTS Electron/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 Efnb1 CMspe−/− mice essentially show a relaxation impairment with exercise intolerance, they progressively switch toward heart failure with 100% KO mice dying after 13 months. CONCLUSIONS This 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.

Engineers always need convenient calculation tools on the field or at the office for evaluating hydraulic characteristics and designing solutions while researchers develop scientific software in most cases non-reusable, invisible, and in the worst case, faulty and unreliable. Funded by the French Biodiversity Office, "Cassiopee" software has first been developed for the design and the verification of upstream and downstream fish passage facilities aggregating multiple tools required for dimensioning: pool-type fishways, pre-barrages, baffle fishways, nature-like fishways, and fish-friendly intakes. "Cassiopee" also includes numerous tools for open flow and pipe flow hydraulics for agriculture and environment. Based on calculation modules, which can be independent or linked in order to carry out complex operations, "Cassiopee" allows an iterative design approach ranging from the definition of the geometric characteristics of the devices to hydraulic simulations of their operating conditions. In a simple and user-friendly interface, it presents the calculation results as clear tables and graphs. Contextual documentation provides detailed information on the different tools and hydraulic formulas used for the calculations. Available in French and English, "Cassiopee" is an open source and free software accessible online (https://cassiopee.g-eau.fr) or as an offline application for Windows, Linux, macOS and Android. An R package is currently under development for advanced users who need to perform intensive calculations without a graphical user interface. Designed as a practical tool resulting from the transfer of research products, it is intended to be widely used by the hydraulic engineering community as a working and educational tool.