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To develop a reproducible and stable closed chest model of ischemic cardiogenic shock in sheep, with high survival rate and potential insight into human pathology. We established a protocol for multi-step myocardial alcoholisation of the left anterior descending coronary artery by percutaneous ethanol injection. A thorough hemodynamic assessment was obtained by invasive and non-invasive monitoring devices. Repeated blood samples were obtained to determine haemoglobin and alcohol concentration, electrolytes, blood gas parameters and cardiac troponin I. After sacrifice, tissue was excised for quantification of infarction and histology. Cardiogenic shock was characterized by a significant decrease in mean arterial pressure (− 33%), cardiac output (− 29%), dP/d t max (− 28%), carotid blood flow (− 22%), left ventricular fractional shortening (− 28%), and left ventricle end-systolic pressure–volume relationship (− 51%). Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. All haemodynamic changes were stable over a three-hour period with a 71% survival rate. The necrotic volume (n = 5) represented 24.0 ± 1.9% of total ventricular mass. No sham exhibited any variation under general anaesthesia. We described and characterized, for the first time, a stable, reproducible sheep model of cardiogenic shock obtained by percutaneous intracoronary ethanol administration.

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 ( Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific  Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

Inflammation of the central nervous system (CNS) induces endothelial blood–brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of “chronic neuroinflammatory tolerance” in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.

Hypertension remains the leading cause of cerebral, cardiac, renal, and retinal vascular damage. However, genetic determinants underlying organ-specific vulnerability are poorly understood, and commonly used mouse models, notably C57BL/6J, often fail to recapitulate severe hypertensive complications seen in humans. This study compares the widely used C57BL/6J mouse strain with the genetically distinct 129S1/SvlmJ strain under hypertensive stress, aiming to identify a model that better reproduces hypertensive target organ damage. Moderate hypertension was induced in 129S1/SvlmJ and C57BL/6J mice using chronic infusion of angiotensin II (600 ng/kg/min). Despite comparable blood pressure elevations, only 129S1/SvlmJ mice developed severe organ damage, including cognitive impairment, pronounced blood-brain barrier disruption, retinal vasculopathy, cardiac hypertrophy, and podocyte lesions with albuminuria. In contrast, C57BL/6J mice exhibited markedly less organ injury under the experimental conditions tested. Transcriptomic analysis of cerebral microvessels identified distinct inflammatory and immune-related signatures between strains, paralleling their vascular phenotypes. These immune profiles appear as hallmarks of strain-specific susceptibility rather than as direct protective or deleterious mechanisms. This study demonstrates that genetic background critically shapes hypertensive complications, identifying the 129S1/SvlmJ strain as a relevant and translational model of hypertensive target organ damage. Beyond reproducing key features of severe hypertension, this model provides a framework to investigate the pathways linking genetic susceptibility, vascular injury, and end-organ damage.

Under neuroinflammatory conditions, astrocytes acquire a reactive phenotype that drives acute inflammatory injury as well as chronic neurodegeneration. We hypothesized that astrocytic Delta-like 4 (DLL4) may interact with its receptor NOTCH1 on neighboring astrocytes to regulate astrocyte reactivity via downstream juxtacrine signaling pathways. Here we investigated the role of astrocytic DLL4 on neurovascular unit homeostasis under neuroinflammatory conditions. We probed for downstream effectors of the DLL4-NOTCH1 axis and targeted these for therapy in two models of CNS inflammatory disease. We first demonstrated that astrocytic DLL4 is upregulated during neuroinflammation, both in mice and humans, driving astrocyte reactivity and subsequent blood-brain barrier permeability and inflammatory infiltration. We then showed that the DLL4-mediated NOTCH1 signaling in astrocytes directly drives IL-6 levels, induces STAT3 phosphorylation promoting upregulation of astrocyte reactivity markers, pro-permeability factor secretion and consequent blood-brain barrier destabilization. Finally we revealed that blocking DLL4 with antibodies improves experimental autoimmune encephalomyelitis symptoms in mice, identifying a potential novel therapeutic strategy for CNS autoimmune demyelinating disease. As a general conclusion, this study demonstrates that DLL4-NOTCH1 signaling is not only a key pathway in vascular development and angiogenesis, but also in the control of astrocyte reactivity during neuroinflammation.

Background Chronic Limb-Threatening Ischemia (CLTI) represents the most advanced stage of Peripheral Artery Disease (PAD) and is associated with dire prognosis, characterized by a substantial risk of limb amputation and diminished life expectancy. Despite significant advancements in therapeutic interventions, the underlying mechanisms precipitating the progression of PAD to CLTI remain elusive. Methods Considering diabetes is one of the main risk factors contributing to PAD exacerbation into CLTI, we compared hind limb ischemia recovery in HFD STZ vs. non-HFD STZ mice to identify new mechanisms responsible for the exacerbation of PAD. Results We used three different mouse models of diabetes and found that blood flow recovery in HFD STZ mice is altered only from day 14 post-surgery. Consistent with this kinetics, we found that angiogenesis and myogenesis which typically occur between day five and day 14 post-surgery are not impaired in mice in which diabetes was induced by a high fat diet and streptozotocin injections (HFD STZ mice). On the contrary, we found that capillary functionality e.i. acquisition of functional intercellular junctions and immune quiescence is impaired in HFD + STZ mice. Notably, 28 days after hind limb ischemia surgery, HFD + STZ mice display significantly increased capillary permeability to IgG and significantly increased levels of ICAM1. This was associated with an increased macrophage infiltration and an impaired myocyte differentiation. Importantly, we used ICAM1-blocking antibodies to demonstrate that increased ICAM1 expression in HFD + STZ mice decreases white blood cell circulation velocity within the microcirculation, which impairs its perfusion. Notably anti-ICAM1 therapy did diminish macrophage infiltration and oxidative stress but not myopathy suggesting that myopathy characterized by small myocytes expressing higher level of MYH2 could be responsible for microangiopathy. Conclusion ICAM1 expression by the microvasculature impairs ischemic muscle reperfusion in HFD + STZ mice. Importantly, the increase in blood flow between day 14 and day 90 post-HLI surgery is not associated with an increased capillary density but with an improved functionality of capillaries.

Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in myocardial infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP. Mosaic loss of the Y chromosome (mLOY), a common marker of clonal hematopoiesis in men, has emerged as a potential candidate for modulating cardiovascular risk associated with CHIP. In this study, we aimed to ascertain the risk linked to each somatic mutation or mLOY and explore whether mLOY could exert an influence on the cardiovascular risk associated with CHIP. We conducted an examination for the presence of CHIP and mLOY using targeted high-throughput sequencing and digital PCR in a cohort of 446 individuals. Among them, 149 patients from the CHAth study had experienced a first MI at the time of inclusion (MI(+) subjects), while 297 individuals from the Three-City cohort had no history of cardiovascular events (CVE) at the time of inclusion (MI(-) subjects). All subjects underwent thorough cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. Our investigation aimed to determine whether mLOY could modulate inflammation, atherosclerosis burden, and atherothrombotic risk associated with CHIP. CHIP and mLOY were detected with a substantial prevalence (45.1% and 37.7%, respectively), and their occurrence was similar between MI(+) and MI(-) subjects. Notably, nearly 40% of CHIP(+) male subjects also exhibited mLOY. Interestingly, neither CHIP nor mLOY independently resulted in significant increases in plasma hs-CRP levels, atherosclerotic burden, or MI incidence. Moreover, mLOY did not amplify or diminish inflammation, atherosclerosis, or MI incidence among CHIP(+) male subjects. Conversely, in MI(-) male subjects, CHIP heightened the risk of MI over a 5 y period, particularly in those lacking mLOY. Our study highlights the high prevalence of CHIP and mLOY in elderly individuals. Importantly, our results demonstrate that neither CHIP nor mLOY in isolation substantially contributes to inflammation, atherosclerosis, or MI incidence. Furthermore, we find that mLOY does not exert a significant influence on the modulation of inflammation, atherosclerosis burden, or atherothrombotic risk associated with CHIP. However, CHIP may accelerate the occurrence of MI, especially when unaccompanied by mLOY. These findings underscore the complexity of the interplay between CHIP, mLOY, and cardiovascular risk, suggesting that large-scale studies with thousands more patients may be necessary to elucidate subtle correlations. This study was supported by the Fondation Cœur & Recherche (the Société Française de Cardiologie), the Fédération Française de Cardiologie, ERA-CVD (« CHEMICAL » consortium, JTC 2019) and the Fondation Université de Bordeaux. The laboratory of Hematology of the University Hospital of Bordeaux benefitted of a convention with the Nouvelle Aquitaine Region (2018-1R30113-8473520) for the acquisition of the Nextseq 550Dx sequencer used in this study. NCT04581057.

Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05–4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations.

Background In recent years, Ecological Momentary Assessment (EMA) has expanded rapidly in healthcare research but its application specifically to the field of cardiology has been limited. This study presents essential information concerning the feasibility and validity of EMA in patients with acute coronary syndrome. Methods Four months after a first-ever acute coronary syndrome, 47 patients completed EMA five times a day for seven consecutive days concerning their current activities, mood and perceived negativity or positivity of daily events. Results Compliance with the repeated electronic assessments was high, and no evidence was found for time-dependent biases such as fatigue or practice effects. The resulting EMA data were found to have high internal validity, high reliability when considering average scores, and low reliability when considering within-person variance. Conclusions We found evidence for the feasibility and intrinsic validity of EMA in patients with acute coronary syndrome. Research examining daily life experiences, symptoms and therapeutic adherence in this population can be reinforced through the use of mobile technologies.