Archives of Cardiovascular Diseases最新文献

{"title":"Role of the lipid kinase PIKfyve in cardiometabolic remodelling during heart failure","authors":"Sourour Ben Harzallah ,&nbsp;Cinato Mathieu ,&nbsp;Kramar Solomiia ,&nbsp;Kunduzova Oksana ,&nbsp;Lezoualc’h Frank ,&nbsp;Tronchere Helene ,&nbsp;Boal Frederic","doi":"10.1016/j.acvd.2025.03.066","DOIUrl":"10.1016/j.acvd.2025.03.066","url":null,"abstract":"<div><h3>Introduction</h3><div>Heart failure (HF) is a major public health issue affecting over 26 million people worldwide. It is characterized by metabolic abnormalities and a mitochondrial dysfunction.</div></div><div><h3>Objective</h3><div>In this context, our study aims to clarify the role of PIKfyve and its lipid product PI5P in the control of cardiometabolic remodelling during HF.</div></div><div><h3>Method</h3><div>To further investigate the link between PIKfyve and cardiac function, we generated a cardiomyocyte-specific KO mouse model (PIKfyve CM-KO). These mice were subjected to transverse aortic constriction (TAC). We performed echocardiography analysis, histology, western-blot, qPCR, and respiration measurement to study the impact of PIKfyve deletion.</div></div><div><h3>Results</h3><div>PIKfyve CM-KO mice showed normal cardiac function in physiological conditions, indicating that PIKfyve is dispensable to maintain basal cardiac function. However, following TAC, PIKfyve CM-KO mice displayed significantly reduced cardiac hypertrophy and fibrotic responses, culminating in improved cardiac function. To further elucidate the underlying molecular mechanisms, we performed RNA sequencing (RNAseq) analysis on cardiac tissue from the PIKfyve CM-KO mice. Our results indicated a downregulation of genes associated with glycogen synthesis, which aligns with our metabolomics data showing a striking 3-fold increase in glucose levels in PIKfyve CM-KO hearts. This suggests a shift in metabolic pathways, potentially favouring glucose utilisation over glycogen storage. Additionally, we observed an upregulation of genes involved in mitochondrial electron transport and respiratory chain assembly. Moreover, we found that PIKfyve CM-KO mice heart tissue presents an increase in cardiac PGC-1β expression, a key regulator of mitochondrial function known for its role in promoting mitochondrial respiration. Surprisingly, despite the upregulation of PGC-1β and the fact that genes involved in mitochondrial electron transport and respiratory chain assembly are increased, we found a reduction in mitochondrial OXPHOS activity in PIKfyve-CM KO mice, both biochemically in heart tissue and by Seahorse analysis in cardiomyocytes. Our current work focuses on the characterization of glucose metabolic pathways in PIKfyve CM-KO mice.</div></div><div><h3>Conclusion</h3><div>Our results suggest a complex interplay between the lipid kinase PIKfyve, the metabolic adaptation and mitochondrial dysfunction during HF.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S204"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro proof-of-concept of a murine monoclonal anti-d-dimer antibody conjugate for in vivo real time imaging of thrombosis","authors":"Jamal Elhasnaoui ,&nbsp;Philippe Robin ,&nbsp;Hennebicq Simon ,&nbsp;Blanc-Béguin Frédérique ,&nbsp;Le Pennec Romain ,&nbsp;Francis Couturaud ,&nbsp;Triper Raphaël ,&nbsp;Faivre-Chauvet Alain ,&nbsp;Salaun Pierre-Yves ,&nbsp;Catherine Lemarié","doi":"10.1016/j.acvd.2025.03.012","DOIUrl":"10.1016/j.acvd.2025.03.012","url":null,"abstract":"<div><h3>Introduction</h3><div>The current gold standard techniques for venous thromboembolism (VTE) diagnosis are compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation/perfusion (V/Q) scan. However, these imaging modalities, although well validated for the exclusion of VTE at the acute phase, do not provide any information on thrombus molecular composition. Targeting D-Dimers (DD) using specific molecular imaging anti-DD probes has the potential to better characterize VTE, ultimately improving diagnosis accuracy for VTE patients.</div></div><div><h3>Objective</h3><div>This study presents a proof-of-concept for using an anti-DD probe for in vivo real time imaging of thrombosis.</div></div><div><h3>Method</h3><div>A murine monoclonal anti-DD IgG antibody was produced and labelled with a water soluble fluochrome (CF555[red], Biotium) and used in in vitro clotting assays to label DD within thrombi under static and flow conditions. Both human and mouse in vitro plasma and whole blood clots were formed by induction of coagulation with human tissue factor (TF). AlexaFluor488(green)-prelabelled fibrinogen and CF350-WGA(blue) were skipped in samples shortly prior to induction of coagulation to label neo-formed fibrin fibers and platelets, respectively. The conjugate binding of DD on real preformed human and murine thrombi was also investigated.</div></div><div><h3>Results</h3><div>The anti-DD IgG-CF555 conjugate was capable to specifically recognise DD in in vitro clots formed either under static (no flow) or flow conditions. Importantly, DD staining profile on in vitro clots was very similar to that on preformed real human and mouse thrombi and to that obtained when the conjugate was incubated with human purified DD fragments. Our anti-DD IgG-CF555 conjugate represents a valuable probe for real time confocal and intravital imaging of thrombus formation and resolution.</div></div><div><h3>Conclusion</h3><div>This study shows that an anti-DD probe may specifically target thrombus components. Our suggested approach for VTE imaging might show higher specificity than current imaging modalities. In vivo preclinical experiments are however needed to confirm these interesting findings.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S176-S177"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic memory of contractile muscle cells in response to hypoxia stimulus: Implication in adaptation to exercise and extreme conditions, in aging and in cardiovascular diseases","authors":"Giorgia Musto ,&nbsp;Samantha Conte ,&nbsp;Farid El Oufir ,&nbsp;Isaure Firoaguer ,&nbsp;Jean-Claude Rostain ,&nbsp;Nabil Adjriou ,&nbsp;Nathalie Lalevée ,&nbsp;Régis Guieu ,&nbsp;Mariano Stornaiuolo ,&nbsp;Giovanna Mottola","doi":"10.1016/j.acvd.2025.03.114","DOIUrl":"10.1016/j.acvd.2025.03.114","url":null,"abstract":"<div><h3>Introduction</h3><div>Muscle memory is defined as the capacity of muscle to respond differently to environmental stimuli in an adaptive or maladaptive manner if the stimuli have been previously encountered. Whether and how this memory is associated to epigenetic changes remains still largely undetermined. Among all stimuli, decrease of oxygen availability (hypoxia) represents a prominent environmental stressor. Chronic hypoxia is a common feature in many cardiac diseases, such as heart failure, ischemic heart disease, stroke. Hypoxia is also very common in elite sport athletes that use hypoxic training to improve performance. Investigating whether and how hypoxia induces epigenetic memory in muscle cells might help to find therapeutic strategies for optimizing athletic, counteracting muscle wasting conditions and age-related muscle loss in the general population, understanding and treating cardiovascular diseases.</div></div><div><h3>Objective</h3><div>To address this question, we studied in contractile muscle cells the effect of repeated hypoxic stimulus on cell functions and DNA methylation state, by focusing on the insulin-like growth factor 2 (IGF2) and H19 region. These genes are regulated by an imprinting control DNA region (ICR), whose methylation status influences selective IGF2 expression to the detriment of the long non-coding RNA encoded by the downstream gene H19.</div></div><div><h3>Method</h3><div>We used a murine myoblast cell line (C2C12) with high proliferative rate, ability to easily differentiate in myotubes and with skeletal and cardiac muscle features. Cells were exposed to normoxia (21% O2) or a first hypoxic stimulus (1% O2) during 24<!--> <!-->h or 48<!--> <!-->h, then cultured for 3 weeks (corresponding to 42 population doublings) and exposed to a second stimulus. ICR region methylation and IGFII and H19 expression were analysed by qRT-PCR et cell functions by flow cytometry.</div></div><div><h3>Results</h3><div>We observed upon an initial hypoxic stimulus, a cell number decrease (<em>P</em> <!-->&lt;<!--> <!-->0.0001*** vs normoxia), accompanied by a decreased ICR methylation (<em>P</em> <!-->&lt;<!--> <!-->0.0001*** vs normoxia) and an upregulation of H19 (<em>P</em> <!-->&lt;<!--> <!-->0.0001*** vs normoxia). After a second stimulus of either 24<!--> <!-->h or 48<!--> <!-->h, all these parameters were again significantly reduced compared to normoxia (<em>P</em> <!-->&lt;<!--> <!-->0.0001***), but remarkably, significantly higher than after the first stimuli.</div></div><div><h3>Conclusion</h3><div>Our results show that a hypoxic stimulus induces epigenetic modification in C2C12 cells and that cells keep memory of the first stimulus by differently respond to a second injury.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S224"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feminizing gender-affirming hormone therapy increases PCSK9 mRNA expression in liver of transfemale mice","authors":"Virginie Grouthier ,&nbsp;Célia Bourguignon ,&nbsp;Coralie Fontaine ,&nbsp;Pierre Mora ,&nbsp;Antoine Tabarin ,&nbsp;Candice Chapouly ,&nbsp;Thierry Couffinhal ,&nbsp;Marie-Ange Renault","doi":"10.1016/j.acvd.2025.03.112","DOIUrl":"10.1016/j.acvd.2025.03.112","url":null,"abstract":"<div><h3>Introduction</h3><div>Transwomen (assigned male at birth and treated with feminizing gender-affirming hormone therapy (f-GAHT) with antiandrogens and estrogens) are reported to develop more cardiovascular disease, especially myocardial infarction with an increased suspicion of atheromatous disease.</div></div><div><h3>Objective</h3><div>Our objective is to understand how f-GAHT may contribute to the development of atherosclerosis. We hypothesize that f-GAHT promotes the development of atherosclerosis by promoting low-grade inflammation and/or modifying lipid metabolism.</div></div><div><h3>Method</h3><div>We have set up an innovative preclinical transfemale mouse model recapitulating the hormonal status of transwomen. More specifically, C57BL/6 WT male mice are orchidectomized at 3-month end of age, and then exposed to estradiol for 9 weeks through the implantation of estradiol delivering pellets. At 18 weeks of age, mice are sacrificed for histological and gene expression analyses. Transfemale mice were compared with male controls.</div></div><div><h3>Results</h3><div>In transfemale mice, no relevant effects on circulating inflammation were observed, particularly on leukocyte counts or serum levels of inflammatory cytokines (especially Il-1β, IL-6, IL-17A, Il-18). Hovewer, f-GAHT induced several metabolic changes. First, we found that f-GAHT reduced weight gain and adipocyte size, then we found that f-GAHT altered the lipid profile by lowering HDL levels (<em>P</em> <!-->=<!--> <!-->0.02) and raising LDL levels in transfemale compared to controls. Moreover, f-GAHT causes hepatic steatosis, which also points to a detrimental metabolic context. Notably, these changes were associated with significantly decreased FGF21 serum levels in transfemale mice compared to controls (<em>P</em> <!-->=<!--> <!-->0.03). FGF21 is a hepatokine that plays an important role in the regulation of lipid metabolism notably by downregulating PCSK9 in hepatocytes. Accordingly, we then highlighted a decrease in FGF21 mRNA expression (<em>P</em> <!-->=<!--> <!-->0.022) and an increase in PCSK9 mRNA expression (<em>P</em> <!-->=<!--> <!-->0.0006), known as favourable for the development of atherosclerosis, in the liver of transfemale mice treated with f-GAHT.</div></div><div><h3>Conclusion</h3><div>F-GAHT in transfemale mice appears to adversely affect lipid metabolism by decreasing FGF21 levels and increasing PCSK9 levels, which could adversely promotes atherosclerosis in tranwomen.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S223"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exchange Proteins directly Activated by cAMP (EPAC): Involvement in electrophysiological remodeling and underlying signaling in human atrial cardiomyocyte","authors":"Arthur Boileve ,&nbsp;Margaux Aize ,&nbsp;Maximin Détrait ,&nbsp;Laura Brard ,&nbsp;Alexandre Lebrun ,&nbsp;Vladimir Saplacan ,&nbsp;Fabien Brette ,&nbsp;Frank Lezoualc’h ,&nbsp;Laurent Sallé","doi":"10.1016/j.acvd.2025.03.089","DOIUrl":"10.1016/j.acvd.2025.03.089","url":null,"abstract":"<div><h3>Introduction</h3><div>EPAC proteins act as downstream effectors of cAMP pathway. EPAC activation lengthens Action Potential Duration (APD) and dysruptes Ca2+ homeostasis in ventricular myocytes. In atria, APD modulations contribute to pathogenesis of Atrial Fibrillation (AF). Recent studies revealed EPAC proteins as a putative AF promotor in mice by APD lengthening. However, the EPAC-induced variation of human atrial cardiomyocyte electrophysiology is not yet described.</div></div><div><h3>Objective</h3><div>To evaluate the influence of EPAC proteins in human atrial cardiomyocytes electrophysiology.</div></div><div><h3>Method</h3><div>Right auricular appendages were collected from patients in Sinus Rhythm (SR) and AF undergoing open-heart surgery. Action Potentials and K+ currents (IK) were recorded in human isolated cardiomyocytes or in cultured HL-1 atrial myocytes with the patch-clamp technique. EPAC proteins were acutely activated or inhibited by pharmacological tools. EPAC proteins levels and phosphorylation states of NO-synthases were measured by Western-Blot.</div></div><div><h3>Results</h3><div>In human atrial cardiomyocytes, EPAC activation with 8-CPTAM (10<!--> <!-->μM) lengthened APD by downregulation of both transient peak and sustained (IKsus) components of repolarizing K+ currents. Pre-treatment of myocytes with selective EPAC1 or EPAC2 pharmacological blockers (AM-001, 20<!--> <!-->μM and ESI-05, 25<!--> <!-->μM, respectively) revealed that both EPAC isoforms participate in this effect. Mechanistically, pharmacological inhibition of NO-synthases (NOS) and PKG significantly reduced the EPAC-induced decrease of IKsus. The inhibition of AMPK, a positive regulator of NOS activity, significantly reduced the EPAC-dependent IKsus alteration, whereas the blockade of Akt, a NOS activator, failed to influence EPAC effect. In HL-1 myocytes, a similar downregulation of IKsus occured after EPAC activation with 8-CPTAM. In addition, 8-CPTAM treatment significantly increased the phosphorylation level of the endothelial isoform of NOS in its activating site Ser1177, whereas AMPK inhibition prevented this increase. Of note, 8-CPTAM treatment did not modify Reactive Oxygen Species levels in HL-1 cells. Interestingly, we found that the EPAC1 isoform, but not EPAC2, was overexpressed in right auricular appendages from AF patients compared to SR patients. Consistent with this finding, the EPAC1 blocker AM-001 significantly rectified the IK alteration in cardiomyocytes from AF patients treated with 8-CPTAM, but not in cells from SR patients.</div></div><div><h3>Conclusion</h3><div>EPAC stimulation lengthens APD by decreasing IK through an AMPK-eNOS-PKG pathway in human atrial cardiomyocytes. Finally, alteration of EPAC1 signaling could promote AF onset.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S215-S216"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of resistance, endurance, and combined exercise trainings on hemodynamic, respiratory, and muscular parameters in Marfan syndrome patients","authors":"Steeve Jouini ,&nbsp;Guillaume Jondeau ,&nbsp;Olivier Milleron ,&nbsp;Ludivine Eliahou ,&nbsp;Damien Vitiello","doi":"10.1016/j.acvd.2025.03.023","DOIUrl":"10.1016/j.acvd.2025.03.023","url":null,"abstract":"<div><h3>Introduction</h3><div>Marfan syndrome is a hereditary connective tissue disorder that frequently involves cardiovascular complications. Adapted physical activity is a promising therapeutic strategy to improve cardiac function and physical fitness in these patients.</div></div><div><h3>Objective</h3><div>To evaluate the impact of three training modalities (endurance, resistance, and combined) on hemodynamic, respiratory, and muscular parameters in Marfan syndrome patients (MSP).</div></div><div><h3>Method</h3><div>Three groups participated in specific 12-week training programs: (1) Endurance; (2) Resistance; and (3) Combined (endurance<!--> <!-->+<!--> <!-->resistance). Pre- and post-training assessments included echocardiography (left ventricle ejection fraction [LVEF], right ventricle/right atrium [RV/RA] gradient, aortic diameters), pulse wave analysis (pulse wave velocity, augmentation index), exercise testing (VO2 max, maximal power), and spirometry (FEV1, FVC).</div></div><div><h3>Results</h3><div>All three modalities improved LVEF (<em>P</em> <!-->&lt;<!--> <!-->0.05). The Endurance group showed the highest average increase (+6.00<!--> <!-->±<!--> <!-->4.00%, <em>P</em> <!-->=<!--> <!-->0.015), corresponding to about a 10% relative improvement from baseline. Arterial stiffness also decreased in all groups, as indicated by significant reductions in pulse wave velocity and augmentation index (<em>P</em> <!-->&lt;<!--> <!-->0.05). The Resistance group demonstrated a notable reduction in the RV/RA gradient (–2.60<!--> <!-->±<!--> <!-->2.88<!--> <!-->mmHg, <em>P</em> <!-->=<!--> <!-->0.037) and a significant gain in muscle strength (+10<!--> <!-->±<!--> <!-->3.5<!--> <!-->kg, <em>P</em> <!-->=<!--> <!-->0.001). The Combined group presented the largest decrease in pulse wave velocity (–0.68<!--> <!-->±<!--> <!-->0.30<!--> <!-->m/s, <em>P</em> <!-->=<!--> <!-->0.009).</div></div><div><h3>Conclusion</h3><div>Exercise training, in its various forms, provides overall benefits for MSP. Resistance training offers substantial hemodynamic advantages, whereas the endurance and combined modalities yield marked improvements in aerobic capacity and vascular compliance. Regular echocardiographic monitoring is crucial to ensure the safety and effectiveness of these exercise interventions in MSP.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S182"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of sex and pregnancy on the development of aortic aneurysm in a mouse model of Marfan syndrome","authors":"Clarisse Simons ,&nbsp;Stéphanie Clerc-Rignault ,&nbsp;Christelle Bielmann ,&nbsp;Karima Bouzourène ,&nbsp;Chiara De Nicola ,&nbsp;Antoine Costa-Racciatti ,&nbsp;Lucia Mazzolai ,&nbsp;Nathalie Rosenblatt-Velin","doi":"10.1016/j.acvd.2025.03.031","DOIUrl":"10.1016/j.acvd.2025.03.031","url":null,"abstract":"<div><h3>Introduction</h3><div>Marfan syndrome (MFS), is a rare vascular disease caused by mutations in the <em>fibrillin1</em> (<em>Fbn1</em>) gene, leading to the development of thoracic aortic aneurysm (TAA). While both sexes are affected, men experience earlier and more frequent aortic complications than women, a disparity also observed in an MFS mouse model (Fbn1C1039G/+). Furthermore, in humans, pregnancy is considered a risk factor for developing aortic dissection.</div></div><div><h3>Objective</h3><div>Thus, we explored the influence of sex and pregnancy on the development of TAA by comparing male and female mice as well as multiparous and nulliparous female mice. In this context we investigated TGF-β and CNP signaling pathways, known to favor aneurysm development if altered.</div></div><div><h3>Method</h3><div>Development of aortic aneurysm was assessed by ultrasound imaging, measuring the sinus and ascending diameter as well as the ascending aorta distance. Measurements were performed in male and female (multiparous and nulliparous) Fbn1± or Fbn1+/+ mice. Western blot was performed on ascending aortae of all mice.</div></div><div><h3>Results</h3><div>Ultrasound imaging revealed significant increase for all aortic measurements in male Fbn1<!--> <!-->±<!--> <!-->mice by 10 weeks of age compared to Fbn1+/+. Similarly, at 34 weeks, multiparous female mice displayed increased values for all aortic measurements, whereas nulliparous females showed only increased ascending aorta distance. Like in males, CNP protein levels decreased in the ascending aortae of 20 (–60%), and 52 (–36%) week-old multiparous Fbn1<!--> <!-->±<!--> <!-->females. Additionally, the aortae of these older mice displayed decreased NPR-C protein levels (–54%) whereas TGF-β signaling pathway was activated through signal transducer protein SMAD (+50%).</div></div><div><h3>Conclusion</h3><div>Our results highlight the importance of separating sexes and offering women with pregnancy better monitoring, as aortic structure alterations seem to be modulated by gestational status. Whether the CNP and its receptor NPR-C can be markers of aneurysm development in humans remains to be elucidated.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S185-S186"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HiPSC-derived sinoatrial node pacemaker cells: A new model to study human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated bradycardia","authors":"Nadia Mekrane ,&nbsp;Eleonora Torre ,&nbsp;Leïla Talssi ,&nbsp;Giuseppe Angelini ,&nbsp;Alain Lacampagne ,&nbsp;Matteo Elia Mangoni ,&nbsp;Albano Meli ,&nbsp;Pietro Mesirca","doi":"10.1016/j.acvd.2025.03.092","DOIUrl":"10.1016/j.acvd.2025.03.092","url":null,"abstract":"<div><h3>Introduction</h3><div>The sinoatrial node (SAN), the heart's primary pacemaker, is essential for maintaining rhythmic activity. SAN dysfunctions (SND) and the induced bradycardia are often linked to genetic mutations, highlighting the need for human-relevant models. Differentiating human induced pluripotent stem cells into SAN-like cells (SAN-hiPSCs) provides an innovative platform to study SND mechanisms. In CPVT mouse models associated with RyR2 heterozygous single-point mutation, reduced L-type calcium current (ICaL) disrupts calcium homeostasis and pacemaker activity, leading to bradycardia. Here, we explore whether similar alterations occur in SAN-hiPSCs derived from a CPVT bradycardia-associated patient.</div></div><div><h3>Objective</h3><div>Our goal was to generate healthy control and patient-derived SAN-hiPSCs carrying the RyR2-H29D mutation and monitor their electrophysiological properties.</div></div><div><h3>Method</h3><div>Control and CPVT patient-derived SAN-hiPSCs were differentiated using a 2D-sandwich-based method, modulating Wnt signaling. Maturity was enhanced by adding small molecules such as triiodothyronine, dexamethasone, and intracellular cyclic AMP (DTA cocktail). Patch-Clamp recordings were performed at day 40 post-differentiation.</div></div><div><h3>Results</h3><div>Firstly, pacemaker profile has been electrophysiologically characterized in control SAN-hiPSCs, also testing adrenergic and cholinergic responses. CPVT SAN-hiPSCs showed a significant reduction in action potential (AP) frequency compared to control (Ctrl: 157.5<!--> <!-->±<!--> <!-->9.9 bpm; CPVT: 38.4<!--> <!-->±<!--> <!-->13.6 bpm). The pacemaker ‘funny’ current (If) was similar between groups (@−135<!--> <!-->mV Ctrl: −21,3<!--> <!-->±<!--> <!-->2,1 pA/pF; CPVT −21,8<!--> <!-->±<!--> <!-->2,6 pA/pF). In CPVT SAN-hiPSCs, a trend toward decreased ICaL was observed compared to control (@-10<!--> <!-->mV Ctrl: −37.6<!--> <!-->±<!--> <!-->9.5 pA/pF; CPVT: −25.9<!--> <!-->±<!--> <!-->4.2 pA/pF). G protein-gated inwardly rectifying potassium current (IKACh) was measured in control but remains under investigation in CPVT cells.</div></div><div><h3>Conclusion</h3><div>CPVT SAN-hiPSCs exhibit a bradycardic phenotype consistent with the clinical features. CPVT induced-bradycardia is not associated with alterations in the If current but it is most likely linked to a reduction in ICaL. Recent studies suggest that genetic ablation or pharmacological inhibition of IKACh can prevent SND-dependent bradycardia, highlighting its potential as a therapeutic target. Future research will focus on inhibiting IKACh in this model using a vector-based approach to restore SAN function in CPVT patients.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S217"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of hyperbaric stress on rat thromboinflammation according to sex and decompression sickness susceptibility","authors":"Jérémy Orsat ,&nbsp;Michel Mandin ,&nbsp;Nadège Marec ,&nbsp;Pierre Pochard ,&nbsp;François Guerrero","doi":"10.1016/j.acvd.2025.03.011","DOIUrl":"10.1016/j.acvd.2025.03.011","url":null,"abstract":"<div><h3>Introduction</h3><div>Decompression sickness (DCS) is a systemic syndrome that can occur after a reduction of environmental pressure, forming bubbles in blood circulation and tissues. The onset of DCS is characterised by different mechanisms including the activation of inflammation and coagulation cascade. Although the contribution of bubbles in triggering DCS is undeniable, various studies seem to show that this stress is not the only one involved and hyperbaric stress seems to induce inflammation. Previous studies suggested that DCS resistance could be associated with an increased blood inflammatory capacity and that these resistance mechanisms could differ between males and females.</div></div><div><h3>Objective</h3><div>This study aims to compare, in vitro, the effect of hyperbaric exposure solely on leukocytes and platelet activation depending on sex and DCS susceptibility.</div></div><div><h3>Method</h3><div>We isolated leukocytes and platelets from the blood of 39 Wistar rats (21 males and 18 females). These cells were split into two groups: atmospheric pressure or hyperbaric protocol. Then, the cells were analysed by flow cytometry. The platelets and different sub-populations of leukocytes were identified, and their activation was analysed thanks to specific markers. 4 weeks later, the rats were exposed to the same hyperbaric protocol to distinguish DCS-sensitive animals from the resistant ones.</div></div><div><h3>Results</h3><div>The percentage variation study between cells stayed at atmospheric pressure and exposed to hyperbaric protocol shows that hyperbaric stress increased the proportion of activated monocytes (MHCII+/CD11b/c Low) in DCS-sensitive rats (<em>P</em> <!-->=<!--> <!-->0.021). The study of the leukocytes &amp; platelets interaction shows that the DCS-sensitive rats have a higher proportion of linked leukocytes-platelets (<em>P</em> <!-->=<!--> <!-->0.049). The percentage variation shows that hyperbaric stress modifies the platelet-leukocyte expression of CD142 (<em>P</em> <!-->=<!--> <!-->0.018) and CD62P with a Sexe*Susceptibility interaction (<em>P</em> <!-->=<!--> <!-->0.0019). Regarding the leukocytes sub-population, we found a Sexe*Susceptibility interaction in the percentage variation of platelets-neutrophils CD62P+/CD11b/c+ (<em>P</em> <!-->=<!--> <!-->0.015).</div></div><div><h3>Conclusion</h3><div>Our study shows that hyperbaric stress induces a higher monocyte activation in DCS-sensitive rats linked to a greater inflammatory profile. It also points that this stress induces leukocytes-platelets interaction that differs according to gender and DCS susceptibility.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S176"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obstructive sleep apnea: A role in carotid plaque instability?","authors":"Sébastien Surget ,&nbsp;Pialoux Vincent ,&nbsp;Emeric Stauffer ,&nbsp;Antoine Millon ,&nbsp;Amandine Thomas-Zanetti","doi":"10.1016/j.acvd.2025.03.005","DOIUrl":"10.1016/j.acvd.2025.03.005","url":null,"abstract":"<div><h3>Introduction</h3><div>Atherosclerosis is a chronic andsystemic inflammatory disease that develops slowly and is reflected by the presence of atherosclerosis plaques in several arterial beds.It is considered the leading cause of cardiovascular disease worldwide. Plaque rupture is the major cause of ischemic stroke or myocardial infarction and can be predicted by atherosclerotic plaque instability. Intraplaque hemorrhage (IPH) is the main factor of plaque instability and is promoted by an hypoxic and pro-inflammatory environment. Obstructive sleep apnea syndrome (OSAS) is strongly associated with cardiovascular diseases and is known to promote early stages of atherosclerosis. OSAS is associated with higher stroke risk. However, it is still largely underdiagnosed in patient with carotid atherosclerotic plaque and its potential role in plaque instability is unknown.</div></div><div><h3>Objective</h3><div>The objective of the present study is to evaluate the prevalence of OSAS in patients with atheroma carotid plaque and to evaluate whether OSAS may promote IPH.</div></div><div><h3>Method</h3><div>In this study, OSAS’ risk is determined with STOP BANG (SB) questionnaire in 147 patients who underwent carotid endarterectomy. All patients with a SB score &gt;<!--> <!-->2 were proposed a polysomnography (PSG). Then, carotid plaques were embedded in paraffin and sections stained with Perl's Blue to evaluate IPH. A score was defined (from 0<!--> <!-->=<!--> <!-->no IPH to 3<!--> <!-->=<!--> <!-->large IPH).</div></div><div><h3>Results</h3><div>Only 12.8% of our population had a sleep test prior to their appointment at the vascular medicine service. However, the SB results show that 89% of our population have at least a moderate risk of OSAS and a PSG should be performed. So far, 13 patients agreed to perform a PSG. Among them, 11 were diagnosed with OSAS requiring treatment. Interestingly, the IPH score measured by Perl's Blue in carotid biopsies is higher in-patient wither higher risk of OSAS (SB<!--> <!-->&gt;<!--> <!-->3) than in low-risk patient (SB<!--> <!-->≤<!--> <!-->3) (1.78 vs 1.05, <em>P</em> <!-->=<!--> <!-->0.04).</div></div><div><h3>Conclusion</h3><div>In conclusion, we demonstrated that OSAS is largely underdiagnosed in our population even if we highlighted a potential role of OSAS in IPH development. Further experiments are ongoing to assess the real prevalence of OSAS by increasing the number of patients doing PSG in our population and to confirm the link between OSAS and IPH.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S172-S173"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}