Archives of Cardiovascular Diseases最新文献

{"title":"Benefits of O-GlcNAcylation stimulation on cardiac output in hemorrhagic shock","authors":"Yann Daniel ,&nbsp;Frédérique Dufour-Gaume ,&nbsp;Augustin Walter ,&nbsp;Audrey Bordone ,&nbsp;Amandine Vergnaud ,&nbsp;Bertrand Rozec ,&nbsp;Nicolas Prat ,&nbsp;Benjamin Lauzier","doi":"10.1016/j.acvd.2025.03.041","DOIUrl":"10.1016/j.acvd.2025.03.041","url":null,"abstract":"<div><h3>Introduction</h3><div>O-GlcNAcylation (O-GlcNAc) is a post-translational modification of cytoplasmic, nuclear and mitochondrial proteins that consists of the addition of a sugar, β-D-N-acetylglucosamine (or GlcNAc), to their serine and threonine residues. It is involved in many biological processes and appears to play an important role in the cell's response to stress and its survival.</div></div><div><h3>Objective</h3><div>The aim of this study was to evaluate whether stimulation of O-GlcNAcylation has a potential effect on hemodynamic parameters, during the early phase of hemorrhagic shock (HS), using NButGT an O-GlcNAcase inhibitor, to increase O-GlcNAc levels.</div></div><div><h3>Method</h3><div>Female large white pigs (35-42<!--> <!-->kg) were subjected to a HS and trauma protocol induced via bilateral femur fractures and passively exsanguinated to 60% of their estimated total blood volume (ETBV) through the jugular catheter, and then randomly treated or not with NButGT (10<!--> <!-->mg/kg). Other animals were retransfused with depleted blood (Whole blood group), and others were exposed only to anesthesia without trauma or bleeding (SHAM group). Invasive hemodynamic monitoring was performed using a pulse index continuous cardiac output (PiCCO) device. Blood samples were collected repeatedly as tissue samples after euthanasia. The time at which 40% of ETBV was drained was defined as the “T0” time. Treatment was injected a the end of exsanguination and 90<!--> <!-->min after “T0”. The procedure was terminated 6<!--> <!-->hours after “T0” (enthanasia of the animals).</div></div><div><h3>Results</h3><div>The proportion of animals who died prematurely without reaching the end of the procedure do not differ by group (<em>P</em>-value of χ² <!-->&gt;<!--> <!-->0.05). Cardiac output was higher in the NButGT group compared with the placebo group, 90<!--> <!-->min after “T0” (&lt;<!--> <!-->0.05), and also 120<!--> <!-->min after “T0”, but without statistical significance (<span><span>Fig. 1</span></span>). Shock index was lower in the NButGT group compared with the placebo group, 90<!--> <!-->min after “T0” (<em>P</em>-value<!--> <!-->&lt;<!--> <!-->0.05), and also 120<!--> <!-->min after “T0”, but without statistical significance.</div></div><div><h3>Conclusion</h3><div>Our results show that NButGT administration could be helpful in minimizing the collapse of cardiac output and the rise in Shock Index in the acute phase of hemorrhagic shock. To our knowledge, this is the first time such results have been reported in a large mammal model. Further experiments will now be carried out, such as the study of O-GlcNAc levels by Western blot in heart cells, to confirm its increase under NButGT action and O-GlcNAc dynamics in this context.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S190-S191"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099561","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":"A subpopulation of 7-day old neonatal rat ventricular cardiomyocytes retains the inherent ability to re-enter the cell cycle delineated by the de novo nestin expression","authors":"Adrien Aubry ,&nbsp;Patrice Naud ,&nbsp;Leblanc Charles-Alexandre ,&nbsp;Angelino Calderone","doi":"10.1016/j.acvd.2025.03.034","DOIUrl":"10.1016/j.acvd.2025.03.034","url":null,"abstract":"<div><h3>Introduction</h3><div>Studies have reported that injury to the 7-day old neonatal rodent heart failed to elicit a regenerative response. It remains presently unknown whether the latter paradigm is attributed in part to an inherent loss of ventricular cardiomyocytes to re-enter the cell cycle.</div></div><div><h3>Objective</h3><div>To examine whether 7-day old neonatal rat ventricular cardiomyocytes can re-enter the cell cycle and express a pattern of gene expression associated with a potential cardiac regenerative response.</div></div><div><h3>Method</h3><div>Ventricular cardiomyocytes (NNVMs) were isolated from 7-day old neonatal Sprague-Dawley rats and treated for 3 days with the phorbol ester phorbol 12,13 dibutyrate (PDBu; 100<!--> <!-->nM) in the absence or presence of the p38a/b MAPK inhibitor SB203580 (10<!--> <!-->mM). Cell cycle re-entry and gene expression was determined by QPCR and Bulk RNA Seq Analysis. Partial apex resection of the 7-day old neonatal rat heart was performed and pups sacrificed 3 days later.</div></div><div><h3>Results</h3><div>80% of the population of untreated 7-day old NNVMs were mononucleated. PDBu treatment for 3-days failed to promote cell cycle re-entry but induced a hypertrophic response delineated by a significant upregulation of Nppa and Nppb mRNAs. SB203580 administration to PDBu treated NNVMs translated to cell cycle re-entry characterized by nuclear 5-bromo-2′-deoxyuridine incorporation and nuclear staining of phosphorylated serine10 of histone 3 of a subpopulation characterized by de novo expression of the intermediate filament protein nestin. The latter paradigm was confirmed by Western blot and QPCR. The appearance/cell cycle re-entry of nestin (+)-NNVMs was associated with a significant mRNA upregulation of a panel of glycolytic enzymes (PDK3, PFKP, PKM, Slc2a1) and concomitant reduction of enzymes implicated in fatty acid oxidation (Cpt1b, Sdha, Acsl1). Three days following partial apex-resected 7-day old neonatal rat heart, the appearance of a subpopulation of NNVMs associated with de novo nestin expression was identified adjacent to the damaged region and significantly re-entered the S-phase and G2-M phase of the cell cycle.</div></div><div><h3>Conclusion</h3><div>A subpopulation of 7-day old neonatal rat ventricular cardiomyocytes possess the inherent ability to re-enter the cell cycle in vitro and in vivo characterized by the selective expression of the intermediate filament protein nestin.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S187-S188"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099590","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":"Regulation of sinus node “pacemaker” L-type Cav1.3 channels by phosphoinositide 3-kinase (PI3K) as a mechanism underlying age-related sinus node dysfunction and bradycardia","authors":"Eleonora Torre ,&nbsp;Ira S. Cohen ,&nbsp;Pietro Mesirca ,&nbsp;Matteo Elia Mangoni","doi":"10.1016/j.acvd.2025.03.036","DOIUrl":"10.1016/j.acvd.2025.03.036","url":null,"abstract":"<div><h3>Introduction</h3><div>Sinus node (SN) dysfunction (SND) is caused by failure to generate a normal SN action potential. SND patients are identified clinically as having sinus bradycardia, generally defined as a heart rate below 50 bpm. The commonest form of SND is related to ageing of the cardiac tissue. Only a few pharmacologic options are currently available to treat transient SND. However, most patients present with chronic symptomatic SND that can be treated only by pacemaker implantation as definitive therapy. In Europe and the U.S., SND now accounts for nearly half a million-pacemaker device implantations per year and this is predicted to double over the next half century. Considering this global burden of SND, innovative pharmacologic and molecular strategies based on novel insights into disease mechanisms are needed for SND treatment. Recently, it has been demonstrated that the ‘funny’-current (If) and heart rate are positively regulated by phosphoinositide 3-kinase (PI3<!--> <!-->K), by a mechanism which is independent of the autonomic nervous system input. Although it is known that heart rate, expression of SN ion channels and PI3<!--> <!-->K activity all decrease with age, the role of PI3<!--> <!-->K in age-related SN bradycardia remains unexplored.</div></div><div><h3>Objective</h3><div>To determine which SN ionic currents are regulated by PI3<!--> <!-->K in age-related SND focusing on the discrimination between Cav1.3 and Cav1.2–mediated L-type Ca2+ currents (ICaL).</div></div><div><h3>Method</h3><div>WT young (2 months old) and aged (24 months old) mice were used to isolate SN cells. 1<!--> <!-->μM Calciseptine (Cas) – a selective Cav1.2 channel blocker – was used to distinguish between regulation by PI3<!--> <!-->K of Cav1.3 and Cav1.2 isoform. Upon perfusion of Cas, the Cas-sensitive current is attributed to Cav1.2, while the resistant component is attributed to Cav1.3. SN cells were incubated for 2<!--> <!-->h with 1<!--> <!-->μM PI-103 to inhibit PI3<!--> <!-->K before patch experiments.</div></div><div><h3>Results</h3><div>We tested the effect of PI-103 on If in SN myocytes from aged mice. PI-103 had no effect on If in terms of current density and shift in activation curve. Aging had no effect on ICav1.2 but ICav1.3 was reduced in old mice. PI-103 reduced only ICav1.3 amplitude without changing ICav1.2 in young mice. PI-103 had no effects on both Cav1.3 and Cav1.2–mediated L-type Ca2+ currents in old mice.</div></div><div><h3>Conclusion</h3><div>Dissection of PI3<!--> <!-->K regulation of Cav1.3 and Cav1.2 channels provides new knowledge on the ionic mechanisms of regulation of intrinsic SN rate by PI3K and L-type Ca2+ channels in adult and aged SN.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S188"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099592","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":"Role of cathepsin O variants in intracranial aneurysm formation","authors":"Maxence Bodet ,&nbsp;Milène Fréneau ,&nbsp;Mary Adel Mrad ,&nbsp;Anne-Clémence Vion ,&nbsp;Richard Redon ,&nbsp;Romain Bourcier ,&nbsp;Gervaise Loirand","doi":"10.1016/j.acvd.2025.03.018","DOIUrl":"10.1016/j.acvd.2025.03.018","url":null,"abstract":"<div><h3>Introduction</h3><div>Intracranial aneurysms (IA) are localized dilations of cerebral arteries affecting 3–5% of the global population, with familial forms representing 10% of cases. Rupture of an IA leads to subarachnoid hemorrhage, a condition with a 33% mortality rate and long-term disabilities in half of the survivors. Using whole-exome sequencing, we identified two rare missense variants in the gene encoding cathepsin O (CTSO) (p.Val316Ile and p.Ala43Val) in two large families with multiple affected subjects. CTSO is a cysteine protease, but its physiological role remains undefined.</div></div><div><h3>Objective</h3><div>The aim of this study is to investigate the expression and function of CTSO in vascular cells to understand how CTSO variants contribute to the predisposition to intracranial aneurysms.</div></div><div><h3>Method</h3><div>CTSO expression was analyzed by Western blot (WB). CTSO variants (p.Val316Ile, p.Ala43Val) were overexpressed in 3T3 cells. SiRNA knockdown of CTSO was performed in rat aortic vascular smooth muscle cells (VSMCs). Fibronectin expression and localization was analyzed by WB and confocal microscopy. Apoptosis of Human umbilical vein endothelial cells (HUVECs) was assessed by TUNEL and adhesion by impedancemetry (xCelligence) and protein activation (WB).</div></div><div><h3>Results</h3><div>Western blot analysis revealed that CTSO is expressed and secreted by primary VSMCs, and its secretion was notably enhanced under mechanical stretch. Overexpression of CTSO variants (p.Val316Ile and p.Ala43Val) resulted in reduced secretion of the mutant proteins compared to the WT. In primary VSMCs, we silenced CTSO expression to mimic the loss of secretion induced by CTSO variants and observed an increase of VSMC adhesion, a decrease in VSMC migration, and an accumulation of fibronectin around the cells. To recapitulate the paracrine effect of VSMC-secreted CTSO on endothelial cells, HUVECs were treated with recombinant CTSO (200<!--> <!-->ng/mL), which had no effect on adhesion speed or apoptosis but significantly reduced vinculin activation at the Y822 phosphorylation site.</div></div><div><h3>Conclusion</h3><div>These findings suggest that CTSO may play a key role in regulating endothelial cell-cell junction dynamics. However, further detailed analyses will be necessary to confirm these findings. Additionally, the data indicate that CTSO influences VSMC functions and extracellular matrix composition. The reduced secretion of CTSO variants may disturb these processes, potentially contributing to arterial wall dysfunction.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S179-S180"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099092","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":"Assessing cardiovascular changes in pregnant women with diabetes: Insights from echocardiography","authors":"Wissal Hamdi ,&nbsp;Syrine Saidane ,&nbsp;Omar Haddar ,&nbsp;Wissal Jaafer ,&nbsp;Chaima Khelifi ,&nbsp;Samar Godcha ,&nbsp;Mechal Mourali ,&nbsp;Khadija Mzoughi","doi":"10.1016/j.acvd.2025.03.108","DOIUrl":"10.1016/j.acvd.2025.03.108","url":null,"abstract":"<div><h3>Introduction</h3><div>Pregnancy induces cardiovascular changes to support maternal and fetal needs. In diabetic women, these adaptations may be disrupted, leading to complications. Echocardiography helps to detect abnormalities in maternal heart function.</div></div><div><h3>Objective</h3><div>This study aimed to compare echocardiographic parameters between diabetic and non-diabetic pregnant women.</div></div><div><h3>Method</h3><div>This cross-sectional study included 36 diabetic pregnant women (Group 1) and 36 non-diabetic pregnant women (Group 2). Exclusion criteria included pregnancy complications, comorbidities, preexisting cardiac conditions, and infections. Participants underwent clinical evaluations, physical exams, and echocardiographic assessments.</div></div><div><h3>Results</h3><div>Both groups had comparable mean ages (30<!--> <!-->±<!--> <!-->6 years for Group 1 vs. 30<!--> <!-->±<!--> <!-->4 years for Group 2, <em>P</em> <!-->=<!--> <!-->0.8). Mean arterial pressure was similar (80<!--> <!-->mmHg for Group 1 vs. 70<!--> <!-->mmHg for Group 2, p<!--> <!-->=<!--> <!-->0.57). No significant difference in heart rate (<em>P</em> <!-->=<!--> <!-->0.11) or RVFS (<em>P</em> <!-->=<!--> <!-->0.11). Cardiac output was also comparable (6.28<!--> <!-->mL/m² for Group 1 vs. 6.0<!--> <!-->mL/m² for Group 2, <em>P</em> <!-->=<!--> <!-->0.66). Significant differences in BMI (29<!--> <!-->±<!--> <!-->5<!--> <!-->kg/m² for Group 1 vs. 33<!--> <!-->±<!--> <!-->7<!--> <!-->kg/m² for Group 2, <em>P</em> <!-->=<!--> <!-->0.03) and BSA (1.9 m² vs. 2.0 m², <em>P</em> <!-->=<!--> <!-->0.03) were observed. Group 1 had lower LVEF (61%) compared to Group 2 (65%) (<em>P</em> <!-->&lt;<!--> <!-->0.01). Ejection systolic volume and inferior vena cava measurements also differed (<em>P</em> <!-->&lt;<!--> <!-->0.01 and <em>P</em> <!-->=<!--> <!-->0.03, respectively).</div></div><div><h3>Conclusion</h3><div>Diabetic pregnant women had higher BMI, BSA, and slightly lower LVEF compared to controls. However, other cardiovascular parameters, including cardiac output, were similar between groups. These findings highlight the need for tailored management and careful monitoring to manage diabetes’ impact on pregnancy.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S221"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099050","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":"Subclinical ventricular dysfunction in rheumatoid arthritis","authors":"Ameni Mardessi,&nbsp;Houaida Mahfoudhi,&nbsp;Sarra Chenik,&nbsp;Taha Yassine Jabloun,&nbsp;Abdedayem Haggui,&nbsp;Nadhem Hajlaoui,&nbsp;Wafa Fehri","doi":"10.1016/j.acvd.2025.03.110","DOIUrl":"10.1016/j.acvd.2025.03.110","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiovascular disease, especially heart failure, is often under diagnosed in patients with rheumatoid arthritis (RA). Heart failure in RA patients presents with distinctives features, such as preserved ejection fraction and higher mortality rates compared to the non-RA population. Despite its accessibility and safety, echocardiography has not been widely recommended for screening in this patient population.</div></div><div><h3>Objective</h3><div>In our study, we aimed to assess the utility of speckle tracking echocardiography in detecting sub clinical ventricular dysfunction</div></div><div><h3>Method</h3><div>We conducted a prospective study that included 36 patients with RA who were being treated at the rheumatology department of the military hospital in Tunis. Weal so enrolled 36 control cases who had undergone echocardiography at the cardiology department of the same hospital, selected based on age, sex, and BMI to match the first group.</div></div><div><h3>Results</h3><div>The mean age of the participants was 51.69<!--> <!-->±<!--> <!-->12.14 years, with a predominance of females, resulting in a sex ratio of 0.33. The mean Body mass index (BMI) was28.17<!--> <!-->±<!--> <!-->4.27<!--> <!-->kg/m². Diabetes mellitus (DM) was the most common comorbidity, occurring in 9 patients (25%). There were no statistically significant differences between the RA and control groups in terms of matching parameters (age, sex, and BMI). No statistically significant differences were observed between the two groups in terms of left ventricular measurements and systolic function, all of which fell within normal ranges, with a median left ventricular ejection fraction (LVEF) of71%. However, the study of diastolic function revealed that 19% of RA patients and 14% of control subjects had grade I diastolic dysfunction, all of whom were over 50 years of age, and none exhibited high filling pressures. When comparing Global Longitudinal Strain (GLS) measurements between the two groups, it was evident that RA patients had significantly lower GLS (<em>P</em> <!-->=<!--> <!-->0.015) than the control group, and sub clinical left ventricular systolic dysfunction was observed exclusively in RA patients. Age and diabetes mellitus were both found to be correlated with GLS in RA patients. Age at the time of RA diagnosis exhibited a weak correlation with GLS (r<!--> <!-->=<!--> <!-->−0.305, <em>P</em> <!-->=<!--> <!-->0.07).</div></div><div><h3>Conclusion</h3><div>Rheumatoid arthritis emerges as a risk factor for cardiovascular disease. The study of myocardial deformation offers a valuable method for screening sub clinical myocardial lesions and facilitating early therapeutic intervention.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S222"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099052","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":"Hypercholesterolemia and proprotein convertase subtilisin/kexin type 9 potentiate inflammation and fibro-calcific remodeling in bioprosthetic aortic valve","authors":"Marine Sallé ,&nbsp;Guillaume Guimbretière ,&nbsp;Pascal Aumond ,&nbsp;Benjamin Le Vely ,&nbsp;Cédric Lemay ,&nbsp;Bertrand Cariou ,&nbsp;Thierry Le Tourneau ,&nbsp;Claire Toquet ,&nbsp;Jean Mérot ,&nbsp;Jean-Christian Roussel ,&nbsp;Romain Capoulade","doi":"10.1016/j.acvd.2025.03.077","DOIUrl":"10.1016/j.acvd.2025.03.077","url":null,"abstract":"<div><h3>Introduction</h3><div>Calcific aortic valve stenosis is the more frequent valvular disease, affecting more than 10% of patients &gt;<!--> <!-->75 years old. Surgical or transcatheter aortic valve replacement is the only treatment available. There is an increased use of bioprosthetic valves (BP), even if the progressive development of structural BP deterioration (SVD) limits their durability. Recent clinical studies highlighted an association between circulating lipid factors, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), Lipoprotein (a) and low-density-lipoprotein (LDL), and SVD. However, the underlying mechanisms remain unknown.</div></div><div><h3>Objective</h3><div>We aim at deciphering the role of hypercholesterolemia and/or PCSK9 on the early processes leading to SVD.</div></div><div><h3>Method</h3><div>Subcutaneous implantation of BP tissue was performed on 10-week-old wild type (WT), PCSK9 knock-out (KO) and PCSK9 overexpressing (PCSK9 OV) mice for 28 days. A qualitative anatomopathological score evaluating cell density, infiltration, and tissue degradation was developed. Infiltrated cells were characterized by IHC and modulated signaling pathways were identified by bulk RNA-sequencing. Mice peritoneal macrophages were stimulated for 6<!--> <!-->hours with PCSK9 and/or oxidized-LDL (ox-LDL).</div></div><div><h3>Results</h3><div>The anatomopathological score was significantly higher in the explanted punches from PCSK9 OV mice as compared to WT and KO (7.0 [4.1–8.4] vs 4.0 [3.0–4.5] and 2.8 [2.0–3.9], respectively; <em>P</em> <!-->=<!--> <!-->0.008). Macrophages and granulocytes were the more abundant infiltrated cell types with a significant increase of granulocytes in PCSK9 OV mice as compared to WT and KO (<em>P</em> <!-->=<!--> <!-->0.01 and <em>P</em> <!-->=<!--> <!-->0.002, respectively). RNA-seq analysis revealed an enrichment of fibro-calcific remodeling signaling pathways in PCSK9 OV mice compared to KO. Macrophages stimulation highlighted differential responses: ox-LDL activated pro-inflammatory signaling pathways whereas PCSK9 promoted pro-calcifying cytokines release.</div></div><div><h3>Conclusion</h3><div>Hypercholesterolemia and/or high PCSK9 levels potentiate the inflammatory response against the BP tissue, with an infiltration of granuloytes and macrophages, and an activation of fibro-calcific signaling pathways. PCSK9 promotes the activation of pro-calcifying cytokines whereas ox-LDL increases pro-inflammatory pathways. This study points out for a specific role of hypercholesterolemia and PCSK9 in the early phases post implantation of BP tissue, with potential implication in the development of SVD.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S209"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099220","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":"Role of a non-coding ZFPM2 locus linked to an increased risk of Brugada syndrome occurrence","authors":"Sarah Godin,&nbsp;Clément Cohen,&nbsp;Thomas Stervinou,&nbsp;Aurore Girardeau,&nbsp;Bibonne Anne,&nbsp;Vital Loizeau,&nbsp;Isabelle Baró,&nbsp;Flavien Charpentier,&nbsp;Guillaume Lamirault,&nbsp;Nathalie Gaborit","doi":"10.1016/j.acvd.2025.03.093","DOIUrl":"10.1016/j.acvd.2025.03.093","url":null,"abstract":"<div><h3>Introduction</h3><div>Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia characterized by an increased risk of sudden death due to ventricular arrhythmias originating from the right ventricle (RV) and its outflow tract. Rare genetic variants in SCN5A gene, which generates the main cardiac sodium current (INa), are involved in only 20% of BrS cases. Genome-wide association studies identified strong polygenic influence of specific common risk haplotypes on BrS occurrence. The present study focuses on the risk allele located in an intronic region of ZFPM2 transcription factor gene, known to be involved in cardiac development but which has not been linked so far to the regulation of cardiac electrical activity.</div></div><div><h3>Objective</h3><div>To study the role of ZFPM2 risk haplotype in cardiac electrical activity using RV cells differentiated from human induced pluripotent stem cells (hiPSCs).</div></div><div><h3>Method</h3><div>A locus depicting epigenetic characteristics of distal enhancer, and that includes the ZFPM2 risk haplotype, has been identified using both CHIP-seq and ATAC-seq data. This locus has been precisely CRISPR-deleted (i-ZFPM2) in a control (WT) hiPSC line. Both lines were differentiated into RV cells using a cardioid protocol adapted from Schmidt C. et al (Cell, 2023). Gene expression, voltage clamp and current clamp experiments were conducted on differentiated cells.</div></div><div><h3>Results</h3><div>Differentiated cells displayed a gene expression profile characteristic of RV tissue. In accordance with the hypothesis that the locus is an enhancer, the expression of ZFPM2 was reduced. Interestingly, the expression of SCN5A was also reduced. Accordingly, the i-ZFPM2 RV cells showed a significant reduction of INa as compared to WT (−61%, <em>P</em> <!-->&lt;<!--> <!-->0.01) with no alteration of biophysical properties of the channel. The amplitude and the dV/dtmax of the action potential were also decreased.</div></div><div><h3>Conclusion</h3><div>Our results suggest that the investigated region regulates ZFPM2 expression in human RV cells and that ZFPM2 participates in the control of cardiac electrical activity through SCN5A regulation. These data may unveil new mechanisms involved in BrS pathophysiology. Further studies will decipher the precise mechanisms by which this regulation occurs.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Pages S217-S218"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099123","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":"Risk factors and prognosis of symptomatic postpartum ovarian vein thrombosis in two French prospective cohort studies","authors":"Eloïse Laouenan ,&nbsp;Claire De Moreuil ,&nbsp;Sara Robin ,&nbsp;Karine Morcel ,&nbsp;François Anouilh ,&nbsp;Cecile Tromeur ,&nbsp;Francis Couturaud ,&nbsp;Emmanuelle Le Moigne","doi":"10.1016/j.acvd.2025.03.009","DOIUrl":"10.1016/j.acvd.2025.03.009","url":null,"abstract":"<div><h3>Introduction</h3><div>Symptomatic postpartum ovarian vein thrombosis (sPOVT), an unusual site of venous thromboembolism (VTE), is a rare complication occurring in 1/500 deliveries, with uncertain prognosis.</div></div><div><h3>Objective</h3><div>To evaluate: (i) the risk factors for sPOVT; (ii) the short-term prognosis, in terms of extension to the inferior vena cava and the left renal and association with pulmonary embolism (PE) or deep vein thrombosis (DVT); and (iii) the risk of recurrent VTE after resuming anticoagulation.</div></div><div><h3>Method</h3><div>A review of all documented cases of sPOVT was conducted using data of two French multicenter prospective cohorts of 20,238 unselected pregnant women and 7102 adult patients with VTE (<span><span>NCT02443610</span><svg><path></path></svg></span>–<span><span>NCT04297085</span><svg><path></path></svg></span>). All sPOVT diagnoses, VTE recurrences and maternal deaths were reviewed and validated by an independent clinical events committee. The Ethics Committee of Brest University Hospital approved the study protocols. Written informed consent was obtained from all participants before inclusion.</div></div><div><h3>Results</h3><div>Among the 13 women with sPOVT, the main VTE risk factors were maternal age ≥<!--> <!-->35 years (<em>n</em> <!-->=<!--> <!-->6;46.2%), obesity (<em>n</em> <!-->=<!--> <!-->3;23.1%), VTE family history (<em>n</em> <!-->=<!--> <!-->4;30.4%), multiple pregnancy (<em>n</em> <!-->=<!--> <!-->3;23.1%), preterm delivery (<em>n</em> <!-->=<!--> <!-->4;30.4%), caesarean delivery (<em>n</em> <!-->=<!--> <!-->3;23.1%) and postpartum infection (<em>n</em> <!-->=<!--> <!-->9;69.2%). At sPOVT diagnosis, four (30.8%) women presented extension to the inferior vena cava or the left renal vein. Among them, one had concomitant PE and one had thrombosis in the contralateral renal vein. None of them had concomitant DVT. During the median (IQR) follow-up of 6.1 years (3.0–7.3), after resuming anticoagulation, one patient had recurrent VTE despite thromboprophylaxis (i.e. muscular vein thrombosis after surgery five years after sPOVT) and one patient died from Hodgkin's lymphoma without VTE recurrence five years after sPOVT.</div></div><div><h3>Conclusion</h3><div>sPOVT appeared frequently associated with proximal clot extension and/or with PE or DVT. These observations support that sPOVT requires early diagnosis and effective anticoagulation for a minimum of three months as recommended for proximal DVT and PE. The risk of recurrence was low, so treating sPOVT similarly to provoked PE or DVT for up to six months seems appropriate. Given the close association between postpartum infection and sPOVT, the thrombotic risk needs to be regularly reassessed during postpartum.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S175"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099420","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":"Long-read RNA sequencing in cardiomyopathies: A new approach for genetic diagnostic with strong potential?","authors":"Laëtitia Rialland ,&nbsp;Elisabeth Legrand De Milleville ,&nbsp;Hélène Madry ,&nbsp;Badreddine Mohand Oumoussa ,&nbsp;Jean Francois Pruny ,&nbsp;Philippe Charron ,&nbsp;Pascale Richard ,&nbsp;Eric Villard","doi":"10.1016/j.acvd.2025.03.060","DOIUrl":"10.1016/j.acvd.2025.03.060","url":null,"abstract":"<div><h3>Introduction</h3><div>Dilated cardiomyopathies (DCM) are inherited diseases, for which genetic diagnostic conditions patient follow-up and family care (major gene <em>TTN</em>). However, current DNA Short Read (SR DNA-Seq) based sequencing diagnostic yield is only 15–25% suggesting methodological limitations. This lack might be mitigated by a RNA Long-Read (LR-RNA-Seq) approach since it allows to detect elusive DNA rearrangements and cryptic aberrant splicing causative mutations, representing an attractive strategy to improve diagnostic yield.</div></div><div><h3>Objective</h3><div>To evaluate feasibility of whole transcriptome LR-RNA-Seq for detection of Single Nucleotide Variants (SNVs) in coding exons and short/complex DNA Structural Variants (SV).</div></div><div><h3>Method</h3><div>We included 26 DCM cases with cardiac RNA available (transplanted hearts). LR-RNA-Seq was conducted on a PromethION24 (ONT) after cDNA library preparation. SNVs and SV were called using a LR dedicated bioinformatic tool (Clair3). True variants calling thresholds were inferred from replication using DNA Sanger sequencing of the same samples.</div></div><div><h3>Results</h3><div>At total, samples were covered with 11.6M reads (± 6.9<!--> <!-->M) among which 85% were long (&gt; 400 pb) and thus used for alignments. We align 90% of this reads, whose mean size was 1094 pb (± 80). Among 33 putative LR-RNA-Seq variants selected within an extended range of Clair3 quality score, 11 were confirmed in DNA, allowing to defined 3 key parameters witnessing for high prior probability variants: total depth<!--> <!-->&gt;<!--> <!-->15X; minor allele frequency<!--> <!-->&gt;<!--> <!-->0.2 and alternative allele depth<!--> <!-->&gt;<!--> <!-->5X (100% sensitivity; 86 % specificity for variant identification). All 3 causal SNV already diagnosed were detected (100%). We also detected 2 new causative truncating variants in the <em>TTN</em> gene in 2 other patients. Finally, we identified a patient with rare monoallelic variants overlapping with TTN locus, suggesting hemizygosity or consanguinity. Genomic DNA qPCR demonstrated haploidy compared to a control diploid locus, strongly suggesting DCM causative TTN deletion in this patient. Overall, the diagnostic yield of LR-RNA-Seq was 23,0 % (6/26), at the upper limit of the reported yields for DCM.</div></div><div><h3>Conclusion</h3><div>Long-read RNA seq appear to be an efficient method to detect coding variants in expressed genes, as well as structural variations. Ongoing analysis of splicing and NMD-related variants in our LR-RNA-Seq data might further increase diagnostic yield. LR-RNA-Seq could become a key strategy to complement, or even overwhelm, SR DNA-Seq in genetic diagnosis.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S201"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099342","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}