Factors associated with patent foramen ovale-related stroke: SAFAS study.

BACKGROUND: Persistent foramen ovale (PFO) contributes to cryptogenic stroke and is associated with stroke recurrence, although the exact mechanism of ischemic events is not fully understood. Several biomarkers have been developed for the prediction of atrial fibrillation after stroke, but there are currently only limited data on their potential value for the diagnosis of PFO-related stroke. METHODS: This study was a prospective single-center study that included all patients hospitalized between March 31, 2018, and January 18, 2020, in the stroke department of the Dijon University Hospital for ischemic stroke without obvious cause and without a history of atrial fibrillation. PFO was systematically screened by transthoracic echocardiography and images were reviewed by an independent cardiologist blinded from clinical data. PFO was defined according to the CLOSE trial criteria: PFO associated with interatrial septal aneurysm or significant interatrial shunt (> 30 microbubbles in the left atrium within three cardiac cycles after right atrial opacification). The potential association of PFO-related stroke with biomarkers of cardiac fibrosis and inflammation such as galectin-3, GDF-15, ST-2, osteoprotegerin and NT-proBNP was tested using multivariate backward stepwise logistic regression. RESULTS: Of the 240 patients included in the SAFAS study, 229 had complete echocardiographic data, and 23 (10%) had PFO-related stroke. Patients with PFO-related stroke were significantly younger (58±14 vs. 69±14, P<0.001), had less frequent previous arterial hypertension (30 vs. 60%, P=0.008), and more frequent cerebellar territory involvement (26 vs. 9%, P=0.014) compared to the other patients. In addition, they had less frequently left atrial dilatation (left atrial index volume>34mL/m2 [9 vs. 35%, P=0.009]). After ROC curve analysis for definition of thresholds, PFO-related stroke patients more often had galectin-3<9.5ng/mL (59 vs. 27%, P=0.002), ST2<13380pg/ml (23 vs. 50%, P=0.007), GDF-15<1200ng/mL (59 vs. 27%, P=0.002), osteoprotegerin<1133pg/mL (82 vs. 58%, P=0.033) and NT-proBNP<300pg/mL (88 vs. 55%, P=0.009). After multivariate analysis, only galectin-3<9.5ng/mL (OR [95% CI] 3.4 [1.18; 9.8], P=0.024) and osteoprotegerin<1133pg/L (OR [95% CI] 5.0 [1.1; 22.9], P=0.038) were independently associated with PFO-related stroke. CONCLUSION: Patients in whom cryptogenic stroke is attributed to a significant PFO have a specific clinical and biological phenotype. Low levels of galectin-3 and osteoprotegerin may help identify patients with PFO-related strokes.

Identification and stable expression of vitellogenin receptor through vitellogenesis in the European eel.

In teleosts, vitellogenin (Vtg) is a phospholipoglycoprotein synthesized by the liver, released into the blood circulation and incorporated into the oocytes via endocytosis mediated by the Vtg receptor (VTGR) to form the yolk granules. The VTGR is crucial for oocyte growth in egg-laying animals but is also present in non-oviparous vertebrates, such as human. The VTGR belongs to the low-density lipoprotein receptor superfamily (LDLR) and is also named very-low-density lipoprotein receptor (VLDLR). In this study, we identified and phylogenetically positioned the VTGR of a basal teleost, the European eel, Anguilla anguilla. We developed quantitative real-time PCR (qRT-PCR) and investigated the tissue distribution of vtgr transcripts. We compared by qRT-PCR the ovarian expression levels of vtgr in juvenile yellow eels and pre-pubertal silver eels. We also analyzed the regulation of ovarian vtgr expression throughout vitellogenesis in experimentally matured eels. The Vtg plasma level was measured by homologous ELISA experimental maturation. Our in silico search and phylogenetical analysis revealed a single vtgr in the European eel, orthologous to other vertebrate vtgr. The qRT-PCR studies revealed that vtgr is mainly expressed in the ovary and also detected in various other tissues such as brain, pituitary, gill, fat, heart, and testis, suggesting some extra-ovarian functions of VTGR. We showed that vtgr is expressed in ovaries of juvenile yellow eels with no higher expression in pre-pubertal silver eels nor in experimentally matured eels. This suggests that vtgr transcription already occurs during early pre-vitellogenesis of immature eels and is not further activated in vitellogenic oocytes. European eel Vtg plasma level increased throughout experimental maturation in agreement with previous studies. Taken together, these results suggest that vtgr transcript levels may not be a limiting step for the uptake of Vtg by the oocyte in the European eel.

Gonadotropin-inhibitory hormone in teleosts: New insights from a basal representative, the eel.

Since its discovery in birds, gonadotropin-inhibitory hormone (GnIH) has triggered investigation in the other groups of vertebrates. In the present study, we have identified a single gnih gene in the European eel (Anguilla anguilla), a representative species of a basal group of teleosts (Elopomorphs). We have also retrieved a single gnih gene in Osteoglossomorphs, as well as in more recently emerged teleosts, Clupeocephala. Phylogeny and synteny analyses allowed us to infer that one of the two gnih paralogs emerged from the teleost-specific whole genome duplication (TWGD or 3R), would have been lost shortly after the 3R, before the emergence of the basal groups of teleosts. This led to the presence of a single gnih in extant teleosts as in other vertebrates. Two gnih paralogs were still found in some teleost species, such as in salmonids, but resulting from the additional whole genome duplication that specifically occurred in this lineage (4R). Eel gnih was mostly expressed in the diencephalon part of the brain, as analyzed by quantitative real-time PCR. Cloning of eel gnih cDNA confirmed that the sequence of the GnIH precursor encoded three putative mature GnIH peptides (aaGnIH-1, aaGnIH-2 and aaGnIH-3), which were synthesized and tested for their direct effects on eel pituitary cells in vitro. Eel GnIH peptides inhibited the expression of gonadotropin subunits (lhß, fshß, and common a-subunit) as well as of GnRH receptor (gnrh-r2), with no effect on tshß and gh expression. The inhibitory effect of GnIH peptides on gonadotropic function in a basal teleost is in agreement with an ancestral inhibitory role of GnIH in the neuroendocrine control of reproduction in vertebrates.

Common SNPs of AmelogeninX (AMELX) and dental caries susceptibility.

Genetic approaches have shown that several genes could modify caries susceptibility; AmelogeninX (AMELX) has been repeatedly designated. Here, we hypothesized that AMELX mutations resulting in discrete changes of enamel microstructure may be found in children with a severe caries phenotype. In parallel, possible AMELX mutations that could explain resistance to caries may be found in caries-free patients. In this study, coding exons of AMELX and exon-intron boundaries were sequenced in 399 individuals with extensive caries (250) or caries-free (149) individuals from nine French hospital groups. No mutation responsible for a direct change of amelogenin function was identified. Seven single-nucleotide polymorphisms (SNPs) were found, 3 presenting a high allele frequency, and 1 being detected for the first time. Three SNPs were located in coding regions, 2 of them being non-synonymous. Both evolutionary and statistical analyses showed that none of these SNPs was associated with caries susceptibility, suggesting that AMELX is not a gene candidate in our studied population.

First evidence for a direct inhibitory effect of kisspeptins on LH expression in the eel, Anguilla anguilla.

The kisspeptin system has emerged as one of the main puberty gatekeepers among vertebrates. The European eel (Anguilla anguilla) is a remarkable model due to its phylogenetical position at the basis of teleosts, and its unique life cycle with a blockade of puberty before reproductive migration. We cloned the full-length coding sequence of a kisspeptin receptor (Kissr) in the eel. Comparison of Kissr sequences assigned the eel Kissr to a basal position in a clade including most of the known teleost Kissr, in agreement with the eel phylogenetical position. Eel Kissr tissue distribution was analyzed by quantitative real-time PCR. Eel Kissr was highly expressed in the brain, especially in the telencephalon and di-/mes-encephalon, while a very low or undetectable expression was observed in various peripheral organs. A high expression of Kissr was also found in the pituitary indicating a possible direct pituitary role of kisspeptin. Primary cultures of eel pituitary cells were performed to investigate the direct effects of kisspeptin on pituitary hormone expression. Human/lamprey kisspeptin exerted a time- and dose-dependent inhibitory effect on LHß expression. All other tested kisspeptins had a similar inhibitory effect on LHß expression. The inhibitory effect of kisspeptins was exerted specifically on LHß as no change was induced on the expression of other glycoprotein hormone subunits (GPα, FSHß and TSHß) nor of growth hormone. These data provide the first evidence for the existence, in the European eel, of a kisspeptin system, which may play a direct inhibitory role on pituitary LHß expression.

[Clinical and economical evaluation of bivalirudin during percutaneous coronary interventions]. / Evaluations clinique et économique de la bivalirudine au cours des procédures d'angioplasties coronaires.

Bivalirudin, with provisional GP IIb/IIIa inhibitor use allows the same protection against ischemic complications while reducing the hemorrhagic complications compared with the systematic association of a GP IIb/IIIa inhibitor plus heparin (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 [Replace-2]). In clinical practice, the use of heparin is not systematically associated with a GP IIb/IIIa inhibitor. That's why we studied the clinical and economic interest of bivalirudin only versus heparin (UFH) only. Opened pragmatic monocentric study carried out in 2007. We made a chronological matching: for each patient treated with bivalirudin, we included the next patient with the same clinical presentation treated with unfractionated heparin. Ninety-two patients were included (46 in each group). The need for a GP IIb/IIIa inhibitor during the PCI was not significantly different between the two groups (p=0.11). No major hemorrhagic complications were observed in the two groups. Prevalence of ecchymosis was not significantly different: 22 % in the UFH group versus 13 % in the bivalirudin group (p=0.27). The average troponin level the next day was significantly higher in the bivalirudin group (p=0,049), although the change in troponin levels before and after the procedure was similar in the two groups. The average cost by patient of anticoagulation by bivalirudin and HNF is very different, respectively 473+/-150 and 51+/-146 euro (p=0.0001). Bivalirudin can be an interesting alternative for patients with a high risk of having complications. But considering its cost this therapy must be used only for selected patients.

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations.

BACKGROUND: Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date. METHODS: The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families. RESULTS: Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan-Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations. CONCLUSION: This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.

Magnetic resonance imaging of ruptured plaques in the rabbit with ultrasmall superparamagnetic particles of iron oxide.

BACKGROUND: Magnetic resonance imaging (MRI) enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO) has previously been evaluated in hyperlipidemic rabbits. The aim of this study was therefore to compare USPIO in ruptured and non-ruptured arteries in an atherosclerotic rabbit model. METHODS: Atherosclerotic-like lesions were induced by the combination of endothelial abrasion and high-cholesterol diet in iliac rabbit arteries (n = 16). Rupture of atherosclerotic lesions was realized by oversized balloon angioplasty in one iliac artery, whereas the contralateral artery was used as control. USPIO (ferumoxtran-10: 1 mmol Fe/kg) was administered immediately (n = 10) or 28 days (n = 6) after injury. MRI and histological analysis were performed 7 and 35 days after injury and in control arteries. RESULTS: In vivo MRI analysis showed extended susceptibility artifact with transluminal signal loss in all ruptured arteries 7 days after injury. In contrast, hyposignal was reduced 35 days following injury (i.e. after healing), and absent in non-ruptured arteries. Similarly, histological analysis of iron uptake was significantly increased 7 days after injury compared to healed-ruptured and control arteries. CONCLUSIONS: Accumulation ofUSPIO is significantly increased in ruptured as compared to non-ruptured arteries in the atherosclerotic rabbit model.

[Gp IIb/IIIa receptor antagonists in acute coronary syndromes with no ST elevation]. / Antagonistes des récepteurs Gp IIb/IIIa dans les syndromes coronaires aigus sans sus décalage du segment ST.

Gp IIb/IIIa receptor antagonists have been the subject of much work in patients presenting with acute coronary syndrome with no ST elevation (ACS ST-). The initial studies (PRISM, PRISM-PLUS, PURSUIT, PARAGON, CAPTURE, GUSTO IV-ACS) were performed at the end of the 1990s and universally showed a significant reduction in an endpoint combining death and myocardial infarction, especially in patients with an elevation of troponin and treated by angioplasty. However, these studies were performed at a time when clopidogrel was not being used regularly for this indication. Four randomised studies have recently re-evaluated the significance of Gp IIb/IIIa blockers prescribed either on admission to coronary intensive care (ELISA-2, PRACTICE) or in the coronary angiography suite during angioplasty (ADVANCE, ISAR-REACT 2) in patients presenting with ACS ST- pre-treated with clopidogrel in association with aspirin and heparin. The results of these studies suggest that Gp IIb/IIIa blockers initiated at the start of angioplasty significantly reduce an endpoint combining death, myocardial infarction and the need for emergency revascularisation. On the other hand, studies in which Gp IIb/IIIa blockers are initiated in coronary intensive care have been negative, but they have only been carried out on small numbers. The results of the ACUITY study comparing bivalirudin and Gp IIb/IIIa blockers in this context have recently been published. Bivalirudin seems to compare well with Gp IIb/IIIa blockers in terms of ischemia, but it significantly reduces the occurrence of hemorrhagic events.

[Coronary angioplasty in the acute phase of a myocardial infarction on a myocardial bridge]. / Angioplastie coronaire à la phase aiguë d'un infarctus du myocarde sur pont myocardique.

A myocardial bridge is usually asymptomatic but can cause myocardial ischemia, myocardial infarction or sudden death. Two occurrences of coronary angioplasty in the acute phase of an anterior myocardial infarction on a myocardial bridge are reported. The first case was first treated only with a balloon, and then with a stent 12 h later after a relapse of angina pectoris and the recurrence of a severe compression. The second case immediately benefited from a stent. A systematic control at six months has shown the absence of restenosis in the first case and an asymptomatic occlusion of the stent in the second case. Its deocclusion has revealed a myocardial bridge downstream of the stent. Myocardial stunning might have caused a decreased systolic compression by the bridge in the first case, and an underestimation of its actual length in the second case. Its regression is held responsible for these two relapses. A long active stent installed at high pressure could be used to treat myocardial bridges during myocardial infarctions.

[Anticoagulants and dental extractions]. / Anticoagulants et extractions dentaires.

Dental extractions in patients under platelet antiaggregant or anticoagulant therapy pose the problem of risk benefit between stopping or carrying on treatment. The difficulties of reequilibrating the INR after a heparin relay have led surgeons and cardiologists to look for alternative solutions. Different means of local haemostasis using products with haemostatic properties or not, or the use of sutures or glues, have given encouraging results but there is too much uncertainty for systematic recommendations to practicians responsible for dental extractions in these patients. The authors propose a technique which has the advantages of associating systematically different methods, making bleeding complications very unusual, without interrupting anticoagulant or antiaggregant therapy.

Usefulness and clinical impact of a fractional flow reserve and angiographic targeted strategy for coronary artery stenting: FROST III, a multicenter prospective registry.

BACKGROUND: Fractional flow reserve (FFR) is correlated with angiographic and intravascular ultrasound assessments of stent placement. Post-stenting FFR has been described as a good predictor of clinical events after 6 months. OBJECTIVE: To evaluate the feasibility and clinical impact of targeting an FFR > 0.95 via incremental in-stent inflation pressures. METHODS: In this multicenter prospective study, 100 consecutive patients underwent FFR measurement at baseline, after balloon predilatation, and after stenting with 4-atm inflation pressure increments from 8 to 20 atmospheres. Inflations were stopped when FFR increased above 0.95 and angiographic stenosis was less than 20%. RESULTS: FFR > 0.95 was achieved in 81% of cases; this FFR target was reached at 8 atm in 47% of patients, 12 atm in 16 %, 16 atm in 15%, and 20 atm in 3%. Fifty percent of patients with adequate angiographic result had an FFR less than 0.95 and needed further higher inflations. FFR was correlated with residual stenosis when the total procedure was evaluated, and this correlation persisted when in-stent inflations alone were considered. Final FFR was significantly correlated with anginal status after 6 months. CONCLUSIONS: Angiography guided PCI does not allow optimization of FFR. Since optimal post stenting FFR is correlated to better anginal status at 6-months, this suggests that FFR guided PCI is required to achieve optimal functional results of PCI.

Possible involvement of gelatinase A (MMP2) and gelatinase B (MMP9) in toxic epidermal necrolysis or Stevens-Johnson syndrome.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are considered to be drug-induced diseases, and are characterized by extensive mucocutaneous disorder and epidermal necrosis which result in the detachment of the epidermis. Inactive and active forms of metalloproteinases (MMP2 and MMP9) secreted by skin explants maintained in organ culture for 72 h and in blister fluid from two TEN and three SJS patients were investigated. Interestingly, lesional skin from both the TEN and the SJS patients cultured for 3 days in conditioned medium showed high levels of both 72 kDa progelatinase A and 66 kDa activated gelatinase A, and the 66 kDa activated form was not observed in cultures of skin from control individuals. Furthermore, indirect immunodetection showed the presence of MMP2 and MMP9 in TEN and SJS patients' skin. Increased gelatinase activity in the culture medium of TEN and SJS skin maintained in organ culture and in blister fluid indicates that these gelatinases may be responsible for the detachment of the epidermis in these drug-induced necrolyses.

In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion.

BACKGROUND: The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. METHODS AND RESULTS: Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43+/-0.30 versus 0.93+/-0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries. CONCLUSIONS: In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.

Drug eluting stents: are human and animal studies comparable?

Animal models of stenting probably predict human responses as the stages of healing are remarkably similar. What is characteristically different is the temporal response to healing, which is substantially prolonged in humans. The prevention of restenosis in recent clinical trials of drug eluting stents may represent a near absent or incomplete phase of intimal healing. Continued long term follow up of patients with drug eluting stents for major adverse cardiac events and angiographic restenosis is therefore imperative.

[Beating heart in "aortic no-touch off-pump" techniques: a simple answer to complex surgical situations]. / Le coeur battant en "no-touch aortique complet": une solution simple à des problémes chirurgicaux complexes.

Three cases reports illustrate the concept of beating heart cardiac surgery and its advantages regarding the prevention of arterial emboli.

[Biochemical markers of myocardial ischemia and necrosis]. / Marqueurs biochimiques d'ischémie et de nécrose myocardique.

The biochemical markers of myocardial ischaemia have to be interpreted according to their kinetics; their interests depend on the clinical presentation. They are helpful to orient to a myocardial ischaemia in front of undefined chest pain, to stratify the outcome of acute coronary syndrome without ST segment elevation, to evaluate the amount of myocardial damage following infarction, to detect the failure of thrombolysis therapy and probably to stratify the post percutaneous coronary intervention outcome.

A tale of two countries: costs and financial incentives for provisional stenting during percutaneous coronary intervention in France and the United States.

Provisional stenting is associated with longer physician time but the use of fewer stents. This randomized controlled trial in tertiary care in French hospitals compared strategies of systematic and provisional stenting. We estimated the costs and financial incentives associated with each strategy, based on individual data on 12-month resource use drawn from a 251-patient database. Resources were evaluated using French costs; data on costs in the United States were drawn from the literature and interviews with hospital administrators in one center. In France 1-year costs were 8,267+/-528 dollars for provisional stenting and 7,973+/-553 dollars for systematic stenting, compared to 18,715 dollars and 18,632 dollars in the United States. Given the uncertainty of longterm results, the choice between stenting strategies might be guided by financial incentives. In the United States financial incentives favor systematic stenting, while in France public hospitals and physicians are neutral.