Antithrombotic Management and Outcomes of Anterior ST-Elevation Myocardial Infarction With New-Onset Wall Motion Abnormalities in Men and Women.

Background: In patients with anterior ST-elevation myocardial infarction (STEMI) and new-onset antero-apical wall motion abnormalities (WMAs), whether the rate of prophylaxis against left ventricular thrombus and outcomes differ between men and women is unknown. Methods: A multicentre retrospective cohort study of patients with STEMI and new-onset antero-apical WMAs treated with primary percutaneous coronary intervention was conducted. Patients with an established indication of oral anticoagulation (OAC) were excluded. The rates of triple therapy (double antiplatelet therapy + OAC) at discharge were compared for women vs men. The rates of net adverse clinical events, a composite of mortality, myocardial infarction, stroke or transient ischemic attack, systemic thromboembolism or Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding at 6 months were compared across sex using a multivariate logistic regression model. Results: A total of 1664 patients were included in the primary analysis, of whom 402 (24.2%) were women and 1262 (75.8%) were men. A total of 138 women (34.3%) and 489 men (38.7%) received a triple therapy prescription at discharge (P = 0.11). At 6 months, 33 women (8.2%) and 96 men (7.6%) experienced a net adverse clinical event (adjusted odds ratio 0.82; 95% confidence interval 0.49-1.37). No difference occurred in the risk of bleeding events and ischemic events between men and women, when these were analyzed separately. Conclusions: The rates of OAC prescription for left ventricular thrombus prophylaxis and clinical outcomes at 6 months were similar in women and men following anterior STEMI with new-onset antero-apical WMAs.

Contexte: On ignore si le taux de prophylaxie contre le thrombus ventriculaire gauche et les résultats thérapeutiques diffèrent entre les hommes et les femmes qui ont subi un infarctus du myocarde avec élévation du segment ST (STEMI) antérieur et ont des anomalies du mouvement pariétal (AMP) antéroapical d'apparition récente. Méthodes: Nous avons mené une étude de cohorte rétrospective multicentrique auprès de patients qui ont subi un STEMI et ont des AMP d'apparition récente traitées par une intervention coronarienne percutanée primaire. Nous avons exclu les patients chez lesquels il existait une indication établie à l'anticoagulation orale (ACO). Nous avons comparé les taux de trithérapie (bithérapie antiplaquettaire + ACO) à la sortie de l'hôpital entre les femmes et les hommes. Nous avons comparé les taux d'événements indésirables cliniques nets, le critère composite de mortalité, d'infarctus du myocarde, d'accident vasculaire cérébral ou d'accident ischémique transitoire, la thromboembolie systémique ou l'hémorragie de type 3 ou 5 selon le Bleeding Academic Research Consortium (BARC) après 6 mois entre les sexes au moyen du modèle de régression logistique multivariée. Résultats: Au sein des 1 664 patients de l'analyse principale, 402 (24,2 %) étaient des femmes et 1262 (75,8 %) étaient des hommes. Un total de 138 femmes (34,3 %) et de 489 hommes (38,7 %) ont reçu une ordonnance de trithérapie à la sortie de l'hôpital (P = 0,11). Après 6 mois, 33 femmes (8,2 %) et 96 hommes (7,6 %) ont subi un événement indésirable net (rapport de cotes ajusté 0,82 ; intervalle de confiance à 95 % 0,49-1,37). Aucune différence n'a été notée dans le risque d'événements hémorragiques et d'événements ischémiques entre les hommes et les femmes lorsque ces événements étaient analysés séparément. Conclusions: Les taux d'ordonnances d'ACO en prophylaxie du thrombus ventriculaire gauche et les résultats cliniques après 6 mois étaient similaires entre les femmes et les hommes à la suite du STEMI antérieur et des AMP antéroapicale d'apparition récente.

Contemporary incidence and predictors of left ventricular thrombus in patients with anterior acute myocardial infarction.

BACKGROUND: The incidence of left ventricular thrombus (LVT) after anterior acute myocardial infarction (AMI) has not been well established in the era of primary percutaneous coronary intervention (pPCI) and potent dual antiplatelet therapy. The objective of this study is to establish the contemporary incidence of LVT in this population, to identify their risk factors, and to examine their association with clinical outcomes. METHODS: A multicenter retrospective cohort study including AMI patients with new-onset antero-apical wall motion abnormalities treated with pPCI between 2009 and 2017 was conducted. The primary outcome was LVT during the index hospitalization. Predictors of LVT were identified using multivariate logistic regression. Net adverse clinical events (NACE), a composite of mortality, myocardial infarction, stroke or transient ischemic attack, systemic thromboembolism or BARC type 3 or 5 bleeding at 6 months were compared between the LVT and no LVT groups. RESULTS: Among the 2136 patients included, 83 (3.9%) patients developed a LVT during index hospitalization. A lower left ventricular ejection fraction (LVEF) [adjusted odds ratio (aOR) 0.97; 95% confidence intervals (CI) 0.94-0.99] and the degree of worse anterior WMA (aOR 4.34; 95% CI 2.24-8.40) were independent predictors of LVT. A NACE occurred in 5 (5.72 per 100 patient-year) patients in the LVT group and in 127 (6.71 per 100 patient-year) patients in the no LVT group at 6 months [adjusted hazard ratio (aHR): 0.87; 95% CI 0.35-2.14]. CONCLUSIONS: The risk of LVT after anterior AMI with new-onset wall motion abnormalities is low, but this complication remains present in the contemporary era of timely pPCI and potent dual antiplatelet therapy .

Impact of clinical variables on outcomes in refractory cardiac arrest patients undergoing extracorporeal cardiopulmonary resuscitation.

Background: In the past two decades, extracorporeal resuscitation (ECPR) has been increasingly used in the management of refractory cardiac arrest (CA) patients. Decision algorithms have been used to guide the care such patients, but the effectiveness of such decision-making tools is not well described. The aim of this study was to compare the rate of survival with a good neurologic outcome of patients treated with ECPR meeting all criteria of a clinical decision-making tool for the initiation of ECPR to those for whom ECPR was implemented outside of the algorithm. Methods: All patients who underwent E-CPR between January 2014 and December 2021 at the Montreal Heart Institute were included in this retrospective analysis. We dichotomized the cohort according to adherence or non-adherence with the ECPR decision-making tool, which included the following criteria: age ≤65 years, initial shockable rhythm, no-flow time <5 min, serum lactate <13 mmol/L. Patients were included in the "IN" group when they met all criteria of the decision-making tool and in the "OUT" group when at least one criterion was not met. Main outcomes and measures: The primary outcome was survival with intact neurological status at 30 days, defined by a Cerebral Performance Category (CPC) Scale 1 and 2. Results: A total of 41 patients (IN group, n = 11; OUT group, n = 30) were included. A total of 4 (36%) patients met the primary outcome in the IN group and 7 (23%) in the OUT group [odds ratio (OR): 1.88 (95% CI, 0.42-8.34); P = 0.45]. However, survival with a favorable outcome decreased steadily with 2 or more deviations from the decision-making tool [2 deviations: 1 (11%); 3 deviations: 0 (0%)]. Conclusion and relevance: Most patients supported with ECPR fell outside of the criteria encompassed in a clinical decision-making tool, which highlights the challenge of optimal selection of ECPR candidates. Survival rate with a good neurologic outcome did not differ between the IN and OUT groups. However, survival with favorable outcome decreased steadily after one deviation from the decision-making tool. More studies are needed to help select proper candidates with refractory CA patients for ECPR.

Oral Anticoagulation for the Prevention of Thromboembolic Events in Patients With Anterior ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: The objective is to assess the comparative effectiveness and safety of dual-antiplatelet therapy (DAPT) vs triple therapy (TT) with DAPT + oral anticoagulant (OAC) in patients with anterior ST-segment elevation myocardial infarction (STEMI) and with new-onset anterior/apical wall-motion abnormalities (WMAs) treated with primary percutaneous coronary intervention (PCI). BACKGROUND: Patients with STEMI and new-onset anterior/apical WMA may benefit from the addition of OAC to prevent left ventricular thrombus and cardioembolic events. METHODS: A multicenter, retrospective cohort study was conducted. Patients with a concomitant indication for OAC were excluded. Patients discharged on TT were compared with patients discharged on DAPT using adjusted Cox proportional hazards analysis and inverse probability of treatment weighting. The primary endpoint was the net adverse clinical event (NACE) rate at 6 months (composite of all-cause mortality, non-fatal MI, stroke, or transient ischemic attack, systemic thromboembolism or type 3 or 5 Bleeding Academic Research Consortium [BARC] bleeding). RESULTS: A total of 1666 patients were included, among which 627 were treated with TT and 1039 were treated with DAPT. A NACE occurred in 55 patients (6.03 per 100 patient-years) in the TT group and in 74 patients (7.18 per 100 patient-years) in the DAPT group (adjusted hazard ratio, 0.86; 95% confidence interval, 0.55-1.32). Adjusted risk of the individual components of the primary endpoint, ischemic events, and bleeding events were similar between both groups (P>.05 for all). CONCLUSIONS: The addition of OAC to DAPT in anterior STEMI patients with new-onset WMA treated with PCI was not associated with a significant reduction in NACE.

Minimal PaO2 threshold after traumatic brain injury and clinical utility of a novel brain oxygenation ratio.

OBJECTIVE: Avoiding decreases in brain tissue oxygenation (PbtO2) after traumatic brain injury (TBI) is important. How best to adjust PbtO2 remains unclear. The authors investigated the association between partial pressure of oxygen (PaO2) and PbtO2 to determine the minimal PaO2 required to maintain PbtO2 above the hypoxic threshold (> 20 mm Hg), accounting for other determinants of PbtO2 and repeated measurements in the same patient. They also explored the clinical utility of a novel concept, the brain oxygenation ratio (BOx ratio = PbtO2/PaO2) to detect overtreatment with the fraction of inspired oxygen (FiO2). METHODS: A retrospective cohort study at an academic level 1 trauma center included 38 TBI patients who required the insertion of a monitor to measure PbtO2. Various determinants of PbtO2 were collected simultaneously whenever a routine arterial blood gas was drawn. A PbtO2/PaO2 ratio was calculated for each blood gas and plotted over time for each patient. All patients were managed according to a standardized clinical protocol. A mixed effects model was used to account for repeated measurements in the same patient. RESULTS: A total of 1006 data points were collected. The lowest mean PaO2 observed to maintain PbtO2 above the ischemic threshold was 94 mm Hg. Only PaO2 and cerebral perfusion pressure were predictive of PbtO2 in multivariate analysis. The PbtO2/PaO2 ratio was below 0.15 in 41.7% of all measures and normal PbtO2 values present despite an abnormal ratio in 27.1% of measurements. CONCLUSIONS: The authors' results suggest that the minimal PaO2 target to ensure adequate cerebral oxygenation during the first few days after TBI should be higher than that suggested in the Brain Trauma Foundation guidelines. The use of a PbtO2/PaO2 ratio (BOx ratio) may be clinically useful and identifies abnormal O2 delivery mechanisms (cerebral blood flow, diffusion, and cerebral metabolic rate of oxygen) despite normal PbtO2.

Derivation and expansion of PAX7-positive muscle progenitors from human and mouse embryonic stem cells.

Cell therapies treating pathological muscle atrophy or damage requires an adequate quantity of muscle progenitor cells (MPCs) not currently attainable from adult donors. Here, we generate cultures of approximately 90% skeletal myogenic cells by treating human embryonic stem cells (ESCs) with the GSK3 inhibitor CHIR99021 followed by FGF2 and N2 supplements. Gene expression analysis identified progressive expression of mesoderm, somite, dermomyotome, and myotome markers, following patterns of embryonic myogenesis. CHIR99021 enhanced transcript levels of the pan-mesoderm gene T and paraxial-mesoderm genes MSGN1 and TBX6; immunofluorescence confirmed that 91% ± 6% of cells expressed T immediately following treatment. By 7 weeks, 47% ± 3% of cells were MYH(+ve) myocytes/myotubes surrounded by a 43% ± 4% population of PAX7(+ve) MPCs, indicating 90% of cells had achieved myogenic identity without any cell sorting. Treatment of mouse ESCs with these factors resulted in similar enhancements of myogenesis. These studies establish a foundation for serum-free and chemically defined monolayer skeletal myogenesis of ESCs.

Forward and reverse genetics through derivation of haploid mouse embryonic stem cells.

All somatic mammalian cells carry two copies of chromosomes (diploidy), whereas organisms with a single copy of their genome, such as yeast, provide a basis for recessive genetics. Here we report the generation of haploid mouse ESC lines from parthenogenetic embryos. These cells carry 20 chromosomes, express stem cell markers, and develop into all germ layers in vitro and in vivo. We also developed a reversible mutagenesis protocol that allows saturated genetic recessive screens and results in homozygous alleles. This system allowed us to generate a knockout cell line for the microRNA processing enzyme Drosha. In a forward genetic screen, we identified Gpr107 as a molecule essential for killing by ricin, a toxin being used as a bioweapon. Our results open the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale.

Rat blastocyst-derived stem cells are precursors of embryonic and extraembryonic lineages.

Despite recent advances in the derivation of rat embryonic stem cells, clear comprehension of the timing and mechanisms underlying rat early embryo lineage selection is lacking. We have previously shown the in vivo contribution of rat embryonic stem-like cells exclusively to developing extraembryonic tissues. To elucidate possible mechanisms governing the in vitro and in vivo behaviors of these rat blastocyst-derived stem cells, we evaluated their developmental capacity by using several approaches. Molecular marker analysis demonstrated the expression profile of genes characterizing not only pluripotency but also extraembryonic endoderm and trophoblast. In vitro differentiation through embryoid body formation showed in vitro pluripotent capacity through differentiation into derivatives of all three embryonic germ layers. Following either blastocyst injection, diploid or tetraploid aggregation, and embryo transfer, these rat blastocyst-derived stem cells also demonstrated in vivo multipotency through contribution to multiple developmentally distinct extraembryonic lineages. Features of phenotypic heterogeneity were revealed following examination of cell line morphology and culture behavior, as well as quantitative analysis of marker expression in discrete undifferentiated and differentiated populations of cells by flow cytometry. We demonstrate for the first time that stem cells derived from the rat blastocyst have the ability to contribute to the embryonic and extraembryonic lineages. Together, these results provide a valuable new model for rat stem cell biology and for the elucidation of early lineage selection in the embryo.

Trophoblast stem cell marker gene expression in inner cell mass-derived cells from parthenogenetic equine embryos.

Although putative horse embryonic stem (ES)-like cell lines have been obtained recently from in vivo-derived embryos, it is currently not known whether it is possible to obtain ES cell (ESC) lines from somatic cell nuclear transfer (SCNT) and parthenogenetic (PA) embryos. Our aim is to establish culture conditions for the derivation of autologous ESC lines for cell therapy studies in an equine model. Our results indicate that both the use of early-stage blastocysts with a clearly visible inner cell mass (ICM) and the use of pronase to dissect the ICM allow the derivation of a higher proportion of primary ICM outgrowths from PA and SCNT embryos. Primary ICM outgrowths express the molecular markers of pluripotency POU class 5 homeobox 1 (POU5F1) and (sex determining region-Y)-box2 (SOX2), and in some cases, NANOG. Cells obtained after the passages of PA primary ICM outgrowths display alkaline phosphatase (AP) activity and POU5F1, SOX2, caudal-related homeobox-2 (CDX2) and eomesodermin (EOMES) expression, but may lose NANOG. Cystic embryoid body-like structures expressing POU5F1, CDX2 and EOMES were produced from these cells. Immunohistochemical analysis of equine embryos reveals the presence of POU5F1 in trophectoderm, primitive endoderm and ICM. These results suggest that cells obtained after passages of primary ICM outgrowths are positive for trophoblast stem cell markers while expressing POU5F1 and displaying AP activity. Therefore, these cells most likely represent trophoblast cells rather than true ESCs. This study represents an important first step towards the production of autologous equine ESCs for pre-clinical cell therapy studies on large animal models.

Derivation, culture, and in vivo developmental capacity of embryonic cell lines from rat blastocysts.

Embryonic stem (ES) cells have been used extensively for site-specific gene targeting in the mouse. The resulting knock-out and knock-in mouse models generated so far have demonstrated their usefulness in biomedical research. However, for many diseases and fields of study, the rat still represents a superior model. The derivation and culture of germline-competent ES cells in the rat would allow the application of site-specific gene targeting technologies to this species of indisputable importance to biomedical research. We have recently shown the derivation, culture, and for the first time, in vivo contribution of rat ES-like cells to developing tissues. This represents an important step forward in making gene targeting technologies available to the rat research community, via development of rat ES cells. Here, we describe the materials, methods and techniques that have been used to obtain rat blastocysts, derive and culture embryonic cell lines from these, and assess the developmental capacity of the cells in vivo.

Rat embryonic stem-like (ES-like) cells can contribute to extraembryonic tissues in vivo.

Despite significant advances achieved through gene targeting in mouse embryonic stem (ES) cells, this technology is presently only available in mice. Because the rat is a species of undeniable importance to biomedical research, attempts at derivation of rat ES cell lines have been ongoing for many years; however, the putative rat ES cell lines that have been reported to date have not yet displayed the ability to contribute in vivo to developing tissues following embryo injection. In contrast to previous studies, we describe herein the successful derivation and characterization of rat ES-like cell lines that not only express markers of undifferentiated cells, alkaline phosphatase (AP) activity and stage-specific embryonic antigen-1 (SSEA-1) cell surface antigen, but also retain expression of Oct4 (also known as Pou5f1) a homeodomain transcription factor and molecular marker of pluripotent cells. Notably, these rat ES-like cells, when injected into blastocysts transferred to pseudopregnant females, can contribute to developing extraembryonic tissues. This report demonstrates for the first time that rat ES-like cells can be derived efficiently, can express a panel of pluripotent cell markers, can be genetically modified in vitro and cryopreserved, and importantly, are capable of contributing to extraembryonic tissues in vivo.

Developmental arrest and cytoskeletal anomalies of rat embryos reconstructed by somatic cell nuclear transfer.

Many factors influence success rates in animal cloning by somatic cell nuclear transfer (SCNT), including cell cycle stage of donor cells and recipient oocytes, the procedure of micromanipulation, and the activation protocol. This study was conducted to determine the effects of cell cycle coordination for cloning rats from fetal fibroblasts (FFs). Moreover, enucleated zygotic and parthenogenetic ooplasts were used for serial cloning with pronuclear and two-cell stage blastomeres derived from SCNT. Metaphase donor cells had a significantly higher cleavage rate than G0/G1-phase FFs with MII oocytes and G2-phase FFs with TII oocytes. However, reconstructed embryos were unable to develop beyond the two-cell stage, neither in vitro nor in vivo. Moreover, the developmental arrest at the two-cell stage was not overcome, even when using serial cloning with zygotic and parthenogenetic recipients. To assess the cytoskeleton after SCNT, reconstructed two-cell stage embryos were harvested at different times after cleavage for immunostaining (anti-alpha-tubulin) and mRNA abundance (beta-actin, alpha-tubulin, alpha-actinin). Reconstructed two-cell embryos showed abnormal microtubule distribution and down-regulated expression of several cytoskeletal transcripts. Therefore, it seems that the developmental arrest of rat SCNT embryos is associated with improper transcription of cytoskeleton genes, presumably resulting in abnormal microtubule distribution.