Immunoengineered MXene nanosystem for mitigation of alloantigen presentation and prevention of transplant vasculopathy.

MXenes are an emerging class of nanomaterials with significant potential for applications in nanomedicine. Amongst MXene technologies, titanium carbide (Ti3C2Tx) nanomaterials are the most mature and have received significant attention to tackle longstanding clinical challenges due to its tailored physical and material properties. Cardiac allograft vasculopathy is an aggressive form of atherosclerosis and a major cause of mortality among patients with heart transplants. Blood vessel endothelial cells (ECs) stimulate alloreactive T-lymphocytes to result in sustained inflammation. Herein, we report the first application of Ti3C2Tx MXene nanosheets for prevention of allograft vasculopathy. MXene nanosheets interacted with human ECs and downregulated the expression of genes involved in alloantigen presentation, and consequently reduced the activation of allogeneic lymphocytes. RNA-Seq analysis of lymphocytes showed that treatment with MXene downregulated genes responsible for transplant-induced T-cell activation, cell-mediated rejection, and development of allograft vasculopathy. In an in vivo rat model of allograft vasculopathy, treatment with MXene reduced lymphocyte infiltration and preserved medial smooth muscle cell integrity within transplanted aortic allografts. These findings highlight the potential of Ti3C2Tx MXene in treatment of allograft vasculopathy and inflammatory diseases.

Long-term survival and quality of life after extracorporeal membrane oxygenation.

OBJECTIVES: Long-term data on patient survivors after extracorporeal membrane oxygenation (ECMO) support remains limited. This study sought to examine the 5-year survival and health-related quality of life (HRQoL) of patients treated with venoarterial (VA)- or venovenous (VV)-ECMO. METHODS: A single-center retrospective chart review and survival analysis was conducted on all patients who required ECMO from December 2007 to June 2019. Cross-sectional HRQoL assessments were performed using 8 standardized questionnaires among survivors. RESULTS: Records for 370 ECMO patients (288 VA-ECMO, 82 VV-ECMO) were reviewed. Survival at 5 years was 33% (VA-ECMO) and 36% (VV-ECMO). Among patients that survived to 30 days, 5-year survival rates were 73% (VA-ECMO) and 71% (VV-ECMO). Sixty surviving patients (56%) had HRQoL assessments (48 VA-ECMO, 12 VV-ECMO). Median follow-up time was 4.2 (VA-ECMO) and 5.7 years (VV-ECMO). Fourteen (29%) VA-ECMO patients and 9 (75%) VV-ECMO patients reported difficulty with any activity of daily living whereas 13 (27%) VA-ECMO patients and 8 (67%) VV-ECMO patients reported difficulty with any instrumental activity of daily living. Eleven (23%) VA-ECMO patients and 7 (58%) VV-ECMO patients reported a high post-traumatic stress disorder score. Low decision regret scores in both cohorts indicated minimal regret that ECMO was initiated. CONCLUSIONS: Five-year clinical and patient-centered outcomes of patients requiring ECMO support is acceptable in those who survived the initial 30 days. Among ECMO survivors, persistent HRQoL concerns were apparent, highlighting the importance of longer-term postdischarge follow-up.

It's not all about ISCHEMIA: the case for coronary artery bypass grafting in stable coronary artery disease.

PURPOSE OF REVIEW: The recent American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Guidelines for Coronary Artery Revascularization have raised concerns on the survival benefits of coronary artery bypass grafting (CABG) over guideline-directed medical therapy (GDMT) in stable coronary artery disease (CAD) and appropriate conduit selection for CABG. This review summarizes the evidence supporting CABG for stable CAD and use of the radial artery as a conduit for CABG. RECENT FINDINGS: CABG has consistently demonstrated a survival benefit over GDMT for patients with stable multivessel CAD. These benefits were more pronounced in patients with diabetes and/or anatomically complex coronary artery disease. The recently published International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial was not designed to and did not include an appropriate patient population to compare revascularization with CABG to GDMT. These results should thus be viewed in the context of previously published studies. Furthermore, increasing evidence suggests that use of a radial artery in CABG is associated with reduced myocardial infarction and repeat revascularization. This should be considered when selecting the appropriate conduits based on underlying patient factors. SUMMARY: Readers should be cautious when applying these guidelines broadly. Appropriate consideration of patient and anatomic factors, and in consultation with a multidisciplinary heart team, is important to achieve the best outcomes for patients.

Development of iPSC-based clinical trial selection platform for patients with ultrarare diseases.

A "Leap-of-Faith" approach is used to treat patients with previously unknown ultrarare pathogenic mutations, often based on evidence from patients having dissimilar but more prevalent mutations. This uncertainty reflects the need to develop personalized prescreening platforms for these patients to assess drug efficacy before considering clinical trial enrollment. In this study, we report an 18-year-old patient with ultrarare Leigh-like syndrome. This patient had previously participated in two clinical trials with unfavorable responses. We established an induced pluripotent stem cell (iPSC)-based platform for this patient, and assessed the efficacy of a panel of drugs. The iPSC platform validated the safety and efficacy of the screened drugs. The efficacy of three of the screened drugs was also investigated in the patient. After 3 years of treatment, the drugs were effective in shifting the metabolic profile of this patient toward healthy control. Therefore, this personalized iPSC-based platform can act as a prescreening tool to help in decision-making with respect to patient's participation in future clinical trials.

A previously undescribed pathogenic variant in FBN1 gene causing Marfan syndrome: a case report.

Background: Marfan syndrome (MFS) is an autosomal dominant multisystem connective tissue disorder with increased risk of aortopathy with a high risk of subsequent life-threatening aortic dissection. Diagnosing this condition is reliant on recognizing clinical features and genetic testing for confirming diagnosis, using the revised Ghent criteria. Case summary: We identified a 49-year-old patient who presented with dyspnoea, with Marfan syndrome (MFS) and a previously unreported variant in the fibrillin-1 gene (FBN1), designated c.7016G>C. Prior to identifying the new gene variant, this patient did not meet the revised Ghent criteria for MFS diagnosis. We present clinical and molecular evidence supporting the likely pathogenic nature of this variant, leading to earlier therapy and intervention. Discussion: The discovery of a new pathogenic gene will expand the current aortopathy and MFS database and may lead to more informed clinical management decisions for the timing and nature of interventions.

Conversion of 2D MXene to Multi-Low-Dimensional GerMXene Superlattice Heterostructure.

Integration of 2D structures into other low-dimensional materials results in the development of distinct van der Waals heterostructures (vdWHSs) with enhanced properties. However, obtaining 2D-1D-0D vdWHSs of technologically useful next generation materials, transition-metal carbide MXene and monoelemental Xene nanosheets in a single superlattice heterostructure is still challenging. Here, the fabrication of a new multidimensional superlattice heterostructure "GerMXene" from exfoliated M3X2T x MXene and hydrogenated germanane (GeH) crystals, is reported. Direct experimental evidence for conversion of hydrothermally activated titanium carbide MXene (A-MXene) to GerMXene heterostructure through the rapid and spontaneous formation of titanium germanide (TiGe2 and Ti6Ge5) bonds, is provided. The obtained GerMXene heterostructure possesses enhanced surface properties, aqueous dispersibility, and Dirac signature of embedded GeH nanosheets as well as quantum dots. GerMXene exhibits functional bioactivity, electrical conductivity, and negative surface charge, paving ways for its applications in biomedical field, electronics, and energy storage.

Current and future transcatheter aortic valve replacement valves.

PURPOSE OF REVIEW: This review analyzes currently available commercial transcatheter aortic valve replacement (TAVR) valves as well as valves in investigational status and those in preclinical testing. The design features and clinical outcomes of the Edwards SAPIEN S3 and Medtronic Evolut PRO+ are described and compared with highlight clinical circumstances where one may be favoured over the other. RECENT FINDINGS: Multiple randomized and nonrandomized trials have compared commercial and investigational TAVR valves. The results of these are summarized and discussed within this review with a focus on how the SAPIEN S3 and Evolut PRO+ both compare to each other as well as various valves in different investigational stages. SUMMARY: TAVR is an innovative and ground-breaking technology that will forever have revolutionized the management of aortic stenosis. Though the technology and valves themselves have come a long way, further developments are necessary if we are to continue to expand its indications and achieve a safer perioperative experience with more durable valves.

Improving outcomes after low-risk coronary artery bypass grafting: understanding phase of care mortality analysis, failure to rescue and recent perioperative recommendations.

PURPOSE OF REVIEW: Avoidable adverse events are responsible for up to 50% of deaths after low-risk coronary artery bypass grafting. This article reviews recent quality improvement efforts to improve outcomes after cardiac surgery. RECENT FINDINGS: Systematic quality improvement methodology in cardiac surgery has improved significantly over the past decade. Contemporary efforts with phase of care mortality analysis (POCMA) focus on identifying and addressing root causes for mortality. Each patient's perioperative course is an interconnected sequence of clinical events, decisions, interventions, and treatment responses occurring across five perioperative phases. A single seminal event within a specific phase of care has been found to often trigger the eventual death of a patient. Several groups have made significant improvements to perioperative outcomes by addressing these avoidable mortality trigger events. Failing that, failure to rescue (FTR) metrics can be used to identify institutional factors responsible for poor perioperative outcomes. This ongoing focus on quality improvement serves to further improve outcomes after low-risk cardiac surgery. SUMMARY: Modern quality improvement methodology, including POCMA and FTR analysis, has the potential to significantly improve outcomes after cardiac surgery. Larger future studies with multiinstitutional data sharing will be key to facilitate ongoing quality improvement and knowledge translation in this field.

Carbon nanomaterials for cardiovascular theranostics: Promises and challenges.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Heart attack and stroke cause irreversible tissue damage. The currently available treatment options are limited to "damage-control" rather than tissue repair. The recent advances in nanomaterials have offered novel approaches to restore tissue function after injury. In particular, carbon nanomaterials (CNMs) have shown significant promise to bridge the gap in clinical translation of biomaterial based therapies. This family of carbon allotropes (including graphenes, carbon nanotubes and fullerenes) have unique physiochemical properties, including exceptional mechanical strength, electrical conductivity, chemical behaviour, thermal stability and optical properties. These intrinsic properties make CNMs ideal materials for use in cardiovascular theranostics. This review is focused on recent efforts in the diagnosis and treatment of heart diseases using graphenes and carbon nanotubes. The first section introduces currently available derivatives of graphenes and carbon nanotubes and discusses some of the key characteristics of these materials. The second section covers their application in drug delivery, biosensors, tissue engineering and immunomodulation with a focus on cardiovascular applications. The final section discusses current shortcomings and limitations of CNMs in cardiovascular applications and reviews ongoing efforts to address these concerns and to bring CNMs from bench to bedside.

Fabrication of Smart Tantalum Carbide MXene Quantum Dots with Intrinsic Immunomodulatory Properties for Treatment of Allograft Vasculopathy.

MXene nanomaterials have sparked significant interest among interdisciplinary researchers to tackle today's medical challenges. In particular, colloidal MXene quantum dots (MQDs) offer the high specific surface area and compositional flexibility of MXene while providing improvements to aqueous stability and material-cell interactions. The current study for the first time reports the development and application of immunoengineered tantalum-carbide (Ta4C3T x ) MQDs for in vivo treatment of transplant vasculopathy. This report comes at a critical juncture in the field as poor long-term safety of other MXene compositions challenge the eventual clinical translatability of these materials. Using rational design and synthesis strategies, the Ta4C3T x MQDs leverage the intrinsic anti-inflammatory and antiapoptotic properties of tantalum to provide a novel nanoplatform for biomedical engineering. In particular, these MQDs are synthesized with high efficiency and purity using a facile hydrofluoric acid-free protocol and are enriched with different bioactive functional groups and stable surface TaO2 and Ta2O5. Furthermore, MQDs are spontaneously uptaken into antigen-presenting endothelial cells and alter surface receptor expression to reduce their activation of allogeneic T-lymphocytes. Finally, when applied in vivo, Ta4C3T x MQDs ameliorate the cellular and structural changes of early allograft vasculopathy. These findings highlight the robust potential of tailored Ta4C3T x MQDs for future applications in medicine.

Development of Fluorine-Free Tantalum Carbide MXene Hybrid Structure as a Biocompatible Material for Supercapacitor Electrodes.

The application of nontoxic 2D transition-metal carbides (MXenes) has recently gained ground in bioelectronics. In group-4 transition metals, tantalum possesses enhanced biological and physical properties compared to other MXene counterparts. However, the application of tantalum carbide for bioelectrodes has not yet been explored. Here, fluorine-free exfoliation and functionalization of tantalum carbide MAX-phase to synthesize a novel Ta4C3Tx MXene-tantalum oxide (TTO) hybrid structure through an innovative, facile, and inexpensive protocol is demonstrated. Additionally, the application of TTO composite as an efficient biocompatible material for supercapacitor electrodes is reported. The TTO electrode displays long-term stability over 10 000 cycles with capacitance retention of over 90% and volumetric capacitance of 447 F cm-3 (194 F g-1) at 1 mV s-1. Furthermore, TTO shows excellent biocompatibility with human-induced pluripotent stem cells-derived cardiomyocytes, neural progenitor cells, fibroblasts, and mesenchymal stem cells. More importantly, the electrochemical data show that TTO outperforms most of the previously reported biomaterials-based supercapacitors in terms of gravimetric/volumetric energy and power densities. Therefore, TTO hybrid structure may open a gateway as a bioelectrode material with high energy-storage performance for size-sensitive applications.

Two-year outcomes from the PARTNER 3 trial: where do we stand?

PURPOSE OF REVIEW: The PARTNER 3 trial was conducted to compare outcomes after transcatheter aortic valve replacement (TAVR) with a balloon-expandable valve and surgical aortic valve replacement (SAVR) in individuals at low surgical risk with aortic stenosis. Recently reported rates of death, stoke and valve thrombosis in the TAVR arm have raised concerns about the longevity of this intervention in low-risk individuals. It is incumbent on all members of the Heart Team to understand the potential consequences of these findings. RECENT FINDINGS: TAVR was initially superior to SAVR at 1 year for a primary composite endpoint of death, stroke and rehospitalization. Results at 2 years now indicate noninferiority. Potential causative factors, comparisons with other transcatheter valves and implications for patients, providers and trainees are explored. Recommendations are additionally provided regarding TAVR and SAVR in individuals with aortic stenosis. SUMMARY: Concerns regarding the longevity of TAVR in low-risk individuals notwithstanding, results from PARTNER 3 indicate that TAVR is at least noninferior to SAVR out to 2 years. Longer follow-up will be required to determine whether these newly founded concerns are justifiable.

Hypoxia-induced downregulation of cyclooxygenase 2 leads to the loss of immunoprivilege of allogeneic mesenchymal stem cells.

Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are reported to hold the potential to treat several immunological and degenerative disorders. However, recent data from animal studies and clinical trials demonstrate that immunogenicity and poor survival of transplanted MSCs impaired the efficacy of cells for regenerative applications. It is reported that initially immunoprivileged under in vitro conditions, MSCs are targeted by the host immune system after transplantation in the ischemic tissues in vivo. We performed in vitro (in MSCs) and in vivo (in the rat model of myocardial infarction [MI]) studies to elucidate the mechanisms responsible for the change in the immunophenotype of MSCs from immunoprivileged to immunogenic under ischemic conditions. We have recently reported that a soluble factor prostaglandin E2 (PGE2) preserves the immunoprivilege of allogeneic MSCs. In the current study, we found that PGE2 levels, which were elevated during normoxia, decreased in MSCs following exposure to hypoxia. Further, we found that proteasome-mediated degradation of cyclooxygenase-2 (COX2, rate-limiting enzyme in PGE2 biosynthesis) in hypoxic MSCs is responsible for PGE2 decrease and loss of immunoprivilege of MSCs. While investigating the mechanisms of COX2 degradation in hypoxic MSCs, we found that in normoxic MSCs, COP9 signalosome subunit 5 (CSN5) binds to COX2 and prevents its degradation by the proteasome. However, exposure to hypoxia leads to a decrease in CSN5 levels and its binding to COX2, rendering COX2 protein susceptible to proteasome-mediated degradation. This subsequently causes PGE2 downregulation and loss of immunoprivilege of MSCs. Maintaining COX2 levels in MSCs preserves immunoprivilege in vitro and improves the survival of transplanted MSCs in a rat model of MI. These data provide novel mechanistic evidence that PGE2 is downregulated in hypoxic MSCs which is responsible for the post-transplantation rejection of allogeneic MSCs. Therefore, our data suggest that the new strategies that target CSN5-COX2 signaling may improve survival and utility of transplanted allogeneic MSCs in the ischemic heart.

Hypoxia-induced increase in Sug1 leads to poor post-transplantation survival of allogeneic mesenchymal stem cells.

Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are immunoprivileged and have the potential to treat numerous degenerative diseases. However, recent reviews of clinical trials report poor long-term survival of transplanted cells in the recipient that turned down the enthusiasm regarding MSC therapies. Increasing evidence now confirm that though initially immunoprivileged, MSCs eventually become immunogenic after transplantation in the ischemic or hypoxic environment of diseased tissues and are rejected by the host immune system. We performed in vitro (in rat and human cells) and in vivo (in a rat model) investigations to understand the mechanisms of the immune switch in the phenotype of MSCs. The immunoprivilege of MSCs is preserved by the absence of cell surface immune antigen, major histocompatibility complex II (MHC-II) molecule. We found that the ATPase subunit of 19S proteasome "Sug1" regulates MHC-II biosynthesis in MSCs. Exposure to hypoxia upregulates Sug1 in MSCs and its binding to class II transactivator (CIITA), a coactivator of MHC-II transcription. Sug1 binding to CIITA in hypoxic MSCs promotes the acetylation and K63 ubiquitination of CIITA leading to its activation and translocation to the nucleus, and ultimately MHC-II upregulation. In both rat and human MSCs, knocking down Sug1 inactivated MHC-II and preserved immunoprivilege even following hypoxia. In a rat model of myocardial infarction, transplantation of Sug1-knockdown MSCs in ischemic heart preserved immunoprivilege and improved the survival of transplanted cells. Therefore, the current study provides novel mechanisms of post-transplantation loss of immunoprivilege of MSCs. This study may help in facilitating better planning for future clinical trials.

The COMPASS trial: practical considerations for application after coronary artery bypass surgery.

PURPOSE OF REVIEW: We review the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial with particular emphasis on patients with a history of remote coronary artery bypass grafting (CABG) and those who were enrolled 4-14 days after CABG. We provide practical guidance for selecting patients with the greatest potential to benefit who have acceptable bleeding risk. In particular, we address concerns about postoperative bleeding and discuss the relative merits of rivaroxaban and aspirin versus P2Y12 inhibition and aspirin. RECENT FINDINGS: The COMPASS trial demonstrated that rivaroxaban and aspirin reduce myocardial infarction, stroke, and cardiovascular death in patients with coronary artery disease, without a demonstrated effect on bypass graft patency in the first postoperative year. SUMMARY: After CABG, cardiac surgeons should consider using the COMPASS regimen in patients at high risk of thrombosis whose risk of bleeding is acceptable. If used, the COMPASS regimen should be continued indefinitely in conjunction with other pharmacological risk reduction therapies to prevent long-term atherothrombotic events.

Hypoxia-induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of mesenchymal stem cells.

Allogeneic mesenchymal stem cells (MSCs) are immunoprivileged and are being investigated in phase I and phase II clinical trials to treat different degenerative and autoimmune diseases. In spite of encouraging outcome of initial trials, the long-term poor survival of transplanted cells in the host tissue has declined the overall enthusiasm. Recent analyses of allogeneic MSCs based studies confirm that after transplantation in the hypoxic or ischemic microenvironment of diseased tissues, MSCs become immunogenic and are rejected by recipient immune system. The immunoprivilege of MSCs is preserved by absence or negligible expression of cell surface antigen, human leukocyte antigen (HLA)-DRα. We found that in normoxic MSCs, 26S proteasome degrades HLA-DRα and maintains immunoprivilege of MSCs. The exposure to hypoxia leads to inactivation of 26S proteasome and formation of immunoproteasome in MSCs, which is associated with upregulation and activation of HLA-DRα, and as a result, MSCs become immunogenic. Furthermore, inhibition of immunoproteasome formation in hypoxic MSCs preserves the immunoprivilege. Therefore, hypoxia-induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of allogeneic MSCs. The outcome of the current study may provide molecular targets to plan interventions to preserve immunoprivilege of allogeneic MSCs in the hypoxic or ischemic environment.

Spinal Epidural Hematoma Secondary to Tenecteplase for ST-Elevation Myocardial Infarction in the Setting of Trauma and Cervical Endplate Fracture.

A 78-year-old woman presented with an inferior ST-segment elevation myocardial infarction in the setting of a fall resulting in facial trauma causing an unrecognized C6 cervical endplate fracture. After administration of tenecteplase, she developed a spinal epidural hematoma requiring intubation for airway protection and cessation of antiplatelet therapies. The need to delay coronary intervention in this setting led to a recurrent inferolateral ST-segment elevation myocardial infarction that eventually required coronary bypass grafting. In the first report of a spinal epidural hematoma after tenecteplase for ST-segment elevation myocardial infarction, we emphasize the need for imaging after significant trauma before initiating thrombolysis.

Une femme de 78 ans a été vue en consultation pour un infarctus du myocarde inférieur avec élévation du segment ST, dans un contexte de trauma facial entraîné par une chute, causant une fracture du plateau vertébral de C6 non diagnostiquée. Après avoir reçu du ténectéplase, la patiente a présenté un hématome épidural rachidien ayant nécessité l'intubation pour protéger les voies respiratoires et l'arrêt des traitements antiplaquettaires. La nécessité de retarder l'intervention coronarienne dans ce contexte a entraîné un nouvel infarctus du myocarde inférolatéral avec élévation du segment ST, ayant par la suite nécessité un pontage aortocoronarien. Relativement au premier rapport d'hématome épidural rachidien survenu après l'administration de ténectéplase pour le traitement de l'infarctus du myocarde avec élévation du segment ST, nous insistons sur l'importance de procéder, avant d'instaurer la thrombolyse, à des examens d'imagerie chez les patients ayant subi un trauma important.