Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease.

OBJECTIVE: To test the efficacy of metformin (MET) during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy. BACKGROUND: Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether MET pretreatment could ameliorate therapeutic decrements associated with MS. METHODS: Yorkshire swine (n = 29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg oral MET or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for 5 weeks before the acquisition of functional and perfusion data immediately before terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups. RESULTS: Regardless of EV administration, animals that received MET exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing, improved perfusion to the most ischemic myocardial region at rest and during pacing, and markedly reduced apoptosis. CONCLUSIONS: MET administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and MS.

Cardioprotection in cardiovascular surgery.

Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.

History of Psychoactive Medication a Risk Factor for Neurocognitive Decline After Cardiac Surgery.

INTRODUCTION: Neurocognitive decline (NCD) is a common complication after cardiac surgery with implications for outcomes and quality of life. Identifying risk factors can help surgeons implement preventative measures, optimize modifiable risk factors, and counsel patients about risk and prognosis. METHODS: Prospective cohort study at a single academic center. 104 patients planned to undergo cardiac surgery were enrolled. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to measure neurocognitive function preoperatively, on postoperative day four, and postoperative day 30. NCD is defined as a change in RBANS scaled score of < -8 from baseline to postoperative day 4. Patient charts were reviewed for medication history: beta-blockers, angiotensin-converting enzyme and angiotensin receptor blockers, calcium channel blockers, statins, oral hypoglycemic agents, and psychoactive medications. Charts were also reviewed to calculate postoperative opioid usage. RESULTS: NCD was detected in 42.9% of patients. Incidence of NCD was significantly higher in patients taking a psychoactive medication (56.8%) than patients not (31.9%), P < 0.03. There was no relationship between historical use of beta-blocker, calcium-channel blocker, statin, or oral hypoglycemic medications and incidence of NCD. Simple linear regression showed no relationship between change in RBANS total scaled score and opioid usage. There was no difference in incidence of NCD at 1 mo. CONCLUSIONS: Patients with a history of taking psychoactive medications prior to cardiac surgery have an increased risk of acute postoperative NCD.

Association Between Marijuana Use and Clinical Outcomes After Coronary Artery Bypass Grafting.

INTRODUCTION: Though marijuana use has been linked to an increase in heart failure admissions, no prior study has explored the association between its use and outcomes after coronary artery bypass grafting (CABG). This study examines the relationship between marijuana use and postoperative outcomes in CABG patients. METHODS: We utilized data from the National Inpatient Sample database from 2008 to 2018 for CABG patients ≥18 y old. Patients were divided into two groups based on marijuana use (abuse/dependency versus nonuse). Primary outcomes include in-hospital mortality, favorable discharge, and length of stay (LOS). Secondary outcomes include acute kidney injury (AKI), acute myocardial infarction (AMI), and transient ischemic attack (TIA)/stroke. A multivariable model, adjusted for confounding variables, was utilized for each outcome. RESULTS: A total of 343,796 patients met inclusion criteria for the study, 590 of which were marijuana users. In both marijuana user and nonuser groups, most patients were male and White with an average age of 56.0 and 66.3 y, respectively. There was a nonsignificant decreased odds of in-hospital mortality among marijuana users (odds ratio [OR] = 0.41, [0.141-1.124]). Marijuana users exhibited significantly decreased odds of home discharge (OR = 1.50, [1.24-1.81]), and increased odds of longer LOS (mean 10.4 d versus 9.8 d; OR = 1.14, [1.09-1.20]), AKI (OR = 1.40, [1.11-1.78]), AMI (OR = 1.56, [1.32-1.84]), and TIA/stroke (OR = 1.64, [1.21-2.22]). CONCLUSIONS: Marijuana use and dependency are associated with increased nonhome discharge, AKI, AMI, TIA/stroke, and longer LOS. Further studies are needed to delineate the pathophysiologic derangements that contribute to these unfavorable post-CABG outcomes.

Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium.

INTRODUCTION: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration. METHODS: Thirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis. RESULTS: SGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes. CONCLUSIONS: SGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.

Increased Coronary Contraction to Thromboxane A2 in Cardiac Surgery Patients With Poorly Controlled Hypertension.

INTRODUCTION: Cardioplegia and cardiopulmonary bypass (CP/CPB) alters coronary arteriolar response to thromboxane A2 (TXA2) in patients undergoing cardiac surgery. Comorbidities, including hypertension (HTN), can further alter coronary vasomotor tone. This study investigates the effects of HTN on coronary arteriolar response to TXA2 pre and post-CP/CPB and cardiac surgery. MATERIALS AND METHODS: Coronary arterioles pre and post-CP/CPB were dissected from atrial tissue samples in patients with no HTN (NH, n = 9), well-controlled HTN (WC, n = 12), or uncontrolled HTN (UC, n = 12). In-vitro coronary microvascular reactivity was examined in the presence of TXA2 analog U46619 (10-9-10-4M). Protein expression of TXA2 receptor in the harvested right atrial tissue samples were measured by immunoblotting. RESULTS: TXA2 analog U46619 induced dose-dependent contractile responses of coronary arterioles in all groups. Pre-CPB contractile responses to U46619 were significantly increased in microvessels in the UC group compared to the NH group (P < 0.05). The pre-CP/CPB contractile responses of coronary arterioles were significantly diminished post-CP/CPB among the three groups (P < 0.05), but there remained an increased contractile response in the microvessels of the UC group compared to the WC and NH groups (P < 0.05). There were no significant differences in U46619-induced vasomotor tone between patients in the NH and WC groups (P > 0.05). There were no differences in expression of TXA2R among groups. CONCLUSIONS: Poorly controlled HTN is associated with increased contractile response of coronary arterioles to TXA2. This alteration may contribute to worsened recovery of coronary microvascular function in patients with poorly controlled HTN after CP/CPB and cardiac surgery.

Global Challenges After a Global Challenge: Lessons Learned from the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed. In this chapter, world-leading scientists from different backgrounds share collectively their views about the pandemic's footprint and discuss challenges that face the international community.

2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The executive summary of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions coronary artery revascularization guideline provides the top 10 items readers should know about the guideline. In the full guideline, the recommendations replace the 2011 coronary artery bypass graft surgery guideline and the 2011 and 2015 percutaneous coronary intervention guidelines. This summary offers a patient-centric approach to guide clinicians in the treatment of patients with significant coronary artery disease undergoing coronary revascularization, as well as the supporting documentation to encourage their use. METHODS: A comprehensive literature search was conducted from May 2019 to September 2019, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, CINHL Complete, and other relevant databases. Additional relevant studies, published through May 2021, were also considered. Structure: Recommendations from the earlier percutaneous coronary intervention and coronary artery bypass graft surgery guidelines have been updated with new evidence to guide clinicians in caring for patients undergoing coronary revascularization. This summary includes recommendations, tables, and figures from the full guideline that relate to the top 10 take-home messages. The reader is referred to the full guideline for graphical flow charts, supportive text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in the development of this guideline.

Reduction in mitochondrial ROS improves oxidative phosphorylation and provides resilience to coronary endothelium in non-reperfused myocardial infarction.

Recent studies demonstrated that mitochondrial antioxidant MnSOD that reduces mitochondrial (mito) reactive oxygen species (ROS) helps maintain an optimal balance between sub-cellular ROS levels in coronary vascular endothelial cells (ECs). However, it is not known whether EC-specific mito-ROS modulation provides resilience to coronary ECs after a non-reperfused acute myocardial infarction (MI). This study examined whether a reduction in endothelium-specific mito-ROS improves the survival and proliferation of coronary ECs in vivo. We generated a novel conditional binary transgenic animal model that overexpresses (OE) mitochondrial antioxidant MnSOD in an EC-specific manner (MnSOD-OE). EC-specific MnSOD-OE was validated in heart sections and mouse heart ECs (MHECs). Mitosox and mito-roGFP assays demonstrated that MnSOD-OE resulted in a 50% reduction in mito-ROS in MHEC. Control and MnSOD-OE mice were subject to non-reperfusion MI surgery, echocardiography, and heart harvest. In post-MI hearts, MnSOD-OE promoted EC proliferation (by 2.4 ± 0.9 fold) and coronary angiogenesis (by 3.4 ± 0.9 fold), reduced myocardial infarct size (by 27%), and improved left ventricle ejection fraction (by 16%) and fractional shortening (by 20%). Interestingly, proteomic and Western blot analyses demonstrated upregulation in mitochondrial complex I and oxidative phosphorylation (OXPHOS) proteins in MnSOD-OE MHECs. These MHECs also showed increased mitochondrial oxygen consumption rate (OCR) and membrane potential. These findings suggest that mito-ROS reduction in EC improves coronary angiogenesis and cardiac function in non-reperfused MI, which are associated with increased activation of OXPHOS in EC-mitochondria. Activation of an energy-efficient mechanism in EC may be a novel mechanism to confer resilience to coronary EC during MI.

Proteomic Assessment of Hypoxia-Pre-Conditioned Human Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Demonstrates Promise in the Treatment of Cardiovascular Disease.

Human bone marrow mesenchymal stem cell derived-extracellular vesicles (HBMSC-EV) are known for their regenerative and anti-inflammatory effects in animal models of myocardial ischemia. However, it is not known whether the efficacy of the EVs can be modulated by pre-conditioning of HBMSC by exposing them to either starvation or hypoxia prior to EV collection. HBMSC-EVs were isolated following normoxia starvation (NS), normoxia non-starvation (NNS), hypoxia starvation (HS), or hypoxia non-starvation (HNS) pre-conditioning. The HBMSC-EVs were characterized by nanoparticle tracking analysis, electron microscopy, Western blot, and proteomic analysis. Comparative proteomic profiling revealed that starvation pre-conditioning led to a smaller variety of proteins expressed, with the associated lesser effect of normoxia versus hypoxia pre-conditioning. In the absence of starvation, normoxia and hypoxia pre-conditioning led to disparate HBMSC-EV proteomic profiles. HNS HBMSC-EV was found to have the greatest variety of proteins overall, with 74 unique proteins, the greatest number of redox proteins, and pathway analysis suggestive of improved angiogenic properties. Future HBMSC-EV studies in the treatment of cardiovascular disease may achieve the most therapeutic benefits from hypoxia non-starved pre-conditioned HBMSC. This study was limited by the lack of functional and animal models of cardiovascular disease and transcriptomic studies.

Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium.

We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, n = 10) or hypoxia-modified EVs (HYP, n = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs.

Assessments of microvascular function in organ systems.

Microvascular disease plays critical roles in the dysfunction of all organ systems, and there are many methods available to assess the microvasculature. These methods can either assess the target organ directly or assess an easily accessible organ such as the skin or retina so that inferences can be extrapolated to the other systems and/or related diseases. Despite the abundance of exploratory research on some of these modalities and their possible applications, there is a general lack of clinical use. This deficiency is likely due to two main reasons: the need for standardization of protocols to establish a role in clinical practice or the lack of therapies targeted toward microvascular dysfunction. Also, there remain some questions to be answered about the coronary microvasculature, as it is complex, heterogeneous, and difficult to visualize in vivo even with advanced imaging technology. This review will discuss novel approaches that are being used to assess microvasculature health in several key organ systems, and evaluate their clinical utility and scope for further development.

Mechanisms and clinical implications of endothelium-dependent vasomotor dysfunction in coronary microvasculature.

Coronary microvascular disease (CMD), which affects the arterioles and capillary endothelium that regulate myocardial perfusion, is an increasingly recognized source of morbidity and mortality, particularly in the setting of metabolic syndrome. The coronary endothelium plays a pivotal role in maintaining homeostasis, though factors such as diabetes, hypertension, hyperlipidemia, and obesity can contribute to endothelial injury and consequently arteriolar vasomotor dysfunction. These disturbances in the coronary microvasculature clinically manifest as diminished coronary flow reserve, which is a known independent risk factor for cardiac death, even in the absence of macrovascular atherosclerotic disease. Therefore, a growing body of literature has examined the molecular mechanisms by which coronary microvascular injury occurs at the level of the endothelium and the consequences on arteriolar vasomotor responses. This review will begin with an overview of normal coronary microvascular physiology, modalities of measuring coronary microvascular function, and clinical implications of CMD. These introductory topics will be followed by a discussion of recent advances in the understanding of the mechanisms by which inflammation, oxidative stress, insulin resistance, hyperlipidemia, hypertension, shear stress, endothelial cell senescence, and tissue ischemia dysregulate coronary endothelial homeostasis and arteriolar vasomotor function.

Rationale and design of the safe and timely antithrombotic removal - ticagrelor (STAR-T) trial: A prospective, multi-center, double-blind, randomized controlled trial evaluating reductions in postoperative bleeding with intraoperative removal of ticagrelor by the drugsorb™-ATR device in patients undergoing cardiothoracic surgery within 48 hours from last ticagrelor dose.

BACKGROUND: Ticagrelor is often administered to patients with acute coronary syndromes. However, when these patients require urgent or emergent cardiothoracic (CT) surgery the presence of ticagrelor significantly increases surgical bleeding. The goal of the current trial is to evaluate the effectiveness and safety of the DrugSorb-ATR hemoadsorption device for the intraoperative removal of ticagrelor to reduce postoperative bleeding in the above patient population. The Safe and Timely Antithrombotic Removal - Ticagrelor (STAR-T) Trial is a multi-center, double-blind, randomized, controlled trial enrolling patients who require cardiothoracic surgery on cardiopulmonary bypass (CPB) within 48 hours of last ticagrelor dose. METHODS: Subjects will be randomized 1:1 to receive either the DrugSorb-ATR device or an identical sham device during CPB. The study will enroll up to 120 subjects at 20 U.S centers, and the primary outcome is the composite of fatal perioperative bleeding, moderate/severe/massive bleeding according to the Universal Definition of Perioperative Bleeding in Cardiac Surgery (UDPB), and 24 hours chest tube drainage. The components of the composite are hierarchically ranked according to clinical significance and the primary analysis will utilize the Win Ratio method. Percent change in ticagrelor levels before and after CPB (drug removal) will be the key secondary endpoint. An independent Clinical Events Committee will adjudicate all clinical endpoints including safety endpoints relating to postoperative thrombotic events. Subjects will be followed through 30 days after the index operation. CONCLUSIONS: The results from STAR-T, if positive, will potentially support FDA market approval for DrugSorb-ATR, and provide a solution to an important unmet clinical need.

Outcomes of diabetic patients with end-stage heart failure listed for heart transplantation: A propensity-matched analysis.

BACKGROUND: We investigated the current trends and outcomes of diabetic patients listed for heart transplants in the U.S. and provided a method for risk-stratification. METHODS: Using data from the United Network for Organ Sharing (UNOS), we identified heart failure patients listed for heart transplants between 2010 and 2019. Diabetic patients were propensity-matched with non-diabetics, and waitlist mortality as well as post-transplant graft survival were compared between the two groups. Further risk-stratification of diabetic patients was done based on the risk factors that independently predict graft failure. RESULTS: 28,928 adult patients (30% diabetic) with end-stage heart failure were added to the waitlist over the study period. In the propensity-matched cohort, waitlist mortality was higher in diabetic patients compared to non-diabetics (HR = 1.13 (95% CI = 1.04-1.22, P = .002). Over the study period, 5739 patients with diabetes were transplanted. In the propensity-matched cohorts of transplant recipients, the rate of graft failure was significantly higher for diabetic patients (23.3%) compared to non-diabetics (20.4%); HR = 1.17, 95% CI = 1.08-1.26, P < .001. We identified 12 risk factors of graft failure among diabetic patients and developed a risk score that further risk-stratify these patients. Diabetic patients at low risk (score≤4) had similar graft survival as patients without diabetes (HR = .91, 95% CI = .82-1.01, P = .06). On the other hand, high-risk diabetic patients had worse graft survival compared to non-diabetics (HR = 1.52, 95% CI = 1.38-1.67, P < .001). CONCLUSION: Among patients with end-stage heart failure, pre-existing diabetes was associated with higher waitlist mortality and worse graft survival. However, with careful patient selection, graft survival is similar to those without diabetes.

Pulmonary hypertension associated with cardiopulmonary bypass and cardiac surgery.

BACKGROUND AND AIM: Pulmonary hypertension (PH) is frequently associated with cardiovascular surgery and is a common complication that has been observed after surgery utilizing cardiopulmonary bypass (CPB). The purpose of this review is to explain the characteristics of PH, the mechanisms of PH induced by cardiac surgery and CPB, treatments for postoperative PH, and future directions in treating PH induced by cardiac surgery and CPB using up-to-date findings. METHODS: The PubMed database was utilized to find published articles. RESULTS: There are many mechanisms that contribute to PH after cardiac surgery and CPB which involve pulmonary vasomotor dysfunction, cyclooxygenase, the thromboxane A2 and prostacyclin pathway, the nitric oxide pathway, inflammation, and oxidative stress. Furthermore, there are several effective treatments for postoperative PH within different types of cardiac surgery. CONCLUSIONS: By possessing a deep understanding of the mechanisms that contribute to PH after cardiac surgery and CPB, researchers can develop treatments for clinicians to use which target the mechanisms of PH and ultimately reduce and/or eliminate postoperative PH. Additionally, learning about the most up-to-date studies regarding treatments can allow clinicians to choose the best treatments for patients who are undergoing cardiac surgery and CPB.

Glycemic control is not associated with neurocognitive decline after cardiac surgery.

BACKGROUND: Whether perioperative glycemic control is associated with neurocognitive decline (NCD) after cardiac surgery was examined. METHODS: Thirty patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) were screened for NCD preoperatively and on postoperative day 4 (POD4). Indices of glucose control were examined. Serum cytokine levels were measured and human transcriptome analysis was performed on blood samples. Neurocognitive data are presented as a change from baseline to POD4 in a score standardized with respect to age and gender. RESULTS: A decline in neurocognitive function was identified in 73% (22/30) of patients on POD4. There was no difference in neurocognitive function between patients with elevated HbA1c levels preoperatively (p = .973) or elevated fasting blood glucose levels the morning of surgery (>126 mg/dl, p = .910), or a higher maximum blood glucose levels during CPB (>180 mg/dl, p = .252), or higher average glucose levels during CPB (>160 mg/dl, p = .639). Patients with postoperative leukocytosis (WBC ≥ 10.5) had more NCD when compared to their baseline function (p = .03). Patients with elevated IL-8 levels at 6 h postoperatively had a significant decline in NCD at POD4 (p = .04). Human transcriptome analysis demonstrated unique and differential patterns of gene expression in patients depending on the presence of DM and NCD. CONCLUSIONS: Perioperative glycemic control does not have an effect on NCD soon after cardiac surgery. The profile of gene expression was altered in patients with NCD with or without diabetes.

Dabigatran Reversal With Idarucizumab in Patients Requiring Urgent Surgery: A Subanalysis of the RE-VERSE AD Study.

OBJECTIVE: To further examine anticoagulation reversal and clinical outcomes in dabigatran treated patients requiring urgent surgery or procedural interventions. BACKGROUND: Idarucizumab, a humanized monoclonal antibody fragment, reverses dabigatran anticoagulation. METHODS: Data from surgical and procedural patients in RE-VERSE AD, a multicenter, open-label, single-arm, prospective cohort of dabigatran reversal were evaluated. A total of 202 patients in this group received 5 g of idarucizumab before surgery or procedures. RESULTS: The interventions included 49 abdominal, 45 orthopedic, 34 vascular, 8 neurologic, and 4 genitourinary surgical procedures, or 29 catheter-based cases, 20 cases for drainage, and 8 diagnostic procedures. Five patients did not undergo their intended intervention after receiving idarucizumab. Complete reversal of the dabigatran anticoagulant effect occurred within minutes in almost all patients, with normal hemostasis in more than 91% of patients. The median time from the first vial of idarucizumab to surgery or procedures was less than 2 hours in all groups except neurosurgery, where it was 3.3 hours. Fresh frozen plasma and packed red cells were the most frequently transfused blood products. Postreversal thromboembolic events occurred in 10 (5%) patients at 30 days, 5 of whom had restarted anticoagulation before the event. Overall 30-day mortality was 12.6%. There were no serious adverse safety signals due to idarucizumab dosing. CONCLUSIONS: Idarucizumab facilitates management of patients requiring urgent procedures by providing rapid dabigatran reversal, and is the only agent of its class studied in surgical patients.

Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future.

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease, or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell-derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery. However, recent revolutionary developments and insight into the potential of personalizing EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.

Lactobacillus plantarum probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.

Yorkshire swine were fed standard diet (n = 7) or standard diet containing applesauce rich in caffeic acid with Lactobacillus plantarum (n = 7) for 3 wk. An ameroid constrictor was next placed around the left coronary circumflex artery, and the dietary regimens were continued. At 14 wk, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated. The L. plantarum-applesauce augmented NF-E2-related factor 2 (Nrf2) in the ischemic myocardium and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the L. plantarum-applesauce supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, whereas levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral-dependent myocardial perfusion was unaffected, whereas arteriolar and capillary densities were reduced as determined by α-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with L. plantarum-applesauce is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density, and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function.NEW & NOTEWORTHY Colonization of the gut microbiome with certain strains of L. Plantarum has been shown to convert caffeic acid readily available in applesauce to 4-vinyl-catechol, a potent activator of the Nrf2 antioxidant defense pathway. In this exciting study, we show that simple dietary supplementation with L. Plantarum-applesauce-mediated Nrf2 activation supports vascular function, ameliorates myocardial ischemic diastolic dysfunction, and upregulates expression of eNOS.