Peripheral arterial disease (PAD) represents a spectrum from asymptomatic stenosis to limb-threatening ischemia. The last decade has seen a tremendous increase in the variety of endovascular devices ...and techniques to treat occlusive disease. Like many evolving technologies, the literature surrounding therapy for endovascular arterial disease consists of mixed-quality manuscripts without clear standardization. Accordingly, critical evaluation of the reported results may be problematic. As such, providers and their patients make treatment decisions without the full benefit of a comparative effectiveness framework. The purpose of this document is to provide a summary for the reporting of endovascular revascularization techniques in the setting of chronic disease. Much of the work in this document is based on prior publications and standards proposed by the Society for Vascular Surgery. We have also made recommendations based on current literature and have attempted to acknowledge shortcomings and areas for future research. The various sections contain summaries of required reporting standards and should serve as a guide for the design of clinical trials and as reference for journal editors and reviewers when considering scientific work pertaining to endovascular therapy for chronic lower extremity arterial disease. An Appendix is provided with commonly used abbreviations in this document.
Recommended reporting standards for lower extremity ischemia were last published by the Society for Vascular Surgery in 1997. Since that time, there has been a proliferation of endovascular therapies ...for the treatment of chronic peripheral arterial disease. The purpose of this document is to clarify and update these standards, specifically for reports on endovascular treatment. The document is divided into sections: Claudication Reporting, Critical Limb Ischemia Reporting, Preintervention Assessment and Nonanatomic Treatment, Intervention, Outcome Measures – Procedural, Outcome Measures – Disease Specific, and Complications.
BACKGROUND AND PURPOSE:Transcarotid artery revascularization (TCAR) is comprised of carotid artery stent placement with cerebral protection via proximal carotid artery clamping and reversal of ...cerebral arterial flow. The aim of the present study was to evaluate the safety and efficacy of TCAR performed by a broad group of physicians with variable TCAR experience.
METHODS:The ROADSTER 2 study is a prospective, open label, single arm, multicenter, postapproval registry for patients undergoing TCAR. Patients considered at high risk for complications from carotid endarterectomy with symptomatic stenosis ≥50% or asymptomatic stenosis ≥80% were included. The primary end point was procedural success, which encompassed technical success plus the absence of stroke, myocardial infarction, or death within the 30-day postoperative period. Secondary end points included technical success and individual/composite rates of stroke, death, and myocardial infarction (MI). All patients underwent independent neurological assessments before the procedure, within 24 hours, and at 30 days after TCAR. An independent clinical events committee adjudicated all major adverse events.
RESULTS:Between 2015 and 2019, 692 patients (Intent to Treat Population) were enrolled at 43 sites. Sixty cases had major protocol violations, leaving 632 patients adhering to the Food and Drug Administration-approved protocol (per-protocol population). The majority (81.2%) of operators were TCAR naïve before study initiation. Patients underwent TCAR for neurological symptoms in 26% of cases, and all patients had high-risk factors for carotid endarterectomy (anatomic-related 44%; physiological 32%; both 24%). Technical success occurred in 99.7% of all cases. The primary end point of procedural success rate in the Intent to Treat population was 96.5% (per-protocol 97.9%). The early postoperative outcomes in the Intent to Treat population included stroke in 13 patients (1.9%), death in 3 patients (0.4%), and MI in 6 patients (0.9%). The composite 30-day stroke/death rate was 2.3%, and stroke/death/MI rate was 3.2%. In the per-protocol population, there were strokes in 4 patients (0.6%), death in one patient (0.2%), and MI in 6 patients (0.9%) leading to a composite 30-day stroke/death rate of 0.8% and stroke/death/MI rate of 1.7%.
CONCLUSIONS:TCAR results in excellent early outcomes with high technical success combined with low rates of postprocedure stroke and death. These results were achieved by a majority of operators new to this technology at the start of the trial. Adherence to the study protocol and peri-procedural antiplatelet therapy optimizes outcomes. Longer-term follow-up data are needed to confirm these early outcomes.
REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT02536378.
Lysine acetylation is a reversible posttranslational modification and is particularly important in the regulation of mitochondrial metabolic enzymes. Acetylation uses acetyl-CoA derived from fuel ...metabolism as a cofactor, thereby linking nutrition to metabolic activity. In the present study, we investigated how mitochondrial acetylation status in the heart is controlled by food intake and how these changes affect mitochondrial metabolism. We found that there was a significant increase in cardiac mitochondrial protein acetylation in mice fed a long-term high-fat diet and that this change correlated with an increase in the abundance of the mitochondrial acetyltransferase-related protein GCN5L1. We showed that the acetylation status of several mitochondrial fatty acid oxidation enzymes (long-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase) and a pyruvate oxidation enzyme (pyruvate dehydrogenase) was significantly upregulated in high-fat diet-fed mice and that the increase in long-chain and short-chain acyl-CoA dehydrogenase acetylation correlated with increased enzymatic activity. Finally, we demonstrated that the acetylation of mitochondrial fatty acid oxidation proteins was decreased after GCN5L1 knockdown and that the reduced acetylation led to diminished fatty acid oxidation in cultured H9C2 cells. These data indicate that lysine acetylation promotes fatty acid oxidation in the heart and that this modification is regulated in part by the activity of GCN5L1.
Recent research has shown that acetylation of mitochondrial fatty acid oxidation enzymes has greatly contrasting effects on their activity in different tissues. Here, we provide new evidence that acetylation of cardiac mitochondrial fatty acid oxidation enzymes by GCN5L1 significantly upregulates their activity in diet-induced obese mice.
Diabetic ketoacidosis in children may cause brain injury. In this randomized, controlled trial, neither the rate of administration nor the sodium chloride content of intravenous fluids significantly ...influenced neurologic outcomes in children with diabetic ketoacidosis.
Mitochondria supply ~90% of the ATP required for contractile function in cardiac cells. While adult cardiomyocytes preferentially utilize fatty acids as a fuel source for oxidative phosphorylation, ...cardiac mitochondria can switch to other substrates when required. This change is driven in part by a combination of extracellular and intracellular signal transduction pathways that alter mitochondrial gene expression and enzymatic activity. The mechanisms by which extracellular metabolic information is conveyed to cardiac mitochondria are not currently well defined. Recent work has shown that adropin – a liver-secreted peptide hormone – can induce changes in mitochondrial fuel substrate utilization in skeletal muscle, leading to increased glucose use. In this study, we examined whether adropin could regulate mitochondrial glucose utilization pathways in cardiac cells. We show that stimulation of cultured cardiac cells with adropin leads to decreased expression of the pyruvate dehydrogenase (PDH) negative regulator PDK4, which reduces inhibitory PDH phosphorylation. The downregulation of PDK4 expression by adropin is lost when GPR19 – a putative adropin receptor – is genetically depleted in H9c2 cells. Loss of GRP19 expression alone increased PDK4 expression, leading to a reduction in mitochondrial respiration. Finally, we show that adropin-mediated GPR19 signaling relies on the p44/42 MAPK pathway, and that pharmacological disruption of this pathway blocks the effects of adropin on PDK4 in cardiac cells. These findings suggest that adropin may be a key regulator of fuel substrate utilization in the heart, and implicates an orphan G-protein coupled receptor in a novel signaling pathway controlling mitochondrial fuel metabolism.
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Transcarotid artery revascularization (TCAR), using interoperative flow reversal is a unique, hybrid operation utilized in treating critical carotid artery stenosis. Over the past decade, TCAR has ...been increasingly used to treat asymptomatic carotid artery disease and has a similar risk profile to traditional carotid endarterectomy. Postoperative length of stay (LOS) has a significant impact on cost-effectiveness and quality outcomes in this expanded setting. The objective of this study is to develop a multivariate regression model to identify key preoperative variables and their impact factor on LOS after TCAR for asymptomatic carotid artery stenosis. We hypothesized that high-risk preoperative patient factors historically identified in carotid endarterectomy would similarly impact LOS after TCAR.
A multi-institution, retrospective study of all adult patients undergoing TCAR with flow-reversal for intraoperative neuroprotection was performed using the Society for Vascular Surgery Vascular Quality Initiative (VQI) from January 2016 to August 2021. Patients with prolonged preoperative hospitalization (preoperative LOS ≥1 day) were excluded to enhance the capture of carotid artery stenosis as the index admission. Univariate analysis was done on preoperative factors against LOS using nonparametric statistical tests. A multivariate model was then constructed using a negative binomial regression. The study population was split into 80% "training" data for model formulation and 20% "test" data for model validation.
Thirteen thousand four hundred eighty-three patients undergoing TCAR for asymptomatic carotid stenosis met the study's inclusion criteria with a median postoperative LOS of 1.82 days. Factors in VQI found to have a significant effect on LOS and retained in the multivariate model were lesion type (restenosis versus atherosclerotic), age, gender, chronic obstructive pulmonary disease, preoperative beta blocker, calcific lesion burden, hypertension status, and race (P < 0.05). The model accurately predicted LOS after TCAR within 1 day for 86.04% and within 2 days for 94.51% of patients in the test population.
This large-scale analysis from 2016 to 2021 spans a considerable expansion in the practice of TCAR for asymptomatic carotid disease. All preoperative variables shown to significantly increase the postoperative LOS were derived from the VQI data set. As LOS is a measure of health-care efficiency and cost-effectiveness, this model can be used to identify patients at risk for increased postoperative LOS. It has the potential to be incorporated into a patient/physician decision support tool to optimize resource planning and patient selection for elective TCAR.
GCN5L1 regulates protein acetylation and mitochondrial energy metabolism in diverse cell types. In the heart, loss of GCN5L1 sensitizes the myocardium to injury from exposure to nutritional excess ...and ischemia/reperfusion injury. This phenotype is associated with the reduced acetylation of metabolic enzymes and elevated mitochondrial reactive oxygen species (ROS) generation, although the direct molecular targets of GCN5L1 remain largely unknown. In this study, we sought to determine the mechanism by which GCN5L1 impacts energy substrate utilization and mitochondrial health. We find that hypoxia and reoxygenation (H/R) leads to a reduction in cell viability and Akt phosphorylation in GCN5L1 knockdown AC16 cardiomyocytes, in parallel with elevated glucose utilization and impaired fatty acid use. We demonstrate that glycolysis is uncoupled from glucose oxidation under normoxic conditions in GCN5L1-depleted cells. We show that GCN5L1 directly binds to the Akt-activating mTORC2 component Rictor, and that loss of Rictor acetylation is evident in GCN5L1 knockdown cells. Finally, we show that restoring Rictor acetylation in GCN5L1-depleted cells reduces mitochondrial ROS generation and increases cell survival in response to H/R. These studies suggest that GCN5L1 may play a central role in energy substrate metabolism and cell survival via the regulation of Akt/mTORC2 signaling.
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