Cerebral protection strategies for type A aortic dissection repair.

Importance: Techniques to preserve neurological function during type A aortic dissection repairs have been broadly discussed in the literature and heavily debated. Despite the effectiveness of various approaches, a consensus lacks on how to maintain optimal cerebral temperature during surgery. This review examines the three predominant cerebral protection strategies in aortic arch reconstructions: straight deep hypothermic circulatory arrest (sDHCA), retrograde cerebral perfusion (RCP), and antegrade cerebral perfusion (ACP). Observations: The signature characteristics of sDHCA, RCP, and ACP are similar-hypothermia, with or without cerebral perfusion. Employing cerebral perfusion techniques may prolong operative times, while ACP permits operation at higher body temperatures, albeit with restricted operative durations. Conclusion: For type A dissection arch reconstructions, sDHCA, RCP, and ACP can be successfully implemented. Factors such as operative times and individual patient conditions should be considered when choosing a cerebral protection strategy.

Right Coronary Artery Button Pseudoaneurysm After the Modified Bentall Procedure.

Anastomoses of the coronary buttons are the Achilles' heel of the modified Bentall procedure (MBP) for the repair of the aortic root and ascending aorta. We present a rare case of post-MBP right coronary artery button pseudoaneurysm in a 30-year-old man. The contained leak, attributed to a pseudoknot in the polypropylene suture, was visualized via computed tomography angiography and transesophageal echocardiogram and repaired under deep hypothermic circulatory arrest.

Lung transplant survival with past and concomitant cardiac revascularization.

BACKGROUND: Coronary artery disease is common among lung transplant (LTx) candidates and has historically been viewed as a contraindication to the procedure. Survival outcomes of lung transplant recipients with concomitant coronary artery disease who had prior or perioperative revascularization remain a topic of conversation. METHODS: A retrospective analysis of all single and double lung transplant patients from Feb, 2012 to Aug, 2021 at a single center was performed (n = 880). Patients were split into 4 groups: (1) those who received a preoperative percutaneous coronary intervention, (2) those who received preoperative coronary artery bypass grafting, (3) those who received coronary artery bypass grafting during transplantation, and (4) those who had lung transplantation without revascularization. Groups were compared for demographics, surgical procedure, and survival outcomes using STATA Inc. A p value< 0.05 was considered significant. RESULTS: Most patients receiving LTx were male and white. Pump type (p = 0.810), total ischemic time (p = 0.994), warm ischemic time (p = 0.479), length of stay (p = 0.751), and lung allocation score (p = 0.332) were not significantly different between the four groups. The no revascularization group was younger than the other groups (p<0.01). The diagnosis of Idiopathic Pulmonary Fibrosis was predominant in all groups except the no revascularization group. The pre-coronary artery bypass grafting group had a higher portion of single LTx procedures (p = 0.014). Kaplan-Meier analysis showed no significantly different survival rates after post-LTx between the groups (p = 0.471). Cox Regression analysis showed diagnosis significantly impacted survival rates (p 0.009). CONCLUSIONS: Preoperative or intraoperative revascularization did not affect survival outcomes in lung transplant patients. Selected patients with coronary artery disease may benefit when intervened during lung transplant procedures.

Intraoperative Red Blood Cell Transfusion and Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: In this international, multicenter study of patients undergoing lung transplantation (LT), we explored the association between the amount of intraoperative packed red blood cell (PRBC) transfusion and occurrence of primary graft dysfunction (PGD) and associated outcomes. METHODS: The Extracorporeal Life Support in LT Registry includes data on LT recipients from 9 high-volume (>40 transplants/y) transplant centers (2 from Europe, 7 from the United States). Adult patients who underwent bilateral orthotopic lung transplant from January 2016 to January 2020 were included. The primary outcome of interest was the occurrence of grade 3 PGD in the first 72 h after LT. RESULTS: We included 729 patients who underwent bilateral orthotopic lung transplant between January 2016 and November 2020. LT recipient population tertiles based on the amount of intraoperative PRBC transfusion (0, 1-4, and >4 units) were significantly different in terms of diagnosis, age, gender, body mass index, mean pulmonary artery pressure, lung allocation score, hemoglobin, prior chest surgery, preoperative hospitalization, and extracorporeal membrane oxygenation requirement. Inverse probability treatment weighting logistic regression showed that intraoperative PRBC transfusion of >4 units was significantly ( P < 0.001) associated with grade 3 PGD within 72 h (odds ratio [95% confidence interval], 2.2 [1.6-3.1]). Inverse probability treatment weighting analysis excluding patients with extracorporeal membrane oxygenation support produced similar findings (odds ratio [95% confidence interval], 2.4 [1.7-3.4], P < 0.001). CONCLUSIONS: In this multicenter, international registry study of LT patients, intraoperative transfusion of >4 units of PRBCs was associated with an increased risk of grade 3 PGD within 72 h. Efforts to improve post-LT outcomes should include perioperative blood conservation measures.

Red Blood Cell Transfusion Prior to Lung Transplantation: Impact on Patient Outcomes.

There is an established association between red blood cell (RBC) transfusion and increased mortality and morbidity in cardiac surgery; however, there is little data demonstrating the influence of blood transfusion while awaiting lung transplantation. Therefore, our study compared the impact of pretransplant RBC transfusion on patient survival and post-transplantation adverse events. Adult lung transplant patient data were extracted retrospectively using the United Network for Organ Sharing thoracic database. Patients were stratified into two groups based on pretransplant transfusion status. In total, 28,217 patients were analyzed in our study (transfused: n = 1,415 and not transfused: n = 26,802). There was an increasing trend in pretransplant transfusion rates from 2006 to 2020. Transfused patients had a higher incidence of adverse events post-transplantation, including dialysis, stroke, and acute organ rejection before discharge. Multivariable survival analysis found an increased mortality risk in patients who required pretransplant transfusion(s) compared to those who did not have a transfusion (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.17-1.41; p < 0.001). There was no significant difference in bronchiolitis obliterans syndrome development between groups (HR: 0.92; 95% CI: 0.82-1.04; p = 0.185). To conclude, our study provides data to suggest that RBC transfusion(s) before lung transplantation are associated with increased patient morbidity and mortality, but have no association with chronic graft rejection development.

Two Staged Single Lung Transplants in the Current Era: A United Network for Organ Sharing Study.

BACKGROUND: We hypothesized that outcomes after 2 staged, contralateral single lung transplantation procedures (SSLTs) may be equivalent to those of double lung transplantation (DLT) by capitalizing on the known long-term survival advantages of DLT. METHODS: Using the United Network for Organ Sharing data set (1987-2018), the largest national data set available, the outcomes of 278 SSLTs were retrospectively analyzed and compared with the outcomes of 21,121 standard DLTs. RESULTS: During SSLT, the median interval between the 2 transplants was 960 days, and the indication for the second transplant was most often chronic lung allograft dysfunction (n = 148; 53.2%) or the same disease that necessitated the first transplant (n = 81; 29.1%). The patients who underwent SSLT were significantly older and had a higher baseline creatinine level than the patients who underwent DLT. Most posttransplantation short-term outcomes were equivalent between the second stage of SSLT and DLT, but renal insufficiency requiring hemodialysis was notably higher after SSLT. There were no differences in long-term survival. In multivariate analysis, baseline creatinine, O2 support at rest, ventilator support at the time of the second transplantation, and posttransplantation renal insufficiency requiring dialysis were independent predictors of 1-year mortality after SSLT. CONCLUSIONS: Over a study period of 30 years, long-term survival after SSLT was comparable with survival after DLT. With further analysis of individual risk profiles, including the contributions of preoperative renal function and functional status, SSLT can be a valuable option for patients who would have undergone single lung transplantation to reap the long-term benefits of a second transplant.

Effect of mode of intraoperative support on primary graft dysfunction after lung transplant.

OBJECTIVE: To clarify the relationship between the use of extracorporeal life support during lung transplantation and severe primary graft dysfunction (PGD), we developed and analyzed a novel multicenter international registry. METHODS: The Extracorporeal Life Support in Lung Transplantation Registry includes double-lung transplants performed at 8 high-volume centers (>40/year). Multiorgan transplants were excluded. We defined severe PGD as grade 3 PGD (PGD3) observed 48 or 72 hours after reperfusion. Modes of support were no extracorporeal life support (off-pump), extracorporeal membrane oxygenation (ECMO), and cardiopulmonary bypass (CPB). To assess the association between mode of support and PGD3, we adjusted for demographic and intraoperative factors with a stepwise, mixed selection, multivariable regression model, ending with 10 covariates in the final model. RESULTS: We analyzed 852 transplants performed between January 2016 and March 2020: 422 (50%) off-pump, 273 (32%) ECMO, and 157 (18%) CPB cases. PGD3 rates at time point 48-72 were 12.1% (51 out of 422) for off-pump, 28.9% for ECMO (79 out of 273), and 42.7% (67 out of 157) for CPB. The adjusted model resulted in the following risk profile for PGD3: CPB versus ECMO odds ratio, 1.89 (95% CI, 1.05-3.41; P = .033), CPB versus off-pump odds ratio, 4.24 (95% CI, 2.24-8.04; P < .001), and ECMO versus off-pump odds ratio, 2.24 (95% CI, 1.38-3.65; P = .001). CONCLUSIONS: Venoarterial ECMO is increasingly used at high-volume centers to support complex transplant recipients during double-lung transplantation. This practice is associated with more risk of PGD3 than off-pump transplantation but less risk than CPB. When extracorporeal life support is required during lung transplantation, ECMO may be the preferable approach when feasible.

Donor Pulmonary Vein Anomalies: What's in Your Toolbox?

Pulmonary vein anomalies are often unrecognized during donor lung procurement. Consequently, they are at high risk for injury, and this leaves the implanting surgeon with an unpleasant surprise. An innovative approach can help resolve the situation. We wish to highlight our experience with an anomalous left upper pulmonary vein and describe a novel reconstruction technique.

Proximal Anastomotic Device Malfunction: Salvage Using Alternative Option.

Embolic stroke is a major complication of cardiac surgery and there have been multiple methods developed to reduce this risk. Recent technology has produced 2 primary devices for producing a bloodless and clampless field to perform aortocoronary graft anastomosis. We present a case with a Class V aorta, deployment failure of one device after aortic punch, and salvage of the aortotomy with the other device.

Cardiac tamponade masquerading as headache: A diagnostic conundrum.

Cardiac tamponade and its protean presentations are well documented. Tamponade presenting after recent cardiac surgery in a patient on anticoagulation is not unknown. However, severe headache as a presenting feature of tamponade is not documented. We describe how one can be misled into investigating causes of headache while the real cause, tamponade, lies hidden.

Prior and Perioperative Revascularization Does Not Affect Survival in Lung Transplant Patients.

BACKGROUND: Coronary artery disease is common in lung transplant patients and has historically been viewed as a contraindication to the procedure. Although this mindset is changing, the effect of prior or perioperative revascularization on lung transplant survival outcomes is not adequately established. METHODS: We performed a single-center retrospective analysis of all single and double lung transplant patients from 2012 to 2018 (n = 468). Patients were split into 4 groups: (1) patients who received a preoperative percutaneous coronary intervention (n = 34), (2) those who received coronary artery bypass grafting (CABG) before transplantation (n = 25), (3) those that received concomitant CABG during transplantation (n = 29), and (4) those who had lung transplantation with no need for revascularization (n = 380). Groups were compared for demographics, surgical procedure, and survival outcomes. RESULTS: The no-revascularization group was statistically younger than the rest (P = .001). The lung allocation score trended toward being higher in the concomitant coronary artery bypass group (P = .03). All groups were predominantly diagnosed with idiopathic pulmonary fibrosis. The proportion of patients with chronic obstructive pulmonary disease was greatest in the group not requiring revascularization (P = .001). Patients with previous CABG were more likely to receive a single lung transplant than a double one (21 versus 4; P = .054). Length of stay, posttransplant survival, and postoperative adverse events were similar among all groups. CONCLUSIONS: Results suggest that preoperative or intraoperative revascularization does not negatively affect survival in lung transplant patients; lung recipients with coronary artery disease have comparable survival when adequately revascularized.

Exposure of Rat Neural Stem Cells to Ethanol Affects Cell Numbers and Alters Expression of 28 Proteins.

Developing brain cells express many proteins but little is known of how their protein composition responds to chronic exposure to alcohol and/or how such changes might relate to alcohol toxicity. We used cultures derived from embryonic rat brain (previously shown to contain mostly neural stem cells; rat NSC, rNSC), exposed them to ethanol (25-100 mM) for up to 96 h and studied how they reacted. Ethanol (50 and 100 mM) reduced cell numbers indicating either compromised cell proliferation, cytotoxicity or both. Increased lipid peroxidation was consistent with the presence of oxidative stress accompanying alcohol-induced cytotoxicity. Proteomics revealed 28 proteins as altered by ethanol (50 mM for 96 h). Some were constituents of cytoskeleton, others were involved in transcription/translation, signal transduction and oxidative stress. Nucleophosmin (NPM1) and dead-end protein homolog 1 (DND1) were further studied by immunological techniques in cultured neurons and astrocytes (derived from brain tissue at embryonic ages E15 and E20, respectively). In the case of DND1 (but not NPM1) ethanol induced similar pattern of changes in both types of cells. Given the critical role of the protein NPM1 in cell proliferation and differentiation, its reduced expression in the ethanol-exposed rNSC could, in part, explain the lower cells numbers. We conclude that chronic ethanol profoundly alters protein composition of rNSC to the extent that their functioning-including proliferation and survival-would be seriously compromised. Translated to humans, such changes could point the way towards mechanisms underlying the fetal alcohol spectrum disorder and/or alcoholism later in life.

BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells.

BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6]napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor-mediated mast cell and basophil degranulation (IC50 = 115 nM) compared with B-cell receptor-mediated activation of B cells (IC50 = 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50 = 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.

A High-Throughput Genetic Complementation Assay in Yeast Cells Identified Selective Inhibitors of Sphingosine Kinase 1 Not Found Using a Cell-Free Enzyme Assay.

Sphingosine kinase 1 (SphK1) is a lipid kinase that phosphorylates sphingosine to produce the bioactive sphingolipid, sphingosine-1-phosphate (S1P), and therefore represents a potential drug target for a variety of pathological processes such as fibrosis, inflammation, and cancer. We developed two assays compatible with high-throughput screening to identify small-molecule inhibitors of SphK1: a purified component enzyme assay and a genetic complementation assay in yeast cells. The biochemical enzyme assay measures the phosphorylation of sphingosine-fluorescein to S1P-fluorescein by recombinant human full-length SphK1 using an immobilized metal affinity for phosphochemicals (IMAP) time-resolved fluorescence resonance energy transfer format. The yeast assay employs an engineered strain of Saccharomyces cerevisiae, in which the human gene encoding SphK1 replaced the yeast ortholog and quantitates cell viability by measuring intracellular adenosine 5'-triphosphate (ATP) using a luciferase-based luminescent readout. In this assay, expression of human SphK1 was toxic, and the resulting yeast cell death was prevented by SphK1 inhibitors. We optimized both assays in a 384-well format and screened ∼10(6) compounds selected from the Boehringer Ingelheim library. The biochemical IMAP high-throughput screen identified 5,561 concentration-responsive hits, most of which were ATP competitive and not selective over sphingosine kinase 2 (SphK2). The yeast screen identified 205 concentration-responsive hits, including several distinct compound series that were selective against SphK2 and were not ATP competitive.

A high-throughput scintillation proximity assay for sphingosine-1-phosphate lyase.

The emergence of sphingosine-1-phosphate lyase (SPL) as a promising therapeutic target for inflammatory diseases has heightened interest in the identification of small molecules that modulate its activity. The enzymatic activity of SPL is typically measured using radiometric or fluorescence-based assays that require a lipid extraction step, or by direct quantitation of reaction products using mass spectrometry (MS). To facilitate testing large numbers of compounds to identify SPL modulators, we developed a robust scintillation proximity assay (SPA) that is compatible with high-throughput screening (HTS). This assay employs recombinant human full-length SPL in insect cell membrane preparations to catalyze the conversion of biotinylated aminosphingosine-1-[(33)P]phosphate (S1(33)P-biotin) to trans-2-hexadecenal-biotin and ethanolamine [(33)P]phosphate. To validate the SPA and confirm the fidelity of its measurement of SPL enzyme activity, we developed a Rapid-Fire MS method that quantitates nonradiolabeled S1P-biotin. In addition, we developed a simple, scalable method to produce S1(33)P-biotin in quantities sufficient for HTS. The optimized SPA screen in 384-well microplates produced a mean plate-wise Z'-statistic of 0.58 across approximately 3,000 plates and identified several distinct structural classes of SPL inhibitor. Among the inhibitors that the screen identified was one compound with an IC50 of 1.6 µM in the SPA that induced dose-dependent lymphopenia in mice.

Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans.

As healthcare progresses toward individualized medicine, understanding how different racial groups respond to lifestyle interventions is valuable. It is established that African Americans have disproportionate levels of cardiovascular disease and impaired vascular health, and clinical practice guidelines suggest lifestyle interventions as the first line of treatment. Recently, the authors reported that 6 months of aerobic exercise improved inflammatory markers, flow-mediated dilation (FMD), and levels of circulating endothelial microparticles (EMPs) in African American adults. This study is a subgroup analysis of the aerobic exercise-induced changes in vascular health and blood pressure (BP) measures, including carotid artery intima-media thickness (IMT), nitroglycerin-mediated dilation (NMD), ambulatory BP, and office BP. Sedentary African American adults (53.4±6.2 years; 21 women and 5 men) showed improved vascular health but no change in BP. Carotid artery IMT decreased 6.4%, plasma nitric oxide levels increased 76.6%, plasma EMP levels decreased, percentage of FMD increased 59.6%, and FMD/NMD ratio increased 36.2% (P<.05 for all). Six months of aerobic exercise training is sufficient to elicit improvements in vascular structure and function in African Americans, even without improvements in BP measures or NMD (ie, smooth muscle function). To our knowledge, this is the first study to report such findings in African Americans.

A standardized exercise intervention differentially affects premenopausal and postmenopausal African-American women.

OBJECTIVE: African-American women represent an understudied population in menopause research yet face greater postmenopausal challenges associated with mortality than their white peers. We investigated the effects of a mild-intensity aerobic exercise training program on markers of mortality risk in both premenopausal and postmenopausal African-American women. METHODS: Sixteen premenopausal women and 19 postmenopausal women underwent 6 months of mild-intensity aerobic exercise training. Measurements included markers of blood lipid and glucose profile, inflammation, kidney function, vascular health, and aerobic fitness before and after the exercise intervention. RESULTS: Before the exercise intervention, the premenopausal and postmenopausal groups only differed in age, low-density lipoprotein, and total cholesterol levels, with the latter two being higher in the postmenopausal group. Both triglycerides and markers of early-stage endothelial dysfunction (CD62E endothelial microparticles) improved in both groups with aerobic exercise training. Aerobic fitness, glomerular filtration rate, body mass index, plasma glucose levels, and markers of late-stage endothelial dysfunction (CD31/CD42b endothelial microparticles) only improved in the premenopausal group. CONCLUSIONS: Mild-intensity aerobic exercise training succeeds in improving some markers of cardiovascular disease and mortality in postmenopausal women. Higher levels of exercise intensity or perhaps additional interventions may need to be considered to further decrease mortality risk in this population.

Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations.

Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we measured the effect of alcohol on metabolism of [3-¹³C]pyruvate in the adult Guinea pig brain cortical tissue slice and compared the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-¹³C]ethanol. Analyses of metabolic profile clusters suggest that the significant reductions in metabolism induced by ethanol (10, 30 and 60 mM) are via action at neurotransmitter receptors, particularly α4ß3δ receptors, whereas very low concentrations of ethanol may produce metabolic responses owing to release of GABA via GABA transporter 1 (GAT1) and the subsequent interaction of this GABA with local α5- or α1-containing GABA(A)R. There was no measureable metabolism of [1,2-¹³C]ethanol with no significant incorporation of ¹³C from [1,2-¹³C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabelled ethanol.