Association of procurement technique with organ yield and cost following donation after circulatory death.

Donation after circulatory death (DCD) could account for the largest expansion of the donor allograft pool in the contemporary era. However, the organ yield and associated costs of normothermic regional perfusion (NRP) compared to super-rapid recovery (SRR) with ex-situ normothermic machine perfusion, remain unreported. The Organ Procurement and Transplantation Network (December 2019 to June 2023) was analyzed to determine the number of organs recovered per donor. A cost analysis was performed based on our institution's experience since 2022. Of 43 502 donors, 30 646 (70%) were donors after brain death (DBD), 12 536 (29%) DCD-SRR and 320 (0.7%) DCD-NRP. The mean number of organs recovered was 3.70 for DBD, 3.71 for DCD-NRP (P < .001), and 2.45 for DCD-SRR (P < .001). Following risk adjustment, DCD-NRP (adjusted odds ratio 1.34, confidence interval 1.04-1.75) and DCD-SRR (adjusted odds ratio 2.11, confidence interval 2.01-2.21; reference: DBD) remained associated with greater odds of allograft nonuse. Including incomplete and completed procurement runs, the total average cost of DCD-NRP was $9463.22 per donor. By conservative estimates, we found that approximately 31 donor allografts could be procured using DCD-NRP for the cost equivalent of 1 allograft procured via DCD-SRR with ex-situ normothermic machine perfusion. In conclusion, DCD-SRR procurements were associated with the lowest organ yield compared to other procurement methods. To facilitate broader adoption of DCD procurement, a comprehensive understanding of the trade-offs inherent in each technique is imperative.

Challenging Paradigm Limits of Retrograde Cerebral Perfusion During Lower Body Circulatory Arrest.

INTRODUCTION: Retrograde cerebral perfusion (RCP) is a safe and effective technique to augment cerebral protection during lower body circulatory arrest in patients undergoing elective hemiarch replacement. However, recommendations guiding optimal temperature, flow rate, and perfusion pressure are outdated and potentially overly limiting. We report our experience using RCP for elective hemiarch replacement with parameters that challenge the currently accepted paradigm. METHODS: This was a single-center, retrospective analysis of 319 adult patients who underwent elective hemiarch replacement between February 2010 and 2021 using hypothermic lower body circulatory arrest with RCP alone, RCP followed by antegrade cerebral perfusion (ACP), or ACP alone. Flow rates were adjusted to maintain cerebral perfusion pressure between 30 and 50 mm Hg for RCP and between 40 and 60 mm Hg for ACP. RESULTS: RCP was used in 22.6% (n = 72) of cases, whereas ACP alone was performed in 77.4% (n = 247) of cases. Baseline patient characteristics were similar between groups. Patients undergoing RCP demonstrated shorter cross-clamp time (97.0 min versus 100.0 min, P = 0.034) and shorter lower body circulatory arrest time (7.0 min versus 10.0 min, P < 0.0001) compared with ACP alone. Nadir bladder temperature was equivalent between groups (27.3°C versus 27.5°C, P = 0.752). There were no significant differences in postoperative complications, neurologic outcomes, or mortality. CONCLUSIONS: Moderate hypothermic lower body circulatory arrest combined with RCP at target perfusion pressures of 30-50 mm Hg in patients undergoing elective hemiarch replacement results in equivalent neurologic outcomes and overall morbidity to cases using ACP alone. These results challenge the currently accepted paradigm for RCP, which typically uses deep hypothermia while keeping perfusion pressures below 25 mm Hg.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery.

BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

Transcriptome signature of ventricular arrhythmia in dilated cardiomyopathy reveals increased fibrosis and activated TP53.

AIMS: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. METHODS AND RESULTS: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT. CONCLUSIONS: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.

Society for Vascular Surgery (SVS) and Society of Thoracic Surgeons (STS) reporting standards for type B aortic dissections.

This Society for Vascular Surgery/Society of Thoracic Surgeons (SVS/STS) document illustrates and defines the overall nomenclature associated with type B aortic dissection. The contents describe a new classification system for practical use and reporting that includes the aortic arch. Chronicity of aortic dissection is also defined along with nomenclature in patients with prior aortic repair and other aortic pathologic processes, such as intramural hematoma and penetrating atherosclerotic ulcer. Complicated vs uncomplicated dissections are clearly defined with a new high-risk grouping that will undoubtedly grow in reporting and controversy. Follow-up criteria are also discussed with nomenclature for false lumen status in addition to measurement criteria and definitions of aortic remodeling. Overall, the document provides a facile framework of language that will allow more granular discussions and reporting of aortic dissection in the future.

Postoperative Complications Are Not Elevated in Well-Compensated ESRD Patients Undergoing Cardiac Surgery: End-Stage Renal Disease Cardiac Surgery Outcomes.

BACKGROUND: Patients with end-stage renal disease (ESRD) are at high risk for cardiac disease requiring surgery, and have been shown to have increased surgical risks. There have been significant improvements in ESRD management, surgical techniques, and patient selection over the past 10 y. We evaluated rates of serious postoperative outcomes in stable, well-dialyzed patients with ESRD undergoing nonemergent cardiac surgery compared to the general cardiac surgery population. METHODS: In this propensity-score matched study, we evaluated 1451 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital (UCH) between 2011 and 2016. Patients with ESRD were compared to nonESRD patients. The primary outcome was a composite endpoint, including 30-d mortality, stroke, postoperative infection, and prolonged intensive care unit (ICU) length of stay (LOS). RESULTS: A total of 35 patients with ESRD met inclusion criteria. These select patients were younger with few comorbidities than the nonESRD population. There were no statistically significant differences in the composite outcome between ESRD and nonESRD patients in the propensity-matched analysis (OR 0.70, CI 0.29-1.72, P = 0.44). There were no significant differences or trends for in-hospital mortality, postoperative stroke, infection, ICU LOS, or hospital LOS between the patients with and without ESRD. CONCLUSIONS: Stable ESRD patients undergoing nonemergent surgery are not at increased risk of major postoperative complications when compared to those without ESRD. Well-compensated ESRD patients should not be excluded from surgical consideration.

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice.

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

Predictors of Acute Kidney Injury Following Aortic Arch Surgery.

BACKGROUND: Acute kidney injury (AKI) following open aortic arch surgery is a frequent complication associated with increased morbidity and mortality. The primary purpose of this study was to evaluate risk factors for postoperative AKI in patients who underwent open aortic arch surgery utilizing hypothermic circulatory arrest (HCA). MATERIALS AND METHODS: Included were 295 patients undergoing surgery between January 2011 and March 2018. AKI was defined according to Kidney Disease: Improving Global Outcomes guidelines. Preoperative and intraoperative variables were stratified by no AKI versus any AKI, and bivariate analysis was performed. Multivariable logistic regression analysis used statistically and clinically significant characteristics from the bivariate analysis. RESULTS: Of the 295 patients, 93 (32%) developed AKI. In the bivariate analysis, significant predictors of AKI included the following: history of hypertension (P < 0.001), diabetes (P = 0.03), operative urgency (P = 0.009), cardiopulmonary bypass (CPB) time (P < 0.0001), HCA time (0.02), total intraoperative transfusions (P = 0.002), and concomitant procedures (coronary artery bypass grafting, or mitral/tricuspid interventions, P = 0.0009). In the multivariable analysis, significant predictors of AKI were history of hypertension (P = 0.03) and CPB time (P = 0.02). Age, operative urgency, circulatory arrest time, and any intraoperative transfusion were not significant in the multivariable analysis. CONCLUSION: In conclusion, given that CPB time is the only modifiable risk factor identified in the analysis, approaches to reducing bypass time should continue to be the focus of decreasing risk for postoperative AKI in HCA cases.

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure.

BACKGROUND: Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures. RESULTS: RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets. CONCLUSIONS: Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.

Reduced shear stress and associated aortic deformation in the thoracic aorta of patients with chronic obstructive pulmonary disease.

OBJECTIVE: Central aortic stiffness and chronic obstructive pulmonary disease (COPD) are associated with increased incidence of devastating aortopathies. However, the exact mechanism leading to elevated aortic stiffness in patients with COPD is unknown. The purpose of this study was to quantify flow and shear hemodynamic indices, known markers of vascular remodeling, in the thoracic aorta of patients with mild to moderate COPD (n = 16) and to compare these results with an age-matched control group (n = 10). METHODS: Four-dimensional flow magnetic resonance imaging has been applied to measure hemodynamic wall shear stress (WSS) at four specific planes along the ascending aorta, aortic arch, and proximal descending aorta for all subjects. Peak systolic WSS and time-averaged WSS, which respectively reflect magnitude and temporal shear variability, were calculated at standardized planes. Aortic deformation was measured by means of relative area change (RAC) at the midlevel of the ascending and descending aorta. RESULTS: Compared with controls, patients with COPD had significantly reduced RAC in the mid ascending aorta (9% vs 18%; P < .0001) and descending aorta (15% vs 19%; P = .0206). Peak systolic WSS in COPD patients was significantly reduced in all considered planes, with the most dramatic difference occurring in the descending aorta (0.46 vs 0.86 N/m2; P < .0001). Peak systolic WSS and time-averaged WSS were both significantly correlated with aortic RAC at each evaluated plane. CONCLUSIONS: Reduced flow shear metrics assessed at specific aortic regions correlated with RAC, a marker of aortic stiffness. Reduced hemodynamic WSS may then contribute to central aortic stiffening and perpetuate the risk for development of severe aortopathy.

Association of variant arch anatomy with type B aortic dissection and hemodynamic mechanisms.

OBJECTIVE: Congenital aortic arch variations are more common in patients with thoracic aortic disease for reasons unknown. Additionally, little is understood about their relation to type B aortic dissections (TBAD) specifically. We investigated the prevalence of variant aortic arch anatomy in patients with TBAD compared with controls. To understand the implications of how variant aortic arch anatomy may contribute to degenerative aortic disease, we compared flow hemodynamics of three variations of aortic arches using four-dimensional flow magnetic resonance imaging (4D flow MRI). METHODS: Arch anatomy on computed tomography imaging was reviewed and compared between patients with TBAD and age/sex-matched controls free of aortic pathology. Arch variants were defined as follows: common origin of innominate and left common carotid artery (bovine arch), aberrant right subclavian artery, and right-sided aortic arch. Demographics, TBAD characteristics, and follow-up data were abstracted. Patients with TBAD with variant and conventional aortic arches were compared. Additionally, three matched healthy controls with conventional, bovine, and aberrant right subclavian artery arches underwent 4D flow MRI evaluation to assess if there were differences in flow patterns by arch type. Indices of regional hemodynamic wall sheer stress were compared. RESULTS: Computed tomography scans of 185 patients with TBAD (mean age, 58.1 ± 12.4 years; 72.4% males; 71.4% Caucasian) and 367 controls (mean age, 62.5 ± 13.4 years; 67% males; 77.9% Caucasian) were reviewed. Variant arch anatomy was more prevalent in patients with TBAD (40.5% vs 24.5%; P < .001). In patients with TBAD, there were no differences in the mean age of presentation and descending thoracic aorta diameter among those with variant or conventional arch anatomy. Patients with TBAD with variant arch anatomy had a higher percentage of dissection related thoracic aortic repairs (54.7% vs 33.6%; P = .004) with repairs occurring predominantly in the acute phase. 4D flow MRI demonstrated a higher systolic wall shear stress along the inner curve of the bovine arch compared with the conventional aberrant right subclavian artery arches. CONCLUSIONS: Variant aortic arch anatomy is significantly more prevalent in patients with TBAD. patients with TBAD with variant arch anatomy had a higher percentage of dissection-related aortic repair. Preliminary 4D flow MRI data show differences in hemodynamic flow patterns between variant and conventional arches. Studies of long-term outcomes based on arch anatomy may offer additional insight to TBAD genesis and possibly influence management decisions.

Simvastatin reduces the TLR4-induced inflammatory response in human aortic valve interstitial cells.

BACKGROUND: Calcific aortic stenosis is a chronic inflammatory disease. Proinflammatory stimulation via toll-like receptor 4 (TLR4) causes the aortic valve interstitial cell (AVIC) to undergo phenotypic change. The AVIC first assumes an inflammatory phenotype characterized by the production of inflammatory mediators such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). This change has been linked with an osteogenic phenotypic response. Statins have recently been shown to have anti-inflammatory properties. We therefore hypothesized that statins may have an anti-inflammatory effect on human AVICs by downregulation of TLR4-stimulated inflammatory responses. Our purposes were (1) to determine the effect of simvastatin on TLR4-induced expression of inflammatory mediators in human AVICs and (2) to determine the mechanism(s) through which simvastatin exert this effect. MATERIALS AND METHODS: Human AVICs were isolated from the explanted hearts of four patients undergoing cardiac transplantation. Cells were treated with simvastatin (50 µM) for 1 h before stimulation with TLR4 agonist lipopolysaccharide (LPS, 0.2 µg/mL). Immunoblotting (IB) was used to analyze cell lysates for ICAM-1 expression, and enzyme-linked immunosorbent assay was used to detect IL-8 and MCP-1 in cell culture media. Likewise, lysates were analyzed for TLR4 and nuclear factor-kappa B activation (IB). After simvastatin treatment, lysates were analyzed for TLR4 levels (IB). Statistics were by analysis of variance (P < 0.05). RESULTS: Simvastatin reduced TLR4-induced ICAM-1, IL-8, and MCP-1 expression in AVICs. Simvastatin down-regulated TLR4 levels and suppressed TLR4-induced phosphorylation of nuclear factor-kappa B. CONCLUSIONS: These data demonstrate the potential of a medical therapy (simvastatin) to impact the pathogenesis of aortic stenosis.

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells.

OBJECTIVE: Extracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease. APPROACH AND RESULTS: Levels of ADAMTS5, matrilin 2, and α-SMA (α-smooth muscle actin) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin 2 and α-SMA. Treatment of normal VICs with soluble matrilin 2 caused an increase in α-SMA level through Toll-like receptors 2 and 4, which was accompanied by upregulation of runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin 2. Matrilin 2 activated nuclear factor (NF) κB and NF of activated T cells complex 1 and induced the interaction of these 2 NFs. Inhibition of either NF-κB or NF of activated T cells complex 1 suppressed matrilin 2's effect on VIC phenotype change. Knockdown of α-SMA reduced and overexpression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs. CONCLUSIONS: Matrilin 2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-κB and NF of activated T cells complex 1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin 2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying calcific aortic valve disease progression.

Right Ventricular Longitudinal Strain In Left Ventricular Assist Device Surgery-A Retrospective Cohort Study.

OBJECTIVES: Right ventricular (RV) failure is common after left ventricular assist device (LVAD) surgery and is associated with higher mortality. Measurement of longitudinal RV strain using speckle-tracking technology is a novel approach to quantify RV function. The authors hypothesized that depressed peak longitudinal RV strain measured by intraoperative transesophageal echocardiography (TEE) examinations would be associated with adverse outcomes after LVAD surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. PARTICIPANTS: Following Institutional Review Board approval, the authors retrospectively identified adult patients who underwent implantation of non-pulsatile LVAD. Exclusion criteria included inadequate TEE images and device explantation within 6 months for heart transplantation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The postoperative adverse event outcome was defined as a composite of one or more of death within 6 months, ≥14 days of inotropes, mechanical RV support, or device thrombosis. Intraoperative TEE images were analyzed for peak RV free wall longitudinal strain by two blinded investigators. Simple logistic regression was used to assess the relationship between adverse outcome and the mean of the strain measurements of the two raters. Agreement between the raters was assessed by intra-class correlation (0.62) and Pearson correlation coefficient (0.63). Of the 57 subjects, 21 (37%) had an adverse outcome. The logistic regression indicated no significant association between RV peak longitudinal strain and adverse events. CONCLUSIONS: In this retrospective study of patients undergoing non-pulsatile LVAD implantation, peak longitudinal strain of the RV free wall was not associated with adverse outcomes within 6 months after surgery. Additional quantitative echocardiographic measures for intraoperative RV assessment should be explored.

Alpha-2 agonist attenuates ischemic injury in spinal cord neurons.

BACKGROUND: Paraplegia secondary to spinal cord ischemia-reperfusion injury remains a devastating complication of thoracoabdominal aortic intervention. The complex interactions between injured neurons and activated leukocytes have limited the understanding of neuron-specific injury. We hypothesize that spinal cord neuron cell cultures subjected to oxygen-glucose deprivation (OGD) would simulate ischemia-reperfusion injury, which could be attenuated by specific alpha-2a agonism in an Akt-dependent fashion. MATERIALS AND METHODS: Spinal cords from perinatal mice were harvested, and neurons cultured in vitro for 7-10 d. Cells were pretreated with 1 µM dexmedetomidine (Dex) and subjected to OGD in an anoxic chamber. Viability was determined by MTT assay. Deoxyuridine-triphosphate nick-end labeling staining and lactate dehydrogenase (LDH) assay were used for apoptosis and necrosis identification, respectively. Western blot was used for protein analysis. RESULTS: Vehicle control cells were only 59% viable after 1 h of OGD. Pretreatment with Dex significantly preserves neuronal viability with 88% viable (P < 0.05). Dex significantly decreased apoptotic cells compared with that of vehicle control cells by 50% (P < 0.05). Necrosis was not significantly different between treatment groups. Mechanistically, Dex treatment significantly increased phosphorylated Akt (P < 0.05), but protective effects of Dex were eliminated by an alpha-2a antagonist or Akt inhibitor (P < 0.05). CONCLUSIONS: Using a novel spinal cord neuron cell culture, OGD mimics neuronal metabolic derangement responsible for paraplegia after aortic surgery. Dex preserves neuronal viability and decreases apoptosis in an Akt-dependent fashion. Dex demonstrates clinical promise for reducing the risk of paraplegia after high-risk aortic surgery.

Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury.

BACKGROUND: Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia-reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia-reperfusion injury after aortic occlusion results from TLR-4-mediated microglial activation in mice. METHODS AND RESULTS: TLR-4 mutant and wild-type mice underwent aortic occlusion for 5 minutes, followed by 60 hours of reperfusion when spinal cords were removed for analysis. Spinal cord cytokine production and microglial activation were assessed at 6 and 36 hours after surgery. Isolated microglia from mutant and wild-type mice were subjected to oxygen and glucose deprivation for 24 hours, after which the expression of TLR-4 and proinflammatory cytokines was analyzed. Mice without functional TLR-4 demonstrated decreased microglial activation and cytokine production and had preserved functional outcomes and neuronal viability after thoracic aortic occlusion. After oxygen and glucose deprivation, wild-type microglia had increased TLR-4 expression and production of proinflammatory cytokines. CONCLUSIONS: The absence of functional TLR-4 attenuated neuronal injury and microglial activation after thoracic aortic occlusion in mice. Furthermore, microglial upregulation of TLR-4 occurred after oxygen and glucose deprivation, and the absence of functional TLR-4 significantly attenuated the production of proinflammatory cytokines. In conclusion, TLR-4-mediated microglia activation in the spinal cord after aortic occlusion is critical in the mechanism of paraplegia after aortic cross-clamping and may provide targets for pharmacological intervention.

Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia.

BACKGROUND: Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation. METHODS: Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 µg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. Functional scoring was done at 6 hours following surgery and 12-hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. RESULTS: Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly attenuated microglial activation and proinflammatory cytokine production in vitro with a greater than twofold reduction in tumor necrosis factor-α. CONCLUSIONS: Alpha 2a agonist, dexmedetomidine treatment at reperfusion preserved neurologic function and neuronal viability. Furthermore, dexmedetomidine treatment resulted in an attenuation of microglial activation and proinflammatory cytokine production both in vivo and in vitro following LPS stimulation. This finding lends insight into the mechanism of paralysis following thoracic aortic interventions and may guide future pharmacologic targets for attenuating spinal cord ischemia and reperfusion.

Noteworthy in Cardiothoracic Surgery 2023.

Noteworthy in Cardiothoracic Surgery 2023 summarizes a few of the most high-impact trials and provocative trends in cardiothoracic surgery and transplantation this past year. Transplantation using organs procured from donation after circulatory death (DCD) continues to increase, and the American Society of Transplant Surgeons released recommendations on best practices in 2023. We review a summary of data on the impact of DCD on heart and lung transplantation. There has been increased interest in extracorporeal life support (ECLS), particularly after the COVID-19 pandemic, and we review the results of the highly discussed ECLS-SHOCK trial, which randomized patients in cardiogenic shock with planned revascularization to ECLS vs usual care. With improving survival outcomes in complex aortic surgery, there is a need for higher-quality evidence to guide which cooling and cerebral perfusion strategies may optimize cognitive outcomes in these patients. We review the short-term outcomes of the GOT ICE trial (Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest), a multicenter, randomized controlled trial of three different nadir temperatures, evaluating outcomes in cognition and associated changes in functional magnetic resonance imaging. Finally, both the Society of Thoracic Surgeons (STS) and the American College of Cardiology, American Heart Association, American College of Chest Physicians and Heart Rhythm Society (ACC/AHA/ACCP/HRS) updated atrial fibrillation guidelines in 2023, and we review surgically relevant updates to the guidelines and the evidence behind them.

Personalizing patient risk of a life-altering event: An application of machine learning to hemiarch surgery.

OBJECTIVE: The study objective was to assess a machine learning model's ability to predict the occurrence of life-altering events in hemiarch surgery and determine contributing patient characteristics and intraoperative factors. METHODS: In total, 602 patients who underwent hemiarch replacement at a high-volume aortic center from 2009 to 2022 were included. Patients were randomly divided into training (80%) and testing (20%) sets with various eXtreme gradient boosting candidate models constructed to predict the risk of experiencing life-altering events, including stroke, mortality, or new renal replacement therapy requirement. A total of 64 input parameters from the index hospitalization were identified, including 24 demographic characteristics as well as 8 preoperative and 32 intraoperative variables. A SHapley Additive exPlanation beeswarm plot was generated to identify and interpret the impact of individual features on the predictions of the final model. RESULTS: A life-altering event was noted in 15% (90/602) of patients who underwent hemiarch replacement, including urgent/emergency cases and dissections. The final eXtreme Gradient Boosting model demonstrated a cross-validation accuracy of 88% on the testing set and was well calibrated as evidenced by a low Brier score of 0.12. The best performing model achieved an area under the receiver operating characteristic curve of 0.76 and an area under the precision recall curve of 0.55. The SHapley Additive exPlanation beeswarm plot provided insights into key features that significantly influenced model prediction. CONCLUSIONS: Machine learning demonstrated superior accuracy in predicting hemiarch patients who would experience a life-altering event. This model may help to guide patients and clinicians in stratifying risk on an individual basis, which may in turn influence clinical decision-making.