The Effect of Laparoscopic Gastric Ischemic Preconditioning Prior to Esophagectomy on Anastomotic Stricture Rate and Comparison with Esophagectomy-Alone Controls.

BACKGROUND: Benign anastomotic stricture is a recognized complication following esophagectomy. Laparoscopic gastric ischemic preconditioning (LGIP) prior to esophagectomy has been associated with decreased anastomotic leak rates; however, its effect on stricture and the need for subsequent endoscopic intervention is not well studied. METHODS: This was a case-control study at an academic medical center using consecutive patients undergoing oncologic esophagectomies (July 2012-July 2022). Our institution initiated an LGIP protocol on 1 January 2021. The primary outcome was the occurrence of stricture within 1 year of esophagectomy, while secondary outcomes were stricture severity and frequency of interventions within the 6 months following stricture. Bivariable comparisons were performed using Chi-square, Fisher's exact, or Mann-Whitney U tests. Multivariable regression controlling for confounders was performed to generate risk-adjust odds ratios and to identify the independent effect of LGIP. RESULTS: Of 253 esophagectomies, 42 (16.6%) underwent LGIP prior to esophagectomy. There were 45 (17.7%) anastomotic strictures requiring endoscopic intervention, including three patients who underwent LGIP and 42 who did not. Median time to stricture was 144 days. Those who underwent LGIP were significantly less likely to develop anastomotic stricture (7.1% vs. 19.9%; p = 0.048). After controlling for confounders, this difference was no longer significant (odds ratio 0.46, 95% confidence interval 0.14-1.82; p = 0.29). Of those who developed stricture, there was a trend toward less severe strictures and decreased need for endoscopic dilation in the LGIP group (all p < 0.20). CONCLUSION: LGIP may reduce the rate and severity of symptomatic anastomotic stricture following esophagectomy. A multi-institutional trial evaluating the effect of LGIP on stricture and other anastomotic complications is warranted.

Prospective Evaluation of a Universally Applied Laparoscopic Gastric Ischemic Preconditioning Protocol Prior to Esophagectomy with Comparison with Historical Controls.

BACKGROUND: Anastomotic leak after esophagectomy is associated with significant morbidity and mortality. Our institution began performing laparoscopic gastric ischemic preconditioning (LGIP) with ligation of the left gastric and short gastric vessels prior to esophagectomy in all patients presenting with resectable esophageal cancer. We hypothesized that LGIP may decrease the incidence and severity of anastomotic leak. METHODS: Patients were prospectively evaluated following the universal application of LGIP prior to esophagectomy protocol in January 2021 until August 2022. Outcomes were compared with patients who underwent esophagectomy without LGIP from a prospectively maintained database from 2010 to 2020. RESULTS: We compared 42 patients who underwent LGIP followed by esophagectomy with 222 who underwent esophagectomy without LGIP. Age, sex, comorbidities, and clinical stage were similar between groups. Outpatient LGIP was generally well tolerated, with one patient experiencing prolonged gastroparesis. Median time from LGIP to esophagectomy was 31 days. Mean operative time and blood loss were not significantly different between groups. Patients who underwent LGIP were significantly less likely to develop an anastomotic leak following esophagectomy (7.1% vs. 20.7%, p = 0.038). This finding persisted on multivariate analysis [odds ratio (OR) 0.17, 95% confidence interval (CI) 0.03-0.42, p = 0.029]. The occurrence of any post-esophagectomy complication was similar between groups (40.5% vs. 46.0%, p = 0.514), but patients who underwent LGIP had shorter length of stay [10 (9-11) vs. 12 (9-15), p = 0.020]. CONCLUSIONS: LGIP prior to esophagectomy is associated with a decreased risk of anastomotic leak and length of hospital stay. Further, multi-institutional studies are warranted to confirm these findings.

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.

Assessment of Discharge Analgesic Prescription Patterns for Hospitalized Patients With Rib Fractures.

INTRODUCTION: There is a paucity of data describing opioid prescribing patterns for trauma patients. We investigated pain medication regimens prescribed at discharge for patients with traumatic rib fractures, as well as potential variables predictive of opioid prescribing. METHODS: A single-center, retrospective analysis was performed of 337 adult patients presenting with ≥1 traumatic rib fractures between January and December 2019. The primary outcome was oral morphine milligram equivalents (MME) prescribed on discharge. A multivariable logistic regression analysis was performed to determine factors independently associated with above median (150) MME prescription at discharge. RESULTS: The majority of patients were male (68.8%) with a median age of 53 y. Blunt trauma accounted for 97.3% of cases with a median Injury Severity Score(ISS) of 10. Locoregional pain procedures were utilized in 16.9% of patients. Opioids were the most common analgesic prescribed at discharge, and 74.1% of patients prescribed opioids on discharge were also prescribed a non-opioid adjunct. On multivariable analysis, daily MME prescribed during hospitalization (OR 1.01, 95% CI 1.01-1.02, P < 0.01) and number of rib fractures (OR 2.26, 95% CI 1.36-3.74, P < 0.01) were predictive of high MME prescribed on discharge. CONCLUSIONS: For patients with traumatic rib fractures, daily MME during hospitalization and number of rib fractures were predictive of high MME prescribing on discharge. Further prospective studies evaluating strategies for pain management and protocolized approaches to opioid prescribing are needed to reduce unnecessary and inappropriate opioid use in this patient population.

Simvastatin Inhibits Histologic Changes Associated with Gastroduodenal Reflux in a Murine Model.

BACKGROUND: Observational studies demonstrate a protective effect of statins on the development and progression of esophageal adenocarcinoma. The role of statins in the prevention of reflux-induced esophageal changes remains unknown. AIMS: Using a mixed gastroduodenal reflux mouse model, we hypothesized that oral administration of simvastatin would attenuate reflux-induced mucosal changes of the distal esophagus. METHODS: Human Barrett's (CPB) and esophageal adenocarcinoma (FLO1 and OE19) cells were treated with simvastatin. Cell proliferation and apoptosis were evaluated using the MTS proliferation and annexin V apoptosis assays, respectively. A reflux mouse model was generated by performing a side-to-side anastomosis between the gastroesophageal junction and first portion of the duodenum (duodeno-gastroesophageal anastomosis, DGEA). DGEA mice were fed a standard or simvastatin-containing diet following surgery. Mice were euthanized 6 weeks post-operatively. RESULTS: Simvastatin significantly decreased proliferation and increased apoptosis in all cell lines. Compared to control animals, mice undergoing DGEA who were fed a standard diet demonstrated a fourfold increase in mucosal thickness and significant increase in proliferating cells (p < 0.0001). DGEA mice fed a simvastatin-containing diet had an attenuated response to reflux, with a significant reduction in mucosal hyperplasia and proliferation (p < 0.0001). DGEA mice fed a simvastatin-containing diet demonstrated significant upregulation of procaspase-3 (p = 0.009) and cleaved caspase-3 (p = 0.034) in the distal esophagus. CONCLUSIONS: We demonstrate for the first time a reduction in reflux-induced histologic changes of the distal esophagus following oral administration of simvastatin in vivo. These findings identify simvastatin as a potential preventative agent to inhibit the development and progression of reflux-induced esophageal injury.

Survival following lung transplantation: A population-based nested case-control study.

BACKGROUND: Lung transplantation is the mainstay of treatment for patients with end-stage respiratory failure. This study sought to evaluate survival following transplantation compared to the general population and quantify standardized mortality ratios (SMRs) using a nested case-control study design. METHODS: Control subjects were nonhospitalized inhabitants of the United States identified through the National Longitudinal Mortality Study. Case subjects were adults who underwent lung transplantation between 1990 and 2007 and identified through the Organ Procurement and Transplantation Network. Propensity-matching (5:1, nearest neighbor, caliper = 0.1) was utilized to identify suitable control subjects based on age, sex, race, and location of residency. The primary study endpoint was 10-year survival. RESULTS: About 14,977 lung transplant recipients were matched to 74,885 nonhospitalized US residents. The 10-year survival rate of lung transplant recipients was 28% (95% confidence interval [CI] = 27%-29%). The population expected mortality rate was 19 deaths/100 person-years while the observed ratio was 104 deaths/100 person-years (SMR = 5.39, 95% CI = 5.35-5.43). The largest discrepancies between observed and expected mortality rates were in females (SMR = 5.97), Hispanic (SMR = 10.70), and single lung recipients (SMR = 5.92). SMRs declined over time (1990-1995 = 5.79, 1996-2000 = 5.64, and 2001-2007 = 5.10). Standardized mortality peaks in the first year after transplant and decreases steadily over time. CONCLUSIONS: Lung transplant recipients experience a fivefold higher SMR compared to the nonhospitalized population. Long-term mortality rates have experienced consistent decline over time.

Statins Inhibit Toll-Like Receptor 4-Mediated Growth of Human Esophageal Adenocarcinoma Cells.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a lethal malignancy with poor prognosis. Pharmacologic inhibitors of inflammation, such as statins, have been shown to decrease the risk of development and progression of esophageal cancer, but the mechanism of this protection is unclear. The objective of this study was to elucidate the effect of statins on toll-like receptor 4-mediated-proliferation of human EAC cells and identify the mechanism responsible for these observed effects. METHODS: Human EAC cells (OE33 and FLO1) were treated with simvastatin or atorvastatin for increasing doses and time periods. Toll-like receptor 4 (TLR4) expression was assessed. Cells were pretreated with statin followed by lipopolysaccharide (LPS). Cell proliferation and expression of signaling proteins were evaluated. FLO1 cells were injected into the flank of nude mice. Mice received intraperitoneal injections of simvastatin, atorvastatin, or control solution and tumor volume was measured. RESULTS: OE33 and FLO1 cells demonstrated decreased TLR4 expression after treatment with simvastatin or atorvastatin for 8 h (P < 0.05). LPS increased proliferation, whereas pretreatment with statin abolished this response (P < 0.05). Statins decreased expression and activation of LPS-induced signaling proteins, including MyD88, TRAF6, Akt, and NF-κB (P < 0.05). Mice receiving daily statin injections demonstrated smaller tumors than control mice (P < 0.001 at day 33). CONCLUSIONS: Treatment of EAC cells with simvastatin or atorvastatin decreases TLR4-mediated proliferation and in vivo tumor growth. Decreased TLR4 expression and subsequent reduction in MyD88-dependent signaling could be a mechanism by which statins act to reduce tumor growth rates.

Secretory Phospholipase A2 Inhibition Attenuates Adhesive Properties of Esophageal Barrett's Cells.

BACKGROUND: Gastroesophageal reflux and Barrett's esophagus are significant risk factors for the development of esophageal adenocarcinoma. Group IIa secretory phospholipase A2 (sPLA2) catalyzes the production of various proinflammatory metabolites and plays a critical role in promoting reflux-induced inflammatory changes within the distal esophagus. We hypothesized that inhibition of sPLA2 in human Barrett's cells would attenuate adhesion molecule expression via decreased activation of nuclear factor kappa B (NF-κB) and decrease cell proliferation, possibly mitigating the invasive potential of Barrett's esophagus. MATERIALS AND METHODS: Normal human esophageal epithelial cells (HET1A) and Barrett's cells (CPB) were assayed for baseline sPLA2 expression. CPB cells were treated with a specific inhibitor of sPLA2 followed by tumor necrosis factor-α. Protein expression was evaluated using immunoblotting. Cell proliferation was assessed using an MTS cell proliferation assay kit. Statistical analysis was performed using the Student's t-test or analysis of variance, where appropriate. RESULTS: CPB cells demonstrated higher baseline sPLA2 expression than HET1A cells (P = 0.0005). Treatment with 30 µM sPLA2 inhibitor significantly attenuated intercellular adhesion molecule-1 (P = 0.004) and vascular cell adhesion molecule-1 (P < 0.0001) expression as well as decreased NF-κB activation (P = 0.002). sPLA2 inhibition decreased cell proliferation in a dose-dependent manner (P < 0.001 for 15, 20, and 30 µM doses). CONCLUSIONS: sPLA2 inhibition in human Barrett's cells decreases cellular adhesive properties and NF-κB activation as well as decreases cell proliferation, signifying downregulation of the inflammatory response and possible attenuation of cellular malignant potential. These findings identify sPLA2 inhibition as a potential chemopreventive target for premalignant lesions of the esophagus.

Barriers and Facilitators in Implementation of an Esophagectomy Care Pathway: a Qualitative Analysis.

INTRODUCTION: A new postoperative esophagectomy care pathway was recently implemented at our institution. Practice pattern change among provider teams can prove challenging; therefore, we sought to study the barriers and facilitators toward pathway implementation at the provider level. METHODS: This qualitative study was guided by the Theoretical Domains Framework (TDF) to study the adoption and implementation of a post-esophagectomy care pathway. Sixteen in-depth interviews were conducted with providers involved with the pathway. Matrix analysis was used to analyze the data. RESULTS: Providers included attending surgeons (n = 6), advanced practice providers (n = 8), registered dietitian (n = 1), and clinic staff (n = 1). TDF domains that were salient across our findings included knowledge, beliefs about consequences, social influences, and environmental context and resources. Identified facilitators included were electronic health record tools, such as note templates including pathway components and a pathway-specific order set, patient satisfaction, and preliminary data indicating clinical benefits such as a reduced anastomotic leak rate. The major barrier reported was a hesitance to abandon previous practice patterns, most prevalent at the attending surgeon level. CONCLUSION: The TDF enabled us to identify and understand the individuals' perceived barriers and facilitators toward adoption and implementation of a postoperative esophagectomy pathway. This analysis can help guide and improve adoption of surgical patient care pathways among providers.

A comparison of short-term outcomes following robotic-assisted vs. open transthoracic diaphragm plication.

Diaphragm paralysis and eventration are rare conditions in adults. Symptomatic patients may benefit from surgical plication of the elevated hemidiaphragm. The objective of this study was to compare short-term outcomes and length of stay following robotic-assisted vs. open diaphragm plication. A multicenter retrospective study was conducted that identified patients undergoing unilateral hemidiaphragm plication from 5/2008 to 12/2020. The first RATS plication was performed in 11/2018. Electronic medical records were reviewed, and outcomes were compared between RATS and open approach. One hundred patients underwent diaphragm plication, including thirty-nine (39.0%) RATS and sixty-one (61.0%) open cases. Patients undergoing RATS diaphragm plication were older (64 years vs. 55 years, p = 0.01) and carried a higher burden of comorbidities (Charlson Comorbidity Index: 2.0 vs. 1.0, p = 0.02). The RATS group had longer median operative times (146 min vs. 99 min, p < 0.01), but shorter median hospital length of stays (3.0 days vs. 6.0 days, p < 0.01). There was a non-significant trend toward a decreased rate of 30-day postoperative complications (20.5% RATS vs. 32.8% open, p = 0.18) and 30-day unplanned readmissions (7.7% RATS vs. 9.8% open, p > 0.99). RATS is a technically feasible and safe option for performing diaphragm plications. This approach increases the surgical candidacy of older patients with a higher burden of comorbid disease without increasing complication rates, while reducing length of hospital stay.

Esophagram should be performed to diagnose esophageal perforation before inter-hospital transfer.

Background: Early recognition of esophageal perforation may prevent morbidity and mortality, and accurate diagnostic imaging facilitates triage. Stable patients with suspected perforation may be transferred to higher levels of care before appropriate work-up and diagnosis confirmation. We reviewed patients transferred for esophageal perforation to critically analyze the diagnostic workflow. Methods: We performed a retrospective review of patients transferred to our tertiary care institution from 2015-2021 for suspected esophageal perforation. Demographics, referring site characteristics, diagnostic studies, and management were analyzed. Bivariate comparisons were performed using Wilcoxon-Mann-Whitney tests for continuous variables and chi-squared or Fisher's exact tests for categorical variables. Results: Sixty-five patients were included. Etiology of suspected perforation was spontaneous in 53.8% and iatrogenic in 33.8%. Most patients were transferred within 24 hours from time of suspected perforation (66.2%). Transferring sites included seven states and were 101-300 miles (32.3%) or >300 miles (26.2%) away. CT imaging was obtained in 96.9% before transfer, most commonly demonstrating pneumomediastinum (46.2%). Only 21.5% of patients had an esophagram before transfer. Following transfer, 36.9% (n=24) were ultimately not found to have esophageal perforation, demonstrated by negative arrival esophagram in 79.1%. In patients with confirmed perforation (n=41), 58.5% had surgery, 26.8% endoscopic intervention, and 14.6% supportive care. Conclusions: After transfer a proportion of patients were ultimately found to not have esophageal perforation, typically demonstrated by negative esophagram upon arrival. We conclude that a recommendation of performing esophagram at the presenting site, when possible, may prevent unnecessary transfers, and will likely reduce costs, conserve resources, and decrease management delays.

Long-Term Patient-Reported Symptom Improvement and Quality of Life after Transthoracic Diaphragm Plication in Adults.

BACKGROUND: Open and robotic-assisted transthoracic approaches for diaphragm plication are accepted surgical interventions for diaphragm paralysis and eventration. However, long-term patient-reported symptom improvement and quality of life (QOL) remains unclear. STUDY DESIGN: A telephone-based survey was developed focusing on postoperative symptom improvement and QOL. Patients who underwent open or robotic-assisted transthoracic diaphragm plication (2008-2020) across three institutions were invited to participate. Patients who responded and provided consent were surveyed. Likert responses on symptom severity were dichotomized and rates before and after surgery were compared using McNemar's test. RESULTS: Forty-one percent of patients participated (43 of 105 responded, mean age 61.0 years, 67.4% male, 37.2% robotic-assisted surgery), with an average time between surgery and survey of 4.1 ± 3.2 years. Patients reported significant improvement in dyspnea while lying flat (67.4% pre- vs 27.9% postoperative, p < 0.001), dyspnea at rest (55.8% pre- vs 11.6% postoperative, p < 0.001), dyspnea with activity (90.7% pre- vs 55.8% postoperative, p < 0.001), dyspnea while bending over (79.1% pre- vs 34.9% postoperative, p < 0.001), and fatigue (67.4% pre- vs 41.9% postoperative, p = 0.008). There was no statistical improvement in chronic cough. 86% of patients reported improved overall QOL, 79% had increased exercise capacity, and 86% would recommend surgery to a friend with a similar problem. Analysis comparing open and robotic-assisted approaches found no statistically significant differences in symptom improvement or QOL responses between the groups. CONCLUSIONS: Patients report significantly improved dyspneic and fatigue symptoms after transthoracic diaphragm plication, regardless of open or robotic-assisted approach. The majority of patients report improved QOL and exercise capacity.

Efficacy of Combined Hiatal Hernia Repair and Transoral Incisionless Fundoplication for Giant Paraoesophageal Hernias: Technique and Early Results.

INTRODUCTION: Data is limited on hybrid transoral incisionless fundoplication (TIF) and hiatal hernia repair in giant paraoesophageal hernia (GPEH). We aimed to assess the safety, patient satisfaction, and symptom resolution following a hybrid paraoesophageal hernia (PEH) repair and TIF in patients with GPEH. PATIENTS AND METHODS: All single-session hybrid TIF combined with minimally invasive PEH repair performed between February 2020 and June 2021 were evaluated. Procedures were performed in the operating room under general anesthesia with robotic or laparoscopic PEH repair followed by TIF. RESULTS: Twelve patients underwent combined surgical hiatal hernia repair and TIF. Primary presenting symptoms included heartburn (75.0%), dysphagia (41.7%), and chronic anemia from Cameron's ulcers (16.7%). The mean hernia defect size was 5.0 cm (range 3.0 to 6.0 cm). Hiatal hernia repairs were performed robotically in 7 patients and laparoscopically in 5 patients. The total mean operative time was 254 minutes (range: 180 to 390 min). One patient reported postoperative dysphagia requiring endoscopic dilation postdischarge with a resolution of symptoms. No gas-bloat symptoms were reported. All patients reported complete resolution of presenting symptoms at the time of follow-up. Postoperative mean follow-up for 4 patients at 6 months with upper endoscopy and pH testing showed an intact valve with no evidence of esophagitis or acid reflux. CONCLUSIONS: In our experience, hybrid hiatal hernia repair and TIF is a safe and effective therapeutic option for patients with GPEH. This hybrid procedure allows for more expeditious completion of the repair and results in lower rates of postfundoplication dysphagia and gas-bloat. Furthermore, this approach requires a less extensive surgical dissection on the greater curvature of the stomach, thereby minimizing the risk of vagal nerve injury and bleeding from the short gastric vessels.

Development of a Modular and Equitable Surgical Simulator.

There is a tremendous need for affordable and accessible surgical simulators in the United States and abroad. Our group developed a portable, modular, inexpensive surgical simulator designed for all levels of surgical trainees, from medical students to cardiothoracic surgery fellows, and adaptable to a variety of surgical specialties. Our goal is to provide a platform for innovative surgery simulation that applies to any learner or resource setting. We describe the development, assembly, and future directions for this simulator.

Direct Innominate Artery Cannulation versus Side Graft for Selective Antegrade Cerebral Perfusion during Aortic Hemiarch Replacement.

BACKGROUND: Selective antegrade cerebral perfusion (SACP) has become our preferred method for cerebral protection during open arch cases. While the initial approach involved sewing a graft to the innominate artery as the arterial cannulation site, our access strategy has since evolved to central aortic cannulation with use of a percutaneous cannula in the innominate for SACP. We hypothesized that SACP delivered via direct innominate cannulation using a 12- or 14-Fr cannula results in equivalent outcomes to cases utilizing a side graft. METHODS: This was a single-center, retrospective analysis of 211 adult patients who underwent elective hemiarch replacement using hypothermic circulatory arrest with SACP via the innominate artery between 2012 and 2020. Urgent and emergent cases were excluded. RESULTS: A side graft sutured to the innominate was utilized in 81% (n = 171) of patients, while direct innominate artery cannulation was performed in 19% (n = 40) of patients. Baseline patient characteristics were similar between groups aside from a higher baseline creatinine in the direct cannulation group (1.3 vs. 0.9, p = 0.032). Patients undergoing direct cannulation demonstrated shorter cardiopulmonary bypass time (132.7 vs. 154.9 minutes, p = 0.020) and shorter circulatory arrest time (8.1 vs. 10.9 minutes, p = 0.004). Nadir bladder temperature did not significantly differ between groups (27.2°C for side graft vs. 27.6°C for direct cannulation, p = 0.088). There were no significant differences in postoperative outcomes. CONCLUSION: Direct cannulation of the innominate artery with a 12- or 14-Fr cannula for SACP during hemiarch replacement is a safe alternative to using a sutured side graft. While cardiopulmonary bypass and circulatory arrest times appear improved, this is likely attributable to accumulation of experience and proficiency in technique. However, direct innominate artery cannulation may facilitate quicker completion of these procedures by eliminating the time necessary to suture a graft to the innominate artery.

Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and ß-catenin Signaling.

BACKGROUND: Recent clinical evidence suggests an association between warfarin use and calcification of the aortic valve. We sought to determine the effect of warfarin on aortic valve interstitial cell (AVIC) osteogenic protein expression and the signaling pathways by which this effect is mediated. METHODS: Human AVICs were isolated from normal aortic valves of patients undergoing cardiac transplantation, whereas diseased AVICs were isolated from patients undergoing aortic valve replacement for aortic stenosis. AVICs were treated with various anticoagulants, and osteogenic protein expression was evaluated using immunoblotting. Phosphorylation of lipoprotein receptor-related protein 6 (LRP6) and extracellular signal-regulated kinase 1/2 (ERK1/2) was evaluated after treatment with warfarin. AVICs were pretreated with LRP6 inhibitor dkk1 and ERK1/2 inhibitor PD98059 followed by treatment with warfarin, and osteogenic protein expression was evaluated. RESULTS: Warfarin, but not heparin or dabigatran, significantly increased Runx-2 and Osx expression in both normal and diseased human AVICs. Upregulation of ß-catenin protein expression and nuclear translocation occurred in diseased AVICs but not normal AVICs after warfarin treatment. Warfarin induced phosphorylation of LRP6 in diseased AVICs only and phosphorylation of ERK1/2 in both normal and diseased AVICs. LRP6 inhibition attenuated warfarin-induced Runx-2 expression in diseased AVICs. ERK1/2 inhibition attenuated warfarin-induced Runx-2 expression in both normal and diseased AVICs. CONCLUSIONS: Warfarin induces osteogenic activity in normal and diseased isolated human AVICs. This effect is mediated by ERK1/2 in both diseased and normal AVICs, but in diseased AVICs ß-catenin signaling also plays a role. These results implicate the role of warfarin in aortic valve calcification and highlight potential mechanisms for warfarin-induced aortic stenosis.

Toll-like Receptor 4 Mediates Reflux-Induced Inflammation in a Murine Reflux Model.

Dysregulation of toll-like receptor (TLR) signaling within the gastrointestinal epithelium has been associated with uncontrolled inflammation and tumorigenesis. We sought to evaluate the role of TLR4 in the development of gastroesophageal reflux-mediated inflammation and mucosal changes of the distal esophagus. Verified human esophageal Barrett's cells with high grade dysplasia (CPB) and esophageal adenocarcinoma cells (OE33) were treated with deoxycholic acid for 24 hours. Cells were pretreated with a TLR4-specific inhibitor peptide 2 hours prior to deoxycholic acid treatment. Inflammatory markers were evaluated using immunoblotting and enzyme-linked immunosorbent assay. A surgical reflux mouse model was generated by performing a side-to-side anastomosis between the second portion of the duodenum and the gastroesophageal junction. Control animals underwent laparotomy with incision and closure of the esophagus superior to the gastroesophageal junction (sham procedure). Esophageal sections were evaluated using hematoxylin and eosin staining and immunohistochemistry. Deoxycholic acid increased expression of inflammatory markers including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin 8. Pretreatment with a TLR4 inhibitor significantly decreased deoxycholic acid-induced inflammatory marker expression. C3H/HeNCrl mice demonstrated a significant increase in mucosal hyperplasia and proliferation following DGEA compared to sham procedure. TLR4 mutant mice (C3H/HeJ) undergoing DGEA demonstrated an attenuated hyperplastic and proliferative response compared to C3H/HeNCrl mice. Inhibition of TLR4 signaling attenuates reflux-induced inflammation in vivo. These findings identify TLR4 inhibition as a potential therapeutic target to halt the progression of pathologic esophageal changes developing in the setting of chronic gastroesophageal reflux disease.

Evaluating the risk of spinal cord ischemia in zone 2 frozen elephant trunk replacement.

BACKGROUND: The appropriate stent length in frozen elephant trunk replacements (FET) remains debated relative to the risk for paraplegia. However, landing the distal end of the stent beyond the curve of the arch facilitates distal reintervention, which is commonly beyond the 10 cm stent coverage when deployed proximal to the left subclavian artery. The aim of this study was to evaluate outcomes following the use of 15 cm stent grafts in zone 2 (z2, distal to the left common carotid). METHODS: Using our single institution-maintained database, 103 zone 2 FET performed from 2016 to 2020 were reviewed. RESULTS: Of the 103 z2, a 15 cm stent graft was used in 51 operations. The indications for FET included acute and chronic aortic dissection, arch aneurysms, and pseudoaneurysms. The incidence of SCI was 0%. Seven deaths (13.7%) occurred. CONCLUSIONS: The data demonstrates the incidence of post-operative paraplegia to be 0% with 15 cm z2 FET. The understanding of SCI in FET should not only include the stent length but also from where it begins.