Association Between Geospatial Access to Trauma Center Care and Motor Vehicle Crash Mortality in the United States.

BACKGROUND: Motor vehicle crashes (MVCs) are a leading cause of preventable trauma death in the United States (US). Access to trauma center care is highly variable nationwide. The objective of this study was to measure the association between geospatial access to trauma center care and MVC mortality. METHODS: This was a population-based study of MVC-related deaths that occurred in 3,141 US counties (2017-2020). ACS and state-verified level I-III trauma centers were mapped. Geospatial network analysis estimated the ground transport time to the nearest trauma center from the population-weighted centroid for each county. In this way, the exposure was the predicted access time to trauma center care for each county population. Hierarchical negative binomial regression measured the risk-adjusted association between predicted access time and MVC mortality, adjusting for population demographics, rurality, access to trauma resources, and state traffic safety laws. RESULTS: We identified 92,398 crash fatalities over the four-year study period. Trauma centers mapped included 217 level I, 343 level II, and 495 level III trauma centers. The median county predicted access time was 47 min (IQR 26-71 min). Median county MVC mortality was 12.5 deaths/100,000 person-years (IQR 7.4-20.3 deaths/100,000 person-years). After risk-adjustment, longer predicted access times were significantly associated with higher rates of MVC mortality (>60 min vs. <15 min; MRR 1.36; 95%CI 1.31-1.40). This relationship was significantly more pronounced in urban/suburban vs. rural/wilderness counties (p for interaction, <0.001). County access to trauma center care explained 16% of observed state-level variation in MVC mortality. CONCLUSIONS: Geospatial access to trauma center care is significantly associated with MVC mortality and contributes meaningfully to between-state differences in road traffic deaths. Efforts to improve trauma system organization should prioritize access to trauma center care to minimize crash fatalities. LEVEL OF EVIDENCE: Level III, Epidemiological.

The evolution and development of a robotic acute care surgery program.

BACKGROUND: Acute care surgeons perform more than 850,000 operations annually on emergency general surgery patients in the United States. Emergency general surgery conditions are associated with a disproportionate excess of patient complications and death. Innovative quality improvement strategies have focused on addressing the excess morbidity and mortality among this patient population. Minimally invasive surgical techniques have been shown to reduce the burden experienced by emergency general surgery patients. Still, limited adoption by acute care surgeons has restricted this application's potential. An institutional robotics acute care surgery program provides acute care surgeons additional opportunities to expand minimally invasive surgery access to emergency general surgery patients irrespective of the time or day of the week. METHODS: A robotics acute care surgery program was developed and implemented at a high-volume academic institution within the division of trauma and acute care surgery. RESULTS: Three attending surgeons and two fellows within the trauma and acute care surgery division had successfully completed a defined robotics clinical pathway. As a result, around-the-clock use of a robotic surgical platform for emergency general surgery cases was implemented with routine use by trained robotic acute care surgeons and practicing fellows. CONCLUSION: The advancement of robotic surgical technology has opened new avenues for surgical application in the emergency setting. The development of a robotic acute care surgery program allows acute care surgeons to diversify their practice while providing greater access to minimally invasive approaches for emergency general surgery patients.

Emergency department versus operating room intubation of patients undergoing immediate hemorrhage control surgery.

BACKGROUND: Hemorrhage control surgery is an essential trauma center function. Airway management of the unstable bleeding patient in the emergency department (ED) presents a challenge. Premature intubation in the ED can exacerbate shock and precipitate extremis. We hypothesized that ED versus operating room intubation of patients requiring urgent hemorrhage control surgery is associated with adverse outcomes at the patient and hospital-levels. METHODS: Patients who underwent hemorrhage control within 60 minutes of arrival at level 1 or 2 trauma centers were identified (National Trauma Data Bank 2017-2019). To minimize confounding, patients dead on arrival, undergoing ED thoracotomy, or with clinical indications for intubation (severe head/neck/face injury or Glasgow Coma Scale score of ≤8) were excluded. Two analytic approaches were used. First, hierarchical logistic regression measured the risk-adjusted association between ED intubation and mortality. Secondary outcomes included ED dwell time, units of blood transfused, and major complications (cardiac arrest, acute respiratory distress syndrome, acute kidney injury, sepsis). Second, a hospital-level analysis determined whether hospital tendency ED intubation was associated with adverse outcomes. RESULTS: We identified 9,667 patients who underwent hemorrhage control surgery at 253 trauma centers. Patients were predominantly young men (median age, 33 years) who suffered penetrating injuries (71%). The median initial Glasgow Coma Scale and systolic blood pressure were 15 and 108 mm Hg, respectively. One in five (20%) of patients underwent ED intubation. After risk-adjustment, ED intubation was associated with significantly increased odds of mortality, longer ED dwell time, greater blood transfusion, and major complications. Hospital-level analysis identified significant variation in use of ED intubation between hospitals not explained by patient case mix. After risk adjustment, patients treated at hospitals with high tendency for ED intubation (compared with those with low tendency) were significantly more likely to suffer in-hospital cardiac arrest (6% vs. 4%; adjusted odds ratio, 1.46; 95% confidence interval, 1.04-2.03). CONCLUSION: Emergency department intubation of patients who require urgent hemorrhage control surgery is associated with adverse outcomes. Significant variation in ED intubation exists between trauma centers not explained by patient characteristics. Where feasible, intubation should be deferred in favor of rapid resuscitation and transport to the operating room. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Angioembolization May Improve Survival in Patients With Severe Hepatic Injuries.

INTRODUCTION: Although reports on angioembolization (AE) show favorable results for severe hepatic trauma, information is lacking on its benefit in the management and mechanisms of injury (MOI). This study examined patient outcomes with severe hepatic injuries to determine the association of in-hospital mortality with AE. The hypothesis is that AE is associated with increased survival in severe hepatic injuries. METHODS: Demographics, age, sex, MOI, shock index (SI), ≥6 units packed red blood cells (PRBCs) per hospital length of stay (LOS), intensive care unit LOS, injury severity score (ISS), and AE were collected. The primary outcome was in-hospital mortality. Patients were stratified into groups according to MOI, AE, and operative vs non-operative management. Multivariable logistic regression determined the independent association of mortality with AE vs no AE and operative vs nonoperative management and modeled the odds of mortality controlling for MOI, AE vs no AE, age and ISS groups, SI >.9, and ≥6 units PRBCs/LOS. RESULTS: From 2013 to 2018, 2462 patients (1744 blunt; 718 penetrating) were treated for severe hepatic injuries. AE was used in only 21% of patients. Mortality rates increased with higher ISS and age. AE was associated with mortality when compared to patients who did not undergo AE. The strongest associations with mortality were ISS ≥25, transfusion ≥ 6 units PRBCs/LOS, and age ≥65 years. CONCLUSIONS: AE is underutilized in severe hepatic trauma. AE may be a valuable adjunct in the treatment of severe hepatic injuries especially in older patients and those needing exploratory laparotomy.

Characterizing the underlying diagnoses for exploratory laparotomies to improve risk-adjustment models of postoperative mortality.

BACKGROUND: Surgeons perform emergent exploratory laparotomies (ex-laps) for a myriad of surgical diagnoses. We characterized common diagnoses for which emergent ex-laps were performed and leveraged these groups to improve risk-adjustment models for postoperative mortality. METHODS: Using American Association for the Surgery of Trauma criteria, we identified hospitalizations where the primary procedure was an emergent ex-lap in the 2012 to 2014 (derivation cohort) and 2015 (validation cohort) Nationwide Inpatient Sample. After tabulating all International Classification of Diseases-9th Rev.-Clinical Modification diagnosis codes within these hospitalizations, we divided them into clinically relevant groups. Using two stepwise regression paradigms-forward selection and backward elimination-we identified diagnostic groups significantly associated with postoperative mortality in multivariable logistic regressions. We evaluated the addition of these groups as individual covariates in risk-adjustment models for postoperative mortality using the area under the receiver operator characteristic curve. All regressions additionally adjusted for clinical factors and hospital clustering. RESULTS: We identified 4127 patients in the derivation cohort (median age, 50 years; 46.0% female; 62.1% white), with an overall mortality rate of 13.4%. Among all patients, we tabulated a total of 164 diagnosis codes, of which 27 (16.5%) may have led to an emergent ex-lap. These 27 codes clinically represented seven diagnostic categories, which captured a majority of the patients (70.4%). Backward elimination and forward selection led to four common diagnosis categories associated with mortality: bleeding, obstruction, shock, and ischemia. Adjusting for these four diagnostic groups in a multivariable logistic regression assessing postoperative mortality increased the area under the receiver operator characteristic curve from 74.5% to 88.2% in the derivation cohort and from 73.8% to 88.2% in the validation cohort. CONCLUSION: Seven diagnostic groups account for the majority of the emergent ex-laps. Adjusting for four groups may improve the accuracy of risk-adjustment models for mortality and validating such analytic standardization may optimize best research practices for EGS procedures. LEVEL OF EVIDENCE: Prognostic and epidemiologic, Level III.

Blood utilization and mortality in victims of gun violence.

BACKGROUND: Blood transfusion can be lifesaving for patients with hemorrhage; however, transfusion requirements for victims of gun violence are poorly understood. STUDY DESIGN AND METHODS: In an urban, Level 1 trauma center, 23,422 trauma patients were analyzed in a retrospective cohort study. Patients with gunshot wounds (GSWs) (n = 2,672; 11.4% of trauma patients) were compared to those with non-GSW traumatic injuries from 2005 to 2017, to assess blood utilization. RESULTS: The GSW cohort was approximately five times more likely to require transfusion (538 of 2672 [20.1%] vs. 798 of 20,750 [3.9%]; p < 0.0001), and the number of blood component units transfused per patient was approximately 10 times greater (3.3 ± 13.5 vs. 0.31 ± 3.8 units/patient; p < 0.0001), compared to the non-GSW cohort. The risk-adjusted likelihood of requiring high-dose transfusion was greater in the GSW cohort (odds ratio, 2.38; 95% confidence interval, 1.14-5.80), and requirements were increased for all four blood components (red blood cells, platelets, plasma, and cryoprecipitate). Patients with GSWs had approximately 14 times greater overall mortality (653 of 2672 [24.4%] vs. 352 of 20,750 [1.7%]; p < 0.0001]. Compared to non-GSW penetrating injuries (e.g., stab wounds), those with GSWs had approximately four times higher transfusion requirements (3.3 ± 13.5 vs. 0.80 ± 3.8 units/patient; p < 0.0001), and approximately eight times greater overall mortality (653 of 2672 [24.4%] vs. 28 of 956 [2.9%]; p < 0.0001). CONCLUSIONS: Compared to other traumatic injuries, GSW injuries are associated with substantially greater blood utilization and mortality. Trauma centers treating GSW injuries should have ready access to all blood components and ability to implement massive transfusions.

Surgeon variation in operating times and charges for emergency general surgery.

BACKGROUND: Patients and hospitals face significant financial burdens from emergency general surgeries (EGSs), which have been termed a public health crisis in the United States. We evaluated hospitalization charges, operating charges, and variations in operating time by surgeon volume for three common EGS procedures. METHODS: Using Maryland's Health Services Cost Review Commission database, we performed a retrospective study of laparoscopic appendectomies, laparoscopic cholecystectomies, and open bowel resections performed by general surgeons among adult patients from July 2012 to September 2014. We compared operating charges to total hospitalization charges and quantified variations in operating time for each procedure. We then divided patients into quartiles based on their surgeon's procedure-specific case volume and used hierarchical linear regressions to calculate differences in both operating time and charges between quartiles. RESULTS: We identified 3194 appendectomies, 4143 cholecystectomies, and 1478 bowel resections. Operating charges accounted for one-quarter (26.9%) of total hospitalization charges and widespread variation existed in operating time (appendectomies: median 79 min [interquartile range 66-100 min], cholecystectomies: 96 min [76-125 min], bowel resections: 155 min [117-209 min]). After adjustment, low-volume surgeons relative to high-volume surgeons did not operate statistically longer for appendectomies (+1%, 95% confidence interval [CI]: -2% to 5%) but operated +16% (95% CI: 12%-20%) longer for cholecystectomies (+14 min) and +40% (95% CI: 30%-50%) longer for bowel resections (+59 min). Adjusted median operating charges from low-volume surgeons relative to high-volume surgeons were $554 (26.7%), $621 (22.0%), and $1801 (47.0%) greater for appendectomies, cholecystectomies, and bowel resections, respectively. CONCLUSIONS: Operating charges contributed substantially to total EGS hospitalization charges, where low-volume surgeons operated longer and had higher operative charges relative to high-volume surgeons. Reducing variations in operating times and charges represents an opportunity to alleviate the financial burden from EGS procedures.

Hospital variation in mortality after emergent bowel resections: The role of failure-to-rescue.

BACKGROUND: Hospital variation in failure-to-rescue (FTR) rates has partially explained nationwide differences in mortality after elective surgeries. To examine the role of FTR among emergency general surgery, we compared nationwide risk-adjusted mortality, complications, and FTR rates after emergent bowel resections. METHODS: We identified patients who underwent emergent small or large bowel resections in the 2010 to 2011 Nationwide Inpatient Sample using the American Association for the Surgery of Trauma criteria. We then calculated risk-adjusted mortality rates for each hospital using multivariable logistic regressions and postestimation, which adjusted for patient age, sex, race and ethnicity, payer status, comorbidities, and hospital clustering. After excluding hospitals with fewer than 10 resections per year, we ranked the remaining hospitals by their risk-adjusted mortality rates and divided them into five quintiles. We compared both risk-adjusted complication rates and FTR rates between the top (lowest mortality) and bottom (highest mortality) quintiles. RESULTS: We identified 21,564 emergent bowel resections, weighted to 105,925 procedures nationwide. The bottom quintile of hospitals had an overall risk-adjusted mortality rate that was 10.9 times higher than that of the top quintile of hospitals (15.3% vs. 1.4%). While risk-adjusted complication rates were similarly high for both the bottom and the top quintiles of hospitals (22.5% vs. 15.7%), the risk-adjusted FTR rates were 10.8 times higher in the bottom quintile of hospitals relative to the top quintile of hospitals (33.4% vs. 3.1%). Using larger hospital volume thresholds yielded similar findings. Furthermore, large variations existed in complication-specific FTR rates (surgical site infection [6.6%] to myocardial infarction [29.4%]). CONCLUSION: Nationwide hospital variation in risk-adjusted mortality rates exist after emergent bowel resections. As complication rates were similar across hospitals, the significantly higher FTR rates at higher-mortality hospitals may drive this variation in mortality. System-level initiatives addressing the management of postoperative complications may improve patient care and reduce variation in outcomes. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level IV.

TGF-α equalizes age disparities in stem cell-mediated cardioprotection.

BACKGROUND: Neonatal mesenchymal stem cells exhibit less cardioprotective potential than their adult counterparts. Transforming growth factor-α (TGF-α) has been shown to stimulate adult stem cell VEGF production, however, it remains unknown whether it may augment neonatal stem cell paracrine function. We hypothesized that TGF-α would equalize adult and neonatal stem cell paracrine function and cardioprotection during acute ischemia/reperfusion. MATERIALS AND METHODS: Bone marrow mesenchymal stem cells isolated from adult and 2.5 wk-old mice were treated with TGF-α (250 ng/mL) for 24 h. VEGF, HGF, IGF-1, IL-1ß, and IL-6 production were measure in vitro, and cells were infused via an intracoronary route using a model of isolated heart perfusion. RESULTS: TGF-α equalized adult and neonatal stem cell VEGF production but did not affect production of HGF, IGF-1, IL-1ß, or IL-6. ERK, p38 MAPK, and JNK phosphorylation were greater in adult cells in response to TGF-α. Whereas infusion of adult but not neonatal stem cells was associated with improved myocardial functional recovery during reperfusion, infusions of either TGF-α-pretreated cell group were associated with the greatest functional recovery. TGF-α equalizes adult and neonatal mesenchymal stem cell VEGF production and cardioprotection in association with differential regulation of ERK, p38 MAPK, and JNK phosphorylation.

Advances in mesenchymal stem cell research in sepsis.

BACKGROUND: Sepsis remains a source of morbidity and mortality in the postoperative patient despite appropriate resuscitative and antimicrobial approaches. Recent research has focused upon additional interventions such as exogenous cell-based therapy. Mesenchymal stem cells (MSCs) exhibit multiple beneficial properties through their capacity for homing, attenuating the inflammatory response, modulating immune cells, and promoting tissue healing. Recent animal trials have provided evidence that MSCs may be useful therapeutic adjuncts. MATERIALS AND METHODS: A directed search of recent medical literature was performed utilizing PubMed to examine the pathophysiology of sepsis, mechanisms of mesenchymal stem cell interaction with host cells, sepsis animal models, and recent trials utilizing stem cells in sepsis. RESULTS: MSCs continue to show promise in the treatment of sepsis by their intrinsic ability to home to injured tissue, secrete paracrine signals to limit systemic and local inflammation, decrease apoptosis in threatened tissues, stimulate neoangiogenesis, activate resident stem cells, beneficially modulate immune cells, and exhibit direct antimicrobial activity. These effects are associated with reduced organ dysfunction and improved survival in animal models. CONCLUSION: Research utilizing animal models of sepsis has provided a greater understanding of the beneficial properties of MSCs. Their capacity to home to sites of injury and use paracrine mechanisms to change the local environment to ultimately improve organ function and survival make MSCs attractive in the treatment of sepsis. Future studies are needed to further evaluate the complex interactions between MSCs and host tissues.

Pretreating mesenchymal stem cells with interleukin-1ß and transforming growth factor-ß synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell-mediated myocardial protection after acute ischemia.

BACKGROUND: Mesenchymal stem cells (MSCs) improve postischemic myocardial function in part through their secretion of growth factors such as vascular endothelial growth factor (VEGF). Pretreating MSCs with various cytokines or small molecules can improve VEGF secretion and MSC-mediated cardioprotection. However, whether 1 cytokine can potentiate the effect of another cytokine in MSC pretreatment to achieve a synergistic effect on VEGF production and cardioprotection is poorly studied. METHODS: MSCs were treated with interleukin (IL)-1ß and/or transforming growth factor (TGF)-ß1 for 24 hours before experiments. VEGF production was determined by enzyme-linked immunosorbent assay. Isolated hearts from adult male Sprague-Dawley rats were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes reperfusion. Hearts (n = 5-7 per group) were randomly infused with vehicle, untreated MSCs, or MSCs pretreated with IL-1ß and/or TGF-ß1. Specific inhibitors were used to delineate the roles of p38 mitogen-activated protein kinase (MAPK) and SMAD3 in IL-1ß- and TGF-ß1-mediated stimulation of MSCs. RESULTS: MSCs cotreated with IL-1ß and TGF-ß1 exhibited synergistically increased VEGF secretion, and they greatly improved postischemic myocardial functional recovery. Ablation of p38 MAPK and SMAD3 activation with specific inhibitors negated both IL-1ß- and TGF-ß1-mediated VEGF production in MSCs and the ability of these pretreated MSCs to improve myocardial recovery after ischemia. CONCLUSION: Pretreating MSCs with 2 cytokines may be useful to fully realize the potential of cell-based therapies for ischemic tissues.

Sca-1+ cardiac stem cells mediate acute cardioprotection via paracrine factor SDF-1 following myocardial ischemia/reperfusion.

BACKGROUND: Cardiac stem cells (CSCs) promote myocardial recovery following ischemia through their regenerative properties. However, little is known regarding the implication of paracrine action by CSCs in the setting of myocardial ischemia/reperfusion (I/R) injury although it is well documented that non-cardiac stem cells mediate cardioprotection via the production of paracrine protective factors. Here, we studied whether CSCs could initiate acute protection following global myocardial I/R via paracrine effect and what component from CSCs is critical to this protection. METHODOLOGY/PRINCIPAL FINDINGS: A murine model of global myocardial I/R was utilized to investigate paracrine effect of Sca-1+ CSCs on cardiac function. Intracoronary delivery of CSCs or CSC conditioned medium (CSC CM) prior to ischemia significantly improved myocardial function following I/R. siRNA targeting of VEGF in CSCs did not affect CSC-preserved myocardial function in response to I/R injury. However, differentiation of CSCs to cardiomyocytes (DCSCs) abolished this protection. Through direct comparison of the protein expression profiles of CSCs and DCSCs, SDF-1 was identified as one of the dominant paracrine factors secreted by CSCs. Blockade of the SDF-1 receptor by AMD3100 or downregulated SDF-1 expression in CSCs by specific SDF-1 siRNA dramatically impaired CSC-induced improvement in cardiac function and increased myocardial damage following I/R. Of note, CSC treatment increased myocardial STAT3 activation after I/R, whereas downregulation of SDF-1 action by blockade of the SDF-1 receptor or SDF-1 siRNA transfection abolished CSC-induced STAT3 activation. In addition, inhibition of STAT3 activation attenuated CSC-mediated cardioprotection following I/R. Finally, post-ischemic infusion of CSC CM was shown to significantly protect I/R-caused myocardial dysfunction. CONCLUSIONS/SIGNIFICANCE: This study suggests that CSCs acutely improve post-ischemic myocardial function through paracrine factor SDF-1 and up-regulated myocardial STAT3 activation.

Transforming growth factor-α enhances stem cell-mediated postischemic myocardial protection.

BACKGROUND: Transforming growth factor-α (TGF-α) has been shown to augment mesenchymal stem cell-mediated cardioprotection during acute ischemia and reperfusion in isolated heart models. To determine whether this pretreatment strategy would be effective in vivo, we hypothesized that the intramyocardial injection of mesenchymal stem cells pretreated with TGF-α after coronary artery ligation would confer greater preservation of cardiac function, reduction in infarct size, and reduction myocardial inflammation. METHODS: Sprague-Dawley rats underwent left anterior descending coronary artery ligation. Ischemic border zones were injected 30 minutes later with vehicle (n = 11), 1 million mesenchymal stem cells (n = 9), or mesenchymal stem cells pretreated with TGF-α (250 ng/mL for 24 hours; n = 10). Cardiac function was assessed by echocardiography at 7 and 28 days after ligation. Infarct size was measured using triphenyltetrazolium chloride. Ischemic border zone cytokine expression was measured 30 days after infarction. RESULTS: Myocardial function after ligation was greatest in hearts injected with cells pretreated with TGF-α in association with reduced ventricular remodeling and infarct size compared with vehicle-injected hearts. Myocardial interleukin 1ß, interleukin 6, and TNF-α concentrations were lower, and Bcl-2 expression was higher, in hearts injected with either cell type. Vascular endothelial growth factor and matrix metalloproteinase-2 expression were highest in hearts that received pretreated cells. CONCLUSIONS: Intramyocardial injection of mesenchymal stem cells pretreated with TGF-α further protects cardiac function and reduces infarct size compared with injection of untreated cells. Pretreating donor cells with TGF-α may be useful for enhancing cell-based therapies for myocardial ischemia.

Pretreatment with intracoronary mimosine improves postischemic myocardial functional recovery.

BACKGROUND: Cytoprotective growth factors such as vascular endothelial growth factor (VEGF) play important roles in myocardial protection from ischemia/reperfusion (I/R). Accumulating evidence suggests that the hypoxia-inducible factor 1 (HIF-1) pathway is a key regulator of VEGF production in the setting of I/R. The prolyl hydroxylase inhibitor mimosine can increase VEGF production through the HIF-1 pathway. We hypothesized that infusion of preischemic intracoronary mimosine would improve myocardial functional recovery after I/R. METHODS: Isolated male rat hearts were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes of reperfusion. Immediately prior to ischemia, ischemic hearts received intracoronary infusions of vehicle or solutions of 0.3, 3, or 30 µM mimosine. Myocardial function was recorded throughout the experiments. Functional data were analyzed with two-way analysis of variance adjusted with the Bonferroni correction. RESULTS: Preischemic myocardial function was equivalent. All hearts had significant reductions in function at the beginning of reperfusion. Hearts treated with 0.3 or 3 µM mimosine infusions exhibited greater recovery of left ventricular developed pressure compared to vehicle. The maximal positive value of the first derivative of pressure (+dP/dt) was greater in hearts treated with 0.3 µM mimosine compared to hearts treated with vehicle. No differences were observed in recovery of end-diastolic pressure or the maximal negative value of the first derivative of pressure (-dP/dt). CONCLUSION: Preischemic intracoronary mimosine infusion improves myocardial functional recovery after I/R.

Systemic pretreatment with dimethyloxalylglycine increases myocardial HIF-1α and VEGF production and improves functional recovery after acute ischemia/reperfusion.

BACKGROUND: Stem cells protect the heart from ischemic damage in part by the release of cytoprotective growth factors, particularly vascular endothelial growth factor (VEGF). Production of VEGF is regulated in part by levels of the transcription factor hypoxia inducible factor 1-α (HIF-1α). Dimethyloxalylglycine (DMOG) prevents the deactivation of HIF-1α and increases VEGF production. However, the effects of systemic DMOG treatment on myocardial tolerance for ischemia are unknown. We hypothesized that systemic pretreatment with DMOG would improve myocardial ischemic tolerance. METHODS: To study this hypothesis, adult male rats were randomly given an intraperitoneal injection of DMOG (40 mg/kg in 1 mL saline, n = 5) or saline (1 mL, n = 6) 24 h before cardiectomy and isolated heart perfusion. All hearts were subjected to 15 min equilibration, 25 min ischemia and 40 min reperfusion. Myocardial function was continuously monitored. Following reperfusion, myocardial homogenates were analyzed for HIF-1α and VEGF production. RESULTS: We observed that hearts in the DMOG group exhibited greater recovery of left ventricular developed pressure LVDP, +dP/dt and -dP/dt. Myocardial HIF-1α and VEGF levels were increased by DMOG therapy. CONCLUSION: In conclusion, systemic pretreatment with DMOG augments post-ischemic myocardial functional recovery through increased HIF-1α levels and greater VEGF production.

Transforming growth factor-alpha does not protect myocardium during acute ischemia/reperfusion.

BACKGROUND: The activation of the epidermal growth factor family of receptors may improve cardiac protection after injury. One epidermal growth factor family ligand, transforming growth factor-alpha, promotes wound healing in multiple tissues in response to oxidative injury and might confer resistance to myocardial depressant factors, although the role of transforming growth factor-alpha in myocardial ischemia/reperfusion injury is unknown. We hypothesized that preischemic infusion of transforming growth factor-alpha would improve myocardial functional recovery after acute ischemia/reperfusion. METHODS: The hearts from adult male rats were isolated and perfused via the Langendorff model. Immediately prior to ischemia, the hearts received an intracoronary infusion of either vehicle or transforming growth factor-alpha (1 ng, 10 ng, or 100 ng). After reperfusion, the hearts were assessed for activation of the prosurvival pathway, Akt. RESULTS: Infusion of transforming growth factor-alpha did not confer any additional functional protection compared with the vehicle, but myocardial tissue analysis revealed significantly increased activation of the Akt pathway in both the 10-ng and 100-ng groups. CONCLUSION: Preischemic infusion of transforming growth factor-alpha does not improve myocardial functional recovery after ischemia/reperfusion injury. Whereas transforming growth factor-alpha treatment does affect actions at the molecular level, these actions do not translate into an observable functional effect. This lack of improvement may point to a relative unimportance of transforming growth factor-alpha in myocardial signaling compared with other epidermal growth factor ligands.

SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury.

Stromal cell-derived factor-1α (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose-dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R.

Interleukin-10 protects the ischemic heart from reperfusion injury via the STAT3 pathway.

BACKGROUND: Cardiac surgery induces the release of inflammatory mediators that can prolong cardiac dysfunction after operative intervention. Interleukin-10 (IL-10), a potent inhibitor of myocardial inflammation, is a known factor in myocardial protection after ischemia/reperfusion (I/R) injury. We hypothesized that IL-10 activity during initial reperfusion is mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. METHODS: Adult rat hearts were isolated and perfused via Langendorff protocol and subjected to global I/R. After determining the effective IL-10 dose, hearts were administered vehicle, IL-10, or IL-10 + Stattic (specific STAT3 inhibitor) 1 min prior to ischemia. After reperfusion, hearts were sectioned and assessed for levels of myocardial inflammatory cytokines and protein. RESULTS: The IL-10 minimum effective dose was 1 µg. IL-10-treated hearts had improved markedly myocardial function after global I/R compared to both vehicle and IL-10 + Stattic groups. In addition, IL-10 treatment was associated with a significant decrease in myocardial interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) and increase in myocardial IL-10. Myocardial STAT3 was elevated markedly in IL-10 treated hearts. CONCLUSION: IL-10 improves myocardial function after acute global I/R and suppresses inflammation through the STAT3 pathway. The administration of anti-inflammatory agents may have potential therapeutic applications in cardiac surgery.

Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia.

Mesenchymal stem cells (MSCs) possess immunomodulatory properties and may curtail the inflammatory response that characterizes sepsis and other systemic inflammatory states. We aimed to determine whether intravenous infusion of MSCs is associated with reduced inflammation and improved myocardial function in a rat model of endotoxemia. Adult Sprague-Dawley rats were administered saline (vehicle) or LPS (5 mg/kg) via tail vein injection. Treatments, either vehicle or 2 × 10(6) MSCs, were infused 1 h later via tail vein. Animals were randomly assigned to the following groups: (a) vehicle + vehicle (control; n = 6), (b) LPS + vehicle (n = 6), or (c) LPS + MSCs (n = 6). Six hours after induction of endotoxemia, left ventricular ejection fraction (EF) and fractional shortening (FS) was assessed via parasternal short-axis M-mode echocardiography. Hearts and serum were collected for determination of cytokine levels via enzyme-linked immunosorbent assay. Animals injected with LPS + vehicle exhibited depressed cardiac function as indicated by a 26% and 37% reduction in EF and FS from baseline, respectively. Treatment with MSCs was associated with improved cardiac function compared with vehicle treatment as indicated by a reduction in EF and FS of only 10% and 17%, respectively (P < 0.05). Myocardial levels of TNF-α, IL-1ß, and IL-6 were elevated in LPS-treated animals versus control. Similarly, serum levels of IL-1ß, IL-6, and IL-10 were increased in LPS-treated animals. Treatment with MSCs, however, was associated with significant reductions in serum levels of IL-1ß and IL-6 and in myocardial levels of TNF-α, IL-1ß, and IL-6. In addition, treatment with MSCs was associated with a further increase in serum IL-10. Infusion of MSCs modulates the systemic inflammatory response and is associated with improved cardiac function during endotoxemia.