Female gender increases risk of stroke and readmission after carotid endarterectomy and carotid artery stenting.

OBJECTIVE: Carotid endarterectomy (CEA) has historically demonstrated a higher rate of perioperative adverse events for female patients. However, recent evidence suggests similar outcomes for CEA between genders. In contrast, fewer studies have examined gender in carotid artery stenting (CAS). Using contemporary data from the American College of Surgeons National Surgical Quality Improvement Program database, we aim to determine if gender impacts differences in postoperative complications in patients who undergo CEA or CAS. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2017 using Current Procedural Terminology and International Classification of Diseases codes for retrospective review. Patients with carotid intervention (CEA or CAS) were stratified into asymptomatic vs symptomatic cohorts to determine the effect of gender on 30-day postoperative outcomes. Symptomatic patients were defined as those with perioperative transient cerebral ischemic attack or stenosis of carotid artery with cerebral infarction. Descriptive statistics were calculated. Risk-adjusted odds of 30-day postoperative outcomes were calculated using multivariate regression analysis with fixed effects for age, race, and comorbidities. RESULTS: There were 106,568 patients with CEA or CAS (104,412 CEA and 2156 CAS). The average age was 70.9 years, and female patients accounted for 39.9% of the population. For asymptomatic patients that underwent CEA or CAS, female gender was associated with significantly higher rates of cerebrovascular accident (CVA)/stroke (13%; P = .005), readmission (10%; P = .004), bleeding complication (32%; P = .001), and urinary tract infection (54%; P = .001), as well as less infection (26%; P = .001). In the symptomatic cohort, female gender was associated with significantly higher rates of CVA/stroke (32%; P = .034), bleeding complication (203%; P = .001), and urinary tract infection (70%; P = .011), whereas female gender was associated with a lower rate of pneumonia (39%; P = .039). Subset analysis found that, compared with male patients, female patients <75 years old have an increased rate of CVA/stroke (21%; P = .001) and readmission (15%; P < .001), whereas female patients ≥75 years old did not. In asymptomatic and symptomatic patients that underwent CEA, female gender was associated with significantly higher rates of CVA/stroke (13%; P = .006 and 31%; P = .044, respectively), but this finding was not present in patients undergoing CAS. CONCLUSIONS: In patients undergoing carotid intervention, female gender was associated with significantly increased rates of postoperative CVA/stroke in the asymptomatic and symptomatic cohorts as well as readmission in the asymptomatic cohort. Female gender was associated with higher rates of CVA/stroke following CEA, but not CAS. We recommend that randomized control trials ensure adequate representation of female patients to better understand gender-based disparities in carotid intervention.

Through-knee amputation is a feasible alternative to above-knee amputation.

OBJECTIVE: Through-knee amputation (TKA) is a rare amputation performed in <2% of all major lower extremity amputations in the United States. Despite biomechanical benefits and improved rehabilitation compared with above-knee amputation (AKA), TKA has largely been abandoned by vascular surgeons because of concerns for poor wound healing. The purpose of this study was to evaluate surgical outcomes of TKA. METHODS: The American College of Surgeons National Surgical Quality Improvement Program between 2005 and 2012 was queried using Current Procedural Terminology codes indicating AKA and TKA. Baseline characteristics were reviewed, and logistic regression analysis was performed to identify predictors of 30-day mortality. Propensity score matching was used to balance comorbidities between AKA and TKA. Operative variables and postoperative complications were compared between the groups. RESULTS: A total of 7469 AKA and 251 TKA patients were identified among 15,932 major lower extremity amputations. Baseline characteristics were examined. White race, chronic obstructive pulmonary disease, dyspnea, emergent operation, steroid use, myocardial infarction, congestive heart failure, high American Society of Anesthesiologists score, old age, preoperative sepsis or septic shock, and dialysis dependency were associated with increased 30-day mortality. Independent lifestyle and smoking (within 1 year) were protective against early death. Baseline comorbidities were not statistically significant after 1:1 propensity score matching. Operative outcomes were similar in both groups (AKA vs TKA). Wound infection (7.2% vs 11.2%; P = .16), dehiscence rate (1.2% vs 0.8%; P = 1.0), and 30-day mortality (9.6% vs 11.2%; P = .66) were comparable. Other outcome parameters, including cardiopulmonary and genitourinary complications, were similar except for a higher likelihood of return to the operating room in the TKA group (27.9% vs 12.4%; P < .01). Postoperative mortality was not associated with TKA (P = .77) or reoperation (P = .42), but it was associated with the patients' physiologic conditions (dyspnea, sepsis, emergent operation, high American Society of Anesthesiologists score, and dependent lifestyle). Predictors of reoperation were contaminated wound (hazard ratio [HR], 2.19; confidence interval [CI], 1.17-3.23; P = .015), sepsis or septic shock (HR, 2.63; CI, 1.37-5.05; P = .004), chronic obstructive pulmonary disease (HR, 2.81; CI, 1.23-6.42; P = .014), and wound infection (HR, 4.91; CI, 2.06-11.70; P < .001). Presence of peripheral vascular disease was not associated with post-TKA reoperation (P = .073). CONCLUSIONS: TKA demonstrated similar postoperative morbidity and mortality compared with AKA. Wound infection and risk of dehiscence were equivalent. TKA did demonstrate a higher rate of reoperation; however, neither TKA nor reoperation predicted postoperative mortality. Patients in stable physiologic condition without active infection can safely undergo elective TKA to maximize rehabilitation potential.

Iliac Stent Migration during Thoracic Endovascular Aortic Aneurysm Repair Resulting in Functional Coarctation.

Iliac arterial disease, unfavorable anatomy, and prior stenting all pose challenges to access in endovascular abdominal aortic repair (EVAR) and thoracic aortic repair (TEVAR). Iliac access injury during T/EVAR may lead to rupture, dissection, thrombosis, or distal ischemia. Some have advocated iliac stent prior to T/EVAR in patients with suboptimal iliac access. The rate of complication and iliac stent migration during subsequent T/EVAR is undocumented. This case report describes a unique instance of self-expanding iliac stent migration during TEVAR which pinched the thoracic aortic endograft causing functional aortic coarctation.

Iliac artery-enteric fistulas following failed pancreatic transplant.

Arterial-enteric fistulas occur from a multitude of causes, especially following surgical manipulation of vasculature. The development of an iliac artery-enteric fistula (IEF) occurs rarely in patients with failed pancreatic transplants. IEFs warrant urgent intervention due to the high mortality from hemorrhagic and septic shock. The diagnosis can be delayed by a lack of suspicion, the low sensitivity of diagnostic tests, and the nonspecific signs of fistulas on computed tomography. The management of IEFs is adapted from guidelines for arterial-enteric fistulas of other causes, with little consensus on ideal vascular reconstruction and postoperative antimicrobial management. The outcomes are limited to the short-term results from case reports and case series. We report two cases of IEFs in patients with a history of simultaneous pancreatic kidney transplant. Our patients underwent successful resolution of gastrointestinal bleeding and sepsis, with definitive management of fistula resection and interposition iliac artery bypass. The index of suspicion for IEFs should be high, and they should be considered as a source of anemia or gastrointestinal bleeding of an unknown source in patients with failed pancreatic transplant. Definitive management should be pursued in patients who can tolerate fistula resection, allograft explant, and arterial reconstruction.

Period frequency of iliofemoral venous occlusive disease by Doppler ultrasound and corresponding treatment in a tertiary care facility.

BACKGROUND: Patients with iliofemoral deep venous thrombosis (DVT) are at highest risk for the postthrombotic morbidity including all aspects of the postthrombotic syndrome. Invasive therapies such as catheter-directed thrombolysis (CDT) and/or mechanical thrombectomy with or without angioplasty and stenting and in some cases open operative thrombectomy improves venous patency, venous valve function, and quality of life in patients with acute iliofemoral DVT. What is the current frequency of acute iliofemoral DVT and how aggressively is it being treated? We hypothesize that the 10-year period frequency of iliofemoral DVT among acute DVT cases is greater than previously reported. Further, we hypothesize that thrombus removal to treat acute iliofemoral DVT is little utilized in current practice. METHODS: Indiana University (IU) vascular laboratory records from January 1, 1998 to December 31, 2008 were searched by CPT code for venous Doppler ultrasound study (n=7240). A random sample based on the IU medical record number of lower extremity Doppler studies was then selected (n=1020) for retrospective chart review. Corresponding clinical information was gathered from the patients' electronic medical record. RESULTS: Acute DVT occurred in 6.8%, and chronic DVT in 8.8% of patients studied (25.7% inpatient, 61.7% female; median age, 56.0 years [range, 4-91 years, 1.1% less than 16 years]). History of previous DVT (33.3%) and cancer (30.4%) were the most common risk factors in patients with acute DVT. Iliofemoral DVT defined as having an iliac or common femoral vein component was identified in 49.3% of acute DVT and in 36.0% of chronic DVT. CDT was utilized in 14.3% and mechanical thrombectomy in 4.8% of acute iliofemoral DVT, and was never used with distal DVT. Warfarin anticoagulation+unfractionated heparin or low-molecular-weight heparin overlap was the most common treatment for acute iliofemoral DVT (100.0%). In 2008, the referral base of our laboratory increased significantly. Acute DVT occurred significantly less often during the 1-year period 2008 (5.3%) than the 10-year period 1998-2007 (7.6%), but iliofemoral+common femoral DVT as a component of acute DVT did not differ significantly. CONCLUSIONS: Iliofemoral DVT may be more frequent than previously reported and represents a significant portion of acute DVT. Current recommendations of acute thrombus removal for the treatment of iliofemoral DVT is underutilized suggesting that perhaps greater education of clinicians and patients regarding invasive therapy for iliofemoral DVT is required.

Mechanisms of sex differences in TNFR2-mediated cardioprotection.

BACKGROUND: TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression after acute ischemia/reperfusion when compared with males. However, it is unknown whether the TNFR2 pathway protects the myocardium from ischemia/reperfusion injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that (1) TNFR2 mediates myocardial protection from ischemia/reperfusion through STAT3, SOCS3, and vascular endothelial growth factor in both sexes; and (2) TNFR2 elicits greater protective signaling in females compared with males. METHODS AND RESULTS: Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females. CONCLUSIONS: Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males.

Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia.

BACKGROUND: Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Our lab has recently shown that gender differences exist in mesenchymal stem cell (MSC) paracrine function. Estrogen is implicated in the cardioprotection found in females. It remains unknown whether 17beta-estradiol (E2) affects MSC paracrine function and whether E2-treated MSCs may better protect injured cardiac tissue. We hypothesize that E2-exposed MSCs infused into hearts prior to ischemia may demonstrate increased vascular endothelial growth factor (VEGF) production and greater protection of myocardial function compared to untreated MSCs. MATERIALS AND METHODS: Untreated and E2-treated MSCs were isolated, cultured, and plated and supernatants were harvested for VEGF assay (enzyme-linked immunosorbent assay). Adult male Sprague-Dawley rat hearts (n = 13) were isolated and perfused via Langendorff model and subjected to 15 min equilibration, 25 min warm global ischemia, and 40 min reperfusion. Hearts were randomly assigned to perfusate vehicle, untreated male MSC, or E2-treated male MSC. Transcoronary delivery of 1 million MSCs was performed immediately prior to ischemia in experimental hearts. RESULTS: E2-treated MSCs provoked significantly more VEGF production than untreated MSCs (933.2 +/- 64.9 versus 595.8 +/- 10.7 pg/mL). Postischemic recovery of left ventricular developed pressure was significantly greater in hearts infused with E2-treated MSCs (66.9 +/- 3.3%) than untreated MSCs (48.7 +/- 3.7%) and vehicle (28.9 +/- 4.6%) at end reperfusion. There was also greater recovery of the end diastolic pressure with E2-treated MSCs than untreated MSCs and vehicle. CONCLUSIONS: Preischemic infusion of MSCs protects myocardial function and viability. E2-treated MSCs may enhance this paracrine protection, which suggests that ex vivo modification of MSCs may improve therapeutic outcome.

Are neonatal stem cells as effective as adult stem cells in providing ischemic protection?

BACKGROUND: Bone marrow stem cells (BMSCs) may be a novel treatment modality for organ ischemia, possibly through beneficial paracrine mechanisms. However, stem cells from older hosts exhibit decreased function during stress. We therefore hypothesized that (1) BMSCs derived from neonatal hosts would provide protection to ischemic myocardium, and (2) neonatal stem cells would enhance postischemic myocardial recovery above that seen with adult stem cell therapy. MATERIALS AND METHODS: Female adult Sprague Dawley rat hearts were subjected to an ischemia/reperfusion protocol via Langendorff isolated heart preparation (15 min equilibration, 25 min ischemia, and 60 min reperfusion). BMSCs were harvested from adult and neonatal mice and cultured through several passages under normal conditions (37 degrees C, 5% CO(2)/air). Immediately prior to ischemia, 1 million adult or neonatal BMSCs were infused into the coronary circulation. Cardiac functional parameters were continuously recorded. RESULTS: Pretreatment with adult BMSCs significantly increased postischemic myocardial recovery as noted by improved left ventricular developed pressure, end diastolic pressure, contractility, and rate of relaxation. Neonatal stem cells, however, did not cause any noticeable improvement in myocardial functional parameters following ischemia. CONCLUSION: Neonatal and adult BMSCs are distinctly different in the degree of beneficial tissue protection that they can provide. The data herein suggests that a critical age exists as to when stem cells become fully activated to provide their beneficial protective properties. Defining the genes that initiate these protective properties may allow for genetic amplification of beneficial signals, and the generation of "super stem cells" that provide maximum protection to ischemic tissues.

Medical therapy does not confer stroke prevention for all patients: identification of high-risk patients with asymptomatic carotid stenosis is still needed.

BACKGROUND: Recent advances in best medical therapy (BMT) has been associated with reduced risk of stroke similar to that observed following surgical carotid revascularization (CR). Thus, it remains uncertain which subset(s) of patients would benefit from prophylactic CR+BMT for asymptomatic carotid stenosis (ACS) over BMT alone. The purpose of this study was to analyze the contemporary experience in the management of >70% ACS in an academic institution, to compare the short- and long-term outcomes of BMT alone against CR+BMT, and to identify risk factors for the development of future cerebrovascular events. METHODS: A retrospective review of all patients with severe ACS between January 2005 and December 2012 at Loyola University Medical Center and its affiliated Edward Hines Jr. Veterans Administration Hospital was conducted. Baseline patient characteristics, medications, and follow-up data were collected from electronic medical records, and treatment outcomes were compared. The random forest method was performed to select potential important variables for the development of late stroke. The recursive partitioning regression analysis (RPRA) was performed to identify the patient subgroup at increased risk of future stroke. RESULTS: Of 409 patients identified; 247 were treated with CR and 162 with BMT. Between these groups with CR+BMT and BMT alone, the mean age was 69.1±8.2 versus 75.5±9.0, respectively (P<0.01). Mean follow-up was 60.7±37.5 months. Early (30-day) outcomes of stroke, acute myocardial infarction or mortality did not differ between the treatment modalities (2.0% CR vs. 0.6% BMT, P=0.41). Probability of freedom from ipsilateral stroke, and any stroke at 1- and 5-year follow-up were also comparable between CR+BMT and BMT alone. However, random forest method and RPRA demonstrated that patients with history of diabetes and remote stroke treated with BMT alone were at a high risk for future stroke (36.4% in total, 7.2% per year). The diabetics with contralateral carotid stenosis >50% who are active smokers are at the highest risk for stroke after CR (20.0% in total, 4.0% per year). CONCLUSIONS: Prophylactic CR+BMT does not provide overall late stroke prevention compared with BMT alone. Diabetics with a history of stroke, in particular, are at an increased risk of stroke despite BMT. Timely CR+BMT for high-risk patients is still indicated.

Delineating the durability outcome differences after saphenous ablation with laser versus radiofrequency.

OBJECTIVE: The mechanism of delivering thermal energy to the vein wall differs between endovenous laser ablation (EVLA) and radiofrequency ablation (RFA). Different mechanisms of ablation may have different effects on the durability of these procedures typically performed for saphenous vein insufficiency. Whether there is a difference in long-term durability outcomes between these two techniques remains uncertain. This study aimed to delineate the durability outcome differences in terms of recurrence rate and pattern. METHODS: A retrospective review identified 270 consecutive patients who underwent saphenous ablation using EVLA or RFA between July 2013 and October 2016. The primary end points were clinical symptom recurrence and anatomic recurrence of reflux. RESULTS: Overall, 343 limbs were included in the study; 246 limbs (183 patients) underwent EVLA and 97 limbs (87 patients) underwent RFA. The mean follow-up time was 112 days for EVLA (range, 2-1153 days) and 106 days for RFA (range, 3-735 days; P = .786). No significant differences were observed between the groups with respect to demographic data, Clinical, Etiological, Anatomical, Pathophysiological classification, or ratio of great saphenous vein to small saphenous vein treated. The mean time to recurrence of symptoms was 219 days longer with EVLA (n = 8; mean, 774 days; range, 187-1042 days) than RFA (n = 4; mean 555 days; range, 341-616 days). Kaplan-Meier estimates for 1- and 3-year freedom from clinical recurrence were 100% and 96% for EVLA and 97% and 93% for RFA, respectively. There was no difference between the two groups (log rank, P = .0666). In cases with recurrent reflux documented on duplex (four in the EVLA group and three in the RFA group), the thigh segment was the most frequently involved site (75% in EVLA, 67% in RFA). Same site recanalization was significantly less frequent in EVLA (0.82% in EVLA vs 2.06% in RFA; P = .0388). New areas of reflux developed at a similar rate between the groups, in 0.82% of EVLA limbs in the anterior accessory saphenous vein and the calf great saphenous vein, and in 1.03% of RFA limbs in the anterior accessory saphenous vein (P = .8436). CONCLUSIONS: The results of our study suggest that the outcomes of EVLA and RFA performed for saphenous vein insufficiency may differ in the long term. The clinical recurrence rates are similar, but the anatomic recurrence patterns may differ, with more frequent treated site recurrence in the RFA group.

Long-Term Hemodynamic Effects After Carotid Artery Revascularization.

OBJECTIVE: The baroreceptor at the carotid body plays an important role in hemodynamic autoregulation. Manipulation of the baroreceptor during carotid endarterectomy (CEA) or radial force from carotid artery angioplasty and/or stenting (CAS) may cause both intraoperative and postoperative hemodynamic instability. The purpose of this study is to evaluate the long-term effects of CEA and CAS on blood pressure (BP), heart rate (HR), and subsequent changes on antihypertensive medications. METHODS: A retrospective chart review was performed to identify patients who underwent CEA or CAS between 2009 and 2015 at a single tertiary care institution. Baseline demographics and comorbidities were recorded. Operative details of the carotid artery endarterectomy and the use of balloon angioplasty during the CAS were analyzed. Hemodynamic parameters such as BP, HR, and antihypertensive medication requirement were evaluated at 3, 6, 12, 24, and 36 months. RESULTS: A total of 289 patients were identified. The average age was 70.6 years old, and males constituted 64.0%. All patients had moderate (>50%) to severe (>70%) carotid stenosis. Of those, 111 (40.5%) patients were symptomatic. Systolic BP (mm Hg) of CAS and CEA were similar over the entire follow-up period. Heart rate (beats/min) remained stable postoperatively. A reduced number of antihypertensive medications was observed in the CAS cohort during the first postoperative year when compared to the preoperative baseline: 2.03 at preop, 1.77 ( P < .01) at 3 months, 1.78 ( P = .02) at 6 months, 1.77 ( P = .02) at 12 months, 1.86 ( P = .09) at 24 months, and 2.03 ( P = =.50) at 36 months. Logistic regression analysis identified that CAS (odds ratio [OR]: 2.52, confidence interval [CI]: 1.09-5.83) and multiple (>2) antihypertensive medication use at baseline (OR: 5.89, CI: 2.62-13.26) were predictors for a reduction in the number of antihypertensive medications following carotid revascularization. CONCLUSION: Surgical intervention for carotid stenosis poses a risk of postoperative hemodynamic dysregulation. Although postoperative BP and HR remained relatively stable after both CAS and CEA, the number of postoperative antihypertensive medications was reduced in the CAS cohort for the first postoperative year when compared to baseline. Patients with multiple antihypertensive agents undergoing CAS should have close postoperative BP monitoring and should be monitored for a possible reduction in their antihypertensive medication regimen.

The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone.

BACKGROUND AND OBJECTIVES: Recent research recognizes gender as a major factor determining the outcomes in trauma, ischemia/reperfusion, shock, and sepsis. In particular, estrogen has been demonstrated to exert protective effects in these settings. The effects of estrogens on the pulmonary vasculature are potent and complex yet not fully understood. A better mechanistic understanding may allow for future therapeutic interventions in pulmonary hypertensive crises after cardiac surgery and during acute lung injury as well as in patients with pulmonary arterial hypertension. DATA SOURCES AND STUDY SELECTION: We searched PubMed for articles in the English language by using the search words pulmonary hypertension, hypoxic pulmonary vasoconstriction, estrogen, estradiol, inflammation, acute injury, ischemia reperfusion, sepsis, trauma, and burns. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full articles were then extracted. References from extracted articles were checked for any additional relevant articles. DATA EXTRACTION AND SYNTHESIS: Estrogen plays a critical role in the improved outcomes in the settings of trauma, shock, sepsis, myocardial ischemia/reperfusion, and acute lung injury. Several new mechanisms of action have been identified. In the pulmonary vasculature, estrogen causes vasodilation and attenuates the vasoconstrictor response to various stimuli, including hypoxia. This is mediated by increased levels of prostacyclin and nitric oxide as well as decreased levels of endothelin-1. In addition, effects on intracellular signaling pathways and several kinases as well as anti-inflammatory mechanisms may contribute as well. Recent studies suggest the importance of acute, nongenomic effects. CONCLUSION: Estrogen exerts a variety of nongenomic actions, which may allow for future therapeutic interventions in pulmonary vascular disease.

Differential IL-6 and VEGF secretion in adult and neonatal mesenchymal stem cells: role of NFkB.

Stem cells have shown promise for the treatment of end organ ischemia. NFkB has been demonstrated to regulate growth factor secretion in human adult bone marrow stem cells (aBMSCs). We hypothesized that: (1) NFkB is an important mediator in aBMSC and neonatal BMSC (nBMSC) VEGF and IL-6 secretion; and (2) inhibition of NFkB will result in a decrease of VEGF and IL-6 in nBMSCs. BMSCs were plated and exposed to TNF (50 ng/ml) or LPS (100 ng/ml), with or without NFkB or IKK inhibition. VEGF and IL-6 were measured via ELISA in 24-h supernatants. Inhibition of NFkB and IKK both demonstrated a decrease in VEGF (p<0.05) in aBMSCs but not nBMSCs. The LPS-stimulated nBMSC with IKK inhibition group was the only exception which demonstrated a decrease in VEGF secretion. However, both NFkB inhibition caused both aBMSCs and nBMSCs to produced less IL-6 after LPS stimulation (p<0.05). Only aBMSCs' secretion of IL-6 decreased with NFkB and IKK inhibition when stimulated with TNF (p<0.05) differing only when TNF-stimulated nBMSCs were inhibited with IKK. VEGF and IL-6 secretion in aBMSCs is dependent on the classic NFkB pathway. However, neonatal BMSC VEGF and IL-6 secretion is stimulant-specific and utilization of the NFkB pathway is more complex.

Vascular endothelial growth factor improves myocardial functional recovery following ischemia/reperfusion injury.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a central growth and survival factor for both the endothelium and the myocardium. Recent evidence also suggests that VEGF may play a critical role in stem-cell-mediated paracrine cardioprotection. However, the acute effect of exogenous VEGF on myocardium after ischemia, indeed whether isolated VEGF alone may be a clinically useful therapeutic modality, remains unknown. We hypothesize that infusion of exogenous VEGF immediately prior to ischemia will improve myocardial functional recovery. MATERIALS AND METHODS: Adult male Sprague Dawley rat hearts were isolated and perfused via Langendorff model. All hearts were subject to 15-min equilibration, 25-min warm global ischemia, and 40-min reperfusion. Experimental hearts received a VEGF infusion of 3 x physiological (13 nM, n = 4), 5x physiological (20 nM, n = 4), or 10x physiological (40 nM, n = 5) immediately prior to ischemia. Controls (n = 5) were infused with perfusate vehicle. Functional indices (left ventricular developed pressure), end diastolic pressure, +/-dP/dt were continuously recorded. RESULTS: End diastolic pressure (mmHg) was elevated in response to ischemia/reperfusion. However, hearts infused with 10x VEGF demonstrated significantly (P < 0.05, analysis of variance and Bonferroni's) decreased end diastolic pressure throughout reperfusion compared to control (49.82 +/- 10.35 mmHg versus 80.73 +/- 6.08 mmHg at end reperfusion). 10x VEGF-treated hearts also exhibited significantly (P < 0.05, analysis of variance and Bonferroni's) greater recovery of left ventricular developed pressure (69.97 +/- 9.69% versus 39.74 +/- 7.01% of equilibration), +dP/dt, and -dP/dt at end reperfusion. However, neither 3 x nor 5x VEGF improved recovery after ischemia. VEGF also did not influence coronary flow after ischemia. CONCLUSION: This is the first demonstration that exogenous VEGF administration acutely improves myocardial functional recovery after ischemia. These findings may help elucidate the role of VEGF in acute stem-cell-mediated paracrine effects and suggests that isolated VEGF may be of therapeutic value.

Females exhibit relative resistance to depressive effects of tumor necrosis factor-alpha on the myocardium.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in myocardial dysfunction following acute injury. It is unknown, however, if a gender-specific response to TNF infusion exists in isolated rat hearts. Elucidating such mechanisms is important to understanding the myocardial gender differences during acute injury. We hypothesize that females will exhibit a relative resistance to TNF-induced myocardial dysfunction compared to males and that menstrual cycle would influence the degree of female myocardial resistance to TNF-induced myocardial functional depression. MATERIALS AND METHODS: Adult male, proestrus female, and metestrus/diestrus female hearts were subjected to 60 min of TNF infusion at 10,000 pg/mL.min via Langendorff. Myocardial contractile function (left ventricular developed pressure, and the positive/negative first derivative of pressure) was continuously recorded. RESULTS: 10,000 pg/mL.min of TNF markedly depressed myocardial function in males compared with other doses of TNF. Myocardial function was significantly decreased in males compared to females following TNF infusion. Additionally, both the proestrus and the metestrus/diestrus females exhibited equal resistance to TNF-induced myocardial dysfunction. CONCLUSION: Our study shows that females exhibit a significantly greater degree of resistance to TNF-induced myocardial depression. Moreover, data from this study suggest that fluctuations in estrogen during the reproductive cycle may have little to no influence on TNF-induced myocardial depression.

The struggle for iron: gastrointestinal microbes modulate the host immune response during infection.

The gastrointestinal track is one source of potential bacterial entry into the host, and the local immune system at the mucosal border is paramount in establishing host immune tolerance and the immune response to invading organisms. Macrophages use iron for production of hydroxy-radical and superoxide reactions, which are necessary for microbial killing. Presumably, as a survival strategy, bacteria, which also require iron for survival, have adapted the ability to sequester iron from the host, thereby limiting the availability to macrophages. As current modes of antimicrobial therapy are evolving, examination of nontraditional therapies is emerging. One such potential therapy involves altering the bacterial micronutrient iron concentration. Necrotizing enterocolitis is a clinical condition where such a strategy makes intuitive sense. This review will describe the immune response to gastrointestinal infection, the mechanisms that the gastrointestinal system uses to absorb intraluminal iron, and the critical role iron plays in the infectious process.

Tumor necrosis factor receptor 1 signaling resistance in the female myocardium during ischemia.

BACKGROUND: Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue after ischemia and reperfusion (I/R). TNF contributes to postischemic myocardial dysfunction and induces proinflammatory signaling, which may be mediated by the 55-kDa TNF receptor (TNFR1). In humans, there is a direct correlation between functional capacity, survival, and circulating TNF levels. Although decreasing the TNF level in animals was beneficial after myocardial ischemia, simply decreasing the bioavailability of TNF in humans with heart failure was not beneficial. This led to the important appreciation that TNF may have beneficial or deleterious effects in the heart, depending on which of its receptors is activated. Females have a lower incidence of heart failure and a higher heart failure survival than males. We hypothesized that TNFR1 signaling resistance occurs in the female myocardium during ischemia. METHODS AND RESULTS: Hearts from male and female TNFR1-knockout and wild-type (WT) mice were subjected to I/R. Female WT mice had better postischemic recovery than did male WT mice, an effect that appeared to be due to TNFR1 signaling resistance in females. Female WT mice had less myocardial depression after TNF infusion despite equivalent TNFR1 expression. Interestingly, TNFR1 ablation improved postischemic myocardial function, decreased activation of p38 mitogen-activated protein kinase, and reduced expression of interleukins-1beta and -6 in males but not in females. Furthermore, WT females expressed more of the suppressor of cytokine signaling protein 3 after I/R, which may in part explain TNFR1 signaling resistance in the female myocardium. CONCLUSIONS: This study demonstrates that sex differences exist in myocardial TNF signaling by TNFR1 after I/R.

The critical role of vascular endothelial growth factor in pulmonary vascular remodeling after lung injury.

The pulmonary vascular endothelial cell plays a crucial role in the regulation of the pulmonary vascular tone and in the maintenance of the barrier function and integrity of the alveolar-capillary membrane. It also plays a major role in coagulation, fibrinolysis, and angiogenesis and participates in inflammatory reactions. Vascular endothelial growth factor (VEGF) is a central growth and survival factor for the endothelial cell. Particularly high levels of VEGF are expressed in the lungs, reflecting the critical role of VEGF for lung development and structural integrity of the adult lung. Vascular endothelial growth factor exerts a variety of physiological and pathophysiological actions in the lung. Recent evidence suggests its involvement in the pathogenesis of lung diseases such as bronchopulmonary dysplasia, acute lung injury, emphysema, and pulmonary hypertension. To summarize the critical effects of VEGF on the pulmonary endothelial cell in the pathogenesis of these diseases, the purposes of this review are to (1) discuss the biological activities and intracellular signaling pathways of VEGF in the lung; (2) summarize the regulatory mechanisms involved in VEGF expression; (3)address the effects of VEGF on endothelial cells in hyperoxia-induced and other forms of lung injury; (4) highlight the endothelial effects of VEGF in the pathogenesis of emphysema; and (5) explore the role of VEGF in the pathogenesis of pulmonary arterial hypertension.

Selective protein kinase C inhibition attenuates pulmonary artery cytokine expression without affecting hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction may be an adaptive response to shunt blood to well-oxygenated areas of the lung, but hypoxia-induced inflammatory cytokine production leads to acute lung injury. We have previously shown that protein kinase C (PKC) mediates both hypoxic pulmonary vasoconstriction and inflammatory cytokine expression from the pulmonary artery; however, the effect of specific PKC isoform inhibition is currently unknown. We hypothesized that inhibition of classical PKC (cPKC) isoforms would attenuate hypoxic pulmonary vasoconstriction and downregulate hypoxia-induced pulmonary artery cytokine expression. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n = 6 per group) during hypoxia (95% N2/5% CO2) in the presence of the nonspecific PKC inhibitor bisindolylmaleimide (1 micromol/L), the cPKC inhibitor Gö 6976 (1 - 10 micromol/L), or vehicle (dimethyl sulfoxide, 0.001%). After 60 min of hypoxia, pulmonary artery rings were analyzed for tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta messenger RNA via reverse transcriptase-polymerase chain reaction. Nonspecific PKC inhibition (bisindolylmaleimide) significantly attenuated hypoxic pulmonary vasoconstriction (44.59 +/- 10.52% vs. 87.06 +/- 10.91% vehicle; P < 0.001) and downregulated hypoxia-induced expression of pulmonary artery TNF-alpha. Specific cPKC inhibition (Gö 6976) attenuated pulmonary artery TNF-alpha expression but had no effect on hypoxic pulmonary vasoconstriction. These data are indicative of the following: (1) nonspecific PKC inhibition attenuates both hypoxic pulmonary vasoconstriction and pulmonary artery TNF-alpha expression, (2) cPKC inhibition downregulates hypoxia-induced pulmonary artery TNF-alpha expression but has no effect on hypoxic pulmonary vasoconstriction, and (3) hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery cytokine expression are independent processes.

Stem cell mechanisms and paracrine effects: potential in cardiac surgery.

Heart disease remains the leading cause of death in the industrialized world. Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Cardiac surgery represents the unique situation where preischemia and postischemia treatment modalities exist that may use stem cell paracrine protection. This review (1) recalls the history of stem cells in cardiac disease and the unraveling of its mechanistic basis for protection, (2) outlines the pathways for stem cell-mediated paracrine protection, (3) highlights the signaling factors expressed, (4) explores the potential of using stem cells clinically in cardiac surgery, and (5) summarizes all human stem cell studies in cardiac disease to date.