Slipping Rib Syndrome in Children: Natural History and Outcomes Following Costal Cartilage Excision.

INTRODUCTION: Slipping rib syndrome (SRS) or subluxation of the medial aspect of the lower rib costal cartilages is an underdiagnosed cause of debilitating pain in otherwise healthy children. Costal cartilage excision may provide definitive symptom relief. However, limited data exist on the natural history, difficulty in diagnosis, and patient-reported outcomes for SRS in children. METHODS: We performed a single-institution descriptive study using chart review and a patient-focused survey for patients who underwent surgery for SRS from 2012 to 2020. Data regarding demographics, symptoms, diagnostic workup, and patient-reported outcomes were collected. RESULTS: Surgical resection was performed in 13 children. The median age at symptom onset was 12.5 y [IQR 9.7, 13.9], with a preponderance of girls (10, 77%). Eight patients participated in competitive athletics at the time of symptom onset. Prior to diagnosis, patients were seen by a median 3 [IQR 2, 5] providers with a median of 4 [IQR 3, 6] non-diagnostic imaging exams performed. The children included in the study underwent surgery for left (8), bilateral (4), and right (1) SRS. Two were lost to follow-up. At median post-op follow-up of 3.5 mo [IQR 1.2, 9.6], 73% (8/11) had returned to full activity. One reported non-limiting persistent pain symptoms. CONCLUSIONS: Lack of knowledge regarding SRS may result in delayed diagnosis, excessive testing, and limitation of physical activity. Operative treatment appears to provide durable relief and should be considered for children with SRS. The challenge remains to decrease the number of non-diagnostic exams and time to diagnosis.

A Narrative Review of Postoperative Anticoagulation Therapy for Congenital Cardiac Disease.

Congenital heart disease encompasses a range of cardiac birth defects. Some defects require early and complex surgical intervention and post-operative thromboprophylaxis primarily for valve, conduit, and shunt patency. Antiplatelet and anticoagulant management strategies vary considerably and may or may not align with recognized consensus practice guidelines. In addition, newer anticoagulant agents are being increasingly used in children, but these medications are not addressed in most consensus statements. This narrative review evaluated the literature from 2011 through 2021 on the topic of postoperative thromboprophylaxis after congenital heart disease operations. The search was focused on the descriptions and results of pediatric studies for replacement and/or repair of heart valves, shunts, conduits, and other congenital heart disease operations. Wide variability in practice exists and, as was true a decade ago, few randomized controlled trials have been conducted. Aspirin, warfarin, and perioperative heparin remain the most commonly used agents with varying dosing, duration, and monitoring strategies, making comparisons difficult. Only recently have data on direct oral anticoagulants been published in children, suggesting evolving paradigms of care. Our findings highlight the need for more research to strengthen the evidence for standardized thromboprophylaxis strategies.

Improved Outcomes of Infant Lung Transplantation Over 3 Decades.

BACKGROUND: Lung transplantation is the definitive surgical treatment for end-stage lung disease. However, infants comprise less than 5% of pediatric cases. This study sought to provide an overview of infant lung transplantation outcomes over the past 3 decades by using linked United Network for Organ Sharing (UNOS) and Pediatric Health Information System (PHIS) data. METHODS: Infants undergoing lung transplantation from 1989 to 2020 in UNOS were reviewed. UNOS and PHIS records for patients who underwent lung transplantation from 1995 to 2020 were linked using date of birth, sex, and date of surgery ± 3 days. The study assessed underlying diagnoses, pretransplant and posttransplant extracorporeal membrane oxygenation support, retransplant-free survival to discharge, hospital experience (≥1 annual transplant for ≥4 years in a 5-year period), operative decade, bronchiolitis obliterans syndrome, long-term survival, and functional status at latest follow-up. RESULTS: A total of 112 lung transplants were performed in 109 infants over 31 years. Of these, 21 patients died before discharge, and 2 underwent repeat transplantation during the same admission. The study linked 80.6% (83 of 103) of UNOS and PHIS records. Hospital survival was lower for infants with idiopathic pulmonary hypertension and those who underwent transplant procedures at less experienced centers. All 7 infants requiring postoperative extracorporeal membrane oxygenation support died. Median freedom from bronchiolitis obliterans syndrome was 8.1 years (interquartile range, 4.6 to 11.6 years). After discharge, median survival was 10.3 years (interquartile range, 6.3 to 14.4 years), with improved 10-year survival for those patients who underwent transplantation from 2010 to 2020 (87.3%) vs 2000 to 2009 (52.4%; P = .098) and 1989 to 1999 (34.1%; P = .004). A total of 84.6% (33 of 39) of survivors had minor or no restrictions at latest follow-up. CONCLUSIONS: Carefully selected infants experience promising short- and long-term outcomes after lung transplantation.

Outcomes 60 years after surgical valvotomy for isolated congenital pulmonary valve stenosis.

Congenital pulmonary valve stenosis (PVS) is a common congenital heart defect. In the infancy of cardiac surgery, open surgical valvotomy or closed surgical transventricular pulmonary valvotomy (Brock procedure) were the mainstays of therapy. We report the longest-known published follow-up of two women who as young children underwent pulmonary valvotomy for PVS and subsequent uncomplicated open pulmonary valve replacement over 60 years later.

Extended sternotomy with lateral neck incision: An alternative approach for children with large apical chest masses with thoracic inlet involvement.

Pediatric tumors in the apex of the thoracic cavity are often diagnosed late due to the absence of symptoms. These tumors can be quite large at presentation with involvement of the chest wall, sympathetic chain, spine, and aortic arch. The tumors can also extend into the thoracic inlet and encircle the brachial plexus. Depending on the diagnosis, treatment may involve chemotherapy with subsequent surgery or require primary resection. Optimal exposure to resect large apical tumors with thoracic inlet extension is a surgical challenge. To date, several surgical techniques have been described to resect these tumors - including both anterior and posterior thoracic approaches. Each of these techniques can be limited by inadequate exposure of the mass. We describe an alternative approach to surgical resection of these masses that employs an extended sternotomy with a lateral neck incision. This report details two successful resections of large left apical masses with thoracic inlet involvement in children using this technique (Level of evidence 4).

Does Ascending Aorta Size Affect Norwood Outcomes in Hypoplastic Left Heart With Aortic Atresia?

BACKGROUND: Conflicting data exist regarding the impact of ascending aorta size on outcomes after the Norwood procedure. Results from multi-institutional studies have largely relied on heterogeneous populations undergoing this surgery for different anatomic defects. Using data from the Single Ventricle Reconstruction Trial, we analyzed the impact of preoperative ascending aortic diameter on Norwood outcomes for patients with aortic atresia variants of hypoplastic left heart syndrome. METHODS: Neonates with aortic atresia and no ventricular septal defect were included and classified into four groups, based on their baseline ascending aorta echocardiographic measurements: less than or equal to 1.5 mm, 1.6 to 1.9 mm, 2.0 to 3.9 mm, and greater than or equal to 4.0 mm. Outcomes included 14-day mortality, transplant-free survival at 1 and 14 months, need for extracorporeal membrane oxygenation, length of ventilation, intensive care, and hospital stay, intensive care unit (ICU)-free days, right ventricular function, and incidence of recoarctation by 14 months. RESULTS: Overall, 292 patients were analyzed. Median length of ICU stay was significantly longer for infants with small aortas, and ICU-free days were significantly lower. There was no difference in length of mechanical ventilation or hospitalization between groups. Long-term right ventricular function and tricuspid regurgitation did not differ. Aortic arch recoarctation incidence was higher in patients with small aortic diameters. Patients with aortas less than or equal to 1.5 mm had decreased 30-day transplant-free survival. CONCLUSIONS: Infants with aortic atresia variants of hypoplastic left heart syndrome and baseline ascending aortic diameter less than or equal to 1.5 mm appear to suffer the greatest morbidity and mortality early after Norwood procedure. These infants also experienced longer stays in the ICU and higher rates of recoarctation. Ascending aortic diameter does not appear to affect long-term ventricular function.

Symptom persistence after vascular ring repair in children.

PURPOSE: Vascular rings are often diagnosed after evaluation for swallowing and breathing difficulties. Data regarding symptoms following vascular ring repair is sparse. We sought to determine whether symptoms persist using chart review and a survey. METHODS: Sixty-three patients underwent open vascular ring repair from July 2007 to May 2018. Data regarding vascular anatomy, demographics, pre- and postoperative symptoms, and chromosomal abnormalities were collected. Freedom from reoperation, 30-day mortality, and complications were assessed. Patient families were contacted for a symptom focused survey. RESULTS: The median age of surgical intervention was 14.4 months (IQR 5.8-34.7 months) for single aortic arches with an aberrant subclavian artery (SAA), and 5.3 months (IQR 1.3-10.1 months) for double aortic arches (DAA) (Table). Prior to surgery, all but two SAA were symptomatic. There was no operative mortality. Three patients required re-exploration for chylothorax, and three required late aortopexy. At last follow-up, 45% (18/40) SAA and 65% (15/23) DAA had post-operative symptoms. Fourteen patient families completed the symptom survey (10 SAA, 4 DAA). Five SAA had breathing and swallowing symptoms, and 3 SAA and 3 DAA had breathing difficulties. CONCLUSIONS: Open vascular ring repair remains a safe repair. However, further investigation of the persistent symptoms in these patients is merited. STUDY TYPE / LEVEL OF EVIDENCE: Retrospective Comparative Study, Level III.

Recanalization of an atretic intramural left main coronary artery after bypass surgery in a pediatric patient with anomalous aortic origin of the left main coronary artery arising from the right sinus of Valsalva.

We report a pediatric patient with nonatherosclerotic chronic total occlusion (CTO) of the left main coronary artery (LMCA) leading to complete LMCA atresia which was successfully recanalized via retrograde techniques through a previous internal mammary bypass graft. After the CTO was treated, the artery was found to be anomalous off the right cusp with an intramural coarse and slit-like orifice. The patient's ischemic symptoms resolved after Percutaneous Coronary Intervention (PCI), and she has continued to do well.

Surgical Versus Percutaneous Closure of PDA in Preterm Infants: Procedural Charges and Outcomes.

BACKGROUND: Studies comparing percutaneous closure of patent ductus arteriosus (PDA) with surgical ligation tend to exclude premature infants and have not assessed procedural charges. We compared our contemporary outcomes and charges of device closure to surgical ligation of PDA in preterm infants. MATERIAL AND METHODS: Preterm infants who underwent isolated PDA closure during their newborn hospitalization (January 2014 to September 2017) were grouped based on intention to treat (surgery versus device closure). Patient demographics, procedural details, and immediate postprocedural outcomes were compared. Procedural charges for device closure versus surgical ligation were compared. RESULTS: Compared with the device group (n = 33), patients undergoing surgical ligation (n = 39) were younger, smaller, and required more preoperative support (P < 0.05). The procedure time was shorter for surgical ligation (P < 0.01). Although there was no procedural mortality in either group, the complication rate was higher for device closure than for surgical ligation (15.2% versus 0%; P = 0.02). The proportion of patients returning to preprocedural respiratory support by 48 h after procedure was similar. There was a higher proportion of surgical patients who required increased inotropic support in the first 24 h after procedure (P = 0.19). The procedural charges for transcatheter device closure were twice as expensive as those for surgical ligation. CONCLUSIONS: In our early experience with percutaneous PDA closure, we found a percutaneous approach in preterm infants feasible and well tolerated. Both surgical ligation and device closure were associated with perioperative or postoperative complications. Procedural charges were higher for percutaneous closure, driven by device charge and catheterization room utilization. Further investigation is needed to establish guidelines for first-line therapy for PDA closure in preterm infants, including cost-benefit analysis.

Anomalous Systemic Artery to the Left Lower Lobe: Literature Review and a New Surgical Technique.

Anomalous systemic arterial supply to the basal segments of the left lower lobe without coexisting pulmonary artery connection is a rare anomaly. Most feel treatment is necessary; however, the ideal strategy is unclear. Treatments described include embolization, pulmonary resection, or anastomosis to the native pulmonary artery. We recently encountered an infant with this anomaly and present a literature review summarizing all recent reports. Additionally, we describe a novel surgical technique to create a tension-free anastomosis utilizing segmental aortic translocation that we employed in our patient due to a large distance between the anomalous vessel and native left pulmonary artery.

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.

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.

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.

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.

Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. STUDY DESIGN: With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. RESULTS: Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. CONCLUSIONS: Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism.

Female stem cells are superior to males in preserving myocardial function following endotoxemia.

Mesenchymal stem cells (MSCs) may offer therapeutic benefit in the setting of sepsis and endotoxemia. Previous studies suggest that MSCs from female donors may possess better protective capabilities than their male counterparts. The present study examined whether female MSCs may offer a greater protective advantage in the setting of endotoxemic cardiac dysfunction compared with male MSCs. Adult male Sprague-Dawley rats were injected intraperitoneally with LPS and then treated with intraperitoneal injections of either saline, female MSCs, or male MSCs. Hearts and serum were then collected for analysis of myocardial function, myocardial protein, and myocardial and serum cytokines. Compared with male MSC or vehicle-treated animals, female MSC treatment resulted in greater preservation of myocardial function (P < 0.001). Serum and myocardial levels of all measured cytokines were comparable between rats given MSCs from male or female donors but substantially improved over rats given vehicle (P < 0.05). Reduced myocardial inflammation correlated with reduced levels of phosphorylated p38 MAPK expression in the myocardium of animals injected with MSCs of either sex (P < 0.05). The Bcl-xL/Bax ratio was increased to a greater extent following treatment with female MSCs vs. male MSCs (P < 0.05). Intraperitoneal administration of MSCs is effective in limiting myocardial inflammation and dysfunction in the rat endotoxemia model. Compared with treatment with their male counterparts, MSC treatment from female donors is associated with greater cardiac protection against acute endotoxemic injury.