Matthew L. Stone

Genetic and Pharmacologic Disruption of Interleukin-1β Signaling Inhibits Experimental Aortic Aneurysm Formation

Objective—Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1&bgr; (IL-1&bgr;) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment. Methods and Results—IL-1&bgr; mRNA and protein levels were significantly elevated in abdominal aortas of 8- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion (wild-type [WT]) compared with saline perfusion. Mice with genetic deletion of IL-1&bgr; (IL-1&bgr; knockout [KO]) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0±5.5% for IL-1&bgr; KO and 52.5±4.6% for IL-1R KO, compared with 89.4±4.0% for WT mice (P<0.005). Correspondingly, IL-1&bgr; KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared with WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=–0.676; P<0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days after AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared with control mice. Conclusion—IL-1&bgr; is critical for AAA initiation and progression, and IL-1&bgr; neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1&bgr; signaling offers a novel pathway for AAA treatment.

Orthotopic heart transplant versus left ventricular assist device: A national comparison of cost and survival

OBJECTIVES Orthotopic heart transplantation is the standard of care for end-stage heart disease. Left ventricular assist device implantation offers an alternative treatment approach. Left ventricular assist device practice has changed dramatically since the 2008 Food and Drug Administration approval of the HeartMate II (Thoratec, Pleasanton, Calif), but at what societal cost? The present study examined the cost and efficacy of both treatments over time. METHODS All patients who underwent either orthotopic heart transplantation (n = 9369) or placement of an implantable left ventricular assist device (n = 6414) from 2005 to 2009 in the Nationwide Inpatient Sample were selected. The trends in treatment use, mortality, and cost were analyzed. RESULTS The incidence of orthotopic heart transplantation increased marginally within a 5-year period. In contrast, the annual left ventricular assist device implantation rates nearly tripled. In-hospital mortality from left ventricular assist device implantation decreased precipitously, from 42% to 17%. In-hospital mortality for orthotopic heart transplantation remained relatively stable (range, 3.8%-6.5%). The mean cost per patient increased for both orthotopic heart transplantation and left ventricular assist device placement (40% and 17%, respectively). With the observed increase in both device usage and cost per patient, the cumulative Left ventricular assist device cost increased 232% within 5 years (from

Ex vivo rehabilitation of non–heart-beating donor lungs in preclinical porcine model: Delayed perfusion results in superior lung function

143 million to

Inhibition of Interleukin-1β Decreases Aneurysm Formation and Progression in a Novel Model of Thoracic Aortic Aneurysms

479 million). By 2009, Medicare and Medicaid were the primary payers for nearly one half of all patients (orthotopic heart transplantation, 45%; left ventricular assist device, 51%). CONCLUSIONS Since Food and Drug Administration approval of the HeartMate II, mortality after left ventricular assist device implantation has decreased rapidly, yet has remained greater than that after orthotopic heart transplantation. The left ventricular assist device costs have continued to increase and have been significantly greater than those for orthotopic heart transplantation. Because of the evolving healthcare economics climate, with increasing emphasis on the costs and comparative effectiveness, a concerted effort at LVAD cost containment and judicious usage is essential to preserve the viability of this invaluable treatment.

Primary Payer Status Is Associated With Mortality and Resource Utilization for Coronary Artery Bypass Grafting

OBJECTIVES Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and the potential for rehabilitation of donor lungs with extended warm ischemic times is unknown. The present study compared the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs. METHODS Mature swine underwent hypoxic arrest, followed by 60 minutes of no-touch warm ischemia. The lungs were harvested and flushed with 4°C Perfadex. Three groups (n = 5/group) were stratified according to the preservation method: cold static preservation (CSP; 4 hours of 4°C storage), immediate EVLP (I-EVLP: 4 hours EVLP at 37°C), and delayed EVLP (D-EVLP; 4 hours of CSP followed by 4 hours of EVLP). The EVLP groups were perfused with Steen solution supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. The lungs then underwent allotransplantation and 4 hours of recipient reperfusion before allograft assessment for resultant ischemia-reperfusion injury. RESULTS The donor blood oxygenation (partial pressure of oxygen/fraction of inspired oxygen ratio) before death was not different between the groups. The oxygenation after transplantation was significantly greater in the D-EVLP group than in the I-EVLP or CSP groups. The mean airway pressure, pulmonary artery pressure, and expression of interleukin-8, interleukin-1β, and tumor necrosis factor-α were all significantly reduced in the D-EVLP group. Post-transplant oxygenation exceeded the acceptable clinical levels only in the D-EVLP group. CONCLUSIONS Uncontrolled non-heart-beating donor lungs with extended warm ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of nonheart-beating donor lungs.

The effect of race and gender on pediatric surgical outcomes within the United States.

Background— Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1&bgr; (IL-1&bgr;) is undetermined. Methods and Results— IL-1&bgr; protein was measured in human TAAs and control aortas, and IL-1&bgr; protein was increased ≈20-fold in human TAAs. To develop an experimental model of TAAs, 8- to10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n=30 per group). Elastase treatment to thoracic aortas resulted in progressive dilation until day 14 with maximal dilation of 99.6±24.7% compared with 14.4±8.2% for WT saline control (P<0.0001). WT TAAs demonstrated elastin fragmentation, smooth muscle cell loss, macrophage infiltration, and increased IL-1&bgr; expression. Next, TAAs were induced in mice deficient of IL-1&bgr; (IL-1&bgr; knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1&bgr; and IL-1R significantly decreased thoracic aortic dilation (IL-1&bgr; knockout=54.2±16.8% and IL-1R knockout=62.6±17.2% versus WT TAA=104.7±23.8%; P<0.001for both). IL-1&bgr; knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1&bgr; and IL-1R knockout aortas had decreased inflammatory cytokine and matrix metalloproteinase 9 expression. Separately, WT mice pretreated with either IL-1R antagonist anakinra (100 mg/kg per day) or vehicle alone (control) underwent elastase treatment. Pretreatment of WT mice with anakinra attenuated TAA formation (control: 99.2±15.5% versus anakinra: 68.3±19.2%; P<0.005). Finally, to investigate treatment of small TAAs, WT mice were treated with anakinra 3 days after TAA induction. Anakinra treatment in WT mice with small TAAs reduced aortic dilation on day 14 (control treatment: 89.1±18.6% versus anakinra treatment: 59.7±25.7%; P=0.01). Conclusions— Periadventitial application of elastase to murine thoracic aortas reproducibly produced aneurysms with molecular and histological features consistent with TAA disease. Genetic and pharmacological inhibition of IL-1&bgr; decreased TAA formation and progression, indicating that IL-1&bgr; may be a potential target for TAA treatment.

Receptor for Advanced Glycation End Products (RAGE) on iNKT Cells Mediates Lung Ischemia-Reperfusion Injury

Background— Medicaid and uninsured populations are a significant focus of current healthcare reform. We hypothesized that outcomes after coronary artery bypass grafting (CABG) in the United States is dependent on primary payer status. Methods and Results— From 2003 to 2007, 1 250 619 isolated CABG operations were evaluated using the Nationwide Inpatient Sample (NIS) database. Patients were stratified by primary payer status: Medicare, Medicaid, uninsured, and private insurance. Hierarchical multiple regression models were applied to assess the effect of primary payer status on postoperative outcomes. Unadjusted mortality for Medicare (3.3%), Medicaid (2.4%), and uninsured (1.9%) patients were higher compared with private insurance patients (1.1%, P<0.001). Unadjusted length of stay was longest for Medicaid patients (10.9±0.04 days) and shortest for private insurance patients (8.0±0.01 days, P<0.001). Medicaid patients accrued the highest unadjusted total costs (

Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury

113 380±386, P<0.001). Importantly, after controlling for patient risk factors, income, hospital features, and operative volume, Medicaid (odds ratio, 1.82; P<0.001) and uninsured (odds ratio, 1.62; P<0.001) payer status independently conferred the highest adjusted odds of in-hospital mortality. In addition, Medicaid payer status was associated with the longest adjusted length of stay and highest adjusted total costs (P<0.001). Conclusions— Medicaid and uninsured payer status confers increased risk adjusted in-hospital mortality for patients undergoing coronary artery bypass grafting operations. Medicaid was further associated with the greatest adjusted length of stay and total costs despite risk factors. Possible explanations include delays in access to care or disparate differences in health maintenance.

NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia-Reperfusion Injury.

PURPOSE The purpose of this study was to examine risk-adjusted associations between race and gender on postoperative morbidity, mortality, and resource utilization in pediatric surgical patients within the United States. METHODS 101,083 pediatric surgical patients were evaluated using the U.S. national KID Inpatient Database (2003 and 2006): appendectomy (81.2%), pyloromyotomy (9.8%), intussusception (6.2%), decortication (1.9%), congenital diaphragmatic hernia repair (0.7%), and colonic resection for Hirschsprungs disease (0.2%). Patients were stratified according to gender (male: 63.1%, n=63,783) and race: white (n=58,711), Hispanic (n=26,118), black (n=9,103), Asian (n=1,582), Native American (n=474), and other (n=5,096). Multivariable logistic regression modeling was utilized to evaluate risk-adjusted associations between race, gender, and outcomes. RESULTS After risk adjustment, race was independently associated with in-hospital death (p=0.02), with an increased risk for black children. Gender was not associated with mortality (p=0.77). Postoperative morbidity was significantly associated with gender (p<0.001) and race (p=0.01). Gender (p=0.003) and race (p<0.001) were further associated with increased hospital length of stay. Importantly, these results were dependent on operation type. CONCLUSION Race and gender significantly affect postoperative outcomes following pediatric surgery. Black patients are at disproportionate risk for postoperative mortality, while black and Hispanic patients have increased morbidity and hospital resource utilization. While gender does not affect mortality, gender is a determinant of both postoperative morbidity and increased resource utilization.

Rapamycin Blocks Fibrocyte Migration and Attenuates Bronchiolitis Obliterans in a Murine Model

Activation of invariant natural killer T (iNKT) cells and signaling through receptor for advanced glycation end products (RAGE) are known to independently mediate lung ischemia–reperfusion (IR) injury. This study tests the hypothesis that activation of RAGE specifically on iNKT cells via alveolar macrophage‐produced high mobility group box 1 (HMGB1) is critical for the initiation of lung IR injury. A murine in vivo hilar clamp model was utilized, which demonstrated that RAGE−/− mice were significantly protected from IR injury. Treatment of WT mice with soluble RAGE (a decoy receptor), or anti‐HMGB1 antibody, attenuated lung IR injury and inflammation, whereas treatment with recombinant HMGB1 enhanced IR injury in WT mice but not RAGE−/− mice. Importantly, lung dysfunction, cytokine production and neutrophil infiltration were significantly attenuated after IR in Jα18−/− mice reconstituted with RAGE−/− iNKT cells (versus WT iNKT cells). In vitro studies demonstrated that, after hypoxia‐reoxygenation, alveolar macrophage‐derived HMGB1 augmented IL‐17 production from iNKT cells in a RAGE‐dependent manner. These results suggest that HMGB1‐mediated RAGE activation on iNKT cells is critical for initiation of lung IR injury and that a crosstalk between macrophages and iNKT cells via the HMGB1/RAGE axis mediates IL‐17 production by iNKT cells causing neutrophil infiltration and lung IR injury.