D A Fullerton

University of Colorado, Denver, Colorado, United States

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Publications (187)592.36 Total impact

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    ABSTRACT: IntroductionEndotoxemia and the systemic inflammatory response syndrome have a significant impact on post-surgery outcome, particularly in the elderly. The cytokine response to endotoxin is altered by aging. We tested the hypothesis that vulnerability to endotoxemic cardiac depression increases with aging due to age-related augmentation of myocardial inflammatory responses.Methods Adult (4 to 6 months) and old (20 to 22 months) C57/BL6 mice were treated with endotoxin (0.5 mg/kg, iv). Left ventricle (LV) function was assessed using a microcatheter system. Chemokines and cytokines in plasma and myocardium were analyzed by enzyme-linked immunosorbent assay (ELISA). Mononuclear cells in the myocardium were examined using immunofluorescence staining.ResultsOld mice displayed worse LV function (cardiac output: 3.0¿±¿0.2 mL/min versus 4.4¿±¿0.3 mL/min in adult mice) following endotoxin treatment. The exaggerated cardiac depression in old mice was associated with higher levels of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC) in plasma and myocardium, greater myocardial accumulation of mononuclear cells, and greater levels of tumor necrosis factor-¿ (TNF-¿), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) in plasma and myocardium. Neutralization of MCP-1 resulted in greater reductions in myocardial mononuclear cell accumulation and cytokine production, and greater improvement in LV function in old mice while neutralization of KC had a minimal effect on LV function.Conclusion Old mice have enhanced inflammatory responses to endotoxemia that lead to exaggerated cardiac functional depression. MCP-1 promotes myocardial mononuclear cell accumulation and cardiodepressant cytokines production, and plays an important role in the endotoxemic cardiomyopathy in old mice. The findings suggest that special attention is needed to protect the heart in the elderly with endotoxemia.
    Critical care (London, England) 09/2014; 18(5):527. · 4.72 Impact Factor
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    ABSTRACT: Calcific aortic valve disease (CAVD) is a chronic inflammatory condition and affects a large number of elderly people. Aortic valve interstitial cells (AVICs) occupy an important role in valvular calcification and CAVD progression. While pro-inflammatory mechanisms are capable of inducing the osteogenic responses in AVICs, the molecular interaction between pro-inflammatory and pro-osteogenic mechanisms remains poorly understood. This study tested the hypothesis that intercellular adhesion molecule-1 (ICAM-1) plays a role in mediating pro-osteogenic factor expression in human AVICs. AVICs were isolated from normal human aortic valves and cultured in M199 medium. Treatment with leukocyte function-associated factor-1 (LFA-1, an ICAM-1 ligand) up-regulated the expression of bone morphogenetic protein-2 (BMP-2) and resulted in increased alkaline phosphatase activity and formation of calcification nodules. Pre-treatment with lipopolysaccharide (LPS, 0.05μg/ml) increased ICAM-1 levels on cell surfaces and exaggerated the pro-osteogenic response to LFA-1, and neutralization of ICAM-1 suppressed this response. Further, ligation of ICAM-1 by antibody cross-linking also up-regulated BMP-2 expression. Interestingly, LFA-1 elicited Notch1 cleavage and NF-κB activation. Inhibition of NF-κB markedly reduced LFA-1-induced BMP-2 expression, and inhibition of Notch1 cleavage with a γ-secretase inhibitor suppressed LFA-1-induced NF-κB activation and BMP-2 expression. Ligation of ICAM-1 on human AVICs activates the Notch1 pathway. Notch1 up-regulates BMP-2 expression in human AVICs through activation of NF-κB. The results demonstrate a novel role of ICAM-1 in translating a pro-inflammatory signal into a pro-osteogenic response in human AVICs and suggest that ICAM-1 on the surfaces of AVICs contributes to the mechanism of aortic valve calcification.
    Biochimica et biophysica acta. 08/2014;
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    ABSTRACT: Aging exaggerates myocardial injury caused by sepsis and up-regulated the expression of cytokines. IL-37 is an anti-inflammatory cytokine, mice with transgenic expression of IL-37 are protected against endotoxic shock, exhibiting reduced lung and kidney damage. We tested the hypothesis that IL-37 protects the aging heart against endotoxemic cardiac depression via suppression of myocardial inflammatory responses. Methods: WT and IL-37 transgenic (tg) mice, males of adult (4-6 months) and aging (18-20 months), were treated with endotoxin (E. coli 011:B4; 0.5 mg/kg i.v.). Left ventricular (LV) function was measured with a pressure-volume microcatheter at 1-6 h after injection. Plasma and myocardial tissue homogenate were prepared for analysis of MCP-1, TNF-α and IL-1β by ELISA. Results: Endotoxin caused greater depression of LV function in WT aging mice, TNF-α and IL-1β in comparison to WT adult mice. Aging IL-37Tg mice had improved ejection fraction and cardiac output after LPS injection that were associated with lower myocardial levels of cytokines. To determine the role of MCP-1 in myocardial production of TNF-α and IL-1β, as well as in LV dysfunction, we treated WT aging mice with MCP-1-neutrlizing antibody and found that neutralization MCP-1 reduced myocardial TNF-α and IL-1β levels and improved LV function. Conclusions: Endotoxemia results in worse LV functional injury in aging WT mice. MCP-1 plays an important role in mediating the production of cardiac depressant cytokines and resultant LV dysfunction. IL-37 improves LV function in aging mice during endotoxemia through suppression of myocardial production of MCP-1 and cardiodepressant cytokines. Thus, IL-37 has the therapeutic potential for cardiac protection in the elderly against functional injury associated with major surgeries. cardiovascres;103/suppl_1/S92-b/CHAPTERSUB75446F1F1CHAPTERsub-75446F1 Figure: Aging IL-37 Tg mice LV function.
    Cardiovascular Research 07/2014; 103(suppl 1):S92. · 5.81 Impact Factor
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    ABSTRACT: The myocardial inflammatory response contributes to cardiac functional injury associated with heart surgery obligating global ischemia and reperfusion (I/R). Toll-like receptors (TLRs) play important roles in the mechanism underlying myocardial I/R injury. The aim of this study was to examine the release of small constitutive heat shock proteins (HSPs) from human and mouse myocardium following global ischemia and the role of extracellular small HSP in myocardial injury.
    Molecular medicine (Cambridge, Mass.). 06/2014;
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    ABSTRACT: Mononuclear cell infiltration in valvular tissue is one of the characteristics in calcific aortic valve disease. The inflammatory responses of aortic valve interstitial cells (AVICs) play an important role in valvular inflammation. However, it remains unclear what may evoke AVIC inflammatory responses. Accumulation of biglycan has been found in diseased aortic valve leaflets. Soluble biglycan can function as a danger-associated molecular pattern to induce the production of proinflammatory mediators in cultured macrophages. We tested the hypothesis that soluble biglycan induces AVIC production of proinflammatory mediators involved in mononuclear cell infiltration through Toll-like receptor (TLR)-dependent signaling pathways.
    Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 05/2014;
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    ABSTRACT: Although calcific aortic stenosis is common, calcification of the other three heart valves is not. The aortic valve interstitial cell (VIC) has been implicated in the pathogenesis of aortic stenosis. Proinflammatory stimulation of aortic VICs induces an osteogenic and inflammatory phenotypic change. We hypothesized that the VICs of the other heart valves do not undergo these changes. Using isolated human VICs from normal aortic, mitral, pulmonary, and tricuspid valves, our purpose was to compare the osteogenic response to proinflammatory stimulation via toll-like receptor 4 (TLR-4). Aortic, pulmonic, mitral, and tricuspid (n = 4 for each valve type) VICs were isolated from hearts valves explanted from patients undergoing cardiac transplantation. Cells were cultured and grown to confluence in passage 2-6 before treatment with Lipopolysaccharide (LPS) (100-200 ng/mL) for 24 or 48 h. Cells were characterized by immunofluorescent staining. TLR-4 expression was analyzed (immunoblotting, flow cytometry). Bone morphogenetic protein 2 and intercellular adhesion molecule 1 production were determined (immunoblotting). Monocyte chemoattractant protein 1 levels were determined by enzyme-linked immunosorbent assay. Statistics were by Mann-Whitney U test. TLR-4 stimulation induced bone morphogenetic protein 2 production only in aortic VICs (P < 0.05). Intra-cellular adhesion molecule 1 production and monocyte chemoattractant protein 1 secretion increased in a similar fashion among TLR-4-stimulated VICs from all four valves. Proinflammatory stimulation induces an osteogenic phenotype in aortic VICs but not mitral, pulmonic, or tricuspid VICs. We conclude that this differential osteogenic response of aortic VICs contributes to the pathogenesis of calcific aortic stenosis.
    Journal of Surgical Research 03/2014; · 2.02 Impact Factor
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    ABSTRACT: Background Lower extremity paralysis continues to complicate aortic interventions. The lack of understanding of the underlying pathology has hindered advancements to decrease the occurrence this injury. The current model demonstrates reproducible lower extremity paralysis following thoracic aortic occlusion. Methods Adult male C57BL6 mice were anesthetized with isoflurane. Through a cervicosternal incision the aorta was exposed. The descending thoracic aorta and left subclavian arteries were identified without entrance into pleural space. Skeletonization of these arteries was followed by immediate closure (Sham) or occlusion for 4 min (moderate ischemia) or 8 min (prolonged ischemia). The sternotomy and skin were closed and the mouse was transferred to warming bed for recovery. Following recovery, functional analysis was obtained at 12 hr intervals until 48 hr. Results Mice that underwent sham surgery showed no observable hind limb deficit. Mice subjected to moderate ischemia for 4 min had minimal functional deficit at 12 hr followed by progression to complete paralysis at 48 hr. Mice subjected to prolonged ischemia had an immediate paralysis with no observable hind-limb movement at any point in the postoperative period. There was no observed intraoperative or post operative mortality. Conclusion Reproducible lower extremity paralysis whether immediate or delayed can be achieved in a murine model. Additionally, by using a median sternotomy and careful dissection, high survival rates, and reproducibility can be achieved.
    Journal of Visualized Experiments 01/2014;
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    ABSTRACT: Aortic valve calcification causes the progression of calcific aortic valve disease (CAVD). Stimulation of aortic valve interstitial cells (AVICs) with lipopolysaccharide (LPS) up-regulates the expression of osteogenic mediators, and NF-κB plays a central role in mediating AVIC osteogenic responses to Toll-like receptor 4 (TLR4) stimulation. Diseased aortic valves exhibit greater levels of oxidized low-density lipoprotein (oxLDL). This study tested the hypothesis that oxLDL augments the osteogenic responses in human AVICs through modulation of NF-κB and Notch1 activation. AVICs isolated from normal human aortic valves were treated with LPS (0.1 µg/ml), oxLDL (20 µg/ml) or LPS plus oxLDL for 48 h. OxLDL alone increased cellular bone morphogenetic protein-2 (BMP-2) levels while it had no effect on alkaline phosphatase (ALP) levels. Cells exposed to LPS plus oxLDL produced higher levels of BMP-2 and ALP than cells exposed to LPS alone. Further, LPS plus oxLDL induced greater NF-κB activation, and inhibition of NF-κB markedly reduced the expression of BMP-2 and ALP in cells treated with LPS plus oxLDL. OxLDL also induced Notch1 activation and resulted in augmented Notch1 activation when it was combined with LPS. Inhibition of Notch1 cleavage attenuated NF-κB activation induced by LPS plus oxLDL, and inhibition of NF-κB suppressed the expression of BMP-2 and ALP induced by the synergistic effect of Jagged1 and LPS. These findings demonstrate that oxLDL up-regulates BMP-2 expression in human AVICs and synergizes with LPS to elicit augmented AVIC osteogenic responses. OxLDL exerts its effect through modulation of the Notch1-NF-κB signaling cascade. Thus, oxLDL may play a role in the mechanism underlying CAVD progression.
    PLoS ONE 01/2014; 9(5):e95400. · 3.53 Impact Factor
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    ABSTRACT: Background Lung cancer stem cells (CSCs) are a subpopulation of cells that drive growth, invasiveness, and resistance to therapy. Inflammatory eicosanoids are critical to maintain this malignant subpopulation. Secretory phospholipase A2 group IIa (sPLA2) is an important mediator of the growth and invasive potential of human lung cancer cells and regulates eicosanoid production. We hypothesized that sPLA2 plays a role in the maintenance of lung CSCs. Methods Cancer stem cells from lung adenocarcinoma cell lines H125 and A549 were isolated using aldehyde dehydrogenase activity and flow cytometry. Protein and mRNA levels for sPLA2 were compared between sorted cells using Western blotting and quantitative reverse transcriptase–polymerase chain reaction techniques. Chemical inhibition of sPLA2 and short-hairpin RNA knockdown of sPLA2 were used to evaluate effects on tumorsphere formation. Results Lung CSCs were isolated in 8.9% ± 4.1% (mean ± SD) and 4.1% ± 1.6% of H125 and A549 cells respectively. Both sPLA2 protein and mRNA expression were significantly elevated in the CSC subpopulation of H125 (p = 0.002) and A549 (p = 0.005; n = 4). Knockdown of sPLA2 significantly reduced tumorsphere formation in H125 (p = 0.026) and A549 (p = 0.001; n = 3). Chemical inhibition of sPLA2 resulted in dose-dependent reduction in tumorsphere formation in H125 (p = 0.003) and A549 (p = 0.076; n = 3). Conclusions Lung CSCs express higher levels of sPLA2 than the non–stem cell population. Our findings that viral knockdown and chemical inhibition of sPLA2 reduce tumorsphere formation in lung cancer cells demonstrate for the first time that sPLA2 plays an important role in CSCs. These findings suggest that sPLA2 may be an important therapeutic target for human lung cancer.
    The Annals of Thoracic Surgery. 01/2014;
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    ABSTRACT: Major surgeries performed in the elderly are increasing with the increase in life expectancy, and such surgeries frequently cause endotoxemia and the systemic inflammatory response. Aging hearts have exaggerated responses to injurious stimuli. Thus, it is important to protect aging hearts during major surgeries. Endotoxin activates TLR4 to induce the production of cardiodepressant cytokines, including TNF-α and IL-1β. IL-37 is an anti-inflammatory cytokine and has been shown to suppress the inflammatory responses caused by endotoxin. We tested the hypothesis that IL-37 protects the aging heart against endotoxemic cardiac depression via suppression of myocardial inflammatory responses. Methods: WT and IL-37 transgenic (tg) mice, males of adult (4-6 months) and aging (18-20 months), were treated with endotoxin (E. coli 011:B4; 0.5 mg/kg i.v.). Left ventricular (LV) function was measured with a pressure-volume microcatheter at 6 h after injection. Plasma and myocardial tissue homogenate were prepared for analysis of MCP-1, TNF-α and IL-1β by ELISA. Results: Endotoxin caused greater depression of LV function in WT aging mice that was associated with exaggerated myocardial production of MCP-1, TNF-α and IL-1β in comparison to WT adult mice. Aging IL-37Tg mice had improved ejection fraction and cardiac output after LPS injection that were associated with lower myocardial levels of MCP-1, TNF-α and IL-1β. To determine the role of MCP-1 in myocardial production of TNF-α and IL-1β, as well as in LV dysfunction, we treated WT aging mice with MCP-1-neutrlizing antibody and found that neutralization MCP-1 reduced myocardial TNF-α and IL-1β levels and improved LV function. Conclusions: Endotoxemia results in worse LV functional injury in aging WT mice. MCP-1 plays an important role in mediating the production of cardiac depressant cytokines and resultant LV dysfunction. IL-37 improves LV function in aging mice during endotoxemia through suppression of myocardial production of MCP-1 and cardiodepressant cytokines. Thus, IL-37 has the therapeutic potential for cardiac protection in the elderly against functional injury associated with major surgeries.
    Shock 01/2014; · 2.61 Impact Factor
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    ABSTRACT: Background Donor lungs acquired from victims of asphyxiation by hanging are not routinely used for lung transplantation because of the associated lung injury. Ex vivo lung perfusion (EVLP) is a technique to evaluate marginal donor lungs before transplantation. We report here our experience with the use of EVLP in donor lungs procured from victims of asphyxia by hanging. Methods Lungs from 5 donors who became brain dead secondary to hanging were evaluated by EVLP. Donor organs were perfused according to trial protocol. Donor lungs were accepted for transplantation if they maintained a PaO2 greater than or equal to 350 mm Hg, had a clear roentgenogram, and had no significant worsening of physiologic metrics. Results Perfused organs included single and double lung blocs, and all were perfused without technical incident. Three of the 5 donor organs evaluated met criteria for transplantation after 3 hours of EVLP and were transplanted. Donor organs rejected for transplantation showed either signs of worsening PaO2 or deterioration of physiologic metrics. There were no intraoperative complications in the patients who underwent transplantation, and all were alive at 30 days. Conclusions We report here the successful use of EVLP to assess donor lungs acquired from victims of asphyxiation by hanging. The use of EVLP in this particular group of donors has the potential to expand the available donor pool. We demonstrate that EVLP is a viable option for evaluating the function of lung allografts before transplantation and would recommend that all donor lungs obtained from hanging victims undergo EVLP to assess their suitability for transplantation.
    The Annals of Thoracic Surgery. 01/2014;
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    ABSTRACT: Postoperative atrial fibrillation (POAF) is a well-recognized complication of cardiac surgery; however, its management remains a challenge, and the implementation and outcomes of various strategies in clinical practice remain unclear. We hypothesize that treatment for POAF is variable, and that it is associated with particular morbidity and mortality following cardiac surgery. We compared patient characteristics, operative procedures, postoperative management, and outcomes between patients with and without POAF following coronary artery bypass grafting (CABG) in the Society of Thoracic Surgeons multicenter Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) registry (2004-2005). Of 2390 patients who underwent CABG, 676 (28%) had POAF. Compared with patients without POAF, those with POAF were older (median age 74 vs 71 years, P < 0.0001) and more likely to have hypertension (86% vs 83%, P = 0.04) and impaired renal function (median estimated glomerular filtration rate 56.9 vs 58.6 mL/min/1.73 m(2) , P = 0.0001). A majority of patients with POAF were treated with amiodarone (77%) and β-blockers (68%); few (9.9%) underwent cardioversion. Patients with POAF were more likely to experience complications (57% vs 41%, P < 0.0001), including acute limb ischemia (1.0% vs 0.4%, P = 0.03), stroke (4.0% vs 1.9%, P = 0.002), and reoperation (13% vs 7.9%, P < 0.0001). Length of stay (median 8 days vs 6 days, P < 0.0001), in-hospital mortality (6.8% vs 3.7%, P = 0.001), and 30-day mortality (7.8 vs 3.9, P < 0.0001) were all worse for patients with POAF. In adjusted analyses, POAF remained associated with increased length of stay following surgery (adjusted ratio of the mean: 1.27, 95% confidence interval: 1.2-1.34, P < 0.0001). Postoperative AF is common following CABG, and such patients continue to have higher rates of postoperative complications. Postoperative AF is significantly associated with increased length of stay following surgery.
    Clinical Cardiology 12/2013; · 1.83 Impact Factor
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    ABSTRACT: Dexmedetomidine, an α-2a adrenergic agonist, given pre- and postoperatively was previously shown to attenuate neuronal injury in a murine model of spinal cord ischemia-reperfusion. In the brain, α-2 agonists have been shown to induce the phosphorylation of cyclic AMP response-element binding protein (CREB), a transcription factor necessary for neuron survival. We hypothesized that the α-2a adrenergic agonist given preoperatively increases CREB-mediated neuroprotective proteins, attenuating neuronal injury and cytoarchitectural decay. Mice (ie, C57BL/6 mice) underwent 5 minutes of aortic occlusion via median sternotomy. Mice received 25 μg/kg dexmedetomidine or equivalent normal saline at 24 hours, 12 hours, and 30 minutes preoperatively. Functional outcomes were recorded at 6 to 48 hours postoperatively when spinal cords were removed for histologic analysis. Spinal cords were examined for protein kinase B, CREB, B-cell lymphoma 2, and brain-derived neurotrophic factor following treatment alone or ischemia-reperfusion surgery. Following aortic occlusion, mice in the treatment group had preserved neurologic function at all time points (P < .05). Histologic analysis showed preserved cytoarchitecture and decreased neuronal injury in the treatment group when compared with ischemic controls. Additionally, analysis of spinal cord homogenate following surgery and pretreatment revealed a significant (P < .05) increase in B-cell lymphoma 2 and brain-derived neurotrophic factor expression and protein kinase B and CREB phosphorylation with α-2a adrenergic agonist pretreatment. Pretreatment with the α-2a agonist dexmedetomidine preserved neurologic function and attenuated neuronal injury following thoracic aortic occlusion in mice. This relationship was associated with an increased phosphorylation of protein kinase B and CREB and subsequent up-regulation of antiapoptotic factor B-cell lymphoma 2 and brain-derived neurotrophic factor. Thus, α-2a receptor agonism-induced CREB phosphorylation and contributes to dexmedetomidine's protective mechanism in the spinal cord following ischemia.
    The Journal of thoracic and cardiovascular surgery 09/2013; · 3.41 Impact Factor
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    ABSTRACT: Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia-reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia-reperfusion injury after aortic occlusion results from TLR-4-mediated microglial activation in mice. TLR-4 mutant and wild-type mice underwent aortic occlusion for 5 minutes, followed by 60 hours of reperfusion when spinal cords were removed for analysis. Spinal cord cytokine production and microglial activation were assessed at 6 and 36 hours after surgery. Isolated microglia from mutant and wild-type mice were subjected to oxygen and glucose deprivation for 24 hours, after which the expression of TLR-4 and proinflammatory cytokines was analyzed. Mice without functional TLR-4 demonstrated decreased microglial activation and cytokine production and had preserved functional outcomes and neuronal viability after thoracic aortic occlusion. After oxygen and glucose deprivation, wild-type microglia had increased TLR-4 expression and production of proinflammatory cytokines. The absence of functional TLR-4 attenuated neuronal injury and microglial activation after thoracic aortic occlusion in mice. Furthermore, microglial upregulation of TLR-4 occurred after oxygen and glucose deprivation, and the absence of functional TLR-4 significantly attenuated the production of proinflammatory cytokines. In conclusion, TLR-4-mediated microglia activation in the spinal cord after aortic occlusion is critical in the mechanism of paraplegia after aortic cross-clamping and may provide targets for pharmacological intervention.
    Circulation 09/2013; 128(26 Suppl 1):S152-6. · 15.20 Impact Factor
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    ABSTRACT: Risk of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) is high, yet the effectiveness of guideline-recommended preoperative prophylaxis in clinical practice remains uncertain. We determined the utilization and variation of preoperative AF prevention and assessed the comparative effectiveness of alternative drugs using the Society of Thoracic Surgeons multicenter Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) registry. Among 2,177 patients who underwent high-risk CABG and/or valve surgery, the mean age was 71 ± 9, 66% were men, 26% had chronic lung disease, and 21% had cerebrovascular disease. Overall use of AF prophylaxis was 84% and varied across sites (range 52% to 100%). The most common preventive agents were beta blockers (72%), followed by calcium antagonists (17%). Postoperatively, 30% (n = 646) developed AF at a median of 2 (25th to 75th percentiles: 1 to 3) days after surgery. Increasing age, height, white race, body mass index >35, New York Heart Association class IV heart failure, preoperative dialysis, and concomitant aortic valve replacement were associated with greater odds of postoperative AF (p <0.05 for all). Preoperative amiodarone use was associated with a trend to reduction of postoperative AF (26%, adjusted odds ratio 0.72 [95% confidence interval 0.51 to 1.00], p = 0.052). After adjustment, the odds of postoperative AF were not statistically different across agents. In conclusion, use of AF prophylaxis before surgery varied significantly. In this high-risk population, we were unable to demonstrate that any of the commonly used preventive agents were associated with lower rates of AF compared with alternatives or no treatment.
    The American journal of cardiology 07/2013; · 3.58 Impact Factor
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    ABSTRACT: Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation. Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 μg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. Functional scoring was done at 6 hours following surgery and 12-hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly attenuated microglial activation and proinflammatory cytokine production in vitro with a greater than twofold reduction in tumor necrosis factor-α. Alpha 2a agonist, dexmedetomidine treatment at reperfusion preserved neurologic function and neuronal viability. Furthermore, dexmedetomidine treatment resulted in an attenuation of microglial activation and proinflammatory cytokine production both in vivo and in vitro following LPS stimulation. This finding lends insight into the mechanism of paralysis following thoracic aortic interventions and may guide future pharmacologic targets for attenuating spinal cord ischemia and reperfusion.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 07/2013; · 3.52 Impact Factor
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    ABSTRACT: BACKGROUND: Mechanisms of inflammation have been implicated in the pathogenesis of aortic stenosis. When stimulated, human aortic valve interstitial cells (AVICs) have been shown to become inflammatory cells. Increased levels of interleukin (IL)-1β have been found in the leaflets of stenotic aortic valves. The purpose of this study was to determine the effects of IL-1β on isolated human AVICs and to determine the intracellular signaling pathway by which the effects are mediated. The results of this study demonstrated that IL-1β induces an inflammatory phenotype in human AVICs. METHODS: Human AVICs were isolated from normal aortic valves from explanted hearts of patients undergoing cardiac transplantation (n = 4) and grown in culture. When grown to confluence, the cells were treated with IL-1β (10 ng/mL). Cell culture media was analyzed for IL-6, IL-8, and monocyte chemoattractant protein-1 (enzyme-linked immunosorbent assay). Cell lysates were analyzed for intercellular adhesion molecule-1 (immunoblot). Inhibition of nuclear factor-κβ was by Bay 11-7085 (5 μM). Inhibition of extracellular signal regulated kinase-1/2 was by PD098059 (20 nM). Statistics were by analysis of variance, with p less than 0.05 significant. RESULTS: Interluekin-1β induced an inflammatory phenotype in human AVICs. The IL-1β stimulation resulted in significantly increased production of the inflammatory cytokines, IL-6 and IL-8, the chemokine monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. Inhibition of nuclear factor-κβ prevented these changes, whereas inhibition of extracellular signal regulated kinase-1/2 had no effect. CONCLUSIONS: Interleukin-1β induced an inflammatory phenotype in human AVICs, which was prevented by inhibition of nuclear factor-κβ. These data implicate IL-1β in the pathogenesis of aortic stenosis.
    The Annals of thoracic surgery 06/2013; · 3.45 Impact Factor
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    ABSTRACT: The aortic valve interstitial cell (AVIC) has been implicated in the pathogenesis of calcific aortic stenosis. When appropriately stimulated, AVICs undergo a phenotypic change from that of a myofibroblast to that of a bone-forming-like cell. An elevated blood level of low-density lipoprotein (LDL) cholesterol is a clinical risk factor for aortic stenosis, and oxidized LDL (ox-LDL) cholesterol has been consistently found in calcified aortic valve leaflets. However, whether it plays a role in the pathogenesis of aortic stenosis is unknown. The process of aortic valve leaflet calcification has been associated with the deposition of calcium phosphate, mediated in part by the phosphate inorganic transporter 1 (PiT-1), a sodium-phosphate ion cotransporter. Therefore, we hypothesized that ox-LDL induces an osteogenic change in human AVICs marked by the induction of PiT-1. Using isolated human AVICs, the purpose of the present study was to examine the effect of ox-LDL on the expression of PiT-1 and the osteogenic factor bone morphogenetic protein 2 (BMP-2), which is a protein necessary for bone formation. Human AVICs were isolated from nonstenotic aortic valves obtained from the explanted hearts of patients undergoing cardiac transplantation (n = 4) and grown in culture. The cells were treated with serum-free media, serum-free media with dimethyl sulfoxide (vehicle control), 40 μg/mL of ox-LDL, or 40 μg/mL of ox-LDL plus 2.5 mM phosphonoformate hexahydrate acid. Phosphonoformate hexahydrate acid is a competitive inhibitor of PiT-1 by mimicking inorganic phosphate. Cell lysis was performed at 24 h after treatment. Cell lysates were analyzed using immunoblot and densitometry for PiT-1 and BMP-2. Statistical analysis was performed using analysis of variance. P < 0.05 was significant. ox-LDL stimulation of AVICs induced an increase in PiT-1 and BMP-2. ox-LDL induced increased production of the phosphate transporter, PiT-1, and the osteogenic factor, BMP-2. Inhibition of PiT-1 with phosphonoformate hexahydrate acid prevented ox-LDL-induced BMP-2 expression. These data offer mechanistic insight into the pathogenesis of calcific aortic stenosis.
    Journal of Surgical Research 05/2013; · 2.02 Impact Factor
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    ABSTRACT: OBJECTIVE: Calcific aortic valve disease is a leading cardiovascular disease in the elderly, and progressive calcification results in the failure of valvular function. Aortic valve interstitial cells (AVICs) from stenotic valves express higher levels of bone morphogenetic protein-2 in response to Toll-like receptor 4 stimulation. We recently found that Toll-like receptor 4 interacts with Notch1 in human AVICs. This study tests the hypothesis that Notch1 promotes the pro-osteogenic response of human AVICs. APPROACH AND RESULTS: AVICs isolated from diseased human valves expressed higher levels of bone morphogenetic protein-2 and alkaline phosphatase after lipopolysaccharide stimulation. The augmented pro-osteogenic response is associated with elevated cellular levels of Notch1 and enhanced Notch1 cleavage in response to lipopolysaccharide stimulation. Inhibition or silencing of Notch1 suppressed the pro-osteogenic response in diseased cells, and the Notch 1 ligand, Jagged1, enhanced the response in AVICs isolated from normal human valves. Interestingly, ERK1/2 and nuclear factor-κB phosphorylation induced by lipopolysaccharide was markedly reduced by inhibition or silencing of Notch1 and enhanced by Jagged1. Inhibition of ERK1/2 or nuclear factor-κB also reduced bone morphogenetic protein-2 and alkaline phosphatase expression induced by lipopolysaccharide. CONCLUSIONS: Notch1 mediates the pro-osteogenic response to Toll-like receptor 4 stimulation in human AVICs. Elevated Notch1 levels and enhanced Notch1 activation play a major role in augmentation of the pro-osteogenic response of AVICs of stenotic valves through modulation of ERK1/2 and nuclear factor-κB activation. These pathways could be potential therapeutic targets for prevention of the progression of calcific aortic valve disease.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2013; · 6.34 Impact Factor
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    ABSTRACT: BACKGROUND: Traditionally, cardiothoracic residency programs are 2 or 3 years in length and require the completion of a general surgery residency. Six-year integrated programs (IP) that directly match fourth-year medical students have been recently developed. Our objective was to examine the curricula of traditional 2-year (T2) and 3-year (T3) programs and compare them to the curricula of IP. METHODS: We requested curricula from the directors of all IP, T2, and T3 programs participating in the 2011 to 2012 match. We compared the median number of months spent on a cardiothoracic (CT) rotation, an adult cardiac rotation, a thoracic rotation, and a congenital rotation, as well as time spent on "other" nonsurgical rotations. Traditional programs were categorized into 1 of 3 pathways: combined cardiothoracic (CCT), adult cardiac (AC), or general thoracic (GT). RESULTS: Integrated programs spend more time on general thoracic rotations when compared with CCT-T2, CCT-T3, AC-T2, and AC-T3 pathways (p = 0.009, p = 0.046, p = 0.001 and p = 0.028, respectively). The IP spend a similar amount of time on CT, adult cardiac, and congenital rotations when compared when 2- and 3-year CCT, AC, and GT pathways. Of note, IP spend significantly more time on "other" nonsurgical rotations than all other pathways (p < 0.001 to 0.008). CONCLUSIONS: Integrated programs should not be considered "cardiac pathways" as they spend a significant amount of time on thoracic rotations. Additional nonsurgical rotations provide an opportunity for residents in IP to develop unique skills not currently provided in traditional programs.
    The Annals of thoracic surgery 04/2013; · 3.45 Impact Factor

Publication Stats

2k Citations
592.36 Total Impact Points

Institutions

  • 1991–2014
    • University of Colorado
      • • Division of Cardiothoracic Surgery
      • • Department of Surgery
      Denver, Colorado, United States
  • 1999–2002
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1997–2002
    • Northwestern University
      • • Division of Thoracic Surgery
      • • Feinberg Cardiovascular Research Institute
      Evanston, IL, United States
  • 1993–1996
    • Wolfson Childrens Hospital
      Jacksonville, Florida, United States
  • 1990–1993
    • Loma Linda University
      • Department of Cardiovascular and Thoracic Surgery
      Loma Linda, CA, United States
  • 1992
    • Riley Hospital for Children
      Indianapolis, Indiana, United States