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Molecular imaging of spinal cord inflammation following thoracic aortic ischemia reperfusion injury
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Scientific Papers: 2014 Clinical Congress
requiring reintervention, amputation rates were lowest in the OVI first-OVI second group (3.1%) and highest in the PVIOVI group (10.2%) (Fisher’s Exact 1-sided p¼0.0391, 2-sided p¼0.0539). Death rates were also lowest in OVI-OVI (1.0%) and highest in PVI-OVI (4.6%) (Fisher’s Exact Test 1-sided p¼0.1329, 2-sided p¼0.2159). When controlling for patient factors and treatment path in multivariable analysis, only Hispanic ethnicity (vs Non-Hispanic) was predictive for amputation (odds ratio 3.278, 95% CI 1.318-8.149, p¼0.0106). CONCLUSIONS: Our findings suggest that OVI-first patients have lower rates of reintervention and that the reintervention treatment pathway optimizing both survival and amputation-free survival is OVI-OVI. The impact of an Enhanced Recovery After Surgery (ERAS) program in elective retroperitoneal abdominal aortic aneurism repair Carlo Feo, MD, FACS, Mattia Portinari, MD, Elpiniki Tsolaki, MD, PhD, Giovanni GR Romagnoni, MD, Simone Targa, MD, Lucia Braccini, MD, Marco Verri, MD, Stefano Camerani, MD, Carlo A Volta, MD, Francesco Mascoli, MD University of Ferrara, Ferrara, Italy INTRODUCTION: Enhanced Recovery After Surgery (ERAS) programs have been shown to reduce time to full enteral feeding, postoperative medical morbidity, and postoperative hospital length of stay (LOS) in elective abdominal aortic aneurism (AAA) repair. The purpose of this historical cohort study was to evaluate the impact of an ERAS protocol applied to patients undergoing elective retroperitoneal AAA repair. METHODS: An ERAS protocol based upon opioid sparing anesthesia-analgesia (thoracic epidural), early oral feeding and enforced mobilization was applied to patients undergoing elective retroperitoneal AAA repair since 2008. All patients (N¼130) operated on in 2008-2013 (ERAS group) were compared to all patients (N¼91) who underwent elective retroperitoneal AAA repair at the same institution in 2005-2007 (control group), before the introduction of ERAS methodology. Data were analyzed by intention to treat, using the chi-square, ANOVA, and Mann-Whitney tests as appropriate. P 0.05 was considered significant.
J Am Coll Surg
TGF-beta/Smad3-induced CXCR4 expression in injured arterial wall promotes intimal hyperplasia Lian-Wang Guo, PhD, Xudong Shi, MD, PhD, Stephen Seedial, Toshio Takayama, MD, PhD, Bowen Wang, BS, Sarah Franco, BS, Daniel DiRenzo, PhD, K Craig Kent, MD University of Wisconsin, Madison, WI INTRODUCTION: It has been demonstrated that upon arterial injury apoptotic cells in the subintimal space produce stromal cell-derived factor-1 (SDF-1alpha), which attracts bone marrowderived, CXCR4-expressing progenitor cells to the arterial wall contributing to intimal hyperplasia (IH). It remains unknown, however, whether locally induced CXCR4 expression in smooth muscle cells (SMCs) plays an important role in neointima formation. Here, we are the first to report that up-regulated TGFbeta/ Smad3 stimulates CXCR4 expression in injured arterial wall which contributes to IH. METHODS: Smad3 was elevated in SMCs via adenoviral expression. mRNA and protein levels of CXCR4 were determined by quantitative RT-PCR and Western blotting, respectively. SMC migration was measured using Transwell assay. The binding of Smad3 to the CXCR4 promoter was determined by chromatin immunoprecipitation assay. Selective depletion of CXCR4 in the arterial wall was achieved by crossing SM22-specific Cre and CXCR4-floxed mice. RESULTS: We found that compared to the control of GFPexpressing SMCs, TGFbetabtreatment of Smad3-expressing SMCs greatly stimulated CXCR4 expression (mRNA, 20 fold; protein, 3 fold) and Smad3 binding to the CXCR4 promoter, SMC migration toward SDF-1alphaa (but not SMC proliferation), and SDF-1alpha-initiated ERK1/2 phosphorylation. Application of a CXCR4-specific inhibitor abolished these effects. While elevated Smad3 enhanced CXCR4 expression and IH in balloon-injured rat carotid arteries, depleting CXCR4 specifically in medial SMCs reduced IH by 60% (0.290.08 vs 0.740.13) in wireinjured mouse femoral arteries. CONCLUSIONS: Our data together suggest that up-regulation of TGFbeta/Smad3 in injured arteries induces CXCR4 expression locally in SMCs which stimulates SMC migration toward SDF1alpha in the neointima and promotes IH.
RESULTS: Demographics and ASA score distribution were comparable in-between groups. No difference could be detected in readmission rate 30 days (0 vs 3%, p¼0.07). Outcome variables in between groups were as follows [Median (IQR 25-75)]:
Molecular imaging of spinal cord inflammation following thoracic aortic ischemia reperfusion injury Hassan Albadawi, MD, John W Chen, MD, PhD, Rahmi Oklu, MD, PhD, Gregory R Wojtkiewicz, MS, Richard P Cambria, MD, Michael T Watkins, MD Massachusetts General Hospital, Boston, MA
CONCLUSIONS: ERAS program in elective retroperitoneal AAA surgical repair significantly reduced morbidity, ICU admission and LOS, functional recovery, and postoperative LOS with no increase neither in mortality nor in the readmission rate.
INTRODUCTION: Paraplegia is an unpredictable complication following surgical reconstruction of the thoracic aorta. Animal models of ischemic spinal cord injury indicate that paraplegia is preceded by inflammation in the cord but to date; this inflammation has not been detected without direct tissue biopsy. Myeloperoxidase (MPO) is a key inflammatory mediator following tissue
Vol. 219, No. 4S, October 2014
injury. These studies were designed to determine whether noninvasive molecular imaging using single photon emission computed tomography and computed tomography (SPECT-CT) using the 111Indium-labeled MPO sensitive sensor can detect MPO activity following spinal cord ischemic injury in a mouse model of thoracic aorta ischemia reperfusion (TAR). METHODS: C57BL6 mice were subjected to 8 minutes TAR at 37 C. At 6 and 24 hours following TAR, SPECT-CT was performed following injection of the MPO sensor 111Indium-bis-5HT-DTPA. Spinal cord tissue inflammation was evaluated in the T11-L5 cord segment for MPO and the inflammatory cells markers Iba-1 and Ly6B using immunohistochemistry. Statistical significance for MPO sensor retention was measured as counts/minute (CPM).
Scientific Papers: 2014 Clinical Congress
e59
RESULTS: TAR resulted in paraplegia after reperfusion which persisted at 24 hours. MPO sensor retention in the thoracolumbar cord was significantly elevated at 6hrs (35555CPM, n¼5) and 24hrs (533126CPM, n¼5) following TAR, compared to sham (13.6 5CPM, n¼5, p<0.05). Histological evaluation revealed few detectable granulocytes, enhanced Iba-1 expression and increased MPO detection indicating increased microglia activation in the spinal cord tissue.
CONCLUSIONS: Increased MPO activity following TAR is associated with local microglia cell lineage activation and minimal neutrophil granulocytes recruitment. SPECT-CT is a useful imaging modality to detect early spinal cord inflammation following TAR.
Scientific Papers: 2014 Clinical Congress
requiring reintervention, amputation rates were lowest in the OVI first-OVI second group (3.1%) and highest in the PVIOVI group (10.2%) (Fisher’s Exact 1-sided p¼0.0391, 2-sided p¼0.0539). Death rates were also lowest in OVI-OVI (1.0%) and highest in PVI-OVI (4.6%) (Fisher’s Exact Test 1-sided p¼0.1329, 2-sided p¼0.2159). When controlling for patient factors and treatment path in multivariable analysis, only Hispanic ethnicity (vs Non-Hispanic) was predictive for amputation (odds ratio 3.278, 95% CI 1.318-8.149, p¼0.0106). CONCLUSIONS: Our findings suggest that OVI-first patients have lower rates of reintervention and that the reintervention treatment pathway optimizing both survival and amputation-free survival is OVI-OVI. The impact of an Enhanced Recovery After Surgery (ERAS) program in elective retroperitoneal abdominal aortic aneurism repair Carlo Feo, MD, FACS, Mattia Portinari, MD, Elpiniki Tsolaki, MD, PhD, Giovanni GR Romagnoni, MD, Simone Targa, MD, Lucia Braccini, MD, Marco Verri, MD, Stefano Camerani, MD, Carlo A Volta, MD, Francesco Mascoli, MD University of Ferrara, Ferrara, Italy INTRODUCTION: Enhanced Recovery After Surgery (ERAS) programs have been shown to reduce time to full enteral feeding, postoperative medical morbidity, and postoperative hospital length of stay (LOS) in elective abdominal aortic aneurism (AAA) repair. The purpose of this historical cohort study was to evaluate the impact of an ERAS protocol applied to patients undergoing elective retroperitoneal AAA repair. METHODS: An ERAS protocol based upon opioid sparing anesthesia-analgesia (thoracic epidural), early oral feeding and enforced mobilization was applied to patients undergoing elective retroperitoneal AAA repair since 2008. All patients (N¼130) operated on in 2008-2013 (ERAS group) were compared to all patients (N¼91) who underwent elective retroperitoneal AAA repair at the same institution in 2005-2007 (control group), before the introduction of ERAS methodology. Data were analyzed by intention to treat, using the chi-square, ANOVA, and Mann-Whitney tests as appropriate. P 0.05 was considered significant.
J Am Coll Surg
TGF-beta/Smad3-induced CXCR4 expression in injured arterial wall promotes intimal hyperplasia Lian-Wang Guo, PhD, Xudong Shi, MD, PhD, Stephen Seedial, Toshio Takayama, MD, PhD, Bowen Wang, BS, Sarah Franco, BS, Daniel DiRenzo, PhD, K Craig Kent, MD University of Wisconsin, Madison, WI INTRODUCTION: It has been demonstrated that upon arterial injury apoptotic cells in the subintimal space produce stromal cell-derived factor-1 (SDF-1alpha), which attracts bone marrowderived, CXCR4-expressing progenitor cells to the arterial wall contributing to intimal hyperplasia (IH). It remains unknown, however, whether locally induced CXCR4 expression in smooth muscle cells (SMCs) plays an important role in neointima formation. Here, we are the first to report that up-regulated TGFbeta/ Smad3 stimulates CXCR4 expression in injured arterial wall which contributes to IH. METHODS: Smad3 was elevated in SMCs via adenoviral expression. mRNA and protein levels of CXCR4 were determined by quantitative RT-PCR and Western blotting, respectively. SMC migration was measured using Transwell assay. The binding of Smad3 to the CXCR4 promoter was determined by chromatin immunoprecipitation assay. Selective depletion of CXCR4 in the arterial wall was achieved by crossing SM22-specific Cre and CXCR4-floxed mice. RESULTS: We found that compared to the control of GFPexpressing SMCs, TGFbetabtreatment of Smad3-expressing SMCs greatly stimulated CXCR4 expression (mRNA, 20 fold; protein, 3 fold) and Smad3 binding to the CXCR4 promoter, SMC migration toward SDF-1alphaa (but not SMC proliferation), and SDF-1alpha-initiated ERK1/2 phosphorylation. Application of a CXCR4-specific inhibitor abolished these effects. While elevated Smad3 enhanced CXCR4 expression and IH in balloon-injured rat carotid arteries, depleting CXCR4 specifically in medial SMCs reduced IH by 60% (0.290.08 vs 0.740.13) in wireinjured mouse femoral arteries. CONCLUSIONS: Our data together suggest that up-regulation of TGFbeta/Smad3 in injured arteries induces CXCR4 expression locally in SMCs which stimulates SMC migration toward SDF1alpha in the neointima and promotes IH.
RESULTS: Demographics and ASA score distribution were comparable in-between groups. No difference could be detected in readmission rate 30 days (0 vs 3%, p¼0.07). Outcome variables in between groups were as follows [Median (IQR 25-75)]:
Molecular imaging of spinal cord inflammation following thoracic aortic ischemia reperfusion injury Hassan Albadawi, MD, John W Chen, MD, PhD, Rahmi Oklu, MD, PhD, Gregory R Wojtkiewicz, MS, Richard P Cambria, MD, Michael T Watkins, MD Massachusetts General Hospital, Boston, MA
CONCLUSIONS: ERAS program in elective retroperitoneal AAA surgical repair significantly reduced morbidity, ICU admission and LOS, functional recovery, and postoperative LOS with no increase neither in mortality nor in the readmission rate.
INTRODUCTION: Paraplegia is an unpredictable complication following surgical reconstruction of the thoracic aorta. Animal models of ischemic spinal cord injury indicate that paraplegia is preceded by inflammation in the cord but to date; this inflammation has not been detected without direct tissue biopsy. Myeloperoxidase (MPO) is a key inflammatory mediator following tissue
Vol. 219, No. 4S, October 2014
injury. These studies were designed to determine whether noninvasive molecular imaging using single photon emission computed tomography and computed tomography (SPECT-CT) using the 111Indium-labeled MPO sensitive sensor can detect MPO activity following spinal cord ischemic injury in a mouse model of thoracic aorta ischemia reperfusion (TAR). METHODS: C57BL6 mice were subjected to 8 minutes TAR at 37 C. At 6 and 24 hours following TAR, SPECT-CT was performed following injection of the MPO sensor 111Indium-bis-5HT-DTPA. Spinal cord tissue inflammation was evaluated in the T11-L5 cord segment for MPO and the inflammatory cells markers Iba-1 and Ly6B using immunohistochemistry. Statistical significance for MPO sensor retention was measured as counts/minute (CPM).
Scientific Papers: 2014 Clinical Congress
e59
RESULTS: TAR resulted in paraplegia after reperfusion which persisted at 24 hours. MPO sensor retention in the thoracolumbar cord was significantly elevated at 6hrs (35555CPM, n¼5) and 24hrs (533126CPM, n¼5) following TAR, compared to sham (13.6 5CPM, n¼5, p<0.05). Histological evaluation revealed few detectable granulocytes, enhanced Iba-1 expression and increased MPO detection indicating increased microglia activation in the spinal cord tissue.
CONCLUSIONS: Increased MPO activity following TAR is associated with local microglia cell lineage activation and minimal neutrophil granulocytes recruitment. SPECT-CT is a useful imaging modality to detect early spinal cord inflammation following TAR.