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Eph-B4 activation reduces neointimal hyperplasia in human saphenous vein
VASCULAR SURGERY II Eph-B4 activation reduces neointimal hyperplasia in human saphenous vein Daniel Wong, BA, Kota Yamamoto, MD, PhD, Clinton D Protack, MD, Michael Hall, MD, Daniel Lu, BS, Willis T Williams, MD, Roland Assi, MD, Nirvana Sadaghianloo, MD, Hualong Bai, MD, Alan Dardik, MD, PhD, FACS Yale School of Medicine, New Haven, CT
Mortality rates of patients with peripheral arterial disease are predicted by the respiratory activities of gastrocnemius mitochondrial complexes I and IV Jonathan Robert Thompson, MD*, Stanley A Swanson, BS, Gleb Haynatzki, PhD, George P Casale, PhD, Jason M Johanning, MD, FACS, Evlampia Papoutsi, BS, Panagiotis Koutakis, MS, Dimitrios Miserlis, MD, Zhen Zhu, MD, Iraklis I Pipinos, MD, PhD, FACS University of Nebraska Medical Center, Omaha, NE INTRODUCTION: Features of peripheral arterial disease (PAD) include advancing myopathy and mitochondrial dysfunction in the ischemic leg of the patient. We have shown that protein concentration and mitochondrial content in the gastrocnemius of PAD patients predicts mortality. In the present study, we tested the hypothesis that respiratory activity of individual mitochondrial electron transport chain (ETC) complexes (I, II, III, and IV) in the gastrocnemius of PAD patients predicts mortality. METHODS: Gastrocnemius biopsies were obtained from PAD patients (N¼187) and the respiratory activity of each ETC complex (I through IV) was determined and normalized to muscle wet weight and citrate synthase activity (standard measure of cellular mitochondrial content). Patient data, including demographic and clinical characteristics and date of last known contact or death, were collected. For each complex, respiratory activities were grouped into tertiles from lowest (1st tertile) to highest (3rd tertile) and hazard ratios were determined by Cox multivariate regression analysis, adjusted for all demographic and clinical characteristics. RESULTS: Of the 187 patients, 38 were deceased with a mean follow-up of 23.0 months. Hazard-Ratio’s were statistically significant (Table) for mitochondrial complex I normalized to muscle weight (1st tertile; highest mortality) and mitochondrial complex IV normalized to both muscle weight and citrate synthase (3rd tertile; highest mortality).
1st tertile
Hazard ratio 2nd tertile
3rd tertile
METHODS: Excess saphenous vein was obtained from patients undergoing bypass surgery. Vein rings were cultured for 14 days with Ephrin-B2/Fc at a concentration of 1-2 ug/ml. Each ring was compared to its matched control for development of intimal hyperplasia and quantitative RT-PCR was performed to assess gene expression. Human umbilical vein endothelial cells were treated with Ephrin-B2/Fc and receptor phosphorylation was detected with western blot. RESULTS: Ephrin-B2/Fc treatment caused a significant increase in Eph-B4 phosphorylation in venous endothelial cells (n¼3). Treatment of vein rings in culture with ephrin-B2/Fc led to an average 44.3% (95% CI -11.6, 98.5 n¼7) reduction in intima:media ratios. Eph-B4 and ephrin-B2 gene expression levels significantly decreased and osteopontin increased in both treated and untreated rings (n¼7). CONCLUSIONS: The Eph-B4 signaling pathway is active in human venous cells and stimulation of Eph-B4 in vitro leads to reduced neoimtimal hyperplasia in saphenous vein rings. Stimulation of the Eph-B4 pathway may be a promising candidate for a clinical trial to reduce vein graft neointimal hyperplasia.
p Value
Complex I/muscle 1.00g weight 3.04*g 1.20* (reference) *0.04, g0.02 Complex IV/muscle 1.00* weight (reference) 2.13 3.24* *0.02 Complex IV/citrate 1.00g *0.004, g synthase 1.84* (reference) 6.41*g 0.0003 CONCLUSIONS: Survival analysis of a contemporaneous population of PAD patients identified relatively low respiratory activity of mitochondrial complex I and relatively high activity of complex IV, in the gastrocnemius, as predictors of increased mortality, independent of other demographic and clinical characteristics.
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
INTRODUCTION: Neointimal hyperplasia is the leading cause of vein graft failure. Interventions aimed at inhibiting smooth muscle proliferation have not succeeded in human studies. Eph-B4 induces venous identity and its expression is lost during venous adaptation. Previous studies have demonstrated that exogenous stimulation of Eph-B4 with its ligand Ephrin-B2 retains venous identity and reduces neointimal hyperplasia during murine vein graft adaptation. However, it is not known whether this pathway is active and can be manipulated in human vein grafts.
Characterization of readmissions after major vascular procedures Mila H Ju, MD, Ryan P Merkow, MD, MS, Mark K Eskandari, MD, FACS, Clifford Y Ko, MD, MSHS, MS, FACS, Karl Y Bilimoria, MD, MS Northwestern University, Chicago, IL INTRODUCTION: Readmission has become a focus of pay-forperformance programs. Vascular surgery patients are frequently readmitted, but baseline and comparative data are unavailable to hospitals specifically for vascular surgery. Our objectives were (1) to characterize readmission rates among major vascular procedures, (2) to identify reasons for unplanned readmissions, and (3) to assess variation in hospital performance.
S158
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.07.372
Mortality rates of patients with peripheral arterial disease are predicted by the respiratory activities of gastrocnemius mitochondrial complexes I and IV Jonathan Robert Thompson, MD*, Stanley A Swanson, BS, Gleb Haynatzki, PhD, George P Casale, PhD, Jason M Johanning, MD, FACS, Evlampia Papoutsi, BS, Panagiotis Koutakis, MS, Dimitrios Miserlis, MD, Zhen Zhu, MD, Iraklis I Pipinos, MD, PhD, FACS University of Nebraska Medical Center, Omaha, NE INTRODUCTION: Features of peripheral arterial disease (PAD) include advancing myopathy and mitochondrial dysfunction in the ischemic leg of the patient. We have shown that protein concentration and mitochondrial content in the gastrocnemius of PAD patients predicts mortality. In the present study, we tested the hypothesis that respiratory activity of individual mitochondrial electron transport chain (ETC) complexes (I, II, III, and IV) in the gastrocnemius of PAD patients predicts mortality. METHODS: Gastrocnemius biopsies were obtained from PAD patients (N¼187) and the respiratory activity of each ETC complex (I through IV) was determined and normalized to muscle wet weight and citrate synthase activity (standard measure of cellular mitochondrial content). Patient data, including demographic and clinical characteristics and date of last known contact or death, were collected. For each complex, respiratory activities were grouped into tertiles from lowest (1st tertile) to highest (3rd tertile) and hazard ratios were determined by Cox multivariate regression analysis, adjusted for all demographic and clinical characteristics. RESULTS: Of the 187 patients, 38 were deceased with a mean follow-up of 23.0 months. Hazard-Ratio’s were statistically significant (Table) for mitochondrial complex I normalized to muscle weight (1st tertile; highest mortality) and mitochondrial complex IV normalized to both muscle weight and citrate synthase (3rd tertile; highest mortality).
1st tertile
Hazard ratio 2nd tertile
3rd tertile
METHODS: Excess saphenous vein was obtained from patients undergoing bypass surgery. Vein rings were cultured for 14 days with Ephrin-B2/Fc at a concentration of 1-2 ug/ml. Each ring was compared to its matched control for development of intimal hyperplasia and quantitative RT-PCR was performed to assess gene expression. Human umbilical vein endothelial cells were treated with Ephrin-B2/Fc and receptor phosphorylation was detected with western blot. RESULTS: Ephrin-B2/Fc treatment caused a significant increase in Eph-B4 phosphorylation in venous endothelial cells (n¼3). Treatment of vein rings in culture with ephrin-B2/Fc led to an average 44.3% (95% CI -11.6, 98.5 n¼7) reduction in intima:media ratios. Eph-B4 and ephrin-B2 gene expression levels significantly decreased and osteopontin increased in both treated and untreated rings (n¼7). CONCLUSIONS: The Eph-B4 signaling pathway is active in human venous cells and stimulation of Eph-B4 in vitro leads to reduced neoimtimal hyperplasia in saphenous vein rings. Stimulation of the Eph-B4 pathway may be a promising candidate for a clinical trial to reduce vein graft neointimal hyperplasia.
p Value
Complex I/muscle 1.00g weight 3.04*g 1.20* (reference) *0.04, g0.02 Complex IV/muscle 1.00* weight (reference) 2.13 3.24* *0.02 Complex IV/citrate 1.00g *0.004, g synthase 1.84* (reference) 6.41*g 0.0003 CONCLUSIONS: Survival analysis of a contemporaneous population of PAD patients identified relatively low respiratory activity of mitochondrial complex I and relatively high activity of complex IV, in the gastrocnemius, as predictors of increased mortality, independent of other demographic and clinical characteristics.
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
INTRODUCTION: Neointimal hyperplasia is the leading cause of vein graft failure. Interventions aimed at inhibiting smooth muscle proliferation have not succeeded in human studies. Eph-B4 induces venous identity and its expression is lost during venous adaptation. Previous studies have demonstrated that exogenous stimulation of Eph-B4 with its ligand Ephrin-B2 retains venous identity and reduces neointimal hyperplasia during murine vein graft adaptation. However, it is not known whether this pathway is active and can be manipulated in human vein grafts.
Characterization of readmissions after major vascular procedures Mila H Ju, MD, Ryan P Merkow, MD, MS, Mark K Eskandari, MD, FACS, Clifford Y Ko, MD, MSHS, MS, FACS, Karl Y Bilimoria, MD, MS Northwestern University, Chicago, IL INTRODUCTION: Readmission has become a focus of pay-forperformance programs. Vascular surgery patients are frequently readmitted, but baseline and comparative data are unavailable to hospitals specifically for vascular surgery. Our objectives were (1) to characterize readmission rates among major vascular procedures, (2) to identify reasons for unplanned readmissions, and (3) to assess variation in hospital performance.
S158
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.07.372