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Decreased angiotensin converting enzyme expression and experimental abdominal aortic aneurysm formation
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ASSOCIATION FOR ACADEMIC SURGERY—ABSTRACTS
years) have undergone a total of 103 MVR operations. The etiology for valve disease was congenital in 55% of patients, rheumatic in 35%, endocarditis in 8%, and myxomatous in 2%. Xenograft bioprosthesis (n ⫽ 13) and mechanical valves (n ⫽ 58) were used in 71 patients at initial MVR. Since 2002, four patients have undergone MVR using a pulmonary autograft (Ross MVR). Results. Hospital mortality was 9%. Mean follow-up was 7.8 years (range; 2 months to 30 years). Twenty-three patients required reoperations (34%) after the initial MVR. Actuarial freedom from reoperation at 30 years was 47%. There were 16 late deaths and four patients underwent heart transplantation. Overall 30-year survival was 69%. Mortality for children under 2 years versus over 2 years was 47% versus 26% (P ⫽ 0.02), for atrioventricular septal defect versus other pathology mortality was 54% versus 26% (P ⫽ 0.05), and for those operated before versus after 1980 it was 57% versus 20% (P ⫽ 0.003). Conclusions. MVR is the only surgical option for nonrepairable mitral valve in children. Until recently we have favored mechanical MVR for children with failed reconstructive surgery. Our recent experience with the Ross MVR and aortic homograft MVR has allowed us to offer select patients the possibility of a more durable tissue valve without the need for long-term anticoagulation. The Ross MVR is particularly attractive in young female patients. P57. Aortic Gene Expression Profile of Ascending Aortic Aneurysms and Acute Ascending Aortic Dissections. X. Wang, MD, PhD, D. Senthil, PhD, Y.H. Shen, MD, PhD, B. Utama, PhD, M. Raveendran, PhD, J.A. Wilks, BA, S.A. Carter, BA, S.A. LeMaire, MD, J.S. Coselli, MD, X. Wang, MD, PhD. Baylor College of Medicine. Purpose. The pathogenesis of thoracic aortic aneurysms and aortic dissections remains poorly understood. Despite increasing investigation, concepts of thoracic aortic aneurysm and dissection pathogenesis still rely heavily on abdominal aortic aneurysm research. We sought to use microarray technology to delve further into molecular pathogenesis of thoracic aortic aneurysms and dissections. We hypothesized that aortic gene expression profiles would differ between ascending aneurysms and dissections. Methods. Intraoperative samples of ascending aorta were obtained during surgical repair of ascending aortic aneurysms and acute ascending aortic dissections (n ⫽ 2 each). Control samples of ascending aorta were obtained from two organ donors. Total RNA was extracted and combined for each group, and biotinylated cDNA probes were generated. The cDNA probes were subjected to GEArray Q series microarrays containing 192 known genes related to extracellular matrix biology, adhesion molecules, and endothelial cell biology. GEArray analysis software determined relative intensities compared to controls. Results. Compared to control tissue, 13 genes (including Enamelysin, Homo thrombospondin2, and Fibronectin1) were increased in both aneurysms and dissections. Seventeen genes were up regulated in the aneurysm group, 26 in the dissection group. Eleven genes were decreased in the aneurysm group, 10 in the dissection group. Comparing only the dissection group with the aneurysm group, 39 genes displayed much higher expression (more than 3-fold) in dissections compared to aneurysms, including Integrin alpha 8 and CD44 antigen. Conclusions. Aortic gene expression in ascending aneurysms and acute dissections differs significantly, suggesting that different pathological mechanisms may be involved. The data extracted from these cDNA arrays will be beneficial for selecting and investigating the roles of significantly altered genes in each disease. We are currently investigating functional roles of the differentially expressed genes in each of the aortic conditions. P58. Heart Failure Reduces the Interaction Between Cyclic GMP and Cyclic AMP. J. Moalem, MD, H.R. Weiss, PhD, T. Davidov, MD, R.R. Rodriguez, MD, B. Molino, MD, M.J. Lazar, MD, P.M. Scholz, MD. UMDNJ--Robert Wood Johnson Medical School.
We hypothesized that the negative functional effects of cyclic GMP (cGMP) are attenuated by cyclic AMP (cAMP) and this interaction is reduced in pacing-induced failure of hypertrophic hearts. 8-Bromocyclic-GMP (8Br) (2 g/kg/min) was infused into the left anterior descending artery (LAD) in eight control, eight ventricular hypertrophy (LVH), and eight pacing-induced failure (failure) dogs. After return to baseline, isoproterenol (0.1 g/kg/min) was infused, followed by 8Br. Regional myocardial work [force ⴱ segment shortening], and O 2 consumption (VO 2) [coronary blood flow ⴱ O 2 extraction] were measured. cGMP levels were determined by radioimmunoassay. 8Br decreased regional work from 3812 ⫾ 839 g ⴱ mm/min by 17% (P ⫽ 0.05) and VO 2 by 29% (P ⫽ 0.05) in control, but not in LVH (from 1073 ⫾ 182 by ⫺10%, VO 2 by ⫺16%) or failure (from 495 ⫾ 145 by ⫺9%, VO 2 by 0%). Isoproterenol increased work by 43% and VO2 by 48% in controls (P ⫽ 0.05) and in LVH (work by 54%, VO 2 by 39%; P ⫽ 0.05) but not in failure (work by ⫺28%, VO 2 by ⫺5%). Subsequently, 8Br had no effect on work or VO 2 in control (⫺2%, ⫺13%), LVH (⫺12%, ⫺30%), or failure (⫹13%, ⫹14%). cAMP levels were elevated by isoproterenol in control (381 ⫾ 115 pmol/g versus 553 ⫾ 199 pmol/g) and LVH (313 ⫾ 55 versus 486 ⫾ 227; P ⫽ 0.05), but not in failure (300 ⫾ 60 versus 284 ⫾ 126). After isoproterenol, 8Br further elevated cAMP in control (687 ⫾ 122; P ⫽ 0.05), but not in LVH or failure. In controls, cAMP attenuates cGMP’s negative functional and metabolic effects. This interaction is blunted in LVH and pacing-induced failure. P59. Decreased Angiotensin Converting Enzyme Expression and Experimental Abdominal Aortic Aneurysm Formation. M.J. Eagleton, MD, E. Lynch, BA, K. Hannawa, BS, C. Pearce, BA, D. Woodrum, MD, V. Grigoryants, MD, G.R. Upchurch, MD, J.C. Stanley, MD. University of Michigan. Introduction. Renin-angiotensin system components have been implicated in vessel wall remodeling, but their relevance to aneurysmal disease has not been defined. This study tested the hypothesis that aortic wall angiotensin and angiotensin II receptor 1 (AT1) up regulation occurs during experimental aneurysm formation, while angiotensin II receptor 2 (AT2) and angiotensin converting enzyme (ACE) are down regulated. Methods. Isolated infrarenal aortic segment in rats were perfused with saline (controls, N ⫽ 5) or porcine pancreatic elastase to induce aneurysms (N ⫽ 5). Seven days later, animals were sacrificed; aortic diameters were measured, and RNA was extracted from the perfused aortic segments. Real-time PCR was used to measure mRNA levels for angiotensin, ACE, AT1, and AT2 (normalized to B-actin). Results from control rats were compared with elastase perfused rats using the unpaired t-test. Results. Elastase perfusion produced mean aortic diameters of 4.07 ⫾ 0.28 mm, while saline controls had mean aortic diameters of 1.65 ⫾ 0.11 mm (P ⫽ 0.01). ACE mRNA levels were 16-fold lower in elastase-perfused animals compared with saline controls (P ⬍ 0.005). Trends toward elevated expression of angiotensin (2.5-fold increase) and AT1 (2.3-fold increase) within elastase perfused aortas existed, but did not reach statistical significance. Conclusions. Experimental aortic aneurysm formation in an elastase-perfused model is associated with the down regulation of aortic wall ACE expression and a trend toward increased expression of angiotensin and its primary receptor AT1. Further investigation into the mechanisms by which these proteins contribute to aneurysm formation in vivo is warranted. P60. Laparascopic Aortic Reinforcement and Endovascular Graft Replacement. T. Kudo, MD, PhD, K.K. Kao, BA, S.D. Nelson, MD, T.D. Reil, MD, J.L. Moy, BS, G.G. Altobelli, B.T. Haas, F.A. Chandra, C.R. Grasia, MD, S.S. Ahn, MD. UCLA Gonda Vascular Center, Department of Surgery, and Department of Pathology, Los Angeles, CA.
ASSOCIATION FOR ACADEMIC SURGERY—ABSTRACTS
years) have undergone a total of 103 MVR operations. The etiology for valve disease was congenital in 55% of patients, rheumatic in 35%, endocarditis in 8%, and myxomatous in 2%. Xenograft bioprosthesis (n ⫽ 13) and mechanical valves (n ⫽ 58) were used in 71 patients at initial MVR. Since 2002, four patients have undergone MVR using a pulmonary autograft (Ross MVR). Results. Hospital mortality was 9%. Mean follow-up was 7.8 years (range; 2 months to 30 years). Twenty-three patients required reoperations (34%) after the initial MVR. Actuarial freedom from reoperation at 30 years was 47%. There were 16 late deaths and four patients underwent heart transplantation. Overall 30-year survival was 69%. Mortality for children under 2 years versus over 2 years was 47% versus 26% (P ⫽ 0.02), for atrioventricular septal defect versus other pathology mortality was 54% versus 26% (P ⫽ 0.05), and for those operated before versus after 1980 it was 57% versus 20% (P ⫽ 0.003). Conclusions. MVR is the only surgical option for nonrepairable mitral valve in children. Until recently we have favored mechanical MVR for children with failed reconstructive surgery. Our recent experience with the Ross MVR and aortic homograft MVR has allowed us to offer select patients the possibility of a more durable tissue valve without the need for long-term anticoagulation. The Ross MVR is particularly attractive in young female patients. P57. Aortic Gene Expression Profile of Ascending Aortic Aneurysms and Acute Ascending Aortic Dissections. X. Wang, MD, PhD, D. Senthil, PhD, Y.H. Shen, MD, PhD, B. Utama, PhD, M. Raveendran, PhD, J.A. Wilks, BA, S.A. Carter, BA, S.A. LeMaire, MD, J.S. Coselli, MD, X. Wang, MD, PhD. Baylor College of Medicine. Purpose. The pathogenesis of thoracic aortic aneurysms and aortic dissections remains poorly understood. Despite increasing investigation, concepts of thoracic aortic aneurysm and dissection pathogenesis still rely heavily on abdominal aortic aneurysm research. We sought to use microarray technology to delve further into molecular pathogenesis of thoracic aortic aneurysms and dissections. We hypothesized that aortic gene expression profiles would differ between ascending aneurysms and dissections. Methods. Intraoperative samples of ascending aorta were obtained during surgical repair of ascending aortic aneurysms and acute ascending aortic dissections (n ⫽ 2 each). Control samples of ascending aorta were obtained from two organ donors. Total RNA was extracted and combined for each group, and biotinylated cDNA probes were generated. The cDNA probes were subjected to GEArray Q series microarrays containing 192 known genes related to extracellular matrix biology, adhesion molecules, and endothelial cell biology. GEArray analysis software determined relative intensities compared to controls. Results. Compared to control tissue, 13 genes (including Enamelysin, Homo thrombospondin2, and Fibronectin1) were increased in both aneurysms and dissections. Seventeen genes were up regulated in the aneurysm group, 26 in the dissection group. Eleven genes were decreased in the aneurysm group, 10 in the dissection group. Comparing only the dissection group with the aneurysm group, 39 genes displayed much higher expression (more than 3-fold) in dissections compared to aneurysms, including Integrin alpha 8 and CD44 antigen. Conclusions. Aortic gene expression in ascending aneurysms and acute dissections differs significantly, suggesting that different pathological mechanisms may be involved. The data extracted from these cDNA arrays will be beneficial for selecting and investigating the roles of significantly altered genes in each disease. We are currently investigating functional roles of the differentially expressed genes in each of the aortic conditions. P58. Heart Failure Reduces the Interaction Between Cyclic GMP and Cyclic AMP. J. Moalem, MD, H.R. Weiss, PhD, T. Davidov, MD, R.R. Rodriguez, MD, B. Molino, MD, M.J. Lazar, MD, P.M. Scholz, MD. UMDNJ--Robert Wood Johnson Medical School.
We hypothesized that the negative functional effects of cyclic GMP (cGMP) are attenuated by cyclic AMP (cAMP) and this interaction is reduced in pacing-induced failure of hypertrophic hearts. 8-Bromocyclic-GMP (8Br) (2 g/kg/min) was infused into the left anterior descending artery (LAD) in eight control, eight ventricular hypertrophy (LVH), and eight pacing-induced failure (failure) dogs. After return to baseline, isoproterenol (0.1 g/kg/min) was infused, followed by 8Br. Regional myocardial work [force ⴱ segment shortening], and O 2 consumption (VO 2) [coronary blood flow ⴱ O 2 extraction] were measured. cGMP levels were determined by radioimmunoassay. 8Br decreased regional work from 3812 ⫾ 839 g ⴱ mm/min by 17% (P ⫽ 0.05) and VO 2 by 29% (P ⫽ 0.05) in control, but not in LVH (from 1073 ⫾ 182 by ⫺10%, VO 2 by ⫺16%) or failure (from 495 ⫾ 145 by ⫺9%, VO 2 by 0%). Isoproterenol increased work by 43% and VO2 by 48% in controls (P ⫽ 0.05) and in LVH (work by 54%, VO 2 by 39%; P ⫽ 0.05) but not in failure (work by ⫺28%, VO 2 by ⫺5%). Subsequently, 8Br had no effect on work or VO 2 in control (⫺2%, ⫺13%), LVH (⫺12%, ⫺30%), or failure (⫹13%, ⫹14%). cAMP levels were elevated by isoproterenol in control (381 ⫾ 115 pmol/g versus 553 ⫾ 199 pmol/g) and LVH (313 ⫾ 55 versus 486 ⫾ 227; P ⫽ 0.05), but not in failure (300 ⫾ 60 versus 284 ⫾ 126). After isoproterenol, 8Br further elevated cAMP in control (687 ⫾ 122; P ⫽ 0.05), but not in LVH or failure. In controls, cAMP attenuates cGMP’s negative functional and metabolic effects. This interaction is blunted in LVH and pacing-induced failure. P59. Decreased Angiotensin Converting Enzyme Expression and Experimental Abdominal Aortic Aneurysm Formation. M.J. Eagleton, MD, E. Lynch, BA, K. Hannawa, BS, C. Pearce, BA, D. Woodrum, MD, V. Grigoryants, MD, G.R. Upchurch, MD, J.C. Stanley, MD. University of Michigan. Introduction. Renin-angiotensin system components have been implicated in vessel wall remodeling, but their relevance to aneurysmal disease has not been defined. This study tested the hypothesis that aortic wall angiotensin and angiotensin II receptor 1 (AT1) up regulation occurs during experimental aneurysm formation, while angiotensin II receptor 2 (AT2) and angiotensin converting enzyme (ACE) are down regulated. Methods. Isolated infrarenal aortic segment in rats were perfused with saline (controls, N ⫽ 5) or porcine pancreatic elastase to induce aneurysms (N ⫽ 5). Seven days later, animals were sacrificed; aortic diameters were measured, and RNA was extracted from the perfused aortic segments. Real-time PCR was used to measure mRNA levels for angiotensin, ACE, AT1, and AT2 (normalized to B-actin). Results from control rats were compared with elastase perfused rats using the unpaired t-test. Results. Elastase perfusion produced mean aortic diameters of 4.07 ⫾ 0.28 mm, while saline controls had mean aortic diameters of 1.65 ⫾ 0.11 mm (P ⫽ 0.01). ACE mRNA levels were 16-fold lower in elastase-perfused animals compared with saline controls (P ⬍ 0.005). Trends toward elevated expression of angiotensin (2.5-fold increase) and AT1 (2.3-fold increase) within elastase perfused aortas existed, but did not reach statistical significance. Conclusions. Experimental aortic aneurysm formation in an elastase-perfused model is associated with the down regulation of aortic wall ACE expression and a trend toward increased expression of angiotensin and its primary receptor AT1. Further investigation into the mechanisms by which these proteins contribute to aneurysm formation in vivo is warranted. P60. Laparascopic Aortic Reinforcement and Endovascular Graft Replacement. T. Kudo, MD, PhD, K.K. Kao, BA, S.D. Nelson, MD, T.D. Reil, MD, J.L. Moy, BS, G.G. Altobelli, B.T. Haas, F.A. Chandra, C.R. Grasia, MD, S.S. Ahn, MD. UCLA Gonda Vascular Center, Department of Surgery, and Department of Pathology, Los Angeles, CA.