[show abstract][hide abstract] ABSTRACT: Paraplegia complicating surgical thoracoabdominal aneurysm (TAA) repair remains an unpredictable and poorly understood phenomenon. The ability to identify patients at increased risk of delayed paraplegia before the process becomes irreversible could allow early interventions to attenuate this risk.
In a rabbit model of infra-renal spinal cord ischemia, serial T2 weighted (T2W) magnetic resonance (MR) imaging was performed 2- and 8 h after the ischemic insult with changes correlated with clinical outcome. Using the axial T2W images, signal intensity measurements of the lateral horns of the spinal cord were acquired, both above (that is, thoracolumbar cord) and below (that is, lumbar cord) the renal arteries. This ratio (lumbar/thoracolumbar cord signal intensity) was evaluated and compared between groups.
No changes were seen in the signal intensity of rabbits that remained neurologically intact. Rabbits with delayed paralysis showed a significant (P<0.01) decrease in signal intensity ratio at 2 h (1.13+/-0.03), while a significant (P<0.01) increase was noted in those rabbits with immediate persistent paralysis (1.43+/-0.04). There was a significant (P<0.01) increase in the signal intensity ratios at 2 h in the delayed paralysis group (1.55+/-0.14), with a further significant (P<0.01) increase at 8 h in the immediate persistent paralysis group (1.76+/-0.07).
Findings on MR imaging can differentiate clinical outcomes in this experimental model of spinal cord ischemia. While further studies are required, MR could be useful in predicting which patients are at risk for delayed paraplegia after TAA repair.
[show abstract][hide abstract] ABSTRACT: Plaque rupture leading to thrombosis and occlusion is a major source of acute coronary syndromes. Methods for accurate detection of thrombosis in veins or arteries may expand our capacity to predict clinical complications and guide therapeutic decisions. We sought to demonstrate the feasibility of in vivo acute thrombus detection using a fibrin-targeted gadolinium based magnetic resonance contrast agent (EP-1242).
Carotid thrombosis was induced in 12 guinea pigs by external injury and blood stasis. MR images were obtained after thrombus formation pre- and post- EP-1242 injection, using a T1-weighted high-resolution fast spin-echo sequence.
An occlusive fibrin-rich thrombus was achieved in all animals. Correlation for thrombus location was excellent between MRI and histology (R=0.94; P<0.001). Contrast-enhanced MRI significantly improved thrombus detection when compared to non contrast-enhanced MRI (100% versus 41.6%; p<0.001). In addition, thrombus signal intensity (SI) was significantly increased after injection (SI(30 min-post)=4.39+/-0.12 versus 1.0; p<0.001). Contrast-to-noise ratio (CNR) was 43.8+/-7.2, 30 min post-injection (P<0.001). No enhancement was seen in the uninjured control arteries.
We demonstrate the feasibility of in vivo MRI for carotid thrombus detection using a novel fibrin-targeted contrast agent. This technique significantly improves detection of small size thrombi in an animal model of occlusive fibrin-rich thrombosis.
[show abstract][hide abstract] ABSTRACT: The function of B-Myb, a negative regulator of vascular smooth muscle cell (SMC) matrix gene transcription, was analyzed in the vasculature.
Mice were generated in which the human B-myb gene was driven by the basal cytomegalovirus promoter, and 3 founders were identified. Mice appeared to develop normally, and human B-myb was expressed in the aortas. Total B-Myb levels were elevated in aortas of adult transgenic versus wild-type (WT) animals and varied inversely with alpha1(I) collagen mRNA expression. However, neonatal WT and transgenic aortas displayed comparable levels of alpha1(I) collagen mRNA, likely resulting from elevated levels of cyclin A, which ablated repression by B-Myb. Aortic SMCs from adult transgenic animals displayed decreased alpha1(I) collagen mRNA levels. To examine the role of B-Myb after vascular injury, animals were subjected to femoral artery denudation, which induces SMC-rich lesion formation. A dramatic reduction in neointima formation and lumenal narrowing was observed in arteries of B-myb transgenic versus WT mice 4 weeks after injury.
Data indicate that B-Myb, which inhibits matrix gene expression in the adult vessel wall, reduces neointima formation after vascular injury. To analyze B-Myb function in the vasculature, mice overexpressing B-myb were generated. Neonates displayed normal alpha1(I) collagen mRNA levels, whereas adults expressed decreased collagen mRNA in aortas and isolated vascular SMCs. On femoral artery denudation, neointima formation was dramatically reduced in B-myb transgenic mice.
[show abstract][hide abstract] ABSTRACT: To test the non-lipid-lowering effects of simvastatin on the response to injury in normolipidemic and hyperlipidemic mice.
Wild-type (WT) mice (n = 40) and hyperlipidemic apolipoprotein-E-deficient (apoE(-/-)) mice (n = 40) received normal chow or chow containing simvastatin 100 mg/kg/day prior to bilateral femoral artery wire injury. Intimal hyperplasia and plasma cholesterol concentration were quantified after 4 weeks. Plasma cholesterol in WT mice treated or untreated with simvastatin was similar (100.9 +/- 6.6 vs. 94.3 +/- 17.5 mg/dl). Simvastatin did not affect intimal hyperplasia. In apoE(-/-) mice, intimal hyperplasia was increased 2.3-fold relative to WT mice (17090 +/- 4998 vs. 39490 +/- 16190; p < 0.001). In apoE(-/- )mice, simvastatin caused a paradoxical increase in plasma cholesterol (1094 +/- 60.3 vs. 658 +/- 66.8 mg/dl; p < 0.001), confirmed by FPLC. This was associated with a further increase in intimal area (39490 +/- 16190 vs. 55420 +/- 22590 mm(2); p < 0.01).
(1). Simvastatin had no effect on plasma cholesterol or the response to arterial injury in normolipidemic WT mice; (2). hyperlipidemia was associated with markedly increased intimal hyperplasia, and (3). simvastatin treatment of apoE(-/-) mice caused paradoxical hyperlipidemia and increased intimal hyperplasia.
Journal of Vascular Research 01/2004; 41(1):75-83. · 2.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to understand the role of ischemic preservation injury and pro-inflammatory cytokine expression in the progression of allograft vasculopathy.
Using the rat aortic transplant model, grafts were stored at 4 degrees C for either 1 or 24 h. Graft vasculopathy was assessed at 4 and 8 weeks after transplantation. Intra-graft cytokine expression was measured at days 1, 3 and, 7 after transplantation.
At 4 weeks, intimal hyperplasia of allografts was greater than isografts (P<0.05). At 8 weeks, all groups had an increase in graft vascular disease compared to the 4-week groups (P<0.05). Allografts preserved for 24 h displayed a greater degree of vessel-wall reaction than both isograft groups and allografts stored for 1 h (P<0.05). An increased expression of the cytokines, TNF-alpha, TGF-beta, IL-2, INF-gamma, IL-1, and IL-6 was noted in the allografts stored for 24 h compared to similarly treated isografts (P<0.05).
Prolonged ischemic preservation injury induced vascular disease in both isografts and allografts. The vessel wall reaction increased over time and was greater in allografts than isografts. The enhanced expression of T cell- and macrophage associated cytokines in allografts compared to isografts, suggested that early pro-inflammatory cytokine expression played an important role in progression of allograft vasculopathy.
Journal of Surgical Research 08/2003; 113(2):201-7. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Syngeneic heterotopic transplantation of segments of descending thoracic aortas containing atherosclerotic lesions from hypercholesterolemic mice into normocholesterolemic recipients has been useful for studies on plaque regression and stabilization. Because lesion development is more rapid and exuberant in the aortic arch, a technique of transplantation of the mouse aortic arch was developed.
C57BL/6, apoE-deficient (apoE-/-) (hypercholesterolemic) mice were fed a Western diet for 22 weeks and used as donors of aortic-arch segments containing atherosclerotic lesions. Twenty syngeneic transplants were performed on age-matched wild-type (normocholesterolemic) mice. Aortic arches containing atherosclerotic lesions were implanted on the abdominal aorta of recipient mice by end-to-side microsurgical anastomosis. Two weeks after transplantation, grafts were noninvasively imaged in vivo by magnetic resonance (MR) microscopy. Grafts harvested four weeks after transplantation were submitted for histological examination.
All recipients survived the entire follow-up period (1 month) without complications. Duration of recipient procedure ranged from 90 to 120 (mean, 105) min; aortic clamping time varied from 45 to 60 min. In vivo MR microscopy demonstrated patency of the grafts and wall thickening that corresponded to the preexisting atherosclerotic lesions. Histology confirmed patency and atherosclerotic thickening of the grafts, and showed no evidence of acute tissue damage.
Syngeneic transplantation of the aortic arch in mice represents a useful alternative model for studies on morphology, imaging, and mechanisms of atherosclerosis. The curvature of the aortic arch is preserved after implantation onto the abdominal aorta, providing clear landmarks for noninvasive assessment using MR.
Journal of Surgical Research 06/2003; 111(2):171-6. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury.
Mice underwent femoral arterial denudation and received recombinant adenovirus, expressing either murine endostatin (n=19) or control adenoviral vector (n=12), by jugular vein injection. Endostatin gene transfer resulted in high serum levels of endostatin. Strong adenoviral gene expression of beta-galactosidase-expressing control vector was detected in liver tissue and was absent in the injured arterial wall at 1 week. Deposits of endostatin protein were detected along the denuded arterial wall and were not seen in the noninjured contralateral artery at 1 week. Endostatin deposits were also absent in the injured artery of control vector-treated animals. Overexpression of endostatin led to decreased reendothelialization and increased apoptosis of luminal endothelial cells 2 and 4 weeks after arterial injury (P<0.05). In addition, endostatin overexpression resulted in increased neointima formation (P<0.05). Endothelial apoptosis and neointima area correlated positively with endostatin serum levels, whereas the degree of reendothelialization correlated negatively with endostatin serum levels (P<0.05). Furthermore, poor reendothelialization correlated with increased neointima formation (P<0.05).
In summary, decreased reendothelialization and enhanced endothelial apoptosis, in response to endostatin overexpression, were associated with increased neointima formation. These findings demonstrate that high serum levels of endostatin are capable of inhibiting endothelial regeneration and promoting arterial lesion growth in conditions of endothelial injury.
[show abstract][hide abstract] ABSTRACT: Restenosis remains a major cause of morbidity and mortality after coronary angioplasty. Injury-induced inflammation, thrombosis, smooth muscle cell (SMC) proliferation, and neointimal formation contribute to restenosis. These events are linked to circulating glucose-derived advanced gycation endproducts (AGE), known to promote cell proliferation, lipid glycoxidation and oxidant stress. This study evaluates the association between dietary AGE content and neointimal formation after arterial injury in genetically hypercholesterolemic mice. Male, 12-week-old, apolipoprotein E-deficient (apoE(-/-)) mice were randomly assigned to receive either a high AGE diet (HAD; AGE=15000 U/mg), or a similar diet with ten-fold lower AGE (LAD; AGE=1500 U/mg). These mice underwent femoral artery injury 1 week later, and were maintained on their diets for an additional 4 weeks. At 4 weeks after injury, significant decrease in neointimal formation was noted in LAD-fed mice. Neointimal area, intima/media ratio, and stenotic luminal area (LA) were less pronounced in the LAD group than the HAD group (P<0.05). These quantitative differences were associated with a marked reduction ( approximately 56%) of macrophages in the neointimal lesions, as well as an obvious reduction of SMC content of LAD-fed mice. The reduction of neointimal formation in the LAD mice correlated with a approximately 40% decrease in circulating AGE levels (P<0.0005). Immunohistochemistry also showed a reduced ( approximately 1.5-fold) deposition of AGE in the endothelia, SMC, and macrophages in neointimal lesions of LAD-fed mice. These results represent the first evidence in vivo for a causal relationship between dietary AGE and the vessel wall response to acute injury, suggesting a significant potential for dietary AGE restriction in the prevention of restenosis after angioplasty.
[show abstract][hide abstract] ABSTRACT: We have previously shown that magnetic resonance microscopy (MRM) accurately quantifies atherosclerosis in Apolipoprotein E deficient (ApoE(-/-)) mice aged 36-84 weeks. The present study tests MRM in the quantification of aortic atherosclerosis over a broader range of lesion severity. Younger mice with less advanced disease were imaged in order to evaluate sensitivity, specificity and maximum practical resolution of MRM. Nineteen mice underwent in vivo MRM. Wall area measurements by MRM and light microscopy (LM) (n=43) were highly correlated (r=0.85, slope=0.88, P<0.0001). Wall areas by MRM ranged from 0.114 to 0.934 (median, 0.334) mm(2). A threshold of 0.35 mm(2), for the upper limit of normal, gave MRM positive predictive value (PPV) for detecting abnormally thickened arteries=89.5% and negative predictive value (NPV)=75%, referred to LM. Lesion shape assessed by LM and MRM were also well correlated (r=0.72, P<0.001). Increased wall area in atherosclerosis was found by MRM (P=0.01) and LM (P<0.0001) to be accommodated entirely by 'positive remodeling', confirming the importance of determining plaque size directly. MRM accurately quantifies mouse aortic atherosclerosis and will enhance studies in this important animal model.
[show abstract][hide abstract] ABSTRACT: Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2(-/-) mice showed a 61.4% reduction (P<0.01) in intimal area and a 62% reduction (P<0.05) in intima/media ratio when compared with CCR2(+/+) littermates. The response of CCR2(+/-) mice was not significantly different from that of CCR2(+/+) mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2(-/-) mice when compared with CCR2(+/+) littermates (P<0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2(-/-) or CCR2(+/+) mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury.
[show abstract][hide abstract] ABSTRACT: Skin grafting provides an effective means of closing chronic wounds. Autografts and allografts are used most often in skin grafting, but Apligraf, a tissue-engineered bilayered human skin equivalent, provides another safe and effective grafting option for treating diabetic, venous, and pressure ulcers. This skin equivalent has an epidermis and dermis similar to human skin, largely due to its derivation from neonatal foreskin. Apligraf is also easily accessible and has shown little immunoreactivity.
Journal of the American Podiatric Medical Association 02/2002; 92(1):19-23. · 0.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: More than 50% of all cancer patients receive some form of radiotherapy for tumor control preoperatively, postoperatively, or as sole treatment. Radiation-induced wounds are a concern for patients and practitioners. Current research investigating alternative treatment strategies offers the hope of improved wound healing and enhanced quality of life for patients with these wounds. This paper reviews the pathophysiology of wounds following radiation treatment, the methods for treating radiation-induced wounds, and experimental treatment strategies that have been investigated.
Advances in Skin & Wound Care 01/2002; 15(5):216-24. · 1.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Many controversies and uncertainties surround resuscitation of hemorrhagic shock caused by vascular trauma. Whereas the basic pathophysiology is better understood, much remains to be learned about the many immunologic cascades that lead to problems beyond those of initial fluid resuscitation or operative hemostasis. Fluid therapy is on the verge of significant advances with substitute oxygen carriers, yet surgeons are still beset with questions of how much and what type of initial fluid to provide. Finally, the parameters chosen to guide therapy and the methods used to monitor patients present other interesting issues.
Surgical Clinics of North America 01/2002; 81(6):1217-62, xi-xii. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: HDL cholesterol levels are inversely correlated with coronary heart disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to affect preexisting advanced atherosclerotic lesions is not known. To approach this issue, we used a novel mouse aortic transplantation model.
ApoE-deficient (EKO) mice were fed a Western-type diet for 6 months, and thoracic aortic segments containing advanced lesions replaced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol approximately 26 mg/dL) or expressing (HDL approximately 64 mg/dL) a human apoAI (hAI) transgene. Both types of recipients had comparable non-HDL cholesterol levels. Five months after transplantation, mice were killed and grafts analyzed. Compared with lesion area in pretransplant mice (0.14+/-0.04 mm(2), mean+/-SEM), there was progression in the EKO recipients (0.39+/-0.06 mm(2), P<0.01). Compared with EKO recipients, hAI/EKO recipients had retarded progression (0.24+/-0.04 mm(2), P<0.05). Immunostaining for CD68 and other macrophage-associated proteins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acyltransferase, and tissue factor, in lesions of pretransplant and EKO recipient mice showed abundant macrophages. In contrast, compared with any other group, lesional macrophage area in hAI/EKO mice decreased >80% (P<0.003), and smooth muscle cell content (alpha-actin staining) increased >300% (P<0.006). The decrease in macrophages and increase in smooth muscle cells was primarily in the superficial subendothelial layer.
Increasing HDL cholesterol levels in EKO mice retards progression of advanced atherosclerotic lesions and remodels them to a more stable-appearing phenotype.