Isolated inferior mesenteric artery revascularization for chronic visceral ischemia.

PURPOSE: Complete visceral artery revascularization is recommended for the treatment of chronic visceral ischemia. However, in rare cases, it may not be possible to revascularize either the celiac or superior mesenteric (SMA) arteries. We have managed a series of patients with isolated revascularization of the inferior mesenteric artery (IMA) and now report our experience gained over a period of three decades. METHODS: Records were reviewed from 11 patients with chronic visceral ischemia who underwent isolated IMA revascularization (n = 8) or who, because of failure of concomitant celiac or SMA repairs, were functionally left with an isolated IMA revascularization (n = 3). All the patients had symptomatic chronic visceral ischemia documented with arteriography. Five patients had recurrent visceral ischemia after failed visceral revascularization, and two patients had undergone resection of ischemic bowel. The celiac or the SMA was unsuitable for revascularization in five cases, and extensive adhesions precluded safe exposure of the celiac or the SMA in five cases. IMA revascularization techniques included: bypass grafting (n = 4), transaortic endarterectomy (n = 4), reimplantation (n = 2), and patch angioplasty (n = 1). RESULTS: There was one perioperative death, and the remaining 10 patients had cured or improved conditions at discharge. One IMA repair thrombosed acutely but was successfully revascularized at reoperation. The median follow-up period was 6 years (range, 1 month to 13 years). Two patients had recurrent symptoms develop despite patent IMA repairs and required subsequent visceral revascularization; interruption of collateral circulation by prior bowel resection may have contributed to recurrence in both patients. Objective follow-up examination with arteriography or duplex scanning was available for eight patients at least 1 year after IMA revascularization, and all underwent patent IMA repairs. There were no late deaths as a result of bowel infarction. CONCLUSION: Isolated IMA revascularization may be useful when revascularization of other major visceral arteries cannot be performed and a well-developed, intact IMA collateral circulation is present. In this select subset of patients with chronic visceral ischemia, isolated IMA revascularization can achieve relief of symptoms and may be a lifesaving procedure.

Long-term results of lower-extremity venous injuries.

OBJECTIVES: To compare the long-term venous function of ligated, simple, and complex repairs and to assess long-term patency in repaired veins. DESIGN: A cohort study of patients with lower-extremity venous injuries treated during a 7-year period. SETTING: A level I urban trauma center. PATIENTS: Twenty-one of the 79 patients with a history of lower-extremity venous injury identified via the trauma registry consented to outpatient evaluation. INTERVENTION: Participating patients underwent a through vascular examination that included color flow duplex venous imaging and air plethysmographic assessment. MAIN OUTCOME MEASURES: The patency of venous repairs, the incidence of chronic deep venous thrombosis, and evidence of chronic venous insufficiency. RESULTS: The venous injuries included 5 iliac, 10 femoral, and 6 popliteal. Six of these injuries were ligated, 11 injuries were simply repaired (lateral venorrhaphy or end-to-end), and 4 were repaired with complex interposition grafts. All repairs were patent, with no evidence of deep venous thrombosis by color flow duplex venous imaging. Seventeen of the 21 patients had symptoms, color flow duplex venous imaging findings, and air plethysmographic data consistent with chronic venous insufficiency, including significant mean differences (P < .03) in outflow fraction, outflow fraction with compression, venous filling index, and residual volume fraction, when compared with the uninjured extremity. The most profound changes followed complex repairs and perioperative fasciotomies. CONCLUSIONS: While the long-term patency of venous repairs is excellent, most patients demonstrate evidence of chronic venous insufficiency after either ligation or repair. Complex venous repairs and fasciotomy are associated with the most severe functional changes.

Monocyte chemoattractant protein-1 is sufficient for the chemotaxis of monocytes and lymphocytes in transgenic mice but requires an additional stimulus for inflammatory activation.

Monocyte chemoattractant protein-1 (MCP-1), a chemotactic cytokine, acts in vitro as a chemotactic and activating factor for multiple types of leukocytes. To determine the chemotactic and activating effects of MCP-1 in vivo, we constructed transgenic mice that express human MCP-1 in type II alveolar epithelial cells and secrete it into the bronchoalveolar space. We found that MCP-1 overexpression led to a marked increase in the numbers of both monocytes and lymphocytes that could be recovered by bronchoalveolar lavage. This accumulation of mononuclear leukocytes could be reversed by the administration of an MCP-1-blocking Ab. In spite of its chemotactic effect, MCP-1 expression did not cause the inflammatory activation of accumulated leukocytes. Lungs of MCP-1 transgenic mice also showed no morphologic evidence of inflammation. However, MCP-1 mice had an increased sensitivity to other inflammatory stimuli. MCP-1 mice treated with either i.p. LPS or i.v. yeast wall glucan developed consolidated pulmonary infiltrates consisting predominantly of macrophages. Nontransgenic mice developed no such infiltrates. These results demonstrate that MCP-1 is chemotactic for monocytes and lymphocytes in vivo and that MCP-1 expression alone does not cause inflammatory activation of cells, but leads to an enhanced inflammatory response upon treatment with other stimuli.

Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2.

We used PCR to amplify proteinase activated receptor-2 (PAR-2) from human kidney cDNA. The open reading frame comprised 1191 bp and encoded a protein of 397 residues with 83% identity with mouse PAR-2. In KNRK cells (a line of kirsten murine sarcoma virus-transformed rat kidney epithelial cells) transfected with this cDNA, trypsin and activating peptide (AP) corresponding to the tethered ligand exposed by trypsin cleavage (SLIGKV-NH2) induced a prompt increase in cytosolic calcium ion concentration ([Ca2+]i). Human PAR-2 (hPAR-2) resided both on the plasma membrane and in the Golgi apparatus. hPAR-2 mRNA was highly expressed in human pancreas, kidney, colon, liver and small intestine, and by A549 lung and SW480 colon adenocarcinoma cells. Hybridization in situ revealed high expression in intestinal epithelial cells throughout the gut. Trypsin and AP stimulated an increase in [Ca2+]i in a rat intestinal epithelial cell line (hBRIE 380) and stimulated amylase secretion in isolated pancreatic acini. In A549 cells, which also responded to trypsin and AP with mobilization of cytosolic Ca2+, AP inhibited colony formation. Thus PAR-2 may serve as a trypsin sensor in the gut. Its expression by cells and tissues not normally exposed to pancreatic trypsin suggests that other proteases could serve as physiological activators.

JE gene expression in an animal model of acute arterial graft rejection.

Transplant arteriosclerosis (TA) is an immune mediated vascular injury that results in rapid intimal thickening and parenchymal ischemia. The monocytes that infiltrate the transplanted organ's vessels may mediate this effect. One of the cell signals that may initiate monocyte infiltration in rat models of acute and chronic vessel wall rejection is the product of the JE gene, a potent and selective chemoattractant for monocytes. We used combined in situ hybridization and immunocytochemistry to localize JE gene expression in specific cell types using a rat aortic transplant model of acute arterial graft rejection. Within 3 days of transplantation, there was JE mRNA expression in adventitial mesenchymal cells, probably fibroblasts, and this signal increased until 10 days post-transplantation. During this period, the number of adventitial monocytes, identified by immunocytochemistry, increased around the mesenchymal cells expressing JE. Intimal JE mRNA expression between 7 and 20 days localized to undefined mesenchymal intimal cells and occasionally blood-borne monocytes. There was no JE gene expression detected in the intima after 20 days. JE mRNA expression at 20 days was limited to alpha-actin-positive vascular smooth muscle cells in the outer aspect of the media. At 40 and 60 days, there was no JE hybridization signal in the media or adventitia despite increasing medial monocyte infiltration. The temporal sequence of JE mRNA expression, starting in the adventitia, intima, and finally the media, preceded or coincided with monocyte/macrophage infiltration. These results support our hypothesis that early JE gene expression may lead to the initial monocyte recruitment in acute vessel wall rejection. Because JE gene expression is downregulated by glucocorticoids, their immunosuppressive effect may be partly due to decreased JE gene expression by transplanted vessels.

Neurogenic thoracic outlet decompression: rationale for sparing the first rib.

A total of 168 primary supraclavicular decompressions were performed on 146 patients with neurogenic thoracic outlet syndrome. This report compares the results of rib resection (supraclavicular anterior and middle scalenectomy and first rib resection) with rib-sparing (supraclavicular anterior and middle scalenectomy alone) operations. All patients with cervical ribs were excluded. In total, 125 rib resections and 43 rib-sparing procedures were performed between 1983 and 1992 by a single surgeon. The patients were otherwise comparable in symptoms and physical signs. During surgery there was a significantly higher proportion of pleural injury associated with rib resection (59%) than with rib-sparing (40%) procedures. The mean hospital stay was also prolonged by 1 day in patients undergoing rib resection (p = 0.005). There was no significant difference in early success between the two groups (83% for rib resection, 91% for rib sparing) and no difference in those resuming employment (52% and 63% respectively). Life-table analysis showed that the two groups have similar long-term results (69% and 76% at 2 years). The only important factor determining clinical outcome in primary supraclavicular thoracic outlet syndrome decompression was the duration of symptoms before operation. Some 83% of patients with symptoms less that 2 years had a successful result compared with only 68% in those with symptoms longer than 2 years (p < 0.05). Spontaneous or post-traumatic neurogenic symptoms responded to operation identically. The theoretical benefit of first rib resection to relieve mechanical compression of the brachial plexus is not evident from this review. Thorough removal of the scalene musculature and other myofascial anomalies, preferably through the supraclavicular approach, leads to less patient morbidity, shortens hospitalization, and is recommended for patients with neurogenic thoracic outlet syndrome requiring operative intervention.

Local expression of inflammatory cytokines in human atherosclerotic plaques.

Human atherosclerotic plaques are heterogeneous tissues containing a number of different cell types, including macrophages, smooth muscle, endothelial and other undefined mesenchymal-appearing cells. Significant numbers of macrophages are found in human atherosclerotic plaques and have been postulated to be a major source of growth factor production during atherogenesis. In vitro evidence suggested that macrophages synthesize PDGF and might therefore contribute to the growth of the vessel wall in atherosclerosis. However, examination of PDGF synthesis in human atheroma by in situ hybridization revealed that while smooth muscle, mesenchymal, and endothelial cells synthesize this growth factor macrophages did not. Our inability to detect PDGF mRNA in macrophages was not due to any problems with hybridization to this cell type. In situ hybridization studies on human atherosclerotic plaques have demonstrated that plaque macrophages contain many different mRNAs other than PDGF including tissue factor, factor XIII, apoprotein E, transforming growth factor beta, and tumor necrosis factor. Recent studies have indicated that macrophages may be a major source as well of another group of inflammatory cytokines which are members of the RANTES/SIS cytokine family. In situ hybridization studies on human carotid endarterectomy specimens using probes specific for the inflammatory cytokines RANTES, LD78, HIMAP, and MCP-1 revealed numerous cells containing the mRNAs encoding for these proteins (5%, 13%, 8%, and 16% of plaque cells respectively). This is in contrast to generally low level expression found in normal human arteries (< 1% of normal medial cells contain these mRNAs). Cells expressing these cytokines were often found associated with inflammatory zones in human atherosclerotic plaques. Serial section immunohistochemistry suggests that macrophages and/or T cells may synthesize these proteins. In addition to localization to macrophages MCP-1 expression was also detected in smooth muscle cells and mesenchymal-appearing cells with many of the morphological characteristics of cells previously seen to express PDGF. In vitro evidence suggests that these proteins may be chemotactic to monocytes and lymphocytes. The finding of increased expression of these mRNAs in human atheroma suggests they may play a role in monocyte trafficking into the atherosclerotic plaque.

Circumferential venolysis and paraclavicular thoracic outlet decompression for "effort thrombosis" of the subclavian vein.

Effort thrombosis of the subclavian vein (Paget-Schroetter syndrome) has long been considered a primary thrombotic process, but recent experience suggests that it may commonly result from repeated mechanical compression. Increased awareness of the pathophysiology of this syndrome can allow timely, improved diagnostic screening and the use of specific surgical intervention to relieve the venous consequences. During the past 15 years we have treated six patients with mechanical compression in the thoracic outlet causing surgically correctable venous occlusive problems. There were four men and two women with an average age of 38 years (range 26 to 53 years). All patients exhibited pain, swelling, and cyanosis of the upper extremity, with worsening venous congestion on abduction of the arm. Five of six patients were originally treated for effort thrombosis of the subclavian vein with arm elevation and anticoagulation; two also underwent immediate thrombolytic therapy with urokinase. Venography was prompted in each case by positional symptoms during follow-up and showed irregular stenosis of the subclavian vein adjacent to the first rib. All patients underwent extended first rib resection and circumferential venolysis (one patient underwent bilateral procedures); one was performed through a transaxillary approach, two through a supraclavicular approach, and four through a new, "paraclavicular" approach. All subclavian veins appeared normal after venolysis. Five of six patients also underwent complete scalenectomy and brachial plexus neurolysis. In each patient, venous and neurogenic symptoms resolved and venography confirmed a patent subclavian vein, with follow-up ranging from 11 months to 13 years (mean 3.8 years).

Thrombin receptor expression in normal and atherosclerotic human arteries.

Thrombin is a multifunctional serine protease generated at sites of vascular injury. A host of thrombin actions on vascular endothelial cells, smooth muscle cells, and macrophages has been defined in cell culture systems, but the in vivo significance of these activities is unknown. We have defined the expression of the recently identified receptor for thrombin in human arteries by both in situ hybridization and immunohistochemistry. In normal-appearing arteries, thrombin receptor was expressed almost exclusively in the endothelial layer. By contrast, in human atheroma, the receptor was widely expressed, both in regions rich in macrophages and in regions rich in vascular smooth muscle cells and mesenchymal-appearing intimal cells of unknown origin. Thrombin receptor was expressed by human vascular endothelial cells and smooth muscle cells in culture and by macrophages obtained by bronchioalveolar lavage, thus demonstrating that all three cell types are indeed capable of expressing the thrombin receptor. These results establish thrombin receptor activation as a candidate for contributing to sclerotic and inflammatory processes in the human vasculature, such as those that occur in atherosclerosis and restenosis.

Surgical recanalization of occluded peripheral arteries.

This article, reflecting on the surgical recanalization of occluded peripheral arteries, has exposed the very essence of vascular surgery. Only the pioneering cardiac anomalies repaired by Gross (patent duct arteriosus, 1938), Blalock and Taussig (tetralogy of Fallot, 1944), and Crafoord and Nylin (coarctation, 1945) and the legendary aortic grafting operations of Oudot (occlusion, 1950) and Dubost and coworkers (aneurysm, 1951) are not a part of this article. The contributions to surgical recanalization of the occluded peripheral arteries are numerous. Some are well conceived, and others are innovative. Perhaps the most significant technique of all, endarterectomy itself, began purely as a serendipitous event. The startling impact of dos Santos' revolutionaly "disobliteration" was realized at once. Intimal injury during the operation did not cause inevitable thrombosis, as historically taught. Thus, all vascular interventions, either endarterectomy, graft repair, or the newer endovascular techniques discussed in this issue, would not have been developed without the understanding of the tolerance of the human intima to injury. Thromboendarterectomy, the basis of surgical recanalization of occluded arteries, unlocked the mystery of arterial rethrombosis after intervention. Recognizing these crucial facts, it will have a lasting place in the expanded discipline of vascular disease and its treatment. Dos Santos, the European founder of endarterectomy, and Wylie, the American pioneer and proponent of endarterectomy, were great friends in life (Fig. 4) and would certainly be pleased to see the further development of technology aimed at the treatment of atherosclerotic obstruction of the peripheral arteries.

"Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.

Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were found to be specific antagonists of receptor activation by thrombin. The effectiveness of these designed antagonists in blocking thrombin-induced platelet activation suggests a model for thrombin-receptor interaction and possible strategies for the development of novel antithrombotic agents.

Thrombin-induced events in non-platelet cells are mediated by the unique proteolytic mechanism established for the cloned platelet thrombin receptor.

We recently isolated a cDNA clone encoding a functional platelet thrombin receptor that defined a unique mechanism of receptor activation. Thrombin cleaves its receptor's extracellular amino terminal extension, unmasking a new amino terminus that functions as a tethered peptide ligand and activates the receptor. A novel peptide mimicking this new amino terminus was a full agonist for platelet secretion and aggregation, suggesting that this unusual mechanism accounts for platelet activation by thrombin. Does this mechanism also mediate thrombin's assorted actions on non-platelet cells? We now report that the novel thrombin receptor agonist peptide reproduces thrombin-induced events (specifically, phosphoinositide hydrolysis and mitogenesis) in CCL-39 hamster lung fibroblasts, a naturally thrombin-responsive cell line. Moreover, these thrombin-induced events could be recapitulated in CV-1 cells, normally poorly responsive to thrombin, after transfection with human platelet thrombin receptor cDNA. Our data show that important thrombin-induced cellular events are mediated by the same unusual mechanism of receptor activation in both platelets and fibroblasts, very likely via the same or very similar receptors.

Monocyte chemoattractant protein-1 in human atheromatous plaques.

Monocytes appear to be central to atherogenesis both as the progenitors of foam cells and as a potential source of growth factors mediating intimal hyperplasia, but the chemical messages which stimulate the influx of monocytes into human atheroma remain unknown. Monocyte chemoattractant protein-1 (MCP-1) is a recently described molecule with powerful monocyte chemotactic activity expressed by monocytes, vascular endothelial cells, and smooth muscle cells in culture. To begin to address the role of MCP-1 in vivo, we examined 10 normal arteries and 14 diseased human arteries for MCP-1 expression by in situ hybridization. MCP-1 mRNA was detected in 16% of 10,768 cells counted in human carotid endarterectomy specimens with highest expression seen in organizing thrombi (33%) and in macrophage rich areas bordering the necrotic lipid core (24%) as compared to the fibrous cap (8%) and the necrotic lipid core itself (5%). Based on immunohistochemical staining of serial sections and on cell morphology, MCP-1 mRNA appeared to be expressed by vascular smooth muscle cells (VSMC), mesenchymal appearing intimal cells (MICs), and macrophages. By contrast, few cells expressing MCP-1 mRNA were found in normal arteries (less than 0.1%). These data suggest a potential role for MCP-1 in mediating monocytic infiltration of the artery wall.