Benchmarking a Center of Excellence in Vascular Surgery: Using Acute Physiology and Chronic Health Evaluation II to Validate Outcomes in a Tertiary Care Institute.

OBJECTIVE: The Society of Vascular Surgery (SVS) has made it a top priority to implement verification of vascular "centers of excellence". Our institutional aortic network was established in 2008 in order to standardize care of patients with suspected acute aortic pathology. The implementation and success of this program has been previously reported. We sought to use our experience as a benchmark for which to develop prognostic modeling to quantify clinical status upon admission and help predict outcomes. Our objective was to validate the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system using a cohort of aortic emergencies transferred by an organized transfer network. METHOD: This was a retrospective, single institution review of patients transferred through an institutional aortic network for acute aortic pathology from 2017-2018. Demographics, comorbidities, aortic diagnosis, APACHE II score, as well as 30-day mortality were recorded. Associations with 30-day mortality were evaluated using two-sample t-tests, ANOVA models, Pearson chi-square tests and Fisher exact tests. Receiver operating characteristic (ROC) curves were fit overall and by pathology to predict 30-day mortality by Apache II total score. RESULTS: There were 395 consecutive transfers were identified. The mean age was 64.7 years. Diagnoses included Type A Dissection (n = 134), Type B (n = 81), Aortic Aneurysm (n = 122), and PAU/IMH (n = 27). Mean APACHE II score on arrival was 12. Overall there were 53 deaths (13.4%) in the cohort. Patients that died had significantly higher Apache II total scores (11.3 vs 16.5, P < .001). The area under the receiver operator characteristic (ROC) curve (AUC) was .66 for the full cohort, indicating a poor clinical prediction test. CONCLUSION: APACHE II score is a poor predictor of 30-day mortality in a large transfer network accepting all aortic emergencies. The authors believe further refining a prognostic model for diverse population will not only help in predicting outcomes but to objectively quantify illness severity in order to have a basis for comparison among institutions and verification of "centers of excellence".

An expanded series of distal bypass using the distal vein patch technique to improve prosthetic graft performance in critical limb ischemia.

OBJECTIVES: The endovascular first approach has led to increasing complexity for surgical bypass especially in those patients without autogenous conduit. The use of vein interposed at the distal anastomosis has been reported to improve the results of prosthetic grafts. This series expands our initial experience with the distal vein patch technique (DVP) reporting a larger cohort with enhanced follow-up. DESIGN: A retrospective review of prospectively collected data was performed for distal bypasses from July 1995 to November 2008. MATERIALS/METHODS: 1296 tibial bypasses were performed with 270 using the DVP technique. Patient demographics included; 49% diabetes, 20% chronic renal failure, 33% prior failed bypass. Indications for revascularization were claudication (9.3%), rest pain (27.8%), gangrene (22.2%), and non-healing ulceration (40.7%). Lack of vein for the bypass conduit resulted from previous failed grafts (55%), coronary bypass (18%), poor quality vein (23%), or prior vein stripping (8%). Follow-up ranged from 1 to 48 months with graft surveillance by pulse exam, ABI, and Duplex ultrasound. Primary patency and limb salvage ± SE were determined by Kaplan-Meier life-table analysis using Rutherford criteria. RESULTS: Bypasses originated from the external iliac (29%), CFA (55%), SFA (13%), popliteal (1%), and prior grafts (2%). Recipient arteries were below knee popliteal (6%), anterior tibial (25%), posterior tibial (30%), and peroneal (39%). Perioperative graft failure occurred in 13 cases with a total of 41 graft failures leading to 39 major amputations. Primary graft patency from one to four years was 79.8%, 75.6% 65.9%, and 51.2%. Corresponding limb salvage rates were 80.6%, 78.0%, 75.7%, and 67.5%. CONCLUSION: Although not addressed by a randomized trial, we believe this expanded series is a more accurate reflection of expected results confirming that the DVP bypass leads to reasonable long-term results for those challenging patients that require prosthetic distal bypass for lower extremity revascularization.

Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation.

Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-beta signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

Critical interactions between TGF-beta signaling/ELF, and E-cadherin/beta-catenin mediated tumor suppression.

Inactivation of the transforming growth factor-beta (TGF-beta) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/- and elf+/- / Smad4+/- mutant mice. We found that embryonic liver fodrin (ELF), a beta-Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell-cell contacts and E-cadherin-beta-catenin-dependent epithelial cell-cell adhesion is disrupted in elf+/- / Smad4+/- mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-beta stimulation. In contrast, elf+/- / Smad4+/- mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-beta signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

RING finger-dependent ubiquitination by PRAJA is dependent on TGF-beta and potentially defines the functional status of the tumor suppressor ELF.

In gastrointestinal cells, biological signals for transforming growth factor-beta (TGF-beta) are transduced through transmembrane serine/threonine kinase receptors that signal to Smad proteins. Smad4, a tumor suppressor, is often mutated in human gastrointestinal cancers. The mechanism of Smad4 inactivation, however, remains uncertain and could be through E3-mediated ubiquitination of Smad4/adaptor protein complexes. Disruption of ELF (embryonic liver fodrin), a Smad4 adaptor protein, modulates TGF-beta signaling. We have found that PRAJA, a RING-H2 protein, interacts with ELF in a TGF-beta-dependent manner, with a fivefold increase of PRAJA expression and a subsequent decrease in ELF and Smad4 expression, in gastrointestinal cancer cell lines (P < 0.05). Strikingly, PRAJA manifests substantial E3-dependent ubiquitination of ELF and Smad3, but not Smad4. Delta-PRAJA, which has a deleted RING finger domain at the C terminus, abolishes ubiquitination of ELF. A stable cell line that overexpresses PRAJA exhibits low levels of ELF in comparison to a Delta-PRAJA stable cell line, where ELF expression is high compared to normal controls. The alteration of ELF and/or Smad4 expression and/or function in the TGF-beta signaling pathway may be induced by enhancement of ELF degradation, which is mediated by a high-level expression of PRAJA in gastrointestinal cancers. In hepatocytes, half-life (t(1/2)) and rate constant for degradation (k(D)) of ELF is 1.91 h and 21.72 min(-1) when coupled with ectopic expression of PRAJA in cells stimulated by TGF-beta, compared to PRAJA-transfected unstimulated cells (t(1/2) = 4.33 h and k(D) = 9.6 min(-1)). These studies reveal a mechanism for tumorigenesis whereby defects in adaptor proteins for Smads, such as ELF, can undergo degradation by PRAJA, through the ubiquitin-mediated pathway.

Distal migration and deformation of the Greenfield vena cava filter.

We have presented two patients in whom distal migration of the Greenfield vena cava filter has resulted in complications. In one patient there was marked deformation of the vena cava filter struts for an unknown reason resulting in perforation of the vena cava filter and the small bowel. In a second patient the distal migration resulted in poor alignment of the filter and recurrent pulmonary emboli. We feel that the Greenfield filter represents an excellent choice for caval interruption but that we would like to draw attention to the complication of distal migration. In addition, we would like to point out deformation of the struts of the Greenfield filter for which we have no explanation and which, to our knowledge, has not been reported previously.

Surgical management of subclavian and axillary vein thrombosis in patients with a functioning arteriovenous fistula.

Until recently, secondary thrombosis of the deep veins of the upper extremity was rarely encountered. The expanding use of the subclavian vein as a route to the central circulation has increased its occurrence, but symptoms are uncommon. Patients on hemodialysis with a functioning arteriovenous fistula become symptomatic with venous hypertension and swelling. Treatment becomes necessary, and fistula ligation is usually recommended; however, this renders the extremity unsuitable for a future life-sustaining access. Patency of grafts in the venous system has been accomplished with a temporary arteriovenous fistula. In six patients with chronic renal failure and a functioning arteriovenous fistula, a polytetrafluoroethylene graft was used to replace or bypass the obstructed vein. Symptoms resolved, and the fistula was preserved in three of the six patients for 1 to 3 years.

Vascular stent deployment in vein bypass grafts: observations in an animal model.

BACKGROUND: An important cause of vein graft failure is anastomotic stenosis caused by myointimal hyperplasia. Intravascular stents may allow balloon dilation of these hyperplastic lesions, thereby increasing secondary graft patency. METHODS: To evaluate intravascular stent deployment in vein grafts, we implanted 26 stents across the anastomotic sites of reversed vein grafts in 13 sheep. Stent deployment was evaluated immediately and at 3, 8, and 24 weeks by arteriography, light microscopy, and scanning electron microscopy. In a second animal cohort, stent-arterial wall contact after deployment was evaluated with intravascular ultrasonography (IVUS). Stents were imaged with IVUS after partial (n = 5) and complete (n = 5) expansion in 10 sheep carotid arteries. RESULTS: Stents were deployed across vascular anastomoses without immediate thrombosis. Partial neointimal coverage occurred after 3 and 8 weeks, with complete coverage by 24 weeks. Complications included distal migration (n = 3), arteriographic stenosis (n = 2), and late graft occlusion (n = 2). Incomplete stent-vessel wall contact at deployment was observed in the stents with complications. IVUS accurately showed stent expansion and the degree of stent-vessel wall contact. CONCLUSIONS: Stents can be deployed in vein grafts with the expectation of neointimal coverage and maintenance of graft patency. IVUS may prove important in guiding optimal stent deployment by providing an assessment of stent-vessel wall contact.

Insulin-like growth factor I receptors in the arteries of the rabbit: autoradiographic mapping and receptor characterization.

Insulin-like growth factor I (IGF-I) is a polypeptide hormone structurally related to insulin with insulin-like metabolic effects. It is a potent mitogen, eliciting cell multiplication in tissue culture by increasing deoxyribonucleic acid and protein synthesis. IGF-I was found to promote the growth of cultured arterial smooth muscle cells. We studied the in situ distribution of IGF-I receptors in different arteries of the rabbit by autoradiography and examined their binding characteristics in the wall of the thoracic aorta. The thoracic and abdominal aortas and carotid, superior mesenteric, renal, and iliac arteries of three adult New Zealand rabbits were harvested and stored at -70 degrees C. Autoradiographic analysis of 125I-labeled IGF-I binding to frozen arterial sections showed that silver-grain density was consistently located in the arterial wall. Binding studies in the thoracic aorta demonstrated high-affinity IGF-I receptors with a dissociation constant of 2 nmol/L and maximum IGF-I binding capacity of 4.17 pmol/mg protein. Inhibition studies with insulin, IGF-I, and IGF-II showed that these binding sites were more specific for IGF-I than for IGF-II or insulin, with a concentration of peptide that inhibits 50% of maximum binding of 1.75 nmol/L, 5 nmol/L, and greater than 100 mumol/L, respectively. The presence of high-affinity, specific IGF-I receptor binding in rabbit arteries suggests that IGF-I plays an important role in regulating the multiplication of arterial smooth muscle cells; a role that may prove important in different pathologic processes.

Retroperitoneal inflow procedures for iliac occlusive vascular disease.

We reviewed our experience over the past six years with retroperitoneal inflow procedures (aortofemoral and iliofemoral bypass grafts) in high-risk patients with aortoiliac occlusive disease. There were 57 limbs in 40 patients. Twenty percent of the patients were diabetic, 80% were smokers, 40% had heart disease, 54% had hypertension, and 25% had symptomatic chronic obstructive pulmonary disease. The average patient age was 64 years. There was no operative mortality and cumulative patency rate by life-table analysis at four years was 84%. The site of the proximal anastomosis (aorta vs iliac) or the configuration of the graft (unifemoral vs bifemoral) did not influence the patency rate. Retroperitoneal inflow procedures are an excellent alternative in patients who present an unacceptably high risk for standard aortofemoral reconstruction.

Role of insulin-like growth factor-I (IGF-I) receptor, IGF-I, and IGF binding protein-2 in human colorectal cancers.

The identification of novel autocrine/paracrine signaling pathways and possible markers represents an important component in the understanding of tumor growth control. In this study, we assessed the potential role of insulin-like growth factor-I (IGF-I), the IGF-I receptor (IGF-IR) and IGF binding protein-2 (IGFBP-2) in human colorectal cancer. Initial studies demonstrating increased IGF-I binding and IGF-IR density in human colon cancer tissue revealed that a component of iodinated (3-[125-I]iodotyrosyl) IGF-I (125I-ICGF-I) binding was not attributable to IGF-IR. Binding studies and Western blot analysis suggested that this second component of 125I-IGF-I binding could be due to IGFBP-2. Further analysis by a specific solution hybridization/RNase protection assay for IGF-IR mRNA levels, IGFBP-2 mRNA levels and in situ hybridization for IGFBP-2 localization, was carried out in nine patients with colon cancer. IGF-IR mRNA levels by RNAse protection assays were unchanged, whereas IGFBP-2 mRNA levels were increased 4-8-fold in patients with colon cancer compared to controls. Three patients with Dukes stage C disease had the highest levels of IGFBP-2 mRNA. In situ hybridization studies localized IGFBP-2 mRNA to malignant cells and not to the surrounding stromal cells, suggesting an autocrine role for IGFBP-2. The discrepancy between increased IGF-I binding, IGF-IR density, IGFBP-2 mRNA and the minimal modulation of the IGF-IR mRNA implies post-transcriptional regulation of IGF-IRs. Our results suggest that IGFBP-2 may be implicated in colon cancer metastases and prognosis. Its usefulness as a potential tumor marker should be further investigated.

Prosthetic bypass with a distal vein patch for limb salvage.

BACKGROUND: Certain patients require tibial bypass for limb salvage without adequate vein available as the conduit. Polytetrafluoroethylene (PTFE) bypasses result in decreased patency prompting the addition of venous tissue at the distal anastomosis as cuffs, collars, and boots. We assessed feasibility and graft patency of a distal vein patch (DVP) interposed between PTFE and the tibial artery. METHODS: Between 7/93 and 7/96, 148 tibial bypasses were performed with 25 (17%) using PTFE/DVP as the conduit. Patient demographics (n = 24) were 11 males and 13 females, mean age of 67, diabetes (n = 15, 57%), renal failure (n = 8, 31%), and excessive cardiac risk (n = 20, 83%). All patients had limb-threatening ischemia with rest pain in 14 (58%) and gangrene/nonhealing ulcer in 10 (42%). Lack of vein was due to previous failed bypass (15,63%), cardiac surgery (5,21%), and unsuitable vein (4,21%). Patients were discharged on coumadin with follow-up at 1 month, 6 months, and annually. RESULTS: PTFE/DVP bypasses originated from the CFA (13,48%), the SFA (3,11 %) and the external iliac artery due to previous groin dissection (9,41 %). Recipient arteries included anterior tibial (7), posterior tibial (8), and peroneal (10). Follow-up ranged from 1 to 36 months. Cumulative graft patency at 6 months and 3 years was 91% and 78%, respectively, by life table analysis. Limb salvage was 91%. CONCLUSION: These early data indicate that tibial bypass with PTFE/DVP as the conduit results in acceptable patency and limb salvage. In the patient without adequate vein, PTFE bypasses to tibial arteries for limb salvage may be improved with a distal vein patch.

Popliteal-to-tibial in situ saphenous vein bypass for limb salvage in diabetic patients.

This study has summarized our results with popliteal-tibial in situ saphenous vein bypass in 26 patients, 25 of whom were diabetic, over a 2 year period. Both above- and below-knee popliteal inflow sites were used for bypass of limb-threatening ischemia. Distal calf or pedal outflow sites were required in all but two patients who had sequential bypass performed to tibial sites. Postoperative ankle-brackial indices were calculated. Eleven patients had transcutaneous mapping surrounding the pedal skin envelope injuries. The mean lowest and highest transcutaneous oxygen values have been reported as a guide to successful healing.

Effect of inflow and outflow sites on the results of tibioperoneal vein grafts.

We have reviewed our experience with the tibial vessel bypass operation and have found the overall patency and limb salvage rates to be acceptable. Patients were divided into two groups based on the site of the proximal anastomosis. In Group I, the proximal anastomosis was at the common femoral artery and in Group II, the proximal anastomosis was at the distal superficial femoral artery or the popliteal artery. The patients in the two groups were similar with regard to indications for operation, age, and sex. However, in Group I, 35 percent of the patients were diabetic and in Group II, 74 percent of the patients were diabetic. In the Group I patients, the 72 month graft patency rate was 65 percent with a limb salvage rate of 75 percent. In the Group II patients, the 72 month patency rate was 81 percent with a limb salvage rate of 89 percent. Some possible explanations for this slightly better result in Group II patients are discussed. All tibial bypasses were divided into three groups based on the recipient tibial artery. Analysis revealed that the 72 month patency rates were as follows: the anterior tibial artery 63 percent, the posterior tibial artery 81 percent, and the peroneal artery 80 percent. These differences were not significant but indicate, as others have recently pointed out, that the peroneal artery is indeed an acceptable recipient artery for tibial bypass surgery.

An in vivo feasibility study of intravascular ultrasound imaging.

Increasingly complex vascular reconstructions and emerging endovascular therapeutic modalities have stimulated the need for improved vascular imaging. To determine the feasibility of in vivo intravascular ultrasound, a miniature probe 1 mm in diameter with a 25 MHz center frequency was used to obtain two-dimensional, 360-degree cross-sectional images. In sheep, 14 superficial femoral arteries were imaged at different sites, and a portion of each vessel was resected for immediate in vitro imaging and histologic examination. In vivo images clearly showed the intima, media, and adventitia of the vessel wall as well as the lumen-intima and media-adventitia interfaces. There was a significant correlation in measured lumen area between resected artery ultrasound images and histologic sections. We conclude that intravascular ultrasound can produce high-resolution dynamic images that demonstrate vessel wall architecture and allow precise calculation of lumen area.

The preoperative angiogram as a predictor of peripheral vascular runoff.

The preoperative angiogram is widely used as a means of assessing peripheral vascular runoff before bypass grafting, but the correlation between preoperative angiographic findings and actual measurements of peripheral vascular resistance has not been adequately examined. To test this correlation, we first devised a simple technique for measuring peripheral resistance and validated it in five dogs. Increases in peripheral resistance were artificially produced by temporarily occluding either the deep or superficial femoral artery or by intravenous administration of phenylephrine hydrochloride, a vasoconstrictor. In each instance, significant increases in resistance could be measured. We then used a similar technique to measure resistance in 23 patients undergoing peripheral bypass surgery. In addition, preoperative angiograms for these 23 patients were independently scored by four readers as 0, 1, 2, or 3 based on the number of patent vessels seen below the knee. Variations in scoring from reader to reader suggested that the present criteria for grading angiograms on this basis are unclear. Moreover, the correlation between angiographic score and measured resistance was poor for three of the four scorers (-0.21 to -0.29, p greater than 0.05). The angiographic scores of one reader, however, correlated reasonably well with the peripheral resistance measured at surgery (-0.59, p = 0.01). These findings demonstrate that current criteria for grading the preoperative angiogram are not sufficiently standardized to reliably predict runoff from a preoperative angiogram. However, these findings also suggest that it may be possible to identify angiographic findings that correlate well with changes in measured resistance.

A modified directional atherectomy catheter for resection of calcified atherosclerotic plaques.

BACKGROUND: The purpose of this study was to determine the feasibility of resecting calcified atherosclerotic plaques in human cadaveric vessels by using a modified directional coronary atherectomy catheter and to correlate these results with bench tests using an in-vitro sea coral model. METHODS: The conventional directional coronary atherectomy catheter was modified by changing the cutter blade to a tungsten carbide material and by increasing the torsional strength of the drive cable. The performance of the modified directional coronary atherectomy (DCA) catheter was compared with the conventional catheter using a sea coral model to simulate calcified material. Then, 10 human ex-vivo arteries (eight with calcification) were treated with both conventional and modified catheters, and the results studied with intravascular ultrasound and confirmed by histologic examination. RESULTS: Using the modified directional coronary atherectomy catheter it was possible to perform effective and consistent longitudinal cutting, and to resect a significantly larger amount of coral (1.0 +/- 0.1 mm2 versus 0.2 +/- 0.1 mm2 with conventional cutter, P < 0.0001). In heavily calcified ex-vivo arteries, the modified catheter was more effective in removing calcified plaques (13 +/- 11 mg versus 3.7 +/- 1.4 mg with conventional cutter, P = 0.07). Intravascular ultrasound confirmed the effective atherectomy (residual area stenosis 28 +/- 16% versus 47 +/- 10% with the conventional device, P < 0.05), and histologic examination showed calcified nodules in the atherectomy samples obtained with the modified cutter (area of calcium 1.43 +/- 0.89 mm2 versus 0.93 +/- 0.83 mm2 with the conventional cutter). CONCLUSIONS: The modified directional coronary atherectomy catheter effectively removed both non-calcified and calcified plaques in the ex-vivo human cadaveric arteries, thus demonstrating the feasibility of directional coronary atherectomy of calcified plaques. This modified device shows promise for treating calcified coronary lesions, especially in larger vessels.

Myointimal hyperplasia: basic science and clinical considerations.

The mechanical injury caused by a bypass procedure or angioplasty of the coronary or peripheral arteries can initiate and maintain the process of myointimal hyperplasia. Myointimal hyperplasia is of great clinical importance. The development of the hyperplastic lesion at the outflow anastomosis of a prosthetic bypass or in autogenous saphenous vein bypass placed in the arterial system is responsible for most bypass failures. It is also the primary cause of restenosis after coronary angioplasty. Myointimal hyperplasia is a complex pathological process of the vascular system characterized by an abnormal proliferation of smooth muscle cells of the vascular wall. Proliferating smooth muscle cells migrate to the subendothelial area and form the hyperplastic lesion, which causes stenosis and obstruction of the vascular lumen. The pathogenesis of myointimal hyperplasia remains under investigation. However, it has been established that both mechanical and chemical factors may induce this process. Arterial injury is believed to stimulate the production of growth factors, such as platelet-derived growth factor (PDGF), which have been shown to stimulate the proliferation of arterial smooth muscle cells and the formation of the hyperplastic lesion in the vascular system. These growth factors and cytokines have been found to be secreted by a variety of cells, including endothelial cells, macrophages, platelets, and arterial smooth muscle cells. Blocking the effects of growth factors such as PDGF or fibroblast growth factor (FGF), by the administration of their antibodies, has been shown to limit the development of the hyperplastic lesion. In this article, we begin with the basic physiology of myointimal hyperplasia. We then address possible therapeutic considerations for the future.

The pathophysiology of atherosclerosis.

Complications resulting from advanced atherosclerosis are the most common indication for vascular reconstructive surgery. Atherosclerosis is a systemic disease affecting the entire arterial tree, but lesions involving the coronary, extracranial cerebral, and lower extremity circulations have the most clinical significance for surgeons. The pathogenesis of atherosclerosis involves a complex series of events, similar to a chronic inflammatory process, with the formation of atherosclerotic plaque as the end result. Injury to the endothelial cell of the artery, resulting in endothelial cell dysfunction, is the first step in the process. Activated endothelial cells attract leukocytes and vascular smooth muscle cells (VSMC), which accumulate and proliferate in the arterial wall. These cellular components produce an excessive amount of connective tissue matrix. The ultimate end point is the formation of a mature fibrous plaque. Symptoms occur when advanced lesions are complicated by plaque rupture, hemorrhage into the plaque, emboli, or thrombosis. A thorough understanding of the pathogenesis of atherosclerosis is essential for the development of strategies for the prevention of the disease, and for the development of new and effective treatments.