Leila Mureebe

2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

Smooth muscle cell migration and proliferation are mediated by distinct phases of activation of the intracellular messenger mitogen-activated protein kinase

PURPOSE Mitogen-activated protein kinase (MAPK) is a ubiquitous signaling protein that has been associated with cellular proliferation; however, its role in cellular migration has not been established. In this study, we investigate the role of MAPK in platelet-derived growth factor (PDGF)-induced migration and proliferation of human vascular smooth muscle cells (SMCs). METHODS SMC migration was measured using a microchemotaxis assay (4 hours), and proliferation was assessed using 3H-thymidine uptake and cell counts. PD098059 was used as a specific noncompetitive inhibitor of MAPK activation. RESULTS Coincubation of SMCs with PD098059 resulted in significant inhibition of PDGF-BB (5 ng/ml)-induced SMC chemotaxis and proliferation. The IC50 for both processes was approximately 10 mumol/L with complete inhibition at 50 mumol/L. Stimulation of SMCs with PDGF produced an early peak in MAPK activity followed by a plateau of activity that persisted for 24 hours. We hypothesized that variations in the temporal activation of MAPK might explain the action of this enzyme on these two disparate cellular events. By adding PD098059 at intervals after stimulation of SMCs with PDGF, we demonstrated an association between MAPK activity within the first 15 minutes and SMC migration, whereas MAPK activity between 1 and 4 hours was associated with SMC proliferation. CONCLUSIONS MAPK activity is essential for both SMC migration and proliferation, and distinct phases of enzyme activation are required to stimulate these two discrete cellular events. Inhibition of this signaling protein may prove to be a useful method for preventing intimal hyperplasia.

Basic Science Review: Current Insights on the Biology and Clinical Aspects of VEGF Regulation

Vascular endothelial growth factor (VEGF) is a key molecule that orchestrates the formation and function of vascular networks. Impaired regulation of angiogenesis is implicated in a number of pathologic states. For instance, neoplasias exhibit uncontrolled angiogenesis, whereas ischemia and states of vascular insufficiency involve reduced VEGF activity. As the role of VEGF has been elucidated in these disease processes, its therapeutic role has been developed. The Food and Drug Administration has approved several anti-VEGF agents for treating colorectal, lung, and kidney cancer. VEGF-inducing agents have also been used experimentally to induce angiogenesis in patients with critical limb ischemia. As more knowledge is gathered about the biology of VEGF and its receptors, there is greater promise for therapeutic modulation of VEGF expression. The purpose of this review is to describe the various therapeutic and biologic factors that regulate the expression of VEGF.

Differential effects of platelet-derived growth factor isotypes on human smooth muscle cell proliferation and migration are mediated by distinct signaling pathways

BACKGROUND Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs). Three isotypes of PDGF (BB, AB, and AA) have been identified; each of these isotypes may have differing effects on the behaviour of vascular SMCs. In this study we evaluated the influence of PDGF isotypes on proliferation and migration of human venous SMCs and explored the signaling pathways through which these effects are mediated. METHODS Proliferation was measured by a 72-hour assay of cell number, and migration was evaluated by a 4-hour microchemotaxis assay. The effects of PDGF isotypes on the activities of the signaling proteins mitogen-activated protein kinase (MAP-K), p 125 focal adhesion kinase (p125FAK), and tensin were measured by immunoprecipitation of these proteins and subsequent phosphorylation on myelin basic protein (in MAP-K) and Western blotting with antiphosphotyrosine (in tensin and p125FAK). RESULTS All three isotypes stimulated SMC proliferation (PDGF-BB > AB > AA). PDGF-BB and -AB, but not -AA, stimulated chemotaxis. All three isotypes activated MAP-K with an intensity that corresponded to their proliferative effects. PDGF-BB and -AB tyrosine phosphorylated tensin and p125FAK, whereas PDGF-AA had no effect on either of these proteins. CONCLUSIONS For human vascular SMCs the physiologic effects and the signaling pathways that mediate these effects are specific for each of the three PDGF isotypes. These data also suggest an association between MAP-K and SMC proliferation and between the proteins, p125FAK and tensin, and migration.

National trends in the repair of ruptured abdominal aortic aneurysms

OBJECTIVE This study evaluated trends in hospitalizations, treatment, and mortality of ruptured abdominal aortic aneurysms (rAAAs) in the United States Medicare population. METHODS The Medicare inpatient database (1995 through 2006) was reviewed for patients with rAAA and AAA by using International Classification of Disease (9th Clinical Modification) codes for rAAA and AAA. Proportions and trends were analyzed by chi(2) analysis, continuous variables by t test, and trends by the Cochran-Armitage test. RESULTS During the study period, hospitalizations with the diagnoses of rAAA declined from 23.2 to 12.8 per 100,000 Medicare beneficiaries (P < .0001), as did repairs of rAAA (15.6 to 8.4 per 100,000; P < .0001). No change was observed in AAA elective repairs. The 30-day mortality rate after open repair of rAAA decreased by 4.9% (from 39.6% to 34.7%; P = .0007 for trend) for the age group 65 to 74 and by 2.4% (from 52.9% to 50.5%, P = .0008) for the age group > or =75. Perioperative mortality after endovascular repair diminished by 13.6% (from 43.5% in 2001 to 29.9% in 2006; P = .0020). Mortality among women was higher than among men (51.1% vs 40.0% in 2006). The demographics of patients treated for rAAA changed to include a greater proportion of women and patients aged > or =75 years. CONCLUSION A significant decrease has occurred in the number of patients who have a diagnosis of rAAA and undergo treatment, but there has been no change in repairs of AAA. The perioperative mortality rate has improved due to the introduction of endovascular repair and a small but progressive improvement in survival after open repair for patients aged 65 to 74 years.

The role of integrins in saphenous vein vascular smooth muscle cell migration.

PURPOSE Smooth muscle cell (SMC) migration is an essential feature of the intimal hyperplastic process that so frequently limits the patency of vascular reconstructions. The purpose of this investigation was to evaluate the effect of a series of integrins, or cell surface receptors that mediate cellular attachment, on platelet-derived growth factor (PDGF) and extracellular matrix (ECM) protein-induced migration of human SMCs. METHODS Immunofluorescence staining was used to search for various integrins and subunits on the surface of SMCs derived from human saphenous vein. Chemotaxis and haptotaxis of SMCs to various matrix proteins and PDGF were assayed using a 48-well microchemotaxis chamber in the presence or absence of antibodies that blocked the function of these integrins. RESULTS Several subunits (beta 1, alpha 2, alpha 5) and one integrin (alpha v beta 3) were identified in saphenous vein SMCs. The beta 1 integrin antibody inhibited chemotaxis to collagen I and IV, laminin, and PDGF. The alpha 2 integrin antibody inhibited collagen I and IV, and laminin-induced chemotaxis. The alpha 5 integrin antibody had no effect on SMC migration. The alpha v beta 3 integrin antibody inhibited chemotaxis to PDGF but not to the ECM proteins. CONCLUSIONS Integrins are necessary for SMC migration induced by PDGF and ECM proteins. The integrin or subunits responsible for facilitating migration varies with the stimulant. Agonists designed to inhibit integrin function might be used to suppress SMC migration and suppress the formation of intimal hyperplasia.

Gender trends in the repair of ruptured abdominal aortic aneurysms and outcomes

BACKGROUND This study evaluated gender-specific trends in the diagnosis and treatment of ruptured abdominal aortic aneurysms (rAAAs) in the United States Medicare population. METHODS The Medicare beneficiary database (1995 through 2006) was examined for patients with rAAAs using International Classification of Diseaes, 9th Edition, Clinical Modification (ICD-9-CM) codes. Codes for endovascular aneurysm repair (EVAR) were only available for the year 2000 forward, and thus, analysis of EVAR was limited to 2000 through 2006. Proportions were analyzed by chi(2) and continuous variables by t-test. Factors associated with 30-day mortality and discharge home after surgery were analyzed by multivariate logistic regression. The effect of gender and repair type (open or EVAR) on death and the probability of discharge to home after repair were also evaluated. RESULTS The rate of hospitalizations per 100,000 Medicare fee-for-service beneficiaries for men decreased by 52% (from 40 to 19) and by 36% for women (from 11 to 7). The observed 30-day mortality rate was overall 7.7% higher for women vs men. The mortality rate for women was higher by 8.9% for open repair and higher by 7.1% for EVAR vs men. Female gender was associated with increased risk of death in multivariate analysis after controlling for age, year, and type of procedure. Women were 9.8% less likely to be discharged to home after rAAA repair, regardless of the type of repair. CONCLUSION In addition to the fact that we have failed to realize a change in the number of women diagnosed with or treated for rAAA, a significant gender difference remains in the outcomes after treatment for rAAA. This differential is present in both the 30-day mortality rate and in the potential to be discharged to home after repair.

Hypercoagulable States: A Review

Vascular surgeons are often asked to evaluate patients with recurrent thromboses or thromboses in unusual locations either arterial or venous. There may be obvious inciting factors, but in many of these patients the possibility of a previously undiagnosed hypercoagulable state must be considered. Hypercoagulable states can be acquired (smoking, medication, change in physiologic status as occurs with pregnancy) or congenital. Congenital hypercoagulable disorders are more prevalent in families or patients with a history of thromboembolic events early in life or multiple miscarriages and include conditions such as protein C or S deficiencies, factor V Leiden mutation, and prothrombin gene variant. This article reviews the hypercoagulable states that are encountered in clinical practice as well as guidelines for testing and goals of therapy.

Argatroban for anticoagulation during cardiopulmonary bypass in an infant

Heparin induced thrombocytopenia (HIT) is a rare, but potentially life‐threatening complication of heparin therapy. In patients with HIT, alternative means of anticoagulation are necessary. The authors present an infant with HIT who required anticoagulation during cardiopulmonary bypass for tricuspid valve excision in the treatment of bacterial endocarditis. The direct thrombin inhibitor, argatroban, was successfully used. Previous reports regarding the use of argatroban and other nonheparin anticoagulants for anticoagulation are reviewed and suggestions regarding argatroban dosing in infants are presented.

Activation of pp60c-src is necessary for human vascular smooth muscle cell migration☆☆☆

BACKGROUND The most widely distributed nonreceptor tyrosine kinase is pp60c-src (src), yet the role of this intracellular signaling protein in cell migration has not been defined. Given that smooth muscle cell (SMC) migration is essential for the development of intimal hyperplasia, we investigated the importance of src in locomotion of human vascular SMC. METHODS SMC migration was evaluated using a microchemotaxis chamber assay and videomicroscopy. Src kinase activity was determined by measuring phosphorylation of a synthetic derivative of p34cdc2, a specific substrate for src. Blocking antibodies to src were introduced using a cytoplasmic microinjection technique. RESULTS Stimulation of SMC with platelet-derived growth factor (PDGF)-BB and AB resulted in an increase in src activation, whereas PDGF-AA did not consistently enhance src activity. These findings correlated with the ability of the PDGF isotypes to stimulate SMC chemotaxis; PDGF-BB and AB produced 7.4 +/- 0.3- and 5.3 +/- 0.5-fold increases in SMC chemotaxis, whereas PDGF-AA inhibited chemotaxis. SMC migration in response to PDGF-BB and serum was significantly inhibited by intracellular injection of a blocking antibody. CONCLUSIONS Our findings reveal an association between agonist-induced src activation and chemotaxis. Moreover, an antibody that inhibits src activation dramatically inhibits migration of individual SMC. We conclude that activation of src is necessary for SMC migration. Because of its importance in SMC migration, either molecular or pharmacologic inhibitors of src may be useful in the control of intimal hyperplasia.