Other articles by Edward R. O'Brien on PubMed

• Hospitalization Costs of Primary Stenting Versus Thrombolysis in Acute Myocardial Infarction: Cost Analysis of the Canadian STAT Study Circulation. Nov, 2003  |   Pubmed ID: 14597591 We previously showed that primary stenting was more effective than accelerated tPA in reducing the 6-month composite of death, reinfarction, stroke, or repeat revascularization for ischemia. This study looks at the hospitalization costs of primary stenting compared with accelerated tPA.
• Novel Antiinflammatory Vascular Benefits of Systemic and Stent-based Delivery of Ethylisopropylamiloride Circulation. Dec, 2004  |   Pubmed ID: 15505102 Recently, we demonstrated that the amiloride derivative ethylisopropylamiloride (EIPA) limits vascular smooth muscle cell growth and migration. The purpose of the present experiments was to determine whether EIPA can also reduce the inflammatory component of atherogenesis and stent neointima formation.
• C-kit-immunopositive Vascular Progenitor Cells Populate Human Coronary In-stent Restenosis but Not Primary Atherosclerotic Lesions American Journal of Physiology. Heart and Circulatory Physiology. Aug, 2004  |   Pubmed ID: 15277195 Progress in the treatment of human in-stent restenosis (ISR) is hampered by an imprecise understanding of the nature of the cells that occlude vascular stents. Recent studies suggest that circulating vascular progenitor cells may mediate vascular repair and lesion formation. Moreover, functional endothelial progenitor cells appear to play a protective role in attenuating vascular lesion formation. Hence, we sought to answer two important questions: 1). Are primitive cells found in ISR lesions? 2). Is the abundance of cultured angiogenic cells (CACs) in patients with ISR different from that in patients with non-ISR lesions or normal controls? Human coronary atherectomy tissue from 13 ISR, 6 postangioplasty restenosis (RS), and 14 primary (PR) atherosclerotic lesions, as well as 15 postmortem coronary artery cross sections from young individuals without atherosclerosis, were studied. All 13 ISR and 4 of 6 RS tissue specimens contained cells that immunolabeled for the primitive cell marker c-kit and smooth muscle alpha-actin, whereas the intima and media of PR lesions and normal arteries were devoid of c-kit-immunopositive cells. The abundance of peripheral blood mononuclear cell-derived CACs was assessed in 10 patients with ISR, 6 patients with angiographically verified patent stents, and 6 individuals with no clinical evidence of coronary artery disease. CACs were less abundant in ISR patients than in non-ISR controls (13.9 +/- 3.1 vs. 22.3 +/- 6.7 cells/high-power field, P < 0.05), and both of these groups had fewer CACs than non-coronary artery disease patients (37.6 +/- 3.8, P < 0.05). These findings suggest a unique pathogenesis for ISR and RS lesions that involves c-kit-immunopositive smooth muscle cells. Moreover, the paucity of CACs in patients with ISR may contribute to the pathogenesis of ISR, perhaps because of attenuated reendothelialization.
• Antagonism of the Alpha4 Integrin Subunit Attenuates the Acute Inflammatory Response to Stent Implantation Yet is Insufficient to Prevent Late Intimal Formation Journal of Leukocyte Biology. Jun, 2004  |   Pubmed ID: 15020653 Mononuclear leukocytes infiltrate the artery wall via integrin-mediated mechanisms and play an integral role in intimal formation after stenting. We sought to determine if acute antagonism of the alpha4 subunit of very late antigen-4 is sufficient for the late attenuation of stent intimal area (IA). Twenty-four hypercholesterolemic rabbits underwent iliac artery balloon injury, followed 2 weeks later by stent implantation, and the animals were randomized to receive an anti-alpha4 antibody (HP1/2) or a nonspecific isotypic control immunoglobulin (1E6) intravenously 1 h before stenting. Compared with controls, HP1/2-treated rabbits showed 50%, 51%, and 44% reductions in the percentage on intimal cells that were macrophages on days 3, 7, and 28 after stenting and a 59% reduction in intimal proliferation on day 3. Although stent IA was reduced by 63% and 48% in the antibody-treated group compared with the control group on days 3 and 7, this difference was not present on day 28. These data highlight the need for sustained, anti-inflammatory therapies for the prevention of stent intimal formation.
• Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL AMI Study) Journal of the American College of Cardiology. Aug, 2005  |   Pubmed ID: 16053952 We compared a strategy of tenecteplase (TNK)-facilitated angioplasty with one of TNK alone in patients presenting with high-risk ST-segment elevation myocardial infarction (STEMI).
• Modulation of Estrogen Signaling by the Novel Interaction of Heat Shock Protein 27, a Biomarker for Atherosclerosis, and Estrogen Receptor Beta: Mechanistic Insight into the Vascular Effects of Estrogens Arteriosclerosis, Thrombosis, and Vascular Biology. Mar, 2005  |   Pubmed ID: 15662019 We sought to discover proteins that associate with estrogen receptor beta (ERbeta) and modulate estrogen signaling.
• 17beta-estradiol Downregulates Tissue Angiotensin-converting Enzyme and ANG II Type 1 Receptor in Female Rats American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. Mar, 2005  |   Pubmed ID: 15550614 Estrogens have been implicated in both worsening and protecting from cardiovascular disease. The effects of 17beta-estradiol (E2) on the cardiovascular system may be mediated, at least in part, by its modulation of local tissue renin-angiotensin systems (RAS). We assessed two critical components, angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT(1)R), in the heart, lung, abdominal aorta, adrenal, kidney, and brain in four groups of female Wistar rats (n = 5-6/group): 1) sham ovariectomized, 2) ovariectomized (OVX) treated with subcutaneous vehicle, 3) OVX treated with 25 mug/day (regular) E2 subcutaneously, and 4) OVX treated with 250 mug/day (high) subcutaneous E2 for 2 or 5 wk. After 2 wk, plasma ACE activity was not altered by OVX, but it was 34-38% lower in OVX + regular E2 and OVX + high E2 rats compared with sham OVX rats, and these decreases were no longer present after 5 wk. After 5 wk, OVX alone increased ACE activity and binding densities, and AT(1)R binding densities by 15-100% in right ventricle, left ventricle (LV), kidney, lung, abdominal aorta, adrenal and several cardiovascular regulatory nuclei in the brain. These effects were, for the most part, prevented by regular E2 replacement and were reversed to decreases by high E2 treatment. This regulation of tissue ACE and AT(1)R is significant as the activity of these tissue RAS contributes to the pathogenesis and/or progression of hypertension, atherosclerosis, and LV remodeling after myocardial infarction.
• Comparison of Early Mortality of Paramedic-diagnosed ST-segment Elevation Myocardial Infarction with Immediate Transport to a Designated Primary Percutaneous Coronary Intervention Center to That of Similar Patients Transported to the Nearest Hospital The American Journal of Cardiology. Nov, 2006  |   Pubmed ID: 17134623 Speed of reperfusion is critical in ST-segment elevation myocardial infarction (STEMI). We assessed the safety and feasibility of an integrated metropolitan approach in which advanced-care paramedics interpret the prehospital electrocardiogram and independently refer patients with STEMI to a designated center for primary percutaneous coronary intervention (PCI). We developed and implemented a protocol in which paramedics trained in electrocardiographic interpretation bypassed the nearest emergency room and referred patients with suspected STEMI directly to a designated primary PCI center (paramedic-referred primary PCI). Outcomes of these patients were compared with those of a retrospective cohort of 225 consecutive patients with STEMI transported by ambulance to the nearest hospital emergency department. We treated 108 consecutive patients with STEMI using ambulance services according to the paramedic-referred primary PCI protocol. Primary PCI was performed in 93.5% versus 8.9% in the control group, and the median door-to-balloon time was 63 versus 125 minutes in the control group (p
• Comparison of Processing and Sectioning Methodologies for Arteries Containing Metallic Stents The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society. Jun, 2006  |   Pubmed ID: 16714423 The histological study of arteries with implanted metallic scaffolding devices, known as stents, remains a technical challenge. Given that the arterial response to stent implantation can sometimes lead to adverse outcomes, including the re-accumulation of tissue mass within the stent (or in-stent restenosis), overcoming these technical challenges is a priority for the advancement of research and development in this important clinical field. Essentially, the task is to section the stent-tissue interface with the least amount of disruption of tissue and cellular morphology. Although many methacrylate resin methodologies are successfully applied toward the study of endovascular stents by a variety of research laboratories, the exact formulations, as well as subsequent processing and sectioning methodology, remain largely coveted. In this paper, we describe in detail a methyl methacrylate resin-embedding methodology that can successfully be applied to tungsten carbide blade, as well as saw and grinding sectioning methods and transmission electron microscopy. In addition, we present a comparison of the two sectioning methodologies in terms of their effectiveness with regard to morphological, histochemical, and immunohistochemical analyses. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
• Regulation of Components of the Brain and Cardiac Renin-angiotensin Systems by 17beta-estradiol After Myocardial Infarction in Female Rats American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. Jul, 2006  |   Pubmed ID: 16455770 The present study tested the hypothesis that 17beta-estradiol (E2) inhibits increases in angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT1R) in the brain and heart after myocardial infarction (MI) and, thereby, inhibits development of left ventricular (LV) dysfunction after MI. Age-matched female Wistar rats were treated as follows: 1) no surgery (ovary intact), 2) ovariectomy + subcutaneous vehicle treatment (OVX + Veh), or 3) OVX + subcutaneous administration of a high dose of E2 (OVX + high-E2). After 2 wk, rats were randomly assigned to coronary artery ligation (MI) and sham operation groups and studied after 3 wk. E2 status did not affect LV function in sham rats. At 2-3 wk after MI, impairment of LV function was similar across MI groups, as measured by echocardiography and direct LV catheterization. LV ACE mRNA abundance and activity were increased severalfold in all MI groups compared with respective sham animals and to similar levels across MI groups. In most brain nuclei, ACE and AT1R densities increased after MI. Unexpectedly, compared with the respective sham groups the relative increase was clearest (20-40%) in OVX + high-E2 MI rats, somewhat less (10-15%) in ovary-intact MI rats, and least (< 10-15%) in OVX + Veh MI rats. However, because in the sham group brain ACE and AT1R densities increased in the OVX + Veh rats and decreased in the OVX + high-E2 rats compared with the ovary-intact rats, actual ACE and AT1R densities in most brain nuclei were modestly higher (< 20%) in OVX + Veh MI rats than in the other two MI groups. Thus E2 does not inhibit upregulation of ACE in the LV after MI and amplifies the percent increases in ACE and AT1R densities in brain nuclei after MI, despite E2-induced downregulation in sham rats. Consistent with these minor variations in the tissue renin-angiotensin system, during the initial post-MI phase, E2 appears not to enhance or hinder the development of LV dysfunction.
• The Interaction and Cellular Localization of HSP27 and ERbeta Are Modulated by 17beta-estradiol and HSP27 Phosphorylation Molecular and Cellular Endocrinology. May, 2007  |   Pubmed ID: 17350752 Recently, we identified heat shock protein 27 (HSP27) as an estrogen receptor-beta (ERbeta) associated protein that acts as a co-repressor of estrogen signaling and serves as a biomarker of atherosclerosis. In this study, we sought to further characterize the subcellular interaction of HSP27 and ERbeta, as well as explore the factors that may modulate this interaction. In vitro we determined that phosphorylated HSP27 is retained in the cytoplasm after treatment with 17beta-estradiol and to a lesser extent with heat shock. Under all experimental conditions ERbeta was found to be slightly more abundant in the cytoplasm compared to the nucleus. HSP27 and ERbeta associate in both the cytoplasm and nucleus, however, co-localization studies reveal that in the presence of 17beta-estradiol, a significant portion of this interaction occurs outside of the nucleus. These data highlight an extranuclear interaction between ERbeta and HSP27 that may be of potential importance in modulating estrogen signaling.
• NM23-H2, an Estrogen Receptor Beta-associated Protein, Shows Diminished Expression with Progression of Atherosclerosis American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. Feb, 2007  |   Pubmed ID: 17272673 While estrogen receptor (ER) profile plays an important role in response to estrogens, receptor coregulators act as critical determinants of signaling. Although the clinical effects of ovarian hormones on various normal and pathological processes are an active area of research, the exact signaling effects on, for example, the vessel wall, are incompletely understood. Hence, we sought to discover proteins that associate with ERbeta, the isoform that shows upregulated mRNA expression after arterial injury. Using a yeast two-hybrid screen we identified NM23-H2, a multifaceted metastasis suppressor candidate protein, as an ERbeta-associated protein. Although NM23-H2 was immunodetected in arteries from young subjects (27 +/- 6 yr, 14 men and 6 women) with benign intimal hyperplasia, expression was diminished in fatty streaks/atheromas and altogether absent in advanced atherosclerotic lesions. Both nm23-H2 mRNA and protein were expressed by vascular cells in vitro. Treatment with 17beta-estradiol and an ERbeta-selective agonist, diarylpropionitrile, increased protein expression of NM23-H2; an effect that was not seen with an ERalpha-selective agonist, propylpyrazole-triol. Estrogen also prompted nuclear localization of NM23-H2 protein in human coronary smooth muscle cells (SMCs). An in vitro mimic of inflammation decreased the expression of NM23-H2 in SMCs, which was restored on addition of estrogen and dependent on the estrogen receptor. In summary, we report the novel association of NM23-H2 with ERbeta and show for the first time its expression in vascular cells and demonstrate regulation of its expression and localization by estrogen. In that the abundance of NM23-H2 diminishes with both the advancement of atherosclerosis and inflammation, this ERbeta-associated protein may play an important role in mediating the vasculoprotective effects of estrogens.
• Extracellular Release of the Atheroprotective Heat Shock Protein 27 is Mediated by Estrogen and Competitively Inhibits AcLDL Binding to Scavenger Receptor-A Circulation Research. Jul, 2008  |   Pubmed ID: 18566345 We recently identified heat shock protein 27 (HSP27) as an estrogen receptor beta (ERbeta)-associated protein and noted its role as a biomarker for atherosclerosis. The current study tests the hypothesis that HSP27 is protective against the development of atherosclerosis. HSP27 overexpressing (HSP27o/e) mice were crossed to apoE-/- mice that develop atherosclerosis when fed a high-fat diet. Aortic en face analysis demonstrated a 35% reduction (P < or =0.001) in atherosclerotic lesion area in apoE-/-HSP27o/e mice compared to apoE-/- mice, but primarily in females. Serum -HSP27levels were 10-fold higher in female apoE-/-HSP27o/e mice compared to males, and there was a remarkable inverse correlation between circulating HSP27 levels and lesion area in both male and female mice (r(2)=0.78, P < or =0.001). Mechanistic in vitro studies showed upregulated HSP27 expression and secretion in macrophages treated with estrogen or acLDL. Moreover, exogenous HSP27 added to culture media inhibited macrophage acLDL uptake and competed for the scavenger receptor A (SR-A)--an effect that was abolished with the SR-A competitive ligand fucoidan and absent in macrophages from SR-A-/- mice. Furthermore, extracellular HSP27 decreased acLDL-induced release of the proinflammatory cytokine IL-1beta and increased the release of the antiinflammatory cytokine IL-10. HSP27 is atheroprotective, perhaps because of its ability to compete for the uptake of atherogenic lipids or attenuate inflammation.
• Letter by Hibbert Et Al Regarding Article, "Smooth Muscle Cells Healing Atherosclerotic Plaque Disruptions Are of Local, Not Blood, Origin in Apolipoprotein E Knockout Mice" Circulation. Apr, 2008  |   Pubmed ID: 18427139
• Contribution of Recipient-derived Cells in Allograft Neointima Formation and the Response to Stent Implantation PloS One. 2008  |   Pubmed ID: 18365026 Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1+/-5.7% and 81.5+/-4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7+/-0.5% and 2.3+/-0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0+/-0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation.
• A Citywide Protocol for Primary PCI in ST-segment Elevation Myocardial Infarction The New England Journal of Medicine. Jan, 2008  |   Pubmed ID: 18199862 If primary percutaneous coronary intervention (PCI) is performed promptly, the procedure is superior to fibrinolysis in restoring flow to the infarct-related artery in patients with ST-segment elevation myocardial infarction. The benchmark for a timely PCI intervention has become a door-to-balloon time of less than 90 minutes. Whether regional strategies can be developed to achieve this goal is uncertain.
• Discovery of NM23-H2 As an Estrogen Receptor Beta-associated Protein: Role in Estrogen-induced Gene Transcription and Cell Migration The Journal of Steroid Biochemistry and Molecular Biology. Jan, 2008  |   Pubmed ID: 17964137 The regulation of the estrogenic responses may be influenced by the proteins that associate with estrogen receptors (ERs) rather than solely with the receptors themselves. ERbeta is expressed in blood vessels and may play an important role in vascular disease. We hypothesized that specific proteins interact with ERbeta to modulate its response to estrogens. By means of a yeast two hybrid screen, we discovered that NM23-H2, a multi-faceted protein associates specifically with ERbeta. NM23-H2 and ERbeta consistently co-localize in a variety of human tissues (e.g. breast tissue), whereas ERalpha and NM23-H2 did not co-localize. Estrogen response element-mediated transcription increased by 97% when NM23-H2 and ERbeta were over-expressed in MCF-7 cells (p< or =0.001). Moreover, there was a synergistic effect of NM23-H2 over-expression with estrogen treatment on the reduction of MCF-7 cell migration (p< or =0.001). These results suggest that NM23-H2 associates with ERbeta and is capable of modulating estrogen-induced gene transcription, as well as cell migration. Hence, NM23-H2 may play an important role in modulating the response to endogenous and exogenous estrogens, perhaps even within the context of vascular disease.
• Primary Percutaneous Coronary Angioplasty with and Without Eptifibatide in ST-segment Elevation Myocardial Infarction: a Safety and Efficacy Study of Integrilin-facilitated Versus Primary Percutaneous Coronary Intervention in ST-segment Elevation Myocardial Infarction (ASSIST) Circulation. Cardiovascular Interventions. Aug, 2009  |   Pubmed ID: 20031736 Primary percutaneous coronary intervention, if performed promptly, is the preferred strategy to restore flow to the infarct-related artery in patients with ST-segment elevation myocardial infarction. We sought to determine whether eptifibatide, a platelet glycoprotein IIb/IIIa inhibitor, given before catheterization would improve clinical outcomes in patients referred for primary percutaneous coronary intervention.
• Heat Shock Protein 27 Protects Against Atherogenesis Via an Estrogen-dependent Mechanism: Role of Selective Estrogen Receptor Beta Modulation Arteriosclerosis, Thrombosis, and Vascular Biology. Nov, 2009  |   Pubmed ID: 19729610 We recently identified HSP27 as an atheroprotective protein that acts extracellularly to prevent foam cell formation and atherogenesis in female but not male mice, where serum levels of HSP27 were increased and inversely correlated with degree of lesion burden. In the current study we sought to determine whether estrogens are required for the observed atheroprotective benefits of HSP27 as well as its extracellular release.
• Inhibition of Endothelial Progenitor Cell Glycogen Synthase Kinase-3beta Results in Attenuated Neointima Formation and Enhanced Re-endothelialization After Arterial Injury Cardiovascular Research. Jul, 2009  |   Pubmed ID: 19454488 Endothelial progenitor cells (EPCs) are circulating pluripotent vascular cells capable of enhancing re-endothelialization and diminishing neointima formation following arterial injury. Glycogen synthase kinase (GSK)-3beta is a protein kinase that has been implicated in the regulation of progenitor cell biology. We hypothesized that EPC abundance and function could be enhanced with the use of an inhibitor of GSK-3beta (GSKi), thereby resulting in improved arterial repair.
• Cardiovascular Complications of Salmonella Enteritidis Infection The Canadian Journal of Cardiology. Oct, 2010  |   Pubmed ID: 20931102 Salmonella has the ability to adhere to damaged endothelium, predisposing individuals to complications rarely seen with other Gram-negative organisms. Potential complications include endocarditis, infected atheroma or aneurysms, myocarditis and pericarditis. The present report describes two cases of Salmonella enteritidis-associated cardiovascular disease. Patient 1 is a young adult who presented with myopericarditis complicated by recurrent cardiac arrests following return from a tropical climate. This patient was successfully treated with a 14-day course of ciprofloxacin. Patient 2 is an elderly man who developed a pseudoaneurysm of the ascending aorta complicating S enteritidis bacteremia, and died of this complication. Recognition of potential complications of salmonellosis, especially in individuals with risk factors, is paramount in correctly diagnosing and managing these patients.
• Heat Shock Protein 27: Clue to Understanding Estrogen-mediated Atheroprotection? Trends in Cardiovascular Medicine. Feb, 2010  |   Pubmed ID: 20656216 Although the use of estrogen replacement therapy for postmenopausal women has been dramatically curtailed due to an unfavorable risk-benefit profile, there remains strong experimental evidence that ovarian hormones have a favorable effect on vessel wall homeostasis. We recently discovered that release of heat shock protein 27 (HSP27) into the serum is atheroprotective and mediated by ovarian hormones, preferentially functioning via estrogen receptor-beta. HSP27 binds scavenger receptor-A, reduces cholesterol uptake in macrophages, and attenuates mediators of vascular inflammation. Therefore, it is attractive to consider HSP27 as the active foot soldier of estrogens and potentially a novel therapeutic opportunity for vascular disease.
• Delayed Re-endothelialization with Rapamycin-coated Stents is Rescued by the Addition of a Glycogen Synthase Kinase-3beta Inhibitor Cardiovascular Research. May, 2010  |   Pubmed ID: 20167573 Drug-eluting stents (DESs) reduce neointima area and in-stent restenosis but delay re-endothelialization. Recently, we demonstrated that pharmacological expansion and functional enhancement of endothelial progenitor cells (EPCs) can be achieved by treatment with a glycogen synthase kinase-3beta inhibitor (GSKi)-even for feeble cells derived from coronary artery disease patients. GSKi treatment enhanced EPC adhesion via up-regulated expression of the alpha-4 integrin, ameliorated re-endothelialization, and reduced neointima formation in denuded murine arteries. Hence, we hypothesized that GSKi-coated stents (GSs) will enhance EPC adhesion and attenuate delayed vascular healing associated with rapamycin, a key DES agent.
• Coronary Stent Fracture CMAJ : Canadian Medical Association Journal = Journal De L'Association Medicale Canadienne. Aug, 2011  |   Pubmed ID: 21444617
• Pre-procedural Atorvastatin Mobilizes Endothelial Progenitor Cells: Clues to the Salutary Effects of Statins on Healing of Stented Human Arteries PloS One. 2011  |   Pubmed ID: 21283543 Recent clinical trials suggest an LDL-independent superiority of intensive statin therapy in reducing target vessel revascularization and peri-procedural myocardial infarctions in patients who undergo percutaneous coronary interventions (PCI). While animal studies demonstrate that statins mobilize endothelial progenitor cells (EPCs) which can enhance arterial repair and attenuate neointimal formation, the precise explanation for the clinical PCI benefits of high dose statin therapy remain elusive. Thus we serially assessed patients undergoing PCI to test the hypothesis that high dose Atorvastatin therapy initiated prior to PCI mobilizes EPCs that may be capable of enhancing arterial repair.
• Bivalirudin for Primary Percutaneous Coronary Interventions: Outcome Assessment in the Ottawa STEMI Registry Circulation. Cardiovascular Interventions. Dec, 2012  |   Pubmed ID: 23149331 Data from randomized trials has demonstrated the superiority of bivalirudin to glycoprotein IIb/IIIa inhibitors plus heparin in patients undergoing primary percutaneous coronary intervention. Real-world performance of bivalirudin in primary percutaneous coronary intervention and the benefit of bivalirudin over heparin remain unknown in an era of routine dual antiplatelet therapy.
• Natural History and Management of Aortocoronary Saphenous Vein Graft Aneurysms: a Systematic Review of Published Cases Circulation. Oct, 2012  |   Pubmed ID: 23109515
• Reduction in Mortality As a Result of Direct Transport from the Field to a Receiving Center for Primary Percutaneous Coronary Intervention Journal of the American College of Cardiology. Oct, 2012  |   Pubmed ID: 23017532 This study sought to determine whether mortality complicating ST-segment elevation myocardial infarction (STEMI) was impacted by the design of transport systems.
• Transradial Versus Transfemoral Artery Approach for Coronary Angiography and Percutaneous Coronary Intervention in the Extremely Obese JACC. Cardiovascular Interventions. Aug, 2012  |   Pubmed ID: 22917453 This study sought to evaluate the safety and efficacy of transradial versus transfemoral access for coronary angiography and percutaneous coronary intervention in patients with a body mass index ≥ 40 kg/m(2).
• Transbrachial Insertion of an Intra-aortic Balloon Pump for High-risk Percutaneous Coronary Intervention Clinical Research in Cardiology : Official Journal of the German Cardiac Society. Oct, 2012  |   Pubmed ID: 22552835
• Infective Endocarditis Presenting As ST-elevation Myocardial Infarction: an Angiographic Diagnosis The Canadian Journal of Cardiology. Jul-Aug, 2012  |   Pubmed ID: 22381910 While systemic embolic events occur with relative frequency in infective endocarditis (IE), coronary embolization remains an uncommon cause of ST elevation myocardial infarction. Herein we report a case of ventricular fibrillation and anterior ST elevation myocardial infarction occurring in a patient initially presenting with septic shock. Angiography proved diagnostic for IE of a native bicuspid aortic valve complicated by root abscess and left anterior descending artery occlusion. Histologic examination of the embolectomy specimen from the left anterior descending artery confirmed the presence of thrombus and bacteria. The present case highlights difficulties in identifying and managing patients with coronary embolism of vegetations from IE.
• Circulating Endothelial Progenitor Cell Levels Are Not Reduced in HIV-infected Men The Journal of Infectious Diseases. Mar, 2012  |   Pubmed ID: 22238473 Reduced levels of endothelial progenitor cells (EPCs) have been associated with increased cardiovascular (CV) risk, but limited data are available on EPC levels in the human immunodeficiency virus (HIV)-infected population. EPCs (CD45(dim)/CD34(+)/kinase domain receptor(+)) from 36 HIV-uninfected and 30 antiretroviral therapy-naive HIV-infected men without known CV risk factors were enumerated using flow cytometry. The mean EPC levels (± standard error of the mean) were 1.4 ± 0.5 cells/μL in the HIV-infected group and 3.7 ± 2.2 cells/μL in the control group (P = .92). EPC levels were not associated with disease parameters, such as CD4 cell count or viral load. Reductions in EPC levels do not seem to explain the increased risk of CV disease among HIV-infected men.
• Heat Shock Protein-27 Attenuates Foam Cell Formation and Atherogenesis by Down-regulating Scavenger Receptor-A Expression Via NF-κB Signaling Biochimica Et Biophysica Acta. Dec, 2013  |   Pubmed ID: 23939398 Previously, we showed an inverse correlation between HSP27 serum levels and experimental atherogenesis in ApoE(-/-) mice that over-express HSP27 and speculated that the apparent binding of HSP27 to scavenger receptor-A (SR-A) was of mechanistic importance in attenuating foam cell formation. However, the nature and importance of the interplay between HSP27 and SR-A in atheroprotection remained unclear. Treatment of THP-1 macrophages with recombinant HSP27 (rHSP27) inhibited acLDL binding (-34%; p
• The Effect of Statins on Circulating Endothelial Progenitor Cells in Humans: a Systematic Review Journal of Cardiovascular Pharmacology. Nov, 2013  |   Pubmed ID: 23933855 Numerous clinical trials have demonstrated early reductions in cardiovascular events occurring independently of the lipid-lowering effects of statins. These pleiotropic effects have been attributed to antiinflammatory properties, to atherosclerotic plaque stabilization, and more recently to mobilization of endothelial progenitor cells (EPCs). Our aim was to evaluate the evidence supporting statin-induced EPC mobilization in humans. We, therefore, performed a computerized literature search and systematic review of randomized trials to determine the effect of statin therapy and statin dosing on circulating EPC numbers. Our literature search identified 10 studies including 479 patients which met inclusion criteria with publication dates ranging from 2005 to 2011. Seven studies compared statin to nonstatin regimens whereas 3 studied low versus high-dose statin therapy. Reported increases in EPC number ranged from 25.8% to 223.5% with a median reported increase of 70.2% when compared to nonstatin regimens with 7 of 10 studies reporting significant increases. Considerable heterogeneity exists in regard to patient population, statin regimens, and the definition of an EPC within the identified studies. In conclusion, randomized studies in humans suggest that statin therapy mobilizes EPCs into the circulation. Larger randomized studies using uniform definitions are needed to definitively establish this effect.
• Serum Heat Shock Protein 27 Levels Represent a Potential Therapeutic Target for Atherosclerosis: Observations from a Human Cohort and Treatment of Female Mice Journal of the American College of Cardiology. Oct, 2013  |   Pubmed ID: 23764828 The aim of this study was to evaluate the potential of serum heat shock protein 27 (HSP27) as a therapeutic target in coronary artery disease.
• Response to Letter Regarding Article, "Bivalirudin for Primary Percutaneous Coronary Interventions: Outcome Assessment in the Ottawa STEMI Registry" Circulation. Cardiovascular Interventions. Apr, 2013  |   Pubmed ID: 23591426
• Neuroimmune Guidance Cue Semaphorin 3E is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention Arteriosclerosis, Thrombosis, and Vascular Biology. May, 2013  |   Pubmed ID: 23430613 The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained are poorly understood. Semaphorins, a class of neuronal guidance molecules, play a critical role in vascular patterning and development, and recent studies suggest that they may also have immunomodulatory functions. The present study evaluates the expression of Semaphorin 3E (Sema3E) in settings relevant to atherosclerosis and its contribution to macrophage accumulation in plaques.
• Chronic Over-expression of Heat Shock Protein 27 Attenuates Atherogenesis and Enhances Plaque Remodeling: a Combined Histological and Mechanical Assessment of Aortic Lesions PloS One. 2013  |   Pubmed ID: 23409070 Expression of Heat Shock Protein-27 (HSP27) is reduced in human coronary atherosclerosis. Over-expression of HSP27 is protective against the early formation of lesions in atherosclerosis-prone apoE(-/-) mice (apoE(-/-)HSP27(o/e)) - however, only in females. We now seek to determine if chronic HSP27 over-expression is protective in a model of advanced atherosclerosis in both male and female apoE(-/-) mice.
• Circulating Endothelial Progenitor Cells in HIV Infection: a Systematic Review Trends in Cardiovascular Medicine. Aug, 2013  |   Pubmed ID: 23395428 Human immunodeficiency virus (HIV)-infected individuals have a cardiovascular disease risk that is almost thrice than that of their HIV-uninfected counterparts. Given the critical role of endothelial progenitor cells (EPCs) in vascular homeostasis and arterial repair postinjury, coupled with their strength as biomarkers predictive of cardiovascular events, interest has arisen in characterizing EPCs in the context of HIV infection. We conducted a systematic review of the literature to determine the current state of knowledge on EPCs in the context of HIV infection. Herein, we summarize the pertinent findings of these studies and discuss important differences in the subpopulations of EPCs examined and the methodologies used for their enumeration which likely contributed to the heterogeneity observed across studies.
• Extracellular HSP27 Acts As a Signaling Molecule to Activate NF-κB in Macrophages Cell Stress & Chaperones. Jan, 2013  |   Pubmed ID: 22851137 Heat shock protein 27 (HSP27) shows attenuated expression in human coronary arteries as the extent of atherosclerosis progresses. In mice, overexpression of HSP27 reduces atherogenesis, yet the precise mechanism(s) are incompletely understood. Inflammation plays a central role in atherogenesis, and of particular interest is the balance of pro- and anti-inflammatory factors produced by macrophages. As nuclear factor-kappa B (NF-κB) is a key immune signaling modulator in atherogenesis, and macrophages are known to secrete HSP27, we sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling in macrophages. Treatment of THP-1 macrophages with rHSP27 resulted in the degradation of an inhibitor of NF-κB, IκBα, nuclear translocation of the NF-κB p65 subunit, and increased NF-κB transcriptional activity. Treatment of THP-1 macrophages with rHSP27 yielded increased expression of a variety of genes, including the pro-inflammatory factors, IL-1β, and TNF-α. However, rHSP27 also increased the expression of the anti-inflammatory factors IL-10 and GM-CSF both at the mRNA and protein levels. Our study suggests that in macrophages, activation of NF-κB signaling by rHSP27 is associated with upregulated expression and secretion of key pro- and anti-inflammatory cytokines. Moreover, we surmise that it is the balance in expression of these mediators and antagonists of inflammation, and hence atherogenesis, that yields a favorable net effect of HSP27 on the vessel wall.
• Percutaneous Coronary Intervention with or Without On-site Coronary Artery Bypass Surgery: a Systematic Review and Meta-analysis International Journal of Cardiology. Jul, 2013  |   Pubmed ID: 22240768 Current American Heart Association guidelines recommend against the performance of elective or primary percutaneous coronary intervention (PCI) without on-site surgical backup (i.e. a class III and IIb recommendation respectively). Despite this, numerous centers have already implemented PCI programs with no on-site surgery backup (NSOS).
• Glycogen Synthase Kinase-3β Inhibition Augments Diabetic Endothelial Progenitor Cell Abundance and Functionality Via Cathepsin B: a Novel Therapeutic Opportunity for Arterial Repair Diabetes. Apr, 2014  |   Pubmed ID: 24296714 Progenitor cell therapy is hindered in patients with diabetes mellitus (DM) due to cellular senescence. Glycogen synthase kinase-3β (GSK3β) activity is increased in DM, potentially exacerbating impaired cell-based therapies. Thus, we aimed to determine if and how GSK3β inhibitors (GSKi) can improve therapeutic efficacy of endothelial progenitor cells (EPC) from patients with DM. Patients with DM had fewer EPCs and increased rates of apoptosis. DM EPCs also exhibited higher levels of GSK3β activity resulting in increased levels of phosphorylated β-catenin. Proteomic profiling of DM EPCs treated with GSKi identified 37 nonredundant, differentially regulated proteins. Cathepsin B (cathB) was subsequently confirmed to be differentially regulated and showed 40% less baseline activity in DM EPCs, an effect reversed by GSKi treatment. Finally, in vivo efficacy of cell-based therapy was assessed in a xenotransplant femoral wire injury mouse model. Administration of DM EPCs reduced the intima-to-media ratio, an effect that was further augmented when DM EPCs were pretreated with GSKi yet absent when cathB was antagonized. In DM, increased basal GSK3β activity contributes to accelerated EPC cellular senescence, an effect reversed by small molecule antagonism of GSK3β, which enhanced cell-based therapy after vascular injury.
• Circulating Endothelial Progenitor Cells and In-stent Restenosis: Friend, Foe, or None of the Above? The Canadian Journal of Cardiology. Jan, 2014  |   Pubmed ID: 24290519
• The Evolution of Coronary Stents: a Brief Review The Canadian Journal of Cardiology. Jan, 2014  |   Pubmed ID: 24286961 Percutaneous coronary intervention is the most prevalent method for coronary artery revascularization. Initial interventions using balloon angioplasty had limited efficacy because coronary dissections, arterial recoil, and neointimal formation led to high rates of abrupt vessel closure and clinical restenosis. With the introduction of coronary stents, vascular dissections were stabilized and arterial recoil was eliminated, but neointimal accumulation remained problematic, resulting in the development of in-stent restenosis (ISR) in 20%-30% of cases. Drug-eluting stents (DESs) were developed to release antiproliferative agents at the site of arterial injury to attenuate neointimal formation. Although DESs have incrementally improved outcomes after percutaneous coronary intervention, delayed re-endothelialization and stent thrombosis remain important challenges. Herein we review the pathophysiology of ISR, stent thrombosis, and briefly summarize the clinical evidence behind first- and second-generation DESs. Moreover, we discuss advancements in our understanding of the pathogenesis of ISR and potential novel therapeutic strategies to improve clinical outcomes.
• Giant Saphenous Vein Graft Aneurysm Presenting As ST-elevation Myocardial Infarction Circulation Journal : Official Journal of the Japanese Circulation Society. 2014  |   Pubmed ID: 24284922
• Heat Shock Protein 27 Attenuates Neointima Formation and Accelerates Reendothelialization After Arterial Injury and Stent Implantation: Importance of Vascular Endothelial Growth Factor Up-regulation FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Feb, 2014  |   Pubmed ID: 24142570 Elevated serum heat shock protein 27 (HSP27) levels are atheroprotective; however, the role of HSP27 after arterial injury is unknown. Human endothelial progenitor cells (EPCs) were treated with recombinant (r)HSP27 (50 μg/ml) or its inactive C1 terminus, and gene expression was characterized before functional studies were performed in vitro and in vivo. Vascular endothelial growth factor (VEGF) was markedly up-regulated by rHSP27 (10- and 6-fold increases in mRNA and secretion, respectively). Pretreatment of EPCs with rHSP27 resulted in a 60% reduction in reendothelialization (RE) time in a scratch assay, an effect that was blocked with VEGF-neutralizing antibodies. Mice overexpressing HSP27 demonstrated more robust mobilization of EPCs at the time of arterial injury, as well as a 67% increase in RE and a 45% reduction in neointima (NI) formation at 28 d. Implantation of rHSP27-eluting stents in rabbit carotid arteries resulted in a marked improvement in RE at 7 and 28 d and transient attenuation of NI formation by 42% at 7 d. Hence, extracellular HSP27 up-regulated VEGF and improved EPC migration in vitro. Augmented systemic or local levels of HSP27 markedly improved RE after vascular injury, an effect that is of particular relevance to the safety profile of vascular stents.