Papers by Benjamin Hibbert
Circulation, Oct 31, 2007
Circulation, Oct 28, 2008
Aims Endothelial progenitor cells (EPCs) are circulating pluripotent vascular cells capable of en... more Aims 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)-3b 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-3b (GSKi), thereby resulting in improved arterial repair. Methods and results Human EPCs were expanded ex vivo, treated with a specific GSKi, and then assessed for both yield and functional characteristics by in vitro assays for adherence, apoptosis, and survival. In vivo functionality of treated human EPCs was assessed in immune-tolerant mice subjected to femoral artery wire injury. Re-endothelialization was assessed at 72 h and neointima formation at 7 and 14 days following injury. GSKi treatment resulted in an improvement in the yield of EPCs and a reduction in apoptosis in cells derived from both healthy controls and patients with coronary artery disease. Treatment also increased vascular endothelial growth factor secretion, up-regulated expression of mRNA for the a-4 integrin subunit, and improved adhesion, an effect which could be abrogated with an a-4 integrin blocking antibody. EPCs without or with ex vivo GSKi treatment enhanced re-endothelialization 72 h following injury as well as reduced neointima formation at 7 days (e.g. endothelial coverage: 7.2 + 1.7% vs. 70.7 + 5.8% vs. 87.2 + 4.1%; intima to media ratios: 1.05 + 0.19 vs. 0.39 + 0.08 vs. 0.14 + 0.02; P , 0.05 for all comparisons), an effect that was persistent at 14 days. Conclusion GSKi improves the functional profile of EPCs and is associated with improved re-endothelialization and reduced neointima formation following injury.
The Canadian journal of cardiology, Jan 14, 2015
Transcatheter Aortic Valve Implantation (TAVI) was initially developed to treat aortic stenosis i... more Transcatheter Aortic Valve Implantation (TAVI) was initially developed to treat aortic stenosis in patients with high risk for surgical intervention. With great initial adoption of the technology and improvements in device design and procedural success TAVI is increasingly being performed in broader populations for diverse indications. This paper is a concise review of the evolving and expanding use of TAVI in the current era.
Canadian Journal of Cardiology, 2015
Transcatheter aortic valve implantation (TAVI) is the definitive therapy for high-risk patients w... more Transcatheter aortic valve implantation (TAVI) is the definitive therapy for high-risk patients with severe aortic stenosis. The aim of this study was to determine the effect of non-transfemoral access on clinical outcomes in TAVI. We conducted a computerized literature search on SCOPUS and selected all studies published in the English language, from 2002 until March 12 2014, that compared transfemoral access with a non-transfemoral access cohort. Two independent reviewers evaluated the studies and extracted data for analysis. A total 17,020 patients (11,079 transfemoral, 5941 non-transfemoral) encompassing 28 studies underwent TAVI between 2007 to 2013. Overall, the 30-day mortality was 4.7% with the transfemoral approach and 8.1% with a non-transfemoral approach (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.49-0.64; P < 0.01). The 1-year mortality was 16.4% with transfemoral access and 24.8% with non-transfemoral access (OR, 0.68; 95% CI, 0.60-0.75; P < 0.01). Transfemoral access was associated with a greater incidence of vascular complications (OR, 2.1; 95% CI, 1.48-2.99; P < 0.01) but a lower rate of surgical conversion (OR, 0.59; 95% CI, 0.42-0.81; P < 0.01) and similar bleeding (OR, 1.01; 95% CI, 0.81-1.27; P = 0.91) compared with non-transfemoral access. The incidence of cerebrovascular events was similar in both groups (1.6% vs 2.1%; OR, 0.86; 95% CI, 0.64-1.15; P = 0.31). Transfemoral access was associated with lower rate of 30-day and 1-year mortality compared with non-transfemoral access for TAVI. Randomized studies are needed to ascertain the effect of alternative access sites on clinical outcomes in prohibitive-risk, high-risk, and intermediate-risk populations, using currently available technologies.
International Journal of Cardiology, 2014
ABSTRACT Transcatheter aortic valve implantation (TAVI) has become the standard of care for very ... more ABSTRACT Transcatheter aortic valve implantation (TAVI) has become the standard of care for very high-risk operative candidates with severe aortic stenosis. However, randomized studies to date have excluded patients with bicuspid aortic valves (BAVs). Despite observational reports, bicuspid aortic valve continues to be considered a relative contraindication. However, patients with BAV and severe aortic stenosis who are high-risk surgical candidates are increasingly referred for consideration of TAVI. Thus, to determine the performance of contemporary TAVI technology in patients with bicuspid aortic valves we performed a systematic review of all published cases.
The Journal of Steroid Biochemistry and Molecular Biology, 2008
The regulation of the estrogenic responses may be influenced by the proteins that associate with ... more 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. ER is expressed in blood vessels and may play an important role in vascular disease. We hypothesized that specific proteins interact with ER 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 ER. NM23-H2 and ER consistently co-localize in a variety of human tissues (e.g. breast tissue), whereas ER␣ and NM23-H2 did not co-localize. Estrogen response element-mediated transcription increased by 97% when NM23-H2 and ER were over-expressed in MCF-7 cells (p ≤ 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 ≤ 0.001). These results suggest that NM23-H2 associates with ER 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.
The FASEB Journal, 2014
Elevated serum heat shock protein 27 (HSP27) levels are atheroprotective; however, the role of HS... more 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 g/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 stentsshock protein 27 attenuates neointima formation and accelerates reendothelialization after arterial injury and stent implantation: importance of vascular endothelial growth factor up-regulation. FASEB J. 28, 000 -000 (2014). www.fasebj.org
PLoS ONE, 2011
Objectives: Recent clinical trials suggest an LDL-independent superiority of intensive statin the... more Objectives: 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.
Journal of the American College of Cardiology, 2013
The aim of this study was to evaluate the potential of serum heat shock protein 27 (HSP27) as a t... more 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.
Journal of Cardiovascular Pharmacology, 2011
Recent studies suggest that modulation of estrogen receptor β (ERβ) may play a crucial role in ma... more Recent studies suggest that modulation of estrogen receptor β (ERβ) may play a crucial role in maintaining vascular homeostasis. We hypothesized that selective ERβ activation will attenuate atherogenesis via anti-inflammatory mechanisms. Atherosclerosis-prone apoE mice were ovariectomized and then fed a high-cholesterol diet with daily subcutaneous injections of the highly selective and potent ERβ agonist (8β-VE2) for 5 weeks. Compared with controls, treatment with 8β-VE2 reduced aortic arch atherosclerotic lesion areas by 34% of total and 75% of dense lesions, while not altering the serum lipid profile. We attribute these observed vascular effects solely to ERβ modulation as (1) treatment with the nonselective ER antagonist ICI 182,780 completely abrogated the beneficial vascular effects of 8β-VE2 and (2) uterine weight (a sensitive indicator of ERα modulation) did not change with 8β-VE2 treatment. Moreover, mice treated with 8β-VE2 had reduced serum interleukin 1β and tumor necrosis factor α levels. Finally, treatment of macrophages in vitro with 8β-VE2 blocked the uptake of acetylated low-density lipoprotein, suppressed the extracellular levels of the inflammatory cytokine tumor necrosis factor α, and enhanced the extracellular levels of the antiatherogenic/anti-inflammatory protein heat shock protein 27. Selective ERβ activation by 8β-VE2 attenuates atherogenesis and is associated with favorable modulation of vascular inflammation.
General and Comparative Endocrinology, 2004
The secretory vesicle protein secretogranin-II (SgII), a precursor for the bioactive peptide secr... more The secretory vesicle protein secretogranin-II (SgII), a precursor for the bioactive peptide secretoneurin, is expressed at all levels of the goldWsh reproductive axis, including the hypothalamus, pituitary and ovaries. These Wndings led us to hypothesize that SgII is involved in reproduction and is physiologically regulated. We investigated the eVects of diVerent sex steroids on pituitary SgII expression throughout the seasonal reproductive cycle of the female goldWsh, as well as the eVects of GnRH and testosterone on pituitary LH subunit, GH, and SgII expression in sexually recrudescent female Wsh using northern blot analysis. We demonstrated that SgII expression levels vary seasonally, with levels being highest in winter and lowest in spring. Sex steroids did not alter SgII expression at any of the time periods studied. In sexually mature goldWsh, injection of a GnRH agonist stimulated the expression of LH and SgII speciWcally in the pars distalis but not the neurointermediate lobe of the pituitary. Although testosterone alone did not alter the expression of either of these genes, it did abolish the stimulatory eVects of GnRH on both LH and SgII expression. This represents the Wrst study where testosterone is shown to modulate SgII expression in the pituitary. 2004 Elsevier Inc. All rights reserved.
General and Comparative Endocrinology, 2005
It is established that dopamine inhibits while GABA stimulates LH release in goldWsh. In this stu... more It is established that dopamine inhibits while GABA stimulates LH release in goldWsh. In this study, we examine dopaminergic regulation of GABAergic activity in the hypothalamus of early recrudescent female goldWsh (Carassius auratus). We utilize a unique technique that permits concomitant quantiWcation and correlation of in vivo GAD65 and GAD67 mRNA with GABA synthesis rate in response to decreased dopamine levels. Catecholamine depletion was achieved by treatment with -methyl-para-tyrosine methyl ester ( MPT; 240 g/g body weight), an inhibitor of tyrosine hydroxylase. Endogenous GABA levels were increased by intraperitoneal administration of -vinyl GABA (GVG; 300 g/g body weight), an inhibitor of the GABA catabolic enzyme GABA transaminase. Dual treatment of GVG + MPT increased serum LH levels 4-fold. However, LH mRNA levels in the pituitary remained stable, suggesting that treatments aVected secretion and not synthesis. In the hypothalamus, GABA synthesis rates increased 30% in response to MPT treatment. This was correlated (r D 0.61; p < 0.05) to increased levels of GAD67 mRNAs but not GAD65 (r D 0.14; p > 0.05). These observations suggest that catecholamines inhibit GABA synthesis in the goldWsh hypothalamus through isoform speciWc regulation of GAD67. 2004 Elsevier Inc. All rights reserved.
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Papers by Benjamin Hibbert