Trevor Simard

Extracellular Release of the Atheroprotective Heat Shock Protein 27 Is Mediated by Estrogen and Competitively Inhibits acLDL Binding to Scavenger Receptor-A

We recently identified heat shock protein 27 (HSP27) as an estrogen receptor beta (ER&bgr;)-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≤0.001) in atherosclerotic lesion area in apoE−/−HSP27o/e mice compared to apoE−/− mice, but primarily in females. Serum HSP27 levels 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 (r2=0.78, P≤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-1&bgr; 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.

The Evolution of Coronary Stents: A Brief Review

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.

Natural History and Management of Aortocoronary Saphenous Vein Graft Aneurysms A Systematic Review of Published Cases

Despite ongoing advances in percutaneous revascularization, coronary artery bypass grafting (CABG) continues to be performed in a large number of patients, with >400 000 operations reported in 2007 in the United States alone.1 Although arterial conduits are generally preferred, saphenous vein grafts (SVGs) continue to be used regularly. First described by Riahi and colleagues2 in 1975, aneurysmal dilatation of aortocoronary SVGs remains a rare yet widely reported phenomenon. Indeed, subsequent literature on the topic consists almost exclusively of case reports and small case series. Thus, the precise incidence of aortocoronary SVG aneurysms (SVGAs) remains difficult to ascertain, although in 1 case series, an incidence of 0.07% was estimated from a review of >5500 grafts at a single institution.3 However, this likely underestimates the true number because SVGAs often remain clinically silent and no guidelines exist to screen for their development. Given the infrequent identification of SVGAs, our current understanding of the epidemiology and pathogenesis of these aneurysms remains limited. Aneurysms are generally defined as a focal dilatation of vessels >1.5 times the proximal reference diameter; however, aneurysmal dilatation of aortocoronary SVGs has led to “giant” aneurysm formation, with reports of cases exceeding 10 cm.4–6 SVGAs are often incidentally identified on imaging, but cases of rupture,7 fistula formation with neighboring anatomy,8 and hemodynamic compromise resulting from compression of adjacent cardiac and vascular structures have been reported.9 To date, 2 reviews have been published that briefly summarize 108 cases of SVGAs.10,11 Traditionally, their management has been surgical—generally resection of the aneurysm with or without bypass of the affected territory. However, with refinement of percutaneous techniques, including the use of Amplatzer devices, covered stents, and arterial coiling, the management options …

Heat Shock Protein 27 Protects Against Atherogenesis via an Estrogen-Dependent Mechanism Role of Selective Estrogen Receptor Beta Modulation

Objective—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. Methods and Results—In vitro estrogens prompted the release of HSP27 from macrophages in an ERβ specific manner that involved exosomal trafficking. Ovariectomy nullified the previously recognized attenuation in aortic lesion area in HSP27o/eapoE−/− mice compared to apoE−/− mice. Supplementation with 17β-estradiol resulted in a >15× increase in uterine weight and attenuation of atherogenesis in all mice, although HSP27o/eapoE−/− had 34% less lesion burden compared to apoE−/− mice. Mice treated with the ERβ-specific agonist, DPN had no effect on uterine weight but a 28% decrease in aortic lesion area in HSP27o/eapoE−/− compared to apoE−/− mice. HSP27 serum levels showed a similar gradual increase with E2 and DPN replacement treatment but did not change in untreated mice. Conclusions—The extracellular release of and atheroprotection provided by HSP27 is estrogen dependent.

Transradial Versus Transfemoral Artery Approach for Coronary Angiography and Percutaneous Coronary Intervention in the Extremely Obese

OBJECTIVES 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). BACKGROUND Coronary angiography is most commonly performed via femoral artery access; however, the optimal approach in extremely obese (EO) patients remains unclear. METHODS Between January 2007 and August 2010, a cohort of consecutive EO patients who underwent coronary angiography was identified in our centers registry of angiography and percutaneous coronary intervention procedures. Of 21,103 procedures, 564 (2.7%) were performed in unique EO patients: 203 (36%) via the transradial approach; and 361 (64%) via the transfemoral approach. RESULTS The primary outcome, a combined endpoint of major bleeding, access site complications, and nonaccess site complications, occurred in 7.5% of the transfemoral group and 2.0% of the transradial group (odds ratio [OR]: 0.30, 95% confidence interval [CI]: 0.10 to 0.88, p = 0.029), an endpoint driven by reductions in major bleeding (3.3% vs. 0.0%, OR: 0.12, 95% CI: 0 to 0.71, p = 0.015), as well as access site injuries (4.7% vs. 0.0%, OR: 0.08, 95% CI: 0 to 0.48, p = 0.002). There were no differences in nonaccess site complications (1.7% vs. 2.0%, OR: 1.50, 95% CI: 0.41 to 5.55), but transradial access procedures were associated with an increase in procedure time and patient radiation dose (p < 0.05). CONCLUSIONS Transfemoral access for coronary angiography and percutaneous coronary intervention was associated with more bleeding and access site complications when compared with a transradial approach. Important reductions in procedural associated morbidity may be possible with a transradial approach in EO patients.

Transcatheter aortic valve implantation in patients with bicuspid aortic valve: A patient level multi-center analysis

OBJECTIVE We sought to evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BiAV). BACKGROUND BiAV remains a relative contraindication to TAVI resulting in exclusion from TAVI trials and thus limiting data on the clinical performance of transcatheter valves in these patients. METHODOLOGY We conducted an international patient level multicenter analysis on outcomes in patients with BiAV undergoing TAVI. The primary outcome of the study was the combined early safety endpoint--a composite of 30 day mortality, stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction, major vascular complication and valve related dysfunction. Secondary endpoints included the individual components of the primary endpoint as well as post-TAVI paravalvular leak (PVL), rehospitalization, new pacemaker insertion and device success rates at 30 days and 1 year. RESULTS A total of 108 patients with BiAV were identified in 21 centers in Canada, Spain, Italy, Poland and Singapore who underwent TAVI between January 2005 and March 2014. The composite primary outcome occurred in one quarter of patients (26.9%)--mainly driven by re-intervention for valve malposition (9.3%). The 30-day and 1 year mortality rates were 8.3% and 16.9% respectively with AR ≥ 3+ occurring in 9.6% of patients. Device success was achieved in 85.2% of cases with pacemaker insertion in 19.4%. While PVL was not associated with an increased risk of 30 day or 1 year mortality--Type I BiAV anatomy with left and right cusp fusion had significantly better outcomes than other valve variants. CONCLUSION In selected patients with BiAV and severe aortic stenosis, TAVI appears both safe and feasible with acceptable clinical outcomes. Clinical studies of TAVI in this patient population are warranted.

Pre-Procedural Atorvastatin Mobilizes Endothelial Progenitor Cells: Clues to the Salutary Effects of Statins on Healing of Stented Human Arteries

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. Methods and Results Statin naïve male patients undergoing angiography for stent placement were randomized to standard therapy without Atorvastatin (n = 10) or treatment with Atorvastatin 80 mg (n = 10) beginning three days prior to stent implantation. EPCs were defined by flow cytometry (e.g., surface marker profile of CD45dim/34+/133+/117+). As well, we also enumerated cultured angiogenic cells (CACs) by standard in vitro culture assay. While EPC levels did not fluctuate over time for the patients free of Atorvastatin, there was a 3.5-fold increase in EPC levels with high dose Atorvastatin beginning within 3 days of the first dose (and immediately pre-PCI) which persisted at 4 and 24 hours post-PCI (p<0.05). There was a similar rise in CAC levels as assessed by in vitro culture. CACs cultured in the presence of Atorvastatin failed to show augmented survival or VEGF secretion but displayed a 2-fold increase in adhesion to stent struts (p<0.05). Conclusions High dose Atorvastatin therapy pre-PCI improves EPC number and CAC number and function in humans which may in part explain the benefit in clinical outcomes seen in patients undergoing coronary interventions.

Pathogenesis of Neointima Formation Following Vascular Injury

Revascularization remains the cornerstone of managing obstructive coronary artery disease. Although percutaneous coronary interventions involving the insertion of metal scaffolds, known as stents, has emerged as the preferred method of restoring vessel patency, as many as 30% of patients will experience a gradual re-narrowing of the lumen caused by neointima (NI) formation, resulting in a condition known as in-stent restenosis (ISR). ISR represents a significant limitation to percutaneous revascularization - however, abrogating NI formation following stent implantation has been hampered by an incomplete understanding of the pathogenesis of in-stent lesions. While numerous mechanisms have been proposed to explain the pathogenesis of ISR, data from human and animal models have yielded conflicting results. Herein, we review key studies of NI development following vascular injury with a focus on the origin of cells participating in NI formation.

Serum Heat Shock Protein 27 Levels Represent a Potential Therapeutic Target for Atherosclerosis: Observations From a Human Cohort and Treatment of Female Mice

OBJECTIVES 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. BACKGROUND Expression of HSP27 in human coronary arteries diminishes with the progression of atherosclerosis, whereas ubiquitous HSP27 overexpression in apolipoprotein E(-/-) (ApoE(-/-)) mice attenuates atherogenesis. However, it remains unclear whether increasing serum HSP27 levels alone is sufficient for atheroprotection. METHODS Low- and intermediate-risk patients undergoing coronary or computed tomography angiography had serum HSP27 levels measured. Elevated serum HSP27 levels in female atheroprone ApoE(-/-) mice were achieved by transplantation with HSP27 overexpressing bone marrow or by administering recombinant HSP27. RESULTS Patients with >50% stenosis in any major epicardial artery had lower HSP27 levels compared with those free of atherosclerosis (median [interquartile range]: 2,176 pg/ml [551-5,475] vs. 6,200 pg/ml [2,575-9,560]; p < 0.001). After a 5-year period of clinical follow-up, low serum HSP27 levels (<50th percentile) were predictive of subsequent major adverse cardiovascular events (hazard ratio: 2.93, 95% confidence interval: 1.06 to 8.12; p = 0.04). In experimental murine models of atherosclerosis, increasing serum HSP27 levels both reduced de novo atherosclerotic lesion formation and enhanced features of plaque stability. CONCLUSIONS In humans, low serum HSP27 levels are associated with the presence of coronary artery disease and prognostic of future adverse clinical events. In mouse models of atherosclerosis, increasing HSP27 levels reduced lesion progression and promoted features of plaque stability. Serum HSP27 levels may represent a potential therapeutic target for atherosclerosis.

The effect of statins on circulating endothelial progenitor cells in humans: a systematic review.

Abstract: 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.