Edward R. O'Brien

Heat shock protein-27 attenuates foam cell formation and atherogenesis by down-regulating scavenger receptor-A expression via NF-κB signaling

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<0.005) and uptake (-38%, p<0.05). rHSP27 reduced SR-A mRNA (-39%, p=0.02), total protein (-56%, p=0.01) and cell surface (-53%, p<0.001) expression. The reduction in SR-A expression by rHSP27 was associated with a 4-fold increase in nuclear factor-kappa B (NF-κB) signaling (p<0.001 versus control), while an inhibitor of NF-κB signaling, BAY11-7082, attenuated the negative effects of rHSP27 on both SR-A expression and lipid uptake. To determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE(-/-) and ApoE(-/-) SR-A(-/-) mice fed with a high fat diet were treated for 3weeks with rHSP25. Compared to controls, rHSP25 therapy reduced aortic en face and aortic sinus atherosclerotic lesion size in ApoE(-/-) mice by 39% and 36% (p<0.05), respectively, but not in ApoE(-/-)SR-A(-/-) mice. In conclusion, rHSP27 diminishes SR-A expression, resulting in attenuated foam cell formation in vitro. Regulation of SR-A by HSP27 may involve the participation of NF-κB signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo.

Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient-Level, International, Collaborative, Multi-Center Analysis

Background The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure—a subject of considerable debate within the field. We performed a patient‐level, multi‐center analysis to definitively address the impact of TR access on radiation exposure. Methods and Results Overall, 10 centers were included from 6 countries—Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose‐area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted‐average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=−0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=−0.8; P=0.006). Ultimately, when a centers balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent. Conclusions The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency—a guiding principle for centers adopting the TR approach.

Heat shock protein‐27 and sex‐selective regulation of muscarinic and proteinase‐activated receptor 2‐mediated vasodilatation: differential sensitivity to endothelial NOS inhibition

Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC‐migration/re‐endothelialization and decreases neo‐intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature endothelial cells (ECs) to alter EC‐mediated vasoreactivity in vivo. Our work focused on endothelial NOS (eNOS)/NO‐dependent relaxation induced by ACh and the coagulation pathway‐activated receptor, proteinase‐activated receptor 2 (PAR2).

Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans

Reduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model (crrm1) that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the crrm1 mutant mice exhibited no VTs at all, indicating that the crrm1 mutant mice are resistant to stress-induced VTs. Intact heart Ca2+ imaging and action potential (AP) recordings showed that the crrm1 mutant mice are more susceptible to fast-pacing induced Ca2+ alternans and AP duration alternans compared with WT mice. The crrm1 mutant mice also showed an increased heart-to-body-weight ratio and incidence of sudden death at young ages. Furthermore, the crrm1 mutant hearts displayed altered Ca2+ transients with increased time-to-peak and decay time (T50), increased ventricular wall thickness and ventricular cell area compared with WT hearts. These results indicate that reduced RyR2 protein expression suppresses stress-induced VTs, but enhances the susceptibility to cardiac alternans, hypertrophy, and sudden death.

Clinical outcomes among patients with extreme obesity undergoing elective coronary revascularization: Evaluation of major complications in contemporary practice☆

BACKGROUND/OBJECTIVESnIndividuals with extreme obesity (EO), defined by a body mass index (BMI) ≥ 40 kg/m(2), constitute an increasingly prevalent population at higher risk of procedural complications. The implications of increasing weight burdens among this subset of patients in the setting of elective coronary revascularization have yet to be adequately studied.nnnMETHODSnWe sought to define major complications in this group at one year following contemporary revascularization strategies by retrospectively analysing a cohort of consecutive EO patients undergoing elective percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The primary endpoint was a composite of peri- and post-procedural complications. Secondary endpoints included a cardiovascular composite and target vessel revascularization (TVR).nnnRESULTSnAdjusted event-free survival curves for the primary endpoint among 133 patients differed significantly with higher BMI (>43.2 kg/m(2)) associated with greater risk (p=0.02). The primary endpoint occurred more frequently with CABG compared to PCI (24.2% vs. 5.0%, p < 0.01), which remained significant after adjusting for differences in baseline variables. Rates of the cardiovascular composite and TVR were comparable.nnnCONCLUSIONSnIncreasing BMI was associated with greater risk for major complications among EO patients undergoing elective coronary revascularization. PCI was associated with fewer complications; however, both revascularization strategies demonstrated equivalent rates of death, MI, and/or stroke. Larger studies may permit a better understanding of the associations between increasing BMI and specific outcomes and to evaluate the role for pre-procedural weight loss in this select population.

Circulating Endothelial Progenitor Cells and In-Stent Restenosis: Friend, Foe, or None of the Above?

Percutaneous coronary intervention with implantation of a metallic or bioresorbable stent remains the cornerstone of modern coronary revascularization. Because of the regularity with which percutaneous coronary intervention is performed, in-stent restenosis (ISR) continues to be a frequent clinical entity despite remarkable advancements in stent technology, including cytostatic drug elution, improved polymer technology, and optimized stent architecture. Remarkably, the precise mechanism of ISR remains incompletely understood and predictive models, including the identification of novel biomarkers, to permit identification of patients who will develop vessel renarrowing is needed. Endothelial progenitor cells (EPCs) were first described by Asahara et al. in 1997 and subsequently this term has been used to describe cells derived from culture-based assays and circulating cells enumerated using flow cytometry. The term, circulating progenitor cells (CPCs), or circulating endothelial progenitors, has typically been reserved to describe cells expressing CD34 with a combination of vascular endothelial growth factor receptor-2 (VEGFR-2 or KDR), and/or CD133. In contrast, culture-based assays that yield angiogenic outgrowth cells have also been used to enumerate “EPCs” with early outgrowth of nonproliferative populations, termed cultured angiogenic cells or CACs. CPCs and CACs have been studied extensively for their role in vascular repair and their association with clinical outcomes. Indeed, the first evidence that highlighted progenitors might be important to artery homeostasis came from rodent models of vascular injury that demonstrated mobilization and homing to the injured vessel wall, improving re-endothelialization and reducing neointima formation. As