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Estrogens have been implicated in both worsening and protecting from cardiovascular disease. The effects of 1713-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 (AT1R), 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 pig/day (regular) E2 subcutaneously, and 4) OVX treated with 250 jig/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 AT1R 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 AT1R 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. [ABSTRACT FROM AUTHOR]

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 α-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 plusmn; 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. [ABSTRACT FROM AUTHOR]

Blood levels of heat shock protein (HSP27) and natural IgG auto‐antibodies to HSP27 (AAbs) are higher in healthy controls compared to cardiovascular disease patients. Vaccination of mice with recombinant HSP25 (rHSP25, murine ortholog of human rHSP27) increased AAb levels, attenuated atherogenesis and reduced plaque inflammation and cholesterol content. We sought to determine if the HSP27 immune complex (IC) altered MΦ inflammation signaling (Toll Like Receptor 4; TLR4), and scavenger receptors involved in cholesterol uptake (SR‐AI, CD‐36). Combining a validated polyclonal IgG anti‐HSP27 antibody (PAb) with rHSP27 enhanced binding to THP‐1 MΦ cell membranes and activation of NF‐κB signaling via TLR4, competing away LPS and effecting an anti‐inflammatory cytokine profile. Similarly, adding the PAb with rHSP27 enhanced binding to SR‐AI and CD‐36, as well as lowered oxLDL binding in HEK293 cells separately transfected with SR‐AI and CD‐36, or THP‐1 MΦ. Finally, the PAb enhanced the uptake and internalization of rHSP27 in THP‐1 MΦ. Thus, the HSP27 IC potentiates HSP27 cell membrane signaling with receptors involved in modulating inflammation and cholesterol uptake, as well as HSP27 internalization. Going forward, we are focusing on the development of HSP27 Immune Complex Altered Signaling and Transport (ICAST) as a means of modulating inflammation. [ABSTRACT FROM AUTHOR]

Heat Shock Protein 27 (HSP27) is a small molecular chaperone that reduces the development of atherosclerosis by lowering plasma cholesterol levels as well as inflammation. Human studies show an inverse correlation between atherosclerotic burden and HSP27 expression, and are supported by murine models in which augmenting HSP27 levels curbs experimental atherogenesis. Natural HSP27 auto-antibodies (AAb) are found in human plasma, however their role in modulating the athero-protective effects of HSP27 is unknown. The purpose of this study is to characterize the biophysical interaction between human recombinant HSP27 and AAb. A validated polyclonal anti-HSP27 IgG antibody (PAb) was used to mimic natural AAb. Homology modeling and secondary structure prediction tools facilitated the design of HSP27 truncation and phosphorylation mutants. Secondary structural changes were identified using Circular Dichroism (CD) and Dynamic Light Scattering (DLS). Similar to prior structural investigations of HSP27, there was a predominance of α-helical content in the N-terminal truncation and dephosphorylation ("AA") mutants. The α-crystallin domain (ACD) predominantly consists of β-strands, with the addition of the N-terminal increasing helical content and the C-terminal maintaining β structure. With increasing ratios of PAb to HSP27 β structure abundance and particle size increased, with a similar trend observed with the N-terminus, C-terminus and ACD peptides but an opposite trend with the phosphorylation peptides. Taken together, these studies provide insights into the interaction of HSP27 and its AAb that ultimately may aid in optimizing the design of HSP27 peptidomimetics with anti-atherogenic potential. • HSP27 has 3 conserved domains the ACD, WDPF and IXI/V. • The N-terminal increases helical content and C-terminal maintains β structure. • Addition of PAb to HSP27 resulted in increased β structure and particle size. • Similar trends were observed with ACD, N and C-terminal peptides. • Study provides insight into the interaction HSP27 and PAb. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress plays an important role in cardiovascular disease (CVD) and atherosclerosis. We aimed to assess the ability of 4-phenylbutyrate (4-PBA), a small chemical chaperone administered via drinking water, to reduce atherosclerotic lesion size in chow-fed apolipoprotein (Apo) e-/- mice and to identify mechanisms that contribute to its antiatherogenic effect. Chow-fed 17-wk-old female Apoe-/- mice treated with 4-PBA-supplemented drinking water for 5 wk exhibited smaller lesions as well as increased plasma levels of heat shock protein (HSP) 25, the mouse homolog of human HSP27, compared with controls. In addition, 4-PBA inhibited cell death and increased HSP27 expression as measured by real-time PCR and immunoblotting, as well as induced nuclear localization of its transcription factor, heat shock factor 1, in human monocyte/macrophage (THP-1) cells. Furthermore, HSP27 small interfering RNA diminished the protective effect of 4-PBA on THP-1 macrophage attachment and differentiation. In summary, drinking water containing 4-PBA attenuated early lesion growth in Apoe-/- mice fed a chow diet and increased expression of HSP25 and HSP27 in macrophages and HSP25 in the circulation of Apoe-/- mice. Given that increased expression of HSP27 is inversely correlated with CVD risk, our findings suggest that 4-PBA protects against the early stages of atherogenesis in part by enhancing HSP27 levels, leading to inhibition of both macrophage cell death and monocyte-macrophage differentiation.--Lynn, E. G., Lhoták, Š., Lebeau, P., Byun, J. H., Chen, J., Platko, K., Shi, C., O'Brien, E. R., Austin, R. C. 4-Phenylbutyrate protects against atherosclerotic lesion growth by increasing the expression of HSP25 in macrophages and in the circulation of Apoe-/- mice. [ABSTRACT FROM AUTHOR]

Previously, we reported that elevated serum levels of heat shock protein 27 (HSP27) are predictive of a lower risk of having a heart attack, stroke, or death from cardiovascular disease. Moreover, augmenting HSP27 (or the murine ortholog, HSP25) attenuated experimental atherogenesis, reduced inflammation, and lowered cholesterol levels. Recently, we noted that HSP27 activates NF-κB via TLR-4, resulting in attenuation of plaque inflammation; however, the precise anti-atherosclerosis mechanisms mediated by extracellular HSP27 are incompletely understood. Our purpose in this study was to investigate the existence of HSP27 in extracellular vesicles (EVs) and whether HSP27 elicited atheroprotective effects on target cells. Here, we provide evidence that HSP27 localizes to EVs derived from THP-1 cells using transmission electron microscopy (TEM) and immunogold labeling, Western blotting, ELISA, and fluorescence-activated cell sorting. TEM imaging indicated that HSP27 is found at the exosomal membrane. Multiple reactor monitor-mass spectrometric analysis of large vesicles, which included microparticles and exosomes, isolated from human plasma, also led to detection of HSP27 using the unique signature peptide, R.LFDQAFGLPR.L. Studies using THP-1 and human embryonic kidney cells show that HSP27-laden exosomes significantly stimulated NF-κB activation (P < 0.001) and release of IL-10 (P < 0.0001), suggesting that HSP27 may be important exosomal cargo with beneficial anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

The recognition of sex differences in cardiovascular disease, particularly the manifestations of coronary artery disease (CAD) in post-menopausal women, has introduced new challenges in not only understanding disease mechanisms but also identifying appropriate clinical means of assessing the efficacy of management strategies. For example, the majority of treatment algorithms for CAD are derived from the study of males, focus on epicardial stenoses, and inadequately account for the small intramyocardial vessel disease in women. However, newer investigational modalities, including stress perfusion cardiac magnetic resonance imaging and positron emission tomography are providing enhanced diagnostic accuracy and prognostication for women with microvascular disease. Moreover, these investigations may soon be complemented by simpler screening tools such as retinal vasculature imaging, as well as novel biomarkers (e.g. heat shock protein 27). Hence, it is vital that robust, sex-specific cardiovascular imaging modalities and biomarkers continue to be developed and are incorporated into practice guidelines that are used to manage women with CAD, as well as gauge the efficacy of any new treatment modalities. This review provides an overview of some of the sex differences in CAD and highlights emerging advances in the investigation of CAD in post-menopausal women. [ABSTRACT FROM AUTHOR]

Background and Purpose: 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).Experimental Approach: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS-dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice.Key Results: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1.Conclusions and Implications: HSPB1 can regulate intact vascular endothelial function to affect NO-mediated vascular relaxation, especially in females. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recently, we demonstrated that heat shock protein (HSP)-27 is protective against the development of experimental atherosclerosis, reducing plaque cholesterol content by more than 30%. Moreover, elevated HSP-27 levels are predictive of relative freedom from clinical cardiovascular events. HSP-27 signaling occurs via the activation of NF-κB, which induces a marked up-regulation in expression of granulocyte-monocyte colony-stimulating factor (GM-CSF), a cytokine that is known to alter ABC transporters involved in reverse cholesterol transport (RCT). Therefore, we hypothesized that HSP-27-derived GM-CSF has a potent role in impeding plaque formation by promoting macrophage RCT and sought to better characterize this pathway. Treatment of THP-1 cells, RAW-Blue cells, and primary macrophages with recombinant HSP-27 resulted in NF-κB activation via TLR-4 and was inhibited by various pharmacologic blockers of this pathway. Moreover, HSP-27-induced upregulation of GM-CSF expression was dependent on TLR-4 signaling. Recombinant (r)HSP-27 treatment of ApoE-/- female (but not male) mice for 4 wk yielded reductions in plaque area and cholesterol clefts of 33 and 47%, respectively, with no effect on GM-CSF-/-ApoE-/- mice. With 12 wk of rHSP-27 treatment, both female and male mice showed reductions in plaque burden (55 and 42%, respectively) and a 60% reduction in necrotic core area but no treatment effect in GM-CSF-/-ApoE-/- mice. In vitro functional studies revealed that HSP-27 enhanced the expression of ABCA1 and ABCG1, as well as facilitated cholesterol efflux in vitro by ~10%. These novel findings establish a paradigm for HSP-27-mediated RCT and set the stage for the development of HSP-27 atheroprotective therapeutics. [ABSTRACT FROM AUTHOR]

Background/objectives Individuals with extreme obesity (EO), defined by a body mass index (BMI) = 40 kg/m², 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. Methods We 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). Results Adjusted event-free survival curves for the primary endpoint among 133 patients differed significantly with higher BMI (> 43.2 kg/m²) 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. Conclusions Increasing 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. [ABSTRACT FROM AUTHOR]

Rho-associated kinase (ROCK) and zipper-interacting protein kinase (ZIPK) have been implicated in diverse physiological functions. ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes. To test the hypothesis that sequential activation of ROCK1 and ZIPK is commonly involved in regulatory pathways, we utilized siRNA to knock down ROCK1 and ZIPK in cultured human arterial smooth muscle cells (SMC). Microarray analysis using a whole-transcript expression chip identified changes in gene expression induced by ROCK1 and ZIPK knockdown. ROCK1 knockdown affected the expression of 553 genes, while ZIPK knockdown affected the expression of 390 genes. A high incidence of regulation of transcription regulator genes was observed in both knockdowns. Other affected groups included transporters, kinases, peptidases, transmembrane and G protein-coupled receptors, growth factors, phosphatases and ion channels. Only 76 differentially expressed genes were common to ROCK1 and ZIPK knockdown. Ingenuity Pathway Analysis identified five pathways shared between the two knockdowns. We focused on cytokine signaling pathways since ROCK1 knockdown up-regulated 5 and down-regulated 4 cytokine genes, in contrast to ZIPK knockdown, which affected the expression of only two cytokine genes (both down-regulated). IL-6 gene expression and secretion of IL-6 protein were up-regulated by ROCK1 knockdown, whereas ZIPK knockdown reduced IL-6 mRNA expression and IL-6 protein secretion and increased ROCK1 protein expression, suggesting that ROCK1 may inhibit IL-6 secretion. IL-1β mRNA and protein levels were increased in response to ROCK1 knockdown. Differences in the effects of ROCK1 and ZIPK knockdown on cell cycle regulatory genes suggested that ROCK1 and ZIPK regulate the cell cycle by different mechanisms. ROCK1, but not ZIPK knockdown reduced the viability and inhibited proliferation of vascular SMC. We conclude that ROCK1 and ZIPK have diverse, but predominantly distinct regulatory functions in vascular SMC and that ROCK1-mediated activation of ZIPK is not involved in most of these functions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). Pretreat-ment of EPCs with rHSP27 resulted in a 60% reduction hi reendothelialization (RE) time in a scratch assay, an effect diat 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 unproved RE after vascular injury, an effect that is of particular relevance to the safety profile of vascular stents. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Abstract: Background: 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). Methods: To evaluate the necessity for on-site surgical backup (SOS) when performing PCI we performed a systematic review and meta-analysis. English-language articles published from 1966 through December 2010 were retrieved using keyword searches of Medline and Scopus, supplemented by letters to authors and reviews of all bibliographies. Article inclusion and data extraction was performed by two independent reviewers. We identified 18 articles published between 1992 and 2009 which contained reported events on 1,150,200 patients. Results: The combined odds ratio calculated using a random effects model for death with NSOS was 0.93 (95% CI, 0.80–1.09). In studies with data reported for primary PCI and elective PCI the OR for death was 0.91 (95% CI, 0.84–1.00) and 1.04 (95% CI, 0.67–1.63). A lack of effect of SOS was maintained when analysis was performed by study type or by either primary or elective PCI. No differences in rates of emergency coronary artery bypass grafting, post procedural myocardial infarction, target vessel revascularization, or cerebrovascular accidents were observed between SOS and NSOS centers. Conclusion: Both primary and elective PCI can safely be performed at NSOS centers without an increase in mortality or PCI related complications. AHA/ACC guidelines should reflect the lack of benefit conferred by on-site surgical backup. In establishing PCI programs, adequate operator/center volumes, patient selection, and geographic/population considerations should take precedence rather than the availability of on-site surgical backup during PCI. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Aims: 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−/−HSP27o/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. Methods and Results: After 12 weeks on a high fat diet, serum HSP27 levels rose more than 16-fold in male and female apoE−/−HSP27o/e mice, although females had higher levels than males. Relative to apoE−/− mice, female apoE−/−HSP27o/e mice showed reductions in aortic lesion area of 35% for en face and 30% for cross-sectional sinus tissue sections – with the same parameters reduced by 21% and 24% in male cohorts; respectively. Aortic plaques from apoE−/−HSP27o/e mice showed almost 50% reductions in the area occupied by cholesterol clefts and free cholesterol, with fewer macrophages and reduced apoptosis but greater intimal smooth muscle cell and collagen content. The analysis of the aortic mechanical properties showed increased vessel stiffness in apoE−/−HSP27o/e mice (41% in female, 34% in male) compare to apoE−/− counterparts. Conclusions: Chronic over-expression of HSP27 is atheroprotective in both sexes and coincides with reductions in lesion cholesterol accumulation as well as favorable plaque remodeling. These data provide new clues as to how HSP27 may improve not only the composition of atherosclerotic lesions but potentially their stability and resilience to plaque rupture. [ABSTRACT FROM AUTHOR]

The article offers information on the use of aortocoronary saphenous vein graft aneurysms in coronary artery bypass grafting surgery which helps in improving blood flow to the heart. It informs that patients treated with SVGAs are most commonly presented with chest pain, shortness of breath and myocardial infarction. It also informs that aneurysmal conduits are commonly grafted to right coronary artery, followed by obtuse marginal and left circumflex arteries.

Objectives: This study sought to determine whether mortality complicating ST-segment elevation myocardial infarction (STEMI) was impacted by the design of transport systems. Background: It is recommended that regions develop systems to facilitate rapid transfer of STEMI patients to centers equipped to perform primary percutaneous coronary intervention (PCI), yet the impact on mortality from the design of such systems remains unknown. Methods: Within the framework of a citywide system where all STEMI patients are referred for primary PCI, we compared patients referred directly from the field to a PCI center to patients transported beforehand from the field to a non–PCI-capable hospital. The primary outcome was all-cause mortality at 180 days. Results: A total of 1,389 consecutive patients with STEMI were assessed by the emergency medical services (EMS) and referred for primary PCI: 822 (59.2%) were referred directly from the field to a PCI center, and 567 (40.8%) were transported to a non–PCI-capable hospital first. Death at 180 days occurred in 5.0% of patients transferred directly from the field, and in 11.5% of patients transported from the field to a non–PCI-capable hospital (p < 0.0001. After adjusting for baseline characteristics in a multivariable logistic regression model, mortality remained lower among patients referred directly from the field to the PCI center (odds ratio: 0.52, 95% confidence interval: 0.31 to 0.88, p = 0.01). Similar results were obtained by using propensity score methods for adjustment. Conclusions: A STEMI system allowing EMS to transport patients directly to a primary PCI center was associated with a significant reduction in mortality. Our results support the concept of STEMI systems that include pre-hospital referral by EMS. [ABSTRACT FROM AUTHOR]

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 (CD45dim/CD34+/kinase domain receptor+) from 36 HIVuninfected 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/lL 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: 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-3β inhibitor (GSKi)—even for feeble cells derived from coronary artery disease patients. GSKi treatment enhanced EPC adhesion via up-regulated expression of the α-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. [ABSTRACT FROM PUBLISHER]

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-β. 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: We developed an integrated-metropolitan-area approach in which all patients with ST-segment elevation myocardial infarction were referred to a specialized center for primary PCI. We sought to determine whether there was a difference in door-to-balloon times between patients who were referred directly from the field by paramedics trained in the interpretation of electrocardiograms and patients who were referred by emergency department physicians. Results: Between May 1, 2005, and April 30, 2006, a total of 344 consecutive patients with ST-segment elevation myocardial infarction were referred for primary PCI: 135 directly from the field and 209 from emergency departments. Primary PCI was performed in 93.6% of patients. The median door-to-balloon time was shorter in patients referred from the field (69 minutes; interquartile range, 43 to 87) than in patients needing interhospital transfer (123 minutes; interquartile range, 101 to 153; P<0.001). Door-to-balloon times of less than 90 minutes were achieved in 79.7% of patients who were transferred from the field and in 11.9% of those transferred from emergency departments (P<0.001). Conclusions: Guideline door-to-balloon-times were more often achieved when trained paramedics independently triaged and transported patients directly to a designated primary PCI center than when patients were referred from emergency departments. N Engl J Med 2008;358:231-40. [ABSTRACT FROM AUTHOR]

Abstract: 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. ERβ is expressed in blood vessels and may play an important role in vascular disease. We hypothesized that specific proteins interact with ERβ 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 ERβ. NM23-H2 and ERβ consistently co-localize in a variety of human tissues (e.g. breast tissue), whereas ERα and NM23-H2 did not co-localize. Estrogen response element-mediated transcription increased by 97% when NM23-H2 and ERβ 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 ERβ 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. [Copyright &y& Elsevier]

Abstract: Recently, we identified heat shock protein 27 (HSP27) as an estrogen receptor-β (ERβ) 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 ERβ, 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 17β-estradiol and to a lesser extent with heat shock. Under all experimental conditions ERβ was found to be slightly more abundant in the cytoplasm compared to the nucleus. HSP27 and ERβ associate in both the cytoplasm and nucleus, however, co-localization studies reveal that in the presence of 17β-estradiol, a significant portion of this interaction occurs outside of the nucleus. These data highlight an extranuclear interaction between ERβ and HSP27 that may be of potential importance in modulating estrogen signaling. [Copyright &y& Elsevier]

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 ERβ, 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 ERβ-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 17β-estradiol and an ERβ-selective agonist, diarylpropionitrile, increased protein expression of NM23-H2; an effect that was not seen with an ERα-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 ERβ 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 ERβ-associated protein may play an important role in mediating the vasculoprotective effects of estrogens. [ABSTRACT FROM AUTHOR]

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 <0.0001 for 2 comparisons). Thrombolytic therapy was prescribed to 80.4% of the control group, with a median door-to-needle time of 41 minutes. In-hospital mortality was 1.9% in the paramedic-referred primary PCI group versus 8.9% in the control group (p = 0.017) and remained significantly lower after statistical adjustment for baseline risk. In conclusion, paramedic-referred primary PCI is a safe and feasible strategy for treating STEMI that is associated with rapid and effective reperfusion and very low in-hospital mortality. [Copyright &y& Elsevier]

The present study tested the hypothesis that 17β-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. [ABSTRACT FROM AUTHOR]

Objectives: 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). Background: Previous trials show that thrombolysis followed by immediate angioplasty for the treatment of STEMI does not improve ischemic outcomes compared with thrombolysis alone and is associated with excessive bleeding complications. Since the publication of these trials, however, significant pharmacological and technological advances have occurred. Methods: We randomized 170 patients with high-risk STEMI to treatment with TNK alone (84 patients) or TNK-facilitated angioplasty (86 patients). The primary end point was a composite of death, reinfarction, recurrent unstable ischemia, or stroke at six months. Results: At six months, the incidence of the primary end point was 24.4% in the TNK-alone group versus 11.6% in the TNK-facilitated angioplasty group (p = 0.04). This difference was driven by a reduction in the rate of recurrent unstable ischemia (20.7% vs. 8.1%, p = 0.03). There was a trend toward a lower reinfarction rate with TNK-facilitated angioplasty (14.6% vs. 5.8%, p = 0.07). No significant differences were observed in the rates of death or stroke. Major bleeding was observed in 7.1% of the TNK-alone group and in 8.1% of the TNK-facilitated angioplasty group (p = 1.00). Conclusions: In patients presenting with high-risk STEMI, TNK plus immediate angioplasty reduced the risk of recurrent ischemic events compared with TNK alone and was not associated with an increase in major bleeding complications. [Copyright &y& Elsevier]

Evaluates myocardial perfusion using rubidium-82 positron emission tomography after myocardial infarction in patients receiving primary stent implantation or thrombolytic therapy. Goal of therapy for acute myocardial infarction; Patient characteristics; Estimate of regional myocardial perfusion.

Working Model for HSP27 Lowering PCSK9 A) E2 upregulates activity of the PCSK9 promoter (via one or more estrogen response elements). HSP27 can blunt this E2-mediated increase in PCSK9 promoter activity by either a direct genomic effect, or an indirect non-genomic effect that blocks the nuclear translocation of estrogen / estrogen receptors. B) The HSP27 immune complex upregulates expression of the LDLR via an NF-κB mediate pathway, resulting in more LDLRs available to bind PCSK9 and direct its lysosomal disposal. The estrogen-inducible protein Heat Shock Protein 27 (HSP27) as well as anti-HSP27 antibodies are elevated in healthy subjects compared to cardiovascular disease patients. Vaccination of ApoE−/− mice with recombinant HSP25 (rHSP25, the murine ortholog), boosts anti- HSP25 levels and attenuates atherogenesis. As estrogens promote HSP27 synthesis, cellular release and blood levels, we hypothesize that menopause will result in loss of HSP27 atheroprotection. Hence, the rationale for this study is to compare the efficacy of rHSP25 vaccination vs. estradiol (E2) therapy for the prevention of post-menopausal atherogenesis. ApoE−/− mice subjected to ovariectomy (OVX) showed a 65 % increase atherosclerotic burden compared to sham mice after 5 weeks of a high fat diet. Relative to vaccination with rC1, a truncated HSP27 control peptide, atherogenesis was reduced by 5-weekly rHSP25 vaccinations (-43 %), a subcutaneous E2 slow release pellet (-52 %) or a combination thereof (-82 %). Plasma cholesterol levels declined in parallel with the reductions in atherogenesis, but relative to rC1/OVX mice plasma PCSK9 levels were 52 % higher in E2/OVX and 41 % lower in rHSP25/OVX mice (p < 0.0001 for both). Hepatic LDLR mRNA levels did not change with E2 treatment but increased markedly with rHSP25 vaccination. Conversely, hepatic PCSK9 mRNA increased 148 % with E2 treatment vs. rC1/OVX but did not change with rHSP25 vaccination. In human HepG2 hepatocytes E2 increased PCSK9 promoter activity 303 %, while the combination of [rHSP27 + PAb] decreased PCSK9 promoter activity by 64 %. The reduction in post-OVX atherogenesis and cholesterol levels with rHSP25 vaccination is associated with increased LDLR but not PCSK9 expression. Surprisingly, E2 therapy attenuates atherogenesis and cholesterol levels post-OVX without altering LDLR but increases PCSK9 expression and promoter activity. This is the first documentation of increased PCSK9 expression with E2 therapy and raises questions about balancing physiological estrogenic / PCSK9 homeostasis and targeting PCSK9 in women – are there effects beyond cholesterol? [ABSTRACT FROM AUTHOR]

A response by Cecilia T. Costiniuk, Benjamin M. Hibbert, Lionel G. Filion, Edward R. O'Brien, and Jonathan B. Angel to a letter to the editor about their article "Circulating endothelial progenitor cell levels are not reduced in HIV-infected men" is presented.

Contexte: De petites études ont donné des résultats divergents au sujet de l'administration de facteur de stimulation des colonies de granulocytes (G-CSF) après l'infarctus aigu du myocarde. On ne dispose d'aucune étude dotée d'une puissance statistique adéquate sur des patients présentant une dysfonction ventricu-laire gauche au moins modérée. Méthodes: On a administré soit du G-CSF (10 µg/kg par jour pendant 4 jours) soit un placebo à des patients présentant des fractions d'éjection ventri-culaire gauche inférieures à 45 % après un infarctus du myocarde affectant la paroi antérieure. Après la randomisation initiale de 86 patients, 41 du groupe sous placebo et 39 du groupe sous G-CSF ont été suivis pendant 6 mois et on a mesuré leur fraction d'éjection ventriculaire gauche par angiographie isotopique. Résultats: La fraction d'éjection moyenne au départ et à 6 semaines s'est révélée similaire dans les groupes sous G-CSF et placebo: 34,8 % (intervalle de confiance [IC] de 95 % 32,6-37.0 %) c. 36,4 % (IC de 95 % 33,5-39,2 %) au départ, et 39,8 % (IC de 95 % 36,2-43,4 %) c. 43.1 % (IC de 95 % 39,2-47,0 %) à 6 semaines. Toutefois, le traitement par G-CSF a été associé à une fraction d'éjection moindre à 6 mois par rapport au placebo (40,8 % [IC de 95 % 37,4-44,2 %] c. 46,0 % [IC de 95 % 42,7-44,3 %]). Les 2 groupes présentaient une fonction ventriculaire gauche améliorée, mais la modification de la fraction d'éjection ventriculaire gauche a été moins importante chez les patients traités par G-CSF que chez ceux qui avaient pris le placebo (5,7 [IC de 95 % 3,4-8,1 points de pourcentage] c. 9,2 [IC de 95 % 6,3-12,1 points de pourcentage]). Au moins un élément du paramètre mixte (événements cardiaques majeurs) a été enregistré chez 8 patients (19 %) de chaque groupe et les taux de revascularisation des vaisseaux cibles ont été similaires. Interprétation: Chez les patients présentant une dysfonction ventriculaire gauche modérée après un infarctus de la paroi antérieure, à 6 mois, le traitement par G-CSF a été associé à une baisse de la fraction d'éjection ventriculaire gauche, mais sans augmentation du risque d'événements cardiaques majeurs. Les futures études sur le G-CSF chez les patients présentant une dysfonction ventriculaire gauche devront faire l'objet d'une étroite surveillance au plan de l'innocuité. Numéro d'enregistrement de l'essai : ClinicalTrials.gov, no. NCT00394498 [ABSTRACT FROM AUTHOR]

Background: Small studies have yielded divergent results for administration of granulocyte colony-stimulating factor (G-CSF) after acute myocardial infarction. Adequately powered studies involving patients with at least moderate left ventricular dysfunction are lacking. Methods: Patients with left ventricular ejection fraction less than 45% after anterior-wall myocardial infarction were treated with G-CSF (10 pg/kg daily for 4 days) or placebo. After initial randomization of 86 patients, 41 in the placebo group and 39 in the G-CSF group completed 6-month follow-up and underwent measurement of left ventricular ejection fraction by radionuclide angiography. Results: Baseline and 6-week mean ejection fraction was similar for the G-CSF and placebo groups: 34.8% (95% confidence interval [Cl] 32.6%-37.0%) v. 36.4% (95% Cl 33.5%-39.2%) at baseline and 39.8% (95% Cl 36.2%-43.4%) v. 43.1% (95% Cl 39.2%-47.0%) at 6 weeks. However, G-CSF therapy was associated with a lower ejection fraction at 6 months relative to placebo (40.8% [95% Cl 37.4%-44.2%] v. 46.0% [95% Cl 42.7%-44.3%]). Both groups had improved left ventricular function, but change in left ventricular ejection fraction was lower in patients treated with G-CSF than in those who received placebo (5.7 [95% Cl 3.4-8.1] percentage points v. 9.2 [95% Cl 6.3-12.1] percentage points). One or more of a composite of several major adverse cardiac events occurred in 8 patients (19%) within each group, with similar rates of target-vessel revascularization. Interpretation: In patients with moderate left ventricular dysfunction following anterior-wall infarction, G-CSF therapy was associated with a lower 6-month left ventricular ejection fraction but no increased risk of major adverse cardiac events. Future studies of G-CSF in patients with left ventricular dysfunction should be monitored closely for safety. Trial registration: ClinicalTrials.gov, no. NCT00394498 [ABSTRACT FROM AUTHOR]