BACKGROUND AND OBJECTIVES:Diabetes Type 1 is characterized by hyperglycemia due to reduced insulin secretion that results from the death of pancreatic β cells. It was suggested that endoplasmic reticulum (ER) stress is associated with the autoimmune-mediated β cell destruction. Glucose regulated protein 78 (GRP78) functions as a key regulator to maintain the ER function. Under stress conditions GRP78 is up-regulated and expressed on the cell surface serving as a signaling receptor. Our first objective was to examine the effects of peptide binding cell surface GRP78 to reduce the deleterious effects of diabetes induced by streptozotocin. The second objective was to demonstrate the ability of the peptide to protect the pancreatic β cells from apoptosis.METHODS:The effect of ADoPep on weight loss, HbA1c levels and anti GRP78 antibody titers was evaluated in a diabetes mouse model. The effect of ADoPep on the pancreatic β Ins1E cell apoptosis was determined by FACS analysis.RESULTS:The administration of ADoPep to diabetic mice retained the weight loss and reduced HbA1c significantly in 60% of mice. Titers of anti GRP78 antibodies increased in 70% of the treated mice. Apoptosis was significantly inhibited in stressed pancreatic β Ins 1E cells.CONCLUSIONS:We demonstrate that administration of the peptide ADoPep to diabetic mice improved type 1 diabetes by preventing pancreatic β cell apoptosis.

Pretreatment with high-dose statins given before percutaneous coronary intervention (PCI) has been shown to have beneficial effects, in particular by reducing peri-procedural myocardial infarction. The mechanism of these lipid-independent beneficial statin effects is unclear. Circulating endothelial progenitor cells (EPCs) have an important role in the process of vascular repair, by promoting re-endothelization following injury. We hypothesized that statins can limit the extent of endothelial injury induced by PCI and promote re-endothelization by a positive effect on EPCs. We, therefore, aimed to examine the effect of high-dose statins given prior to PCI on EPCs profile.

Objectives The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI).Background Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover.Methods Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables.Results Sixty-two patients were included (mean age: 57.5 +/- 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI.Conclusions The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment. (C) 2014 by the American College of Cardiology Foundation

Aims: Endothelial progenitor cells (EPCs) have an important role in repair following vascular injury. However, in patients with diabetes, EPC number and function are markedly reduced. It is unclear whether intensive glycaemic control can modify EPC properties in diabetic patients. We aimed to examine whether glycaemic control can improve EPC number and function in patients with long-standing uncontrolled type 2 diabetes.Methods and Results: Thirty-five patients with treated type 2 diabetes and HgA1c >= 8.5% were included. Patients were tested at baseline and after 3-4 months of an intensive glycaemic control programme, with the aim of achieving HgA1c of 7%. The diabetes group was compared to 20 patients without diabetes (control). Circulating EPC levels were assessed by flow cytometry for expression of VEGFR2, CD133, and CD34. The capacity of the cells to form colony-forming units (CFUs), and their migration and viability were quantified after 1 week of culture. Patients with diabetes (mean age 61.1 +/- 7 years, 28.6% women, disease duration of 19.2 +/- 8 years) had a baseline HgA1c of 9.4 +/- 0.8%. After the glycaemic control period, HgA1c decreased to 8 +/- 0.8%. Circulating EPC levels increased significantly after the intensive control period and reached a level similar to the control group. The number of EPC CFUs also increased significantly after glycaemic control but remained lower than the control group. All EPC functional assays improved following the glycaemic control.Conclusions: In patients with uncontrolled long-standing type 2 diabetes, intensive glycaemic control was associated with an increase in the levels of circulating EPCs, and improvement in their functional properties.

BackgroundEverolimus provides effective immune suppression (IS) after heart transplant (HTx). Its pharmacologic properties differentiate everolimus from other IS drugs. A non-invasive immune monitoring (IM) assay test appears to predict the immune state in HTx recipients on standard calcineurin-inhibitor-based IS. The utility of IM in HTx recipients on everolimus-based IS was evaluated.MethodsBetween June 2005 and June 2011, 34 adult HTx recipients followed up at our center received everolimus and had 381 IM assays that were performed at six months to 16-yr post-transplant. Results of the IM assay were correlated with infection and rejection episodes that occurred during the IM testing.ResultsIn the everolimus-based IS group, there were 18 infectious episodes and four rejection episodes. The average IM score was significantly lower during infection than at steady state (188 +/- 122 vs. 338 +/- 137 ng/mL ATP, p < 0.001) and not significantly different during rejection when compared with steady state (430 +/- 132 vs. 338 +/- 137 ng/mL ATP, p = 0.5).ConclusionsThe non-invasive IM assay predicts infectious risk in HTx recipients on everolimus-based IS. Its inconclusive association with rejection was probably due to the small number of rejections. Serial longitudinal IM may allow proper adjustment of everolimus doses.

INTRODUCTION:Endothelial progenitor cells (EPCs) have an important role in the process of vascular injury repair. Platelets have been shown to mediate EPC recruitment, maturation and differentiation. Yet, the mechanism underlying this interaction is unclear. We, therefore, aimed to examine whether direct contact between platelets and EPCs is essential for the positive platelets-EPC effect, and to investigate the main mediators responsible for the improvement in EPCs function.METHODS:Human EPCs were isolated from donated buffy coats and cultured in either: 1. EPCs co-incubated with platelets placed in a 1 µm-Boyden chamber. 2. EPCs incubated with or without platelets in the presence or absence of bFGF/PDGF Receptor inhibitor (PDGFRI). After 7 days culture, EPCs ability to form colonies, proliferate and differentiate was examined. Culture supernatants were collected and growth factors levels were evaluated using ELISA. Growth factors mRNA levels in EPCs were evaluated using RT-PCR.RESULTS AND CONCLUSIONS:After 7 days culture, EPCs functional properties were higher following co-incubation with platelets (directly or indirectly), implying that direct contact is not essential for the platelet's positive effect on EPCs. This effect was reduced by PDGFRI inhibition. Additionally, higher levels of PDGFB in EPCs-platelets supernatant and higher levels of PDGFC mRNA in EPCs co-incubated with platelets were found. In contrast, FGF and other potential mediators that were examined and inhibited did not significantly affect the interaction between platelets and EPCs. Thus, we conclude that PDGF has a central role in the interaction between platelets and EPCs. Further study is required to examine additional aspects of EPC-platelets interaction.

Background and aim: Whether there remains a sex bias in the use of interventional procedures and medications at the acute stage of AMI remains uncertain. We assessed the use of invasive strategies and early medications across European regions in the EHS 2009 snapshot registry. Methods: 47 member countries participated, with 677 active centres, which collected data on 4236 patients admitted with AMI < 48 hours of symptom onset during a one-week period in December 2009, of whom 2563 (61%) had STEMI. Participating countries were grouped into 5 main regions, adapted from the United Nations geoscheme for Europe. Multivariate logistic regression was used to determine independent correlations with the use of invasive strategies or medications. Results: Women were older than men (71±13 vs 64±13 years), and presented less frequently with STEMI (57% vs 62%). Overall, coronary angiography (62% vs 72%), PCI (48% vs 59%) and primary PCI (36% vs 43%) were used significantly less in women. Likewise, aspirin (96 vs 98%), clopidogrel (87 vs 92%), GPIIb/IIIa inhibitors (18 vs 28%), statins (87 vs 92%), beta-blockers (82 vs 85%) were less used in women, with similar trends in all 5 regions. After adjustment on age, risk factors, and previous history, however, use of an invasive strategy (OR 0.88; 0.73-1.05), or primary PCI in STEMI (OR 0.90; 0.73-1.11) did not significantly differ; PCI, however, was used significantly less often (OR 0.83; 0.70-0.97). Among medications, use of aspirin, beta-blockers and ACE-I did not differ according to gender; clopidogrel (OR0.70; 0.54-0.90), GPIs (OR 0.70; 0.57-0.86) and statins (OR 0.66; 0.52-0.85) were less used in women. Consistent trends were noted across all regions. In-hospital death was 9.3% in women and 5.0% in men (P<0.001), with a trend persisting after multivariate adjustment (OR 1.30; 0.98-1.75, P=0.07). This trend disappeared after adding use of invasive strategy into the multivariate model (OR 1.06; 0.50-2.27). Conclusion: The use of an invasive strategy was essentially similar in men and women, although PCI was more seldom used in women; in contrast, several medications, including antiplatelet agents were less used in women. Trends were consistent across all regions.

Background: Retroperitoneal bleeding (RPB) is an unusual but potentially fatal vascular complication occurring after cardiac catheterization (CC). Contemporary data of RPB in the era of dual antiplatelet therapy and vascular closure devices are lacking. Methods: We retrospectively examined all RPB cases that occurred after CC in the Rabin Medical Center between the years 2005 and 2011. Results: Of 26,487 patients who underwent CC, a total of 48 patients (mean age 60.9 ± 13.8 years, 52.1% female) with RPB were identified (0.18%). The indication for CC was acute coronary syndrome (43.7%), myocardial infarction (35.4%), stable angina pectoris (8.3%), hemodynamic studies for valvular heart disease (10.4%) and others (2.1%). Coronary intervention was performed in 34 patients (70.9%) and a vascular closure device (VCD) was used in 16 patients (33.3%). Seventy-seven percent of patients were treated with clopidogrel, 20.8% with glycoprotein IIb-IIIa inhibitors and 85.4% with anticoagulation during CC. Median time to diagnosis of bleeding was 9.0 h, while the median time to bleeding differed between patients with and without a VCD (12 vs. 5 h, respectively). The clinical presentation of RPB was hemorrhagic shock in 39.6% of patients and 50.0% required at least one blood transfusion. Patients were managed either with conservative treatment (79.2%), angiography stenting (14.6%) or vascular surgery (6.2%). A total of 3 patients died during hospitalization, of which RPB was the etiology in 2 (4.2%). Conclusions: RPB which is a rare complication of CC is associated with younger age and female gender, as compared to patients without RPB. Onset of bleeding can be delayed in patients with VCDs. With careful and early diagnosis, most patients with RPB after CC can be managed conservatively.

Objective This study sought to assess the feasibility of performing myocardial perfusion imaging (MPI) with half the technetium activity using ordered-subset expectation maximization with resolution recovery (OSEM-RR), an iterative reconstruction software developed to improve count statistics and acquisition time. Methods Two hundred eighteen patients referred for MPI were randomly allocated to undergo stress-rest or rest-stress protocols with standard full-dose (FD) injections of technetium (Tc)-99m sestamibi or half-dose (HD) injections and OSEM-RR processing. Dose activities were adjusted individually by weight. The groups were compared for image quality and clinical results. Results The groups were similar for mean patient age, weight, and body mass index, sex distribution, pre-test probability of CAD and CAD prevalence. Mean Tc-99m activities for the low-dose and high-dose stages were as follows: FD group: 429 ± 85 MBq and 1132 ± 200 MBq; HD group: 263 ± 129 MBq and 629 ± 85 MBq ( P < .0001 for both). Mean effective dose per study was 13.6 ± 1.4 mSv in the FD group and 7.7 ± 1.0 mSv in the HD group ( P < .001). Over all image quality was good-to-excellent in 98% and 95% of the groups, respectively. However, when we analyzed the low-dose stage separately, image quality was slightly worse in the HD than the FD, though still within the good-to excellent range. Conclusions MPI with nearly half the radiation dose is feasible with good image quality.

TAVR is an emerging technique for the treatment of severe symptomatic aortic stenosis (AS). Few data reported the long-term outcomes of patients undergoing TAVR. Thus, we aimed to focus on the prolonged results of the TAVR procedure. We analyzed the outcomes of 190 TAVR treated patients that were

BackgroundThe study sought to assess the clinical profile, outcome, and predictors for mortality of “real‐world” high‐risk severe aortic stenosis patients according to the mode of treatment assigned.MethodsPatients were referred to a dedicated clinic for meticulous screening and multidisciplinary team assessment and 343 were finally assigned treatment (age 81.3 ± 7.2 years, 42.3% men): transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN or CoreValve device, 100 (29.2%); surgical aortic valve replacement (SAVR), 61 (17.8%); balloon valvuloplasty (as definitive therapy), 27 (7.9%); medication only, 155 (45.2%). No patient was lost to follow‐up.ResultsThe balloon valvuloplasty group had a significantly higher 1‐month mortality rate (18.5%) than the TAVR group (3%, P = 0.006) and medical therapy group (3.9%; P = 0.004), without significant difference from the SAVR group (11.5%, P = 0.5). One‐year cumulative survival was significantly higher in the TAVR group (92%) than in the other groups (SAVR 71%, balloon valvuloplasty 61.5%, medication 65%; all P < 0.001). Among survivors, 1‐year rates of high functional class (NYHA I/II) were as follows: TAVR, 84.6%; SAVR, 63.3%; balloon valvuloplasty, 18.2%; medication, 21.4% (TAVR vs. SAVR, P = 0.04; SAVR vs. balloon valvuloplasty or medical therapy, P = 0.01). On multivariate regression analysis, renal failure (hazard ratio [HR] = 5.3, P < 0.001), not performing TAVR (HR = 4.9, P < 0.001), and pulmonary pressure (10 mm Hg, HR = 1.2, P = 0.02) were independent predictors of 1‐year mortality.ConclusionsTAVR, performed in carefully selected high‐risk patients, is associated with an excellent survival rate and high functional class. Patients treated with another of the available modalities, including SAVR, had a worse outcome, regardless of which alternative treatment they receive. © 2012 Wiley Periodicals, Inc.

BACKGROUND:Manual coronary thrombus aspiration was associated with improved outcomes of ST-elevation myocardial infarction (STEMI) patients. We aimed to evaluate the outcome of aspiration in a "real-world" setting of primary percutaneous coronary intervention (PPCI). METHODS AND MATERIALS:We analyzed the outcome of STEMI patients who underwent PPCI (initial Thrombolysis in Myocardial Infarction flow grade 0/1), comparing patients who underwent aspiration (ASP) to those who had standard (STD) therapy. Various subgroups outcomes were further analyzed. Clinical end points included mortality and major adverse cardiovascular events (MACE) at 30 days and at 1 year. RESULTS:One thousand thirty-five consecutive patients were included: 189 (18.26%) with ASP and 846 (81.74%) with STD. ASP patients were younger (58±12 vs. 61±13, P<.05) and had higher incidence of direct stenting compared to STD patients (34% vs. 16.7%, P<.05). No significant differences were noted in the outcome of ASP vs. STD at 30 days (mortality rate 4.2% vs. 4.5%, P=.9; MACE 6.9% vs. 9.8%, P=.2) and at 1 year (mortality rate 8.0% vs. 8.3%, P=.9; MACE 20.0% vs. 22.3%, P=.5). A significant advantage in favor of ASP was evident in patients with proximal culprit lesions, anterior infarcts, and right ventricular involvement. CONCLUSIONS:Although this was largely a negative study, when STEMI involved a large jeopardized myocardium, aspiration was associated with sustained improved clinical outcomes.

The importance of global economic level on AMI outcomes : Data from the Euro Heart Survey 2009 AMI snapshot

Objectives: Patients with antiphospholipid antibody syndrome (APS) have an increased risk of atherothrombotic complications. There are limited data regarding the outcome of patients with APS who undergo percutaneous coronary intervention (PCI). Accordingly, we aimed to assess the long-term outcomes of these patients. Methods: Nineteen APS patients who underwent PCI between the years 2003 and 2008 were compared to 380 patients who had undergone PCI during the same period (PCI group) and were matched by age (±5 years), gender, diabetes and hypertension. In addition, APS patients were compared to 1,458 patients with ST segment elevation myocardial infarction (MI) who were treated with PCI during the same period. Six-month to 4-year clinical outcomes were evaluated. Results: The indication for PCI in the APS group was acute coronary syndrome in 52.6% of patients. After 1 year of follow-up, patients with APS had higher rates of target vessel revascularization than the other two groups, which translated to higher rates of major adverse cardiac events. There were no differences in MI or mortality rates between the groups. Conclusions: Patients with APS who undergo PCI have worse long-term clinical outcomes, driven by higher rates of revascularization, than other patients undergoing PCI. Further study is warranted to examine the mechanisms underlying these findings.

Objectives: Acute ST elevation myocardial infarction (STEMI) presenting with cardiogenic shock (CS) is associated with dismal prognosis. In the last years, significant advances have been made in reperfusion techniques and pharmacological treatment. Therefore, we aimed to assess the outcome of these patients during the past decade and identify major factors that impact their prognosis. Methods: We identified 170 patients who presented with STEMI, CS, and underwent primary percutaneous coronary intervention (PCI) between 2001 and 2011. Patients were allocated into two groups based on period of presentation: 2001–2005 (n = 70) and 2006–2011 (n = 100). Clinical outcomes up to 6 months were evaluated. Results: Patients in the latter period were younger, and had lower rates of renal failure and higher rates of stent use. Despite these differences, mortality did not differ and remained high in both periods (52–59% at 6 months). Time frames from onset of symptoms to arrival to the emergency department and to performance of coronary intervention were similar in both periods. Intra-aortic balloon pump use was similar in both periods. In multivariate analysis, factors associated with 1-month mortality were: diabetes (OR = 3.6, 1.4–9.4, p = 0.007), LVEF <40% (OR = 1.8, 1.3–2.6, p = 0.001), GFR <60 ml/min/m2 (OR = 1.8, 1.3–2.4, p < 0.009) and glycoprotein IIb/IIIa inhibitor use (OR = 0.5, 0.2–1.1, p = 0.08). The combination of diabetes and renal failure was associated with particularly high mortality. Conclusions: Prognosis of patients presenting with STEMI, CS, and treated with primary PCI during the past decade, remains poor. Better risk-stratification may help improve their grave outcome.

High on-treatment platelet reactivity (HTPR) despite clopidogrel therapy is associated with adverse cardiac events after acute myocardial infarction (AMI). Most studies to date have assessed clopidogrel response at a single time point before or after percutaneous coronary intervention (PCI). It is unclear, however, whether the HTPR phenotype is stable over time. Therefore, we aimed to examine response to clopidogrel in patients with AMI treated with PCI over a 6-month period. Patients (n = 57) with AMI treated with PCI were assessed for response to clopidogrel at 3 time points: in hospital, 30 days, and 6 months after index hospitalization. Response to clopidogrel was determined by the VerifyNow P2Y12 assay (reported as P2Y12 response units) and multiple electrode aggregometry (MEA; reported as aggregation units). HTPR was defined as ≥235 P2Y12 response units or ≥47 aggregation units. Patients' mean age was 54.5 ± 10.9 years, 91% were men, 19% had diabetes, and 74% were admitted with ST-segment elevation MI. HTPR based on MEA was observed in 22.8% of patients in hospital, 26.3% at 30 days, and 17.5% at 6 months (p = NS). HTPR based on the VerifyNow assay was observed in 38.6% of patients in hospital, 28.1% at 30 days, and 33.3% at 6 months (p = NS). Individual HTPR phenotypic assignment at baseline was stable in 73.7% (based on MEA) and 70.2% (based on VerifyNow) of patients at 6-month follow-up. In conclusion, this is the first study evaluating the stability of clopidogrel response over time after AMI. Rates of HTPR to clopidogrel therapy appear to be relatively stable up to 6 months after AMI.