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Background In patients with Normal Glucose Tolerance (NGT) some causes of ischemic heart disease (IHD) were not completely investigated. The role both of metabolic milieu and adipokines in IHD progression was not fully investigated. Our aim was to assess the link between adipokines plasma levels, insulin resistance (IR) and IHD in NGT patients undergoing Percutaneous Coronary Intervention (PCI). Methods AIRE is a single-center prospective longitudinal observational study investigating the IHD outcome of NGT subjects who underwent coronary revascularization by PCI in a third level cardiology center at A.O. dei Colli Hospital, University of Campania “Luigi Vanvitelli”. Six hundred seventy-nine subjects hospitalized in 2015 for coronary arteriography not suffering from Acute Coronary Syndrome (ACS) in the previous 4 weeks, as well as from all conditions could affect glycemic plasma levels and IR status, were assessed for eligibility. Fifty-four patients with neither history of diabetes nor Altered Fasting Glucose (AFG)/Impaired Fasting Glucose (IGT) after Oral Glucose Tolerance Test (OGTT) were finally enrolled. Primary endpoint was the assessment of the relationship of adipokines and HOMA-IR with the occurrence of restenosis in NGT subjects. As secondary endpoint we assessed the association of the same adipokines and IR with overall ACS events after PCI in NGT subjects. Results The 54 NGT patients enrolled were mainly males (85%), with a median age of 60 years [IQR 58–63 years]. Only 4 patients (7.4%) experimented restenosis. Median follow-up was equal to 29.5 months [IQR 14.7–34 months]. Adiponectin levels were independently associated to restenosis (OR 0.206; 95% CI 0.053–0.796; p = 0.000). Instead HOMA-IR and adiponectin appeared independently associated both to de novo IHD (OR 9.6*10 13 ; 95% CI 3.026–3.08*10 27 ; p = 0.042 and OR 0.206; 95% CI 0.053–0.796; p = 0.000, respectively) and overall new PCI (OR 1.5*10 11 ; 95% CI 2.593–8.68*10 21 ; p = 0.042 and OR 0.206; 95% CI 0.053–0.796; p = 0.000, respectively). Moreover, we fixed a potential cut-off for adiponectin for risk of restenosis (≤ 8.5 µg/mL) and overall new PCI (≤ 9.5 µg/mL). Conclusion IR and cytokines play a role in progression of any stage of IHD also in NGT subjects. Our results in this setting of patients, though the relatively small sample size, represent a novelty. Future studies on larger populations are needed to analyze more in depth adipokines and insulin resistance role on IHD progression in non-diabetic people.

To evaluate the prognostic impact of diabetes mellitus (DM) in patients with Infective Endocarditis (IE). 375 patients with diagnosis of IE referred to our Hospital between 1994-2017 were retrospectively included; diabetes was reported in 129 (34.4%). Diabetic patients were older than non-diabetic (66±1 vs. 57±2 years, p<0.001) and showed a higher prevalence of comorbidities such as hypertension (75 vs. 54%, p<0.001), coronary artery disease (30 vs. 12%, p<0.001) and history of heart failure (HF; 24 vs. 13%, p = 0.021). Echocardiography showed a higher incidence of paravalvular complications (82 vs. 64%, p<0.001) and a lower left ventricular ejection fraction (LVEF; 52±11 vs. 55±10%, p = 0.001) in diabetic than in non-diabetic patients. In-hospital mortality was higher in diabetic patients (83 vs. 74%; p = 0.030). At logistic regression, history of HF (OR = 3.1, 95%CI: 1.87-5.29, p<0.001) resulted an independent predictor of in-hospital death. At long-term follow-up [median 24(7-84) months], the Kaplan-Meier analysis showed a significantly lower survival free from all-cause death in the group with diabetes (Log-rank<0.001). At the propensity score adjusted Cox multivariable analysis, DM (HR = 1.76, 95%CI: 1.18-2.6, p = 0.005), age (HR = 1.03, 95%CI: 1.02-1.05, p<0.001), intravenous drug users (HR = 5.42, 95%CI: 2.55-11.51, p<0.001) and low LVEF (HR = 0.98, 95%CI: 0.96-0.99, p = 0.013) were independently associated to a higher mortality. In patients with IE, DM is associated to a higher prevalence of anatomic complications and a more impaired LVEF. Diabetic patients show a significantly lower survival both in hospital and during follow-up compared to the non-diabetic ones.

Thrombolysis remains the treatment of choice in ST-segment elevation myocardial infarction (STEMI) when primary percutaneous coronary intervention (PCI) cannot be done within 90 min. However, the best subsequent management of patients after thrombolytic therapy remains unclear. To assess the best management, we randomised patients with STEMI treated by thrombolysis and abciximab at a non-interventional hospital to immediate transfer for PCI, or to standard medical therapy with transfer for rescue angioplasty. 600 patients aged 75 years or younger with one or more high-risk features (extensive ST-segment elevation, new-onset left bundle branch block, previous myocardial infarction, Killip class >2, or left ventricular ejection fraction ≤35%) in hospitals in France, Italy, and Poland were treated with half-dose reteplase, abciximab, heparin, and aspirin, and randomly assigned to immediate transfer to the nearest interventional centre for PCI, or to management in the local hospital with transfer only in case of persistent ST-segment elevation or clinical deterioration. The primary outcome was a composite of death, reinfarction, or refractory ischaemia at 30 days, and analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number 00220571. Of the 299 patients assigned to immediate PCI, 289 (97·0%) underwent angiography, and 255 (85·6%) received PCI. Rescue PCI was done in 91 patients (30·3%) in the standard care/rescue PCI group. The primary outcome occurred in 13 patients (4·4%) in the immediate PCI group compared with 32 (10·7%) in the standard care/rescue PCI group (hazard ratio 0·40; 95% CI 0·21–0·76, log rank p=0·004). Major bleeding was seen in ten patients in the immediate group and seven in the standard care/rescue group (3·4% vs 2·3%, p=0·47). Strokes occurred in two patients in the immediate group and four in the standard care/rescue group (0·7% vs 1·3%, p=0·50). Immediate transfer for PCI improves outcome in high-risk patients with STEMI treated at a non-interventional centre with half-dose reteplase and abciximab.

The investigators performed a network meta-analysis of randomized trials comparing the effectiveness of currently available strategies for the treatment of drug-eluting stent (DES) restenosis. Despite the widespread use of DES in patients who undergo percutaneous coronary intervention, the optimal treatment for DES restenosis remains poorly defined. A systematic search of electronic resources was performed. The primary end point was diameter stenosis at follow-up angiography. Seven trials were included, enrolling a total of 1,586 patients with 1,728 restenotic lesions. The following treatment options were found: balloon angioplasty (BA) in 343 patients (19.3%), iopromide-based paclitaxel-eluting balloons (PEB) in 343 (21.6%), sirolimus-eluting stents in 441 (27.8%), paclitaxel-eluting stents in 462 (29.1%), and everolimus-eluting stents in 34 (2.2%). Compared with BA, PEB (−17.74%, 95% credible interval [CI] −25.17% to −11.31%), everolimus-eluting stents (−14.93%, 95% CI −33.47% to 1.16%), paclitaxel-eluting stents (−15.3%, 95% CI −22.96% to −8.35%), and sirolimus-eluting stents (−11.08%, 95% CI −17.89% to −3.4%) had similar reductions in diameter stenosis at follow-up angiography. PEB (85%) and everolimus-eluting stents (68%) had the greatest probabilities for being the best treatment option. Furthermore, PEB were the best treatment in terms of late luminal loss (85%) and binary restenosis (85%). BA had the lowest efficacy with respect to all study end points. In conclusion, in patients with DES restenosis, repeat DES implantation and iopromide-based PEB are valid alternatives. However, PEB had greater angiographic efficacy and therefore should be considered the new benchmark comparator in the treatment of DES restenosis. The use of BA should be discouraged in patients with DES restenosis. •Although several strategies have been proposed, the optimal treatment for DES restenosis remains poorly defined.•To address this issue, we performed a network meta-analysis of randomized trials to evaluate the effectiveness of different treatment options in patients with DES restenosis.•We found that in patients with DES restenosis, repeat DES implantation and iopromide-based PEBs are valid alternatives. However, PEBs had greater angiographic efficacy and therefore should be considered the new benchmark comparator in the treatment of DES restenosis.•The use of balloon angioplasty should be discouraged in patients with DES restenosis.

Transfemoral approach (TFA) remains the most common vascular access for percutaneous coronary intervention (PCI) in many countries. However, in the last years several randomized trials compared transradial approach (TRA) with TFA in patients with acute coronary syndrome (ACS), but only few studies were powered to estimate rare events. The aim of the current study was to clarify whether TRA is superior to TFA approach in patients with ACS undergoing percutaneous coronary intervention. A meta-analysis, meta-regression and trial sequential analysis of safety and efficacy of TRA in ACS setting was performed. Medline, the Cochrane Library, Scopus, scientific session abstracts and relevant websites were searched. Data concerning the study design, patient characteristics, risk of bias, and outcomes were extracted. The primary endpoint was death. Secondary endpoints were: major bleeding and vascular complications. Outcomes were assessed within 30 days. Eleven randomized trials involving 9,202 patients were included. Compared with TFA, TRA significantly reduced the risk of death (odds ratio [OR] 0.70; 95% confidence interval [CI], 0.53-0.94; p = 0.016), but this finding was not confirmed in trial sequential analysis, indicating that sufficient evidence had not been yet reached. Furthermore, TRA compared with TFA reduced the risk of major bleeding (OR 0.60; 95% CI, 0.41-0.88; p = 0.008) and vascular complications (OR 0.35; 95% CI, 0.28-0.46; p<0.001); these findings were supported by trial sequential analyses. In patients with ACS undergoing PCI, a lower risk of death was observed with TRA. Nevertheless, the association between mortality and TRA in ACS setting should be interpreted with caution because it is based on insufficient evidence. However, because of the clinical relevance associated with major bleeding and vascular complications reduction, TRA should be recommended as first-choice vascular access in patients with ACS undergoing cardiac catheterization.

The Italian Elderly ACS study was the first randomized controlled trial comparing an early aggressive with an initially conservative strategy in patients with non–ST-segment elevation acute coronary syndromes aged ≥75 years, with the results showing no significant benefit of early aggressive therapy. The aim of this study was to evaluate the outcomes of trial patients, according to the treatment actually received during hospitalization. The trial enrolled 313 patients. The primary end point was the composite of death, myocardial infarction (MI), disabling stroke, and repeat hospital stay for cardiovascular causes or bleeding within 1 year. All patients in whom coronary angiography was performed during initial hospitalization were defined as having undergone invasive treatment (182 patients), whereas all patients who did not undergo coronary angiography were classified as medically managed (conservative treatment [CT] group, 131 patients). The primary end point occurred in 53 patients (40.5%) in the CT group and 45 patients (24.7%) in the invasive treatment group (hazard ratio 0.56, 95% confidence interval 0.37 to 0.83, p = 0.003). The invasive treatment group showed significantly lower rates of MI (6% vs 13% in the CT group; hazard ratio 0.43, 95% confidence interval 0.20 to 0.92, p = 0.034) and the aggregate of death and MI (14.3% vs 27.5% CT group; hazard ratio 0.48, 95% confidence interval 0.29 to 0.81, p = 0.004). In conclusion, elderly patients with non–ST-segment elevation acute coronary syndromes treated invasively experienced significantly better survival free from the composite of all-cause mortality, nonfatal MI, disabling stroke, and repeat hospitalization for cardiovascular causes or bleeding.

G-protein-coupled receptor (GPCR) kinases, GRKs, are known as serine/threonine kinases that regulate GPCR signaling, but recent findings propose functions for these kinases besides receptor desensitization. Indeed, GRK5 can translocate to the nucleus by means of a nuclear localization sequence, suggesting that this kinase regulates transcription events in the nucleus. To evaluate the effect of GRK5-IκBα interaction on NFκB signaling, we induced the overexpression and the knockdown of GRK5 in cell cultures. GRK5 overexpression causes nuclear accumulation of IκBα, leading to the inhibition of NFκB transcriptional activity. Opposite results are achieved by GRK5 knockdown through siRNA. A physical interaction between GRK5 and IκBα, rather than phosphorylative events, appears as the underlying mechanism. We identify the regulator of gene protein signaling homology domain of GRK5 (RH) and the N-terminal domain of IκBα as the regions involved in such interaction. To confirm the biological relevance of this mechanism of regulation for NFκB, we evaluated the effects of GRK5-RH on NFκB-dependent phenotypes. In particular, GRK5-RH overexpression impairs apoptosis protection and cytokine production in vitro and inflammation and tissue regeneration in vivo. Our results reveal an unexpected role for GRK5 in the regulation of NFκB transcription activity. Placing these findings in perspective, this mechanism may represent a therapeutic target for all those conditions involving excessive NFκB activity.

Heart Failure (HF) is a syndrome, which implies the existence of different phenotypes. The new categorization includes patients with preserved ejection fraction (HFpEF), mid-range EF (HFmrEF), and reduced EF (HFrEF) but the molecular mechanisms involved in these HF phenotypes have not yet been exhaustively investigated. Sirt1 plays a crucial role in biological processes strongly related to HF. This study aimed to evaluate whether Sirt1 activity was correlated with EF and other parameters in HFpEF, HFmrEF, and HFrEF. Seventy patients, HFpEF (n = 23), HFmrEF (n = 23) and HFrEF (n = 24), were enrolled at the Cardiology Unit of the University Hospital of Salerno. Sirt1 activity was measured in peripheral blood mononuclear cells (PBMCs). Angiotensin-Converting Enzyme 2 (ACE2) activity, Tumor Necrosis Factor-alpha (TNF-α) and Brain Natriuretic Peptide (BNP) levels were quantified in plasma. HFpEF showed lower Sirt1 and ACE2 activities than both HFmrEF and HFrEF (p < 0.0001), without difference compared to No HF controls. In HFmrEF and HFrEF a very strong correlation was found between Sirt1 activity and EF (r2 = 0.899 and r2 = 0.909, respectively), and between ACE2 activity and Sirt1 (r2 = 0.801 and r2 = 0.802, respectively). HFrEF showed the highest TNF-α levels without reaching statistical significance. Significant differences in BNP were found among the groups, with the highest levels in the HFrEF. Determining Sirt1 activity in PBMCs is useful to distinguish the HF patients’ phenotypes from each other, especially HFmrEF/HFrEF from HFpEF.

The main regulator of neovascularization is Vascular Endothelial Growth Factor (VEGF). We recently demonstrated that QK, a de novo engineered VEGF mimicking peptide, shares in vitro the same biological properties of VEGF, inducing capillary formation and organization. On these grounds, the aim of this study is to evaluate in vivo the effects of this small peptide. Therefore, on Wistar Kyoto rats, we evaluated vasomotor responses to VEGF and QK in common carotid rings. Also, we assessed the effects of QK in three different models of angiogenesis: ischemic hindlimb, wound healing and Matrigel plugs. QK and VEGF present similar endothelium-dependent vasodilatation. Moreover, the ability of QK to induce neovascularization was confirmed us by digital angiographies, dyed beads dilution and histological analysis in the ischemic hindlimb as well as by histology in wounds and Matrigel plugs. Our findings show the proangiogenic properties of QK, suggesting that also in vivo this peptide resembles the full VEGF protein. These data open to new fields of investigation on the mechanisms of activation of VEGF receptors, offering clinical implications for treatment of pathophysiological conditions such as chronic ischemia.

The causes of death within 1 year of hospital admission in patients with non–ST-segment elevation acute coronary syndromes are ill defined, particularly in patients aged ≥75 years. From January 2008 through May 2010, we enrolled 645 patients aged ≥75 years with non–ST-segment elevation acute coronary syndromes: 313 in a randomized trial comparing an early aggressive versus an initially conservative approach, and 332, excluded from the trial for specific reasons, in a parallel registry. Each death occurring during 1 year of follow-up was adjudicated by an independent committee. The mean age was 82 years in both study cohorts, and 53% were men. By the end of the follow-up period (median 369 days, interquartile range 345 to 391), 120 patients (18.6%) had died. The mortality was significantly greater in the registry (23.8% vs 13.1%, p = 0.001). The deaths were classified as cardiac in 94% of the cases during the index admission and 68% of the cases during the follow-up period. Eighty-six percent of the cardiac deaths were of ischemic origin. In a multivariate logistic regression model that included the variables present on admission in the whole study population, the ejection fraction (hazard ratio 0.95, 95% confidence interval 0.94 to 0.97; p <0.001), hemoglobin level (hazard ratio 0.85, 95% confidence interval 0.76 to 0.94; p = 0.001), older age (hazard ratio 1.05, 95% confidence interval 1.01 to 1.10, p = 0.010), and creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.97 to 0.99; p = 0.030) were the independent predictors of all-cause death at 1 year. In conclusion, within 1 year after admission for non–ST-segment elevation acute coronary syndromes, most deaths in patients aged ≥75 years have a cardiac origin, mostly owing to myocardial ischemia.