Preclinical models of atherosclerosis. The future of Hybrid PET/MR technology for the early detection of vulnerable plaque.

Cardiovascular diseases are the leading cause of death in developed countries. The aetiology is currently multifactorial, thus making them very difficult to prevent. Preclinical models of atherothrombotic diseases, including vulnerable plaque-associated complications, are now providing significant insights into pathologies like atherosclerosis, and in combination with the most recent advances in new non-invasive imaging technologies, they have become essential tools to evaluate new therapeutic strategies, with which can forecast and prevent plaque rupture. Positron emission tomography (PET)/computed tomography imaging is currently used for plaque visualisation in clinical and pre-clinical cardiovascular research, albeit with significant limitations. However, the combination of PET and magnetic resonance imaging (MRI) technologies is still the best option available today, as combined PET/MRI scans provide simultaneous data acquisition together with high quality anatomical information, sensitivity and lower radiation exposure for the patient. The coming years may represent a new era for the implementation of PET/MRI in clinical practice, but first, clinically efficient attenuation correction algorithms and research towards multimodal reagents and safety issues should be validated at the preclinical level.

Nitric oxide prevents aortic neointimal hyperplasia by controlling macrophage polarization.

OBJECTIVE: Nitric oxide synthase 3 (NOS3) prevents neointima hyperplasia by still unknown mechanisms. To demonstrate the significance of endothelial nitric oxide in the polarization of infiltrated macrophages through the expression of matrix metalloproteinase (MMP)-13 in neointima formation. APPROACH AND RESULTS: After aortic endothelial denudation, NOS3 null mice show elevated neointima formation, detecting increased mobilization of LSK (lineage-negative [Lin]-stem-cell antigen 1 [SCA1]+KIT+) progenitor cells, and high ratios of M1 (proinflammatory) to M2 (resolving) macrophages, accompanied by high expression of interleukin-5, interleukin-6, MCP-1 (monocyte chemoattractant protein), VEGF (vascular endothelial growth factor), GM-CSF (granulocyte-macrophage colony stimulating factor), interleukin-1ß, and interferon-γ. In conditional c-Myc knockout mice, in which M2 polarization is defective, denuded aortas showed extensive wall thickening as well. Conditioned medium from NOS3-deficient endothelium induced extensive repolarization of M2 macrophages to an M1 phenotype, and vascular smooth muscle cells proliferated and migrated faster in conditioned medium from M1 macrophages. Among the different proteins participating in cell migration, MMP-13 was preferentially expressed by M1 macrophages. M1-mediated vascular smooth muscle cell migration was inhibited when macrophages were isolated from MMP-13-deficient mice, whereas exogenous administration of MMP-13 to vascular smooth muscle cell fully restored migration. Excess vessel wall thickening in mice lacking NOS3 was partially reversed by simultaneous deletion of MMP-13, indicating that NOS3 prevents neointimal hyperplasia by preventing MMP-13 activity. An excess of M1-polarized macrophages that coexpress MMP-13 was also detected in human carotid samples from endarterectomized patients. CONCLUSIONS: These findings indicate that at least M1 macrophage-mediated expression of MMP-13 in NOS3 null mice induces neointima formation after vascular injury, suggesting that MMP-13 may represent a new promising target in vascular disease.

Appropriateness of surgery performed for abdominal aortic aneurysm at tertiary hospitals in Spain.

BACKGROUND: The aim of this study was to analyze the appropriateness of the type of repair (open or endovascular) performed for abdominal aortic aneurysm (AAA) in five university hospitals in Spain, according to evidence-based recommendations. METHODS: A multicenter, retrospective cross-sectional study of patients with AAA who underwent elective open surgical repair (OSR) or endovascular aneurysm repair (EVAR). Data were collected on demographic and clinical variables and type of surgical repair. A pair of vascular surgeons from each participating hospital performed a blinded assessment based on GRADE recommendations. The concordance between the two evaluators and the agreement between their evidence-based recommendation and the procedure performed were assessed. RESULTS: A total of 186 patients were selected; 179 were included. Mean age was 72.5 years (standard deviation [SD], 8.4), mean Charlson Comorbidity Index (CCI) was 2.04 (SD, 1.9). OSR was performed in 53.2% (N.=99) and EVAR in 46.8% (N.=87) of cases. Overall, 65.9% (118/179) of interventions performed were considered appropriate: 50% (47/94) of OSRs and 83.5% (71/85) of EVARs. The patient characteristics were similar for all the hospitals, but the chosen surgical technique did show significant differences among these centers. There were no significant differences among the hospitals in the proportion of cases judged as appropriate, either overall (P=0.346) or for each type of procedure (P=0.531 and P=0.538 for OSR and EVAR, respectively). CONCLUSIONS: In this study, most of the AAA repairs performed were appropriate according to GRADE recommendations. A higher proportion of EVARs were considered appropriate than OSRs. Choice of AAA repair should be standardized using evidence-based clinical practice guidelines, while incorporating patient preferences, to reduce the existing variability and ensure appropriate selection of AAA repair technique.

Descriptive and follow-up study of patients treated surgically for abdominal aortic aneurysm at tertiary hospitals in Spain.

BACKGROUND: The aim of this study was to assess potential variability in the clinical characteristics and treatment of patients undergoing elective surgery for abdominal aortic aneurysm (AAA) across five hospitals in Spain. METHODS: Multicenter, retrospective cohort study of patients diagnosed with AAA and treated with open surgical repair (OSR) or endovascular aneurysm repair (EVAR). We evaluated clinical and demographic variables, including comorbidity (Charlson Comorbidity Index [CCI]); anatomic characteristics; surgical risk (ASA Score); aneurysm characteristics; and in-hospital and overall mortality. All patients were followed for three years. RESULTS: A total of 186 patients were included, mean age 72.5 (standard deviation [SD], 8.4), mean CCI 2.04 (SD, 1.9). The surgical technique was EVAR in 46.8% of cases (N.=87) and OSR in 53.2% (N.=99). The in-hospital mortality rate was 2.2%, with no differences between groups. The overall mortality rate during follow-up (mean, 2.9 years) was 24.1% for EVAR versus 8.1% for the OSR group (odds ratio [OR], 3.62; 95% confidence interval [CI], 3.60-3.64; P=0.004). EVAR was the only independent risk factor for mortality (OR, 3.89; 95% CI: 3.87-3.92; P=0.004). Inter-center variability in the type of surgery was high, with EVAR accounting for 19.4% to 75% of the surgical procedures, depending on the treating center (P<0.001). CONCLUSIONS: In this study the in-hospital mortality rates for elective EVAR and OSR were similar. However, after the follow-up, patients who underwent EVAR had a three-fold greater mortality rate than those treated with OSR. There was substantial inter-hospital variability, underscoring the need to standardize treatment selection in patients who undergo elective surgery for AAA repair.

Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.

Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases (MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout (KO) mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO) in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF). NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.

EMMPRIN-Targeted Magnetic Nanoparticles for In Vivo Visualization and Regression of Acute Myocardial Infarction.

UNLABELLED: Inhibition of extracellular matrix (ECM) degradation may represent a mechanism for cardiac protection against ischemia. Extracellular matrix metalloproteinase inducer (EMMPRIN) is highly expressed in response to acute myocardial infarction (AMI), and induces activation of several matrix metalloproteinases (MMPs), including gelatinases MMP-2 and MMP-9. We targeted EMMPRIN with paramagnetic/fluorescent micellar nanoparticles conjugated with the EMMPRIN binding peptide AP-9 (NAP9), or an AP-9 scrambled peptide as a negative control (NAPSC). We found that NAP9 binds to endogenous EMMPRIN in cultured HL1 myocytes and in mouse hearts subjected to ischemia/reperfusion (IR). Injection of NAP9 at the time of or one day after IR, was enough to reduce progression of myocardial cell death when compared to CONTROL and NAPSC injected mice (infarct size in NAP9 injected mice: 32%±6.59 vs CONTROL: 46%±9.04 or NAPSC injected mice: 48%±7.64). In the same way, cardiac parameters were recovered to almost healthy levels (LVEF NAP9 63% ± 7.24 vs CONTROL 42% ± 4.74 or NAPSC 39% ± 6.44), whereas ECM degradation was also reduced as shown by inhibition of MMP-2 and MMP-9 activation. Cardiac magnetic resonance (CMR) scans have shown a signal enhancement in the left ventricle of NAP9 injected mice with respect to non-injected, and to mice injected with NAPSC. A positive correlation between CMR enhancement and Evans-Blue/TTC staining of infarct size was calculated (R:0.65). Taken together, these results point to EMMPRIN targeted nanoparticles as a new approach to the mitigation of ischemic/reperfusion injury.

Risk Stratification of Patients With Acute Symptomatic Pulmonary Embolism Based on Presence or Absence of Lower Extremity DVT: Systematic Review and Meta-analysis.

BACKGROUND: For patients diagnosed with acute pulmonary embolism (PE), the prognostic significance of concomitant DVT lacks clarity. METHODS: We performed a meta-analysis of studies that enrolled patients with acute PE to assess the prognostic value of concomitant DVT for the primary outcome of 30-day all-cause mortality and the secondary outcome of 90-day PE-related adverse events. We conducted unrestricted searches of PubMed and Embase from 1980 through September 30, 2014, and used the terms "deep vein thrombosis," "pulmonary embolism," and "prognos*." We used a random-effects model to pool study results, Begg rank-correlation method to evaluate for publication bias, and I(2) testing to assess for heterogeneity. RESULTS: The meta-analysis included a total of nine studies (10 cohorts, as one study had two cohorts) with 8,859 patients. Of the seven cohorts with 7,868 participants who had PE and provided results on the primary outcome, 4,379 (56%) had concomitant DVT; 272 of 4,379 (6.2%) patients with concomitant DVT died 30 days after the diagnosis of PE compared with 133 of 3,489 (3.8%) without DVT. Concomitant DVT had a significant association with 30-day all-cause mortality in all patients (seven cohorts; OR, 1.9; 95% CI, 1.5-2.4; I(2) = 0%). Concomitant DVT was not significantly associated with 90-day PE-related adverse outcomes (five cohorts; OR, 1.6; 95% CI, 0.8-3.4; I(2) = 75%). CONCLUSIONS: In patients diagnosed with acute symptomatic PE, concomitant DVT was significantly associated with an increased risk of death within 30 days of PE diagnosis.

Lipocalin-2 deficiency or blockade protects against aortic abdominal aneurysm development in mice.

AIMS: To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Expression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real-time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2-/-). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2-/- mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2-/- or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2-/- mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG. CONCLUSION: Either Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA.

Efectos de la ivabradina en la frecuencia cardiaca y los parámetros hemodinámicos en un modelo porcino de shock cardiogénico / Effects of ivabradine on heart rate and hemodynamic parameters in a swine model of cardiogenic shock

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