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Anticoagulation is the first-line approach in the prevention and treatment of pulmonary embolism. In some instances, however, anticoagulation fails, or cannot be administered due to a high risk of bleeding. Inferior vena cava filters are metal alloy devices that mechanically trap emboli from the deep leg veins halting their transit to the pulmonary circulation, thus providing a mechanical alternative to anticoagulation in such conditions. The Greenfield filter was developed in 1973 and was later perfected to a model that could be inserted percutaneously. Since then, this model has been the reference standard. The current class I indication for this device includes absolute contraindication to anticoagulants in the presence of acute thromboembolism and recurrent thromboembolism despite adequate therapy. Additional indications have been more recently proposed, due to the development of removable filters and of progressively less invasive techniques. Although the use of inferior vena cava filters has solid theoretical advantages, clinical efficacy and adverse event profile are still unclear. This review analyzes the most important studies related to such devices, open issues, and current guideline recommendations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Grant FOR READINGS/SPEECHES AT CONFERENCES: Chiesi, GSK, Firma, Guidotti, Sanofi, Astrazeneca. Project with drug development: Chiesi and Astrazeneca. Project without drug development: GSK., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aim: Chronic thromboembolic pulmonary disease (CTEPD) is a progressive condition caused by fibrotic thrombi and vascular remodeling in the pulmonary circulation despite prolonged anticoagulation. We evaluated clinical factors associated with CTEPD, as well as its impact on functional capacity, pulmonary haemodynamics at rest and after exercise, and right ventricle (RV) morphology and function., Methods: We compared 33 consecutive patients with a history of acute pulmonary embolism and either normal pulmonary vascular imaging (negative Q-scan, group 1, n = 16) or persistent defects on lung perfusion scan (positive Q-scan) despite oral anticoagulation at 4 months (group 2, n = 17). Investigations included thrombotic load, the Pulmonary Embolism Severity Index (PESI) score, functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), cardiopulmonary exercise test (CPET) and echocardiographic parameters at rest and after exercise (ESE), at 4 and at 24 months., Results: Compared with group 1, group 2 featured a higher PESI score (p = 0.02) and a higher thrombotic load (p = 0.004) at hospital admission. At 4 months, group 2 developed exercise-induced pulmonary hypertension (Ex-PH) at CPET (p < 0.001) and ESE (p < 0.001). At 24 months group 2 showed higher NT-proBNP (p < 0.001), WHO-FC (p < 0.001), systolic (p<0.001) and diastolic (p = 0.037) RV dysfunction and worse RV-arterial coupling (p < 0.001) despite maintaining a low or intermediate echocardiographic probability of PH., Conclusions: This is the first "proof of concept" study showing that patients with a positive Q-scan frequently develop Ex-PH and RV functional deterioration as well as reduced functional capacity, generating the hypothesis that Ex-PH could help detect the progression to CTEPD., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Aims: To evaluate the effect of the ESC/EAS 2019 dyslipidaemia guidelines on patient management of lipid-lowering therapy in patients with acute coronary syndrome (ACS), through a survey designed to compare post-ACS patient management in 2022 with that in 2018., Methods: Online questionnaires focused on lipid profile and medications were used to gather data from 2650 ACS patients in 6 European countries, treated between March-June 2022 (ACS EuroPath IV survey). These data were compared with data collected from 2650 patients who participated in the ACS EuroPath I survey (conducted in 2018)., Results: Lipid testing was performed in 90% of patients and was done sooner after admission in 2022 versus 2018 (mean 1.4 vs 1.7 days). Increased testing for non-HDL-C, lipoprotein(a), and ApoB was observed over time. At discharge, most patients (≥90%) were receiving lipid-lowering therapy. Prescribing patterns differed, with a higher proportion of patients receiving statin plus ezetimibe combination therapy in 2022 versus 2018 (34% vs 13%). LDL-C levels were lower in 2022 versus 2018 at admission and at 1st, 2nd and 3rd post-discharge follow-up points. More patients achieved low-density lipoprotein cholesterol (LDL-C) goals in 2022 versus 2018 at the first follow-up (average 14 vs 16 weeks since discharge; <70 mg/dL [1.8 mmol/L]: 34% vs 20%; <55 mg/dL [1.4 mmol/L]: 18% vs 10%) and at subsequent follow-up points., Conclusion: LDL-C goal achievement has improved since the release of the 2019 guidelines, but lipid management in post-ACS patients remains suboptimal., Competing Interests: Declaration of Competing Interest UL has received honoraria, lecture fees or research grants from Amgen, Daiichi Sankyo, Novartis and Sanofi. ALC has received honoraria, lecture fees or research grants from: AstraZeneca, Aegerion, Amryt, Amarin, Daiichi Sankyo, Esperion, Ionis Pharmaceuticals, Kowa, Medscape, Mylan, Merck, Menarini, Novartis, Peer Voice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi and The Corpus. The work of ALC relevant to this publication is supported by Ministero della salute Ricerca corrente. RDC has received honoraria, lecture fees or research grants from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Roche, Novartis, AstraZeneca, Milestone, Menarini, Guidotti, Lilly, Merck and Portola. AS has received honoraria, lecture fees or research grants from Amgen, Daiichi Sankyo, Ferrer, Getinge, Novartis, Pfizer, Sanofi and Zoll. AZ has received honoraria, consulting or lecture fees from Sanofi, Amgen and Novartis. FS has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Bayer, Novartis, Novo Nordisk, Sanofi Aventis, Recordati, Servier, Mylan and AstraZeneca. JWJ/his department has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Netherlands Heart Institute and the European Community Framework KP7 Programme., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-vitamin K antagonist oral anticoagulants (NOACs) have revolutionized treatment of atrial fibrillation. Although benefits of anticoagulation therapy are clear, a minority of patients still experience treatment inefficacy or harm. All NOACs have varying degree of renal clearance, which may significantly affect plasma concentrations. Pivotal clinical trials have explored the effects of dose reduction in patients with chronic renal disease. None of these have, however, specifically addressed the need for a dose up-titration in patients with renal hyperfiltration, in whom lower drug plasma levels are to be expected. A signal for lower efficacy in this patient subset has recently emerged. We systematically assessed the peer-reviewed scientific literature on this topic, including a recently reported randomized pharmacokinetic study in renal hyperfiltrators also reporting on ischemic and bleeding events. We conclude that the reduction in NOAC plasma levels in AF patients with renal hyperfiltration is limited in extent and, does not translate into a clinically meaningful reduction in efficacy for NOACs as compared to vitamin K antagonists (VKAs) in such patients. At the current state of knowledge, NOAC current dosing should not be altered in patients with high-normal renal function., Competing Interests: Declaration of Competing Interest AH: no disclosures. CZ: no disclosures. RPG declares the following: Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital from Anthos and Daiichi Sankyo; Honoraria for Lecture / CME programs from Daiichi Sankyo, Medical Education Resources, Menarini, Merck, Pfizer, SAJA, Servier, Shanghai Medical Telescope; Consultant fees from AstraZeneca, CryoLife, Daiichi Sankyo, Hengrui, Janssen, Pfizer, and Samsung. Dr. Giugliano is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Merck, Novartis, Pfizer, The Medicines Company. RDC reports grants from Boehringer Ingelheim, Bayer, BMS/Pfizer Alliance, Daiichi-Sankyo, Menarini, Roche, Novartis, Sanofi, Merck, Portola, AstraZeneca, Amgen and Guidotti, all outside the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Vascular smooth muscle cells (SMC) possess a unique cytoplasticity, regulated by transcriptional, translational and phenotypic transformation in response to a diverse range of extrinsic and intrinsic pathogenic factors. The mature, differentiated SMC phenotype is physiologically typified transcriptionally by expression of genes encoding "contractile" proteins, such as SMα-actin (ACTA2), SM-MHC (myosin-11) and SM22α (transgelin). When exposed to various pathological conditions (e.g., pro-atherogenic risk factors, hypertension), SMC undergo phenotypic modulation, a bioprocess enabling SMC to de-differentiate in immature stages or trans-differentiate into other cell phenotypes. As recent studies suggest, the process of SMC phenotypic transformation involves five distinct states characterized by different patterns of cell growth, differentiation, migration, matrix protein expression and declined contractility. These changes are mediated via the action of several transcriptional regulators, including myocardin and serum response factor. Conversely, other factors, including Kruppel-like factor 4 and nuclear factor-κB, can inhibit SMC differentiation and growth arrest, while factors such as yin yang-1, can promote SMC differentiation whilst inhibiting proliferation. This article reviews recent advances in our understanding of regulatory mechanisms governing SMC phenotypic modulation. We propose the concept that transcription factors mediating this switching are important biomarkers and potential pharmacological targets for therapeutic intervention in cardiovascular disease., Competing Interests: Declaration of Competing Interest PF is a founder and CEO of Pharmahungary Group, a group of R&D companies. There are no other disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Porto-pulmonary arterial hypertension (PoPAH) is a form of pulmonary arterial hypertension (PAH) that affects patients with cirrhosis, and - to a lesser extent - patients with non-cirrhotic liver diseases. Compared with other forms of PAH, PoPAH is more prevalent in male, in older subjects, and is characterized by lower mean pulmonary arterial pressure (mPAP) and lower pulmonary vascular resistance (PVR) with higher cardiac output. Despite more favorable hemodynamics and functional class, patients with PoPAH have a significantly worse survival than patients with other forms of PAH, likely because of liver-related events and therapeutic barriers to PAH-specific therapy. Furthermore, here cardiopulmonary and hepatic complications may affect treatment efficacy. These patients have been excluded from most randomized clinical trials testing PAH-specific treatments. To date, there is only one study investigating efficacy, safety, tolerability and pharmacokinetics of PAH-specific therapy in patients with PoPAH in a randomized placebo-controlled setting. In this trial the use of the endothelin-1 receptor antagonist macitentan showed clear hemodynamic benefit without safety concerns. However, the drug effects on functional capacity and mortality remain unclear. Here we review the current knowledge on the pathophysiology and management of PoPAH and report a case vignette of a patient with PoPAH due to hepatorenal polycystic disease., Competing Interests: Declaration of Competing Interest All authors are in agreement with the content of the manuscript. None of the authors has any potential conflict of interest with regard to the work here described, No conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Pathophysiological mechanisms behind cardio-pulmonary impairment in heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction are likely different. We analysed them using combined cardiopulmonary-exercise stress echocardiography (CPET-ESE)., Methods: We matched 1:1 subjects with HFrEF (n = 90) and HFpEF (n = 90) for age, sex, body mass index (BMI), peak oxygen consumption, and minute ventilation/carbon dioxide production slope. All patients underwent a symptom-limited graded ramp bicycle CPET-ESE compared with 40 age-, sex- and BMI-matched healthy controls., Results: During a median follow-up of 25 months, we observed 22 deaths and 80 HF hospitalisations, with similar distribution between HFpEF and HFrEF. Compared with HFrEF, HFpEF had a higher prevalence of metabolic syndrome (p = 0.02) with higher levels of high-sensitivity C-reactive protein and uric acid (p < 0.01). The multipoint mean pulmonary artery pressure/cardiac output (mPAP/CO) slope showed equally increased values in HFrEF and HFpEF (3.5 ± 1.8 and 3.7 ± 1.5 mmHg/L/min) compared with controls (1.8 ± 1.1 mmHg/L/min; p < 0.0001). During exercise, HFpEF displayed more adverse interaction of right ventricle-pulmonary artery (RV-PA; tricuspid annular plane systolic excursion/systolic pulmonary artery pressure: 0.40 ± 0.2 vs 0.47 ± 0.2 mm/mmHg in HFrEF; p < 0.01) and left atrium-left ventricle (LA-LV; LA reservoir strain/LV global longitudinal strain: 1.5 ± 0.8 vs 2.2 ± 1.1 in HFrEF; p < 0.01). The latter were independent predictors of mPAP/CO slope, along with hs-CRP (adjusted R2: 0.21; p < 0.0001)., Conclusion: Despite similar disease severity, HFpEF and HFrEF show different pathophysiological mechanisms. HFpEF is characterised by a worse LA-LV and RV-PA interaction than HFrEF, with more prevalent low-grade systemic inflammation. In HFpEF, these features may have a role in exercise-induced pulmonary hypertension., (Copyright © 2022. Published by Elsevier Inc.)

Background and Aims: Unfractionated-heparin (UFH) is the first-choice parenteral anticoagulant during invasive percutaneous procedures and its effect is monitored by the activated coagulation time (ACT). The effects of the non-vitamin K antagonist oral anticoagulants (NOACs) on the ACT and on ACT prolongation by UFH were not clearly established. We assessed the ACT prolongation induced by different UFH concentrations in blood samples of patients taking the four types of currently marketed NOACs and in patients not taking anticoagulants., Methods and Results: We measured the ACT in patients on dabigatran 110 mg (n = 8), rivaroxaban (n = 10), apixaban (n = 9) and edoxaban (n = 10) at supposed peak plasma concentrations, before and after in vitro addition of 3 UFH concentrations, corresponding to doses of 2000, 5000 and 10,000 IU. Seven non-anticoagulated patients served as controls. Patients in the 5 groups did not differ significantly for age, body weight and glomerular filtration rate. Baseline ACTs (s, mean ± SD) were 192 ± 27, 124 ± 14, 132 ± 14, 151 ± 30 and 134 ± 7 in dabigatran 110, rivaroxaban, apixaban, edoxaban and controls, respectively (P < 0.05 for dabigatran vs the other NOACs). We found a linear prolongation of the ACT with the in vitro UFH addition (P < 0.001), but prolongation was similar between the NOACs and controls., Conclusions: Dabigatran induces a moderate, significant ACT prolongation. None of the NOACs affects the UFH-induced ACT prolongation in the commonly used UFH range. The dose of UFH currently recommended to achieve the target ACT should thus be used irrespective of whether patients are taking NOACs or not., (Copyright © 2022. Published by Elsevier Inc.)

Background: Ponatinib (PON), a third-generation tyrosine kinase inhibitor (TKI), has proven cardiovascular toxicity, with no known preventing agents usable to limit such side effect. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a new class of glucose-lowering agents, featuring favorable cardiac and vascular effects., Aims: We assessed the effects of the SGLT2 inhibitors empagliflozin (EMPA) and dapagliflozin (DAPA) on human aortic endothelial cells (HAECs) and underlying vasculo-protective mechanisms in an in vitro model of PON-induced endothelial toxicity., Methods and Results: We exposed HAECs to PON or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nmol/L) or dapagliflozin (DAPA) for 0-48 h exposure times. Compared with vehicle, incubations of HAECs with PON significantly reduced cell viability (0.56 ± 0.11 vs 0.23 ± 0.05 absorbance units, p < 0.01), increased the number of senescent cells at β-gal-assay (PON 9 ± 4 vs basal DMSO 3 ± 1 β-Gal + cells/field, p < 0.01), decreased tubulization in Matrigel (PON PON: 6 ± 1 vs basal DMSO 12 ± 1 tubuli number/field, p < 0.05) with a non-statistically significant trend of PON to decrease the number of autophagic cells at immunofluorescence assay and flow cytometry. EMPA reverted the effects of PON on cell viability (E 500 + PON 0.24 ± 0.05 vs PON 0.56 ± 0.11 absorbance units, p < 0.01) and induced autophagy (E 500 7 ± 4.3 vs basal DMSO 2.6 ± 2.3 mean fluorescence vs PON 2.6 ± 2.4 mean fluorescence, p < 0.05). EMPA and DAPA also reversed the effects of PON on cell senescence (E 500 + PON 4 ± 1 and DAPA 100 4 ± 2 vs PON 9 ± 4 β-Gal + cells/field, p < 0.01) and improved cell tubulization (E 500 + PON 21 ± 3 vs PON 6 ± 1 tubuli number/field, p < 0.05; DAPA 100 + PON 16 ± 2 vs PON 6 ± 1 tubuli number/field, p < 0.05)., Conclusion: EMPA and DAPA attenuate the vasculo-toxic effect exerted by PON by reverting endothelial cell senescence and dysfunction. These findings support the design of clinical studies exploring the vasculo-protective effects of EMPA or DAPA on PON-induced vascular toxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the year 2021 we celebrate the 80th anniversary of the first clinical use of vitamin K antagonists (VKAs), the mainstay of prevention and long-term treatment of thromboembolic disease. The discovery and development of oral anticoagulants is one of the most important chapters in the history of medicine, a goal pursued by physicians trying to combat the clinical manifestations of thrombosis since ancient times. Until the last decade, VKAs were the only oral anticoagulants available and used in clinical practice. Today, their clinical use has progressively shrunk, as the non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly replacing VKAs in various conditions after the successful completion of several large randomized controlled trials. Currently, new research is tackling upstream components of the intrinsic pathway - particularly factor XI and factor XII - for the development of new, even safer anticoagulants promising to reduce bleeding without compromising efficacy. This review highlights the evolution of oral anticoagulant therapy tracing the key stages of a long and fascinating history that has unfolded from the first part of the twentieth century until today, indeed an intriguing journey where serendipity is intertwined with the tenacious work of many researchers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aim: Exercise-induced pulmonary hypertension (Ex-PH) may represent the earliest sign of pulmonary arterial hypertension (PAH) in human immunodeficiency virus (HIV) patients. We investigated its association with clinical and immunological status, virologic control, and response to antiviral therapy., Methods: In 32 consecutive HIV patients with either low (n = 29) or intermediate probability (n = 3) of PH at rest, we evaluated the association of isolated ExPH with: time to HIV diagnosis; CD4+ T-cell count; clinical progression to acquired immunodeficiency syndrome (AIDS); development of resistance to antiretroviral therapy (ART); HIV RNA levels; time to beginning of ART; current use of protease inhibitors; combination of ART with boosters (ritonavir or cobicistat); immuno-virologic response to ART; and ART discontinuation. Isolated ExPH at stress echocardiography (ESE) was defined as absence of PH at rest and systolic pulmonary arterial pressure (sPAP) >45 mmHg or a >20 mmHg increase during low-intensity exercise cardiac output (<10 L/min)., Results: In our cohort, 22% (n = 7) of the enrolled population developed ExPH which was inversely related to CD4+ T-cell count (p = 0.047), time to HIV diagnosis (p = 0.014) and time to onset of ART (p = 0.041). Patients with ExPH had a worse functional class than patients without ExPH (p < 0.001). ExPH and AIDS showed a trend (p = 0.093) to a direct relationship. AIDS patients had a higher pulmonary vascular resistance compared to patients without ExPH (p = 0.020) at rest echocardiography., Conclusions: The presence of isolated ExPH associates with a worse clinical status and poor immunological control in HIV patients. Assessment of ExPH by ESE may help identify subgroups of HIV patients with a propensity to develop subclinical impairment of pulmonary circulation following poor control of HIV infection., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: The ideal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) is still unknown. In this meta-analysis, we aimed to compare very short-term (1-3 months), short-term (6 months), standard-term (12 months) and long-term (>12 months) DAPT durations for efficacy and safety., Methods: Overall DAPT comparisons were classified as "any shorter-term"/"any longer-term" DAPT. The primary outcome was a composite of major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke and cardiovascular death). The primary safety outcome was major bleeding., Results: Twenty-six studies comprising 103.394 patients were included. Compared with standard-term DAPT duration, very short-term DAPT duration with subsequent drop of aspirin (RR 1.06, 95% CI, 0.95-1.18, p = 0.26) or drop of the P2Y 12  inhibitor (RR 0.92, 95% CI, 0.72-1.16, p = 0.47) was not associated with a higher risk of MACE. Any longer-term compared with any shorter-term DAPT durations led to a significantly lower risk of MACE (RR 0.88, 95% CI, 0.81-0.96, p = 0.002), but a significantly higher risk of BARC 3-5 major bleeding events (RR 1.63, 95% CI, 1.22-2.17, p = 0.001). In the ACS subgroup receiving prasugrel or ticagrelor but not clopidogrel, any longer-term DAPT duration was associated with a significantly lower risk of MACE compared to any shorter-term DAPT duration (RR 0.84, 95% CI, 0.77-0.92, p = 0.0001)., Conclusion: DAPT may be shortened to 1-3 months in patients with low ischemic but high bleeding risk followed by aspirin or P2Y 12 monotherapy. Prasugrel or ticagrelor based DAPT may be extended to >12 months in case of high ischemic and low bleeding risk., Prospero Registration No: CRD42020163719., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diabetes mellitus (DM) and atrial fibrillation (AF) are known risk factors for ischemic stroke. Recent data, however, suggest that only insulin-treated DM is a risk factor for ischemic stroke among AF patients., Objectives: To evaluate the risk of stroke in patients with insulin and noninsulin treated DM., Methods: We included AF patients undergoing coronary angiography in Western Denmark between 2003 and 2016. Patients were categorized as 1) insulin treated DM, 2) noninsulin treated DM, or 3) nonDM patients. The main outcome was ischemic stroke >30 days after CAG., Results: AF patients (n = 21,223) were included, of whom 17,181 (81%) did not have DM, 2890 (14%) had noninsulin-treated DM and 1152 (5%) had insulin-treated DM. Median follow-up was 5.3 years. Ischemic stroke rates were 0.83 per 100 person-years for nonDM, 1.19 for noninsulin-treated DM and 1.40 for insulin-treated DM. Insulin-treated DM (adjusted hazard ratio (HR adj ) 1.48, 95% CI 1.15-1.91) and noninsulin-treated DM patients (HR adj 1.30, 95% CI 1.09-1.54) had higher risks of ischemic stroke than nonDM patients. There was no difference between insulin-treated DM and noninsulin-treated DM (HR adj 1.09, 95% CI 0.82-1.46). Stratification by coronary artery disease yielded comparable risk estimates., Conclusion: In patients with AF, DM increases the risk of ischemic stroke, regardless of treatment., (Copyright © 2020. Published by Elsevier Inc.)

Aim: Cell therapies are hampered by poor survival and growth of grafts. We tested whether forced co-expression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD) improves post-infarct revascularization and tissue repair by adipose tissue-derived mesenchymal stromal cells (AT-MSCs)., Methods and Results: We transplanted AT-MSCs overexpressing MYOCD and TERT in a murine model of acute myocardial infarction (AMI). We characterized paracrine effects of AT-MSCs. When transplanted into infarcted hearts of C57BL/6 mice, AT-MSCs overexpressing TERT and MYOCD decreased scar tissue and the intra-scar CD3 and B220 lymphocyte infiltration; and increased arteriolar density as well as ejection fraction compared with saline or mock-transduced AT-MSCs. These effects were accompanied by higher persistence of the injected cells in the heart, increased numbers of Ki-67 + and CD117 + cells, and the expression of cardiac actin and β-myosin heavy chain. Intramyocardial delivery of the secretome and its extracellular vesicle (EV)-enriched fraction also decreased scar tissue formation and increased arteriolar density in the murine AMI model. Proteomic analysis of AT-MSCs-EV-enriched fraction predicted the activation of vascular development and the inhibition of immune cell trafficking. Elevated concentrations of miR-320a, miR-150-5p and miR-126-3p associated with regulation of apoptosis and vasculogenesis were confirmed in the AT-MSCs-EV-enriched fraction., Conclusions: AT-MSCs overexpressing TERT and MYOCD promote persistence of transplanted aged AT-MSCs and enhance arteriolar density in a murine model of AMI. EV-enriched fraction is the component of the paracrine secretion by AT-MSCs with pro-angiogenic and anti-fibrotic activities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hyperglycemia plays a role in promoting insulin resistance in adipocytes, hepatocytes and myocytes. Its effects on insulin signaling in endothelial cells remain, however, incompletely understood., Aim: To investigate the proteomic and metabolomic profiles of human aortic endothelial cells (HAECs) exposed to insulin, normal glucose (NG), high glucose (HG) or its hyperosmolar control high mannitol (HM), and to examine whether and how HG or HM may promote insulin resistance., Methods and Results: We exposed HAECs to HG and HM in shorter (3 h) and longer-term experiments (24 h), followed by insulin treatment for 45 min. Label-free proteomics and network analysis showed a downregulation of proteins linked to the PI3K-Akt/mTOR/eNOS signaling pathway in HAECs. Metabolomic profiling showed decreased levels of "odd-chain acylcarnitines" such as C3. At immunoblotting, HG or HM blunted insulin ability to activate the PI3K/AKT/eNOS pathway, which was reverted through a silencing of aquaporin 1 (AQP1) and Tonicity enhancer binding protein (TonEBP), while inducing p-P38 and pERK1/2., Conclusions: HG impairs the PI3K/AKT/eNOS pathway and shifts insulin signaling towards the activation of mitogenic and pro-inflammatory effectors, such as p38 and ERK1/2. These effects may explain the progression of insulin resistance as a result of endothelial glucotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aims: Pulmonary hypertension (PH) is associated with higher mortality and morbidity after valvular heart surgery, mainly through its adverse effect on right ventricular hemodynamic. Recently, the European Society of Cardiology (ESC) PH guidelines introduced a PH probability grading that lists additional parameters related to right ventricular dimensions. We evaluated the impact of such score on short- and mid-term outcomes in patients undergoing left heart valvular surgery., Methods and Results: We included 60 consecutive patients (mean age 70 ± 9 years) undergoing left heart valvular surgery with or without coronary artery bypass. Patients were divided into 3 groups according to the PH probability: "low" (n = 18), "intermediate" (n = 18), or "high" (n = 24). The high PH probability group had higher rate of World Health Organization-Functional Class (WHO-FC) III and IV, hemodynamic complications, deaths, major bleeding events and infections after heart surgery than the other groups. A "high" PH probability was associated with reduced right ventricular systolic function, as measured by the fractional area change (FAC), but not with the tricuspid annular plane systolic excursion (TAPSE)., Conclusion: The high PH probability as evaluated by the ESC PH echocardiographic probability model, is associated with increased short- and mid-term mortality and morbidity and reduced right ventricular systolic function after cardiac surgery, Thus, additional echocardiographic parameters assessing PH probability are valuable tools to stratify risk in patients undergoing cardiac surgery., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Since the first successful launch of the Veterans Administration(VA) cooperative studies in the late 1960s, the increasing access to blood pressure lowering medications has significantly contributed to improving longevity and quality of life in hypertensive patients. Since then, insights into the pathogenesis of hypertension have shown a mechanistic role for reactive oxygen species (ROS) in all phases of disease progression, suggesting the potential utility of antioxidant therapies to counteract symptoms and, at the same time, treat a fundamental mechanism of the disease. Despite these progresses, hypertension still remains the main contributor to the global incidence of cardiovascular disease and the leading cause of morbidity and mortality worldwide. We here briefly review and update the role of ROS and ROS-dependent metalloproteinase activation in the maladaptive remodeling of the vascular wall in hypertension. Such understanding should provide new Potential sites of action for antioxidant therapies as an integrated therapeutic approach to hypertension and its consequences., (Copyright © 2019. Published by Elsevier Inc.)

Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500 years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70 years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Atherosclerosis is a chronic inflammatory disorder of the large and medium-size arteries characterized by the subendothelial accumulation of cholesterol, immune cells, and extracellular matrix. At the early onset of atherogenesis, endothelial dysfunction takes place. Atherogenesis is further triggered by the accumulation of cholesterol-carrying low-density lipoproteins, which acquire properties of damage-associated molecular patterns and thereby trigger an inflammatory response. Following activation of the innate immune response, mainly governed by monocytes and macrophages, the adaptive immune response is started which further promotes atherosclerotic plaque formation. In this review, an overview is given describing the role of damage-associated molecular patterns, NLRP3 inflammasome activation, and innate and adaptive immune cells in the atherogenesis process., (Copyright © 2018. Published by Elsevier Inc.)

Diabetic macroangiopathy - a specific form of accelerated atherosclerosis - is characterized by intra-plaque new vessel formation due to excessive/abnormal neovasculogenesis and angiogenesis, increased vascular permeability of the capillary vessels, and tissue edema, resulting in frequent atherosclerotic plaque hemorrhage and plaque rupture. Mechanisms that may explain the premature and rapidly progressive nature of atherosclerosis in diabetes are multiple, and to a large extent still unclear. However, mechanisms related to hyperglycemia certainly play an important role. These include a dysregulated vascular regeneration. In addition, oxidative and hyperosmolar stresses, as well as the activation of inflammatory pathways triggered by a dysregulated activation of membrane channel proteins aquaporins, have been recognized as key events. Here, we review recent knowledge of cellular and molecular pathways of macrovascular disease related to hyperglycemia in diabetes. We also here highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment., (Copyright © 2018. Published by Elsevier Inc.)

Diabetic microangiopathy, including retinopathy, is characterized by abnormal growth and leakage of small blood vessels, resulting in local edema and functional impairment of the depending tissues. Mechanisms leading to the impairment of microcirculation in diabetes are multiple and still largely unclear. However, a dysregulated vascular regeneration appears to play a key role. In addition, oxidative and hyperosmolar stress, as well as the activation of inflammatory pathways triggered by advanced glycation end-products and toll-like receptors, have been recognized as key underlying events . Here, we review recent knowledge on cellular and molecular pathways of microvascular disease in diabetes. We also highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Characterized by progressive elevation of mean pulmonary artery pressure and pulmonary vascular resistance, pulmonary arterial hypertension (PAH) is an important health problem that contributes to right heart failure. Pulmonary arterial remodeling and constriction are two prominent features of PAH. It is a traditional view that increasing pulmonary blood flow and pressure, aerobic exercise does more harm than good to the pulmonary vasculature in PAH. However, recent studies have documented a potential benefit of low-intensity aerobic exercise for PAH patients. Here the current mini-review outlines the evidence and challenges for this additional tool in our armamentarium to combat this ominous disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Although the treatment of acute coronary syndromes (ACS) has advanced considerably, the ability to detect, predict, and prevent complications of atherosclerotic plaques, considered the main cause of ACS, remains elusive. Several imaging tools have therefore been developed to characterize morphological determinants of plaque vulnerability, defined as the propensity or probability of plaques to complicate with coronary thrombosis, able to predict patients at risk. By utilizing both intravascular and noninvasive imaging tools, indeed prospective longitudinal studies have recently provided considerable knowledge, increasing our understanding of determinants of plaque formation, progression, and instabilization. In the present review we aim at 1) critically analyzing the incremental utility of imaging tools over currently available "traditional" methods of risk stratification; 2) documenting the capacity of such modalities to monitor atherosclerosis progression and regression according to lifestyle modifications and targeted therapy; and 3) evaluating the potential clinical relevance of advanced imaging, testing whether detection of such lesions may guide therapeutic decisions and changes in treatment strategy. The current understanding of modes of progression of atherosclerotic vascular disease and the appropriate use of available diagnostic tools may already now gauge the selection of patients to be enrolled in primary and secondary prevention studies. Appropriate trials should now, however, evaluate the cost-effectiveness of an aggressive search of vulnerable plaques, favoring implementation of such diagnostic tools in daily practice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Patients after an acute coronary syndrome (ACS) are at increased risk of recurrent thrombotic events, justifying the search for additional antithrombotic treatments. The pathophysiology of ACS involves arterial thrombus formation, in turn occurring because of a combination of platelet activation and fibrin formation, with thrombin playing a key role in both. Antiplatelet therapy, targeting the thromboxane pathway and the ADP P2Y12 receptor has been widely accepted for secondary prevention after an ACS. Now, data from recent clinical trials in such patients also encourage the pursuit of inhibiting thrombin formation or thrombin-mediated platelet activation in addition to antiplatelet therapy. This "triple pathway inhibition", including inhibition of thrombin activity or thrombin receptor(s), is currently an option in pure ACS, but already a must in the setting of ACS accompanied by atrial fibrillation (AF), where anticoagulants have been shown to be much more effective than antiplatelet agents in preventing stroke. We here discuss the challenges of managing combined thrombin activity or receptor inhibition and antiplatelet therapy in all such patients. Translating this into practice still requires further studies and patient tailoring to fully exploit its potential., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Previous studies have shown the antiinflammatory, antioxidant and antiangiogenic properties by pure olive oil polyphenols; however, the effects of olive oil phenolic fraction on the inflammatory angiogenesis are unknown. In this study, we investigated the effects of the phenolic fraction (olive oil polyphenolic extract, OOPE) from extra virgin olive oil and related circulating metabolites on the VEGF-induced angiogenic responses and NADPH oxidase activity and expression in human cultured endothelial cells. We found that OOPE (1-10 μg/ml), at concentrations achievable nutritionally, significantly reduced, in a concentration-dependent manner, the VEGF-induced cell migration, invasiveness and tube-like structure formation through the inhibition of MMP-2 and MMP-9. OOPE significantly (P<0.05) reduced VEGF-induced intracellular reactive oxygen species by modulating NADPH oxidase activity, p47phox membrane translocation and the expression of Nox2 and Nox4. Moreover, the treatment of endothelial cells with serum obtained 4 h after acute intake of extra virgin olive oil, with high polyphenol content, decreased VEGF-induced NADPH oxidase activity and Nox4 expression, as well as, MMP-9 expression, as compared with fasting control serum. Overall, native polyphenols and serum metabolites of extra virgin olive oil rich in polyphenols are able to lower the VEGF-induced angiogenic responses by preventing endothelial NADPH oxidase activity and decreasing the expression of selective NADPH oxidase subunits. Our results provide an alternative mechanism by which the consumption of olive oil rich in polyphenols may account for a reduction of oxidative stress inflammatory-related sequelae associated with chronic degenerative diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Burdened by high morbidity and mortality, neonatal pulmonary hypertension (PH) is a life-threatening pathophysiological condition that progressively elevates the mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Pulmonary vascular remodeling and vasoconstriction are recognized pathophysiological features of the disease. Neonatal PH is a serious pathological condition in which persistent PH of the newborn causes hypoxemia and right-to-left extrapulmonary shunting of blood flow, leading to right heart failure and serious life-threatening complications. Recently, the role of growth factors in the pathogenesis of neonatal PH has attracted much attention. Here we provide an update on the ongoing research regarding the epigenetic regulation of the insulin growth factor (IGF)-1/IGF-1 receptor pathway, with insight into the potential regulatory role such regulation in the pathogenesis of neonatal PH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Preclinical and clinical studies have suggested that specific subsets of cells isolated from the bone marrow or peripheral blood, collectively named endothelial progenitor cells (EPCs), play an essential role in neovascularization and are biomarkers of atherosclerosis, inversely related to the presence and progression of the disease. Conclusive evidence for both the pathophysiological and the biomarker role of these cells is, however, missing, with lack of a unique and universally accepted interpretation for their role, and the absence of general agreement to prompt their use by the practicing clinician. In fact, the engraftment of EPCs after injection into ischemic areas is poor, their secretome is still largely unknown, and there are still many confounding factors-such as co-morbidities and medications-that limit their use as a faithful biomarker of disease. Here we briefly review the literature on EPCs and discuss their significance in cardiovascular disease both as mediators and as biomarkers, including current methods for their identification., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Clopidogrel resistance is more common in patients with loss-of-function CYP2C19 genotypes. Since adenylate cyclase (AC) and soluble guanylate cyclase (sGC) pathways are variably impaired in patients with ischaemic heart disease, we tested the relevance of these determinants in patients undergoing acute loading with clopidogrel (600 mg) prior to non-emergent coronary stenting., Methods: Inhibitory effects of prostaglandin E1 (PGE1, an AC activator) and sodium nitroprusside (NP, a sGC activator) on platelet aggregation were determined at baseline and compared with platelet responses to clopidogrel (4 h after administration) assessed as ∆ADP, and Platelet Reactivity Index (∆PRI). Data were analysed according to CYP2C19 genotype., Results: In patients without loss of function mutations (n=18), ∆ADP but not ∆PRI, was directly correlated with baseline PGE1 responsiveness (rs=0.62, p=0.005)). NP responsiveness did not predict ∆ADP. However there was no relationship between clopidogrel responses and either PGE1 or NP responsiveness in patients with loss of function mutations. Multivariate correlates of clopidogrel response were both the genotype status (β=-0.609, p<0.001) and the baseline response to PGE1 (β=0.303, p=0.03)., Conclusions: While genetically impaired bio-activation markedly limits acute (4 h) clopidogrel response, impaired AC signalling provides an additional cause for clopidogrel resistance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Insights from the "-omics" science have recently emphasized the need to implement an overall strategy in medical research. Here, the development of Systems Medicine has been indicated as a potential tool for clinical translation of basic research discoveries. Systems Medicine also gives the opportunity of improving different steps in medical practice, from diagnosis to healthcare management, including clinical research. The development of Systems Medicine is still hampered however by several challenges, the main one being the development of computational tools adequate to record, analyze and share a large amount of disparate data. In addition, available informatics tools appear not yet fully suitable for the challenge because they are not standardized, not universally available, or with ethical/legal concerns. Cardiovascular diseases (CVD) are a very promising area for translating Systems Medicine into clinical practice. By developing clinically applied technologies, the collection and analysis of data may improve CV risk stratification and prediction. Standardized models for data recording and analysis can also greatly broaden data exchange, thus promoting a uniform management of CVD patients also useful for clinical research. This advance however requires a great organizational effort by both physicians and health institutions, as well as the overcoming of ethical problems. This narrative review aims at providing an update on the state-of-art knowledge in the area of Systems Medicine as applied to CVD, focusing on current critical issues, providing a road map for its practical implementation., (Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Thromboxane (TX) A2, prostaglandin endoperoxides and F2-isoprostanes exert their effects through a TX-prostanoid (TP) receptor, also expressed in endothelial cells. We investigated a role of the TP receptor in the endothelial expression of tissue factor (TF), a key trigger to thrombosis., Methods and Results: Human umbilical vein endothelial cells (HUVEC) exposed to the TP receptor agonist U46619 featured a concentration-dependent increase in TF surface exposure and procoagulant activity. HUVEC pre-incubation with the TP receptor antagonist S18886, followed by stimulation with either U46619 or tumor necrosis factor-α (TNF-α), attenuated TF surface exposure and activity compared with stimulated control. Aspirin or indomethacin, while inhibiting cyclooxygenase (COX)-1 and -2 activities, did not mimic this effect. Probing of underlying mechanisms by selective pharmacological and gene silencing experiments showed that S18886 reduced U46619- or TNF-α-induced TF expression inhibiting ROS production, NAD(P)H oxidase and PKC activation. In addition, S18886 also inhibited ERK activation in the presence of both U46619 and TNF-α alone, while inhibition of JNK activation only occurred in the presence of U46619., Conclusion: The endothelial TP receptor contributes to TF surface exposure and activity induced not only by known TP receptor agonists, but also by TNF-α. Such findings expand the therapeutic potential of TP receptor inhibition., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Heparan sulfate proteoglycans (HSPGs) are present in several compartments and cell types in blood vessels. Their expression, as well as the activity of their degrading enzyme heparanase, are strongly regulated, with changes in gene expression, protein levels, and activity in response to environmental and metabolic stresses, including diabetes. HSPGs likely play an important role in the development and progression of atherosclerosis. Many functions of HSPGs, such as the promotion of monocyte adhesion, smooth muscle cell proliferation, and low density lipoproteins (LDL) binding, are determined by interactions between cells and specific regions of the HSPG core proteins. Here we review the role of HSPGs expressed in vascular wall in atherosclerotic vascular disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Sodium-hydrogen exchangers (NHE) are among the main regulators of cell volume and intracellular concentration of hydrogen and sodium ions. By indirectly affecting sodium/calcium exchange across the plasma membrane, NHE can also influence the intracellular concentration of calcium. Excess activation of NHE or inappropriate sodium extrusion due to failure of ATP-dependent Na(+)/K(+) transport system can be deleterious during cardiac or peripheral organ ischemia. Besides being responsible for the regulation of intracellular pH and sodium-calcium inward currents, NHE isoform 1 (NHE-1), which is predominantly expressed in the cardiovascular system, influences the tone of the vessel wall in response to a variety of stimuli, including hypertonic stress. Because of the extensive involvement of NHE-1 in cardiac myocyte contracture and necrosis, stunning, reperfusion arrhythmias, as well as hypertension and myocardial diseases such as diabetic cardiomyopathy, efforts have been made in developing inhibitors of this transporter. We here review the biology and regulation of NHE, focusing on current knowledge of the role of NHE-1 as a potential target in the development of novel compounds that could play a role in cardiovascular homeostasis, both in physiological and pathological conditions., (© 2013 Elsevier Inc. All rights reserved.)

The clinical efficacy of the P2Y12 receptor antagonist clopidogrel as an agent to prevent thrombotic events predominantly reflects its anti-aggregatory effects. Stent thrombosis in particular is more likely to occur in patients in whom clopidogrel effect is limited. "Resistance" to clopidogrel in general should theoretically arise either because of a reduction in plasma concentration of the active metabolite and/or of the downstream intracellular biochemical changes underlying antiplatelet effects. We therefore postulate that "resistance" to clopidogrel arises via a combination of pharmacogenetic, pharmacokinetic and intracellular biochemical mechanisms. Considerable attention has been so far directed to the finding that stent thrombosis occurs more frequently in patients with loss-of-function mutations of CYP2C19, thus limiting clopidogrel bioactivation. Furthermore, a number of drug-drug interactions may marginally impair responsiveness to clopidogrel, largely via impairment of bioactivation. However, population data also suggest that clopidogrel "resistance" occurs more frequently in patients with acute coronary syndromes than in normal subjects, and that "resistance" is particularly common in obese subjects and with diabetes. Here we critically review available literature and speculate on the possibility that non-genetic causes of clopidogrel "resistance" may arise from impairments of the intracellular signaling cascade initiated by P2Y12 receptor inhibition. In such cases, "resistance" to clopidogrel may also theoretically occur with other P2Y12 receptor antagonists, irrespective of the need for bioactivation. Delineation of this non-genetic component of "resistance" to P2Y12 inhibitors may facilitate the development of optimal therapeutic strategies for high-risk cardiovascular patients., (© 2013.)

The new anticoagulants (NOACs) tested for prevention or treatment of venous thromboembolism (VTE), stroke prevention in atrial fibrillation (AF), and acute coronary syndromes (ACS) differ in bioavailability, metabolism, route of excretion and interaction with other drugs, but have remarkably similar pharmacokinetics, with very similar half lives. However the choice of dosing regimens in different clinical conditions has been different for the various NOACs, and has been established on the basis of widely different considerations, including the clinical setting (venous versus arterial thrombosis), the indications (prophylaxis versus treatment), the likelihood of concomitant antiplatelet drugs, and marketing opportunities; these latter were based on the knowledge that patients' compliance is generally better with once daily than with twice daily dosing. Current prevailing wisdom is that peak plasma drug concentrations are important determinants of bleeding: since a fractioning of the total daily dose into a twice daily regimen reduces peak plasma drug concentrations compared with once daily dosing, this should maximize safety. However, recent pharmacokinetic analyses of a phase II study with edoxaban in AF found that bleeding, with the same daily dosing, was less frequent with once daily dosing than with twice daily dosing, and correlated - better than other pharmacokinetic parameters - through drug concentrations. Higher rates of bleeding have been also reported with the twice daily versus once daily dosing of darexaban in a phase II study in ACS. These results may lead to a rethinking on the pathophysiology of bleeding in the setting of anticoagulation., (© 2013.)

The transcription factor nuclear factor-κB (NF-κB) is a main regulator of the expression of several genes involved in the activation of inflammation, cell proliferation, cell immunity and apoptosis. Excess or inappropriate activation of NF-κB has been observed in human inflammatory diseases, including atherosclerosis. Because of the extensive involvement of NF-κB signaling in human diseases, efforts have been made in developing inhibitors of this pathway. Here we will provide an overview of the biology of NF-κB activation pathways. We will here especially focus on current knowledge of the role of the classical ("canonical") NF-κB activation pathway as a potential therapeutic target for anti-atherosclerotic therapies in clinical applications, and discuss classical and novel therapeutic strategies to reduce its prolonged activation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Although the mechanisms by which insulin-resistance and hyperglycemia lead to cardiovascular disease are still incompletely understood, all mechanisms apparently converge on the vessel wall and the endothelium as a common disease target. Endothelial cells play a crucial role in vascular homeostasis, providing a functional barrier and modulating several signals involved in vasomotion, as well as antiplatelet, anti-inflammatory, anti-proliferative, and anti-oxidant properties of the vessel wall. Endothelial cell dysfunction occurs early in diabetes and insulin resistance states. Since atherosclerosis may result from an imbalance between the magnitude of vascular injury and the capacity of repair, a role has been recently postulated for a defective mobilization of vascular progenitors, including endothelial progenitor cells, in the pathogenesis of vascular disease. Here we summarize the evidence for such an occurrence. We also here highlight how new insights into pathways of vascular damage in diabetes may indicate new targets for preventive and treatment strategies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Diabetes-induced micro- and macrovascular complications are the major causes of morbidity and mortality in diabetic patients. While hyperglycemia is a key factor for the pathogenesis of diabetic microvascular complications, it is only one of the multiple factors capable of increasing the risk of macrovascular complications. Hyperglycemia induces vascular damage probably through a single common pathway - increased intracellular oxidative stress - linking four major mechanisms, namely the polyol pathway, advanced glycation end-products (AGEs) formation, the protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways. In addition, in conditions of insulin resistance, i.e., preceding the onset of type 2 diabetes, the phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway is selectively inhibited, while the mitogen activated protein (MAP)-kinase pathway remains largely unaffected, thus allowing compensatory hyperinsulinemia to elicit pro-atherogenic events in vascular smooth muscle and endothelial cells, including increased cell proliferation, and the expression of plasminogen activator inhibitor-1, as well as of proinflammatory cytokines and endothelial adhesion molecules., (Copyright © 2011 Elsevier Inc. All rights reserved.)