Aldo Bonaventura

The Role of Inflammation in Cardiovascular Outcome

Purpose of ReviewThe aim of this review is to update the pathophysiological role of innate immune response in the cardiovascular (CV) disease outcomes, particularly focusing on coronary atherosclerosis and heart failure.Recent FindingsInflammatory processes comprised with the innate immunity reaction are believed to actively trigger CV disease development and final clinical events. For instance, by releasing proteases and neutrophil extracellular traps, neutrophil recruitment and activation might strongly influence atherosclerotic plaque stability. Similarly, neutrophils drive the early inflammatory response following a myocardial infarction. However, these cells contribute themselves to infarct healing by orchestrating monocyte/macrophage recruitment and polarization within the ischemic myocardium. Given their heterogeneity and plasticity, the balance between recruitment, proliferation, and polarization of monocyte/macrophage is a further leading determinant of advanced plaque maturation. Moreover, timely shift from a pro-inflammatory to a resolving macrophage phenotype may influence cardiac remodeling as well as development of heart failure (HF). Alongside macrophage recruitment and activation into the remote, non-ischemic myocardium also contributes to cardiac remodeling and HF development.SummaryInnate immune response is a tightly regulated process where a timely modulation of the balance between damaging and resolving properties critically impacts on CV outcome. Further progress may improve the determination of the prognostic relevance of inflammatory biomarkers on clinical CV outcome.

Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke.

After an acute ischemic stroke (AIS), inflammatory processes are able to concomitantly induce both beneficial and detrimental effects. In this narrative review, we updated evidence on the inflammatory pathways and mediators that are investigated as promising therapeutic targets. We searched for papers on PubMed and MEDLINE up to August 2016. The terms searched alone or in combination were: ischemic stroke, inflammation, oxidative stress, ischemia reperfusion, innate immunity, adaptive immunity, autoimmunity. Inflammation in AIS is characterized by a storm of cytokines, chemokines, and Damage-Associated Molecular Patterns (DAMPs) released by several cells contributing to exacerbate the tissue injury both in the acute and reparative phases. Interestingly, many biomarkers have been studied, but none of these reflected the complexity of systemic immune response. Reperfusion therapies showed a good efficacy in the recovery after an AIS. New therapies appear promising both in pre-clinical and clinical studies, but still need more detailed studies to be translated in the ordinary clinical practice. In spite of clinical progresses, no beneficial long-term interventions targeting inflammation are currently available. Our knowledge about cells, biomarkers, and inflammatory markers is growing and is hoped to better evaluate the impact of new treatments, such as monoclonal antibodies and cell-based therapies.

Cellular recruitment in myocardial ischaemia/reperfusion injury.

Myocardial infarction (MI) is strictly linked to atherosclerosis. Beyond the mechanical narrowing of coronary vessels lumen, during MI a great burden of inflammation is carried out. One of the crucial events is represented by the ischaemia/reperfusion injury, a complex event involving inflammatory cells (such as neutrophils, platelets, monocytes/macrophages, lymphocytes and mast cells) and key activating signals (such as cytokines, chemokines and growth factors). Cardiac repair following myocardial infarction is dependent on a finely regulated response involving a sequential recruitment and the clearance of different subsets of inflammatory cells.

The Role of Adipocytokines in Coronary Atherosclerosis

Purpose of ReviewThe aim of this review is to overview the pathophysiological role of adipocytokines in atherogenesis, focusing on their potential role as biomarkers of coronary disease.Recent FindingsSeveral lines of evidence indicated adipose tissue not only as depot but rather as an endocrine organ. In this context, the balance between pro- and anti-inflammatory adipocytokines has been shown to critically regulate vascular homeostasis in both physiological and pathophysiological conditions. Overweight and obesity are characterized by dysfunctional adipose tissue and then the prevalence of pro-inflammatory mediators, with a detrimental effect on vascular health. As opposite to adiponectin, pro-inflammatory adipocytokines, such as leptin and resistin, promote endothelial dysfunction and inflammatory processes involved in atherosclerotic plaque progression and vulnerability. Therefore, many adipocytokines have been investigated as potential biomarkers of cardiovascular (CV) risk, but their role has not yet been clearly established. Furthermore, the perivascular adipose tissue recently emerged as a critical modulator of atherosclerotic processes, due to the close interaction with the underlying vascular tissue.SummaryThe ongoing discovery of new adipocytokines and the complex pathophysiological role of the different adipose tissue depots strongly contribute to define the complexity of adipocytokines network. Understanding those complex interactions may allow determining new potential biomarkers of CV risk and potential therapeutic targets.

The Pathophysiological Role of Neutrophil Extracellular Traps in Inflammatory Diseases

Neutrophil pathogen-killing mechanism termed neutrophil extracellular traps (NETs) has been recently identified. NETs consist of chromatin and histones along with serine proteases and myeloperoxidase and are induced by a great variety of infectious and non-infectious stimuli. NETosis is a kind of programmed neutrophil death characterized by chromatin decondensation and release of nuclear granular contents, mainly driven by peptidylarginine deiminase 4 citrullination of histones. Although classically related to the protection against infectious pathogens, nowadays NETs have been described as a player of several pathophysiological processes. Neutrophil dysregulation has been demonstrated in the pathogenesis of most representative vascular diseases, such as acute coronary syndrome, stroke and venous thrombosis. Indeed, NETs have been identified within atherosclerotic lesions and arterial thrombi in both human beings and animal models. Moreover, an imbalance in this mechanism has been proposed as a critical source of modified and/or externalized autoantigens in autoimmune and inflammatory diseases. Finally, an update on the role of NETs in the pathogenesis of cancer has been included. In the present review, based on papers released on PubMed and MEDLINE up to July 2017, we point to update the knowledge on NETs, from their structure to their roles in infectious diseases as well as in cardiovascular diseases, autoimmunity, metabolic disorders and cancer, with a look to future perspectives and therapeutic opportunities.

Regulation and function of extracellular nicotinamide phosphoribosyltransferase/visfatin

Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine-enzyme, which was described as to play bioactivities both in the intracellular and in the extracellular environment. However, while the functions of intracellular NAMPT (iNAMPT) are well known, much less is known on extracellular NAMPT (eNAMPT), also called visfatin or pre-B cell colony-enhancing factor. iNAMPT catalyzes the rate-limiting step in the NAD+ biosynthesis pathway from nicotinamide. Its inhibition severely reduces intracellular NAD+ levels, achieving anti-inflammatory and anti-cancer effects. eNAMPT can be detected in the human circulation and in many extracellular environments. Studies show that eNAMPT can act as a growth factor, as an enzyme, and as a cytokine, but its true mechanism of secretion and its physiological functions are still debated. Increased levels of eNAMPT have been associated with different metabolic disorders and cancers. eNAMPT was demonstrated to modulate the pathways involved in the pathophysiology of obesity, diabetes, atherosclerosis, and cardiovascular events by regulating the oxidative stress response, apoptosis, and inflammation. In cancer, eNAMPT was shown to play a pivotal role in modulating cancer cell metabolism, in promoting epithelial-to-mesenchymal transition and in shaping the tumor microenvironment. In line with these functions, circulating eNAMPT levels are frequently increased in cancer patients. Given these pleiotropic roles of eNAMPT in human disease, this protein has attracted attention as a therapeutic target. In this narrative review, we will discuss recent evidence on eNAMPT-driven signalling, highlighting the emerging pathophysiological roles of this protein in different disorders and the potential therapeutic opportunities linked to its targeting.

Serum levels of osteopontin predict major adverse cardiovascular events in patients with severe carotid artery stenosis

BACKGROUND Inflammatory mediators in the blood stream and within plaques are key determinants in atherogenesis. Here, we investigated serum osteopontin (OPN) as a potential predictor of poor outcome in patients with severe carotid atherosclerosis. METHODS Carotid plaques and serum were collected from patients asymptomatic (n=185) or symptomatic (n=40) for ischemic stroke. Plaques were stained for lipids, smooth muscle cells, neutrophils, M1 and M2 macrophage subsets and matrix metallopropteinase-9 (MMP-9). Serum levels of OPN and interleukin-6 (IL-6) were determined by colorimetric enzyme-linked immunosorbent assays. RESULTS Symptomatic patients showed a two-fold increase in serum OPN levels. In both symptomatic and asymptomatic patients, OPN levels positively correlated with intraplaque count of neutrophils, total macrophages, and MMP-9 content. In asymptomatic patients, OPN levels also positively correlated with lipids and M1 macrophage subsets. Receiver operating characteristic curve analysis identified serum OPN concentration of 70ng/ml as the best cut-off value to predict major adverse cardiovascular events (MACEs). Patients with high OPN levels had more vulnerable plaque phenotype and reduced levels of HDL-cholesterol and IL-6 as compared to low OPN levels. Kaplan-Meier curve confirmed that patients with OPN levels >70ng/ml had more MACEs at a 24-month follow-up. In the multivariate survival analysis, OPN levels >70ng/ml predicted MACEs, independently of age, gender, and symptomatic status. CONCLUSION High circulating OPN levels were strongly correlated with vulnerability parameters within plaques and predict MACEs in patients with severe carotid artery stenosis. Although confirmation is needed from larger trials, OPN could be a promising clinical tool to assess atherosclerotic outcomes.

Plasma palmitoylethanolamide (PEA) as a potential biomarker for impaired coronary function

BACKGROUND Among endocannabinoid (EC)-related mediators, Oleoyl-ethanolamide (OEA) and Palmitoyl-ethanolamide (PEA), two endogenous PPARα agonists with lipolytic and anti-inflammatory action, respectively, are being actively investigated. Here, we assessed the potential association between plasma levels of PEA and OEA and coronary function in a cohort including normal, overweight, obese, and morbidly obese (MOB) individuals. METHODS Myocardial perfusion and endothelium-related myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with 13N-ammonia positron emission tomography/computed tomography. OEA and PEA were extracted from human plasma by liquid-liquid extraction, separated by liquid chromatography and quantified by mass spectrometry. Serum levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1) were measured by colorimetric enzyme-linked immunosorbent assay. RESULTS Circulating levels of PEA and VCAM-1 were increased in MOB as compared to normal weight subjects. Circulating levels of OEA and PEA were associated with body mass index, but not with adhesion molecules. Increases of PEA levels were associated with and predictive of worsened coronary function in MOB and the overall cohort studied. CONCLUSION Plasma levels of PEA are increased in MOB patients and associated with coronary dysfunction as a functional precursor of CAD process. Larger trials are needed to confirm PEA as a potential circulating biomarker of coronary dysfunction in both MOB patients and the general population.

Intraplaque Expression of C-Reactive Protein Predicts Cardiovascular Events in Patients with Severe Atherosclerotic Carotid Artery Stenosis

Serum c-reactive protein (CRP) was suggested for the assessment of intermediate cardiovascular (CV) risk. Here, systemic or intraplaque CRP levels were investigated as predictors of major adverse cardiovascular events (MACEs) in patients with severe carotid stenosis. CRP levels were assessed in the serum and within different portions (upstream and downstream) of carotid plaques of 217 patients undergoing endarterectomy. The association between CRP and intraplaque lipids, collagen, neutrophils, smooth muscle cells (SMC), and macrophage subsets was determined. No correlation between serum CRP and intraplaque biomarkers was observed. In upstream portions, CRP content was directly correlated with intraplaque neutrophils, total macrophages, and M1 macrophages and inversely correlated with SMC content. In downstream portions, intraplaque CRP correlated with M1 and M2 macrophages. According to the cut-off point (CRP > 2.9%) identified by ROC analysis in upstream portions, Kaplan-Meier analysis showed that patients with high CRP levels had a greater rate of MACEs. This risk of MACEs increased independently of age, male gender, serum CRP, and statin use. In conclusion, in patients with severe carotid artery stenosis, high CRP levels within upstream portions of carotid plaques directly and positively correlate with intraplaque inflammatory cells and predict MACEs at an 18-month follow-up period.

Update on the role of Pentraxin 3 in atherosclerosis and cardiovascular diseases

Pentraxin 3 (PTX3) is an acute-phase protein that was recently demonstrated to play pleiotropic activities in cardiovascular (CV) diseases. Tumor necrosis factor and interleukins up-regulates PTX3 transcription in different cell types (i.e. endothelial cells, phagocytes, smooth muscle cells, fibroblasts and glial cells) involved in atherogenesis. By interacting with numerous ligands, PTX3 acts as a modulatory molecule of complement system, inflammatory response, angiogenesis, and vascular/tissue remodeling. Experimental data point to a beneficial role of PTX3 in atherosclerotic plaque development and vulnerability. Animal studies indicated a protective role of PTX3 signaling in ischemic/reperfusion injury and failing heart. Clinical studies have so far provided contrasting results, highlighting a debated role of PTX3 as an active mediator of endothelial dysfunction, atherosclerotic plaque vulnerability and worse outcome after ischemic events. Therefore, substantial evidence suggests a dual role of PTX3 as modulator or amplifiers of the innate immune response. The final result of PTX3 activation might be determined by a fine tuning of time, space and environmental signals. The aim of this review is to provide an overview of biological properties of PTX3 in CV diseases and to discuss the ability of PTX3 to act as a crossroad between pro- and anti-inflammatory pathways.