Role Of Inflammation In Atherogenesis Research Articles

Neutrophil-lymphocyte ratio in patients with coronary heart disease

Introduction. Despite significant advances in the diagnosis and treatment of patients with cardiovascular pathology, it is diseases associated with atherosclerosis that are still the main cause of mortality and disability. Atherosclerosis is based on local inflammation of the vascular wall and disruption of the lipid profile. Neutrophillymphocyte ratio is an indicator that can serve as a new diagnostic criterion of atherosclerotic changes. Materials and methods. The study enrolled 240 patients with coronary heart disease (150 men and 90 women). The subjects gave voluntary informed consent to participate in the study. All patients with CHD underwent coronary angiography, echocardiography and general blood analysis. Statistical processing of the results was performed using "Microsoft Office Excel" for Windows and "Statistica 10.0" software. Mann-Whitney test was used to assess the statistical significance of differences between the two groups for any parameters in the distribution of features other than normal. The Spearman rank correlation coefficient and its significance were used to assess the relationship between the two traits. Results. An increase in NLS values with progression of atherosclerotic coronary lesion severity was found; an inverse correlation between NLS value and LV ejection fraction (EF) was detected. Discussion. Our results, demonstrating an increase in this index with increasing severity of atherosclerotic lesions of the coronary arteries, are consistent with the literature data. Conclusion. Taking into account the fundamental role of inflammation in atherogenesis, as well as the difficulties of routine determination of expensive markers in everyday practice, the inclusion of an uncomplicated and economically affordable index of LVEF to assess the severity of coronary atherosclerosis and stratify the risk of adverse outcomes in patients with CHD is of undoubted scientific and practical interest and dictates the need for further study of its use in various patient cohorts.

Inflammation and ischemic heart disease: The next therapeutic target?

Inflammation plays an important role in several stages of the cardiovascular continuum. In recent decades a plethora of studies have provided new data highlighting the role of inflammation in atherogenesis and atherothrombosis in two-way interactions with various cardiovascular risk factors and further influencing these dynamic processes. The concept of targeting residual inflammatory risk among individuals with ischemic heart disease (IHD) is therefore gaining increasing attention. Recently, several landmark randomized controlled trials have assessed different pharmacological approaches that may mitigate this residual risk. The results of some of these studies, such as CANTOS with canakinumab and COLCOT and LoDoCo2 with colchicine, are promising and have provided data to support this concept. Moreover, though several aspects remain to be clarified, these trials have shown the potential of modulating inflammation as a new target to reduce the risk of cardiovascular events in secondary prevention patients. In the present review, we aim to present a pragmatic overview of the complex interplay between inflammation and IHD, and to critically appraise the current evidence on this issue while presenting future perspectives on this topic of pivotal contemporary interest.

IL18-family Genes Polymorphism Is Associated with the Risk of Myocardial Infarction and IL18 Concentration in Patients with Coronary Artery Disease

ABSTRACT Background Atherogenesis is mainly determined by endothelial dysfunction, lipid metabolism disorders and inflammation. The atherogenesis-related inflammatory process is a complex interaction between serum blood lipoproteins, inflammatory cells, endothelial and smooth muscle cells and extracellular matrix; the role of chronic inflammation in atherogenesis was proposed. Material and Methods A pathogenetic role of polymorphism in NF-kB pathway genes in coronary artery disease and associated pathological conditions has been suggested in a case-control retrospective study. 260 coronary artery disease patients permanently living in a large industrial region of Russian Federation (Kemerovo region) were recruited in the study. We examined nine single nucleotide polymorphisms in IL18, IL18R1 and IL18RAP genes by polymerize chain reaction; and serum blood level of IL18 by enzyme-linked immunosorbent assay. Results Polymorphic variants rs13015714 (IL18R1) and rs917997 (IL18RAP) are associated with the risk of myocardial infarction and high serum levels of IL18. Minor alleles of rs13015714 and rs917997 sites are associated with high risk of developing multifocal atherosclerosis and arterial hypertension in patients with stable coronary artery disease after myocardial infarction. Conclusions Thus, polymorphism in the genes of IL18 receptor is determine the IL18 contents and important in the development of coronary atherosclerosis, associated pathological conditions and the risk of acute coronary events; prospective monitoring of patients with early clinical signs of adverse events is required to confirm the role of IL18, IL18R1, and IL18RAP genes polymorphism in atherogenesis.

<p>Reflections on Atherosclerosis: Lesson from the Past and Future Research Directions</p>

The clinical manifestations of atherosclerosis are nowadays the main cause of death in industrialized countries, but atherosclerotic disease was found in humans who lived thousands of years ago, before the spread of current risk factors. Atherosclerotic lesions were identified on a 5300-year-old mummy, as well as in Egyptian mummies and other ancient civilizations. For many decades of the twentieth century, atherosclerosis was considered a degenerative disease, mainly determined by a passive lipid storage, while the most recent theory of atherogenesis is based on endothelial dysfunction. The importance of inflammation and immunity in atherosclerosis’s pathophysiology was realized around the turn of the millennium, when in 1999 the famous pathologist Russell Ross published in the New England Journal of Medicine an article entitled “Atherosclerosis – an inflammatory disease”. In the following decades, inflammation has been a topic of intense basic research in atherosclerosis, albeit its importance has ancient scientific roots. In fact, in 1856 Rudolph Virchow was the first proponent of this hypothesis, but evidence of the key role of inflammation in atherogenesis occurred only in 2017. It seemed interesting to retrace the key steps of atherosclerosis in a historical context: from the teachings of the physicians of the Roman Empire to the response-to-injury hypothesis, up to the key role of inflammation and immunity at various stages of disease. Finally, we briefly discussed current knowledge and future trajectories of atherosclerosis research and its therapeutic implications.

Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).

Coronary artery disease (CAD) is the leading cause of death worldwide. Despite notable advances in understanding the nature of atherosclerotic processes and the use of effective medications such as statins, there remains a significant residual risk. Even after optimal medical treatments and precise revascularisations, the recurrence of MI remains at approximately one-third for 5 years after an acute coronary syndrome (ACS). Over the past two decades, compelling data from animal and human studies has clearly identified atherosclerosis as an inflammatory disease of the arterial wall, but clinical applications related to this accumulated knowledge are still scarce. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence that an anti-inflammatory intervention with the monoclonal antibody canakinumab reduces cardiovascular events in well-treated CAD patients without affecting LDL cholesterol levels. This article presents a brief description of the role of inflammation in atherogenesis and examines selected anti-inflammatory interventions and their potential use in CAD-affected individuals.

Serum Fetuin-A, A New Potential Biomarker for Diagnosis of IHD in Menopausal Women.

Background: The role of inflammation in atherogenesis would suggest, a great deal of work looking for inflammatory markers that are risk factors for IHD. The most extensively examined markers are fibrinogen, C-reactive protein, IL-6, homocysteine, and fetuin-A. Objective: The present study is focusing on role of biomarker fetuin-A in the diagnosis of IHD in menopausal female. Methodology: This study involved 76 menopause women suffering of IHD (42 patients with AMI and 34 with angina) and 20 healthy menopause women as control. Patients were divided into subgroups according to the presence of DM and hypertension. Serum Fetuin-A level is estimated in each group. Results: There is significant reduction in serum fetuin-A levels in menopausal women with IHD. Diabetes mellitus and hypertension associated with significant decrease in serum fetuin-A levels in menopausal women with IHD. Conclusion: Serum fetuin-A can be used as biomarker for diagnosis of angina and AMI in menopausal women. Both DM and hypertension have detrimental effect on serum fetuin-A levels.

Variation of some oxidative stress and inflammatory markers in acute ischemic stroke

Background: The role of inflammation in atherogenesis and appearance of the tissue lesions in ischemic stroke are demonstrated /INS;and more recently there are strong indirect evidences that oxidative stress, by free radical production, detains/INS; a major contribution in ischemic brain injury.

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.

Inflammation and the Development of Atherosclerosis

Atherosclerosis is a progressive disease causally associated with multiple cardiovascular risk factors, including dyslipidemia. Without effective intervention, atherosclerosis becomes evidenced clinically as coronary artery and cerebrovascular disease, both of which remain the leading causes of death worldwide. Multiple lines of investigation indicate a central role for inflammation in atherosclerotic plaque progression, vulnerability and thrombogenicity. Randomized clinical trials have documented the benefit of lipid-lowering therapy for both primary and secondary prevention of cardiovascular events. Statins, a class of drugs that lower cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, have been shown to slow the progression of the atheroma and the frequency of associated clinical events to an extent that cannot be attributed solely to LDL reduction. The non-LDL or pleiotropic effects of statins are attributed to anti-inflammatory activity, enhanced endothelial function, and inhibition of oxidative stress. In this review, we discuss the role of inflammation in atherogenesis along with the effects of statins in slowing this process through LDL-dependent and -independent mechanisms.

Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications

Atherosclerosis is the pathological process that underlies the development of cardiovascular disease, a leading cause of mortality. Atherosclerotic plaque formation is driven by the recruitment of inflammatory monocytes into the artery wall, their differentiation into macrophages and the subsequent transformation of macrophages into cholesterol-laden foam cells. Models of hypercholesterolaemia such as the ApoE (apolipoprotein E)-/- mouse and the application of transgenic technologies have allowed us to undertake a thorough dissection of the cellular and molecular biology of the atherosclerotic disease process. Murine models have emphasized the central role of inflammation in atherogenesis and have been instrumental in the identification of adhesion molecules that support monocyte recruitment, scavenger receptors that facilitate cholesterol uptake by macrophages and other macrophage activation receptors. The study of mice deficient in multiple members of the chemokine family, and their receptors, has shown that chemokines play a critical role in promoting atherosclerotic plaque formation. In the present review, we will discuss novel therapeutic avenues for the treatment of cardiovascular disease that derive directly from our current understanding of atherogenesis gained in experimental animal models.

Neopterin and Cardiovascular Disease: Growing Evidence for a Role in Patient Risk Stratification

Compelling evidence has emerged in recent years regarding the implications of inflammation in the pathogenesis of atherosclerosis and its complications (1). The growing appreciation of the role of inflammation in atherogenesis, atheromatous plaque growth, and plaque disruption has triggered interest as to whether circulating inflammatory biomarkers may help to identify subjects at risk of future cardiovascular events. Of all currently available biomarkers, high-sensitivity C-reactive protein (hsCRP)1 appears to have the best profile as an independent predictor of increased coronary risk (2). Despite being a nonspecific acute-phase reactant, hsCRP has been shown in large epidemiological and clinical studies to be an independent predictor of cardiovascular events (3), i.e., myocardial infarction, stroke, and death in patients with angina (4) and apparently healthy subjects. Because hsCRP is not a specific marker of vascular inflammation, however, the search for highly sensitive and specific markers of risk continues unabated. Evidence from our group (5)(6)(7)(8) and others (9)(10) in recent years indicates that neopterin, an immune modulator produced by activated macrophages, may be useful for cardiovascular risk stratification in patients with coronary artery disease. In this issue of Clinical Chemistry , Grammer et al. (11 …

Sleep — An Affair of the Heart

Sleep — An Affair of the Heart

Inflammatory biomarkers in coronary artery disease

Current evidence supports that inflammation is a major driving force underlying the initiation of coronary plaques, their unstable progression, and eventual disruption; patients with a more pronounced vascular inflammatory response have a poorer outcome. Biomarkers are generally considered to be proteins or enzymes - measured in serum, plasma, or blood - that provide independent diagnostic and prognostic value by reflecting an underlying disease state. In the case of coronary artery disease (CAD), inflammatory biomarkers, have been extensively investigated; more evidence exists for C-reactive protein (CRP). Using high sensitivity (hs) assays, epidemiologic data demonstrate an association between hs-CRP and risk for future cardiovascular morbidity and mortality among those at high risk or with documented CAD. Moreover, a series of prospective studies provide consistent data documenting that mild elevation of baseline levels of hs-CRP among apparently healthy individuals is associated with higher long-term risk for cardiovascular events. Yet, the predictive value of hs-CRP is found to be independent of traditional cardiovascular risk factors. Recent studies suggest that, besides CRP, other inflammatory biomarkers such as cytokines [interleukin (IL)-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], soluble CD40 ligand, serum amyloid A (SAA), selectins (E-selectin, P-selectin), myeloperoxidase (MPO), matrix metalloproteinases (MMPs), cellular adhesion molecules [intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1)], placental growth factor (PlGF) and A(2) phospholipases may have a potential role for the prediction of risk for developing CAD and may correlate with severity of CAD. Finally, indications suggest that the increased risk associated with inflammation may be modified with certain preventive therapies and biomarkers may help to identify the individuals who would benefit most from these interventions.

Atherosclerotic Plaque Stability—What Determines the Fate of a Plaque?

Although the understanding of the underlying pathology of atherosclerosis has improved in recent years, the disease is still the main cause of death globally. Current evidence has implicated the role of inflammation in atherogenesis and plaque destabilization. Thus, inflammatory cytokines may attenuate interstitial collagen synthesis, increase matrix degradation, and promote apoptosis in several atheroma-associated cell types, and all these cellular events may enhance plaque vulnerability. Several cell types found within the lesion (ie, monocyte/macrophages, T cells, mast cells, platelets) contribute to this immune-mediated plaque destabilization, and a better understanding of these processes is a prerequisite for the development of new treatment strategies in these individuals. Such knowledge could also facilitate a better identification of high-risk individuals. In the present study, these issues will be discussed in more detail, particularly focusing on the interactions between matrix degradation, apoptotic, and inflammatory processes in plaque destabilization.

Where Do We Go From Here?

A compelling body of evidence indicates that rheumatoid arthritis (RA) substantially increases the risk for early myocardial infarction (MI), silent ischemia, and sudden death. This evidence includes a growing literature on the role of inflammation in atherogenesis, population-based and clinical epidemiology studies on cardiovascular disease (CVD) in patients with RA, and a smaller number of randomized trials of antirheumatic drugs, as reviewed in this supplement. 1 Salmon J.E. Roman M.J. Subclinical atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Am J Med. 2008; 121: S3-S8 Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar , 2 Gabriel S.E. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med. 2008; 121: S9-S14 Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar , 3 Wilson P.W.F. Evidence of systemic inflammation and estimation of coronary artery disease risk: a population perspective. Am J Med. 2008; 121: S15-S20 Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar , 4 Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med. 2008; 121: S21-S31 Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar RA, therefore, could and should now be considered an independent cardiovascular (CV) risk factor, with an approximate 1.5- to 2.0-fold increase in risk in persons with RA not accounted for by established CV risk factors. The magnitude of risk is similar to that of the established risk factors. This is a clinically important issue for several reasons, as described by Gabriel 2 Gabriel S.E. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med. 2008; 121: S9-S14 Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar in her studies of the Rochester RA cohort. First, she and others emphasize that the excess overall mortality in patients with RA is largely attributable to CV death. Although RA causes chronic symptoms and sometimes leads to disability, it appears that its link to coronary heart disease and congestive heart failure is the mechanism by which it causes premature death. Second, the excess CVD and CV death appear to occur especially at relatively young ages, in the range of 40 to 60 years. Third, the Rochester RA cohort data demonstrate persuasively that, whereas CV mortality has declined remarkably since the late 1960s, patients with RA have not shared in this decline, and, despite all the advances in risk factor management and acute and long-term cardiologic care, these patients have the same CV mortality rates as they did in the 1960s. The association of RA with silent ischemia and sudden cardiac death, and its curious reduced rate of angina pectoris, may explain why CV mortality rates seem to have been resistant to advances in CV mortality reduction. The apparent increase in MI risk in the setting of a reduced degree of atherosclerosis provides a mechanism for this observation, suggesting that patients with RA more frequently have unstable atherosclerotic plaques compared with non-RA patients.

Neopterin, CD4+CD28− lymphocytes and the extent and severity of coronary artery disease

Objectives Macrophages and pro-inflammatory CD3+CD4+CD28− T lymphocytes are involved in atherosclerotic plaque destabilization. Whether neopterin, a macrophage-specific activation-marker, and circulating CD3+CD4+CD28− cells are also related to the severity and extent of coronary artery disease (CAD) in stable patients is still unclear. Methods Coronary angiograms of 30 patients with stable angina pectoris were graded using the Gensini severity and an extent score. Patients were grouped according to the median of each score. Lymphocyte subsets were determined by FACS analysis and neopterin by radioimmunoassay. Peripheral endothelial function of the brachial artery (FMD) shown to correlate with cardiovascular risk factors was evaluated using high-resolution ultrasound. Results More extensive CAD was associated with increased neopterin levels (8.3 ± 3.3 vs. 5.5 ± 1.2 nmol/L, p < 0.001) and increased CD3+CD4+CD28− cells (3.1 ± 1.6 vs. 2.0 ± 1.2%, p < 0.05). A high Gensini severity score was associated with increased neopterin levels (7.8 ± 2.7 vs. 6.3 ± 1.7 nmol/L, p < 0.05), but not with CD3+CD4+CD28− cells. Neopterin correlated with both the extent ( r = 0.59, p < 0.001) and the Gensini score ( r = 0.57, p < 0.003). FMD was not correlated with both scores. Conclusions Neopterin and CD3+CD4+CD28− lymphocytes are associated with CAD extent in stable patients, thereby emphasizing the inherent role of inflammation in atherogenesis itself beyond plaque destabilization. Neopterin's correlation with CAD severity might be additionally useful in identifying patients eligible for revascularization procedures.

Review of the Evidence for the Clinical Utility of Lipoprotein-Associated Phospholipase A 2 as a Cardiovascular Risk Marker

A substantial body of peer-reviewed studies has been published validating the role of inflammation in atherogenesis and supporting lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) as a cardiovascular risk marker independent of and additive to traditional risk factors. As with elevated high-sensitivity C-reactive protein, an elevated Lp-PLA(2) level approximately doubles the risk for primary and secondary cardiovascular events. Interestingly, when both inflammatory markers are increased together, they provide an even greater predictive capability to help identify very-high-risk individuals who would benefit most from aggressive lipid-lowering therapy. High levels of Lp-PLA(2) are present in inflamed, rupture-prone plaques, and it appears that Lp-PLA(2) is released from these plaques into the circulation. Over 25 prospective epidemiologic studies have demonstrated the association of elevated Lp-PLA(2) levels with future coronary events and stroke-11 of 12 prospective studies have shown a statistically significant association between elevated Lp-PLA(2) and primary coronary or cardiovascular events, 12 of 13 have shown a statistically significant association with recurrent coronary or cardiovascular events, and 6 studies have shown a positive association with stroke. Lp-PLA(2) should be viewed today as an important cardiovascular risk marker whose utility is as an adjunct to the major risk factors to adjust absolute risk status and thereby modify low-density lipoprotein cholesterol goals. The low biologic fluctuation and high vascular specificity of Lp-PLA(2) makes it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA(2) marker serially. Ultimately, Lp-PLA(2) may also be classified as a risk factor, but this should not detract from its utility today as a risk marker.

Mast Cells as Mediators and Modulators of Atherogenesis

The central role of inflammation in atherogenesis has gained broad acceptance and has revolutionized our understanding of this common disease. This recognition has heightened interest in identifying the specific mediators and mechanisms that contribute to the interplay between risk factors (traditional and emerging), inflammation, and the altered biology of the arterial wall that regulates plaque development and complication.1 In particular, leukocytes have come to occupy center stage as the major cellular effectors of inflammation. When these inflammatory cells join endothelial and smooth-muscle cells in the artery wall, they spur much of the biology that drives atherogenesis and plaque complication. Article p 2516 The list of leukocyte subtypes involved in arterial inflammation has entered a flourishing phase of refinement. Our understanding of leukocyte involvement in atherogenesis has gone through several strata of discovery and probing. During the initial descriptive phase, the use of rigorous molecular markers buttressed venerable morphological observations and verified the presence of various leukocyte classes within lesions.2 Later, a phase of experimental validation established the causal relationship between leukocyte accumulation in lesions and the aspects of atherogenesis.3–5 Next, continuing mechanistic exploration has probed the precise molecular pathways by which a given leukocyte population can promote or otherwise modify disease.6 Ultimately, the human relevance of in vitro and animal experiments requires observations in human tissues and in patients. The saga of the macrophage in atherosclerosis followed this pattern. Initial morphological observations supported an early role of monocyte recruitment in the formation of experimental atherosclerotic lesions in rabbits—observations that extend back to the middle of the last century.7 With the advent of rigorously characterized monoclonal antibodies, studies in the 1980s solidly documented the presence of mononuclear phagocytes in human and experimental atherosclerotic plaques.8–10 Subsequent studies in the closing decade of the last century highlighted …

Novel model of inflammatory neointima formation reveals a potential role of myeloperoxidase in neointimal hyperplasia

Atherosclerosis, which is characterized by neointima formation, is an inflammatory disease. However, there is no inflammatory product-elicited neointimal model to support the causal role of inflammation in atherogenesis. We reported previously that leukocyte-derived MPO induces vascular injury responses such as endothelial dysfunction. We now test the role of MPO in inflammatory neointima formation. We infused temporarily isolated rat common carotid arteries with MPO (200 nM) and incubated for 1 h. We found that although MPO itself did not induce any neointima formation 2 wk after treatment, in the presence of its substrate, hydrogen peroxide, MPO was able to elicit neointimal hyperplasia. We further confirmed that MPO-induced neointimal hyperplasia is mediated by its product, hypochlorous acid (HOCl). HOCl elicited apoptosis both in intima and media followed by vascular proliferative response and resulted in neointima formation with a heterogeneous cell population. Both histological and functional features of HOCl-treated vessels are similar to those in atherosclerotic lesions. To our knowledge, this is the first direct in vivo demonstration of neointimal formation induced by a product of the inflammatory cascade. The results suggest that MPO may be a mediator for pathological neointima growth. This novel neointimal model could be useful for studying inflammation and atherosclerosis.

We-W32:1 Role of inflammation in atherogenesis and in plaque instability

We-W32:1 Role of inflammation in atherogenesis and in plaque instability