Inflammation Atherosclerosis And Coronary Artery Disease Pdf

inflammation atherosclerosis and coronary artery disease pdf

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Atherosclerosis is a multifactorial disease triggered and sustained by different risk factors such as dyslipidemia, arterial hypertension, diabetes mellitus, smoke, etc. Since a couple of decades, a pivotal role for inflammation in its pathogenesis has been recognized and proved at molecular levels, and already described in many animal models. Despite all this knowledge, due to the complexity of the specific inflammatory process subtending atherosclerosis and to the fact that inflammation is also a protective response against microorganisms, no anti-inflammatory therapy has been rendered available in the therapeutic armamentarium against atherosclerosis and vascular events till when canakinumab in the first ad-hoc randomized clinical trial RCT proved for the first time that targeting specifically inflammation lowers cardiovascular CV events.

Inflammation, Atherosclerosis and Coronary Artery Disease

Atherosclerosis is a multifactorial disease triggered and sustained by different risk factors such as dyslipidemia, arterial hypertension, diabetes mellitus, smoke, etc. Since a couple of decades, a pivotal role for inflammation in its pathogenesis has been recognized and proved at molecular levels, and already described in many animal models. Despite all this knowledge, due to the complexity of the specific inflammatory process subtending atherosclerosis and to the fact that inflammation is also a protective response against microorganisms, no anti-inflammatory therapy has been rendered available in the therapeutic armamentarium against atherosclerosis and vascular events till when canakinumab in the first ad-hoc randomized clinical trial RCT proved for the first time that targeting specifically inflammation lowers cardiovascular CV events.

From the genetic side, in the 90's and early , several genetic markers in inflammatory pathway have been explored searching for an association with athero-thrombosis which gave seldom consistent results. Then, in the genomic era, plenty of genetic markers covering most of the genome have been analyzed at once without a priori information.

The results coming from genome wide association studies GWAS have pinpointed some loci closed to inflammatory molecules consistently associated with atherosclerosis and CV consequences revamping the strict link between inflammation and atherosclerosis and suggesting some tailored target therapy. Whole-exome and whole-genome sequencing will come soon showing new and old loci associated with atherosclerosis suggesting new molecular targets or underlying which inflammatory pathway could be most attractive to target for blocking atherosclerosis even in its early stages.

Atherosclerosis is an inflammatory disease Ross, ; Libby, Accumulation of leukocytes in the subendothelial space is an early step in the formation of atherosclerotic lesions. Lots of adhesion molecules or receptors for leukocytes expressed on the surface of the arterial endothelial cell probably participate in the recruitment of leukocytes to the nascent atheroma. Proinflammatory cytokines can act at different stages in the process: interleukin 1 IL-1 and tumor necrosis factor TNF can regulate the expression of adhesion molecules involved in early and late leukocyte recruitment.

Indeed, IL-1 and TNF can induce local production of growth factors, including fibroblast growth factors FGF and platelet-derived growth factor PDGF which attract smooth-muscle cells from the tunica media into the intima. Finally, other cytokines and growth factors may be important in the evolution to a more advanced fibrous plaque which may be protective against plaque rupture: i.

When all these conditions are excluded, CRP, even in the lower range of detection, could be useful to monitor subclinical inflammatory state deriving from atherosclerosis Libby and Ridker, The Jupiter trial have already shown that patients with 2. Thus, after this trial it was still plausible that the reduced LDL-cholesterol levels and not the reduced grade of inflammation mostly contributed to this beneficial result. Secretory phospholipase A2 sPLA2 and lipoprotein-associated phospholipase A2 Lp-PLA2 were identified in animal and observational studies in humans, as potential risk factors for coronary heart disease due to their putative effects on lipids and inflammation Rosenson et al.

Nevertheless, two randomized clinical trials RCTs , exploring the possible efficacy of darapladib, a Lp-PLA2 inhibitor, in patients after an acute coronary syndrome ACS or stable coronary atherosclerosis, did not find any difference in CV and cerebrovascular events as compared to placebo O'Donoghue et al.

A genetic variant, rs of the sPLA2 gene was associated with lower level of sPLA2 but not with major vascular events. Beside the current large availability of anti-inflammatory drugs in the medical field, targeting specifically inflammation in humans remains challenging.

In fact, most of available anti-inflammatory medications have adverse effects which render their use, as a chronic therapy to prevent CV events, not feasible and some of them have proved to be deleterious. Nevertheless, at least a clue can be drawn by exploring clinical trials which in post-hoc analyses evaluated these drugs for their potential role in CV risk or observational surveys related to patients which need these drugs for other indications, such as chronic inflammatory or degenerative diseases.

Among the anti-inflammatory therapies, the non-steroidal anti-inflammatory drugs NSAIDs are the most common used drugs worldwide in acute inflammatory disease, chronic therapy for osteoarthritis or other painful debilitating diseases. Quite recently, in a network meta-analysis including 31 trials which analyzed either NSAIDs and coxibs, both rofecoxib and lumiracoxib were associated with an increased risk of MI whereas ibuprofen and diclofenac with the risk of stroke.

Trelle et al. Major vascular events, and especially coronary events were increased by coxibs, diclofenac, and ibuprofen. Methotrexate MTX is an anti-inflammatory drug widely used for the treatment of chronic inflammatory disorders such as rheumatoid arthritis and psoriasis. A systematic review and meta-analysis exploring the effect of MTX on major CV outcomes searched for cohorts, case-control studies, and randomized trials Micha et al.

The authors suggested that MTX could be a useful drug to decrease CV risk and these findings were in line with other meta-analyses Roubille et al. About possible effects of corticosteroids, Roubille and co-authors explored studies in patients with rheumatoid and psoriatic arthritis.

Corticosteroids were associated with an increased risk of cardiovascular events regardless of the inflammatory disease Roubille et al.

This was probably due to the well-known adverse cardiometabolic effects of this class of drugs. The same meta-analysis indicated that in rheumatoid arthritis, TNF inhibitors can reduce the risk of CV events. These data confirmed findings of previous meta-analyses and large registries Barnabe et al. Thus, TNF may represent an anti-inflammatory drug for atherosclerosis, even though its potent adverse effects and high cost makes its use for this treatment unlikely. Another biological therapy for chronic plaque psoriasis targets interleukin 12 IL and interleukin 23 IL Two meta-analyses explored their possible effect on CV risks.

Ryan et al. The study was underpowered to detect a difference in CV endpoints. In September , the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study CANTOS trial irrupted in the scientific field unequivocally proving for the first time that targeting specifically inflammation is useful for patients with atherosclerosis Ridker et al.

A control placebo group was included in the study. Due to financial considerations, the final sample size was reduced but the follow-up was extended. Interestingly the primary endpoint was reached in significantly less patients assigned to canakinumab then placebo. On the other hand, more deaths from infections were detected in the canakinumab group Ridker et al.

Thus, a definitive point for the inflammatory hypothesis has been finally reached: atherosclerosis is an inflammatory disease which can be targeted by a specific anti-inflammatory therapy. But the drug to use remains still undefined. In fact, at least for canakinumab, there are simple considerations which will limit its widespread use: first the weight of the increase of deaths from infections may counterbalance the decrease in CV events; second the price of this therapy is still not easily affordable Harrington, Clinical trials to test a cheaper anti-inflammatory drug for atherosclerosis, the MTX, are still ongoing Everett et al.

Anti-inflammatory targets are probably multiplex and many drugs could target different steps in the inflammatory process. In this regard, many genetic studies and especially genome wide association studies GWAS have pinpointed new molecular candidates that might represent specific targets for the inflammatory process in atherosclerosis rather than other inflammatory disease. Thus, genetics could be one of the key to detect molecular targets which specifically address CV inflammation.

In the remaining of the review, we focus our attention on some interesting examples between the screened studies where inflammatory loci were identified by the genome wide strategy to support the inflammatory hypothesis.

Even if we acknowledge that our search is not exhaustive, since it is not a systematic review, we have found and reported beyond some significant examples of genes and SNPs in inflammatory loci potentially implicated in coronary disease. CXCL12 is a gene located on 10q It is involved in vascular repair and remodeling through endothelial progenitor cell recruitment, and it is expressed in atherosclerotic lesion by contributing to macrophages migration that promote formation of complicated and unstable plaques by maintaining a pro-inflammatory microenvironment Farouk et al.

The association between two SNPs rs and rs on 10q In fact, both rs [per allele odds ratio OR 1. In the same year, data of the Wellcome Trust Case Control Consortium and of the German Myocardial Infarction Family Study enrolling MI patients lower than 60 years and 1, healthy controls were combined and confirmed previously published results Samani et al.

Kathiresan et al. Successively, this observation has been replicated in a Chinese Han population of 2, coronary atherosclerosis patients and 1, controls undergoing coronary angiography. Accordingly, rs at 10q However, after adjustment by sex and age this association resulted not yet significant. Anyhow, although this gene appears to be quite interesting, most of the tested SNPs are not functional, and the conflicting results obtained prompt to be cautious about a solid implication of this gene in coronary atherosclerosis.

SH2B3 , also known as LNK , encodes for an intracellular adaptor protein expressed in vascular endothelial cells and functions as a negative regulator in many pathways, as cytokine signaling pathways Fitau et al.

In a mouse model of atherosclerosis, it has been demonstrated that this gene is up-regulated over five-fold as endothelial cells change from normal to the atherosclerotic disease state Erbilgin et al. Gudbjartsson et al. Since eosinophils are leukocytes involved in initiation and propagation of inflammatory responses, the accumulation of eosinophils in the thrombus could contribute to the genesis and progression of thrombus Jiang et al.

Saade et al. Previously reported results about rs and rs were not confirmed in this population. Different results were more recently reported by Assimes et al. Ji et al. Also for this gene the first findings were not constantly replicated but, differently from CXCL12 , at least the rs determines an amino acid change and is located inside the gene.

Even if more research is needed, it sounds also attracting the common positivity in GWAS for hypertension. HLA is a set of cell surface proteins essential for the acquired immune system by playing an important role in inflammation and T cell responses and mediating the interactions between leucocytes. An association between a HLA locus, 6p Sinisalo et al.

Taking together, the results of these studies are not convincing about a pivotal role of HLA in atherosclerosis. To identify loci that predispose to MI, Reilly et al. The authors hypothesized that the AB0 association could be attributable to the glycotransferase-deficient enzyme that encodes the AB0 blood group 0 phenotype previously proposed to protect against MI Reilly et al.

It has been hypothesized that blood group antigens could be directly involved in atherosclerotic inflammatory process Wu et al. In the locus 9p21 was identified as the strongest genetic susceptibility locus for CAD and MI independently by three different research groups Burton et al. One year later, Schunkert confirmed the association between chromosome 9p These proteins are cyclin-dependent kinase inhibitors involved in the regulation of cell proliferation, aging, senescence and apoptosis in many cell types and result abundantly expressed in atherosclerotic lesions Holdt et al.

Several SNPs in the 9p More recently, a consistent association between two variants in the 9p For rs, unconditional logistic regression analysis revealed that the G allele increased MI risk with OR of 1.

This locus remains still one of the most promising for coronary atherosclerosis, being detected in most of the GWAS performed and subtending genes of putative effect. Nevertheless, the exact mechanism and the gene responsible is to be definitely proved.

IL5 is an interleukin produced by T helper-2 cells with a role in the inflammatory process characterizing the development and progression of atherosclerosis and CAD Hansson, The IL6-mediated activation of IL6R, a receptor located on the leukocytes and hepatocytes membrane, stimulates the proinflammatory cascade including hepatic production of acute phase reactants C-reactive protein and fibrinogen Schuett et al. Moreover, the AspAla rs in IL6R was not associated with several traditional risk factors such as blood pressure, adiposity, hyperglycaemia, cholesterol, and smoking but with the concentration IL-6, C-reactive protein, fibrinogen, and coronary heart disease implying a causal role for this inflammatory pathway IL6R Genetics Consortium Emerging Risk Factors Collaboration et al.

Howson et al. Accordingly, the consequence of a not conserved barrier can be the development of chronic inflammatory diseases such as atherosclerosis Privratsky et al. These are a few examples of how genetics can and will be able to in the near future identify molecules or pathways as tailored anti-inflammatory therapeutic targets in atherosclerosis.

Despite the inflammatory core of atherosclerosis has been well described, a straightforward anti-inflammatory therapy for targeting inflammation is still missing in the physician's armamentarium.

Therapy with biological drugs is attractive but probably too expensive to be largely available. Newer targets are needed and genetics can help with this issue. In the upcoming genomic era, both whole-exome and whole-genome sequencing will pinpoint new and old loci associated with atherosclerosis identifying new molecular targets or characterizing which inflammatory pathway could be a suitable target to block atherosclerosis even in its early stages.

Both authors contributed to the drafting and completion of the final version of the manuscript.

Inflammation, atherosclerosis, and coronary artery disease.

Cardiovascular disease CVD remains the leading cause of mortality and morbidity worldwide. Atherosclerosis is responsible for the majority of cardiovascular disorders with inflammation as one of its driving processes. Cardiovascular disease CVD remains the leading cause of mortality and morbidity worldwide, despite major improvements in treatment and outcomes. CVD is a group of diseases that effects the heart and blood vessels including coronary artery disease CAD , cerebrovascular disease, and peripheral artery disease [ 1 , 2 ]. CAD is characterized by the accumulation of atherosclerotic plaque in the coronary arteries and its major clinical consequence is an acute myocardial infarction MI [ 3 ]. Atherosclerosis is a progressive disease that is characterized by the accumulation of lipids, inflammatory cells, and fibrous elements in arterial plaques. It is the driving force in CAD and interventions that aim to influence the development, progression, and stability of atherosclerotic lesions are of pivotal importance.

PDF | ecent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of.

Inflammation, atherosclerosis, and coronary artery disease

Our knowledge of the pathophysiology of atherosclerosis and the development of acute coronary syndrome ACS has progressed over the last few decades thanks to the large number of studies on the proliferation of smooth muscle cells, growth factors, and the biology of the vascular bed. The prominent role played by inflammation in the pathogenesis of atherosclerosis has become apparent over the last decade. The role of inflammation at the start of atherosclerotic processes and during their progression and in the complications present in the plaques has been well established through many clinical and experimental studies. On the other hand, investigation of different pathways and identification of what triggers this inflammatory process may unveil new therapeutic targets.

Atherosclerosis is a chronic inflammatory disease.

Coronary Artery Disease (CAD)

Coronary artery disease is caused by plaque buildup in the wall of the arteries that supply blood to the heart called coronary arteries. Plaque is made up of cholesterol deposits. Plaque buildup causes the inside of the arteries to narrow over time. This process is called atherosclerosis.

Key words:. Global, regional, and national age-sex specific all-cause and cause-specific mortality for cau of death, a systematic analysis for the Global Burden of Disease Study Lancet London, England [Internet] ;

Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogenesis of atherosclerotic CAD. View PDF. Save to Library.

Inflammation, atherosclerosis, and coronary artery disease.

Research into inflammation, atherosclerosis and coronary artery disease, including observational studies, clinical trials, epidemiology, and advances in applied translational research. The supplement is intended to include overviews of new concepts in pathophysiology, natural history, diagnostic strategies, and treatment approaches. Article types include original clinical and basic research articles, case reports, commentaries, meeting reports, methodology, perspectives.

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