Spyridon Papaioannou

Oxidative Stress and Early Atherosclerosis: Novel Antioxidant Treatment

Atherosclerotic lesions initiate in regions characterized by low shear stress and reduced activity of endothelial atheroprotective molecules such as nitric oxide, which is the key molecule managing vascular homeostasis. The generation of reactive oxygen species from the vascular endothelium is strongly related to various enzymes, such as xanthine oxidase, endothelial nitric oxide synthase and nicotinamide-adenine dinucleotide phosphate oxidase. Several pharmaceutical agents, including angiotensin converting enzyme inhibitors, angiotensin receptors blockers and statins, along with a variety of other agents, have demonstrated additional antioxidant properties beyond their principal role. Reports regarding the antioxidant role of vitamins present controversial results, especially those based on large scale studies. In addition, there is growing interest on the role of dietary flavonoids and their potential to improve endothelial function by modifying the oxidative stress status. However, the vascular-protective role of flavonoids and especially their antioxidant properties are still under investigation. Indeed, further research is required to establish the impact of the proposed new therapeutic strategies in atherosclerosis.

Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease

It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from l-arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH2) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives.

The Role and Predictive Value of Cytokines in Atherosclerosis and Coronary Artery Disease

Atherosclerosis is currently regarded as a chronic inflammatory disease that is mediated by several types of cells and molecules. Emphasis has been placed on the role of cytokines and the way they act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are invariably expressed by all cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leukocytes and other vascular residing cells. In the present paper our aim is to review current information on the role of the most commonly discussed cytokines in the process of atherogenesis and to discuss the prognostic significance of these cytokines in atherosclerosis and coronary artery disease.

High platelet reactivity is associated with vascular function in patients after percutaneous coronary intervention receiving clopidogrel

BACKGROUND In the present study, we evaluated the association of platelet reactivity with vascular function in patients after percutaneous coronary intervention receiving clopidogrel treatment. METHODS We enrolled 150 patients with stable CAD receiving clopidogrel regimen (75 mg/d), 1 month after percutaneous coronary intervention. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as an index of arterial wave reflections. High on treatment platelet reactivity (HPR) was evaluated using VerifyNow Assay. VerifyNow reports its results in P2Y12 reaction units (PRU), and the diagnostic cutoff value is 230 PRU. Patients were evaluated prospectively up to 24 months. The primary end point was a composite of death from cardiovascular causes, nonfatal major cardiovascular events and hospitalization for cardiovascular causes. RESULTS There was no difference in the basic clinical and demographic characteristics between subjects with HPR and non-HPR. Subjects with high on treatment platelet reactivity and PRU>230 had significantly increased PWV (8.81 ± 2.25 m/s vs. 7.69 ± 1.95 m/s, p = 0.001) and AIx (25.27 ± 8.67% vs. 20.87 ± 10.57%, p = 0.04) compared to subjects with PRU≤230. PWV was also associated with PRU (r = 0.23, p = 0.02). HPR was associated with significantly increased risk of primary end point [HR = 5.38, 95%CI:(1.15, 26.04), p = 0.03]. CONCLUSIONS Increased platelet reactivity is associated with impaired arterial stiffness in patients after percutaneous coronary intervention receiving clopidogrel treatment, highlighting another clinical factor implicated in individual platelet response to antiplatelet therapy. Moreover, increased platelet reactivity is associated with adverse outcome in these patients.

The Interaction Between Gender and Diabetes Mellitus in the Coronary Heart Disease Risk

BACKGROUND Cardiovascular disease (CVD) despite the advances in medical management keeps on as the primary cause of morbidity and mortality for both genders in Western societies. Sex differences though modify the clinical picture as well as the effectiveness of treatment. METHODS AND RESULTS In this literature review article we searched publications in Englishlanguage on MEDLINE and the Cochrane Database from the beginning of the databases to January 2016. Among the specific key words and phrases we used were Diabetes Mellitus; Gender; Coronary artery disease; Stroke and Cardiovascular disease. Various studies have found that diabetic women have increased risk of coronary heart disease than their male counterparts; however, further research into this field has questioned this finding and there is much controversy among many researchers. Women have a different risk factor profile, are usually treated less effectively than men, and have a variance in the levels of sex hormones throughout their life which complicate the study and understanding of the mechanisms involved in insulin resistance, diabetes mellitus and cardiovascular risk profile. CONCLUSION The connection between diabetes mellitus and cardiovascular disease is variable according to gender and further studies are needed to elucidate the lenient differentiations in gender specific hormones, risk factor profile, and therapeutic implications between genders.

Coronary Artery Atherosclerosis in Hypertensive Patients: The Role of Fibrinogen Genetic Variability

INTRODUCTION AND OBJECTIVES We examined whether the rs180070 and rs2070011 polymorphisms of the fibrinogen gene could affect the risk of coronary artery disease in hypertensive patients by modifying the inflammatory process and coagulation. METHODS A total of 744 participants underwent coronary angiography due to symptoms of stable angina, while hypertension was present in 332 patients. RESULTS The presence of the A allele (rs180070) was associated with significantly high levels of fibrinogen in hypertensive patients (P=.05). On multivariate analysis, A homozygosity (rs180070) (β = 0.257 ± 18.6; P<.001), but not hypertension status (β = 0.05 ± 11.9; P=.29) was an independent predictor of fibrinogen levels. In hypertensive patients, higher fibrinogen levels>443mg/dL (odds ratio = 3.50; 95% confidence interval, 1.14-10.90; P=.029), but not A homozygosity (odds ratio = 3.00; 95% confidence interval, 0.78-11.90; P = .110) were independent predictors of the presence of coronary artery disease. Moreover, interleukin-6 levels were higher in A homozygotes for the rs180070 polymorphism compared with all other genotypes (P=.046). Indeed, this genotype was the only adjusted independent predictor of interleukin-6 levels (β = 0.151 ± 0.642; P=.032). It was also associated with higher D-dimer levels in hypertension compared with G allele carriers (P=.048). CONCLUSIONS The presence of A homozygosity (rs180070) is associated with increased levels of inflammatory mediators and a higher incidence of angiographic coronary artery disease. Importantly, fibrinogen is an independent predictor of the angiographic presence of coronary artery disease in hypertensive patients.

Statins and Inflammation in Cardiovascular Disease

BACKGROUND Chronic inflammation and immune system activation underlie a variety of seemingly unrelated cardiac conditions including not only atherosclerosis and the subsequent coronary artery disease but also peripheral artery disease, hypertension with target organ damage and heart failure. The beneficial effects of HMG-CoA reductase inhibitors or statins are mainly attributed to their ability to inhibit hepatic cholesterol biosynthesis. Beyond their lipid lowering activity, ample evidence exists in support of their potent anti-inflammatory properties which initiate from the inhibition of GTPase isoprenylation, activating a cataract of secondary pathways and extend to the inhibition and blocking of immune cell activation and interaction. OBJECTIVE To summarize the anti-inflammatory mechanisms of statins in clinical and experimental settings in cardiovascular disease. METHODS A systematic search of PubMed and the Cochrane Database was conducted in order to identify the majority of trials, studies, current guidelines and novel articles related to the subject. RESULTS In vitro, statins have immuno-modulatory and anti-inflammatory effects, and they can exert anti-atherosclerotic effects independently of their hypolipidemic actions. In addition, positive results have emerged from mechanistic and experimental studies on the active role of HMG-CoA reductase inhibitors in HF. By extrapolating those data in clinical setting, we further understand how HMG-CoA reductase inhibitors can beneficially affect not only systolic but also diastolic HF. CONCLUSION In this review article, we present the basic pathophysiologic data supporting the anti-inflammatory actions of statins in clinical and experimental settings and we link these mechanisms with confirmatory clinical data on the potent non lipid lowering effects of HMG-CoA reductase inhibitors.

Biomarkers in atrial fibrillation and heart failure.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice and an important contributor to cardiovascular morbidity and mortality. Although the exact mechanisms behind AF are not completely elucidated, the underlying pathophysiological changes have been well described. Predisposal factors for AF include the older age, the increased left atrial size, the decreased left atrial function, the presence of heart failure and left ventricular systolic dysfunction and the presence of coronary heart disease or pulmonary or mitral valve disease. In addition to these factors, emerging evidence demonstrate that myocardial strain, fibrosis and inflammation, are associated with AF as well as the pathogenesis of the arrhythmia. The natruretic peptide system including Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP) and C-type Natriuretic Peptide (CNP) is indicative of the level of myocardial strain which may predispose to AF. As a result, the aforementioned peptides are increased in AF patients. The levels of myocardial fibrosis biomarkers, such as ST2 and Galectin-3, are elevated suggesting atrial structural abnormalities, while the increased levels of CRP and Interleukin-6 supplement the inflammatory profile of AF patients. Emerging data for the aforementioned biomarkers are discussed in the present review.

Redox State in Atrial Fibrillation Pathogenesis and Relevant Therapeutic Approaches

BACKGROUND Myocardial redox state is a critical determinant of atrial biology, regulating cardiomyocyte apoptosis, ion channel function, and cardiac hypertrophy/fibrosis and function. Nevertheless, it remains unclear whether the targeting of atrial redox state is a rational therapeutic strategy for atrial fibrillation prevention. OBJECTIVE To review the role of atrial redox state and anti-oxidant therapies in atrial fibrillation. METHOD Published literature in Medline was searched for experimental and clinical evidence linking myocardial redox state with atrial fibrillation pathogenesis as well as studies looking into the role of redoxtargeting therapies in the prevention of atrial fibrillation. RESULTS Data from animal models have shown that altered myocardial nitroso-redox balance and NADPH oxidases activity are causally involved in the pathogenesis of atrial fibrillation. Similarly experimental animal data supports that increased reactive oxygen / nitrogen species formation in the atrial tissue is associated with altered electrophysiological properties of atrial myocytes and electrical remodeling, favoring atrial fibrillation development. In humans, randomized clinical studies using redox-related therapeutic approaches (e.g. statins or antioxidant agents) have not documented any benefits in the prevention of atrial fibrillation development (mainly post-operative atrial fibrillation risk). CONCLUSION Despite strong experimental and translational data supporting the role of atrial redox state in atrial fibrillation pathogenesis, such mechanistic evidence has not been translated to clinical benefits in atrial fibrillation risk in randomized clinical studies using redox-related therapies.

HIGH LEVELS OF FIBRINOGEN, BUT NOT FIBRINOGEN GENETIC VARIANTS PREDICT CORONARY ARTERY DISEASE IN SUBJECTS WITH HYPERTENSION AND DIABETES MELLITUS TYPE 2

It is well established that hypertension (HTN) and diabetes mellitus (DM) are strongly associated with coronary artery disease (CAD). In addition, controversial data exist related to the role of fibrinogen genetic variants in atherosclerosis-CAD. Therefore, we examined the effects of the rs180070