Georgia Vogiatzi

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.

Clinical Utility of Biomarkers in Premature Atherosclerosis

Atherosclerosis is a very complex procedure responsible for the development of coronary artery disease which is the leading cause of death in the civilized world. The obvious pandemic character of atherosclerosis augments the need to discover an ideal biomarker, which will be able to facilitate the clinical diagnosis of the atherosclerosis from the physicians especially in the early stages of the atherosclerotic process. Among the biomarkers that are already used there are classical ones, such as c-reactive protein, interleukins, tumour necrosis factor, apolipoproteins, fibrinogen, homocysteine, and novel promising ones such as lipoprotein-associated phospholipase, asymmetric dimethylarginine, myeloperoxidase, cathepsins and cystatin C. The possibility of combining circulating biomarkers with other methods such as non-invasive and invasive imaging is clinically attractive because this could contribute to the improved diagnosis and understanding of premature atherosclerosis pathogenesis.

Is there a role for erythropoietin in cardiovascular disease

Importance of the field: Despite the advances in the cardiovascular field, cardiovascular diseases remain an important health problem with a high mortality rate. Novel therapeutic attempts that target myocardial ischemia and heart failure offer attractive adjuncts and/or alternatives to commonly employed regimens. The development of novel laboratory technologies over the last decade has led to substantial progress in bringing new therapies to the bedside. Areas covered in this review: Current experimental and clinical trials in the use of erythropoietin (EPO) in cardiovascular diseases are reviewed. What the reader will gain: This review will widen knowledge of the therapeutic potential of EPOs non-erythropoietic beneficial effects in a clinical cardiovascular setting. Take home message: Results from preclinical trials regarding the non-erythropoietic effects of erythropoietin are really encouraging. Further clinical studies are warranted to define the beneficial role of EPO in the clinical setting of coronary artery disease, heart failure and peripheral artery disease.

Exercise capacity and haemodynamic response among 12,327 individuals with cardio-metabolic risk factors undergoing treadmill exercise:

Aims Haemodynamic parameters during and after exercise test seem to have a role in predicting cardiovascular events. We sought to evaluate the potential different responses in exercise capacity, heart rate and blood pressure levels in relation to major cardiovascular disease risk factors, among individuals undergoing exercise tolerance testing. Methods and results Consecutive individuals (N = 12,327), aged 55 ± 11.8 years, underwent exercise tolerance testing, using the Bruce protocol. Obese participants showed higher values of peak systolic and diastolic blood pressure (p < 0.01), with no heart rate differences. Diabetic patients presented increased systolic blood pressure across the test (p = 0.02) and decreased tolerance to exercise (p = 0.05), but without differences in diastolic blood pressure or heart rate. Hypertensives showed exaggerated blood pressure, chronotropic response and decreased capacity to exercise (p < 0.001 for all). Smokers had increased baseline systolic blood pressure, peak diastolic blood pressure and recovery heart rate and decreased tolerance to exercise (p < 0.001 for all). For all high-risk subgroups, exercise testing was more often positive. Age-stratified analysis revealed different patterns: all four risk factors significantly decreased peak metabolic equivalent in subjects <50 years old (p < 0.05 for all), while in participants between 50 and 69 years old, diabetes mellitus (p = 0.03), hypertension (p = 0.04) and smoking (p = 0.01) predicted achieved metabolic equivalent. For patients of ≥ 70 years old, obesity (p = 0.006) and hypertension (p = 0.02) decreased peak metabolic equivalent and systolic blood pressure recovery. In subjects without pre-existing cardiovascular disease and negative exercise tolerance testing (7064 subjects, mean age: 52.4 ± 12.1 years, 62.9% males), age, obesity, hypertension and female gender inversely and independently predicted peak metabolic equivalent. Conclusions High-risk individuals showed different haemodynamic responses when undergoing exercise tolerance testing, reflecting independent pathophysiological pathways.

The Role of Oxidative Stress

Oxidative stress occurs due to the combination of excess reactive oxygen species and insufficient antioxidant capacity. Oxidative stress has been correlated with endothelial dysfunction, the pathogenesis of atherosclerosis as well as with high incidence of cardiovascular disease. A variety of antioxidants have been studied, during the past few years, for the prevention and treatment of atherosclerosis. This chapter provides contemporary data concerning pathophysiology of oxidative stress and its relation to atherogenesis.

Genetic variability of matrix metalloproteinase genes in cardiovascular disease.

It is well established that matrix metalloproteinases (MMPs) contribute to the degradation of the extracellular matrix of coronary plaque and contribute to the thinning of the fibrous cap. As a result, the atheromatous plaque becomes unstable and prone to rupture with consequent clinical manifestations including acute coronary syndromes. Moreover, genetic polymorphisms of MMPs have been found to be associated with the concentration of circulating MMPs, and over the past decade, considerable efforts have been devoted to explore the relationships between MMPs polymorphisms and myocardial infarction risk among various populations. However, existing studies have yielded inconsistent results. Some observations have suggested that genetic variation that affects the expression of MMPs may contribute to the occurrence of myocardial infarction, whereas others reported no support for an association of MMPs polymorphisms with myocardial infarction susceptibility. Furthermore, the interpretation of these studies has been complicated by the use of different populations or different control sources. Therefore, further studies are required to evaluate the role of matrix metalloproteinases and especially the associated genetic polymorphisms in cardiovascular disease.

Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance

Heart failure (HF) is a common cardiac syndrome, whose pathophysiology involves complex mechanisms, some of which remain unknown. Diabetes mellitus (DM) constitutes not only a glucose metabolic disorder accompanied by insulin resistance but also a risk factor for cardiovascular disease and HF. During the last years though emerging data set up, a bidirectional interrelationship between these two entities. In the case of DM impaired calcium homeostasis, free fatty acid metabolism, redox state, and advance glycation end products may accelerate cardiac dysfunction. On the other hand, when HF exists, hypoperfusion of the liver and pancreas, b-blocker and diuretic treatment, and autonomic nervous system dysfunction may cause impairment of glucose metabolism. These molecular pathways may be used as therapeutic targets for novel antidiabetic agents. Peroxisome proliferator-activated receptors (PPARs) not only improve insulin resistance and glucose and lipid metabolism but also manifest a diversity of actions directly or indirectly associated with systolic or diastolic performance of left ventricle and symptoms of HF. Interestingly, they may beneficially affect remodeling of the left ventricle, fibrosis, and diastolic performance but they may cause impaired water handing, sodium retention, and decompensation of HF which should be taken into consideration in the management of patients with DM. In this review article, we present the pathophysiological data linking HF with DM and we focus on the molecular mechanisms of PPARs agonists in left ventricle systolic and diastolic performance providing useful insights in the molecular mechanism of this class of metabolically active regiments.

Anti-inflammatory agents in peripheral arterial disease

HIGHLIGHTSExisting cardiovascular drugs yield secondary benefits by reducing inflammation.Broad‐based or targeted anti‐inflammatory treatment of atherosclerosis is promising.Canakinumab, monoclonal antibody against IL‐1&bgr; treatment in coronary patients reduced cardiovascular events.More evidence is needed on antiinflammatory agents use in PAD.The field of immunomodulation in atherosclerosis treatment is rapidly evolving. &NA; Inflammation is pivotally involved in coronary and peripheral atherosclerotic disease. This established concept is based on both experimental animal models of vascular inflammation and Mendelian randomization studies demonstrating a causal relationship between pro‐inflammatory cytokines (e.g. interleukin‐6) and cardiovascular disease risk. More recently, the reduction of cardiovascular events by use of an interleukin‐1&bgr; inhibitor (canakinumab) has revived interest in the use of anti‐inflammatory agents for the treatment of atherosclerotic disease, including peripheral arterial disease. In this mini review article we provide an update on the pleiotropic anti‐inflammatory properties of approved drugs for use in cardiovascular disease (e.g. antiplatelets, statins, PCSK9 inhibitors) and discuss the role of targeted or untargeted anti‐inflammatory atheroprotection in peripheral arterial disease by agents such as colchicine, methotrexate, anti‐TNF‐&agr; agents and monoclonal antibodies against interleukin‐signaling.

Effects of oral and non-insulin injectable antidiabetic treatment in hypertension: a systematic review

BACKGROUND Diabetes mellitus type 2 (T2DM) often co-exists with hypertension, and this aggregation of co-morbidities amplifies the risk for future cardiovascular events. Therefore, it appears crucial to understand the essence of choosing oral and non-insulin injectable anti-diabetic drugs (ADs) with a favorable hemodynamic impact that could partially attenuate the increased baseline cardiovascular risk. OBJECTIVE We sought to evaluate the effect of ADs on blood pressure (BP) indices and to assess the potential role of certain ADs towards hypertension treatment. METHOD We performed a systematic review of the literature searching MEDLINE via Pubmed for all human studies implementing ADs, either individually or in combinations. RESULTS Metformin was found to reduce BP in small cohorts but failed to confirm its beneficial effect in a metaanalysis of 41 studies. Thiazolidinediones are associated with BP lowering but are contraindicated in patients with heart failure. Sulfonylureas, on the other hand, may increase BP, while a-glucosidase inhibitors, DPP-4 inhibitors, and SGLT2 inhibitors activate favorable pathophysiologic mechanisms serving as potential BP lowering agents. Relevant BP reduction was established for GLP-1 Ras in most clinical trials. CONCLUSION The favorable hemodynamic impact of certain classes of ADs might provide synergistic or incremental therapeutic benefits in high-risk patients suffering from both T2DM and hypertension. Additional randomized trials designed under the hypothesis of the emerging beneficial hemodynamic effect of ADs are expected to provide more robust evidence and to guide the optimization of combined treatment strategies in this challenging group of 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.