Long-term risk, clinical management, and healthcare resource utilization of stable patients with coronary artery disease and post-myocardial infarction in Greece - TIGREECE study.

BACKGROUND: In light of the scarcity of evidence, TIGREECE evaluated the clinical management and long-term outcomes of patients at high risk for an atherothrombotic event who have suffered a myocardial infarction (MI), managed by cardiologists/internists in routine hospital and private office settings in Greece. METHODS: TIGREECE, a multicenter, 3-year prospective cohort study, enrolled patients ≥50 years old, with a history of MI 1-3 years before enrollment and with at least one of the following risk factors: age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, and creatinine clearance 15-60 mL/min. The primary outcome was a composite of MI, unstable angina with urgent revascularization, stroke, or all-cause death. RESULTS: Between 5 June 2014 and 25 July 2015, 305 eligible consented patients (median age: 67.3 years; 81.3% males; 14.8% active smokers; 80.7% overweight/obese) were enrolled; 52.5% had ≥2 qualifying risk factors. The median time from the index MI [ST-segment elevation myocardial infarction (STEMI) in 51.1%, non-STEMI in 33.1%] to enrollment was 1.7 years. Of the patients, 65.9% had been discharged on dual antiplatelet therapy. At enrollment, 94.4% were receiving antiplatelets: 60.0% single [acetylsalicylic acid (ASA): 43.3%; clopidogrel: 15.7%] and 34.4% dual (ASA + clopidogrel: 31.8%) therapy. The Kaplan-Meier estimated 3-year primary composite event rate was 9.3% [95% confidence interval (CI): 6.4-13.0), and the ischemic composite event rate was 6.7% (95% CI: 4.2-9.9). CONCLUSIONS: Study results indicate that in the routine care of Greece one in ten patients experience a recurring cardiovascular event or death, mainly of ischemic origin, 1-3 years post-MI.

Oxidative imbalance increases the risk for colonic polyp and colorectal cancer development.

BACKGROUND: The role of oxidative stress in the pathogenesis of colorectal carcinoma (CRC) has garnered considerable interest recently. Specific oxidative factors have been implicated in the pathogenesis of adenomatous polyps and ultimately adenocarcinoma. AIM: To evaluate the effect of oxidative imbalance as quantified by specific serological markers in the development of sporadic colon adenocarcinoma. METHODS: A total of 170 patients that underwent endoscopy of the lower gastrointestinal tract in a tertiary center within 3 years were included in the study. They were allocated in three groups; those with sporadic colon adenocarcinoma (n = 56, 32.9%), those with colonic polyps (n = 33, 19.4%) and healthy controls (n = 81, 47.7%). All patients were evaluated for oxidant activity and antioxidant capacity with serum measurements of specific markers such as vitamins A, 25(OH) D3, E, C, B12, folic acid, glutathione, selenium (Se), zinc (Zn), free iron (Fe2+), and malondialdehyde and results were compared between groups. RESULTS: Serum levels of vitamins C, E, D, Se, Zn, vitamin B12 and total antioxidant capacity were significantly lower in the combined neoplasia/polyp group than in the control group (P = 0.002, P = 0.009, P < 0.001, P < 0.001, P < 0.001, P = 0.020 and P < 0.001, correspondingly). Increased levels of vitamin E (P = 0.004), vitamin D (P < 0.001), Se (P < 0.001) and Zn (P < 0.001) seem to bestow a protective effect on the development of CRC. For vitamin D (P < 0.001) and Zn (P = 0.036), this effect seems to extend to the development of colon polyps as well. On the other hand, elevated serum levels of malondialdehyde are associated with a higher risk of CRC (OR = 2.09 compared to controls, P = 0.004). Regarding colonic polyp development, increased concentrations of vitamin Α and Fe2+ are associated with a higher risk, whereas lower levels of malondialdehyde with a lower risk. CONCLUSION: Increased oxidative stress may play an important role in the pathogenesis and progression of CRC. Antioxidants' presence may exert a protective effect in the very early stages of colon carcinogenesis.

Impact of peroxiredoxin-6 expression on colon adenocarcinoma.

PURPOSE: Peroxiredoxins (Prdxs) represent a family of proteins that act as antioxidant enzymes and are involved in a variety of metabolic functions including mainly the intracellular hydrogen peroxide (H2O2) levels reduction. Especially, Prdx-6 protein encoded by the PRDX6 gene (1q25.1) regulates also phospholipid modifications and induces response to oxidative stress and injuries. Our aim was to investigate the expression of Prdx-6 in colon adenocarcinoma (CA). METHODS: A series of 30 formalin-fixed, paraffin-embedded primary CAs tissue sections were used and analyzed. Immunohistochemistry was performed using an anti-Prdx-6 antibody. Digital image analysis was also implemented for evaluating objectively the protein expression levels on the corresponding stained cells. RESULTS: Prdx-6 protein overexpression (increased immunostaining levels) was observed in 12/30 (40%) cases, whereas 18/30 (60%) CA tissues demonstrated low to moderate protein levels, respectively. Prdx-6 overall expression was strongly associated with the stage of the examined tumors (p=0.011), whereas other statistical significances were not assessed (inflammatory infiltration: p=0.364; carcinoma location: p=0.93; differentiation grade: p=0.517; tumor diameter: p=0.983; ulceration: p=0.622). CONCLUSIONS: Prdx-6 overexpression is observed in a significant subset of CAs correlating with aggressive biological behavior (advanced stage). Prdx-6 is a crucial enzyme for oxidative stress/injury endogenous cell response and should be an interesting agent as a biomarker and potential therapeutic target.

Cost-effectiveness of apixaban vs. other new oral anticoagulants for the prevention of stroke: an analysis on patients with non-valvular atrial fibrillation in the Greek healthcare setting.

BACKGROUND AND OBJECTIVES: Three new oral anticoagulants (NOACs) are currently approved for stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objective of this analysis was to assess the cost effectiveness of apixaban against other NOACs for the prevention of stroke in patients with NVAF in Greece. METHODS: A Markov model that evaluated clinical events, quality-adjusted life expectancy, and costs for patients treated with apixaban or other NOACs formed the basis of the analysis. Clinical events were modeled for a lifetime horizon, based on clinical efficacy data from an indirect comparison, using the ARISTOTLE, ROCKET-AF, and RE-LY clinical trials. Resource use associated with patient monitoring was elicited via a panel of experts (cardiologists and internists). Cost calculations reflect the local clinical setting and followed a third-party payer perspective (Euros, discounted at 3 %). RESULTS: Apixaban was projected to reduce the occurrence of clinical events and increase quality-adjusted life expectancy and incremental costs of treatment compared with other NOACs. Taking into account costs of medications, patient monitoring, and management of events, the incremental cost-effectiveness ratios for apixaban 5 mg twice daily vs. dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily were estimated at €9907/quality-adjusted life-year (QALY), €13,727/QALY, and €6936/QALY gained, respectively. Extensive sensitivity analyses indicated that results were robust over a wide range of inputs. CONCLUSIONS: Based on the results of this analysis, apixaban can be a cost-effective alternative to other NOACs for the prevention of stroke in patients with NVAF in Greece.

Inflammation markers in essential hypertension.

Essential hypertension is a common health disorder with uncertain etiology and unclear pathophysiology. There is evidence that various systems interact in uncertain ways and mechanisms to cause hypertension. It is also well known that inflammation is a key feature in the initiation, progression and clinical implication of several cardiovascular diseases. Recently, it has become evident that the immune system and inflammatory response are also essential in the pathogenesis of hypertension. Many inflammation markers such as CRP, cytokines, and adhesion molecules have been found elevated in hypertensive patients supporting the role of inflammation in the pathogenesis of hypertension. Also, in normotensive individuals, these markers have been associated with the risk of developing hypertension, whereas in hypertensive patients they have been associated with target organ damage as well as with the risk for future cardiovascular events. Thus, understanding the role of inflammation in hypertension provides new insights for novel therapeutic approaches, targeting inflammation for the treatment of hypertension and its complications.

Diagnostic value of soluble adhesion molecule kinetics in patients with suspected myocardial ischemia undergoing dobutamine stress echocardiography.

INTRODUCTION: Previous studies have shown an exercise-induced increase in circulating adhesion molecules (sICAM-1 and sVCAM-1) in patients with coronary artery disease (CAD). The aim of this study was to evaluate the diagnostic role of changes in serum adhesion molecules in the setting of a dobutamine stress echocardiogram (DSE). METHODS: Thirty patients (18 men and 12 women aged 63.3 ± 10.67 years) with suspected myocardial ischemia underwent a DSE in our department's laboratory of echocardiography in order to identify inducible ischemia. Dobutamine was infused in incremental doses from 5 µg/kg/min up to 40 µg/kg/min. Blood samples were drawn at baseline as well as at peak stress and circulating adhesion molecules sVCAM-1 and sICAM-1 levels were measured by ELISA. Patients with a positive DSE underwent coronary arteriography within 2 weeks of the DSE study. RESULTS: Sixteen patients had a positive DSE for inducible ischemia while 14 had a negative test. Among the patients with positive DSE, 12 had angiographically significant CAD as well as statistically significantly higher levels of sICAM-1 than DSE negative patients (n=14), both at baseline (302.57 ± 43.37 vs. 267.47 ± 28.03 ng/mL, p=0.028) and at peak stress (322.07 ± 49.64 vs. 260.43 ± 36.45 ng/mL, p=0.001). A significant increase from baseline to peak stress was also noted in this group (from 302.57 ± 43.37 to 322.07 ± 49.64 ng/mL, p=0.043). There were no statistically significant differences in the levels of sVCAM-1 between groups at baseline and there was no change from baseline to peak stress. CONCLUSION: Plasma levels of sICAM-1 were found to be elevated in subjects with a positive DSE and angiographically significant CAD compared to patients with a negative DSE, both before and after inducible ischemia. In contrast, no changes were noted regarding sVCAM-1 levels.

Association of asymmetric dimethylarginine levels with treadmill-stress-test-derived prognosticators.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide production. The purpose of this study was to assess the correlation between ADMA and treadmill stress test outcome parameters with known prognostic value, in patients with intermediate risk for coronary artery disease (CAD). METHODS: Study participants were referred for treadmill exercise stress test (EST) due to symptoms of suspected CAD. Participants with prior history of CAD, cerebrovascular events, peripheral artery disease, systemic inflammatory disease or use of anti-inflammatory agents were excluded. ADMA levels were measured before EST. RESULTS: The study prospectively enrolled 209 individuals (165 males, aged 58.1±10.9). A significant negative correlation was detected between ADMA and maximal exercise time (r=-0.556, p<0.001), metabolic equivalents (METs) (r=-0.555, p<0.001) and Duke treadmill score (DTS) (r=-0.347, p<0.001). Subjects who exercised to ≥10 METs (n=114) had lower ADMA levels than those who achieved <7 METs (n=30) (0.58±0.06 vs 0.87±0.08µmol/L, p<0.001), and those with DTS<5 (n=63) had higher ADMA (0.75±0.19 vs 0.64±0.15µmol/L, p<0.001) compared to those with DTS ≥5 (n=146). In multivariable analysis, ADMA remained an independent predictor of DTS (R(2)=0.210; beta=-10.5; 95% confidence interval -14.9 to -6.2; adjusted p<0.001) and METs (R(2)=0.500; beta -8.5; 95% confidence interval -9.7 to -6.0; adjusted p<0.001) after adjustment for age, BMI, gender, diabetes, smoking status, dyslipidemia, hypertension and family history of premature CAD. CONCLUSION: ADMA is correlated to EST parameters with proven prognostic value. This implies that ADMA itself might be a useful prognosticator in patients with suspected CAD.

Myeloperoxidase: expressing inflammation and oxidative stress in cardiovascular disease.

Myeloperoxidase (MPO), a heme protein released by leukocytes, is one of the most widely studied during the last decades molecule that plays a crucial role in inflammation and oxidative stress in the cellular level. It has become increasingly recognized that MPO performs a very important role as part of the innate immune system through the formation of microbicidal reactive oxidants, whilst it affects the arterial endothelium with a number of mechanisms that include modification of net cellular cholesterol flux and impairment of Nitric Oxide (NO)-induced vascular relaxation. In that way, MPO is implicated into both the formation and propagation of atheromatosis and there is substantial evidence that it also promotes ischemia through destabilization of the vulnerable plaque. Numerous studies have added information on the notion that MPO and its oxidant products are part of the inflammatory cascade initiated by endothelial injury and they are significantly overproduced at the site of arterial inflammation. Subsequent studies achieved quantification of this observation showing significant elevations of the systemic levels of MPO in a wide spectrum of cardiovascular disease scenarios with acute coronary syndromes and heart failure being the most studied. This review highlights key-aspects of MPO's pathophysiological properties and summarizes the role of MPO as a diagnostic and prognostic tool for a number of cardiovascular pathologies.

Adiponectin: merely a bystander or the missing link to cardiovascular disease?

Adiponectin, a newly discovered adipose-tissue secreting hormone, is a major regulator of a wide spectrum of physiological processes, such as energy metabolism, inflammation and vascular homeostasis. Emerging data suggest that adiponectin is the link between obesity and obesity-related disorders with cardiovascular disease. Adiponectin is a dominant insulin-sensitive adipokine and, in contrast to other adipose-tissue derived cytokines, it has major anti-diabetic, antiatherogenic and anti-inflammatory properties. Adiponectin has been extensively studied in the context of several aspects and risk factors of cardiovascular disease such as obesity, diabetes type I and II, coronary heart disease, hypertension, heart failure, cerebrovascular disease and smoking. The aim of this article is to summarize the acquired so far knowledge on adiponectin in relation to cardiovascular disease, to review its main biological and biochemical characteristics, to highlight the main mechanisms of adiponectin-driven beneficial effects on vasculature and briefly to refer to the basic correlations of adiponectin with the important aforementioned aspects of cardiovascular disease.

Asymmetric Dimethylarginine (ADMA): a promising biomarker for cardiovascular disease?

Asymmetric Dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) production. ADMA is generated from methylation of arginine residues by protein arginine methyltransferases (PRMTs) and subsequent proteolysis, while its elimination is achieved mainly by degradation with dimethylarginine dimethylaminohydrolase (DDAH). Oxidative stress, endothelial nitric oxide synthase (eNOS) inhibition, eNOS uncoupling, inflammation and shear stress play a pivotal role in ADMA pathophysiology by managing PRMT/DDAH expression and NO synthesis and leading to a common result - endothelial dysfunction. Endothelial dysfunction seems to be the common finding in studies investigating the role of ADMA in cardiovascular disease (CVD). High-performance liquid chromatography (HPLC), mass spectrometry (MS) and enzyme-linked immunosorbent assay (ELISA) are the existing methods for ADMA quantification. However, none of them fulfils all the criteria to be characterized as "gold standard". ADMA is significantly associated with risk factors for CVD and almost with every disease of the cardiovascular system; showing an independent, strong prognostic value for mortality and future cardiovascular events. This article aims to review the current knowledge about ADMA biology and metabolism, pathophysiological mechanisms implicating ADMA in CVD, methods for the determination of ADMA and its association with CVD risk factors and established CVDs.

High sensitivity troponin in cardiovascular disease. Is there more than a marker of myocardial death?

Cardiovascular disease is the leading cause of death worldwide and coronary artery disease is its most prevalent manifestation, associated with high mortality and morbidity. In clinical practice cardiac troponins (cTn) are the cornerstone of the diagnosis, risk stratification and thus selection of the optimal treatment strategy in patients with acute coronary syndrome. According to the third update of the universal definition of myocardial infarction (MI) cTn is the preferred cardiac biomarker of myocardial necrosis in the setting of acute myocardial ischemia. Over the last years newer high sensitivity cardiac troponin (hs-cTn) assays have been developed that are more sensitive than conventional assays, have low limit of detection, low imprecision and low reference limits, but due to variability, the deployment of a standardization and harmonization method is required before their wide use in clinical practice. Recent studies have shown that their utilization seems to improve the diagnostic accuracy detecting MI in patients presenting with chest pain. However, the improved sensitivity comes along with a decreased specificity, though serial cTn measurements and the detection of early changes could improve the specificity and the overall diagnostic performance. Moreover, apart from their use in the diagnosis and risk stratification of MI and acute coronary syndromes, hs-cTn assays seem to have a key role in risk stratification and short and long-term prognosis in a variety of cardiovascular modalities such as stable coronary disease, heart failure and acute pulmonary embolism. In addition, studies have suggested that cTns may be used as a biomarker in the primary prevention of cardiovascular disease leading to the identification of high-risk populations or individuals with silent heart disease.

Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations.

Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.

Chromogenic in situ hybridization analysis of EGFR gene copies in colon adenocarcinoma based on intra-operative imprints and tissue microarrays.

BACKGROUND: Although Epidermal Growth Factor Receptor (EGFR) over expression is a frequent event in colon adenocarcinoma (CA), identification of EGFR gene deregulation mechanisms--combined to k-ras mutations--remains the basic criterion for rational application of anti-EGFR targeted therapeutic strategies. AIM: To detect EGFR gene numerical alterations in CA based on a combination of intra-operative imprints and the corresponding tissue microarrays. METHODS: 60 paraffin embedded primary CAs were cored at 1.5 mm diameter and transferred to the final microarray block. Chromogenic in situ hybridization (CISH) was performed using EGFR gene and chromosome 7 centromeric probes in the tissue microarray and also in the corresponding intra-operative imprints. RESULTS: CISH analysis detected 4/60 (6.6%) EGFR gene amplified cases, whereas chromosome 7 aneuploidy was identified in 11/60 (18.3%) cases. Significant association was established by correlating stage to chromosome 7 (p=0.024). A high value of concordance (kappa=1) was observed comparing overall gene status based on the tissue cores and the corresponding imprints, whereas EGFR/CEN 7 copies were more numerous in imprints than in tissue microarrays (p=0.03). CONCLUSIONS: Intra-operative imprint cytology provides accurate and fast results in detecting EGFR gene/chromosome 7 centromeric signals by CISH due to the nuclear integrity and monolayer formation of the examined cells. Based on this molecular analysis, gastroenterologists and oncologists can handle those patients in a rational way regarding targeted therapies. Furthermore, chromosome 7 aneuploidy is associated with a more advanced stage in CA.

Chromogenic in situ hybridization analysis of Epidermal Growth Factor Receptor gene/chromosome 7 numerical aberrations in hepatocellular carcinoma based on tissue microarrays.

Although Epidermal Growth Factor Receptor (EGFR) overexpression is observed frequently in hepatocellular carcinomas (HCC), specific gene deregulation mechanisms remain unknown. Our aim was to investigate the prognostic significance of the combined protein and gene/chromosome 7 numerical alterations. Using tissue microarray technology, thirty-five (n = 35) paraffin embedded histologically confirmed HCCs were cored and re-embedded in a paraffin block. Immunohistochemistry was performed for the determination of EGFR protein levels and evaluated by the performance of digital image analysis. Chromogenic in situ hybridization was also performed based on the use of EGFR gene and chromosome 7 centromeric probes, respectively. EGFR overexpression was observed in 26/35 (74.2%) cases and was correlated to the grade of the tumors and also to the history of the patients (p = 0.013, p = 0.036, respectively). Numerical alterations regarding gene and chromosome 7 were identified in 4/35 (11.4%) and 12/35 (43.2%) cases associated to the grade of the tumors (p = 0.019, p = 0.001, respectively) and to the survival rate of the patients (p = 0.037, p = 0.001, respectively). EGFR overall expression was also correlated to the gene copies (p = 0.020). EGFR gene numerical alterations -although rare- and also chromosome 7 aneuploidy maybe affect prognosis in HCC patients. To our knowledge this is the first chromogenic in situ hybridization analysis based on tissue microarrays in hepatocellular carcinoma.