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AIMS We aimed to demonstrate whether coronary microvascular function is improved after ticagrelor administration compared to clopidogrel administration in STEMI subjects undergoing thrombolysis. METHODS AND RESULTS MIRTOS is a multicentre study of ticagrelor versus clopidogrel in STEMI subjects treated with fibrinolysis. We enrolled 335 patients

Introduction. In 1706, Raymond de Vieussens described a proximal inter-coronary pathway connecting the conus branch of the right coronary artery (RCA) with an infundibular branch of the left anterior descending artery (LAD) or directly with the proximal LAD. Later, in the 19th century, this anatomical structure would be named in his honour “Vieussens’ arterial ring” (VAR). VAR serves as a collateral pathway in case of coronary artery disease. Case presentation. We present the case of a 58-year-old male with a concurrent ostial chronic total occlusion of the LAD and an acute thrombotic occlusion of the proximal RCA, that survived via a Vieussens’ arterial ring. Conclusions. The existence of collateral circulation holds a crucial role in the manifested symptoms and the prognosis of patients with ischaemic heart disease. The connection between the conus branch and the LAD (VAR) may provide adequate circulation to either the left or right coronary arterial system, preserving the left ventricular ejection fraction and allowing patients to survive even the most severe myocardial infarctions.

Introduction: Contrast-induced acute kidney injury (CI-AKI) is a frequent complication of percutaneous coronary interventions (PCI). Various groups have developed and validated risk scores for CI-AKI. Although the majority of these risk scores achieve an adequate accuracy, their usability in clinical practice is limited and greatly debated. Objective: With the present study, we aimed to prospectively assess the diagnostic performance of recently published CI-AKI risk scores (up to 2018) in a cohort of patients undergoing PCI. Methods: We enrolled 1,247 consecutive patients (80% men, mean age 62 ± 10 years) treated with elective or urgent PCI. For each patient, we calculated the individual CI-AKI risk score based on 17 different risk models. CI-AKI was defined as an increase of ≥25% (liberal) or ≥0.5 mg/dL (strict) in pre-PCI serum creatinine 48 h after PCI. Results: CI-AKI definition and, therefore, CI-AKI incidence have a significant impact on risk model performance (median negative predictive value increased from 85 to 99%; median c-statistic increased from 0.516 to 0.603 using more strict definition criteria). All of the 17 published models were characterized by a weak-to-moderate discriminating ability mainly based on the identification of “true-negative” cases (median positive predictive value 19% with liberal criterion and 3% with strict criterion). In none of the models, c-statistic was >0.800 with either CI-AKI definition. Novel, different combinations of the >35 independent variables used in the published models either by down- or by up-scaling did not result in significant improvement in predictive performance. Conclusions: The predictive ability of all models was similar and only modest, derived mainly by identifying true-negative cases. A new approach is probably needed by adding novel markers or periprocedural characteristics.

Despite the progress of cardiovascular medicine, ischemia-reperfusion injury can contribute to increased mortality and prolonged hospitalization after myocardial infarction. Ischemia-reperfusion injury pathophysiology encompasses many cells including cardiomyocytes, fibroblasts, mesenchymal stromal cells, vascular endothelial and smooth muscle cells, platelets, polymorphonuclear cells, macrophages, and T lymphocytes. However, specific mechanisms for all contributing cells and molecular pathways are still under investigation. What is definitely known is that endothelial dysfunction, immunity activation and inflammatory response are crucial events during ischemia-reperfusion injury while toll-like receptors, inflammasomes, reactive oxygen species, intracellular calcium overload and mitochondrial permeability transition pore opening consist of key molecular mediators. Indicatively, cardiac fibroblasts through inflammasome activation mediate the initial inflammatory response. Cardiac mesenchymal stromal cells can respond to myocardial injury by pro-inflammatory activation. Endothelial cell activation contributes to the impaired vasomotion, inflammation and thrombotic events and together with platelet activation leads to microcirculation dysfunction and polymorphonuclear cells recruitment promoting inflammation. Polymorphonuclear cells and monocytes/macrophages subsets are critically involved in the inflammation process by producing toxic proteolytic enzymes and reactive oxygen species. T cells subsets are also involved in several stages of ischemia-reperfusion injury. In this review, we summarize the specific contribution of each of the above cells and the related molecular pathways in the pathophysiology of ischemia-reperfusion injury.

Background: Type 2 diabetes mellitus (DM) is associated with a considerable risk of cardiovascular and renal diseases, including heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated unprecedented cardiorenal protective effects in large-scale clinical trials of patients with or without diabetes and either established cardiovascular disease (CV) or multiple CV risk factors. Objective: Herein we aim to focus on the role of SGLT2 inhibitors regarding the improvement in heart failure outcomes and the proposed mechanisms of action by which these drugs confer their beneficial effect. Methods: PubMed, Embase, and Google Scholar databases were searched to identify eligible articles that are comprehensively summarized and discussed in this study. Results: The most commonly discussed mechanisms of action are diuresis and natriuresis, reduction in preload, afterload, and ventricular mass, as well as stimulation of erythropoietin production and improved myocardial energetics. SGLT2 inhibitors improve outcomes in patients with established heart failure (HF) and reduce the risk of death and HF admissions in patients with established chronic HF with reduced ejection fraction (HFrEF), either with or without diabetes. Conclusion: Potential key mechanisms that may explain the notable cardioprotective benefits of SGLT2 inhibitors have been outlined. These agents have recently received class Ia recommendation in specific groups of people with DM to lower the risk of hospitalization for HF and risk of death, while these benefits may also extend to people without diabetes. It remains to be seen whether they will also emerge as treatment approaches in the acute phase of CV episodes.

Neutrophils through the release of neutrophil extracellular traps (NETs) containing active tissue factor (TF) are key components of thrombo-inflammation. Platelets-neutrophils interplay in ST elevation myocardial infarction (STEMI) promotes NET formation via inorganic polyphosphates (polyP) released by thrombin-activated platelets. NETs, however, are also induced by biomaterials in a platelet-independent manner. Considering the possible pleiotropic effects of Ticagrelor beyond platelet inhibition and the clinical need for novel antithrombotic strategies targeting inflammation, we investigated the effects of Ticagrelor on polyP and stent-induced NETs in STEMI. Neutrophils from healthy individuals and patients receiving Ticagrelor were stimulated with polyP or drug-eluting stents (DES) to produce NETs. To induce TF expression, neutrophils were further incubated with plasma obtained from the infarct-related artery (IRA) of STEMI patients. The effects of Ticagrelor on NETs and TF loading were assessed using fluorescence microscopy, flow cytometry, myeloperoxidase(MPO)/DNA complex ELISA, and a Western blot. Ticagrelor interrupts platelet&ndash, neutrophil interaction by attenuating NETs induced by polyP. However, Ticagrelor does not affect polyP secretion from thrombin-activated platelets. Similarly, the intracellular production of TF in neutrophils triggered by IRA plasma is not hindered by Ticagrelor. Furthermore, DES induce NETs and synchronous stimulation with IRA plasma leads to the formation of thrombogenic TF-bearing NETs. Ticagrelor inhibits stent-induced NET release. These findings suggest a novel immune-modulatory effect of Ticagrelor when it attenuates the formation of thrombogenic NETs.

Background and aims Numerous low-density lipoprotein (LDL) calculating equations for more accurate estimation have emerged. With the present study, we assessed the clinical impact of implementing novel equations in terms of risk reclassification and LDL treatment goals in myocardial infarction (MI) patients. Methods This was a post-hoc analysis of a prospective acute MI cohort study. We enrolled 805 consecutive patients presenting with acute MI. Patients with high triglyceride levels (>400 mg/dL) were excluded. In the remaining 773 acute MI patients, LDL cholesterol levels were calculated using 12 different equations including the Friedewald equation. Each patient was categorized into a 5-scale risk strata scheme according to baseline LDL cholesterol levels. Moreover, ΔLDL cholesterol (change in LDL cholesterol levels to achieve the Results Mean levels and distribution of LDL cholesterol were significantly different compared to those derived from the Friedewald equation. Net reclassification improvement (NRI) analysis, as well as heat maps, showed that this re-categorization had no significant impact on prognostic terms (NRI ranged from −6.1% to 5.9% with p values > 0.05 for each comparison). Statistically significant differences were observed in ΔLDL cholesterol levels between each one of the novel equations and the Friedewald equation. Conclusions Novel LDL cholesterol calculating equations are not associated with a clinically significant risk re-classification in MI patients. In addition, use of these novel equations may have an impact on assessing potency of hypolipidemic therapy use in secondary prevention as far as succeeding lipid treatment goals in MI patients.

Neutrophils and neutrophil-released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN-λ1/IL-29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST-segment elevation myocardial infarction (STEMI), we show that IFN-λ1/IL-29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet-neutrophil interaction plays a major role in NET-induced thromboinflammation, we further studied how IFN-λ1/IL-29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet-derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN-λ1/IL-29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl3 -induced arterial thrombosis that IFN-λ2/IL-28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN-λ1/IL-29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background: GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic t...

Context: The role of cardiac pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices has increasingly prominent in cardiac disease management in the last 50 years. Evidence Acquisition: We reviewed the literature for cardiovascular implantable electronic device (CIED)-related infections, their diagnosis, treatment, complications, and long-term treatment. Results: The most common signs of CIED infection include inflammatory changes in the generator pocket area. Evidence of dehiscence of the infected skin due to percutaneous exposure to the generator or even its leads is commonly reported. Timely diagnosis and subsequent treatment of patients with possible CIED infections are vital, which could otherwise affect prognosis. In the case of CIED-related infections close to the surface of the pocket site without the direct involvement of the device, removal is not deemed necessary. The oral administration of antibiotics with antistaphylococcal activity is suggested for 7 to 10 days. If there is the infection of bloodstream or endocarditis, the extraction of the entire system is considered mandatory along with antimicrobial therapy. Patients who suffer from CIED infections and cannot be subjected to device removal using percutaneous or surgical methods must be given long-term antimicrobial suppressive therapy. Such cases are those who are expected to have a short-term life expectancy or do not accept device removal. Conclusions: CIED infection is life-threatening. Early diagnosis is crucial to the survival of the patients. The use of antibiotics and a conservative approach without the CIED system removal may not be enough to cure this condition.

Purpose Menopause-related changes may affect regional but also morphological characteristics of adipose tissue. We sought to assess the clinical value of echogenicity of subcutaneous adipose tissue (SAT) and preperitoneal adipose tissue (pPAT) in postmenopausal women without cardiovascular disease. Methods In 244 consecutively recruited postmenopausal women, subclinical atherosclerosis was assessed in the femoral and carotid arteries by intima-media thickness (IMT) and atheromatous plaques using high-resolution ultrasonography. In 41 women with a second visit (median follow-up 41.5 months), carotid atherosclerosis was re-evaluated. Images of SAT and pPAT were ultrasonographically acquired, and their echogenicity was evaluated by grayscale mean (GSMn) using a dedicated software. A control group of 20 healthy premenopausal women was used for comparisons in fat echogenicity. Results SAT GSMn but not pPAT was higher in postmenopausal as compared with healthy premenopausal women and was independently associated with metabolic markers of adiposity including body mass index (BMI) and waist circumference (WC). SAT GSMn was associated with carotid IMT and the presence and number of atheromatous plaques [adjusted OR 2.44 and 2.32 per 1-SD increase in GSMn (95% CIs 1.55 to 3.93 and 1.55 to 3.45), respectively]. SAT GSMn conferred incremental value over traditional risk factors, insulin resistance, BMI, and WC for the detection of subclinical atherosclerosis. Increased baseline SAT GSMn was associated with increased rate of progression in carotid IMT. Conclusions SAT echogenicity may serve as a qualitative marker of adiposity, conferring incremental clinical value over BMI and WC in postmenopausal women. Further investigation is warranted to assess the utility of ultrasonography-derived fat echogenicity as a screening method for morbid obesity.

Infiltration of neutrophils into colonic mucosa has been associated with the severity of ulcerative colitis (UC). We investigated the effect of disease microenvironment on the release of neutrophil extracellular traps (NETs) as well as the involved mechanisms in NETosis and whether certain NET proteins are correlated with disease phenotype. Peripheral blood neutrophils, sera, and colonic tissue were collected from treatment-naive and mesalazine-treated patients with active UC, treatment-naive patients with active Crohn’s disease, patients suffering from infectious colitis, or healthy individuals (controls). Analysis of colonic biopsy specimens and peripheral blood neutrophils for the presence of NET-related markers using immunofluorescence confocal microscopy, ELISA, immunoblotting, flow cytometry, and quantitative PCR were performed. In vitro cell and tissue culture systems were further deployed. The local inflammatory response in colon in UC, but not Crohn’s disease, is characterized by the presence of NETs carrying bioactive IL-1β and thrombogenic tissue factor. The inflammatory environment of UC is able to induce neutrophil activation, IL-1β expression, and NET release, as shown both ex vivo and in vitro. REDD1 expression, as a mediator linking inflammation, autophagy, and NET release, was also specifically associated with the inflammatory response of UC. We show that neutrophil expression of REDD1 in colon tissue and the presence of IL-1β in neutrophils/NETs provide candidate biomarkers for the differential diagnosis of inflammatory colitis and possible targets for the treatment of UC, suggesting that UC shares common features with autoinflammatory disorders.

Introduction Theatre models in medical education have been used worldwide in order to train medical students and graduates in managing various situations. However, the literature reports little regarding its appeal to trainees. We conducted a medical seminar, entitled Emergency Cases School, which employed such techniques. Actors simulated the actions of doctors and patients involved in various emergency cases, in front of a large audience, in a specially modified theatre hall which resembled the emergency room environment. Methods A total of 303 undergraduate medical students participated in the seminar. The audience evaluated the course with the DREEM questionnaire, along with two extra questions: Q1. ‘Do you think that the course will prove itself beneficial to your clinical skills?’ and Q2. ‘Would you suggest the course to another student?’, in a 0–4 scoring scale. Of the attendees, 281 (92.7%) answered the questionnaire. Results The overall DREEM score was 140.32 (±23.39) out of 150, which is interpreted as ‘More positive than negative’. The results of Q1 and Q2 were 3.07 (±0.78) and 3.65 (±0.61), respectively. Discussion The Emergency Cases School received positive feedback as a theatre educational tool, targeted to a large audience. With the advantage of the realistic setting of an emergency room, along with its low-budget needs, this course model could function as a creative alternative of the more traditional lecturing teaching techniques.

BACKGROUND Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). OBJECTIVE We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. METHODS We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. RESULTS The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p

Background Several risk factors for contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) have been identified. The cumulative effect of these risk factors on renal function has been assessed with the development of risk score models in a number of studies. However, concerns were raised that estimates of the risk attributable to individual factors may be unreliable. We sought to develop a simple risk score for developing CIN after PCI irrespective of use of prophylactic measures and also capturing the effect of pre-intervention medication and presence of various co-morbidities. Methods Consecutive patients treated with elective or urgent PCI at our cardiac catheterization laboratory were enrolled (derivation cohort n=488, validation cohort n=200). CIN was defined as increase ≥25% and/or ≥0.5mg/dl in serum creatinine at 48h after PCI vs baseline. Multivariable logistic regression analysis was then performed to identify independent predictors of CIN (pre-existing renal disease, metformin use, history of previous PCI, peripheral arterial disease and ≥300ml of contrast volume). Results The incidence of CIN in the development cohort was 10.2% with a significant trend across increasing score values (p Conclusions The proposed risk score is easily applicable and allows for practically simple risk assessment compared to other published scores while at the same time overcomes drawbacks of previous model designs.

Neutrophils and neutrophil-released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN-λ1/IL-29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST-segment elevation myocardial infarction (STEMI), we show that IFN-λ1/IL-29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet-neutrophil interaction plays a major role in NET-induced thromboinflammation, we further studied how IFN-λ1/IL-29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet-derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN-λ1/IL-29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl

Objective We examined trans-radial approach (TRA) use in coronary angiographies (CAs) as well as in percutaneous coronary interventions (PCIs) in specific regions of Greece, its distribution in public and private catheterization laboratories (CLs) and its preference by operators. Reliable data regarding the use of TRA are not available in Greece. Methods The study was performed in northern and central Greece, which constitutes 35.32% of the national population. This study focused on the years 2004, 2009 and 2013. Results There are 12 CLs. CAs performed using TRA were 0.43% in 2004, 12.28% in 2009 and 39.81% in 2013, whereas PCIs performed using TRA were 0.38%, 9.20% and 39.48%, respectively. Operators familiar with TRA, but who performed TRA electively, were 13.33% in 2004, 60.38% in 2009 and 42.37% in 2013. However, operators performing TRA routinely were 2.2%, 5.66%, and 49.15%, respectively. In 2013, there was a 3.76% decrease in CAs and 4.51% decrease in PCIs compared to 2009; in private CLs, there was a 29.63% decrease in CAs and 34.72% decrease in PCIs performed, which was contradictory to the 27.27% increase observed in CAs and 29.83% increase in PCIs in public CLs. Conclusions This is the first study to reveal the volumes and trends in interventions performed via TRA across central and northern Greece. TRA has gained a reputation among operators in both public and private CLs. Due to the financial crisis in Greece, catheterizations have been diminished, whereas private CLs have lost a great amount of their turnover.

Background Familial Mediterranean fever (FMF) is an IL-1β–dependent autoinflammatory disease caused by mutations of Mediterranean fever (MEFV) encoding pyrin and characterized by inflammatory attacks induced by physical or psychological stress. Objective We investigated the underlying mechanism that links stress-induced inflammatory attacks with neutrophil activation and release of IL-1β–bearing neutrophil extracellular traps (NETs) in patients with FMF. Methods RNA sequencing was performed in peripheral neutrophils from 3 patients with FMF isolated both during attacks and remission, 8 patients in remission, and 8 healthy subjects. NET formation and proteins were analyzed by using confocal immunofluorescence microscopy, immunoblotting, myeloperoxidase-DNA complex ELISA, and flow cytometry. Samples from patients with Still's disease and bacterial infections were used also. Results The stress-related protein regulated in development and DNA damage responses 1 (REDD1) is significantly overexpressed during FMF attacks. Neutrophils from patients with FMF during remission are resistant to autophagy-mediated NET release, which can be overcome through REDD1 induction. Stress-related mediators (eg, epinephrine) decrease this threshold, leading to autophagy-driven NET release, whereas the synchronous inflammatory environment of FMF attack leads to intracellular production of IL-1β and its release through NETs. REDD1 in autolysosomes colocalizes with pyrin and nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3. Mutated pyrin prohibits this colocalization, leading to higher IL-1β levels on NETs. Conclusions This study provides a link between stress and initiation of inflammatory attacks in patients with FMF. REDD1 emerges as a regulator of neutrophil function upstream to pyrin, is involved in NET release and regulation of IL-1β, and might constitute an important piece in the IL-1β–mediated inflammation puzzle.

Objective— Hyperlipidemia is associated with platelet hyperactivity. In the present study, we evaluated the binding of oxidized low-density lipoprotein (oxLDL) on the surface of circulating platelets in patients with stable coronary artery disease and acute coronary syndromes and its possible association with platelet activation. Furthermore, the role of oxLDL binding on platelet adhesion to collagen and endothelial cells in vitro as well as after carotid ligation in mice was investigated. Methods and Results— Using flow cytometry, patients with acute coronary syndromes (n=174) showed significantly enhanced oxLDL binding compared with patients with stable coronary artery disease (n=182; P =0.007). Platelet-bound oxLDL positively correlated with the degree of platelet activation (expression of P-selectin and activated fibrinogen receptor; P −/− mice fed a high cholesterol diet. Conclusion— Increased platelet-bound oxLDL in patients with acute coronary syndromes may play an important role in atherothrombosis, thus providing a potential future therapeutic target.

To assess the difference in the prevalence of invariant Natural Killer T (iNKT) lymphocytes between hyperlipidemic and control individuals and to evaluate changes in iNKT cell levels after 6 months lipid lowering therapy. A total of 77 hyperlipidemic individuals (54 ± 5 years) were assigned to simvastatin 40 mg or ezetimibe 10 mg daily for 6 months. Fifty individuals with normal cholesterol levels were used as control. iNKT cells were measured by flow cytometry in peripheral blood. Patients with hypercholesterolemia had significantly lower iNKT cell levels (percentage on the lymphocyte population) compared to control group (0.16 ± 0.04% vs 0.39 ± 0.08%, p = 0.03). iNKT cells significantly increased after 6 months treatment with simvastatin (from 0.15 ± 0.04% to 0.28 ± 0.11%, p = 0.03) but not with ezetimibe (from 0.16 ± 0.05% to 0.17 ± 0.06%, p = 0.55). Simvastatin treatment did not alter the activation status of iNKT cells as measured by HLA-DR expression. Changes of iNKT cells were independent from changes in total (r 2 = 0.009, p = 0.76) or LDL cholesterol (r 2 = 0.008, p = 0.78) reached by simvastatin. Hyperlipidemic patients have reduced numbers of iNKT in peripheral circulation compared to individuals with normal cholesterol levels. Their number is increasing after long term administration of simvastatin 40 mg but not after ezetimibe.

A new mechanism for clinical instability in coronary artery disease (CAD) has been proposed where erythrocytes could play an active role in atherosclerotic plaque growth and rupture. Clinical studies showed increased total cholesterol levels in the membrane of circulating erythrocytes (CEM) in acute coronary syndrome (ACS) patients compared to patients with chronic stable angina (CSA). We investigated the independent and incremental discriminating value of CEM along with N-terminal propeptide of BNP (NT-proBNP), high sensitivity C-reactive protein (hs CRP), myeloperoxidase (MPO) and apolipoprotein B (apoB) with regard to CAD clinical presentation.519 consecutive angina patients were assessed; 252 had CSA (195 men, 62 ± 9 years) and 267 had ACS (213 men, 62 ± 10 years).CEM levels and serum concentrations of NT-proBNP, hs CRP, MPO and apoB were measured upon study admission.Simple logistic regression models showed that all biomarkers could distinguish ACS, nevertheless CEM with greater potency (OR 9.26 95%CI 6.31-13.59, p0.001). Multiple logistic regression models after adjustment for all the variables that were different between the 2 groups as well as for other biomarkers showed that CEM continued to be a significant and an independent predictor of ACS (OR 22.27 95%CI 10.63-46.67, p0.001). An increment of the C-statistic was also shown when CEM levels were incorporated in the predictive model (including traditional vascular risk factors and new well established biomarkers i.e. hs CRP, MPO, apoB and NT-proBNP).The present study showed that CEM levels are associated with clinical instability in CAD patients in an independent and incremental manner.

This review attempts to present a focused summary of selected areas of the rapidly growing knowledge regarding the red blood cells role in atherosclerotic plaque progression and instability. A summary of the characteristics of the erythrocyte membranes is provided, followed by a brief review of the in vitro and in vivo work that has helped clarify their role in atherosclerosis. Mechanisms by which erythrocytes enter the atherosclerotic plaque and contribute to its progression and instability are presented. Finally, some elements that may be clinically important regarding erythrocytes in coronary artery disease are discussed.

Background Amyloid-β (1-40) (Aβ40) is implicated in mechanisms related to plaque destabilization and correlates with adverse outcomes in stable coronary artery disease. Objective To determine the prognostic and reclassification value of baseline circulating levels of Aβ40 after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Design Retrospective cohort study using data from 2 independent prospective cohorts, the Heidelberg study (n = 1145) and the validation multicenter international APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation) study (n = 734). Setting Academic hospitals in 7 European countries. Participants Patients with adjudicated NSTE-ACS followed for a median of 21.9 and 24.9 months in the Heidelberg and APACE studies, respectively. Measurements All-cause mortality was the primary end point. Results Amyloid-β (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio [HR] for 80th vs. 20th percentiles, 1.66 [95% CI, 1.06 to 2.61; P = 0.026]; APACE cohort HR, 1.50 [CI, 1.15 to 1.96; P = 0.003]). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 [CI, 1.04 to 1.18; P = 0.001]; APACE cohort HR, 1.39 [CI, 1.02 to 1.88; P = 0.036]). Amyloid-β (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P Limitation At low concentrations of Aβ40, dose-response associations with mortality differed between cohorts, possibly because of varying blood preparations used to measure Aβ40. Conclusion Circulating Aβ40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aβ40 as a novel biomarker in NSTE-ACS should be further explored and validated. Primary funding source German Cardiac Society.

BACKGROUND Studies have suggested that collagen accumulation in the aortic wall may contribute to the stiff aorta in arterial hypertension. However, data in human hypertension are limited. In this investigation, relations between markers of collagen metabolism and aortic function in patients with arterial hypertension were evaluated. METHODS We studied 72 hypertensive patients (age 53 +/- 5 years) and 27 age- and gender-matched normotensive individuals. Elastic properties of the aorta were assessed by aortic pulse wave velocity (carotid-to-femoral pulse wave velocity (PWVc-f)). Free amino-terminal propeptides of precollagen type I (PINP, reflecting collagen I synthesis), serum telopeptides of collagen type I (CITP, an index of collagen I degradation), free amino-terminal propeptides on precollagen type III (PIIINP, reflecting collagen III metabolism), prometalloproteinase-1 (proMMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined by commercially available immunoassays. RESULTS Patients with arterial hypertension had greater PWVc-f (P = 0.01); and higher levels of PINP/CITP compared to control (P = 0.04). PWVc-f was significantly associated with PINP/CITP ratio (analysis of variance (ANOVA), P = 0.03). Hypertensive patients had significantly higher levels of proMMP-1/TIMP-1 (P = 0.04); PWVc-f was significantly associated with proMMP-1 (ANOVA, P = 0.03) and proMMP-1/TIMP-1 (ANOVA, P = 0.04). Associations between PWVc-f and proMMP-1 and between PWVc-f and PINP/CITP ratio remained significant after adjustment for PWVc-f confounders and antihypertensive treatment. CONCLUSIONS Alterations in collagen turnover that favor collagen type I synthesis; as well as proMMP-1 expression are related to increased aortic stiffness in treated hypertensive individuals without left ventricular (LV) hypertrophy.

Not all patients respond to angiotensin converting enzyme (ACE)-inhibitor equally. Genetic or other phenotypic variations might be useful in predicting the therapeutic efficacy of these drugs. With the present study we assessed the prognostic impact of ACE-inhibitor in chronic heart failure patients with different degrees of collagen metabolism as assessed by serum levels of a collagen type I degradation marker (CITP). One hundred ninety-six (126 male, 69 ± 10 years) chronic heart failure patients were studied prospectively for 12 months regarding survival. Serum concentrations of CITP were measured at study entry. Chronic heart failure patients were divided into groups according to whether (n = 114) or not (n = 82) they received ACE-inhibitor as well as to their CITP levels. Survival (52.2%) was significantly lower in ACE-inhibitor naive patients with high CITP levels compared to ACE-inhibitor naive patients with low CITP levels (83.3%, P = 0.003), to ACE-inhibitor users with low CITP levels (80%, P = 0.006) and to ACE-inhibitor users with high CITP levels (70.4%, P = 0.015). ACE-inhibitor related improvement in mortality was most predominant in chronic heart failure patients with high CITP levels. CITP levels possibly reflecting an activated status of the renin–angiotensin–aldosterone system, may be of clinical relevance since they identify a subgroup of patients that is more susceptible to treatment with an ACE-inhibitor.

High cholesterol content of erythrocyte membranes (CEM) levels is present in patients with acute coronary syndromes (ACS). Intraplaque hemorrhage and erythrocyte lysis contribute to the deposition of cholesterol on the atherosclerotic plaque and to plaque rupture. With the present study we assessed the effect of statin therapy on CEM levels, a novel marker of coronary artery disease (CAD) instability during a 1-year follow-up in CAD patients.212 consecutive eligible (158 men, 62 +/- 10 years) patients undergoing diagnostic coronary angiography for the assessment of angina pectoris were assessed. The study population comprised of 84 chronic stable angina (CSA) patients and 128 ACS patients. All study participants were commenced on statin treatment in equipotent doses and were followed for up to 1 year (at - 1, - 3, - 6 and - 12 months).Repeated measurements analysis of variance after appropriate adjustment showed a significant decrease (p0.001) in CEM content during follow up. CEM levels were decreasing at each time point (1 month : 100 microg/mg 95%CI 94.3-105.6, 3 months : 78.1 microg/mg 95%CI 73.2-83, 6 months : 67.2 microg/mg 95%CI 63.1-71.2, 1 year : 45.3 microg/mg 95%CI 42.2-48.3) compared to admission (112.1 microg/mg 95% CI 105.9-118.3) and to all previous measurements.The present study showed, that use of statins is associated with a reduction in CEM, an emerging marker of clinical instability and plaque vulnerability in CAD patients. The pleiotropic effects of statins at the cell membrane level represent a promising novel direction for research in CAD.

Background Cardiovascular complications are common in beta-thalassemia major (β-TM), mainly attributed to increased cardiac iron depositions. Early cardiovascular involvement in patients without cardiac symptoms and without cardiac iron overload has not been adequately investigated. Methods Twenty six patients (11 males) with β-TM, on chelation therapy, age 23±4 years without cardiac iron overload (measured by magnetic resonance imaging), and 30 age and gender matched healthy controls were included in the study. Carotid–femoral and carotid–radial pulse wave velocity (PWVc-f and PWVc-r) and augmentation index (AI) were measured by SphygmoCor device; carotid intima-media thickness; left ventricular (LV) dimensions and function; left atrial (LA) volume and function were assessed by echocardiography. Results Patients with β-TM had higher PWVc-f (8.4±1.4 vs 7.2±1.1 m/s, p =0.002) and augmentation index (21.7±10.9 vs 14.7±9.7%, p =0.04) indicating decreased aortic elastic properties; greater LV mass index (72.0±13.3 vs 63.8±11.5 g/m 2 , p =0.04) and greater LA volumes. Multivariate logistic regression analysis revealed that higher PWVc-f was independently associated with higher LV mass [OR 1.74 95%CI (1.09–2.88), p =0.026]; and greater LA dimensions [OR 1.68 95%CI (1.04–2.72), p =0.035]. Conclusions In the absence of cardiac iron overload, asymptomatic patients with β-TM demonstrated aortic stiffening associated with increased LV mass and LA enlargement. These alterations may represent signs of early cardiovascular involvement.

OBJECTIVES Myocardial collagen content as a fundamental component of extracellular matrix, is altered in pathological states including heart failure (HF). Serum peptides related to myocardial collagen synthesis and degregation can be measured and may be used as indices of myocardial collagen turnover. The present study was undertaken to assess the hypothesis that resolution of acute decompensation of chronic HF is associated with changes in serum peptides related to collagen synthesis and degregation. METHODS AND RESULTS Serum concentrations of the amino-terminal propetide of procollagen type I (PINP) and the carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were determined at the time of admission and discharge in 156 patients (100 men, 68 +/- 10 years) with acute decompensation of chronic HF. A significant decrease (-3.5 ng/ml 95% CI -5.3/-1.6 ng/ml, P < 0.001) of PINP was observed whereas CITP levels were significantly increased (+ 0.04 ng/ml 95% CI 0.01-0.08 ng/ml, P = 0.031) at discharge compared to admission. CONCLUSIONS Findings of the present study showed that serum indices of myocardial collagen turnover were changed significantly in a short period of time during the improvement of acute decompensation of chronic HF.

Aims Previous experimental studies have suggested that platelet stromal-cell-derived factor-1 (SDF-1) regulates mobilization and recruitment of haematopoietic progenitor cells supporting revascularization in mice. However, there are no clinical data available regarding platelet-bound SDF-1 in patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the platelet-surface expression of SDF-1 in patients with ACS. Methods and results Patients with ACS ( n = 418) showed a significantly enhanced SDF-1 expression on admission compared with those with stable angina pectoris (SAP, n = 486) [SAP (mean fluorescence intensity (MFI) ± SD): 13.48 ± 5.27; ACS: 18.45 ± 12.85; P < 0.001) independent of cardiovascular risk factors and medication. Enhanced platelet-bound SDF-1 expression was found in patients with reduced left ventricular ejection fraction (LVEF

Platelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) +/- standard deviation): 1(st) vs. 4(th): 20.44 +/- 6.1 vs. 18.62 +/- 3.7; p=0.012; 2(nd)vs.3(rd):21.2+/-8.5vs.18.76+/-3.7;P=0.03; 2(nd)vs.4(th): 21.2+/-8.5vs.18.62+/-3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1(st) vs. 4(th): 11.2 +/- 6.8 vs. 12.3 +/- 9; p=0.057; 2(nd) vs. 3(rd): 16.3 +/- 16 vs.12.7 +/- 5.3; p=0.138; 2(nd) vs. 4(th): 16.3 +/- 16 vs.11 +/- 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1(st)vs.4(th): 1.6 +/- 0.6 vs. 1.2 +/- 0.4; p=0.046; 1(st) vs. 3(rd): 1.6 +/- 0.6 vs. 1.1 +/- 0.5; p=0.038; 2(nd) vs. 3(rd): 1.9 +/- 0.8 vs. 1.1 +/- 0.5; p=0.04; 2(nd) vs. 4(th): 1.9 +/- 0.8 vs. 1.2 +/- 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.

Aims Studies have shown that erythrocyte membranes are present within necrotic cores in atherosclerotic plaques, and that circulating erythrocytes in patients with acute coronary syndrome (ACS) have increased total cholesterol content (CEM). Interleukin-8 (IL-8) binds to erythrocytes and during intraplaque haemorrhage it is released into the plaque and thus may contribute to inflammatory cascade and atherosclerotic plaque instability. The present study was undertaken to test the hypothesis that erythrocyte membrane IL-8 is elevated in patients with ACS compared with those with chronic stable angina (CSA). Methods and results Consecutive patients who presented with CSA ( n = 120, 92 men, 62 ± 9 years), ACS ( n = 118, 90 men, 62 ± 10 years) or with chest pain who had normal coronary arteries ( n = 36, 26 men, 60 ± 7 years), were studied prospectively. IL-8 concentrations in erythrocyte membranes (rIL-8) and in plasma (pIL-8), C-reactive protein (CRP) and CEM were measured. rIL-8 levels [mean ± 1 SD (standard deviation)] were higher in ACS (102.9 ± 70.1 pg/mL) compared with CSA (44.7 ± 22.8 pg/mL) ( P < 0.001). No difference in pIL-8 levels between the two coronary artery disease groups was observed ( P = 0.280). Serum CRP levels were correlated with rIL-8 levels ( r = 0.294, P < 0.001); no association was found between CRP and pIL-8 levels ( r = 0.025, P = 0.706). Further, rIL-8 had an independent association with ACS, when CRP and CEM were taken into consideration. Conclusion This study shows for the first time that rIL-8 content was significantly higher in ACS, compared with CSA. These findings endorse results from our previous studies suggesting that erythrocytes may play an important role in the development of unstable atherosclerotic plaque.

The present study was undertaken to assess the effect of statins on collagen type I degradation and C-reactive protein in patients with coronary artery disease and atrial fibrillation. One hundred six patients with coronary artery disease and atrial fibrillation were studied: 40 (36 men, mean age 72 +/- 8 years) treated with a statin and 66 (48 men, mean age 74 +/- 9 years) not treated with a statin. Serum concentrations of carboxy-terminal telopeptide of collagen type I, an index of collagen type I degradation, and high-sensitivity C-reactive protein were measured in all patients. Carboxy-terminal telopeptide of collagen type I levels were significantly higher (p0.001) in statin-treated patients (0.64 ng/ml, 95% confidence interval [CI] 0.57 to 0.71) compared with nonstatin-treated patients (0.38 ng/ml, 95% CI 0.31 to 0.44). These changes were independent of cholesterol levels (before or after therapy). Statin-treated patients had significantly lower (p0.001) C-reactive protein levels (0.25 mg/dl, 95% CI 0.23 to 0.28) compared to statin nonusers (1.1 mg/dl, 95% CI 0.92 to 1.25). In conclusion, this study suggests that therapy with statins in patients with coronary artery disease and atrial fibrillation is associated with an increase in collagen degradation and an attenuation of inflammation, independently of cholesterol lowering.

The present study was undertaken to assess the impact of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphisms on circulating markers of collagen type I synthesis and degradation, and also to study the effect of therapy with ACE inhibitors on these markers in hypertensive patients with atrial fibrillation (AF).ACE I/D genotypes were assessed in 158 hypertensive patients (71 +/- 9 years; 72 male) with AF and 174 patients with arterial hypertension in sinus rhythm (SR) (71 +/- 9 years; 88 male). Serum concentrations of amino-terminal propeptide of pro-collagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were measured.Of the 332 study participants, 74 (22.3%) were I/I, 158 (47.6%) were I/D and 100 (30.1%) were D/D carriers. Genetic variation in ACE significantly influenced serum CITP levels in AF patients (p = 0.011). CITP levels were lower in D allele carriers (DD and ID) compared with I/I carriers. There was no difference in PINP levels between the different ACE genotype groups (p = 0.302). Patients treated with ACE inhibitors had higher CITP levels compared with those not treated (p = 0.036).This study suggests that the presence of the D allele in hypertensive patients with AF is associated with attenuation of type-I collagen degradation, and that therapy with ACE inhibitors increases degradation of collagen type I. The data indicate a subgroup of patients with AF and arterial hypertension who may benefit to a greater extent from therapy with ACE inhibitors, thus, providing a basis for pharmacogenetics.

Aims To investigate the hypothesis that circulating levels of collagen type I degradation or synthesis markers are associated with the presence and pattern of atrial fibrillation (AF). Methods and results We assessed the serum concentrations of amino-terminal propeptide of procollagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively, in 98 paroxysmal AF (PAF) patients (65 ± 14 years, 62 men), in 80 persistent AF (PsAF) patients (73 ± 8 years, 32 men), in 114 permanent AF (PmAF) patients (73 ± 10 years, 54 men), and in 180 patients in sinus rhythm (SR) (66 ± 13 years, 88 men) who represented a control group. Serum CITP levels were higher ( P < 0.001) in AF patients [0.41 ng/mL, 95% confidence interval (CI) 0.38–0.44] when compared with SR patients (0.29 ng/mL, 95% CI 0.26–0.33) and were significantly different between the three AF pattern groups ( P < 0.001). Patients with PAF (0.31 ng/mL, 95% CI 0.26–0.36) had lower CITP levels when compared with patients with PsAF (0.41 ng/mL, 95% CI 0.34–0.47) ( P = 0.006), as well as with PmAF patients (0.49 ng/mL 95% CI, 0.43–0.56) ( P < 0.001). Levels of CITP tended to be lower ( P = 0.219) in PsAF patients when compared with sustained AF patients. No differences were found in PINP levels between AF and SR study groups ( P = 0.637) as well as between the three AF pattern groups ( P = 0.301). Conclusion In the clinical setting, circulating levels of collagen type I degradation marker are associated with both type and duration of AF. Further studies are needed to evaluate the clinical use of serum concentrations of CITP as a potential diagnostic, prognostic, and therapeutic target in patients with AF.

Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques. Acute coronary syndromes may be precipitated by MMPs through degradation of the fibrous cap and subsequent plaque disruption. Serine proteases such as plasmin activate MMPs and may contribute to plaque events. Thrombolysis with recombinant tissue plasminogen activator (rtPA) is widely used for treatment of acute ST segment elevation myocardial infarction (STEMI). In the present study we assessed whether thrombolytic therapy with rtPA in patients with STEMI influences serum levels of MMP-2 and MMP-9.We recruited 108 patients (92 men, mean age 64 +/- 12 years) with STEMI, of whom 84 (78%) received thrombolytic treatment with rtPA and 24 (22%) did not. MMP-2 and MMP-9 levels were assessed at hospital admission (baseline), and at 24 and 72 h after admission, using a commercially available ELISA.Overall, MMP-9 levels were higher in the thrombolysis group compared to patients without thrombolysis (p0.001). Thrombolysis treatment significantly affected the change in MMP-9 levels during the 72-h study period (p0.001).The present study showed that thrombolysis could affect circulating levels of MMP-9 in STEMI patients. Whether this effect may lead to plaque instability deserves further investigation.

Background: Extracellular matrix metabolism (ECM) has an important role in left ventricular (LV) remodeling in chronic heart failure (CHF). Matrix metalloproteinases (MMPs) are involved in the regulation of extracellular matrix (ECM) metabolism. We investigated the effect of levosimendan, a novel calcium sensitizer, on serum levels of MMP-2. Methods: Our study population consisted of 60 consecutive patients with advanced heart failure who were admitted to hospital with an acute decompensation of their CHF. Patients were randomized to levosimendan (n = 30; 18 men, aged 65 ± 3 years) or placebo (n = 30; 15 men, aged 67 ± 4 years). Serum MMP-2 levels were assessed before and after treatment with levosimendan or placebo, using a commercially available ELISA. Results: Serum levels of MMP-2 were reduced from 427 ng/ml 95%CI 372–484 to 371 ng/ml 95%CI 329–413 in the levosimendan treated group and from 433 ng/ml 95%CI 422–444 to 425 ng/ml 95%CI 414–436 in the placebo group. Repeated measurements ANOVA showed that treatment with levosimendan significantly affected levels of MMP-2 (p = 0.019). Conclusions: The present study showed that levosimendan may beneficially affect ECM remodeling in patients with acutely decompensated CHF. Whether these effects translate into added clinical benefits, as suggested by an improved ejection fraction in the levosimendan group, deserves further investigation.

It is well known that atrial fibrillation is associated with high incidence of thromboembolic events, propably due to a prothrombotic or hypercoagulable state. However, it is unclear whether or not there is any difference of this prothrombotic state in the clinical subgroups of atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. From the other side the role of the arrhythmia duration on the changes of coagulative variables in atrial fibrillation patients is not clearly enough.

Background: Guidelines suggest use of cardiovascular risk categories and high intensity statins for patients with acute coronary syndromes (ACS). We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. Methods: We enrolled 687 ACS patients (mean