Stavros Apostolakis

Inflammation in Atrial Fibrillation

Atrial fibrillation (AF) is associated with increased risk for stroke and systemic embolism. There is plausible evidence linking inflammation to the initiation and perpetuation of AF and AF-related thrombosis. Various inflammatory markers (C-reactive protein, tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-8) have been associated with AF. Proposed mechanisms linking inflammation and the prothrombotic AF state include endothelial activation/damage, production of tissue factor from monocytes, increased platelet activation, and increased expression of fibrinogen. The present review aims to provide an update on the association of inflammation and AF, including the impact of inflammatory markers on clinical presentation and outcome of AF patients.

Factors Affecting Quality of Anticoagulation Control Among Patients With Atrial Fibrillation on Warfarin : The SAMe-TT2R2 Score

BACKGROUND When oral anticoagulation with adjusted-dose vitamin K antagonist (VKA) is used, the quality of anticoagulation control (as reflected by the time in therapeutic range [TTR] of the international normalized ratio [INR]) is an important determinant of thromboembolism and bleeding. Our objective was to derive a validated scheme using patient-related clinical parameters to assess the likelihood of poor INR control among patients with atrial fibrillation (AF) on VKA therapy. METHODS The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial population was randomly divided into derivation and internal validation cohorts using a 1:1 ratio. We used linear regression analysis to detect the clinical factors associated with TTR and binary logistic regression to evaluate the predictive performance of a model incorporating these factors for different cutoff values of TTR. The derived model was validated externally in a cohort of patients receiving anticoagulant therapy who were recruited prospectively. RESULTS In the linear regression model, nine variables emerged as independent predictors of TTR: female sex (P < .0001), age < 50 years (P < .0001), age 50 to 60 years (P = .02), ethnic minority status (P < .0001), smoking (P = .03), more than two comorbidities (P < .0001), and being treated with a β-blocker (P = .02), verapamil (P = .02), or, inversely, with amiodarone (P = .05). We incorporated these factors into a simple clinical prediction scheme with the acronym SAMe-TT₂R (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]). The score demonstrated good discrimination performance in both the internal and external validation cohorts (c-index, 0.72; 95% CI, 0.64-0.795; and c-index, 0.7; 95% CI, 0.57-0.82, respectively). CONCLUSIONS Common clinical and demographic factors can influence the quality of oral anticoagulation. We incorporated these factors into a simple score (SAMe-TT₂R₂) that can predict poor INR control and aid decision-making by identifying those patients with AF who would do well on VKA (SAMe-TT₂R₂ score = 0-1), or conversely, those who require additional interventions to achieve acceptable anticoagulation control (SAMe-TT₂R₂ score ≥ 2).

Performance of the HEMORR2HAGES, ATRIA, and HAS-BLED Bleeding Risk–Prediction Scores in Patients With Atrial Fibrillation Undergoing Anticoagulation: The AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) Study

OBJECTIVES The objective of this study was to compare the predictive performance of bleeding risk-estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing anticoagulation. BACKGROUND Three bleeding risk-prediction schemes have been derived for and validated in patients with AF: HEMORR(2)HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Τhe relative predictive values of these bleeding scores have not previously been compared. METHODS We analyzed the dataset from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with adjustable-dose oral vitamin K antagonist therapy in patients with AF. The principal safety outcome was any clinically relevant bleeding event, which was a composite of major bleeding plus clinically relevant nonmajor bleeding. RESULTS The HAS-BLED score performed best in predicting any clinically relevant bleeding, reflected both in net reclassification improvement (10.3% and 13% improvement compared with HEMORR(2)HAGES and ATRIA, respectively) and receiver-operating characteristic (ROC) analyses (c-indexes: 0.60 vs. 0.55 and 0.50 for HAS-BLED vs. HEMORR(2)AGES and ATRIA, respectively). Using decision-curve analysis, the HAS-BLED score demonstrated superior performance compared with ATRIA and HEMORR(2)HAGES at any threshold probability for clinically relevant bleeding. HAS-BLED was the only score that demonstrated a significant predictive performance for intracranial hemorrhage (c-index: 0.75; p = 0.03). An ATRIA score >3 was not significantly associated with the risk for any clinically relevant bleeding on Cox regression or on ROC analysis (c-index: 0.50; p = 0.87). CONCLUSIONS All 3 tested bleeding risk-prediction scores demonstrated only modest performance in predicting any clinically relevant bleeding, although the HAS-BLED score performed better than the HEMORR(2)HAGES and ATRIA scores, as reflected by ROC analysis, reclassification analysis, and decision-curve analysis. Only HAS-BLED demonstrated a significant predictive performance for intracranial hemorrhage. Given its simplicity, the HAS-BLED score may be an attractive method for the estimation of oral anticoagulant-related bleeding risk for use in clinical practice, supporting recommendations in international guidelines.

Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology

Summary.  Objectives: Monocytes include several subsets with different and sometimes divergent roles in immunity, atherogenesis and reparative processes. Objectives: We aimed to perform detailed immunophenotypic and functional characterization of human monocyte subsets. Patients/methods: Analysis of surface markers of blood and bone marrow monocyte subsets and functional characterization of blood monocyte subsets in healthy volunteers was performed using flow cytometry. Results: In the present study, we show the presence of three subsets which could be unequivocally distinguished by surface expression of CD14, CD16 and CCR2 as CD14+CD16−CCR2+(Mon1), CD14+CD16+CCR2+(Mon2) and CD14lowCD16+CCR2−(Mon3) subsets. In comparison with the classic Mon1, the Mon2 subset had the highest expression of Tie2, CXCR4, CD163, CD115, receptors to inter‐cellular adhesion molecule‐1 (ICAM‐1), vascular endothelial growth factor (VEGF), and the highest surface levels of apolipoprotein B and ferritin. In contrast, Mon3 had maximal expression of VCAM‐1 receptors and CD204. The Mon2 and Mon3 subsets had significantly lower activity of the NFκB pathway than Mon1. Mon1 and Mon2 had similar phagocytic activity, which was significantly higher compared with Mon3. All three subsets were present in bone marrow, although the relative proportion of Mon2 in bone marrow was about 2.5‐fold higher compared with that seen in blood. Significant differences in cytokine production in response to endotoxin stimulation were observed between the three monocyte subsets. Conclusion: Given their immunophenotypic similarity, the newly characterized Mon2 population may represent the previously reported pluripotent progenitor/pro‐angiogenic monocytes.

Interleukin 8 and cardiovascular disease

Since the establishment of the inflammatory basis of atherosclerosis, several pro- or anti-inflammatory agents have been examined as potential mediators of the biochemical pathways of lesion formation. Interleukin (IL)-8 was first characterized in 1987. Since then, knowledge regarding its role in leucocyte trafficking and activation has advanced rapidly, especially in the field of cardiovascular disease. In the scientific literature, there is sufficient evidence to support beyond any doubt the involvement of IL-8 in the establishment and preservation of the inflammatory micro-environment of the insulted vascular wall. However, how the information derived from in vitro studies and animal models can be applied in clinical practice has yet to be determined. In the present review, the available evidence regarding the role of IL-8 in cardiovascular disease is presented, and future perspectives are discussed.

Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.

Performance of the HEMORR 2 HAGES, ATRIA, and HAS-BLED Bleeding Risk–Prediction Scores in Nonwarfarin Anticoagulated Atrial Fibrillation Patients

To the Editor: Estimation of bleeding risk is a crucial step in the management of patients with atrial fibrillation (AF). Three bleeding risk–prediction schemes have been derived and validated exclusively in AF populations: HEMORR2HAGES, HAS-BLED, and ATRIA ([1,2][1]). In the present analysis,

Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial

AIMS Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF). METHODS AND RESULTS AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 ± 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl ≥60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort. CONCLUSION Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.

Reversal of tumor resistance to apoptotic stimuli by alteration of membrane fluidity: therapeutic implications.

In recent years, significant development and improvement have been observed in the treatment of cancer; however, relapses and recurrences occur frequently and there have not been any current therapies to treat such cancers. Cancers resistant to conventional therapies develop several mechanisms to escape death-inducing stimuli. A poorly understood mechanism is the involvement of the cancer cell plasma membrane composition and architecture and their involvement in regulating drug-inducing stimuli leading to cell death. Although the basic structure of the biological membrane was established 80 years ago, study of the physical properties of lipid bilayers still provides significant information regarding membrane organization and dynamics. Membrane fluidity is probably the most important physicochemical property of cell membranes. Alterations of membrane fluidity can seriously affect functional properties of the cell and induction of apoptotic pathways resulting in cell death. The role of membrane fluidity in the apoptotic process is clearly exemplified as it is seriously disrupted as a result of cell injury. The molecular signaling pathways leading to apoptosis are currently promising areas of research investigation and lead to unravel the underlying molecular mechanisms of tumor cells resistance to apoptotic stimuli and hence the development of new effective therapeutic agents. Recent findings indicate that most anticancer agents induce apoptosis, directly or indirectly, through alterations of tumor cell membrane fluidity. The present chapter summarizes the relationship between alterations of tumor cell membrane fluidity and tumor cell response to apoptotic-inducing stimuli. Several potential therapeutic applications directed at tumor cell membrane fluidity are proposed.

IL-1 cytokines in cardiovascular disease: diagnostic, prognostic and therapeutic implications.

Interleukins (ILs) are key mediators in the chronic vascular inflammatory response underlying several aspects of cardiovascular disease. Due to their powerful pro-inflammatory potential, and the fact that they are highly expressed by almost all cell types actively implicated in atherosclerosis, members of the IL-1 cytokine family were the first to be investigated in the field of vessel wall inflammation. The IL-1 family is comprised of five proteins that share considerable sequence homology: IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-18 (also known as IFNgamma-inducing factor), and the newly discovered ligand of the ST2L receptor, IL-33. Expression of IL-1s and their receptors has been demonstrated in atheromatous tissue, and serum levels of IL-1-cytokines have been correlated with various aspects of cardiovascular disease and their outcome. In vitro studies have confirmed pro-atherogenic properties of IL-1alpha, IL-1beta and IL-18 such as, up-regulation of endothelial adhesion molecules, the activation of macrophages and smooth muscle cell proliferation. In contrast with this, IL-1Ra, a natural antagonist of IL-1, possesses anti-inflammatory properties, mainly through the endogenous inhibition of IL-1 signaling. IL-33 was identified as a functional ligand of the, till recently, orphan receptor, ST2L. IL-33/ST2L signaling has been reported as a mechanically activated, cardioprotective paracrine system triggered by myocardial overload. As the roles of individual members of the IL-1 family are being revealed, novel therapies aimed at the modulation of interleukin function in several aspects of cardiovascular disease, are being proposed. Several approaches have produced promising results. However, none of these approaches has yet been applied in clinical practice.