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Abstract: Heart failure with reduced ejection fraction (HFrEF) has been associated with poor prognosis, reduced quality of life, and increased healthcare expenditure. Despite tremendous advances in HFrEF management, reduced survival and a high rate of hospitalization remain unsolved issues. Furthermore, HFrEF morbidity and economic burden are estimated to increase in the following years; hence, new therapies are constantly emerging. In the last few years, a series of landmark clinical trials have expanded our therapeutic armamentarium with a ground-breaking change in HFrEF-related outcomes. Sodium-glucose co-transporter 2 inhibitors (mainly dapagliflozin and empagliflozin) have already revolutionized the management of HFrEF patients via a significant reduction in cardiovascular mortality and heart failure hospitalizations. Furthermore, vericiguat and omecamtiv mecarbil have emerged as promising and novel disease-modifying therapies. The former restores the impaired cyclic guanosine monophosphate pathway, and the latter stimulates cardiac myosin without marked arrhythmogenesis. Both vericiguat and omecamtiv mecarbil have been shown to reduce heart failure admissions. Sacubitril/valsartan is an established and effective therapy in HFrEF patients and should be considered as a replacement for angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs). Lastly, inflammasome activity is implicated in HFrEF pathophysiology, and the role of anti-inflammatory agents in HFrEF trajectories is readily scrutinized, yet available therapies are ineffective. This mini-review summarizes the major and most recent studies in this field, thus covering the current advances in HFrEF therapeutics.

Early arrhythmia recurrence within the 3-month blanking period is a common event that historically has been attributed to reversible phenomena. While its mechanistic links remain obscure, accumulating evidence support the argument of shortening the blanking period. We aimed to elucidate the association between early and late arrhythmia recurrence after atrial fibrillation cryoablation.The MEDLINE database, ClinicalTrials. gov, medRxiv, and Cochrane Library were searched for studies evaluating early and late arrhythmia recurrence rates in patients undergoing cryoablation for atrial fibrillation. Data were pooled by meta-analysis using a random-effects model. The primary endpoint was late arrhythmia recurrence.Early arrhythmia recurrence was found predictive of decreased arrhythmia-free survival after evaluating 3975 patients with paroxysmal or persistent atrial fibrillation who underwent cryoablation (odds ratio [OR]: 5.31; 95% confidence interval [CI]: 3.75-7.51). This pattern remained unchanged after subanalyzing atrial fibrillation type (paroxysmal; OR: 7.16; 95% CI: 4.40-11.65 and persistent; OR: 7.63; 95% CI: 3.62-16.07) as well as cryoablation catheter generation (first generation; OR: 5.15, 95% CI: 2.39-11.11 and advanced generation; OR: 5.83, 95% CI: 3.68-9.23). Studies permitting antiarrhythmic drug utilization during the blanking period or examining early recurrence as a secondary outcome were found to be a significant source of statistical heterogeneity.Our findings suggest that early arrhythmia recurrence is predictive of late outcomes after cryoablation for atrial fibrillation. Identifying which patients deserve earlier reintervention is an open research avenue.

The global burden of atrial fibrillation (AF) is constantly increasing, necessitating novel and effective therapeutic options. Sodium glucose co-transporter 2 (SGLT2) inhibitors have been introduced in clinical practice as glucose-lowering medications. However, they have recently gained prominence for their potential to exert substantial cardiorenal protection and are being evaluated in large clinical trials including patients with type 2 diabetes and normoglycemic adults. In this review we present up-to-date available evidence in a pathophysiology-directed manner from cell to bedside. Preclinical and clinical data regarding a conceivable antiarrhythmic effect of SGLT2 inhibitors are beginning to accumulate. Herein we comprehensively present data that explore the potential pathophysiological link between SGLT2 inhibitors and AF. With regard to clinical data, no randomized controlled trials evaluating SGLT2 inhibitors effects on AF as a pre-specified endpoint are available. However, data from randomized controlled trial post-hoc analysis as well as observational studies point to a possible beneficial effect of SGLT2 inhibitors on AF. Meta-analyses addressing this question report inconsistent results and the real magnitude of AF prevention by SGLT2 inhibition remains unclear. Still, while (i) pathophysiologic mechanisms involved in AF might be favorably affected by SGLT2 inhibitors and (ii) emerging, yet inconsistent, clinical data imply that SGLT2 inhibitor-mediated cardiorenal protection could also exert antiarrhythmic effects, the argument of whether these novel drugs will reduce AF burden is unsettled and mandates appropriately designed and adequately sized randomized controlled studies.

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

BackgroundAcute myocardial infarction (MI) is a major clinical manifestation of coronary artery disease. Post-MI morbidity and mortality can be reduced by lifestyle changes and aggressive risk factor modification. These changes can be applied more effectively if the patient is actively involved in the process. The hypothesis of this study was that an educational programme in post-MI patients could lead to reduced incidence of cardiovascular events.MethodsPost-MI patients were prospectively randomised into two groups. Patients in the intervention arm were scheduled to attend an 8-week-long educational programme on top of usual treatment, while controls received optimal treatment. The primary endpoint was the composite of all-cause death, MI, cerebrovascular event and unscheduled hospitalisation for cardiovascular causes. Endpoint adjudication was blinded.Results329 patients (238 men) were included, with a mean follow-up time of 17±4 months. In the primary analysis, mean primary end point-free survival time was 597 days (95% CI 571 to 624) in controls, compared with 663 days (95% CI 638 to 687) in the intervention group (pConclusionThese results suggest that a relatively short adult education programme offered to post-MI patients has beneficial effects, resulting in reduced risk of cardiovascular events.Trial registration numberNCT04007887.

Transcatheter aortic valve implantation (TAVI) led to the foundation of the subspecialty of structural heart interventions and created an emerging area of clinical and technical issues. Soon after TAVI introduction into clinical practice, boundaries were expanded with utilization of valve-in-valve (V-i-V) techniques. V-i-V comprised a diverse subset of patients including TAVI within TAVI, TAVI within a degenerated surgically implanted bioprosthesis, or even TAVI-in-TAVI-in-surgical bioprosthesis. In the present review, we summarize the available literature and present initial experience on the field in Greece.

Atrial fibrillation (AF) and diabetes mellitus (DM) are commonly encountered in clinical practice. Although, the long term macrovascular and microvascular sequela of DM are well validated, the association between the less prevalent type 1 DM (T1DM) and atrial arrhythmogenesis is poorly understood. In the present review we highlight the current experimental and clinical data addressing this complex interaction. Animal studies support that T1DM, characterized by insulin deficiency and glycemic variability, impairs phosphatidylinositol 3‑kinase (PI3K)/protein kinase B signaling pathway. This pathway holds a central role in atrial electrical and structural remodeling responsible for arrhythmia initiation and maintenance. The molecular ''footprint'' of T1DM in atrial myocytes seems to involve a state of increased oxidative stress, impaired glucose transportation, ionic channel dysregulation and eventually fibrosis. On the contrary only a few clinical studies have examined the role of T1DM as an independent risk factor for AF development, and are discussed here. Further research is needed to solidify the real magnitude of this association and to investigate the clinical implications of PI3K molecular signaling pathway in atrial fibrillation management.

Inherited cardiomyopathies are a known cause of heart failure, although the pathways and mechanisms leading from mutation to the heart failure phenotype have not been elucidated. There is strong evidence that this transition is mediated, at least in part, by abnormal intracellular Ca(2+) handling, a key ion in ventricular excitation, contraction and relaxation. Studies in human myocytes, animal models and in vitro reconstituted contractile protein complexes have shown consistent correlations between Ca(2+) sensitivity and cardiomyopathy phenotype, irrespective of the causal mutation. In this review we present the available data about the connection between mutations linked to familial hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathy, right ventricular arrhythmogenic cardiomyopathy/dysplasia (ARVC/D) as well as left ventricular non-compaction and the increase or decrease in Ca(2+) sensitivity, together with the results of attempts to reverse the manifestation of heart failure by manipulating Ca(2+) homeostasis.

Background Radial artery occlusion (RAO) remains the Achilles' heel of transradial coronary procedures. Standard over lower systemic anticoagulation levels are believed to reduce RAO rates but this is ill-supported by scientific evidence. We compared whether standard in comparison with less intensive anticoagulation was superior in preventing vessel closure. Methods and results The two arms of this analysis included 731 pooled patients with the same inclusion and exclusion criteria. We assessed forearm arterial access site occlusion rate by unfractionated heparin (UFH) dose in an individual participant data meta-analysis of this randomized study and of consecutive eligible patients from our previous trial. We randomized 308 consecutive patients undergoing transradial coronary angiography with 5 French (5Fr) catheters without need to crossover to receive 2500 or 5000UFH units. The primary end-point was the ultrasonographically determined vessel occlusion rate. Incident RAOs in the randomized arm were 15.9% vs. 14%, in the low and standard UFH dose, respectively (p=0.7). Corresponding figures for forearm arterial occlusion rates in the pooled population were 13.0% vs. 9.9% (relative risk: 1.3, 95% confidence interval — CI: 0.88–1.98; p=0.2). Procedural and fluoroscopy duration was less than 15 and 3min, respectively. The mean UFH dose difference was 3.52 (95% CI: −0.45 to 7.49) units per kilo body weight between occluded (n=84) and patent forearm arteries (n=647); (p=0.053). Conclusions Incident forearm arterial occlusions were high despite using 5Fr catheters for a short-lasting procedure. Systemic anticoagulation with standard over lower UFH dose did not reduce the frequency of RAOs after coronary angiography.

Background— The autonomic system is an important determinant of atrial arrhythmogenesis. Current evidence indicates that a combined sympathovagal drive is most commonly responsible for eliciting atrial fibrillation (AF) episodes. The purpose of this study was to test whether moxonidine, a centrally acting sympathoinhibitory agent, can lead to a reduction in postablation AF recurrence. Methods and Results— This was a prospective, double-blinded, randomized study of 291 hypertensive patients with symptomatic paroxysmal AF who were scheduled to undergo pulmonary vein isolation. Patients were randomly assigned to receive either moxonidine (0.2–0.4 mg daily) or placebo, along with standard antihypertensive treatment. No significant differences in blood pressure levels were observed between the 2 groups. In the primary outcome analysis, mean recurrence-free survival was 467 days (95% CI, 445–489 days) in the moxonidine group as compared with 409 days (95% CI, 381–437 days) in control subjects (log rank test, P =0.006). The calculated 12-month recurrence rate estimates were 36.9% in the control group and 20.0% in the moxonidine group ( P =0.007). Moxonidine treatment was associated with lower recurrence risk after adjustment for age, body mass index, number of AF episodes in the previous year, and left atrial diameter (adjusted hazard ratio, 0.35 [95% CI, 0.22–0.55]; P Conclusions— Treatment with moxonidine is associated with less AF recurrences after ablation treatment for drug-refractory AF in patients with hypertension. The observed effect does not appear to depend on the antihypertensive action of this agent. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01791699.

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).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.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, p0.001), metabolic equivalents (METs) (r=-0.555, p0.001) and Duke treadmill score (DTS) (r=-0.347, p0.001). Subjects who exercised to ≥10 METs (n=114) had lower ADMA levels than those who achieved7 METs (n=30) (0.58±0.06 vs 0.87±0.08μmol/L, p0.001), and those with DTS5 (n=63) had higher ADMA (0.75±0.19 vs 0.64±0.15μmol/L, p0.001) 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 p0.001) and METs (R(2)=0.500; beta -8.5; 95% confidence interval -9.7 to -6.0; adjusted p0.001) after adjustment for age, BMI, gender, diabetes, smoking status, dyslipidemia, hypertension and family history of premature CAD.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.

Objectives: The purpose of this study was to test the efficacy of a 6-month course of anti-inflammatory treatment with colchicine in improving functional status of patients with stable chronic hear...

Colchicine, a natural and ancient drug still used today, is traditionally considered the staple therapy for gout and a second-line treatment for pericarditis, as well as a basic part of familial Mediterranean fever and Behcet's disease management. It is commonly classified as an anti-inflammatory agent, although its mechanism of action does not involve the arachidonic acid pathway affected by non-steroid anti-inflammatory drugs and glucocorticoids. Colchicine inhibits microtubule polymerization by binding to tubulin, thus affecting any process that requires cytoskeletal changes, including cell mitosis and neutrophil motility. Recent studies suggest that colchicine may prove to be useful in a much wider spectrum of cardiovascular diseases than previously suspected, rekindling the interest in this old drug. In this review we briefly present the biochemical characteristics, mechanism of action and side-effects of colchicine, as well as examine what is currently known about the promising role of colchicine in cardiovascular medicine beyond pericardial disease.

There is substantial evidence that the autonomic system plays an important part in the pathogenesis of atrial fibrillation (AF). It appears that, although some patients have a preponderantly sympathetic or vagal overactivation leading to AF, a combined sympathovagal drive is most commonly responsible for AF triggering. The purpose of this hypothesis-generating study was to test whether moxonidine, a centrally acting sympathoinhibitory agent, on top of optimal antihypertensive treatment, can lead to a decrease in AF burden in hypertensive patients with paroxysmal AF. This was a prospective, double-blind, 1-group, crossover study. Hypertensive patients with paroxysmal AF sequentially received treatment with placebo and moxonidine for two 6-week periods, respectively. The change in AF burden (measured as minutes of AF per day in three 48-hour Holter recordings) between the 2 treatment periods was the primary outcome measure. Fifty-six patients (median age 63.5 years, 35 men) were included. During moxonidine treatment, AF burden was reduced from 28.0 min/day (interquartile range [IQR] 15.0 to 57.8) to 16.5 min/day (IQR 4.0 to 36.3; p0.01). European Heart Rhythm Association symptom severity class decreased from a median of 2.0 (IQR 1.0 to 2.0) to 1.0 (IQR 1.0 to 2.0; p = 0.01). Systolic blood pressure levels were similar in the 2 treatment periods, whereas diastolic blood pressure was lower (p0.01) during moxonidine treatment. The most frequent complaint was dry mouth (28.6%). No serious adverse events were recorded. In conclusion, treatment with moxonidine, a centrally acting sympathoinhibitory agent, results in reduction of AF burden and alleviation of AF-related symptoms in hypertensive patients with paroxysmal AF.

Soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) has been shown to have both pro- and anti-apoptotic activities and is associated to better prognosis in heart failure. The aim of this study was to determine the transcardiac concentration gradient of sTRAIL and inflammatory biomarkers after AF cardioversion and assess their relation to AF recurrence.We measured transcardiac gradients (coronary sinus concentration minus aortic root concentration) of sTRAIL, C-reactive protein (hsCRP) and interleukin-6 (IL-6) in patients with non-valvular AF after electrical cardioversion. Six-month AF recurrence was the study endpoint.There were no differences in sTRAIL and hsCRP concentrations in peripheral venous blood between patients with and without AF recurrence (p=0.066 and 0.149, respectively), while IL-6 was higher in patients with recurrence (p=0.032). Only sTRAIL showed a significant transcardiac gradient [3 pg/mL (IQR 1-4 pg/mL); p=0.01]. sTRAIL gradient was 4 pg/mL (IQR 3-5 pg/mL) in patients without recurrence versus -1 pg/mL (IQR -2-1 pg/mL) in those with recurrence (p0.001). IL-6 (p=0.281) and hsCRP (p=0.979) aortic concentrations were not significantly different from coronary sinus concentrations. In multivariate analysis, sTRAIL transcardiac gradient (beta -0.81, p=0.004) remained a negative predictor of AF recurrence.This study demonstrates the existence of a significant transcardiac sTRAIL concentration gradient in patients with non-valvular AF, inversely associated to AF recurrence. These results suggest production of sTRAIL by the heart and a protective role against substrate-altering processes in AF-prone atria. This could have implications for TRAIL-targeting therapies currently under development.

Objectives The aim of the present study was to assess the efficacy of remote ischemic post-conditioning (RIPC) by repeated intermittent balloon inflations in preventing acute kidney injury (AKI) in patients with a non–ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). Background AKI complicating PCI is associated with increased morbidity and mortality. Remote ischemic preconditioning, using cycles of upper limb ischemia-reperfusion as a conditioning stimulus, has been recently shown to prevent AKI in patients undergoing elective coronary angiography. Methods Eligible patients were randomized to receive RIPC by cycles of inflation and deflation of the stent balloon during PCI or a sham procedure (control patients). The primary endpoint was AKI, defined as an increase of ≥0.5 mg/dl or ≥25% in serum creatinine within 96 h from PCI. The 30-day rate of death or re-hospitalization for any cause was one of the secondary endpoints. Results A total of 225 patients were included (median age, 68 years; 36% female). The AKI rate in the RIPC group was 12.4% versus 29.5% in the control group (p = 0.002; odds ratio: 0.34; 95% confidence interval: 0.16 to 0.71). The number needed to treat to avoid 1 case of AKI was 6 (95% confidence interval: 3.6 to 15.2). The 30-day rate of death or re-hospitalization for any cause was 22.3% in the control group versus 12.4% in RIPC patients (p = 0.05). Conclusions RIPC by serial balloon inflations and deflations during PCI was found to confer protection against AKI in patients with a non–ST-segment elevation myocardial infarction undergoing PCI. The reduction in the rate of AKI translated into a clear trend (of borderline significance) toward better 30-day clinical outcome.

Objectives This study sought to test the hypothesis that colchicine treatment after percutaneous coronary intervention (PCI) can lead to a decrease in in-stent restenosis (ISR). Background ISR rates are particularly high in certain patient subsets, including diabetic patients, especially when a bare-metal stent (BMS) is used. Pharmacological interventions to decrease ISR could be of clinical relevance. Methods Diabetic patients with contraindication to a drug-eluting stent, undergoing PCI with a BMS, were randomized to receive colchicine 0.5 mg twice daily or placebo for 6 months. Restenosis and neointima formation were studied with angiography and intravascular ultrasound 6 months after the index PCI. Results A total of 196 patients (63.6 ± 7.0 years of age, 128 male) were available for analysis. The angiographic ISR rate was 16% in the colchicine group and 33% in the control group (p = 0.007; odds ratio: 0.38, 95% confidence interval: 0.18 to 0.79). The number needed to treat to avoid 1 case of angiographic ISR was 6 (95% confidence interval: 3.4 to 18.7). The results were similar for IVUS-defined ISR (odds ratio: 0.42; 95% confidence interval: 0.22 to 0.81; number needed to treat = 5). Lumen area loss was 1.6 mm2 (interquartile range: 1.0 to 2.9 mm2) in colchicine-treated patients and 2.9 mm2 (interquartile range: 1.4 to 4.8 mm2) in the control group (p = 0.002). Treatment-related adverse events were largely limited to gastrointestinal symptoms. Conclusions Colchicine is associated with less neointimal hyperplasia and a decreased ISR rate when administered to diabetic patients after PCI with a BMS. This observation may prove useful in patients undergoing PCI in whom implantation of a drug-eluting stent is contraindicated or undesirable.

Objectives The aim of this study was to test the hypothesis that moderate procedural sedation can reduce the incidence of radial artery spasm. Background Transradial access for left heart catheterization and percutaneous coronary intervention is increasingly used for emergent and elective procedures, in lieu of the femoral approach. However, increased rates of access site crossover have been reported, with radial artery spasm being a major contributor to this effect. Methods Patients undergoing elective transradial percutaneous coronary intervention were prospectively randomized to receive fentanyl and midazolam during the procedure or no treatment (control subjects). The primary endpoint was angiographically confirmed radial artery spasm. Patient discomfort was quantified with a visual analogue scale. Results Two thousand thirteen patients (age 64.5 ± 8.4 years) were randomized. Spasm occurred in 2.6% of the treatment group versus 8.3% of control subjects (p Conclusions Routine administration of relatively low doses of an opioid/benzodiazepine combination during transradial interventional procedures is associated with a substantial reduction in the rate of spasm, the need for access site crossover, and the procedure-related level of patient discomfort.

Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

Natriuretic neuropeptides (ANP, BNP, CNP) are produced primarily in the cardiac atria under normal conditions. The main stimulus for ANP and BNP peptide synthesis and secretion is cardiac wall stress. Cardiac ventricular myocytes constitute the major source of BNP-related peptides. Ventricular NT-proBNP production is upregulated in cardiac failure and locally in the area surrounding a myocardial infarct. NT-proBNP is cleared passively by organs with high rate of blood flow (muscle, liver, kidney). It has a longer half life than BNP and higher plasma concentration. BNP and NTproBNP tend to be higher in women and lower in obese individuals. They are also higher in elderly, in left ventricular tachycardia, right ventricular overload, myocardial ischemia, hypoxaemia, renal dysfunction, liver cirrhosis, sepsis and infection. NT-proBNP is useful both in the diagnosis and prognosis of heart failure and is considered to be a gold standard biomarker in heart failure similar to BNP. A cut-off point 300 pg/ml has 99% sensitivity, 60%specificity and NPV 98%for exclusion of acute heart failure. NT proBNP has also a strong prognostic value of death in acute and chronic heart failure and also predicts short and long term mortality in patient with suspected or confirmed unstable CVD. Natriuretic peptides are also prognostic markers for the RV (Right Ventricular) Dysfunction. Their release is due to myocardial stretch from right ventricular pressure overload.Finally, there are data supporting that NT-proBNP might be useful to put a time frame on atrial fibrillation of unknown onset.

Objectives The purpose of the present study was to test the potential of colchicine, an agent with potent anti-inflammatory action, to reduce atrial fibrillation (AF) recurrence after pulmonary vein isolation in patients with paroxysmal AF. Background Proinflammatory processes induced by AF ablation therapy have been implicated in postablation arrhythmia recurrence. Methods Patients with paroxysmal AF who received radiofrequency ablation treatment were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo. C-reactive protein (CRP) and interleukin (IL)-6 levels were measured on day 1 and on day 4 of treatment. Results In the 3-month follow-up, recurrence of AF was observed in 27 (33.5%) of 80 patients of the placebo group versus 13 (16%) of 81 patients who received colchicine (odds ratio: 0.38, 95% confidence interval: 0.18 to 0.80). Gastrointestinal side-effects were the most common symptom among patients receiving active treatment. Diarrhea was reported in 7 patients in the colchicine group (8.6%) versus 1 in the placebo group (1.3%, p = 0.03). Colchicine led to higher reductions in CRP and IL-6 levels: the median difference of CRP and IL-6 levels between days 4 and 1 was −0.46 mg/l (interquartile range: −0.78 to 0.08 mg/l) and −0.10 mg/l (−0.30 to 0.10 pg/ml), respectively, in the placebo group versus −1.18 mg/l (−2.35 to −0.46 mg/l) and −0.50 pg/ml (−1.15 to −0.10 pg/ml) in the colchicine group (p Conclusions Colchicine is an effective and safe treatment for prevention of early AF recurrences after pulmonary vein isolation in the absence of antiarrhythmic drug treatment. This effect seems to be associated strongly with a significant decrease in inflammatory mediators, including IL-6 and CRP.

We hypothesized that uptitration of β blockade and adjustment of pacing parameters to achieve a prevalence of single chamber atrial inhibited rate-responsive (AAIR) pacing in patients with dual-chamber implantable cardioverter--defibrillators (ICDs) would result in maximization of β-blocker dosage and thus decrease appropriate ICD therapies. We included patients with ischemic or dilated cardiomyopathy and implanted ICDs without contraindications to β blockers and atrioventricular conduction disturbances. Two 6-month periods were compared: clinically guided phase (pacing function set at back-up dual-chamber rate-responsive pacing mode at a lower rate of about 40 beats/min) and pacing-guided phase, during which β-blocker dosage was titrated with a target of achieving90% AAIR pacing (lower rate 60 beats/min). Sixty-one patients (64.2 ± 8.3 years old) were included. During the pacing-guided phase the target of ≥90% AAIR pacing was achieved in 80.3% of patients. Mean metoprolol dose during the clinically guided phase was 96.7 ± 29.4 versus 127.0 ± 39.6 mg/day in the pacing-guided phase (p0.001). Appropriate ICD therapies were recorded in 35 patients (57.4%) during the clinically guided phase versus 20 (32.8%) during the pacing-guided phase (p0.001; 1.15 and 0.48 appropriate ICD therapies per patient, respectively, p0.001). In multivariate analysis, AAIR pacing and β-blocker dose were inversely related to appropriate ICD therapies. In conclusion, a pacing-guided approach for maximizing β-blocker doses guided by maximizing AAIR pacing in patients with ICDs may be beneficial compared to the conventional strategy. This pacing-guided approach led to higher daily β-blocker doses, which were correlated to fewer appropriate ICD therapies.

The aim of this prospective, open-label, cohort study was to compare the effect of muscle functional electrical stimulation (FES) on endothelial function to that of conventional bicycle training. Eligible patients were those with New York Heart Association class II or III heart failure symptoms and ejection fractions ≤ 0.35. Two physical conditioning programs were delivered: FES of the muscles of the lower limbs and bicycle training, each lasting for 6 weeks, with a 6-week washout period between them. Brachial artery flow-mediated dilation (FMD) and other parameters were assessed before and after FES and the bicycle training program. FES resulted in a significant improvement in FMD, which increased from 5.9 ± 0.5% to 7.7 ± 0.5% (95% confidence interval for the difference 1.5% to 2.3%, p0.001). Bicycle training also resulted in a substantial improvement of endothelial function. FMD increased from 6.2 ± 0.4% to 9.2 ± 0.4% (95% confidence interval for the difference 2.5% to 3.5%, p0.001). FES was associated with a 41% relative increase in FMD, compared to 57% with bicycle exercise (95% confidence interval for the difference between the relative changes 1.2% to 30.5%, p = 0.034). This resulted in attaining a significantly higher FMD value after bicycle training compared to FES (9.2 ± 0.4% vs 7.7 ± 0.5%, p0.001). In conclusion, the effect of muscle FES in patients with heart failure on endothelial function, although not equivalent to that of conventional exercise, is substantial. Muscle FES protocols may prove very useful in the treatment of patients with heart failure who cannot or will not adhere to conventional exercise programs.

CRT and Coronary Flow Reserve. Background: Cardiac resynchronization therapy (CRT) has become a mainstay in heart failure management. There are also indications that upgrading of existing pacemakers to CRT systems may be of benefit. The aim of this study was to assess the effect of biventricular (BiV), compared with right ventricular (RV), pacing, on coronary flow reserve (CFR), in patients with ischemic cardiomyopathy. Methods and Results: From our database of heart failure patients implanted with BiV pacemakers, 20 patients (10 responders and 10 non-responders to CRT) were randomly selected. Left anterior descending artery coronary flow reserve was measured invasively, under BiV and RV pacing, using intracoronary adenosine to induce hyperemia. In all the 20 patients, there was a significant difference in the pairwise comparison between CFR recorded during BiV and RV pacing (mean difference 0.15, 95% confidence interval 0.07–0.23, P = 0.001). When comparing responders to non-responders, there was a significant difference as to the effect of BiV, compared with RV, pacing on CFR: mean difference (BiV minus RV CFR) was 0.26 ± 0.06 (95% confidence interval 0.13–0.39; P = 0.002), while in non-responders the difference was 0.04 ± 0.03 (95% confidence interval −0.02 to 0.10; P = 0.168). Conclusion: BiV pacing is overall associated to higher CFR, compared with RV DDD pacing. This difference is almost exclusively attributable to the beneficial effect of CRT on coronary flow reserve in CRT-responders. This effect may contribute to the beneficial action of resynchronization in the failing heart and can be viewed in the context of reports of the usefulness of upgrading RV pacemakers to CRT systems. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1233-1239, November 2010)

Objectives We sought to determine the potential of remote ischemic periconditioning (RIPC), and its combination with morphine, to reduce reperfusion injury in primary percutaneous coronary interventions. Background Remote ischemic post-conditioning is implemented by applying cycles of ischemia and reperfusion on a remote organ, which result in release of circulating factors inducing the effects of post-conditioning on the myocardium. Methods A total of 96 patients (59 men) were enrolled. The patients were randomized to groups as follows: 33 to each treatment group (Group A: RIPC; Group B: RIPC and morphine) and 30 to the control group (Group C). Measures of efficacy were achievement of full ST-segment resolution (primary), and reduction of ST-segment deviation score and peak troponin I during hospitalization. Results A higher proportion of patients in Groups A (73%) and B (82%) achieved full ST-segment resolution after percutaneous coronary intervention, compared with control patients (53%) (p = 0.045). Peak troponin I was lowest in Group B, 103.3 ± 13.3 ng/ml, in comparison to peak levels in Group A, 166.0 ± 28.0 ng/ml, and the control group, 255.5 ± 35.5 ng/ml (p = 0.0006). ST-segment deviation resolution was 87.3 ± 2.7% in Group B, compared with 69.9 ± 5.1% in Group A and 53.2 ± 6.4% in the control group (p = 0.00002). In paired comparisons between groups, Group B did better than the control group in terms of both ST-segment reduction (p = 0.0001) and peak troponin I (p = 0.004), whereas Group A differences from the control group did not achieve statistical significance (p = 0.054 and p = 0.062, respectively). Conclusions These findings demonstrate a cardioprotective effect of RIPC and morphine during primary percutaneous coronary intervention for the prevention of reperfusion injury. This is in agreement with observations that the beneficial effect of RIPC is inhibited by the opioid receptor blocker naloxone.

a Cardiology Department and Cardiac Catheterization Laboratory, Athens General Hospital “G. Gennimatas”, Athens, Greece b 1st Department of Cardiology, University of Athens Medical School, Hippokrateion Hospital, Athens, Greece c Department of Cardiology, University of Patras Medical School, Patras, Greece d Cardiac Catheterization Laboratory, Yale-New Haven Hospital, Yale School of Medicine, New Haven, CT, USA

coronary intervention on bifurcation lesions Spyridon Deftereos , Georgios Giannopoulos , Dimitris Tousoulis ⁎, Konstantinos Raisakis , Andreas Kaoukis , Charalambos Kossyvakis , Vasiliki Panagopoulou , Olga Ntzouvara , Aggeliki Mavrogianni , Nikolaos Michelakakis , Konstantinos Toutouzas , Vlasios Pyrgakis , Georgios Bobotis , Michael W. Cleman , Christodoulos Stefanadis b a Department of Cardiology, Athens General Hospital “G. Gennimatas”, Athens, Greece b 1st Department of Cardiology, Hippokrateion Hospital, University of Athens Medical School, Athens, Greece c 2nd Department of Cardiology, “G. Papageorgiou” Hospital, Thessaloniki, Greece d Cardiac Catheterization Laboratory, Yale-New Haven Hospital, Yale School of Medicine, New Haven, CT, USA

Objective Radial artery spasm may hinder completion of transradial angiography or PCI, leading to access site crossover, prolonged procedure times and complications. The aim of this study was to derive a radial artery spasm risk score in patients undergoing elective percutaneous coronary intervention (PCI), prospectively validate it, and apply it in a real-life clinical setting. Methods The study population consisted of 3 cohorts of patients undergoing elective PCI with transradial access: the derivation cohort (N=1006), the validation cohort (N=576) and the intervention cohort (N=140), consisting of patients with high risk score, in whom intensified spasm-preventive measures were applied. Results Multivariable analysis in the derivation cohort showed that 5 weighted factors could be used to construct a risk score for spasm: body-mass index, height, current smoking, hypertension and peripheral artery disease (c-statistic 0.945, with an optimal cut-off of 4). In the validation cohort, the cut-off of 4 predicted spasm with a sensitivity of 84.5% and a specificity of 74.7%. In the intervention cohort, which included only patients with a spasm-risk score of ≥4, the rate of spasm was drastically reduced (odds ratio 0.32, 95% confidence interval 0.17–0.61), compared to the corresponding high spasm risk subgroup of patients of the validation cohort. Conclusion A spasm risk score can be used to predict radial artery spasm during elective transradial PCI. Using this score, a high spasm risk patient subgroup can be identified, where intensive spasm-preventive measures can lead to a significant reduction in the frequency of spasm.

We sought to test the hypothesis that virtual histology characteristics of the culprit lesion in patients with ST-elevation myocardial infarction are associated with blood flow restoration after thrombolysis.Consecutive patients referred for coronary angiography after successful thrombolysis were included in this correlational cross-sectional study. Evaluation with intravascular ultrasound (IVUS) and virtual histology of the culprit arterial segment was performed in all cases.Forty-eight patients (60.5 ± 10.7 years) were included. TIMI flow grade 3 was found in 24 (50%). Diabetes was strongly associated with lower TIMI flow 3 rate (26.7% vs 60.6%; p = 0.029) and there was a significant difference in the time to thrombolysis (2.0 ± 0.8 hours in those with TIMI flow 3 vs 3.0 ± 0.7 hours in TIMI flow grades 1-2; p0.001). Patients with TIMI flow grades 3 and 1-2 had similar absolute total plaque volume (152.8 ± 59.3mm(3) vs 147.5 ± 92.3mm(3); p = 0.817) and absolute necrotic core (NC) volume (31.2 ± 13.9 mm(3) vs 33.6 ± 23.2mm(3); p = 0.671). However, there were significant differences in the relative NC content, both in proportion to the whole plaque volume (26.3% vs 29.9%; p = 0.016) and as an area fraction at the largest NC site (31.5% vs 40.3%; p0.001).The NC content of atherosclerotic plaques is meaningful for flow restoration after the occurrence of a coronary event. This finding highlights the importance of plaque composition, as studied with virtual histology, not only for the sequence of processes leading to an acute plaque-related event, but also for thrombus formation and lysis, following the occurrence of such an event.

Background-The autonomic system is an important determinant of atrial arrhythmogenesis. Current evidence indicates that a combined sympathovagal drive is most commonly responsible for eliciting atrial fibrillation (AF) episodes. The purpose of this study was to test whether moxonidine, a centrally acting sympathoinhibitory agent, can lead to a reduction in postablation AF recurrence. Methods and Results-This was a prospective, double-blinded, randomized study of 291 hypertensive patients with symptomatic paroxysmal AF who were scheduled to undergo pulmonary vein isolation. Patients were randomly assigned to receive either moxonidine (0.2-0.4 mg daily) or placebo, along with standard antihypertensive treatment. No significant differences in blood pressure levels were observed between the 2 groups. In the primary outcome analysis, mean recurrence-free survival was 467 days (95% CI, 445-489 days) in the moxonidine group as compared with 409 days (95% CI, 381-437 days) in control subjects (log rank test, P=0.006). The calculated 12-month recurrence rate estimates were 36.9% in the control group and 20.0% in the moxonidine group (P=0.007). Moxonidine treatment was associated with lower recurrence risk after adjustment for age, body mass index, number of AF episodes in the previous year, and left atrial diameter (adjusted hazard ratio, 0.35 [95% CI, 0.22-0.55]; P

BACKGROUND Our group previously showed that colchicine treatment is associated with decreased early recurrence rate after ablation for atrial fibrillation (AF). OBJECTIVE The purpose of this study was to test the mid-term efficacy of colchicine in reducing AF recurrences after a single procedure of pulmonary vein isolation in patients with paroxysmal AF. Assessment of quality-of-life (QOL) changes was a secondary objective. METHODS Patients with paroxysmal AF who were scheduled for ablation were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo and were followed for a median of 15 months (with a 3-month blanking period). QOL was assessed with a general-purpose health-related QOL tool (26-item World Health Organization QOL questionnaire) at baseline and after 3 and 12 months. RESULTS Two hundred twenty-three randomized patients underwent ablation, and 206 patients were available for analysis (144 male, age 62.2 +/- 5.8 years). AF recurrence rate in the colchicine group was 31.1% (32/103) vs 49.5% (51/103) in the control group (P = .010), translated in a relative risk reduction of 37% (odds ratio 0.46, 95% confidence interval 0.26-0.81). The number needed to treat was 6 (95% confidence interval 3.2-19.8). Physical domain QOL scores at 12 months were 63.6 +/- 13.8 in the colchicine group and 52.5 +/- 18.1 in controls, whereas psychological domain scores were 56.1 +/- 13.7 vs 44.7 +/- 17.3, respectively (P < .001, for both). CONCLUSION Colchicine treatment after pulmonary vein isolation for paroxysmal AF is associated with lower AF recurrence rates after a single procedure. This reduction is accompanied by corresponding improvements in physical and psychological health-related QOL scores.

Background Our group previously showed that colchicine treatment is associated with decreased early recurrence rate after ablation for atrial fibrillation (AF). Objective The purpose of this study was to test the mid-term efficacy of colchicine in reducing AF recurrences after a single procedure of pulmonary vein isolation in patients with paroxysmal AF. Assessment of quality-of-life (QOL) changes was a secondary objective. Methods Patients with paroxysmal AF who were scheduled for ablation were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo and were followed for a median of 15 months (with a 3-month blanking period). QOL was assessed with a general-purpose health-related QOL tool (26-item World Health Organization QOL questionnaire) at baseline and after 3 and 12 months. Results Two hundred twenty-three randomized patients underwent ablation, and 206 patients were available for analysis (144 male, age 62.2 ± 5.8 years). AF recurrence rate in the colchicine group was 31.1% (32/103) vs 49.5% (51/103) in the control group ( P = .010), translated in a relative risk reduction of 37% (odds ratio 0.46, 95% confidence interval 0.26–0.81). The number needed to treat was 6 (95% confidence interval 3.2–19.8). Physical domain QOL scores at 12 months were 63.6 ± 13.8 in the colchicine group and 52.5 ± 18.1 in controls, whereas psychological domain scores were 56.1 ± 13.7 vs 44.7 ± 17.3, respectively ( P Conclusion Colchicine treatment after pulmonary vein isolation for paroxysmal AF is associated with lower AF recurrence rates after a single procedure. This reduction is accompanied by corresponding improvements in physical and psychological health-related QOL scores.

The "holy grail" of modern interventional cardiology is the salvage of viable myocardial tissue in the distribution of an acutely occluded coronary artery. Thrombolysis and percutaneous coronary interventions, provided they can be delivered on time, can interrupt the occlusion and save tissue. At the same time restoring the patency of the coronary vessels and providing the ischemic myocardium with blood can cause additional tissue damage. A key element of ischemic and reperfusion injury and major determinant of the evolution of damage in the injured myocardium is the inflammatory response. The innate immune system initiates and directs this response which is a prerequisite for subsequent healing. The complement cascade is set in motion following the release of subcellular membrane constituents. Endogenous 'danger' signals known as danger-associated molecular patterns (DAMPs) released from ischemic and dying cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved Toll like receptors (TLRs). Reactive oxygen species (ROS) generation directly induces pro-inflammatory cascades and triggers formation of the inflammasome. The challenge lies into designing strategies that specifically block the inflammatory cascades responsible for tissue damage without affecting those concerned with tissue healing.

The purpose of this study was to test the efficacy of a 6-month course of anti-inflammatory treatment with colchicine in improving functional status of patients with stable chronic heart failure (CHF).CHF has been shown to be associated with inflammatory activation. Inflammation has been designated as a therapeutic target in CHF.Patients with stable CHF were randomly assigned to colchicine (0.5 mg twice daily) or placebo for 6 months. The primary endpoint was the proportion of patients achieving at least one-grade improvement in New York Heart Association class.Two hundred sixty-seven patients were available for final evaluation of the primary endpoint: its rate was 11% in the control group and 14% in the colchicine group (odds ratio: 1.40; 95% confidence interval: 0.67 to 2.93; p = 0.365). The rate of the composite of death or hospital stay for heart failure was 9.4% in the control group, compared with 10.1% in the colchicine group (p = 0.839). The changes in treadmill exercise time with treatment were insignificant and similar in the 2 groups (p = 0.938). C-reactive protein and interleukin-6 were both significantly reduced in the colchicine group (-5.1 mg/l and -4.8 pg/ml, respectively; p 0.001 for both, compared with the control group).According to this prospective, randomized study, anti-inflammatory treatment with colchicine in patients with stable CHF, although effective in reducing inflammation biomarker levels, did not affect in any significant way patient functional status (in terms of New York Heart Association class and objective treadmill exercise tolerance) or the likelihood of death or hospital stay for heart failure.

Colchicine, a natural and ancient drug still used today, is traditionally considered the staple therapy for gout and a second-line treatment for pericarditis, as well as a basic part of familial Mediterranean fever and Behcet's disease management. It is commonly classified as an anti-inflammatory agent, although its mechanism of action does not involve the arachidonic acid pathway affected by non-steroid anti-inflammatory drugs and glucocorticoids. Colchicine inhibits microtubule polymerization by binding to tubulin, thus affecting any process that requires cytoskeletal changes, including cell mitosis and neutrophil motility. Recent studies suggest that colchicine may prove to be useful in a much wider spectrum of cardiovascular diseases than previously suspected, rekindling the interest in this old drug. In this review we briefly present the biochemical characteristics, mechanism of action and side-effects of colchicine, as well as examine what is currently known about the promising role of colchicine in cardiovascular medicine beyond pericardial disease.

Background— The ulnar artery is rarely selected for coronary angiography or percutaneous coronary intervention despite the expanding use of the transradial approach. We aimed to establish noninferiority of a default transulnar relative to transradial approach in terms of feasibility and safety. Methods and Results— This was a prospective, randomized, multicenter, parallel-group study involving 902 patients at 5 sites eligible to undergo diagnostic coronary angiography and percutaneous coronary intervention. Patients were randomized in a 1:1 ratio to either transradial approach (reference intervention) or transulnar approach (experimental intervention) regardless of the Allen test results. The primary end point was a composite of cross-over to another arterial access, major adverse cardiovascular events, and major vascular events of the arm at 60 days. The study was prematurely terminated after the first interim analysis because of inferiority of the transulnar approach. Although the difference in the primary end point became inconclusive after adjustment for operator clustering (24.30%; 99.99% confidence interval [CI], −7.98% to 56.58%; P =0.03 at α=0.0001), need for cross-over in the transulnar group remained inferior to transradial access site with a difference of 26.34% (95% CI, 11.96%–40.69%; P =0.004). Conclusions— As a result of higher cross-over rates, a first-line transulnar strategy was proven inferior to the transradial approach for coronary procedures. At present, the transulnar route should not be regarded as an acceptable alternative to the transradial access site. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01364532.

With the advent of transcatheter aortic valve implantation (TAVI), many AS patients, formerly considered inoperable, can receive effective treatment. The relief of the left ventricular pressure overload could lead, in some cases, to the occurrence of dynamic intracavity pressure gradients (DIG) with deleterious clinical impact. This phenomenon resembles the physiology seen in hypertrophic obstructive cardiomyopathy. We report a case in which alcohol septal ablation was used as a bail-out therapy for the acutely developed intracavity obstruction after TAVI. Potential dynamic intracavity gradients should always be excluded in the acutely deteriorated patient postoperatively. Alcohol septal ablation can be considered as a salvage therapeutic tool when other therapies are ineffective to treat subvalvular obstruction.

In this brief report, we present our experience from placing temporary pacing electrodes through peripheral venous access sites, at bedside, in a series of patients needing temporary pacing.Consecutive patients requiring temporary pacing were selected. The median cubital or the basilic vein of the left upper extremity were used for catheterization at the bedside in all cases.25 patients (17 men, age 64.6 ± 11.8) were included. The procedure was successful in 21 cases (84%), 18 of which were completed without the need for fluoroscopic guidance. The pacing leads remained for 4.2 ± 2.2 days. As expected, no serious complications related to venous puncture were observed. Although patients were allowed to be mobilized within the ward and engage in limited movements of the catheterized arm, in only one case was the lead displaced, requiring repositioning.We provide observational evidence that the use of peripheral venous access for temporary pacing lead insertion (with no fluoroscopic guidance, as default strategy) is a safe and feasible choice that might be considered as an alternative to central vein catheterization.

The aim of this study was to test the hypothesis that moderate procedural sedation can reduce the incidence of radial artery spasm.Transradial access for left heart catheterization and percutaneous coronary intervention is increasingly used for emergent and elective procedures, in lieu of the femoral approach. However, increased rates of access site crossover have been reported, with radial artery spasm being a major contributor to this effect.Patients undergoing elective transradial percutaneous coronary intervention were prospectively randomized to receive fentanyl and midazolam during the procedure or no treatment (control subjects). The primary endpoint was angiographically confirmed radial artery spasm. Patient discomfort was quantified with a visual analogue scale.Two thousand thirteen patients (age 64.5 ± 8.4 years) were randomized. Spasm occurred in 2.6% of the treatment group versus 8.3% of control subjects (p0.001; odds ratio [OR]: 0.29). The number needed to treat to avoid 1 case of spasm was 18 (95% confidence interval [CI]: 12.9 to 26.6). The access site crossover rate was 34% lower in the treatment group: 9.9% versus 15.0% (OR: 0.62; 95% CI: 0.48 to 0.82). Patient discomfort visual analogue scale score was 18.8 ± 12.5 in the treatment group versus 27.4 ± 17.4 in control subjects (p0.001). No significant differences were observed in the 30-day rate of death or repeat hospital stay for any cause: 4.6% versus 4.5% (OR: 1.02; 95% CI: 0.67 to 1.56).Routine administration of relatively low doses of an opioid/benzodiazepine combination during transradial interventional procedures is associated with a substantial reduction in the rate of spasm, the need for access site crossover, and the procedure-related level of patient discomfort.

Objectives: Soluble tumor necrosis factor-related apoptosis inducing ligand (sTRAIL) has been shown to exert protective action against atherosclerosis. The aim of this study was to investigate potential associations of coronary sTRAIL levels with indices of in-stent neointimal hyperplasia. Methods: 67 patients who underwent percutaneous coronary intervention with drug-eluting stent were followed up at approximately 12 months with determination of coronary sTRAIL concentration, angiography and intravascular ultrasound evaluation of the stent sites. Results: Mean sTRAIL concentration was 72.2 ± 2.8 pg/ml. sTRAIL was negatively correlated to indices of neointimal hyperplasia and positively correlated to in-stent minimum lumen area (p < 0.001). Neointimal obstruction and maximal in-stent cross-sectional neointima burden in patients in the upper sTRAIL quartile were 3.8 ± 1.2 and 12.6 ± 3.3%, respectively, versus 14.0 ± 0.7 and 49.8 ± 2.7% in the lower quartile (p < 0.001 for both). sTRAIL levels were significantly lower in patients with binary restenosis (48.7 ± 3.0 vs. 75.2 ± 2.9 pg/ml; p < 0.001). In the multivariate analysis, sTRAIL was an independent predictor of neointimal hyperplasia. Conclusion: This study demonstrates a negative association of sTRAIL to in-stent neointima formation. The potential pathophysiologic substrate of this effect implicates modulation of apoptosis in various cell types. These observations should prompt further evaluation of the link between sTRAIL and in-stent restenosis.

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.