Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study.

BACKGROUND: Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST-segment-elevation myocardial infarction. Colchicine is a substance with potent anti-inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. METHODS AND RESULTS: Patients presenting with ST-segment-elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase-myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST-segment-elevation myocardial infarction. One hundred fifty-one patients were included (60 in the MRI substudy). The area under the creatine kinase-myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754-6940) ng·h(-1)·mL(-1) in the colchicine group in comparison with 6184 (IQR, 4456-6980) ng·h(-1)·mL(-1) in controls (P<0.001). Indexed MRI-late gadolinium enhancement-defined infarct size was 18.3 (IQR, 7.6-29.9) mL/1.73 m(2) in the colchicine group versus 23.2 (18.5-33.4) mL/1.73 m(2) in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0-25.3) % and 19.8 (IQR, 13.7-29.8) %, respectively (P=0.034). CONCLUSIONS: These results suggest a potential benefit of colchicine in ST-segment-elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

Central sympathetic inhibition to reduce postablation atrial fibrillation recurrences in hypertensive patients: a randomized, controlled study.

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<0.001). 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.

The burden of atrial fibrillation and heart failure in hospitalized patients: A real-world survey in a nationwide snapshot.

PURPOSE: Atrial fibrillation (AF) and heart failure (HF) are common and commonly coexisting cardiovascular diseases in hospitalized patients. We report the absolute number and interrelation between AF and HF, assess the daily burden of both diseases on the healthcare system, and describe the medical treatment in a real-world, nationwide conducted snapshot survey. METHODS: A questionnaire was equally distributed to various healthcare institutions. Data on the baseline characteristics, prior hospitalizations, and medical treatments of all hospitalized patients with AF and HF at a predefined date were collected and analyzed. RESULTS: Seventy-five cardiological departments participated in this multicenter Greek nationwide study. A total of 603 patients (mean age, 74.5 ± 11.4 years) with AF, HF, or the combination of both were nationwide admitted. AF, HF, and the combination of both were registered in 122 (20.2%), 196 (32.5%), and 285 (47.3%) patients, respectively. First-time hospital admission was recorded in 273 (45.7%) of 597 patients, whereas 324 (54.3%) of 597 patients had readmissions in the past 12 months. Of the entire population, 453 (75.1%) were on beta-blockers (BBs), and 430 (71.3%) were on loop diuretics. Furthermore, 315 patients with AF (77.4%) were on oral anticoagulation, of whom 191 (46.9%) were on a direct oral anticoagulant and 124 (30.5%) were on a vitamin K antagonist. CONCLUSION: Hospitalized patients with AF and/or HF have more than one admission within a year. Coexistence of AF and HF is more common. BBs and loop diuretics are the most commonly used drugs. More than three-quarters of the patients with AF were on oral anticoagulation.

Inverse association of coronary soluble tumor necrosis factor-related apoptosis inducing ligand (sTRAIL) levels to in-stent neointimal hyperplasia.

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.

Radial artery flow-mediated dilation predicts arterial spasm during transradial coronary interventions.

BACKGROUND: Transradial coronary catheterization has emerged over the last years as a favorable catheterization practice, based on evidence that it is associated with less vascular complications and shorter hospital stays. However, access site crossover appears to be more frequent when the initial route is the transradial one, one of the main reasons being arterial spasm. We hypothesized that radial flow-mediated dilation (FMD) measurements could be used as a preprocedural method to assess the likelihood of arterial spasm. METHODS: The study population consisted of patients scheduled for transradial diagnostic catheterization in whom ad hoc percutaneous coronary intervention (PCI) was performed. FMD was measured 1-2 days before PCI. The primary endpoint of the study was operator-defined (operators were blinded as to the FMD results) radial artery spasm. RESULTS: A total of 172 patients (110 male, age 65.3 ± 9) were included. Radial artery spasm was recorded in 13 patients (7.6%). FMD showed a very significant univariate association with the occurrence of spasm (P < 0.001) and was the most important predictor of spasm in the multivariate logistic regression analysis (beta -3.15; P < 0.001), followed by baseline radial artery diameter (P = 0.04), the number of catheters used (P = 0.049) and the administered volume of contrast medium (P = 0.017). CONCLUSION: Preprocedural FMD is a significant predictor of arterial spasm before elective transradial PCI. It is a low cost, safe, and feasible noninvasive modality, whose results might be taken into account when deciding on the vascular access route for an elective procedure, the size of sheaths or catheters to be used or the intensity of antispasm medication.

Differential effect of biventricular and right ventricular DDD pacing on coronary flow reserve in patients with ischemic cardiomyopathy.

UNLABELLED: 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.

The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design.

OBJECTIVE: Colchicine has been utilized safely in a variety of cardiovascular clinical conditions. Among its potential mechanisms of action is the non-selective inhibition of NLRP3 inflammasome which is thought to be a major pathophysiologic component in the clinical course of patients with COVID-19. GRECCO-19 will be a prospective, randomized, open-labeled, controlled study to assess the effects of colchicine in COVID-19 complications prevention. METHODS: Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) and clinical picture that involves temperature >37.5 oC and at least two out of the: i. sustained coughing, ii. sustained throat pain, iii. Anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg will be included. Patients will be randomised (1:1) in colchicine or control group. RESULTS: Trial results will be disseminated through peer-reviewed publications and conference presentations. CONCLUSION: GRECCO-19 trial aims to identify whether colchicine may positively intervene in the clinical course of COVID-19. (ClinicalTrials.gov Identifier: NCT04326790).

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis. Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003). Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution. Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.

Peri-procedural Anticoagulation in Catheter Ablation for Atrial Fibrillation: A Review.

Catheter ablation for rhythm control in atrial fibrillation has been recognized as an established treatment. Patients with atrial fibrillation suffer from an increased risk of thromboembolic events. Long-term stroke risk and mortality have been shown to be reduced after catheter ablation, still the procedure per se is associated with an additive peri-procedural thromboembolic risk. Maintenance of the thrombotic - bleeding equilibrium in such patients during interventional procedures is compelling. Lack of data from randomized studies along with the recent introduction of novel oral anticoagulants in clinical practice has resulted in a wide variance of antithrombotic treatment approaches. Procedural interruption of anticoagulants, switching of anticoagulation scheme (i.e. from novel oral anticoagulants to vitamin K antagonists), bridging with heparin, timing of re-initiation of therapy and/or utilization of novel oral anticoagulants have all been points of dispute. In the present review we present the available data regarding optimal peri-procedural anticoagulation strategies in patients undergoing catheter ablation for atrial fibrillation.

Myocardial deformation imaging unmasks subtle left ventricular systolic dysfunction in asymptomatic and treatment-naïve HIV patients.

BACKGROUND: Patients infected by the human immunodeficiency virus (HIV) and receiving highly active antiretroviral therapy have a higher incidence of cardiovascular disease than healthy subjects, but little is known about cardiac function in asymptomatic and treatment-naïve patients. We sought to study cardiac function in asymptomatic HIV-infected, treatment-naïve patients. METHODS: We studied 41 HIV-infected and treatment-naïve patients and 20 age- and sex-matched healthy controls. Patients with cardiac symptoms, history of cardiac disease or NT-proBNP >100 pg/mL were excluded. We addressed cardiac function using standard echocardiography along with tissue Doppler (TDI) measurements, including strain/strain rate assessment. RESULTS: Standard echocardiographic parameters did not differ between groups, except for transmitral E wave velocity (64.8 ± 14 cm/s in HIV vs 76.1 ± 10 cm/s in controls, p = 0.002). In contrast, TDI mitral and tricuspid annulus s velocity and all strain/strain rate measurements were significantly lower in HIV patients: s lateral, 10.2 ± 2.4/11.3 ± 0.7, p = 0.011; s septal, 8.1 ± 1.6/8.7 ± 0.8, p = 0.045; s tricuspid, 13.4 ± 2.3/14.9 ± 1.3, p = 0.002; strain/strain rate, septal (strain/strain rate, 15.1 ± 5.7/-0.9 ± 0.3, 25.3 ± 1.7/-1.9 ± 0.2, p < 0.001), anterior (16.7 ± 3/-1.0 ± 0.1, 26.7 ± 1.7/-1.9 ± 0.2, p < 0.001), lateral (16.0 ± 6/-1.0 ± 0.1, 27.5 ± 1.8/-2.2 ± 0.3, p < 0.001) and posterior (15.2 ± 5.8/-1.0 ± 0.2, 26.2 ± 1.8/-2.2 ± 0.3, p < 0.001) left ventricular wall. CONCLUSIONS: HIV infection itself is accompanied by subclinical systolic dysfunction, not apparent to standard echocardiography that can be unmasked though using sensitive echocardiographic techniques.

Assessment of health-related quality of life in a greek symptomatic population with atrial fibrillation: correlation with functional status and echocardiographic indices.

INTRODUCTION: Atrial fibrillation (AF) is known to have an unfavorable impact on quality of life. The purpose of this study was to assess the health-related quality of life (HRQOL) in a symptomatic population with AF seeking medical advice in a tertiary hospital, as well as to explore the relationship between HRQOL, functional status, and echocardiographic indices of left ventricular (LV) systolic and diastolic function. METHODS: The study sample consisted of 108 symptomatic patients suffering from AF who presented in the emergency department or were admitted to the cardiology department in an urban Greek tertiary hospital between January 1 and May 31, 2012. HRQOL was assessed using the SF-36 and EQ-5D instruments. RESULTS: In the study sample, AF was newly diagnosed in 16.5% of the patients, paroxysmal/persistent in 43.6% and permanent in 39.9%. The mean levels of physical and mental summary components of the SF-36 were 40.28 and 40.89, respectively. The EQ-VAS mean score was 59.63%, while the EQ-5D Europe VAS index and the York A1 Tariff index were 0.586 and 0.547, respectively. Reliability analysis found Cronbach's to be 0.890 for the SF-36 and 0.701 for the EQ-5D. Convergent validity was proved to be at satisfactory levels. Impaired HRQOL was associated with worse NYHA class and echocardiographic indices of impaired LV systolic and diastolic function. Apart from higher NYHA class, other predisposing factors for lower HRQOL were female sex, advanced age, low physical activity, and higher levels of brain natriuretic peptide. CONCLUSIONS: Symptomatic AF patients report impaired HRQOL. Functional status and echocardiographic indices of LV systolic and diastolic function appear to affect HRQOL significantly in these patients. The SF-36 and the EQ-5D are shown to be reliable and valid instruments in assessing HRQOL in patients with AF.

Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study.

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 heart failure (CHF). BACKGROUND: CHF has been shown to be associated with inflammatory activation. Inflammation has been designated as a therapeutic target in CHF. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

NTproBNP: an important biomarker in cardiac diseases.

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.

Cystatin C: an emerging biomarker in cardiovascular disease.

Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It's near constant production rate, the fact that it is freely filtered from the glomerular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing understanding of the role of cysteinyl cathepsins in the pathophysiology of CVD inspired researchers to explore the potential association of cys-C with CVD. Throughout the spectrum of CVD (peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure, coronary artery disease) adverse outcomes and risk stratification have been associated with high plasma levels of cys-C. The exact mechanisms behind the observed correlations have not been comprehensively clarified. Plausible links between high cys-C levels and poor cardiovascular outcome could be impaired renal function, atherogenesis and inflammatory mediators, remodeling of myocardial tissue and others (genetic factors, aging and social habits). The scope of the present article is to systematically review the current knowledge about cys-C biochemistry, metabolism, methods of detection and quantification and pathophysiological associations with different aspects of CVD.

Association of post-cardioversion transcardiac concentration gradient of soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) and inflammatory biomarkers to atrial fibrillation recurrence.

OBJECTIVES: 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. DESIGN AND METHODS: 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. RESULTS: 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 (p<0.001). 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. CONCLUSION: 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.

Moderate procedural sedation and opioid analgesia during transradial coronary interventions to prevent spasm: a prospective randomized study.

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 < 0.001; 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 (p < 0.001). 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). 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.

Effectiveness of moxonidine to reduce atrial fibrillation burden in hypertensive patients.

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; p <0.01). 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 (p <0.01) 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.

Colchicine treatment for the prevention of bare-metal stent restenosis in diabetic patients.

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 mm(2) (interquartile range: 1.0 to 2.9 mm(2)) in colchicine-treated patients and 2.9 mm(2) (interquartile range: 1.4 to 4.8 mm(2)) 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.

Novel oral anticoagulants in the treatment of acute coronary syndromes: is there any room for new anticoagulants?

Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS.

Novel direct factor IIa and Xa inhibitors: mechanisms of action and preclinical studies.

The need to overcome certain limitations of the existing anticoagulant agents (heparin, LMWH and VKAs) and to achieve more convenient long-term anticoagulation has fueled the quest for the "ideal anticoagulant", an agent that would exert at least similar antithrombotic effects with a substantially improved pharmacologic profile and significantly less bleeding complications. The major disadvantages of the traditional agents were the narrow therapeutic window with serious drug and food interactions and the need for regular blood monitoring. Coagulation factors IIa and Xa have proved the most attractive pharmacologic targets due to their key role in the coagulation process and the opportunity of blocking thrombin generation before the level of thrombin production that results in amplification of the anticoagulant effect while preserving some of thrombin hemostatic effect. This review summarizes the mechanism of action of some of the most promising novel oral direct factor IIa and Xa inhibitors with a focus on published preclinical trials that led to their clinical development.