Christos Angelidis

Colchicine for Prevention of Early Atrial Fibrillation Recurrence After Pulmonary Vein Isolation : A Randomized Controlled Study

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 < 0.01 for both comparisons). 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.

Myeloperoxidase: expressing inflammation and oxidative stress in cardiovascular disease.

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

In-hospital switching of oral P2Y12 inhibitor treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention: Prevalence, predictors and short-term outcome

BACKGROUND P2Y12 inhibitor switching has appeared in clinical practice as a consequence of prasugrel and ticagrelor availability, apart from clopidogrel, for use in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS In the context of the GReek AntiPlatelet REgistry (GRAPE) we assessed the prevalence, predictive factors and short-term outcome of in-hospital P2Y12 inhibitor switching in 1794 ACS patients undergoing PCI. RESULTS Switching occurred in 636 (35.5%) patients of which in the form of clopidogrel to a novel agent, novel agent to clopidogrel and between prasugrel and ticagrelor in 574 (90.4%), 34 (5.3%) and 27 (4.3%) patients, respectively. Presentation to non PCI-capable hospital, bivalirudin use, age ≥75 years (inverse predictor), and regional trends emerged as predictive factors of switching to a novel agent. At combined in-hospital and one-month follow-up, propensity matched pairs analysis showed no differences in major adverse cardiovascular (MACE) or bleeding events between switching from clopidogrel to a novel agent vs novel agent constant administration. More Bleeding Academic Research Consortium type 1, type 2 and any type events and fewer MACE were seen when switching from clopidogrel to a novel agent vs only clopidogrel administration (23.7%, 3.8%, 30.6%, 1.2% vs 8.9%, 1.2%, 12.0%, 3.8% with P < .001, P = .03, P < .001 and P = .03 respectively). CONCLUSIONS In a real-life experience with contemporary antiplatelet treatment in ACS patients undergoing PCI, in-hospital switching represents common clinical practice. Clinical factors and regional practice differences seem to affect this strategys choice, while switching to a novel agent may be associated with higher risk of bleeding.

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. Its 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.

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 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 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.

Double Versus Standard Loading Dose of Ticagrelor : Onset of Antiplatelet Action in Patients With STEMI Undergoing Primary PCI

To the Editor: Early and strong platelet inhibition is highly desirable in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Ticagrelor, which has direct action on the P2Y12 receptor and no need for previous metabolic

CorrespondenceResearch CorrespondenceDouble Versus Standard Loading Dose of Ticagrelor: Onset of Antiplatelet Action in Patients With STEMI Undergoing Primary PCI

To the Editor: Early and strong platelet inhibition is highly desirable in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Ticagrelor, which has direct action on the P2Y12 receptor and no need for previous metabolic

Usefulness of colchicine to reduce perioperative myocardial damage in patients who underwent on-pump coronary artery bypass grafting.

The objective of the present study was to test whether a perioperative course of colchicine, in patients who underwent standard coronary artery bypass grafting, would result in reduced postoperative increase of myocardial injury biomarker levels. Patients were prospectively randomized to colchicine or placebo starting 48 hours before scheduled coronary artery bypass grafting and for 8 days thereafter (0.5 mg twice daily). The primary outcome parameter was maximal high-sensitivity troponin T (hsTnT) concentration within 48 hours after surgery. Secondary outcome measures were maximal creatine kinase-myocardial brain fraction (CK-MB) levels and area under the curve (AUC) of hsTnT and CK-MB concentrations; 59 patients were included. Maximal hsTnT was 616 pg/ml (396 to 986) in the colchicine group versus 1,613 pg/ml (732 to 2,587) in controls (p = 0.002). Maximal CK-MB was 44.6 ng/ml (36.6 to 68.8) and 93.0 ng/ml (48.0 to 182.3), respectively (p = 0.002). The median AUC for hsTnT was 40,755 pg h/ml (20,868 to 79,176) in controls versus 20,363 pg h/ml (13,891 to 31,661) in the colchicine group (p = 0.002). AUCs for CK-MB were 2,552 ng h/ml (1,564 to 4,791) in controls and 1,586 ng h/ml (1,159 to 2,073) in the colchicine group (p = 0.003). The main complaints associated with colchicine were, as expected, gastrointestinal, with 5 patients (16.7%) in the colchicine group reporting diarrhea versus 1 control (3.4%) (p = 0.195). In conclusion, a short perioperative course of colchicine was effective in attenuating postoperative increases of hsTnT and CK-MB compared with placebo. This finding, which needs confirmation in a larger clinical trial powered to assess clinical endpoints, suggests a potential role for this agent in reducing cardiac surgery-related myocardial damage.

Onset of Antiplatelet Action With High (100 mg) Versus Standard (60 mg) Loading Dose of Prasugrel in Patients With ST-Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention Pharmacodynamic Study

Background—In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, a suboptimal degree of platelet inhibition for the first 2 hours after the standard 60 mg loading dose of prasugrel has been described. Methods and Results—In a prospective, 3-center, nonrandomized, controlled study, 2 sequential groups of P2Y12 inhibitor-naive consecutive patients were loaded with either 100 mg (n=47) or 60 mg (n=35) of prasugrel. Platelet reactivity was assessed by VerifyNow at hours 0, 0.5, 1, 2, and 4. At hour 2, there was a strong trend for the primary end point of platelet reactivity (in P2Y12 reaction units) to be lower (least squares estimates of the mean difference [95% confidence interval], −45.5 [−91.2 to 0.3]; P=0.051), whereas platelet reactivity percentage inhibition (median, first to third quartile) was higher (75.5% [24%–91.8%] versus 23.5% [0%–78.3%]; P=0.02) in the 100-mg compared with 60-mg loading dose group. At hour 2, prasugrel 100 mg over 60 mg loading dose significantly reduced high platelet reactivity rates from 28.6% to 8.5% (≥230 P2Y12 reaction units threshold; P=0.036) and from 31.4% to 10.6% (≥208 P2Y12 reaction units threshold; P=0.024), whereas resulted in lower rate of ⩽20% platelet inhibition (23.4% versus 51.4%; P=0.009). Conclusions—In patients with ST-segment–elevation myocardial infarction treated with primary percutaneous coronary intervention, a higher (100 mg) than the standard loading dose of prasugrel results in greater and more consistent platelet inhibition, yet this will need to be further validated in additional studies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835353.

MicroRNAs and the Heart: Small Things Do Matter

MicroRNAs are small RNA molecules and constitute a relatively novel class of gene expression regulators, found in the great majority of eukaryotic cells. Their role in human physiology and pathology is actively being researched with new exciting discoveries continuously coming to the forefront. MicroRNAs play a crucial role in the biogenesis and function of the cardiovascular system and act as important regulators of various metabolic and signaling pathways in cardiovascular disease. In this review there will be a summary on current knowledge about the expression, regulation and function of microRNAs in the most common diseases of the cardiovascular system as well as a presentation of and discussion about their promising future role as new biomarkers and therapeutic targets.