Peripheral blood mononuclear cell hyperresponsiveness in patients with premature myocardial infarction without traditional risk factors.

An increasing number of patients develop an atherothrombotic myocardial infarction (MI) in the absence of standard modifiable risk factors (SMuRFs). Monocytes and macrophages regulate the development of atherosclerosis, and monocytes can adopt a long-term hyperinflammatory phenotype by epigenetic reprogramming, which can contribute to atherogenesis (called "trained immunity"). We assessed circulating monocyte phenotype and function and specific histone marks associated with trained immunity in SMuRFless patients with MI and matched healthy controls. Even in the absence of systemic inflammation, monocytes from SMuRFless patients with MI had an increased overall cytokine production capacity, with the strongest difference for LPS-induced interleukin-10 production, which was associated with an enrichment of the permissive histone marker H3K4me3 at the promoter region. Considering the lack of intervenable risk factors in these patients, trained immunity could be a promising target for future therapy.

Near-infrared spectroscopy predicts events in men and women: Results from the Lipid Rich Plaque study.

Background: The Lipid Rich Plaque (LRP) study demonstrated that near-infrared spectroscopy imaging of non-obstructive lesions identified patients and segments at higher risk for subsequent non-culprit major adverse cardiac events (NC-MACE). Whether this is true for both men and women is not known. In this post hoc analysis of the LRP study, we sought to investigate whether the maximum 4-mm Lipid Core Burden Index (maxLCBI4mm) was of similar predictive value in men and women for NC-MACE. Methods: Patients with an evaluable maxLCBI4mm were stratified on the basis of sex at birth. A Cox proportional-hazards model was used to assess the predictive value of maxLCBI4mm on future NC-MACE at the patient and plaque levels. The primary endpoint was cumulative incidence of NC-MACE at 24 months. Results: Among 1271 patients, 388 (30.5%) were women. Women were older and had a higher cardiovascular risk profile. Cumulative incidence of NC-MACE at 24 months was 10.3% for women and 7.6% for men (log-rank p = 0.11). When comparing maxLCBI4mm > 400 to maxLCBI4mm ≤ 400, the hazard ratio (HR) for future NC-MACE was not significantly different between sexes: 2.10 (95% confidence interval [CI]: 1.28-3.44; p = 0.003) for men and 2.24 (95% CI: 1.18-4.28; p = 0.014) for women (p = 0.87). At the plaque level, the HR comparing maxLCBI4mm > 400 to maxLCBI4mm ≤ 400 was 3.49 (95% CI: 1.60-7.60, p = 0.002) for men and 4.79 (95% CI: 2.02-11.38, p < 0.001) for women, which was not significantly different (p = 0.57). Conclusions: The maxLCBI4mm was of similar predictive value for NC-MACE within 24 months in men and women.

Cardiac Troponin Composition Characterization after Non ST-Elevation Myocardial Infarction: Relation with Culprit Artery, Ischemic Time Window, and Severity of Injury.

BACKGROUND: Troponin composition characterization has been implicated as a next step to differentiate among non-ST elevation myocardial infarction (NSTEMI) patients and improve distinction from other conditions with troponin release. We therefore studied coronary and peripheral troponin compositions in relation to clinical variables of NSTEMI patients. METHODS: Samples were obtained from the great cardiac vein (GCV), coronary sinus (CS), and peripheral circulation of 45 patients with NSTEMI. We measured total cTnI concentrations, and assessed both complex cTnI (binary cTnIC + all ternary cTnTIC forms), and large-size cTnTIC (full-size and partially truncated cTnTIC). Troponin compositions were studied in relation to culprit vessel localization (left anterior descending artery [LAD] or non-LAD), ischemic time window, and peak CK-MB value. RESULTS: Sampling occurred at a median of 25 hours after symptom onset. Of total peripheral cTnI, a median of 87[78-100]% consisted of complex cTnI; and 9[6-15]% was large-size cTnTIC. All concentrations (total, complex cTnI, and large-size cTnTIC) were significantly higher in the CS than in peripheral samples (P < 0.001). For LAD culprit patients, GCV concentrations were all significantly higher; in non-LAD culprit patients, CS concentrations were higher. Proportionally, more large-size cTnTIC was present in the earliest sampled patients and in those with the highest CK-MB peaks. CONCLUSIONS: In coronary veins draining the infarct area, concentrations of both full-size and degraded troponin were higher than in the peripheral circulation. This finding, and the observed associations of troponin composition with the ischemic time window and the extent of sustained injury may contribute to future characterization of different disease states among NSTEMI patients.

Multi-Site Coronary Vein Sampling Study on Cardiac Troponin T Degradation in Non-ST-Segment-Elevation Myocardial Infarction: Toward a More Specific Cardiac Troponin T Assay.

Background Cardiac troponin T ( cTnT ) is seen in many other conditions besides myocardial infarction, and recent studies demonstrated distinct forms of cTnT . At present, the in vivo formation of these different cTnT forms is incompletely understood. We therefore performed a study on the composition of cTnT during the course of myocardial infarction, including coronary venous system sampling, close to its site of release. Methods and Results Baseline samples were obtained from multiple coronary venous system locations, and a peripheral artery and vein in 71 non- ST -segment-elevation myocardial infarction patients. Additionally, peripheral blood was drawn at 6- and 12-hours postcatheterization. cTnT concentrations were measured using the high-sensitivity- cTnT immunoassay. The cTnT composition was determined via gel filtration chromatography and Western blotting in an early and late presenting patient. High-sensitivity - cTnT concentrations were 28% higher in the coronary venous system than peripherally (n=71, P<0.001). Coronary venous system samples demonstrated cT n T-I-C complex, free intact cTnT , and 29 kD a and 15 to 18 kD a cTnT fragments, all in higher concentrations than in simultaneously obtained peripheral samples. While cT n T-I-C complex proportionally decreased, and disappeared over time, 15 to 18 kD a cTnT fragments increased. Moreover, cT n T-I-C complex was more prominent in the early than in the late presenting patient. Conclusions This explorative study in non- ST -segment-elevation myocardial infarction shows that cTnT is released from cardiomyocytes as a combination of cT n T-I-C complex, free intact cTnT , and multiple cTnT fragments indicating intracellular cTnT degradation. Over time, the cT n T-I-C complex disappeared because of in vivo degradation. These insights might serve as a stepping stone toward a high-sensitivity- cTnT immunoassay more specific for myocardial infarction.

[Weight-dependent dosing of aspirin; the pharmacological and cardiological perspective]. / Gewichtsafhankelijk doseren van aspirine.

A recent meta-analysis by Rothwell and colleagues, presented in The Lancet, of studies using aspirin as primary prevention showed that the effectiveness of the medication was weight-dependent. We discuss the results from both a pharmacological and cardiological perspective to assess the conclusions of this study. The observed result in the meta-analysis could possibly be explained by applying pharmacological principles; however, from a cardiological point of view the extent to which it has an influence on clinical practice is questionable. Notably, the included studies were conducted relatively long ago and results are, therefore, difficult to translate to a more contemporary population; furthermore, it is important to note that in current cardiology practice aspirin is not indicated as primary prevention. Nonetheless, given the complex interaction between patient-related factors and medication in the current population with multiple comorbidities, the present study provides food for thought regarding personalization of therapy.

A multi-site coronary sampling study on CRP in non-STEMI: Novel insights into the inflammatory process in acute coronary syndromes.

BACKGROUND AND AIMS: Inflammation has become a key element in cardiovascular disease, and recently, new anti-inflammatory interventions have shown promising results. In this context, CRP levels have been thoroughly studied in vitro and in animals, but studies in humans are scarce and insights into its release, site(s) of production and uptake are not uniform. METHODS: We performed a biomarker study with multi-site sampling in the coronary circulation, in non-ST elevation MI (NSTEMI) patients with coronary angiography and right-sided catheterisation. Trans-lesional gradients were obtained by sampling distal to the culprit lesion, in patients with a suitable anatomy. To asses trans-cardiac gradients, blood was sampled from the systemic circulation, coronary sinus (CS) and great cardiac vein. Concentrations of CRP were measured with a high-sensitivity assay. RESULTS: In 42 patients, a median systemic venous CRP concentration of 4.97 mg/L was observed. There was no evidence of a trans-lesional gradient (4.59 mg/L versus 4.56 mg/L, p = 0.278; n = 14). A significant decrease in CRP concentration was observed between systemic arterial and CS samples (4.88 mg/L versus 4.44 mg/L; p < 0.001; n = 42). This trans-cardiac gradient was irrespective of time of presentation, infarct size and culprit lesion location. The gradient was not only driven by blood that ran through the injured myocardium, but also by lower CRP concentrations in the coronary veins that drain non-infarcted myocardium. CONCLUSIONS: In the context of NSTEMI, we observed a trans-cardiac decrease in CRP, which may indicate the first human in vivo proof of a net CRP uptake by the myocardium, with a role for CRP both in the injured and adjacent myocardium.

Randomized evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with the COMBO dual therapy stent: rationale and design of the REDUCE trial.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients treated with drug eluting stents (DES) is still under debate. Recent meta-analyses on ≤6months versus 12months DAPT suggest that bleeding rates can be reduced, without a higher rate of thrombotic complications. In particular, the COMBO dual therapy stent, being associated with early re-endothelialization, may allow for a reduction of the duration of DAPT without increasing the thrombotic risk, while reducing the risk of bleeding complications. AIM: The aim of the REDUCE trial is to demonstrate the non-inferiority of a combined efficacy and safety endpoint of a short-term 3months DAPT strategy as compared to standard 12-month DAPT strategy in ACS patients treated with the COMBO stent. DESIGN: A prospective, multicenter, randomized study designed to enroll 1500 patients with ACS treated with the COMBO stent. Patients will be randomized before discharge in a 1:1 fashion to either 3 or 12months of DAPT. A clinical follow-up is scheduled at 3, 6, 12, and 24months. The primary endpoint is the time to event as defined by the occurrence of one of the following: all cause mortality, myocardial infarction, stent thrombosis, stroke, target vessel revascularization or bleeding (Bleeding Academic Research Council type II, III and V) within 12months. The study has recruited patients since July 2014, and the results are expected in 2017. SUMMARY: A reduction of the DAPT duration in ACS patients after PCI without affecting the thrombotic risk is an attractive option with regard to the associated bleeding risk. The REDUCE trial will be the first to investigate the efficacy and safety of a 3-month DAPT strategy compared to a 12-month DAPT strategy in an ACS only population treated with the COMBO stent.