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Background PLATO study showed that Ticagrelor (Ti) significantly reduced the rate of death from vascular causes, myocardial infarction or stroke without a significant increase of major bleeding vs Clopidogrel (Cl). Previous studies demonstrated the stronger direct anti-platelet effect of Ti versus Cl. Few data exist about the indirect anti-platelet properties and pleiotropic effects, eventually involved in the positive effect of Ti on acute coronary syndrome (ACS) outcome. Aim As Ti has multiple pleiotropic effects, we sought to assess whether the different outcome of Ti versus Cl in NSTE-ACS patients could be explained, at least in part, by different modulation of circulating microRNA (miRNA). The primary endpoint was to characterize the effect of the two different P2Y12 inhibitors on miRNA expression. Secondary endpoint was to correlate miRNA profile to clinical outcome. Methods Thirty-one patients with a diagnosis of NSTE-ACS were enrolled in this study. Patients were randomized for Ti or Cl assumption before undergoing PCI. Clinical characteristics were homologues between Ti and Cl groups. Blood samples were drawn at different time point (T0, T1 and T2) to test miRNA modulation and stability (T0, at baseline; T1, three hours after drug administration; T2, twenty-four hours after coronarography). Plasma RNA was extracted and pooled for microarray PCR based panel of ninety miRNA analysis. MiRNA expression was normalized on the global mean of each patient. Levels of circulating miRNAs were compared using statistical tests, assuming significance at P Results A panel of seven circulating miRNAs associated with atherosclerosis, thrombosis and inflammation were selected for validation (miR-652-3p; miR-26-5p; miR-25-3p; miR-let7c; miR-155-5p; miR-222-3p; miR-223-3p). Microarray analysis showed an opposite modulation of most miRNAs at T0, T1 and T2 in patients with Cl or Ti treatment. In particular, Cl group showed an upregulation of most miRNAs, while Ti administration caused their down-regulation. Of the seven miRNA selected for validation, miR-652-3p, expression at T1 showed a significantly modulation in patients in Cl treatment compared to Ti (T1 Cl 2,637±1,092, T1 Ti 0,660±0,171; p=0.03). MiRNA-652-3p has a validated pro-atherogenic role. On five-years follow, an higher rate (40%) of cardiovascular events (new ACS, recurrent ischemia and stent thrombosis) was reported in the Cl group compare to Ti. Indeed, no one death or bleeding occurred. Conclusion This data suggest that Ti has a protective role down-regulating pro-atherogenic and pro-thrombotic miRNAs (miR-652-3p, miR-let7c, miR-223-3p, miR-155-5p) and promoting the expression of anti-atherogenic miRNAs (miR-25-3p) when compared to Cl. This may contribute to explain the positive effect on clinical outcome of Ti. Although the small number of patients, this pilot study gives another evidence about the multiple positive pleiotropic effect of Ti. Figure 1. miRNA 652-3p expression Funding Acknowledgement Type of funding source: None

BACKGROUND: Perilipin 2 (PLIN2) is a protein that potentially facilitates atherogenesis in native coronary arteries or arteries with an implanted drug-eluting stent (DES). The aim of the study was to determine PLIN2 protein levels in peripheral monocytes of enrolled subjects and compare them between patients with native coronary artery disease (CAD) and those with an in-stent restenosis (ISR) due to neoatherosclerosis occurring >1 year after DES implantation. METHODS: Forty-two patients were prospectively enrolled in the study in 3:1 fashion and underwent coronary catheterization. Both groups were angiographically matched for CAD burden with respect to the number of diseased vessels. Neoatherosclerosis was determined by intracoronary optical coherence tomography (OCT) among patients with ISR. RESULTS: Patients with ISR due to neoatherosclerosis had significantly higher PLIN2 protein levels in peripheral blood monocytes compared to patients with native CAD (342.47 ± 75.63[SE] versus 119.51 ± 20.95, p < 0.001). PLIN2 protein levels did not significantly differ between unstable and stable disease phenotype (125.59 ± 131.02 vs. 146.14 ± 111.87, p = 0.109). CONCLUSIONS: In this explorative study, PLIN2 protein levels are significantly increased in patients with neoatherosclerosis, irrespective of clinical presentation, implicating that it might play a pathogenetic role in accelerated atherosclerosis after DES implantation. Further larger clinical studies are warranted to confirm these initial findings.

BACKGROUND Multidrug resistance protein-4 (MRP4) is an ATP binding cassette membrane transporter, actively involved in the efflux of important pharmacological and physiological molecules. Recently, its over-expression has been associated with reduced aspirin (ASA) efficacy after by-pass surgery. MicroRNAs (miRNAs) are small molecules of non-coding RNA involved in the regulation of many physiological and pathophysiological pathways, are abundant in platelets, and can be modulated by several drugs. In the present study, we assessed the role of platelet miRNAs in modulating MRP4 function in response to ASA. METHODS MRP4 mRNA expression has been analyzed by RealTime PCR in platelets from patients on chronic ASA treatment versus a control group. A panel of miRNAs was run on the pool of each cohort. MiRNAs validation was performed by RealTime PCR. To verify whether MRP4 is the target of miR-26b also in platelets, miR-26b was transfected in platelet and DAMI cells with miRNA mimic technology. MRP4 expression was evaluated by flow cytometry and western blotting. RESULTS We observed a higher MRP4 mRNA expression in platelets of patients under ASA treatment compared to the control group (p

Aim : To assess eosinophil cationic protein (ECP) and C-reactive protein (CRP) serum levels at three time points according to different stent types. Methods : 54 patients (age 64 ± 10 years, male 78%), undergoing Bare Metal Stent (BMS) ( n = 11), mammalian Target Of Rapamycin (mTOR)-inhibitor DES ( n = 27) and mTOR-inhibitor bioabsorbable DES (BES) ( n = 16) implantation for stable angina (SA) or non-ST-elevation acute coronary syndromes (NSTE-ACS), were prospectively enrolled. ECP and CRP serum levels were assessed before revascularization, at 1-month and at 1-year after the procedure. Moreover, 21 patients found to have inducible ischemia or angina symptoms at 6 month-stress test underwent 1-year follow-up (FU) angiography. Results : Baseline and 1-month ECP levels were similar among the 3 groups, whilst 1-year ECP was significantly higher in m-TOR-DES [8.61 (6.55–19.77) μg/ml] compared with m-TOR-BES [2.03 (1.78–5.53) μg/ml] and BMS-treated patients [2.23 (1.45–8.95) μg/ml] ( p = 0.02), without significant difference between BES and BMS. CRP was similar among the 3 groups at all time points. 1-year ECP significantly correlated with late loss in patients undergoing FU angiography ( r = 0.64, p = 0.002), while CRP did not ( p = NS). Conclusions : Our finding suggests that mTOR-DES stent type is associated with an increase of ECP levels at 1-year, possibly reflecting a persistent eosinophil activation triggered by permanent polymer.

Clinical examination and m-mode, b-mode, and two-dimensional speckle tracking evaluations with X-Strain® software were carried out in two dogs with dilated cardiomyopathy before and during therapy. During follow-up, the two dogs presented not only in better clinical condition, but also with improvements in m-mode and b-mode indices, as well as increased values of strain and strain rate. Consequently, X-Strain® evaluation should be included in routine echocardiography to better understand the pathogenesis and evolution of disease characterized by reduced myocardial contractility, optimize the therapeutic protocol during follow-up, and contribute to finding the range of normal values for strain and strain rate in the dog.

Multidrug resistence protein-4 is an ATP Binding Cassette membrane transporter, actively involved in the efflux of important pharmacological and physiological compounds. It is found on platelet membrane and its over-expression has been show to induce aspirin (ASA) resistence in patients after by

SummaryA study was carried out to establish whether erythromycin stearate was bacteriostatic or bactericidal at the concentrations reached in the bronchial secretion. Twenty-two patients suffering from an acute attack of chronic bronchitis, sustained by streptococci, diplococci, staphylococci or H. infuenzae sensitive to erythromycin, were treated with 1500 mg erythromycin per day until symptoms regressed, usually within 3 to 5 days. The results showed that after treatment there was a dramatic reduction in the number of bacterial colonies cultured from the bronchial secretion and marked changes in bacterial morphology were seen using electron microscopy. Further evidence of bactericidal activity was provided by the rapid clinical response of the patients.

SummaryIn vivo and in vitro studies were carried out to assess the levels in bronchial mucus of ampicillin, amoxycillin, bacampicillin, cefotaxime and erythromycin, and to compare their minimum bactericidal concentrations and killing rate against hospital strains of Staphylococcus aureus, Streptococcus pyogenes and Haemophilus influenzae. Both the percentage ratios of serum/mucus concentration peaks and of serum/mucus area under the concentration time curve values were higher for erythromycin than for the other antibiotics. Determination of the minimum bactericidal concentrations showed that the bacterial strains were sensitive to small quantities of erythromycin, and the time necessary to sterilize inocula varied from 4 to 16 hours.

Almost all antibiotics are known to appear in saliva and bronchial secretions, at least in trace amounts. However, in these secretions certain antibiotics reach concentrations equivalent to or even higher than the M.I.C. for numerous bacterial strains or genera that are responsible for the most common respiratory disorders. Such pharmacokinetic data are therefore of great interest for the choice of the most suitable antibiotic therapy for a bacterial infection of the respiratory system. The exact mechanism underlying penetration of antibiotics into the lung, of their secretion into saliva, or at least all of the factors involved, are still unknown [1]. Antibiotics reach the bronchopulmonary system and saliva in two completely different ways. Salivary secretion is related to pharmacokinetic processes and to the degree of tropism for tissues, because the salivary glands do not offer any appreciable barrier to antibiotic penetration. On the contrary, the concentration of antibiotics in the respiratory system seems to be completely independent of serum levels, and in healthy subjects bronchopulmonary concentrations are usually much lower (30–40 times) than those in the serum. These pharmacokinetic data led to the conclusion that there must be a blood-lung, or rather a blood-bronchi, barrier that may be even less permeable than the better-known blood-brain barrier [2]. However, certain antibiotics reach surprisingly high (macrolides, lincomycin, rifampin, chloramphenicol) or at least therapeutic (ampicillin, cefalosporins) levels in the bronchi. This phenomenon has led some authors to suggest the existence of a mechanism of active transport able to concentrate some antibiotics selectively in bronchial mucus [3,4].