Prevention of M2 polarization and temporal limitation of differentiation in monocytes by extracellular ATP.

BACKGROUND: Elevated levels of extracellular adenosine triphosphate (ATP) modulate immunologic pathways and are considered to be a danger signal in inflammation, lung fibrosis and cancer. Macrophages can be classified into two main types: M1 macrophages are classically activated, pro-inflammatory macrophages, whereas M2 macrophages are alternatively activated, pro-fibrotic macrophages. In this study, we examined the effect of ATP on differentiation of native human monocytes into these macrophage subtypes. We characterized M1 and M2 like macrophages by their release of Interleukin-1beta (IL-1ß) and Chemokine (C-C motif) ligand 18 (CCL18), respectively. RESULTS: Monocytes were stimulated with ATP or the P2X7 receptor agonist Benzoylbenzoyl-ATP (Bz-ATP), and the production of various cytokines was analyzed, with a particular focus on CCL18 and IL-1ß, along with the expression of different purinergic receptors. Over a 72 h period of cell culture, monocytes spontaneously differentiated to M2 like macrophages, as indicated by an increased release of CCL18. Immediate stimulation of monocytes with ATP resulted in a dose-dependent reduction in CCL18 release, but had no effect on the concentration of IL-1ß. In contrast, delayed stimulation with ATP had no effect on either CCL18 or IL-1ß release. Similar results were observed in a model of inflammation using lipopolysaccharide-stimulated human monocytes. Stimulation with the P2X7 receptor agonist Bz-ATP mimicked the effect of ATP on M2-macrophage differentiation, indicating that P2X7 is involved in ATP-induced inhibition of CCL18 release. Indeed, P2X7 was downregulated during spontaneous M2 differentiation, which may partially explain the ineffectiveness of late ATP stimulation of monocytes. However, pre-incubation of monocytes with PPADS, Suramin (unselective P2X- and P2Y-receptor blockers) and KN62 (P2X7-antagonist) failed to reverse the reduction of CCL18 by ATP. CONCLUSIONS: ATP prevents spontaneous differentiation of monocytes into M2-like macrophages in a dose- and time-dependent manner. These effects were not mediated by P2X and P2Y receptors.

Recurrent syncope after a finger injury and induced monomorphic ventricular tachycardia: Really Brugada syndrome?

Brugada syndrome is an arrhythmogenic disease with often fatal outcome in otherwise healthy and young individuals. Anamnesis and ECG are cornerstones in a syncope workup. In our case, a 27-year-old male presented to the emergency department due to recurrent syncope. Repeated 12­lead-ECGs revealed a type 2 Brugada pattern. A positive drug challenge suggested a Brugada syndrome and electrophysiological testing reproducibly induced monomorphic ventricular tachycardia. Consequently, an ICD was implanted for secondary prevention. On 2-year follow-up, the patient remained free from other arrhythmic events or ICD interventions.

Right coronary artery motion analysis: a novel method to measure right ventricular systolic function by selective coronary angiography.

Right ventricular systolic dysfunction is prognostic in various cardiovascular diseases. Right ventricular systolic function is not commonly assessed in the catheterization laboratory. Therefore, we developed a novel, reproducible method to measure right ventricular systolic function during selective coronary angiography. We analyzed the angiographic systolic translational motion and maximum speed of the right coronary artery (RCA) in 97 consecutive patients and compared it to the tricuspid annular plane systolic excursion (TAPSE) as measured by echocardiography. All measurements were performed by two independent operators on two occasions. Inter-observer variability and intra-observer variability were excellent for RCA motion distance and for RCA maximum speed. There was a significant correlation of the RCA motion distance and RCA maximum speed with the TAPSE measured by echocardiography (Pearson's correlation for RCA distance: r = 0.59, p < 0.001, r2 = 0.35; for RCA speed: r = 0.40, p < 0.001, r2 = 0.16). The area under the receiver operating curve for the RCA motion distance was 0.88 (95% CI 0.80-0.96) for discrimination of normal and abnormal right ventricular systolic function. A cut-off value less than 22.3 mm systolic RCA motion had a specificity of 93.3% and a sensitivity of 75.6% for identifying an abnormal right ventricular systolic function. Analysis of the RCA motion is a reproducible and reliable method to measure right ventricular systolic function during selective coronary angiography. It is a simple and useful tool to assess right ventricular function in the catheterization laboratory and may serve for risk assessment for right ventricular failure. CLINICAL TRIAL REGISTRATION: Data for this study was collected retrospectively from Swiss Transcatheter Aortic Valve Implantation Registry (NCT01368250). https://clinicaltrials.gov/show/NCT01368250 .