SUMMARY Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin 43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin 2-expressing macrophages improves atrioventricular conduction, while conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF) which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacologic experiments. The pharmacovigilance database, VigiBase ® was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for four weeks results in inducible AF, left atrial enlargement, myocardial fibrosis and inflammation. This effect was reproduced in mice lacking BTK but not in mice treated with four-weeks of acalabrutinib, a more specific BTK inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving C-terminal src kinase (CSK) as the strongest candidate for ibrutinib induced AF. Cardiac specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in Vigibase ® confirmed increased reporting of AF associated with kinase inhibitors blocking Csk vs non-Csk inhibitors, with a reporting odds-ratio of 8.0 [95% CI 7.3-8.7, p<0.0001]. Conclusions: These data identify Csk inhibition as the mechanism by which ibrutinib leads to AF. Clinical Trial Registration: URL: www.clinicaltrials.gov Unique Identifier: NCT03530215

Gout and serum uric acid independently associate with total and cardiovascular mortality. These risks increase with rising uric acid concentrations.

IntroductionPhysical activity is beneficial for individual health, but endurance sport is associated with the development of arrhythmias like atrial fibrillation. The underlying mechanisms leading to this increased risk are still not fully understood. MicroRNAs are important mediators of proarrhythmogenic remodeling and have potential value as biomarkers in cardiovascular diseases. Therefore, the objective of our study was to determine the value of circulating microRNAs as potential biomarkers for atrial remodeling in marathon runners (miRathon study).Methods30 marathon runners were recruited into our study and were divided into two age-matched groups depending on the training status: elite (ER, ≥55 km/week, n = 15) and non-elite runners (NER, ≤40 km/week, n = 15). All runners participated in a 10 week training program before the marathon. MiRNA plasma levels were measured at 4 time points: at baseline (V1), after a 10 week training period (V2), immediately after the marathon (V3) and 24h later (V4). Additionally, we obtained clinical data including serum chemistry and echocardiography at each time point.ResultsMiRNA plasma levels were similar in both groups over time with more pronounced changes in ER. After the marathon miR-30a plasma levels increased significantly in both groups. MiR-1 and miR-133a plasma levels also increased but showed significant changes in ER only. 24h after the marathon plasma levels returned to baseline. MiR-26a decreased significantly after the marathon in elite runners only and miR-29b showed a non-significant decrease over time in both groups. In ER miRNA plasma levels showed a significant correlation with LA diameter, in NER miRNA plasma levels did not correlate with echocardiographic parameters.ConclusionMiRNAs were differentially expressed in the plasma of marathon runners with more pronounced changes in ER. Plasma levels in ER correlate with left atrial diameter suggesting that circulating miRNAs could potentially serve as biomarkers of atrial remodeling in athletes.

Dobson L, Conway C, Hanley A, Johnson A, Costello S, O’Grady A, Connolly Y, Magee H, O’Shea D, Jeffers M & Kay E (2010) Histopathology57, 27–38 Image analysis as an adjunct to manual HER-2 immunohistochemical review: a diagnostic tool to standardize interpretationAims:Accurate determination of HER-2 status is critical to identify patients for whom trastuzumab treatment will be of benefit. Although the recommended primary method of evaluation is immunohistochemistry, numerous reports of variability in interpretation have raised uncertainty about the reliability of results. Recent guidelines have suggested that image analysis could be an effective tool for achieving consistent interpretation, and this study aimed to assess whether this technology has potential as a diagnostic support tool.Methods and results:Across a cohort of 275 cases, image analysis could accurately classify HER-2 status, with 91% agreement between computer-aided classification and the pathology review. Assessment of the continuity of membranous immunoreactivity in addition to intensity of reactivity was critical to distinguish between negative and equivocal cases and enabled image analysis to report a lower referral rate of cases for confirmatory fluorescence in situ hybridization (FISH) testing. An excellent concordance rate of 95% was observed between FISH and the automated review across 136 informative cases.Conclusions:This study has validated that image analysis can robustly and accurately evaluate HER-2 status in immunohistochemically stained tissue. Based on these findings, image analysis has great potential as a diagnostic support tool for pathologists and biomedical scientists, and may significantly improve the standardization of HER-2 testing by providing a quantitative reference method for interpretation.

Falls are a major public health problem in the elderly population. The associated health care cost is great. It has therefore become an important public health matter to evaluate those interventions that might be effective in reducing the risk of falls. Risk factors that predict an increased risk of falling are described. We discuss interventions that can be employed in the community to reduce the risk of falls and associated injuries by discipline, including physiotherapy, occupational therapy, and physician-led interventions. We also discuss the cost-effectiveness of such interventions.

The observed disparity in endoscopic performance between surgical and gastroenterology trainees suggests the need for a combined or unitary approach to endoscopy training for specialist medical and surgical trainees.

The FFR values and FD-OCT anatomical parameters MLA, MLD were found to be significantly correlated. In the overall group, the FD-OCT-measured MLA and MLD have shown moderate diagnostic efficiency in the functional evaluation of significant stenosis. FD-OCT-measured MLA has high diagnostic efficiency in identifying severe coronary stenosis in vessels having reference diameter < 3 mm.