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McKie, M.

Publications and source records attributed to McKie, M..

2 recordsLinked to original sources
bioRxiv2025

Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate

BACKGROUNDAtrial fibrillation (AF) susceptibility is heightened in endurance athletes but the underlying mechanisms are incompletely understood. Because pulmonary vein (PV) myocyte triggers are critical determinants of AF, we investigated PV electrophysiological remodelling in animal models of the athletes heart. METHODSThe following experiments were performed in canines and mice after 16 or 6 weeks, respectively, of daily exercise training (ExT), and compared to sedentary (Sed) controls: ECG recording, echocardiography, pharmacological autonomic block, extrastimulus pacing, multielectrode array mapping, monophasic and intracellular action potential (AP) recording with custom-designed pattern recognition analysis, histology, RNAseq and spatial in situ transcriptomics. RESULTSAF propensity was significantly increased in ExT animals. Mapping studies identified heightened rotational activity in the PV-left atrial (LA) junction of ExT vs. Sed canines in vivo, and enhanced automaticity, triggered activity and AP duration variability ex vivo in ExT canines and mice. Intracellular recordings in mouse PV cardiomyocytes determined at least six AP subtypes with increased frequency of pacemaker-like APs in ExT PV, concomitant with increased expression of pacemaking HCN4, Cav1.3 and Cav3.1 channels. PV spontaneous excitability was also significantly enhanced. Subcellular resolution spatial transcriptomics in mouse PV-LA identified diffuse ion channel remodelling and activation of established AF-promoting pro-inflammatory and pro-fibrotic cytokines and chemokines in ExT PV cardiomyocytes. Conduction slowing in the ExT PV-LA junction was attributable to: gap junction remodelling, reduced Na+ channel expression and increased extracellular matrix deposition with enhanced myofibroblast number and proximity to PV cardiomyocytes. CONCLUSIONSEndurance exercise elicits proarrhythmic electro-anatomical remodelling of the PV-LA junction with enhanced pacemaking ion channel expression and immune-inflammatory pathway activation in PV myocytes as prominent contributors. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIThis work is the first demonstration that endurance training results in proarrhythmic electrophysiological remodelling of PV sleeve myocytes and extracellular matrix deposition in the PV-LA junction. C_LIO_LIWe register electrical and molecular heterogeneity of the PV-LA junction at single cell and subcellular resolution, and for the first time identify the molecular events that underlie increased proarrhythmic activity of the trained PV. These include enhanced pacemaking ion channel expression (e.g., HCN4, Cav1.3, and Cav3.1), pro-inflammatory cytokine activation (e.g., TNF, IL-6), increased myofibroblasts and extracellular matrix deposition. C_LI What are the clinical implications?O_LIWe identify the molecular determinants of PV proarrhythmic activity in the trained heart and present new therapeutic targets for AF prevention in athletes. C_LIO_LIOur findings provide mechanistic rationale for the efficacy of pulmonary vein isolation for AF in athletes. C_LI

physiology↗
bioRxiv2021

Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated primary human airway cells

BackgroundThere are limited effective prophylactic treatments for SARS-CoV-2 infection, and limited early treatment options. Viral cell entry requires spike protein binding to the ACE2 receptor and spike cleavage by TMPRSS2, a cell surface serine protease. Targeting of TMPRSS2 by either androgen blockade or direct inhibition is already in clinical trials in early SARS-CoV-2 infection. MethodsThe likely initial cells of SARS-CoV-2 entry are the ciliated cells of the upper airway. We therefore used differentiated primary human airway epithelial cells maintained at the air-liquid interface (ALI) to test the impact of targeting TMPRSS2 on the prevention of SARS-CoV-2 infection. ResultsWe first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor antagonist, had no impact on SARS-Cov-2 infection. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, camostat is rapidly metabolised in the circulation in vivo, and systemic bioavailability after oral dosing is low. We therefore modelled local airway administration by applying camostat to the apical surface of the differentiated ALI cultures. We demonstrated that a brief exposure to topical camostat is effective at restricting SARS-CoV-2 viral infection. ConclusionThese experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.

microbiology↗