Biology subjects

Hoeker, G. S.

Publications and source records attributed to Hoeker, G. S..

2 recordsLinked to original sources

bioRxiv2023

EXTRACELLULAR PERINEXAL SEPARATION IS A PRINCIPAL DETERMINANT OF CARDIAC CONDUCTION

RationaleCardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular volume. Ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs. ObjectiveDetermine the relationship between ventricular CV and structural changes to micro and nano-scale extracellular spaces. MethodsConduction and connexin43 (Cx43) gap junction protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with albumin, mannitol, dextran 70kDa, or dextran 2MDa. Peak sodium current was quantified from isolated guinea pig ventricular myocytes. Extracellular resistance (Re) was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. ResultsCV was significantly reduced by mannitol, and increased by albumin, dextran 70kDa and 2MDa. The combination of albumin and dextran 70kDa decreased CV relative to albumin alone. Re was reduced by mannitol, not significantly changed by albumin, and increased by both dextran 70kDa and dextran 2MDa. Cx43 gap junction expression and conductance, and peak sodium current were not significantly altered by the osmotic agents. The perinexal width in response to osmotic agents, in order of narrowest to widest, was: albumin with dextran 70kDa, albumin or dextran 2MDa alone, dextran 70kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. ConclusionsCardiac conduction does not correlate with bulk tissue impedance, but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume in ventricular myocardium is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.

biophysics↗

bioRxiv2022

Acute adenoviral cardiac infection elicits an arrhythmogenic substrate prior to inflammatory myocardial remodeling and myocarditis

BackgroundViral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases, and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate prior to significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species-specificity, models of infection are lacking and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse Adenovirus Type-3 (MAdV-3) was previously reported as cardiotropic, yet has not been utilized to understand mechanisms of cardiac infection and pathology. MethodsWe have developed MAdV-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart prior to an appreciable immune response or gross cardiomyopathy. ResultsOptical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against MAdV-3 induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of MAdV-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 (HAdV-5) increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. ConclusionsTogether, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.

pathology↗