bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/434456

Arrhythmia Mechanisms and Spontaneous Calcium Release: II - From Calcium Spark to Re-entry and Back

Colman, M. A.
View original source ↗Export metadata ↓

Abstract

MotivationThe role of sub-cellular spontaneous calcium release events (SCRE) in the development of arrhythmia associated with atrial and ventricular tachycardia and fibrillation has yet to be investigated in detail. SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. Furthermore, they can promote the substrate for conduction abnormalities. However, the potential interactions with re-entrant excitation have yet to be explored. The primary aim of this study was therefore to apply a novel computational approach to understand the multi-scale coupling between re-entrant excitation and SCRE.\n\nMethodsA general implementation of Spontaneous Release Functions - which reproduce the calcium dependent SCRE dynamics of detailed cell models at a significantly reduced computational cost - was used to reproduce SCRE in tissue models. Arrhythmic dynamics, such as rapid pacing and re-entry, were induced in the tissue models and the resulting interactions with SCRE were analysed.\n\nResultsIn homogeneous tissue, the emergence of a spontaneous beat from a single source was observed and the positive role of coupling was demonstrated. Conduction block could be promoted by SCRE by both inactivation of the fast sodium channel as well as focal pacing heterogeneity interactions. Sustained re-entrant excitation promoted calcium overload, and led to the emergence of focal excitations both after termination of re-entry and also during re-entrant excitation. These results demonstrated a purely functional mechanism of re-entry and focal activity localisation, related to the unexcited spiral wave core.\n\nConclusionsSCRE may interact with tissue excitation to promote and perpetuate arrhythmia through multiple mechanisms, including functional localisation and mechanism switching. These insights may be particularly relevant for successful pharmacological management of arrhythmia.

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Colman, M. A.. 2018-10-03. Arrhythmia Mechanisms and Spontaneous Calcium Release: II - From Calcium Spark to Re-entry and Back. https://doi.org/10.1101/434456

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Selective activation of estrogen receptors modulates electrical activity and insulin secretion in human EndoC-βH1 cells

Estrogen receptors (ERs), ER and ER{beta} have important roles in the physiology of the endocrine pancreas in animal models, but the effects of ER activation on insulin-secreting human cells are still poorly understood. Here, we investigated the role of ER and ER{beta} as modulators of electrical activity and insulin secretion in the insulin-secreting human cell line EndoC-{beta}H1. Immunocytochemical analysis revealed a widespread cellular distribution of ER, while ER{beta} was predominantly localized outside the nucleus. We observed that both estradiol (E2) and the ER{beta} agonist diarylpropionitrile (DPN) led to a decrease in insulin secretion in the absence of stimulatory glucose concentrations, without affecting insulin content. Patch-clamp experiments revealed that a 48-hour treatment with either the ER agonist PPT or DPN resulted in depolarization of the resting membrane potential, increased action potential firing frequency, and altered the action potential waveform in EndoC-{beta}H1 cells. PPT increased voltage-dependent Ca2+ channel currents, while DPN reduced K+ and Na+ currents. These results suggest that activation of ER and ER{beta} modulates beta-cell electrical activity through distinct pathways involving ion channels. The effects of E2, PPT, and DPN were not caused by altered expression levels of ion channel genes after 48 hours of treatment. This suggests that these receptors act extranuclearly without affecting gene expression. Together, our findings demonstrate that selective activation of ER and ER{beta} modulates beta-cell excitability through distinct electrophysiological mechanisms and that E2 and DPN reduce basal insulin secretion in human EndoC-{beta}H1 cells. These results support ER and ER{beta} as potential targets for modulating human pancreatic beta-cell function.

physiology↗
bioRxiv2026

Body weight modifies the efficacy of lifespan-extending interventions in ad libitum-fed mice

Geroprotective interventions are often assessed by extension of lifespan in ad libitum-fed mice. Increased lifespan could therefore reflect rescue of adverse phenotypes of unhealthy controls. We analysed body weight and survival for 33,780 mice in the Interventions Testing Program (ITP) to test whether treatment effects varied with body weight. In males, each added standard deviation of attained adult weight made treatment 6% more favourable (HR 0.94), more apparent for interventions that lowered body weight (HR 0.90). Median lifespan increase rose from 6.2% in mice in the lightest quartile to 20.2% in the heaviest pre-dosing weight quartile among those experiments, mainly because control survival declined more steeply with weight than that of the intervention group. The effect of body weight was consistent across 13 of 14 compounds and reflected weight attained during adulthood rather than in early life. Weight-dependence of intervention effects was weak in ITP females, possibly because median survival of controls exceeded that of every sampled non-ITP female control group. Amelioration of weight-associated risk is therefore implicated as a major contributor to lifespan increases relative to heavy, short-lived controls. The geroprotective effects of these interventions may thus be less apparent in metabolically healthier mice or humans.

physiology↗
bioRxiv2026

Single-nucleus analysis reveals renal STAT1/CEBPB signaling as a modifiable relay of proinflammatory FGF23 effects in diabetic kidney disease

Background Circulating fibroblast growth factor 23 (FGF23) rises dramatically in chronic kidney disease, particularly in diabetic kidney disease (DKD). At high concentrations, and with declining Klotho, FGF23 has been linked to renal inflammation. The cell types and transcriptional programs mediating these off-target actions remain undefined. We asked whether the diseased kidney responds to FGF23 differently from the healthy kidney, and whether any disease-specific response could be targeted. Methods Male and female DBA/2J mice received streptozotocin or vehicle to induce DKD. On day 56, mice received a single dose intravenous injection of FGF23 (0.3 g) or vehicle, with tissue collected 1 h later for single-nucleus RNA sequencing, differential expression and regulon (inferred transcription factor activity) analysis. Candidate pathways were tested in precision-cut kidney slices using the CEBPB inhibitor ST-101. Results Streptozotocin-treated male mice developed early DKD with a 6-fold increase in urinary albumin/creatinine ratio and 50% higher blood urea nitrogen with preserved glomerular filtration rate. All major renal cell types were annotated. Canonical FGF23 signaling was intact in disease, with segment-specific target induction conserved in both conditions (e.g. Cyp24a1 in PT-S1 and DCT1). Superimposed on this were disease-restricted responses, including Wsb1 in DCT1 and Pdk4 in PT-S2, PST, DCT1 and DCT2. Regulon analysis revealed DKD-specific induction of CEBPB regulon activity by FGF23 across all analyzed tubular segments, and of STAT1 in several segments. Pre-treatment with a CEBPB inhibitor suppressed CEBPB activity, downstream NF-KB and pro-inflammatory gene sets, and immune-like cell abundance in diseased slices. Conclusion In the diabetic kidney, FGF23 engages a STAT1-CEBPB-NF-{kappa}B axis absent from healthy kidney and extending beyond its canonical Klotho-dependent target segments, identifying CEBPB as a potential treatment target for FGF23's pathological inflammatory actions.

physiology↗