Biology subjects

Mott, L. R.

Publications and source records attributed to Mott, L. R..

3 recordsLinked to original sources

bioRxiv2026

Sex-specific electrophysiology and cholinergic responses underlie differential mechanisms of arrhythmia vulnerability in rabbit atria

BackgroundSex differences in the epidemiology of atrial fibrillation are well-documented; however, the underlying mechanisms remain poorly understood. This gap in knowledge is compounded by limited data on sex-specific atrial electrophysiology in the absence of disease. ObjectivesThe aim of this study was to investigate sex differences in atrial electrophysiology and arrhythmia susceptibility in a translationally-relevant rabbit model. MethodsDual optical mapping of transmembrane voltage and Ca2+ was performed on intact atria of young (3.5-5 months) male and female rabbit hearts. Baseline atrial electrophysiology and arrhythmia susceptibility were investigated using rapid pacing and premature stimulation and further tested with the parasympathomimetic carbachol. Sex and regional differences in gene expression were assessed using qPCR. ResultsFemales exhibited similar action potential duration (APD), but greater APD heterogeneity across the atria at slower rates, along with longer Ca2+ transient durations compared to males. Greater APD heterogeneity in females was rate-dependent and comparable to males at faster pacing frequencies; however, it was associated with greater susceptibility to transient reentrant arrhythmias with premature stimuli. After carbachol application, males had heightened vulnerability to arrhythmia. This was associated with cholinergic-mediated APD shortening in both atria in males, but only in the right atrium in females. Sex differences in carbachol responses were linked to variations in muscarinic receptor and acetylcholine-activated potassium channel gene expression. ConclusionsThese findings demonstrate sex and regional differences in atrial electrophysiology at baseline and in response to cholinergic stimulation in the healthy heart that may contribute to sex-specific mechanisms of arrhythmia.

physiology↗

bioRxiv2025

Multi-parametric imaging of spatio-temporal cAMP signaling, transmembrane potential, and intracellular calcium in the Langendorff-perfused heart

The spatiotemporal dynamics of intracellular second messengers and signaling molecules, including cyclic adenosine monophosphate (cAMP), have been studied extensively in isolated cardiomyocytes using Forster resonance energy transfer (FRET)-based reporters. However, little is known about how molecular signaling events affect tissue-level function. Optical mapping of transmembrane potential (Vm) and intracellular calcium (Ca2+i) is frequently performed in isolated intact hearts to reveal tissue-level electrophysiological function but cannot reveal molecular underpinnings. Here, we developed a novel multi-parametric optical imaging system that enables multi-parametric recording of four wavelengths to visualize cAMP and real-time electrophysiological responses (Vm and Ca2+i) by utilizing concurrent FRET imaging and dual optical mapping (FRE-DOM) in the intact heart from a cardiac-specific FRET-based cAMP reporter mouse. We showed that cAMP is strongly and heterogeneously activated throughout the heart (atria and ventricles) in response to {beta}-AR stimulation, the time course of which matches heart rate, action potential, and Ca2+ responses. This novel imaging system will provide insight into the relationship between cAMP signaling, electrophysiology, and arrhythmogenesis at high spatio-temporal resolution.

bioengineering↗

bioRxiv2023

Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart

Nicotine is the primary addictive component in tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. However, the underlying mechanisms are unclear. To address this, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days prior to performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the 1st - 3rd thoracic vertebrae, and {beta}-adrenergic responsiveness was additionally evaluated as changes in heart rate (HR) following norepinephrine (NE) perfusion. Baseline ex vivo HR and SNS stimulation threshold were increased in NIC vs. CT (P = 0.004 and P = 0.003 respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC vs. CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS reduced the PCL at which alternans emerged in CT but not NIC hearts. NIC exposed hearts also tended to have slower and reduced HR responses to NE perfusion. While fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content vs. CT. These results suggest both sympathetic hypo-innervation of the myocardium and diminished {beta}-adrenergic responsiveness with NIC. This autonomic remodeling may underlie the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with continued long-term usage. NEW & NOTEWORTHYHere we show that chronic nicotine exposure was associated with increased heart rate, lower threshold for alternans and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to the sympathetic hypo-innervation of the myocardium and diminished {beta}- adrenergic responsiveness observed following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this pro-arrhythmic remodeling.

physiology↗