A5091371189- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Atrial Fibrillation Management and Outcomes
- Cardiac Arrhythmias and Treatments
- CRISPR and Genetic Engineering
- Cardiomyopathy and Myosin Studies
- Receptor Mechanisms and Signaling
- bioluminescence and chemiluminescence research
- Cardiac pacing and defibrillation studies
- Phosphodiesterase function and regulation
- Cardiac Fibrosis and Remodeling
- Cardiovascular Function and Risk Factors
- Neuroscience and Neural Engineering
- Nicotinic Acetylcholine Receptors Study
- Pluripotent Stem Cells Research
- Cardiac Imaging and Diagnostics
- Peptidase Inhibition and Analysis
- Adipose Tissue and Metabolism
- Neuroscience and Neuropharmacology Research
- Physiological and biochemical adaptations
- Protease and Inhibitor Mechanisms
- Cardiac Ischemia and Reperfusion
- Genetics, Aging, and Longevity in Model Organisms
- Cellular transport and secretion
- Heart Rate Variability and Autonomic Control
Manchester Academic Health Science Centre
2014-2024
University of Manchester
2015-2024
University of Utah
2023
Cardiovascular Research Center
2016-2019
Health Sciences Centre
2015
Manchester Royal Infirmary
2013
Katharinenhospital
2011
University of Leeds
2000-2004
In ventricular myocytes, the majority of structures that couple excitation to systolic rise Ca(2+) are located at transverse tubular (t-tubule) membrane. failing ventricle, disorganization t-tubules disrupts contraction coupling. The t-tubule membrane is virtually absent in atria small mammals resulting spatiotemporally distinct profiles intracellular release on stimulation atrial and cells. aims this study were determine (i) whether myocytes from a large mammal (sheep) possess t-tubules,...
Transverse (t) tubules are surface membrane invaginations that present in all mammalian cardiac ventricular cells. The apposition of L-type Ca(2+) channels on t with the sarcoplasmic reticulum (SR) constitutes a "calcium release unit" and allows close coupling excitation to rise systolic Ca(2+). T virtually absent atria small mammals, therefore from SR occurs initially at periphery cell then propagates into interior. Recent work has, however, shown occurrence atrial myocytes sheep. As...
Transverse tubules (t-tubules) regulate cardiac excitation-contraction coupling and exhibit interchamber interspecies differences in expression. In disease, t-tubule loss occurs affects the systolic calcium transient. However, mechanisms controlling maintenance whether these factors differ between species, chambers, a disease setting remain unclear.To determine role of Bin/Amphiphysin/Rvs domain protein amphiphysin II (AmpII) regulating transient.T-tubule density was assessed by di-4-ANEPPS,...
Atrial fibrillation (AF) is characterized by sustained high atrial activation rates and arrhythmogenic cellular Ca2+ signaling instability; however, it not clear how a rate instability may be related. Here, we subcellular after 5 days of in rabbit model. While some changes were similar to those persistent AF, identified distinct pattern stabilized signaling. sparks, waves, sarcoplasmic reticulum (SR) leak, SR content largely unaltered. Based on computational analysis, these findings...
CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up 16% efficiency in generating conditional (cKO or floxed) alleles by microinjection 2 single guide RNAs (sgRNA) single-stranded oligonucleotides as donors (referred herein "two-donor floxing" method).We re-evaluate two-donor method from a consortium 20 laboratories across...
Abstract Dysferlin is a 237 kDa membrane‐associated protein characterised by multiple C2 domains with diverse role in skeletal and cardiac muscle physiology. Mutations DYSF are known to cause various types of human muscular dystrophies, collectively as dysferlinopathies, some patients developing cardiomyopathy. A myriad vitro membrane repair studies suggest that dysferlin plays an integral the complex muscle. In comparison, less about heart, but mounting evidence suggests dysferlin's similar...
Abstract Aims Atrial fibrillation (AF) is a commonly occurring arrhythmia after cardiac surgery (postoperative AF, poAF) and associated with poorer outcomes. Considering that reduced atrial contractile function predictor of poAF Ca2+ plays an important role in both excitation–contraction coupling arrhythmogenesis, this study aims to test whether alterations intracellular handling contribute impaired contractility the arrhythmogenic substrate predisposing patients poAF. Methods results Right...
Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form disorganization transverse tubule network. Indeed, survival rates for HF are worse than many common cancers have not improved over time. Tadalafil clinically relevant drug that blocks phosphodiesterase 5 with high specificity used to treat erectile dysfunction. Using sheep model advanced HF, we show tadalafil treatment improves contractile function, reverses...
The force-frequency response is an important physiological mechanism regulating cardiac output changes and accompanied in vivo by beta-adrenergic stimulation. We sought to determine the role of sarcoplasmic reticulum (SR) Ca2+ content L-type current (ICa-L) frequency systolic transient alone during Experiments (on single rat ventricular myocytes) were designed be as possible. Under clamp stimulation SR increased line with (1-8 Hz) but was maximal at 6 Hz. voltage clamp, increasing decreased...
Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca2+ homeostatic and molecular mechanisms causing blunted β-adrenergic (β-AR) response in HF.We induced HF by tachypacing sheep; intracellular concentration was measured voltage-clamped ventricular myocytes. In HF, transient amplitude peak L-type current (ICa-L) were reduced (to 70 ± 11% 50 3.7% control, respectively, P <0.05) whereas sarcoplasmic reticulum (SR) content unchanged....
The atria contribute 25% to ventricular stroke volume and are the site of commonest cardiac arrhythmia, atrial fibrillation (AF). initiation contraction in is similar that ventricle involving a systolic rise intracellular Ca(2+) concentration ([Ca(2+)](i)). There are, however, substantial inter-species differences way regulated cells. These consequence well-developed functionally relevant transverse (t)-tubule network large mammals, including humans, its virtual absence smaller laboratory...
The glycine-tyrosine-glycine (GYG) sequence in the p-loop of K+ channel subunits lines a narrow pore through which ions pass single file intercalated by water molecules. Mutation motif can give rise to non-selective channels, but it is clear that other structural features are also required for selectivity because, instance, recently identified class cyclic nucleotide-gated pacemaker channels has GYG poorly selective. We show mutation charged glutamate and arginine residues behind filter...
AimsDuring activation of cardiac myocytes, less than 1% cytosolic Ca is free; the rest bound to buffers, largely SERCA, and troponin C. Signalling by phosphorylation, as occurs during β-adrenergic stimulation, changes Ca-binding affinity these proteins may affect systolic transient. Our aim was determine effects stimulation on buffering differentiate between roles SERCA troponin.