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Article ; Online: Adrenoceptor sub-type involvement in Ca

Saxena, Priyanka / Myles, Rachel C / Smith, Godfrey L / Workman, Antony J

Pflugers Archiv : European journal of physiology

2022 Volume 474, Issue 12, Page(s) 1311–1321

Abstract: Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type ... ...

Abstract	Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca
MeSH term(s)	Animals ; Humans ; Rabbits ; Atrial Fibrillation/physiopathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/physiology ; Norepinephrine/pharmacology ; Norepinephrine/physiology ; Prazosin/pharmacology ; Receptors, Adrenergic, alpha-2 ; Heart Atria/cytology ; Receptors, Adrenergic, beta/physiology ; Receptors, Adrenergic, alpha/physiology ; Adrenergic alpha-Antagonists/pharmacology ; Adrenergic beta-Antagonists/pharmacology ; Calcium Channels, L-Type/physiology
Chemical Substances	Norepinephrine (X4W3ENH1CV) ; Prazosin (XM03YJ541D) ; Receptors, Adrenergic, alpha-2 ; Receptors, Adrenergic, beta ; Receptors, Adrenergic, alpha ; Adrenergic alpha-Antagonists ; Adrenergic beta-Antagonists ; Calcium Channels, L-Type
Language	English
Publishing date	2022-09-22
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-022-02746-z
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Article: Role of Reduced Sarco-Endoplasmic Reticulum Ca

Wang, Lianguo / Myles, Rachel C / Lee, I-Ju / Bers, Donald M / Ripplinger, Crystal M

Frontiers in physiology

2021 Volume 12, Page(s) 656516

Abstract: Sarcoplasmic reticulum (SR) ... ...

Abstract	Sarcoplasmic reticulum (SR) Ca
Language	English
Publishing date	2021-05-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.656516
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Article ; Online: Cardiotoxic effects of angiogenesis inhibitors.

Dobbin, Stephen J H / Petrie, Mark C / Myles, Rachel C / Touyz, Rhian M / Lang, Ninian N

Clinical science (London, England : 1979)

2021 Volume 135, Issue 1, Page(s) 71–100

Abstract: The development of new therapies for cancer has led to dramatic improvements in survivorship. Angiogenesis inhibitors represent one such advancement, revolutionising treatment for a wide range of malignancies. However, these drugs are associated with ... ...

Abstract	The development of new therapies for cancer has led to dramatic improvements in survivorship. Angiogenesis inhibitors represent one such advancement, revolutionising treatment for a wide range of malignancies. However, these drugs are associated with cardiovascular toxicities which can impact optimal cancer treatment in the short-term and may lead to increased morbidity and mortality in the longer term. Vascular endothelial growth factor inhibitors (VEGFIs) are associated with hypertension, left ventricular systolic dysfunction (LVSD) and heart failure as well as arterial and venous thromboembolism, QTc interval prolongation and arrhythmia. The mechanisms behind the development of VEGFI-associated LVSD and heart failure likely involve the combination of a number of myocardial insults. These include direct myocardial effects, as well as secondary toxicity via coronary or peripheral vascular damage. Cardiac toxicity may result from the 'on-target' effects of VEGF inhibition or 'off-target' effects resulting from inhibition of other tyrosine kinases. Similar mechanisms may be involved in the development of VEGFI-associated right ventricular (RV) dysfunction. Some VEGFIs can be associated with QTc interval prolongation and an increased risk of ventricular and atrial arrhythmia. Further pre-clinical and clinical studies and trials are needed to better understand the impact of VEGFI on the cardiovascular system. Once mechanisms are elucidated, therapies can be investigated in clinical trials and surveillance strategies for identifying VEGFI-associated cardiovascular complications can be developed.
MeSH term(s)	Angiogenesis Inhibitors/adverse effects ; Animals ; Cardiotoxicity/pathology ; Cardiotoxicity/physiopathology ; Clinical Trials as Topic ; Humans ; Models, Biological ; Vascular Endothelial Growth Factor A/metabolism ; Ventricular Dysfunction, Left/physiopathology
Chemical Substances	Angiogenesis Inhibitors ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2021-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20200305
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Article ; Online: Sperm Toolbox-A selection of small molecules to study human spermatozoa.

Gruber, Franz S / Richardson, Anthony / Johnston, Zoe C / Myles, Rachel / Norcross, Neil R / Day, David P / Georgiou, Irene / Sesma-Sanz, Laura / Wilson, Caroline / Read, Kevin D / Martins da Silva, Sarah / Barratt, Christopher L R / Gilbert, Ian H / Swedlow, Jason R

PloS one

2024 Volume 19, Issue 2, Page(s) e0297666

Abstract: Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit ... ...

Abstract	Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.
MeSH term(s)	Humans ; Male ; Sperm Motility ; Semen ; Spermatozoa/metabolism ; Acrosome Reaction ; Fertility
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0297666
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Article ; Online: Initiation of ventricular arrhythmia in the acquired long QT syndrome.

Alexander, Cherry / Bishop, Martin J / Gilchrist, Rebecca J / Burton, Francis L / Smith, Godfrey L / Myles, Rachel C

Cardiovascular research

2022 Volume 119, Issue 2, Page(s) 465–476

Abstract: Aims: Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), ... ...

Abstract	Aims: Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS). Methods and results: Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (P < 0.0001 vs. control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and peak VGs were more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs. 44 ± 27 ms, P < 0.0001) and spatially (1.0 ± 0.7 vs. 3.6 ± 0.9 mm, P < 0.0001). PVCs were initiated at estimated voltages of ∼ -40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with ICaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of ICaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL, respectively) abolished both PVCs and TdP in the continued presence of aLQTS. Conclusion: These data demonstrate that ICaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS.
MeSH term(s)	Animals ; Rabbits ; Calcium ; Long QT Syndrome ; Torsades de Pointes/chemically induced ; Action Potentials ; Ventricular Premature Complexes ; DNA-Binding Proteins ; Electrocardiography
Chemical Substances	Calcium (SY7Q814VUP) ; DNA-Binding Proteins
Language	English
Publishing date	2022-06-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvac103
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Article ; Online: Adverse Outcomes Associated With Interleukin-6 in Patients Recently Hospitalized for Heart Failure With Preserved Ejection Fraction.

Mooney, Leanne / Jackson, Colette E / Adamson, Carly / McConnachie, Alex / Welsh, Paul / Myles, Rachel C / McMurray, John J V / Jhund, Pardeep S / Petrie, Mark C / Lang, Ninian N

Circulation. Heart failure

2023 Volume 16, Issue 4, Page(s) e010051

Abstract: ... Biomarkers including hsCRP (high-sensitivity C-reactive protein) were assessed.: Results: The range of IL ...

Abstract	Background: Inflammation may play a role in the pathophysiology of heart failure with preserved ejection fraction. We examined whether circulating levels of interleukin-6 identify patients at greater risk of adverse outcomes following hospitalization with heart failure with preserved ejection fraction. Methods: We assessed relationships between interleukin-6 (IL-6) tertiles (T1-3) and all-cause death, cardiovascular death, and subsequent heart failure hospitalization (sHFH) in 286 patients recently hospitalized with heart failure with preserved ejection fraction. Associations between IL (interleukin)-6 and outcomes were examined in a Cox-regression model adjusted for risk factors including BNP (B-type natriuretic peptide). Biomarkers including hsCRP (high-sensitivity C-reactive protein) were assessed. Results: The range of IL-6 (pg/mL) in each tertile was T1 (0.71-4.16), T2 (4.20-7.84), and T3 (7.9-236.32). Compared with T1, patients in the highest IL-6 tertile were more commonly male (56% versus 35%) and had higher creatinine (117±45 versus 101±36 μmol/L), hsCRP (11.6 [4.9-26.6]mg/L versus 2.3[1.1-4.2] mg/L). In univariable analysis, rates of all-cause death, cardiovascular death, and sHFH were higher in T3 versus T1. All-cause and cardiovascular death rates remained higher in T3 versus T1 after adjustment ( Conclusions: In patients recently hospitalized with heart failure with preserved ejection fraction, IL-6 is an independent predictor of all-cause mortality, cardiovascular death, and sHFH after adjustment for risk factors including BNP. These findings are of particular relevance in the context of current anti-IL-6 drug development.
MeSH term(s)	Humans ; Male ; Heart Failure/diagnosis ; Heart Failure/therapy ; Heart Failure/complications ; Interleukin-6 ; Stroke Volume/physiology ; C-Reactive Protein ; Prognosis ; Natriuretic Peptide, Brain
Chemical Substances	Interleukin-6 ; C-Reactive Protein (9007-41-4) ; Natriuretic Peptide, Brain (114471-18-0)
Language	English
Publishing date	2023-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429459-7
ISSN	1941-3297 ; 1941-3289
ISSN (online)	1941-3297
ISSN	1941-3289
DOI	10.1161/CIRCHEARTFAILURE.122.010051
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Article ; Online: A novel method for the percutaneous induction of myocardial infarction by occlusion of small coronary arteries in the rabbit.

Freeman, Michael / Huethorst, Eline / Boland, Erin / Dunne, Michael / Burton, Francis / Denning, Chris / Myles, Rachel / Smith, Godfrey

American journal of physiology. Heart and circulatory physiology

2024 Volume 326, Issue 3, Page(s) H735–H751

Abstract: Arrhythmic sudden cardiac death (SCD) is an important cause of mortality following myocardial infarction (MI). The rabbit has similar cardiac electrophysiology to humans and is therefore an important small animal model to study post-MI arrhythmias. The ... ...

Abstract	Arrhythmic sudden cardiac death (SCD) is an important cause of mortality following myocardial infarction (MI). The rabbit has similar cardiac electrophysiology to humans and is therefore an important small animal model to study post-MI arrhythmias. The established approach of surgical coronary ligation results in thoracic adhesions that impede epicardial electrophysiological studies. Adhesions are absent following a percutaneously induced MI, which is also associated with reduced surgical morbidity and so represents a clear refinement of the approach. Percutaneous procedures have previously been described in large rabbits (3.5-5.5 kg). Here, we describe a novel method of percutaneous MI induction in smaller rabbits (2.5-3.5 kg) that are readily available commercially. New Zealand White rabbits (
MeSH term(s)	Humans ; Male ; Rabbits ; Animals ; Swine ; Coronary Vessels/diagnostic imaging ; Coronary Vessels/surgery ; Coronary Vessels/pathology ; Myocardial Infarction/pathology ; Heart ; Coronary Occlusion/complications ; Coronary Occlusion/diagnostic imaging ; Cardiac Surgical Procedures/adverse effects ; Arrhythmias, Cardiac/complications ; Percutaneous Coronary Intervention/adverse effects
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00657.2023
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Article ; Online: Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes.

Lachaud, Quentin / Aziz, Muhamad Hifzhudin Noor / Burton, Francis L / Macquaide, Niall / Myles, Rachel C / Simitev, Radostin D / Smith, Godfrey L

Cardiovascular research

2021 Volume 118, Issue 15, Page(s) 3112–3125

Abstract: Aims: Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents ... ...

Abstract	Aims: Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells. Methods and results: APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK. Conclusion: Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.
MeSH term(s)	Animals ; Rabbits ; Ion Channels ; Myocytes, Cardiac/physiology
Chemical Substances	Ion Channels
Language	English
Publishing date	2021-11-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvab375
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Article ; Online: Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis.

Nature communications

2024 Volume 15, Issue 1, Page(s) 2398

Abstract: The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to ... ...

Abstract	The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment.
MeSH term(s)	Humans ; Arthritis, Rheumatoid ; Axl Receptor Tyrosine Kinase ; c-Mer Tyrosine Kinase/genetics ; c-Mer Tyrosine Kinase/metabolism ; Inflammation/metabolism ; Interleukin-6/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Synovial Membrane/metabolism
Chemical Substances	Axl Receptor Tyrosine Kinase ; c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Interleukin-6 ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; IL6 protein, human ; MERTK protein, human (EC 2.7.10.1) ; AXL protein, human
Language	English
Publishing date	2024-03-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46564-6
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Article ; Online: Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias.

Gardner, Ryan T / Ripplinger, Crystal M / Myles, Rachel C / Habecker, Beth A

Circulation. Arrhythmia and electrophysiology

2016 Volume 9, Issue 2, Page(s) e001359

MeSH term(s)	Animals ; Arrhythmias, Cardiac/diagnosis ; Arrhythmias, Cardiac/etiology ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/physiopathology ; Heart/innervation ; Heart Rate ; Humans ; Myocardium/metabolism ; Myocardium/pathology ; Nerve Degeneration ; Neuronal Plasticity ; Norepinephrine/metabolism ; Risk Factors ; Sympathetic Nervous System/metabolism ; Sympathetic Nervous System/physiopathology
Chemical Substances	Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2016-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2426129-4
ISSN	1941-3084 ; 1941-3149
ISSN (online)	1941-3084
ISSN	1941-3149
DOI	10.1161/CIRCEP.115.001359
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