P321Subthreshold delayed afterdepolarizations form a substrate for conduction block in the infarcted heart

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
F Campos ◽  
Y Shiferaw ◽  
G Plank ◽  
M J Bishop
Keyword(s):  
Sodium Current ◽  
Conduction Block ◽  
Computational Modelling ◽  
Border Zone ◽  
Loss Of Function ◽  
Physical Sciences ◽  
Tissue Conductivity ◽  
Infarcted Heart ◽  
Coupling Interval ◽  
Delayed Afterdepolarizations

Abstract Funding Acknowledgements National Institute for Health Research; British Heart Foundation; and The Wellcome Trust and Engineering and Physical Sciences Research Council. Background Delayed afterdepolarizations (DADs) due to spontaneous calcium (Ca) release (SCR) events from the sarcoplasmic reticulum have been implicated with a variety of arrhythmias. Such SCR events have also been reported in cells that survive in the infarct border zone (BZ). While the potential of Ca-mediated DADs to become suprathreshold and propagate in the form of ectopic beats has been well characterized, the role of subthreshold DADs in arrhythmia formation in the infarcted heart remains to be elucidated. Purpose To use computational modelling to investigate whether subthreshold Ca-mediated DADs may form a substrate for conduction block and reentry in the BZ. Our hypothesis is that subthreshold DADs can hinder local tissue excitability in critical infarct BZ regions by inactivating the fast sodium current (INa), leading to temporary unidirectional conduction block providing a trigger for arrhythmogenesis. Methods We developed an idealized infarct model of the left ventricle. The infarct region consisted of a non-conducting scar transcended by an isthmus of cells that survived myocardial infarction (border zone). These cells were made prone to Ca-mediated DADs described by a phenomenological model of SCR events. The model was pre-paced at the apex followed by a 1500ms-pacing pause to see whether DADs would emerge. An extra beat with a longer coupling interval (CI) was then applied. The following electrophysiological changes resulting from remodeling processes in the isthmus were simulated to assess their contribution to the arrhythmogenic potential of subthreshold DADs: INa loss-of-function due to a (2.5mV and 5mV) negative-shift in the steady-state channel inactivation; 50% reduction in tissue conductivity; and increased levels of fibrosis (up to 50%). Results On average, Ca-mediated DADs reached their maximum value 1065ms after the last paced beat (Fig. A). Despite this, in the default electrophysiological setup, simulations with extra beats with 1000ms > CI > 1100ms did not result in conduction block in any of the experiments. When repeated with combined changes of reduced tissue conductivity and fibrosis, subthreshold DADs were still unable to create a substrate for block. However, when combined with a 5mV-shift in INa inactivation, block at isthmus’ mouth proximal to the stimulus site was detected for extra beats 1010 ms ≥ CI ≥ 1070ms (see Fig. B). The cause of block was due to a subthreshold DAD occurring just prior to the arrival of the extra beat. All blocked beats degenerated into reentry. Conclusions Under most physiological conditions, subthreshold DADs are unlikely to provide a substrate for unidirectional block. However, under conditions of decreased excitability, subthreshold DADs can hinder tissue excitability in the infarcted region leading to conduction block and reentry. Abstract Figure. DAD-mediated conduction block in the BZ

scholarly journals Electrophysiological and anatomical factors determine arrhythmic risk in acute myocardial ischaemia and its modulation by sodium current availability

2020 ◽  
Vol 11 (1) ◽  
pp. 20190124 ◽  
Author(s):  
Hector Martinez-Navarro ◽  
Xin Zhou ◽  
Alfonso Bueno-Orovio ◽  
Blanca Rodriguez
Keyword(s):  
Right Ventricle ◽  
Myocardial Ischaemia ◽  
High Performance ◽  
Sodium Current ◽  
Conduction Block ◽  
Border Zone ◽  
Acute Ischaemia ◽  
Current Availability ◽  
Artery Disease ◽  
The Right

Acute myocardial ischaemia caused by coronary artery disease is one of the main causes of sudden cardiac death. Even though sodium current blockers are used as anti-arrhythmic drugs, decreased sodium current availability, also caused by mutations, has been shown to increase arrhythmic risk in ischaemic patients. The mechanisms are still unclear. Our goal is to exploit perfect control and data transparency of over 300 high-performance computing simulations to investigate arrhythmia mechanisms in acute myocardial ischaemia with variable sodium current availability. The human anatomically based torso-biventricular electrophysiological model used includes representation of realistic ventricular anatomy and fibre architecture, as well as ionic to electrocardiographic properties. Simulations show that reduced sodium current availability increased arrhythmic risk in acute regional ischaemia due to both electrophysiological (increased dispersion of refractoriness across the ischaemic border zone) and anatomical factors (conduction block from the thin right ventricle to thick left ventricle). The asymmetric ventricular anatomy caused high arrhythmic risk specifically for ectopic stimuli originating from the right ventricle and ventricular base. Increased sodium current availability was ineffective in reducing arrhythmic risk for septo-basal ectopic excitation. Human-based multiscale modelling and simulations reveal key electrophysiological and anatomical factors determining arrhythmic risk in acute ischaemia with variable sodium current availability.

BDV-syndrome: An emerging syndrome with profound obesity and neurodevelopmental delay resembling Prader-Willi syndrome

2021 ◽  
Author(s):  
Elisabeth Bosch ◽  
Moritz Hebebrand ◽  
Bernt Popp ◽  
Theresa Penger ◽  
Bettina Behring ◽  
...  
Keyword(s):  
Clinical Features ◽  
Large Scale ◽  
Hypogonadotropic Hypogonadism ◽  
Computational Modelling ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Human Phenotype ◽  
Neurodevelopmental Delay ◽  
Missense Variants ◽  
Severely Obese

Abstract Context CPE encodes carboxypeptidase E, an enzyme which converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, four individuals from two families with core clinical features including morbid obesity, neurodevelopmental delay and hypogonadotropic hypogonadism, harbouring biallelic loss-of-function CPE variants, were reported. Objective We describe four affected individuals from three unrelated consanguineous families, two siblings of Syrian, one of Egyptian and one of Pakistani descent, all harbouring novel homozygous CPE loss-of-function variants. Methods After excluding Prader-Willi syndrome, exome sequencing was performed in both Syrian siblings. The variants identified in the other two individuals were reported as research variants in a large scale exome study and in ClinVar database. Computational modelling of all possible missense alterations allowed assessing CPE tolerance to missense variants. Results All affected individuals were severely obese with neurodevelopmental delay and other endocrine anomalies. Three individuals from two families shared the same CPE homozygous truncating variant c.361C>T, p.(Arg121*), while the fourth carried the c.994del, p.(Ser333Alafs*22) variant. Comparison of clinical features with previously described cases and standardization according to the Human Phenotype Ontology indicated a recognisable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes. Conclusions Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognisable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism and hypothyroidism. BDV syndrome resembles Prader-Willi syndrome. Our findings suggested that missense variants may also be clinically relevant.

scholarly journals pigkMutation underliesmachobehavior and affects Rohon-Beard cell excitability

2015 ◽  
Vol 114 (2) ◽  
pp. 1146-1157 ◽  
Author(s):  
V. Carmean ◽  
M. A. Yonkers ◽  
M. B. Tellez ◽  
J. R. Willer ◽  
G. B. Willer ◽  
...  
Keyword(s):  
Action Potential ◽  
Sensory Neurons ◽  
Sodium Current ◽  
Genetic Defect ◽  
Sensory Cells ◽  
Loss Of Function ◽  
Wild Type ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Touch Response

The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons.

scholarly journals Sodium channel β1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis

2020 ◽  
Vol 295 (30) ◽  
pp. 10380-10393 ◽  
Author(s):  
Alexandra A. Bouza ◽  
Julie M. Philippe ◽  
Nnamdi Edokobi ◽  
Alexa M. Pinsky ◽  
James Offord ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Sodium Channel ◽  
Tyrosine Phosphorylation ◽  
Sodium Current ◽  
Epileptic Encephalopathy ◽  
Proteolytic Processing ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Intramembrane Proteolysis ◽  
Regulated Intramembrane Proteolysis

Voltage-gated sodium channel (VGSC) β1 subunits are multifunctional proteins that modulate the biophysical properties and cell-surface localization of VGSC α subunits and participate in cell–cell and cell–matrix adhesion, all with important implications for intracellular signal transduction, cell migration, and differentiation. Human loss-of-function variants in SCN1B, the gene encoding the VGSC β1 subunits, are linked to severe diseases with high risk for sudden death, including epileptic encephalopathy and cardiac arrhythmia. We showed previously that β1 subunits are post-translationally modified by tyrosine phosphorylation. We also showed that β1 subunits undergo regulated intramembrane proteolysis via the activity of β-secretase 1 and γ-secretase, resulting in the generation of a soluble intracellular domain, β1-ICD, which modulates transcription. Here, we report that β1 subunits are phosphorylated by FYN kinase. Moreover, we show that β1 subunits are S-palmitoylated. Substitution of a single residue in β1, Cys-162, to alanine prevented palmitoylation, reduced the level of β1 polypeptides at the plasma membrane, and reduced the extent of β1-regulated intramembrane proteolysis, suggesting that the plasma membrane is the site of β1 proteolytic processing. Treatment with the clathrin-mediated endocytosis inhibitor, Dyngo-4a, re-stored the plasma membrane association of β1-p.C162A to WT levels. Despite these observations, palmitoylation-null β1-p.C162A modulated sodium current and sorted to detergent-resistant membrane fractions normally. This is the first demonstration of S-palmitoylation of a VGSC β subunit, establishing precedence for this post-translational modification as a regulatory mechanism in this protein family.

scholarly journals Model of Bipolar Electrogram Fractionation and Conduction Block Associated With Activation Wavefront Direction at Infarct Border Zone Lateral Isthmus Boundaries

2014 ◽  
Vol 7 (1) ◽  
pp. 152-163 ◽  
Author(s):  
Edward J. Ciaccio ◽  
Hiroshi Ashikaga ◽  
James Coromilas ◽  
Bruce Hopenfeld ◽  
Daniel O. Cervantes ◽  
...  
Keyword(s):  
Conduction Block ◽  
Border Zone ◽  
Infarct Border Zone ◽  
Infarct Border

scholarly journals MicroRNA-1 transfected embryonic stem cells enhance cardiac myocyte differentiation and inhibit apoptosis by modulating the PTEN/Akt pathway in the infarcted heart

2011 ◽  
Vol 301 (5) ◽  
pp. H2038-H2049 ◽  
Author(s):  
Carley Glass ◽  
Dinender K. Singla
Keyword(s):  
Cell Differentiation ◽  
Cardiac Myocyte ◽  
Heart Function ◽  
Es Cells ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Border Zone ◽  
Es Cell ◽  
Infarcted Heart ◽  
Myocyte Differentiation

microRNAs (miRs) have emerged as critical modulators of various physiological processes including stem cell differentiation. Indeed, miR-1 has been reported to play an integral role in the regulation of cardiac muscle progenitor cell differentiation. However, whether overexpression of miR-1 in embryonic stem (ES) cells (miR-1-ES cells) will enhance cardiac myocyte differentiation following transplantation into the infarcted myocardium is unknown. In the present study, myocardial infarction (MI) was produced in C57BL/6 mice by left anterior descending artery ligation. miR-1-ES cells, ES cells, or culture medium (control) was transplanted into the border zone of the infarcted heart, and 2 wk post-MI, cardiac myocyte differentiation, adverse ventricular remodeling, and cardiac function were assessed. We provide evidence demonstrating enhanced cardiac myocyte commitment of transplanted miR-1-ES cells in the mouse infarcted heart as compared with ES cells. Assessment of apoptosis revealed that overexpression of miR-1 in transplanted ES cells protected host myocardium from MI-induced apoptosis through activation of p-AKT and inhibition of caspase-3, phosphatase and tensin homolog, and superoxide production. A significant reduction in interstitial and vascular fibrosis was quantified in miR-1-ES cell and ES cell transplanted groups compared with control MI. However, no statistical significance between miR-1-ES cell and ES cell groups was observed. Finally, mice receiving miR-1-ES cell transplantation post-MI had significantly improved heart function compared with respective controls ( P < 0.05). Our data suggest miR-1 drives cardiac myocyte differentiation from transplanted ES cells and inhibits apoptosis post-MI, ultimately giving rise to enhanced cardiac repair, regeneration, and function.

scholarly journals Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation

2019 ◽  
Vol 125 (1) ◽  
pp. 55-70 ◽  
Author(s):  
Bijun Chen ◽  
Shuaibo Huang ◽  
Ya Su ◽  
Yi-Jin Wu ◽  
Anis Hanna ◽  
...  
Keyword(s):  
Growth Factor ◽  
Milk Fat ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Receptor Expression ◽  
Border Zone ◽  
Macrophage Function ◽  
Infarcted Heart ◽  
Anti Inflammatory

Rationale: TGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad pathways. The in vivo role of TGF-β signaling in regulation of macrophage function is poorly understood. We hypothesized that in the infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling. Objective: To investigate the role of macrophage-specific TGF-β Smad3 signaling in a mouse model of myocardial infarction and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function. Methods and Results: TGF-βs markedly activated Smad3 in macrophages, without affecting Smad-independent pathways. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β release. MyS3KO (myeloid cell–specific Smad3 knockout) mice had no baseline defects but exhibited increased late mortality and accentuated dilative postmyocardial infarction remodeling. Adverse outcome in infarcted MyS3KO mice was associated with perturbations in phagocytic activity, defective transition of macrophages to an anti-inflammatory phenotype, scar expansion, and accentuated apoptosis of border zone cardiomyocytes. In vitro, Smad3 null macrophages exhibited reduced expression of genes associated with eat-me signals, such as Mfge8 (milk fat globule-epidermal growth factor factor 8), and reduced capacity to produce the anti-inflammatory mediators IL (interleukin)-10 and TGF-β1, and the angiogenic growth factor VEGF (vascular endothelial growth factor). Mfge8 partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Impaired anti-inflammatory actions of Smad3 null macrophages were associated with marked attenuation of phagocytosis-induced PPAR (peroxisome proliferator-activated receptor) expression. MyS3KO mice had no significant alterations in microvascular density and interstitial fibrosis in remodeling myocardial segments. Conclusions: We demonstrate that Smad3 critically regulates function of infarct macrophages, by mediating acquisition of a phagocytic phenotype and by contributing to anti-inflammatory transition. Smad3-dependent actions in macrophages protect the infarcted heart from adverse remodeling.

scholarly journals Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

2020 ◽  
Author(s):  
Zeina R Al Sayed ◽  
Robin Canac ◽  
Bastien Cimarosti ◽  
Carine Bonnard ◽  
Jean-Baptiste Gourraud ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Electrical Conduction ◽  
Sodium Current ◽  
Single Gene ◽  
Gene Mutations ◽  
Cardiac Conduction ◽  
Human Model ◽  
Loss Of Function ◽  
Cardiac Electrical Activity

Abstract Aims Several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Methods and results Using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Conclusion Altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases.

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