“Trapped reentry” as a dormant source of acute focal arrhythmia and fractionated atrial electrograms under sinus rhythm

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T De Coster ◽  
A.S Teplenin ◽  
I Feola ◽  
T.J Van Brakel ◽  
A.A.F De Vries ◽  
...  
Keyword(s):  
Sinus Rhythm ◽  
Acute Onset ◽  
Neonatal Rat ◽  
Funding Source ◽  
Geometrical Properties ◽  
Conduction Pathway ◽  
Atrial Electrograms ◽  
Public Grant ◽  
Source Sink

Abstract Background Diseased atria are characterised by functional and structural heterogeneities (e.g. dense fibrotic regions), which add to abnormal impulse generation and propagation, like ectopy and block. These heterogeneities are thought to play a role in the origin of complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) in atrial fibrillation (AF) patients, but also in the onset and perpetuation (e.g. reentry) of this disorder. The underlying mechanisms, however, remain incompletely understood. Purpose To test the hypothesis that dense local fibrotic regions could create an electrically isolated conduction pathway in which reentry can be established via ectopy and block to become “trapped” (giving rise to CFAEs under SR), only to be “released” under dynamic changes at a connecting isthmus (causing acute focal arrhythmia (FA)). Methods The geometrical properties of such an electrically isolated pathway, under which reentry could be trapped and released, were explored in vitro using optogenetics by creating conduction blocks of any shape by means of light-gated depolarizing ion channels (CatCh) and patterned illumination. Insight from these studies was used for complementary computational investigation in virtual human atria to assess clinical translation and to provide deeper mechanistic insight. Results Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes, revealed that reentry could indeed be established and trapped by creating an electrically isolated pathway with a connecting isthmus causing source-sink mismatch. This proves that a tachyarrhythmia can exist locally with SR prevailing in the bulk of the monolayer. Next, it was confirmed under which conditions reentry could escape this pathway by widening of the isthmus (i.e. overcoming the source-sink mismatch), thereby converting this local dormant arrhythmic source into an active driver with global impact (i.e. acute monolayer-wide FA). This novel phenomenon was shown in circuits <0.7cm2, adding to their probability to exist in human atria. Computational 3D studies revealed that the conditions for “trapped reentry” and its release can indeed be realized in human atria. Unipolar epicardial pseudo-electrograms derived from these simulations showed CFAEs at the site of “trapped reentry” in coexistence with normal electrograms showing SR in the bulk of the atria. Upon release of the reentry through reduction of gap junctional coupling, acute FA occurred, affecting the complete atria as evidenced by wave front and electrogram visualization. Conclusion This study reveals that “trapped reentry”, a previously undesignated phenomenon, can explain the origin of two designated ones: the observation of CFAEs under SR and acute onset of FA. Further exploration of the concept of “trapped reentry” may not only expand our understanding of AF initiation and perpetuation, but also termination, including ablation strategies by site-directed targeting. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This study was funded by the European Research Council (Starting grant 716509) to D.A. Pijnappels

1275First evidence of "trapped reentry" as dormant source of acute atrial fibrillation and fractionated atrial electrograms under sinus rhythm

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
T De Coster ◽  
A S Teplenin ◽  
I Feola ◽  
T J Van Brakel ◽  
A A F De Vries ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sinus Rhythm ◽  
Acute Onset ◽  
Neonatal Rat ◽  
Geometrical Properties ◽  
Conduction Pathway ◽  
Atrial Electrograms ◽  
Underlying Mechanisms ◽  
Source Sink

Abstract Funding Acknowledgements This study was supported by the European Research Council (Starting grant 716509) to D.A. Pijnappels. Background Diseased atria are characterised by functional and structural heterogeneities (e.g. dense fibrotic regions), which add to abnormal impulse generation and propagation, like ectopy and block. These heterogeneities are thought to play a role in the origin of complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) in atrial fibrillation (AF) patients, but also in the onset and perpetuation (e.g. reentry) of this disorder. The underlying mechanisms, however, remain incompletely understood. Purpose To test the hypothesis that dense local fibrotic regions could create an electrically isolated conduction pathway in which reentry can be established via ectopy and block to become "trapped" (giving rise to CFAEs under SR), only to be "released" under dynamic changes at a connecting isthmus (causing acute onset of AF). Methods The geometrical properties of such an electrically isolated pathway, under which reentry could be trapped and released, were explored in vitro using optogenetics by creating conduction blocks of any shape by means of light-gated depolarizing ion channels (CatCh) and patterned illumination. Insight from these studies was used for complementary computational investigation in virtual human atria to assess clinical translation and to provide deeper mechanistic insight. Results Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes, revealed that reentry could indeed be established and trapped by creating an electrically isolated pathway with a connecting isthmus causing source-sink mismatch. This proves that a tachyarrhythmia can exist locally with SR prevailing in the bulk of the monolayer. Next, it was confirmed under which conditions reentry could escape this pathway by widening of the isthmus (i.e. overcoming the source-sink mismatch), thereby converting this local dormant arrhythmic source into an active driver with global impact (i.e. acute monolayer-wide fibrillation). This novel phenomenon was shown in circuits <0.7cm², adding to their probability to exist in human atria. Computational 3D studies revealed that the conditions for "trapped reentry" and its release can indeed be realized in human atria. Unipolar epicardial pseudo-electrograms derived from these simulations showed CFAEs at the site of "trapped reentry" in coexistence with normal electrograms showing SR in the bulk of the atria.  Upon release of the reentry through reduction of gap junctional coupling, acute onset of AF occurred, affecting the complete atria as evidenced by wave front and electrogram visualization. Conclusion This study reveals that trapped reentry, a previously unknown phenomenon, can explain the origin of two known ones: the observation of CFAEs under SR and acute onset of AF. Further exploration of the concept of "trapped reentry" may not only expand our understanding of AF initiation and perpetuation, but also termination, including ablation strategies by site-directed targeting.

scholarly journals Distinguishing sinus rhythm from atrial fibrillation on single-lead ECGs using a deep neural network

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Oudkerk Pool ◽  
B.D De Vos ◽  
J.M Wolterink ◽  
S Blok ◽  
M.J Schuuring ◽  
...  
Keyword(s):  
Neural Network ◽  
Atrial Fibrillation ◽  
Sinus Rhythm ◽  
Roc Curve ◽  
Model Development ◽  
Independent Set ◽  
Funding Source ◽  
National Budget ◽  
Validation Set ◽  
Public Grant

Abstract Background The growing availability of mobile phones increases the popularity of portable telemonitoring devices. An atrial fibrillation diagnosis can be reached with a recording of 30s on such telemonitoring devices. However, current commercially available automatic algorithms still require approval by experts. Purpose In this research we aimed to build an artificial intelligence (AI) algorithm to improve automatic distinction of atrial fibrillation (AF) from sinus rhythm (SR), to ultimately save time, costs, and to facilitate telemonitoring programs. Methods We developed a deep convolutional neural network (CNN), based on a residual neural network (ResNet), tailored to single-lead ECG analysis. The CNN was trained using publicly available single-lead ECGs from the 2017 PhysioNet/ Computing in Cardiology Challenge. This dataset consists of 60% SR, 9% AF, 30% alternative rhythm, and 1% noise ECGs. The 8528 available ECGs were divided into a training (90%) and validation set (10%) for model development and hyperparameter optimization. Results The trained CNN was applied to an independent set containing single-lead ECGs of 600 patients equally divided into two groups: SR and AF. Both groups comprised of 300 unique ECGs (SR; 60% male, 63±11 years, AF; 38% male, 56±14 years). In distinguishing between AF and SR, the method achieved an accuracy of 0.92, an F1-score of 0.91, and area under the ROC-curve of 0.98. Conclusion The results demonstrate that distinguishing SR and AF by a fully automatic AI algorithm is feasible. This approach has the potential to reduce cost by minimizing expert supervision, especially when extending the algorithm to other heart rhythms, like premature atrial/ventricular contractions and atrial flutter. Figure 1. ROC curve Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dekkerbeurs - Hartstichting

Cytochemical Evidence for Presynatic β-Adrenergic Regulation of Secretion in the Developing Rat Submandibular Gland

1977 ◽  
Vol 35 ◽  
pp. 430-431
Author(s):  
L.S. Cutler
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Submandibular Gland ◽  
Neonatal Rat ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Parotid Glands ◽  
Adrenergic Agonist ◽  
Rat Submandibular Gland

Many studies previously have shown that the B-adrenergic agonist isoproterenol and the a-adrenergic agonist norepinephrine will stimulate secretion by the adult rat submandibular (SMG) and parotid glands. Recent data from several laboratories indicates that adrenergic agonists bind to specific receptors on the secretory cell surface and stimulate membrane associated adenylate cyclase activity which generates cyclic AMP. The production of cyclic AMP apparently initiates a cascade of events which culminates in exocytosis. During recent studies in our laboratory it was observed that the adenylate cyclase activity in plasma membrane fractions derived from the prenatal and early neonatal rat submandibular gland was retractile to stimulation by isoproterenol but was stimulated by norepinephrine. In addition, in vitro secretion studies indicated that these prenatal and neonatal glands would not secrete peroxidase in response to isoproterenol but would secrete in response to norepinephrine. In contrast to these in vitro observations, it has been shown that the injection of isoproterenol into the living newborn rat results in secretion of peroxidase by the SMG (1).

The in vitro neonatal rat spinal cord preparation: a new insight into mammalian locomotor mechanisms

2004 ◽  
Vol 190 (5) ◽  
pp. 343-357 ◽  
Author(s):  
F. Clarac ◽  
E. Pearlstein ◽  
J. F. Pflieger ◽  
L. Vinay
Keyword(s):  
Spinal Cord ◽  
Neonatal Rat ◽  
Rat Spinal Cord ◽  
Insight Into

Usefulness of collaboration between mathematical models and cell engineering for elucidating complex disease mechanisms and discover effective drugs

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Kohjitani ◽  
A Kashiwa ◽  
T Makiyama ◽  
F Toyoda ◽  
Y Yamamoto ◽  
...  
Keyword(s):  
Mathematical Model ◽  
In Silico ◽  
Complex Disease ◽  
Ion Selectivity ◽  
Public Institution ◽  
Cell Engineering ◽  
Funding Source ◽  
Patch Clamp Technique ◽  
In Silico Model

Abstract Background A missense mutation, CACNA1C-E1115K, located in the cardiac L-type calcium channel (LTCC), was recently reported to be associated with diverse arrhythmias. Several studies reported in-vivo and in-vitro modeling of this mutation, but actual mechanism and target drug of this disease has not been clarified due to its complex ion-mechanisms. Objective To reveal the mechanism of this diverse arrhythmogenic phenotype using combination of in-vitro and in-silico model. Methods and results Cell-Engineering Phase: We generated human induced pluripotent stem cell (hiPSC) from a patient carrying heterozygous CACNA1C-E1115K and differentiated into cardiomyocytes. Spontaneous APs were recorded from spontaneously beating single cardiomyocytes by using the perforated patch-clamp technique. Mathematical-Modeling Phase: We newly developed ICaL-mutation mathematical model, fitted into experimental data, including its impaired ion selectivity. Furthermore, we installed this mathematical model into hiPSC-CM simulation model. Collaboration Phase: Mutant in-silico model showed APD prolongation and frequent early afterdepolarization (EAD), which are same as in-vitro model. In-silico model revealed this EAD was mostly related to robust late-mode of sodium current occurred by Na+ overload and suggested that mexiletine is capable of reducing arrhythmia. Afterward, we applicated mexiletine onto hiPSC-CMs mutant model and found mexiletine suppress EADs. Conclusions Precise in-silico disease model can elucidate complicated ion currents and contribute predicting result of drug-testing. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists

scholarly journals Quantitative 4D Flow CMR analysis of intracardiac blood flow energetics in ischemic cardiomyopathy patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Riva ◽  
A Camporeale ◽  
F Sturla ◽  
S Pica ◽  
L Tondi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemic Cardiomyopathy ◽  
Inverse Correlation ◽  
Lv Function ◽  
Funding Source ◽  
4D Flow ◽  
Anterior Myocardial Infarction ◽  
National Budget ◽  
4D Flow Cmr ◽  
Public Grant

Abstract Background Ischemic cardiomyopathy (ICM) is often associated with negative LV remodelling after myocardial infarction, sometimes resulting in impaired LV function and dilation (iDCM). 4D Flow CMR has been recently exploited to assess intracardiac hemodynamic changes in presence of LV remodelling. Purpose To quantify 4D Flow intracardiac kinetic energy (KE) and viscous energy loss (EL) and investigate their relation with LV dysfunction and remodelling. Methods Patients with prior anterior myocardial infarction underwent a CMR study with 4D Flow sequences acquisition; they were divided into ICM (n=10) and iDCM (n=10, EDV>208 ml and EF<40%). 10 controls were used for comparison. LV was semi-automatically segmented using short axis CMR stacks and co-registered with 4D Flow. Global KE and EL were computed over the cardiac cycle. NT-proBNP measurements were correlated with average and peak values, during systole and diastole. Results Both LV volume and EF significantly differ (P<0.0001) between iDCM (EDV=294±56 ml, EF=24±8%), ICM (EDV=181±32 ml, EF=34±6%) and controls (EDV=124±29 ml, EF=72±5%). If compared to controls, both ICM and iDCM showed significantly lower KE (P≤0.0008); though lower than controls, EL was higher in iDCM than ICM. Within the iDCM subgroup, diastolic mean KE and peak EL reported good inverse correlation with NT-proBNP (r=−0.75 and r=−0.69, respectively). EL indexed (ELI) to average KE during systole was higher in the entire ischemic group as compared to controls (ELI(ischemic) = 0.17 vs. ELI(controls) = 0.10, P=0.0054). Conclusions 4D Flow analyses effectively mapped post-ischemic LV energetic changes, highlighting the disproportionate intraventricular EL relative to produced KE; preliminary good correlation between LV energetic changes and NT-proBNP will deserve further investigation in order to contribute to early detection of heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health

A cool modality to restore sinus rhythm

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
O Yasin ◽  
A Sugrue ◽  
M Van Zyl ◽  
A Ladejobi ◽  
J Tri ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Body Temperature ◽  
Sinus Rhythm ◽  
Animal Experiments ◽  
Funding Source ◽  
Atrial Pacing ◽  
Exact Test ◽  
Chi Squared ◽  
Cool Device ◽  
Atrial Defibrillation

Abstract Background Slowing electrical conduction by cooling the myocardium can be used for defibrillation. We previously demonstrated the efficacy of a small cold device placed in oblique sinus (OS) in terminating atrial fibrillation (AF). However, the parameters needed to achieve effective atrial defibrillation are unknown. Purpose Assess effect of the size of cooled myocardium on frequency of AF termination in acute canine animal models. Methods Sternotomy was performed under general anesthesia in 10 acute canine experiments. AF was induced using rapid atrial pacing and intra-myocardial epinephrine and acetylcholine injections. Once AF sustained for at least 30s, either a cool (7–9°C) or placebo (body temperature) device was placed in the OS. Four device sizes were tested; ½X½, ¾X¾, and 1X1 inch devices and two ¾X¾ inch devices placed side by side simultaneously. Time to AF termination was recorded. Chi-squared or Fisher's exact test were used to compare the frequency of arrhythmia termination with cooling versus placebo. Results A total of 166 applications were performed (89 cool vs 77 placebo) in 10 animal experiments. Overall, AF terminated in 82% of the cooling applications vs. 67.5% of placebo (P=0.03, Figure 1). For the ½X½ inch device 88% of cold applications restored sinus rhythm vs. 63.6% for placebo (P=0.05). The frequency of sinus restoration for cold ¾X¾, 1X1 and two ¾X¾ side by side devices was 86.7%, 83.3% and 70% respectively. Time to sinus restoration when achieved was within three minutes was also not significantly changed. Conclusion Placing a cool device in the oblique sinus can terminate AF and efficacy is not affected by the size of device. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): MediCool Technologies

scholarly journals Contacts to the healthcare system prior to out-of-hospital cardiac arrests

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Zylyftari ◽  
S.G Moller ◽  
M Wissenberg ◽  
F Folke ◽  
C.A Barcella ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
General Population ◽  
Healthcare System ◽  
Early Identification ◽  
Sudden Cardiac Arrest ◽  
Funding Source ◽  
Horizon 2020 ◽  
One Year ◽  
Public Grant ◽  
Hospital Cardiac Arrest

Abstract Background Patients who suffer a sudden out-of-hospital cardiac arrest (OHCA) may be preceded by warning symptoms and healthcare system contact. Though, is currently difficult early identification of sudden cardiac arrest patients. Purpose We aimed to examine contacts with the healthcare system up to two weeks and one year before OHCA. Methods OHCA patients were identified from the Danish Cardiac Arrest Registry (2001–2014). The pattern of healthcare contacts (with either general practitioner (GP) or hospital) within the year prior to OHCA of OHCA patients was compared with that of 9 sex- and age-matched controls from the background general population. Additionally, we evaluated characteristics of OHCA patients according to the type of healthcare contact (GP/hospital/both/no-contact) and the including characteristics of contacts, within two weeks prior their OHCA event. Results Out of 28,955 OHCA patients (median age of 72 (62–81) years and with 67% male) of presumed cardiac cause, 16,735 (57.8%) contacted the healthcare system (GP and hospital) within two weeks prior to OHCA. From one year before OHCA, the weekly percentages of contacts to GP were relatively constant (26%) until within 2 weeks prior to OHCA where they markedly increased (54%). In comparison, 14% of the general population contacted the GP during the same period (Figure). The weekly percentages of contacts with hospitals gradually increased in OHCA patients from 3.5% to 6.5% within 6 months, peaking at the second week (6.8%), prior to OHCA. In comparison, only 2% of the general population had a hospital contact in that period (Figure). Within 2 weeks of OHCA, patients contacted GP mainly by telephone (71.6%). Hospital diagnoses were heterogenous, where ischemic heart disease (8%) and heart failure (4.5%) were the most frequent. Conclusions There is an increase in healthcare contacts prior to “sudden” OHCA and overall, 54% of OHCA-patients had contacted GP within 2 weeks before the event. This could have implications for developing future strategies for early identification of patients prior to their cardiac arrest. Figure 1. The weekly percentages of contacts to GP (red) and hospital (blue) within one year before OHCA comparing the OHCA cases to the age- and sex-matched control population (N cases = 28,955; N controls = 260,595). Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020

scholarly journals Conditioned medium-preconditioned EPCs enhanced the ability in oligovascular repair in cerebral ischemia neonatal rats

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ning Zhou ◽  
Lei Wang ◽  
Ping Fu ◽  
Zihao Cui ◽  
Yuhang Ge ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Western Blot ◽  
Conditioned Medium ◽  
Cognitive Outcome ◽  
Adult Brain ◽  
Neonatal Rat ◽  
Vascular Density ◽  
Cxcr4 Axis

Abstract Background Oligovascular niche mediates interactions between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs). Disruption of OPC-endothelium trophic coupling may aggravate the progress of cerebral white matter injury (WMI) because endothelial cells could not provide sufficient support under diseased conditions. Endothelial progenitor cells (EPCs) have been reported to ameliorate WMI in the adult brain by boosting oligovascular remodeling. It is necessary to clarify the role of the conditioned medium from hypoxic endothelial cells preconditioned EPCs (EC-pEPCs) in WMI since EPCs usually were recruited and play important roles under blood-brain barrier disruption. Here, we investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI. Methods In vitro, OPC apoptosis induced by the conditioned medium from oxygen-glucose deprivation-injured brain microvascular endothelial cells (OGD-EC-CM) was analyzed by TUNEL and FACS. The effects of EPCs on EC damage and the expression of cytomokine C-X-C motif ligand 12 (CXCL12) were examined by western blot and FACS. The effect of the CM from EC-pEPCs against OPC apoptosis was also verified by western blot and silencing RNA. In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia and treated with EPCs or EC-pEPCs at P7, and then angiogenesis and myelination together with cognitive outcome were evaluated at the 6th week. Results In vitro, EPCs enhanced endothelial function and decreased OPC apoptosis. Meanwhile, it was confirmed that OGD-EC-CM induced an increase of CXCL12 in EPCs, and CXCL12-CXCR4 axis is a key signaling since CXCR4 knockdown alleviated the anti-apoptosis effect of EPCs on OPCs. In vivo, the number of EPCs and CXCL12 protein level markedly increased in the WMI rats. Compared to the EPCs, EC-pEPCs significantly decreased OPC apoptosis, increased vascular density and myelination in the corpus callosum, and improved learning and memory deficits in the neonatal rat WMI model. Conclusions EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.

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