scholarly journals 3293 Region Specific Dysregulation of Dopaminergic Signaling in Mice Displaying Excessive Over-Grooming

2019 ◽  
Vol 3 (s1) ◽  
pp. 19-20
Author(s):  
Daniel Foster ◽  
Samantha Yohn ◽  
Muhammad Mahmood ◽  
Madigan Lavery ◽  
Daniel O’Brien ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Repetitive Behaviors ◽  
Optical Stimulation ◽  
Fast Scan Cyclic Voltammetry ◽  
Postsynaptic Protein ◽  
Electrical Pulses ◽  
Dopamine Signaling ◽  
And Control ◽  
Excessive Grooming

OBJECTIVES/SPECIFIC AIMS: The objective of this study was to determine if dopamine signaling is altered in a mouse model displaying excessive self-grooming and further elucidate the potential utility of compounds targeting the striatal DA system in modulating repetitive behaviors. METHODS/STUDY POPULATION: Here, we report studies using fast-scan cyclic voltammetry (FSCV) in mice lacking the postsynaptic protein SAP90/PSD95-associated protein (SAPAP3 KO mice) as well as control littermates. Rodent self-grooming provides a behavioral output with which one can monitor repetitive, self-directed, patterned behavior that has great translational value to OCD-like disorders. Total time spent grooming was monitored in SAPAP3KO mice and control littermates. To further examine the role of DA in regulating repetitive grooming behaviors the magnitude and kinetics of DA transients were assessed using FSCV in ex vivo slice preparations as well as in anesthetized mice in vivo. DA transients were elicited in the dorsolateral striatum (DLS), dorsomedial striatum (DMS); and nucelus accumbens core (NAcc). In some experiments mice were crossed with DAT-Cre animals and channelrhodopsin 2 (ChR2) was virally expressed in DA neurons to allow optical stimulation of DA transients. RESULTS/ANTICIPATED RESULTS: As previously reported, SAPAP3 KO mice showed excessive grooming compared to control littermates at the age assessed (4-5 months). DA transients evoked by a single electrical pulse in slices from SAPAP3 KO mice were not significantly different from those observed in slices from control littermates in any of the regions tested including the DLS, DMS and NAcc. However, when four electrical pulses were applied at a frequency of 10Hz to mimic DA neuron bursting, the magnitude of DA transients observed in the DMS and NAcc of SAPAP3 mice were greater than those evoked in control littermates.Interestingly, phasic stimulation produced similar DA transients in the DLS of both genotypes suggesting that phasic DA signaling was not globally altered. To confirm this finding we crossed SAPAP3 KO mice with DAT-Cre mice and injected ChR2 containing virus into the midbrain to selectively express ChR2 in DA neurons. Transients were then optically evoked resulting in selective activation of DA neurons. Optical stimulation produced a pronounced enhancement of DA release in SAPAP3 KO mice specifically in the DMS and only following phasic-like stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: These exciting findings suggest that DA signaling in SAPAP3KO mice is dysregulated in a very precise manner that is sub-region specific as well as dependent on the pattern of stimulation. These results suggest that targeted therapies that can modulate these specific modes of dopaminergic signaling in these distinct striatal subregions could provide improved efficacy in OCD patients that are resistant to SSRI treatment.

scholarly journals Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
J. Ellegood ◽  
S. P. Petkova ◽  
A. Kinman ◽  
L. R. Qiu ◽  
A. Adhikari ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Altered Expression ◽  
Developmental Growth ◽  
And Behavior

Abstract Background One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Methods A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. Results We validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/− cerebellum. During neonatal development, Arid1b+/− mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/− mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/− mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male–female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. Limitations The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. Conclusions This study represents a full validation and investigation of a novel model of Arid1b+/− haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

scholarly journals Sensitization of Rapid Dopamine Signaling in the Nucleus Accumbens Core and Shell After Repeated Cocaine in Rats

2010 ◽  
Vol 104 (2) ◽  
pp. 922-931 ◽  
Author(s):  
Nii A. Addy ◽  
David P. Daberkow ◽  
Jeremy N. Ford ◽  
Paul A. Garris ◽  
R. Mark Wightman
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Release ◽  
Cocaine Exposure ◽  
Sprague Dawley ◽  
Nucleus Accumbens Core ◽  
Fast Scan Cyclic Voltammetry ◽  
Uptake Inhibition ◽  
Sprague Dawley Rats ◽  
Dopamine Signaling

Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine pre-exposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent Km of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects.

scholarly journals Recent Advances in the Detection of Neurotransmitters

Chemosensors ◽  
2018 ◽  
Vol 6 (1) ◽  
pp. 1 ◽  
Author(s):  
Bo Si ◽  
Edward Song
Keyword(s):  
Ex Vivo ◽  
Simultaneous Detection ◽  
High Sensitivity ◽  
Mental Illnesses ◽  
Electrochemical Sensing ◽  
Fast Scan Cyclic Voltammetry ◽  
In Vivo Detection ◽  
Recent Developments ◽  
Materials Used

Neurotransmitters are chemicals that act as messengers in the synaptic transmission process. They are essential for human health and any imbalance in their activities can cause serious mental disorders such as Parkinson’s disease, schizophrenia, and Alzheimer’s disease. Hence, monitoring the concentrations of various neurotransmitters is of great importance in studying and diagnosing such mental illnesses. Recently, many researchers have explored the use of unique materials for developing biosensors for both in vivo and ex vivo neurotransmitter detection. A combination of nanomaterials, polymers, and biomolecules were incorporated to implement such sensor devices. For in vivo detection, electrochemical sensing has been commonly applied, with fast-scan cyclic voltammetry being the most promising technique to date, due to the advantages such as easy miniaturization, simple device architecture, and high sensitivity. However, the main challenges for in vivo electrochemical neurotransmitter sensors are limited target selectivity, large background signal and noise, and device fouling and degradation over time. Therefore, achieving simultaneous detection of multiple neurotransmitters in real time with long-term stability remains the focus of research. The purpose of this review paper is to summarize the recently developed sensing techniques with the focus on neurotransmitters as the target analyte, and to discuss the outlook of simultaneous detection of multiple neurotransmitter species. This paper is organized as follows: firstly, the common materials used for developing neurotransmitter sensors are discussed. Secondly, several sensor surface modification approaches to enhance sensing performance are reviewed. Finally, we discuss recent developments in the simultaneous detection capability of multiple neurotransmitters.

scholarly journals Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol

2021 ◽  
Vol 15 ◽  
Author(s):  
Sarah Threlfell ◽  
Amir Saeid Mohammadi ◽  
Brent J. Ryan ◽  
Natalie Connor-Robson ◽  
Nicola J. Platt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Radioligand Binding ◽  
Ex Vivo ◽  
Striatal Dopamine ◽  
Fast Scan Cyclic Voltammetry ◽  
Striatal Slices ◽  
Neuronal Protein ◽  
Biochemical Assays ◽  
Dopamine Signaling ◽  
Da Release

Striatal dopamine transporters (DAT) powerfully regulate dopamine signaling, and can contribute risk to degeneration in Parkinson’s disease (PD). DATs can interact with the neuronal protein α-synuclein, which is associated with the etiology and molecular pathology of idiopathic and familial PD. Here, we tested whether DAT function in governing dopamine (DA) uptake and release is modified in a human-α-synuclein-overexpressing (SNCA-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in ex vivo acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in SNCA-OVX mice. Compared to background control α-synuclein-null mice (Snca-null), the SNCA-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA]o) and on short-term plasticity (STP) in DA release, indicating DATs play a greater role in limiting DA release and in driving STP. We found that DAT membrane levels and radioligand binding sites correlated with α-synuclein level. Furthermore, DAT function in Snca-null and SNCA-OVX mice could also be promoted by applying cholesterol, and using Tof-SIMS we found genotype-differences in striatal lipids, with lower striatal cholesterol in SNCA-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in SNCA-OVX mice reduced the effects of DAT-inhibitors on evoked [DA]o. Together these data indicate that human α-synuclein in a mouse model of PD promotes striatal DAT function, in a manner supported by extracellular cholesterol, suggesting converging biology of α-synuclein and cholesterol that regulates DAT function and could impact DA function and PD pathophysiology.

176 EFFECT OF HYPERTHERMIA ON DEVELOPMENTAL COMPETENCE OF GERMINAL-STAGE OOCYTES: IN VIVO AND EX VIVO STUDIES IN MICE

2006 ◽  
Vol 18 (2) ◽  
pp. 196
Author(s):  
Z. Roth ◽  
A. Aroyo ◽  
S. Yavin ◽  
A. Arav
Keyword(s):  
Thermal Stress ◽  
Estrous Cycle ◽  
Ex Vivo ◽  
Treated Group ◽  
Developmental Competence ◽  
Behavioral Tests ◽  
Blastocyst Formation ◽  
Developmental Potential ◽  
And Control

Mammalian oocytes are susceptible to thermal stress at various stages of follicular development. The present study was performed to determine the effects of maternal hyperthermia on germinal vesicle (GV)-stage oocytes in mice. Evaluation parameters included (a) the oocyte's ability to become fertilized, (b) ex vivo embryonic development, (c) pregnancy outcome, and (d) quality of offspring. Female mice (CB6F1) were synchronized with pregnant mare serum gonadotropin (PMSG) followed by hCG 48 h later. One hour after hCG administration, control mice were kept under normo-thermal conditions (22�C, 45% RH), whereas the treated mice were exposed to thermal stress (40�C, 70% RH) for 1.5 to 2 h to induce a rise of 1.8�C in rectal temperature. After a 1-h recovery period, both treated and control mice were paired with stud males overnight. In Exp. 1, mated mice were sacrificed 20 h after hCG administration and embryos were recovered and cultured in vitro. The number of putative zygotes recovered was counted, and cleavage and blastocyst-formation rates were recorded on Days 1 and 5 post-fertilization, respectively. Examination of oocyte developmental stage during hyperthermia induction revealed that oocytes were at the GV stage. The percentage of putative zygotes that cleaved into the two-cell stage was higher (P < 0.05) in the control (91.2 � 1.3) than in the treated group (84.5 � 1.7). In addition, blastocyst-formation rate was higher in the control (P < 0.05; 84.3 � 1.8%) than in the treated group (57 � 2.6%). In Exp. 2, females were left with the stud males until litter delivery. The date of delivery and the number of pups were documented. Eight-week-old offspring were submitted to behavioral (locomotor activity and episodic memory) tests. The one-way ANOVA procedure of JAMPIN (SAS Institute, Inc., Cary, NC, USA, 2004) was used for statistical analysis. The percentage of females that gave birth during the first and second estrous cycles after hyperthermia induction was 59% and 71% for treated and control groups, respectively. The average number of pups in the first estrous cycle was lower (P < 0.05) for the treated group, and only became equal to that in the control group in the third estrous cycle. Behavioral tests did not reveal any differences between pups from the two experimental groups. In summary, GV-stage oocytes from stimulated ovaries are highly sensitive to thermal stress, since induction of maternal hyperthermia during this stage disrupts oocyte developmental competence both in vivo and ex vivo. However, oocytes that survive thermal stress exhibit normal developmental potential, since heat-stressed mice produced normal pups, at least as reflected by offspring behavioral tests. Thus, strategies designed to protect the ovarian pool of oocytes from thermal stress are likely to improve fertility in heat-stressed females.

scholarly journals Simultaneous measurement and quantitation of 4-hydroxyphenylacetic acid and dopamine with fast-scan cyclic voltammetry

The Analyst ◽  
2015 ◽  
Vol 140 (9) ◽  
pp. 3039-3047 ◽  
Author(s):  
Mimi Shin ◽  
Sam V. Kaplan ◽  
Kayla D. Raider ◽  
Michael A. Johnson
Keyword(s):  
Cell Culture ◽  
Cyclic Voltammetry ◽  
Simultaneous Measurement ◽  
Ex Vivo ◽  
Neuronal Function ◽  
Fast Scan Cyclic Voltammetry ◽  
Tissue Samples ◽  
Caged Compounds ◽  
Hydroxyphenylacetic Acid

Caged compounds have been used extensively to investigate neuronal function in a variety of preparations, including cell culture,ex vivotissue samples, andin vivo.

scholarly journals Relative reactivity of platelets from thrombopoietin- and interleukin-6- treated dogs

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4158-4163 ◽  
Author(s):  
J Peng ◽  
P Friese ◽  
RF Wolf ◽  
P Harrison ◽  
T Downs ◽  
...  
Keyword(s):  
Platelet Function ◽  
Interleukin 6 ◽  
Ex Vivo ◽  
Adenosine Diphosphate ◽  
Thiazole Orange ◽  
Experimental Conditions ◽  
Fibrinogen Binding ◽  
Flow Cytometric Measurement ◽  
And Control

Previous reports have shown that interleukin-6 (IL-6) enhances the responsiveness of platelets to thrombin stimulation and has modest thrombocytopoietic effects in vivo. Thrombopoietin (TPO; mpl ligand) has been shown to have dramatic thrombocytopoietic effect in vivo, but little is known of its capacity to alter platelet function. In this study, a direct comparison of the effects of IL-6 and TPO on platelet function in dogs has been performed, with modest doses of TPO (1 microgram/kg/d) chosen to match or moderately exceed the platelet counts achieved with IL-6 (40 micrograms/kg/d) for 10 days. Platelet responsiveness to thrombin stimulation was assessed in TPO-treated, IL- 6-treated, and control dogs by flow cytometric measurement of P- selectin expression. On day 5, the dose of thrombin promoting half maximal stimulation (EC50) of platelets was not significantly changed in TPO-treated dogs, whereas in IL-6-treated dogs the EC50 decreased to 73.1% +/- 6.1% (mean +/- 1 SD; n = 5) of control values (P < 0.01). These experiments were performed on both gel-filtered platelets and washed whole blood, indicating that the observed changes in EC50 were caused by cytokine-mediated alteration of platelets rather than plasma components. Because it has been shown that thiazole orange specifically labels a subpopulation of dog platelets that is less than 24 hours old, the thrombin responsiveness of these young, newly synthesized platelets was determined. The EC50 of thiazole orange-positive platelets from IL- 6-treated dogs decreased dramatically by day 5 to 46.5% +/- 13.1% (n = 4) of control values (P < 0.001), whereas TPO-treated dogs did not significantly change. When TPO was directly incubated with platelets ex vivo, no effects on either thrombin-mediated P-selectin expression or adenosine diphosphate-induced fibrinogen binding were observed. These data show that IL-6 alters platelet function, as measured by reactivity to thrombin, whereas TPO does not. This divergence in function is observed even though TPO is equally, or more, effective at promoting platelet production under these experimental conditions.

scholarly journals Interfacial fluid transport is a key to hydrogel bioadhesion

2019 ◽  
Vol 116 (3) ◽  
pp. 738-743 ◽  
Author(s):  
Raphaël Michel ◽  
Léna Poirier ◽  
Quentin van Poelvoorde ◽  
Josette Legagneux ◽  
Mathieu Manassero ◽  
...  
Keyword(s):  
Fluid Transport ◽  
Ex Vivo ◽  
Porcine Liver ◽  
Superabsorbent Hydrogel ◽  
Liver Capsule ◽  
In Vivo Experiments ◽  
Hydrogel Membranes ◽  
Interfacial Fluid ◽  
And Control

Attaching hydrogels to soft internal tissues is a key to the development of a number of biomedical devices. Nevertheless, the wet nature of hydrogels and tissues renders this adhesion most difficult to achieve and control. Here, we show that the transport of fluids across hydrogel−tissue interfaces plays a central role in adhesion. Using ex vivo peeling experiments on porcine liver, we characterized the adhesion between model hydrogel membranes and the liver capsule and parenchyma. By varying the contact time, the tissue hydration, and the swelling ratio of the hydrogel membrane, a transition between two peeling regimes is found: a lubricated regime where a liquid layer wets the interface, yielding low adhesion energies (0.1 J/m2 to 1 J/m2), and an adhesive regime with a solid binding between hydrogel and tissues and higher adhesion energies (1 J/m2 to 10 J/m2). We show that this transition corresponds to a draining of the interface inducing a local dehydration of the tissues, which become intrinsically adhesive. A simple model taking into account the microanatomy of tissues captures the transition for both the liver capsule and parenchyma. In vivo experiments demonstrate that this effect still holds on actively hydrated tissues like the liver capsule and show that adhesion can be strongly enhanced when using superabsorbent hydrogel meshes. These results shed light on the design of predictive bioadhesion tests as well as on the development of improved bioadhesive strategies exploiting interfacial fluid transport.

Effects Of Bay g 6575 On Platelets And On Vascular PGI2 Production

1981 ◽  
Author(s):  
D E MacIntyre ◽  
E W Salzman
Keyword(s):  
Vascular Tissue ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Duration Of Action ◽  
Antithrombotic Activity ◽  
Vascular Rings ◽  
And Control ◽  
Induced Aggregation

Bay g 6575 (1-[2-(β-naphthyloxy) ethyl]-3-methy1-2-pyrazolin-5-one) exerts a protective effect in several animal models of thrombosis. To elucidate its mechanism of action, we examined the effects of Bay g 6575 on platelets and on vascular PGI2 production. In vitro addition of Bay g 6575 (200 μM) to human citrated platelet rich plasma (PRP) did not inhibit aggregation induced by ADP or U44069, or augment inhibition of ADP-induced aggregation by PGD2, PGE1, PGI2 or papaverine. When added to isolated human or rat vascular rings, Bay g 6575 (200 μM) did not stimulate production of PGI2 or 6-oxo-PGF1α. Ex vivo studies one hour after administration of Baya g 6575 to rabbits (10 mg/kg, i.a.) or rats (100 mg/kg, p.o.) revealed no inhibition of ADP-induced aggregation or enhancement of the level of “circulating” PGI2 as measured by bio-immunoassay. When production of anti-aggregating activity by vascular rings from Bay g 6575 treated (B) and Control (C) rats were compared, in 6 of 8 experiments B inhibited more than C and B produced more 6-oxo-PGF1α than C (mean increase in B ± s.d.=74.3 ± 35.7%, range 42-135%). Production of antiaggregatory activity by “exhausted” C rings was enhanced by B>C platelet free plasma. In all cases, the inhibitor of aggregation produced by B and C rings acted on both human and rat PRP, and its effects could be reversed by anti-PGI1 antibodies that neutralize PGI2>6-oxo-PGE1>PGD2. When exogenous PGI2 was incubated with (exhausted) aspirin treated vascular rings, the duration of action of PGI2 was longer in the presence of B rings than C rings.Bay g 6575 has no direct effects on platelets or on vascular tissue. Its antithrombotic activity appears to be caused by regulation of PGI2 synthesis and metabolism, an effect mediated by factors, possibly Bay g 6575 metabolites, present in plasma after in vivo administration.

scholarly journals Ablation scar in a single pulmonary vein causes proarrhythmic mechanical destabilization in healthy sheep atria

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
LA Gottlieb ◽  
F Vaillant ◽  
E Abell ◽  
D El-Hamrani ◽  
J Naulin ◽  
...  
Keyword(s):  
Pulmonary Vein ◽  
Refractory Period ◽  
Ex Vivo ◽  
Radial Strain ◽  
Local Strain ◽  
Mechanical Effect ◽  
Antiarrhythmic Effect ◽  
Local Ablation ◽  
And Control

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Catharina Hospital, Eindhoven Medtronic (unrestricted research grant) Background Ablative pulmonary vein isolation (PVI) prevents AF in 60% of AF patients. The absence of an antiarrhythmic effect of PVI is poorly understood. Atrial and PV stretch is proarrhythmic but the mechanical effect of PV ablation scar on AF arrhythmogenesis is unknown. We hypothesize that single ablation scars are potentially proarrhythmic because they create heterogeneous stretch. Purpose To evaluate the mechanical effect of a purposely incomplete PVI ablation scar on left atrial (LA) electrophysiology. Methods Functional cardiac MRIs in vivo in sheep (n = 11) before and 3-months after incomplete PVI by radiofrequency in the right PV (RPV) were analyzed with a feature-tracking algorithm to obtain local strain in the LA. The ablated hearts were explanted and perfused with 1:5 blood:Krebs solution in a dual-chamber working-heart set-up. Diagnostic multi-electrode endocardial catheters were positioned in the RPV and left PV (LPV). Premature stimulation was performed in each PV in low (∼12mmHg) and high (∼25mmHg) LA pressure. Twelve control hearts without ablation scar underwent similar ex vivo investigation. Results The maximum longitudinal strain of the myocardial wall between the RPV and LPV increased  from 20.2 ± 6.2% to 33.5 ± 16.0% (before vs. after ablation, respectively; p = 0.032), whereas the maximum radial strain of the LA septum close to the RPV decreased from 45.6 ± 9.7% to 35.8 ± 7.3% (before vs. after ablation, respectively; p = 0.035). Sustained AF (&gt;30s) was more often induced during stimulation in hearts with ablation scar than in control (25.0% and 11.5% of induction attempts (n = 76 and n = 87) in ablated and control hearts, respectively; p = 0.025). In ablated hearts, an increase in LA pressure augmented AF inducibility (12.8% vs. 37.8% of induction attempts (n = 39 vs. n = 37), low vs. high LA pressure, respectively; p = 0.023), whereas this was not the case in control hearts (4.4% vs. 19.0% of induction attempts (n = 45 vs. n = 42), low vs. high LA pressure; p = 0.289). The number of spontaneous premature atrial complexes (PACs) not leading to AF were similar in ablated and control hearts (0 ± 0 vs. 0 ± 2 total PACs within 20ms of refractory period during premature stimulation protocol, respectively; p = 0.411). The diastolic stimulation threshold of RPV was higher in the ablated than in control hearts (90 ± 63 vs. 79 ± 31mA, respectively; p = 0.049). The refractory period was similar in the ablated and control hearts (237 ± 62 vs. 235 ± 55ms, respectively; p = 0.873). Conclusion Local ablation scar caused regionally disparate bio-mechanical changes in proximity to ablative energy delivery and increased inducibility of sustained AF especially during increased LA stretch. This was associated with decreased tissue excitability without changes in refractoriness. A single incomplete PVI ablation scar therefore is proarrhythmic. Development of ablation lesion sets that homogenize atrial mechanics and electrophysiology may improve AF ablation success.

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