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 ◽  
...  

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 (>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.

2006 ◽  
Vol 18 (2) ◽  
pp. 196
Author(s):  
Z. Roth ◽  
A. Aroyo ◽  
S. Yavin ◽  
A. Arav

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.


Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4158-4163 ◽  
Author(s):  
J Peng ◽  
P Friese ◽  
RF Wolf ◽  
P Harrison ◽  
T Downs ◽  
...  

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.


2019 ◽  
Vol 116 (3) ◽  
pp. 738-743 ◽  
Author(s):  
Raphaël Michel ◽  
Léna Poirier ◽  
Quentin van Poelvoorde ◽  
Josette Legagneux ◽  
Mathieu Manassero ◽  
...  

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.


2019 ◽  
Vol 3 (s1) ◽  
pp. 19-20
Author(s):  
Daniel Foster ◽  
Samantha Yohn ◽  
Muhammad Mahmood ◽  
Madigan Lavery ◽  
Daniel O’Brien ◽  
...  

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.


Author(s):  
D E MacIntyre ◽  
E W Salzman

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.


2021 ◽  
Vol 15 ◽  
Author(s):  
Shun Hao ◽  
Julia Yvonne Gestrich ◽  
Xin Zhang ◽  
Mengbo Xu ◽  
Xinwei Wang ◽  
...  

Ecdysone, an essential insect steroid hormone, promotes larval metamorphosis by coordinating growth and maturation. In Drosophila melanogaster, prothoracicotropic hormone (PTTH)-releasing neurons are considered to be the primary promoting factor in ecdysone biosynthesis. Recently, studies have reported that the regulatory mechanisms of PTTH release in Drosophila larvae are controlled by different neuropeptides, including allatostatin A and corazonin. However, it remains unclear whether neurotransmitters provide input to PTTH neurons and control the metamorphosis in Drosophila larvae. Here, we report that the neurotransmitters acetylcholine (ACh) affect larval development by modulating the activity of PTTH neurons. By downregulating the expression of different subunits of nicotinic ACh receptors in PTTH neurons, pupal volume was significantly increased, whereas pupariation timing was relatively unchanged. We also identified that PTTH neurons were excited by ACh application ex vivo in a dose-dependent manner via ionotropic nicotinic ACh receptors. Moreover, in our Ca2+ imaging experiments, relatively low doses of OA caused increased Ca2+ levels in PTTH neurons, whereas higher doses led to decreased Ca2+ levels. We also demonstrated that a low dose of OA was conveyed through OA β-type receptors. Additionally, our electrophysiological experiments revealed that PTTH neurons produced spontaneous activity in vivo, which provides the possibility of the bidirectional regulation, coming from neurons upstream of PTTH cells in Drosophila larvae. In summary, our findings indicate that several different neurotransmitters are involved in the regulation of larval metamorphosis by altering the activity of PTTH neurons in Drosophila.


1984 ◽  
Vol 52 (01) ◽  
pp. 085-089 ◽  
Author(s):  
Ian R Wanless

SummaryHypercholesterolemic men and monkeys have shortened platelet survival but attempts to demonstrate this in rabbits have been unsuccessful. The present study examines platelet survival in cholesterol-fed rabbits. Platelets were double-labelled in vitro with 51Cr and 14C-serotonin or in vivo by intravenous injection of 14C-serotonin.In the double-label experiments 51Cr survival was always shorter than 14C survival but changes in survival of one label were accompanied by similar changes in the other label. Survival was shortened after 4 and 7 weeks of cholesterol feeding. This was demonstrated when the donor platelets were from normal rabbits for both cholesterol and control recipients but no shortening was demonstrated when cholesterol-rich platelets were injected into cholesterol-fed recipients and normal platelets were injected into the control rabbits. When 14C-serotonin was injected intravenously 14C survival was the same as when platelets were labelled ex vivo prior to injection and 14C survival was shortened in rabbits fed cholesterol for 1,2, and 6 weeks.These results indicate that cholesterol-feeding shortens platelet survival. This effect may be masked if the test platelets are not identical in both test and control groups.


2021 ◽  
Vol 22 (20) ◽  
pp. 11158
Author(s):  
Salima El Moussaoui ◽  
Mireia Mallandrich ◽  
Núria Garrós ◽  
Ana Cristina Calpena ◽  
Maria José Rodríguez Lagunas ◽  
...  

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient’s well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae’s structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa.


2007 ◽  
Vol 293 (6) ◽  
pp. H3602-H3607 ◽  
Author(s):  
Ronen Durst ◽  
Haim Danenberg ◽  
Ruth Gallily ◽  
Raphael Mechoulam ◽  
Keren Meir ◽  
...  

Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling. Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts. For the in vivo studies, the left anterior descending coronary artery was transiently ligated for 30 min, and the rats were treated for 7 days with CBD (5 mg/kg ip) or vehicle. Cardiac function was studied by echocardiography. Infarcts were examined morphometrically and histologically. For ex vivo evaluation, CBD was administered 24 and 1 h before the animals were killed, and hearts were harvested for physiological measurements. In vivo studies showed preservation of shortening fraction in CBD-treated animals: from 48 ± 8 to 39 ± 8% and from 44 ± 5 to 32 ± 9% in CBD-treated and control rats, respectively ( n = 14, P < 0.05). Infarct size was reduced by 66% in CBD-treated animals, despite nearly identical areas at risk (9.6 ± 3.9 and 28.2 ± 7.0% in CBD and controls, respectively, P < 0.001) and granulation tissue proportion as assessed qualitatively. Infarcts in CBD-treated animals were associated with reduced myocardial inflammation and reduced IL-6 levels (254 ± 22 and 2,812 ± 500 pg/ml in CBD and control rats, respectively, P < 0.01). In isolated hearts, no significant difference in infarct size, left ventricular developed pressures during ischemia and reperfusion, or coronary flow could be detected between CBD-treated and control hearts. Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo. Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.


2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.


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