Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs

2005 ◽  
Vol 288 (2) ◽  
pp. H511-H516 ◽  
Author(s):  
Dezhi Xing ◽  
Anne Louise Kjølbye ◽  
Jørgen S. Petersen ◽  
James B. Martins
Keyword(s):  
Ventricular Tachycardia ◽  
Gap Junction ◽  
Plasma Concentrations ◽  
Three Dimensional ◽  
In Vitro Study ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Triggered Activity

The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in α-chloralose-anesthetized, open-chest dogs 1–4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 ± 0.1 nM, 77 vs. 75%; 7.8 ± 0.4 nM, 86 vs. 77%; and 78.8 ± 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.

scholarly journals Angiotensin II effects on ischemic focal ventricular tachycardia are predominantly mediated through myocardial AT2 receptor

2009 ◽  
Vol 297 (5) ◽  
pp. H1889-H1898 ◽  
Author(s):  
Rakesh Gopinathannair ◽  
Ashok K. Chaudhary ◽  
Dezhi Xing ◽  
Debra Ely ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Angiotensin Ii ◽  
Enzyme Inhibitors ◽  
Three Dimensional ◽  
Coronary Artery Occlusion ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Artery Occlusion ◽  
Converting Enzyme Inhibitors ◽  
Triggered Activity

Ischemic focal ventricular tachycardia (VT) occurs in animals and humans. Angiotensin-converting enzyme inhibitors and receptor blockers reduce sudden death in patients with ischemic heart disease. In our dog model of coronary artery occlusion (CAO), we tested the hypothesis that angiotensin II (AGII) will selectively promote focal VT and that the specific AT2 blocker PD-123319 (PD), or AT1 blocker losartan, will affect this VT. Anesthetized dogs ( n = 90) underwent CAO, followed by three-dimensional activation mapping of inducible VT. Dogs without VT in 1–3 h after CAO received AGII, and those with VT received either PD or losartan. Focal endocardium excised from ischemic sites was studied in vitro with standard microelectrode. Of 33 dogs with no inducible VT, AGII infusion resulted in sustained VT of only focal Purkinje origin in 13 (39%) compared with 0 of 20 dogs with saline. Of 26 dogs with inducible VT at baseline, given PD, reinduction was blocked in 8 of 10 ( P < 0.05) focal VT, but only 1 of 15 with reentry. In contrast, of 11 dogs given losartan, reinduction of either mechanism was not blocked. In vitro triggered activity in Purkinje was blocked by PD in 13 of 19 ( P < 0.05), but not by losartan in 8. Also, triggered activity was promoted by AGII, losartan, or the combination in 9 of 12 tissues. AGII promotes only focal, mainly Purkinje ischemic VT. PD, but not losartan, preferentially blocked focal VT, which is likely due to triggered activity due to delayed afterdepolarizations in Purkinje.

Triggered activity due to delayed afterdepolarizations in sites of focal origin of ischemic ventricular tachycardia

2004 ◽  
Vol 287 (5) ◽  
pp. H2078-H2084 ◽  
Author(s):  
Dezhi Xing ◽  
James B. Martins
Keyword(s):  
Ventricular Tachycardia ◽  
Three Dimensional ◽  
In Vitro Study ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Triggered Activity ◽  
Anesthetized Dogs ◽  
Delayed Afterdepolarizations ◽  
First Time

This study for the first time systematically evaluated the site of origin of focal ventricular tachycardia (VT) induced 1–3 h after acute coronary artery ligation in dogs. We determined whether delayed afterdepolarizations (DADs) and triggered activity (TA) are more often recorded from ischemic endocardium excised from focal sites of VT origin. A total of 145 α-chloralose-anesthetized dogs were studied: in 54 dogs without inducible VT, normal or ischemic endocardium was investigated in vitro; in 91 dogs, inducible VT was studied by three-dimensional activation mapping, with in vitro study of 51 endocardial foci compared with 40 endocardial ischemic sites not of VT origin. Incidence of DADs (71% vs. 33%, P < 0.05) and TA (32% vs. 11%, P < 0.05) was greater in ischemic than in normal Purkinje tissues. Purkinje sites of origin of focal VT demonstrated the greatest frequency of DADs (92%, P < 0.05) and TA (75%, P < 0.05), with repetitive TA predominating. Similar results were obtained in endocardial sites of origin. Action potentials were mildly depolarized and prolonged in the focal sites of origin. These abnormalities were stable up to 2.5 h of recording. This study demonstrated that DADs and TA may underlie a majority of focal VTs in ischemic endocardium and Purkinje tissue.

Overdrive pacing of early ischemic ventricular tachycardia: evidence for both reentry and triggered activity

2005 ◽  
Vol 288 (3) ◽  
pp. H1124-H1130 ◽  
Author(s):  
David O. Arnar ◽  
Dezhi Xing ◽  
James B. Martins
Keyword(s):  
Ventricular Tachycardia ◽  
Cycle Length ◽  
Three Dimensional ◽  
Coronary Artery Occlusion ◽  
Canine Model ◽  
Artery Occlusion ◽  
Triggered Activity ◽  
Three Dimensional Mapping ◽  
Cycle Lengths ◽  
Overdrive Pacing

Entrainment can be a useful method to identify reentry as a mechanism of ventricular tachycardia (VT). In this study, we evaluated the effect of gradually decreasing cycle lengths of overdrive pacing for stable VT induced in a canine model 1–3 h after coronary occlusion. Intact dogs underwent anterior descending coronary artery occlusion after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Overdrive pacing was attempted if the animals had sustained hemodynamically stable VT, looking for evidence of entrainment. Subsequent three-dimensional mapping determined the mechanism of VT. Fifteen of the 21 dogs studied demonstrated entrainment with overdrive pacing by progressive QRS fusion alone ( 1 ), the first nonpaced QRS entrained to the paced cycle length only ( 7 ), or both ( 7 ). Five of these 15 dogs also had postpacing acceleration of the VT at a subsequent faster pacing cycle length. The mechanism of acceleration in four was a change to a VT with a focal origin. The prepacing mechanism in all 15 dogs was subsequently mapped to reentry. Regarding the six VTs, which demonstrated no evidence for entrainment, the site of earliest activity was mapped to a focal origin in all. These data showing entrainment of inducible reentrant VTs and lack of such for focal VTs support that the focal VTs seen in this study are unlikely the result of microreentry but possibly a mechanism as triggered activity.

scholarly journals Selective Astrocytic Endothelin-1 Overexpression Contributes to Dementia Associated with Ischemic Stroke by Exaggerating Astrocyte-Derived Amyloid Secretion

2015 ◽  
Vol 35 (10) ◽  
pp. 1687-1696 ◽  
Author(s):  
Victor KL Hung ◽  
Patrick KK Yeung ◽  
Angela KW Lai ◽  
Maggie CY Ho ◽  
Amy CY Lo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cognitive Deficits ◽  
In Vitro Study ◽  
Artery Occlusion ◽  
Spatial Learning And Memory ◽  
Dependent Manner ◽  
Endothelin 1 ◽  
Endothelin B

Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood–brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF- a, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.

scholarly journals Role of glyoxalases in wound healing process: an in vitro study

2021 ◽  
Vol 165 ◽  
pp. 39
Author(s):  
Francesca Lombardi ◽  
Silvano Santini ◽  
Paola Palumbo ◽  
Valeria Cordone ◽  
Virginio Bignotti ◽  
...  
Keyword(s):  
Wound Healing ◽  
Healing Process ◽  
In Vitro Study ◽  
Vitro Study ◽  
Wound Healing Process

scholarly journals The Role of Pre-Clinical 3-Dimensional Models of Osteosarcoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5499
Author(s):  
Hannah L. Smith ◽  
Stephen A. Beers ◽  
Juliet C. Gray ◽  
Janos M. Kanczler
Keyword(s):  
Three Dimensional ◽  
Chorioallantoic Membrane ◽  
3D Models ◽  
In Ovo ◽  
Future Directions ◽  
3 Dimensional ◽  
In Vivo Animal Models

Treatment for osteosarcoma (OS) has been largely unchanged for several decades, with typical therapies being a mixture of chemotherapy and surgery. Although therapeutic targets and products against cancer are being continually developed, only a limited number have proved therapeutically active in OS. Thus, the understanding of the OS microenvironment and its interactions are becoming more important in developing new therapies. Three-dimensional (3D) models are important tools in increasing our understanding of complex mechanisms and interactions, such as in OS. In this review, in vivo animal models, in vitro 3D models and in ovo chorioallantoic membrane (CAM) models, are evaluated and discussed as to their contribution in understanding the progressive nature of OS, and cancer research. We aim to provide insight and prospective future directions into the potential translation of 3D models in OS.

Three-dimensional stiffness in a thoracolumbar en-bloc spondylectomy model: A biomechanical in vitro study

2007 ◽  
Vol 22 (9) ◽  
pp. 957-964 ◽  
Author(s):  
A.C. Disch ◽  
A. Luzzati ◽  
I. Melcher ◽  
K.D. Schaser ◽  
F. Feraboli ◽  
...  
Keyword(s):  
Three Dimensional ◽  
In Vitro Study ◽  
Vitro Study ◽  
En Bloc ◽  
En Bloc Spondylectomy ◽  
Bloc Spondylectomy

scholarly journals Genotoxicity and inflammatory potential of stainless steel welding fume particles: an in vitro study on standard vs Cr(VI)-reduced flux-cored wires and the role of released metals

2021 ◽  
Author(s):  
Sarah McCarrick ◽  
Valentin Romanovski ◽  
Zheng Wei ◽  
Elin M. Westin ◽  
Kjell-Arne Persson ◽  
...  
Keyword(s):  
Dna Damage ◽  
In Vitro Study ◽  
Human Monocyte ◽  
Welding Fumes ◽  
Welding Fume ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Cored Wires

AbstractWelders are daily exposed to various levels of welding fumes containing several metals. This exposure can lead to an increased risk for different health effects which serves as a driving force to develop new methods that generate less toxic fumes. The aim of this study was to explore the role of released metals for welding particle-induced toxicity and to test the hypothesis that a reduction of Cr(VI) in welding fumes results in less toxicity by comparing the welding fume particles of optimized Cr(VI)-reduced flux-cored wires (FCWs) to standard FCWs. The welding particles were thoroughly characterized, and toxicity (cell viability, DNA damage and inflammation) was assessed following exposure to welding particles as well as their released metal fraction using cultured human bronchial epithelial cells (HBEC-3kt, 5–100 µg/mL) and human monocyte-derived macrophages (THP-1, 10–50 µg/mL). The results showed that all Cr was released as Cr(VI) for welding particles generated using standard FCWs whereas only minor levels (< 3% of total Cr) were released from the newly developed FCWs. Furthermore, the new FCWs were considerably less cytotoxic and did not cause any DNA damage in the doses tested. For the standard FCWs, the Cr(VI) released in cell media seemed to explain a large part of the cytotoxicity and DNA damage. In contrast, all particles caused rather similar inflammatory effects suggesting different underlying mechanisms. Taken together, this study suggests a potential benefit of substituting standard FCWs with Cr(VI)-reduced wires to achieve less toxic welding fumes and thus reduced risks for welders.

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