Anti‐arrhythmic investigations in large animal models of atrial fibrillation

2021 ◽  
Author(s):  
Arnela Saljic ◽  
Thomas Jespersen ◽  
Rikke Buhl
Keyword(s):  
Atrial Fibrillation ◽  
Animal Models ◽  
Large Animal ◽  
Large Animal Models

P935Can we predict the occurrence of persistent atrial fibrillation in large animal models to improve study efficiency?

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
N Denham ◽  
C M Pearman ◽  
G W P Madders ◽  
C E R Smith ◽  
A W Trafford ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Models ◽  
Conduction Velocity ◽  
P Wave ◽  
Right Atrial ◽  
Ethical Review ◽  
Large Animal ◽  
Ovine Model ◽  
Future Studies ◽  
Large Animal Models

Abstract Funding Acknowledgements British Heart Foundation Project Grant FS/17/54/33126 Background A key consideration when using animals in research is maximising experimental efficiency to minimise the number of animals required. Large animal models have proven an invaluable tool for establishing pathophysiological mechanisms underpinning atrial fibrillation (AF) and testing novel therapeutics, however animals may be resistant to developing the arrhythmias required. While the relationships between atrial refractory periods, conduction velocity, surface area, and vulnerability to fibrillation have been established in clinical practice, these parameters are not regularly used to design animal studies of persistent AF (PsAF). Purpose We investigated whether routinely collected baseline parameters could be used to improve experimental efficiency in an ovine model, by predicting the development of PsAF as opposed to arrhythmia resistance. The aims were to: reduce the number of animals used in future studies, and avoid prolonged experiments in animals likely to be resistant to AF. Methods All procedures were conducted with respect to the Animals [Scientific Procedures] Act, UK, 1986; and were approved by the local ethical review board. The ovine model consisted of healthy adult Welsh mountain sheep that underwent implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 30 second bursts of 50Hz and sheep were monitored over an eight week period for PsAF. Eight variables were collected at time of implant including weight (kg), left atrial diameter (LAD; cm), P wave duration (msec), PR interval (msec), atrial effective refractory period (ERP; msec), atrial conduction velocity (CV; m/s), AF inducibility with 50Hz bursts (secs), and rate threshold of atrial action potential alternans (msec). Analysis of the data was performed using multiple logistic regression and receiver-operator characteristic (ROC) curves. Regression coefficients are presented as natural logarithm of odds ratios (OR) with 95% confidence intervals (CI). Results Seventeen sheep were included in this study. Five (29%) developed PsAF whereas twelve (71%) were resistant (non-sustained or no AF). Univariate analysis found none of the parameters alone could predict PsAF, however ERP (OR -0.05, CI -.01 to 0.01, p = 0.089) and LAD (OR 8.1, CI -1.6 to 17.5, p = 0.095) suggested a combination may be predictive. A multivariate analysis using Fibrillation number (calculated as LAD / [ERP X CV]) was predictive (OR 26.9, CI 1.1 to 52.7; p = 0.04], with an area under ROC curve of 0.85 (p = 0.027). Conclusions Fibrillation number can predict the development of PsAF in healthy sheep. Practically speaking, this means animals with: a larger LAD, shorter ERP and slower CV are more likely to develop PsAF. These findings can be used to optimise the design of future studies, particularly by reducing the number of animals required.

scholarly journals Optimising Large Animal Models of Sustained Atrial Fibrillation: Relevance of the Critical Mass Hypothesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Nathan C. Denham ◽  
Charles M. Pearman ◽  
George W. P. Madders ◽  
Charlotte E. R. Smith ◽  
Andrew W. Trafford ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Models ◽  
Confidence Intervals ◽  
Conduction Velocity ◽  
Characteristic Curve ◽  
Critical Mass ◽  
Right Atrial ◽  
Large Animal ◽  
Future Studies ◽  
Large Animal Models

BackgroundLarge animal models play an important role in our understanding of the pathophysiology of atrial fibrillation (AF). Our aim was to determine whether prospectively collected baseline variables could predict the development of sustained AF in sheep, thereby reducing the number of animals required in future studies. Our hypothesis was that the relationship between atrial dimensions, refractory periods and conduction velocity (otherwise known as the critical mass hypothesis) could be used for the first time to predict the development of sustained AF.MethodsHealthy adult Welsh mountain sheep underwent a baseline electrophysiology study followed by implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 50 Hz bursts of 30 s duration over an 8-week period whilst sheep were monitored for AF.ResultsEighteen sheep completed the protocol, of which 28% developed sustained AF. Logistic regression analysis showed only fibrillation number (calculated using the critical mass hypothesis as the left atrial diameter divided by the product of atrial conduction velocity and effective refractory period) was associated with an increased likelihood of developing sustained AF (Ln Odds Ratio 26.1 [95% confidence intervals 0.2–52.0] p = 0.048). A receiver-operator characteristic curve showed this could be used to predict which sheep developed sustained AF (C-statistic 0.82 [95% confidence intervals 0.59–1.04] p = 0.04).ConclusionThe critical mass hypothesis can be used to predict sustained AF in a tachypaced ovine model. These findings can be used to optimise the design of future studies involving large animals.

scholarly journals Longitudinal study of electrical, functional and structural remodelling in an equine model of atrial fibrillation

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Eva Zander Hesselkilde ◽  
Helena Carstensen ◽  
Mette Flethøj ◽  
Merle Fenner ◽  
Ditte Dybvald Kruse ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Models ◽  
Ion Channel ◽  
Control Group ◽  
Large Animal ◽  
Large Animal Models ◽  
New Therapeutic Approaches ◽  
Atrial Remodelling ◽  
Channel Expression ◽  
Bona Fide

Abstract Background Large animal models are important in atrial fibrillation (AF) research, as they can be used to study the pathophysiology of AF and new therapeutic approaches. Unlike other animal models, horses spontaneously develop AF and could therefore serve as a bona fide model in AF research. We therefore aimed to study the electrical, functional and structural remodelling caused by chronic AF in a horse model. Method Nine female horses were included in the study, with six horses tachypaced into self-sustained AF and three that served as a time-matched sham-operated control group. Acceleration in atrial fibrillatory rate (AFR), changes in electrocardiographic and echocardiographic variables and response to medical treatment (flecainide 2 mg/kg) were recorded over a period of 2 months. At the end of the study, changes in ion channel expression and fibrosis were measured and compared between the two groups. Results AFR increased from 299 ± 33 fibrillations per minute (fpm) to 376 ± 12 fpm (p < 0.05) and atrial function (active left atrial fractional area change) decreased significantly during the study (p < 0.05). No changes were observed in heart rate or ventricular function. The AF group had more atrial fibrosis compared to the control group (p < 0.05). No differences in ion channel expression were observed. Conclusion Horses with induced AF show signs of atrial remodelling that are similar to humans and other animal models.

scholarly journals Large Animal Models for Investigating Cell Therapies of Stress Urinary Incontinence

2021 ◽  
Vol 22 (11) ◽  
pp. 6092
Author(s):  
Bastian Amend ◽  
Niklas Harland ◽  
Jasmin Knoll ◽  
Arnulf Stenzl ◽  
Wilhelm K. Aicher
Keyword(s):  
Urinary Incontinence ◽  
Stress Urinary Incontinence ◽  
Animal Models ◽  
Clinical Situation ◽  
Surgical Instruments ◽  
Health Concern ◽  
Large Animal ◽  
Knock Out ◽  
Cell Therapies ◽  
Large Animal Models

Stress urinary incontinence (SUI) is a significant health concern for patients affected, impacting their quality of life severely. To investigate mechanisms contributing to SUI different animal models were developed. Incontinence was induced under defined conditions to explore the pathomechanisms involved, spontaneous recovery, or efficacy of therapies over time. The animal models were coined to mimic known SUI risk factors such as childbirth or surgical injury. However, animal models neither reflect the human situation completely nor the multiple mechanisms that ultimately contribute to the pathogenesis of SUI. In the past, most SUI animal studies took advantage of rodents or rabbits. Recent models present for instance transgenic rats developing severe obesity, to investigate metabolic interrelations between the disorder and incontinence. Using recombinant gene technologies, such as transgenic, gene knock-out or CRISPR-Cas animals may narrow the gap between the model and the clinical situation of patients. However, to investigate surgical regimens or cell therapies to improve or even cure SUI, large animal models such as pig, goat, dog and others provide several advantages. Among them, standard surgical instruments can be employed for minimally invasive transurethral diagnoses and therapies. We, therefore, focus in this review on large animal models of SUI.

Animal models of hypoxic-ischemic encephalopathy: optimal choices for the best outcomes

2017 ◽  
Vol 28 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Lan Huang ◽  
Fengyan Zhao ◽  
Yi Qu ◽  
Li Zhang ◽  
Yan Wang ◽  
...  
Keyword(s):  
Animal Models ◽  
Small Animal ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Large Animal ◽  
Large Animal Models ◽  
Neurological Research ◽  
Serious Disease ◽  
Ischemic Encephalopathy

AbstractHypoxic-ischemic encephalopathy (HIE), a serious disease leading to neonatal death, is becoming a key area of pediatric neurological research. Despite remarkable advances in the understanding of HIE, the explicit pathogenesis of HIE is unclear, and well-established treatments are absent. Animal models are usually considered as the first step in the exploration of the underlying disease and in evaluating promising therapeutic interventions. Various animal models of HIE have been developed with distinct characteristics, and it is important to choose an appropriate animal model according to the experimental objectives. Generally, small animal models may be more suitable for exploring the mechanisms of HIE, whereas large animal models are better for translational studies. This review focuses on the features of commonly used HIE animal models with respect to their modeling strategies, merits, and shortcomings, and associated neuropathological changes, providing a comprehensive reference for improving existing animal models and developing new animal models.

Echocardiography Evaluation of a Novel Stable Ovine Heart Failure Model Suitable for Cardiovascular Device Testing

2011 ◽  
Author(s):  
Peter W. Walsh ◽  
Craig S. McLachlan ◽  
Leigh Ladd ◽  
Arie Blitz ◽  
R. Mark Gillies ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Models ◽  
Large Animal ◽  
Failure Model ◽  
Large Animal Models ◽  
Surgical Model ◽  
Coronary Ligation ◽  
Rapid Ventricular Pacing ◽  
Heart Failure Model ◽  
Underlying Pathology

Numerous large animal models of chronic cardiac ischemia have been developed to explore either pathological mechanisms and or device interventions in developed heart failure models. Traditionally chronic heart failure in large animal models such as sheep or pigs has been induced by either coronary ligation with or without reperfusion. Coronary ligation is often attempted in the open chest surgical model or more recently in the closed chest animal via angiography [1]. Both techniques can be challenging and also induce high mortality with the risk of myocardial stunning and resultant shock and or lethal arrhythmias. There is also difficulty in developing stable heart failure across cases where infarct sizes can be variable. One strategy to over come this variability has been via rapid ventricular pacing, however inducing heart failure does not induce sustained heart failure in many cases if the pacing is switched off, and additionally pacing does not induce some of the underlying pathology seen in the development of heart failure [1].

scholarly journals Review: Tissue Engineering of Small-Diameter Vascular Grafts and Their In Vivo Evaluation in Large Animals and Humans

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 713
Author(s):  
Shu Fang ◽  
Ditte Gry Ellman ◽  
Ditte Caroline Andersen
Keyword(s):  
Animal Models ◽  
Vascular Grafts ◽  
Small Diameter ◽  
Large Animal ◽  
Large Animal Models ◽  
Graft Outcome ◽  
Limited Success ◽  
Large Animals

To date, a wide range of materials, from synthetic to natural or a mixture of these, has been explored, modified, and examined as small-diameter tissue-engineered vascular grafts (SD-TEVGs) for tissue regeneration either in vitro or in vivo. However, very limited success has been achieved due to mechanical failure, thrombogenicity or intimal hyperplasia, and improvements of the SD-TEVG design are thus required. Here, in vivo studies investigating novel and relative long (10 times of the inner diameter) SD-TEVGs in large animal models and humans are identified and discussed, with emphasis on graft outcome based on model- and graft-related conditions. Only a few types of synthetic polymer-based SD-TEVGs have been evaluated in large-animal models and reflect limited success. However, some polymers, such as polycaprolactone (PCL), show favorable biocompatibility and potential to be further modified and improved in the form of hybrid grafts. Natural polymer- and cell-secreted extracellular matrix (ECM)-based SD-TEVGs tested in large animals still fail due to a weak strength or thrombogenicity. Similarly, native ECM-based SD-TEVGs and in-vitro-developed hybrid SD-TEVGs that contain xenogeneic molecules or matrix seem related to a harmful graft outcome. In contrast, allogeneic native ECM-based SD-TEVGs, in-vitro-developed hybrid SD-TEVGs with allogeneic banked human cells or isolated autologous stem cells, and in-body tissue architecture (IBTA)-based SD-TEVGs seem to be promising for the future, since they are suitable in dimension, mechanical strength, biocompatibility, and availability.

Production of Adeno-Associated Virus Vectors in Cell Stacks for Preclinical Studies in Large Animal Models

10.3791/62727 ◽  
2021 ◽  
Author(s):  
Amira D. Rghei ◽  
Brenna A. Y. Stevens ◽  
Sylvia P. Thomas ◽  
Jacob G. E. Yates ◽  
Benjamin M. McLeod ◽  
...  
Keyword(s):  
Animal Models ◽  
Large Animal ◽  
Preclinical Studies ◽  
Adeno Associated Virus ◽  
Virus Vectors ◽  
Large Animal Models

Large animal models for the study of ovarian follicular dynamics in women

2012 ◽  
Vol 78 (8) ◽  
pp. 1733-1748 ◽  
Author(s):  
G.P. Adams ◽  
J. Singh ◽  
A.R. Baerwald
Keyword(s):  
Animal Models ◽  
Large Animal ◽  
Large Animal Models ◽  
Follicular Dynamics
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