Coronary Microvascular Dysfunction in Cardiovascular Disease: Lessons from Large Animal Models

RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.

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Large animal models of cardiovascular disease

Cell Biochemistry and Function ◽

10.1002/cbf.3173 ◽

2016 ◽

Vol 34 (3) ◽

pp. 113-132 ◽

Cited By ~ 42

Author(s):

H. G. Tsang ◽

N. A. Rashdan ◽

C. B. A. Whitelaw ◽

B. M. Corcoran ◽

K. M. Summers ◽

...

Keyword(s):

Cardiovascular Disease ◽

Animal Models ◽

Large Animal ◽

Large Animal Models

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Kinetics of monocytotropic Ehrlichia infections, new insights from large animal models

10.32469/10355/15844 ◽

2011 ◽

Author(s):

Ryan Thomas Stoffel

Keyword(s):

Animal Models ◽

Large Animal ◽

Large Animal Models ◽

Kinetics Of

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Anti‐arrhythmic investigations in large animal models of atrial fibrillation

British Journal of Pharmacology ◽

10.1111/bph.15417 ◽

2021 ◽

Cited By ~ 1

Author(s):

Arnela Saljic ◽

Thomas Jespersen ◽

Rikke Buhl

Keyword(s):

Atrial Fibrillation ◽

Animal Models ◽

Large Animal ◽

Large Animal Models

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Large Animal Models for Investigating Cell Therapies of Stress Urinary Incontinence

International Journal of Molecular Sciences ◽

10.3390/ijms22116092 ◽

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.

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

Reviews in the Neurosciences ◽

10.1515/revneuro-2016-0022 ◽

2017 ◽

Vol 28 (1) ◽

pp. 31-43 ◽

Cited By ~ 12

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.

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

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53824 ◽

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].

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

Cells ◽

10.3390/cells10030713 ◽

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.

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