RESEARCH ARTICLEAnimal model considerations to evaluate prosthetic tricuspid valve implants
Introduction
Trace or mild tricuspid regurgitation is found in >65% of healthy humans and the prevalence of moderate or severe tricuspid regurgitation increases with age and concomitant heart disease (Klein et al., 1990; Topilsky et al., 2019). It is a public health problem and surgical treatments are associated with poor outcomes (Kilic et al., 2013). Several transcatheter approaches to tricuspid valve repair and replacement exist and could be a good option for patients, with encouraging initial clinical trial outcomes (Taramasso et al., 2019). Tricuspid medical device development is a burgeoning field, and suitable preclinical animal models are required to validate investigational products.
Tricuspid valve anatomy is complex and highly variable in humans (Silver et al., 1971). It remains a topic of some current anatomical and pathophysiological debate (Buzzatti et al., 2018; Dahou et al., 2019): there is no clear answer on when to treat a tricuspid insufficiency and what to do. In animals, data on tricuspid valve anatomy are limited.
Whether it be for valve repair, valve replacement or annuloplasty, a robust animal model must combine several similarities to a human heart. We focused on the characteristics of hearts affected by functional tricuspid regurgitation. A repair or replacement device has to fit the tricuspid valve, therefore the size of the tricuspid annulus is the first key consideration. Then, by order of importance, cardiac surgeons and interventionalists consider: leaflet composition; subvalvular apparatus including chordae tendinae and papillary muscles; remodelling of right heart chambers and tricuspid annulus shape; presence or absence of a moderator band; and distance to the coronary sinus, to the right coronary artery, to the vena cava and to the atrioventricular node. In patients these criteria are evaluated by ultrasound, computed tomography or cardiac magnetic resonance. Despite great improvements in these modalities, their definition is still not good enough to describe subtle but critical anatomical details which we therefore address in the current study through direct observation.
So as to identify the best preclinical models that most closely parallel human anatomy for validation of novel tricuspid surgical and transcatheter devices, we decided to investigate the complex and variable anatomy of the tricuspid valve from explanted hearts. Our study compared human hearts to those of three main species used in preclinical cardiac medical device research: pigs, sheep and dogs (Camacho et al., 2016). We compared key points in the choice of animal models, such as tricuspid annulus size, valvular and subvalvular apparatus and presence of a moderator band.
Section snippets
Sample
Sixty-nine animal hearts were collected from the IMMR laboratory (75014, Paris, France), including 22 dogs, 21 sheep and 26 pigs. Dogs were 1–4 years old, female adult Golden Retrievers, weighing 22–34 kg. Sheep were 2–4 years old, female adult Ile-de-France, weighing 50–80 kg. Pigs were 3–8 months old, female crossbred Large White — Landrace, weighing from 45 to 115 kg. The animals underwent different non-cardiac surgical procedures in approved research studies, and samples were collected only
Human heart dissection
Dissection of the 12 human hearts did not reveale any abnormal morphological findings of the tricuspid valve and subvalvular apparatus. However, we observed calcifications in the right coronary artery in one heart and on the aortic and mitral leaflets in another. Two other hearts had pacemaker leads placed in the right ventricle.
Tricuspid annulus circumference
Tricuspid annulus circumference was measured in 81 hearts. In 12 human hearts, it varied from 109 to 146 mm in eight women (mean = 123,8; s.d. = 12,1) and from 127 to
Discussion
Designing new surgical and transcatheter devices to treat tricuspid valvular diseases requires an animal model with tricuspid valve characteristics comparable to those of diseased human patients. Sheep, pigs and dogs are commonly used in preclinical studies of cardiac surgical devices (Camacho et al., 2016). In order to avoid comorbidity complications in disease-model animals and to limit cost, most preclinical studies are performed with healthy models (Taramasso et al., 2015; Camacho et al.,
Conclusion
This study allowed us to confirm that sheep and pigs are appropriate animal models in the preclinical phase of most tricuspid valve device development. However, the optimal choice will depend on the intended intervention and treatment period. Seventy to 90 kg pigs seem to be a good model with a tricuspid annulus circumference similar to the one of human patients suffering with functional tricuspid regurgitation. Their overall anatomy is similar, but they are healthy and growing animals, and
Funding
This research did not receive any specific grant from finding agencies in the public, commercial, or not-for-profit sectors.
Ethical statement
I undersigned, Olivier Chevènement, declare to have respected Ethical guidelines for journal publication and ensure that the work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) and the EU Directive 2010/63/EU.
CRediT authorship contribution statement
Olivier Chevènement: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data curation, Writing - original draft, Writing - review & editing, Visualization, Supervision, Project administration. Nicolas Borenstein: Conceptualization, Methodology, Validation, Resources, Writing - review & editing, Visualization, Supervision. Robert Kieval: Writing - review & editing, Visualization. Laurence Fiette: Writing - review & editing. Fabienne Aujard: Conceptualization,
References (25)
- et al.
Anatomy of the tricuspid valve, pathophysiology of functional tricuspid regurgitation, and implications for percutaneous therapies
Interv. Cardiol. Clin.
(2018) - et al.
Anatomy and physiology of the tricuspid valve
JACC Cardiovasc. Imaging
(2019) - et al.
An ovine model of chronic stable heart failure
J. Card. Fail.
(2000) - et al.
Percutaneous technique for creation of tricuspid regurgitation in an ovine model
J. Vasc. Interv. Radiol.
(2007) - et al.
Trends and outcomes of tricuspid valve surgery in North America: an analysis of more than 50,000 patients from the Society of Thoracic Surgeons database
Ann. Thorac. Surg.
(2013) - et al.
Age-related prevalence of valvular regurgitation in normal subjects: a comprehensive color flow examination of 118, volunteers
J. Am. Soc. Echocardiogr.
(1990) - et al.
Outcomes after current transcatheter tricuspid valve intervention: mid-term results from the international TriValve registry
JACC Cardiovasc. Interv.
(2019) - et al.
Burden of tricuspid regurgitation in patients diagnosed in the community setting
JACC Cardiovasc Imaging
(2019) - et al.
Morphometric study of the tricuspid valve in dogs
Anat. Histol. Embryol.
(2008) - et al.
Is tricuspid valve really tricuspid?
Anat. Cell Biol.
(2017)
Large mammalian animal models of heart disease
J. Cardiovasc. Dev. Dis.
Anatomical study of rheumatic tricuspid valve diseases: application to the study of various valvuloplasties
Ann. Chir. Thorac. Cardiovasc.
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Anatomical features for an adequate choice of the experimental animal model in biomedicine: III. Ferret, goat, sheep, and horse
2022, Annals of AnatomyCitation Excerpt :Sheep compact bone is largely plexiform until they are 3–4 years old, at which point primary osteonal bone is set down, which is modified to the secondary bone at 7–9 years (Pearce et al., 2007; Reinwald and Burr, 2008). Sheep have long been used as a model for cardiovascular research, particularly for testing heart valves (Chevènement et al., 2021) as models of heart failure because of myocardial ischemia, and for practicing coronary artery bypass surgery. Sheep have a valve size, architecture, and function that are comparable to that of humans (DiVincenti et al., 2014), and their body size allows easy access to the pulmonary and aortic valves (Ribitsch et al., 2020).