Tricuspid regurgitation: which animal model to simulate the functional form?

Animal modeling facing the challenge of tricuspid regurgitation

Tricuspid regurgitation (TR) affects more than 70 million people worldwide and has emerged as an independent predictor of mortality. While the functional form (FTR) is largely predominant (70 to 90% of cases), its clinical heterogeneity — combining annular dilation and right heart remodeling — complicates the standardization of care. Current guidelines (AHA/ACC) remain vague regarding the optimal interventional timing for asymptomatic patients.

This review evaluates the relevance of large animal experimental models, which are essential to overcome the anatomical and hemodynamic limitations of small mammals. The specific objective is to clarify the strengths and limitations of existing platforms to guide researchers in selecting a model corresponding to specific clinical phenotypes (primary vs. functional TR). The study postulates that a rigorous selection of the induction mechanism — whether surgical by resection or percutaneous by traction — is decisive for faithfully simulating chronic remodeling and validating the efficacy of future tricuspid repair devices.

Technical review methodology

This source is a scientific literature review evaluating large animal experimental models used for the study of tricuspid regurgitation (TR). The objective is to compare the translational relevance of different experimental platforms for the development of surgical and transcatheter therapies.

• Synthesis design: Comparative analysis of the strengths and limitations of animal models according to clinical phenotypes of TI (primary vs. functional).
• Studied models: The review focuses on canine and porcine models, chosen for their anatomical and hemodynamic proximity to the human heart, as opposed to small-sized models.
• Analyzed induction protocols:
  • Direct structural interventions for primary TR: resection of valve leaflets and lesion of the subvalvular apparatus (chordae).
  • Transcatheter approaches: use of grasping forceps and navigation guides to induce malcoaptation.
• Evaluation criteria: The authors analyzed the ability of each model to induce right-sided chamber remodeling (right atrial and ventricular dilation), tricuspid annular dilation, and right ventricular functional decline.
• Follow-up and reproducibility: Evaluation of TI durability and post-induction survival rates in the short and long term (up to 12 months for certain chronic models).

Performance of primary tricuspid regurgitation (TR) models

Data from direct structural intervention models highlight a close correlation between the extent of valvular involvement and the severity of the induced insufficiency. Two major approaches are distinguished by their reproducibility and their long-term remodeling profile.

Canine surgical model (Xie et al.)

The surgical resection approach of the tricuspid leaflets in dogs allows for precise grading of the pathology. Observations show stability of the regurgitation over a 12-month period:

In terms of safety, the reported survival rate is 100% at one year, confirming the viability of this model for the study of chronic right heart remodeling.

Porcine percutaneous model (Yan et al.)

The use of a transcatheter approach via an 8.5-Fr steerable sheath to exert traction on the subvalvular apparatus has demonstrated high technical efficacy. The immediate clinical results are as follows:

• Technical success: Severe TR was achieved in 90.91% of subjects (10/11).
• Overall severity: 100% of the animals presented moderate to severe RT immediately after induction.
• Per-procedural complications: Episodes of transient ventricular tachycardia (VT) or ventricular fibrillation (VF) were observed in 63.64% of subjects during the induction phase.

These direct lesion models effectively simulate primary RT, although the percutaneous model exhibits notable rhythmic instability during the acute phase, in contrast to the more invasive but stable surgical approach.

The challenge of animal models in tricuspid regurgitation: clinical decoding

The management of tricuspid regurgitation (TR) remains a major therapeutic challenge, affecting more than 70 million people. The authors of this review highlight a clinical reality: the choice of animal model is decisive for the validity of future surgical and transcatheter therapies. Two modeling approaches for primary TR are distinguished by their methodology and complications.

On one hand, the canine model by Xie et al. prioritizes durability. By performing surgical resection of one or two leaflets (with chordae), they achieve immediate severe TR (grade IV to IV+). The major interest for the clinician lies in the 12-month follow-up: the study reports progressive annular dilation and a decline in right ventricular function, faithfully mimicking the chronic remodeling observed in human pathology. This model offers remarkable stability with 100% survival at one year.

Conversely, the approach of Yan et al. follows the minimally invasive trend with a percutaneous porcine model. While the technical success is high (90.91% of severe TR induced), the price to pay is acute hemodynamic instability. The study reports that 63.64% of subjects presented transient ventricular tachycardia or fibrillation during traction on the subvalvular apparatus. This is a critical point: the aggressiveness of the percutaneous maneuver requires constant rhythmic monitoring, reflecting the potential risks of complex transcatheter interventions.

Summary of results

This review highlights the superiority of large animal models for faithfully reproducing human anatomy and hemodynamics of tricuspid regurgitation (TR). It establishes a crucial distinction between direct structural injury models (primary TR) and chamber remodeling models, which are essential for simulating functional TR, representing 70 to 90% of clinical cases.

In concrete terms, for the practitioner:

• Therapeutic targeting: Precisely identify the TR phenotype (primary vs. functional), as current repair techniques and transcatheter devices are designed to address distinct malcoaptation mechanisms (direct lesion vs. annular dilation).
• Technology Assessment: For the adoption of new percutaneous devices, prioritize data from large animal models, the only platforms capable of validating procedural feasibility and clinical safety under real-world conditions.
• Global management: Consider TR not as an isolated valvular leak, but as a reflection of right heart remodeling; the choice of intervention timing must integrate this dynamic of annular dilation and leaflet tethering.

Technical lexicon of the study

Functional tricuspid regurgitation (FTR): Predominant form of the pathology (70 to 90% of cases), resulting not from intrinsic valve damage, but from right cavity remodeling leading to a coaptation defect.

Annular dilation: Pathological enlargement of the tricuspid valve fibrous annulus, often secondary to pressure or volume overload, mechanically contributing to valvular insufficiency.

Tethering (Leaflet anchoring): Traction exerted on the valve leaflets by ventricular or atrial remodeling, limiting their mobility and preventing a tight closure of the valve.

Subvalvular apparatus: Structure comprising the chordae tendineae and papillary muscles; its manipulation or lesion in experimental models allows for the induction of primary tricuspid regurgitation.

Right cavity remodeling: Structural alterations of the right atrium (RA) and right ventricle (RV) that act as independent predictors of mortality and morbidity in the absence of treatment.

Direct structural intervention model: Experimental approach consisting of specifically injuring the leaflets or chordae (often by resection) to simulate primary tricuspid regurgitation and study the subsequent chronic remodeling.

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