A Novel Rheumatic Mitral Valve Disease Model with Ex Vivo Hemodynamic and Biomechanical Validation

Abstract

Purpose: Rheumatic heart disease is a major cause of mitral valve (MV) dysfunction, particularly in disadvantaged areas and developing countries. There lacks a critical understanding of the disease biomechanics, and as such, the purpose of this study was to generate the first ex vivo porcine model of rheumatic MV disease by simulating the human pathophysiology and hemodynamics.

Methods: Healthy porcine valves were altered with heat treatment, commissural suturing, and cyanoacrylate tissue coating, all of which approximate the pathology of leaflet stiffening and thickening as well as commissural fusion. Hemodynamic data, echocardiography, and high-speed videography were collected in a paired manner for control and model valves (n = 4) in an ex vivo left heart simulator. Valve leaflets were characterized in an Instron tensile testing machine to understand the mechanical changes of the model (n = 18).

Results: The model showed significant differences indicative of rheumatic disease: increased regurgitant fractions (p < 0.001), reduced effective orifice areas (p < 0.001), augmented transmitral mean gradients (p < 0.001), and increased leaflet stiffness (p = 0.025).

Conclusion: This work represents the creation of the first ex vivo model of rheumatic MV disease, bearing close similarity to the human pathophysiology and hemodynamics, and it will be used to extensively study both established and new treatment techniques, benefitting the millions of affected victims.

Keywords: Cardiac biomechanics; Ex vivo model; Heart simulation; Mitral valve; Pathophysiology; Rheumatic heart disease.

Figure 1.

(A) Representative porcine mitral valve mounted in a 3D-printed elastomeric sewing ring. Top images for figures A-C are the superior view and bottom images are the inferior view with visibility of the chordae and papillary muscles. Figures A-C all picture the same mitral valve throughout the experimental procedures. (B) The mitral valve after heat treatment, which models a pathological rheumatic mitral valve. (C) The mitral valve after heat treatment and inducing commissural fusion via suture and cyanoacrylate tissue adhesive techniques.

Figure 2.

(A) Labeled diagram of the ex vivo left heart simulator. (B) The baseline control mitral valve during systole. Figures B-E were all captured in our ex vivo left heart simulator with high-speed videography. (C) The baseline mitral valve during diastole. (D) The rheumatic mitral valve model during systole. (E) The rheumatic mitral valve model during diastole.

Figure 3.

Mechanical mitral valve leaflet testing setup using an Instron tensile testing machine. (A) Mechanical failure of a control leaflet sample during uniaxial tension testing. (B) Failure of a rheumatic model leaflet during uniaxial tension testing.

Figure 4.

Labeled box plots of experimental hemodynamic and mechanical data. Blue boxes correspond to control valves while orange boxes correspond to rheumatic model valves. Top row data, (A) mitral valve regurgitant fraction, (B) intracyclic ventricular mean pressure, (C) mitral valve effective orifice area, and (D) mean transmitral echocardiographically measured pressure gradient, are paired metrics recorded in our ex vivo left heart simulator (n=4) and bottom row data, (E) mitral valve leaflet thickness, (F) mitral valve leaflet stiffness, and (G) mitral valve leaflet stress relaxation slope, are independent metrics recorded in an Instron tensile testing machine (n=18). Note that all displayed metrics of our control and rheumatic model valves describe behavior expected of a rheumatic mitral valve relative to a healthy valve.

Figure 5.

(A) Mean mitral valve flow measurements of control (Baseline) and rheumatic model experimental conditions for porcine mitral valves throughout the cardiac cycle (n=4). (B) Mean aortic and ventricular pressure measurements throughout the cardiac cycle of control (Baseline) and rheumatic model experimental conditions for porcine mitral valves (n=4). Shaded regions for both figures indicate standard error.

Figure 6.

Representative parasternal long-axis echocardiography color flow mapping images taken of the mitral valve during ex vivo analysis in our left heart simulator. Red dotted lines in both figures serve to identify mitral valve leaflets. (A) Color flow mapping of control mitral valve during systole. (B) Color flow mapping of the rheumatic model during systole. Note the presence of a prominent central eccentric regurgitant flow jet indicative of mild to moderate mitral regurgitation. (C) Color flow mapping of the control valve during diastole. (D) Color flow mapping of the rheumatic model during diastole. As a disclaimer, since ex vivo experimentation does not generate echocardiographic images from typical clinical angles, these images may be unfamiliar to a trained clinician. In our setup, images were generated using S5–1 probes from a directly superior angle of the mitral valve.