Feature Article

Implementing and conducting a robust and efficient in vitro test validation protocol for transcatheter heart valve devices is complex. This article proposes a method to reduce cost and to optimise the development cycle of these products.

FIGURE 1: Example of a dual activation chamber duplicator and its measurement capabilities:9 3D velocity contours within the left atrium using multi-plane stereoscopic particle image velocimetry (PIV) (top left), 3D echocardiograpghy of a mitral valve prosthesis (top middle) and 2D velocity map within the left ventricle using PIV.

Guidance on how to assess the hydro-dynamic performance of heart valves under steady and pulsatile flow conditions is provided in ISO 5840 (Table I). Parameters such as pressure drop,⁵ effective orifice area, leakage rate, regurgitant volumes^6,7 and velocity flow fields can be obtained using a dual chamber pulsatile tester with transparent anatomical models of ventricular and atrial chambers.^8,9 Dual chamber pulse duplicators are particularly well suited to assess the hydrodynamic performance of aortic and mitral artificial heart valves because they offer the possibility of simulating ventricle and atrial muscle contractions and relaxation with independent hydraulic activation systems. For example, they allow the simulation of pulmonary hypertension and/or atrial fibrillation following mitral valve replacement, or the concomitant effect of aortic valve replacement with a low compliance aorta. Unlike single activation testers, comparative studies⁹ have shown that dual chamber pulse duplicator simulated volume and pressure waveforms, as well as pressure-volume loops, are found to be accurate and similar to in vivo physiological cardiac haemodynamic. As required in ISO 5840, particle image velocimetry can be conducted to characterise complex three-dimensional (3D) flow dynamics inside realistic aorta, left ventricle and atrium geometries of the dual chamber pulse duplicators (Figure 1).⁹ If not executed and controlled properly, hydro-dynamic heart valve test results may exhibit significant variability, which is not inherent to the samples, but to the test bench and/or test procedure themselves. False negative or false positive results could lead to costly research and development (R&D) design decisions.

FIGURE 2: Cardiac cavities within a dual activation chamber duplicator. Left ventricle is in yellow and left atrium is in pale red.

Hydrodynamic heart valve test results are often affected by stent, leaflets and delivery systems interactions. Positioning errors, deployment accuracy, migration and conformability to the native valve with various heterogeneous shapes and degree of calcification and stenosis, can affect heart valve performance. For example, transcatheter valves with low outward radial force would not properly comply with a highly calcified noncircular annulus. This could induce detrimental paravalvular leaks. In this context, in vitro hydrodynamic tests must carefully consider the diseased native valve model that is used. Orifice shape, rigidity and the cross-sectional area used to support the native valve in the tester are therefore of major importance when testing transcatheter heart valves. To reduce the paravalvular leakage flow, stent oversizing is generally employed. Thus, valve oversizing has to be taken into consideration during assessment of valve hydrodynamic performance.

FIGURE 3: Hysteresis curve of a NiTi stent during three successive radial compression/expansion using a radial expansion force gauge tester.

Durability testing is critical to assess the long-term performance of the device during prolonged physiological loading conditions. Dual designs as in trans-catheter heart valves systems add significant complexity to fatigue resistance studies because both the valve and stent components need to be tested. Standard valve fatigue testers must be fitted with a special chamber to host stented valves with high struts. Heart valve fatigue testers will only test valve leaflets opening or closing, leaflet sutures (commissures) and stent strut resistance in the axial direction for 200 million cycles.² Test frequencies rarely exceed 15 Hz, and lead to prolonged test time that can last six months or more. Cyclic radial fatigue testing requires a different approach using accelerated conditions to simulate 10 years of a real-life metallic stent.³ If the natural frequency of the device permits it, the stent can be tested at approximately 50 Hz by avoiding detrimental resonance effect.¹⁰ Testers that eliminate dependence and rigorous control of tube compliance are preferred for fatigue studies. Online high-resolution optical inspections should be conducted periodically to detect early onset of failure and avoid prolonging studies unnecessarily. However, these two independent tests do not cover the effect of radial loading on leaflets and suture fatigue and integrity. High stress fields that are generated within the stent during accelerated fatigue testing can cause stent failure modes that may induce valve performance deficiency. Combining both tests would seem relevant to avoid critical and premature failure as a result of the dual effect of stent and valve interactions.

Mastering both stent and heart valve testing appears to be generally accessible to some companies with existing heart valve and interventional business. Yet, there are a significant number of companies that cannot claim this dual expertise and do not have the resource capabilities to test heart valve and stent device combinations. Investment limitations could force small companies to overlook testing strategy in their development plans. Prior successful experience with disassociated stent and catheter development programmes leads companies to undertake complete heart valve validation testing and undermines basic design performance studies. In turn, this risky choice brings significant complexity to companies’ overall development plans and leads to unnecessarily lengthy and costly validation programmes.