The evolution of cardiac valve bioprostheses is a medical milestone we encounter daily. Reflecting Cooley’s maxim, “apply, simplify, modify,” certain surgeons, aided by engineers and biophysicists, have significantly advanced these devices, which are now implanted in hundreds of thousands worldwide annually.

Cardiac bioprostheses emerged following the experience with mechanical devices, aimed at avoiding anticoagulation and its associated complications. In 1966, Carpentier described a method to reduce inflammatory reactions on biological tissue by using glutaraldehyde to chemically treat porcine valves. By creating cross-links between collagen molecules, this treatment protected the tissue from denaturation and immunologically inactivated it through surface antigen modification. Later, by mounting the entire porcine valve on a stent, an appropriate three-dimensional spatial relationship between the leaflets was achieved, simplifying implantation and enhancing the device’s functionality and durability. In 1971, Ionescu mounted artificial bovine pericardial leaflets on a stent, a concept quickly adopted by the newly established Edwards Lifesciences® for the development of their well-known bioprostheses.

Since then, the emergence of new devices and refinement of existing ones shaped clinical practice over the last three decades of the past century, leading up to the advent of TAVI. Essentially, these changes focused on three aspects: First, the choice of biological tissue, including the porcine aortic valve (whole or fragmented, discarding the leaflet bearing the muscular moderator band as in the Medtronic Mosaic® or the Abbott Epic®) or animal pericardium. The latter incorporates equine, porcine, or bovine origins, providing an increasing level of hemodynamic flow and mechanical stress based on a better ratio of collagen and elastic fibers. Second, the assembly of biological tissue, either mounted inside or outside the stent, as well as the flexibility of the stent itself. Notably, the promising Mitroflow®/Crown® design with pericardial sheets mounted outside the stent encountered significant challenges. Although the St. Jude Trifecta® solved stent deformability issues and preserved pericardial coverage on leaflet-stent contact surfaces, results remained suboptimal regarding structural degeneration. Third, tissue fixation continued to rely on glutaraldehyde, augmented with various, often proprietary, anticalcification treatments.

During the rebranding of Mitroflow® to Crown®, a new anticalcification treatment (PRT: phospholipid reduction treatment) was introduced, while Abbott® employs Linx®, Medtronic® uses AOA®, and platforms like Livanova Perceval Plus® incorporate FREE (formaldehyde-free aldehyde storage). These treatments focus on minimizing phospholipids, derived from the glycocalyx of cell membranes on the biological tissue surface, and covering free aldehyde radicals after tissue fixation, as both are known sites for calcium ion deposition in the bloodstream, promoting structural degeneration of the leaflets.

Edwards Lifesciences® introduced RESILIA® pericardial tissue in 2014, a new fixation concept based on three principles. The most significant was a washing process that removed many active radicals responsible for oxidation and calcium deposits. Furthermore, the remaining radicals were covered, acting not only on aldehydes but also on similar agents. Lastly, glycerolization, which replaces water in biological tissue with alcohols (ethanol and glycerol), enables sterilization with ethylene oxide and preservation in a dry atmosphere, eliminating the need for a liquid solution or aldehyde. The initial experience was published in a comparative series of mitral valve implants in sheep, using both conventional pericardium and RESILIA® tissue. Although the results showed significantly lower degeneration rates and greater durability compared to the traditional platform, clinical results were necessary to validate these findings.

The EU Feasibility Trial was the first study that obtained CE marking for RESILIA® tissue, investigating its safety and performance in aortic valve replacement prostheses. Subsequently, the COMMENCE trial expanded the patient population from the previous study, and along with the RESILIENCE trial (ongoing, for patients under 65 years), aims to broaden the indications for these bioprostheses by examining their long-term durability. The benchmark set by Bourguignon et al. with the series of long-term results for the Carpentier Edwards Perimount/Magna® prosthesis represents the gold standard of cardiac bioprosthesis performance, a goal that both surgical and transcatheter platforms seek to surpass.

The COMMENCE study recruited patients between 2013 and 2016, including 698 patients in a prospective, non-randomized, uncontrolled, international study with 27 participating centers. The results have been reported in successive updates, with the current analysis completing the 5-year follow-up. This study stands out for its transparency in follow-up, with 190 losses, 69 due to mortality and the remainder due to patient choice, except for only 26 cases where no justification was found. At 5 years, there are 499 patients with complete follow-up, with 37 patients for whom data were unavailable at the time of publication. The 5-year results are excellent, with an overall survival rate of 89%, valve-related event-free survival of 97%, and reoperation-free rate of 98.7%. No thrombosis cases were recorded, with an endocarditis rate of 2.2%, significant paravalvular leakage rate of 0.5%, and no registered cases of structural degeneration.

Recently, at the STS congress, results for the 195 patients with 7-year follow-up data from the initial recruitment were presented, showing a survival rate of 85.4%, reoperation-free survival of 97.2%, 15 endocarditis cases (rate of 2.7%), and 2 cases of structural degeneration (rate of 0.7%). These last two cases were resolved with a TAVI-in-valve procedure in the first and reoperation with mechanical prosthesis replacement in the second. Throughout the follow-up, mean gradients of the bioprostheses remained stable between 11.1 and 9.4 mmHg, covering all available sizes from 19 to 29 mm.

With these results, the authors conclude that the safety and mid-term hemodynamic performance of the aortic prosthesis with RESILIA® tissue are encouraging, justifying continued follow-up and promoting its use extension to other bioprosthesis platforms.

COMMENTARY:

As Bavaria himself stated, “all previous bioprosthesis trials have shown structural deterioration beginning around five years, with rates between 1.5% and 5%. Therefore, we can conclude that the five- and seven-year structural deterioration curve is exceptionally favorable in the COMMENCE study. Although we must await ten-year data, these results are highly encouraging for the RESILIA® tissue platform. Furthermore, the stable maintenance of the mean gradient, the virtually insignificant levels of paravalvular aortic insufficiency, and the relatively low rates of adverse events like endocarditis and thrombosis all indicate no concerning signals in these areas compared to historical trial outcomes of other cardiac valves.”

Given the findings presented, it appears reasonable to expand the clinical use of RESILIA® tissue. This could be applied to various scenarios, such as aortic valve implantation in patients aged 55 to 65 years, who have a long life expectancy, and who reject or have contraindications to oral anticoagulation (provided they are adequately informed). In addition, it would incorporate Edwards INSPIRIS® support for future TAVI-in-valve procedures. This could also apply to Bentall-De Bono procedures in analogous contexts, utilizing a valved graft with a bioprosthesis or, when available, the eagerly awaited Edwards KONECT RESILIA® valved conduit in Europe. For atrioventricular valves, the Edwards MITRIS RESILIA® bioprosthesis may also be an option, supported by its corresponding COMMENCE mitral study, now with four-year follow-up, although with a smaller sample size of 82 patients (98.7% structural degeneration-free survival and stable mean gradients between 3.8 and 4.3 mmHg).

While the clinical superiority of RESILIA® tissue cannot be confirmed until at least ten years of follow-up are completed, it is worth noting one of the limitations of the COMMENCE study. The structural degeneration criteria used do not align with those established by Capodanno et al. in the widely accepted VARC criteria, applicable to percutaneous devices and increasingly used for surgical bioprostheses. The COMMENCE study’s more lenient criteria consider structural degeneration due to dysfunction or deterioration, excluding degeneration from thrombosis and/or endocarditis, either necessitating reintervention or discovered at autopsy. As such, most structural degeneration cases detected would derive from new valve procedures (surgical or percutaneous) and may have been underestimated, as some patients may not have been considered candidates for reoperation or TAVI-in-valve. The authors justified the deviation from the VARC criteria to the FDA commission that approved the trial, noting that VARC criteria, in their 2017 version 3, define valve dysfunction in four ways: structural, non-structural, thrombosis, and endocarditis. For structural dysfunction, VARC includes morphological criteria, which are debated, as well as functional criteria such as:

• An increase in mean gradient compared to post-implant baseline >10 mmHg for moderate degeneration and >20 mmHg for severe degeneration.
• Moderate or severe intraprosthetic regurgitation (depending on the degree of degeneration), new or worsening of known previous regurgitation.
• Mean gradient >20 mmHg for moderate grade or >40 mmHg for severe grade, without specifying the time of detection.

This last criterion should be reviewed, as it suggests a prosthesis-patient mismatch situation (non-structural dysfunction) typically defined by effective valve area proportion in relation to body surface area (<0.65 cm²/m² for severe grade and <0.85 cm²/m² for moderate grade).

To conclude, we welcome efforts to enhance surgical devices in a changing world where significant investment is directed towards transcatheter therapies. We should not assume that, with durability concerns in mind and awaiting long-term TAVI results, surgery will not again become a testing ground for interventional approaches should long-term outcomes fall short of expectations. While it is conceivable that an “Edwards SAPIEN RESILIA®” will soon be introduced (presumably to be named Edwards SAPIEN 3 Ultra®), we hope that beyond the remarkable properties of this “miraculous” tissue, preservation of the leaflet architecture on commissural posts and avoidance of crimping damage to pericardium will differentiate surgical from percutaneous prostheses. Until then, we can only wait.

REFERENCE:

Bavaria JE, Griffith B, Heimansohn DA, Rozanski J, Johnston DR, Bartus K, et al.; COMMENCE Trial Investigators. Five-year Outcomes of the COMMENCE Trial Investigating Aortic Valve Replacement With RESILIA Tissue. Ann Thorac Surg. 2023 Jun;115(6):1429-1436. doi: 10.1016/j.athoracsur.2021.12.058.