The burden of cardiovascular mortality and morbidity is constantly increasing in Western countries and, at the same time, acquired and congenital valvular diseases are a growing field of interest. Even though it is known that repairing a diseased valve is better than replacing it (especially when it comes to the mitral valve), this is not always possible.
In this commentary, Damiano Regazzoli and Azeem Latib review how a bioresorbable valve may enable diseased aortic and pulmonary valves to to be replaced with a living heart valve.
Each new valve prosthesis introduces a new disease process: while both mechanical and biological valves are associated with similar survival rates, higher rates of bleeding are reported with mechanical prostheses (due to anticoagulant therapies) and higher rates of reoperation are seen with biological prostheses (due to structural valve deterioration).
Over the last 10 years, the introduction of transcatheter valve interventions and transcatheter valve-in-valve procedures have lowered the age threshold for preferring a biological valve over a mechanical one.
However, current biological prosthetic valves, including cryopreserved donor valves, have two main limitations:
- The use of foreign materials is proven to lead to chronic inflammatory processes that cause prosthetic leaflets to become fibrous and calcific, thus limiting their durability
- That the valves are non-living structures that do not adapt to functional demand changes, which inherently limits their durability in comparison to a viable valve replacement; this aspect is obviously fundamental in paediatric or young patients.
These are the reasons behind the growing interest in bioresorbable valve therapies. Classical tissue-engineered heart valves are made of cells that are harvested, expanded in vitro and seeded on a rapidly-degrading scaffold before implantation. However, over the last 20 years, the translation of this process to the clinic has proven difficult, mainly due to the complexity of the procedure and suboptimal long-term in vivo performance secondary to valve leaflet retraction by the seeded cells. In the last few years a novel approach has emerged to create living valves at the site of destination inside the heart. In a process called endogenous tissue restoration, a malfunctioning valve is replaced by a cell-free scaffold that gradually transforms into a living valve by recruiting endogenous cells and using the body as a “bioreactor” to facilitate this process (Figure).
Preclinical studies and pathological insights in animal models (mainly sheep, which are known to be a reliable model of accelerated valvular calcification) has shown that valves obtained with this process, implanted both in aortic and pulmonary position, are less prone to calcific degeneration than current biological prostheses. It is unknown whether this will result in improved biocompatibility, less leaflet thickening or thrombosis and improved durability but this will be evaluated in animal studies and early human trials, and is surely promising for the field of valve replacement. Furthermore, haemodynamic parameters of the engineered valves (both surgical and transcatheter valves are currently under development) seem to be good up to 24 months.
The capability of endogenous tissue restoration to adapt in a growing patient has already commenced evaluation in humans. For example, five paediatric patients received an engineered cavo-pulmonary graft as second step of a modified Fontan procedure and were followed for up to 12 months after surgery. No significant adverse events were reported and no early degeneration or stenosis of the graft (that are the most frequent complications of the procedure when using a prosthetic conduit) was seen at echocardiographic and MRI follow-up.
As with any new technology, several challenges remain to be overcome:
- As the reabsorption process is mediated by inflammation and tissue replacement, the risk of neovascularisation cannot be excluded and may lead to leaflet thickening and eventually to accelerated degradation of the valve
- The tissue replacement may be hampered when these materials are implanted in the aortic position, where native valve calcifications and high velocity flows may modify the reabsorption dynamics (especially if performed through a transcatheter procedure).
However, if these potential limitations can be overcome and early data are confirmed, it can be hypothesised that endogenous tissue restoration may redefine heart valve replacement therapy in the next 10 years, with the potential advantages of long-lasting durability and biocompatibility.
Damiano Regazzoli and Azeem Latib are both at the Interventional Cardiology Unit, Cardiology and Cardiothoracic Surgery Department, San Raffaele University Hospital, Milan, Italy.