Better think twice—revisiting an old idea with the aid of modern techniques

The societal burden of valvular heart disease is growing steadily in parallel with an increasingly ageing population. It is currently estimated that between 2017 and 2050, the world’s population aged 60+ years will jump from 960 to >2000 million [1]. The impact of acquired heart valve disease, such as aortic valve stenosis, for the individual patient is substantial, as it will ultimately lead to either surgical or transcatheter heart valve replacement. Given the projected increase in lifespan in the population, it is likely these patients will undergo 2 or more procedures, as the overwhelming majority of elderly patients opt for biological heart valve prostheses [2]. In congenital heart disease, the impact of valve malformations may even be more significant, as outlined in a recent long-term analysis of almost 1000 patients in need of pulmonary valve replacement. At 30 years, 50% of the patients had undergone 5 or more surgical and/or interventional procedures on their pulmonary valve [3]. Biological heart valve replacement is the procedure of choice in pulmonary valve replacement, and decellularized allogenic heart valves have emerged as the new gold standard in the past 5 years, replacing cryopreserved homografts [4]. Decellularized xenogenic heart valves have so far shown disappointing, and sometimes dangerous, results when used for pulmonary valve replacement [5], or as patch material in aortic valve repair [6]. Decellularization has, to date, appeared to be an insufficient strategy to avoid the massive immune response seen towards tissue components derived from animals. The contribution of Bozso et al. in the current edition of the EJCTS—‘Recellularization of Xenograft Heart Valves Reduces the Xenoreactive Immune Response in an in vivo Rat Model’—provides an interesting perspective in this context. Decellularized guinea pigs valve constructs were recellularized with autologous rat mesenchymal stem cells before implantation in the abdominal aorta of rats. The authors are to be credited especially for the quantification of the xenogenic immune response within their experiments. They were able to show that recellularization significantly reduced the initial immune activation, similar to the extent of the immune response to autologous tissue. These results should be interpreted with some caution as the authors used a non-anatomic implantation model, and it has been notoriously difficult to translate immunological results in animal heart valve experiments to clinical application in the past. However, this study may nevertheless revive the idea of pre-seeding decellularized xenogenic heart valve matrices. Dohmen et al. [7] published their initial auspicious experience using decellularized porcine heart valves reseeded with autologous vascular endothelial cells over a decade ago, but the concept was subsequently not further pursued. In light of newly available porcine heart valves derived from genetically modified animals, e.g. with triple alpha-Gal knock-out, this tissue could be considered for use as the basis for decellularized heart valve constructs, not only for pulmonary valve replacement, but also for more frequently occurring aortic valve and mitral procedures. In addition, modern stem cell recellularization using induced pluripotent stem cells (iPS) offers an additional avenue, as iPS are not subject to ethical restrictions and can be obtained with low burden to the patient. Autologeous iPS recellularization of xenogenic decellularized heart valves matrices for use as either as complete xenogenic heart valves, or in the form of stented decellularized xenogenic pericardial mitral and aortic valves, may open up a promising approach to evade the initial cellular and humoral immune response within the patient. Ongoing research in iPS cell lines may also enable the creation of universal cell lines with the help of modern silencing techniques, which could omit the time- and cost-related restrictions in individual iPS cell line production. Therefore, it may be time to think twice about the use of decellularized xenogenic heart valves, looking beyond the disappointing results of the past, and revisit this approach with the help of modern techniques.