Alpha-Gal-specific humoral immune response and reported clinical consequence for cardiac valve replacement in patients below 65 years: moving beyond conjecture

We congratulate the EJCTS for publishing the Editorial ‘Immunoreaction to xenogeneic tissue in cardiac surgery: alpha-Gal and beyond’ [1]. This Editorial deserves a comment that relates to proper citation policy [2] and manifests European clinical practice. It was Peter Zilla, an Austrian-born cardiac surgeon working at the Groote Schuur Hospital in Cape Town, who speculated for the first time that a humoral immune response is responsible for the degeneration of glutaraldehyde-fixed bioprostheses utilized in valve replacement surgery [3]. The presence of ‘the’ xenogeneic antigen alpha-Gal as well as the elicited humoral immune response was comprehensively described for the first time in 2005 [4]. In 2009, it was evidenced that the implantation of bioprostheses induces a long-lasting alpha-Gal-specific IgG immune response in valve recipients [5]. Park et al. [6] corroborated the above data and demonstrated a robust age-dependent alpha-Gal-specific humoral response following the implantation of porcine xenografts in adults below 65 years of age. Recently, new insights were published indicating that alpha-Gal-bearing scaffolds utilized in transcatheter aortic valve implantation initiate a similar humoral immune response. This resulted in the formation of IgG3 antibodies against alpha-Gal, neutrophil granulocyte activation (NETosis), C3a complement activation and the secretion of the decoy receptor sST2 in the context of an inflammatory reaction [7]. This holistic immunological research in recipients of bioprostheses provides an indication of why patients below 65 years, who received a bioprosthesis as compared to mechanical valves, have significantly increased morbidity and mortality [8, 9]. What is the notion of all data presented in the literature? Physicians working in the field of cardiology and cardiac surgery should adhere to currently published ESC guidelines when advising patients about available treatment options for aortic valve diseases to act in accordance with the best interest of the patients [10]. We are convinced that outcome research has clearly shown that the overzealous implantation of bioprostheses in patients below 65 years of age in Europe has dire consequences. With this Editorial in the European Journal of Cardio-Thoracic Surgery, the alpha-Gal-specific immune response has reached the mainstream of knowledge and might cause a swift change of current implantation strategies. To summarize, (i) alpha-Gal-bearing scaffolds are digested in an age-dependent fashion; (ii) a new chapter in cardiology and cardiac surgery will be opened when the device industry offers alpha-Gal-deficient bioprostheses; and (iii) adherence to ESC guidelines and its age limitations for the implantation of bioprostheses will save lives. We hope that these comments will be received as a constructive call for this acclaimed Editorial to re-evaluate current implantation strategies.