Edward Buratto, MBBS, PhD, and Igor E. Konstantinov, MD, PhD, FRACS
Central Message.
The inflammatory response appears to play an important role in aortic valve calcification.
See Article page 1.
The mechanism behind the development of the aortic stenosis is not fully understood. Although it is becoming increasingly clear that valvular calcification is an integral part of acquired aortic stenosis, attempts at preventive therapy have been utterly disappointing.1
In this issue of the Journal, Erkhem-Ochir and colleagues2 attempted to shed light on the association of immune checkpoint markers with inflammatory infiltration and the progression of calcification of aortic valve leaflets. In their study of surgically resected aortic valve leaflets, they demonstrated an association between high levels of programmed death (PD) ligand 1 (PDL-1) expression, inflammation, and severity of leaflet calcification. Interestingly, the increased PDL-1 was associated with increased infiltration by cytotoxic T cells (CD8) and macrophages and decreased levels of T regulatory cells (Figure 1). These fascinating findings suggest that the progression of aortic stenosis may be related to alterations in the balance of inflammatory and regulatory immune cells. As the balance tips toward inflammation, there is increased PDL-1 expression; however, whether this increased PDL-1 expression is a cause or a consequence of the altered inflammatory status remains unclear. The causation here, if any, is yet to be established.
Figure 1.
Schematic of progression of the aortic valve calcifications. Treg, Regulatory T lymphocyte; PDL-1, programmed death ligand 1; CD8, cluster of differentiation 8.
There has been a great deal of interest in the role of PDL-1 in oncology in recent years.3,4 The expression of PDL-1 in tumor cells acts on PD-1 receptors on cytotoxic T cells, resulting in dysfunction of these cytotoxic T cells. Thus, PDL-1 expression appears to enhance immune system evasion by tumor cells. Recently, the PD-1 receptor and PDL-1 have become important therapeutic targets, and monoclonal antibodies directed at these targets have shown impressive efficacy in treating advanced non–small cell lung cancer.3,4 It is interesting to reconcile our understanding of PDL-1 in malignancy with its potential role in calcific aortic stenosis. In malignancy, expression of PDL-1 acts to decrease the immune response and allow cancer cells to evade immune system. Conversely, Erkhem-Ochir and colleagues have shown that increased PDL-1 expression is associated with increased inflammation in the setting of aortic stenosis. Whether the PDL-1 expression causes the increased inflammation or is a consequence of already increased inflammation, potentially representing a counter-regulatory mechanism to alleviate the ongoing inflammatory response, remains unclear. Further studies will be needed to tease out these details and determine whether PDL-1 could represent a novel therapeutic target to slow the progression of aortic stenosis. The importance of preventing calcification cannot be overemphasized, particularly for the longevity of aortic valve repair or reconstruction with or without patch material.5, 6, 7, 8, 9
Although the fascinating findings of this preliminary study are not conclusive, this is an important step forward in our understanding of calcific aortic stenosis.
Footnotes
Disclosures: The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
References
- 1.Rossebø A.B., Pedersen T.R., Boman K., Brudi P., Chambers J.B., Egstrup K., et al. SEAS Investigators Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–1356. doi: 10.1056/NEJMoa0804602. [DOI] [PubMed] [Google Scholar]
- 2.Erkhem-Ochir B., Tatsuishi W., Yokobori T., Ohno T., Hatori K., Handa T., et al. Inflammatory and immune checkpoint markers are associated with the severity of aortic stenosis. J Thorac Cardiovasc Surg Open. 2021;5:1–12. doi: 10.1016/j.xjon.2020.11.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rhodin K.E., Rucker A.J., Ready N.E., D'Amico T.A., Antonia S.J. The immunotherapeutic landscape in non–small cell lung cancer and its surgical horizons. J Thorac Cardiovasc Surg. 2020;159:1616–1623. doi: 10.1016/j.jtcvs.2019.08.138. [DOI] [PubMed] [Google Scholar]
- 4.Sepesi B., Cascone T. Commentary: neoadjuvant checkpoint inhibitors in resectable non-small cell lung cancer-ready for prime time? J Thorac Cardiovasc Surg. 2020;159:1624–1625. doi: 10.1016/j.jtcvs.2019.09.042. [DOI] [PubMed] [Google Scholar]
- 5.Buratto E., Konstantinov I.E. Aortic valve surgery in children. J Thorac Cardiovasc Surg. August 3, 2020 doi: 10.1016/j.jtcvs.2020.06.145. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
- 6.Konstantinov I.E., Ivanov Y.Y. Commentary: aortic valve calcification: a new story with a twist? J Thorac Cardiovasc Surg. 2019 doi: 10.1016/j.jtcvs.2019.11.025. [In press] [DOI] [PubMed] [Google Scholar]
- 7.Baird C.W., Sefton B., Chavez M., Sleeper L.A., Marx G.R., del Nido P.J. Congenital aortic and truncal valve reconstruction utilizing the Ozaki technique: short-term clinical results. J Thorac Cardiovasc Surg. February 19, 2020 doi: 10.1016/j.jtcvs.2020.01.087. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
- 8.Wiggins L.M., Mimic B., Issitt R., Ilic S., Bonello B., Marek J., et al. The utility of aortic valve leaflet reconstruction techniques in children and young adults. J Thorac Cardiovasc Surg. 2020;159:2369–2378. doi: 10.1016/j.jtcvs.2019.09.176. [DOI] [PubMed] [Google Scholar]
- 9.Ozaki S., Kawase I., Yamashita H., Uchida S., Takatoh M., Kiyohara N. Midterm outcomes after aortic valve neocuspidization with glutaraldehyde-treated autologous pericardium. J Thorac Cardiovasc Surg. 2018;155:2379–2387. doi: 10.1016/j.jtcvs.2018.01.087. [DOI] [PubMed] [Google Scholar]