Discussion
Calcification of the native aortic valve is present even after AVR. The pathogenesis is multifactorial; factors such as mechanical forces lead to endothelial dysfunction2, altered flow dynamics11, production of inflammatory cytokines by the prosthetic material (titanium)10 and xenoantigens such as Galα3Gal- and the corresponding anti-Gal antibodies contributing to valve damage20. The participation of cytokines before AVR and after the intervention has been studied to define whether this inflammatory damage requires timely therapy to prolong prosthetic durability9.
Among the cytokines studied, IL-4 activates collagen synthesis, promotes fibrosis progression, and inhibits inflammatory cytokines production21. Its secretion occurs in response to microorganisms, prosthetic material, volumetric, or pressure overload22. In this study, elevated levels of IL-4 were found in patients treated with a mechanical prosthetic implant; however, this increase was not associated with prosthetic dysfunction, rheumatic heart disease, gender, or the time to progress after PrVA placement. The elevation of IL-4 could be associated with the inflammation that occurs post-surgery, promoting the alternative activation of macrophages into M2 cells, increasing repair macrophages (M2), and decreasing when interacting with IL-10 and TGF-β. These changes contribute to valve tissue repair23, and our results confirm this judgment.
We further found an increase in OPN in patients that received mechanical and biological valve prostheses without statistically significant difference. However, this finding had only been demonstrated in dysfunctional biological prostheses24. One explanation for this finding is the evidence that in calcified porcine aortic valves, there is an increase in OPN, which activates osteogenic signaling25.
We found low levels of OPG in mechanical prostheses; in relation, this finding has been found that low levels of OPG lead to an osteoclastic transformation of the valve26, and on the other hand, there is a negative correlation between native AVA and OPG27.
Increased ET-1 and endothelin receptor-A levels have been identified in patients with native AS28, and endothelin A and B receptors are located on the leaflets’ tips and surface29. There is a transient increase following myocardial damage after AVR and a concomitant diastolic dysfunction30; however, this does not persist, and it decreases in conjunction with brain natriuretic peptide (BNP) after improvement of the ventricular function due to decreased LV afterload31. In our work, the ET-1 level was similar between mechanical or nonfunctional biological prostheses. However, in mechanical prostheses with prosthetic dysfunction and the first five years after AVR, ET-1 was found to increase; this finding is like to previous studies in dysfunctional biological valves24.
IL-1β induces inflammation through the inhibition of factor-κβ and AVICs32; therefore, its participation in the extracellular matrix remodeling will condition the proliferation of interstitial cells and the expression of MPPs3, and also a dysfunction has also been found in the anti-inflammatory mechanism of the interleukin receptor antagonist 1β. In this research, the levels of IL-1β were similar in patients receiving biological and mechanical prostheses with and without dysfunction. However, in dysfunctional prostheses to a long-term time (more than ten years), there was a decrease in IL-1β, which suggests that its participation is broad and varies according to comorbidities, the prosthesis material gender, and time of evolution.
Before AVR, the inflammatory process will continue and persist; however, anti-inflammatory therapy should be proposed after implantation. The transformation process of AIVCs leads to postoperative valve dysfunction since they change to a myofibroblast phenotype that is activated in the presence of transforming growth factor beta1 (TGF-β1)33-35. Recently proposed therapies such as l-arginine prevent osteogenic differentiation of AVICs and reduce matrix calcification regarding therapeutics. This effect is obtained through the modulation of proteins involved in the cellular redox system, the extracellular matrix’s remodeling, and the inflammatory activation of AVICs36.
Prostheses’ advantages and disadvantages are well defined, including inflammation in the early and late postoperative periods. Studies that include punctual monitoring still require exploration through systematic randomized clinical trials to improve valve prostheses’ functionality.