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.