Aortic Valve Stenosis Clinical Trial
Official title:
Evaluation of the Inflammatory Response and Long-term Calcification in Post-operated Aortic Valve Replacement Patients.
Background
Calcification of the aortic valve affects more than 26% of adult patients over 65 years of
age and is the main indication for valve replacement in the United States of America.
Previous evidence shows that aortic valve calcification is an active biological process
associated with inflammation. The only actual treatment for severe aortic stenosis is
surgical aortic valve replacement (AVR). The materials with which the different types of
prostheses are manufactured could induce inflammation per se. Biological prostheses, an
incomplete cell removal process and therefore, the presence of residual proteins of animal
origin, could induce the immune system's response. In the manufacturing bioprosthesis at the
"Ignacio Chávez" National Institute of Cardiology (INC), an evaluation was carried out in the
early, and late post-surgical period, it was shown that the inflammatory response after six
months is similar to that produced by mechanical prosthesis.
This study's main objective is to evaluate the inflammatory response in patients with
post-operated AVR due to biological or mechanical prosthetic valve through different plasma
biomarkers in long-term follow-up.
Research question
What is the inflammatory response and calcification in patients who undergo aortic valve
replacement for a manufactured prosthesis at the "Ignacio Chávez" National Institute of
Cardiology in the long-term follow-up?
Hypothesis
Manufactured bioprostheses at the "Ignacio Chávez" National Institute of Cardiology show a
similar or lower inflammatory response to imported bioprostheses or mechanical prostheses
associated with less valve dysfunction and more outstanding durability.
Evaluation of the inflammatory response and long-term calcification in post-operated aortic
valve replacement patients.
Background
Calcification of the aortic valve affects more than 26% of adult patients over 65 years of
age and is the main indication for valve replacement in the United States of America. In
Mexico, there is no exact figure for the prevalence and incidence of aortic stenosis.
Previous evidence shows that aortic valve calcification is an active biological process,
associated with inflammation and increased levels of intracellular adhesion molecule 1
(ICAM-1), pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin
6 (IL-6), interleukin 1 (IL-1), interleukin 17 (IL-17), interleukin 18 (IL-18), extracellular
matrix proteins (MMP-1), tenascin-C7, osteopontin and bone sialoprotein followed by
osteogenic differentiation.
Osteoprotegerin (OPG) / RANK / RANK ligand also plays a regulatory role in bone metabolism;
however, in bioprostheses, the role they play in dysfunction does not seem to be clear. They
have been found in patients with early coronary atherosclerosis, and a significant increase
in endothelial progenitor cells with osteoblasts, osteocalcin (OCN) and phenotype (EPN-OCN)
and it has been shown that it is an important prognostic marker in valvular calcification. In
the final stage of the disease, expression of TGFβ1 and VAP-1 has been found; both genes are
triggers of the calcification process without any association with osteogenic transformation,
which is not influenced by statins' use; however, first use alters its expression.
The only actual treatment for severe aortic stenosis is surgical aortic valve replacement
(AVR). However, even after the procedure, the inflammatory response persists in almost half
of the patients. It has been shown that there is no correlation between age, gender, smoking,
ventricular geometry, transvalvular aortic gradient, and the persistence of the inflammatory
state after valve replacement. Even more, the materials with which the different types of
prostheses are manufactured could induce inflammation per se. Biological prostheses, an
incomplete cell removal process and therefore the presence of residual proteins of animal
origin, could induce a response of the immune system through the xenoantigen Gal-3-Gal- and
its corresponding anti-Gal antibodies that have been associated with valve prosthetic damage.
The presence of metallic components such as titanium could act as a trigger for the
inflammatory response. As regards the hemodynamic profile of the bioprosthesis, it is unknown
whether it is correlated with an inflammatory response. In the manufacturing bioprosthesis at
the "Ignacio Chávez" National Institute of Cardiology (INC), an evaluation was carried out in
the early, and late post-surgical period, it was shown that the inflammatory response after
six months is similar to that produced by mechanical prosthesis.
This study's main objective is to evaluate the inflammatory response in patients with
post-operated AVR due to biological or mechanical prosthetic valve through different plasma
biomarkers in long-term follow-up.
Problem Statement
The pattern of the inflammatory response and long-term calcification of the prosthetic valve
manufactured in the National Institute of Cardiology "Ignacio Chávez" is not known, in the
study carried out by Soto López and Cols in which patients undergoing prosthetic valve change
were evaluated in a state of early and late post-surgical (6 months) it was observed that
there is no difference between biological or mechanical prosthesis. We believe that the
inflammatory process associated with the INC bioprosthesis persists over time. However, it
could be even less than an imported bioprosthesis or mechanical prosthesis, so it is
necessary to evaluate its inflammatory pattern in long-term follow-up.
Justification
Degenerative aortic stenosis is a significant health problem, and its treatment through valve
replacement modifies morbidity and mortality. There are currently more than 5000 prostheses
implanted in the INC, and the leading cause of dysfunction is calcification. The long-term
inflammatory response in INC bioprostheses has not been evaluated to date, identifying, and
comparing the inflammatory pattern between these bioprostheses could identify potential
therapeutic targets. Demonstrating non-inferiority and a similar or less inflammatory pattern
could provide one more reason to start its generalized use in public health institutions in
the country.
Research question
What is the inflammatory response and calcification in patients who undergo aortic valve
replacement for a manufactured prosthesis at the "Ignacio Chávez" National Institute of
Cardiology in the long-term follow-up?
Aims
Primary objectives
• Quantify the long-term inflammatory response of INC bioprostheses implanted in the aortic
position.
Secondary objectives
- Compare the long-term inflammatory response of INC bioprostheses implanted in the aortic
position to imported bioprostheses and mechanical prostheses.
- The inflammatory response of post-bioprosthesis operated patients will be compared with
a control group.
Hypothesis
Null hypothesis
The inflammatory response is more significant in manufactured bioprostheses at the "Ignacio
Chávez" National Institute of Cardiology, associated with more significant prosthetic valve
dysfunction.
Alternative hypothesis
Manufactured bioprostheses at the "Ignacio Chávez" National Institute of Cardiology show a
similar or lower inflammatory response to imported bioprostheses or mechanical prostheses,
which is associated with less valve dysfunction and more outstanding durability.
Methodology
Design type
Observational, longitudinal, descriptive ambispective cohort study.
Sample size
The sample size of 56 patients (14 patients per group) was calculated using a test for
difference of independent proportions, with a power of 80 %, probability of error of 0.5,
based on the RANK concentration from the previous studies.
Statistic analysis.
The normality of continuous variables will be sought with the Shapiro Wilks test. According
to the distribution, continuous variables will be expressed as mean ± standard deviation or
median and interquartile ranges. The categorical variables will be expressed in number and
percentage. Comparisons will be made using the Chi-square test or Fisher's exact test for
categorical variables; For dimensional variables, the Student's t-test or Mann-Whitney's U
test will be used. The differences will be considered statistically significant when the
value of p is less than 0.05.
Schedule of activities.
The preparation of the protocol and review by the ethics committee will be carried out in the
months of June to August 2017, the obtaining of the information will take place from August
2017 to February 2018, the obtaining of the inflammatory profile will be carried out in the
months of March 2018 to July 2019, the information processing will take place in August and
December 2019, the review by the committee will be enhanced in January to July 2020 and the
disclosure of results It is carried out during the months of November to December 2020.
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