Evaluation of the Inflammatory Response in Post-operated Aortic Valve Replacement Patients.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Evaluation of the Inflammatory Response and Long-term Calcification in Post-operated Aortic Valve Replacement Patients.

Conditions
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Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Calcification, Prosthetic Valve Malfunction

Intervention / Treatment
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* Diagnostic Test: Determination of cytokines
* Diagnostic Test: Two-dimensional transthoracic echocardiogram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over 18 years of age underwent an aortic valve exchange for an INC bioprosthesis, imported bioprosthesis, or mechanical prosthesis. Patients with follow-up two-dimensional transthoracic echocardiography. Patients who agree to take a blood sample for an inflammatory profile. Exclusion Criteria: Patients in whom more than one cardiac prosthesis was implanted in any valve position. Inflammatory and connective tissue disease (systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome). Patients undergoing aortic valve replacement due to prosthetic valve dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Biological prostheses INC<br>Prosthetic valve manufactured in the National Institute of Cardiology Ignacio Chávez. | Diagnostic Test: Determination of cytokines<br>* Subsequently, a blood sample will be taken from which the processing will be as follows: 6 ml of peripheral blood will be taken in tubes with a yellow cap and inert gel and clot retractor, immediately afterward it will be placed on ice, it will be transported to the laboratory where it will be centrifuged at 2500 rpm for 15 minutes at 4 degrees centigrade, immediately afterward 500 µl of serum will be aliquoted and stored at minus 75 ° C until later analysis. The general methodology for sandwich ELISA will be used.<br>Diagnostic Test: Two-dimensional transthoracic echocardiogram<br>* With prior informed consent, a two-dimensional transthoracic echocardiogram will be obtained by an echocardiographer certified by the Mexican Council of Cardiology (CMC) with a Phillips EPIC 7 echocardiography, 2D Arrary 3D Convex (1-6 Mhz) transducer.<br>|
| Imported Biological aortic prostheses<br>St Jude EPIC and Carpentier-Edwards Perimount | Diagnostic Test: Determination of cytokines<br>* Subsequently, a blood sample will be taken from which the processing will be as follows: 6 ml of peripheral blood will be taken in tubes with a yellow cap and inert gel and clot retractor, immediately afterward it will be placed on ice, it will be transported to the laboratory where it will be centrifuged at 2500 rpm for 15 minutes at 4 degrees centigrade, immediately afterward 500 µl of serum will be aliquoted and stored at minus 75 ° C until later analysis. The general methodology for sandwich ELISA will be used.<br>Diagnostic Test: Two-dimensional transthoracic echocardiogram<br>* With prior informed consent, a two-dimensional transthoracic echocardiogram will be obtained by an echocardiographer certified by the Mexican Council of Cardiology (CMC) with a Phillips EPIC 7 echocardiography, 2D Arrary 3D Convex (1-6 Mhz) transducer.<br>|
| Mechanical prostheses<br>St Jude Masters HP, Carbomedics Standart, ON-X Life Technologies, Edwards Mira, Carbomedics Orbis, Medtronic Hall and Medtronic ATS. | Diagnostic Test: Determination of cytokines<br>* Subsequently, a blood sample will be taken from which the processing will be as follows: 6 ml of peripheral blood will be taken in tubes with a yellow cap and inert gel and clot retractor, immediately afterward it will be placed on ice, it will be transported to the laboratory where it will be centrifuged at 2500 rpm for 15 minutes at 4 degrees centigrade, immediately afterward 500 µl of serum will be aliquoted and stored at minus 75 ° C until later analysis. The general methodology for sandwich ELISA will be used.<br>Diagnostic Test: Two-dimensional transthoracic echocardiogram<br>* With prior informed consent, a two-dimensional transthoracic echocardiogram will be obtained by an echocardiographer certified by the Mexican Council of Cardiology (CMC) with a Phillips EPIC 7 echocardiography, 2D Arrary 3D Convex (1-6 Mhz) transducer.<br>|
| Control<br>In subjects who come to donate blood products altruistically, in the blood bank service of the INC, with prior informed consent, the subjects will be matched with PO patients of CVA by age and gender. | Diagnostic Test: Determination of cytokines<br>* Subsequently, a blood sample will be taken from which the processing will be as follows: 6 ml of peripheral blood will be taken in tubes with a yellow cap and inert gel and clot retractor, immediately afterward it will be placed on ice, it will be transported to the laboratory where it will be centrifuged at 2500 rpm for 15 minutes at 4 degrees centigrade, immediately afterward 500 µl of serum will be aliquoted and stored at minus 75 ° C until later analysis. The general methodology for sandwich ELISA will be used.<br>Diagnostic Test: Two-dimensional transthoracic echocardiogram<br>* With prior informed consent, a two-dimensional transthoracic echocardiogram will be obtained by an echocardiographer certified by the Mexican Council of Cardiology (CMC) with a Phillips EPIC 7 echocardiography, 2D Arrary 3D Convex (1-6 Mhz) transducer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantify the long-term inflammatory response of INC bioprostheses implanted in the aortic position. | Serum measurements of RANK, RANKL, IL-10 (pg/cc), IL-1 (pg/cc), IL-6(pg/cc), ICAM-1 (pg/cc), MMP-9, endothelin-1, osteopontin, osteprogesterin, and TNF-alpha (pg/cc) will be performed. | An average of 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the long-term inflammatory response of INC bioprostheses implanted in the aortic position to imported bioprostheses and mechanical prostheses. | Serum measurements of RANK, RANKL, IL-10 (pg/cc), IL-1 (pg/cc), IL-6(pg/cc), ICAM-1 (pg/cc), MMP-9, endothelin-1, osteopontin, osteprogesterin, and TNF-alpha (pg/cc) will be performed. | An average of 6 months | 
| The inflammatory response of post-bioprosthesis operated patients will be compared with a control group. | Serum measurements of RANK, RANKL, IL-10 (pg/cc), IL-1 (pg/cc), IL-6(pg/cc), ICAM-1 (pg/cc), MMP-9, endothelin-1, osteopontin, osteprogesterin, and TNF-alpha (pg/cc) will be performed. | Through study completion, an average of 6 years |