Aortic Valve DiseaseNCT04557345
Evaluation of the Inflammatory Response in Post-operated Aortic Valve Replacement Patients.
An observational study of Aortic Valve Disease and Aortic Valve Stenosis, run by Instituto Nacional de Cardiologia Ignacio Chavez at 1 site in Mexico.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Calcification
- What is being tested?
- Determination of cytokines and Two-dimensional transthoracic echocardiogram
- How many people
- 80 participants
- Where
- 1 siteMexico
- Study dates
- 1 Jan 1990to 1 Aug 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Patients who have had a biological prosthetic valve implanted in aortic position manufactured at the National Institute of Cardiology "Ignacio Chávez" with an anti-calcifying system, imported biological prosthetic aortic valve or mechanical aortic valve from January 1990 to May 2020.
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Calcification, Prosthetic Valve Malfunction
- Being tested
- Determination of cytokines, Two-dimensional transthoracic echocardiogram
- Medical subject headings
- Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve, Calcification of
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Determination of cytokinesDiagnostic test
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.
Two-dimensional transthoracic echocardiogramDiagnostic test
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.
| Study group | Role | What they receive |
|---|---|---|
| Biological prostheses INC | Prosthetic valve manufactured in the National Institute of Cardiology "Ignacio Chávez". Receives: Diagnostic Test: Determination of cytokines; Diagnostic Test: Two-dimensional transthoracic echocardiogram | |
| Imported Biological aortic prostheses | St Jude EPIC and Carpentier-Edwards Perimount Receives: Diagnostic Test: Determination of cytokines; Diagnostic Test: Two-dimensional transthoracic echocardiogram | |
| Mechanical prostheses | St Jude Masters HP, Carbomedics Standart, ON-X Life Technologies, Edwards Mira, Carbomedics Orbis, Medtronic Hall and Medtronic ATS. Receives: Diagnostic Test: Determination of cytokines; Diagnostic Test: Two-dimensional transthoracic echocardiogram | |
| Control | 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. Receives: Diagnostic Test: Determination of cytokines; Diagnostic Test: Two-dimensional transthoracic echocardiogram |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: An average of 6 years
Secondary outcomes (2)
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.
Measured: 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.
Measured: Through study completion, an average of 6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2020
- Study start1 Jan 1990
- Primary completion1 Aug 2020
- Study completion1 Aug 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Aortic Valve DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Other
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Instituto Nacional de Cardiologia Ignacio Chavez
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Maria Elena Soto, MsC and PhD, Instituto Nacional de Cardiologia Ignacio Chavez
- Investigators
- Maria Elena Soto Lopez, PhD, Principal investigator, Instituto Nacional de Cardiologia Ignacio Chavez
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04557345
- Sponsor's protocol ID
- 17-1033
- Status last verified
- Sep 2020
- First submitted
- 28 Aug 2020
- Last updated
- 21 Sep 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: It is not yet known if there will be a plan to make IPD available.
Publications
Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993 Apr;21(5):1220-5. doi: 10.1016/0735-1097(93)90249-z.
PubMed 8459080Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):162-8. doi: 10.1161/ATVBAHA.107.156752. Epub 2008 Nov 20.
PubMed 19023094Galeone A, Brunetti G, Oranger A, Greco G, Di Benedetto A, Mori G, Colucci S, Zallone A, Paparella D, Grano M. Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand. Int J Cardiol. 2013 Nov 15;169(4):296-304. doi: 10.1016/j.ijcard.2013.09.012. Epub 2013 Oct 5.
PubMed 24148916Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kilic R, Sarikoc A, Brueckmann M, Vahl C, Hagl S, Haase KK, Borggrefe M. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 2003 Oct;170(2):205-11. doi: 10.1016/s0021-9150(03)00284-3.
PubMed 14612199Madhur MS, Funt SA, Li L, Vinh A, Chen W, Lob HE, Iwakura Y, Blinder Y, Rahman A, Quyyumi AA, Harrison DG. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1565-72. doi: 10.1161/ATVBAHA.111.227629. Epub 2011 Apr 7.
PubMed 21474820Naito Y, Tsujino T, Wakabayashi K, Matsumoto M, Ohyanagi M, Mitsuno M, Miyamoto Y, Hao H, Hirota S, Okamura H, Masuyama T. Increased interleukin-18 expression in nonrheumatic aortic valve stenosis. Int J Cardiol. 2010 Oct 8;144(2):260-3. doi: 10.1016/j.ijcard.2009.01.022. Epub 2009 Feb 13.
PubMed 19217172Satta J, Melkko J, Pollanen R, Tuukkanen J, Paakko P, Ohtonen P, Mennander A, Soini Y. Progression of human aortic valve stenosis is associated with tenascin-C expression. J Am Coll Cardiol. 2002 Jan 2;39(1):96-101. doi: 10.1016/s0735-1097(01)01705-3.
PubMed 11755293Kennedy JH, Henrion D, Wassef M, Shanahan CM, Bloch G, Tedgui A. Osteopontin expression and calcium content in human aortic valves. J Thorac Cardiovasc Surg. 2000 Aug;120(2):427. doi: 10.1067/mtc.2000.106968. No abstract available.
PubMed 10917976Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoc A, Kilic R, Brueckmann M, Lang S, Zahn I, Vahl C, Hagl S, Dempfle CE, Borggrefe M. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol. 2004 Jan;36(1):57-66. doi: 10.1016/j.yjmcc.2003.09.015.
PubMed 14734048Caira FC, Stock SR, Gleason TG, McGee EC, Huang J, Bonow RO, Spelsberg TC, McCarthy PM, Rahimtoola SH, Rajamannan NM. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006 Apr 18;47(8):1707-12. doi: 10.1016/j.jacc.2006.02.040. Epub 2006 Mar 20.
PubMed 16631011Cao H, Li Q, Li M, Od R, Wu Z, Zhou Q, Cao B, Chen B, Chen Y, Wang D. Osteoprotegerin/RANK/RANKL axis and atrial remodeling in mitral valvular patients with atrial fibrillation. Int J Cardiol. 2013 Jul 1;166(3):702-8. doi: 10.1016/j.ijcard.2011.11.099. Epub 2011 Dec 15.
PubMed 22178057Gossl M, Modder UI, Atkinson EJ, Lerman A, Khosla S. Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis. J Am Coll Cardiol. 2008 Oct 14;52(16):1314-25. doi: 10.1016/j.jacc.2008.07.019.
PubMed 18929243Gossl M, Khosla S, Zhang X, Higano N, Jordan KL, Loeffler D, Enriquez-Sarano M, Lennon RJ, McGregor U, Lerman LO, Lerman A. Role of circulating osteogenic progenitor cells in calcific aortic stenosis. J Am Coll Cardiol. 2012 Nov 6;60(19):1945-53. doi: 10.1016/j.jacc.2012.07.042. Epub 2012 Oct 10.
PubMed 23062532Anger T, Carson W, Weyand M, Daniel WG, Hoeher M, Garlichs CD. Atherosclerotic inflammation triggers osteogenic bone transformation in calcified and stenotic human aortic valves: still a matter of debate. Exp Mol Pathol. 2009 Feb;86(1):10-7. doi: 10.1016/j.yexmp.2008.11.001. Epub 2008 Nov 19.
PubMed 19084515Agmon Y, Khandheria BK, Jamil Tajik A, Seward JB, Sicks JD, Fought AJ, O'Fallon WM, Smith TF, Wiebers DO, Meissner I. Inflammation, infection, and aortic valve sclerosis; Insights from the Olmsted County (Minnesota) population. Atherosclerosis. 2004 Jun;174(2):337-42. doi: 10.1016/j.atherosclerosis.2004.01.028.
PubMed 15136064
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Inflammatory Response and Long-term Calcification in Post-operated Aortic Valve Replacement Patients.
- ClinicalTrials.gov ID
- NCT04557345
- Acronym / sponsor ID
- 17-1033
- Conditions
- Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Calcification, Prosthetic Valve Malfunction
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Instituto Nacional de Cardiologia Ignacio ChavezUniversity, hospital or other
- Study start
- 1 Jan 1990 (actual)
- Primary completion
- 1 Aug 2020 (actual)
- Study completion
- 1 Aug 2020 (actual)
- First posted
- 21 Sep 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Observational model
- Cohort
- Time perspective
- Other
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Biological prostheses INC | – | Diagnostic Test: Determination of cytokines, Diagnostic Test: Two-dimensional transthoracic echocardiogramProsthetic valve manufactured in the National Institute of Cardiology "Ignacio Chávez". |
| Imported Biological aortic prostheses | – | Diagnostic Test: Determination of cytokines, Diagnostic Test: Two-dimensional transthoracic echocardiogramSt Jude EPIC and Carpentier-Edwards Perimount |
| Mechanical prostheses | – | Diagnostic Test: Determination of cytokines, Diagnostic Test: Two-dimensional transthoracic echocardiogramSt Jude Masters HP, Carbomedics Standart, ON-X Life Technologies, Edwards Mira, Carbomedics Orbis, Medtronic Hall and Medtronic ATS. |
| Control | – | Diagnostic Test: Determination of cytokines, Diagnostic Test: Two-dimensional transthoracic echocardiogramIn 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Patients who have had a biological prosthetic valve implanted in aortic position manufactured at the National Institute of Cardiology "Ignacio Chávez" with an anti-calcifying system, imported biological prosthetic aortic valve or mechanical aortic valve from January 1990 to May 2020.
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Determination of cytokinesSubsequently, 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. | Diagnostic test | Biological prostheses INC, Control, Imported Biological aortic prostheses, Mechanical prostheses |
| Two-dimensional transthoracic echocardiogramWith 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. | Diagnostic test | Biological prostheses INC, Control, Imported Biological aortic prostheses, Mechanical prostheses |
Primary outcome
Quantify the long-term inflammatory response of INC bioprostheses implanted in the aortic position.
Time frame: An average of 6 years
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.
2 secondary outcomes
Compare the long-term inflammatory response of INC bioprostheses implanted in the aortic position to imported bioprostheses and mechanical prostheses.
Time frame: An average of 6 months
The inflammatory response of post-bioprosthesis operated patients will be compared with a control group.
Time frame: Through study completion, an average of 6 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2020.
- Background: PubMed 8459080Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993 Apr;21(5):1220-5. doi: 10.1016/0735-1097(93)90249-z.
- Background: PubMed 19023094Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):162-8. doi: 10.1161/ATVBAHA.107.156752. Epub 2008 Nov 20.
- Background: PubMed 24148916Galeone A, Brunetti G, Oranger A, Greco G, Di Benedetto A, Mori G, Colucci S, Zallone A, Paparella D, Grano M. Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand. Int J Cardiol. 2013 Nov 15;169(4):296-304. doi: 10.1016/j.ijcard.2013.09.012. Epub 2013 Oct 5.
- Background: PubMed 14612199Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kilic R, Sarikoc A, Brueckmann M, Vahl C, Hagl S, Haase KK, Borggrefe M. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 2003 Oct;170(2):205-11. doi: 10.1016/s0021-9150(03)00284-3.
- Background: PubMed 21474820Madhur MS, Funt SA, Li L, Vinh A, Chen W, Lob HE, Iwakura Y, Blinder Y, Rahman A, Quyyumi AA, Harrison DG. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1565-72. doi: 10.1161/ATVBAHA.111.227629. Epub 2011 Apr 7.
- Background: PubMed 19217172Naito Y, Tsujino T, Wakabayashi K, Matsumoto M, Ohyanagi M, Mitsuno M, Miyamoto Y, Hao H, Hirota S, Okamura H, Masuyama T. Increased interleukin-18 expression in nonrheumatic aortic valve stenosis. Int J Cardiol. 2010 Oct 8;144(2):260-3. doi: 10.1016/j.ijcard.2009.01.022. Epub 2009 Feb 13.
- Background: PubMed 11755293Satta J, Melkko J, Pollanen R, Tuukkanen J, Paakko P, Ohtonen P, Mennander A, Soini Y. Progression of human aortic valve stenosis is associated with tenascin-C expression. J Am Coll Cardiol. 2002 Jan 2;39(1):96-101. doi: 10.1016/s0735-1097(01)01705-3.
- Background: PubMed 10917976Kennedy JH, Henrion D, Wassef M, Shanahan CM, Bloch G, Tedgui A. Osteopontin expression and calcium content in human aortic valves. J Thorac Cardiovasc Surg. 2000 Aug;120(2):427. doi: 10.1067/mtc.2000.106968. No abstract available.
- Background: PubMed 14734048Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoc A, Kilic R, Brueckmann M, Lang S, Zahn I, Vahl C, Hagl S, Dempfle CE, Borggrefe M. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol. 2004 Jan;36(1):57-66. doi: 10.1016/j.yjmcc.2003.09.015.
- Background: PubMed 16631011Caira FC, Stock SR, Gleason TG, McGee EC, Huang J, Bonow RO, Spelsberg TC, McCarthy PM, Rahimtoola SH, Rajamannan NM. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006 Apr 18;47(8):1707-12. doi: 10.1016/j.jacc.2006.02.040. Epub 2006 Mar 20.
- Background: PubMed 22178057Cao H, Li Q, Li M, Od R, Wu Z, Zhou Q, Cao B, Chen B, Chen Y, Wang D. Osteoprotegerin/RANK/RANKL axis and atrial remodeling in mitral valvular patients with atrial fibrillation. Int J Cardiol. 2013 Jul 1;166(3):702-8. doi: 10.1016/j.ijcard.2011.11.099. Epub 2011 Dec 15.
- Background: PubMed 18929243Gossl M, Modder UI, Atkinson EJ, Lerman A, Khosla S. Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis. J Am Coll Cardiol. 2008 Oct 14;52(16):1314-25. doi: 10.1016/j.jacc.2008.07.019.
- Individual participant dataSharing planned: Undecided. It is not yet known if there will be a plan to make IPD available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maria Elena Soto Lopez, PhD principal investigator
Instituto Nacional de Cardiologia Ignacio Chavez
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Aortic Valve Disease and Aortic Valve Stenosis, run by Instituto Nacional de Cardiologia Ignacio Chavez at 1 site in Mexico.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Quantify the long-term inflammatory response of INC bioprostheses implanted in the aortic position. (time frame: An average of 6 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04557345, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2020.