Transthyretin Amyloidosis Clinical Trial
Official title:
Assessment of the Association of New Biomarkers (GDF15, ST2, Galectin-3, TIMP-1, MMP-9, NfL) and Plasma Prothrombotic Potential in the Course of Cardiac Transthyretin Amyloidosis
The development of cardiac amyloidosis is caused by the deposition of misfolded, insoluble proteins in the extracellular matrix of tissues. An important element of the clinical picture of the disease is the increased risk of thromboembolic complications, independent of the occurrence of atrial fibrillation, and the presence of intracardiac thrombi. The pathomechanism may be related to an increase in filling pressure or amyloid infiltration leading to myocardial damage and endothelial dysfunction, which may activate the prothrombotic inflammatory cascade, resulting in increased thrombogenic potential. Currently, there is limited published data on the potential role of new heart failure biomarkers in the assessment of ATTR cardiomyopathy, particularly in the assessment of asymptomatic carriers of pathogenic TTR variants. Moreover, there are few literature reports on the direct assessment of the coagulation system in this group of patients, and the pathomechanism of the increased thromboembolic risk is unexplored. Purpose of the study: To assess the diagnostic value of biomarkers related to heart failure (growth differentiation factor-15 (GDF15), soluble suppression of tumorigenicity-2 (ST2), galectin-3), amyloidosis ( TTR, tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9, matrix metalloproteinase-9), neurofilament light chain (NfL)) and the generation potential thrombin as a marker of the prothrombotic state in the course of ATTR. Methods: This prospective, single-center study will include consecutive patients diagnosed with ATTR cardiomyopathy (GROUP 1, n=30), asymptomatic carriers of pathogenic TTR variants (GROUP 2, n=30), and a matched control group of healthy volunteers (GROUP 3 , n=20). Material for research was collected and secured from all study participants. After giving informed consent, all patients will be tested using the ELISA method from peripheral blood (enzyme-linked immunosorbent assay) GDF15, ST2, TTR, TIMP-1, MMP-9, galectin-3, NfL. The values of these biomarkers will be compared in subgroups and correlated with clinical data, laboratory test results, echocardiography including analysis of left ventricular global strain (GLS), and scintigraphy. Additionally, the prothrombotic potential of plasma will be tested in both groups of patients using the calibrated automatic thrombogram (CAT) method, in accordance with the protocol previously used in the laboratory Expected results: The project will provide information on the value of biomarkers in the assessment of ATTR cardiomyopathy, especially in the assessment of asymptomatic carriers of pathogenic TTR variants, which may translate into the creation of a diagnostic algorithm for early identification of the development of the disease. Moreover, it will allow us to determine whether patients with cardiac ATTR are characterized by a prothrombotic state, which has not yet been described in the literature and may have potential clinical implications.
Status | Recruiting |
Enrollment | 100 |
Est. completion date | July 11, 2024 |
Est. primary completion date | July 11, 2024 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: the study will include consecutive patients diagnosed with ATTR cardiomyopathy (GROUP 1, n=30), asymptomatic carriers of pathogenic TTR variants (GROUP 2, n=30), and a matched control group of healthy volunteers (GROUP 3, n=20) 1. age over 18 2. expressing informed written consent 3. clinical criteria (one of the following for a given group): 1. ATTR cardiomyopathy (GROUP 1), 2. asymptomatic carrier of the pathogenic variant of the TTR gene (GROUP 2), 3. no diagnosed ATTR cardiomyopathy and no pathogenic variant of the TTR gene (GROUP 3). Exclusion criteria: 1. age under 18 years of age 2. failure to provide informed written consent 3. pregnancy and lactation Exclusion Criteria: |
Country | Name | City | State |
---|---|---|---|
Poland | John Paul II Hospital | Kraków |
Lead Sponsor | Collaborator |
---|---|
John Paul II Hospital, Krakow |
Poland,
Authors/Task Force Members:; McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022 Jan;24(1):4-131. doi: 10.1002/ejhf.2333. — View Citation
Castiglione V, Franzini M, Aimo A, Carecci A, Lombardi CM, Passino C, Rapezzi C, Emdin M, Vergaro G. Use of biomarkers to diagnose and manage cardiac amyloidosis. Eur J Heart Fail. 2021 Feb;23(2):217-230. doi: 10.1002/ejhf.2113. Epub 2021 Feb 21. — View Citation
Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, Burazor I, Caforio ALP, Damy T, Eriksson U, Fontana M, Gillmore JD, Gonzalez-Lopez E, Grogan M, Heymans S, Imazio M, Kindermann I, Kristen AV, Maurer MS, Merlini G, Pantazis A, Pankuweit S, Rigopoulos AG, Linhart A. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021 Apr 21;42(16):1554-1568. doi: 10.1093/eurheartj/ehab072. — View Citation
Gawor M, Holcman K, Franaszczyk M, Lipowska M, Michalek P, Teresinska A, Bilinska ZT, Rubis P, Kostkiewicz M, Szot W, Podolec P, Grzybowski J. Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis. Cardiol J. 2022;29(6):985-993. doi: 10.5603/CJ.a2020.0104. Epub 2020 Aug 13. — View Citation
Holcman K, Dziuk M, Grzybowski J, Teresinska A, Malkowski B, Jedrzejuk D, Brockhuis B, Czepczynski R, Tomkiewicz-Pajak L, Kostkiewicz M. The scintigraphic diagnosis of cardiac amyloidosis. An expert opinion endorsed by the Section of Nuclear Medicine of the Polish Cardiac Society and the Polish Nuclear Medicine Society. Nucl Med Rev Cent East Eur. 2022;25(2):142-147. doi: 10.5603/NMR.a2022.0033. — View Citation
Ticau S, Sridharan GV, Tsour S, Cantley WL, Chan A, Gilbert JA, Erbe D, Aldinc E, Reilly MM, Adams D, Polydefkis M, Fitzgerald K, Vaishnaw A, Nioi P. Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis. Neurology. 2021 Jan 19;96(3):e412-e422. doi: 10.1212/WNL.0000000000011090. Epub 2020 Oct 21. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Biomarkers | To assess the diagnostic value of growth differentiation factor-15 (GDF15) in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment | |
Primary | Thrombin as a marker | To assess the generation potential thrombin as a marker of the prothrombotic state in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group | baseline evaluation at the day of enrolment | |
Primary | Biomarkers | To assess the diagnostic value of soluble suppression of tumorigenicity-2 (ST2) in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment | |
Primary | Biomarkers | To assess the diagnostic value of galectin-3 in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment | |
Primary | Biomarkers | To assess the diagnostic value of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment | |
Primary | Biomarkers | To assess the value of TTR in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment | |
Primary | Biomarkers | To assess the diagnostic value of matrix metalloproteinase-9 (MMP-9)in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment | |
Primary | Biomarkers | To assess the diagnostic value of neurofilament light chain (NfL) in the course of ATTR compared to asymptomatic pathogenic TTR variant gene carriers and control group. | baseline evaluation at the day of enrolment |
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