New Biomarkers and Plasma Prothrombotic Potential in Cardiac Transthyretin Amyloidosis

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06345235
• Other study ID #: ID DEC-2023/07/X/NZ5/00141
• Status: Recruiting
• Start date: July 11, 2023
• Est. completion date: July 11, 2024

Study information

• Verified date: April 2024
• Source: John Paul II Hospital, Krakow
• Contact: Katarzyna Holcman, MD
• Phone: 608214249
• Email: katarzyna.holcman[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

Introduction: The development of cardiac amyloidosis is caused by the deposition of misfolded, insoluble proteins in the extracellular matrix of tissues. More than 30 precursor proteins can form amyloid fibrils, but two types account for 95% of cases of amyloid cardiomyopathy (CA): immunoglobulin light chain (AL) amyloidosis and transthyretin amyloidosis (ATTR). There are two forms of ATTR - acquired wild-type ATTR (ATTRwt) and the hereditary form (ATTRm), developing on the basis of mutations in the transthyretin (TTR) gene. Among patients with CA, as the disease progresses, heart failure develops, and if left untreated, the disease leads to death within 6 months to 3 years. Due to the unique pathology of the disease, the clinical picture includes the development of: peripheral polyneuropathy, autonomic dysfunction, and an increased risk of thromboembolic complications. 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. Scintigraphy has become a key technique in identifying patients with ATTR - in the absence of a detectable monoclonal protein, it allows for a non-invasive diagnosis of ATTR. Due to the development of disease-specific therapies (stabilizing drugs, gene therapy), it is important to diagnose the disease at an early stage, when the symptoms are relatively mild, and the implementation of treatment allows to stop the development of the disease and reduce mortality. 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. The results will be compared with reference values for the control group. All tests will be performed by qualified and experienced staff.

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. The obtained results can be used as starting data for further research on the coagulation system in ATTR in subsequent scientific projects.

Recruitment information / eligibility

• 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:

Related Conditions & MeSH terms

• Amyloid Neuropathies, Familial
• Amyloidosis
• Transthyretin Amyloidosis

Intervention

Diagnostic Test:
• blood test
Assessment of the association of new biomarkers (GDF15, ST2, galectin-3, TIMP-1, MMP-9, NfL) and plasma prothrombotic potential in groups 1, 2, 3

Locations

Country	Name	City	State
Poland	John Paul II Hospital	Kraków

Sponsors (1)

Lead Sponsor	Collaborator
John Paul II Hospital, Krakow

Country where clinical trial is conducted

Poland, 

References & Publications (6)

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

Outcome

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