New Biomarkers and Plasma Prothrombotic Potential in Cardiac Transthyretin Amyloidosis

NCT06345235 | Recruiting

• 1 other identifier: ID DEC-2023/07/X/NZ5/00141
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Transthyretin Amyloidosis

Keywords

transthyretin amyloidosis; GDF15; ST2; galectin-3; TIMP-1; MMP-9; NfL; plasma prothrombotic potential; amyloidosis; cardiomyopathy

Outcome Measures

Primary Outcomes (8)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

Study Arms (3)

with ATTR cardiomyopthy

blood sample

Diagnostic Test: blood test

TTR variant carier and no ATTR cardiomyopthy

blood sample

Diagnostic Test: blood test

controls

blood sample

Diagnostic Test: blood test

Interventions

blood test DIAGNOSTIC_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

TTR variant carier and no ATTR cardiomyopthy; controls; with ATTR cardiomyopthy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

100 consecutive patients

You may qualify if:

• 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)
• age over 18
• expressing informed written consent
• clinical criteria (one of the following for a given group):
• ATTR cardiomyopathy (GROUP 1),
• asymptomatic carrier of the pathogenic variant of the TTR gene (GROUP 2),
• no diagnosed ATTR cardiomyopathy and no pathogenic variant of the TTR gene (GROUP 3).

You may not qualify if:

• age under 18 years of age
• failure to provide informed written consent
• pregnancy and lactation

Sponsors & Collaborators

• John Paul II Hospital, Krakow: lead

Study Sites (1)

John Paul II Hospital

Krakow, 31-202, Poland

RECRUITING

Related Publications (6)

• 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.

  PMID: 32789836 BACKGROUND

• 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.

  PMID: 35929128 BACKGROUND

• 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.

  PMID: 33087494 BACKGROUND

• 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.

  PMID: 33527656 BACKGROUND

• 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.

  PMID: 33825853 BACKGROUND

• 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.

  PMID: 35083827 BACKGROUND

MeSH Terms

Conditions

Amyloidosis, Hereditary, Transthyretin-Related; Amyloidosis; Cardiomyopathies

Interventions

Hematologic Tests

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Central Study Contacts

Katarzyna Holcman, MD

CONTACT

608214249; katarzyna.holcman@gmail.com

Study Design

• Study Type: observational
• Observational Model: FAMILY BASED
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 27, 2024
• First Posted: April 3, 2024
• Study Start: July 11, 2023
• Primary Completion: July 11, 2024
• Study Completion: July 11, 2024
• Last Updated: April 19, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1)