Research progress on biomarkers of transthyretin cardiac amyloidosis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Tingting ¹ , WANG Ying ¹ ,  CAO Yunfeng ²

1. School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, P. R. China;
2. Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200032, P. R. China;

Corresponding?author：

CAO Yunfeng, Email: 1693554678@qq.com

Keywords：

Transthyretin cardiac amyloidosis; biomarkers; transthyretin tetramer; review

DOI：

10.7507/1007-4848.202409081

Video：

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Transthyretin cardiac amyloidosis (ATTR-CA) is a form of restrictive cardiomyopathy characterized by the abnormal deposition of transthyretin in the myocardial interstitium, presenting with clinical manifestations such as heart failure, atrial fibrillation, and cardiac conduction system disorders. The significant individual variability in the symptomatology of ATTR-CA patients poses considerable challenges for precise diagnosis. This study provides a review of biomarkers associated with ATTR-CA and highlights the TTR tetramer as a potential novel indicator. The amyloid deposition in ATTR-CA is closely related to the dissociation of TTR tetramers; however, the TTR tetramer is not included among the biomarkers currently used in clinical practice. Investigating the concentration, profile, and dissociation rate of TTR tetramers holds profound significance for the early detection and prognostic assessment of ATTR-CA. This article synthesizes the research on traditional biomarkers of ATTR-CA and emphasizes the potential application value of TTR tetramers in disease diagnosis and prognostic evaluation.

1.	Brito D, Albrecht FC, de Arenaza DP, et al. World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM). Glob Heart, 2023, 18(1): 59.
2.	中華醫學會心血管病學分會心力衰竭學組, 中華心血管病雜志編輯委員會. 轉甲狀腺素蛋白心臟淀粉樣變診斷與治療中國專家共識. 中華心血管病雜志, 2021, 49(4): 324-332.Heart Failure Group of Chinese Society of Cardiology, Editorial Board of Chinese Journal of Cardiology. Chin J Cardiol, 2021, 49(4): 324-332.
3.	郭軍紅, 王卓然. 轉甲狀腺素蛋白淀粉樣變性多發性神經病. 中華神經科雜志, 2024, 57(5): 497-503.Guo JH, Wang ZR. The progress in diagnosis and treatment of transthyretin amyloid polyneuropathy. Chin J Contemp Neurol Neurosurg, 2024, 57(5): 497-503.
4.	Ueda M. Transthyretin: Its function and amyloid formation. Neurochem Int, 2022, 155(5): 105313.
5.	Casta?o A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J, 2017, 38(38): 2879-2887.
6.	Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: A population-based autopsy study. Ann Med, 2008, 40(3): 232-239.
7.	Tubben A, Tingen HSA, Prakken NHJ, et al. Prevalence of wild-type transthyretin amyloidosis in a prospective heart failure cohort with preserved and mildly reduced ejection fraction: Results of the Amylo-VIP-HF study. Eur J Heart Fail, 2024, 26(3): 695-698.
8.	黎鑄, 秦儉, 羅素新, 等. 轉甲狀腺素蛋白淀粉樣變心肌病生物標志物的研究進展. 心血管病學進展, 2023, 44(12): 1120-1124.Li Z, Qin J, Luo SX, et al. Biomarkers in Transthyretin Amyloid Cardiomyopathy. Adv Cardiovasc Dis, 2023, 44(12): 1120-1124.
9.	Castiglione V, Franzini M, Aimo A, et al. Use of biomarkers to diagnose and manage cardiac amyloidosis. Eur J Heart Fail, 2021, 23(2): 217-230.
10.	Vergaro G, Aimo A, Campora A, et al. Patients with cardiac amyloidosis have a greater neurohormonal activation than those with non-amyloidotic heart failure. Amyloid, 2021, 28(4): 252-258.
11.	Kuyama N, Takashio S, Nakamura K, et al. Coexisting transthyretin and atrial natriuretic peptide amyloid on left atrium in transthyretin amyloid cardiomyopathy. J Cardiol Cases, 2024, 29(6): 261-264.
12.	Haga T, Okumura T, Harada Y, et al. Clinical clues for suspecting wild-type transthyretin cardiac amyloidosis in patients with monoclonal gammopathy of undetermined significance: A case report. Egypt Heart J, 2024, 76(1): 74.
13.	Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol, 2016, 68(10): 1014-1020.
14.	Geladari EV, Vallianou NG, Evangelopoulos A, et al. Cardiac troponin levels in patients with chronic kidney disease: "Markers of high risk or just noise''? Diagnostics (Basel), 2024, 14(20): 2316.
15.	Gillmore JD, Damy T, Fontana M, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J, 2018, 39(30): 2799-2806.
16.	Garcia-Pavia P, Bengel F, Brito D, et al. Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J Heart Fail, 2021, 23(6): 895-905.
17.	Hood CJ, Hendren NS, Pedretti R, et al. Update on disease-specific biomarkers in transthyretin cardiac amyloidosis. Curr Heart Fail Rep, 2022, 19(5): 356-363.
18.	Santos D, Coelho T, Alves-Ferreira M, et al. Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M). Eur J Hum Genet, 2016, 24(5): 756-760.
19.	Cioffi CL, Raja A, Muthuraman P, et al. Identification of transthyretin tetramer kinetic stabilizers that are capable of inhibiting the retinol-dependent retinol binding protein 4-transthyretin interaction: Potential novel therapeutics for macular degeneration, transthyretin amyloidosis, and their common age-related comorbidities. J Med Chem, 2021, 64(13): 9010-9041.
20.	Ruberg FL, Blaner WS, Chiuzan C, et al. Design and rationale the SCAN-MP (screening for cardiac amyloidosis with nuclear imaging in minority populations) study. J Am Heart Assoc, 2023, 12(8): e028534.
21.	Jadhao AG, Gaikwad KB, Yadav RR. Serum retinol binding protein 4 in individuals with essential hypertension and type 2 diabetes: A cross-sectional study. J Family Med Prim Care, 2024, 13(9): 3748-3752.
22.	Luigetti M, Di Paolantonio A, Guglielmino V, et al. Neurofilament light chain as a disease severity biomarker in ATTRv: Data from a single-centre experience. Neurol Sci, 2022, 43(4): 2845-2848.
23.	Loser V, Benkert P, Vicino A, et al. Serum neurofilament light chain as a reliable biomarker of hereditary transthyretin-related amyloidosis-A Swiss reference center experience. J Peripher Nerv Syst, 2023, 28(1): 86-97.
24.	Ticau S, Sridharan GV, Tsour S, et al. Neurofilament light chain as a biomarker of hereditary transthyretin-mediated amyloidosis. neurology, 2021, 96(3): e412-e422.412-422.
25.	Gentile L, Coelho T, Dispenzieri A, et al. A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Orphanet J Rare Dis, 2023, 18(1): 350.
26.	González-Moreno J, Gragera-Martínez á, Rodríguez A, et al. Biomarkers of axonal damage to favor early diagnosis in variant transthyretin amyloidosis (A-ATTRv). Sci Rep, 2024, 14(1): 581.
27.	Vijayakumar S, Pabon AR, Clerc OF, et al. Quantitative 99mTc-pyrophosphate myocardial uptake: Changes on transthyretin stabilization therapy. J Nucl Cardiol, 2024, 39: 102019.
28.	Greve AM, Christoffersen M, Frikke-Schmidt R, et al. Association of low plasma transthyretin concentration with risk of heart failure in the general population. JAMA Cardiol, 2021, 6(3): 258-266.
29.	Luigetti M, Vitali F, Romano A, et al. Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: A pilot study. Sci Rep, 2024, 14(1): 18281.
30.	Gentile L, Mazzeo A, Briani C, et al. Long-term treatment of hereditary transthyretin amyloidosis with patisiran: Multicentre, real-world experience in Italy. Neurol Sci, 2024, 45(9): 4563-4571.
31.	Tubben A, Markousis-Mavrogenis G, Meems LMG, et al. Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF. Cardiovasc Res, 2024, 120(14): 1727-1736.
32.	Pedretti R, Wang L, Yakubovska A, et al. Structure-based probe reveals the presence of large transthyretin aggregates in plasma of ATTR amyloidosis patients. JACC Basic Transl Sci, 2024, 9(9): 1088-1100.
33.	Wang S, Guan L, Sun Y, et al. An ultra performance liquid chromatography method for transthyretin variants screening and heart failure assisting diagnosis. Clin Chim Acta, 2024, 553(1): 117709.

1. Brito D, Albrecht FC, de Arenaza DP, et al. World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM). Glob Heart, 2023, 18(1): 59.
2. 中華醫學會心血管病學分會心力衰竭學組, 中華心血管病雜志編輯委員會. 轉甲狀腺素蛋白心臟淀粉樣變診斷與治療中國專家共識. 中華心血管病雜志, 2021, 49(4): 324-332.Heart Failure Group of Chinese Society of Cardiology, Editorial Board of Chinese Journal of Cardiology. Chin J Cardiol, 2021, 49(4): 324-332.
3. 郭軍紅, 王卓然. 轉甲狀腺素蛋白淀粉樣變性多發性神經病. 中華神經科雜志, 2024, 57(5): 497-503.Guo JH, Wang ZR. The progress in diagnosis and treatment of transthyretin amyloid polyneuropathy. Chin J Contemp Neurol Neurosurg, 2024, 57(5): 497-503.
4. Ueda M. Transthyretin: Its function and amyloid formation. Neurochem Int, 2022, 155(5): 105313.
5. Casta?o A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J, 2017, 38(38): 2879-2887.
6. Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: A population-based autopsy study. Ann Med, 2008, 40(3): 232-239.
7. Tubben A, Tingen HSA, Prakken NHJ, et al. Prevalence of wild-type transthyretin amyloidosis in a prospective heart failure cohort with preserved and mildly reduced ejection fraction: Results of the Amylo-VIP-HF study. Eur J Heart Fail, 2024, 26(3): 695-698.
8. 黎鑄, 秦儉, 羅素新, 等. 轉甲狀腺素蛋白淀粉樣變心肌病生物標志物的研究進展. 心血管病學進展, 2023, 44(12): 1120-1124.Li Z, Qin J, Luo SX, et al. Biomarkers in Transthyretin Amyloid Cardiomyopathy. Adv Cardiovasc Dis, 2023, 44(12): 1120-1124.
9. Castiglione V, Franzini M, Aimo A, et al. Use of biomarkers to diagnose and manage cardiac amyloidosis. Eur J Heart Fail, 2021, 23(2): 217-230.
10. Vergaro G, Aimo A, Campora A, et al. Patients with cardiac amyloidosis have a greater neurohormonal activation than those with non-amyloidotic heart failure. Amyloid, 2021, 28(4): 252-258.
11. Kuyama N, Takashio S, Nakamura K, et al. Coexisting transthyretin and atrial natriuretic peptide amyloid on left atrium in transthyretin amyloid cardiomyopathy. J Cardiol Cases, 2024, 29(6): 261-264.
12. Haga T, Okumura T, Harada Y, et al. Clinical clues for suspecting wild-type transthyretin cardiac amyloidosis in patients with monoclonal gammopathy of undetermined significance: A case report. Egypt Heart J, 2024, 76(1): 74.
13. Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol, 2016, 68(10): 1014-1020.
14. Geladari EV, Vallianou NG, Evangelopoulos A, et al. Cardiac troponin levels in patients with chronic kidney disease: "Markers of high risk or just noise''? Diagnostics (Basel), 2024, 14(20): 2316.
15. Gillmore JD, Damy T, Fontana M, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J, 2018, 39(30): 2799-2806.
16. Garcia-Pavia P, Bengel F, Brito D, et al. Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J Heart Fail, 2021, 23(6): 895-905.
17. Hood CJ, Hendren NS, Pedretti R, et al. Update on disease-specific biomarkers in transthyretin cardiac amyloidosis. Curr Heart Fail Rep, 2022, 19(5): 356-363.
18. Santos D, Coelho T, Alves-Ferreira M, et al. Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M). Eur J Hum Genet, 2016, 24(5): 756-760.
19. Cioffi CL, Raja A, Muthuraman P, et al. Identification of transthyretin tetramer kinetic stabilizers that are capable of inhibiting the retinol-dependent retinol binding protein 4-transthyretin interaction: Potential novel therapeutics for macular degeneration, transthyretin amyloidosis, and their common age-related comorbidities. J Med Chem, 2021, 64(13): 9010-9041.
20. Ruberg FL, Blaner WS, Chiuzan C, et al. Design and rationale the SCAN-MP (screening for cardiac amyloidosis with nuclear imaging in minority populations) study. J Am Heart Assoc, 2023, 12(8): e028534.
21. Jadhao AG, Gaikwad KB, Yadav RR. Serum retinol binding protein 4 in individuals with essential hypertension and type 2 diabetes: A cross-sectional study. J Family Med Prim Care, 2024, 13(9): 3748-3752.
22. Luigetti M, Di Paolantonio A, Guglielmino V, et al. Neurofilament light chain as a disease severity biomarker in ATTRv: Data from a single-centre experience. Neurol Sci, 2022, 43(4): 2845-2848.
23. Loser V, Benkert P, Vicino A, et al. Serum neurofilament light chain as a reliable biomarker of hereditary transthyretin-related amyloidosis-A Swiss reference center experience. J Peripher Nerv Syst, 2023, 28(1): 86-97.
24. Ticau S, Sridharan GV, Tsour S, et al. Neurofilament light chain as a biomarker of hereditary transthyretin-mediated amyloidosis. neurology, 2021, 96(3): e412-e422.412-422.
25. Gentile L, Coelho T, Dispenzieri A, et al. A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Orphanet J Rare Dis, 2023, 18(1): 350.
26. González-Moreno J, Gragera-Martínez á, Rodríguez A, et al. Biomarkers of axonal damage to favor early diagnosis in variant transthyretin amyloidosis (A-ATTRv). Sci Rep, 2024, 14(1): 581.
27. Vijayakumar S, Pabon AR, Clerc OF, et al. Quantitative 99mTc-pyrophosphate myocardial uptake: Changes on transthyretin stabilization therapy. J Nucl Cardiol, 2024, 39: 102019.
28. Greve AM, Christoffersen M, Frikke-Schmidt R, et al. Association of low plasma transthyretin concentration with risk of heart failure in the general population. JAMA Cardiol, 2021, 6(3): 258-266.
29. Luigetti M, Vitali F, Romano A, et al. Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: A pilot study. Sci Rep, 2024, 14(1): 18281.
30. Gentile L, Mazzeo A, Briani C, et al. Long-term treatment of hereditary transthyretin amyloidosis with patisiran: Multicentre, real-world experience in Italy. Neurol Sci, 2024, 45(9): 4563-4571.
31. Tubben A, Markousis-Mavrogenis G, Meems LMG, et al. Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF. Cardiovasc Res, 2024, 120(14): 1727-1736.
32. Pedretti R, Wang L, Yakubovska A, et al. Structure-based probe reveals the presence of large transthyretin aggregates in plasma of ATTR amyloidosis patients. JACC Basic Transl Sci, 2024, 9(9): 1088-1100.
33. Wang S, Guan L, Sun Y, et al. An ultra performance liquid chromatography method for transthyretin variants screening and heart failure assisting diagnosis. Clin Chim Acta, 2024, 553(1): 117709.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

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