Which biomarkers can be used for risk stratification in ATTR cardiac amyloidosis?
Effective treatment for patients with transthyretin cardiac amyloidosis requires timely diagnosis and precise risk stratification to identify patients at higher risk of cardiovascular events, heart failure progression, and death. Currently, there are several scoring systems based on commonly available laboratory parameters. Here is a brief overview.
Cardiac Amyloidosis and Its Diagnosis
Transthyretin cardiac amyloidosis (ATTR-CM) is a cardiomyopathy resulting from the deposition of misfolded transthyretin protein in the heart muscle. This condition often causes heart failure with preserved ejection fraction, particularly in the elderly. Historically, ATTR-CM was considered a rare disease, but with the implementation of a non-invasive diagnostic algorithm in clinical practice, its incidence is rising.
Risk Stratification
After diagnosis, it is crucial to focus on risk stratification to identify patients at higher risk of cardiovascular events and death.1 Several prognostic scoring systems based mainly on laboratory parameters have been proposed.
Mayo Score
The first of these is the so-called Mayo score, proposed in 2016 by a group of physicians from the American Mayo Clinic. This score classifies patients into 3 stages based on serum levels of troponin T (TnT; upper limit 50 ng/L) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP; upper limit 3000 ng/L). The 4-year survival rate was 57% in stage I (both parameters below the upper limit), 42% in stage II (one parameter above the limit), and 18% in stage III (both parameters above the limit).2 The score is not validated for patients with hereditary ATTR. A problem also arises with new, more sensitive troponin T assays, which provide different numerical values compared to earlier methods.1
NAC Score
The NAC staging system proposed in 2018 by a group of physicians from the University of London3 also uses NT-proBNP (upper limit 3000 ng/L), and the second parameter is the estimated glomerular filtration rate (eGFR, upper limit 0.45 mL/min/1.73 m2). In a cohort of 869 British patients with ATTR-CM, the median survival was 69.2 months in stage I, 46.7 months in stage II, and 24.1 months in stage III. The scoring system was externally validated in an independent cohort of 318 French patients.3
Given the increasing number of early-diagnosed patients, a very early stage Ia was defined, with NT-proBNP levels < 500 ng/L (< 1000 ng/L in the case of atrial fibrillation) requiring low doses of loop diuretics (< 0.75 mg/kg). Patients in stage Ia had a higher median survival compared to the rest of the patients in stage I (> 100 vs. 75 months).4
Compared to the NAC system, the Mayo score provides less effective prognostic differentiation, especially between stages I and II.5
Other Scoring Systems
Recently, several clinical markers have emerged with the potential to improve the accuracy of these two scoring systems. Diuretic dose and NYHA functional class have been shown to be strong independent predictors of all-cause mortality, a composite endpoint of all-cause mortality, and heart transplantation.6 To identify patients at high risk of end-stage heart failure, a score developed by physicians from Heidelberg University, which includes high-sensitivity TnT ( hsTnT > 55 ng/L), NT-proBNP levels (> 6330 ng/L), and QRS complex duration (> 104 ms), appears to be useful.7
Conclusion
In recent years, several scoring systems for predicting risk in patients with ATTR have been proposed. These systems, based on laboratory parameters, use only a few variables, ensuring ease of use but also presenting limitations in predicting disease course. For more accurate risk prediction, a multiparametric approach that considers information from electrocardiography, echocardiography, cardiopulmonary exercise tests, and cardiac magnetic resonance imaging is likely needed.
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Sources:
1. Scirpa R., Cittadini E., Mazzocchi L. et al. Risk stratification in transthyretin-related cardiac amyloidosis. Front Cardiovasc Med 2023 Mar 21; 10: 1151803, doi: 10.3389/fcvm.2023.1151803.
2. Grogan M., Scott C. G., Kyle R. A. 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, doi: 10.1016/j.jacc.2016.06.033.
3. Gillmore J. D., Damy T., Fontana M. et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J 2018; 39 (30): 2799–2806, doi: 10.1093/eurheartj/ehx589.
4. Law S., Bezard M., Petrie A. et al. Characteristics and natural history of early-stage cardiac transthyretin amyloidosis. Eur Heart J 2022 Jul 14; 43 (27): 2622–2632, doi: 10.1093/eurheartj/ehac259.
5. Cappelli F., Martone R., Gabriele M. et al. Biomarkers and prediction of prognosis in transthyretin-related cardiac amyloidosis: direct comparison of two staging systems. Can J Cardiol 2020; 36 (3): 424–431, doi: 10.1016/j.cjca.2019.12.020.
6. Cheng R. K., Levy W. C., Vasbinder A. et al. Diuretic dose and NYHA functional class are independent predictors of mortality in patients with transthyretin cardiac amyloidosis. JACC CardioOncol 2020; 2 (3): 414–424, doi: 10.1016/j.jaccao.2020.06.007.
7. Kreusser M. M., Volz M. J., Knop B. et al. A novel risk score to predict survival in advanced heart failure due to cardiac amyloidosis. Clin Res Cardiol 2020; 109 (6): 700–713, doi: 10.1007/s00392-019-01559-y.
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