“Sic parvis magna” – Sir Francis Drake
Perceptions of amyloidosis have changed dramatically over the recent years following major advances in diagnosis and therapeutic strategies (1), especially in the field of cardiac amyloidosis (2). Recognition of disease and confirmation of final diagnosis, clinical management and treatment approaches represent ongoing challenges (3). The article Research Topic on “Proceedings and predictions in cardiac amyloidosis: unsolved mysteries and challenges for the future” has been conceived to discuss the latest advances and gray areas to address (4, 5) in amyloidosis from the perspective of international experts in the field.
Cardiac amyloidosis is commonly caused by systemic light chain amyloidosis or transthyretin amyloidosis (6). Systemic light chain amyloidosis is an acquired condition which is caused by a clonal plasma or B-cell expansion (monoclonal gammopathy) producing amyloidogenic immunoglobulin (Ig) light chains (7). Transthyretin amyloidosis is caused by deposition of misfolded or cleaved transthyretin protein in organs. This condition may be hereditary, in presence of destabilizing genetic mutations, or non-hereditary (wild type form) in the absence of genetic mutations (1, 8). Advances in cardiac magnetic resonance imaging and cardiac scintigraphy with bone tracers have revolutionized the diagnosis of cardiac amyloidosis (9, 10). Porcari et al. address the change in epidemiology of light chain and transthyretin cardiac amyloidosis following the development of non-invasive diagnostic criteria, highlighting the difference in patient characteristics at presentation and outcome compared to the past. Receiving a diagnosis of cardiac amyloidosis or carrying a gene mutation with the associated risk of developing disease in the future has a psychological impact on patients and their families, which is investigated (Smorti et al.).
With the exception of transthyretin cardiac amyloidosis which can now be diagnosed non-invasively in ~70% of cases, histological analysis remains the definitive method for diagnosis and typing of amyloid (11). Clinical decision-making relies on histological information to provide patient-tailored clinical management, which includes Congo red staining used in combination with polarized light microscopy and immunohistochemistry (6), along with a mass spectrometry-based proteomic approach for amyloid typing (12). Riefolo et al. provide a thoughtful review on the contemporary histological approach to amyloidosis, with a focus on endomyocardial biopsy. The essential contribution of histology for typing amyloid fibril proteins is discussed in depth, especially in rare forms and challenging scenarios to orient treatment strategies.
Although histological studies reports a remarkable prevalence of disease (6), the epidemiology of amyloidosis, especially cardiac amyloidosis, is unknown worldwide (13). Caponetti et al. provide a comprehensive perspective on the association between underlying cardiac amyloidosis and specific clinical setting, potentially serving as tool to redefine screening approaches to amyloidosis in the real world (13). The authors underline the unique contribution of carpal tunnel syndrome that can precede the diagnosis of cardiac amyloidosis by 5 to 9 years (14). Among patients with bilateral surgery and ventricular thickening, the prevalence of transthyretin cardiac amyloidosis ranges from 14% in patients ≥60 years without occupational risk factors, to 33% considering only men (13, 15, 16). The authors emphasize how the adoption of sex-specific criteria to define cardiac amyloidosis might potentially result in earlier diagnoses (17, 18), and they discuss the results of a national survey of prevalence and accuracy of echocardiographic red flags of cardiac amyloidosis in consecutive patients undergoing routine echocardiography (AC-TIVE study) (19, 20), demonstrating a prevalence of transthyretin cardiac amyloidosis of 1% in the Italian population. Echocardiography is essential to raise suspicion of cardiac amyloidosis and provides multi-parametric assessment of systolic and diastolic cardiac. However, The value of left ventricle ejection fraction is limited in the setting of cardiac amyloidosis as discussed by Matteo et al.. The authors underline the potential advantages of other parameters for assessing cardiac contraction such as stroke volume (21), which might be an earlier marker of systolic dysfunction.
Cardiac amyloidosis has been traditionally considered an invariably fatal disease, but the scenario has changed following the development of disease-modifying treatments. The contemporary clinical course of transthyretin cardiac amyloidosis is characterized by progressive heart failure and arrhythmias (22). Scirpa et al. and Razvi et al. summarize the strengths and limitations of the main disease-specific staging systems developed to estimate survival and address the gray area of pre-symptomatic stage (23, 24) and foresee that a multi-parametric approach will result in a more accurate risk prediction (25). Tomasoni et al. address the advances in therapeutic strategies aimed at reducing the deposition of transthyretin amyloid in organs or hepatic synthesis of transthyretin through (26):
-
Stabilization of the transthyretin tetramer to prevent dissociation (27, 28);
-
Disruption of the messenger RNA (mRNA) in the hepatocyte with either small interfering RNA (29) or antisense oligonucleotides (30);
-
Transthyretin gene editing to prevent the production of the relevant mRNA (31);
-
Recognition of the transthyretin fibrils by the immune system and acceleration of their removal from vital organs with monoclonal antibodies (1);
Quarta et al. provides an expert opinion on the latest anti-fibril therapy in both light chain and transthyretin amyloidosis, which holds great potential for the application of depletion therapy in the foreseeable future.
Although amyloidosis is considered a contraindication to cardiac transplant, partly due to a perceived risk of amyloid recurrence in the allograft, cardiac transplant is a concrete therapeutic option for patients with light chain and transthyretin amyloidosis. Razvi et al. provide novel finding that “Cardiac transplant is well-tolerated, restores functional capacity and improves prognosis in transthyretin cardiac amyloidosis. Post-cardiac transplant 1-year survival was 100%, 3-year survival was 92%, and 5-year survival was 90%. All but one surviving patient were New York Heart Association functional class I. Bone scintigraphy did not show evidence of cardiac allograft amyloid infiltration at 12 years post cardiac transplant.” Notably, the authors provide the first evidence that the risk of amyloid recurrence in the cardiac allograft is low, thus suggesting that transthyretin amyloidosis does not represent a contraindication to cardiac transplant and that this treatment option should not be denied in patients with feasible characteristics. Future dedicated research is required to select the best candidates to cardiac transplant.
The epidemiology of cardiac amyloidosis is rapidly changing due to enhanced recognition of disease and the possibility of non-invasive diagnosis for transthyretin amyloidosis. Many gray areas have to be addressed (32). An exciting horizon of possibilities awaits to be explored in amyloidosis.
Statements
Author contributions
AP, GS, and JG contributed to the conception, design, manuscript preparation, and revision. All authors read and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1.
Porcari A Fontana M Gillmore JD . Transthyretin cardiac amyloidosis. Cardiovasc Res. (2023) 118:3517–35. 10.1093/cvr/cvac119
2.
Gillmore JD Maurer MS Falk RH Merlini G Damy T Dispenzieri A et al . Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. (2016) 133:2404–12. 10.1161/CIRCULATIONAHA.116.021612
3.
Lane T Fontana M Martinez-Naharro A Quarta CC Whelan CJ Petrie A et al . Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. (2019) 140:16–26. 10.1161/CIRCULATIONAHA.118.038169
4.
Aimo A Rapezzi C Vergaro G Giannoni A Spini V Passino C et al . Management of complications of cardiac amyloidosis: 10 questions and answers. Eur J Prev Cardiol. (2020) 28:1000–5. 10.1177/2047487320920756
5.
Porcari A Hutt DF Grigore SF Quigley AM Rowczenio D Gilbertson J et al . Comparison of different technetium-99m-labelled bone tracers for imaging cardiac amyloidosis. Eur J Prev Cardiol. (2022) 30:e4–6. 10.1093/eurjpc/zwac237
6.
Porcari A Bussani R Merlo M Varrà GG Pagura L Rozze D et al . Incidence and characterization of concealed cardiac amyloidosis among unselected elderly patients undergoing post-mortem examination. Front Cardiovasc Med. (2021) 8:749523. 10.3389/fcvm.2021.749523
7.
Wechalekar AD Fontana M Quarta CC Liedtke M . AL amyloidosis for cardiologists: awareness, diagnosis, and future prospects. JACC Cardio Oncology. (2022) 4:427–41. 10.1016/j.jaccao.2022.08.009
8.
Porcari A Razvi Y Masi A Patel R Ioannou A Rauf MU et al . Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy. Eur J Heart Fail. (2023) 25:515–24. 10.1002/ejhf.2776
9.
Martinez-Naharro A Baksi AJ Hawkins PN Fontana M . Diagnostic imaging of cardiac amyloidosis. Nat Rev Cardiol. (2020) 17:413–26. 10.1038/s41569-020-0334-7
10.
Rauf MU Hawkins PN Cappelli F Perfetto F Zampieri M Argiro A et al . Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis. Eur Heart J. (2023) 44:2187–98. 10.1093/eurheartj/ehad139
11.
Porcari A Baggio C Fabris E Merlo M Bussani R Perkan A et al . Endomyocardial biopsy in the clinical context: current indications and challenging scenarios. Heart Fail Rev. (2022) 28:123–35. 10.1007/s10741-022-10247-5
12.
Wechalekar AD Gillmore JD Hawkins PN . Systemic amyloidosis. Lancet. (2016) 387:2641–54. 10.1016/S0140-6736(15)01274-X
13.
Aimo A Merlo M Porcari A Georgiopoulos G Pagura L Vergaro G et al . Redefining the epidemiology of cardiac amyloidosis. A systematic review and meta-analysis of screening studies. Eur J Heart Fail. (2022) 24:2342–51. 10.1002/ejhf.2532
14.
Milandri A Farioli A Gagliardi C Longhi S Salvi F Curti S et al . Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies. Eur J Heart Fail. (2020) 22:507–15. 10.1002/ejhf.1742
15.
Porcari A Pagura L Longo F Sfriso E Barbati G Murena L et al . Prognostic significance of unexplained left ventricular hypertrophy in patients undergoing carpal tunnel surgery. ESC Hear Fail. (2022) 9:751–60. 10.1002/ehf2.13606
16.
Sperry BW Reyes BA Ikram A Donnelly JP Phelan D Jaber WA et al . Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. (2018) 72:2040–50. 10.1016/j.jacc.2018.07.092
17.
Patel RK Ioannou A Razvi Y Chacko L Venneri L Bandera F et al . Sex differences among patients with transthyretin amyloid cardiomyopathy—from diagnosis to prognosis. Eur J Heart Fail. (2022) 24:2355–63. 10.1002/ejhf.2646
18.
Aimo A Tomasoni D Porcari A Vergaro G Castiglione V Passino C et al . Left ventricular wall thickness and severity of cardiac disease in women and men with transthyretin amyloidosis. Eur J Heart Fail. (2023) 25:510–4. 10.1002/ejhf.2824
19.
Merlo M Pagura L Porcari A Cameli M Vergaro G Musumeci B et al . Unmasking the prevalence of amyloid cardiomyopathy in the real world: results from Phase 2 of the AC-TIVE study, an Italian nationwide survey. Eur J Heart Fail. (2022) 24:1377–86. 10.1002/ejhf.2504
20.
Merlo M Porcari A Pagura L Cameli M Vergaro G Musumeci B et al . A national survey on prevalence of possible echocardiographic red flags of amyloid cardiomyopathy in consecutive patients undergoing routine echocardiography: study design and patients characterization—the first insight from the AC-TIVE Study. Eur J Prev Cardiol. (2022) 29:e173–7. 10.1093/eurjpc/zwab127
21.
Chacko L Karia N Venneri L Bandera F Passo BD Buonamici L et al . Progression of echocardiographic parameters and prognosis in transthyretin cardiac amyloidosis. Eur J Heart Fail. (2022) 24:1700–12. 10.1002/ejhf.2606
22.
Porcari A Rossi M Cappelli F Canepa M Musumeci B Cipriani A et al . Incidence and risk factors for pacemaker implantation in light-chain and transthyretin cardiac amyloidosis. Eur J Heart Fail. (2022) 24:1227–36. 10.1002/ejhf.2533
23.
Gillmore JD Damy T Fontana M Hutchinson M Lachmann HJ Martinez-Naharro A et al . A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. (2018) 39:2799–806. 10.1093/eurheartj/ehx589
24.
Grogan M Scott CG Kyle RA Zeldenrust SR Gertz MA Lin G et al . Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. (2016) 68:1014–20. 10.1016/j.jacc.2016.06.033
25.
Tomasoni D Aimo A Merlo M Nardi M Adamo M Bellicini MG et al . Value of the HFA-PEFF and H2 FPEF scores in patients with heart failure and preserved ejection fraction caused by cardiac amyloidosis. Eur J Heart Fail. (2022) 24:2374–86. 10.1002/ejhf.2616
26.
Emdin M Aimo A Rapezzi C Fontana M Perfetto F Seferović PM et al . Treatment of cardiac transthyretin amyloidosis: an update. Eur Heart J. (2019) 40:3699–706. 10.1093/eurheartj/ehz298
27.
Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M et al . Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. (2018) 379:1007–16. 10.1056/NEJMoa1805689
28.
Berk JL Suhr OB Obici L Sekijima Y Zeldenrust SR Yamashita T et al . Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. (2013) 310:2658–67. 10.1001/jama.2013.283815
29.
Adams D Gonzalez-Duarte A O'Riordan WD Yang CC Ueda M Kristen AV et al . Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. (2018) 379:11–21. 10.1056/NEJMoa1716153
30.
Benson MD Waddington-Cruz M Berk JL Polydefkis M Dyck PJ Wang AK et al . Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. (2018) 379:22–31. 10.1056/NEJMoa1716793
31.
Gillmore JD Gane E Taubel J Kao J Fontana M Maitland ML et al . CRISPR-Cas9 In Vivo Gene editing for transthyretin amyloidosis. N Engl J Med. (2021) 385:493–502. 10.1056/NEJMoa2107454
32.
Porcari A Merlo M Rapezzi C Sinagra G . Transthyretin amyloid cardiomyopathy: An uncharted territory awaiting discovery. Eur J Intern Med. (2020) 82:7–15. 10.1016/j.ejim.2020.09.025
Summary
Keywords
amyloidosis, transthyretin, light chain (AL) amyloidosis, prognosis, treatments
Citation
Porcari A, Sinagra G and Gillmore JD (2023) Editorial: Proceedings and predictions in cardiac amyloidosis: unsolved mysteries and challenges for the future. Front. Med. 10:1232212. doi: 10.3389/fmed.2023.1232212
Received
31 May 2023
Accepted
05 July 2023
Published
17 July 2023
Volume
10 - 2023
Edited and reviewed by
Victoria Bunik, Lomonosov Moscow State University, Russia
Updates
Copyright
© 2023 Porcari, Sinagra and Gillmore.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Aldostefano Porcari aldostefano.porcari@nhs.net
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.