Guidelines in a New Era for Cardiac Amyloidosis
Last Updated: November 22, 2024
Remarkable progress in both the diagnosis and treatment of all forms of cardiac amyloidosis in the past few years has facilitated increased attention to this disorder. As with any new trend, there is potential for misinterpretation and error along the way. The latest AHA Scientific Statement on cardiac amyloidosis provides expert guidance for both diagnosis and treatment, with particular focus on transthyretin cardiac amyloidosis (ATTR-CM)1. The authors nicely cover several high priorities, beginning with a high index for suspicion among cohorts of patients commonly seen in clinical practice: those with heart failure and preserved ejection fraction (HFpEF), bilateral carpal tunnel syndrome, biceps tendon rupture, peripheral or autonomic neuropathy, spinal stenosis, and certain demographic features in which ATTR-CM is more common. Despite increased attention to cardiac amyloidosis, many patients are still not recognized until very late stages. Although not explicitly written in this manuscript, clinicians should at least consider the possibility of cardiac amyloidosis in anyone with otherwise unexplained HFpEF.
One study investigating the prevalence of cardiac amyloidosis used death certificate data to determine geographical disparities in the reporting of amyloidosis mortality in the USA over 36 years, ending in 20152. Among 30,764 individuals with amyloidosis listed as the cause of death, the rate was highest in African American men (12.36 per 1,000,000) as compared to Caucasian men (6.20 per 1,000,000). The mortality among African American women (6.48 per 1,000,000) was also higher than among Caucasian women (< 4 per 1,000,000)2. Despite these racial differences, the reported mortality from cardiac amyloidosis in the Southeast USA was lower than in the Northeast and Midwest USA. These findings are in sharp discordance with the much higher proportion of African Americans in states in the Southeast USA, highlighting the need for greater awareness in these communities.
Depending on your age and time in training, most of what you previously learned about cardiac amyloidosis is probably outdated and potentially wrong. For instance, low QRS voltage on ECG is a late finding in cardiac amyloidosis present in fewer than half of people with biopsy-proven ATTR-CM, in contrast with earlier studies recommending low QRS voltage on ECG as an adjunct for screening before endomyocardial biopsy1, 3, 4. Although there are no randomized clinical trials to address optimal management of heart failure in this population, this expert panel also outlines the rationale not to use guideline-directed heart failure therapy for those with cardiac amyloidosis, even in the context of a reduced ejection fraction. In contrast with dilated cardiomyopathy, a disease in which neurohormonal activation mediates ventricular dilation with adverse remodeling, the small LV cavity size and limited stroke volume for ATTR-CM do not improve with antagonizing these neurohormones. These factors also make cardiac output highly dependent on heart rate within the physiologic range, and beta-blockers or other rate-slowing medications do not improve symptoms or outcomes with cardiac amyloidosis.
Genetics of ATTR
This and other documents emphasize the value of imaging techniques to make a clear diagnosis of ATTR CM, once light chain amyloid (AL) is excluded1, 5. If a monoclonal gammopathy or skewed ratio of kappa and lambda free immunoglobulin light chains is present in blood or urine, then a biopsy of affected tissue must be performed to discern AL from ATTR5. Widespread use of mass spectrometry analysis of amyloid in tissues will help to avoid inappropriate use of chemotherapies directed against plasma cells when amyloid is due to TTR deposition. After making a diagnosis of ATTR-CM, this Scientific Statement delves into the critical importance of next distinguishing familial disease (ATTRv) from non-familial disease (ATTRwt). Rationale for this recommendation arises from the need to counsel and assess risk in first-degree relatives, to assess prognosis, and to choose appropriate treatments. Oddly, for unclear reasons, certain genotypes also have higher or lower risk of amyloidosis involvement in other tissues.
Nomenclature for pathogenic variants in TTR can be confusing, due to historic numbering of the amino acids in the mature protein circulating in the blood. After synthesis, a signal sequence consisting of twenty amino acids must be cleaved from the N-terminus of TTR to permit proper oligomerization6. When one uses nomenclature recommended by the Human Genome Organization, residue numbering begins with the initial methionine for the full-length protein, and three letters instead of one should be used for amino acid designation7. Accordingly, the most common pathogenic variant in TTR in the USA was traditionally called V122I, but most clinical genetic laboratories now denote this as p.Val142Ile. Remarkably, 3.4% of African Americans carry this tendency to ATTR-CM8. The penetrance for this pathogenic TTR variant is unknown, but one recent retrospective analysis of two biobank studies found that 44% of individuals with this allele age > 50 years had heart failure, while only 11% were diagnosed as ATTR-CM9. Among TTR V122I carriers age > 70 years, the rate of heart failure or cardiomyopathy was 70%, and it was 100% among those V122I carriers greater than 80 years of age9.
Many other pathogenic variants occur in this gene. To date, over 120 different destabilizing mutations are recognized, with very few non-functional or gain-of-function variants10. Because the mature protein has only 127 residues, reports exist for substitution of most amino acids in this protein. Mass spectrometry for amyloidosis sometimes identifies mutant peptides, although this is not adequate for genotyping. One study of 56 people who had biopsy-proven ATTR with liquid chromatography tandem mass spectrometry found that 9/56 (16%) had additional value in TTR gene sequencing11. Genetic testing facilitated recognition of homozygosity for the V122I variant in two of these individuals, and mass spectrometry failed to detect several other known pathogenic variants11. Although Table 3 in this Scientific Statement only includes wild-type and 3 pathogenic variants, clinicians should be aware that many other genotypes may underlie misfolded TTR. A gain-of-function variant (T119M) provided the first evidence that TTR tetramer stabilization could improve outcomes for people with destabilizing mutations12. This forms the basis for a new drug in development to stabilize TTR13.
Treatment for ATTR-CM
With expensive and highly promoted novel pharmacologic treatments, this document also provides guidance about when to use certain new medications, and when their prescriptions do not meaningfully help our patients1. Very recently, there were absolutely no FDA-approved therapies for ATTR. With a clinical trial showing benefit of the repurposed nonsteroidal anti-inflammatory drug diflunisal for this condition, as well as recent approval by the US FDA of three new treatments to stabilize the TTR tetramer or reduce its production, we recently entered a new era for both research and clinical practice for this disorder14-17. Clinicians can no longer justify avoiding the diagnosis because of a paucity of therapeutic options. As the authors of the scientific statement acknowledge, the financial toxicity of these expensive treatments must be considered along with a paucity of other adverse effects.
The clinical and scientific communities working with ATTR and other forms of amyloidosis should not be satisfied by the current treatments for this devastating condition. For most people who receive them, the rate of worsening slows, but the disease does not halt or reverse. In contrast, in AL amyloid, intensive chemotherapy and complete response with resolution of amyloidogenic light chain production can sometimes lead to reversal of amyloid in affected tissues18. Better strategies to stabilize the TTR tetramer, to silence its production more effectively, and potentially to remove dense amyloid plaques from affected organs could lead to improved outcomes in the future.
Unanswered questions
Although the scientific community has made a lot of progress with ATTR, this new era carries so many questions about how to diagnose and treat optimally. While Scientific Statements normally focus on established data, the authors confidently embrace the many unknowns in amyloidosis, including a list of factors involved with the diagnosis, prognosis, progression of disease, and uncertainty with treatments1. This should help to guide established researchers, large and small pharmaceutical companies, and physician-scientists who are new to ATTR, helping to pave the way to better care for a condition that is not so rare.
Depending on your age and time in training, most of what you previously learned about cardiac amyloidosis is probably outdated and potentially wrong. For instance, low QRS voltage on ECG is a late finding in cardiac amyloidosis present in fewer than half of people with biopsy-proven ATTR-CM, in contrast with earlier studies recommending low QRS voltage on ECG as an adjunct for screening before endomyocardial biopsy1, 3, 4. Although there are no randomized clinical trials to address optimal management of heart failure in this population, this expert panel also outlines the rationale not to use guideline-directed heart failure therapy for those with cardiac amyloidosis, even in the context of a reduced ejection fraction. In contrast with dilated cardiomyopathy, a disease in which neurohormonal activation mediates ventricular dilation with adverse remodeling, the small LV cavity size and limited stroke volume for ATTR-CM do not improve with antagonizing these neurohormones. These factors also make cardiac output highly dependent on heart rate within the physiologic range, and beta-blockers or other rate-slowing medications do not improve symptoms or outcomes with cardiac amyloidosis.
Genetics of ATTR
This and other documents emphasize the value of imaging techniques to make a clear diagnosis of ATTR CM, once light chain amyloid (AL) is excluded1, 5. If a monoclonal gammopathy or skewed ratio of kappa and lambda free immunoglobulin light chains is present in blood or urine, then a biopsy of affected tissue must be performed to discern AL from ATTR5. Widespread use of mass spectrometry analysis of amyloid in tissues will help to avoid inappropriate use of chemotherapies directed against plasma cells when amyloid is due to TTR deposition. After making a diagnosis of ATTR-CM, this Scientific Statement delves into the critical importance of next distinguishing familial disease (ATTRv) from non-familial disease (ATTRwt). Rationale for this recommendation arises from the need to counsel and assess risk in first-degree relatives, to assess prognosis, and to choose appropriate treatments. Oddly, for unclear reasons, certain genotypes also have higher or lower risk of amyloidosis involvement in other tissues.
Nomenclature for pathogenic variants in TTR can be confusing, due to historic numbering of the amino acids in the mature protein circulating in the blood. After synthesis, a signal sequence consisting of twenty amino acids must be cleaved from the N-terminus of TTR to permit proper oligomerization6. When one uses nomenclature recommended by the Human Genome Organization, residue numbering begins with the initial methionine for the full-length protein, and three letters instead of one should be used for amino acid designation7. Accordingly, the most common pathogenic variant in TTR in the USA was traditionally called V122I, but most clinical genetic laboratories now denote this as p.Val142Ile. Remarkably, 3.4% of African Americans carry this tendency to ATTR-CM8. The penetrance for this pathogenic TTR variant is unknown, but one recent retrospective analysis of two biobank studies found that 44% of individuals with this allele age > 50 years had heart failure, while only 11% were diagnosed as ATTR-CM9. Among TTR V122I carriers age > 70 years, the rate of heart failure or cardiomyopathy was 70%, and it was 100% among those V122I carriers greater than 80 years of age9.
Many other pathogenic variants occur in this gene. To date, over 120 different destabilizing mutations are recognized, with very few non-functional or gain-of-function variants10. Because the mature protein has only 127 residues, reports exist for substitution of most amino acids in this protein. Mass spectrometry for amyloidosis sometimes identifies mutant peptides, although this is not adequate for genotyping. One study of 56 people who had biopsy-proven ATTR with liquid chromatography tandem mass spectrometry found that 9/56 (16%) had additional value in TTR gene sequencing11. Genetic testing facilitated recognition of homozygosity for the V122I variant in two of these individuals, and mass spectrometry failed to detect several other known pathogenic variants11. Although Table 3 in this Scientific Statement only includes wild-type and 3 pathogenic variants, clinicians should be aware that many other genotypes may underlie misfolded TTR. A gain-of-function variant (T119M) provided the first evidence that TTR tetramer stabilization could improve outcomes for people with destabilizing mutations12. This forms the basis for a new drug in development to stabilize TTR13.
Treatment for ATTR-CM
With expensive and highly promoted novel pharmacologic treatments, this document also provides guidance about when to use certain new medications, and when their prescriptions do not meaningfully help our patients1. Very recently, there were absolutely no FDA-approved therapies for ATTR. With a clinical trial showing benefit of the repurposed nonsteroidal anti-inflammatory drug diflunisal for this condition, as well as recent approval by the US FDA of three new treatments to stabilize the TTR tetramer or reduce its production, we recently entered a new era for both research and clinical practice for this disorder14-17. Clinicians can no longer justify avoiding the diagnosis because of a paucity of therapeutic options. As the authors of the scientific statement acknowledge, the financial toxicity of these expensive treatments must be considered along with a paucity of other adverse effects.
The clinical and scientific communities working with ATTR and other forms of amyloidosis should not be satisfied by the current treatments for this devastating condition. For most people who receive them, the rate of worsening slows, but the disease does not halt or reverse. In contrast, in AL amyloid, intensive chemotherapy and complete response with resolution of amyloidogenic light chain production can sometimes lead to reversal of amyloid in affected tissues18. Better strategies to stabilize the TTR tetramer, to silence its production more effectively, and potentially to remove dense amyloid plaques from affected organs could lead to improved outcomes in the future.
Unanswered questions
Although the scientific community has made a lot of progress with ATTR, this new era carries so many questions about how to diagnose and treat optimally. While Scientific Statements normally focus on established data, the authors confidently embrace the many unknowns in amyloidosis, including a list of factors involved with the diagnosis, prognosis, progression of disease, and uncertainty with treatments1. This should help to guide established researchers, large and small pharmaceutical companies, and physician-scientists who are new to ATTR, helping to pave the way to better care for a condition that is not so rare.
Citation
Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J, Ruberg FL; on behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association [published online ahead of print June 1, 2020]. Circulation. doi: 10.1161/CIR.0000000000000792.
References
- Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J and Ruberg FL. AHA Scientific Statement Cardiac Amyloidosis: Evolving Diagnosis and Management. Circulation. 2020;in press.
- Alexander KM, Orav J, Singh A, Jacob SA, Menon A, Padera RF, Kijewski MF, Liao R, Di Carli MF, Laubach JP, Falk RH and Dorbala S. Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015: Potential Underdetection of Cardiac Amyloidosis. JAMA Cardiology. 2018;3:865-870.
- Sivaram CA, Jugdutt BI, Amy RWM, Basualdo CA, Haraphongse M and Shnitka TK. Cardiac Amyloidosis: Combined Use of Two-Dimensional Echocardiography and Electrocardiography in Noninvasive Screening Before Biopsy. Clinical Cardiology. 1985;8:511-518.
- Cyrille NB, Goldsmith J, Alvarez J and Maurer MS. Prevalence and Prognostic Significance of Low QRS Voltage Among the Three Main Types of Cardiac Amyloidosis. The American Journal of Cardiology. 2014;114:1089-1093.
- Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AWJM, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C and Hawkins PN. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133:2404-2412.
- Bellovino D, Morimoto T, Pisaniello A and Gaetani S. In Vitro and in Vivo Studies on Transthyretin Oligomerization. Experimental Cell Research. 1998;243:101-112.
- Wain HM, Bruford EA, Lovering RC, Lush MJ, Wright MW and Povey S. Guidelines for Human Gene Nomenclature. Genomics. 2002;79:464-470.
- Jacobson DR, Alexander AA, Tagoe C, Garvey WT, Williams SM, Tishkoff S, Modiano D, Sirima SB, Kalidi I, Toure A and Buxbaum JN. The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Molecular Genetics & Genomic Medicine. 2016;4:548-556.
- Damrauer SM, Chaudhary K, Cho JH, Liang LW, Argulian E, Chan L, Dobbyn A, Guerraty MA, Judy R, Kay J, Kember RL, Levin MG, Saha A, Van Vleck T, Verma SS, Weaver J, Abul-Husn NS, Baras A, Chirinos JA, Drachman B, Kenny EE, Loos RJF, Narula J, Overton J, Reid J, Ritchie M, Sirugo G, Nadkarni G, Rader DJ and Do R. Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry. JAMA. 2019;322:2191-2202.
- Connors LH, Lim A, Prokaeva T, Roskens VA and Costello CE. Tabulation of human transthyretin (TTR) variants. Amyloid. 2003;10:160-184.
- Brown EE, Lee YZJ, Halushka MK, Steenbergen C, Johnson NM, Almansa J, Tedford RJ, Cingolani O, Russell SD, Sharma K and Judge DP. Genetic testing improves identification of transthyretin amyloid (ATTR) subtype in cardiac amyloidosis. Amyloid. 2017;24:92-95.
- Hammarström P, Wiseman RL, Powers ET and Kelly JW. Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics. Science. 2003;299:713-716.
- Judge DP, Heitner SB, Falk RH, Maurer MS, Shah SJ, Witteles RM, Grogan M, Selby VN, Jacoby D, Hanna M, Nativi-Nicolau J, Patel J, Rao S, Sinha U, Turtle CW and Fox JC. Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2019;74:285-295.
- Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T, Rybin DV, Bisbee AB, Ando Y, Ikeda S-i, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ and Consortium ftDT. Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial. JAMA. 2013;310:2658-2667.
- Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB and Rapezzi C. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. New England Journal of Medicine. 2018;379:1007-1016.
- Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang C-C, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin K-P, Vita G, Attarian S, Planté-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA and Suhr OB. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. New England Journal of Medicine. 2018;379:11-21.
- Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Planté-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceição I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA and Coelho T. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. New England Journal of Medicine. 2018;379:22-31.
- Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnacki D, Finn K, Dubrey S, Faller DV, Wright DG, Falk RH and Skinner M. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood. 1996;88:2801-6.
Science News Commentaries
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --
Pub Date: Monday, Jun 01, 2020
Author: Daniel P. Judge, MD
Affiliation: