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Transthyretin cardiac amyloidosis*: an underdiagnosed cause of heart failure1-3
*Also known as transthyretin amyloid cardiomyopathy (ATTR-CM).ATTR cardiac amyloidosis is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1-3
ATTR-CM is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1
ATTR-CM is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1
ATTR-CM is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1
ATTR-CM is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1
ATTR-CM is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1
ATTR-CM is an underdiagnosed, progressive, and infiltrative disease that is often overlooked as a cause of heart failure1
ATTR cardiac amyloidosis is a type of amyloidosis that results in thickened heart walls due to increasing amyloid fibril deposition.3

Untreated patients with ATTR cardiac amyloidosis have a median survival of ~2-3.5 years after diagnosis.4,5

Impact of ATTR cardiac amyloidosis on the heart

Illustrative representation.

Early diagnosis of ATTR cardiac amyloidosis is critical as prognosis worsens rapidly, with1-3,5,6:
  • continued amyloid deposition,
  • subsequent advancing organ dysfunction,
  • significant reduction in quality of life, and 
  • ultimately death

ATTR cardiac amyloidosis is a type of amyloidosis that may lead to organ dysfunction and significant mortality3-5,7,8

Amyloidosis is a multisystemic disease caused by the deposition of amyloid fibrils in the heart and other organs over time.3,9 These amyloid fibrils are aggregates of the thyroxine and retinol transporter protein transthyretin (TTR).10

TTR is mainly produced in the liver and is assembled into a tetramer, or 4-leaf clover shape that normally dissociates and reforms.3,10 In ATTR cardiac amyloidosis, mutations and/or aging promote dissociation into monomers, which then misfold and aggregate to form amyloid fibrils.3,10

Illustrative representation.12

ATTR cardiac amyloidosis is one of the more frequent types of cardiac amyloidosis—the next being AL (or immunoglobulin light chain amyloidosis), which is caused by amyloid fibrils known as monoclonal immunoglobulin light chains.13,14 It is important to clinically differentiate between ATTR cardiac amyloidosis and AL, as they have different clinical courses, and AL requires immediate treatment by a hematologist/oncologist.13,14

Main types of amyloidosis13

Because amyloid fibrils can deposit in different parts of the body, including the heart and nerves, some patients may present with a mixed phenotype, namely, symptoms of both cardiomyopathy and polyneuropathy.10,15

The 2 subtypes of ATTR cardiac amyloidosis

In ATTR cardiac amyloidosis, the change that destabilizes the protein tetramers can be either a TTR gene mutation or age-related.10

Typical characteristics of wtATTR-CM
  • Idiopathic, due to age-related changes in stability of the TTR protein3,4,16
  • Historically, most common among Caucasian men17-19
  • >60 years age at onset4,16,18,19
  • ~3.5 years median survival if untreated after diagnosis4,18

Clinical presentations

  • Heart failure: in 2 studies, ~7-13% of older patients had heart failure with preserved ejection fraction (HFpEF)20,21†‡
  • Cardiac arrhythmias, particularly atrial fibrillation5,17,18
  • Low-flow aortic stenosis5,22,23
  • History of bilateral carpal tunnel syndrome: ~50% of patients experience symptoms as many as 5-7 years prior to diagnosis5,17,24,25
Typical characteristics of hATTR-CM
  • 50-60 years age at onset26,27
  • ~2-3 years median survival if untreated after diagnosis5
  • Hereditary, due to a mutation in the transthyretin (TTR) gene3,9,13,14§ 
  • >120 mutations of TTR 28,29
    • V122I is the most common in the US and is carried by 3%-4% of African Americans, though not all will develop the disease5,17,30

Clinical presentations in patients with V122I II

  • Heart failure: 94% of patients had predominant cardiac involvement30,31
  • Neurological or gastrointestinal symptoms17
  • History of bilateral carpal tunnel syndrome: second most frequent symptom (47%)24,31
Advanced hATTR-CM in untreated patients is associated with rapid progression, serious cardiac complications, and increased mortality, regardless of phenotype.1,2,5,6,17
Suspect the signs >

Suspect and act: multidisciplinary collaboration is critical to earlier suspicion and diagnosis5,32-34

Patients with ATTR cardiac amyloidosis can present with additional manifestations, such as atrial fibrillation, bilateral carpal tunnel syndrome, or peripheral neuropathy.5,25

A well-coordinated healthcare team with expertise in different specialties and diagnostic modalities can offer patients comprehensive care when diagnosing ATTR cardiac amyloidosis.34

Sign up to stay connected for information about suspecting and diagnosing ATTR cardiac amyloidosis.

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A prospective analysis in 108 patients (61% women, age range: 57-74 years) seen at the Johns Hopkins University HFpEF clinic who underwent endomyocardial biopsy to evaluate myocardial tissue histopathology. Approximately 10% had ATTR cardiac amyloidosis confirmed.20A prospective, cross-sectional, single-centre study at a tertiary university hospital in Madrid, Spain. Included 120 patients ≥60 years of age (59% women, mean age: 82 ± 8 years) admitted for HFpEF, with left ventricular (LV) ejection fraction ≥50% and LV hypertrophy ≥12 mm. 99mTechnetium-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy used to confirm ATTR cardiac amyloidosis. wtATTR was confirmed in ~13% (95% CI: 7.2-19.5) of the patients.21Not all patients who carry a TTR mutation will go on to have clinical signs and symptoms of this disease.2,30,35,36The most common mutations in the US responsible for a cardiac phenotype are V122I, T60A, and V30M.1799mTc-PYP is not FDA approved for the diagnosis of ATTR cardiac amyloidosis. Please consult individual labeling for risks.37ATTR=transthyretin amyloidosis.
References:Law S, Gillmore JD. When to suspect and how to approach a diagnosis of amyloidosis. Am J Med. 2022;135(suppl 1):S2-S8.Kittleson M, Ruberg FL, Ambardekar AV, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient with Cardiac Amyloidosis: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023;S0735-1097(22)07423-X.Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716.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.Maurer MS, Elliott P, Comenzo R, et al. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377.Ioannou A, Patel RK, Razvi Y, et al. Impact of earlier diagnosis in cardiac ATTR amyloidosis over the course of 20 years. Circulation. 2022;146(22):1657-1670.Bajwa F, O'Connor R, Ananthasubramaniam K. Epidemiology and clinical manifestations of cardiac amyloidosis. Heart Fail Rev. 2022;27(5):1471-1484.Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16-26.Benson MD, Buxbaum JN, Eisenberg DS, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. 2018;25(4):215-229.Liz MA, Coelho T, Bellotti V, et al. A narrative review of the role of transthyretin in health and disease. Neurol Ther. 2020;9(2):395-402.Jain A, Zahra F. Transthyretin amyloid cardiomyopathy. NCBI Bookshelf. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022;1-17. Nativi-Nicolau J, Maurer MS. Amyloidosis cardiomyopathy: update in the diagnosis and treatment of the most common types. Curr Opin Cardiol. 2018;33(5):571-579.Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212.Donnelly JP, Hanna M. Cardiac amyloidosis: an update on diagnosis and treatment. Cleve Clin J Med. 2017;84(12 suppl 3):12-26. Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9):e006075.Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891.Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (transthyretin amyloid outcome survey). J Am Coll Cardiol. 2016;68(2):161-172.Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098.Ruberg FL, Maurer MS, Judge DP, et al. Prospective evaluation of the morbidity and mortality of wild-type and V1221 mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164(2):222-228.e1.Hahn VS, Yanek LR, Vaishnav J, et al. Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. JACC Heart Fail. 2020;8(9):712-724.González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594.Cavalcante JL, Rijal S, Abdelkarim I, et al. Cardiac amyloidosis is prevalent in older patients with aortic stenosis and carries worse prognosis. J Cardiovasc Magn Reson. 2017;19(98):1-12.Ternacle J, Krapf L, Mohty D, et al. Aortic stenosis and cardiac amyloidosis: JACC Review topic of the week. JAm Coll Cardiol. 2019;74(21):2638-2651.aus dem Siepen F, Hein S, Prestel S, et al. Carpal tunnel syndrome and spinal canal stenosis: harbingers of transthyretin amyloid cardiomyopathy? Clin Res Cardiol. 2019;108(12):1324-1330.Nativi-Nicolau JN, Karam C, Khella S, Maurer MS. Screening for ATTR amyloidosis in the clinic: overlapping disorders, misdiagnosis, and multiorgan awareness. Heart Fail Rev. 2022;27(3):785-793.Rapezzi C, Quarta CC, Riva L, et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol. 2010;7(7):398-408.Adams D, Algalarrondo V, Polydefkis M, et al. Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression. Orphanet J Rare Dis. 2021;16(1):411.Gertz M, Adams D, Ando Y, et al. Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner. BMC Fam Pract. 2020;21(1):198.Rowczenio DM, Noor I, Gillmore JD, et al. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat. 2014;35(9):E2403-E2412.Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin 3TTRX V122I allele in 14 333 African-Americans. Amyloid. 2015;22(2):171-174.Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-614.Heidenreich PA, Bozhurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2022;145(18):e895-e1032.Irabor B, McMillan JM, Fine NM. Assessment and management of older patients with transthyretin amyloidosis cardiomyopathy: Geriatric cardiology, frailty assessment and beyond. Font Cardiovasc Med. 2022;9:863179.Sperry BW, Khoury JA, Raza S, Rosenthal JL. Comprehensive approach to cardiac amyloidosis care: considerations in starting an amyloidosis program. Heart Fail Rev. 2022;27(5):1559-1565.Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR epidemiology, genetics, and prognostic factors. Methodist Debakey Cardiovasc J. 2022;18(2):17-26.Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678.Miller EJ, Campisi R, Shah NR, et al. Radiopharmaceutical supply disruptions and the use of 99mTc-hydroxymethylene diphosphonate as an alternative to 99mTc-pyrophosphate for the diagnosis of transthyretin cardiac amyloidosis: an ASNC Information Statement. J Nucl Cardiol. 2022;29(5):2748-2760.
Understanding ATTR cardiac amyloidosis diagnosis: primary care provider resource

Learn how primary care providers can play a key role in earlier diagnosis of ATTR cardiac amyloidosis. 


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