Suspect transthyretin cardiac amyloidosis* using clinical signs1-3*Also known as transthyretin amyloid cardiomyopathy (ATTR-CM).
ATTR cardiac amyloidosis can manifest in a variety of ways due to multiorgan involvement.1-3 ATTR cardiac amyloidosis diagnosis is often delayed or missed, which is why a multidisciplinary healthcare team can help in earlier and accurate diagnosis.1-4
Routine heart failure assessments such as echocardiogram, electrocardiogram (ECG) and cardiac molecular magnetic resonance imaging (CMR) can help raise suspicion of ATTR cardiac amyloidosis in addition to noncardiac clues.1
Example
By increasing your suspicion of ATTR cardiac amyloidosis, you can identify patients who may require further testing to make an accurate diagnosis.5-7
Example
By increasing your suspicion of ATTR-CM, you can identify patients who may require further testing to make an accurate diagnosis.1,5,7,8
Consider these red flags, especially in combination, to help raise suspicion and the need for further testing
Heart failure with preserved ejection fraction (HFpEF) or other cardiac conditions (eg, severe aortic stenosis† or arrhythmias) in patients typically over the age of 608-10
Intolerance to standard heart failure therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers3,11
Discordance between QRS voltage on electrocardiography and left ventricular (LV) wall thickness12,13
Diagnosis of orthopedic conditions, including bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, and/or hip and knee arthroplasty5-7
Increased LV wall thickness on echocardiogram without explanation (eg, hypertension)1,3
Nervous system dysfunction, including polyneuropathy and autonomic dysfunction, including gastrointestinal symptoms and/or unexplained weight loss2,14
Suspicion of cardiac involvement should prompt an immediate cardiac evaluation to assess for ATTR cardiac amyloidosis.1,4
Suspicion of cardiac involvement should prompt an immediate cardiac evaluation to assess for ATTR-CM.6
The location of ATTR deposition determines whether patients present with a cardiac, noncardiac, or mixed phenotype.x
The location of ATTR deposition determines whether patients present with a cardiac, noncardiac, or mixed phenotype.2,15-17
Heart- Patients may become intolerant to several traditional heart failure therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers.3,11
- Symptoms include HFpEF or other cardiac conditions, such as severe aortic stenosis† and arrythmias, echo showing increased LV wall thickness, and discordance between QRS voltage on ECG and an increase in LV wall thickness.1,8-10,12,13,18
Biceps tendon- Deposition in the biceps tendon may lead to degeneration, rupture, and compression of surrounding tissues.6,19
- Spontaneous distal biceps tendon rupture is unlikely in adults aged 56 to 74 years and its presence in a patient with HFpEF should raise suspicion: 33% of patients with wild-type ATTR cardiac amyloidosis (wtATTR-CM) experience spontaneous rupture of the distal biceps tendon.2,6‡
Eyes- Deposits in the eyes can lead to development of dark floaters, abnormal blood vessel formation, pupillary abnormalities, and dry eye.20,21
- Vitreous involvement is the most frequent ocular manifestation, with women being more affected than men: in a retrospective study, 24% of patients with hereditary ATTR cardiac amyloidosis (hATTR-CM) had ocular involvement.20
GI tract- Deposition generally occurs in the submucosal tissue where endoscopy does not show significant findings and biopsies are not often used, so most GI signs are usually overlooked or dismissed.22,23
- Symptoms include chronic diarrhea or diarrhea alternating with constipation, unintentional weight loss associated with early satiety, and a typical absence of abdominal pain.21
Kidneys- For some patients, renal amyloid deposition may involve early activity in the renal medulla and manifestations are correlated with glomerular and vascular involvement, and not with tubulointerial involvement.24
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Renal impairment and proteinuria are typical symptoms: 15% of patients with wtATTR-CM and 20% of patients with V122I hATTR-CM have shown renal impairment.25
Lumbar spine- Deposition causes thickening of the ligamentum flavum and subsequent spinal canal narrowing.5,8
- Lumbar spinal stenosis is one of the noncardiac manifestations in patients with wtATTR-CM: 44% of patients with this symptom were observed to have deposits identified through immunohistochemistry in ligament specimens.2,19
Median nerve carpal tunnel- Deposition is thought to infiltrate the tenosynovial tissue and cause compression of the median nerve.26,27
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This syndrome is an extracardiac manifestation of ATTR cardiac amyloidosis and may precede clinical heart failure symptoms by several years—as many as 5 to 7 years in ~50% of patients with wtATTR-CM.28,29
Peripheral nerves- Deposition in the nerves can cause damage by mechanical compression, direct blood vessel invasion, and possibly through toxic effects of the amyloid fibrils.30
- The mixed presentation underscores the importance of a multidisciplinary approach that includes early and continued assessment of neuropathy and cardiomyopathy.31
Soft tissue- Deposition in ligaments, tendons, articular cartilage, and soft tissue throughout the body hardens the synovium and joint capsule, directly causing symptoms of osteoarthritis or eliciting a painful inflammatory response.7,19
- Patients with cardiac amyloidosis are over 5 times more likely to have undergone hip arthroplasty.7
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Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178.Quarta CC, Solomon SD, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-1849.Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49(1):9-13.Coelho T, Maurer MS, Suhr OB. THAOS – The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76.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.Planté-Bordeneuve V, Norgren N. Transthyretin familial amyloid polyneuropathy: delineating the individual disease risk to improve management of patients and carriers. Future Neurol. 2011;6(4):437-440Benson 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.Rapezzi C, Merlini G, Quarta CC, et al. Systematic cardiac amyloidosis: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212.Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011;42(9):1259-1264.Reynolds MM, Veverka KK, Gertz MA, et al. Ocular manifestations of familial transthyretin amyloidosis. Am J Ophthalmol. 2017;183:156-162.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.Freudenthaler S, Hegenbart U, Schonland S, et al. Amyloid in biopsies of the gastrointestinal tract—a retrospective observational study on 542 patients. Virchows Arch. 2016;468(5):569-577.Iida T, Yamano H, Nakase H. Systemic amyloidosis with gastrointestinal involvement: diagnosis from endoscopic and histological views. J Gastroenterol Hepatol. 2018;33(3):583-590.Lobato L, Beirão I, Guimaraes SM, et al. Familial amyloid polyneuropathy type I (Portuguese): distribution and characterization of renal amyloid deposits. Am J Kidney Dis. 1998;31(6):940-946.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.Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17):2040-2050.Uchiyama S, Sekijima Y, Tojo K, et al. Effect of synovial transthyretin amyloid deposition on preoperative symptoms and postoperative recovery of median nerve function among patients with idiopathic carpal tunnel syndrome. J Orthop Sci. 2014;19(6):913-919.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.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.Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733-748.Grogan M, Hawkins PN, Kristen AV, et al. Identifying mixed phenotype: evaluating the presence of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis with cardiomyopathy. J Card Fail. 2019;25(8):S9-S10.