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Clinical Clues    |    Additional Key Considerations


Suspect Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

     ATTR-CM presents with heart failure symptoms. Learn how to recognise the clues to make a diagnosis.1-3
            HIDDEN IN PLAIN SIGHT—SUSPECT ATTR-CMmagglass_beige

The diagnosis of ATTR-CM is often delayed or missed. Routine heart failure assessment, such as echocardiography and electrocardiography (ECG), along with advanced imaging techniques, can help identify clues on the diagnostic pathway. By increasing your suspicion of ATTR-CM, you can identify patients who may require further testing to make a diagnosis.1-4

Consider the Following Clinical Clues, Especially in Combination, to Raise Suspicion for ATTR-CM and the Need for Further Testing

                    DOWNLOAD THE HIDDEN CLUES                    
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HEART FAILURE WITH PRESERVED EJECTION FRACTION in patients typically over 605-7
  • In ATTR-CM, diastolic function is impaired due to amyloid fibril deposition in the myocardium, resulting in thicker and inelastic ventricles, thereby decreasing stroke volume. It is not until the later stages of ATTR-CM disease that ejection fraction drops8-10
  • Imaging clues, such as reduced longitudinal strain with apical sparing, may help increase suspicion1,8
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INTOLERANCE to standard heart failure therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers1,4,11
  • Patients can develop a decrease in stroke volume, which can lead to low blood pressure. As a result, they can develop an intolerance to blood pressure–lowering therapies4,11
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DISCORDANCE between QRS voltage on ECG and left ventricular (LV) wall thickness seen on echocardiography12-14
  • The classic ECG feature of ATTR-CM is a discordance between QRS voltage and LV mass ratio1,14,15
  • The amplitude of the QRS voltage is not reflective of the increased LV wall thickness, because the increase is due to extracellular amyloid protein deposition rather than myocyte hypertrophy1
    • Absence of a low QRS voltage does not, however, rule out amyloidosis, as low voltage can vary among cardiac amyloidosis etiologies6,12,14,16,17

ECG and echocardiography images showing discordance of limb lead QRS voltages and the degree of LV wall thickness in a patient with cardiac amyloidosis
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DIAGNOSIS of carpal tunnel syndrome or lumbar spinal stenosis4,16,18-24
  • Bilateral carpal tunnel syndrome and lumbar stenosis are often seen in ATTR-CM due to amyloid deposition in these areas4,16,18-24
  • Bilateral carpal tunnel syndrome in ATTR-CM often precedes cardiac manifestations by several years19,25,26
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ECHOCARDIOGRAPHY showing increased LV wall thickness6,12,20,27,28
  • Increased wall thickness without a clear explanation (ie, hypertension) should raise suspicion for cardiac amyloidosis1,3
  • Extracellular amyloid deposition results in an increased LV wall thickness that tends to be greater in ATTR-CM than in immunoglobulin light chain amyloid fibril protein (AL) cardiac amyloidosis, with reported thicknesses for ATTR-CM often being more than 15 mm12,14,20,28
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NERVOUS SYSTEM: Autonomic nervous system dysfunction, including gastrointestinal complaints or unexplained weight loss6,20,29,30
  • Gastrointestinal complaints due to autonomic dysfunction include diarrhoea and constipation31
  • Orthostatic hypotension due to autonomic dysfunction is another symptom that may occur with ATTR-CM6,20,29

 

ADDITIONAL KEY CONSIDERATIONS 

There are several additional signs/symptoms that could be clues for cardiac amyloidosis and ATTR-CM, which include:

Strain imaging showing apical sparing or apical preservation1,3,8,12,28 

Longitudinal strain seen on echocardiography is reduced in the basal and midwall area; however, the apical strain is spared or preserved1,3,8,12,28

A history of bicep tendon rupture31,32

A diagnosis of hypertrophic cardiomyopathy1,3,33

Arrhythmias such as atrial fibrillation (most common) or other conduction abnormalities, which may require a pacemaker5,6,14,16,33,34

Aortic stenosis (AS) and ATTR-CM may occur in elderly patients, notably those with a low-flow, low-gradient AS pattern35-37

Hip and knee arthroplasty38

cardiac amyloidosis the need for early diagnosis

Echocardiology in cardiac amyloidosis. a-b Granular echogenic appearance of the ventricular wall with the clear hypertrophy and some pericardial effusion. Left ventricular ejection fraction is preserved (c), septial tissue Doppler longitudinal movement is reduced (d). Longitudinal strain analysis from the 3 apical views showing characteristic apical sparing (bull's eye) with reduced strain at the mid and basal level (e). 

Reproduced from Oerlemans MIFJ, Rutten KHG, Minnema MC, Raymakers RAP, Asselbergs FW, de Jonge N. Cardiac amyloidosis: the need for early diagnosis. Neth Heart J. 2019;27(11):525-536. doi: 10.1007/s12471-019-1299-1, under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).


The Hidden Clinical Clues of ATTR-CM

Discover how a cardiologist suspects ATTR-CM

In the first video, a colleague asked Dr. Detective for help with a tough case. Watch to see how looking for certain signs and symptoms can point to ATTR-CM. 

 

 

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References:
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2. AlJaroudi WA, Desai MY, Tang WH, Phelan D, Cerqueira MD, Jaber WA. Role of imaging in the diagnosis and management of patients with cardiac amyloidosis: state of the art review and focus on emerging nuclear techniques. J Nucl Cardiol. 
2014;21(2):271-283.
3. Rapezzi C, Lorenzini M, Longhi S, et al. Cardiac amyloidosis: the great pretender. Heart Fail Rev. 2015;20(2):117-124.
4. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003.
5. 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.
6. 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.
7. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122.
8. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018;28(1):10-21.
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10. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;2(6):670-679.
11. Castaño A, Drachman BM, Judge D, Maurer MS. 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.
12. 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.
13. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13.
14. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014;114(7):1089-1093.
15. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286-1300.
16. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation. 2016;133(3):282-290.
17. Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005;165(12):1425-1429.
18. 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.
19. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63.
20. 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.
21. 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.
22. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228.
23. Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol. 2015;28(2):201-207.
24. 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.
25. Papoutsidakis N, Miller EJ, Rodonski A, Jacoby D. Time course of common clinical manifestations in patients with transthyretin cardiac amyloidosis: delay from symptom onset to diagnosis. J Card Fail. 2018;24(2):131-133.
26. 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. 
27. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448.
28. Ternacle J, Bodez D, Guellich A, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging. 2016;9(2):126-138.
29. 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.
30. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131.
31. 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.
32. Geller HI, Singh A, Alexander KM, et al. Association between ruptured distal biceps tendon and wild-type transthyretin cardiac amyloidosis. JAMA. 2017;318(10):962-963.
33. González-López E, Gagliardi C, Dominguez F, et al. Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths. Eur Heart J. 2017;38(24):1895-1904.
34. Givens RC, Russo C, Green P, Maurer MS. Comparison of cardiac amyloidosis due to wild-type and V122I transthyretin in older adults referred to an academic medical center. Aging Health. 2013;9(2):229-235.
35. Castaño A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J. 2017;38(38):2879-2887.
36. Galat A, Guellich A, Bodez D, et al. Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg? Eur Heart J. 2016;37(47):3525-3531.
37. Treibel TA, Fontana M, Gilbertson JA, et al. Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic valve replacement. Circ Cardiovasc Imaging. 2016;9(8). doi: 10.1161/CIRCIMAGING.116.005066.
38. Rubin J, Alvarez J, Teruya S, et al. Hip and knee arthroplasty are common among patients with transthyretin cardiac amyloidosis, occurring years before cardiac amyloid diagnosis: can we identify affected patients earlier? Amyloid. 2017;24(4):226-230. doi: 10.1080/13506129.2017.1375908.

PP-RDP-IRL-0077 Date of Preparation : April 2020