SUSPECTING ATTR

ATTR is an often-overlooked cause of heart failure1-4

Time to diagnosis is typically delayed by an average of ~6 years,* in part because symptoms of ATTR-CM overlap with other common conditions.1-5 ATTR may underlie HFpEF, coexist with degenerative AS, be preceded by bilateral carpal tunnel syndrome, or misdiagnosed as HCM.

Prevalence of ATTR-CM in screening studies:

HFpEF ~1 in 8 people aged 60 or older with HFpEF had an underlying cause of ATTR-CM6-8

Carpal tunnel syndrome ~6 in 10 patients with ATTR-CM had bilateral carpal tunnel syndrome 5 to 10 years before cardiac manifestations9-13

Aortic
stenosis ~1 in 6 older adults with AS undergoing TAVR may have ATTR-CM. For those with low-flow, low-gradient AS, that number may be ~2x higher14†

Hypertrophic cardiomyopathy ~1 in 5 patients aged 50 or older with hypertrophic cardiomyopathy had ATTR-CM15‡

ATTR-CM & As Differential Diagnosis Brochure
ATTR-CM vs HCM Differential Diagnosis Flashcard
*
In a targeted literature review, mean time to diagnosis ranged from 1.3 to 7.2 years.
†
From a study of 151 patients (mean age 84 years +/- 6 years) with degenerative AS.14
‡
Based on an epidemiological study of 766 patients with an HCM diagnosis.15
AS
aortic stenosis;
ATTR
transthyretin-mediated amyloidosis;
ATTR-CM
cardiomyopathy of transthyretin-mediated amyloidosis;
HCM
hypertrophic cardiomyopathy;
HFpEF
heart failure with preserved ejection fraction;
TAVR
transcatheter aortic valve replacement;
TTR
transthyretin.

Use electrocardiography, echocardiography, and cardiac MRI to help raise clinical suspicion for patients with red-flag symptoms

Electrocardiography12,18,19

Sinus rhythm with marked 1st degree AV block, low limb lead QRS voltage, left bundle branch block
Atrial fibrillation, anterolateral and inferior infarcts (pseudo‑infarcts)
Look for:
  • Low QRS voltage relative to LV wall thickness
  • Pseudo-infarction, AV conduction delays (e.g., atrial fibrillation)
While electrocardiographs may help raise clinical suspicion of ATTR, they lack specificity to diagnose ATTR-CM alone.

Echocardiography7,18,20-25

2D echocardiogram
Look for:
  • Left ventricular (LV) wall thickness ≥12 mm
  • Thickening of valves/septum
  • Refractile myocardium (granular sparkling)
  • Biatrial enlargement
  • Pericardial effusion
Longitudinal strain bull's-eye map
Look for:
Reduction in longitudinal strain with relative apical sparing
  • Presents in a "cherry-on-top" pattern
  • Red indicates normal longitudinal strain at apex
  • Pink and blue indicate abnormal longitudinal strain at mid/basal LV
Tissue Doppler Imaging (TDI)
Look for:
Diastolic dysfunction
  • Abnormal E/A ratio, E/e' ratio, and TDI lateral e'
  • 5-5-5 pattern in TDI tracings is seen in more advanced cardiac amyloidosis
Look for:
Reduction in longitudinal strain with relative apical sparing
  • Presents in a "cherry-on-top" pattern
  • Red indicates normal longitudinal strain at apex
  • Pink and blue indicate abnormal longitudinal strain at mid/basal LV
Look for:
Diastolic dysfunction
  • Abnormal E/A ratio, E/e' ratio, and TDI lateral e'
  • 5-5-5 pattern in TDI tracings is seen in more advanced cardiac amyloidosis
While echocardiographs may help raise clinical suspicion of ATTR, they lack specificity to diagnose ATTR-CM alone.

Cardiac MRI16,18,21,26,27,28

Look for:
  • Diffuse subendocardial or transmural late gadolinium enhancement
  • LV wall thickening
  • ECV expansion (≥30%)
Left ventricular hypertrophy
Late gadolinium enhancement 
While cardiac MRIs may help raise clinical suspicion of ATTR, they lack specificity to diagnose ATTR-CM alone.
NEXT Diagnosing ATTR

A=late (atrial) mitral inflow velocity; AV=atrioventricular; cMRI=cardiac magnetic resonance imaging; E=early mitral inflow velocities; e'=early diastolic mitral annulus velocity; ECV=extracellular volume fraction; MRI=magnetic resonance imaging; QRS=Q wave, R wave, S wave.

References:

  1. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57.
  2. Mohty D et al. Arch Cardiovasc Dis. 2013;106(10):528-540.
  3. Maurer MS et al. Circ Heart Fail. 2019;12(9):e006075.
  4. Maurer MS et al. J Am Coll Cardiol. 2016;68(2):161-172.
  5. Rozenbaum MH et al. Cardiol Ther. 2021;10(1):141-159.
  6. Lo Presti S et al. Crit Pathw Cardiol. 2019;18(4):195-199.
  7. González-López E et al. Eur Heart J. 2015;36(38):2585-2594.
  8. Garcia-Pavia P et al. Rev Esp Cardiol. 2025;78(4):301-310.
  9. Grogan M et al. J Am Coll Cardiol. 2022;80(10):978-981.
  10. Milandri A et al. Eur J Heart Fail. 2020;22(3):507-515.
  11. Ruberg FL et al. J Am Coll Cardiol. 2019;73(22):2872-2891.
  12. Witteles RM et al. JACC Heart Fail. 2019 Aug;7(8):709-716.
  13. aus dem Siepen F et al. Clin Res Cardiol. 2019;108(12):1324-1330.
  14. Castaño A et al. Eur Heart J. 2017;38(38):2879-2887.
  15. Garcia-Pavia P et al. ESC Heart Failure. 2024;11:4314-4324.
  16. Kittleson MM et al. Circulation. 2020;142(1):e7-e22.
  17. Nativi-Nicolau JN et al. Heart Fail Rev. 2022;27(3):785-793.
  18. Dharmarajan K et al. J Am Geriatr Soc. 2012;60(4):765-774.
  19. Maloberti A et al. Int J Cardio Cardiovasc Risk Prev. 2024;21:200271.
  20. Kittleson MM et al. J Am Coll Cardiol. 2023;81(11):1076-1126.
  21. Maurer MS et al. Circulation. 2017;135(14):1357-1377.
  22. Falk RH et al. Heart Fail Rev. 2015;20(2):125-131.
  23. Baptista P et al. Cureus. 2023;doi:10.7759/cureus.33364
  24. Cuddy S et al. J Am Soc Echocardiogr. 2022;35(9):A31-A40.
  25. Dorbala S et al. Circ Cardiovasc Imaging. 2021;14(7):e000029.
  26. Quarta G et al. Br J Radiol. 2011;84 Spec No 3(Spec Iss 3):S296-S305.
  27. Kittleson MM et al. J Am Coll Cardiol. 2025;S0735-1097(25):07719-8.
  28. Sheikh A et al. J Am Coll Cardiol. 2025:S0735-1097(25)10065-X. doi:10.1016/j.jacc.2025.10.054