ATTR-CM IS

A MULTISYSTEM,
PROGRESSIVE,

FATAL DISEASE1-4

Pathophysiology of ATTR2,5-8

ATTR is caused by changes in TTR, a tetrameric protein primarily synthesized in the liver.5

TETRAMER DISSOCIATION
TTR tetramers become less stable and dissociate into monomers and fragments.
MONOMER AGGREGATION
TTR monomers and fragments misfold and aggregate into pathogenic amyloid deposits.
AMYLOID DEPOSITION
TTR amyloid deposits accumulate in the heart, nerves, gastrointestinal tract, and other tissues, causing damage that leads to clinical symptoms.
DISEASE PROGRESSION
Continued accumulation of amyloid deposits results in worsening clinical symptoms over time.
THERE ARE 2 FORMS OF ATTR3,7,9
hATTR
hATTR is caused by a genetic variant in the TTR gene, and can manifest as polyneuropathy or cardiomyopathy.
wtATTR
wtATTR, although more common than hATTR, is related to aging and typically manifests as cardiomyopathy. The etiology of wtATTR is unknown.

Multisystem involvement is a hallmark of ATTR1,2,7,10

While patients may initially present with symptoms of cardiomyopathy or polyneuropathy, multisystem involvement, fast progression, and/or intolerance to common cardiovascular medications* are red-flag symptoms of ATTR and highlight the urgency for diagnosis.1‑4,7,10,11

Consider the cardiac, musculoskeletal, and neurologic symptoms typical of ATTR:

A diagram showing cardiac signs and symptoms of ATTR amyloidosis A diagram showing cardiac signs and symptoms of ATTR amyloidosis
A diagram showing musculoskeletal symptoms of ATTR amyloidosis A diagram showing musculoskeletal symptoms of ATTR amyloidosis
A diagram showing neurologic symptoms of ATTR amyloidosis A diagram showing neurologic symptoms of ATTR amyloidosis

Not a comprehensive list of all the symptoms associated with ATTR amyloidosis.

Each patient may not experience all of these symptoms or may not experience them at the same time.

*Patients with ATTR-CM can have intolerance to standard medications for heart failure including ARNi, ACEi, ARB, or β blockers.

EARLY DIAGNOSIS OF ATTR-CM IS CRITICAL. LEARN HOW TO RECOGNIZE THE RED-FLAG SYMPTOMS.3,7

NEXT Identify ATTR-CM

ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNi=angiotensin receptor-neprilysin inhibitor; ATTR=transthyretin-mediated amyloidosis; ATTR‑CM=cardiomyopathy of transthyretin-mediated amyloidosis; GI=gastrointestinal; hATTR=hereditary transthyretin-mediated amyloidosis; HFpEF=heart failure with preserved ejection fraction; TTR=transthyretin; UTI=urinary tract infection; wtATTR=wild-type transthyretin-mediated amyloidosis.

References:

  1. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis. J Am Coll Cardiol. 2016;68(2):161-172. doi:10.1016/j.jacc.2016.03.596
  2. Kittleson MM, Ruberg FL, Ambardekar AV, et al. 2023 ACC Expert Consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis. J Am Coll Cardiol. 2023;81(11):1076-1126. doi:10.1016/j.jacc.2022.11.022
  3. Kourelis TV, Gertz MA. Improving strategies for the diagnosis of cardiac amyloidosis. Expert Rev Cardiovasc Ther. 2015;13(8):945-961. doi:10.1586/14779072.2015.1069181
  4. Rozenbaum MH, Large S, Bhambri R, et al. Impact of delayed diagnosis and misdiagnosis for patients with transthyretin amyloid cardiomyopathy (ATTR-CM): a targeted literature review. Cardiol Ther. 2021;10(1):141-159. doi:10.1007/s40119-021-00219-5
  5. Shin SC, Robinson‐Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733-748. doi:10.1002/msj.21352
  6. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. doi:10.1136/jnnp-2014-308724
  7. 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. 2021;27(3):785‑793. doi:10.1007/s10741‑021‑10080‑2
  8. Hazenberg BPC. Amyloidosis. Rheum Dis Clin North Am. 2013;39(2):323-345. doi:10.1016/j.rdc.2013.02.012
  9. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8(1):31. doi:10.1186/1750-1172-8-31
  10. Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2020;142(1). doi:10.1161/cir.0000000000000792
  11. 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. doi:10.1161/circheartfailure.119.006075
  12. Brito D, Albrecht FC, de Arenaza DP, et al. World Heart Federation consensus on transthyretin amyloidosis cardiomyopathy (ATTR‑CM). Global Heart. 2023;18(1):59. doi:10.5334/gh.1262
  13. Dharmarajan K, Maurer MS. Transthyretin cardiac amyloidoses in older North Americans. J Am Geriatr Soc. 2012;60(4):765‑774. doi:10.1111/j.1532‑5415.2011.03868.x
  14. Campbell CM, Baiyee CAMT, et al. Orthopaedics history preceding diagnosis of cardiac amyloidosis: timing and variation by subtype. Poster presented at: International Symposium on Amyloidosis; 2020; Virtual.
  15. Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716. doi:10.1016/j.jchf.2019.04.010