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Wild-Type vs Hereditary    |    Clinical Presentation     |    Underdiagnosis


Understanding Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

Cardiac amyloidosis develops when amyloid fibrils deposit into the extracellular space of the heart, leading to progressive cardiac dysfunction.1,2 The most common amyloid fibril proteins that can infiltrate the heart and lead to cardiac amyloidosis are immunoglobulin light chain amyloid fibril protein (AL) and transthyretin amyloid fibril protein (ATTR).1-5

attr_cm_flowchart

It is important to clinically differentiate between ATTR and AL, as they have different clinical courses,5 and AL requires immediate medical treatment.6 

 

 


WILD-TYPE VS HEREDITARY ATTR-CM


Wild-type ATTR-CM (wtATTR-CM) is idiopathic7 and is not considered to be a hereditary disease.1   


     

Wild-type ATTR-CM (wtATTR-CM)

Also Known As7,11

  • Senile cardiac amyloidosis
  • Senile systemic amyloidosis
  • Age-related amyloidosis

 

Patient Considerations 

  • Ethnicity: predominantly white7,11
  • Mostly men7,11,12
  • Symptom onset typically over the age of 60 years10
  • Heart failure7,11,12
  • Cardiac arrhythmias, particularly atrial fibrillation3,7,11,12
  • History of bilateral carpal tunnel syndrome7,12,13

Prognosis

Median survival: ~3.5 years7,12,14

 

 

ENCOUNTERING ATTR-CM

Meet Dr. Detective, a cardiologist who specializes in diagnosing tough cases. Watch as he suspects and then detects that his patient has ATTR-CM.


Hereditary ATTR-CM (hATTR-CM)* is due to a mutation in the TTR gene.1 Inherited mutations in TTR are common in patients of African (Val122Ile), Irish (Thr60Ala), Italian (Ile68Leu), and Danish (Leu111Met) descent.3,8-10
 
 

Hereditary ATTR-CM (hATTR-CM)

Also Known As 

  • Variant ATTR (ATTRv)1
  • ATTRm1
  • Mutant ATTR4
  • Hereditary amyloidosis15
  • Familial amyloid cardiomyopathy16

Patient Considerations

  • Men and women11
  • Age of symptom onset depends on the mutation, but may occur as early as 30-40 (Japan, Portugal, Denmark) 50-60 (Sweden, France, United States) 40-50 (Italy) 45-50 (Ireland)9, 10
  • Heart failure11
  • Neurological symptoms (peripheral and autonomic)11
  • Gastrointestinal symptoms11
  • History of bilateral carpal tunnel syndrome11

Prognosis

Median survival: ~2 to 3 years3

 

 CLINICAL PRESENTATION OF ATTR-CM IN PATIENTS WITH wtATTR AND hATTR*

Patients with wtATTR and hATTR* present with heart failure and other cardiac symptoms.4,7,11,17
Please see other common signs and symptoms in the image below.

        Common Signs and Symptoms in wtATTR and hATTR4,7,11,12,17-20

attr_cm_bodyimage

Cardiac

  • Fatigue
  • Shortness of breath
  • Oedema
  • Arrhythmias
  • Heart failure with preserved ejection fraction
  • Aortic stenosis


Soft Tissue

  • Lumbar stenosis
  • Ruptured distal biceps tendon

GI

  • Diarrhoea
  • Constipation
  • Nausea
  • Early satiety

Neurologic

  • CTS
  • Peripheral neuropathy
  • Orthostasis
  • Weakness

*Also known as variant ATTR.1
CTS, carpal tunnel syndrome; GI, gastrointestinal.

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ATTR-CM IS AN UNDERDIAGNOSED CAUSE OF HEART FAILURE

    PARTICULARLY HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)21,22

In 2 studies, wtATTR deposits were identified in the hearts of 13%-17% of older patients with HFpEF.21,22

In a study conducted in Spain of 120 HFpEF patients 60 years or older, wtATTR was confirmed in 13% (13.3%; 95% CI: 7.2-19.5) of the patients21

In a study of 140 autopsied patients, 109 of whom had HFpEF, cardiac wtATTR deposits were found in 17% of the patients22

Know the clues to look for to avoid missing a diagnosis. Learn the clues

 

NEXT SECTION: SUSPECT THE CLUES OF ATTR-CM

References: 
1. 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):215-219.
2. Narotsky DL, Castaño A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32(9):1166.e1-1166.e10. 
3. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 
4. 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. 
5. 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. 
6. Donnelly JP, Hanna M. Cardiac amyloidosis: An update on diagnosis and treatment. Cleve Clin J Med. 2017;84(12)(suppl 3):12-26.
7. 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.  
8. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid. 2015;22(3):171-174. 
9. 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. 
10. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286-1300.
11Maurer 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. 
12. 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. 
13. 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. 
14. 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;68:1014-1020. 
15. Tuzovic M, Yang EH, Baas AS, et al. Cardiac amyloidosis: diagnosis and treatment strategies. Curr Oncol Rep. 2017;19(7):46. 
16. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84. 
17. 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.  
18. 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. 
19. 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. 
20. 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. 
21. 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.  
22. 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. 

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