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Understanding Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

Amyloidosis is a multisystemic disease in which TTR proteins with unstable structures misfold and aggregate into amyloid fibrils, which deposit in the heart and other organs.1 The most common amyloid fibril proteins that can infiltrate the heart and lead to cardiac amyloidosis1 are immunoglobulin light chain amyloid fibril protein (AL) and transthyretin amyloid fibril protein (ATTR).2-5

Most Common Types of Cardiac Amyloidosis

ATTR amyloidosis5

AL amyloidosis5

Wild-type ATTR (wtATTR)5

Hereditary ATTR (hATTR)1

Also known as variant1
Learn more

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

ATTR-CM IS A LIFE-THREATENING, PROGRESSIVE, INFILTRATIVE, RARE DISEASE THAT CAN OFTEN BE OVERLOOKED AS A CAUSE OF HEART FAILURE6,7

Once diagnosed, untreated patients with ATTR-CM have a median survival of ~2 to 3.5 years3

heart image
heart image

Illustrative representation.

EARLY DIAGNOSIS OF ATTR-CM IS CRITICAL, AS PROGNOSIS WORSENS RAPIDLY WITH CONTINUED AMYLOID DEPOSITION, SUBSEQUENT ADVANCING ORGAN DYSFUNCTION, AND SIGNIFICANT REDUCTION IN QUALITY OF LIFE.3,6

MAIN TYPES OF CARDIAC AMYLOIDOSIS

It is important to clinically differentiate between ATTR-CM and AL, as they have different clinical courses, and AL requires immediate treatment.5,8

Most Common Types of Cardiac Amyloidosis

ATTR-CM5

AL amyloidosis5

Wild-type ATTR-CM (wtATTR-CM)5

Hereditary ATTR-CM (hATTR-CM)1

Wild-type vs HEREDITARY ATTR-CM

Wild-type ATTR-CM(wtATTR-CM) is idiopathic7 and is not considered to be a hereditary disease.1 It is thought to account for the majority of all ATTR-CM cases.8

Hereditary ATTR (hATTR)* occurs due to a mutation in the TTR gene (learn more).In the United States, the most common mutation causing the cardiac form of the disease (hATTR-CM) is the valine-to-isoleucine substitution at position 122 (V122I).8 This mutation affects almost exclusively the African American population, with a prevalence of about 3%-4%.3,9 The second most common mutation is T60A,which occurs predominantly in people of Irish descent.3 Not all patients who carry a TTR mutation will go on to have clinical signs and symptoms of this disease.

*Also known as variant ATTR.1

Wild-type ATTR-CM (wtATTR-CM)

wtATTR-CM is idiopathic and is not considered to be a hereditary disease.1,9

LEARN MORE ABOUT wtATTR-CM

Patient Considerations

Men
  • Ethnicity: predominantly white7,8
  • Mostly men7,8,10
  • Symptom onset typically over the age of 60 years11
  • Heart failure7,8,10
  • Cardiac arrhythmias,
    particularly atrial fibrillation3,7,8,10
  • History of bilateral carpal
    tunnel syndrome7,10,12

Prognosis

  • Median survival: ~3.5 years7,10,13

Hereditary ATTR-CM (hATTR-CM)

hATTR-CM occurs due to a mutation in the transthyretin (TTR) gene.1

LEARN MORE ABOUT hATTR-CM

Patient Considerations

men women
  • African American, African,
    or Afro-Caribbean descent (V122I)3,8
  • Irish descent (T60A)3
  • Men and women8
  • Symptom onset may occur as early as 50-60 years of age11,16
  • Heart failure8
  • Neurological symptoms
    (peripheral and autonomic)8
  • Gastrointestinal symptoms8
  • History of bilateral carpal
    tunnel syndrome8

Prognosis

  • Median survival: ~2 to 3 years3

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.

 

MECHANISM OF DISEASE

In ATTR-CM, TTR proteins with unstable structures misfold and aggregate into amyloid fibrils, which deposit in the heart and other organs.1,4

mechanism of disease
mechanism of disease

Illustrative representation.

Amyloid body of Evidence (ABE) Is Here  To show you some of the clues that should Raise your suspicion of ATTR-CM 

Meet ABE. Looking at this model, you can see some common ATTR deposition sites and how ATTR amyloidosis can lead to ATTR-CM.

CLICK TO EXPLORE ABE

hattr

Amyloid Body of Evidence (ABE) is an artistic representation.

ATTR, transthyretin amyloid fibril protein; ATTR-CM, transthyretin amyloid cardiomyopathy.

© 2021 Pfizer Inc. All rights reserved. September 2021 PP-R1D-USA-0850

EARLY, ACCURATE DIAGNOSIS OF ATTR-CM MAY BENEFIT PATIENT CARE AND LEAD TO IMPROVED OUTCOMES.6

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

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.

 

GET SUSPECT AND DETECT ATTR-CM UPDATES

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Explore Deposition Sites On Amyloid Body Of Evidence (ABE)

Each of the orange hotspots represents a different amyloid deposition site. Once clicked, you will see detailed information about the selected area.

CARDIAC DEPOSITION
NONCARDIAC DEPOSITION

ABE is an artistic representation and is not intended to visually demonstrate the precise quantity of amyloid deposition or how the disease might progress over time. Cardiac and noncardiac red flags in combination should raise suspicion of ATTR‑CM.1

References

  1. Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716.
EYE
EYE

As we move closer to examine ABE's eyes, you will notice the amyloid deposits. These deposits can lead to the development of dark floaters, abnormal blood vessel formation, pupillary abnormalities, and dry eye.1 TTR is synthesized in the choroid plexuses of the brain as well as in the retina.2

In a study of 54 patients with hATTR‑CM, 24% had ocular involvement. Vitreous involvement was the most common ocular manifestation, with women being affected more than men.2

Amyloid Body of Evidence (ABE) is an artistic representation.

hATTR‑CM, hereditary transthyretin amyloid cardiomyopathy; TTR, transthyretin.

References

  1. 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;21:198. doi:10.1186/s12875-020-01252-4
  2. Reynolds MM, Veverka KK, Gertz MA, et al. Ocular manifestations of familial transthyretin amyloidosis. Am J Ophthalmol. 2017;183:156-162. doi:10.1016/j.ajo.2017.09.001
Heart Icon
HEART

Here you can see the difference between a normal heart and a heart with ATTR amyloidosis.

Normal heart
ATTR amyloidosis heart

Illustrative representation.

About ATTR‑CM

ATTR amyloidosis is a disease in which unstable amyloid fibrils deposit in the heart and other organs.1 These deposits in the heart are what can cause ATTR‑CM—resulting in increased stiffness and heart failure.

It’s also important to know that patients with these deposits who remain untreated experience a progressive thickening of the cardiac walls.2

Cardiac clues of ATTR‑CM:

  • HFpEF or other cardiac conditions, such as severe AS* and arrhythmias, in patients typically over the age of 603-5
  • In advanced cardiac amyloidosis, patients may become intolerant to several traditional heart failure therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers6
  • Discordance between QRS voltage on ECG and an increase in LV wall thickness7,8
  • Echo showing increased LV wall thickness7

Tools like echo with strain analysis and ECG, along with advanced imaging techniques, can help identify clues on the diagnostic pathway. By becoming familiar with the characteristic signs of ATTR‑CM via echo imaging, you can better identify patients who may require further testing to make a diagnosis.9,10

RECOGNIZING THE DISEASE

By increasing your suspicion of ATTR‑CM, you can identify patients who may require further testing to make a diagnosis.9,10,12 Once ATTR‑CM is suspected, a diagnosis can be made noninvasively with:

  • Nuclear scintigraphy (planar and SPECT)
  • Testing to rule out AL amyloidosis11,13,14

Among older patients with HFpEF, ~7% to ~13% had wild-type ATTR‑CM deposits identified in the heart3,15†‡

If clinical suspicion for cardiac amyloidosis remains high despite a negative or inconclusive scintigraphy scan, consider an EMB with Congo red staining and apple-green birefringence—which can definitively confirm ATTR‑CM.11

Amyloid Body of Evidence (ABE) is an artistic representation.

*Notably those with a low-flow, low-gradient AS pattern.4

A prospective, cross-sectional, single-center study at a tertiary university hospital in Madrid, Spain. Included 120 patients ≥60 years of age (59% women, mean age: 82 ± 8 years) admitted for HFpEF, with LV ejection fraction ≥50% and LV hypertrophy ≥12 mm. 99mTC-DPD scintigraphy used to confirm ATTR‑CM.3

A prospective analysis in 108 patients (61% women, age range: 57-74 years) seen at the Johns Hopkins University HFpEF Clinic who underwent endomyocardial biopsy to evaluate myocardial tissue histopathology.15

99mTc-DPD, 99mtechnetium-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid; AL, immunoglobulin light chain amyloid fibril protein; AS, aortic stenosis; ECG, electrocardiography; echo, echocardiography; EMB, endomyocardial biopsy; HFpEF, heart failure with preserved ejection fraction; LV, left ventricular; SPECT, single-photon emission computed tomography.

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. Quarta CC, Kruger JL, Falk RH. Cardiac amyloidosis. Circulation. 2012;126(12):e178-e182. doi:10.1161/CIRCULATIONAHA.111.069195
  3. 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.
  4. Castaño A, Narotsky D, 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.
  5. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891.
  6. 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.
  7. 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.
  8. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13.
  9. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003.
  10. 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.
  11. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of imaging [published online ahead of print August 29, 2019]. J Nucl Cardiol. doi:10.1007/s12350-019-01760-6
  12. 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.
  13. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412.
  14. Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. 99mTc-Pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidosis. Circ Cardiovasc Imaging. 2013;6(2):195-201.
  15. Hahn VS, Yanek LR, Vaishnav J, et al. Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. JACC Heart Fail. 2020;8(9):712-724. doi:10.1016/j.jchf.2020.04.007
BICEPS TENDON
BICEPS TENDON

ABE’s arm is potentially at risk of a biceps tendon rupture that may result from TTR amyloid deposition in the biceps tendon, similar to carpal tunnel syndrome.1 Severe amyloid deposition may lead to the degeneration, rupture, and compression of surrounding tissues.2

While spontaneous biceps tendon rupture is a rare occurrence among adults aged 56 to 74 years, its presence in a patient with HFpEF should raise suspicion for wtATTR‑CM.1

A study found that spontaneous rupture of the distal biceps tendon was observed in 33% of patients with wtATTR‑CM.1

Amyloid Body of Evidence (ABE) is an artistic representation.

HFpEF, heart failure with preserved ejection fraction; TTR, transthyretin; wtATTR‑CM, wild-type transthyretin amyloid cardiomyopathy.

References

  1. 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.
  2. 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.
KIDNEY
KIDNEY

Research has shown that renal impairment and proteinuria are clinical features of ATTR amyloidosis. For most patients, renal amyloid deposition is known to involve early activity in the renal medulla. Glomerular and vascular involvement becomes more prominent in patients with urinary abnormalities.1

A 2015 evaluation of the Transthyretin Amyloid Outcome Survey revealed the presence of renal impairment in 15% of patients with wtATTR‑CM and 20% of patients with hATTR‑CM who had the V122I mutation.2

Amyloid Body of Evidence (ABE) is an artistic representation.

hATTR‑CM, hereditary transthyretin amyloid cardiomyopathy; wtATTR‑CM, wild-type transthyretin amyloid cardiomyopathy.

References

  1. Lobato L, Beirao 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. doi:10.1053/ajkd.1998.v31.pm9631837
  2. 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.
GI Tract
GI Tract

ABE has many of the most common symptoms of amyloid-related GI disturbances—including chronic diarrhea or diarrhea alternating with constipation, unintentional weight loss associated with early satiety, and a typical absence of abdominal pain.1

Patients with hATTR‑CM have been found to have greater amyloid deposition in the upper GI tract compared with the lower.2

In the Transthyretin Amyloid Outcome Survey, 59% of patients reported at least 1 GI symptom: unintentional weight loss occurred in 28.3%, early satiety in 25.1%, alternating diarrhea and constipation in 22.9%, and fecal incontinence in 5.6%.3

Unfortunately, these clues within the GI tract are often overlooked or dismissed. Because amyloid deposition generally occurs in the submucosal tissue, minimally invasive tests fail to identify it.2

Amyloid Body of Evidence (ABE) is an artistic representation.

GI, gastrointestinal; hATTR‑CM, hereditary transthyretin amyloid cardiomyopathy.

References

  1. 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;21:198. doi:10.1186/s12875-020-01252-4
  2. Obici L, Suhr OB. Diagnosis and treatment of gastrointestinal dysfunction in hereditary TTR amyloidosis. Clin Auton Res. 2019;29(Suppl 1):55-63. doi:10.1007/s10286-019-00628-6
  3. Wixner J, Mundayat R, Karayal ON, Anan I, Karling P, Suhr OB; on behalf of the THAOS investigators. THAOS: gastrointestinal manifestations of transthyretin amyloidosis – common complications of a rare disease. Orphanet J Rare Dis. 2014;9:61.
Lumbar Spine
Lumbar Spine

Lumbar spinal stenosis is a known clinical predictor of ATTR‑CM and may precede heart failure symptoms by several years.1,2 In ATTR amyloidosis, TTR amyloid deposition can lead to the narrowing of the lumbar spinal canal and compression of nerves in the lower limbs.2 Lumbar spinal stenosis may also be a frequent noncardiac manifestation of wtATTR‑CM.3

One study identified TTR amyloid deposits in the ligamentum flavum of specimens from 44.4% of patients with lumbar spinal stenosis.4

Amyloid Body of Evidence (ABE) is an artistic representation.

TTR, transthyretin; wtATTR‑CM, wild-type transthyretin amyloid cardiomyopathy.

References

  1. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891.
  2. 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.
  3. Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716.
  4. 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.
Peripheral Nerve
Peripheral Nerve

Recent studies have shown that patients with hATTR‑CM commonly show the signs and symptoms of polyneuropathy. As you can see, ABE has noticeable TTR amyloid deposits in the nerves. This can cause damage by mechanical compression, direct blood vessel invasion, and possibly through toxic effects of the amyloid fibrils.1

This mixed presentation underscores the importance of early and continued assessment of neuropathy and cardiomyopathy through a multidisciplinary approach.2,3

Amyloid Body of Evidence (ABE) is an artistic representation.

hATTR‑CM, hereditary transthyretin amyloid cardiomyopathy; TTR, transthyretin.

References

  1. Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733-748.
  2. 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(suppl 8):S9-S10.
  3. Garcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur J Heart Fail. 2021;10.1002/ejhf.2140. doi:10.1002/ejhf.2140
Soft Tissue
Soft Tissue

Using ABE’s knee as an example, we see how TTR amyloid can deposit in ligaments, tendons, articular cartilage, and soft tissue throughout the body. This can harden the synovium and joint capsule and directly cause symptoms of osteoarthritis or elicit a painful inflammatory response.1

A study found that total knee arthroplasty was performed in up to 17.9% of male patients aged 60 to 69 years and 17.1% of male patients aged 70 to 79 years with ATTR‑CM.1

Amyloid Body of Evidence (ABE) is an artistic representation.

TTR, transthyretin.

Reference

  1. 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
Carpal Tunnel
Carpal Tunnel

ABE has a history of bilateral carpal tunnel syndrome—often one of the early manifestations of ATTR‑CM. In ATTR‑CM,carpal tunnel syndrome is believed to be caused by TTR amyloid deposition infiltrating the tenosynovial tissue, causing compression of the median nerve.1,2

It’s important to remember that bilateral carpal tunnel syndrome is a common extracardiac manifestation of ATTR‑CM and may precede clinical heart failure symptoms by several years.3

Among patients with wtATTR‑CM, ~60% experienced carpal tunnel syndrome as many as 5 to 9 years before the wtATTR‑CM diagnosis.4

So, if you have an older patient with unresolved heart failure symptoms as well as bilateral carpal tunnel syndrome and a history of multiple surgeries, it should raise your suspicion.

Amyloid Body of Evidence (ABE) is an artistic representation.

TTR, transthyretin; wtATTR‑CM, wild-type transthyretin amyloid cardiomyopathy.

References

  1. 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.
  2. 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.
  3. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891.
  4. Stern LK, Kittleson MM. Updates in cardiac amyloidosis diagnosis and treatment. Curr Oncol Rep. 2021;23(4):47. doi:10.1007/s11912-021-01028-8