About ATTR-CM

About ATTR-CM

Transthyretin amyloid cardiomyopathy (ATTR-CM)—a disease that may be present in patients with heart failure1-3
Transthyretin amyloid cardiomyopathy—a fatal, underdiagnosed cardiomyopathy caused by aggregated misfolded proteins, called amyloid fibrils, that accumulate in the myocardium
  • Subtypes of ATTR-CM1,2:
    • Wild-type ATTR (wtATTR)
    • Hereditary ATTR (hATTR}
    —In the United States, Val122lle and Thr60Ala are the most common mutations that typically manifest as cardiomyopathy symptoms4
  • Transthyretin amyloid cardiomyopathy is frequently misdiagnosed, and delayed diagnosis can lead to significant clinical consequences for patients4
  • Patients present with symptoms of heart failure and may also present with other manifestations, such as atrial fibrillation and carpal tunnel syndrome, often bilateral3,4
  • Once diagnosed, untreated patients have a median survival of ~2 to 3.5 years4
In 2 studies,
wtATTR DEPOSITS WERE IDENTIFIED IN THE HEARTS OF 13%-17% OF OLDER PATIENTS WITH HFpEF5,6
 
Study descriptions5,6
Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction
The study by González-López et al. was a prospective, cross-sectional, single-center study at a tertiary university hospital in Madrid, Spain, to determine the prevalence of wtATTR-CM among elderly patients admitted to the hospital due to HFpEF. The study prospectively screened all patients ≥60 years of age admitted for HFpEF. The study population included 120 HFpEF patients (59% women, mean age: 82±8 years) with LV ejection fraction ≥50% and LV hypertrophy ≥12 mm. All eligible patients were offered a DPD scintigraphy scan to confirm transthyretin amyloid cardiomyopathy.
Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction
The study by Mohammed et al. was a single-center study conducted at the Mayo Clinic to assess the frequency of left ventricular amyloid in HF patients with HFpEF. The study included 240 autopsied patients (109 patients with HFpEF, 57% women, age at death: 76±13 years) with an antemortem diagnosis of HFpEF without clinically apparent amyloid.
HF=heart failure; LV=left ventricular.

HFpEF=heart failure with preserved ejection fraction.

REFERENCES
1. 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.
2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213.
3. Narotsky DL, Castano 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.
4. 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.
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. 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.

Symptom presentation

Signs and symptoms that may present in patients with
ATTR-CM1-13
  • ATTR-CM is underdiagnosed or often misdiagnosed; therefore, a high index of clinical suspicion is important in diagnosing this fatal, progressive disease1
  • Transthyretin amyloidosis is a heterogeneous disorder with multiorgan involvement. Therefore, patients with ATTR-CM present with varied signs and symptoms which may include cardiac as well as noncardiac manifestations that may not typically be present in other cardiovascular diseases1
  • Please note, VYNDAMAX is not indicated to treat all of the below symptoms of ATTR-CM

REFERENCES
1. 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.
2. Reynolds M, Veverka K, Gertz M, et al. Ocular manifestations of familial transthyretin amyloidosis. Am J Ophthamol. 2017;183:156-162.
3. González-López E, López-Sainz A, Garcia-Pavia P. Diagnosis and treatment of transthyretin cardiac amyloidosis. Rev Esp Cardiol. 2017;70(11):991-1004.
4. Narotsky DL, Castano 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.
5. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003.
6. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018;28(1):10-21.
7. 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.
8. 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.
9. 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):54-63.
10. Rubin J, Alvarez J, Teruya S, et al. Hip and knee arthroplasty are common among patients with transthyretin cardiac amyloidosis, occurring years before cardiac amyloidosis: can we identify affected patients earlier? Amyloid.
2017;24(4):226-230.
11. Dang J, Abulizi M, Moktefi A, et al. Renal infarction and its consequences for renal function in patients with cardiac amyloidosis. Mayo Clin Proc. 2019. https://doi.org/10.1016/j.mayocp.2019.02.012
12. Gillmore JD, Damy T, Fontana M, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799-2806.
13. 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;63(2):161-172.

Clinical clues

Recognize some of the common clinical clues of ATTR-CM
  • ATTR-CM is underdiagnosed or often misdiagnosed; therefore, a high index of clinical suspicion is important in diagnosing this fatal, progressive disease1
  • Transthyretin amyloidosis is a heterogeneous disorder with multiorgan involvement. Therefore, patients with ATTR-CM present with varied signs and symptoms which may include cardiac as well as noncardiac manifestations that may not typically be present in other cardiovascular diseases1
  • Please note, VYNDAMAX is not indicated to treat all of the below symptoms of ATTR-CM
Cardiac1-7
  • HFpEF
  • Intolerance to standard HF therapies
  • Low voltage relative to LV mass
  • Echocardiography showing increased LV wall thickness
  • Aortic stenosis
  • Cardiac arrhythmias (ie, atrial fibrillation)
Noncardiac1,4,8,9
  • Carpal tunnel syndrome
  • Lumbar spinal stenosis
  • Gastrointestinal complaints
  • Peripheral and autonomic nervous system dysfunction

REFERENCES
1. 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.
2. Narotsky DL, Castano 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. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003.
4. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018;28(1):10-21.
5. 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.
6. 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):54-63.
7. Mints YY, Doros G, Berk JL, et al. Features of atrial fibrillation in wild‐type transthyretin cardiac amyloidosis: a systematic review and clinical experience. ESC Heart Fail.
2018;5(5):772-779.
8. 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.
9. 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;63(2):161-172.

Diagnosing ATTR-CM

ATTR-CM is a progressive disease—recognize the tools to support earlier diagnosis
Nuclear scintigraphy—a noninvasive approach1-4
  • 99mTechnetium-pyrophosphate (99mTc-PYP) is a widely available radioactive tracer that can be used as an adjunct to diagnosis for ATTR-CM, though it is not FDA-approved for this use*
  • A multicenter international study demonstrated 99% sensitivity for nuclear scintigraphy in diagnosing ATTR-CM (visual grade 1-3), and a separate analysis within the study demonstrated 100% specificity for visual grading 2 or 3 with concurrent testing to rule out AL
  • American Society of Nuclear Cardiology (ASNC) Practice Points highlight the importance of PYP cardiac imaging in diagnosing ATTR-CM noninvasively and thereby guide patient management
  • If clinical suspicion remains high for cardiac amyloidosis in spite of a negative or inconclusive 99mTc-PYP scan, biopsy should be considered

Endomyocardial biopsy (EMB)5
  • Requires histology with Congo red staining with apple-green birefringence to diagnose cardiac amyloidosis
  • To determine amyloid type, immunohistochemistry tests and/or mass spectrometry should be performed
  • Patients may experience diagnostic delay for a number of reasons, including risk of complications and the need for specialized centers and expertise

Genetic testing6
  • Following a diagnosis of ATTR-CM, genetic counseling and gene sequencing are recommended to determine if a patient has the hereditary form of the disease
*Please consult individual labeling for risks.
Multicenter study conducted to determine the diagnostic value of bone scintigraphy in ATTR-CM patients. Of 1217 evaluable patients, 374 underwent endomyocardial biopsy, and 843 were diagnosed with the presence and type or absence of amyloid on the basis of extracardiac histology combined with echocardiography with or without cardiac magnetic resonance imaging (CMR).1
Rule out of AL: testing for the presence of monoclonal protein via serum and urine immunofixation + serum free light chain assay.6

REFERENCES
1. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412.
2. Bokhari S, Morgenstern R, Weinberg R, et al. Standardization of 99mTechnetium pyrophosphate, imaging methodology to diagnose TTR cardiac amyloidosis. J Nucl Cardiol. 2018;25(1):181-190.
3. Bhambhvani P, Hage FG. Nuclear imaging of cardiac amyloidosis. "We've only just begun." J Nucl Cardiol. 2018;25(1):191-194.
4. American Society of Nuclear Cardiology (ASNC). ASNC cardiac amyloidosis practice points: 99mtechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. https://www.asnc.org/files/19110%20ASNC%20Amyloid%20Practice%20Points%20WEB(2).pdf. Published February 2016. Updated February 2019. Accessed June 5, 2019.
5. Narotsky DL, Castano 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.
6. 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.