ATTRwt Amyloidosis Symptoms

Cardiomyopathy (CM) is the hallmark of ATTRwt (ATTRwt-CM) [1,2]; symptoms are often vague and nonspecific, which may cause a delay in diagnosis or a misdiagnosis; patients commonly present with cardiac abnormalities, such as HFpEF and diastolic dysfunction, which are also characteristic of an elderly population
  • Heart involvement is seen in almost all symptomatic patients, presenting as progressive heart failure; conduction abnormalities and atrial fibrillation are also common [1]
  • Amyloid deposits in the heart make the heart wall stiffen and work inefficiently; eventually this leads to congestive HF with symptoms such as shortness of breath, leg swelling, fatigue, nausea, and an irregular heartbeat or palpitations [8]
    • Nonspecific symptoms may be mistaken for signs of aging, resulting in delayed diagnosis and treatment initiation [3,4]
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Notes: HF = heart failure; HFpEF = heart failure with preserved ejection fraction
Glossary:
 
  • Arrhythmia, heart beating too fast or too slow with an irregular rhythm​
  • Cardioembolic stroke, a type of stroke in which the heart pumps a blood clot or plaque debris to the brain, where it blocks blood supply and damages brain tissue​
Deep Dive
Amyloidosis associated with aging
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Compare ATTRv presentation
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ALXN: Acoramidis ​for the Treatment of ATTR-CM: Training Deck. November 22, 2021. 34_Acoradmidis Training Deck_22Nov21 FINAL. Citing: 
 
  1. Muchtar E, et al. J Intern Med. 2021;289:268-292.
  2. Koike H, Katsuno M. Neurol Ther. 2020;9:317-333. 
  3. Kittleson MM, et al. Circulation. 2020;142:e7-e22. Erratum in: Circulation. 2021;144:e11.
  4. Yamamato H, Yokochi T. ESC Heart Fail. 2019;6:1128-1139.
  5. Cuddy SAM, Faulk RH. Can J Cardiol. 2020;36:396-407.
  6. Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
  7. Emdin M, et al. Eur Heart J. 2019;40:3699-3706.     
  8. Amyloidosis Research Consortium. Wild-type Amyloidosis. https://arci.org/about-amyloidosis-old/wild-type-amyloidosis/. Accessed December 1, 2021.
  9. Inomata T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-!ag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.​

ATTRwt-CM Symptoms Among Patients in Japan

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Heart failure (HF) is consistently reported as the most common initial symptom of ATTRwt-CM and contributes substantially to disease burden; carpal tunnel syndrome (CTS) is also a frequently reported early symptom [1-2]
Patients with ATTRwt-CM at Kumamoto University Hospital in Japan [1]
(N=129 consecutive patients, 2002-2019)
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HF was both the most common initial symptom reported (49%) and the most common symptom leading to diagnosis (61%)
Initial Symptoms of ATTRwt in a National Survey [2]
(N=51* patients, 2012-2014)
HF was also the most common initial symptom and clinical manifestation in a nationwide survey of providers at hospitals throughout Japan, which identified data from 51 ATTRwt patients at 10 institutions; at the time of diagnosis:
  • •30/51 (59%) of patients had cardiac conduction problems and arrhythmias reported
  • •Mean±SD left ventricular ejection fraction (LVEF) at diagnosis was reported as 49.8 ±13.8% among 39/51 patients; cardiac MRI was reported in only 5 patients
  • •25/51 (49%) of patients had renal dysfunction reported
* While this study drew from providers across Japan, key limitations are the low response rate and small sample size
  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing: Yamada T, Takashio S, Arima Y, Nishi M, Morioka M, Hirakawa K, et al. Clinical characteristics and natural history of wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829-37.
  2. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing: Sekijima Y, Yazaki M, Ueda M, Koike H, Yamada M, Ando Y. First nationwide survey on systemic wild-type ATTR amyloidosis in Japan. Amyloid. 2018;25(1):8-10.

 

Symptoms and Impact

Because ATTR can affect multiple organ systems, it can display a variety of clinical and symptomatic characteristics—those with ATTR-CM suffer from chronic and progressive heart failure as the typical pathologic manifestation but other systems may be affected
  • ATTR patient and family experience focus groups were convened in collaboration with 2 patient organizations*
  • Participants were asked to identify the symptoms with the greatest effect on their physical health and on their QoL (defined as the ability to participate in the tasks and activities that were important to them)
ATTR-CM & ATTR-PN Reported Symptoms by Organ System
ATTR-CM group: N=10 (7 patients**, 3 caregivers)
ATTR-PN group: N=15 (10 patients, 5 caregivers
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  • ATTR-CM participants reported several directly related to the heart, including shortness of breath, A-fib, and arrhythmias
  • Intolerance to activity, inability to exercise, insomnia, and fatigue were most troubling for ATTR-CM patients—many were life-long sports / exercise devotees [1]
* The Northern California Amyloidosis Support Group (an Amyloidosis Research Consortium affiliate) and the Alianza Argentina de Pacientes; ** note: the ATTR-CM group included 4 ATTRwt-CM patients and 3 ATTRv-CM 
Notes: Study Methods: In collaboration with two patient organizations: the Northern California Amyloidosis Support Group (affiliated with the Amyloidosis Research Consortium), and the Alianza Argentina de Pacientes, researchers convened a focus group for ATTR-CM patients and family members in San Francisco, California, and ATTR-PN patients and their family members in Buenos Aires, Argentina. The ATTR- CM group included the following: 4 male patients with wild-type ATTR cardiomyopathy (ATTRwt-CM), 2 male patients and 1 female patient with hereditary (mutant) ATTR cardiomyopathy (ATTRm-CM), and the partners of three of the patients in the group. The ATTR-PN focus group included 10 patients and 5 family members. 
  1. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 16, 70 (2021). https://doi.org/10.1186/s13023-021-01706-7.

Overlap with CTS and Other Degenerative Orthopedic Conditions

Evidence also suggests ATTRwt is underdiagnosed as a cause of degenerative orthopedic conditions such as bilateral CTS, lumbar spinal stenosis, and biceps tendon rupture
Bilateral CTS is one of the earliest symptoms that appears in patients with ATTRwt, usually before cardiac symptoms when patients are in their 50s to 70s [1]
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A perfect “O” sign for evaluation of CTS; the patient is unable to make a neat circle with the thumb and index finger [1]
  • 40-50% of ATTRwt patients have a history of CTS [1]
    • However, a recent DGK position paper suggests it may be as high as 70% in certain areas [5]
    • Per a Netherlands report, CTS prevalence in the general population was higher in women (5.8% vs. 0.6%); in contrast, CTS was observed in 23 of 51 (45%) ATTRwt-CM patients in a Japanese nationwide survey with 82% male patients3
    • Prior studies also suggest CTS is more frequently observed in Japanese patients with ATTRwt-CM than in patients in Western countries (24–54% in Japan vs. 6–33% in Western countries) [3]
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  • Mean length of time from CTS onset to ATTRwt diagnosis is 6.9 years [1]
    • Suggesting that, unlike AL-A, ATTRwt develops over the long term [1]
Notes: AL-A = Amyloid light-chain amyloidosis; CTS = carpal tunnel syndrome; DGK = German Cardiac Society
Other comorbidities reported in ATTR amyloidosis include spinal canal stenosis (14–22%), cubital tunnel syndrome, rotator cuff tear, biceps tendon rupture, and quadriceps tendon rupture [1]
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  • In patients undergoing surgery for degenerative lumbar spinal stenosis, almost all had amyloid in surgical specimens of the ligamentum flavum, and transthyretin (TTR) was identified immunohistochemically as the causative protein in 1/3 of resected tissues [4]
  • Among patients with ATTRwt-CA, biceps tendon rupture has been observed in 33%, occurring in the dominant arm in 95% and bilaterally in 24% of patients [4]
  1. Kitaoka H, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020. 84(9), 1610-1671. https://doi.org/10.1253/circj.CJ-20-0110.
  2. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol 2018; 72: 2040 – 2050. PMID: 30336828.
  3. Inomata, T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.
  4. Adam Castaño A, Maurer S. Cardiac Amyloidosis in Heart Failure: a Companion to Braunwald's Heart Disease (Fourth Edition), 2020. See also  Thoracic Key: Cardiac Amyloidosis. https://thoracickey.com/cardiac-amyloidosis-4/. Accessed November 3, 2021.
  5. Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3
  6. Image: Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/carpal-tunnel-release

Comorbidities in Japanese Retrospective Study

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Using a broad definition*, a retrospective study of the Japan MDV database from January 2010 to September 2018, estimated ~3,992 patients were diagnosed with ATTRwt and the following comorbidities
Comorbidities Occurring in > 15% of Patients, Jan. 2010 to Sept. 2018
(Percentage of N=3,992 ATTRwt Patients*)
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Study Methodology Notes
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  • ATTR-CM definitions were based on ≥1 ICD-10 code(s) and no specific ATTR code; less conservative vs. other studies requiring ≥2 codes, thus it may include patients not ultimately diagnosed with ATTR-CM
  • Broad includes familial amyloidosis, secondary amyloidosis, amyloid CM, generalized amyloidosis, CA, senile amyloidosis, senile TTR amyloidosis, amyloidosis, primary amyloidosis, and primary systemic amyloidosis
  • Alexion interprets the representativeness of these results with caution, given the lack of a specific ATTR code, no information on tissue biopsy and demographics, and clinical characteristics that were inconsistent with prior information on ATTRwt patients
Notes: A-fib = atrial fibrillation; CA = cardiac amyloidosis; CKD = chronic kidney disease; CM = cardiomyopathy; HF = heart failure; MDV = Medical Data Vision
  1. Winburn I, Ishii T, Sumikawa T, Togo K, Yasunaga H. Estimating the Prevalence of Transthyretin Amyloid Cardiomyopathy in a Large In-Hospital Database in Japan. Cardiol Ther. 2019;8(2):297-316.

Conditions that Confound an ATTRwt Diagnosis

The lack of specificity of most symptoms of ATTRwt often leads patients to mistake them for signs of aging [1-3]; furthermore, despite escalating awareness on ATTR-CM, diagnosis is often delayed due to misdiagnosis or incorrect attribution of the multiplicity of symptoms to more common medical conditions [11]
Some diseases that complicate differential diagnosis are:
Cardiac diseases [2,3]
  • The most frequent misdiagnoses include
    • Hypertensive cardiomyopathy
    • Hypertrophic cardiomyopathy
    • Ischemic heart disease
    • HFpEF
    • Aortic stenosis (AS)
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ATTR is likely an underdiagnosed cause of common CV conditions in older adults, e.g.:
  • Among patients with HFpEF over age 75 at autopsy, 32% have amyloid deposits[13]
    • 13% of hospitalized HFpEF patients who underwent nuclear scintigraphy had ATTRwt-CA[13]
  • Similarly, nuclear scintigraphy in patients undergoing TAVR for severe calcific AS revealed a cardiac ATTR prevalence of 16% overall and 22% among men[10],[13]
AL amyloidosis [3,7,8]
  • Patients with AL amyloidosis have several of the same cardiomyopathies seen in patients with cardiac ATTR amyloidosis
Other diseases [7,8,12]
  • Diabetes mellitus (diabetic neuropathy)
  • Chronic alcoholism
  • Other amyloidosis
  • Fabry’s disease, anxiety, irritable bowel syndrome, other cardiomyopathies, ocular disorders, and vitamin B12 deficiency
  • CIDP, inherited sensory and autonomic polyneuropathy, idiopathic axonal polyneuropathy, leprous neuropathy
  • Monoclonal gammopathy–associated neuropathy
Moreover, differentiation from MGUS, a pre-malignant plasma cell disorder that may progress to primary amyloidosis, is also essential in patients developing CA [14]
  • In a US retrospective analysis (n=140 ATTRwt-CM patients), 39% had MGUS [14]
  • A moderate increase in circulating FLCs is not necessarily pathological because up to 5% of adults aged 50(+) years and up to 40% of patients with ATTRwt-CM have MGUS [11,14]
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Notes: AL = Amyloid light-chain; CA = cardiac amyloidosis; CIDP = chronic inflammatory demyelinating polyneuropathy; CV = cardiovascular; FLC = free light chain; HFpEF = heart failure with preserved ejection fraction; MGUS = monoclonal gammopathy of undetermined significance; TAVR= transcatheter aortic valve replacement
Glossary:
 
  • Chronic inflammatory demyelinating polyneuropathy, a rare disorder that affects nerves and causes numbness, pain, and weakness in the arms and legs ​
  • Idiopathic axonal polyneuropathy, a condition in which the axons of nerves are damaged without any known cause​
  • Ischemic, a condition in which there is inadequate blood supply to a specific area due to blockage of blood vessels​
  • QoL, quality of life​
  • Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which an abnormal protein — known as monoclonal protein or M protein — is in the blood. This abnormal protein is formed within the bone marrow.
ALXN: Acoramidis ​for the Treatment of ATTR-CM: Training Deck. November 22, 2021. 34_Acoradmidis Training Deck_22Nov21 FINAL. Citing:
 
  1. 1 Cuddy SAM, Faulk RH. Can J Cardiol. 2020;36:396-407.
  2. Yamamato H, Yokochi T. ESC Heart Fail. 2019;6:1128-1139.
  3. Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
  4. Lane T, et al. Circulation. 2019;140:16-26.
  5. Gertz MA. Am J Manag Care. 2017;23(7 suppl):S107-S112.
  6. Muchtar E, et al. J Intern Med. 2021;289:268-292.
  7. Adams D, et al. J Neurol. 2021;268:2109-2122.
  8. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 
  9. Garcia-Pavia, P., Bengel, F., Brito, D., Damy, T., Duca, F., Dorbala, S., Nativi-Nicolau, J., Obici, L., Rapezzi, C., Sekijima, Y. and Elliott, P.M. (2021), Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J Heart Fail, 23: 895-905. https://doi.org/10.1002/ejhf.2198.
  10. Fontana, Marianna. Jul. 9, 2020. Cardiac amyloidosis: Clinical manifestations and diagnosis. UptoDate. https://www.uptodate.com/contents/cardiac-amyloidosis-clinical-manifestations-and-diagnosis?search=ATTR&source=search_result&selectedTitle=1~30&usage_type=default&display_rank=1.
  11. Rintell, D., Heath, D., Braga Mendendez, F. et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis 16, 70 (2021). https://doi.org/10.1186/s13023-021-01706-7.
  12. https://bmcfampract.biomedcentral.com/articles/10.1186/s12875-020-01252-4/tables/2.
  13. Adam Castaño A, Maurer S. Cardiac Amyloidosis in Heart Failure: a Companion to Braunwald's Heart Disease (Fourth Edition), 2020. See also  Thoracic Key: Cardiac Amyloidosis. https://thoracickey.com/cardiac-amyloidosis-4/. Accessed November 3, 2021.
  14. Inomata, T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.
  15. Balciunaite G, et al. Transthyretin cardiac amyloidosis in aortic stenosis: Prevalence, diagnostic challenges, and clinical implications. Hellenic J Cardiol. 2020. DOI: https://doi.org/10.1016/j.hjc.2019.10.004.