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Review
. 2021 Aug;8(4):2647-2659.
doi: 10.1002/ehf2.13473. Epub 2021 Jun 17.

Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm

Takayuki Inomata  1 , Nobuhiro Tahara  2 , Kazufumi Nakamura  3 , Jin Endo  4 , Mitsuharu Ueda  5 , Tomonori Ishii  6 , Yoshinobu Kitano  6 , Jun Koyama  7
Affiliations
Review

Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm

Takayuki Inomata et al. ESC Heart Fail. 2021 Aug.

Abstract

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is caused by the deposition of wild-type transthyretin (TTR) amyloid fibrils in the heart. The age at diagnosis of ATTRwt-CM is reported to be approximately 70-80 years, and patients commonly present with non-disease-specific cardiac abnormalities, such as heart failure with preserved ejection fraction and diastolic dysfunction. The disease can be fatal if left untreated, with an approximate survival of 3-5 years from diagnosis. An oral TTR stabilizer, tafamidis, has enabled early intervention for the treatment of ATTRwt-CM. However, awareness of ATTRwt-CM remains low, and misdiagnosis and a delay in diagnosis are common. This review discusses the epidemiology, characteristics, treatment strategy, and red-flag symptoms and signs of ATTRwt-CM based on the published literature, as well as recent advances in diagnostic modalities that enable early and accurate diagnosis of the disease. We also discuss an algorithm for early and accurate diagnosis of ATTRwt-CM in daily clinical practice. In our diagnostic algorithm, a suspected diagnosis of ATTRwt-CM should be triggered by unexplained left ventricular hypertrophy (LVH), which is LVH that cannot be explained by an increased afterload due to hypertension or valvular disease. In addition, heart failure symptoms, laboratory test results (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, or high-sensitivity troponin I), electrocardiogram and imaging (echocardiogram or cardiac magnetic resonance) data, age (≥60 years), and medical history suggestive of ATTRwt-CM (e.g. carpal tunnel syndrome) should be examined. Detailed examinations using bone scintigraphy and monoclonal protein detection tests followed by tissue biopsy, amyloid typing, and TTR genetic testing are warranted for a definite diagnosis of ATTRwt-CM.

Keywords: ATTRwt-CM; Biopsy; Carpal tunnel syndrome; HFpEF; Scintigraphy; Tafamidis.

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Conflict of interest statement

Takayuki Inomata has received consulting fees or honoraria from Daiichi‐Sankyo Co., Japan Medtronics Co., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Pfizer Inc., Bristol‐Myers Squibb, and Boehringer Ingelheim GmbH. M.U. has received consulting fees or honoraria, support for travel to meetings, and administrative support for writing assistance, medicines, or equipment from Pfizer Inc. for the submitted work and reports financial relationships outside of the submitted work with Pfizer Inc. and Alnylam Pharmaceuticals Inc. Tomonori Ishii and Y.K. are full‐time employees of Pfizer Pharmaceuticals K.K. J.K. has received consulting fees or honoraria and support for travel to meetings from Pfizer Inc. N.T., K.N., and J.E. report no conflicts of interest.

Figures

Figure 1
Figure 1
Sequential diagnostic algorithm for ATTRwt‐CM. 99mTc‐PYP, 99mTechnetium‐pyrophosphate; ATTRv‐CM, variant transthyretin amyloid cardiomyopathy; ATTRwt‐CM, wild‐type transthyretin amyloid cardiomyopathy; CMR, cardiac magnetic resonance; CTS, carpal tunnel syndrome; ECG, electrocardiogram; FLC, free light chain; hs‐TnI, high‐sensitivity troponin I; hs‐TnT, high‐sensitivity troponin T; LVH, left ventricular hypertrophy; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; TTR, transthyretin.
Figure 2
Figure 2
Representative ECG image of a patient with ATTRwt‐CM. ECG showing QS pattern in the right pre‐cordial leads, left atrial loading, and cardiac conduction system disorder, including first‐degree atrioventricular block and left anterior fascicular block. Low voltage in limb leads on ECG may be less common at an early stage of ATTRwt‐CM. ATTRwt‐CM, wild‐type transthyretin amyloid cardiomyopathy; ECG, electrocardiogram.
Figure 3
Figure 3
Representative TTE image of a patient with ATTRwt‐CM (A–D). TTE 2D images show asymmetrical LV hypertrophy with granular sparkling appearance, valve thickening, interatrial septum, and right ventricular wall (arrow heads). Left atrium is enlarged despite sinus rhythm, indicating LV diastolic dysfunction. (E, F) Transmitral flow velocity pattern and LV tissue Doppler imaging show severe LV diastolic dysfunction. (G) 2D speckle‐tracking imaging reveals reduced longitudinal strain at basal and mid‐ventricular wall segments, known as the relative apical sparing pattern. (A) Parasternal long‐axis view, (B) mitral valve level, (C) atrioventricular level in parasternal short‐axis view, and (D) apical four‐chamber view. 2D, two‐dimensional; ATTRwt‐CM, wild‐type transthyretin amyloid cardiomyopathy; LV, left ventricular; TTE, transthoracic echocardiography.
Figure 4
Figure 4
Representative CMR image of a patient with ATTRwt‐CM in (A) short‐axis view and (B) four‐chamber view showing a characteristic pattern of global sub‐endocardial LGE, which also can be located in the atrial wall and right ventricle (arrows). ATTRwt‐CM, wild‐type transthyretin amyloid cardiomyopathy; CMR, cardiac magnetic resonance; LGE, late gadolinium enhancement.
Figure 5
Figure 5
Representative 99mTc‐PYP scintigraphy image of a patient with ATTRwt‐CM. Planar images of (A) anterior and (B) LAO views. (C) SPECT image of axial view. Myocardial uptake of 99mTc‐PYP is greater than bone uptake (Grade 3). 99mTc‐PYP, 99mTechnetium‐pyrophosphate; ATTRwt‐CM, wild‐type transthyretin amyloid cardiomyopathy; LAO, left anterior oblique; SPECT, single‐photon emission computed tomography.
See this image and copyright information in PMC

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