Clinical recommendations to diagnose and monitor patients with transthyretin amyloid cardiomyopathy in Asia

Abstract Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a debilitating and life‐threatening condition with a heterogeneous clinical presentation. Recent guidelines from the United States and Europe have been published to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies for patients with ATTR‐CM. These guidelines highlight the importance of an early diagnosis to optimize therapeutic outcomes, specifying the use of tests and imaging techniques to allow accurate, noninvasive diagnosis of ATTR‐CM. However, as regional practice variations across Asia may limit access to healthcare, availability of specific tests, and expertise in assessing diagnostic images, there is an ongoing need to provide an Asian perspective on these clinical guidelines. This review article provides practical recommendations for the diagnosis and monitoring of patients with ATTR‐CM in Asia, highlighting the need for additional guidelines to support a broad and diverse population, consider differing healthcare systems and diagnostic testing availability, and provide a flexible yet robust algorithm.


| INTRODUCTION
Amyloidosis is a debilitating systemic disease characterized by the extracellular deposition of insoluble misfolded amyloid proteins in one or more organs. 1,2 Cardiac amyloidosis, an under-recognized cause of heart failure (HF), leads to restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium and is the major contributor to poor prognosis in patients with systemic amyloidosis. [2][3][4] While more than 30 proteins can form the amyloid fibrils responsible for cardiac amyloidosis, monoclonal immunoglobulin light-chain amyloid (AL) and transthyretin amyloid (ATTR) are the two main amyloid types that infiltrate the heart. 2 Of note, ATTR can be found in patients with (hereditary type) or without (wild type) genetic defects.
While transthyretin amyloid cardiomyopathy (ATTR-CM) has historically been considered rare, an estimation of "real-life" prevalence remains a challenge because it is frequently under-recognized by clinicians. 3 In addition, ATTR-CM leads to reduced quality of life and death. 5 Following a diagnosis of ATTR-CM in untreated patients, median survival remains poor. [6][7][8] Guidelines from the American Heart Association (AHA) and European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases have recently been published to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies for patients with ATTR-CM. 3,9 Of note, early identification of affected individuals has been highlighted as being a critical factor in the optimization of therapeutic outcomes. 3 Guidelines from the Japanese Circulation Society Joint Working Group on the diagnosis and management of cardiac amyloidosis were published in 2020, with a simple staging system combining high-sensitivity cardiac troponin T, brain natriuretic peptide (BNP), and estimated glomerular filtration rate, more recently reported to be useful in predicting prognosis in Japanese patients with wild-type ATTR-CM. 10,11 The Taiwan Society of Cardiology and the Society of Nuclear Medicine of the Republic of China support the application of technetium-99m pyrophosphate ([99m]Tc-PYP) scintigraphy in the diagnosis of ATTR-CM. 12 However, similar guidelines and recommendations are not available for other Asian countries.
Cardiac amyloidosis, including ATTR-CM, is not widely recognized in Asian scientific literature suggesting that it may be underdiagnosed. 1,[13][14][15][16] A Japanese study has revealed an increasing trend in mortality associated with amyloidosis, and in particular a marked increase in mortality among men over the past 6 years. 17 Moreover, while the AHA guidelines detail the use of readily available tests and imaging techniques to allow accurate, noninvasive diagnosis of ATTR-CM (without confirmatory endomyocardial biopsies), regional practice variations across Asia may limit access to healthcare, availability of specific tests, and expertise in assessing diagnostic images. Consequently, the overall patient pathway may also vary between different healthcare systems.
This manuscript is primarily based on a discussion at an Expert Panel Meeting titled 'Clinical recommendations to diagnose/monitor patients with ATTR-CM in Asia', held virtually on March 26, 2021.

| SUSPECTING ATTR-CM
Given the nonspecific presenting symptoms of cardiac amyloidosis, diagnosis relies on a high index of clinical suspicion. 3,9,18 "Red flags" refer to signs and symptoms of cardiac amyloidosis that support a high degree of suspicion, most of which can be identified from an initial physical examination and assessment of patient history, and which should prompt screening. A summary of possible red flags for cardiac amyloidosis is shown in Table 1. The presence of any of these in a patient should result in referral to specialized medical centers for further diagnostic workup by a cardiologist and/or neurologist.
Neurological red flags for ATTR-CM include sensorimotor polyneuropathy (paresthesia and weakness), autonomic dysfunction (alternating diarrhea/constipation; orthostatic hypotension), and a family history of polyneuropathy, while orthopedic red flags include carpal tunnel syndrome, lumbar spinal stenosis, rupture of biceps tendon, and muscle weakness/sarcopenia. Table 2 14,20,21 ; clinical experience suggests that these differences in presenting pathologies are also found in different populations of Asian patients. [22][23][24][25] Concomitant ATTR amyloidosis and severe aortic stenosis has been reported to be a relatively common finding in the elderly Indian population. 26 For hereditary ATTR in the Asian population, Ala97Ser (p.A97S) appears to be the most commonly identified mutation 23 Panel recommendations for suspecting ATTR-CM are shown in Table 3.
The varying incidence of ATTR-CM by gender across Asian countries suggests patient gender is not a suitable red flag. However, there have been reports of men having onset of ATTR at an earlier age compared with women. 15 37 and clinical experience suggests ≥40 years in Japan. Limited data currently available on patient age in wild-type ATTR-CM suggest that age at diagnosis does not differ between female and male patients, although female patients tend to be older than male patients at the onset of cardiac symptoms. 35 Clinical experience suggests that wild-type ATTR-CM is typically seen in older Asian patients aged ≥70 years.

| The diagnostic pathway for ATTR-CM
Initial steps in the diagnostic pathway for ATTR-CM are the presence of red flags which suggest the presence of amyloidosis, followed by the initiation of the cardiac workup to assess the patient ECG and echocardiography (Table 4 and Figure 1). Echocardiography is widely available in Asia and is the initial imaging test of choice for diagnosis of cardiac amyloidosis. Infiltration of ventricular walls produces an appearance of hypertrophy with non-dilated or small ventricles.
Relative apical sparing of longitudinal strain is a key feature. 38 The presence of any irregularities in myocardial contraction fraction and/or ejection fraction (caused by deformation of myocardium/shortening of Panel recommendations for the diagnosis of ATTR-CM are shown in Table 3. • Low voltage in ECG, specifically with respect to LV wall thickness, remains an important red flag for patients in Asia with ATTR-CM (no available data to support a specific minimum value that should raise suspicion) • ECG voltage can vary from low to normal, and even to high, in Asian patients. 27,28 However, clinical experience suggests that a "relative" low voltage (compared with LV wall thickness) is possibly the most important sign of cardiac amyloidosis • Indices involving voltage strength/LV wall thickness/apical strain values may provide quantified measures which suggest the presence of amyloidosis (relative "apical sparing" in regional wall motion abnormality in strain image) • While AF is common in cardiac amyloidosis, the presence of arrhythmia is too broad to be a designated red flag. However, AF and high degree atrioventricular block in patients with unexplained LVH may increase suspicion of cardiac amyloidosis 29,30 • The presence of amyloid deposits identified during further testing in addition to LVH are suggestive of ATTR-CM • Aortic stenosis (particularly in those individuals with low-flow lowgradient aortic stenosis) in addition to RV thickening should also be considered as a red flag for ATTR-CM • Hypertension that resolves over time, and intolerance to angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or beta-blockers, are useful signs for suspecting ATTR-CM 31

Diagnosis of ATTR-CM
• While PYP scintigraphy is now quite widely available across most of Asia, scans may be positive even in AL amyloidosis 32 or in patients with hypertrophic cardiomyopathy, 27,33 highlighting the need to test for serum and urine ALs concurrently with 99mTc-PYP scintigraphy in patients with suspected ATTR-CM • AL amyloidosis and ATTR-CM can co-exist in the same patient, thus highlighting the need for parallel PYP scintigraphy and AL testing • Scintigraphy and AL testing are dependent upon operator expertise and correct interpretation can be inconclusive and return falsepositive results (see 3.2. Potential barriers limiting choice of confirmatory diagnostic procedure in Asia) • Ambiguous results from PYP scintigraphy and AL testing may require an endomyocardial biopsy and further subtyping, such as mass spectrometry, to confirm a diagnosis of ATTR-CM • While abdominal fat biopsy or aspiration is cost-effective and could be done before cardiac biopsy is considered, it lacks the sensitivity to exclude ATTR-CM 34  It is important to note that in some Asian countries, HF may be generally under-managed or simply "not on the healthcare agenda," with limited numbers of cardiologists in the public sector (compared T A B L E 4 Initial diagnostic approach for a patient in Asia suspected of having ATTR-CM. Content-based on clinical experience and available AHA/ESC guidelines. 3,9 Clinical approach Key findings suggestive of ATTR-CM

Red flags
Initial physical examination and patient history may support a suspicion of ATTR-CM and lead to subsequent referral to a cardiac specialist ECG Specific ECG features that suggest ATTR-CM include low/relative low voltage versus ventricular wall thickness Echocardiography Specific echocardiography findings that suggest ATTR-CM: • Appearance of hypertrophy with small/non-dilated ventricles: a value of 12 mm is deemed to be the appropriate cutoff value to determine abnormal LV wall thickness in patients with ATTR-CM* (although a value of ≥14 mm may be more specific in countries with limited resources) • HFpEF • Relative apical sparing of longitudinal strain (i.e., the ratio of apical longitudinal strain/average of mid and basal longitudinal strain >1.0), with high sensitivity (93%) and specificity (82%) 38 • Aortic stenosis (particularly in patients with low-flow, low-gradient severe aortic stenosis)

| GENETIC TESTING AND SUBSEQUENT MONITORING OF ATTR DISEASE
According to the AHA guidelines and ESC Position Statement, if ATTR-CM is identified, then genetic sequencing of the TTR gene is required to distinguish hereditary ATTR from wild-type ATTR disease. 3,9 Panel recommendations for the genetic testing of and screening for ATTR-CM are shown in Table 3.
Additional clinical evidence is needed to support a robust followup strategy for those asymptomatic patients with genetically positive ATTR-CM and their family members. Ueda et al. (2020) suggest that physical examination, biopsy, blood testing, renal function, blood pressure, ECG, echocardiography, and ophthalmologic assessment should be performed as a minimal level of examination annually, while in-depth assessment of these parameters, along with PYP myocardial scintigraphy, should be performed every 3-5 years. 49 In the absence of evidence and suitable biomarkers, clinical experience suggests that PYP screening or CMR, repeated at 3-5-year intervals, or at the onset of symptoms, maybe a suitable approach. This monitoring strategy is similar to that used for those patients with It is important for clinicians to understand that the onset of cardiomyopathy may be earlier than HF in general.

| ASSESSMENT OF TREATMENT RESPONSE AND DISEASE PROGRESSION
There remains no accepted definition of ATTR-CM progression or response to therapy. 3  While the timely diagnosis of cardiac amyloidosis is challenging, a high level of clinical suspicion using red flags and genetic testing, along with suitable additional testing options (dependent upon availability) are key for the early diagnosis of ATTR-CM. The emergence and increasing availability of newer noninvasive imaging techniques can be used to provide prognostic information, potentially obviating the need for endomyocardial biopsy in some patients.
The diagnostic pathway for patients in Asia with suspected ATTR-CM needs to acknowledge differences in country-specific/ regional healthcare systems, along with the availability of subsequent testing and sufficient operator expertise required to confirm a diagnosis. Of note, clinicians in Asia need to be mindful of equivocal and 'imperfect' scenarios in the ATTR-CM diagnostic journey, where testing/imaging results are ambiguous or may be confused by the presence of complex comorbidities. Importantly, there is an ongoing need for multi-institutional/country collaborations to optimize the diagnosis of ATTR-CM in a region such as Asia. While a patient registry for ATTR-CM has been created in Singapore, 54 there is an ongoing need for other Asian countries to do the same to allow patient data to be shared between them and support robust research