99m Technetium-pyrophosphate scintigraphy: a practical guide for early diagnosis of transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the cardiac deposition of insoluble amyloid fibrils formed by misfolded transthyretin proteins and is associated with various cardiac symptoms, such as progressive heart failure, conduction disturbance, and arrhythmia. The implementation of 99m technetium (99m Tc)-labelled bone radiotracer scintigraphy for diagnosing ATTR-CM has enabled accurate diagnosis of the disease with high sensitivity and specificity and positioned this diagnostic modality as an integral part of disease diagnostic algorithms. In 2020, 99m Tc-pyrophosphate scintigraphy received exceptional approval for Japanese national health insurance reimbursement as a diagnostic method of ATTR-CM. Nevertheless, the utility of 99m Tc-labelled bone radiotracer scintigraphy and the importance of an early diagnosis of suspected ATTR-CM using this technique have yet to be internalized as common practice by general cardiologists, and guidance on daily clinical scenarios to consider this technique for a diagnosis of suspected ATTR-CM is warranted. In this review, we discuss the utility of 99m Tc-labelled bone radiotracer scintigraphy for the early diagnosis of ATTR-CM based on published literature and the outcomes of an advisory board meeting. This review also discusses clinical scenarios that could support early diagnosis of suspected ATTR-CM as well as common pitfalls, correct implementation, and future perspectives of 99m Tc-labelled bone radiotracer scintigraphy in daily clinical practice. The clinical scenarios to consider 99m Tc-labelled bone radiotracer scintigraphy in daily practice may include, but are not limited to, patients with a family history of the hereditary type of disease; elderly patients (aged ≥60 years) with unexplained cardiac findings (e.g. cardiac hypertrophy associated with abnormalities on an electrocardiogram, heart failure with preserved ejection fraction associated with unexplained left ventricular hypertrophy, and heart failure with reduced ejection fraction associated with atrial fibrillation and left ventricular hypertrophy); and patients with cardiac hypertrophy associated with diastolic dysfunction, right ventricular/interatrial septum/valve thickness, left ventricular sparkling, or apical sparing. Cardiac hypertrophy and persistent elevation in cardiac troponin in elderly patients are also suggestive of ATTR-CM. 99m Tc-labelled bone radiotracer scintigraphy is also recommended in patients with characteristic cardiac magnetic resonance findings (e.g. diffuse subendocardial late gadolinium enhancement patterns, native T1 increase, and increase in extracellular volume) or patients with cardiac hypertrophy and bilateral carpal tunnel syndrome.

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

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.