Two types of amyloid commonly infiltrate the myocardium—immunoglobulin light chain (AL or primary systemic) amyloid and transthyretin (TTR) amyloid. Transthyretin-related amyloidoses (ATTR) may be either hereditary (caused by autosomal dominant mutations in the TTR gene) or acquired (due to misaggregation of wild-type transthyretin). ATTR amyloidosis is an increasingly common cause of HFpEF and must be excluded in patients suspected of HF [
63,
64]. The amyloid is deposited in the myocardium and/or peripheral nervous system [
65]. The most common cardiac symptoms are dyspnea, angina, edema, and syncope [
66]. Non-cardiac manifestations include peripheral neuropathy, characterized by symptoms of neuropathic pain, numbness, and loss of muscle strength in the lower extremities. Gastrointestinal symptoms such as diarrhea and weight loss result as a consequence of autonomic neuropathy or autonomic nerve dysfunction of unknown etiology [
67,
68]. Other autonomic manifestations include erectile dysfunction, orthostatic hypotension, and neurogenic bladder [
69]. In addition, symptoms such as lumbar spinal stenosis may appear [
70,
71]. Distal biceps tendon spontaneous rupture is also common in patients with transthyretin cardiac amyloidosis [
72]. Ando et al. have also reported vitreous body inclusions of the cotton wool type, which are pathognomonic for ATTR amyloidosis [
69]. Carpal tunnel syndrome (CTS) is an early presenting sign of disease, preceding the onset of HF by up to 5–9 years [
73]. The prevalence of ATTR amyloidosis among patients with CTS is 7–8%, compared to 4–5% in the general population [
74,
75]. CTS manifests as pain and sensory disturbances in the lateral distribution of the hand, as well as hand weakness observed in cases of severe focal neuropathy [
76]. Biopsy and histopathologic analysis used to be required to identify amyloidosis. Congo red or Direct Fast Scarlet 4BS staining binds to amyloid fibrils and characteristic apple-green birefringence under polarized light microscopy is noted. However, imaging techniques as well as genetic testing are becoming increasingly important [
77‐
79]. Echocardiography and cardiac magnetic resonance may reveal features suggestive of amyloidosis, such as thickened LV wall, atrial septum and valves, small LV cavity size, biatrial enlargement, elevated RV systolic pressure, granular sparkling appearance of the myocardial wall, pericardial effusion, restrictive filling pattern, and reduced ventricular strain with relative apical sparing pattern. However, it is not sufficient for the diagnosis [
80‐
83]. Nuclear imaging techniques employing technetium-99 (
99mTc) labeled diphosphonopropanodicarboxylic acid (
99mTc-DPD), pyrophosphate (
99mTc-PYP), or methylenediphosphonic acid (
99mTc-MDP), once used as a bone scintigraphy, provide a novel, non-invasive diagnostic approach with relatively high sensitivity (> 90%) and specificity (86%) [
84,
85]. Intense uptake of
99mTc-DPD in the myocardium with lower or absent uptake in the bones suggests ATTR amyloidosis. Positive bone scintigraphy in patients without monoclonal gammopathy characterizes 100% specificity [
86]. It enables to establish the diagnosis without the need of histology [
84].