Multimodal Validation and Disease Stage Dependency of ATTR Cardiomyopathy Red Flags in Patients With LV Thickening

INTRODUCTION: Timely diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) is critical to improving outcomes and remains challenging. Guidelines recommend assessing for red flags (RFs) to facilitate ATTR-CM detection, but their diagnostic validation remains incomplete. This study aimed to multidimensionally validate these RFs in patients with left ventricular thickening (LVT). METHODS: Prospective registry study including all patients with LVT and standardized workup at tertiary amyloidosis center. For validated RFs, "high-risk" (specificity for ATTR-CM>90%) and "low-risk" (false-negative rate<5%) findings were predefined. RESULTS: 425 patients (321 ATTR-CM,104 control group) were included. Heart failure (97%) and polyneuropathies (78%) were among most sensitive clinical findings, while bilateral carpal tunnel syndrome (bCTS) was more specific (80%) but less sensitive (45%). Diverse ECG changes were common, yet mostly unspecific. Marked elevations of NT-proBNP and troponin were most discriminative among non-imaging RFs (Youden's index[YI]:59%). Apical sparing (Apical-to-Basal-strain-ratio≥2.0) was the most effective, stage-independent echocardiographic parameter (YI62%), followed by biatrial enlargement, advanced diastolic dysfunction, and LVGLS impairment (YI48-55%). Normal ECG without conduction disorders history and normal levels of both NT-proBNP and hs-troponin-T constituted "low-risk" findings. Heart failure with concomitant bCTS, peripheral low voltage, right ventricular dysfunction, 5-5-5 sign, restrictive filling pattern and apical sparing with LVGLS impairment represented "high-risk" RFs. Contrary to most non-imaging RFs, most echocardiographic RFs showed association with advancing disease stage (p<0.05). All aforementioned RFs were associated with ATTR-CM independently of age, sex, and LVT-severity (p<0.05). CONCLUSIONS: ATTR-CM is frequently associated with validated RFs that differ in their diagnostic characteristics, which should be considered when evaluating for ATTR-CM.