Prediagnostic Electrocardiographic Abnormalities in Transthyretin Amyloid Cardiomyopathy: A Longitudinal Observational Study

<b>Background:</b> Early diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) remains challenging. Although ECG and morphological abnormalities at diagnosis are well-described, their temporal evolution has not been systematically evaluated. This study characterized the prevalence and longitudinal progression of electrical and structural cardiac abnormalities preceding ATTR-CM diagnosis. <b>Methods:</b> We retrospectively analyzed patients with confirmed ATTR-CM evaluated at a specialist amyloidosis center between 2006 and 2023. Diagnosis was established by grade 2-3 myocardial uptake on 99mTc-DPD scintigraphy. Standard 12-lead ECGs and transthoracic echocardiograms were reviewed at diagnosis and at baseline, 3-5 years earlier. <b>Results:</b> Sixty-three patients (79% men; mean age 77 ± 8 years) were studied, including 33 (52%) with hereditary ATTR (ATTRv) and 30 (48%) with wild-type ATTR (ATTRwt). Overall, 95% had a NAC score ≤ 2, consistent with less advanced disease at diagnosis. During the prediagnostic phase, 79% of patients exhibited pathological ECGs. Non-specific ST-T abnormalities (40%), prolonged QTc (38%), left-axis deviation (35%), first-degree AV block (33%) and anterior infarction pattern (33%) were each observed in at least one-third of patients. From baseline to diagnosis, significant prolongation was observed in the PR interval (+26 ms), QRS duration (+11 ms), and QTc interval (+22 ms) (<i>p</i> < 0.001 for all), and a leftward shift observed in the electrical axis (-12.03°, <i>p</i> = 0.011). Low voltage was uncommon at both time points. Although interventricular septal thickness increased significantly (+3.42 mm; <i>p</i> < 0.001), left ventricular ejection fraction and dimensions were relatively stable. <b>Conclusions:</b> In this proof-of-concept study, electrical remodeling precedes functional changes and outperforms low voltages to raise clinical suspicion of ATTR-CM.