Wild Type Transthyretin Amyloid Cardiomyopathy Hidden Under Ablation‐Refractory Atrial Arrhythmias and the Potential Contribution of Tafamidis in Rhythm Control

An octogenarian man with a history of multiple catheter ablation failures for atrial fibrillation and tachycardia was diagnosed with transthyretin amyloid cardiomyopathy. After 1 year of tafamidis therapy, the patient experienced spontaneous restoration of sinus rhythm, and follow-up image of 99mTc-pyrophosphate scintigraphy revealed a marked decrease of tracer accumulation. The involvement of amyloid cardiomyopathy in atrial arrhythmias is being increasingly reported, with a recent study reporting a striking 7% atrial biopsy positive among patients undergoing catheter ablation for atrial fibrillation (AF) 1, 2. Tafamidis, a transthyretin stabilizer, is a disease-modifying drug for transthyretin amyloid cardiomyopathy (ATTR-CM). It has been shown to delay disease progression, reduce hospitalization, and improve survival 3. However, its potential effects on arrhythmia burden remain largely unexplored. At our institution, we gave diagnosis to wild type ATTR-CM in 27 patients between 2021 to 2024 based on pathology and/or 99mTc-Pyrophosphate (PYP) scintigraphy, of which 12 (44.4%) patients were complicated with AF or atrial tachycardia (AT) at the time of diagnosis (Figure 1). Among them, 4 (14.8%) patients had a history of catheter ablation prior to ATTR-CM diagnosis, and all patients had suffered recurrence at the time of diagnosis. Importantly, we encountered a case of ATTR-CM in which spontaneous restoration of sinus rhythm from long-standing ablation-refractory AT was observed after prescribing tafamidis. An 80-year-old man with prostate cancer underwent 99mTc-PYP scintigraphy during routine evaluation for osseous metastasis. The scan unexpectedly revealed tracer accumulation around the heart, raising suspicion of cardiac amyloidosis (Figure 2A). He was referred to our department for further evaluation. The patient had a long history of atrial arrhythmia. At age 67, he underwent pulmonary vein isolation (PVI) for AF. Recurrence with AT prompted a second procedure at age 72, during which roof and bottom lines were added. Despite these interventions, AT relapsed, and at age 76, a third ablation targeting the mitral isthmus was performed for mitral isthmus dependent flutter. Nonetheless, arrhythmia recurred shortly thereafter and persisted. Pharmacological rhythm control with flecainide 50 mg twice daily was tested but could not achieve sinus rhythm. Given the repeated failures along with minimal symptoms, rhythm-control strategy was abandoned, and the patient had been referred to his family clinician with dabigatran 110 mg twice daily (Figure 3A–C). At presentation to our department, the patient remained in AT (Figure 3D). Echocardiogram demonstrated increased left ventricular wall thickness with preserved ejection fraction. Retrospective review revealed evidence of wall thickening dating back at least 4 years at the time of his third ablation (Figure 4). Laboratory testing showed mildly elevated high-sensitivity troponin I and brain natrium peptide (BNP) (48.3 and 109.6 pg/mL, respectively). The patient's estimated glomerular filtration rate (eGFR) was 54.0 mL/min/1.73m2. Repeat 99mTc-PYP scintigraphy combined with a single photon emission computed tomography (SPECT) confirmed Grade 3 myocardial accumulation (Figure 2B). Cardiac biopsy from the right ventricle revealed amyloid deposition, and immunohistochemistry confirmed transthyretin type. Genetic testing excluded hereditary variants, diagnosing wild type ATTR-CM. Thus, tafamidis 61 mg once daily was initiated. Two months after starting tafamidis without any other changes to drug therapy, routine follow-up ECG revealed spontaneous restoration of sinus rhythm for the first time in over 4 years (Figure 3E). While he experienced a relapse to AT the following month, the cycle length of AT was slower (Figure 3F). At 1 year he again regained sinus rhythm and has since maintained it for six consecutive months (Figure 3G). Follow-up 99mTc-PYP scintigraphy demonstrated a notable reduction in myocardial tracer uptake compared with baseline (Figure 2C). Laboratory follow-up showed that high-sensitivity troponin I and BNP had decreased to 26.4 and 100.5 pg/mL. The patient reported symptomatic improvement, with reduced dyspnea and increased activity tolerance. Atrial arrhythmias are highly prevalent in ATTR-CM due to structural and functional atrial remodeling. Amyloid infiltration leads to atrial stiffness, fibrosis, and conduction heterogeneity. Catheter ablation, although widely performed, carries high recurrence rates especially in cases with multiple focal ATs and complex atrial flutters 4. It is unclear since when this particular patient developed ATTR-CM, but we speculate the disease was at least in its early stages around the time of his third catheter ablation due to thickening of the left ventricular walls shown in the echocardiogram. In this patient, although the causality cannot be definitively established, temporal observations raise the possibility that tafamidis contributed to the modification of arrhythmogenic substrates. Theoretically, reduced amyloid infiltration could improve atrial compliance and conduction, thereby lowering arrhythmogenicity. Tafamidis shows an immediate effect in the improvement of the 6-min walk test and the Kansas City Cardiomyopathy Questionnaire 3. On that basis, it is possible that substrate improvement associated with AT termination, observed first at 2 months of tafamidis therapy, may also have started immediately. The reduction in high-sensitivity troponin I and myocardial tracer uptake in 99mTc-PYP scintigraphy suggests a reduction in amyloid burden, consistent with tafamidis' therapeutic effect. Furthermore, the patient was likely in the early stage of the disease, as suggested by the mildly elevated cardiac biomarkers and minimal renal impairment, which may have allowed him to receive maximal benefit from tafamidis. Our institutional experience highlights two points. First, given that 14.8% of patients had a history of ablation-refractory atrial arrhythmia, it is important to consider the possibility of ATTR-CM as a hidden diagnosis in such cases. Earlier recognition could potentially alter management strategies and guide the use of disease-modifying therapies. Second, it raises the hypothesis that tafamidis may contribute to rhythm control even for ablation-refractory atrial arrhythmia, offering an additional benefit beyond its established role in heart failure outcomes. The authors would like to thank Dr. Giichi Nitta for his contribution in raising awareness of cardiac amyloidosis at our institution. The authors have nothing to report. Written informed consent for the submission and publication of this report was obtained from the patient in accordance with the guidelines of the Committee on Publication Ethics (COPE). The authors declare no conflicts of interest. Data supporting the findings of this study are available from the corresponding author upon reasonable request.