In Response to: Reconsider the Indication of Implantable Cardioverter Defibrillator in Patients With Cardiac Amyloidosis

We thank Dr.'s Kataoka and Imamura for their insightful commentary on our study evaluating the prevalence and prognostic implications of nonsustained ventricular arrhythmias in patients with wild-type transthyretin cardiac amyloidosis (ATTR-wt CA) [1]. The treatment of bradycardia with permanent pacemakers (PPM) in ATTR-wt CA patients is an important consideration, as sinus node dysfunction and atrioventricular conduction abnormalities are highly prevalent and can be an early manifestation of the disease. The prevalence of PPM use in this population has varied in the literature, with a higher proportion reported in ATTR-wt CA than other subtypes and many patients may undergo PPM implantation even before CA diagnosis [2]. The authors argue that most of the mortality in patients with CA is linked to bradycardia. However, we caution that attributing mortality to a primary bradyarrhythmia is challenging, especially in retrospective evaluations. Bradycardia can be present in end-stage pump failure and cardiac arrest with pulseless electrical activity, but the bradycardia itself is most often a manifestation rather than the root cause of the failing heart. It is unlikely that an in situ PPM would have a meaningful impact in preventing such fatal events due to end-stage heart failure. However, we agree with the authors that in patients with CA a lower threshold for PPM implantation may be reasonable. We also agree that when an implantable cardioverter-defibrillator (ICD) is indicated, the subcutaneous ICD should be less preferred due to the lack of pacing function. The value of prophylactic ICDs in ATTR-wt CA is a complex issue. Various single-center studies have failed to convincingly demonstrate an improvement in survival in ATTR-wt CA patients treated with ICDs and the routine use of primary prevention ICDs in this population is not recommended [3]. This is likely attributable to the competing mortality risks between VT/VF, progressive heart failure, and noncardiac comorbidities in ATTR-wt CA. Our study was not designed to address whether NSVT should alter the ICD decision-making and we do not advocate for ICD use in the CA patient with NSVT. However, the association between NSVT and increased risk of sustained VA and all-cause mortality (composite endpoint) should be considered in the setting of the rapidly evolving treatment landscape in ATTR-wt CA. Advances in earlier diagnosis, targeted disease-modifying therapies, and heart failure therapies have improved the prognosis of ATTR-wt CA [4, 5]. In light of improved heart failure survival, the threshold to consider ICD implantation may be lower as the competing risk of heart failure mortality is lower. There is also a critical need to better risk stratify patients treated with transthyretin protein stabilizers or suppressors for their risk of sustained VT/VF. We also agree that a better understanding of the correlations between NSVT and other outcomes including cardiac function trajectory and hospital readmissions may affect the decision-making toward ICD utilization. Regarding the arrhythmogenic mechanisms and anatomical areas of VT origin in our cohort, unfortunately 12-lead electrocardiogram tracings were available only in a very small number of patients among those who had documented sustained VT. The majority of VT episodes were documented by ICD electrograms, Holter monitors, and inpatient telemetry. Based on the available documentation, both reentrant and automatic VT mechanisms were likely present among the totality of VT episodes in our cohort. Further, it was difficult to retrospectively ascertain the patient's physical activity at the time of their VT/VF event. We generally would not anticipate rigorous physical activity to be a common occurrence in the elderly and often frail ATTR-wt CA population. We thank again Dr.'s Kataoka and Imamura for highlighting these important considerations, many of which require further study.