An investigation of risk factors for cardiac amyloidosis and the effect of the presence of red flag signs on cardiovascular endpoints in patients with cardiac conduction defect in whom an intracardiac device was implanted

INTRODUCTION: Cardiac amyloidosis (CA) is a progressive infiltrative disease resulting from the deposition of misfolded precursor proteins in the extracellular matrix of the myocardium. It may develop due to the deposition of misfolded monoclonal amyloid light chains (AL-CA) arising from plasma cell disorders or the accumulation of misfolded transthyretin proteins (ATTR-CA). ATTR-CA, increasingly recognized in recent years, allows for early diagnosis through red flag findings and established risk scores, and survival outcomes have significantly improved with specific therapies such as tafamidis. Recent studies have shown that ATTR-CA is detected in 15% of patients with heart failure with preserved ejection fraction (HFpEF) and in 13% of patients undergoing TAVI for aortic valve disease. Red flag findings, such as cardiac conduction defects (especially atrioventricular blocks), are observed with a prevalence ranging from 9.5% to 20% in patients with ATTR-CA. Many risk scores used in the diagnostic evaluation of ATTR-CA have been validated in populations with HFpEF and aortic valve disease. However, in patients with cardiac conduction defects who have undergone intracardiac device implantation, the validation of these scoring systems and their impact on cardiovascular outcomes remain unclear. This study aims to investigate the effects of the T-AMYLO score and red flag findings on cardiovascular outcomes in patients with cardiac conduction defects requiring intracardiac device implantation. MATERIALS AND METHODS: This study was designed as a single-center, retrospective, observational, and cross-sectional cohort study. It included approximately 3,000 patients who underwent intracardiac device implantation between 2015 and 2024. Following the application of appropriate inclusion and exclusion criteria, 1,107 patients with unexplained cardiac conduction defects who underwent device implantation were analyzed. Clinical and laboratory data, as well as ECG and echocardiography findings, were collected from hospital records, national health databases, and, when necessary, by contacting patients. Device types and implantation indications were obtained from the hospital's Arrhythmia and Electrophysiology unit. The T-AMYLO score and risk group for each patient were calculated, and the presence of red flag findings was assessed. Retrospective analysis of ECG records allowed for the calculation of the total QRS/LVWT ratio for 546 patients. The effects of the T-AMYLO score and red flag findings for cardiac amyloidosis on the primary endpoints, defined as all-cause mortality, non-fatal myocardial infarction (MI), and non-fatal stroke, were evaluated. Independent predictors of these endpoints were analyzed using multivariate Cox regression analysis. The impact of the T-AMYLO score and total red flag count on survival was assessed using Kaplan-Meier curves and ROC curve analysis. The study protocol was prepared in compliance with the Helsinki Declaration and approved by the local ethics committee (IUC Ethics Committee, Serial No: E-74555795-050.04-1036119) RESULTS: Of the 1,107 patients analyzed, 442 (39.9%) had AV block, 354 (32.0%) had sick sinus syndrome (SSS) or symptomatic sinus bradycardia, 210 (19.0%) had atrial fibrillation with a slow ventricular response, and 101 (9.1%) had non-AV block cardiac conduction defects requiring device implantation. The implanted devices included 32.8% single-ventricular lead devices and 67.2% dual atrial and ventricular lead devices. Patients with primary endpoint events were older (74 vs. 82 years, p<0.001) and predominantly male (46.3% vs. 58.7%, p<0.001). These patients more frequently had AV block (35.5% vs. 46.0%, p<0.001) or slow ventricular response AF indications (15.7% vs. 23.4%, p<0.001). Additionally, single-ventricular lead devices were more common in patients with primary endpoint events (20.1% vs. 29.6%; 5.3% vs. 13.2%, p<0.001). Patients experiencing primary endpoints had higher T-AMYLO scores (1.0 vs. 2.9, p<0.001) and a greater total number of red flag findings (4.5 vs. 5.5, p<0.001). Similarly, patients with intermediate or high T-AMYLO scores had more frequent events (11.5% vs. 21.7%; 4.7% vs. 8.3%, p<0.001, respectively). Regression analysis identified high T-AMYLO scores (HR: 1.02, p=0.002), the presence of aortic valve disease (HR: 1.29, p=0.030), HF with LVEF >40% (HR: 1.42, p=0.037), AV block (HR: 1.48, p=0.013), and peripheral neuropathy (HR: 1.52, p=0.002; only for all-cause mortality) as independent predictors of primary endpoint events and all-cause mortality. Kaplan-Meier analysis revealed significantly lower survival rates in patients with intermediate or high T-AMYLO scores and in those with six or more red flag findings (p<0.001). The total red flag count demonstrated superior predictive power for all-cause mortality compared to the T-AMYLO score (AUC: 0.655 vs. 0.581, p<0.001). CONCLUSION: The association of the T-AMYLO risk score and red flag findings with cardiovascular outcomes in patients with cardiac conduction defects requiring device implantation highlights the need for validation of risk scores like T-AMYLO in this patient population. Investigating such risk scores and red flag findings, particularly in patients with unexplained cardiac conduction defects requiring device implantation, could facilitate the early diagnosis of cardiac amyloidosis and contribute significantly to reducing mortality. Keywords: cardiac amyloidosis, cardiac conduction defects, T-AMYLO score, red flag findings, CIED