Distinct predictors of mortality and conduction disease in AL cardiac amyloidosis

Abstract Introduction: For hematologists managing light-chain (AL) cardiac amyloidosis, risk stratification is complicated by the dual threats of progressive heart failure and life-threatening conduction system disease. While the Mayo Stage predicts survival, the determinants of incident conduction disease remain less well defined. A comprehensive model is needed to clarify the simultaneous impact of clinical stage, cardiac function, and therapy on both survival and electrical complications. This study aimed to identify distinct predictors of overall survival and new conduction disease in AL cardiac amyloidosis. Methods: This is a single-center retrospective cohort study of patients with biopsy- or imaging-confirmed AL cardiac amyloidosis treated from 2008–2024. After exclusions for missing data, final cohorts were established for each endpoint. Two primary time-to-event endpoints were analyzed: 1) all-cause mortality (full cohort, n=320) and 2) development of any new conduction abnormality (among patients without baseline conduction disease, n=128). Multivariable Cox proportional hazards models assessed the impact of baseline covariates, including receipt of chemotherapy, demographics, clinical characteristics (Mayo Stage, NYHA class), and cardiac function (ejection fraction, global longitudinal strain GLS). Proportional hazards assumptions were verified for all models. Results The final cohort included 320 patients with a mean age of 73.7 (±11.0) years; 61.6% were male. The population presented with advanced cardiac involvement, evidenced by a mean ejection fraction of 50.9% (±12.3), a severely impaired mean GLS of -10.2 (±4.3), and a high prevalence of NYHA Class III/IV symptoms (62.2%). At baseline, 18.8% of patients had pre-existing heart block. Over a median follow-up of 36 months, 62 of 128 at-risk patients (48.4%) developed a new conduction abnormality. In the multivariable analysis for overall survival (C-index=0.725), the receipt of chemotherapy was the strongest factor associated with improved survival (HR 0.27; 95% CI 0.18-0.42; p0.001). Factors associated with worse survival included advanced age (HR 1.04; p0.001), higher NYHA class (HR 1.53; p0.001), higher Mayo Stage (HR 1.23; p=0.035), and lower ejection fraction (HR 0.99; p=0.037). In the same adjusted model, gender, race, history of syncope, and presence of obstructive CAD were not statistically significant predictors of survival. In a separate multivariable model for the development of new conduction disease (C-index=0.645), the receipt of chemotherapy was again the only significant protective factor, dramatically reducing the risk (HR 0.17; 95% CI 0.05-0.59; p=0.005). In this model, other baseline factors including age, NYHA class, Mayo Stage, and ejection fraction were not significant predictors of progressive conduction disease. Conclusion: The drivers of mortality and conduction disease in AL cardiac amyloidosis are related but distinct. While factors like age and NYHA class predict overall survival, our analysis reveals that the receipt of amyloid-directed chemotherapy has a profound dual benefit, it is the most powerful factor for improving survival and is also independently protective against the progression of conduction system disease. These findings support the need for distinct surveillance strategies, recognizing that effective hematologic therapy modifies both survival and arrhythmic risk in this high-risk population.