Prognostic Value of Left Ventricular18F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis
Authors: Clerc Olivier F. , Datar Yesh , Cuddy Sarah AM , Bianchi Giada , Taylor Alexandra , Benz Dominik C , Robertson Matthew , Kijewski Marie Foley , Jerosch-Herold Michael , Kwong Raymond Y , Ruberg Frederick L , Liao Ronglih , Di Carli Marcelo F , Falk Rodney H , Dorbala Sharmila 
Published: September 2023

Background

Myocardial immunoglobulin light-chain (AL) amyloid deposits trigger heart failure, cardiomyocyte stretch and myocardial injury, leading to adverse cardiac outcomes. Positron emission tomography/computed tomography (PET/CT) with18F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden, but its prognostic value is not known. Therefore, we aimed to evaluate the prognostic value of LV amyloid burden quantified by18F-florbetapir PET/CT and to identify mechanistic pathways mediating its association with outcomes.

Methods

Eighty-one participants with newly-diagnosed systemic AL amyloidosis were prospectively enrolled and underwent18F-florbetapir PET/CT. LV amyloid burden was quantified using18F-florbetapir LV percent injected dose (%ID). Mayo AL stage was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and difference between involved and uninvolved free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months.

Results

Among participants (median age 61 years, 57% males), 36% experienced MACE. Incidence of MACE increased across tertiles of LV amyloid burden from 7% to 63% (p<0.001). LV amyloid burden was significantly associated with MACE in univariable analysis (hazard ratio 1.45, 95% confidence interval 1.15-1.82, p=0.002). However, this association became non-significant in multivariable analyses adjusted for Mayo AL stage. Mediation analysis showed that the association between18F-florbetapir LV %ID and MACE was primarily mediated by NT-proBNP (p<0.001), a marker of cardiomyocyte stretch and component of Mayo AL stage.

Conclusion

In this first study to link cardiac18F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by LV %ID predicted MACE in AL amyloidosis. But this effect was not independent of Mayo AL stage. LV amyloid burden was associated with MACE primarily via NT-pro-BNP, a marker of cardiomyocyte stretch and component of Mayo AL stage. These findings provide novel insights into the mechanism through which myocardial AL amyloid leads to MACE.

Clinical Perspective

In systemic light-chain (AL) amyloidosis, cardiac involvement is the key determinant of adverse outcomes. Usually, prognosis is based on the Mayo AL stage, determined by troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the difference between involved and uninvolved immunoglobulin free light chain levels (dFLC). Cardiac amyloid burden is not considered in this staging. In the present study, we used the amyloid-specific radiotracer18F-florbetapir to quantify left ventricular (LV) amyloid burden in 81 participants with newly-diagnosed AL amyloidosis and evaluated its prognostic value on major adverse outcomes (MACE: all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months). We found that higher LV amyloid burden by18F-florbetapir positron emission tomography/computed tomography (PET/CT) was strongly associated with MACE. However, this association became non-significant after adjustment for the Mayo AL stage. Mediation analysis offered novel pathophysiological insights, implying that LV amyloid burden leads to MACE predominantly through cardiomyocyte stretch and light chain toxicity (by NT-proBNP), rather than through myocardial injury (by troponin T), also considering the severity of plasma cell dyscrasia (by dFLC). This mediation by NT-proBNP may explain why the association with outcomes was non-significant with adjustment for Mayo AL stage. Together, these results establish quantitative18F-florbetapir PET/CT as a valid method to predict adverse outcomes in AL amyloidosis. These results support the use of18F-florbetapir PET/CT to measure the effects of novel fibril-depleting therapies, in addition to plasma cell therapy, to improve outcomes in systemic AL amyloidosis.