RESUMO
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) with 18 F-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 by 18 F-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 underwent 18 F-florbetapir PET/CT. LV amyloid burden was quantified using 18 F-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 between 18 F-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 cardiac 18 F-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 radiotracer 18 F-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 by 18 F-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 quantitative 18 F-florbetapir PET/CT as a valid method to predict adverse outcomes in AL amyloidosis. These results support the use of 18 F-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.
RESUMO
BACKGROUND: Echocardiographic deformation-based ratios and novel multi-parametric scores have been suggested to discriminate transthyretin cardiac amyloidosis (ATTR-CM) from other causes of increased left ventricular wall thickness among patients referred for ATTR-CM evaluation. Their relative predictive accuracy has not been well studied. We sought to (1) identify echocardiographic parameters predictive of ATTR-CM and (2) compare the diagnostic accuracy of these parameters in patients with suspected ATTR-CM referred for technetium-99m-pyrophosphate scintigraphy. METHODS: Echocardiograms from 598 patients referred to 3 major amyloidosis centers for technetium-99m-pyrophosphate to detect ATTR-CM were analyzed, including longitudinal strain (LS) analysis. Deformation ratios (septal apex to base ratio, relative apical sparing, ejection fraction to global LS), a multi-center European increased wall thickness score, and Mayo Clinic derived ATTR score (transthyretin cardiac amyloidosis score) were calculated. A logistic regression model was used to identify the parameters that best associated with a diagnosis of ATTR-CM. Comparison of the diagnostic capacity of the parameters was performed by receiver operating characteristic curves and the area under the curve (AUC). RESULTS: Over half of the subjects (54.2%) were diagnosed with ATTR-CM (78% were men, median age of 76 years). Age, inferolateral wall thickness, and basal LS were the strongest predictors of ATTR-CM, AUC of 0.87 (95% CI: 0.83, 0.90), superior to the increased wall thickness score AUC of 0.78 (95% CI: 0.73, 0.83; P=0.004). An inferolateral wall thickness of ≥14 mm (AUC: 0.73) was as accurate as the published cut-offs for transthyretin cardiac amyloidosis score and septal apex to base (AUC: 0.72 and 0.69, P=0.8 and P=0.1, respectively), and was superior to ejection fraction to global LS and relative apical sparing (AUC: 0.64 and 0.53, P<0.001, respectively). A cut-off of ≥-8% for average basal LS (AUC: 0.76, CI: 0.72-0.79) had a similar area under the curve to transthyretin cardiac amyloidosis score (TCAS) (P=0.2); outperforming the other indices (P<0.01). CONCLUSION: Inferolateral wall thickness and average basal LS performed as well as or better than more complex echo ratios and multiparametric scores to predict ATTR-CM.