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. 2024 Aug;17(8):911-922.
doi: 10.1016/j.jcmg.2024.05.002. Epub 2024 Jul 10.

Prognostic Value of Left Ventricular 18F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis

Olivier F Clerc  1 , Yesh Datar  1 , Sarah A M Cuddy  2 , Giada Bianchi  3 , Alexandra Taylor  1 , Dominik C Benz  1 , Matthew Robertson  4 , Marie Foley Kijewski  5 , Michael Jerosch-Herold  4 , Raymond Y Kwong  4 , Frederick L Ruberg  6 , Ronglih Liao  7 , Marcelo F Di Carli  8 , Rodney H Falk  9 , Sharmila Dorbala  10
Affiliations

Prognostic Value of Left Ventricular 18F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis

Olivier F Clerc et al. JACC Cardiovasc Imaging. 2024 Aug.

Abstract

Background: Positron emission tomography/computed tomography (PET/CT) with 18F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known.

Objectives: The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes.

Methods: A total of 81 participants with newly diagnosed AL amyloidosis underwent 18F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and 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, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage.

Conclusions: In this first study to link cardiac 18F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE.

Keywords: (18)F-florbetapir; adverse outcomes; cardiomyopathy; light-chain (AL) amyloidosis; mediation analysis; positron emission tomography (PET).

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by the National Institutes of Health. Dr Dorbala was supported by grants R01 HL 130563; K24 HL 157648; AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Falk was supported by a grant R01 HL 130563. Dr Liao was supported by grants AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Ruberg was supported by grants R01 HL 130563; R01 HL 093148. Dr Bianchi was partially supported by a grant K08 CA245100; and has received consulting fees from Prothena. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy was supported by grants NIH 1K23HL166686-01 and AHA 23CDA857664NIH; and has received an investigator-initiated research grant from Pfizer; and has received consulting fees from BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr DiCarli has received a research grant from Gilead and Alnylam Pharmaceuticals; in-kind research support from Amgen; and consulting fees from Sanofi, MedTrace Pharma, and Valo Health. Dr Kwong has received grant funding from Alynlam Pharmaceuticals. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Caelum Biosciences; and research funding from GlaxoSmithKline and Akcea. Dr Ruberg has received consulting fees from AstraZeneca, and Attralus; and has received research support from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr Dorbala has received consulting fees from Pfizer, GE Health Care, and Novo Nordisk; and investigator-initiated grants from Pfizer, GE Healthcare, Attralus, Siemens, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Cardiac Amyloid Quantification with 18F-Florbetapir PET/CT
18F-florbetapir PET/CT showed clear differences in left ventricular uptake, color-coded in %ID/mL (radiotracer concentration metric related to %ID). %ID/mL: Percent injected dose by milliliter. LV: Left ventricular. PET/CT: Positron emission tomography/computed tomography.
Figure 2.
Figure 2.. Outcome Analysis Within 12 Months Based on LV Amyloid Burden
Kaplan-Meier analysis and the log-rank test were performed on adverse outcomes within 12 months by levels of LV amyloid burden based on tertiles of 18F-florbetapir LV %ID. For MACE, we found p<0.001 for trend across tertiles, and pairwise testing showed: low vs. middle tertile p=0.011, middle vs. high tertile p=0.056, and low vs. high tertile p<0.001. For all-cause death, we found p=0.024 for trend across tertiles, and pairwise testing showed: low vs. middle tertile p=0.127, middle vs. high tertile p=0.462, and low vs. high tertile p=0.064. Pairwise tests were adjusted for multiple testing using the Benjamini-Hochberg procedure. Using log-rank statistic maximization, the optimal LV %ID cut-off value was >2.0% to predict both MACE and all-cause death. %ID: Percent injected dose. LV: Left ventricular. MACE: Major adverse cardiac events (all-cause death, heart failure hospitalization or cardiac transplantation).
Figure 3.
Figure 3.. Mediation Analysis Between LV Amyloid Burden and MACE Within 12 Months
This causal mediation model quantified how LV amyloid burden (as 18F-florbetapir LV %ID, yellow) predicts 12-month MACE (orange) directly, indirectly by mediation through cardiomyocyte stretch and heart failure (as NT-proBNP, blue), and/or indirectly by mediation through myocardial injury (as troponin T, blue), adjusted for confounding by circulating light chains (as dFLC, green). Arrows represent the direction of assumed causality, with grey dashed arrows for statistically non-significant associations. Results are presented as regression coefficients with *p<0.05, **p<0.01 and ***p<0.001. Overall, LV 18F-florbetapir LV %ID was associated with MACE (total effect [TE]: −31214, 95%CI −20334452 – −647, p<0.001). This effect essentially occurred through an indirect pathway by NT-proBNP (average causal mediation effect [ACME]: −36265, 95%CI −27054344 – −796, p<0.001), while the direct pathway to MACE was minor and statistically non-significant (average direct effect [ADE]: 5052, 95%CI −168448 – 3619652, p=0.558). The indirect pathway through troponin T and the confounding effect by dFLC were also statistically non-significant. Therefore, the effect of LV amyloid burden on MACE was essentially mediated by cardiomyocyte stretch and heart failure as NT-proBNP. %ID: Percent injected dose. ACME: Average causal mediation effect. ADE: Average direct effect. CI: Confidence interval. dFLC: Difference in immunoglobulin free light chains. LV: Left ventricular. MACE: Major adverse cardiac events (all-cause death, heart failure hospitalization or cardiac transplantation). NT-proBNP: N-terminal pro-B-type natriuretic peptide. TE: Total effect.
Fig 4 Central Illustration:
Fig 4 Central Illustration:. Prognostic Value of LV 18F-Florbetapir Uptake in AL Amyloidosis
This central illustration presents the LV uptake of 18F-florbetapir in a participant with AL cardiomyopathy, a Kaplan-Meier analysis of MACE by tertiles of LV 18F-florbetapir uptake (as %ID) showing a highly significant association, and a mediation model, where the effect of 18F-florbetapir LV %ID on MACE was essentially mediated by NT-proBNP (blue arrows), a marker of cardiomyocyte stretch and heart failure, while other model pathways were not significant (dashed gray arrows). %ID: Percent injected dose. AL: Light-chain amyloidosis. LV: Left ventricular. MACE: Major adverse cardiac events (all-cause death, heart failure hospitalization or cardiac transplantation). PET/CT: Positron emission tomography/computed tomography.
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