Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis: Redefining Early Disease?

Abstract

Objectives: The purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[¹⁸F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis.

Background: Cardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness.

Methods: A total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [¹⁸F]florbetapir PET/CT to evaluate cardiac amyloid burden.

Results: The active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [¹⁸F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min^-1, and the lowest cardiac function by global longitudinal strain (GLS), median GLS -11% (IQR: -8% to -13%). The remission-CA group had expanded extracellular volume (ECV) and [¹⁸F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min^-1), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [¹⁸F]florbetapir RI in 50%.

Conclusions: Evidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [¹⁸F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145).

Keywords: [(18)F]florbetapir; cardiac amyloidosis; cardiac magnetic resonance; echocardiography; light chain amyloidosis; longitudinal strain imaging; positron emission tomography.

FIGURE 1. Cardiac Phenotype by LV Myocardial [¹⁸F]florbetapir Uptake and CMR in AL Amyloidosis

Images from each of the 3 study groups (active AL-CA [A], remission AL-CA [B], active AL-no CA [C and D]) are shown in Figures 1 and 2. The active AL-no CA group was further divided into preclinical cardiac involvement or not based on [¹⁸F]florbetapir RI >0.06 min⁻¹ (C) or <0.06 min⁻¹ (D). This figure shows [¹⁸F]florbetapir PET/CT fusion axial images (top), CMR end-diastolic cine still (second row), CMR LGE (third row), and ECV maps (bottom). Subjects in the active AL-CA (A), remission AL-CA (B), active AL-no CA with [¹⁸F]florbetapir RI >0.06 min-1 (C), groups have LV myocardial [¹⁸F]florbetapir uptake and CMR evidence of cardiac amyloid deposition, with transmural LGE and abnormally elevated ECV values. The subject in the last column (D) had no LGE and a normal ECV, with minimal (if any) LV myocardial [¹⁸F]florbetapir uptake. [¹⁸F]florbetapir = fluorine-18-labeled florbetapir; AL-CA = light chain cardiac amyloidosis; CMR = cardiac magnetic resonance; ECV = extracellular volume; GLS = global longitudinal strain; LGE = late gadolinium enhancement; PET/CT = positron emission tomography/computed tomography; LGE = late gadolinium enhancement; RI = retention index; SA-LGE-PSIR = short axis-late gadolinium enhancement-phase sensitive inversion recovery; SA-SSFP = short axis-steady state free precession.

FIGURE 2. Segmental Distribution of GLS, ECV, and [¹⁸F]florbetapir RI in the Entire Study Cohort

A 16-segment polar plot of GLS (top), 16-segment polar plot of ECV (second row), and a 17- segment polar plot of [¹⁸F]florbetapir RI (bottom row) in (left to right) active cardiac amyloidosis (A), remission cardiac amyloidosis (B), and (C) active AL-no CA with a [¹⁸F]florbetapir RI >0.06 min⁻¹ and (D) active AL-no CA with a [¹⁸F] florbetapir RI <0.06 min⁻¹. Values represented in the polar plots are the median of each parameter. Subjects in groups A and B have impaired GLS, whereas those in groups C and D have normal GLS. ECV is expanded in all 4 groups but more markedly in A and B than in C and D. Cardiac amyloid deposition detected by [¹⁸F] florbetapir PET/CT is highest in group A and lowest in group D. Abbreviations are as in Figure 1.

FIGURE 3. Distribution of GLS Values in the Study Groups

The dotted black line represents the cutoff value to diagnose presence or absence of cardiac amyloidosis. The dotted blue line represents the upper threshold of normal observed in healthy controls, as reported in other studies. The p value listed in the figure is the across group comparison. *p < 0.005 for between-group differences with active-CA as the reference group. Abbreviations as in Figure 1.

FIGURE 4. Distribution of [¹⁸F]Florbetapir RI Values in the Study Groups

Groups are defined by the presence of consensus criteria for cardiac involvement and AL disease activity. The dotted blue line represents the cutoff value to diagnose the presence or absence of cardiac amyloidosis. The dotted black line represents the upper threshold of normal observed in healthy controls, as reported in other studies. The p value is the cross-group comparison. *p < 0.005 for between-group differences with active-CA as the reference group. Abbreviations are as in Figure 1.

FIGURE 5. Distribution of ECV Values in the Study Groups

The dotted blue line represents the cutoff value to diagnose the presence or absence of cardiac amyloidosis. The dotted black line represents the upper threshold of normal observed in healthy controls, as reported in other studies. The p value listed in the figure is the cross-group comparison. *p < 0.005 for between-group differences with active-CA as the reference group. Abbreviations as in Figure 1.

FIGURE 6. Prevalence of Abnormal Indexes of Cardiac Amyloid Deposition in Cardiac AL Groups

(A) Active-Ca and remission-CA and (B) in the noncardiac active CA group. Conventional criteria for the diagnosis of cardiac AL amyloidosis (A) identifies subjects with advanced infiltration with ubiquitous abnormalities in [¹⁸F]florbetapir RI, LGE, ECV, GLS, and NT-proBNP. Importantly, in subjects diagnosed as not having cardiac involvement by conventional criteria (B), a substantial proportion were identified to have early cardiac involvement by imaging biomarker abnormalities in RI, ECV, LGE, and GLS. NT-proBNP = N-terminal pro–B-type natriuretic peptide; other abbreviations as in Figure 1.

CENTRAL ILLUSTRATION. Imaging From Early to Advanced Stages of Myocardial AL Amyloid Deposition.

The inciting event in the pathogenesis of AL amyloidosis in the heart is AL amyloid deposition, which can now be imaged by imaging with a targeted amyloid tracer [¹⁸F] florbetapir PET/CT. Amyloid deposition expands ECV and releases cardiac biomarkers, which are probably very early manifestations in AL cardiac amyloidosis. With progressive myocardial AL amyloid deposition, several typical cardiac structural and functional changes become evident, which are likely to represent more advanced stages of AL amyloidosis and can be imaged by echocardiography. Heart failure typically indicates advanced amyloid infiltration that is typically associated with poor prognosis. Light-chain toxicity also has a role in myocardial dysfunction. [¹⁸F]florbetapir = fluorine-18-labeled florbetapir; ECV = extracellular volume; FLC = free light chain level; PET/CT = positron emission tomography/computed tomography