Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis

Abstract

Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis in everyday clinical practice, but the diagnosis continues to be made in patients with late-stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain cardiac amyloidosis, in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late-phase clinical trials. In this review, we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis, and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected cardiac amyloidosis can impact the prognosis of patients in the modern era.

Keywords: amyloidosis; cardiomyopathies; echocardiography; heart failure, diastolic; immunoglobulin light chains; magnetic resonance imaging; prealbumin; radionuclide imaging.

Figure 1

Mayo staging system for risk stratifying subjects with AL-CA in which one point is assigned for each of the following: NT-pro-BNP ≥ 1800 pg/mL, Troponin T ≥0.025 ng/mL, and difference in serum free light chains ≥ 18 mg/dL. Those with highest score have the worst prognosis (Panel A). Survival from the 3-month landmark of 300 patients with AL amyloidosis based on hematologic response. The proportion of stage III patients was not significantly different among the four hematologic response groups. CR, complete response; NR, no response; PR, partial response; VGPR, very good partial response and py, person-year; (Panel B). Prognostic relevance of cardiac response and progression criteria showing survival from the 6-month landmark of 377 patients with immunoglobulin light chain (AL) amyloidosis and baseline N-terminal natriuretic peptide type B (NT-proBNP)>650 ng/L according to NT-proBNP response and progression (Panel C). Survival according to NT-proBNP response in an ongoing phase 3 trial comparing melphalan-dexamethasone with melphalan-bortezomib-dexamethasone (NCT01277016) (Panel D).

Figure 2

Sequence of still images showing typical echocardiographic features of cardiac amyloidosis. A: 2-D Parasternal long axis showing concentric left ventricular hypertrophy, bright myocardium and left atrial dilatation. B: 2-D Parasternal short axis showing concentric left ventricular hypertrophy and bright myocardium. C: 2-D Apical four chamber view showing concentric left ventricular hypertrophy and biatrial dilatation D: Pulsed wave Doppler of mitral inflow showing an increase in E/A ratio, normal E wave deceleration time but a marked reduction in transmitral A wave velocity. E: Pulsed wave Doppler of pulmonary vein inflow showing marked diastolic prominence and increased duration and peak velocity of atrial reversal compared to the transmitral signal. F: Pulsed tissue Doppler of the lateral mitral annulus showing marked reduction in apical systolic and diastolic velocities (normal velocities being: >6 cm/sec and >8 cm/sec, respectively). Images courtesy of Professor Elliott, University College London, UK

Figure 3

Upper left panel: Subcostal 2D echocardiogram showing some the typical findings in advanced cardiac amyloidosis. A: Biatrial enlargement, B: Thickened interatrial septum (and valves), C: Thickening of RV free wall and D: Concentric LVH and hyperechoic myocardial texture; Upper right panel: Apical 4-chamber peak systolic strain image illustrating relatively well-preserved apical strain with significant basal impairment. This is seen in the series of curves and the bull’s-eye color-coded strain image, Lower left panel: Patient with atrial fibrillation and moderate to severely impaired LV function. Echocardiogram showed increased myocardial density and concentric LVH with moderate aortic stenosis. Cardiac MRI showed biventricular hypertrophy, moderate aortic stenosis, and diffuse fibrosis, in excess of that expected for LVH and aortic valve disease. A) Early whole body planar DPD image. B) 3h Delayed whole body planar image showing cardiac retention of racer and reduced bony uptake; Perugini Grade 2. C), D), and E) 2 chamber, short axis, and 4 chamber PSIR LGE cardiac MR images showing diffuse fibrosis. Images courtesy of Professor Elliott, University College London, UK Lower right panel: Fused Florbetapir PET/MR imaging. A) Native T1 map shows high (>1400) values pre-contrast. B) ECV map, the ECV/interstitial space expansion is as high as blood. C) LGE image- There is differential fibrosis, between the ‘core’ of the interventricular septum and the epi- and endocardial borders (white vs red arrows) and also in the lateral wall, which implies a non-uniform amyloid distribution. D) Fused Florbetapir PET/MR uptake with a LV basal septal predominance. Images courtesy of Dr Leon Menezes, University College London, UK

Figure 4

Diagnostic algorithm for patients with suspected amyloid cardiomyopathy. The grading system for bone scintigraphy is Grade 0 – absent cardiac uptake; Grade 1 – mild uptake less than bone; Grade 2 - moderate uptake equal to bone; Grade 3 - high uptake greater than bone. AApoA1 indicates apolipoprotein A-I; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; and PYP, pyrophosphate (from Gilmore, Circulation 2016)

Figure 5

Disease modifying targets in TTR cardiac amyloidosis