Prognosis in Cardiac Amyloidosis by LGE

JACC: CARDIOVASCULAR IMAGING

VOL. 9, NO. 6, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-878X/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jcmg.2015.11.028

EDITORIAL COMMENT

Prognosis in Cardiac Amyloidosis by LGE Ready for Prime Time?* Marianna Fontana, MD

D

uring the 10 years since the first study on

with cardiac light-chain (AL) amyloidosis. Seventy-six

cardiac magnetic resonance (CMR) in car-

consecutive patients with histologically proven AL

diac amyloidosis was published (1), the

amyloidosis who underwent CMR for suspected car-

technique has transformed our approach to this dis-

diac involvement were studied. CMR was performed

ease, providing a second opinion on cardiac structure

within 3 months of diagnosis. Patients were followed

and

for a median of 34.4 months. Forty deaths (53%)

function

and

yielding

unique

information

through tissue characterization. Diagnostic algo-

occurred, with survival probabilities at 1, 3, and 5

rithms integrating clinical presentation, electrocardi-

years of 60%, 53%, and 48%, respectively. The CMR

ography, echocardiography and blood biomarkers can

protocol comprised a standard clinical scan for the

obviate the need for myocardial biopsy in some pa-

acquisition of ventricular volumes along with LGE

tients, but clinical uncertainty frequently prevails,

imaging. As part of their acquisition protocol, the

and detection of early cardiac amyloidosis remains a

authors used a standard sequence to generate a set of

challenging goal.

images at different inversion time (TI) values to select

The key advantage of CMR over echocardiography

the optimal TI to null normal myocardium (commonly

is its unique ability to provide information on tissue

known according to the vendor-specific nomencla-

composition (1). After administration of an extrinsic

ture as a TI scout, cine inversion recovery, or Look-

gadolinium-based contrast agent, CMR in cardiac

Locker sequence). The authors then analyzed LGE

amyloidosis shows a characteristic pattern of global

images and categorized the LGE pattern into 3 cate-

subendocardial late gadolinium enhancement (LGE)

gories (global, focal patchy, and none) using a com-

coupled with abnormal myocardial and blood pool

bined approach of conventional LGE visual analysis

gadolinium kinetics (1). Enthusiasm after the initial

together with inspection of the differences in

report has translated to wide dissemination of the

myocardial/blood pool nulling on the TI scout.

technique with no standardized approaches. Varying

Troponin and N-terminal pro-brain natriuretic pep-

degrees of experience have resulted in heterogeneity

tide (NT-proBNP) levels were used to categorize

of the LGE patterns described, differing diagnostic

patients with the Mayo staging system. Patients were

accuracy, and conflicting results regarding prognosis

also characterized by 12-lead resting electrocardiog-

(2–5). Given the prognostic significance of LGE pat-

raphy and transthoracic echocardiography, albeit

terns in a range of cardiac diseases, it is important to

without longitudinal deformation measurements.

understand why these results are so conflicting in cardiac amyloidosis.

The principal finding of this study was the independent prognostic role of global LGE over the Mayo

SEE PAGE 680

In this issue of iJACC, Boynton et al. (6) present a report on the prognostic impact of LGE in patients

staging system in patients with cardiac AL amyloidosis. The Mayo staging system (7) is the current gold standard for risk stratifying patients with cardiac AL amyloidosis, and it consequently influences treatment. The range of chemotherapeutic options that target

monoclonal

light-chain

production

has

*Editorials published in JACC: Cardiovascular Imaging reflect the views of

expanded substantially in recent years. Successful free

the authors and do not necessarily represent the views of JACC:

light-chain suppression is associated in most cases

Cardiovascular Imaging or the American College of Cardiology. From the National Amyloidosis Centre, University College London (UCL) Medical School, Royal Free Hospital, London, United Kingdom. Dr.

with a reduction in serum NT-proBNP concentration and improved prognosis. The rapid fall in NT-proBNP

Fontana has reported that she has no relationships relevant to the

levels is presumed to reflect removal of any toxic

contents of this paper to disclose.

effects that light-chain aggregates may have and/or

688

Fontana

JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 6, 2016 JUNE 2016:687–9

Editorial Comment

cessation of the previously rapid accumulation of new

A key task in the development of LGE imaging

amyloid deposition. This study deepens our under-

in cardiac amyloidosis will be the transition to

standing in this setting, supporting the independent

more robust and standardized approaches. Several

prognostic role of LGE, a marker of amyloid infiltra-

options are available, including comparison with

tion, in the risk stratification of patients with cardiac

T1 maps or extracellular volume maps (both reflect-

AL amyloidosis. Furthermore, it adds nuance to the

ing amyloid deposits), analysis of TI scout, or the

hypothesis of the pathophysiological importance of

use of standardized scanning protocols with a pre-

existing amyloid deposits in disease progression (8).

determined or fixed TI (1,5,6,10). However, all of

Although these findings redefine the role of

these strategies are time-consuming and prone to the

measuring myocardial infiltration, can we incorporate

inherent errors of subjective interpretation. Phase-

them into clinical practice? CMR with LGE has unique

sensitive inversion recovery reconstruction (PSIR)

advantages over the traditional approach but also has

is emerging as the most accurate method to assess

several limitations. The LGE technique uses gadolin-

LGE in cardiac amyloidosis (9). The tissue with

ium chelates. These purely extracellular agents accu-

the least gadolinium always appears nulled using

mulate passively in the gaps between cells. Because

this reconstruction technique, thus eliminating the

the

in

practical difficulties of accurate TI selection. The

amyloidosis and the gadolinium kinetics is slower, a

routine implementation of PSIR, now available from

larger amount of gadolinium per unit volume will be

all CMR manufacturers, could have highly favorable

present in the myocardium with amyloid infiltration.

diagnostic and prognostic implications. However,

interstitium

is

substantially

expanded

The operator will then visually select a parameter

PSIR does not quantify myocardial infiltration, which

(TI) so that background myocardium returns no

is fundamental to track changes over time and

signal—that is, it is “nulled” and appears black on the

monitor the response to treatment. T1 mapping,

images—and abnormal myocardium with a higher

an emerging CMR technique, can now quantify

concentration of gadolinium appears white. This

the

strategy is very effective when regional differences

amyloid

exist in gadolinium retention, but the technique

assessment of myocardial infiltration can now be

becomes very challenging in diseases in which all

achieved through visualization with LGE imaging and

myocardium can be affected, such as amyloidosis. In

quantification with T1 mapping. This allows us to

an attempt to overcome these problems, the authors

dichotomize the myocardium into its cellular and

adopted a combined approach and defined global LGE

interstitial components, thus gaining insights into

myocardial deposits

as being present when there was diffuse hyper-

both

enhancement on LGE imaging, when the myocardium

response (11).

the

extracellular (11).

infiltrative

A

volume,

more

process

and

reflecting

comprehensive

the

myocyte

was unable to be nulled adequately, or when the

Over time, tissue characterization with CMR has

myocardium nulled before the blood pool on a TI scout.

great potential to become an established part of the

Although this approach helps in avoiding misclassifi-

standard clinical pathway for evaluating cardiac

cation of the global patterns, it does not fully avoid the

amyloidosis. This and other work (1,5,6,9) is changing

risk of misinterpreting regional localization of patho-

our understanding of cardiac amyloidosis, moving

logic conditions (LGE basal rather than apical and

beyond the model of toxicity caused by pre-amyloid

mid-myocardial rather than global subepicardial). The

light-chain aggregates in the pathophysiology of

authors also described a “patchy LGE pattern” that is

cardiac infiltration. Amyloid deposits within the

thought to be related to incorrect TI settings (9) and did

interstitium undoubtedly have a fundamental role in

not explain how uncertain situations, such as in-

the evolution of disease and are currently the target

stances when the blood pool and myocardium null

of novel therapeutic agents in clinical development

simultaneously, were addressed. The timing of the TI

(8). CMR is now well positioned to make a major

scout relative to administration of gadolinium was not

contribution to the development and evaluation of

fixed in the study protocol, jeopardizing the validity of

new treatments and to guide the clinical manage-

the interpretation, because image acquisition too early

ment of our patients.

or too late could lead to erroneous results. Perfusion heterogeneity in the dense amyloid substance makes

REPRINT

the kinetics more complex, with potential misinter-

Dr. Marianna Fontana, National Amyloidosis Centre,

REQUESTS

AND

CORRESPONDENCE:

pretation of multiple perfusion defects in a global

Division of Medicine, University College London

pattern with patchy LGE. Finally, no true standard was

(UCL), Royal Free Hospital, Rowland Hill Street, Lon-

used for validation, leaving uncertainty about the

don NW3 2PF, United Kingdom. E-mail: m.fontana@

effectiveness of the approach used.

ucl.ac.uk.

Fontana

JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 6, 2016 JUNE 2016:687–9

Editorial Comment

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7. Dispenzieri A, Gertz M, Kyle R, et al. Serum cardiac troponins and N-terminal pro-brain natri-

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KEY WORDS amyloidosis, enhancement, magnetic resonance imaging, outcomes, prognosis

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