Baars, E.N.

Beek, A.M.

Brouwer, W.P

Hofman, M.B.M.

Marcu, C.B.

Niessen, H.W.M.

Robbers, L.F.H.J.

Rossum, A.C. van

van Rossum, A.C.

NARCIS 

T1 mapping shows increased extracellular matrix size in the myocardium due to amyloid depositions

Lourens F.H.J. Robbers

Emma N. Baars

Wessel P. Brouwer

Aernout M. Beek

Mark B.M. Hofman

Hans W.M. Niessen

Albert C. van Rossum

C. Bogdan Marcu

Crossref

Circulation Cardiovascular Imaging

T1 Mapping Shows Increased Extracellular Matrix Size in the Myocardium Due to Amyloid Depositions

DSpace at VU

Cardiovascular Images
T1 Mapping Shows Increased Extracellular Matrix Size in
the Myocardium Due to Amyloid Depositions
Lourens F.H.J. Robbers, MD, MSc; Emma N. Baars, BSc; Wessel P. Brouwer, MD;
Aernout M. Beek, MD, PhD; Mark B.M. Hofman, PhD; Hans W.M. Niessen, MD, PhD;
Albert C. van Rossum, MD, PhD; C. Bogdan Marcu, MD
Amyloidosis is a systemic infiltrative disorder in whichinsoluble protein fibrils are deposited in the extracellular
matrix (ECM). The prognosis is predominantly determined
by cardiac involvement because the amyloid depositions lead
to a restrictive cardiomyopathy. Although endomyocardial
biopsy is the gold standard for diagnosing cardiac amyloid-
osis, the associated risk for complications favors a noninva-
sive approach by using various cardiac imaging methods,
whereas tissue diagnosis is made on a noncardiac biopsy.
Accurate diagnosis of cardiac amyloidosis becomes difficult
when a secondary cause of myocardial wall thickening (eg,
hypertension) is present as well. Cardiac MRI is an excellent
tool for assessment of systolic and diastolic function, myo-
cardial thickness, and amyloid deposition with late gadolin-
ium enhancement imaging.1 Late gadolinium enhancement
imaging is a qualitative technique, which relies on the
presence of normal myocardium to visualize infiltrated,
enhanced tissue. Therefore, diffuse deposition of amyloid is
difficult to highlight, because regional differences in signal
intensities may be absent. T1-mapping is a cardiac MR
technique, which allows absolute quantification of T1 values
of the myocardium and enables assessment of ECM expan-
sion present in cardiac amyloidosis.
A 71-year-old man with a medical history of hypertension
presented with suspicion of congestive heart failure. A
12-lead electrocardiography showed atrial fibrillation and
Figure 1. Electrocardiography on admission showing low voltages in the extremity leads, suggestive of cardiac amyloidosis.
Received March 7, 2012; accepted March 12, 2012.
From the Departments of Cardiology (L.F.H.J.R., W.P.B., A.M.B., A.C.v.R., C.B.M.), Physics and Medical Technology (E.N.B., M.B.M.H.), and
Pathology (H.W.M.N.), VU University Medical Center, Amsterdam, The Netherlands.
The online-only Data Supplement is available with this article at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/
CIRCIMAGING.112.973438/-/DC1.
Correspondence to Lourens F.H.J. Robbers, MD, MSc, Research Fellow, Cardiovascular MRI, VU Medical Center, ZH 4 D 36, PO Box 7057, 1007
MB Amsterdam, The Netherlands. E-mail l.robbers@vumc.nl
(Circ Cardiovasc Imaging. 2012;5:423-426.)
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org DOI: 10.1161/CIRCIMAGING.112.973438
423
low voltages in the extremity leads (Figure 1). Surprisingly,
echocardiography demonstrated severe concentric hypertro-
phy with a preserved left ventricular systolic function (Figure
2). Due to the discrepancy between hypertrophy and low
voltages, cardiac amyloid was suspected and cardiac MR
imaging was performed using a clinical 1.5-T scanner
(Avanto; Siemens, Erlangen, Germany). Despite atrial fibril-
lation, images were of diagnostic quality. Functional assess-
ment showed a left ventricular ejection fraction of 53% and
wall thickness of 16 mm. Both atria were dilated and small
pericardial and pleural effusions were present (online-only
Data Supplement movie). To differentiate between
hypertension-induced hypertrophy and increased myocardial
mass due to amyloid depositions with subsequent increase in
ECM, T1 mapping was performed before and at 5 and 10
minutes after 0.2 mmol/kg Gd-DOTA (Dotarem; Guerbet,
Villepinte, France) contrast administration. This gadolinium-
based contrast agent does not cross intact cellular membranes
and distributes only in the extracellular space. T1 mapping
was performed with a single short axis slice modified
Figure 3. Late gadolinium enhancement shows difficulties in
finding the correct inversion time with inversion of the blood
pool signal and the myocardium at almost similar T1 relaxation
times (slice thickness 8.0 mm, time of repetition 650 ms, field of
view matrix 192186; inversion time A: 200 ms, B: 225 ms).
Figure 4. Late gadolinium enhancement shows some midmyo-
cardial patchy gadolinium enhancement in the lateral wall, likely
representing more pronounced regional involvement (marked
with an asterisk, inversion time 300 ms, slice thickness 8.0 mm,
time of repetition 650 ms, field of view matrix 192186).
Figure 5. T1 mapping was performed on a short axis slice by cal-
culation of the T1 relaxation times for each of the 6 equiangular
segments. Segmentation was performed by using the American
Heart Association standard 17-segment model. LV indicates left
ventricular; IS, inferoseptum; AS, anteroseptum; AN, anterior; AL,
anterolateral; IL, inferolateral; IN, inferior; N/A, not applicable.
Figure 2. Echocardiography (PSSAX) shows left ventricular
hypertrophy. No evident granular sparkling of the myocardium
was visible.
424 Circ Cardiovasc Imaging May 2012
look-locker inversion-recovery sequence obtained during
breath-holding. After T1-mapping, late gadolinium enhance-
ment imaging was performed using an inversion recovery
gradient echo sequence. Signal suppression of normal myo-
cardial tissue was difficult (Figures 3 and 4). To assess
whether the increased mass was due to an increase in ECM
size or due to cellular hypertrophy, ECM size was estimated
by assessing the myocardial distribution volume of Gd-
DOTA. This myocardial distribution volume consists of both
the extracellular, extravascular space and the tissue plasma
space. This tissue plasma space fraction is in the order of
0.045 but cannot be separately assessed by MRI. T1 relax-
ation times were calculated for the blood pool and 6 isoan-
gular segments of myocardium at the midventricular level
(Figure 5). With the T1 relaxation times of myocardium and
blood pool before and after contrast administration and
correcting for hematocrit value (viz 0.37 l/L), the myocardial
distribution volume was calculated.2,3 Analysis revealed a
sharply increased myocardial distribution volume of Gd-
DOTA in all segments (49%5% of the myocardium; range,
44%–58%; Table) compared with previously described val-
ues of 24%3% in normal and 34%3% in hypertensive
patients.4 These findings reinforced the suspicion of amyloid-
osis and subcutaneous adipose tissue biopsy was performed,
confirming the diagnosis (Figure 6).
Using T1 mapping, we were able to show that myocardial
amyloid deposition was not only limited to the enhanced
areas on late gadolinium enhancement, but that it was a
generalized process resulting in a diffuse increase in myocar-
dial ECM volume. Figure 7 is an example of a different
patient with cardiac amyloidosis. The cardiac tissue biopsy
shows amyloid depositions giving rise to an increased ECM
volume. T1 mapping has been used in patients with cardiac
amyloidosis, although only for assessing T1 relaxation
times.1 If cardiac amyloidosis is suspected and late gadolin-
ium enhancement imaging is difficult due to diffuse infiltra-
tion, absolute quantification of myocardial distribution vol-
ume of an extracellular agent as an indication of ECM size
may have additional value, especially if other causes for
hypertrophy are present. Further analysis by comparison of
T1 mapping and estimation of the ECM size in different
pathophysiological processes causing myocardial wall thick-
ening is necessary to assess the true applicability of this
promising technique in clinical practice.
Acknowledgments
We thank the patient for his cooperation in providing us with the data
and images.
Disclosures
Dr Hofman received a research grant from Research Support
Siemens, Zoetermeer, The Netherlands. Dr Niessen received re-
search grants from The Netherlands Organisation for Scientific
Research. Dr van Rossum received research grants Medtronic,
Heerlen, The Netherlands; Biotronic, Nijmegen, The Netherlands;
and Abbott Vascular, Hoofddorp, The Netherlands.
Figure 6. Congo red staining of abdominal subcutaneous adi-
pose tissue biopsy showing red strands of amyloid fibrils
among the extracellular matrix (magnification 200).
Table. T1 Relaxation Times and Calculated Volumes of
Distribution of the Blood Pool and the Myocardial Segments
Location
T1 Relaxation
Time Before
Gd-DOTA
T1 Relaxation
Time 5 Min
After
Gd-DOTA
T1 Relaxation
Time 10 Min
After
Gd-DOTA
Calculated
Volume of
Distribution
LV blood pool 1558 237 350 N/A
IS 1121 273 400 48%
AS 1096 275 397 48%
AN 1105 274 399 48%
AL 1061 289 413 58%
IL 1078 281 399 46%
IN 1071 291 411 44%
By relating the T1 relaxation times of the blood pool and the myocardium,
before and after contrast administration and after blood hematocrit correction
using the formula Vd(m)(1hematocrit)
(1/T1)myo.post(1/T1)myo.pre
(1/T1)blood.post(1/T1)blood.pre, the
myocardial volume of distribution of the extracellular agent (ie, extracellular
matrix size) could be calculated, which was evidently increased.
LV indicates left ventricular; IS, inferoseptum; AS, anteroseptum; AN,
anterior; AL, anterolateral; IL, inferolateral; IN, inferior; N/A, not applicable.
Figure 7. Hematoxylin–eosin staining of cardiac tissue biopsy
(different patient with cardiac amyloidosis) showing pinkish
depositions (arrow) of amyloid fibrils (magnification 100).
Robbers et al T1-Mapping in Cardiac Amyloid Depositions 425
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KEY WORDS: amyloid  magnetic resonance imaging  pathology  T1
mapping  tissue characterization
426 Circ Cardiovasc Imaging May 2012


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T1 mapping shows increased extracellular matrix size in the myocardium due to amyloid depositions

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