Journal of the American College of Cardiology Vol. 51, No.

10, 2008
© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2007.10.049

Cardiovascular Magnetic Resonance

in Clinically Suspected Cardiac Amyloidosis
Noninvasive Imaging Compared to Endomyocardial Biopsy

Holger Vogelsberg, MD,* Heiko Mahrholdt, MD,* Claudia C. Deluigi, MD,* Ali Yilmaz, MD,*
Eva M. Kispert, RN,* Simon Greulich, MD,* Karin Klingel, MD,† Reinhard Kandolf, MD,†
Udo Sechtem, MD*
Stuttgart and Tuebingen, Germany

Objectives We sought to evaluate the diagnostic performance of cardiovascular magnetic resonance imaging (CMRI) for
detection of cardiac amyloidosis compared with endomyocardial biopsy (EMB) in a clinical routine setting.

Background For the clinical workup of heart failure with restrictive filling, pattern cardiac amyloidosis is an important differ-
ential diagnosis that is difficult to verify with current noninvasive techniques, especially in the presence of myo-
cardial hypertrophy.

Methods A total of 33 consecutive patients underwent both CMRI and EMB for workup of heart failure with restrictive fill-
ing pattern in combination with myocardial hypertrophy (n ⫽ 24) and/or clinical conditions often associated with
cardiac amyloidosis (n ⫽ 18).

Results Cardiac amyloidosis was detected by EMB in 15 of the 33 patients. In patients with biopsy-proven cardiac amy-
loidosis, CMRI revealed a distinct pattern of late gadolinium enhancement, which was distributed over the entire
subendocardial circumference, extending in various degrees into the neighboring myocardium. This pattern was
found in 12 of the 15 patients diagnosed with cardiac amyloidosis by EMB, compared with only 1 individual in
the group of 18 patients diagnosed with other myocardial diseases. Consequently, using this pattern as a diag-
nostic criterion, the sensitivity of CMRI for diagnosing cardiac amyloidosis was 80%, yielding a specificity of
94%. The positive predictive value was 92%, and the negative predictive value was 85%.

Conclusions In patients with biopsy-proven cardiac amyloidosis, late gadolinium enhancement frequently occurs in a peculiar
pattern. On the basis of the gold standard, EMB, noninvasive CMRI can be used to diagnose or rule out cardiac
amyloidosis with good sensitivity and excellent specificity in a clinical routine setting. (J Am Coll Cardiol 2008;
51:1022–30) © 2008 by the American College of Cardiology Foundation

In the clinical workup of patients with diastolic heart failure
and myocardial hypertrophy, cardiac amyloidosis is an
important differential diagnosis (1). Effective treatments for
See page 1031
some forms of cardiac amyloidosis exist, but treatment
options are extremely limited once severe symptoms of heart
failure become clinically apparent. Consequently, the early
diagnosis of cardiac amyloidosis may significantly improve
the clinical outcome (1).
From the *Division of Cardiology, Robert Bosch Medical Center, Stuttgart, Germany;
and the †Department of Molecular Pathology, University of Tuebingen, Tuebingen,
Germany. The first 2 authors contributed equally to this article and they both share
first authorship of this article.
Manuscript received July 16, 2007; revised manuscript received September 24,
2007, accepted October 31, 2007.
The gold standard for diagnosing cardiac amyloidosis is
endomyocardial biopsy (EMB) (2), but this technique is
invasive, limited to experienced centers, and thus not widely
available. Hence, in clinical practice, the diagnosis of cardiac
amyloidosis rests mainly on echocardiographic findings,
supported by the clinical history, and a diagnostic noncar-
diac biopsy (3,4). However, diagnosis by echocardiography
has limitations (5), particularly if hypertrophy from other
causes is present. Other noninvasive methods also have
limitations (6), including electrocardiography (7) or scinti-
graphic techniques (8,9).
Recent pilot data (10,11) suggest that noninvasive car-
diovascular magnetic resonance imaging (CMRI) using late
gadolinium enhancement (LGE) may be a valuable tool for
diagnosing cardiac amyloidosis. This technique has proven
clinical value for noninvasive tissue characterization in
several cardiac diseases (12) and may overcome many
JACC Vol. 51, No. 10, 2008 Vogelsberg et al. 1023
March 11, 2008:1022–30 CMRI in Cardiac Amyloidosis

limitations of other noninvasive methods in the clinical 10 mm (slice thickness 6 mm) Abbreviations
setting of suspected cardiac amyloidosis (13). from base to apex. In-plane res- and Acronyms
Consequently, we sought to evaluate the diagnostic per- olution was typically 1.2 ⫻
CMRI ⴝ cardiovascular
formance of CMRI for detection of cardiac amyloidosis 1.8 mm. Cine CMRI was per- magnetic resonance
compared with the gold-standard EMB in a routine clinical formed using a steady-state free- images/imaging
setting in consecutive patients admitted for workup of heart precession sequence. The LGE EMB ⴝ endomyocardial
failure with restrictive filling pattern in combination with images were acquired on average biopsy
myocardial hypertrophy and/or conditions often associated 5 min (10) after administrating LGE ⴝ late gadolinium
with cardiac amyloidosis. gadodiamide 0.1 mmol/kg (Omni- enhancement

scan, Amersham-Health, Braun-

Methods
Patient population. Between 2003 and 2006, 33 consecu-
tive patients underwent both CMRI and EMBs for workup
of heart failure with restrictive filling pattern in combination
with myocardial hypertrophy (n ⫽ 24) and/or conditions
often associated with cardiac amyloidosis (n ⫽ 18) such as
systemic amyloidosis (n ⫽ 4), multiple myeloma (n ⫽ 5),
lymphoma (n ⫽ 2), end-stage renal failure (n ⫽ 3), or other
conditions (n ⫽ 4). To allow evaluation of the diagnostic
performance of CMRI in a clinical routine setting, patients
with dyspnea at rest, atrial fibrillation, ventricular arrhyth-
mias, and other frequent cardiac disorders such as coronary
artery disease were not excluded. All patients gave written
informed consent and were included in the study.
CMRI protocol. Electrocardiographically gated CMRI
was performed in breath-hold using a 1.5-T Magnetom
Sonata (Siemens Medical Systems, Erlangen, Germany).
Both cine and LGE short-axis CMRI were prescribed every
schweig, Germany) using a seg-
mented inversion recovery gradient echo technique, constantly
adjusting the inversion time to null normal myocardium (14).
In addition, fat-saturated and T2-weighted images were ob-
tained to allow differentiation among subepicardial LGE,
epicardial fat, and pericardial effusion.
In cardiac amyloidosis, however, it may be difficult to
determine the optimal inversion time that will null normal
myocardium, as it may be unclear which myocardial areas
are normal (10). Thus, we first acquired multiple images of
the same view using different inversion times. If a large
portion of left ventricular myocardium (i.e., ⬎50%) goes
through the null point earlier than the left ventricular cavity
and this region is not in an obvious coronary artery
distribution territory, this area is highly likely to represent
myocardial disease such as cardiac amyloid. Consequently,
the inversion time was then adjusted to null the remaining
myocardial areas (Fig. 1).

Multiple Contrast CMRI of the Same Short-Axis View Using

Figure 1
Different TI Acquired Beginning at 4 Min After Contrast Injection

At inversion time (TI) ⫽ 80 ms, all structures are below the null point and appear gray on the image. At TI ⫽ 120 ms, a large portion of the subendocardial left ventricu-
lar (LV) myocardium (white arrows) goes through the null point earlier than the LV cavity, which crosses the null point at a TI of 200 ms (white circle). Because this
region (subendocardial circumference and right ventricle) is obviously not a coronary artery distribution territory, this area is highly likely to represent myocardial disease
such as cardiac amyloid (high signal at 240 ms). The myocardium surrounding this region is likely to be normal, as it is nulled at a TI of 240 ms (white arrows in black
framed image). CMRI ⫽ cardiovascular magnetic resonance imaging.
1024 Vogelsberg et al. JACC Vol. 51, No. 10, 2008
CMRI in Cardiac Amyloidosis March 11, 2008:1022–30

CMRI analysis. Cine and contrast images were evaluated
separately by 2 blinded observers as described elsewhere
(15,16). In brief, endocardial and epicardial borders were
outlined on the short-axis cine images. Volumes, myocardial
mass, and ejection fraction were derived by summation of
epicardial and endocardial contours.
Regional parameters were assessed, dividing each short
axis into 12 circumferential segments (Fig. 2). For each
segment, the extent of LGE was analyzed using the NIH
image analysis software package (National Institutes of
Health, Bethesda, Maryland), and the results were
expressed as a percentage of the area of the outer, middle,
and inner third of each segment.
Myocardial biopsy protocol. At least 5 endomyocardial
biopsies were taken from the region showing LGE, as
described elsewhere (16). In patients without the presence
of LGE, at least 4 biopsies were taken from the right
ventricle (septum) and usually also another 4 biopsies from
left ventricular lateral wall to minimize sampling errors.
Histopathological analysis. The EMBs were stained with
Masson’s trichrome and examined by light microscopy.
Cardiac amyloidosis was diagnosed using Congo red stain-
ing by demonstration of the typical green birefringence
under cross-polarized light. Additionally, electron micros-
copy for visualization of amyloid deposits was performed to
rule out Congo red negative amyloidosis (Fig. 2).
To diagnose/exclude inflammatory heart disease, paraffin
tissue sections were treated with an avidin-biotin immuno-
peroxidase method (Vectastain-Elite ABC Kit, Vector,
Burlingame, California) with application of the following
monoclonal antibodies: CD3 (T-cells, Novocastra Labora-
tories, Newcastle, United Kingdom), CD68 (macrophages,
natural killer cells, DAKO, Hamburg, Germany), and
LGE Analysis
EMB WORK UP
HLA-DR-alpha (DAKO). Myocardial inflammation
indicative of myocarditis was defined as the detection of
ⱖ14 infiltrating leukocytes/mm2 (CD3⫹ T lymphocytes
and/or CD68⫹ macrophages) (17).
Statistical analysis. Data for continuous variables are ex-
pressed as mean value ⫾ SD, whereas data for categorical
variables are expressed as the number and the percentage of
patients. Comparisons between groups were done using a
2-tailed unpaired Student t test for normally distributed and
Mann-Whitney U test for non-normally distributed con-
tinuous variables. For categorical variables, we used the
chi-square test and Fisher exact test where appropriate. The
difference between 2 groups was defined to be statistically
significant if the 2-tailed p value was ⬍0.05.
The authors had full access to the data and take respon-
sibility for its integrity. All authors have read and agree to
the manuscript as written.
Results
Patient characteristics. All patients presented with various
degrees of dyspnea limiting their exercise tolerance (n ⫽ 29)
or experienced dyspnea at rest (n ⫽ 4). Three patients
reported atypical chest pain, and 3 other patients had atrial
fibrillation. Most patients did not have evidence for systemic
amyloidosis upon presentation, except 4 in whom systemic
amyloidosis was demonstrated by noncardiac biopsy. Nine
patients had significant coronary artery disease, defined as
coronary artery stenosis ⬎50% in diameter. All patients
with coronary artery disease had already been revascularized
if possible and were receiving appropriate medication. On
the basis of coronary angiography at the time point of EMB,
additional coronary intervention was not indicated in any of

* *

A B C D E
Figure 2 Contrast Short-Axis CMRI and EMB Work Up of Patient #17

(Top row) Contrast short-axis CMRI of Patient #17 (basal slice on the left with subsequent 6-mm slices toward the apex shown to the right; there is a 4-mm gap
between slices; TI ⫽ 220 ms). For contrast CMRI analysis, each short-axis image was divided into 12 circumferential segments by applying a grid, as demonstrated in
the upper row. (Bottom row) Histopathological workup of endomyocardial biopsy (EMB) samples for cardiac amyloidosis included Masson’s trichrome staining with amy-
loid deposits (arrows) between myocytes (A), Congo red staining (B) with demonstration of typical red/green birefringence (ⴱ) under cross-polarized light (C), as well as
electron microscopy visualizing amyloid deposits between myocytes expanding the extracellular volume (D and E). LGE ⫽ late gadolinium enhancement; other abbrevia-
tions as in Figure 1.
JACC Vol. 51, No. 10, 2008 Vogelsberg et al. 1025
March 11, 2008:1022–30 CMRI in Cardiac Amyloidosis

Patient Characteristics
Table 1 Patient Characteristics

Amyloid LGE
Patient # Age (yrs) EF (%) EDV (ml) IVS Max (mm) LV Mass (g) LGE (Y/N) PAP LGE (Y/N) Pattern (Y/N) EMB Result
1 55 66 64 15 116 1 1 1 AMYLO
2 76 45 165 20 236 1 1 1 AMYLO
3 50 68 171 17 234 1 0 0 LVH⫹MYO
4 68 66 116 9 88 0 0 0 LVH
5 64 39 185 13 158 1 0 0 MYO
6 79 69 121 11 145 0 0 0 LVH
7 72 62 139 22 172 1 1 1 AMYLO
8 69 69 137 21 234 1 1 1 AMYLO
9 74 50 102 22 176 1 1 1 AMYLO
10 68 48 111 13 183 1 0 0 MYO
11 80 83 103 11 124 1 0 0 LVH
12 68 65 76 12 81 1 0 0 LVH
13 76 72 138 22 249 1 1 1 AMYLO
14 44 56 107 13 107 0 0 0 HCM
15 52 40 85 17 205 1 1 0 HCM
16 72 69 111 18 156 1 0 0 AMYLO
17 64 36 191 18 293 1 1 1 AMYLO
18 77 61 125 10 106 0 0 0 UNCLEAR
19 65 57 150 20 294 1 0 0 LVH
20 70 72 116 10 115 1 0 0 MYO
21 62 37 228 10 172 0 0 0 MYO
22 34 49 208 16 322 1 1 1 HCM
23 62 39 105 14 191 1 0 0 MYO
24 84 57 163 14 201 1 1 1 AMYLO
25 68 87 134 14 163 0 0 0 MYO
26 34 49 108 15 181 1 0 0 MYO⫹LVH
27 47 30 54 15 101 1 0 1 AMYLO
28 71 60 143 19 276 1 1 1 AMYLO
29 44 77 84 13 114 1 1 1 AMYLO
30 47 72 100 16 170 1 1 1 AMYLO
31 61 55 201 9 163 1 0 0 AMYLO
32 67 62 112 16 175 1 0 0 HCM
33 81 27 128 10 158 0 0 0 AMYLO
All 64 ⫾ 13 57 ⫾ 15 130 ⫾ 41 15 ⫾ 4 178 ⫾ 62 79% 39% 39% N/A

All ⫽ average or percentage; AMYLO ⫽ amyloidosis; Amyloid LGE Pattern ⫽ diffuse subendocardial late gadolinium enhancement distribution, as displayed in Figure 4; EDV ⫽ end-diastolic volume; EF ⫽
ejection fraction; EMB ⫽ endomyocardial biopsy; HCM ⫽ hypertrophic cardiomyopathy; IVS ⫽ interventricular septum; LGE ⫽ late gadolinium enhancement; LV ⫽ left ventricular; LVH ⫽ secondary left
ventricular hypertrophy; Max ⫽ maximum; MYO ⫽ myocarditis; N/A ⫽ not applicable; PAP LGE ⫽ late gadolinium enhancement in papillary muscles.

these patients. Other clinical characteristics of all patients
can be viewed in Table 1.
Histopathological results. The EMB was performed
without complications in all 33 patients. In 15 patients,
cardiac amyloidosis was identified by histopathological
workup as described earlier. In the remaining 18 patients,
EMB revealed myocarditis (n ⫽ 6), secondary left ventric-
ular hypertrophy (n ⫽ 5), hypertrophic cardiomyopathy
(n ⫽ 4), or combinations of those entities, as displayed in
Table 1. In 1 patient (Patient #18), small amounts of
nonspecific interstitial myocardial fibrosis were detected, but
no definite diagnosis could be made.
In the group of patients with significant coronary artery
disease (n ⫽ 9), cardiac amyloidosis was detected in 3 patients,
which was not significantly different from all patients without
coronary artery disease (p ⫽ 0.5). All 4 patients with known
systemic amyloidosis also had evidence of cardiac amyloid-
osis by EMB.
CMRI results. We performed CMRI in all 33 patients,
including 4 patients with dyspnea at rest and 3 patients with
atrial fibrillation. Although breathing and trigger artifacts
occurred more frequently in those 7 patients, image quality
was sufficient for analysis in all 33 patients. Late gadolinium
enhancement was present in 26 of the 33 patients (79%).
Baseline CMRI characteristics such as ejection fraction,
end-diastolic volume, ventricular mass, and maximum ven-
tricular wall thickness can be viewed in Table 1.
Several different patterns of LGE were present in this
patient population. In 13 patients, LGE was distributed
over the entire subendocardial circumference, extending
in various degrees into the neighboring myocardium (Fig.
3). In 6 other patients, we found focal intramural LGE in
1026 Vogelsberg et al. JACC Vol. 51, No. 10, 2008
CMRI in Cardiac Amyloidosis March 11, 2008:1022–30

Figure 3 Typical Contrast CMRI of 2 Patients Diagnosed With Cardiac Amyloidosis by EMB

In both patients, LGE was diffusely distributed in large areas of the left ventricle involving the entire subendocardium (TI ⫽ 230 ms in both patients). Interestingly, the
subepicardial myocardium is affected only in areas of transmural LGE. Note that LGE is also located in the papillary muscles (white arrowheads). Histologic images
include Mason’s trichrome with amyloid deposits between myocytes (black arrows, large right panels) and Congo red staining (inset right panels) demonstrating typical
green birefringence under cross-polarized light. Abbreviations as in Figures 1 and 2.

the left interventricular septum, often originating from
the right ventricular insertion points (Fig. 4), as well as
subepicardial LGE, located mainly in the left ventricular
Patient 15
Patient 20
lateral wall, in 4 patients (Fig. 4). The remaining patients had
focal areas of LGE in various locations of the left ventricular
myocardium. Late gadolinium enhancement located in the

Contrast CMR Imaging Trichrome

Figure 4 Typical Contrast CMRI of 2 Patients Diagnosed With Other Myocardial Diseases

One patient demonstrated focal intramural LGE at the right ventricular insertion points, which is a typical finding in hypertrophic cardiomyopathy (top row, white arrows,
TI ⫽ 320 ms). This diagnosis was confirmed by histopathology demonstrating myocyte hypertrophy (red cells) and interstitial fibrosis as shown by Masson’s trichrome
staining (blue areas between myocytes, black arrows). Note that LGE is also present in the inferior papillary muscle in this patient (thin white arrow). The second
patient was diagnosed with myocarditis exhibiting enhanced numbers of interstitial CD68⫹ macrophages as well as interstitial edema. Molecular pathology revealed
PVB19 in the myocardium. The white arrows in the bottom panel point to typical subepicardial LGE in the left ventricular inferolateral wall (TI ⫽ 300 ms). Note that the
pattern of LGE found in these patients is completely different from the LGE pattern that is usually present in patients with biopsy proven cardiac amyloidosis (Fig. 3).
Abbreviations as in Figures 1 and 2.
JACC Vol. 51, No. 10, 2008 Vogelsberg et al. 1027
March 11, 2008:1022–30 CMRI in Cardiac Amyloidosis

Late Gadolinium
Versus Endomyocardial
Enhancement
Biopsy
Late Gadolinium Enhancement
Table 3
Versus Endomyocardial Biopsy

Amyloid LGE Pattern No/Other LGE All

Cardiac amyloid by EMB 12 3 15
Other patients 1 17 18
All 13 20 33

Sensitivity (LGE) ⫽ 80%; specificity (LGE) ⫽ 94%; positive predictive value (LGE) 92%; negative
predictive value (LGE) ⫽ 85%.
Abbreviations as in Table 1.

not significantly different between the cardiac amyloidosis

Spatial Distribution of LGE in
Figure 5
Patients With and Without Amyloid
Spatial distribution of the mean values for segmental extent of LGE values are
represented as gray-scale maps in basal, mid-, and apical short-axis slices in
all patients diagnosed with cardiac amyloidosis by endomyocardial biopsy (top
row) and all other patients (bottom row). In patients with biopsy-proven car-
diac amyloidosis, LGE is typically distributed diffusely in large areas of the left
ventricle, mainly involving the subendocardial area circumferentially, whereas
the subepicardial myocardium is less affected. Abbreviations as in Figure 2.
group and all other patients, except the thickness of the
interventricular septum (Table 2). Interestingly, all 3
patients initially presenting with atrial fibrillation did not
have cardiac amyloidosis by EMB. One was diagnosed with
myocarditis, 1 with secondary left ventricular hypertrophy in
the setting of hypertension, and 1 with hypertrophic car-
diomyopathy.
Using the amyloid LGE pattern as a diagnostic criterion,
the sensitivity of CMRI to detect cardiac amyloidosis was
80% compared with the gold-standard EMB, yielding an
excellent specificity of 94%. Positive and negative predictive
values of typical amyloid LGE pattern are displayed in
Table 3.

papillary muscles could be observed in 13 of 33 patients (Figs.
3 and 4).
Comparing cardiac amyloidosis patients with all other
patients. In the group of patients with biopsy-proven
cardiac amyloidosis, LGE was typically distributed over the
entire subendocardial circumference, extending in various
degrees into the neighboring myocardium (Figs. 3 and 5).
This pattern (amyloid LGE pattern) (Fig. 5) was found in
12 of the 15 patients diagnosed with cardiac amyloidosis by
EMB, compared with only 1 individual in the group of 18
patients diagnosed with other myocardial diseases (Table 2).
In addition to presentation with amyloid LGE pattern,
patients with cardiac amyloidosis were much more likely to
demonstrate LGE in the papillary muscles than were
patients without cardiac amyloidosis (Table 2). All other
clinical characteristics, including ejection fraction, left ven-
tricular end-diastolic volume, and myocardial mass, were
Comparison of Patients With Cardiac Amyloidosis Versus Other Patients
Table 2 Comparison of Patients With Cardiac Amyloidosis Versus Other Patients
Discussion
This study is unique in that the diagnostic performance of
CMRI for detection of cardiac amyloidosis is evaluated by
direct comparison of CMRI results to the gold-standard
EMB in clinical routine patients. Our data indicate a
distinct LGE distribution pattern in cardiac amyloidosis
(Fig. 5) that can be used to noninvasively diagnose or rule
out cardiac amyloidosis in a clinical routine setting with
good sensitivity (80%) and excellent specificity (94%).
Histopathological results. Using EMB as a gold standard,
we could identify 15 individuals with cardiac amyloidosis
among our group of patients presenting for workup of
diastolic heart failure and/or myocardial hypertrophy. This
high prevalence of 45% is most likely explained by our
inclusion criteria, because in addition to signs of heart
failure with restrictive filling pattern, most patients had
myocardial hypertrophy (n ⫽ 24) and/or had conditions

Amyloidosis (n ⴝ 15) Others (n ⴝ 18) p Value OR 95% CI (OR ⫽ 1)

Age (yrs) 66 ⫾ 13 62 ⫾ 14 0.26 — —
EF (%) 56 ⫾ 16 58 ⫾ 15 0.96 — —
EDV (ml) 128 ⫾ 43 130 ⫾ 42 0.93 — —
IVS max (mm) 17 ⫾ 4 13 ⫾ 3 0.011 — —
LV mass (g) 188 ⫾ 59 166 ⫾ 66 0.31 — —
LGE (n) 14 (93%) 11 (61%) 0.05 8.38 0.9–428.5
PAP LGE (n) 11 (80%) 2 (11%) 0.0004 19.29 2.7–248.2
Amyloid LGE pattern (n) 12 (80%) 1 (5%) 0.000014 54.73 5.3–2,993.9

Bold indicates statistical significance; 2-tailed p value ⬍0.05.

Amyloid LGE pattern ⫽ diffuse subendocardial LGE distribution, as displayed in Figure 5; CI ⫽ confidence interval; OR ⫽ odds ratio (Fisher exact
test); other abbreviations as in Table 1.
1028 Vogelsberg et al.
CMRI in Cardiac Amyloidosis
often associated with cardiac amyloidosis (n ⫽ 18), such as
systemic amyloidosis (n ⫽ 4), multiple myeloma (n ⫽ 5),
lymphoma (n ⫽ 2), end-stage renal failure (n ⫽ 3), or
others (n ⫽ 4).
The EMB revealed cardiac amyloidosis in all 4 patients
with known systemic amyloidosis. In the presence of dia-
stolic heart failure and hypertrophy in those patients, this
finding is not surprising. However, in 11 of the remaining
29 patients without any evidence of systemic amyloidosis,
EMB also revealed cardiac amyloidosis. This suggests that
cardiac amyloidosis without any evidence of systemic amy-
loidosis might occur more frequently than currently sus-
pected (18). This would be of clinical importance, because
in the clinical routine the diagnosis of cardiac amyloidosis is
made only if a noncardiac biopsy shows amyloid and
echocardiography demonstrates a pattern suggestive of car-
diac involvement (3,4). Thus, if cardiac amyloidosis can
frequently occur without systemic amyloidosis, an unknown
number of patients with cardiac amyloidosis might remain
undiagnosed until severe symptoms of heart failure of
unknown origin force them to undergo EMB. Because
treatment options are extremely limited once severe symptoms
of heart failure become clinically apparent, the early identifi-
cation of those patients may significantly improve their clinical
outcome (1).
In the remaining 18 patients without any histological evi-
dence of cardiac or systemic amyloidosis, the most frequent
diagnosis was myocarditis, followed by secondary left ventric-
ular hypertrophy and hypertrophic cardiomyopathy (Table 1).
One would expect a relatively high prevalence of secondary
hypertrophy and hypertrophic cardiomyopathy in elderly pa-
tients presenting with diastolic heart failure (19), but the high
prevalence of myocarditis in our patient population is some-
what surprising. However, this finding may be explained by
2 facts: first, myocarditis is also known to cause diastolic
heart failure (20), which was an inclusion criteria for this
study; second, the general prevalence of myocarditis might
be underestimated because the clinical diagnosis of myocar-
ditis is often difficult to achieve (21,22).
CMRI results. Late gadolinium enhancement was present
in 79% of patients, indicating that LGE is a frequent
finding in clinical routine patients presenting for workup of
heart failure with restrictive filling pattern in combination
with myocardial hypertrophy and/or conditions often asso-
ciated with cardiac amyloidosis.
In the group with biopsy-proven cardiac amyloidosis, we
found a distinct pattern of myocardial LGE. Twelve of the
15 patients had LGE distributed over the entire subendo-
cardial circumference, extending in various degrees into the
neighboring myocardium (Figs. 3 and 5). This finding is in
line with the report of Maceira et al. (10) describing a
substantially lower T1 relaxation time in the subendocar-
dium of patients with cardiac amyloidosis after administra-
tion of gadolinium using a T1 mapping CMRI technique.
However, our finding of a distinct “amyloid LGE pattern”
contradicts the conclusions of Perugini et al. (11) that the
JACC Vol. 51, No. 10, 2008
March 11, 2008:1022–30
distribution of LGE in cardiac amyloidosis is highly vari-
able. This discrepancy may be explained by the fact that
Perugini et al. (11) started the acquisition of contrast images
10 to 15 min after gadolinium injection. Because LGE in
cardiac amyloidosis fades with equalization of T1 between
the subendocardium and subepicardium approximately 8
min after gadolinium injection owing to altered contrast
agent kinetics (10), the late start of image acquisition at 15
min after gadolinium administration might have signifi-
cantly affected imaging results in the study of Perugini et al.
(11).
Importantly, the distinct pattern of LGE in cardiac
amyloidosis, as described in the current study, may be
explained by the uneven transmural distribution of amyloid
seen in necropsy. Becker et al. (23) reported that cardiac
amyloid deposits are predominantly located diffusely in the
subendocardial region and that they may even produce a
“sandy sensation” when the formalin-fixed subendocardial
area is palpated during post-mortem examination (23).
Maceira et al. (10) also found a subendocardially pro-
nounced distribution of amyloid protein in their study
(subendocardium 42.4%, subepicardium 17.6%). Because
amyloidosis causes accumulation of abnormal interstitial
protein, resulting in an enlargement of the extracellular
space, it is highly likely that on the basis of the general
mechanism of LGE (12), amyloid deposits alone will result
in LGE in the absence of significant myocardial fibrosis or
necrosis. However, if amyloid deposits result in LGE, it
conceptually follows that the pattern of LGE in patients
with cardiac amyloidosis is supposed to match the distribu-
tion of cardiac amyloid protein demonstrated post-mortem.
Figure 6 compares a long-axis contrast CMRI from a
patient included in this study to a necropsy image from a
different cardiac amyloidosis patient published by Becker et
al. (23). The typical diffuse LGE affecting the subendocar-
Contrast CMR in patient 2 Necropsy from Becker AE and Anderson HR
Figure 6 Contrast Long-Axis CMR Compared to Necroscopy
Long-axis contrast CMRI (Left) patient #2 (TI ⫽ 230 ms). (Right) necropsy
sample of a different patient diagnosed with cardiac amyloidosis. Interestingly,
the pattern of diffuse LGE originating from the subendocardium nicely matches
the pattern of pale subendocardial amyloid deposits indicated by white arrow-
heads in the necropsy sample. Right panel adapted with permission from (23).
Abbreviations as in Figures 1 and 2.
JACC Vol. 51, No. 10, 2008
March 11, 2008:1022–30
dial areas nicely matches the pale subendocardial regions of
amyloid deposits in the necropsy case.
However, despite this match between LGE and the
distribution of amyloid seen in necropsy, it needs to be kept
in mind that in the present study 3 patients with biopsy-
proven cardiac amyloidosis did not demonstrate this typical
“amyloid LGE pattern” (Patients #16, #31, and #33).
Patient #31 had significant left anterior descending artery
stenosis, and CMRI showed typical subendocardial LGE in
the left anterior descending artery territory indicative of
nontransmural myocardial infarction. In this patient, EMB
revealed only very small amounts of cardiac amyloid due to
multiple myeloma. Thus, this very small amount of cardiac
amyloid was most probably beyond the spatial resolution of
CMRI (12), which typically was about 1.2 ⫻ 1.8 mm in
plane. This mechanism may also explain the absence of any
LGE in Patient #33. Patient #16 had patchy subendocardial,
as well as diffuse intramural posterolateral LGE, maybe reflect-
ing heterogeneous cardiac amyloid deposition, as reported to
occur in some patients by post-mortem exam (24).
Interestingly, in 1 other patient (Patient #22) in whom
the typical LGE pattern of cardiac amyloidosis was present,
no evidence of cardiac or systemic amyloidosis could be
found by histopathology. One possible explanation for this
finding might be that the “amyloid LGE pattern” may also
occur in other myocardial diseases. However, it is also
possible that Patient #22 was erroneously assigned to the
“no amyloidosis” group because of a sampling error in
endomyocardial biopsies. In fact, the clinical history of this
patient with a systemic disease, hepatomegaly, as well as
echocardiographic and CMRI findings would be much
more indicative of cardiac amyloidosis than of hypertrophic
cardiomyopathy, as suggested by EMB.
Comparing cardiac amyloidosis patients with all other
patients. Comparing patients with biopsy-proven cardiac
amyloidosis with patients without amyloidosis, we did not
find a significant difference in left ventricular ejection
fraction, end-diastolic volume, or myocardial mass (Table
2). These data, furthermore, underscore the difficulties of
diagnosing cardiac amyloidosis based on morphological or
functional features. Interestingly, the average thickness of
the interventricular septum was significantly different be-
tween the groups. Patients with cardiac amyloidosis had an
average septal thickness of 17 ⫾ 4 mm compared with 13 ⫾
3 mm in nonamyloid patients, which is consistent with
echocardiographic data (25). In the clinical routine, how-
ever, this sign is not helpful in making the diagnosis of
cardiac amyloidosis, because advanced patient age (64 ⫾ 13
years in the present study) and common comorbidities such
as hypertension render septal ventricular hypertrophy
nonspecific to the underlying disease process (5,13,19).
Moreover, cardiac amyloidosis can be present in patients
without any septal hypertrophy (e.g., Patients #31 and
#33 in Table 1).
In the present study, the incidence of LGE located within
the papillary muscles was significantly higher in patients
Vogelsberg et al. 1029
CMRI in Cardiac Amyloidosis
with cardiac amyloidosis than in all other patients (Table 2).
This finding is consistent with post-mortem data (23)
reporting amyloid deposits in the entire subendocardial
region, including the papillary muscles. Some authors (26)
have also described the papillary muscles to be “more dense
than normal” on echocardiographic images as an additional
feature of myocardial “sparkling” observed by echocardiog-
raphy in cardiac amyloidosis patients. However, changes in
echocardiographic technology have rendered this finding
less noticeable in the current clinical routine (25). In the
present study, papillary LGE was almost always seen in
combination with “amyloid LGE pattern” except for 2 cases
of hypertrophic cardiomyopathy (Patients #15 and #22)
(Fig. 4). Thus, the role of papillary LGE for the diagnosis
of cardiac amyloidosis needs to be further investigated.
Clinical implications. On the basis of our findings, non-
invasive CMRI can be used to identify patients with cardiac
amyloidosis with good sensitivity and excellent specificity
compared with the gold-standard EMB. Importantly, this
was shown in a clinical routine setting, because patients with
dyspnea at rest, atrial fibrillation, and other frequent cardiac
disorders such as coronary artery disease were not excluded.
Thus, in the future it may be possible to establish the
diagnosis of cardiac amyloidosis on the basis of clinical
criteria in combination with the presence of the “amyloid
LGE pattern.” In those patients, treatment may be initiated
without the need for EMB, except if the exact type of
amyloid is needed for therapy planning. However, if no
“amyloid LGE pattern” is present, EMB will probably
remain necessary to detect “CMRI-negative” amyloidosis or
other myocardial pathology.
Although still a small sample, the data of the present
study point to a lower index of suspicion required to
begin the search for amyloid with this new technique.
This is also underscored by the fact that our data suggest
that cardiac amyloidosis might occur more frequently
without any evidence of systemic amyloidosis than cur-
rently suspected.
Nevertheless, before any evidence-based clinical recommen-
dations can be made, all these findings need to be further
investigated in a larger patient population and a multicenter
setting.
In addition to the diagnosis of cardiac amyloidosis itself,
contrast CMRI provides direct information on the spatial
distribution of cardiac amyloid protein in the myocardium
and thus might be proven useful by further investigations to
monitor progression or regression of cardiac amyloid de-
positions, with or without therapy. However, because of
recent reports of nephrogenic systemic fibrosis (27), the use
of gadolinium-based contrast agents may be limited in
patients with severe renal problems. This also needs further
investigation, as well as the question whether CMRI tech-
niques without gadolinium-based contrast agents may be
helpful in identifying cardiac amyloidosis in the subgroup of
renal patients.
1030 Vogelsberg et al.
CMRI in Cardiac Amyloidosis
Conclusions
On the basis of the gold-standard EMB, noninvasive CMRI
can be used to diagnose or rule out cardiac amyloidosis with
good sensitivity and excellent specificity in a clinical routine
setting. In patients with biopsy-proven cardiac amyloidosis,
LGE frequently occurs in a peculiar pattern, diffusely distrib-
uted over the entire subendocardial circumference and extend-
ing in various degrees into the neighboring myocardium. This
pattern may directly reflect the spatial distribution of amyloid
protein in the myocardium.
Reprint requests and correspondence: Dr. Heiko Mahrholdt,
Robert Bosch Medical Center, Auerbachstrasse 110, 70376 Stutt-
gart, Germany. E-mail: Heiko.Mahrholdt@rbk.de.
REFERENCES
1. Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart. A
comprehensive review. Arch Intern Med 2006;166:1805–13.
2. Duston MA, Skinner M, Shirahama T, Cohen AS. Diagnosis of
amyloidosis: analysis of four years’ experience. Am J Med 1987;82:
412– 4.
3. Falk RH, Skinner M. The systemic amyloidoses: an overview. Adv
Intern Med 2000;45:107–37.
4. Hamer JP, Janssen S, van Rijswijk MH, Lie KI. Amyloid cardiomy-
opathy in systemic non-hereditary amyloidosis: clinical, echocardio-
graphic and electrocardiographic findings in 30 patients with AA and
24 patients with AL amyloidosis. Eur Heart J 1992;13:623–7.
5. Klein AL, Hatle LK, Burstow DJ, et al. Doppler characterization of
left ventricular diastolic function in cardiac amyloidosis. J Am Coll
Cardiol 1989;13:1017–26.
6. Dubrey SW, Cha K, Anderson J, et al. The clinical features of
immunoglobulin light chain (AL) amyloidosis with heart involvement.
Q J Med 1998;91:141–57.
7. Reisinger J, Dubrey SW, Lavalley M, Skinner M, Falk RH. Electro-
physiologic abnormalities in AL (primary) amyloidosis with cardiac
involvement. J Am Coll Cardiol 1997;30:1046 –51.
8. Hawkins PN, Myers MJ, Epenetos AA, Caspi D, Pepys MB. Specific
localization and imaging of amyloid deposits in vivo using 123I-
labeled serum amyloid P component. J Exp Med 1988;167:903–13.
9. Hawkins PN, Pepys MB. Imaging amyloidosis with radiolabelled
SAP. Eur J Nucl Med 1995;22:595–9.
JACC Vol. 51, No. 10, 2008
March 11, 2008:1022–30
10. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic
resonance in cardiac amyloidosis. Circulation 2005;111:122– 4.
11. Perugini E, Rapezzi C, Piva T, et al. Non-invasive evaluation of the
myocardial substrate of cardiac amyloidosis by gadolinium cardiac
magnetic resonance. Heart 2006;92:343–9.
12. Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed
enhancement cardiovascular magnetic resonance assessment of non-
ischaemic cardiomyopathies. Eur Heart J 2005;26:1461–74.
13. Kwong RY, Falk RH. Cardiovascular magnetic resonance in cardiac
amyloidosis. Circulation 2005;111:122– 4.
14. Simonetti OP, Kim RJ, Fieno DS, et al. An improved MR-imaging
technique for the visualization of myocardial infarction. Radiology
2001;218:215–23.
15. Mahrholdt H, Wagner A, Holly T, et al. Reproducibility of infarct
size measurements by contrast-enhanced MRI. Circulation 2002;106:
2322–7.
16. Mahrholdt H, Goedecke C, Wagner A, et al. CMR Assessment of
human myocarditis; a comparison to histology and molecular pathol-
ogy. Circulation 2004;109:1250 – 8.
17. Klingel K, Sauter M, Bock CT, Szalay G, Schnorr JJ, Kandolf R.
Molecular pathology of inflammatory cardiomyopathy. Med Microbiol
Immunol 2004;193:101–7.
18. Arbustini E, Verga L, Concardi M, et al. Electron and immuno-
electron microscopy of abdominal fat identifies and characterizes
amyloid fibrils in suspected cardiac amyloidosis. Amyloid 2002;9:
108 –14.
19. Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis,
detection, and prognosis. Circulation 2000;102:470 –9.
20. Tschope C, Bock CT, Kasner M, et al. High prevalence of cardiac
parvovirus B19 infection in patients with isolated left ventricular
diastolic dysfunction. Circulation 2005;111:879 – 86.
21. Phillips M, Robinowitz M, Higgins J, et al. Sudden cardiac death in
air force recruits. JAMA 1986;256:2696 –9.
22. Wesslen L, Pahlson C, Lindquist O, et al. An increase in sudden
unexpected cardiac deaths among young Swedish orienteers during
1979-1992. Eur Heart J 1996;17:902–10.
23. Becker AE, Anderson HR. Cardiac Pathology. New York, NY: Raven
Press, 1983.
24. Smith TJ, Kyle R, Lie JT. Clinical significance of histopathologic
patterns of cardiac amyloidosis. Mayo Clin Proc 1984;59:547–55.
25. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of
biopsy-proven cardiac amyloidosis. J Am Coll Cardiol 2004;43:410 –5.
26. Pierard L, Verheugt FW, Meltzer RS, Roelandt J. Echocardiographic
aspects of cardiac amyloidosis. Acta Cardiol 1981;36:455– 61.
27. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic
fibrosis: risk factors and incidence estimation. Radiology 2007;
243:148 –57.