Keywords Amyloidosis - cardiac - magnetic resonance imaging - TI scout
Introduction
Amyloidosis refers to a diverse group of hereditary or acquired disorders characterized
by extracellular deposition of insoluble proteins which results in organ dysfunction.[1 ] Cardiac involvement is an important contributory factor to poorer outcome in amyloidosis.[2 ] Myocardial mass, ventricular wall thickness, interatrial septal thickness, diastolic
function, and myocardial late gadolinium enhancement (LGE) are all described surrogate
markers of increased cardiac amyloid load.[3 ] Magnetic resonance imaging (MRI) is the best available modality for assessment of
myocardial structure and function. Time of inversion scout (TIS) sequence, which is
done routinely before LGE imaging to choose nulling time of myocardium, shows nulling
of myocardium before or coincident with blood pool in cardiac amyloidosis with 77%
sensitivity and 96% specificity.[4 ] Previous studies have advocated performing TIS and LGE imaging at times varying
from 5 to 15min after contrast injection in suspected amyloidosis.[3 ],[5 ],[6 ],[7 ] We hypothesize that early reversal of nulling pattern in inversion scout sequence
predicts higher myocardial amyloid load. In this study, we highlight the behavior
of myocardium and blood pool on the TIS sequence at various time periods post gadolinium
injection in amyloidosis and explore the possibility of assessing severity of amyloid
deposition with TIS sequence.
Materials and Methods
Patients with suspected amyloidosis referred to the Radiology department for cardiac
MRI from January 2010 to July 2017 were identified from the RIS-PACS database using
the search term “amyloidosis.” The cardiac MRI findings and clinical charts of these
patients were reviewed. Those patients who had amyloid deposition on endomyocardial
biopsy, amyloid deposition in other tissues on biopsy along with MRI features consistent
with cardiac amyloidosis, and plasma cell dyscrasia on serum electrophoresis along
with MRI features consistent with cardiac amyloidosis were considered as confirmed
cases of cardiac amyloidosis. Those patients who had clinical suspicion of amyloidosis
based on echocardiography or urine Bence Jones protein positivity and typical MRI
features of cardiac amyloidosis without biopsy or electrophoresis confirmation were
considered as likely cases of cardiac amyloidosis.[8 ],[9 ],[10 ] Patients who had an alternate diagnosis based on clinical or imaging findings and
patients who had proven plasma cell dyscrasia without MRI features of cardiac involvement
were excluded from our study. All patients except one were normotensive. The patient
with hypertension was on regular treatment. None of the patients had valvular heart
disease. Serum creatinine was within normal limits in all patients.
Cardiac MRI studies were performed on 1.5T scanners (Siemens Avanto or Siemens Avanto
Fit, Siemens healthcare, Erlangen, Germany) using dedicated multichannel cardiac coils.
Our cardiac MRI protocol consisted of axial, four-chamber, two-chamber, three-chamber,
and short axis cine steady-state free precession images and late enhancement imaging
following bolus injection of gadolinium-based contrast agent (gadopentetate dimeglumine,
Magnevist; Bayer Healthcare Pharmaceuticals, New Jersey, USA) at a dose of 0.1 mmol/kg.
Short-axis TIS sequences were performed at mid cavity level at 5 (TIS5min ) and 10 (TIS10min ) min following contrast injection. Short-axis TIS sequences were additionally performed
at 3min (TIS3min ) in four patients and 7min (TIS7min ) in five patients of our study. The acquisition parameters for the TIS sequence were
as follows: 1.18 ms time to echo, 23.8 ms repetition time, 50° flip angle, 8 mm slice
thickness, 340 mm field of view, and 170 × 118 matrix. Time of inversion was done
at different times starting from 87.5 ms with sequential increase of 22.5 ms up to
~1100 ms. The average time of acquisition of TIS sequence was ~15–20 s.
Left ventricular mass (LVM) and left ventricular function (LVF) were calculated using
proprietary “Argus” software (Siemens Healthcare, Erlangen, Germany). Endocardial
contours were manually drawn in end diastole and end systole and epicardial contours
in end diastole using the pencil tool. The trabeculae and papillary muscles were included
as part of the left ventricular cavity. Indexed end diastolic volume (EDVI), indexed
end systolic volume (ESVI), indexed LVM, and the pattern of LGE of myocardium were
assessed. Based on the pattern of LGE, patients were categorized into two groups,
one with global subendocardial enhancement involving not more than one-third of the
myocardial thickness (Group A) and the other with subendocardial enhancement involving
more than one-third of wall thickness of myocardial wall or transmural enhancement
(Group B).
The temporal pattern of myocardial nulling was noted with respect to blood in the
TIS images. In each of the TIS image series, the possible outcomes were (1) blood
nulls before myocardium, (2) blood nulls coincident with myocardium, and (3) blood
nulls after myocardium. The last nulling pattern is named as reversed nulling pattern
(RNP). These patterns are represented in [Figure 1 ].
Figure 1: Representative images from inversion scout sequence showing normal nulling pattern
(blood nulling before myocardium) in the second row, coincident nulling pattern (blood
nulling at the same time as myocardium) in the third row, and reversed nulling pattern
(myocardium nulling before blood) in the fourth row. The inversion time is mentioned
in the first row
Furthermore, patients were subdivided into two groups based on whether RNP was seen
in TIS5min or not (Groups 1 and 2, respectively). The mean and standard deviation of myocardial
mass index of these two groups were calculated. The presence of any difference in
the myocardial mass index between these two groups was assessed by Mann–Whitney U
test with a P value of <0.05 being considered significant. The presence of any significant difference
in extent of LGE between groups 1 and 2 was assessed by Fisher’s exact test.
Results
A total of 30 patients (mean age 56.4 years, males = 23 and females = 7) were included
in our study. The LVF, LVM, and TIS characteristics of our patients are summarized
in [Table 1 ]. Twelve patients were confirmed cases (patients 1–12 in [Table 1 ]) and 18 patients were likely cases of amyloidosis (patients 13–30 in [Table 1 ]). All the 30 patients had global subendocardial or global transmural enhancement
on LGE. Of the 12 patients with confirmed amyloidosis, 3 had endomyocardial biopsy
and 9 had plasma cell dyscrasia on serum electrophoresis or bone marrow biopsy.
Table 1
Left ventricular parameters and TIS characteristics of our patients with amyloidosis
No.
Age/sex
EDVI* (mL/m2 )
EF† (%)
LVMI‡ (g/m2 )
TIS§
5min
TIS10min
*End diastolic volume index; †Ejection fraction; ‡Left ventricular mass index; §Time
of inversion scout; || Not available; **Myocardial nulling before blood; Coincident nulling of myocardium
and blood; Blood before myocardium
1
43/M
61
54
127
NA11
M**
2
61/F
58
53
43
NA
M
3
53/M
58
50
97
M
M
4
65/M
44
54
72
C††
M
5
60/M
55
33
71
C
M
6
50/M
39
40
54
M
M
7
60/F
77
27
108
M
M
8
68/M
51
35
82
NA
M
9
37/M
123
29
87
NA
M
10
41/F
47
38
54
C
M
11
52/M
41
61
103
B‡‡
M
12
47/F
NA
NA
NA
M
M
13
76/M
83
34
97
M
M
14
61/M
47
44
90
NA
M
15
43/F
68
29
81
NA
M
16
49/M
56
39
96
B
B
16
62/M
65
35
74
NA
M
18
46/M
54
45
63
NA
M
19
52/M
71
34
91
NA
M
20
59/F
71
51
95
M
M
21
55/M
74
42
100
M
M
22
55/M
84
58
65.5
C
M
23
64/F
77
68
59.6
NA
C
24
58/M
103
25
81.6
B
C
25
60/M
104
48
95.2
M
M
26
65/M
127
44
126.8
M
M
27
63/M
74
39
84
M
M
28
67/M
56
51
100
M
M
29
60/M
87
45
86.5
NA
M
30
82/M
41
61
86.8
M
M
The mean and standard deviation of EDVI, ESVI, and ejection fraction of the patients
were 68.8 ± 22.8 mL/m2 , 39.8 ± 17.6 mL/m2 , and 43.7 ± 10.9%, respectively. Global subendocardial enhancement involving up to
one-third of wall thickness was the most common pattern observed (n = 22, 73.3%). The rest (n = 8, 26.7%) showed global subendocardial enhancement more than one-third of wall
thickness or transmural enhancement.
TIS10min was done in all 30 patients and TIS5min was done in 19 patients. TIS3min and TIS7min were done in four and five patients respectively. The distribution of nulling pattern
in our study is given in [Table 2 ]. We observed that the nulling pattern in an individual patient can evolve depending
on the time elapsed post contrast injection, which was best represented by patient
number 10. In this patient, blood nulled before myocardium at TIS3min , blood and myocardial nulling were coincident at TIS5min , and myocardial nulling preceded blood (RNP) at TIS7min and TIS10min . Of the four patients with TIS3min , three had normal nulling pattern and one had reverse nulling pattern (25%). All
the patients with TIS7min had reverse nulling pattern (100%). Group 1, in whom RNP was seen in TIS5min (n = 11), had mean myocardial mass index of 94.87 ± 17.63 g/m2 , while those in Group 2 in whom RNP was not seen (n = 7) had mean myocardial mass index of 77.61 ± 17.21 g/m2 . Group 1 had significantly higher myocardial mass index than Group 2 with a U-value
of 18 (P = 0.035) as calculated by Mann–Whitney U-test. No statistically significant difference
was seen in the extent of global late enhancement between Groups 1 and 2 on Fisher’s
exact test (P = 0.536). No statistically significant difference was seen in indexed myocardial
mass in the two categories of extent of late enhancement (Groups A and B) on Mann–Whitney
U test, although the mean indexed myocardial mass was higher in Group B (P = 0.054).
Table 2
Nulling pattern on TIS* in our patients
TIS
Reversed nulling pattern
Coincident nulling pattern
Normal nulling pattern
Total
*Time of inversion scout
TIS3min
1
0
3
4
TIS5min
12
4
3
19
TIS7min
5
0
0
5
TIS10min
27
2
1
30
Discussion
The common types of systemic amyloidosis based on the chemical structure of deposited
proteins are AL, AA, ATTR, and Ab2 M. AL type is the most common subtype. The AL subtype, seen in the setting of plasma
cell dyscrasias or monoclonal gammopathy of unknown significance (MGUS), and the ATTR
subtype, caused by mutations on gene encoding transthyretin cause cardiomyopathy.
The AA subtype associated with chronic systemic inflammatory disorders and the Ab2 M subtype which occurs in patients with long-standing end-stage renal failure on hemodialysis
usually do not affect the heart.[11 ]
Cardiac involvement in amyloidosis causes biventricular diastolic dysfunction and
atrial dilation due to myocardial amyloid infiltration. At late stages, it progresses
to systolic dysfunction. Amyloid can act as a substrate for arrhythmia. Most patients
have associated pleural and pericardial effusions. Clinical manifestations include
exercise intolerance, palpitations, and syncope. Electrocardiogram shows low- voltage
complexes, despite ventricular wall thickening. Echocardiography shows ventricular
hypertrophy and a characteristic speckled appearance of the myocardium. Although echocardiography
is well-established as a tool for assessing myocardial structure and function, it
falls short in tissue characterization and is operator-dependent.[12 ] MRI gives detailed assessment of the cardiac structure and function and is considered
the gold standard.
The LGE sequence shows the characteristic pattern of global subendocardial enhancement
in amyloidosis.[12 ] Pandey et al . have showed that RNP at TIS10min can be a very useful adjunct to other cardiac MRI sequences in diagnosing cardiac
amyloidosis.[4 ] They observed that myocardium nulls before or coincident with the blood pool in
patients with amyloidosis in TIS sequence done at 10min post gadolinium injection
as opposed to the normal pattern observed in patients with other diagnoses or no cardiac
abnormality, where the blood pool nulls before myocardium. The reversal of nulling
which is said to be characteristic of amyloidosis happens due to two reasons. One
reason is that myocardial amyloid deposition causes increase in extracellular space
resulting in gadolinium accumulation and shortening of the myocardial T1 time. The
other reason is that systemic amyloid load tends to extract the gadolinium from the
blood pool, thus causing relative prolongation of the blood T1 time. This additive
two-fold effect essentially causes myocardial T1 to become shorter than blood T1 following
gadolinium administration. Thus, early RNP could possibly predict higher myocardial
amyloid load and higher systemic amyloid load.
Our study shows that the nulling pattern in TIS in amyloidosis is time-dependent and
is likely related to the load of amyloid deposition. This also explains the practical
difficulties and variability of findings in TIS and LGE in patients with cardiac amyloidosis.
We observed RNP in 90% of patients at 10min, whereas the corresponding figure was
58% at 5min. Thus, RNP was more accurate at TIS10min to diagnose amyloidosis when compared with TIS5min . As the routine cardiac MRI protocols are different in different institutions with
regard to the timing of the TIS and delayed enhancement sequences, this temporal variability
assumes importance. It is important to note that in three of our patients (patient
no. 16, 23, and 24 in [Table 1 ]) in the likely amyloidosis group, RNP was not observed at even 10min. Interestingly,
patient no. 22 showed evolution from normal nulling pattern at 5min to coincident
nulling at 10min. This raises possibility that RNP could occur at a time later than
10min in these patients and requires further investigation by more delayed TIS sequences
done at 15 or even 20min after contrast injection.
Increased myocardial load in amyloidosis correlates with poor survival.[13 ] Left ventricular myocardial mass, wall thickness, LGE, N-terminal pro-brain natriuretic
peptide, and cardiac troponins are prognostic markers for predicting survival in cardiac
amyloidosis.[10 ],[14 ],[15 ],[16 ],[17 ],[18 ],[19 ],[20 ] Our results show statistically significant increased LVM in patients with early
RNP compared with those with late RNP. Gadolinium kinetics are altered in amyloidosis,
and lower difference between the subendocardial T1 and subepicardial T1 in amyloidosis
has been shown to correlate with worse prognosis.[15 ] White et al . used TIS sequences at 5–10min after contrast injection to assess the ability of
qualitative assessment of T1 of the myocardium with respect to blood pool in predicting
mortality.[21 ] They qualitatively assessed T1 by observing the nulling pattern based on the concept
that T1 is proportional to the nulling time, that is, the earlier the nulling, the
shorter the T1. They observed that the presence of diffuse enhancement by visual assessment
of myocardial T1 was a strong predictor of mortality. They performed TIS sequence
at a single time point post contrast injection in each patient, unlike our study where
multiple time periods post contrast injection were studied. Our study did not show
statistically significant difference in the extent of LGE in those with early RNP
compared with those with late RNP. This is likely related to the absence of patients
without late enhancement and small number of total patients in our study. The three
patients in our study with amyloidosis based on endomyocardial biopsy had subendocardial
enhancement up to one-third of wall thickness.
Another recent development in assessing myocardial amyloid deposition is T1 mapping
using cardiac MRI. In amyloidosis, myocardial T1 is prolonged. T1 mapping has been
shown to accurately diagnose and prognosticate cardiac amyloidosis.[22 ],[23 ] This was not evaluated in our study. The important difference between T1 mapping
and temporal variability of nulling pattern is that variability of nulling pattern
is influenced by both myocardial and systemic amyloid load, while myocardial T1 is
solely a myocardial property. Moreover, we did not correlate our results with other
modalities such as serum amyloidP component scintigraphy[24 ] which reflects systemic amyloid load. N-terminal pro-brain natriuretic peptide and
cardiac troponins were not assessed. This study was limited by small sample size for
TIS3min and TIS7min . One of our patients did not have optimal short-axis cine stack of images and LVF
was not calculated. Endomyocardial biopsy was not done in the majority of our patients.
However, endomyocardial biopsy is an invasive procedure with its own attendant risks
and can be associated with pitfalls due to sampling errors.[25 ] The ability of early RNP to predict survival requires further research with prospective
study and larger sample size.
Conclusion
The nulling pattern of myocardium and blood pool in cardiac amyloidosis shows temporal
variability with earlier onset of reverse nulling pattern in TIS sequence showing
trend toward more LVM and possibly more severe amyloid load. Performing TIS sequence
at multiple time points post contrast injection may provide prognostic information
in patients with cardiac amyloidosis; however, this requires validation with a prospective
study having larger sample size. Although TIS images are advisable at multiple time
points, 10min or later images rather than the earlier images would be more useful
to diagnose cardiac amyloidosis based on RNP.
