Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction

Abstract

Aims:
To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myocardial fibrosis.

Methods and results:
We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fibrosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n = 32] and aortic stenosis [(AS), n = 25)]. Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed. Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between health and disease [area under the curves (P-value): 0.94 (0.88-0.99); 0.87 (0.79-0.94); 0.61 (0.49-0.72)], secondly, relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r = 0.582 (P = 0.027), r = 0.524 (P = 0.046), r = 0.443 (P = 0.150)], and thirdly, with native T2 [r = 0.628(P < 0.001), r = 0.459 (P = 0.003), r = 0.211 (P = 0.083)]. The respective relationships for extracellular volume fraction with CVF [r = 0.489 (P = 0.044), r = 0.417 (0.071), r = 0.353 (P = 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was significantly higher compared to controls, and associated with levels of C-reactive protein and troponin.

Conclusion:
T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as associations with diffuse myocardial fibrosis.

Full text

Comparison of MOLLI, shMOLLLI, and SASHA
in discrimination between health and disease
and relationship with histologically derived
collagen volume fraction
Nicholas Child
1,2
, Gonca Suna
2,3
, Darius Dabir
1,4
, May-Lin Yap
1
, Toby Rogers
1,3
,
Misha Kathirgamanathan
1
, Eduardo Arroyo-Ucar
1,5
, Rocio Hinojar
1
, Islam
Mahmoud
1
, Christopher Young
6
, Olaf Wendler
7
, Manuel Mayr
2
, Banher Sandhu
1
,
Geraint Morton
8
, Marion Muhly-Reinholz
9
, Stefanie Dimmeler
9
, Eike Nagel
1,10
, and
Valentina O. Puntmann
1,10,11
*
1
Department of Cardiology, Guys and St Thomas’ NHS Trust, Westminster Bridge Road, London, UK;
2
Cardiovascular Division, King’s College London, The Rayne Institute. St
Thomas’ Hospital, Westminster Bridge Road, London SE5 9RS, UK;
3
Department of Cardiology, King’s College Hospital NHS Trust, Denmark Hill, London, UK;
4
Department of
Radiology, University of Bonn, Regina-Pacis-Weg 3, Bonn, Germany;
5
Department of Cardiology, University of Hospital, Paseo de la Castellana, La Paz, Madrid, Spain;
6
Department of Cardiothoracic Surgery, Queen Alexandra Hospital, Guys and St Thomas’ NHS Trust, Westminster Bridge Road, London, UK;
7
Department of Cardiothoracic
Surgery, King’s College Hospital, Denmark Hill, London, UK;
8
Department of Cardiology, Portsmouth Hospitals NHS Trust, Southwick Hill Road, Portsmouth, UK;
9
Institute for
Cardiovascular Regeneration, University of Frankfurt, German Centre of Cardiovascular Research, (DZHK), Theodor-Stern-Kai 7, Frankfurt, Germany;
10
Institute of Experimental
and Translational Cardiovascular Imaging, Goethe University Hospital Frankfurt, German Centre of Cardiovascular Research, (DZHK), Theodor-Stern-Kai 7, Frankfurt, Germany;
and
11
Department of Cardiology, Goethe University Hospital Frankfurt, German Centre of Cardiovascular Research, (DZHK), Theodor-Stern-Kai 7, Frankfurt, Germany
Received 25 June 2017; editorial decision 30 October 2017; accepted 31 October 2017
Aims To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myo-
cardial fibrosis.
........................................................................ ............. ............. ............. .................. ......................................................... .........
Methods
and results
We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-
Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and
SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fib-
rosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n= 32] and aortic stenosis [(AS), n= 25)].
Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed
using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed.
Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between
health and disease [area under the curves (P-value): 0.94 (0.88–0.99); 0.87 (0.79–0.94); 0.61 (0.49–0.72)], secondly,
relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r= 0.582 (P= 0.027), r= 0.524
(P= 0.046), r= 0.443 (P= 0.150)], and thirdly, with native T2 [r= 0.628(P< 0.001), r= 0.459 (P= 0.003), r= 0.211
(P= 0.083)]. The respective relationships for extracellular volume fraction with CVF [r= 0.489 (P= 0.044), r= 0.417
(0.071), r= 0.353 (P= 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was
significantly higher compared to controls, and associated with levels of C-reactive protein and troponin.
........................................................................ ............. ............. ............. .................. ......................................................... .........
Conclusion T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as asso-
ciations with diffuse myocardial fibrosis.
䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏
Keywords T1 mapping •MOLLI •shMOLLI •SASHA •collagen
* Corresponding author. Tel: þ49-69-6301-86760; Fax: þ49-69-6301-7983. E-mail: vppapers@icloud.com
Published on behalf of the European Society of Cardiology. All rights reserved. V
CThe Author 2017. For permissions, please email: journals.permissions@oup.com.
European Heart Journal - Cardiovascular Imaging (2017) 00, 1–9
doi:10.1093/ehjci/jex309
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Introduction
Myocardial T1 mapping provides a novel concept in quantitative tis-
sue characterization, yielding a value, unlike relying on visually recog-
nizable contrast differences. Thus, T1 mapping measurements can be
used to relay biologically important properties in a quantitative man-
ner, including the presence and severity of abnormal myocardium in
many cardiac conditions. T1 indices have a potential to improve clini-
cal diagnosis and risk stratification, particularly in conditions with dif-
fuse myocardial involvement.
1
Despite the surge in evidence, the
immediate clinical translation of these techniques is complicated by
multiple variants of similar T1 mapping sequences. Each sequence
and its modification yield different normal values and ranges, and
show variable diagnostic performance in detection of abnormalities
in human myocardium. Thus, each sequence will represent an individ-
ual diagnostic test, necessitating an individual clinical validation and
standardization.
2
T1 mapping sequences employed in myocardial characterization
differ principally in magnetization preparation by either an inversion
recovery (IR) or a saturation recovery (SR) prepulse (reviewed in
Higgins et al.
3
) The many variants of these two approaches are further
distinguished by different schemes of image acquisition (e.g. number
of prepulses/images/pauses) and readout parameters [flip angle (FA),
time delay, adiabatic prepulse, etc]. The sequence most commonly
reported is based on the IR sequence MOdified Look-Locker
(MOLLI). Following its original publication,
4
numerous MOLLI var-
iants have been developed either to achieve shorter breath-holds
5,6
or greater T1 accuracy.
7
SR sequences benefit from a much shorter
period of T1 relaxation following a SR preparation
8,9
and absence of
history of magnetization of prior heartbeats, thus, shortening the
overall acquisition time and improving the T1 accuracy, respectively.
All T1 mapping methods are continuously and actively modified
(‘optimized’) in terms of protocol parameters, scanner software ver-
sions, practical scanning methodology and methods of analysis, as
well as manufacturer-specific implementations. In this study, we
undertook sequence comparison of the 3 most commonly reported
T1 mapping sequences—within the same individual—to examine
their bioequivalence, or performance in vivo, in terms of diagnostic
accuracy, relationships with histologically derived collagen volume
fraction (CVF), and their T2 sensitivity by comparison with T2 map-
ping, in two model diseases of diffuse myocardial fibrosis; non-ischae-
mic dilative cardiomyopathy (NIDCM) and aortic stenosis (AS).
Methods
Consecutive patients from Guys and St. Thomas’ and Kings College
Hospitalswere invitedto participate in this study:
(1) Patients with NIDCM
10
(n= 32). Prior to their enrolment, the diag-
nosis was confirmed by cardiovascular magnetic resonance (CMR)
on the basis of increased LV end-diastolic volume indexed to body
surface area and reduced LV ejection fraction (EF < 50%) compared
with published reference ranges normalized for age and sex.
11
Several of these subjects were included in our previous
publications.
10,12,13
(2) Patients with severe AS (n= 25) were identified from cardiology
and cardiothoracic surgery outpatient clinics. AS was the leading
valve problem based on Doppler echocardiographic demonstration
of mean aortic valve pressure gradient >40mmHg.
14
(3) Asymptomatic and normotensive subjects (n= 26), taking no regular
medication and with no significant medical history and normal CMR
findings, including volumes and mass, served as controls.
12,15
Control subjects were recruited as a part of the parallel project into
the normal values.
16
The subgroup was selected to provide an age-
gender matched control group to the AS group.
Exclusion criteria for all subjects are detailed in supplementary material.
Blood samples for haematocrit in AS patients were obtained contem-
poraneously at the time of the CMR procedure, whereas in patients
with NIDCM these were based on the clinical blood tests.
10
Analysis of
serological cardiac biomarkers, including N-terminal-pro brain natriu-
retic peptide (NT-BNP), type 1 procollagen C-terminal propeptide
(PICP), high-sensitive (hs-) troponin and hs-C-reactive protein (CRP),
was performed using commercial platforms. The study protocol was
reviewed and approved by the local ethics committee, and written
informed consent was obtained from all participants. All procedures
were carried out in accordance with the Declaration of Helsinki (2013).
Image acquisition and analysis
All sequence parameters are detailed in the Supplementary material.
Subjects underwent a routine clinical protocol for cardiac volumes and
mass (with cine imaging) and tissue characterization with T1 mapping and
late gadolinium enhancement (LGE) imaging using 3-Tesla MRI scanner
equipped with advanced cardiac package and multi-transmit technology
(Achieva, Philips Healthcare, Best, The Netherlands).
10,12,17
T1 mapping
was performed using two MOLLI variants [the original MOLLI
4,10,12
and
Shortened MOdified Look-Locker Inversion recovery (shMOLLI)
5
]and
a SR variant, SAturation recovery single-SHot Acquisition (SASHA).
8
Sequences were acquired in random order (to avoid bias) in a single mid-
ventricular short axis (SAX) slice, prior to and 15minutes after intravenous
administration of gadobutrol (0 .2 mmol/kg per body weight, Gadovist
V
R
,
Bayer Healthcare, Leverkusen, Germany). T2 mapping was performed in
the same geometry using a hybrid gradient and spin echo GraSE sequence.
CMR analysis was performed using commercially available software
(CVI42
V
R
, Circle Cardiovascular Imaging Ltd, Calgary, Canada) following
standardized post-processing recommendations.
10,18
LGE images were
visually examined for the presence of regional scar tissue in two phase-
encoding directions and confirmed as positive if the visually positive
regions had a SI > 4 standard deviations (SD) from normal regions.
17
Recovery rate of T1 and T2 relaxation for all sequences was measured
conservatively within the septal myocardium, using PRIDE (Philips, Best,
The Netherlands), as previously described and validated.
12,15
Areas of
LGE were excluded from the mapping regions of interests (ROI). Care
was taken to avoid contamination of myocardial signal with the blood
pool. In addition to T1-values of native and post-contrast myocardium
the gadolinium extracellular partition coefficient, the haematocrit-cor-
rected extracellular volume fraction (ECV) was calculated.
19
Myocardial biopsies and histological analysis
Several (n>_ 3 per person) intraoperative deep endomyocardial biopsy
(EMB) samples were obtained in 12 AS patients using either biopsy for-
ceps (Novatome, Scholten
V
R
) or direct surgical excision, as per choice of
operator. EMBs were sampled from the mid-portion of the interventricu-
lar septum, avoiding the basal fibrotic membranous part. Sample prepara-
tion and analysis approach are described in supplementary material.
Mean percent fibrosis (CVF), fibrosis heterogeneity (SD between fields),
patient heterogeneity (interquartile range, IQR), and inter-observer coef-
ficient of variation (CoV) are reported.
2N. Child et al.
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Statistical analysis
Statistical analysis was performed using SPSS software (SPSS Inc.,
Chicago, IL, USA, version 23.0). Normality of distributions was tested
using Wilks-Shapiro statistic. Categorical data are expressed as percen-
tages, and continuous variables as mean ± SD or median (interquartile
range), as appropriate. Comparisons of the means between groups were
performed using one way ANOVA (with Bonferroni post hoc tests for the
differences from controls). Associations between variables were
detected by bivariate linear regression analyses. Repeatability of measure-
ments were assessed using intraclass-correlations (ICC). Receiver oper-
ating characteristic (ROC) curves was used in discrimination between
health and disease. All values are reported as mean±SD and a P-value of
less than 0.05 was considered statistically significant.
Results
A total of 83 subjects completed the imaging protocol with the 3 T1
mapping sequences. Subject characteristics and CMR results are pre-
sented in Supplementary data online, Table S1.Groupsweresimilar
for age, gender, heart rate and diastolic blood pressure, whereas the
body-mass index and systolic BP were significantly higher in AS
patients. Compared to controls, both patient groups had significantly
higher indexed left ventricular (LV) volumes, LV mass, left atrial size,
and lower LV and RV ejection fraction (P< 0.05 for all). All patients
with AS has increased LV wall thickness>_12 mm, measured in dia-
stole. Non-ischaemic LGE was present in a total of 10 NIDCM (31%)
and 5 AS (20%) patients. Patients had significantly higher mean E/e0
on transthoracic echocardiography, as well as the levels of serological
cardiac biomarkers.
Native T1 and ECV data show progressively larger imprecision
and variation in normal controls from MOLLI to ShMOLLI to SASHA
(see Supplementary data online, Table S2).
9,20
Compared with con-
trols, native T1 and ECV were significantly higher in both patient
groups for MOLLI and shMOLLI sequences (P< 0.01), whereas
SASHA only revealed a significant difference between controls and
patients with NIDCM. Post-contrast T1 values were significantly
different for the MOLLI sequence but not shMOLLI or SASHA
(Table 2). Native T2 was raised in NIDCM and AS patients, signifi-
cantly in the latter group.
ROC curves in discrimination between health and disease (all
patients) are presented in Figure 1, with respective area under the
curves [(AUCs), 95% confidence interval (95% CI)] for all T1 map-
ping indices and sequences listed in Table 1. Native T1 for MOLLI
showed the greatest ability to discriminate between health and
disease [AUC: 0.94 (0.88–0.99), P< 0.001; comparisons of AUCs:
MOLLI vs. shMOLLI, SASHA and T2: P= 0.064, P< 0.001, P=0.01,
respectively]. Native T2 also showed a strong ability to differentiate
between health and disease [AUC: 0.81 (0.73–0.89), P<0.001].
Native T1 by MOLLI was an independent discriminator between
health and disease (v
2
=52,P< 0.001).
Results of myocardial histology and associations with T1 mapping
indices are presented in Table 2(Figures 2and 3). Procedurally, all
EMBs were uneventful (n= 12). The mean histological CVF was
25.6% (intersubject IQR 10.1–43.2%, SD 18.6). There was an excel-
lent agreement between the two observers (r= 0.95, P<0.01;
MD ± SD = 5.9± 4.6). Correlations between CVF with all T1 map-
ping indices for various sequences are included in Table 2(Figure 4).
There was moderate significant association for native T1 with MOLLI
and shMOLLI, whereas correlation with SASHA was not significant.
For ECV only MOLLI showed a significant association. Native T2
showed a mild but not significant association with CVF (r= 0.271,
P= 0.24). Table 3summarizes the correlations with serological
markers for all T1 mapping indices in AS and NIDCM patients. Native
T1 with MOLLI and shMOLLI, post-contrast T1 with MOLLI, and
native T2 showed significant associations with N-terminal prohor-
mone of brain natriuretic peptide (NT-proBNP), hs-troponin and
CRP, but not PICP. Repeatability of measurements (ICCs) are
reported in Supplementary Material.
Discussion
We demonstrate that T1 mapping sequences differ considerably in
their performance in myocardial tissue characterization, as evidenced
by differential ability to discriminate between health and disease and
by diverse associations with myocardial CVF and T2 mapping. More
specifically, our findings reveal that native T1 using MOLLI sequences
show an excellent diagnostic performance in detecting the differen-
ces in myocardium between controls and patients. Myocardial T1
mapping with MOLLI sequences showed the strongest relationship
with histologically derived CVF and with T2 mapping.
A number of previous studies reported on associations with tissue
collagen content or discrimination between health and disease (sum-
marized in Figure 4,modifiedfrom
1
) We expand these findings by
comprehensive and standardized intraindividual acquisition of more
than one sequence and analysis of all T1 indices. Compared with a
previous reports we found similar associations for native T1 with
CVF for shMOLLI.
22
For MOLLI, previous studies reported diverse
....................................................................................................................................................................................................................
Table 1 Discrimination between health and disease
Native T1 Post-contrast T1 ECV
Controls vs. all patients AUC (95% CI) Sig (P-value) AUC (95% CI) Sig (P-value) AUC (95% CI) Sig (P-value)
MOLLI 0.94 (0.88–0.99) <0.001 0.66 (0.54–0.77) 0.005 0.73 (0.64–0.83) <0.001
ShMOLLI 0.87 (0.79–0.94) <0.001 0.64 (0.52–0.75) 0.02 0.67 (0.58–0.79) <0.001
SASHA 0.61 (0.49–0.72) 0.067 0.62 (0.50–0.73) 0.04 0.59 (0.46–0.72) 0.02
Native T2 0.81 (0.73–0.89) <0.001 / / / /
The comparative performance of each sequence to discriminate between health and disease controls and all patients) for native T1, post-contrast T1 and ECV, using ROC-
curve analysis to derive AUC.
Comparison of MOLLI, shMOLLI, and SASHA 3
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associations for native T1 and CVF ranging between 0.15 and 0.77,
1
and our results add to the favourable side of that range. Associations
for ECV, however, were much lower for both shMOLLI
23,24
and
MOLLI.
34
Several possible reasons may explain these findings, espe-
cially the type of sequences, given the implementation and opti-
mization of shMOLLI and SASHA on a new vendor platform. The use
of motion correction, types of post-processing softwares and
approaches, the type and dose of gadolinium contrast, histological
dyes, reading methods, etc., may all influence the measurements. The
severity of myocardial damage can vary considerably between the
patients included at the different sites; which in such small samples
may be a major factor. Although the biopsies were performed during
open-heart surgery, inclusion of replacement fibrosis during the
tissue sampling is difficult to control. This complication of human
EMBs in introducing the sampling errors is also well recognized.
32,35
We strived for exclusion of LGE given our strong focus on to the dif-
fuse myocardial disease, yet, we acknowledge that definition of
‘diffuse’ will depend on the spatial resolution of the LGE technique
allowing to differentiate localized patterns of fibrosis from the
remaining tissue, unlike averaging them within one voxel. The post-
processing approach in studies that have not accounted for the
regional variations or inadvertent inclusion of blood partial volume in
myocardial T1 values,
30,31,36
may reveal different results than in the
studies using conservative septal ROI.
15,26,37
The discriminatory
power of ECV values may also suffer from dependency on two sepa-
rate measurements. Finally, the association between CVF and ECV by
Figures 1 Native T1 (A), post-contrast T1 (B), and ECV (C) in discrimination between health and disease for three sequences in all patients against
healthy controls using ROC curve analysis.
4N. Child et al.
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....................................................................................................................................................................................................................
Table 2 Summary of studies reporting on association between CVF and T1 mapping indices modified and adapted
from
1
(with permission)
Collagen volume
fraction%
Sequence Pearson r
(Sig)
No. of patients
(cardiac disease)
GCAs (dose
and type)
T1 Index Histological
staining
Aortic stenosis
Flett et al.
21
GRE-IR 0.94 (0.001) 18 (0.2 mmol/kg
gadoterate
meglumine)
ECV (EQ) Picrosirius red
Bull et al.
22
shMOLLI 0.655 (0.002) 19 Native T1 Picrosirius red
Fontana et al.
23
GRE-IR 0.78 (<0.01) 18 (0.2 mmol/kg
gadoterate
meglumine)
ECV (EQ) Picrosirius red
shMOLLI 0.83 (<0.01)
White et al.
24
shMOLLI 0.83 (<0.01) 18 (0.2 mmol/kg
gadoterate
meglumine)
ECV (bolus) Picrosirius red
0.84 (<0.01) ECV (EQ)
de Meester de
Ravenstein et al.
25
MOLLI 3(3)3(3)5 (FA35) -0.15 (0.64) 12 (0.2 mmol/kg
gadobutrol)
Native T1 Picrosirius red
-0.64 (0.024) Post-contrast T1
0.91 (0.001) ECV
Lee et al.
26
MOLLI 3(3)3(3)5(FA35) 0.77 (<0.01) 10 Native T1 Picrosirius red
Child MOLLI 3(2)3(2)5(FA50) 0.582 (0.027) 12 (0.2 mmol/kg
gadobutrol)
Native T1 Masson-trichrome
0.47 (0.065) Post-contrast T1
0.498 (0.044) ECV
shMOLLI 0.524 (0.046) Native T1
0.45 (0.140) Post-contrast T1
0.417 (0.071) ECV
SASHA 0.442 (0.150) Native T1
0.27 (0.411) Post-contrast T1
0.353 (0.287) ECV
Heart failure
Iles et al.
27
VAST -0.7 (0.03) 9 (IHD) (0.2 mmol/kg
gadopentetate
dimeglumine)
Post-contrast T1 Picrosirius red
Sibley et al.
28
Look-Locker -0.57 (<0.001) 47 (NICMs) (0.2 mmol/kg
gadodiamide)
Post-contrast T1 Masson
trichrome
Mascherbauer et al.
29
GRE-IR -0.98 (<0.01) 9 (HFpPEF) (0.2 mmol/kg
gadobutrol)
Post-contrast T1 Masson
Trichrome/
Congo-red
Miller et al.
30
MOLLI 3(3)3(3)5(FA 35) 0.199 (0.437) 6 (IHD) (0.2 mmol/kg
(gadopentetate
dimeglumine)
Native T1 Picrosirius red
-0.21 (0.69) Post-contrast T1
0.945 (0.004) ECV (bolus)
Aus dem Siepen et al.
31
MOLLI 3(3)3(3)5(FA 35) 0.85 (0.01) 45 (DCM) (0.2 mmol/kg
gadopentetate
dimeglumine)
ECV (bolus) Acid Fuchsin
Orange-G
Iles et al.
32
VAST 0.73 (<0.001) 4 (1 IHD, 3 DCM) (0.2 mmol/kg
gadopentetate
dimeglumine)
LGE Masson
Trichrome-0.64 (0.002) Post-contrast T1
Kammerlander et al.
33
MOLLI 5(3)3 (FA 35) for
native acquisition
0.493 (<0.002) 36 (mixed group) (0.1mmol/kg of
gadobutrol)
ECV (bolus) Tissue FAXS
MOLLI 4(1)3(1)2(FA 35) for
post-contrast acquisition
Hypertrophic cardiomyopathy
Flett et al.
21
GRE-IR R
2
= 0.62(0.08),
Tau = 0.52
8 (0.2 mmol/kg
gadoterate
meglumine)
ECV Picrosirius red
Continued
Comparison of MOLLI, shMOLLI, and SASHA 5
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MOLLI found in the present study (r= 0.498) compares favourably to
the result using tissue FAXS technology
33
(r=0.493).
A further interesting finding is the correlation of T1 indices with
T2 mapping. This observation communicates an important influence
of transverse relaxation, which appears to be captured within the
myocardial T1 mapping, consistent with previous reports highlighting
the proneness of MOLLI variants to the T2-related errors.
20
The
effect of magnetization transfer (MT) in MOLLI variants, may be
resulting from acquisition of multiple images after each preparation
pulse.
3,20,38
The difference in FA between implementation of our
MOLLI sequence
4,10,12
vs. ShMOLLI
5
(50vs. 35) explains the
greater SNR and possibly also the more pronounced T2 and MT
effects for MOLLI. Whereas the development of techniques, which
are highly accurate for T1 with minimal contamination by T2 or MT
or other effects is important for post-contrast T1 acquisitions (i.e.
‘true T1 mapping’), the advantages of the T2-proneness for native T1
mapping—high precision and diagnostic accuracy, yielding higher sen-
sitivity to myocardial pathophysiology, can from the clinical stand-
point not be overlooked. Clearly, further research is warranted to
elucidate these clinically relevant effects.
Lastly, we reveal for the first time that in AS, myocardial native T2
is significantly raised. As it is not significantly associated with myocar-
dial collagen content, it may suggest myocardial oedema.
39–42
Abody
of evidence substantiates the role of inflammatory cellular and
extracellular processes in myocardial plasticity and remodelling in
response to increased LV wall stress,
43,44
including a reactivation of
hypertrophic foetal gene programme with phenotypical expression
of natriuretic peptides, such as NT-pro BNP, which was also found
elevated in the present study.
44–47
Increased hs-troponin and CRP
levels and relationship with T1 and T2 indices in AS patients may lend
....................................................................................................................................................................................................................
Table 2 Continued
Collagen volume
fraction%
Sequence Pearson r
(Sig)
No. of patients
(cardiac disease)
GCAs (dose
and type)
T1 Index Histological
staining
Iles et al.
32
VAST -0.71 (0.01) 8 (0.2 mmol/kg
gadopentetate
dimeglumine)
Post-contrast T1 Masson-
trichrome
Types of sequences and a staining method used, as well as numbers of patients included, is also reported., GCAs, gadolinium contrast agents, IHD, ischaemic heart disease;
HFpEF, heart failure with preserved ejection fraction; NICM, non-ischaemic cardiomyopathy; GRE-IR, gradient echo-inversion recovery; VAST, variable sampling of k-space in
time.
Figures 2 Representative images of patients with AS—Case 1. (A) Histological analysis with Mason Trichrome reveals mild-moderate interstitial
fibrosis (CVF = 16%). MOLLI measurement reveal native T1 1068 ms (B) and ECV = 26%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D)
view and AV valve view, revealing significantly reduced AV opening (AV area by planimetry 0.56cm
2
). There is no evidence of late gadolinium
enhancement (F). NTproBNP 634 ng/L.
6N. Child et al.
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Figures 3 Representative images of patients with AS—Case 2. (A) Histological analysis with Mason Trichrome reveals considerable myocardial fib-
rosis (CVF 37%). MOLLI measurement in mid-ventricular SAX slice show native T1 1130 ms (B) and ECV 32%. Cine imaging in mid-systole: 3-cham-
ber (C), LVOT (D) view and AV valve view, reduced AV opening (AV area by planimetry 0.37 cm
2
). Evidence of non-ischaemic late gadolinium
enhancement in basal anteroseptal and inferolateral segments—red arrows (green arrow points to the basal RV structures, including RV outflow
tract and pulmonary valve) (F). NTproBNP 1381 ng/L.
Figure 4 Correlations between T1 mapping measurements and histologically derived CVF—native T1 (A–C)andECV(D–F).
Comparison of MOLLI, shMOLLI, and SASHA 7
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a further support to the notion that myocardial oedema, alongside
interstitial fibrosis,
48
represents a detectable process in extracellular
matrix remodelling in hypertrophic cardiac conditions.
Study limitations
A few limitations apply. This is a single centre, single-vendor and sin-
gle field-strength comparison study in a sample size, which is based
on the previous studies using the identical MOLLI sequence.
12
EMBs
were performed within the conservative constraints of ethical appro-
val for an invasive procedure performed purely for research pur-
poses. We strived to include a sufficient number of patients required
to achieve a significant correlation for native T1 with MOLLI
sequence (type I error; a< 0.05) (Type II error; b=0.8;n= 8), which
was also reconfirmed by a post hoc analysis. However, the sample size
was not powered to inform on the superiority of correlations
between the mapping techniques. The study-design, i.e. head-to-head
comparison, and standardized approach to imaging and histology
obtained within the same subject, eliminates several important meth-
odological biases, which make comparisons between studies using
single techniques difficult. We believe that our results provide a use-
ful guide to the type of much needed evidence, required to support
an informed clinical use of T1 mapping sequences.
Conclusions
We demonstrate that T1 mapping indices and sequences differ in
their bioequivalence for detection of abnormal myocardium, which is
characterized by diffuse interstitial myocardial fibrosis. Native T1
with MOLLI sequences provides the strongest discriminatory accu-
racy in characterization of human myocardium.
Supplementary data
Supplementary data are available at European Heart Journal - Cardiovascular
Imaging online.
Acknowledgments
We would like to acknowledge the support of Cardiology and
Cardiothoracic Surgery departments at Guy’s and St Thomas’ and
King’s College Hospitals NHST Trusts; cardiac radiographers for
obtaining the high-quality imaging studies; Philips Clinical Scientists for
support: David M. Higgins, PhD; Bernhard Schnackenburg, PhD;
Christian Stehning, PhD; Eltjo Haselhoff, PhD.
Funding
Department of Health through the National Institute for Health Research
(NIHR) comprehensive Biomedical Research Centre award to Guy’s &
St. Thomas’ NHS Foundation Trust in partnership with King’s College
London and King’s College Hospital NHS Foundation Trust. Histological
comparisons in aortic stenosis patients were supported by Medical
Research Council - Confidence in Concept 2012’ administered through
King’s Health Partners project grant (MRJBACR). N.C. was funded by an
educational grant from St. Jude Medical. VP, EN, SD, MR-M are supported
by the German Centre of Cardiovascular Research (DZHK).
Conflict of interest: None declared.
References
1. Puntmann VO, Peker E, Chandrashekhar Y, Nagel E. T1 mapping in characteriz-
ing myocardial disease. Circ Res 2016;119:277–99.
2. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints:
preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:
89–95.
3. Higgins DM, Moon JC. Review of T1 mapping methods: comparative effective-
ness including reproducibility issues. Curr Cardiovasc Imaging Rep 2014;7:9252.
4. Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU, Ridgway
JP. Modified Look-Locker inversion recovery (MOLLI) for high-resolutionT1
mapping of the heart. Magn Reson Med 2004;52:141–6.
............................................ .............................................. ........... ......................................................................
....................................................................................................................................................................................................................
Table 3 Correlations between T1 and T2 mapping indices and serological markers in AS patients (n525) using
Pearson correlation (r-statistic)
AS patients (n525) NIDCM patients (n534)
T2 mapping (ms) NT-proBNP hs-Troponin hs-CRP PICP NT-proBNP hs-Troponin hs-CRP PICP
MOLLI
Native T1 (ms) 0.628** 0.404* 0.324* 0.550** 0.284 0.441* 0.145 0.362* 0.316
Post-contrast T1 (ms) -0.22 -0.470* -0.334 -0.351* -0.091 -0.328 -0.122 -0.291 -0.172
ECV (%) 0.248* 0.327 0.272 0.216 0.070 0.315 0.171 0.226 0.231
ShMOLLI
Native T1 (ms) 0.459** 0.379* 0.217 0.409* 0.32 0.427* 0.160 0.350* 0.293
Post-contrast T1 (ms) -0.16 -0.311 -0.201 -0.308 -0.19 -0.247 -0.114 -0.314 -0.189
ECV (%) 0.236* 0.234 0.195 0.142 0.068 0.285 0.125 0.164 0.193
SASHA
Native T1 (ms) 0.211 0.095 0.099 0.213 0.083 0.136 0.083 0.291 0.233
Post-contrast T1 (ms) 0.027 -0.055 -0.025 -0.139 -0.069 -0.049 -0.053 -0.129 -0.061
ECV (%) 0.471 0.032 0.112 0.217 0.134 0.047 0.193 0.116 0.053
Native T2 0.414* 0.366* 0.382* 0.118 0.362* 0.162 0.351* 0.148
P-value of < 0.05 was statistically significant; * P< 0.05, ** P< 0.01.
8N. Child et al.
Downloaded from https://academic.oup.com/ehjcimaging/advance-article-abstract/doi/10.1093/ehjci/jex309/4725042
by guest
on 11 December 2017

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
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.
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.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5. Piechnik SK, Ferreira VM, Dall’Armellina E, Cochlin LE, Greiser A, Neubauer S
et al. Shortened Modified Look-Locker Inversion recovery (ShMOLLI) for clinical
myocardial T1-mapping at 1.5 and 3 T within a 9 heartbeat breathhold. J
Cardiovasc Magn Reson 2010;12:69.
6. Lee JJ, Liu S, Nacif MS, Ugander M, Han J, Kawel N et al. Myocardial T1 and
extracellular volume fraction mapping at 3 tesla. J Cardiovasc Magn Reson 2011;
13:75.
7. Radunski UK, Lund GK, Stehning C, Schnackenburg B, Bohnen S, Adam G et al.
CMR in patients with severe myocarditis. JACC Cardiovasc Imaging 2014;7:667–75.
8. Chow K, Flewitt JA, Green JD, Pagano JJ, Friedrich MG, Thompson RB.
Saturation recovery single-shot acquisition (SASHA) for myocardial T1mapping.
Magn Reson Med 2014;71:2082–95.
9. Roujol S, Weinga¨rtner S, Foppa M, Chow K, Kawaji K, Ngo LH et al. Accuracy,
precision, and reproducibility of four T1 mapping sequences: a head-to-head
comparison of MOLLI, ShMOLLI, SASHA, and SAPPHIRE. Radiology 2014;272:
683–9.
10. Puntmann VO, Carr-White G, Jabbour A, Yu C-Y, Gebker R, Kelle S et al. T1-
mapping and outcome in nonischemic cardiomyopathy. JACC Cardiovasc Imaging
2016;9:40–50.
11. Natori S, Lai S, Finn JP, Gomes AS, Hundley WG, Jerosch-Herold M et al.
Cardiovascular function in multi-ethnic study of atherosclerosis: normal values
by age, sex, and ethnicity. AJR Am J Roentgenol 2006;186:S357–65.
12. Puntmann VO, Voigt T, Chen Z, Mayr M, Karim R, Rhode K et al. Native T1
mapping in differentiation of normal myocardium from diffuse disease in hyper-
trophic and dilated cardiomyopathy. JACC Cardiovasc Imaging 2013;6:475–84.
13. Puntmann VO, Arroyo Ucar E, Hinojar Baydes R, Ngah NB, Kuo YS, Dabir D
et al. Aortic stiffness and interstitial myocardial fibrosis by native T1 are inde-
pendently associated with left ventricular remodeling in patients with dilated car-
diomyopathy. Hypertension 2014;64:762–8.
14. Authors/Task Force members, Vahanian A, Alfieri O, Andreotti F, Antunes MJ,
Baron-Esquivias G, Baumgartner H et al. Guidelines on the management of valvu-
lar heart disease (version 2012): the Joint Task Force on the Management of
Valvular Heart Disease of the European Society of Cardiology (ESC) and the
European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012;
33:2451–96.
15. Rogers T, Dabir D, Mahmoud I, Voigt T, Schaeffter T, Nagel E et al.
Standardization of T1 measurements with MOLLI in differentiation between
health and disease—the ConSept study. J Cardiovasc Magn Reson 2013;15:78.
16. Dabir D, Child N, Kalra A, Rogers T, Gebker R, Jabbour A et al. Reference values
for healthy human myocardium using a T1 mapping methodology: results from
the International T1 multicenter cardiovascular magnetic resonance study.
J Cardiovasc Magn Reson 2014;16:34.
17. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E; Society for
Cardiovascular Magnetic Resonance. Standardized cardiovascular magnetic reso-
nance (CMR) protocols 2013 update. J Cardiovasc Magn Reson 2013;15:91.
18. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG
et al. Standardized image interpretation and post processing in cardiovascular
magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR)
Board of Trustees Task Force on Standardized Post Processing. J Cardiovasc
Magn Reson 2013;15:35.
19. Jerosch-Herold M, Sheridan DC, Kushner JD, Nauman D, Burgess D, Dutton D
et al. Cardiac magnetic resonance imaging of myocardial contrast uptake and
blood flow in patients affected with idiopathic or familial dilated cardiomyopathy.
Am J Physiol Heart Circ Physiol 2008;295:H1234–42.
20. Kellman P, Hansen MS. T1-mapping in the heart: accuracy and precision.
J Cardiovasc Magn Reson 2014;16:2.
21. Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM et al.
Equilibrium contrast cardiovascular magnetic resonance for the measurement of
diffuse myocardial fibrosis: preliminary validation in humans. Circulation 2010;122:
138–44.
22. Bull S, White SK, Piechnik SK, Flett AS, Ferreira VM, Loudon M et al. Human
non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart
2013;99:932–7.
23. Fontana M, White SK, Banypersad SM, Sado DM, Maestrini V, Flett AS et al.
Comparison of T1 mapping techniques for ECV quantification. Histological vali-
dation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification
equilibrium contrast CMR. J Cardiovasc Magn Reson 2012;14:88.
24. White SK, Sado DM, Fontana M, Banypersad SM, Maestrini V, Flett AS et al.T1
mapping for myocardial extracellular volume measurement by CMR. JACC
Cardiovasc Imaging 2013;6:955–62.
25. de Meester de Ravenstein C, Bouzin C, Lazam S, Boulif J, Amzulescu M, Melchior
Jet al. Histological validation of measurement of diffuse interstitial myocardial
fibrosis by myocardial extravascular volume fraction from Modified Look-Locker
imaging (MOLLI) T1 mapping at 3 T. J Cardiovasc Magn Reson 2015;17:1268.
26. Lee S-P, Lee W, Lee JM, Park E-A, Kim H-K, Kim Y-J et al. Assessment of diffuse
myocardial fibrosis by using MR imaging in asymptomatic patients with aortic
stenosis. Radiology 2015;274:359–69.
27. Iles L, Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN et al.
Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic res-
onance contrast-enhanced T1 mapping. J Am Coll Cardiol 2008;52:1574–80.
28. Sibley CT, Noureldin RA, Gai N, Nacif MS, Liu S, Turkbey EB et al. T1 mapping
in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy.
Radiology 2012;265:724–32.
29. Mascherbauer J, Marzluf BA, Tufaro C, Pfaffenberger S, Graf A, Wexberg P et al.
Cardiac magnetic resonance postcontrast T1 time is associated with outcome in
patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging
2013;6:1056–65.
30. Miller CA, Naish JH, Bishop P, Coutts G, Clark D, Zhao S et al. Comprehensive
validation of cardiovascular magnetic resonance techniques for the assessment of
myocardial extracellular volume. Circ Cardiovasc Imaging 2013;6:373–83.
31. Aus Dem Siepen F, Buss SJ, Messroghli D, Andre F, Lossnitzer D, Seitz S et al.T1
mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantifica-
tion of diffuse myocardial fibrosis and comparison with endomyocardial biopsy.
Eur Heart J Cardiovasc Imaging 2015;16:210–6.
32. Iles LM, Ellims AH, Llewellyn H, Hare JL, Kaye DM, McLean CA et al. Histological
validation of cardiac magnetic resonance analysis of regional and diffuse intersti-
tial myocardial fibrosis. Eur Heart J Cardiovasc Imaging 2015;16:14–22.
33. Kammerlander AA, Marzluf BA, Zotter-Tufaro C, Aschauer S, Duca F, Bachmann
Aet al. T1 mapping by CMR imaging. JACC Cardiovasc Imaging 2016;9:14–23.
34. Schelbert EB, Sabbah HN, Butler J, Gheorghiade M. Employing extracellular vol-
ume cardiovascular magnetic resonance measures of myocardial fibrosis to foster
novel therapeutics. Circ Cardiovasc Imaging 2017;10:e005619.
35. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U et al. The
role of endomyocardial biopsy in the management of cardiovascular disease: a
scientific statement from the American Heart Association, the American College
of Cardiology, and the European Society of Cardiology. Circulation 2007;116:
2216–33.
36. Chin CWL, Semple S, Malley T, White AC, Mirsadraee S, Weale PJ et al.
Optimization and comparison of myocardial T1 techniques at 3T in patients with
aortic stenosis. Eur Heart J Cardiovasc Imaging 2014;15:556–65.
37. Child N, Yap ML, Dabir D, Rogers T, Suna G, Sandhu B et al. T1 values by con-
servative septal postprocessing approach are superior in relating to the intersti-
tial myocardial fibrosis: findings from patients with severe aortic stenosis.
J Cardiovasc Magn Reson 2015;17:P49.
38. Robson MD, Piechnik SK, Tunnicliffe EM, Neubauer S. T1measurements in the
human myocardium: the effects of magnetization transfer on the SASHA and
MOLLI sequences. Magn Reson Med 2013;70:664–70.
39. Hinojar R, Foote L, Arroyo Ucar E, Jackson T, Jabbour A, Yu C-Y et al. Native
T1 in discrimination of acute and convalescent stages in patients with clinical
diagnosis of myocarditis. JACC Cardiovasc Imaging 2015;8:37–46.
40. Lurz P, Luecke C, Eitel I, Fo¨hrenbach F, Frank C, Grothoff M et al.
Comprehensive cardiac magnetic resonance imaging in patients with suspected
myocarditis. J Am Coll Cardiol 2016;67:1800–11.
41. Ferna´ ndez-Jime´ nez R, Garcı´a-Prieto J, Sa´nchez-Gonza´lez J, Agu¨ ero J, Lo
´pez-
Martı´n GJ, Gala´n-Arriola C et al. Pathophysiolo gy underlying the bimodal edema
phenomenon after myocardial ischemia/reperfusion. J Am Coll Cardiol 2015;66:
816–28.
42. Ugander M, Bagi PS, Oki AJ, Chen B, Hsu L-Y, Aletras AH et al. Myocardial
edema as detected by pre-contrast T1 and T2 CMR delineates area at risk asso-
ciated with acute myocardial infarction. JACC Cardiovasc Imaging 2012;5:596–603.
43. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370–80.
44. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F et al.
Cardiac inflammation contributes to changes in the extracellular matrix in
patients with heart failure and normal ejection fraction. Circ Heart Fail 2011;4:
44–52.
45. van Heerebeek L, Franssen CPM, Hamdani N, Verheugt FWA, Somsen GA,
Paulus WJ. Molecular and cellular basis for diastolic dysfunction. Curr Heart Fail
Rep 2012;9:293–302.
46. Frey N, Olson EN, Hill JA. Mechanisms of stress-induced cardiac hypertrophy. In:
Muscle. Elsevier; 2012. p481–94.
47. Lazzeroni D, Rimoldi O, Camici PG. From left ventricular hypertrophy to dys-
function and failure. Circ J 2016;80:555–64.
48. Dimmeler S, Zeiher AM. Netting insights into fibrosis. N Engl J Med 2017;376:
1475–7.
Comparison of MOLLI, shMOLLI, and SASHA 9
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