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1
Differential diagnosis of left ventricular (LV) hypertrophy
(LVH) remains challenging in clinical practice, in particu-
lar between hypertrophic cardiomyopathy (HCM) and increased
LV wall thickness (LVWT) because of systemic hypertension.
Reactive LVH that develops in response to an extrinsic increase
in cardiac work, such as in hypertension, is distinguished from
LVH because of familial HCM, in which the stimulus for
increase in LVWT is intrinsic to the genetically altered cardio-
myocyte.1 HCM is characterized by diffuse myocardial disease,
defined by structurally dysmorphic myocytes, architectural loss
of parallel arrangement, and disarray of fibers and fascicles, as
well as genetically driven alterations of extracellular matrix with
accumulation of interstitial fibrosis.1–9 Cardiovascular magnetic
resonance (CMR) provides means of phenotyping the complex
Background—The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice,
in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic
hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–
gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting
diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as
to detect genetically driven interstitial changes in the G+P− subjects.
Methods and Results—Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects
(n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar
imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1
and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001),
including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of
hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly
higher in G+P− subjects (P<0.0001) and 65% of G+P− subjects had a native T1 value >2 SD above the mean of the normal
range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume
fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls.
Conclusions—Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early
changes in G+P− subjects. (Circ Cardiovasc Imaging. 2015;8:e003285. DOI: 10.1161/CIRCIMAGING.115.003285.)
Key Words: cardiac magnetic resonance ◼ hypertension ◼ hypertrophic cardiomyopathy
◼ left ventricular hypertrophy ◼ T1 mapping
© 2015 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org DOI: 10.1161/CIRCIMAGING.115.003285
Received February 23, 2015; accepted October 27, 2015.
From the Department of Cardiovascular Imaging (R.H., N.V., N.C., B.G., T.R., E.A.U., C.C., G.C.-W., E.N., V.O.P.) and Division of Cardiovascular Sciences
(S.K.), King’s College London, London, United Kingdom; Cardiovascular Department, University Hospital Ramón y Cajal, Madrid, Spain (R.H.); Department
of Cardiology, St. Vincent’s Hospital and The Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (A.J., C.-Y.Y.); German Heart
Institute Berlin, Berlin, Germany (R.G., A.D., S.K.); and Division of Internal Medicine III, Department of Cardiology (V.O.P.) and Institute for Experimental
and Translational Cardiovascular Imaging, DZHK Centre for Cardiovascular Imaging (E.N.), Goethe University Frankfurt, Frankfurt, Germany.
The Data Supplement is available at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/CIRCIMAGING.115.003285/-/DC1.
Correspondence to Valentina O. Puntmann, MD, PhD, Division of Internal Medicine III, Department of Cardiology, University Hospital Frankfurt,
Goethe University Frankfurt, Frankfurt, Germany. E-mail vppapers@icloud.com
T1 Mapping in Discrimination of Hypertrophic
Phenotypes: Hypertensive Heart Disease and Hypertrophic
Cardiomyopathy
Findings From the International T1 Multicenter Cardiovascular Magnetic
Resonance Study
Rocio Hinojar, MD, MRes; Niharika Varma, MBBS, BSc; Nick Child, BM, MRCP;
Benjamin Goodman, MSc; Andrew Jabbour, MD, PhD; Chung-Yao Yu; MBBS, MD;
Rolf Gebker, MD, PhD; Adelina Doltra, MD, PhD; Sebastian Kelle, MD, PhD;
Sitara Khan, MD, PhD; Toby Rogers, MD; Eduardo Arroyo Ucar, MD; Ciara Cummins, MSc;
Gerald Carr-White, MBBS, PhD; Eike Nagel, MD, PhD; Valentina O. Puntmann, MD, PhD
Cardiomyopathies
See Editorial by Schelbert and Moon
See Clinical Perspective
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2 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
underlying pathophysiology and may be able to discern the
fundamentally different substrates based on the different patho-
physiological pathways in these 2 conditions (Figure 1).8–12
Although T1 mapping supports detection of diffuse myocardial
disease, late gadolinium enhancement (LGE) helps with visual-
izing regional changes, such as replacement fibrosis in pheno-
typically subexpressed HCM gene carriers (G+P− subjects) and
overt HCM disease. In compensated LVH because of hyperten-
sion—that is before extensive structural and metabolic remodel-
ing with cavity dilatation and functional impairment (eccentric
remodeling)—findings reflect physiological adaptations with an
increased cellular size because of addition of new, but functional
myofibrilles in-parallel and in-series, enabling the ventricle
to generate greater forces and to outweigh the increased wall
stress.11,13–17 Interstitial fibrosis and the expansion of extra-
cellular space in hypertension herald decompensation with
eccentric remodeling and heart failure.12–15,18–22 In this study,
we investigated the ability of CMR to discern hypertrophic
phenotypes based on detection of diffuse myocardial disease
and regional fibrosis by myocardial T1 mapping and LGE,
respectively, first, in overt LVH, and second, in phenotypically
subexpressed HCM gene carriers.
Methods
Consecutive subjects enrolled in the International T1 multicentre
CMR study and meeting inclusion criteria below were included in
this study. The multicenter-imaging consortium has been described
previously (details in the Data Supplement).23 The study protocol was
reviewed and approved by the respective institutional ethics commit-
tees and written informed consent was obtained from all participants.
All procedures were carried out in accordance with the Declaration of
Helsinki (2000). Inclusion criteria for respective patients groups were
based on accepted diagnostic criteria1,24–26 using CMR measurements:
Group 1
Patients with HCM (n=95), by demonstration of an LVH (>15 mm)
associated with a nondilated LV in the absence of increased LV wall
stress or another cardiac or systemic disease that could result in a
similar magnitude of hypertrophy.1,24 All patients with HCM had an
expressed phenotype with typically asymmetrical septal hypertrophy
of increased LVWT, permitting unequivocal clinical diagnoses. HCM
patients with previous septal ablation or myectomy were not included.
Group 2
Patients With Hypertension and Compensated LVH
Evidence of treated essential hypertension (n=69; systolic blood pres-
sure of >140 mm Hg; diastolic blood pressure of >95 mm Hg) and
the presence of concentric LVH defined as >12 mm in the basal sep-
tal and inferolateral segments25 and without evidence of dilated LV
cavity (end-diastolic diameter≤5.4 cm for women and ≤5.9 cm for
men)26,27 on transthoracic echocardiography.
Group 3
G+P− first-degree relatives of patients with HCM, identified carriers
of the relevant sarcomere–gene mutations, but had no evidence of
LVH (LVWT≤13 mm; n=23).1,7–9
Group 4
Twenty-three normotensive age- and sex-matched healthy subjects,
not taking any regular medications and normal CMR findings includ-
ing normal LV mass indices, served as the control group to group 3.
The datasets of control subjects were included in a previously pub-
lished article.23
Exclusion criteria for all subjects were history of athletic activity,
known diagnosis of amyloidosis or Anderson–Fabry disease, known
history of coronary artery disease or previous coronary intervention,
as well as the generally accepted contraindications to CMR (implant-
able devices, cerebral aneurysm clips, cochlear implants, and severe
claustrophobia), or a history of renal disease with a current epidermal
growth factor receptor of <30 mL/min per 1.73 m2.
Cardiovascular Magnetic Resonance
All subjects underwent a routine clinical protocol for volumes
and mass and tissue characterization using a 3-tesla MR scanner
equipped with advanced cardiac package and multitransmit tech-
nology (Achieva, Philips Healthcare, Best, The Netherlands) after
professional recommendation for standardized acquisition28 and as
previously described.23,29 Details of imaging acquisition and post-
processing are provided in the Data Supplement. Cine imaging was
used for complete coverage of gapless short-axis slices as well as
Figure 1. Representatives images of hypertensive LVH (HTN) and hypertrophic cardiomyopathy (HCM). Top , End-diastolic cine images.
Bottom, Late gadolinium enhancement (LGE) imaging. A, HTN. Arrows highlight an ischemic scar in the lateral wall. B, Concentric HCM with
no areas of LGE. C, HCM with areas of LGE. Arrows highlight the areas of LGE in the superior and inferior right ventricular insertion points.
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3 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
long-axis views. LGE imaging was performed in identical geome-
tries ≈20 minutes after administration of 0.2 mmol/kg body weight
gadobutrol (Gadovist, Bayer Healthcare, Leverkusen, Germany) T1
mapping was performed by using modified Look-Locker imaging
((3(3)3(3)5)) acquisition in a single midventricular short-axis slice,
before contrast administration and to scar imaging, respectively.
Image Analysis
Assessment of cardiac volumes and LV mass was performed af-
ter recommendations for standardized postprocessing30 using
commercially available software (CircleCVI 42, Calgary, Canada; for
details see Data Supplement). LGE images were visually examined
for the presence of regional fibrosis showing as bright areas within
the myocardium in corresponding longitudinal views and by exclu-
sion of potential artifacts.31 LGE was quantified using regions defined
as >50% of maximal signal intensity of the enhanced area (full width
at half maximum).30,31 Myocardial crypts were considered present as
visually as structural abnormalities consisting of narrow, deep blood–
filled invaginations considered on cine viewing to penetrate >50% of
the thickness of adjoining myocardium during diastole, perpendicular
Table 1. Patient Characteristics, Global Morphological, and Functional Measures Based on Cardiovascular Magnetic Resonance
Measurements
Controls (n=23) G+P− subjects (n=23) HCM (n=95) HTN (n=69) Significance (P value)
Age, y 44±15 41±18 55±14 54±13 <0.0001
Sex, male n (%) 14 (61) 16 (69) 64 (68) 45 (65) 0.6
BSA, m21.6±0.1 1.8±0.1 1.96±0.2 2.01±0.2 0.03
Systolic BP, mm Hg 119±10 120±15 120±20* 147±20 0.003
Diastolic BP, mm Hg 79±7 77±9 78±12 83±10 0.24
Heart rate, bpm 65±11 67±17 70±12 74±15 0.05
NYHA, stage
Stage I (n, %) 23(100) 19 (83) 62 (65) 39 (57) <0.001
Stage II (n, %) … 4 (17) 21 (22) 27 (39)
Stage III (n, %) … … 12 (13) 3 (4)
Diastolic dysfunction, grade
Normal (n, %) 23(100) 17 (74)† 19 (20) 15 (22) <0.001
Grade I (inverted E/A ratio) (n, %) … 6 (26) 58 (61) 50 (72)
Grade II (pseudonormalization) (n, %) … … 18 (19)* 4 (6)
E/E′ (septal) 5±2 7±4 13±4 11±6 0.007
Deceleration time (ms) 153±13 161±12 212±16 199±10 <0.001
LV-EDV index, mL/m277±12 80±17 75±17 74±22 0.22
LV ejection fraction % 63±8 62±8 64±10 62±11 0.7
RV ejection fraction % 61±10 60±9 66±9 63±9 0.001
LV mass index, mg/m258±16 56±14 97±29* 70±19 <0.0001
Maximal LVWT, mm 8±1 9±2 19±4* 14±5 <0.0001
LGE
Present (n, %) 0 2 (9) 65 (68)* 16 (23) <0.0001
LGE extent (FWHM) … 1.1±0.9 5.5±4.8* 2.6±2.0 <0.001
RV insertion points (n, %) 0 0 30 (46)* 1 (1) <0.0001
Ischemic pattern (n, %) 0 0 3 (3)* 7 (10) <0.0001
T1 mapping
Septal native T1 (ms) 1044±18 1105±17† 1169±41* 1058±29 <0.0001
SAX native T1 (ms) 1023±44 1055±55 1102±58* 1033±68 0.001
Septal postcontrast T1 (ms) 446±70 434±67 379±47* 429±60 <0.001
SAX postcontrast T1 (ms) 466±37 424±79 390±44 422±66 0.07
Septal λ0.43±0.1 0.45±0.08 0.52±0.09* 0.44±0.07 <0.0001
Septal ECV 0.24±0.06 0.25±0.04 0.31±0.06* 0.24±0.04 <0.0001
SAX λ0.44±0.1 0.46±0.1 0.51±0.1 0.46±0.1 0.25
SAX ECV 0.23±0.07 0.24±0.06 0.30±0.09 0.24±0.06 0.31
Abnormal native T123 (n, %) 0 (0) 15 (65)† 92 (98)* 3 (4) <0.0001
Abnormal native T123 (n, %) 0 (0) 15 (65)† 92 (98)* 3 (4) <0.0001
One-way ANOVA or χ2 tests, as appropriate for the type of the data, P<0.05 is considered significant. BP indicates blood pressure; BSA, body surface area; , ECV,
extracellular volume; EDV, end-diastolic volume; FWHM, full width at half maximum; HCM, hypertrophic cardiomyopathy; HTN, hypertensive LVH; LV, left ventricular,
NYHA, New York Heart Association; LGE, late gadolinium enhancement; LVWT, LV wall thickness; RV, right ventricular; and SAX, short-axis slice.
Post-hoc tests for significant differences between *HCM vs HTN and †for G+P− subjects vs controls, respectively.
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4 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
(45–135°) to the endocardial border of otherwise normal compacted
myocardium and evidence of subtotal or total obliteration during sys-
tole by surrounding tissue, as previously described.32
T1-mapping analysis was performed blinded to the underly-
ing diagnosis (including the cine and LGE imaging) by measuring
myocardial T1 relaxation in a midventricular short-axis slice using
conservative septal sampling, as previously described and validated
(details in the Data Supplement).23,29,33 T1 values were also reported
for the complete midventricular short-axis slice. A total of 4 HCM
subjects, where LGE overlapped with the septal region of interest for
T1 mapping, were excluded. In addition to native T1, the hematocrit-
corrected extracellular volume fraction (ECV), a marker of extracel-
lular contrast agent accumulation, was also calculated.23,34
Statistical Analysis
Descriptive analysis, comparisons of the groups and assessment of
associations have been performed using standard approaches (details
in the Data Supplement). Categorical data are expressed as percent-
ages, and continuous variables as mean±SD or median (interquartile
range). All tests were 2-tailed and a P value of <0.05 was considered
significant. Univariate and multivariate logistic regression was used
to test the ability of CMR measures to discriminate between the HCM
and hypertensive groups, as well as controls versus G+P− subjects.
Sensitivity, specificity and discriminatory accuracy, cut-off values
and area under the curve, were derived using receiver-operating char-
acteristics curve analysis. Results of further subgroup analyses are
presented in the Data Supplement.
Results
Subject characteristics are presented in Table 1. Compared
with patients with hypertension, those with HCM had higher
LV mass and LVWT (P<0.0001). Both LVH groups had
diastolic impairment; more patients with HCM had grade
II. G+P− subjects were similar to controls in functional and
morphological measures. LGE was present in 68% of patients
with HCM, 46% of which showed areas of LGE at one or both
right ventricular insertion points. In the hypertensive group,
16 patients demonstrated LGE of which 10 were demonstrat-
ing an ischemic pattern. Two G+P− subjects of patients with
HCM showed a nonischemic patch of LGE (Figure 2).
Comparisons of the Groups for T1 Mapping Indices
Native T1 and ECV were significantly higher in HCM
compared with hypertensive patients (Table 1; Figure 3;
P<0.0001), including in subanalysis of subjects without vis-
ible LGE (HCMLGE− versus hypertensionLGE−, native T1 [ms]:
1165±36 versus 1059±29; ECV: 0.31±0.06 versus 0.26±0.04;
P<0.0001 for all; Figures in the Data Supplement). There
was no difference in T1-mapping indices in HCM patients
with or without LGE (HCMLGE+ versus HCMLGE−, native T1
[ms]: 1170±44 versus 1165±36; ECV: (%) 0.32±0.06 versus
0.31±0.06; P>0.05 for all). Various morphological types of
HCM (concentric, septal, apical, or mid-LVH) were simi-
lar in T1 values (P>0.05 for all). Ninety-three patients with
HCM (98%) had abnormal T1 values.23 Controlling for the
magnitude of LVWT (≥15 mm),1,24 Patients with HCM had
significantly higher T1-mapping indices compared with
hypertension15mm subgroup (HCM versus hypertension15mm
[n=19]; native T1 [ms]: 1169±41 versus 1059±38; ECV:
0.32±0.04 versus 0.26±0.04; P<0.001 for all).
Comparisons Between G+P− Subjects versus Controls
Compared with controls, native T1 was significantly higher in
G+P− subjects (P<0.0001), whereas ECV values were similar
(P=0.49). A total of 15 G+P− subjects (65%) had an abnormal
native T1 value.23
Compared with hypertension13mm subgroup (n=24, age,
years: 49±9), G+P− subjects had significantly raised native
T1 (native T1 [ms], G+P− subjects versus hypertension13mm:
Figure 2. Representative images of
hypertrophic cardiomyopathy (HCM) rela-
tives (G+P− subjects). Top, End-diastolic
cine. Bottom, Late gadolinium enhance-
ment (LGE) imaging. A, HCM relative
with 12-mm left ventricular wall thickness
(LVWT) at the septum (line) and no areas
of LGE. B, HCM relative with normal
LVWT and areas of subtle and diffuse
LGE in the lateral wall (arrows).
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5 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
1105±17 versus 1056±31; P<0.0001), whereas ECV values
were similar between the groups (P=0.62). T1 values were
similar in the hypertension13mm and hypertension15mm sub-
groups (native T1 [ms]: 1056±31 versus 1059±18; P=0.51;
ECV: 0.24±3 versus 0.24±4; P=0.79). Reproducibility results
are provided in the Data Supplement.
Analysis of Relationships
In HCM subjects, there was positive association between
native T1 and indexed LV mass (r=0.47, P<0.001), maxi-
mal LVWT (r=0.44, P<0.001), and E/E′ (r=0.33, P=0.034),
whereas patients with hypertension showed no significant
associations between these variables (r=0.19, r=0.13, r=0.01,
P>0.05, respectively; Figure 4). New York Heart Association
showed no association with native T1 in any group.
Discrimination Between Hypertrophic Phenotypes
In multivariate binary logistic regression analysis including
ECV, the presence of LGE, maximal LVWT, and LV mass
index (Tables 2 and 3), native T1 was identified as the indepen-
dent parameter in discrimination between HCM and hyperten-
sion with sensitivity 96%, specificity 98%, and discriminatory
accuracy 97%. In discrimination between G+P− subjects and
controls native T1 was the only significant variable (Tables 2
and 3; Figures 5). Results of further subgroup analyses are
included in the Data Supplement.
Discussion
In selected patient populations with hypertrophic phenotypes,
we provide a proof-of-concept that myocardial T1 mapping
can be instrumental in discrimination between HCM and
hypertension: first, T1-mapping indices are significantly dif-
ferent, and second, native T1 was identified as the strongest
independent discriminator, also when controlling for LGE
and similar magnitudes of LVWT. We further show that
G+P− subjects have significantly raised native T1 compared
with controls, as well as patients with mild hypertension. This
important finding may support detection of subexpressed dis-
ease as well as separation of these subjects from borderline
cases with mild hypertension. Our findings propose a novel
systematic approach toward discrimination of common con-
ditions presenting with overt or borderline hypertrophic phe-
notypes and potentially supporting differential management
pathways, in terms of screening and treatment, respectively.
Difficulties in discrimination of overt hypertrophic phe-
notypes preclude the appropriate diagnosis, risk assessment,
and clinical management. Currently, the diagnosis of HCM
is based on the finding of LVH with LVWT≥15 mm in the
absence of increase in LV wall stress. This approach com-
monly fails to support unequivocal confirmation of disease, or
alternatively, its exclusion.1,24 The complex underlying histo-
pathology1–6 and the consequent functional changes in HCM
provide a conundrum of myocardial abnormalities, including
replacement fibrosis, reduced ventricular deformation, and
increased diastolic stiffness.7–12 Detecting these abnormali-
ties have all been shown to help with disease confirmation in
overt LVH.1,24 Visualization of replacement fibrosis by LGE,
most commonly located in right ventricular insertion points,
is particularly helpful in differential diagnosis,1,11 as well as
risk stratification.35–37 However, ≈40% of patients with HCM
show no evidence of LGE. Although the LGE relates to the
regionally separated myocardial abnormality, T1-mapping
techniques support noninvasively detection of diffuse myo-
cardial involvement.7–9,12,18,19 We and others have previously
shown that patients with HCM have abnormal T1 indices con-
cordant with diffuse myocardial disease, even in the absence
of LGE, as well as in the areas outside overt LGE.7–9,12 We
now provide a further evidence that T1 mapping can support
clinically relevant discrimination between HCM and hyper-
tension, also in the subset of subjects without overt LGE and
when controlling for similar magnitudes of LVWT. Of note,
HCM patients group exhibited increased native T1 between 2
and 5 SD above the mean of the reference range, whereas in
patients with hypertension native T1 were concentrated within
the 2 SD.23 Our findings further resonate with a recent study in
patients with hypertension, which demonstrated native T1 val-
ues were higher compared with their respective normotensive
reference group, however, within 2 SD of the respective refer-
ence range.38 In summary, these findings accord with existing
knowledge on the respective underlying pathophysiology.4–6,13
Previous studies revealed that the genetically driven dif-
fuse myocardial process is fundamental in development of
HCM and an early consequence of sarcomere mutations rather
Figure 3. Box plots for native T1 (A) and extracellular volume
fraction (ECV; B) in controls, G+P− subjects, hypertrophic cardio-
myopathy (HCM) and hypertensive (HTN) patients.
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6 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
than a downstream response to the LVH, outflow obstruction,
or sequel to microvascular disease.7–9 Our findings corroborate
the observations of previous reports by showing the relation-
ship between native T1 and LVWT and LV mass, indicating
association between diffuse myocardial involvement and phe-
notypic expression of disease.12,20,39 In this study, diffuse myo-
cardial abnormalities, evidenced by abnormally high native
T1,23 were found in nearly all patients with HCM (98%),
indicating that overt HCM with native T1 within the normal
range is exceedingly rare. Two thirds of G+P− subjects in our
study exhibited abnormal native T1, suggesting that diffuse
disease is present and detectable in the absence of an overt
phenotype.7–9 As more families undergo genetic testing and
phenotypic assessment for HCM, a new preclinical population
is growing.1,24 Genetic diagnosis aids to identify the relevant
sarcomere mutations in subexpressed relatives, potentially at
risk for development of future disease. Native T1 may serve
to identify those with subclinical myocardial abnormalities,
complementary to genetic testing in identifying the sub-
clinical expression of disease. Given that diffuse myocardial
remodeling may be a dynamic process, monitoring native T1
as oppose to LVWT might provide a more reliable means of
monitoring disease progression.
Previous observations revealed higher prevalence of myo-
cardial crypts in patients with HCM and G+P− subjects, suggest-
ing that they represent markers of HCM disease.32,40,41 Although
Table 2. Results of ROC and Binary Logistic Regression Analysis of CMR Parameters for Discrimination in HCM vs HTN Subjects
Biomarkers AUC (95% CI) Cut-Off Values Specificity (95% CI) Sensitivity (95% CI) PPV (95% CI) NPV (95% CI)
Diagnostic Accuracy
(95% CI)
HCM vs HTN
Univariate analysis
Septal native T1, ms 0.97 (0.94–1.00)** 1110 98 (94–99) 96 (90–98) 97 (93–98) 98 (91–99) 97 (92–99)
SAX native, ms 0.79 (0.70–0.89)** 1067 77 (67–89) 71 (58–82) 71 (58–82) 73 (63–81) 71 (61–81)
Septal ECV 0.76 (0.67–0.84)** 0.29 71 (63–81) 76 (67–84) 74 (65–81) 71 (61–81) 73 (63–82)
SAX ECV 0.66 (0.54–0.75) 0.30 63 (49–70) 70 (58–78) 72 (59–73) 61 (54–67) 63 (51–73)
LGE (present) 0.76 (0.64–0.82)** … 68 (61–74) 76 (67–84) 80 (72–87) 63 (56–70) 71 (64–78)
Maximal LVWT, mm 0.93 (0.92–0.99)** 16 84 (78–88) 91 (81–95) 92 (85–96) 81 (73–85) 87 (79–90)
LV mass (index), g/m20.82(0.73–0.87)** 0.84 64 (54–71) 80 (73–86) 75 (68–80) 71 (60–78) 73 (65–79)
Multivariate analysis
Wald Exp(B) (95% CI)
Native T1, ms 26.1 1.121 (1.057–1.217)** 98 (94–99) 96 (90–99) 96 (90–99) 98 (94–99) 97 (93–99)
For further subgroup analyses see Data Supplement. Variables not included (significance [P value]): ECV (0.173); LGE (present; 0.01); Maximal LVWT (0.003);
LV mass (index; 0.60). For the model: χ2: 127, P<0.001; −2Log LH: 47.9, Cox and Snell R2: 0.63, Nagelkerke R2: 0.85. AUC indicates area under the curve; CI,
confidence interval; CMR, cardiovascular magnetic resonance; ECV, extracellular volume fraction; HCM, hypertrophic cardiomyopathy; HTN, hypertensive LVH; LGE,
late gadolinium enhancement; LH, likelihood; LV, left ventricle; LVWT, LV wall thickness; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver-
operating characteristics; and SAX, short-axis slice.
P value of <0.05 was considered significant. *P<0.05, **P<0.01.
Figure 4. Bivariate correlation between native T1 and left ventricle (LV) mass and LV wall thickness. Hypertrophic cardiomyopathy (HCM)
subjects showed a positive correlation between native T1 and indexed LV mass (r=0.47, P<0.01) and maximal left ventricular wall thick-
ness (LVWT; r=0.44, P<0.01). Patients with hypertensive LVH (HTN) showed no significant associations between native T1 and indexed
LV mass and LVWT.
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7 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
not reproduced in larger and broader cohorts,32,40 none of G+P−
subjects in the present cohort showed crypts, and the proportion
of these were similar between hypertensive and HCM groups,
indicating that crypts are more visible with increased LVWT as
well as preserved global systolic function.32,40
A few limitations apply to this study. Prospective studies in
large and broad populations are required to validate our findings
for widespread use. We strived to exclude patients with overt
LVH phenocopies including subjects with history of substan-
tial athletic activity,42 as well as known cardiac amyloidosis or
known Anderson–Fabry disease.1,24 A small number of patients
excluded because of overlap of LGE with septal region of inter-
est is unlikely to have caused a significant bias; on the contrary,
this approach permitted a blinded read to the underlying diag-
nosis and the proof-of-concept, that the effects found are not
because of the LGE type of scar. The chosen LVWT cut-offs,
although based on the diagnostic criteria, may seem arbitrary
against the increasingly apparent recognition that HCM repre-
sents a continuum of disease across the spectrum of LVWT.8–10
Superior discrimination based on native T1 compared with ECV
may relate to the T1-mapping methodology based on modified
Look-Locker imaging and its greater precision of native myo-
cardial measurements, concordant with the previous results in
discrimination between normal and diffusely diseased myocar-
dium of us and others.12,20,29,33,38,39 We recognize that native T1
and ECV are complementary measures of different, but related
Table 3. Results of ROC and Binary Logistic Regression Analysis of CMR Parameters for Discrimination in Controls vs G+P−
Subjects
Biomarkers AUC (95% CI) Cut-Off Values Specificity (95% CI) Sensitivity (95% CI) PPV (95% CI) NPV (95% CI)
Diagnostic Accuracy
(95% CI)
Controls vs G+P− subjects
Septal native T1, ms 0.97 (0.94–1.00)** 1089 96 (91–99) 87 (79–91) 92 (79–97) 97 (92–99) 92 (81–98)
SAX native T1, ms 0.78 (0.69–0.87)** 1056 76 (64–88) 69 (56–77) 67 (54–75) 70 (61–78) 68 (56–78)
Septal ECV 0.65 (0.48–0.82) … … … … …
SAX ECV
Native T1, ms 0.97 (0.94–1.00)** 1089 96 (91–99) 87 (79–91) 92 (79–97) 97 (92–99) 92 (81–98)
ECV 0.65 (0.48–0.82), NS … … … … …
LGE (present) 0.54 (0.38–0.71), NS … … … … …
Maximal LVWT, mm 0.75 (0.61–0.89)NS
LV mass (index), g/m20.49 (0.31–0.65), NS … … … … …
Multivariate analysis
Wald Exp(B) (95% CI)
Native T1, ms 11.2 1.139 (1.055–1.230)** 91 (78–96) 91 (79–98) 92 (79–98) 91 (77–98) 92 (77–98)
For further subgroup analyses see Data Supplement. Variables not included (significance [P value]): ECV (0.51); LGE (present; 0.87); Maximal LVWT (0.004); LV
mass (index; 0.32). For the model: χ2: 45.5, P<0.001; −2Log LH: 18.3, Cox and Snell R2: 0.63, Nagelkerke R2: 0.84. AUC indicates area under the curve; CI, confidence
interval; CMR, cardiovascular magnetic resonance; ECV, extracellular volume fraction; LGE, late gadolinium enhancement; LH, likelihood; LV, left ventricle; LVWT, LV wall
thickness; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver-operating characteristics; and SAX, short-axis slice.
P value of <0.05 was considered significant. *P<0.05, **P<0.01.
Figure 5. Receiver-operating characteristics (ROC) curves in discrimination between hypertrophic cardiomyopathy (HCM) vs hypertensive
LVH (HTN; A) and controls vs G+P− subjects (B). ECV, extracellular volume fraction; LGE, late gadolinium enhancement; and LVWT, left
ventricular wall thickness.
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8 Hinojar et al Native T1 in Discrimination Between Hypertension and HCM
aspects of the myocardium. Our demonstration that native T1
can detect the earliest changes in HCM myocardium endorses
the importance of considering both parameters in defining the
natural history of myocardial changes in genopositive indi-
viduals. Such an integrated approach is essential to develop
timely interventions targeting underlying molecular and struc-
tural events to halt or reverse disease progression and improve
outcomes.
In conclusion, our study demonstrates that T1-mapping
indices may discriminate between overt LVH because
of HCM or hypertension with high accuracy. We further
show that native T1 value may serve as a novel, noninva-
sive, and clinically robust biomarker to detect early expres-
sion of diffuse myocardial involvement in subexpressed
G+P− subjects.
Sources of Funding
This study was supported by Department of Health via the National
Institute for Health Research comprehensive Biomedical Research
Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in part-
nership with King’s College London and King’s College Hospital
National Health Service Foundation Trust. This study was also sup-
ported by the King’s BHF Centre of Research Excellence. Dr Hinojar
was supported by the Spanish Cardiology Society. Dr Yu is supported
by Victor Chang Cardiac Research Institute. Dr Child is supported by
Saint Jude Medical. Dr Nagel is supported by the German Centre for
Cardiovascular Research (DZHK) and the German Federal Ministry
for Education and Research (BMBF).
Disclosures
Drs Puntmann and Nagel hold a patent of invention for a method for
differentiation of normal myocardium from diffuse disease using T1
mapping in nonischemic cardiomyopathies and others (based on PR-
MS 33.297, PR-MS 33.837, PR-MS 33.654; with no financial inter-
est). The other authors report no conflicts.
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CLINICAL PERSPECTIVE
Using selected patient populations with hypertrophic phenotypes, we provide a proof-of-concept that myocardial T1 map-
ping may be instrumental in discrimination between HCM and hypertension. T1-mapping indices are significantly higher
in HCM in comparison with hypertension also when controlling for LGE and similar magnitudes of LVWT. Native T1
was the strongest independent discriminator between these 2 conditions. We further show that a majority of gene positive
subjects have raised native T1 in the absence of phenotypically expressed disease (G+P−). Our findings propose a novel
systematic approach toward discrimination of common conditions presenting with overt or borderline hypertrophic pheno-
types, potentially supporting differential treatment pathways, as well as a screening tool for subclinical cardiomyopathy in
G+P− subjects.
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SUPPLEMENTARY MATERIAL
T1 Mapping in Discrimination of Hypertrophic Phenotypes - Hypertensive Heart
Disease and Hypertrophic Cardiomyopathy: Findings from the International T1
Multicenter CMR Study
Hinojar et al: Native T1 in Discrimination between HTN and HCM
Rocio Hinojar 1,2, MD; Mres; Niharika Varma1, MBBS; Bsc; Nick Child1, BM MRCP;
Benjamin Goodman1, MSc; Andrew Jabbour3, MD, PhD; Chung-Yao Yu3; MBBS, MD;
Rolf Gebker,4 MD, PhD; Adelina Doltra4, MD, PhD; Sebastian Kelle4, MD, PhD;
Sitara Khan5, MD, PhD; Toby Rogers1, MD; Eduardo Arroyo Ucar1, MD;
Ciara Cummins1, MSc; Gerald Carr-White1, MBBS, PhD; Eike Nagel1,7, MD, PhD;
Valentina O. Puntmann1, 6*, MD, PhD
Supplemental Methods
Patient characteristics were recorded for all subjects, including age, gender, body mass index,
and presence of traditional cardiovascular risk factors. NYHA stage, systolic/diastolic blood
pressure and parameters of diastolic function by transthoracic echocardiography were also
recorded.
Genotyped relatives (G+P-) were identified as a part of routine clinical work-up in selected
subject with considerable pretest likelihood as carriers of hereditary cardiac condition as a
cascade genetic screening of the relatives of patients with overt disease [1]. Sequencing
methodologies were performed for the most commonly implicated sarcomere protein genes,
as per guidelines [1].
Multicenter-imaging consortium has been described previously [2]. A standardized T1-
mapping sequence and imaging protocol, developed and validated at King’ s College London
(KCL) [2-5], were distributed to CMR centers identified via the worldwide Philips Healthcare
clinical science network that hold individual partnership research agreements allowing for
adequate clinical science support and provision of compatible sequences and scanner software
packages. Imaging parameters were unified across participating sites. Inter-centre
comparisons of measured T1 values at each location for each field strength, as well as
reproducibility and transferability of postprocessing have been reported previously [2-5].
Imaging parameters
All cine CMR were performed using a balanced steady-state free precession sequence in
combination with parallel imaging (SENSitivity Encoding, factor 2) and retrospective gating
during a gentle expiratory breath- hold (TE/TR/flip-angle: 1.7ms/3.4ms/60°, spatial resolution
1.8x1.8x8 mm) [4,6].
Late gadolinium enhancement (LGE) was performed using gapless whole heart coverage of
short axis (SAX) slices 20 minutes after administration of 0.2 mmol/kg body weight
gadobutrol (Gadovist®, Bayer, Leverkusen, Germany) using a mid-diastolic inversion
prepared 2-dimensional gradient echo sequence (TE/TR/flip-angle 2.0 msec/3.4 msec/25°,
acquired voxel size 1.4x1.4x8mm) with an individually adapted prepulse delay to achieve
optimally nulled myocardium [4,6].
Balanced steady state free precession single breath-hold modified Look-Locker Imaging
(MOLLI, (3(3)3(3)5)) was used for T1 mapping and performed in a single midventricular
short axis slice at mid-diastole, prior to contrast administration and to LGE imaging,
respectively (TE/TR/flip-angle: 1.64msec/3.3msec/50°, acquired voxel size 1.8 x 1.8 x 8 mm,
phase encoding steps n=166, 11 images corresponding to different inversion times
((3(3)3(3)5) MOLLI scheme), adiabatic prepulse to achieve complete inversion)[2-5]. The
acquisitions were checked for motion and artifacts as well as for goodness of fit immediately
after acquisition. Poor quality acquisitions were repeated.
Image analysis
Assessment of cardiac volumes and LV mass was performed following recommendations for
standardized postprocessing [7]. Endocardial LV borders were manually traced at end-
diastole and end-systole. The papillary muscles were included as part of the LV cavity
volume. LV end-diastolic (EDV) and end-systolic (ESV) volumes were determined using rule
of discs. Ejection fraction (EF) was computed as EDV-ESV/EDV. All volumetric indices
were normalized to body surface area (BSA).
T1 mapping analysis
We have previously shown that T1 mapping acquisition in a single midventricular SAX slice
and conservative septal measurements are feasible in clinical routine [2-5]. Standardization of
T1 measurements using conservative septal myocardial sampling within the midventricular
SAX slice, is in part based on the findings that this geometry is acquired with good
reproducibly, as well as sufficient LVWT to avoid blood contamination of the T1 signal and
does not suffer from partial volume effects found in the basal or apical slices [5]. This
approach intends to capture diffuse disease, not seen by LGE, and to be representative of
diffuse myocardial involvement of the whole myocardium [4], allowing us to capture the
global effects of genetically induced diffuse myocardial disease in HCM as well as
abnormalities driven by increased afterload in HTN [1]. The advantage of whole-heart T1
mapping and its feasibility for the use of clinical practice is presently unknown and subject to
further technical development [8].
T1 mapping analysis was performed blinded to the underlying diagnosis (including the cine
and LGE imaging (RH and NV) by measuring myocardial T1 relaxation in a midventricular
SAX slice using conservative septal sampling as previously described and validated [2-5].
Blinded read was made possible by a prospective review of all studies, ensuring that there
was no overlap of LGE within the septal ROI of T1 mapping acquisition (Figures 1S and 2S).
Upon review a total of 4 HCM patients were excluded from the analysis. Care was also taken
to avoid unintentional partial volume inclusion by contamination with the signal from the
blood pool. Following offline image co-registration and motion correction, T1 values were
determined by fitting an exponential model to the measured data applying Look-Locker, noise
and heart rate correction. Assessment of interstudy, inter- and intra-observer reproducibility
has been previously reported [2-5]. In addition to T1-values of native and post-contrast
myocardium the partition coefficient λ and the hematocrit-corrected extracellular volume
fraction (ECV) as markers of extracellular contrast agent accumulation were calculated [9].
Statistical analysis
Statistical analysis was performed using SPSS software (version 22.0; SPSS, Chicago, IL,
USA). Normality of distributions was tested with the Kolmogorov-Smirnov statistic.
Categorical data are expressed as percentages, and continuous variables as mean±SD or
median (interquartile range), as appropriate. For comparison of 2 and more than 2 normally
distributed variables, Student t test, one-way analysis of variance (with Bonferroni post-hoc
test) for continuous variables and chi-square tests for categorical variables were used, as
appropriate. Assessment of reproducibility was performed using Bland Altman approaches.
Associations were explored by linear regression analyses. The ability of significant variables
to discriminate between the groups and subgroups was tested using univariate and
multivariate binary logistic regression; cut-off values and area-under-the curve (AUC) was
derived using the receiver operating characteristics (ROC) curve.
Comparisons were made for the two main clinical dilemmas: firstly, HCM vs. HTN; and
secondly, G+P- subjects vs. controls. Further subgroup analyses were made for:
HCM vs. HTN subjects with no evidence of LGE (HCMLGE- vs. HTN LGE-);
HCM vs. HTN15mm (HTN subjects matching the LVWT-based diagnostic criteria for
equivocal disease (LVWT ≥ 15 mm);
G+P- subjects vs. HTN13mm (matching diagnostic criteria of LVWT 13 mm for G+P-
subjects) [1,10-12].
All tests were two-tailed and a P value of less than 0.05 was considered significant.
Supplemental results
General characteristics
HTN patients had higher systolic blood pressure (p<0.05). Five HTN subjects had diet-
controlled type II diabetes mellitus.
Gene analysis in G+P- subjects revealed presence of MYBPC3 (n=11, 49%), MYH7 (n=9,
39%) and TNNT2 (n=3, 13%).
Myocardial crypts were present in 5% of HCM subjects, in 6% of HTN.
No subjects in the control group or G+/P- showed eGFR less than 60 ml/min. However, 3
patients in HTN group (4%) and 4 in the HCM group (4%) showed moderately impaired renal
function.
Native T1 and ECV comparisons in HTN and HCM subgroups with no LGE were
significantly increased in HCM LGE- compared to HTN LGE- population (HCMLGE- vs. HTN
LGE-, native T1 (msec): 1165±36 vs. 1059±29; ECV 0.31±0.06 vs. 0.26±0.04; p<0.0001 for
all) (Figure 3S).
There was an association between hematocrit and ECV, which was somewhat stronger for
men than women (men: r=-0.42, p<0.001, women: r=-0.37, p<0.01). There was no significant
correlation between hematocrit and native T1 (men: r=-0.11, p=0.12, females: r=-0.09,
p=0.17).
Reproducibility and variability of measurements
Assessment of interstudy, inter- and intraobserver reproducibility and its relation to
pathological changes in LV geometry and LVWT have been reported previously [5].
In assessment of the present observers (R.H, N.V), T1 mapping showed excellent intra-
observer (r=0.98, p < 0.01) and inter-observer (r=0.96, p < 0.01) agreement for all subject
groups (6 patients of each groups, 24 patients in total). In comparison to native myocardial T1
values, λ showed consistently higher intra-observer coefficient of variation (CoV, native T1:
1.0%; λ: 6.6%) and inter-observer coefficient of variation (native T1: 1.8%; λ: 7.7%) for all
subject groups.
Supplemental discussion
T1 mapping acquisition in a single midventricular SAX slice is feasible in clinical routine [2-
5]. It is employed on assumption that it is representative of diffuse involvement affecting
myocardium uniformly [4]. The advantage of whole-heart T1 mapping and its feasibility for
the use of clinical practice is presently unknown; a single study showed that whereas
corresponding segments show little variation between the apical, midventricular and basal
slices, regional variation of values persist within the slice [8], complicating the use of
absolute segmental values. Standardization of T1 measurements using conservative septal
myocardial sampling within the midventricular SAX slice, is additionally based on the
findings that this geometry is acquired with good reproducibly, as well as sufficient LVWT to
avoid blood contamination of the T1 signal and does not suffer from partial volume effects
found in the basal or apical slices. While measuring native T1 requires standardization we
have overcome this issue by a unified sequence shared between the participating sites. Native
T1 is also independent of influences such as water exchange or the inaccuracies inherent in
the determination of blood T1 required to control for the individual clearance and distribution
of contrast agents [9]. While native T1 may not solely reflect the changes within the
extracellular space, the above mentioned issues related to indices may explain the better
separation of groups based on native T1.
Supplemental references
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M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H,
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Rapezzi C, Rutten FH, Tillmanns C, Watkins H; Authors/Task Force members. 2014
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the European Society of Cardiology (ESC). Eur Heart J. 2014;35:2733-79.
2. Dabir D, Child N, Kalra A, Rogers T, Gebker R, Jabbour A, Plein S, Yu CY, Otton
J, Kidambi A, McDiarmid A, Broadbent D, Higgins DM, Schnackenburg B, Foote L,
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myocardium using a T1 mapping methodology: results from the International T1
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Nagel E, Puntmann VO. T1 values by conservative septal postprocessing approach
are superior in relating to the interstitial myocardial fibrosis: findings from patients
with severe aortic stenosis. J Cardiovasc Magn Reson. 2015;17(S1):49
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Supplemental Tables
Table 1S. Results of ROC and binary logistic regression analysis of CMR parameters for discrimination between HCM vs. HTN15mm, G+P- subjects
vs. HTN13mm, and HCM LGE- vs. HTNLGE-. For further subgroup analyses see Supplementary material (AUC - area-under-the curve, ROC - receiver
operating characteristics, PPV positive predictive value, NPV – negative predictive value, LH- likelihood, LV – left ventricular, LVWT – LV wall thickness,
LGE – late gadolinium enhancement, ECV – extracellular volume, *p<0.05, **p<0.01).
Biomarkers AUC (95%CI),
p-value
Cut-off
values
Specificity
(95%CI)
Sensitivity
(95%CI)
PPV
(95%CI)
NPV
(95%CI)
Diagnostic
Accuracy
(95%CI)
HCM vs. HTN15mm
Univariate analysis
Native T1 (msec) 0.98 (0.94-1.00)** 1102 97 (91-99) 98 (93-99) 99 (92-99) 91 (86-97) 98 (91-99)
ECV 0.78 (0.67-0-89)** 0.26 69 (68-73) 73 (59-76) 72 (66-72) 58 (30-62) 71 (59-76)
LGE (present) 0.69 (0.55-0.91)* / 70 (37-91) 68 (65-70) 95 (90-99) 19 (9-25) 69 (62-73)
Multivariate analysis
Wald Exp(B) (95%CI)
Native T1 (msec) 12.7 1.092(1.051-1.131)** 96 (89-99) 98 (92-99) 99 (91-99) 91 (85-98) 98 (91-99)
Variables not included (Sig. (p-value)): ECV (0.175); LGE(present) (0.04)
For the model: Chi2: 31, p<0.001; -2Log LH: 25.2, Cox&Snell R2: 0.29, Nagelkerke R2: 0.61
G+P- subjects vs. HTN13mm
Native T1 (msec) 0.86(0.78-0.95)** 1095 95 (88-98) 65 (48-75) 83 (62-95) 87 (81-91) 86 (77-92)
ECV 0.63(0.50-0.77) / / / / /
LGE (present) 0.45(0.31-0.59) / / / / /
LV mass (index) (g/m2 ) 0.41(0.26-0.55) / / / / /
Maximal LVWT (mm) 0.47(0.31-0.59) / / / / /
Multivariate analysis not performed, as native T1 is the only significant variable.
HCM LGE- vs. HTNLGE-
Native T1 (msec) 0.98 (0.94-1.00)** 1106 96(85-99) 98(92-99) 98(91-99) 96(85-99) 98(89-99)
ECV 0.78 (0.65-0.87)** 0.26 59(40-76) 67(59-75) 80(70-88) 43(29-56) 67(53-75)
LV mass (index) (g/m2) 0.85 (0.75-0.94)** 84 76(61-87) 86(-78-92) 86(78-92) 76(61-87) 83(78-92)
Maximal LVWT (mm) 0.91 (0.86-0.98)** 16 86(73-95) 90(83-95) 92(84-97) 83(70-91) 89(79-95)
Multivariate analysis
Wald Exp(B) (95%CI)
Native T1 (msec) 16.1 1.079 (1.040-1.120)** 96(84-99) 98(90-99) 98(90-99) 96(84-99) 97(88-99)
Variables not included (Sig. (p-value)): ECV (0.62); maximal LVWT (0.009); LV mass(index): (0.31)
For the model: Chi2: 61, p<0.001; -2Log LH: 39, Cox&Snell R2: 0.61, Nagelkerke R2: 0.82
Supplemental Figures and Figure Legends
Figure 1S. An illustrative example where LGE overlaps with septal ROI within the imaging
slice.
Figure 2S. Flowchart of patients’ inclusion.
Figure 3S. Native T1 and ECV comparisons in HTN and HCM subgroups with no LGE were
significantly increased in HCM LGE- compared to HTN LGE- population (HCMLGE- vs. HTN
LGE-, native T1 (msec): 1165±36 vs. 1059±29; ECV 0.31±0.06 vs. 0.26±0.04; p<0.0001 for
all).
Figure 1S.
Figure 2S.
Figure 3S.
Ucar, Ciara Cummins, Gerald Carr-White, Eike Nagel and Valentina O. Puntmann
Yu, Rolf Gebker, Adelina Doltra, Sebastian Kelle, Sitara Khan, Toby Rogers, Eduardo Arroyo
Rocio Hinojar, Niharika Varma, Nick Child, Benjamin Goodman, Andrew Jabbour, Chung-Yao
Cardiovascular Magnetic Resonance Study
and Hypertrophic Cardiomyopathy: Findings From the International T1 Multicenter
T1 Mapping in Discrimination of Hypertrophic Phenotypes: Hypertensive Heart Disease
Print ISSN: 1941-9651. Online ISSN: 1942-0080
Copyright © 2015 American Heart Association, Inc. All rights reserved.
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is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Cardiovascular Imaging
doi: 10.1161/CIRCIMAGING.115.003285
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