Download Intermediate-Signal-Intensity Late Gadolinium

Intermediate-Signal-Intensity Late Gadolinium
Enhancement Predicts Ventricular Tachyarrhythmias in
Patients With Hypertrophic Cardiomyopathy
Evan Appelbaum, MD, MMSc; Barry J. Maron, MD; Selcuk Adabag, MD, MS;
Thomas H. Hauser, MD, MMSc, MPH; John R. Lesser, MD; Tammy S. Haas, RN;
Anne B. Riley, MD; Caitlin J. Harrigan, BA; Francesca N. Delling, MD; James E. Udelson, MD;
C. Michael Gibson, MS, MD; Warren J. Manning, MD; Martin S. Maron, MD
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Background—In hypertrophic cardiomyopathy (HCM), the arrhythmic potential associated with a variety of left
ventricular myocardial signal intensities evident on contrast-enhanced cardiovascular magnetic resonance with late
gadolinium enhancement (LGE) is unresolved.
Methods and Results—In 145 HCM patients (43⫾15 years old), visually identified areas of LGE in left ventricle were
analyzed quantitatively for intermediate (ⱖ4 but ⬍6 SD) and high (ⱖ6 SD above the mean signal intensity of normal
myocardium) LGE signal intensity (LGE-SI). Ambulatory Holter ECGs were obtained within 7.8⫾8.3 weeks of
cardiovascular magnetic resonance. HCM patients with nonsustained ventricular tachycardia, ventricular couplets, and
premature ventricular contractions showed greater amounts of intermediate LGE-SI (17⫾7 versus 10⫾10 g, 16⫾10
versus 10⫾11 g, and 13⫾8 versus 10⫾13 g, respectively; P⫽0.003 to ⬍0.001) and greater amounts of high LGE-SI
(15⫾6 versus 10⫾8 g, 14⫾9 versus 10⫾12 g, and 12⫾7 versus 10⫾8 g, respectively; P⫽0.02– 0.003) than patients
without these arrhythmias. In HCM patients with either nonsustained ventricular tachycardia, couplets, or premature
ventricular contractions, the extent of intermediate LGE-SI exceeded that of high LGE-SI (17⫾7 versus 15⫾6 g, 16⫾10
versus 14⫾9 g, and 13⫾8 versus 12⫾7 g, respectively; P⫽0.01– 0.04). In addition, the receiver operating characteristic
area under the curve established intermediate LGE-SI as a better discriminator of patients with nonsustained ventricular
tachycardia than was high LGE-SI, with 7 additional patients with this arrhythmia identified.
Conclusions—In patients with HCM, intermediate LGE-SI is a better predictor of ventricular tachyarrhythmias (including
nonsustained ventricular tachycardia, a risk factor for sudden death) than is high LGE-SI. Longitudinal studies in larger
HCM cohorts are justified to define the independent prognostic impact of intermediate LGE-SI. (Circ Cardiovasc
Imaging. 2012;5:78-85.)
Key Words: magnetic resonance imaging 䡲 cardiomyopathy, hypertrophic 䡲 gadolinium 䡲 tissues
䡲 arrhythmias, cardiac
H
ypertrophic cardiomyopathy (HCM) is the most common
genetic heart disease and the leading cause of sudden
cardiac death in young people.1–7 Despite considerable advances, risk stratification in HCM remains challenging, and not
all at-risk patients are appropriately identified by use of contemporary strategies.6,8 –10 Ventricular tachyarrhythmias emanating
from a structurally abnormal left ventricular (LV) myocardium
with substantial areas of replacement fibrosis have emerged as a
potential mechanism responsible for sudden death in HCM.11–14
Recently, late gadolinium enhancement (LGE; ie, likely myo-
cardial fibrosis) identified by contrast-enhanced cardiovascular
magnetic resonance (CMR) has been associated with an increased risk of ventricular tachyarrhythmia and adverse outcome, which suggests that LGE may represent a novel marker of
risk in HCM.15–31
Editorial see p 2
Clinical Perspective on p 85
Most contrast-enhanced CMR studies in HCM have considered only those areas of LV myocardium with high LGE
Received November 23, 2010; accepted October 27, 2011.
From the PERFUSE Core Laboratory and Data Coordinating Center (E.A., D.M.G., W.J.M.) and Department of Medicine (E.A., T.H.H., F.N.D.,
C.M.G., W.J.M.) and Department of Radiology (W.J.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; The
Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation (B.J.M., S.A., J.R.L., T.S.H.), Minneapolis MN; Division of Cardiology,
VA Medical Center (S.A.), Minneapolis, MN; and Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center (C.J.H., J.E.U.,
M.S.M.), Boston, MA.
Guest Editor for this article was Leon Axel, MD, PhD.
Correspondence to Evan Appelbaum, MD, Beth Israel Deaconess Medical Center, RW453 East Campus, 330 Brookline Ave, Boston, MA 02215.
E-mail [email protected]
© 2011 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
78
DOI: 10.1161/CIRCIMAGING.111.963819
Appelbaum et al
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signal intensity (LGE-SI) as clinically relevant with respect to
outcome.15,22,23,25,32,33 However, regions of mixed intermediate and high LGE-SI detected in patients with HCM have
been shown to correlate with increased myocardial collagen
on postmortem analysis, yet their independent clinical significance and relation to ventricular tachyarrhythmias remain
unresolved.34 In patients with atherosclerotic coronary artery
disease who have experienced a prior myocardial infarction,
areas of intermediate LGE-SI (ie, regions of “tissue heterogeneity”) identify patients at increased risk for ventricular
tachyarrhythmias and cardiovascular death.35–39 Therefore, in
the present study of a large HCM cohort, we have assessed
the prevalence, extent, and relationship of intermediate
LGE-SI to a number of important demographic and clinical
variables, including nonsustained ventricular tachycardia
(NSVT, an established risk factor for sudden death in HCM)
and other ventricular tachyarrhythmias on ambulatory Holter
monitoring.
Methods
Study Patients
Inclusion Criteria
From April 2003 to January 2007, consecutive HCM patients eligible
for magnetic resonance imaging were evaluated with contrastenhanced CMR and 24-hour ambulatory Holter ECGs (n⫽288) at the
Minneapolis Heart Institute Foundation (Minneapolis, MN; n⫽176)
and Tufts Medical Center (Boston, MA; n⫽112). Median interval
between the 2 studies was 2 months (ⱕ3 months in 81% of patients,
ⱕ6 months in 98%, and maximum interval of 7 months in 1.3%).
Diagnosis of HCM was based on the demonstration by echocardiography and/or CMR of a hypertrophied LV (wall thickness
ⱖ13 mm) associated with a nondilated cavity in the absence of
another cardiac or systemic disease that could produce the magnitude
of hypertrophy and/or arrhythmia evident.6 Patients included in the
analysis were those with visual evidence of LGE (145/288, or 50%
of the cohort) on contrast-enhanced CMR imaging (see “CMR
Analysis”). Selected patients in the present study cohort (n⫽72) have
been part of other analyses.15
Exclusion Criteria
During the same time period, those HCM patients with implanted
pacemakers or defibrillators (n⫽10), end-stage patients (LV ejection
fraction ⬍50%; n⫽15), and those with a history of cardiac arrest or
sustained ventricular tachycardia (n⫽5), a family history of sudden
cardiac death (n⫽10), an abnormal blood pressure response to
exercise (⬍20-mm Hg increase in systolic blood pressure from rest
to peak; n⫽6), or any other contraindication to magnetic resonance
imaging (n⫽5) were excluded from the study.
Cardiovascular Magnetic Resonance
CMR was performed on a Philips Gyroscan ACS-NT 1.5T (Philips
Medical Systems, Amsterdam, Netherlands) or Siemens Sonata or
Avanto 1.5T (Siemens Medical Systems; Erlangen, Germany)
whole-body CMR scanner with a commercial cardiac-surface coil.
Cine images were acquired in contiguous LV short-axis orientation
with an ECG-gated, breath-hold, steady state free-precession sequence with full LV coverage (8-mm slice thickness, 2-mm interslice
gap, in-plane spatial resolution 2⫻2 mm, 30-ms temporal resolution). LGE was performed 15 minutes after the intravenous administration of 0.2 mmol/kg gadolinium-DTPA (Magnevist; Schering,
Berlin, Germany) with a 2-dimensional breath-hold, segmented
inversion-recovery sequence (inversion time optimized by the LookLocker sequence [inversion time scout] to null normal myocardium)
acquired in the same orientation (short-axis stack) as the cine images,
with the following imaging parameters: 8-mm slice thickness, 2-mm
interslice gap, repetition time 4.3 ms, echo time 2.1 ms, flip angle
LGE and Ventricular Arrhythmias in HCM
79
15°, field of view 320 mm, matrix 160⫻160, and spatial resolution
2⫻2⫻8 mm.
CMR Analysis
All CMR analyses were performed with commercially available
software (QMassMR version 7.1.0; Medis Inc, Leiden, Netherlands).
LV endocardial and epicardial borders on both cine and LGE images
were measured by planimetry, with special care taken to exclude
papillary muscles and intertrabecular blood pool. LV wall thickness,
volumes, mass, and ejection fraction were measured from the cine
short-axis images by standard techniques.40
The LV short-axis stack of LGE images was first assessed visually
for the presence of LGE by 2 independent, blinded, experienced
readers (E.A., C.J.H.), with any disagreement adjudicated by a senior
observer with ⬎10 years of CMR experience (W.J.M.). Areas of LV
LGE were identified visually by consensus in 145 (50%) of the 288
HCM patients, who constituted the final study cohort. The mean
grayscale signal intensity (SI) and SD for normal LV myocardium
were measured for each patient, with a region of interest placed in a
portion of nulled myocardium (ie, without LGE on visual inspection)
on 3 consecutive midventricular short-axis slices and averaged
(Figure 1).
To determine the optimal grayscale threshold for the identification
of intermediate LGE-SI versus normal myocardium, we performed
an analysis on the first 50 HCM patients with LGE, comparing the
signal intensity of areas of normal and intermediate signal intensity
by visual measurement versus a series of semiautomated grayscale
thresholds. In this a priori analysis, we determined that values ⱖ4 SD
but ⬍6 SD above the mean signal intensity of normal myocardium
demonstrated the most robust correlation to visual assessment for
intermediate LGE-SI compared with an SD threshold of ⱖ5 but ⬍6
SD (r⫽0.904, P⬍0.0001). Pixels that were ⬍4 SD above the mean
of normal (low signal intensity) correlated best with visually nulled
myocardium (r⫽0.911, P⬍0.0001) and were therefore considered
within a signal intensity range for normal myocardium. We previously have demonstrated a grayscale threshold of ⱖ6 SD above
normal myocardium to have the strongest correlation with that of
high LGE-SI quantified by visual assessment.33 To avoid partial
volume averaging, areas of intermediate LGE-SI were required to be
⬎1 pixel width (⬎2 mm) if contiguous with high LGE-SI).
With these semiautomated grayscale threshold signal intensity
cutoff values, areas of LGE were analyzed in 2 groups: (1) High
LGE-SI (ie, the amount of LV myocardium with a grayscale
threshold ⱖ6 SD above the mean signal intensity of normal
myocardium) and (2) intermediate LGE-SI (ie, calculated by subtracting the amount of myocardium at ⱖ6 SD from that at ⱖ4 SD;
Figure 1). In addition, we analyzed the combination of intermediate
and high LGE-SI. The amount of LGE for each group was expressed
in grams of myocardium and as a proportion (percentage) of total LV
myocardial mass.
The location of intermediate and high LGE-SI within LV myocardium was classified as follows: Ventricular septum, LV free wall,
and points of insertion of the right ventricle into the septum. In
addition, LGE was considered transmural if it involved ⱖ75% wall
thickness in any segment. Intermediate LGE-SI was considered
contiguous with high LGE-SI when the vast majority of intermediate
LGE-SI was localized to the periphery of regions of high LGE-SI, as
visualized on both the short- and long-axis imaging planes. Intermediate LGE-SI was considered remote from high LGE-SI when these
2 areas of LGE were separated by normal myocardium. Intermediate
LGE-SI and the combination of the 2 were correlated with clinical
and functional/morphological CMR imaging parameters.
Ambulatory Holter ECGs
Ambulatory Holter ECG recordings were obtained in a standard
fashion with a portable tape recorder and modified V1 and V5 leads.
Holter ECG recordings were scanned on a DelMar Reynolds
AccuPlus (model 403) Holter Analysis System (Del Mar Reynolds
Medical, Irvine, CA). In patients with ⬎1 Holter ECG, the recording
closest to the CMR study was analyzed. NSVT was defined as 3 or
more consecutive premature complexes at a heart rate ⱖ100 bpm.11
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Circ Cardiovasc Imaging
A
January 2012
B
Figure 1. Method of late gadolinium enhancement
(LGE) quantification in hypertrophic cardiomyopathy. A, Cardiac magnetic resonance midventricular
short-axis LGE image in a 48-year-old male patient
with hypertrophic cardiomyopathy showing considerable hyperenhancement (white arrows) in the
ventricular septum and a designated region of
interest (ROI; orange circle) in the inferior wall that
provides a mean signal intensity for a representative region of encircled normal myocardium. RV
indicates right ventricle; LV, left ventricle. B, High
LGE-SI (red shading). In the same image, manual
contouring of the endocardial border (red line) and
epicardial border (green line) of the LV for volumetric and functional quantification and automated
grayscale threshold ⱖ6 SDs above the mean signal intensity of the ROI. C, Grayscale threshold ⱖ4
SDs above the ROI (red shading), which includes
both high and intermediate LGE-SI. D, Intermediate LGE-SI (red shading), identified by subtracting
LGE ⱖ4 SD from ⬍6 SD.
LV
A
B
RV
ROI
C
D
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Statistical Analyses
Continuous data are expressed as mean⫾SD. Categorical variables are presented as counts and percentages. Clinical and
demographic characteristics of the LGE groups were compared
with a 2-sample t test for continuous variables and ␹2 or Fisher
exact tests for categorical variables expressed as proportions.
Paired comparisons were performed with the Wilcoxon signed
rank test. ANOVA was used to determine differences in means
between multiple groups, with post hoc testing with the Bonferroni correction for multiple testing. The ability of intermediate
LGE-SI, high LGE-SI, or their combination to discriminate
patients with NSVT on Holter ECG was assessed with the
receiver operating characteristic (ROC) area under the curve with
95% confidence intervals. The optimal cutoff in each ROC was
determined by maximizing the accuracy of the test. ROC areas
under the curve were compared by use of methods for correlated
data. All comparisons were 2-tailed, with Pⱕ0.05 considered
significant. SPSS software version 10.0 (SPSS Inc, Chicago, IL)
or SAS version 9.1 (SAS Institute, Cary, NC) was used for all
analyses.
Results
Study Population
Baseline demographics for the 145 study patients are presented in Table 1. The majority were male (56%) and in New
York Heart Association class 1 (n⫽93; 64%); 40 patients
(28%) were in class 2, and 12 (8%) had class 3 symptoms.
Maximum LV wall thickness was 24⫾5 mm (range 13–
36 mm). A minority of patients (n⫽24; 17%) had an LV
outflow tract gradient at rest ⱖ30 mm Hg.
Ambulatory Holter ECG
On 24-hour ambulatory Holter monitoring, 120 patients
(83%) with LGE had ventricular arrhythmias, including 119
(82%) with isolated premature ventricular contractions (range
1–5800, median 191), 58 (40%) with ventricular couplets
(range 1–110, median 6), and 46 (32%) with NSVT. The
number of NSVT runs was 1 to 6, with 3 to 58 beats in the
Table 1. Baseline Clinical and CMR Characteristics in 145
HCM Patients
Variable
All Patients
Age, y
43⫾15
Male, %
56
Maximal LV wall thickness, mm
24⫾5
Syncope, n (%)
18 (12)
Mean NYHA class
1.3⫾0.5
LV outflow tract obstruction at rest
(⬎30 mm Hg), n (%)
24 (17)
Medications, n (%)
␤-Blockers
83 (57)
Calcium channel blockers
33 (23)
Disopyramide
4 (3)
CMR measurements, mean⫾SD
LV mass, g
210⫾87
LV mass index, g/m2
107⫾34
LV ejection fraction, %
High LGE-SI, g (%)
Intermediate LGE-SI, g (%)
Combination of high and intermediate
LGE-SI, g (%)
70⫾11
11⫾15 (5.5⫾7.2)
13⫾8 (6.5⫾4.6)
24⫾23 (12.1⫾11.9)
CMR indicates cardiovascular magnetic resonance; HCM, hypertrophic
cardiomyopathy; LV, left ventricular; NYHA, New York Heart Association;
LGE-SI, late gadolinium enhancement signal intensity.
Appelbaum et al
A
81
B
LV
ROI
RV
C
D
D
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longest burst at ventricular rates of 130⫾28 per minute (range
109 –235 per minute).
Late Gadolinium Enhancement
Intermediate and high LGE-SI was present in all 145 HCM
study patients, with intermediate LGE-SI occupying 13⫾8 g
(6.5⫾4.6% of LV myocardium), high LGE-SI 11⫾15 g
(5.5⫾7.2%), and both combined 24⫾23 g (12.1⫾11.9%; Table
1). In most patients (n⫽105; 72%), intermediate LGE-SI exceeded high LGE-SI (1.4⫾10.7 g or 1.0⫾5.3%; P⬍0.001).
AA
Figure 2. Intermediate late gadolinium enhancement signal intensity (LGE-SI) contiguous with high
LGE-SI. A, Cardiac magnetic resonance midventricular short-axis LGE image showing hyperenhancement (white arrows) at the junction of the
right ventricular (RV) free wall with ventricular septum and a designated region of interest (ROI;
orange circle) encircling normal, nulled myocardium
in the posterior (inferior) portion of septum. LV indicates left ventricle. B, Automated grayscale threshold
ⱖ6 SDs above the mean SI of normal myocardium
of the ROI, representing high LGE-SI (arrows; red
shading). C, Grayscale threshold ⱖ4 SDs above normal myocardium representing intermediate and high
LGE-SI (red shading). D, Intermediate LGE-SI (red
shading) identified by subtracting LGE quantified at
ⱖ6 SD from that of ⱖ4 SD, with most intermediate
LGE-SI being contiguous with regions of high
LGE-SI.
Location of LGE
In most patients (n⫽84; 58%), areas of intermediate LGE-SI
were evident at the periphery of (and contiguous with) high
LGE-SI and were present in a variety of areas of the LV
chamber: Ventricular septum (n⫽8), LV free wall (n⫽20),
junction of right ventricular wall with ventricular septum
(n⫽16), or a combination of these sites (n⫽40; Figure 2). In
61 patients (42%), areas of intermediate LGE-SI were contiguous with high LGE-SI and also were found in (often
multiple) regions remote from high LGE-SI (Figure 3).
B
B
LV
ROI
RV
CC
LGE and Ventricular Arrhythmias in HCM
DD
Figure 3. Intermediate late gadolinium enhancement signal intensity (LGE-SI) contiguous with and
remote from high LGE-SI. A, Cardiac magnetic
resonance midventricular short-axis LGE image
showing hyperenhancement (white arrow) in the
anterior ventricular septum and a designated
region of interest (ROI; orange circle) encircling
normal, nulled myocardium in the posterior septum. RV indicates right ventricle; LV, left ventricle.
B, Automated grayscale threshold ⱖ6 SDs above
the mean signal intensity of the ROI indicating high
LGE-SI (arrows; red shading). C, Grayscale threshold ⱖ4 SDs above normal myocardium identifying
intermediate and high LGE-SI (red shading),
remote from (white arrow) and contiguous with
high LGE-SI. D, Subtraction of LGE at ⱖ6 SD from
that quantified at ⱖ4 SD, indicating intermediate
LGE-SI (red shading) remote from (white arrow)
and contiguous with the regions of high LGE-SI.
82
Circ Cardiovasc Imaging
January 2012
1
0.9
0.8
Sensitivity
0.7
0.6
Intermediate SI-LGE (AUC 0.72)
0.5
High SI-LGE (AUC 0.65)
0.4
Combination (AUC 0.68)
0.3
0.2
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Figure 4. Relationship of the quantity (in grams) of intermediate
late gadolinium enhancement signal intensity (LGE-SI) and high
LGE-SI to the severity of ventricular arrhythmias on 24-hour
ambulatory (Holter) ECG in 145 patients with hypertrophic cardiomyopathy. LGE indicates late gadolinium enhancement;
None, no ventricular arrhythmia; PVC, premature ventricular
contractions; Couplet, ventricular couplets; and NSVT, nonsustained ventricular tachycardia.
Relation of Extent of LGE to
Ventricular Tachyarrhythmias
Premature Ventricular Contractions
The extent of intermediate and high LGE-SI was greater
among HCM patients with premature ventricular contractions
than among those without them (13⫾8 versus 10⫾10 g,
P⬍0.001, and 12⫾7 g versus10⫾8 g, P⫽0.003, respectively;
Figure 4). In patients with premature ventricular contractions,
the extent of intermediate LGE-SI exceeded that of high
LGE-SI (13⫾8 versus 12⫾7 g; P⫽0.01).
Ventricular Couplets
The amount of intermediate and high LGE-SI was greater
among HCM patients with ventricular couplets than among
those without them (16⫾10 versus 10⫾10 g, P⬍0.001, and
14⫾9 versus 10⫾8 g, P⫽0.02, respectively; Figure 4). In
patients with ventricular couplets, the extent of intermediate
LGE-SI exceeded that of high LGE-SI (16⫾10 versus 14⫾9 g;
P⫽0.04).
Nonsustained Ventricular Tachycardia
The amount of intermediate and high LGE-SI was greater
among HCM patients with NSVT than among those without
NSVT (17⫾7 versus 10⫾10 g, P⫽0.003, and 15⫾6 versus
10⫾8 g, P⬍0.001, respectively). In patients with NSVT, the
amount of intermediate LGE-SI exceeded that of high
LGE-SI (17⫾7 versus 15⫾6 g, P⫽0.01; Figure 4).
With ROC analysis, the area under the curve demonstrated
a trend for intermediate LGE-SI to be a better discriminator
for identifying HCM patients with NSVT (0.72 [95% confidence interval 0.60 – 0.83]) than high LGE-SI (0.65 [95%
confidence interval 0.52– 0.77]; P⫽0.174) or the combination
of intermediate and high LGE-SI (0.68 [95% confidence
interval 0.56 – 0.80]; P⫽0.129; Figure 5). By determining the
optimal cutoff for extent of LGE relative to NSVT from the
ROC analysis (intermediate LGE-SI ⱖ12 g, high LGE-SI ⱖ8 g,
and their combination ⱖ19 g), intermediate LGE-SI identified 7
additional HCM patients with NSVT (37 of 46) compared with
high LGE-SI (30 of 46), and 2 more than the combination of
0.1
0
0
0.2
0.4
0.6
0.8
1
1-Specificity
Figure 5. Receiver operating characteristic curve assessing the
performance of intermediate late gadolinium enhancement signal intensity (LGE-SI), high LGE-SI, and their combination to
identify patients with hypertrophic cardiomyopathy with nonsustained ventricular tachycardia on 24-hour ambulatory (Holter)
ECG. AUC indicates area under the curve.
high and intermediate LGE-SI (35 of 46; Table 2; Figure 6).
Within each LGE-SI group, there was no significant relationship
between the occurrence of ventricular tachyarrhythmias and the
location of LGE or transmural distribution.
Association of LGE With CMR and
Clinical Characteristics
There was no significant relationship between the extent of
intermediate or high LGE-SI and maximal LV wall thickness
(best r⫽0.03; P⫽0.09), LV mass index (best r⫽0.02;
P⫽0.4), or ejection fraction (best r⫽⫺0.3; P⫽0.07). In
addition, there was no difference in age, use of cardioactive
drugs, New York Heart Association functional class, presence of LV outflow tract obstruction, or history of syncope
among patients with greater than the median compared with
those with less than the median of LGE for intermediate or
high LGE-SI (P⫽0.22 and 0.30, respectively).
Discussion
Contrast-enhanced CMR has emerged as a novel imaging
technique to identify myocardial fibrosis in patients with
HCM.26,28 –30 Several recent CMR studies have demonstrated
an increased risk of ventricular tachyarrhythmias and adverse
outcome among HCM patients with LGE, which suggests that
hyperenhancement may be a marker for an unstable electric
substrate.11,15,16,25,27 These earlier studies primarily considered areas of myocardium with high LGE-SI as most relevant
for the generation of potentially life-threatening ventricular
arrhythmias. Areas of intermediate LGE-SI are also present in
HCM patients,34 but despite their relationship to increased
myocardial collagen on postmortem analysis, they remain of
uncertain clinical significance. Therefore, we thought it
timely to focus on determining the prevalence of intermediate
LGE-SI and its association with ventricular tachyarrhythmias
in HCM.
Appelbaum et al
Table 2.
LGE and Ventricular Arrhythmias in HCM
83
Relation of Ventricular Arrhythmia to LGE-SI in 145 HCM Patients
No. of
Patients (%)
Intermediate
LGE-SI, g (%LV)
High LGE-SI,
g (%LV)
Combined Intermediate
and High LGE-SI, g (%LV)
17⫾7 (8.2⫾3.3)*
15⫾6 (7.2⫾2.4)†
32⫾11 (15.1⫾5.5)‡
10⫾8 (4.2⫾3.3)
21⫾16 (9.1⫾6.3)
NSVT
Present
46 (32)
Absent
99 (68)
10⫾10 (4.8⫾3.8)
Present
58 (40)
16⫾10 (7.5⫾4.2)*
Absent
87 (60)
10⫾11 (4.8⫾3.9)
Ventricular couplets
14⫾9 (5.5⫾2.1)†
10⫾12 (4.2⫾4.0)
28⫾9 (13.3⫾4.5)‡
22⫾16 (9.2⫾6.1)
PVCs
Present
119 (82)
Absent
26 (18)
13⫾8 (6.2⫾3.9)*
10⫾13 (4.8⫾4.1)
12⫾7 (4.7⫾3.0)†
26⫾16 (11.1⫾7.2)‡
10⫾8 (4.2⫾3.3)
21⫾17 (9.1⫾6.4)
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LGE-SI indicates late gadolinium enhancement signal intensity; HCM, hypertrophic cardiomyopathy; %LV, percent
of left ventricle; NSVT, nonsustained ventricular tachycardia; PVCs, premature ventricular contractions.
*Statistically significant with respect to absence of the arrhythmia; P⬍0.003.
†Statistically significant with respect to absence of the arrhythmia; P⬍0.02.
‡Statistically significant with respect to absence of the arrhythmia; P⬍0.005.
We found regions of both intermediate and high LGE-SI
present in all HCM patients demonstrating LGE. In patients
with ventricular tachyarrhythmias, including NSVT (a recognized risk factor for sudden death in HCM),11 the amount of
intermediate LGE-SI exceeded that of high LGE-SI. Furthermore, based on our ROC analysis, the magnitude of intermediate LGE-SI proved to be the most reliable LGE discriminator for identifying HCM patients with ambulatory NSVT.
Indeed, after we determined the optimal cutoff value for
identifying NSVT in each LGE subgroup, intermediate
LGE-SI identified 7 additional HCM patients with NSVT
who would not otherwise have been recognized if the CMR
images had been analyzed only with respect to high LGE-SI.
A
B
LV
RV
C
E
Finally, intermediate LGE-SI alone was even a stronger
predictor of NSVT than the combination of intermediate and
high LGE-SI.
Therefore, the present observations introduce 2 novel
principles with respect to the interpretation of LGE in patients
with HCM: (1) Not all LGE is equivalent as a clinical marker
of risk for ventricular tachyarrhythmias, because our data
suggest that intermediate LGE-SI identifies an abnormal
myocardial substrate more prone to ventricular
tachyarrhythmias than high LGE-SI. This principle represents
a paradigm shift from the strategy currently exercised in
analyzing LGE on CMR images, in which areas of lesser
LGE-SI have been largely ignored. (2) The magnitude of
D
Figure 6. A 54-year-old male patient with
hypertrophic cardiomyopathy with nonsustained ventricular tachycardia (NSVT)
on ambulatory Holter ECG monitor predicted by the quantity of intermediate late
gadolinium enhancement signal intensity
(LGE-SI) but not high LGE-SI or their
combination. A, Cardiac magnetic resonance LGE short-axis image (midventricle)
showing enhancement (white arrow) in the
interventricular septum. RV indicates right
ventricle; LV, left ventricle. B, Extensive
regions of intermediate LGE-SI (red shading) amounting to 12.4 g or 7.9% (greater
than optimal receiver operating characteristic [ROC] cutoff). C, Small area high
LGE-SI (red shading) amounting to 3.2 g
or 1.8% (less than optimal ROC cutoff). D,
The combination of intermediate and high
LGE-SI amounting to 15.6 g or 9.6% (less
than optimal ROC cutoff). E, Holter monitor showing a 10-beat run of NSVT (the
patient had 6 such bursts of NSVT in a
24-hour period).
84
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January 2012
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LGE may be more important for the identification of patients
at risk for the generation of ventricular tachyarrhythmias than
only the presence of LGE.
Indeed, when we compared the present data with those of
Adabag et al15 (based on the presence of high-signal-intensity
LGE in HCM), the extent of intermediate signal intensity in
patients in the present study was associated with a 2-fold
increase in NSVT. Whether or not recognition of intermediate
LGE-SI myocardium on contrast-enhanced CMR studies can
be extrapolated into the clinical arena to identify individual
HCM patients at risk of potentially lethal arrhythmias and
sudden death is unresolved at this time and beyond the scope
of the present investigation.
Nevertheless, these data establish a new concept with
respect to the interpretation of LGE in HCM, which now
appears to be a more heterogeneous entity in which areas of
lesser signal intensity should also be taken into consideration.
The potential impact of lower LGE-SI has been explored in
other disease states, most extensively in ischemic cardiomyopathy, in which such areas (termed “border zones”) appear
on the periphery but contiguous with the high-signal-intensity
core myocardial infarction.37 Indeed, the extent of the “border
zone” area identifies patients with ischemic cardiomyopathy
at increased risk for ventricular tachyarrhythmias and adverse
outcome, with histopathological studies demonstrating these
regions to be composed of substantial tissue heterogeneity,
including a mixture of isolated myocytes and fibrosis.35,36,38,39
The present data may extend this concept to patients with
HCM. However, several obstacles to clarifying the histopathological basis of either high or intermediate LGE-SI in
the typical HCM phenotype with preserved LV systolic
function remain, including (as in the present cohort) (1) lack
of an HCM animal model suitable for study by CMR and (2)
the impracticality associated with coordinating the comparison of postmortem HCM hearts with contrast-CMR studies
previously obtained in the same patients.
It is possible that these early observations may ultimately
lead to enhanced identification of the HCM subset with
increased susceptibility to sudden death. However, at this
juncture, the role of intermediate LGE in risk stratification
and selection of patients for primary prevention implantable
cardioverter-defibrillators is unresolved given the lack of
long-term follow-up data in this cohort. Nevertheless, our
data underscore the potential value of assessing the extent and
character of LGE (rather than only the presence of LGE) for
predicting outcome in HCM. The study of larger patient
cohorts followed up for long periods of time will be necessary
to acquire the robust statistical power necessary to clarify the
independent prognostic impact that intermediate LGE-SI may
have as a risk-stratification strategy in HCM.
Disclosures
None.
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CLINICAL PERSPECTIVE
A number of recent cardiac magnetic resonance studies have demonstrated an increased risk of ventricular
tachyarrhythmias and adverse outcome among patients with hypertrophic cardiomyopathy with late gadolinium enhancement (LGE), which suggests that it may be a marker for an unstable electric substrate. These studies primarily considered
areas of myocardium with high LGE signal intensity as most relevant for generating potentially life-threatening ventricular
arrhythmias. Our present observations introduce 2 novel principles with respect to the interpretation of LGE in patients with
hypertrophic cardiomyopathy: (1) Not all LGE is equivalent as a clinical marker of risk for ventricular tachyarrhythmias,
because our data suggest that intermediate signal intensity identifies an abnormal myocardial substrate more prone to
ventricular tachyarrhythmias than high-intensity LGE. This principle represents a paradigm shift from the strategy currently
exercised in analyzing LGE on cardiac magnetic resonance images, in which areas of lesser signal intensity have been
largely ignored. (2) The magnitude of LGE may be more important for identifying patients at risk for generating ventricular
tachyarrhythmias than merely the presence of LGE. Despite these important observations, the role of LGE in risk
stratification and selection of patients for primary prevention implantable cardioverter-defibrillators is unresolved, given
the lack of amply powered outcome studies. Nevertheless, the present data underscore the potential importance of assessing
the extent and character of LGE (rather than only the presence of LGE) for predicting outcome in hypertrophic
cardiomyopathy and should therefore be measured in a larger patient study designed to clarify the incremental prognostic
value of LGE.
Intermediate-Signal-Intensity Late Gadolinium Enhancement Predicts Ventricular
Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy
Evan Appelbaum, Barry J. Maron, Selcuk Adabag, Thomas H. Hauser, John R. Lesser, Tammy
S. Haas, Anne B. Riley, Caitlin J. Harrigan, Francesca N. Delling, James E. Udelson, C.
Michael Gibson, Warren J. Manning and Martin S. Maron
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Circ Cardiovasc Imaging. 2012;5:78-85; originally published online December 1, 2011;
doi: 10.1161/CIRCIMAGING.111.963819
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