Download Clinical Profile and Significance of Delayed Enhancement in

Clinical Profile and Significance of Delayed Enhancement in
Hypertrophic Cardiomyopathy
Martin S. Maron, MD; Evan Appelbaum, MD; Caitlin J. Harrigan, BA; Jacki Buros, BA;
C. Michael Gibson, MD, MS; Connie Hanna, RN; John R. Lesser, MD; James E. Udelson, MD;
Warren J. Manning, MD; Barry J. Maron, MD
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 11, 2017
Background—Contrast-enhanced cardiovascular magnetic resonance with delayed enhancement (DE) can provide in vivo
assessment of myocardial fibrosis. However, the clinical significance of DE in hypertrophic cardiomyopathy (HCM)
remains unresolved.
Methods and Results—Cine and cardiovascular magnetic resonance with DE were performed in 202 HCM patients (mean
age, 42⫾17 years; 71% male), DE was compared with clinical and demographic variables, and patients were followed
up for 681⫾249 days for adverse disease events. DE was identified in 111 (55%) HCM patients, occupying 9%⫾11%
of left ventricular myocardial volume, including ⬎25% DE in 10% of patients. The presence of DE was related to
occurrence of heart failure symptoms (P⫽0.05) and left ventricular systolic dysfunction (P⫽0.001). DE was present in
all patients with ejection fraction ⱕ50% but also in 53% (102/192) of patients with preserved ejection fraction
(P⬍0.001); %DE was both inversely related to (r⫽⫺0.3; P⬍0.001) and an independent predictor of ejection fraction
(r⫽⫺0.4; P⬍0.001). DE (7%⫾7% of left ventricle) was present in 54 patients who were asymptomatic (and with
normal ejection fraction). Over the follow-up period, the annualized adverse cardiovascular event rate in patients with
DE exceeded that in patients without DE but did not achieve statistical significance (5.5% versus 3.3%; P⫽0.5).
Conclusions—In a large HCM cohort, DE was an independent predictor of systolic dysfunction but with only a modest
relationship to heart failure symptoms. These data suggest an important role for myocardial fibrosis in the clinical course
of HCM patients but are not sufficient at this time to consider DE as an independent risk factor for adverse prognosis.
(Circ Heart Fail. 2008;1:184-191.)
Key Words: heart failure 䡲 MRI 䡲 fibrosis 䡲 hypertrophic cardiomyopathy
H
ypertrophic cardiomyopathy (HCM) is the most common
genetic heart disease and the leading cause of sudden
cardiac death in the young and is also associated with heart
failure, disability, and death at any age.1– 8 In HCM, left
ventricular (LV) myocardial fibrosis provides a structural substrate, which has been implicated in promoting heart failure as
well as risk for arrhythmic sudden death.9 –15 Contrast-enhanced
cardiovascular magnetic resonance (CMR) with delayed enhancement (DE) imaging can reliably detect myocardial fibrosis
in vivo and has been reported to be an important determinant of
outcome in ischemic heart disease and nonischemic dilated
cardiomyopathy.16 –28 However, the clinical significance of DE
in HCM remains unresolved.25,26,29 Therefore, we sought to
investigate DE in a large HCM cohort by characterizing its
prevalence, morphological profile, and relation to clinical and
demographic features and prognosis.
Clinical Perspective see p 191
Methods
Selection of Patients
We prospectively evaluated 202 HCM patients presenting to centers
at Tufts Medical Center (Boston, Mass) and the Minneapolis Heart
Institute Foundation (Minneapolis, Minn) between April 2002 and
November 2006. The initial clinical evaluation was defined as the
time of the CMR examination at each institution. The duration of
follow-up from CMR to the most recent evaluation (October 1, 2007)
or death was 681⫾249 days; no patient was lost to follow-up. LV
outflow tract obstruction was defined as a peak instantaneous
outflow gradient ⱖ30 mm Hg, assessed by continuous-wave Doppler
echocardiography under resting conditions.8 No study patient underwent an alcohol septal ablation or surgical septal myectomy
procedure.
We excluded significant atherosclerotic coronary artery disease
(⬎50% stenosis in 1 major artery) as a cause of pre-existent
Received January 22, 2008; accepted May 23, 2008.
From the Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Mass (M.S.M., J.E.U.); Department of
Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (E.A., C.M.G., W.J.M.); PERFUSE
Angiographic Core Laboratory and Data Coordinating Center, Harvard Medical School, Boston, Mass (E.A., C.J.H., J.B., C.M.G., W.J.M.); and the
Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minn (C.H., J.R.L., B.J.M.).
Guest editor for this article was Eric R. Bates, MD.
Correspondence to Martin S. Maron, MD, Tufts Medical Center, #70, 800 Washington Street, Boston, Massachusetts 02111. E-mail
[email protected]
© 2008 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
184
DOI: 10.1161/CIRCHEARTFAILURE.108.768119
Maron et al
myocardial scars in study patients with DE by virtue of 2 specific
clinical or CMR criteria: (1) no study patient experienced an acute
coronary event associated with increased cardiac enzymes or Q
waves on ECG and (2) in all patients with DE distributed in a single
coronary vascular territory, hemodynamically significant coronary
artery disease was excluded by arteriography or computed tomography angiogram. In addition, among the 6 patients with transmural or
subendocardial DE distributed across multiple coronary artery vascular territories, 4 were ⬍40 years of age with no coronary artery
disease risk factors, whereas 2 were ⬎40 years of age and, because
of an LV ejection fraction ⬍50% (ie, end stage), underwent coronary
arteriography, which demonstrated in both the absence of significant
coronary artery disease.
All study patients signed a statement previously approved by the
internal review boards of the respective participating institutions,
agreeing to the use of their medical information for research
purposes. The authors had full access to and take full responsibility
for the integrity of the data. All authors have read and agreed to the
manuscript as written.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 11, 2017
Definitions
Diagnosis of HCM was based on 2D echocardiographic and CMR
documentation of a hypertrophied and nondilated LV in the absence
of another cardiac or systemic disease capable of producing a similar
magnitude of hypertrophy at some point in the clinical course of each
patient.1,2,6,30 Sudden death was defined as sudden and unexpected
collapse in patients who previously had a relatively uneventful
clinical course. Progression of heart failure was defined as an
advancement of at ⱖ1 New York Heart Association (NYHA)
functional class during the follow-up period. In addition, potentially
lethal events in which patients received appropriate implanted
defibrillator interventions (shocks or antitachycardia pacing triggered by ventricular tachycardia/fibrillation) were regarded as equivalent to sudden death.
CMR
CMR imaging was performed (Gyroscan ACS-NT 1.5T, Philips,
Best, the Netherlands, and Sonata 1.5T, Siemens, Erlangen, Germany) using steady-state, free-precession breath-hold cines in 3
long-axis planes and sequential 10 mm short-axis slices (no gap)
from the atrioventricular ring to apex. DE images were acquired 15
minutes after the intravenous administration of 0.2 mmol/kg of
gadolinium-DTPA (Magnevist, Schering; Berlin, Germany) with a
breath-hold 2D segmented inversion-recovery sequence acquired in
the same views as the cine images. The inversion time ranged from
240 to 300 ms and was chosen to null normal myocardial signal.
LV volume, mass, and ejection fraction were measured using
standard volumetric techniques and analyzed with commercially
available software (MASS version 6.1.6, Medis, Inc, the Netherlands).31 Volume and mass measurements were indexed to body
surface area. Maximal LV wall thickness was defined as the greatest
dimension at any site within the LV wall. The LV was assessed
according to the American Heart Association 17-segment model.32
To ascertain the presence of DE, all tomographic short-axis LV
slices from base to apex were inspected visually to identify an area
of completely nulled myocardium. The mean signal intensity (and
SD) of normal myocardium was calculated, and a threshold ⱖ6 SDs
exceeding the mean was used to define areas of DE.18,27,33,34 Areas
of artifact (ie, blood pool, incomplete nulling of fat and pericardial
fluid) were excluded from the analysis by manually adjusting the
individual contours. Total volume of DE (expressed in grams) was
calculated by summing the planimetered areas of DE in all short-axis
slices and was expressed as a proportion of total LV myocardium
(%DE).
DE analysis was performed by 1 experienced reader (C.J.H.; 2
years of CMR experience, including the assessment of ⬎800 CMR
studies, of which 600 involved the quantification of DE). These
readings were reviewed and confirmed by a second expert reader
(E.A.; ⬎7 years of CMR experience). Both these independent
observers were blinded to patient identity and clinical profile. Any
Delayed Enhancement in HCM
185
discrepancies between the 2 readers were adjudicated by a senior
observer (W.J.M).
To assess interobserver variability for the presence of DE, a
second reader (E.A.) independently reanalyzed all CMR studies.
Among the studies in which there was agreement between the 2
readers on the presence of DE, reader E.A. reanalyzed 20 randomly
selected studies to determine the interobserver variability for extent
of DE. To assess intraobserver variability, reader C.J.H. reanalyzed
all 202 CMR studies 4 to 6 months after the initial interpretation,
blinded to the previous results.
Statistical Analysis
Continuous data are expressed as mean⫾SD. Clinical and demographic characteristics of the 2 patient groups (DE and non-DE) were
compared with the Wilcoxon rank-sum test for continuous variables
and ␹2 or Fisher exact tests for categorical variables. Clinical
features of the study patients were compared with the extent of DE
with the Wilcoxon rank-sum test or Kruskal-Wallis equality-ofpopulations rank test for categorical variables and Spearman’s rank
correlation coefficient (␳) for continuous variables.
The primary clinical end point used in this study was a composite
of the following adverse cardiovascular events: sudden death, appropriate implantable cardioverter difibrillator (ICD) discharge, and
progressive heart failure symptoms of ⱖ1 NYHA class. Patient-level
characteristics were modeled as linear regressions in unadjusted and
adjusted analyses. Per-segment data clustered within a patient were
assessed by linear mixed-effects models with a random intercept per
patient. Probability values of ⬍0.05 were considered significant.
Calculations were performed with Stata SE version 9.2 (StataCorp,
College Station, Tex). Kaplan-Meier event rates were calculated to
accommodate for differential length of follow-up between patients.
The comparison of event rates among patients with and without DE
was performed using a log-rank test for equality of survivor
functions. Among patients with DE, the relationship between %DE
and the likelihood of subsequent cardiovascular events was evaluated
using a univariate Cox model.
Results
Patient Characteristics
Baseline clinical and demographic characteristics of the 202
study patients at initial evaluation are summarized in Table 1.
Mean age was 42⫾17 years; 144 (71%) were male. NYHA
class was 1.5⫾0.7 and maximal LV wall thickness was
22⫾5 mm (range, 14 to 37 mm).
Morphological Features of DE
Prevalence and Extent
DE was present in 111 (55%) of the HCM patients, and %DE
was 9%⫾11% (range, 0.2% to 51%), which was equivalent to
19⫾21 g (range, 0.4 to 85 g) and included 11 patients (10%)
with %DE ⱖ25% (Table 1).
Location and Distribution
DE was most commonly located in both the ventricular
septum and LV free wall (n⫽35; 32%) but was also confined
to the LV free wall (n⫽29; 26%), the septum (n⫽27; 24%),
the area of right ventricular insertion into the ventricular
septum (n⫽15; 13%), and the LV apex (n⫽5; 5%).
DE was transmural (occupying ⱖ75% of LV wall thickness) in 58 patients (52%) in the following segmental
distribution: septum (n⫽10), LV free wall (n⫽21), septum
and LV free wall (n⫽25), and apex (n⫽2). In the remaining
53 patients (48%), DE was nontransmural in the following
distribution: midmyocardial (n⫽17), right ventricular insertion areas (n⫽12), subendocardial (n⫽9), subepicardial
186
Circ Heart Fail
Table 1.
September 2008
Demographic and Clinical Characteristics of 202 HCM Patients with CMR
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No. (%) of patients
Age, y
Male, n (%)
Body surface area (g/m2)
NYHA class, n (%)
I
II
III/IV
Mean
EF, n (%)
ⱖ60%
51%[en]59%
ⱕ50%
Basal LVOT gradient ⱖ30 mm Hg, n (%)
Maximum LV thickness, mm
LV mass, g
LV mass index, g/m2
LA dimension, mm
LVED dimension, mm
DE (range), g
% LV with DE (range)
All Patients
DE (⫹)
DE (⫺)
202 (100)
42⫾17
144 (71)
1.97⫾0.3
111 (55)
43⫾17
78 (70)
1.96⫾0.3
91 (45)
40⫾18
66 (73)
1.99⫾0.3
123 (61)
54 (27)
25 (12)
1.5⫾0.7
61 (55)
31 (28)
19 (17)
1.6⫾0.8
62 (68)
23 (26)
6 (7)
1.4⫾0.6
182 (90)
10 (5)
10 (5)
48 (24)
22⫾5
211⫾80
107⫾34
67⫾11
52⫾7
N/A
N/A
92 (83)
9 (8)
10 (9)
26 (23)
23⫾5
219⫾85
113⫾37
69⫾10
53⫾7
19⫾21 (0.4 to 85)
9⫾11 (0.2 to 51)
90 (99)
1 (1)
0 (0)
22 (24)
20⫾4
201⫾72
100⫾28
65⫾11
51⫾6
N/A
N/A
P value*
–
0.3
0.7
0.6
0.05
0.03
0.001
0.9
⬍0.001
0.114
0.02
0.027
0.097
–
–
LVOT indicates left ventricular outflow tract; LVED, left ventricular end-diastolic; N/A, not applicable.
*Based on comparison between DE (⫹) and DE (⫺) patients.
(n⫽8), and ⱖ2 of these nontransmural distributions (n⫽7)
(Figure 1).
Relation of DE to Heart Failure Symptoms
A relationship was identified between presence of DE and
heart failure symptoms. DE was most common in patients
with severe (NYHA class III–IV; 19/25 [76%]) and moderate
symptoms (NYHA class II; 31/54 [57%]) and was also
present in 61 of 123 (50%) asymptomatic patients (P⫽0.05;
Table 1 and Figure 2). %DE was 8.9%⫾9.6% in asymptomatic patients and 9.9⫾13.4% in those with heart failure
symptoms (NYHA classes II–IV) (P⫽0.2; Figure 3).
A
B
Patients with areas of transmural DE were no more likely
to have heart failure symptoms than were patients with
nontransmural DE (P⫽0.7). DE specifically confined to the
area of right ventricular insertion into the ventricular septum
was unrelated to heart failure symptoms (P⫽0.5). %DE in
these areas was relatively small and less than in other patients
with DE (3.0%⫾2.2% versus 10.2⫾12%; P⫽0.008).
Relation of DE to Ejection Fraction
DE was present in all 10 patients with ejection fraction (EF)
ⱕ50% (ie, end-stage phase; each transmural), in 9 of 10
(90%) with EF 51% to 59%, and in 92 of 182 (51%) with EF
C
VS
D
E
F
LV
VVS
V
S
S
RV
Figure 1. LV short-axis delayedenhanced CMR images from 6 HCM
patients showing diverse patterns of DE.
A, Extensive transmural area in the anterior ventricular septum (VS) extending
into the contiguous anterior free wall
(arrow). A small focal area of DE is also
present in the region of the right ventricular insertion into the posterior septum
(double arrow). B, Multifocal midmyocardial distribution within the septum
(arrows). C, Predominate transmural DE
in the inferolateral LV free wall (arrows).
D, DE on the right ventricular side of
septum (arrows) and subepicardial area
in the contiguous anterior free wall (double arrow). E, Subendocardial distribution
within septum and anterior wall (arrows).
F, Focal area (arrow) of DE at right ventricular insertion with posterior septum.
% of Patients with DE
Maron et al
187
LV Outflow Obstruction
Patients with DE were no more likely to have LV outflow
obstruction at rest than were patients without DE (P⫽0.9).
Among patients with obstruction, there was no significant
relationship between %DE and magnitude of LV outflow
gradient at rest (r⫽0.2; P⫽0.23).
80
p=0.05
70
Delayed Enhancement in HCM
60
50
40
30
20
10
0
I
II
III/IV
NYHA Class at Study Entry
Figure 2. Comparison of DE presence in HCM patients with
NYHA classes I, II, and III/IV.
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ⱖ60% (P⫽0.001) (Table 2). Also, %DE was more extensive
in patients with EF ⱕ50% compared with those with EF 51%
to 59% or ⱖ60% (27% versus 12% versus 7%, respectively;
P⫽0.004) (Figure 4), and an inverse relationship was present
between EF and %DE (r⫽⫺0.3; P⬍0.001).
Multivariable Cox regression analysis (including LV outflow obstruction, maximal wall thickness, mass index, enddiastolic dimension, age, gender, left atrial size, and NYHA
functional class) showed %DE as an independent predictor of
EF (r⫽⫺0.4; 95% CI, ⫺0.6 to ⫺0.2; P⬍0.001).
Of the 182 patients with EF ⱖ60%, 54 (30%) were both
asymptomatic (NYHA class I) and had DE occupying
7%⫾7% (range, 1% to 34%) of LV myocardium (Table 2),
including 26 with transmural DE. Twenty-three other patients
(12%) with EF ⱖ60% experienced only mild symptoms
(NYHA class II) had DE occupying 9%⫾12% of LV (range,
0.2% to 51%), including 9 with transmural DE.
Relation of DE to Other Demographic and
Clinical Variables
Age and Gender
Patients with DE were 43⫾17 years of age (range, 1 to 79
years), including 23 (21%) who were ⱕ30 years of age and
21 (19%) who were ⱖ60 years of age. Patients with and
without DE did not differ significantly with respect to age
(P⫽0.3); also, %DE was unassociated with age (r⫽0.05;
P⫽0.8). Presence of DE did not differ with respect to gender
(57% [female] versus 54% [male]; P⫽0.7)
LV Wall Thickness and Mass
Patients with DE had greater maximal LV wall thickness
(23⫾5 mm) and LV mass index (113⫾37 g/m2) than patients
without DE (20⫾4 mm and 100⫾28 g/m2; P⬍0.001 and
P⫽0.02, respectively). A significant relationship was evident
between DE and segmental LV wall thickness (P⫽0.002).
DE was present in 15 of 112 (13%) LV segments ⱕ15 mm,
93 of 1216 (8%) LV segments 16 to 20 mm, 131 of 1216
(9%) LV segments 21 to 25 mm, 73 of 608 (12%) LV
segments 26 to 30 mm, and 50 of 288 (17%) LV segments
ⱖ30 mm.
Reproducibility for the Presence and Extent of DE
For presence of DE, the intraobserver and interobserver
agreements were 96% and 93%, respectively. For the intraobserver and interobserver quantifications of DE extent, the
mean differences in measurement were 1.4⫾9 g (11%) and
5.4⫾18 g (3.4%), respectively (␬⫽0.5 and ␬⫽0.2, respectively; both P⬍0.001).
Relation of DE to Clinical Outcome
Over the follow-up period, adverse cardiovascular events
occurred in 11 patients, including 7 patients with DE (2 with
sudden death, 2 with appropriate ICD discharge, and 3 with
progressive heart failure symptoms) and 4 patients without
DE (3 with sudden death and 1 with progressive heart
failure).
Annual cardiovascular event rate in HCM patients with DE
exceeded that in patients without DE (5.5% versus 3.3%),
although this comparison did not achieve statistical significance (P⫽0.5; hazard ratio, 1.45 [95% CI, 0.43 to 4.97])
(Figure 5). Extent of DE did not differ between patients with
and without adverse cardiovascular events (9⫾11% versus
11⫾15%; P⫽0.97). Patients with transmural or nontransmural DE showed no difference in event rate (7% per year versus
6% per year; P⫽0.89).
Discussion
A
B
LV
vs
RV
LV
vs
RV
Figure 3. Midventricular short-axis delayed enhanced image
from 2 HCM patients, both with extensive DE but with significantly different clinical courses. A, NYHA class III with an EF of
40% and 30% DE in LV. B, NYHA class I with an EF of 65%
and 46% DE in LV. VS indicates ventricular septum; RV, right
ventricle.
Contrast-enhanced CMR imaging provides a novel and noninvasive method for in vivo identification and quantification
of myocardial fibrosis.16 –18,20,21,35,36 In patients with dilated
cardiomyopathy or after myocardial infarction due to coronary artery disease, the presence of DE has been reported to
be an independent predictor of ventricular arrhythmias and
cardiovascular mortality.22–24,28,36 In HCM, myocardial scars
have been commonly reported in necropsy studies9 and by
fixed defects on myocardial perfusion imaging15 and it has
been suggested that DE represents myocardial fibrosis in this
disease, 9,11–13,25,29,37– 42 as initially recognized by Choudhury
et al.11 However, whether DE in HCM are associated with
adverse clinical consequences similar to those in coronary
artery disease and other nonischemic cardiomyopathies is
unresolved. Therefore, we have sought here, in a sizeable
188
Circ Heart Fail
Table 2.
September 2008
Clinical and Demographic Findings According to EF in HCM Patients with DE
Patients, n
Age, y
Total
ⱖ60%
51%–59%
ⱕ50%
111
92
9
10
43⫾17
43⫾17
46⫾17
43⫾22
0.9
P value
–
Male, n (%)
78 (70)
66 (72)
5 (56)
7 (70)
0.6
LV end-diastolic dimension, mm
53⫾7
52⫾6
53⫾9
58⫾9
0.14
Maximum LV thickness, mm
23⫾5
24⫾5
20⫾3
20⫾5
0.008
LV mass, g
219⫾85
226⫾89
171⫾31
203⫾70
0.08
LV mass index, g/m
113⫾37
116⫾37
91⫾21
110⫾43
0.08
DE, g
19⫾21
16⫾18
19⫾23
47⫾28
0.005
%DE
9⫾11
7⫾8
12⫾17
27⫾17
0.004
NYHA class, n (%)
0.4
61 (55)
54 (59)
4 (44)
3 (30)
II
31 (30)
23 (25)
3 (33)
5 (50)
III/IV
19 (17)
15 (16)
2 (22)
2 (20)
DE pattern, n (%)
0.013
Transmural
58 (53)
44 (49)
4 (44)
10 (100)
Nontransmural
53 (48)
48 (51)
5 (56)
0 (0)
Only subepicardial
8 (7)
8 (9)
0 (0)
0 (0)
Only midmyocardial
17 (15)
16 (17)
1 (11)
0 (0)
Only subendocardial
9 (8)
9 (10)
0 (0)
0 (0)
ⱖ2 nontransmural distributions
7 (6)
7 (8)
0 (0)
0 (0)
12 (11)
8 (9)
4 (44)
0 (0)
Only at RV insertion into LV
0.006
0.029
RV indicates right ventricle.
30
25
P=0.004
20
15
10
1.00
0.95
0.90
0.85
DE (-)
DE (+)
p=0.5
0.80
5
0
and the occurrence of heart failure symptoms. Indeed, ⬎75%
of our HCM patients with advanced and disabling symptoms
showed areas of DE, often involving extensive areas of LV
myocardium. Furthermore, the present data demonstrate an
inverse relationship between the presence and extent of DE
and LV EF, with DE an independent determinant of systolic
dysfunction (ie, end-stage phase, with EF ⱕ50%).43 Patients
in the end stage showed transmural and extensive DE
occupying on average ⬇25% of LV myocardium, greatly
exceeding that in our patients with preserved LV function.
These findings are consistent with 2 recent case reports in
which the explanted hearts of patients in the end stage of
HCM were analyzed in detail to show a morphological
Event-free rate
HCM cohort studied with CMR, to characterize the clinical
significance of DE and to analyze its relationship to a variety
of disease variables.
DE by contrast-enhanced CMR was present in ⬇50% of
patients in our HCM study cohort, a prevalence somewhat
less than that previously reported by other investigators.11,38
In addition, when present, the extent of DE proved to be
substantial, occupying on average ⬇10% of overall LV
myocardial volume. This extent of DE observed in HCM is
similar to that reported after myocardial infarction,19,23 raising the consideration of whether myocardial fibrosis or
scarring in this genetic cardiomyopathy is a determinant of
increased risk for sudden death or disease progression due to
heart failure.
In this regard, our data demonstrate a modest relationship
between the presence (but not necessarily the extent) of DE
% Myocardium with DE
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I
0
≤50
≥60
51-59
Ejection Fraction (%)
Figure 4. Comparison of %DE in HCM patients with EF ⱕ50%,
51% to 59%, and ⱖ60%.
0.5
1
1.5
2
2.5
3
Follow-up Duration (years)
Figure 5. Kaplan-Meier survival estimates for the composite
end-point of sudden death, appropriate ICD discharge, and progressive heart failure symptoms in patients with and without DE.
Maron et al
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correlation between CMR-DE and extensive areas of myocardial fibrosis.39,42 The recognition that CMR has the capability to identify the end-stage phase of HCM by virtue of
calculated EF and myocardial fibrosis has important clinical
implications, as end-stage patients experience a high rate of
unfavorable disease consequences, including progressive
heart failure (often requiring heart transplantation) and sudden unexpected death (prompting consideration for prophylactic defibrillator implantation).1,2,43 However, whether extensive DE identified by CMR will ultimately prove to be a
primary marker and prospectively portend susceptibility for
progression to the end stage before development of systolic
dysfunction is presently unresolved. Nevertheless, taken together, the present data demonstrating an association between
DE and both heart failure and systolic dysfunction suggest
that myocardial fibrosis has an important role in symptom
production and adverse remodeling among HCM patients.
On the other hand, we also identified a sizeable and novel
subgroup of asymptomatic patients with preserved EF in
whom, paradoxically, extensive and often transmural myocardial DE was present. Furthermore, many of these patients
with substantial amounts of DE have already achieved advanced ages, free of LV remodeling, arrhythmia-related
events, or heart failure. That these patients have not experienced adverse consequences from their myocardial fibrosis
over many years suggests that DE may result in very different
clinical consequences within the broad clinical spectrum of
this disease. Our findings also underscore the principle that
complex and multifactorial pathophysiologic mechanisms are
likely responsible for disease progression in HCM and that
myocardial fibrosis may not be the sole or primary determinant of adverse consequences.4,44 Nevertheless, given the
present data and uncertainty in this area, it would seem
judicious for HCM patients with DE to undergo regular
clinical surveillance (including serial CMR imaging) for
prospective detection of changes in symptoms and LV
remodeling.
Moon et al,38 using HCM risk factors as surrogates for
sudden death events in a retrospective study, suggested that
DE may fulfill the aspiration as a predictor for future
arrhythmic events and prognosis. However, whereas our
prospective (short-term) outcome data obtained over an
average of almost 2 years showed the adverse cardiovascular
event rate to be numerically higher in association with the
presence of DE, this difference did not achieve statistical
significance. This outcome analysis was clearly underpowered considering the low event rate characteristic of HCM. A
substantially longer follow-up period will be required in a
particularly large patient population to achieve adequately
powered positive or negative data in this respect. Therefore,
it is possible that longer longitudinal observation periods (ie,
⬇5 to 7 years) will allow the presence (or extent) of DE to be
fully analyzed and emerge as a possible independent risk
factor for sudden death and disease progression.
In addition, it is conceivable that novel CMR-based techniques for identifying specific areas of histologically abnormal myocardium, such as reported in coronary artery disease
(using intermediate signal intensity thresholding to define the
infarct border zone),23 may also emerge as a more reliable
Delayed Enhancement in HCM
189
predictor in this patient population. Although it is premature
at this early juncture to broadly apply DE by contrastenhanced CMR as a primary risk stratification strategy to
HCM, it may nevertheless be reasonable in selected patients
(and on a case-by-case basis) to assign weight to DE as an
arbitrator in reaching difficult clinical decisions for primary
prevention ICDs,45 particularly when ambiguity remains regarding risk level after the assessment of conventional risk
factors.46,47
To define DE in this analysis, we chose a methodology
which used the cutoff point of ⱖ6 SDs above the mean signal
intensity of normal myocardium. At present, a general consensus is lacking on this criterion (particularly in nonischemic
cardiomyopathy), with previous investigators using a variety
of strategies for the identification of DE, including visual
assessment (without thresholding)34,48 and also 2-SD34,48 and
6-SD thresholds.18,27,33,34,48 In our experience, the amount of
DE quantified with the 6-SD technique most closely approximates that assessed by visual inspection, with the 2-SD
cutoff point yielding 22% greater amounts of DE than 6
SDs.49 Therefore, our decision to use a 6-SD threshold was
based on the view that it provides the highest specificity for
detection and quantification of myocardial fibrosis.16,33,34
Indeed, considering the extensive amount of DE in the
patients reported here using this methodology, it is unlikely
that we have significantly underestimated the extent of
fibrosis present in our HCM cohort.
In conclusion, in a large hospital-based population of HCM
patients, DE was common and often occupied significant
proportions of LV myocardium. DE was associated with heart
failure symptoms and a strong determinant of LV dysfunction
(ie, end-stage phase). Paradoxically, significant amounts of
DE were also present in many asymptomatic (or mildly
symptomatic) HCM patients with preserved LV function.
Therefore, DE (ie, myocardial fibrosis) appears to have an
important role in the clinical course of many HCM patients
but may also be associated with substantially different disease
consequences. Nevertheless, at present, DE cannot yet be
regarded as an independent risk factor for adverse disease
outcome and risk for sudden death in HCM, and prudent
restraint is justified before broadly applying the results of
contrast-enhanced CMR to clinical decision-making strategies in this disease. These present data also underscore the
necessity of long-term follow-up studies to ultimately define
the prognostic significance of this newly identified CMRbased component of the cardiomyopathic process in HCM.
Disclosures
None.
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CLINICAL PERSPECTIVE
In hypertrophic cardiomyopathy (HCM), a myocardial substrate of fibrosis and scarring has been implicated in promoting
heart failure and providing a nidus for the generation of ventricular tachyarrhythmias. Contrast-enhanced cardiovascular
magnetic resonance with delayed enhancement (DE) now provides a novel, noninvasive method for detecting myocardial
fibrosis in vivo in HCM patients. These data report on the clinical profile and significance of DE (ie, fibrosis) in a large
cohort of HCM patients. DE was identified in the majority of HCM patients (55%), occupying on average 10% of total left
ventricular mass. The extent of DE was inversely related to (r⫽⫺0.3; P⬍0.001) and an independent predictor of (r⫽⫺0.4;
P⬍0.001) LV systolic function; patients showing systolic dysfunction (ejection fraction ⬍50%) demonstrated the greatest
amount of DE. The presence of DE was modestly related to the occurrence of heart failure symptoms (P⫽0.05), with DE
in ⬎75% of patients with advanced limiting symptoms. Paradoxically, substantial amounts of DE were also identified in
patients with normal systolic function, many of whom had achieved advanced ages, free of adverse disease consequences.
Over a short-term follow-up period, patients with DE experienced more adverse disease events than those without DE,
although this difference did not achieve statistical significance. These data demonstrate that DE may result in different
clinical consequences within the broad HCM clinical spectrum and strongly support the need for further follow-up studies
to more definitively define the prognostic significance of DE in this complex disease.
Clinical Profile and Significance of Delayed Enhancement in Hypertrophic
Cardiomyopathy
Martin S. Maron, Evan Appelbaum, Caitlin J. Harrigan, Jacki Buros, C. Michael Gibson, Connie
Hanna, John R. Lesser, James E. Udelson, Warren J. Manning and Barry J. Maron
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Circ Heart Fail. 2008;1:184-191; originally published online June 23, 2008;
doi: 10.1161/CIRCHEARTFAILURE.108.768119
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