clinical profile and significance of delayed enhancement...
TRANSCRIPT
Circulation
Journal of the American Heart Association
Heart Failure
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Clinical Profile and Significance of Delayed Enhancement in
Hypertrophic Cardiomyopathy
Martin S. Maron, MD¹, Evan Appelbaum, MD2,3, Caitlin J. Harrigan, BA³, Jacki Buros,
BA³, C. Michael Gibson, MD, MS2,3, Connie Hanna, RN4 John R. Lesser, MD4, James
E. Udelson, MD¹, Warren J. Manning, MD2,3 and Barry J. Maron, MD4
¹ Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts-New England
Medical Center, Boston, Massachusetts; ²Department of Medicine, Cardiovascular
Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts; ³PERFUSE Core Laboratory and Data Coordinating Center, Harvard
Medical School, Boston, Massachusetts. 4The Hypertrophic Cardiomyopathy Center,
Minneapolis Heart Institute Foundation, Minneapolis MN
Running title: Delayed Enhancement in HCM
Word count: 5,000
Disclosures: None of the authors have any relevant disclosures or conflicts of interests.
Address for Correspondence: Martin S. Maron, MD Tufts-New England Medical Center, #70 750 Washington Street Boston, Massachusetts 02111 Email: [email protected] Tel: 617 636-8066 Fax: 617-636-5913
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ABSTRACT
Background. Contrast-enhanced cardiovascular magnetic resonance (CMR) 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 CMR-DE were performed in 202 HCM patients (42±17
years; 71% male) and DE was compared to 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 LV myocardial
volume, including >25% DE in 10% of patients. Presence of DE was related to
occurrence of heart failure symptoms (p=0.05) and LV systolic dysfunction (p=0.001).
DE was present in all patients with ejection fraction (EF) ≤ 50%, but also in 53%
(102/192) of patients with preserved EF (p<0.001); %DE was both inversely related to
(r= -0.3; p<0.001) and an independent predictor of EF (r= -0.4; p<0.001). Delayed
enhancement (7±7% of LV) was present in 54 patients who were asymptomatic (and with
normal EF). 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 % vs. 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.
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Key Words: MRI, hypertrophic cardiomyopathy, fibrosis
Abstract Word Count: 252
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Author Disclosure Statement
Martin S. Maron, MD: None
Evan Appelbaum, MD: None
Caitlin J. Harrigan, BA: None
Jacki Buros BA: None
C. Michael Gibson, MD: None
Connie Hanna, RN: None
John R. Lesser, MD: None
James E. Udelson, MD: None
Warren J. Manning, MD: None
Barry J. Maron, MD: None
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Hypertrophic 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 non-ischemic 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, and morphologic profile, as well as its relation to clinical
and demographic features and prognosis.
METHODS
Selection of patients
We prospectively evaluated 202 HCM patients presenting to centers at Tufts-New
England Medical Center (Boston, MA) and Minneapolis Heart Institute Foundation
(Minneapolis, MN) between April 2002 to 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 ≥30 mmHg, assessed by continuous-wave
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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 (CAD) (>50%
stenosis in one major artery) as a cause of pre-existent myocardial scars in study patients
with DE by virtue of two specific clinical and/or CMR criteria: 1) No study patient
experienced an acute coronary event associated with increased cardiac enzymes or Q
waves on ECG; 2) in all patients with DE distributed in a single coronary vascular
territory, hemodynamically significant CAD was excluded by arteriography or CT
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 CAD risk factors, while 2 patients were >40 years and because of an LV ejection
fraction <50% (ie., end stage) underwent coronary arteriography, which demonstrated in
both the absence of significant CAD.
All study patients signed a statement previously approved by the Internal Review
Board (IRB) 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.
Definitions
Diagnosis of HCM was based on two-dimensional echocardiographic and CMR
documentation of a hypertrophied and nondilated LV in the absence of another cardiac or
systemic disease capable of producing 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
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unexpected collapse in patients who had previously had a relatively uneventful clinical
course. Progression of heart failure was defined as an advancement of at least one NYHA
functional class during the follow-up period. In addition, potentially lethal events in
which patients received appropriate implanted defibrillator interventions (shocks or anti-
tachycardia pacing triggered by ventricular tachycardia/fibrillation) were regarded as
equivalent to sudden death.
Cardiovascular magnetic resonance (CMR)
CMR imaging was performed (Philips Gyroscan ACS-NT 1.5T, Best, Netherlands
and Siemens Sonata 1.5T, 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 two-dimensional segmented inversion-recovery sequence
acquired in the same views as the cine images. The inversion time (TI) ranged from 240-
300 ms and was chosen to null normal myocardial signal.
LV volumes, mass and ejection fraction (EF) were measured using standard
volumetric techniques, and analyzed with commercially available software (MASS®,
version 6.1.6 Medis, Inc., Netherlands)(31). Volume and mass measurements were
indexed to body surface area (BSA). 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.
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Mean signal intensity (and standard deviation) of normal myocardium was calculated and
a threshold ≥6 SD 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 [g]) 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 one experienced reader, C.J.H. (with 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.; with over 7 years of CMR experience). Both these independent
observers were blinded to patient identity and clinical profile. Any discrepancies between
the two 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 re-analyzed all CMR studies. Among the studies in which there was
agreement between the two readers on the presence of DE, reader E.A. re-analyzed 20
randomly selected studies in order to determine the interobserver variability for extent of
DE. To assess intraobserver variability, reader C.J.H. re-analyzed 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 ± standard deviation (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 chi-square or Fisher exact
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tests for categorical variables. Clinical features of the study patients were compared to the
extent of DE with the Wilcoxon rank-sum test or Kruskal-Wallis equality-of-populations
rank test for categorical variables, and Spearman's rank correlation coefficient (rho) for
continuous variables.
The primary clinical end-point used in this study was a composite of adverse
cardiovascular events: sudden death, appropriate ICD discharge and progressive heart
failure symptoms of ≥1 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.
P-values of p<0.05 were considered significant. Calculations were performed with Stata
SE version 9.2 (College Station, TX). 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 amount
of 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).
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Morphologic features of DE
Prevalence and extent. DE was present in 111 (55%) of the HCM patients.
Percent DE volume of LV myocardium was 9±11% (range 0.2 to 51%), equivalent to
19±21 g (0.4 to 85 g), and including 11 patients (10%) with % DE ≥25% (Table 1).
Location and distribution. DE was most commonly located in both ventricular
septum and LV free wall (n = 35; 32%), but was also confined to the LV free wall (n =
29; 26%), septum (n=27; 24%), the area of right ventricular insertion into ventricular
septum (n=15; 13%), and LV apex (n=5; 5%).
DE was transmural (occupying ≥75% 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: mid-myocardial (n= 17), right ventricular
insertion areas (n=12), subendocardial (n=9), subepicardial (n=8), or ≥2 of these non-
transmural 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 (class III/IV; 19/25 [76%]) and moderate
symptoms (class II; 31/54[57%]), and was also present in 61 of 123 asymptomatic
patients (50%)(p=0.05; Table 1)(Figure 2). %DE was 8.9±9.6% in asymptomatic patients
and 9.9±13.4% in those with heart failure symptoms (classes II-IV)(p=0.2; Figure 3).
Patients with areas of transmural DE were no more likely to have heart failure
symptoms than patients with non-transmural DE (p=0.7). DE specifically confined to the
area of RV insertion into ventricular septum was unrelated to heart failure symptoms
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(p=0.5). % DE in these areas was relatively small and less than in other patients with DE
(3.0±2.2% vs. 10.2±12%; p=0.008).
Relation of DE to ejection fraction
DE was present in all 10 patients with EF ≤ 50% (i.e., end-stage phase; each
transmural), in 9 of 10 (90%) with EF 51-59%, and in 92 of 182 (51%) with EF ≥ 60%
(p=0.001)(Table 2). Also, % DE was more extensive in patients with EF ≤ 50%
compared to those with 51-59% or ≥ 60% (27% vs. 12% vs. 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, end-diastolic 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 ≥ 60%, 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 ≥60%
experienced only mild symptoms (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 1-79),
including 23 (21%) ≤30 years and 21 (19%) ≥60 years. Patients with and without DE did
not differ significantly with respect to age (p=0.3); also, %DE was unassociated with age
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(r= 0.05; p = 0.8). Presence of DE did not differ with respect to gender (female 57% vs.
male 54%; p = 0.7)
LV outflow obstruction. Patients with DE were no more likely to have LV outflow
obstruction at rest than 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).
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 0.02, respectively). A significant relationship was
evident between DE and segmental LV wall thickness (p=0.002). DE was present in:
15/112 (13%) LV segments ≤15 mm; 93/1216 (8%) 16-20 mm; 131/1216 (9%) 21-
25mm; 73/608 (12%) 26-30 mm; and 50/288 (17%) with ≥30 mm.
Reproducibility for the Presence and Extent of DE. For the presence of DE the
intraobserver and interobserver agreement was 96% and 93%, respectively. For the
intraobserver and interobserver quantification of DE extent the mean differences in
measurement were 1.4±9 g or 11% and 5.4±18 g or 3.4%, respectively (κ=0.5; κ=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 one with progressive heart failure).
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Annual cardiovascular event rate in HCM patients with DE exceeded that in
patients without DE (5.5% vs.3.3%), although this comparison did not achieve statistical
significance (p=0.5; hazard ratio 1.45 [95% CI, 0.43-4.97])(Figure 5). Extent of DE did
not differ between patients with and without adverse cardiovascular events (9±11% vs.
11±15%; p=0.97). Patients with transmural or non-transmural DE showed no difference
in event rate (7 %/year vs. 6 %/year; p=0.89).
DISCUSSION
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 following 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 studies (9) and by fixed defects on
myocardial perfusion imaging (15) 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 is associated with adverse clinical
consequences similar to those in coronary artery disease and other non-ischemic
cardiomyopathies is unresolved. Therefore, we have sought here, in a sizeable 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 about 50% of patients in our HCM
study cohort, a prevalence somewhat less than that previously reported by other
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investigators (11,38). In addition, when present, the extent of DE proved to be
substantial, occupying on average about 10% of overall LV myocardial volume. This
extent of DE observed in HCM is similar to that reported following 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 and the occurrence of heart failure symptoms.
Indeed, over 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 ejection fraction, with DE an independent determinant of systolic dysfunction
(ie., end-stage phase, with ejection fraction ≤50%)(43). Indeed, patients in the end-stage
showed transmural and extensive DE occupying on average about 25% of LV
myocardium, greatly exceeding that in our patients with preserved LV function. These
findings are consistent with two recent case reports in which the explanted hearts of
patients in the end-stage of HCM were analyzed in detail to show a morphologic
correlation between CMR-delayed enhancement 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
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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 prior to 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 suggests 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, while our prospective (short-term) outcome
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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., about 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 predictor in this patient population.
Although it is premature at this early juncture to broadly apply DE by contrast-enhanced
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 employed the cut-
off of ≥ 6 standard deviations above the mean signal intensity of normal myocardium. At
present, a general consensus is lacking on this criterion (particularly in non-ischemic
cardiomyopathy) with previous investigators using a variety of strategies for the
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identification of DE, including visual assessment (without thresholding)(34,48) and also
2 SD (34,48) 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 cut-off yielding 22% greater amounts of DE than 6 SD (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
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 CMR-based component of the
cardiomyopathic process in HCM.
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LEGENDS
Figure 1. Left ventricular short-axis delayed-enhanced CMR images from 6
HCM patients showing diverse patterns of DE. A.) extensive transmural
area in anterior ventricular septum (VS) extending into contiguous anterior
free wall (arrow). Small focal area of DE is also present in the region of
right ventricular insertion into posterior septum (double arrow); B.)
multifocal mid-myocardial distribution within septum (arrows); C.)
predominate transmural DE in inferolateral LV free wall (arrows); D.) DE
on right ventricular side of septum (arrows) and subepicardial area in
contiguous anterior free wall (double arrow); E.) subendocardial
distribution within septum and anterior wall (arrows); F.) focal area
(arrow) of DE at right ventricular (RV) insertion with posterior septum
(VS). RV=right ventricle; VS=ventricular septum
Figure 2. Comparison of DE presence in HCM patients with NYHA classes I, II
and III/IV.
Figure 3. Mid-ventricular short-axis delayed enhanced image from two HCM
patients, both with extensive DE, but with significantly different clinical
courses. A.) NYHA functional class III with EF = 40% and 30% DE in
LV; B.) NYHA functional class I with EF = 65% and 46% DE in LV.
VS=ventricular septum; RV=right ventricle
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Figure 4. Comparison of % DE in HCM patients with EF ≤50%, 51-59% and
≥60%.
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.
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Funding Sources: None
REFERENCES
1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA.
2002;287:1308-20.
2. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman
CE, Shah PM, Spencer WH, 3rd, Spirito P, Ten Cate FJ, Wigle ED. American
College of Cardiology/European Society of Cardiology clinical expert consensus
document on hypertrophic cardiomyopathy. A report of the American College of
Cardiology Foundation Task Force on Clinical Expert Consensus Documents and
the European Society of Cardiology Committee for Practice Guidelines. J Am
Coll Cardiol. 2003;42:1687-713.
3. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic
cardiomyopathy. Clinical spectrum and treatment. Circulation. 1995;92:1680-92.
4. Autore C, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance
of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in
relation to the severity of symptoms. J Am Coll Cardiol. 2005;45:1076-80.
5. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon
NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification
of high risk patients. J Am Coll Cardiol. 2000;36:2212-8.
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6. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of
left ventricular hypertrophy and risk of sudden death in hypertrophic
cardiomyopathy. N Engl J Med. 2000;342:1778-85.
7. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation
identification to mechanistic paradigms. Cell. 2001;104:557-67.
8. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F,
Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome
in hypertrophic cardiomyopathy. N Engl J Med. 2003;348:295-303.
9. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic
cardiomyopathy and sudden death in the young: pathologic evidence of
myocardial ischemia. Hum Pathol. 2000;31:988-98.
10. Lombardi R, Betocchi S, Losi MA, Tocchetti CG, Aversa M, Miranda M,
D'Alessandro G, Cacace A, Ciampi Q, Chiariello M. Myocardial collagen
turnover in hypertrophic cardiomyopathy. Circulation. 2003;108:1455-60.
11. Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD, Klocke FJ, Bonow
RO, Judd RM, Kim RJ. Myocardial scarring in asymptomatic or mildly
symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol.
2002;40:2156-64.
12. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the
left ventricular collagen network in young patients with hypertrophic
cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000;35:36-44.
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
Circulation
Journal of the American Heart Association
Heart Failure
22
13. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic
cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease.
Heart. 2000;84:476-82.
14. Fassbach M, Schwartzkopff B. Elevated serum markers for collagen synthesis in
patients with hypertrophic cardiomyopathy and diastolic dysfunction. Z Kardiol.
2005;94:328-35.
15. O'Gara PT, Bonow RO, Maron BJ, Damske BA, Van Lingen A, Bacharach SL,
Larson SM, Epstein SE. Myocardial perfusion abnormalities in patients with
hypertrophic cardiomyopathy: assessment with thallium-201 emission computed
tomography. Circulation. 1987;76:1214-23.
16. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn
JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to
irreversible injury, infarct age, and contractile function. Circulation.
1999;100:1992-2002.
17. Fieno DS, Kim RJ, Chen EL, Lomasney JW, Klocke FJ, Judd RM. Contrast-
enhanced magnetic resonance imaging of myocardium at risk: distinction between
reversible and irreversible injury throughout infarct healing. J Am Coll Cardiol.
2000;36:1985-91.
18. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow
RO, Judd RM. The use of contrast-enhanced magnetic resonance imaging to
identify reversible myocardial dysfunction. N Engl J Med. 2000;343:1445-53.
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
Circulation
Journal of the American Heart Association
Heart Failure
23
19. Mahrholdt H, Wagner A, Holly TA, Elliott MD, Bonow RO, Kim RJ, Judd RM.
Reproducibility of chronic infarct size measurement by contrast-enhanced
magnetic resonance imaging. Circulation. 2002;106:2322-7.
20. Pennell DJ. Cardiovascular magnetic resonance: twenty-first century solutions in
cardiology. Clin Med. 2003;3:273-8.
21. Lima JA, Desai MY. Cardiovascular magnetic resonance imaging: current and
emerging applications. J Am Coll Cardiol. 2004;44:1164-71.
22. Assomull RG, Prasad SK, Lyne J, Smith G, Burman ED, Khan M, Sheppard MN,
Poole-Wilson PA, Pennell DJ. Cardiovascular magnetic resonance, fibrosis, and
prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48:1977-85.
23. Yan AT, Shayne AJ, Brown KA, Gupta SN, Chan CW, Luu TM, Di Carli MF,
Reynolds HG, Stevenson WG, Kwong RY. Characterization of the peri-infarct
zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful
predictor of post-myocardial infarction mortality. Circulation. 2006;114:32-9.
24. Kwong RY, Chan AK, Brown KA, Chan CW, Reynolds HG, Tsang S, Davis RB.
Impact of unrecognized myocardial scar detected by cardiac magnetic resonance
imaging on event-free survival in patients presenting with signs or symptoms of
coronary artery disease. Circulation. 2006;113:2733-43.
25. Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed enhancement
cardiovascular magnetic resonance assessment of non-ischaemic
cardiomyopathies. Eur Heart J. 2005;26:1461-74.
26. Rochitte CE, Tassi EM, Shiozaki AA. The emerging role of MRI in the diagnosis
and management of cardiomyopathies. Curr Cardiol Rep. 2006;8:44-52.
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
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Journal of the American Heart Association
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24
27. Nazarian S, Bluemke DA, Lardo AC, Zviman MM, Watkins SP, Dickfeld TL,
Meininger GR, Roguin A, Calkins H, Tomaselli GF, Weiss RG, Berger RD, Lima
JA, Halperin HR. Magnetic resonance assessment of the substrate for inducible
ventricular tachycardia in nonischemic cardiomyopathy. Circulation.
2005;112:2821-5.
28. Kramer CM. The expanding prognostic role of late gadolinium enhanced cardiac
magnetic resonance. J Am Coll Cardiol. 2006;48:1986-7.
29. Kim RJ, Judd RM. Gadolinium-enhanced magnetic resonance imaging in
hypertrophic cardiomyopathy: in vivo imaging of the pathologic substrate for
premature cardiac death? J Am Coll Cardiol. 2003;41:1568-72.
30. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ,
Seidman CE, Young JB. Contemporary definitions and classification of the
cardiomyopathies: an American Heart Association Scientific Statement from the
Council on Clinical Cardiology, Heart Failure and Transplantation Committee;
Quality of Care and Outcomes Research and Functional Genomics and
Translational Biology Interdisciplinary Working Groups; and Council on
Epidemiology and Prevention. Circulation. 2006;113:1807-16.
31. Grothues F, Smith GC, Moon JC, Bellenger NG, Collins P, Klein HU, Pennell
DJ. Comparison of interstudy reproducibility of cardiovascular magnetic
resonance with two-dimensional echocardiography in normal subjects and in
patients with heart failure or left ventricular hypertrophy. Am J Cardiol.
2002;90:29-34.
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
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Journal of the American Heart Association
Heart Failure
25
32. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK,
Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial
segmentation and nomenclature for tomographic imaging of the heart. A
statement for healthcare professionals from the Cardiac Imaging Committee of the
Council on Clinical Cardiology of the American Heart Association. Int J
Cardiovasc Imaging. 2002;18:539-42.
33. Beek AM, Kuhl HP, Bondarenko O, Twisk JW, Hofman MB, van Dockum WG,
Visser CA, van Rossum AC. Delayed contrast-enhanced magnetic resonance
imaging for the prediction of regional functional improvement after acute
myocardial infarction. J Am Coll Cardiol. 2003;42:895-901.
34. Bondarenko O, Beek AM, Hofman MB, Kuhl HP, Twisk JW, van Dockum WG,
Visser CA, van Rossum AC. Standardizing the definition of hyperenhancement in
the quantitative assessment of infarct size and myocardial viability using delayed
contrast-enhanced CMR. J Cardiovasc Magn Reson. 2005;7:481-5.
35. Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K, Rosen
B, Lima JA, Calkins H, Bluemke DA. Noninvasive detection of myocardial
fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-
enhancement magnetic resonance imaging. J Am Coll Cardiol. 2005;45:98-103.
36. Bello D, Fieno DS, Kim RJ, Pereles FS, Passman R, Song G, Kadish AH,
Goldberger JJ. Infarct morphology identifies patients with substrate for sustained
ventricular tachycardia. J Am Coll Cardiol. 2005;45:1104-8.
37. Knaapen P, van Dockum WG, Bondarenko O, Kok WE, Gotte MJ, Boellaard R,
Beek AM, Visser CA, van Rossum AC, Lammertsma AA, Visser FC. Delayed
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
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Journal of the American Heart Association
Heart Failure
26
contrast enhancement and perfusable tissue index in hypertrophic
cardiomyopathy: comparison between cardiac MRI and PET. J Nucl Med.
2005;46:923-9.
38. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell DJ.
Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium
cardiovascular magnetic resonance. J Am Coll Cardiol. 2003;41:1561-7.
39. Papavassiliu T, Schnabel P, Schroder M, Borggrefe M. CMR scarring in a patient
with hypertrophic cardiomyopathy correlates well with histological findings of
fibrosis. Eur Heart J. 2005;26:2395.
40. Wilson JM, Villareal RP, Hariharan R, Massumi A, Muthupillai R, Flamm SD.
Magnetic resonance imaging of myocardial fibrosis in hypertrophic
cardiomyopathy. Tex Heart Inst J. 2002;29:176-80.
41. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N, Weil J,
Zenovich AG, Maron BJ. Utility of cardiac magnetic resonance imaging in the
diagnosis of hypertrophic cardiomyopathy. Circulation. 2005;112:855-61.
42. Moon JC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M, Petrou M,
Pennell DJ. The histologic basis of late gadolinium enhancement cardiovascular
magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol.
2004;43:2260-4.
43. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR,
Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical
profile, and significance of left ventricular remodeling in the end-stage phase of
hypertrophic cardiomyopathy. Circulation. 2006;114:216-25.
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
Dow
nloaded from
Circulation
Journal of the American Heart Association
Heart Failure
27
44. Maron MS, Zenovich AG, Casey SA, Link MS, Udelson JE, Aeppli DM, Maron
BJ. Significance and relation between magnitude of left ventricular hypertrophy
and heart failure symptoms in hypertrophic cardiomyopathy. Am J Cardiol.
2005;95:1329-33.
45. Maron BJ MM, Lesser JR, Hauser RG, Haas T, Harrigan CJ, Appelbaum E, Main
ML, Roberts WC. Sudden death events in hypertrophic cardiomyopathy can occur
in the absence of criteria for high risk status. Am J Cardiol;In press.
46. Maron BJ, Estes NA, 3rd, Maron MS, Almquist AK, Link MS, Udelson JE.
Primary prevention of sudden death as a novel treatment strategy in hypertrophic
cardiomyopathy. Circulation. 2003;107:2872-5.
47. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE,
Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA, 3rd, Favale S,
Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja
G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention
of sudden cardiac death in hypertrophic cardiomyopathy. Jama. 2007;298:405-12.
48. Amado LC, Gerber BL, Gupta SN, Rettmann DW, Szarf G, Schock R, Nasir K,
Kraitchman DL, Lima JA. Accurate and objective infarct sizing by contrast-
enhanced magnetic resonance imaging in a canine myocardial infarction model. J
Am Coll Cardiol. 2004;44:2383-9.
49. Harrigan CJ, Maron MS, Maron BJ, Peters DC, Gibson CM, Manning WJ,
Appelbaum E. Accuracy and Reproducibility of Quantifying Myocardial Fibrosis
in Hypertrophic Cardiomyopathy using Delayed Enhancement Cardiovascular
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
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Magnetic Resonance Techniques. J Cardiovasc Magn Reson. 11th Annual SCMR
Scientific Sessions. 2008; 2027:281
by guest on June 19, 2018http://circheartfailure.ahajournals.org/
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All Patients
DE (+)
DE (-)
p-value٭
No. (%) patients 202 (100) 111 (55) 91 (45) Age, y 42±17 43±17 40±18 0.3 Male, n (%) 144 (71) 78 (70) 66 (73) 0.7 Body surface area (g/m2)
1.97±0.3 1.96±0.3 1.99±0.3 0.6
NYHA class, n (%) 0.05 I 123 (61) 61 (55) 62 (68) II 54 (27) 31 (28) 23 (26) III/IV 25 (12) 19 (17) 6 (7) Mean 1.5±0.7 1.6±0.8 1.4±0.6 0.03 Ejection fraction, n (%) 0.001 ≥60% 182 (90) 92 (83) 90 (99) 51-59% 10 (5) 9 (8) 1 (1) ≤50% 10 (5) 10 (9) 0 (0) Basal LVOT gradient ≥30 mmHg, n (%)
48 (24) 26 (23) 22 (24) 0.9
Max LV thickness, mm 22±5 23±5 20±4 <0.001 LV mass, g 211±80 219±85 201±72 0.114 LV mass index, g/m2 107±34 113±37 100±28 0.02 LA dimension (mm) 67±11 69±10 65±11 0.027 LVED dimension (mm) 52±7 53±7 51±6 0.097 DE (g), (range) N/A 19±21 (0.4 to 85) N/A % LV with DE, (range) N/A 9±11 (0.2 to 51) N/A
Table 1. Demographic and Clinical Characteristics of 202 HCM Patients with CMR
Abbreviations: DE, delayed enhancement; LV, left ventricle; LVOT, left ventricular outflow tract; NYHA, New York Heart Association; Max=maximum; N/A, not applicable
Symbol: Based on comparison between DE (+) and DE (-) patients٭
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Total ≥60 % 51-59% ≤ 50% p-value
Patients, n 111 92 9 10
Age, y 43±17 43±17 46±17 43±22 0.9
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
Max 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 I 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) 0.006
Non-transmural 53 (48) 48 (51) 5 (56) 0 (0)
Only Subepicardial 8 (7) 8 (9) 0 (0) 0 (0) 0.029
Only Midmyocardial 17 (15) 16 (17) 1 (11) 0 (0)
Only Subendocardial 9 (8) 9 (10) 0 (0) 0 (0) ≥2 Non-transmural distributions 7 (6) 7 (8) 0 (0) 0 (0)
Only at RV Insertion into LV 12 (11) 8 (9) 4 (44) 0 (0)
Table 2. Clinical and Demographic Findings According to Ejection Fraction in HCM Patients with Delayed Enhancement
Abbreviations: DE, delayed enhancement; LV, left ventricle; NYHA, New York Heart Association; Max=maximum; RV, right ventricle
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B.B. C.C.A.A.
VS
D.D. E.E. F.
LVVSVS
RV
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Figure 2
80E
60
70
wit
h D p=0.05
40
50
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w
20
30
Pat
ie
0
10
20
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f P
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%
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A. B.Figure 3
LVLV LVLVLVLV LVLV
vs vsRVRV
RVRV
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Figure 4
25 P=0.004
20
15
5
10
0
5
0≤50 51-59 ≥60
Ejection Fraction (%) by guest on June 19, 2018 http://circheartfailure.ahajournals.org/ Downloaded from
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Figure 5
0 95
1.00
0 90
0.95
0 85
0.90
0.80
0.85p=0.5
DE (-)DE (+)
0 0.5 1 1.5 2 2.5 3Follow-up Duration (years)Follow-up Duration (years)
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John R. Lesser, James E. Udelson, Warren J. Manning and Barry J. MaronMartin Maron, Evan Appelbaum, Caitlin Harrigan, Jacki Buros, C. Michael Gibson, Connie Hanna,Clinical Profile and Significance of Delayed Enhancement in Hypertrophic Cardiomyopathy
Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2008 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online June 23, 2008;Circ Heart Fail.
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