Download Influence of Myocardial Fibrosis on Left Ventricular Diastolic Function

Influence of Myocardial Fibrosis on Left Ventricular
Diastolic Function
Noninvasive Assessment by Cardiac Magnetic Resonance and Echo
Antonella Moreo, MD; Giuseppe Ambrosio, MD, PhD, FAHA; Benedetta De Chiara, MD;
Min Pu, MD; Tam Tran, BS; Francesco Mauri, MD; Subha V. Raman, MD, MSEE
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Background—Fibrosis is a common end point of many pathological processes affecting the myocardium and may alter
myocardial relaxation properties. By measuring myocardial fibrosis with cardiac magnetic resonance and diastolic function
with Doppler echocardiography, we sought to define the influence of fibrosis on left ventricular diastolic function.
Methods and Results—Two hundred four eligible subjects from 252 consecutive subjects undergoing late postgadolinium
myocardial enhancement (LGE) cardiac magnetic resonance and Doppler echocardiography were investigated. Subjects
with normal diastolic function exhibited no or minimal fibrosis (median LGE score, 0; interquartile range, 0 to 0). In
contrast, the majority of patients with cardiomyopathy (regardless of underlying cause) had abnormal diastolic function
indices and substantial fibrosis (median LGE score, 3; interquartile range, 0 to 6.25). Prevalence of LGE positivity by
diastolic filling pattern was 13% in normal, 48% in impaired relaxation, 78% in pseudonormal, and 87% in restrictive
filling (P⬍0.0001). Similarly, LGE score was significantly higher in patients with deceleration time ⬍150 ms
(P⬍0.012), and it progressively increased with increasing left ventricular filling pressure estimated by tissue Doppler
imaging– derived E/E⬘ (P⬍0.0001). After multivariate analysis, LGE remained significantly correlated with degree of
diastolic dysfunction (P⫽0.0001).
Conclusions—Severity of myocardial fibrosis by LGE significantly correlates with the degree of diastolic dysfunction in a broad
range of cardiac conditions. Noninvasive assessment of myocardial fibrosis may provide valuable insights into the
pathophysiology of left ventricular diastolic function and therapeutic response. (Circ Cardiovasc Imaging. 2009;2:437-443.)
Key Words: diastole 䡲 myocardium 䡲 collagen 䡲 MRI 䡲 echocardiography
D
gations thus far have been restricted to evaluating cardiac
fibrosis in tissue biopsies or at autopsy.12–14
Late postgadolinium myocardial enhancement (LGE) by
cardiac magnetic resonance (CMR) has long been used to
detect the presence of scar after myocardial infarction.15
More recently, LGE-CMR has been shown to provide an
accurate noninvasive means of detecting myocardial fibrosis due to various forms of nonischemic cardiomyopathy
and has been validated against histopathologic examination.16,17 Distinct hyperenhancement patterns occur in
different myocardial disorders that all share tissue disarray, fibrosis, and inflammation.18 –22 Regardless of initial
etiology, myocyte injury ultimately leads to increased
myocardial collagen content and expanded interstitial
space.23 Extracellular contrast agents such as gadolinium
chelates accumulate in such regions, leading to hyperenhancement on imaging that takes advantage of gadolinium’s T1-shortening effects.
iastolic dysfunction significantly influences prognosis in
chronic heart disease across multiple etiologies; it is
present in virtually all patients with heart failure1– 4 as well as
in less severe conditions.5–7 From a mechanistic point of
view, it can be traced to abnormalities of left ventricular (LV)
distensibility, filling, or relaxation.8 These alterations may
coexist and act in synergy to influence LV diastolic function.8
Clinical Perspective on p 443
Accumulating evidence indicates that myocardial fibrosis
contributes to the pathogenesis of diastolic dysfunction.9,10
This is conceivable because the structural properties of the
heart are determined not only by the myocyte network but
also by interstitial connective tissue. Thus, changes in the
amount and composition of the extracellular matrix should
affect the diastolic properties of the LV.11 However, our
ability to investigate this issue in patients has long been
hampered by lack of suitable methodology, because investi-
Received November 25, 2008; accepted August 5, 2009.
From Ohio State University (A.M., M.P., T.T., S.V.R.), Columbus, Ohio; Niguarda Hospital (A.M., B.D.C., F.M.), Milan, Italy; and University of
Perugia School of Medicine (G.A.), Perugia, Italy.
Presented in part at the 57th Annual Scientific Session of the American College of Cardiology, Chicago, Ill, March 2008.
Guest Editor for this article was James D. Thomas, MD, FACC.
Correspondence to Subha V. Raman, MD, Division of Cardiovascular Medicine, Ohio State University, 473 W 12th Ave, Suite 200, Columbus, OH
43210. E-mail [email protected]
© 2009 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
437
DOI: 10.1161/CIRCIMAGING.108.838367
438
Circ Cardiovasc Imaging
November 2009
In the present study, we used LGE-CMR combined with
established Doppler flow and tissue velocity measurement
techniques24 to investigate noninvasively whether myocardial
fibrosis influences diastolic function.
Methods
The study population comprised patients referred for CMR with LGE
and in whom echocardiography with Doppler assessment of transmitral flow and tissue Doppler imaging was performed within 30
days of CMR. All patients were in stable sinus rhythm. Of 252
patients screened, 22 were excluded because of complex congenital
heart disease, 12 had mitral stenosis or valve prosthesis, 12 had
constrictive pericarditis or significant pericardial effusion, and 2 had
prior surgical ventricular restoration. CMR and echo studies were
independently analyzed by expert investigators unaware of imaging
and clinical data. This study was performed with institutional review
board approval.
CMR Acquisition and Analysis
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All scans were acquired with a 1.5-T magnetic resonance scanner
(MAGNETOM Avanto, Siemens Medical Solutions, Inc, Erlangen,
Germany). Multislice short-axis cine imaging used ECG-triggered,
steady-state free precession (slice thickness, 8 mm; interslice gap,
2 mm) acquired from the atrioventricular ring to the apex.25 Late
gadolinium imaging was performed 5 to 10 minutes after intravenous
gadolinium-DTPA contrast administration (0.2 mmol/kg) using a
T1-weighted inversion-recovery gradient echo sequence,26 optimizing the inversion time for adequate myocardial suppression and scar
visualization.
Magnetic resonance examinations were analyzed by an experienced CMR physician blinded to patient history and echocardiographic data. LV volumes, mass, and ejection fraction (EF) were
measured from contiguous short-axis cine images using endocardial and
epicardial contours at end-systole and end-diastole with Simpson’s rule,
in which the volumes from each short-axis slice were summed to
obtain global measures. Wall motion score index (WMSI) was
calculated using a standard 17-segment model27 and 4-point scoring
system (0, normal/hyperkinetic; 1, hypokinetic; 2, akinetic; 3,
paradoxical/dyskinetic). Regional WMSIs were obtained by summing the basal, mid, and apical segment scores in each region, as
follows: anterior (anterior and anterolateral), septal (anteroseptal and
inferoseptal), and inferior (inferior and inferolateral).
Similarly, LGE was rated by visual assessment blinded to echocardiographic and clinical data as 0 (none), 1 (nontransmural), or 2
(transmural) in each of the 17 myocardial segments. The LGE score
was computed for each patient as the 17-segment sum of these
ratings. Regional LGE scores (anterior, septal, and inferior) were
calculated similarly to the above described regional WMSI scores.
Echocardiography Acquisition and Analysis
Standard echocardiographic and Doppler recordings were performed
by experienced sonographers. Echo images were stored in digital
format for subsequent off-line analysis by experienced investigators
unaware of CMR results. The Vivid-7 System (Vingmed-General
Electric, Milwaukee, Wis), Sonos 5500 (Philips Medical Systems,
Andover, Mass), and ie33 (Philips Medical Systems) with a 3.5-MHz
probe were used for echocardiography. Mitral diastolic inflow was
interrogated using pulsed-wave Doppler from the apical 4-chamber
view with the sample volume placed at the level of the mitral leaflet
tips. Mitral early diastolic peak (E-wave) and late peak (A-wave)
velocities, E/A ratio, and deceleration time (DT) of mitral early
velocity were measured.5,28,29 Tissue Doppler was obtained at the
apical 4-chamber view with the sample volume placed at the lateral
mitral annulus. Early diastolic mitral annulus peak velocity was
measured, and ratio of transmitral diastolic peak velocity to the
mitral annular diastolic peak velocity (E/E⬘) was calculated.24,30 Data
were averaged over 3 cardiac cycles. Classification of diastolic
function as normal, mild dysfunction (impaired relaxation), moderate dysfunction (pseudonormal), and severe dysfunction (restrictive
filling pattern) was performed according to standard criteria.5,28,29
The E/E⬘ ratio was used to estimate LV filling pressures. Based on
the E/E⬘ cutoff value of 10, patients were categorized as having
normal or elevated filling pressure.30
Statistical Analysis
Continuous variables are expressed as median and interquartile
ranges (IQRs) or mean ⫾95% confidence intervals. Differences
between groups were compared using Student t test and Mann–
Whitney U test when the distribution of the variable was asymmetrical; the Fisher exact test was used for categorical variables.
Spearman correlation was used to test the correlation between
continuous variables; differences between groups were tested by
ANOVA with Bonferroni post hoc test. Association between
E/E⬘or E⬘ and LGE was first evaluated by quadratic model
(LGE⫽⫺␤0⫹␤1E/E⬘⫺␤2E/E⬘2; LGE⫽␤0⫺␤1E⬘⫹␤2E⬘2). Then, associations between E/E⬘ and age, echocardiographic, and CMR data
were evaluated by linear regression analysis. Only variables significant at univariate analysis were entered into a multiple linear
regression analysis. Statistical significance was set at a probability
value ⬍0.05. Statistical analyses were carried out with the Statistical
Package for the Social Sciences (SPSS Inc, Chicago, Ill) release 13.0
for Windows.
Results
Patient Characteristics
From January to August 2007, 204 suitable subjects were
identified. Of these, 42 (20%) had no evidence of structural heart
disease; these patients were typically referred for CMR because
of a questionable abnormality seen on echocardiography or to
rule out arrhythmogenic right ventricular cardiomyopathy in the
setting of isolated ventricular premature beats. The remaining
patients had various cardiac diagnoses; their clinical and demographic characteristics are summarized in Table 1.
CMR Findings
In the overall population, CMR-derived median LVEF was 50%
(IQR, 27% to 58%), end-diastolic and end-systolic volumes
indexed to body surface area were 72 (59 to 97) mL/m2 and 36
(26 to 63) mL/m2, respectively, and LV mass index was 65 (50
to 89) g/m2.
All cardiac segments were adequately visualized by CMR
in every patient. One hundred four (51%) patients demonstrated LGE positivity in 1 or more segments; of the 515
LGE-positive segments, distribution pattern of LGE was
transmural in 216 segments (42%), and nontransmural in 299
(58%). Importantly, no LGE-positive segments were detected
in subjects without structural heart disease. In contrast, LGE
positivity was common in patients with cardiomyopathy,
being present in 89% of patients with ischemic cardiomyopathy, in 59% of those with dilated cardiomyopathy, and in
67% of those with hypertrophic cardiomyopathy. The median
LGE score was 0 (IQR, 0.00 to 0.00) in subjects without
structural heart disease compared with 3 (IQR, 0 to 6.25) in
patients with cardiomyopathy (P⬍0.0001). Severity of LGE
score showed a significant inverse correlation with LV EF
(r⫽⫺0.51; P⬍0.0001).
Echocardiographic Findings
A pattern of abnormal diastolic filling based on mitral inflow
velocities was seen in 113 patients (51%); furthermore, 26
Moreo et al
Table 1. Baseline Demographic, Clinical, and Imaging
Characteristics (nⴝ204 Patients)
Variable
n (%)
Male
Median (IQR)
121 (59)
Age, y
53 (40–66)
Diabetes
53 (26)
Hypertension
107 (52)
Heart disease
None
42 (20)
Ischemic cardiomyopathy
71 (35)
Idiopathic dilated cardiomyopathy
22 (11)
Hypertrophic cardiomyopathy
Other cardiomyopathy
Simple congenital heart disease*
Other
6 (3)
28 (14)
9 (4)
26 (13)
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CMR
End-diastolic volume indexed, mL/m2
72 (59–97)
End-systolic volume indexed, mL/m2
36 (26–63)
Ejection fraction, %
50 (27–58)
LV mass index, g/m
2
65 (50–89)
Echocardiography
E wave, cm/s
0.89 (0.7–1.040)
A wave, cm/s
0.66 (0.49–0.87)
Mitral E/A ratio
1.34 (0.91–1.87)
Mitral deceleration time, ms
206 (165–240)
Mitral annular E⬘, cm/s
E/E⬘
0.1 (0.07–0.12)
8.65 (6.37–12.20)
*Simple congenital heart disease included bicuspid aortic valve, repaired
tetralogy of Fallot without residual shunt, congenital pulmonic stenosis, and
atrial septal defect without associated anomalies.
(16%) had severely impaired diastolic filling, as indicated by
a DT ⬍150 ms.5,28,29
Assessment of LV diastolic function was completed by
measuring E/E⬘ by tissue Doppler, as this parameter provides
an accurate, relatively load-independent estimate of LV
Myocardial Fibrosis and LV Diastolic Function
439
filling pressure31,32; diastolic impairment with increased LV
filling pressure (E/E⬘⬎10)30 was present in 80 patients (39%).
Diastolic Function and LGE
Overall, 63 (31%) subjects had normal diastolic function by
concomitant presence of all 3 criteria, that is, normal mitral
inflow pattern, DTⱖ150 ms, and E/E⬘ⱕ10. Importantly, no
LGE was detected in the majority (87%) of these subjects
with entirely normal diastolic function; overall, median LGE
score in these patients was 0 (IQR, 0.00 to 0.01). Across the
entire study population, LGE positivity was significantly associated with all parameters of diastolic dysfunction. Median LGE
score in subjects who showed normal filling was 0 (IQR, 0.00 to
0.01), but it significantly and progressively increased with
increasing severity of filling impairment, reaching 4 (IQR, 2 to
10) in patients with restrictive filling pattern (Figure 1;
P⬍0.0001). Similarly, mean⫾SD LGE scores progressively
increased from normal (0.3⫾0.1) to impaired relaxation
(2.8⫾0.6), pseudonormal (6.2⫾0.8) and restrictive filling
(7.2⫾1.3). Similarly, LGE was significantly higher in patients in
whom deceleration time was ⬍150 ms, compared with patients
with normal deceleration time (Figure 2; P⫽0.012). Finally,
degree of fibrosis as assessed by LGE score also significantly
increased with increasing severity of LV filling pressure estimated by E/E⬘ (ⱕ10 versus ⬎10) (Figure 3; P⬍0.0001).
Conversely, of the 100 LGE-negative patients, 86 had normal
diastolic function by E/E⬘ⱕ10.
At the individual level, fibrosis by LGE was directly and
significantly correlated with E/E⬘ (LGE⫽⫺1.477⫹0.538
E/E⬘⫺0.003 E/E⬘; SE of ␤0⫽1.325, ␤1⫽0.203, ␤2⫽0.006;
r⫽0.444; P⬍0.001); similarly, LGE was also significantly
related to the E⬘ component (LGE⫽11.006 to 102.935
E⬘⫹257.109 E⬘2; SE of ␤0⫽1.989, ␤1⫽35.625, ␤2⫽143,547;
r⫽0.356; P⬍0.001). Analysis of patients divided into those with
EFⱖ50% and those with EF⬍50% showed that the relationship
between LGE and diastolic function remained statistically significant in both groups (P⬍0.001; r⫽0.28 and 0.44, respectively). Additional plots of the individual LGE scores and
diastolic function parameters are shown in Figure 4.
Figure 1. LGE score as a function of LV
diastolic function indicated progressive
significant increase in fibrosis with each
successive grade of diastolic dysfunction.
Box-and-whisker plot indicates medians
and IQRs along with outliers that fall
above the confidence interval.
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Circ Cardiovasc Imaging
November 2009
Figure 2. LGE score was significantly higher, indicating greater fibrosis in patients with short DTs
(⬍150 ms). Box-and-whisker plot indicates medians and IQRs along with outliers that fall above
the confidence interval.
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␹2 analysis showed a significant association between LGE
positivity and presence or absence of any diastolic dysfunction (␹2⫽53, P⬍0.0001). Univariate analysis showed significant correlations between diastolic dysfunction assessed by
E/E⬘ and age, diabetes, hypertension, type of heart disease,
EF, WMSI, and LGE score (P⬍0.05 for all). After multivariate analysis, only age, diabetes, and LGE score remained
significantly and independently correlated with the degree of
diastolic dysfunction (Table 2). We checked collinearity for
variables, and the tolerance was near 0.9 for all variables.
Discussion
In a large cross-sectional study that included a broad range of
cardiac conditions as well as patients without structural heart
disease, we found that the presence and severity of LV
Figure 3. LGE score as a function of estimated LV end-diastolic
pressure showed significant differences between patients with
E/E⬘ⱕ10 versus E/E⬘⬎10. Box-and-whisker plot indicates medians and IQRs along with outliers that fall above the confidence
interval.
diastolic dysfunction was consistently associated with myocardial enhancement on LGE-CMR. Intact cardiomyocytes
do not show LGE positivity, underscoring the ability of LGE
to demonstrate altered myocardial composition that contributes to impaired diastolic function. Previous reports had
shown a relationship between degree of cardiac fibrosis and
diastolic dysfunction10 –13,33; however, those studies relied on
evaluation of collagen deposition as assessed by histological
examination of tissue specimens. Although accurate, those
investigations were obviously limited with respect to number
of patients studied and because of relative exclusion of
subjects with no structural heart disease. To our knowledge,
ours is the first study to investigate the relationship between
LV diastolic dysfunction and severity and location of myocardial fibrosis in a large cohort of patients with cardiac
impairment.
LV filling and myocyte relaxation show a complex interplay during diastole, which is influenced by many factors
including loading conditions, systolic emptying, myocardial
ischemia, heart rate, and intracellular calcium cycling.34
Physical properties of the myocardium also play a very
relevant role in dictating LV behavior during diastole.9 In this
respect, collagen is an important constituent of the myocardial extracellular matrix, and changes in its structure can
affect diastolic function. Increased tissue collagen deposition
alters the viscoelasticity of the myocardium impairing relaxation, diastolic recoil (ie, “suction”), and passive stiffness.
The collagen network of the heart consists of epimysial,
perimysial, and endomysial components, around which muscle
fibers are oriented.9 The LV develops a negative diastolic
pressure (suction) when coiled perimysial fibers release the
energy stored during systolic compression; this contributes to
diastolic filling that is not entirely passive. Microdisarray and
macrodisarray of these components, especially of perimysial
fibers, have been implicated in the pathogenesis of diastolic
dysfunction.33 Although undoubtedly relevant to understanding
Moreo et al
Myocardial Fibrosis and LV Diastolic Function
441
Figure 4. Individual values for DT versus LGE score (left) and E/E⬘ versus LGE score (right) are shown.
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the pathophysiology of diastole, systematic investigation of
cardiac fibrosis and of its relationship with diastolic function has
long been hampered by lack of suitable methodology.
LGE-CMR is a well-established technique to noninvasively detect foci of collagen deposition in vivo. Importantly,
it has been documented that LGE results show a good
correlation with direct histological findings.35,36 Although
originally associated with infarct scar visualization in ischemic
heart disease, distinct patterns of hyperenhancement have subsequently been described in dilated cardiomyopathy, hypertrophic cardiomyopathy, and other myocardial diseases.18 –20,22,37,38
Our population included subjects without structural heart
disease as well as patients with a wide spectrum of heart
diseases of different etiology; the percentages of LGE positivity that we found in those various conditions compares
well with what has been previously reported.21,22
By using a noninvasive approach, we were able to explore
subjects spanning across a wide range of cardiac fibrosis and,
at the same time, a wide range of degrees of diastolic
function. This is important because impaired diastolic function can be found in many subjects with no overt cardiac
disease or even as the initial cardiac manifestation of aging.
We confirmed in our study the well-known correlation
between aging and myocardial relaxation impairment, demonstrating that age was correlated with diastolic function in
multivariate analysis.
Table 2. Multivariate Analysis of Variables Associated With
Increased LV Filling Pressure
␤
SE
P Value
0.046
0.02
0.021*
Diabetes
2.788
0.80
0.001*
Hypertension
0.204
0.71
0.776
Etiology of heart disease
0.76
0.41
0.067
⫺0.026
0.03
0.428
Age
Ejection fraction
WMSI
0.657
1.18
0.57
LGE
0.271
0.07
0.0001*
r2 model⫽0.35.
␤ indicates linear regression coefficient; SE, standard errors of the
regression coefficient.
*P⬍0.05 considered significant.
Because the degree of diastolic impairment may vary with
the severity of disease, it is crucial to be able to detect and
differentiate severity of diastolic dysfunction. We investigated diastolic function by a multipronged approach based on
well-established echocardiographic techniques. One is
pulsed-wave Doppler evaluation of transmitral inflow velocities; by this approach, distinct filling patterns have been
described representing various degrees of diastolic impairment, from normal LV filling to restrictive physiology.5,8 The
most benign alteration, termed impaired relaxation (grade I)
and characterized by prolonged deceleration time of early
diastolic filling and decreased E/A, is associated with delayed
relaxation in the presence of normal LV filling pressures. At
the other end of the spectrum, a restrictive filling pattern
(grade III) is characterized by shortened deceleration time,
increased E/A, and shortened relaxation time and reflects
high LV filling pressures. The pseudonormal filling pattern
(grade II) is considered a condition of intermediate severity.
Our data are consistent with this concept of a gradient of
severity in diastolic dysfunction, paralleled by a relationship
between degree of diastolic impairment and extent of myocardial fibrosis by LGE-CMR (Figure 1). This finding was
confirmed when impairment of diastolic filling dynamics was
established with respect to deceleration time of early atrial
empting. It is well established that DT⬍150 ms denotes a
condition of severe impairment of diastolic emptying associated with increased atrial pressures and poor systolic function.5,28,29 Our data indicated that patients with DT⬍150 ms
have significantly greater myocardial fibrosis (Figure 2).
Doppler evaluation of LV filling may be influenced by
both preload and afterload. To overcome this limitation, we
simultaneously assessed diastolic function using mitral annular velocity by tissue Doppler imaging (TDI)—a sensitive,
reliable, and relatively load-independent index of diastolic
function.24 Again, we demonstrated progressive increase in
extent of fibrosis with progressive increase in LV filling
pressure as estimated by TDI (Figure 3). Indeed, there was a
significant correlation between either E⬘ or E/E⬘ and the
degree of LGE enhancement.
We did not find any significant correlation between E/E⬘
and etiology of heart disease; in addition to the severity of
fibrosis, only its location in the septum was significantly and
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Circ Cardiovasc Imaging
November 2009
independently associated with E/E⬘, and this regardless of
etiology. We have no immediate explanation for the observed
correlation between E/E⬘ and septal fibrosis, although it may
underscore the role of the septum in LV filling, either directly
or as a consequence of altered interventricular dependence,
which in turn may affect diastolic function.39
Limitations
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In the present study, we did not attempt to dissect out the
various components of diastole, as analysis of how fibrosis
affects precise mechanisms of diastolic function was beyond
the scope of this study. Absence of invasive measurement of
atrial and ventricular pressures is another limitation because
LV diastolic filling is sensitive to loading conditions. However, among noninvasive surrogates, TDI-derived E⬘ and
E/E⬘ have been shown to correlate well with direct pressurevolume measurements obtained through conductance catheters.24 Furthermore, we examined subjects in stable hemodynamic and clinical conditions. This, along with the fact that
the relationship between LGE and diastolic function was
consistently reproduced when using either LV filling patterns
by pulsed-wave Doppler or TDI parameters, indicates that our
findings were unlikely to be an effect of different loading
conditions. Distinction among specific cardiac conditions was
not done; rather, the goals of this work were to (1) consider
diastolic function as a common end point in patients with a
broad spectrum of disorders and those with normal cardiac
structure and (2) demonstrate altered myocardial tissue characterization as potential substrate for diastolic dysfunction.
We did not use techniques such as myocardial tagging to
assess diastolic function by CMR40; these could be used in
future studies.
Whereas we used a semiquantitative LGE score for practical implementation, direct signal intensity– based measurements would represent true quantification of LGE data. Age
probably affects fibrosis even in the absence of cardiac
disease; however, our patients without cardiac disease were
relatively young, precluding further analysis of this relationship. Although accumulating histopathologic studies indicate
that LGE probably represents fibrosis in patients with stable
cardiac disease,36 –38,41 accruing microscopy correlates may
expand our understanding of the precise histopathologic
signature responsible for LGE positivity. Finally, the current
resolution of CMR can detect only areas of fibrosis that are
macroscopically visible; thus, collagen infiltration at the
microscopic level goes undetected, though it also probably
contributes to diastolic dysfunction. Diffuse interstitial fibrosis, not readily appreciated by visual inspection of LGE
images, may have been present in those patients deemed LGE
negative but found to have some degree of diastolic dysfunction. Future studies using CMR-based T1 mapping, a quantitative approach to measuring collagen volume fraction
noninvasively, may overcome this limitation.42
Implications
There is increasing recognition of the importance in assessing
diastolic function for both diagnosis and prognosis across a
broad spectrum of cardiac conditions. Common to these
conditions is reactive or replacement fibrosis that alters
myocardial architecture and mechanical properties, and, as
indicated in our work, produces measurable changes in
diastolic function. Noninvasive evaluation of myocardial
fibrosis allows analysis of a much larger number of patients
than is feasible with direct tissue examination. In addition,
this approach lends itself well to serial measurements in
investigating disease progression as well as treatment effects.
Another implication of our findings is the observation that
etiology, in and of itself, appears to be less relevant than the
presence and distribution of myocardial fibrosis in the pathophysiology of fibrosis-mediated diastolic impairment, because presence and severity of diastolic dysfunction were
associated with presence and extent of fibrosis in various
forms of underlying cardiac disease.
Conclusions
In patients with various degrees of cardiac impairment, the
extent of cardiac fibrosis reliably predicts the degree of diastolic
dysfunction. LGE-CMR provides a powerful means to noninvasively assess extent and location of myocardial fibrosis caused
by a variety of cardiac diseases. This, coupled with classification
of diastolic function by echocardiography, provides insights into
the mechanism of LV diastolic dysfunction.
Sources of Funding
This study was supported by National Heart, Lung, and Blood
Institute grant R01 HL095563 (to S.V.R.).
Disclosures
Dr Raman receives research support from Siemens.
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CLINICAL PERSPECTIVE
Myocardial fibrosis develops as a final common end point in response to a broad range of cardiac pathologies such as
ischemia, inflammation, hypertension, and valvular heart disease. Clinically, these conditions may produce signs and
symptoms related to increased myocardial stiffness that may result from replacement or reactive fibrosis. This study used
late gadolinium enhancement cardiac magnetic resonance to noninvasively quantify myocardial fibrosis and Doppler
echocardiography to detect and classify severity of left ventricular diastolic dysfunction. Regardless of etiology, the
presence and severity of diastolic dysfunction increased with the greater extent of myocardial fibrosis. This work suggests that
late gadolinium enhancement cardiac magnetic resonance may be useful to identify the myocardial substrate for impaired
relaxation and provides a rationale for its use as an end point in developing novel therapeutics for diastolic dysfunction.
Influence of Myocardial Fibrosis on Left Ventricular Diastolic Function: Noninvasive
Assessment by Cardiac Magnetic Resonance and Echo
Antonella Moreo, Giuseppe Ambrosio, Benedetta De Chiara, Min Pu, Tam Tran, Francesco
Mauri and Subha V. Raman
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Circ Cardiovasc Imaging. 2009;2:437-443; originally published online September 3, 2009;
doi: 10.1161/CIRCIMAGING.108.838367
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