Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis
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JACC: CARDIOVASCULAR IMAGING VOL. 12, NO. 2, 2019
ª 2019 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY LICENSE (http://creativecommons.org/licenses/by/4.0/).
FOCUS ISSUE: IMAGING IN AORTIC STENOSIS: PART II
STATE-OF-THE-ART PAPER
Imaging and Impact of
Myocardial Fibrosis in Aortic Stenosis
Rong Bing, MBBS, BMEDSCI,a João L. Cavalcante, MD,b Russell J. Everett, MD, BSC,a Marie-Annick Clavel, DVM, PHD,c
David E. Newby, DM, PHD, DSC,a Marc R. Dweck, MD, PHDa
ABSTRACT
Aortic stenosis is characterized both by progressive valve narrowing and the left ventricular remodeling response that
ensues. The only effective treatment is aortic valve replacement, which is usually recommended in patients with severe
stenosis and evidence of left ventricular decompensation. At present, left ventricular decompensation is most frequently
identified by the development of typical symptoms or a marked reduction in left ventricular ejection fraction
284 Bing et al. JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019
Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis FEBRUARY 2019:283–96
ABBREVIATIONS remains AVR, either by surgical aortic valve fibrosis and left ventricular decompensation in aortic
AND ACRONYMS replacement (SAVR) or transcatheter aortic stenosis, the imaging techniques that can be used to
valve replacement (TAVR) approaches. The detect it, and how these might be employed to track
AVR = aortic valve
replacement
uptake of TAVR has grown exponentially myocardial health and optimize the timing of AVR.
CI = confidence interval
(3,8), as interventions that were initially
offered only to elderly, inoperable patients PATHOLOGY
CMR = cardiac magnetic
resonance are now being performed in younger, lower-
CT = computed tomography
risk patients with excellent results (9–13). It is useful to consider aortic stenosis as a disease of
Decisions about if, when, and how to inter- both the valve and the myocardium (4). In addition,
ECV% = extracellular volume
fraction vene have therefore become increasingly the importance of arterial stiffness and systemic
HR = hazard ratio complex, requiring careful assessment of in- pulsatile arterial load cannot be underestimated in
iECV = indexed extracellular dividual patients within a multidisciplinary this elderly population (18,19). A detailed discussion
volume heart team. of events within the valve is beyond the scope of this
LGE = late gadolinium Current guidelines recommend interven- review (20); however, an understanding of the path-
enhancement tion in patients with severe aortic stenosis ological factors driving the hypertrophic remodeling
SAVR = surgical aortic valve and evidence of left ventricular decompen- response and its subsequent decompensation are
replacement
sation. Most commonly this is in the form of critical to understanding the rationale for myocardial
TAVR = transcatheter aortic
development of typical symptoms, but other fibrosis imaging (Central Illustration).
valve replacement
markers include a reduction in ejection Progressive valve narrowing causes pressure
fraction
JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019 Bing et al. 285
FEBRUARY 2019:283–96 Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis
C ENTR AL I LL U STRA T I O N Summary of Left Ventricular Remodeling and Decompensation in Patients With
Aortic Stenosis
Increased afterload Cellular hypertrophy
Supply-demand ischemia
Mechanical stress Diffuse fibrosis
Myofibroblast infiltration
Extracellular matrix expansion
Replacement fibrosis
Myocyte cell death
Heart failure
Cardiac death
Bing, R. et al. J Am Coll Cardiol Img. 2019;12(2):283–96.
Schematic of the left ventricular remodeling response in aortic stenosis, describing the transition from hypertrophy to fibrosis, heart failure, and cardiac death.
histological studies have now demonstrated an asso- (Table 1). These approaches have been used to assess
ciation between myocardial fibrosis at the time of myocardial fibrosis in a range of cardiovascular
AVR and both impaired recovery of left ventricular conditions including aortic stenosis and are described
systolic function and poor long-term outcomes in the following text.
following valve replacement (17,27–29). Although it is
CARDIAC MAGNETIC RESONANCE. CMR provides
certainly plausible that myocardial fibrosis might
unparalleled soft tissue characterization and can be
directly contribute to such outcomes, a causal
used to identify and measure both diffuse and
relationship is yet to be demonstrated.
replacement forms of fibrosis in a single scan without
IMAGING MODALITIES FOR THE ASSESSMENT the use of ionizing radiation. When utilized together,
OF MYOCARDIAL FIBROSIS the CMR techniques described in the following
text offer the best available method of capturing
Although myocardial biopsy and histological analysis the full spectrum of fibrotic changes within the left
are still considered the gold standard assessments of ventricular myocardium (26).
myocardial fibrosis, they have several important Late gadolinium enhancement. Gadolinium-based
limitations precluding their routine clinical applica- contrast agents (GBCAs) partition into areas of
tion. Myocardial biopsy is an invasive procedure extracellular expansion (myocardial edema, necrosis,
that carries an attendant risk of complications (30). infiltration, or fibrosis). Interpretation of delayed
Additionally, as only small areas of the myocardium imaging using GBCAs requires clear differences in
can be sampled, biopsy is prone to sampling error. By signal intensity between healthy and diseased
contrast, modern imaging techniques, in particular myocardium in a relatively discrete distribution.
those provided by cardiovascular magnetic resonance Consequently, late gadolinium enhancement (LGE) is
(CMR), allow comprehensive, noninvasive assess- an excellent marker of focal replacement fibrosis,
ments of fibrosis across the entire myocardium as but is insensitive for the detection of more diffuse
well as quantification of its functional consequences interstitial fibrosis.
286 Bing et al. JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019
Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis FEBRUARY 2019:283–96
validated imaging method for detecting myocardial
T A B L E 1 Performance of Different Imaging Modalities in Aortic Stenosis
fibrosis in aortic stenosis. Multiple independent
Ventricular Diffuse Replacement Long-Term studies have described a noninfarct (or mid-wall)
Severity Performance Fibrosis Fibrosis Prognosis
pattern of LGE in patients with aortic stenosis that
TTE þþþ þþþ - - þþþ
is distinct from the pattern of scarring seen in other
CT þþ þþ þ þ þ
CMR þ þþþ
pathologies such as myocardial infarction (Figure 1).
Native T1 þþ þ þ On histology, noninfarct LGE co-localizes with
ECV%/iECV þþ þ þ microscars and replacement fibrosis, whereas clinical
LGE - þþþ þþþ studies have validated it against other markers of left
FT - þþþ - - þ ventricular decompensation and demonstrated a
close association with advanced left ventricular hy-
CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; ECV% ¼ extracellular volume fraction;
FT ¼ feature tracking; iECV ¼ indexed extracellular volume; LGE ¼ late gadolinium enhancement; pertrophy, increased myocardial injury, electrocar-
TTE ¼ transthoracic echocardiogram.
diographic changes, impaired diastolic and systolic
function, and reduced exercise capacity (25,39–41).
Once noninfarct LGE becomes established, it pro-
LGE is now well established and widely used as a gresses rapidly. Although the process is arrested
method for detecting replacement myocardial fibrosis by aortic valve intervention, replacement fibrosis
in a broad range of cardiovascular conditions such as appears irreversible once established. Thus, the
ischemic cardiomyopathy, nonischemic dilated car- burden of replacement fibrosis a patient accumulates
diomyopathy, cardiac sarcoidosis, cardiac amyloid- while waiting for valve intervention persists with
osis, myocarditis, and hypertrophic cardiomyopathy them until death (42). The clinical implications are
(31–38). In each condition, replacement fibrosis important, as noninfarct LGE is associated with a poor
detected by LGE serves as an independent and long-term prognosis. Indeed, 5 studies and a recent
powerful predictor of mortality and adverse cardio- meta-analysis (43) have confirmed noninfarct LGE
vascular events. LGE is also the most studied and best to be an independent predictor of mortality, of
F I G U R E 1 Late Gadolinium Enhancement Patterns in Aortic Stenosis
A B C D
Each panel shows short-axis (top) and corresponding long-axis (bottom) late gadolinium images from cardiac magnetic resonance scans. (A to C) Focal noninfarct late
gadolinium enhancement typical of the replacement fibrosis seen in aortic stenosis. (D) Subendocardial late gadolinium enhancement in coronary artery territories,
consistent with scar due to infarction rather than focal noninfarct fibrosis. Areas of infarction such as these should be excluded when calculating extracellular volume
fraction. Red arrows indicate areas of late gadolinium enhancement.
JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019 Bing et al. 287 FEBRUARY 2019:283–96 Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis incremental value to valve assessments, comorbidity, extracellular environments, while the addition of a and left ventricular ejection fraction (28,41,44–46) GBCA facilitates targeted interrogation of the extra- (Table 2). cellular space. The poor prognosis associated with non-infarct Various protocols for T 1 mapping have been stud- LGE appears to persist long after AVR is performed, ied (49). The original Look-Locker technique (50) has in keeping with the irreversible nature of replacement been largely superseded by modern variations. The fibrosis. In the largest study to date, the British modified Look-Locker imaging sequence (51) is the Society for Cardiovascular Magnetic Resonance Valve most studied inversion-recovery technique, whereas Consortium performed comprehensive CMR assess- variants such as the shortened modified Look-Locker ments in over 650 patients with severe aortic stenosis imaging sequence require a shorter breath hold (52). just prior to SAVR or TAVR (46). At a median follow- Optimization of protocols has improved accuracy, up of 3.6 years, LGE (present in 50% of patients) acquisition time, and ease of use via reduction in was a powerful independent predictor of all-cause heart rate dependence and breath holds. Moreover, (26.4% vs. 12.9%; p < 0.001) and cardiovascular post-processing and analysis of T1 mapping data can mortality (15.0% vs. 4.8%; p < 0.001) following now be performed with fast and reproducible tech- AVR. Furthermore, this association appeared niques utilizing standardized protocols. T 1 mapping dose-dependent: with every 1% increase in left techniques are now readily accessible in many CMR ventricular myocardial scar burden, all-cause and units and will be discussed below. cardiovascular mortality increased by 11% and 8%, Native T1. As fibrosis increases, native T 1 values respectively (hazard ratio [HR]: 1.11; 95% confidence increase. Quantitative T1 measurements therefore interval [CI]: 1.05 to 1.17; p < 0.001; and HR: 1.08; allow detection of focal or diffuse fibrosis without the 95% CI: 1.01 to 1.17; p < 0.001). Similar effects use of GBCAs, although the T 1 signal also changes were observed for both infarct and noninfarct LGE. with other pathological processes such as edema or Noninfarct LGE was also demonstrated to be an myocardial infiltration. Native T 1 has been utilized independent predictor of both all-cause and cardio- in conditions such as myocardial infarction, myocar- vascular mortality. ditis, dilated cardiomyopathy, cardiac amyloid, and LGE is reliable, well-validated, and easily inte- Fabry disease (48), and has demonstrated significant grated into the standard workflow, with post- prognostic power beyond that of LGE alone (53,54). processing and qualitative analysis Although less robust, data is also emerging for native readily performed in
288 Bing et al. JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019
Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis FEBRUARY 2019:283–96
T A B L E 2 CMR Studies Investigating Myocardial Fibrosis in Aortic Stenosis
Study (Ref. #) Year n Population CMR Biopsy Findings
Native T1 Studies
Bull et al. (55) 2013 109 Severe AS undergoing SAVR 1.5-T 19 Native T1 correlated with CVF (r ¼ 0.65; p ¼ 0.002) and
Asymptomatic moderate or severe AS Native T1 increased with disease severity.
shMOLLI
Lee et al. (56) 2015 80 Asymptomatic moderate 3-T 20 Native T1 correlated with histology (r ¼ 0.777; p < 0.001)
or severe AS Native T1 and TTE measures of diastolic dysfunction, and was
MOLLI increased compared with control patients, with overlap.
ECV Studies
Flett et al. (62) 2010 18 Severe AS undergoing SAVR 1.5-T 18 ECV% correlated with CVF (r2 ¼ 0.86; p < 0.001).
ECV%
EQ-CMR
FLASH-IR
Fontana et al. (77) 2012 18 Severe AS undergoing SAVR 1.5-T 18 ECV% correlated with CVF (r2 ¼ 0.685). ShMOLLI was superior
ECV% to FLASH-IR.
EQ-CMR shMOLLI
FLASH-IR
White et al. (66) 2013 18 Severe AS undergoing SAVR 1.5-T 18 ECV% by both methods correlated with CVF
ECV% (r2 ¼ 0.69; p < 0.01 and r2 ¼ 0.71; p < 0.01).
EQ-CMR DynEQ-CMR
shMOLLI
Flett et al. (78) 2012 63 Severe AS undergoing SAVR 1.5-T — ECV% was increased compared with control subjects, with
ECV% overlap. At 6 months, LVH had regressed but diffuse
EQ-CMR fibrosis was unchanged.
FLASH-IR
LGE Studies
Weidemann et al. (27) 2009 46 Severe AS undergoing AVR LGE 46 LGE appeared to be concordant with histology (88% with
severe fibrosis had $2 positive segments; 89% with no
fibrosis had no positive segments) and did not regress at
9 months post-AVR.
Azevedo et al. (28) 2010 28 Severe AS undergoing AVR 1.5-T 28 LGE was present in 61%.
LGE LGE correlated with histology (r ¼ 0.67; p < 0.001).
LGE was an independent predictor of all-cause mortality
(HR: 1.26; 95% CI: 1.03–1.54; p ¼ 0.02).
Debl et al. (79) 2006 22 Symptomatic AS 1.5-T — LGE was present in 27%.
LGE LGE correlated with more severe AS and LVH.
Rudolph et al. (80) 2009 21 Any AS 1.5-T — LGE was present in 62%.
LGE LGE correlated with increased LV mass and end-diastolic
volume index.
Dweck et al. (44) 2011 143 Moderate or severe AS 1.5-T — LGE present in 66%.
LGE Midwall LGE present in 38%.
Midwall LGE was an independent predictor of all-cause
mortality (HR: 5.35; 95% CI: 1.16–24.56; p ¼ 0.03).
Baron-Rochette et al. 2014 154 Severe AS undergoing AVR 1.5-T — LGE present in 29%.
(45) LGE LGE was an independent predictor of all-cause mortality
(HR: 2.8; 95% CI: 1.1 to 6.9; p ¼ 0.025).
Rajesh et al. (81) 2017 109 Severe AS 1.5-T — LGE present in 43%.
LGE Midwall LGE present in 31%.
LGE predicted heart failure/hospitalization and a fall in
LVEF but did not predict mortality.
Musa et al. (46) 2018 674 Severe AS undergoing AVR 1.5-T, 3-T — LGE present in 51%.
LGE Noninfarct LGE present in 33%.
Scar associated with all-cause (26.4% vs 12.9%; p < 0.001)
and cardiovascular (15.0% vs 4.8%; p < 0.001) mortality
in a dose-dependent fashion (for every 1% increase in scar,
HR: 1.11; 95% CI: 1.05–1.17; p < 0.001 for all-cause and HR:
1.08; 95% CI: 1.01–1.17; p < 0.001 for cardiovascular
mortality).
Infarct and noninfarct scar were both associated with adverse
outcomes.
de Meester et al. (82) 2015 12 Severe AS undergoing SAVR 3-T 12 LGE was present in 17 of 31 patients (from total cohort).
Native T1 Only ECV% correlated with histology (r ¼ 0.79; p ¼ 0.011).
ECV%
LGE
MOLLI
Kockova et al. (57) 2016 31 Severe AS undergoing SAVR 1.5-T 31 Patient with severe MF (>30%) on histology had higher native
Native T1 T1 times and ECV%. Native T1 $1,010 ms and ECV $0.32
ECV% had AUC of 0.82 and 0.85, respectively, for severe MF.
MOLLI
Continued on the next pageJACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019 Bing et al. 289
FEBRUARY 2019:283–96 Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis
T A B L E 2 Continued
Study (Ref. #) Year n Population CMR Biopsy Findings
Chin et al. (41) 2017 166 Any AS 3-T 11 Midwall LGE was present in 27%.
iECV iECV correlated with histology (r ¼ 0.87; p < 0.001) and was
LGE increased compared with control subjects.
MOLLI iECV þ LGE predicted unadjusted all-cause mortality (36 vs.
8 deaths/1,000; p ¼ 0.009).
Treibel et al. (26) 2018 133 Severe AS undergoing AVR 1.5-T 133 LGE was present in 60%; noninfarct pattern was more
ECV% common.
LGE Complex MF patterns. LGE, but not ECV%, correlated with CVF
MOLLI in all biopsies (r2 ¼ 0.28; p < 0.001) but more in biopsies
with endocardium (r2 ¼ 0.501; p < 0.001). Combined
LGE þ ECV% best predicted LV remodeling and functional
capacity.
Child et al. (83) 2018 25 Severe AS 3-T 12 Noninfarct LGE was present in 20%.
Native T1 Sequences differed in discrimination between health and
ECV% disease as well as association with CVF. Native T1 with
LGE MOLLI correlated best (r ¼ 0.582; p ¼ 0.027).
MOLLI, shMOLLI,
SASHA
Chin et al. (59) 2014 20 Any AS 3-T — ECV displayed excellent scan-rescan reproducibility and was
Native T1 higher in AS than control subjects. Native T1 was not as
ECV% reproducible and was not significantly higher in AS than
MOLLI control subjects.
Chin et al. (40), 2014 122 Any AS 3-T — Midwall LGE was present in 28%.
Shah et al. (39) ECV% ECV% and LGE were associated with elevated TnI and ECG
LGE evidence of strain.
MOLLI
Dusenberry et al. (84) 2014 35 Congenital AS 1.5-T — LGE was present in 24%.
ECV% ECV% was increased compared to control patients and
LGE correlated with TTE measures of diastolic dysfunction.
Look-Locker
Treibel et al. (25) 2018 116 Severe AS undergoing AVR 1.5-T — At 1 yr, cellular and matrix volume regressed. LGE was
iECV unchanged.
LGE
MOLLI
Everett et al. (42) 2018 99 61 asymptomatic AS 38 severe AS 1.5-T, 3-T — Midwall LGE was present in 26%.
undergoing AVR iECV LGE progressed from baseline and was most rapid in patients
LGE with more severe stenosis.
In patients undergoing AVR, iECV reduced by 11% (4%–16%)
but there was no change in LGE.
Lee et al. (58) 2018 127 Moderate or severe AS 3-T — LGE was present in 32.3%.
Native T1 Native T1 was increased compared with control patients,
LGE with overlap.
MOLLI Native T1 and LGE were independent predictors of poor
prognosis.
AS ¼ aortic stenosis; AUC ¼ area under the curve; CI ¼ confidence interval; CMR ¼ cardiac magnetic resonance; CVF ¼ collagen volume fraction; DynEQ-CMR ¼ dynamic equilibrium contract-cardiac magnetic
resonance; ECV% ¼ extra-cellular volume fraction; EQ-CMR ¼ equilibrium contrast cardiac magnetic resonance; FLASH-IR ¼ fast low angle single shot inversion recovery; HR ¼ hazard ratio; iECV ¼ indexed
extracellular volume; LGE ¼ late gadolinium enhancement; LVEF ¼ left ventricular ejection fraction; LVH ¼ left ventricular hypertrophy; MOLLI ¼ modified Look-Locker inversion recovery; SASHA ¼
saturation recovery single-shot acquisition; SAVR ¼ surgical aortic valve replacement; shMOLLI ¼ shortened modified Look-Locker inversion recovery; TnI ¼ troponin I; TTE ¼ transthoracic echocardiography.
holds major appeal as a marker of diffuse fibrosis that and even within the same individual on different
does not require contrast administration and is days. Standardized normal values are again lacking,
favored as a technique by various experts in the field, and consequently, post-contrast T 1 mapping is not
its specific role in aortic stenosis requires further in widespread use.
research. Extracellular volume fraction. The extracellular volume
Post-contrast T1 mapping. GBCAs do not cross cell fraction (ECV%) corrects post-contrast myocardial T 1
membranes and therefore distribute throughout mapping values for blood pool and pre-contrast
the extracellular space in the myocardium. Post- myocardial T 1 , thereby accounting for differences in
contrast T 1 mapping techniques therefore allow blood concentrations of GBCAs. By incorporating the
more specific interrogation of the extracellular hematocrit, ECV% calculates the fraction of the
space due to gadolinium’s shortening effects on T1 myocardium comprised by the extracellular space
relaxation times. Unfortunately, standardization according to the formula ECV% ¼ ( D [1/T1 myo]/D [1/
of post-contrast T1 mapping values is difficult due to T1blood ]) (1 hematocrit), where D (1/T1) is the
variation in gadolinium kinetics between patients difference in myocardial or blood T 1 pre- and290 Bing et al. JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019
Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis FEBRUARY 2019:283–96
F I G U R E 2 T 1 Mapping
1600 ms 1000 ms 60%
0 ms 0 ms 0%
Native T1 Map Post-Contrast T1 Map ECV% Map
1300 800 35
Extracellular Volume Fraction (%)
p = 0.29 p = 0.58 p < 0.001
750
1250
Myocardial T1 (ms)
Myocardial T1 (ms)
30
700
1200
650
25
1150
600
1100 550 20
Healthy Patients with Healthy Patients with Healthy Patients with
Volunteers Aortic Stenosis Volunteers Aortic Stenosis Volunteers Aortic Stenosis
Three different cardiac magnetic resonance T1 maps are demonstrated. Native T1 and post-contrast T1 maps are generated by the signal intensity encoded within each
voxel, depending on the T1 relaxation time; color coding according to T1 times is applied for visual reference. ECV% maps are generated using the formula ECV% ¼
(D[1/T1myo]/D[1/T1blood]) (1 hematocrit), where D(1/T1) is the difference in myocardial or blood T1 pre-contrast and post-contrast. ECV% can be used to assess the
proportion of the myocardium comprised by extracellular space. Note that there is significant overlap between health and disease with native and post-contrast T1, in
contrast to ECV%. Graphs adapted from Chin et al. (59) by permission of Oxford University Press. ECV% ¼ extracellular volume fraction; iECV ¼ indexed extracellular
volume.
post-contrast (62). A key feature of myocardial ECV% potentially corrects for differences in T1 values
fibrosis is the deposition of excess collagen in the on different scanners and sequences, making it
interstitial space and the subsequent expansion of the appealing as a technique for multicenter research.
extracellular space. ECV% has therefore been inves- A number of clinical studies have validated ECV%
tigated as a method for detecting diffuse myocardial against histology in aortic stenosis and have demon-
fibrosis in a range of cardiovascular conditions strated the association between ECV% and other
including myocardial infarction, nonischemic car- markers of LV decompensation, including ECG
diomyopathy, and aortic stenosis (63,64). changes of hypertrophy and strain and elevation
Current scanning techniques assume a dynamic in biomarkers such as troponin and N-terminal
equilibrium between blood and myocardium w10 to pro-brain natriuretic peptide (26,39–41) (Table 2).
15 mins after a bolus injection of contrast (65,66). A ECV% also demonstrates excellent scan-rescan
synthetic ECV% has also been described that derives reproducibility (59), while guidelines to standardize
hematocrit from the longitudinal relaxation rate of post-processing have been developed and recom-
blood, obviating the need for blood sampling (67), mend that areas of noninfarct LGE are included and
while a more recent noninvasive point-of-care probe areas of infarct LGE excluded from regions of interest
to derive hematocrit has demonstrated promising in ECV% calculation (69). However, data assessing the
results when compared with both standard and syn- prognostic value of ECV% in aortic stenosis are
thetic ECV% (68). ECV% has thus become easier to limited, and overlap between disease groups is again
measure and more clinically applicable. Moreover, observed. In addition, the effect of AVR on ECV%JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019 Bing et al. 291
FEBRUARY 2019:283–96 Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis
F I G U R E 3 iECV calculation
iECV: Biomarker of the Total Myocardial Fibrosis
Burden Indexed to Patient Size
ECV% = (Δ(1/T1myo) / Δ(1/
T1blood)) × (1 - hematocrit)
Indexed Extracellular Volume (mL/m2)
50
iECV = myocardial volume 40
indexed to BSA × ECV%
30
Myocardial volume
20
10
P < 0.0001
0
1 1 Controls Mild Moderate Severe
AS Severity
Cut off for extracellular expansion
Pre-contrast T1 Post-contrast T1
The cardiac magnetic resonance short-axis images provide examples of the pre-contrast and post-contrast contours required to calculate
iECV. Systolic and diastolic contours are drawn using the short-axis stack to calculate myocardial volume, which is necessary to derive iECV.
Color look-up tables have not been applied to the T1 images. iECV provides a surrogate of the total myocardial fibrosis burden according to the
formula demonstrated in the figure. iECV demonstrates good correlation with histological fibrosis burden and severity of aortic stenosis.
Graph adapted from Chin et al. (41), Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/. BSA ¼ body
surface area; other abbreviations as in Figure 2.
may be somewhat counterintuitive as values can in- Chin et al. (41) demonstrated that a threshold of
crease after surgery—a weakness of assessing the 22.5 ml/m 2 (derived from 37 age- and sex-matched
extracellular component of the myocardium as a healthy volunteers and defined as 2 SDs above the
fraction of the ventricular mass when both the mean) could be used to differentiate healthy
intracellular and extracellular compartments are un- myocardium from diseased myocardium infiltrated
dergoing reverse remodeling (25). by diffuse fibrosis, and in doing so, identify patients
Indexed extracellular volume. Whereas ECV% provides with early evidence of left ventricular decompensa-
a percentage estimate, the indexed extracellular tion and adverse long-term outcome (41).
volume (iECV) quantifies the total left ventricular iECV and ECV% have recently been used in
extracellular myocardial volume indexed to body combination to study changes in the composition of
surface area by multiplying ECV% by the indexed left the intracellular and extracellular compartments
ventricular myocardial volume: iECV ¼ ECV% before and after AVR. This has provided important
indexed left ventricular myocardial volume (Figure 3). insights into left ventricular remodeling and reverse
Furthermore, cellular volume can be calculated: remodeling after relief of loading conditions.
(1 ECV%) left ventricular volume). This can also Changes in iECV are not accounted for by changes in
be indexed to body surface area. In combination with total left ventricular mass alone. Prior to AVR, iECV
LV mass, ECV% and iECV can together provide an (representing total extracellular matrix, or fibrosis,
understanding of ventricular remodeling and reverse burden) and left ventricular mass appear to increase
remodeling with respect to both the cellular and in a broadly balanced manner so that ECV% remains
extracellular myocardial compartments. Two studies largely unchanged. Following AVR, left ventricular
have utilized iECV or matrix volume as a novel mass decreases. Cellular and extracellular mass
assessment of myocardial fibrosis burden (25,41), regress, but cellular mass regresses more rapidly,
with iECV demonstrating a close association with thereby resulting in an apparently paradoxical in-
histological fibrosis assessments. Importantly, iECV crease in ECV% as the ratio of matrix to total mass is
appears to provide greater discrimination between increased (25,42). iECV, however, decreases as it
disease states than other T1 mapping parameters. represents the extracellular matrix as a total volume,292 Bing et al. JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019
Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis FEBRUARY 2019:283–96
multicenter prognostic studies that are ultimately
F I G U R E 4 Schematic for the Development of Myocardial Fibrosis in Aortic Stenosis
and Response to AVR
required. Of the T1 mapping parameters currently in
use, we believe that ECV% and iECV currently pro-
AVR vide the most complete understanding of cellular and
extracellular remodeling in aortic stenosis, although
native T1 provides important advantages, particularly
with regard to ease of calculation and the avoidance
Severity
of contrast administration.
OTHER IMAGING MODALITIES. Alternative imaging
techniques to assess myocardial fibrosis in aortic
stenosis are limited. Research into computed tomog-
raphy (CT) assessments of myocardial fibrosis re-
Time
mains exploratory, with only limited data available
Baseline 1 year 2 year
that has largely focused on measuring ECV on CT
scans performed after the administration of iodinated
contrast agents (Table 3). These techniques are
worthy of further investigation given the widespread
LV Cellular Mass Diffuse Fibrosis Replacement Fibrosis use of CT imaging in patients being considered for
TAVR and the emerging utility of CT calcium scoring
As aortic stenosis progresses, left ventricular (LV) mass gradually increases, followed as a marker of stenosis severity. Strain imaging on
by the development of diffuse fibrosis. Replacement fibrosis occurs later but accelerates echocardiography or CMR can be a valuable nonin-
rapidly once established. Following relief of pressure-loading conditions after aortic valve vasive tool to evaluate and quantify myocardial
replacement (AVR), LV cellular mass and extracellular matrix both regress at different
deformation before any identifiable changes in ejec-
rates. The burden of replacement fibrosis, however, persists. The insets show short-
tion fraction; however, despite an association with
axis cardiac magnetic resonance late gadolinium enhancement imaging slices of a patient
with aortic stenosis. At baseline, there is focal late gadolinium enhancement representing imaging markers of myocardial fibrosis (27,29) and
discrete focal replacement fibrosis (white arrow). After 1 year, the burden of this potential prognostic utility (70,71), this approach is
replacement fibrosis has increased with the development of several new discrete unable to measure myocardial fibrosis directly.
deposits (red arrows). The patient subsequently underwent AVR. One year later,
despite regression of LV mass, there is no regression of replacement fibrosis FUTURE DIRECTIONS
(white arrows).
Myocardial fibrosis is well established as a hallmark
pathological feature of left ventricular decompensa-
rather than a percentage. The reduction in iECV is tion in patients with aortic stenosis; yet, it is
therefore in keeping with the potential for reversal not routinely assessed in clinical practice. In part, this
of diffuse fibrosis. This effect has been confirmed has reflected the limitations of myocardial biopsy,
independently by 2 different groups in separate co- many of which have now been overcome with
horts and stands in contrast to the irreversible na- advanced noninvasive imaging. The next step is to
ture of replacement fibrosis as assessed by LGE assess whether these imaging techniques will prove
(Figure 4). iECV requires further exploration and of clinical value in monitoring myocardial health,
validation but is a promising method to track identifying left ventricular decompensation, and
myocardial fibrosis. optimizing the timing of AVR.
In summary, T 1 mapping is an exciting and LGE is the best validated of these approaches, is
emerging research field in aortic stenosis research relatively simple to perform and analyze, and is
that provides the only method of identifying revers- supported by powerful prognostic data. Whether
ible diffuse myocardial fibrosis. It holds particular noninfarct LGE can be used to optimize the timing of
potential as a method to track myocardial health over valve intervention is currently being tested in
time, with important clinical implications. Standard- the EVOLVED (Early Valve Replacement Guided by
ization of sequences and protocols have resulted in Biomarkers of LV Decompensation in Asymptomatic
reproducible and powerful prognostic T 1 mapping Patients With Severe AS) trial (NCT03094143) (47)
data in a variety of myocardial disease states (Figure 5). This multicenter randomized controlled
(41,53,54,58). However, T 1 mapping in aortic stenosis trial will recruit asymptomatic patients with severe
is in a relatively early stage of development. Further aortic stenosis for CMR imaging. Those patients with
work is required to establish validated thresholds to noninfarct LGE will then be randomized 1:1 to early
aid decision making, paving the way for future valve intervention (SAVR or TAVR) versus theJACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019 Bing et al. 293
FEBRUARY 2019:283–96 Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis
T A B L E 3 CT to Detect Myocardial Fibrosis
Study (Ref. #) Year n Population CT Biopsy CMR Findings
Bandula et al. (85) 2013 23 Severe AS undergoing SAVR Iohexol equilibrium 23 shMOLLI ECVCT correlated with ECVCMR (r ¼ 0.73; p < 0.001)
bolus and and histological fibrosis (r ¼ 0.71; p < 0.001).
infusion protocol
Hong et al. (86) 2016 20 Rabbits Dual-energy CT 20 3-T ECVCT correlated with ECVCMR (r ¼ 0.89;
4 healthy Iopamidol bolus MOLLI p < 0.001) and histological fibrosis (r ¼ 0.925;
16 DCM p < 0.001).
Treibel et al. (87) 2017 73 Validation cohort: 64-detector 18 — Good correlation between synthetic and
28 severe AS 27 amyloid Iohexol bolus conventional ECVCT (r2 ¼ 0.96; p < 0.001).
18 severe AS underdoing SAVR Good correlation between synthetic and
conventional ECVCT and histology (both
r2 ¼ 0.50; p < 0.001).
ECVCT was higher in amyloidosis.
Nacif et al. (88) 2012 24 11 healthy 320-detector — 3-T Correlation between CMR and CT (r ¼ 0.82;
13 HF Iopamidol bolus 3(3)5 MOLLI p < 0.001).
ECV lower in healthy patients for both CMR and
CT (p ¼ 0.03).
Nacif et al. (89) 2013 24 9 healthy 320-detector — — Mean 3D ECV significantly higher in HFrEF than
10 HFrEF Iopamidol bolus other groups (p ¼ 0.02).
5 HFpEF
Treibel et al. (90) 2015 47 27 severe AS 26 amyloid 64-detector — 1.5-T shMOLLI ECVCT at 5 min and 15 min correlated with ECVCMR
Iodixanol dynamic (r2 ¼ 0.85; r2 ¼ 0.74; p < 0.001).
equilibrium bolus ECVCT was higher in amyloidosis and correlated
protocol with markers of severity.
Lee et al. (91) 2016 30 7 healthy Dual-energy CT — 3-T Good agreement between ECVCT and ECVCMR on
6 HCM Iopamidol bolus 3(3)5 MOLLI per-subject (Bland-Altman bias 0.06%; 95% CI:
9 DCM 1.19–1.79) and per-segment level.
4 amyloid
4 sarcoid
CT ¼ computed tomography; DCM ¼ dilated cardiomyopathy; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; other ab-
breviations as in Table 2.
conventional approach of watchful waiting until
F I G U R E 5 Proposed Integration of Myocardial Fibrosis Into the Classical Description
symptom development or clinical heart failure. To of the Natural History of Aortic Stenosis
mitigate the costs of CMR, patients will initially be
screened with high-sensitivity troponin and an elec-
trocardiogram, both of which are predictors of non-
infarct LGE (72); only those patients with an abnormal CMR EVOLVED - early AVR
• Native T1
electrocardiogram or a troponin $6 ng/l will proceed • ECV% CMR
Outcome
• iECV • LGE Routine AVR
to CMR. The primary endpoint is a composite of
• Strain
all-cause mortality and unplanned aortic stenosis–
related hospital admissions. This is the first random-
ized trial to offer targeted early intervention in
patients with myocardial fibrosis and left ventricular
decompensation, and the results will be of great in-
Time
terest. Similar randomized controlled trials will ulti-
Diffuse Fibrosis Replacement Fibrosis Symptoms
mately be required to establish the clinical utility of
other myocardial fibrosis assessments, given that
Adaption of the outcome curve originally proposed by Braunwald in 1968 (76). Prior to
aortic valve intervention is not without risk.
the onset of symptoms, there is a long latent period in aortic stenosis where subclinical
CMR assessments of diffuse fibrosis in aortic ste- myocardial changes take place, including the development of reversible diffuse fibrosis
nosis require further validation but offer the potential followed by irreversible replacement fibrosis. These changes may be assessed with the
to identify the earlier stages of myocardial disease imaging modalities denoted in the figure. Exploratory data suggest that diffuse fibrosis
is associated with an adverse long-term outcome in aortic stenosis. The prognostic data
and track myocardial health with time. T1 mapping is
related to the noninfarct pattern of late gadolinium enhancement (LGE) as a marker of
the only available imaging technique that is able to
replacement fibrosis is comparatively robust, establishing LGE as a powerful indepen-
offer an assessment of diffuse fibrosis, and as such, it dent predictor of long-term clinical outcomes. According to current guidelines and
is crucial that ongoing research is conducted to pro- routine clinical practice, AVR is performed after the onset of symptoms. Future and
vide standardization of sequences and protocols ongoing trials, including the EVOLVED trial, are required to determine whether targeted
early intervention utilizing cardiac magnetic resonance (CMR) to detect fibrosis will lead
across sites and vendors to delineate clear cutoffs for
to improved clinical outcomes. Abbreviations as in Figures 2 and 4.
health and disease in aortic stenosis. As T 1 mapping294 Bing et al. JACC: CARDIOVASCULAR IMAGING, VOL. 12, NO. 2, 2019
Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis FEBRUARY 2019:283–96
research expands, this approach may offer clear ad- bias, which remains an issue in the published
vantages over LGE. For example, future investigation medical data (75).
of antifibrotic therapies will require biomarkers to
monitor myocardial health and treatment effects; T 1 CONCLUSIONS
mapping will be indispensable in this regard.
Further work to investigate the role of emerging Myocardial fibrosis plays a key role in the patho-
CT techniques is also warranted, particularly as physiology of aortic stenosis. Modern imaging tech-
they may be more easily integrated into current niques now allow assessment of both replacement
clinical care pathways and workflows than and diffuse interstitial fibrosis as well as their func-
CMR. There has also been early investigation of tional consequences. These techniques hold promise
collagen- and elastin-specific CMR contrast agents, in tracking myocardial health in patients with aortic
which may provide greater contrast to noise ratio stenosis, aiding risk stratification and potentially
compared with current GBCAs, but further advances optimizing the timing of aortic valve intervention,
in this field are awaited (73,74). Finally, there is with ongoing trials currently testing the clinical effi-
considerable interest in developing novel positron- cacy of these approaches.
emission tomography tracers to measure myocar-
dial fibrosis activity, in contrast to the structural ADDRESS FOR CORRESPONDENCE: Dr. Marc R.
and functional assessments that have been devel- Dweck, BHF Centre for Cardiovascular Science, Uni-
oped to date. We await further studies to demon- versity of Edinburgh, Chancellors Building, 47 Little
strate this potential. As interest in this field France Crescent, Edinburgh, Midlothian EH16 4TJ,
progresses and new techniques emerge, it is of United Kingdom. E-mail: Marc.dweck@ed.ac.uk.
course important to be cognizant of publication Twitter: @MarcDweck.
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