JACC: CARDIOVASCULAR IMAGING VOL. 11, NO.

12, 2018

PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION

THE IMAGING TIME CAPSULE

Progress in Cardiovascular Imaging

Christopher K. Kramer, MD, Leslee J. Shaw, PHD, Y. Chandrashekhar,
for the JACC: Cardiovascular Imaging Editors

O ver the years, JACC: Cardiovascular Imaging

has witnessed and showcased some of
the most important advances in cardiovas-
cular imaging. However, the dizzying pace of prog-
values. It brings us one step closer to fully automated
simultaneous
interaction.
quantification with minimal

CHAMBER REMODELING. Arterial properties influ-

user

ress in cardiac imaging makes it impossible for the

busy clinician to keep up with current trends and
future developments. While we believe that our
expert reviews and editorials help our readers
manage this torrent to some extent, it may still be
difficult to get an overview of the whole field, and
especially for individual modality-related advances,
through this continuous drip-drip of information.
Therefore, we collated important themes and central
messages from papers published recently in JACC:
Cardiovascular Imaging that the Editors felt would
summarize important advances among all of the mo-
dalities we deal with in cardiac imaging. Only orig-
inal research, which we strongly believe is the only
vehicle that can meaningfully advance science, will
be featured in this compilation; the content was cho-
sen for scientific research impact and/or clinical util-
ity. This exercise was completed earlier this year,
and the very recent developments after that date
will be addressed in the next iteration of this
overview.
CARDIAC CHAMBERS: MORPHOLOGY,
STRUCTURE, FUNCTION, AND PROGNOSIS
QUANTIFICATION. One of the more exciting areas is
automated chamber quantification—the ability to
rapidly estimate left ventricular (LV)/left atrial (LA)
size and volumes—which will improve workflow and
allow the echo personnel to concentrate on more
high-value tasks. This becomes even more important
given the rapid uptake in 3-dimensional (3D) trans-
thoracic echocardiography (TTE). A novel automated
software (1) was able to show good agreement and
reproducibility compared with assessment by expert
readers and cardiac magnetic resonance (CMR)
ence patterns of remodeling but effect on longitudi-
nal alterations is less known. This large study (n ¼
607) showed that carotid-femoral pulse wave veloc-
ity, a measure of arterial stiffness, measured at
baseline predicted progression to concentric LV
remodeling over 4.7 years (2). Central pulse pressure
predicted increased LV mass as well as worsening of
LV diastolic function in women. Tracking arterial
stiffness might in theory allow intervention in the
pre–heart failure (HF) stage.
Chamber remodeling with exercise is an important
issue, because differentiation between physiological
and pathological changes is crucial. This group (3)
studied 1,083 elite athletes (41% female; mean age
21.8  5.7 years) and found that most athletes had
normal LV geometry. Women had slightly more
eccentric hypertrophy, and concentric hypertrophy/
remodeling was extremely uncommon—finding this
in symptomatic female athletes may denote disease.
LV remodeling in elite division I football players
shows interesting patterns (4). A total of 82% of
linemen showed concentric left ventricular hyper-
trophy (LVH), but with decreased global longitudinal
strain (GLS) (a pathological LVH), whereas nonline-
men had eccentric LVH with increased GLS (possibly a
more physiological LVH). Not all forms of athlete’s
heart may be a physiological adaptation, and some
forms of sport might need efforts to minimize such
remodeling?
Similar to prolonged exposure to hypertension,
cumulative exposure to hyperglycemia might influ-
ence remodeling but has not been systematically
studied. The CARDIA (Coronary Artery Risk Devel-
opment in Young Adults) investigators (5) looked at
3,179 subjects and stratified the subgroups of severity

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2018.10.014

1884 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 1 Representative Recordings of Longitudinal Strain Imaging in Patients With and Without Improvement in
LVEF During Follow-Up

Longitudinal Strain Imaging

A Representative Case A Representative Case
With Improvement in EF Without Improvement in EF
RALSR: 0.38 RALSR: 0.75

Anterior Anterior
30 30
-7 -6
Ant- Ant- Ant- Ant-
Sep -5 Lat Sep -7 Lat
-7 -4 -5 -3
-5 -2 -4 -6 -5 -5
-3 -2 -7 -9

-8 -5 -9 -9
-7 -3 -4 -7 -8 -9
-6 -4 -2 -5
Inf- -3 Inf- Inf- -4 Inf-
Sep Lat Sep Lat
-5 -4
-30 -30
Inferior Inferior

Reprinted with permission from Kusunose et al. (7). RALSR ¼ relative apical longitudinal strain ratio.

and duration. A longer duration of diabetes predicted
worse LV mass and poor control increased odds of
having systolic dysfunction. Insulin resistance also
behaved similarly. Increasing cumulative exposure to
diabetes mellitus (DM) or higher insulin resistance,
beginning in early adulthood, might mean worse
remodeling outcomes later in life.
PROGNOSIS IN THE REMODELED HEART AND IN
CARDIOMYOPATHIC VARIANTS. LV strain is prog-
nostic in most cardiac conditions, but whether serial
changes predict major adverse cardiac events (MACE)
is unclear. This study (n ¼ 388) in asymptomatic hy-
pertensive patients with abnormal LV geometry
showed that LV strain (GLS) predicted MACE, inde-
pendent of and incremental to clinical parameters
and LVH (6). Deterioration in GLS (but not so much
the changes of LV morphology and LV circumferential
function) was also associated with MACE. A multi-
parametric risk score including GLS may better define
the risk of MACE.
Tachycardia-induced cardiomyopathy is revers-
ible, but who will recover remains unclear (7). High
relative apical longitudinal strain (LS) ratio (average
apical LS/[average basal LS þ average mid LS]), a
marker of strain distribution, was highly predictive of
a lack of future recovery (hazard ratio: 22.9 per 1 SD).
A relative apical longitudinal strain ratio of 0.61 was
sensitive (71%) and specific (90%) for recovery (area
under the curve [AUC]: 0.88). A total of 42% of pa-
tients with presumptive tachycardia-induced cardio-
myopathy did not recover (Figure 1). Strain
distribution might be useful for clinical evaluation
and might guide treatment of index arrhythmia.
Cardiac involvement is strongly detrimental in
amyloid light chain (AL) amyloidosis, and GLS is an
exquisite predictor, but its incremental value in pa-
tients with preserved LV ejection fraction (EF) re-
mains unclear. In one of the largest studies (8) of
patients with biopsy-proven AL amyloidosis, GLS
(machines from multiple vendors) predicted all-cause
mortality over established clinical, echocardio-
graphic, and serological markers. Interestingly, GLS
provided prognostic value even in patients with no
evidence of cardiac involvement. Deformation imag-
ing may have most value in the early stages of the
disease.
Adults with sickle cell disease (SCD) die of cardio-
pulmonary complications, but the pathophysiology
remains obscure. In a clinical study and meta-
analysis, SCD showed a unique form of cardiomyop-
athy: restrictive physiology superimposed on a
hyperdynamic state (9). The LV dilates as diastolic
dysfunction progresses (unlike other restrictive car-
diomyopathies), and the dilated LV is hyperdynamic.
This unique restrictive cardiomyopathy may explain
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1885
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 2 CMR and Cardiac Spectral CT Imaging

A B

(A) Late gadolinium enhancement imaging on cardiac magnetic resonance (CMR) in a 4-chamber view that reveals subepicardial myocardial
inflammation involving the lateral and apical wall (arrows). (B) Corresponding spectral computed tomographic (CT) imaging with late iodine
enhancement (arrows). Reprinted with permission from Bouleti et al. (10).

the increased mortality seen in patients with SCD
with only mild pulmonary hypertension.
DIAGNOSTIC STRATEGIES. Myocarditis can present
as acute coronary syndromes (ACS), and CMR may
not be possible in all patients. Spectral cardiac
computed tomography (CT) characterizes tissue
based on late iodine enhancement and could be an
alternative (10). In patient-based analysis, the sensi-
tivity of spectral CT was 100%. On a segment-to-
segment comparison, overall accuracy (95%) and
interobserver variability were good (Figure 2). This
proof-of-concept study suggests that spectral CT
could be an easier alternative to CMR. Single case
studies do not usually find a home at JACC: Cardio-
vascular Imaging, but very occasionally there is a case
report with major implications. Given the worldwide
implications of the Ebola epidemic, we showcased
the first case of myocarditis diagnosed with CMR in
Ebola virus disease (11).
Diastolic dysfunction is a huge problem, but
consensus criteria may not be the best way to char-
acterize the myriad of pathophysiological elements in
these patients. This group (12) asked if modern data
analytic techniques like cluster analysis of deforma-
tion parameters might provide a Doppler-
independent assessment of LV diastolic function.
Simultaneous speckle-tracking of the LA and LV
showed strong correlations with the conventional
indexes and revealed 3 patient groupings of
increasing severity of diastolic dysfunction (Figure 3).
Advanced computational techniques coupled with
data-driven analytics might provide rapid phenotypic
characterization of LV diastolic function; more inter-
estingly, this could be automated (e.g., interpretation
and assessment of diastolic dysfunction), thus
enabling precision medicine. Conventional methods
for diastolic function are cumbersome and do not
accurately reflect its progression. Could LA strain
imaging, an attractive measure of LA function, be
better? A study with derivation and validation co-
horts (13) showed that peak LA strain was signifi-
cantly different between various degree of
dysfunction. LA strain could be measured in most
patients, and diagnostic thresholds had an accuracy
of 95%. LA strain measurements could allow accurate
categorization of diastolic dysfunction (Figure 4).
Multiple diagnostic modalities are used for cardiac
sarcoidosis, but their relative roles are unclear. In 321
patients with biopsy-proven sarcoidosis (14), CMR
was the most sensitive as well as specific test (AUC:
0.984); it detected subclinical disease in 9% of
asymptomatic patients without electrocardiographic
(ECG) abnormalities and in 5% without any abnor-
malities at all initially. Late gadolinium enhancement
(LGE) predicted adverse prognosis (hazard ratio: 5.68;
95% confidence interval: 1.74 to 18.49). Echocardi-
ography had high positive predictive value (84%), but
low sensitivity (27%) and thus low overall diagnostic
value as a screening test.
1886 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 3 Clustering Dendrograms for Conventional Variables and Their STE Correspondents

au bp

98 75
98 93 98 93 100 98
100 100
100 97 100 99
96 93 98 90
97 97
97 92

Cluster dendrogram
with AU/BP values (%)

2D-LAVmax
STE-LAVmax

E/e’
VRE/SREAV

A
VR/AAV

e’/a
VRE/VRAAV
SRE/SRAAV
E

E/A

VR-EAV
a’
SR-AAV

e’
s’
SR-EAV
SR-SAV
Distance: euclidean

0 15

Clustering dendrograms using STE and conventional variables together. The dissimilarity matrix is given as a heat map of Euclidean distance
(red). The AU (red numbers) and BP (green numbers) were calculated. AU values are shown only for leaflets that had an AU >95%
(considered statistically significant). Significant proximity of variables in the clustering leaflets was decided using 2-dimensional LAVmax, E/e0 ,
A-wave velocity, and a0 velocity were shown to be in perfect proximity with their STE counterparts STE-LAVmax, VR-E/SR-EAV, VR-AAV, and
SR-AAV, respectively (AU ¼ 97%, 96%, 98%, and 100%, respectively). The conventional parameters e0 /a0 and E/A were also in significant
proximity to their STE counterparts SR-E/SR-AAV, and VR-E/VR-AAV, respectively (AU ¼ 98%) and also between e0 and s0 and their STE
counterparts SR-EAV and SR-SAV, respectively (AU ¼ 100%). AU ¼ approximately unbiased probability; 2D ¼ 2-dimensional; VR-E ¼ rate of
volume expansion at early diastole. Reprinted with permission from Omar et al. (12).

INTERESTING PHYSIOLOGY INSIGHTS. Patients had a paradoxical decrease in forward LVSV during
with advanced HF can shift to the descending PLL, and this strongly predicted adverse outcomes
limb of the Starling curve, where preload cannot in addition to traditional echocardiography pa-
increase in stroke volume (SV). Passive leg lifting rameters (15). Functional mitral regurgitation
(PLL), a simple maneuver that increases preload, seemed to explain this descending limb of the
can be used to test for this phenomenon. In a Starling curve. PLL might be a useful maneuver
study of 35 patients with EF <40%, nearly 50% for prognosticating.
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1887
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 4 Composite LA Strain Curves for Individual DD Grades

Normal Grade 1
50 50

40 40
Peak LA Strain (%)

Peak LA Strain (%)

30 30

20 20

10 10
40
0 0

30
Peak LA Strain (%)

20

10

Grade 2 0 Grade 3
50 50

40 Normal Grade 2 40
Peak LA Strain (%)

Peak LA Strain (%)

Grade 1 Grade 3
30 30

20 20

10 10

0 0

At the 4 corners, composite LA strain curves are depicted as mean of each subgroup (solid lines) with SD (dotted lines). Center panel shows all 4 LA strain curves in a
single plot to facilitate comparisons. LA ¼ left atrial. Reprinted with permission from Singh et al. (13).

Exercise echocardiography allows early diagnosis
of pulmonary vascular disease, but its accuracy is
unclear. In a study that compared exercise echocar-
diography and exercise CMR with simultaneous
invasive pressures, pulmonary vascular and right
ventricular (RV) function could be reliably estimated
with exercise echocardiography and correlated well
with RV function on CMR (16). Exercise echocardi-
ography can be a valid screening tool for early iden-
tification of pulmonary vascular disease. Could
exercise-induced changes in LA dynamics trigger
RV-to–pulmonary circulation uncoupling and venti-
lation inefficiency? Exercise
showed that impaired LA strain was associated with
RV-to-pulmonary circulation uncoupling and exercise
ventilation inefficiency. Therapeutic interventions
attenuating this might have important benefits (17).
Can RV contractile function and RV-PA coupling
identify clinical phenotypes and predict outcome in
heart failure with preserved ejection fraction
(HFpEF)? Tricuspid annular plane systolic excursion
(TAPSE) to pulmonary artery systolic pressure (PASP)
ratio tertiles showed progressively worsening levels
of natriuretic peptides, systemic and pulmonary he-
modynamics, as well as abnormal exercise aerobic
capacity and ventilatory inefficiency. RV-PA coupling
can be a good risk marker and might be a targetable
parameter in patients with HFpEF (18). Endurance
exercise is a risk factor for developing atrial
arrhythmia and may work through atrial remodeling.
Exercise-induced change in atrial function might help
echocardiography clarify this association. Echocardiography was per-
formed in 55 healthy adults at baseline and after a
race of varying degrees of strenuousness. Compre-
hensive 4-chamber function assessment showed
acute exercise dose-dependent RA and RV dysfunc-
tion. Such episodes, if repetitive, might lead to atrial
remodeling and arrhythmias (19).
1888 JACC: Imaging Editors
Progress in Cardiovascular Imaging
RV size sometimes overlaps with that seen in
arrhythmogenic RV cardiomyopathy, and it is
important to know the impact of sex and kind of sport
on RV remodeling limits. A study of 1,009 Olympic
athletes (mean age 24  6 years) showed significant
RV remodeling, especially in males and those with
endurance practice; up to one-third of athletes
exceeded the normal Arrhythmogenic Right Ventric-
ular Cardiomyopathy (ARVC) Task Force limits (20).
New criteria might be needed to differentiate these 2
groups reliably. How to best risk-stratify subjects
with early ARVC? A study of 162 such patients showed
that ECG parameters, RV diameter, and RV mechani-
cal dispersion (MD) were markers of previous
arrhythmic events, and combining electrical and
echocardiographic parameters improved identifica-
tion of subjects with arrhythmic events in early ARVC
disease (21).
What are the LV remodeling trajectories a normal
adult’s life, and why do some individuals maintain LV
systolic function? In a large community-based study
(asymptomatic, 10-year follow-up), aging was asso-
ciated with the development of LV concentric
remodeling (22). LV mass and worsening risk factors
predicted reduced regional myocardial shortening,
and controlling them (e.g., antihypertensive medica-
tions) maintained cardiac function. Increased torsion
of the myocardial wall was seen with progressive
concentric remodeling and may be a compensatory
mechanism to maintain systolic function with age.
GLS is very sensitive for infiltrative diseases like
cardiac amyloidosis or sarcoidosis, but how does it
compare to CMR and histology? This was explored
(23) in 53 patients with amyloidosis. Both GLS and
amyloid deposits showed a basal-to-apical gradient,
and GLS correlated well with LGE and amyloid
burden; mean GLS and number of segments with LGE
could not differentiate the 3 CA types. LS abnormal-
ities reflect the amyloid burden, and apical GLS
independently predicts MACE (Figure 5).
Does increased adrenergic activity play a role in
takotsubo cardiomyopathy (TTC)? A prospective
study (n ¼ 32 patients and 20 control subjects) using
123–meta-iodobenzylguanidine (mIBG) imaging
showed myocardial sympathetic hyperactivity and
elevated plasma epinephrine in the subacute phase of
TTC: mIBG parameters but not plasma epinephrine
normalized on follow-up, mirroring the remission of
LV function and supporting a possible role of adren-
ergic hyperactivity in TTC (24).
CARDIO-ONCOLOGY. The prevalence and risk fac-
tors for valvular dysfunction (VD) in adult lymphoma
survivors after stem cell transplantation is unclear.
This Norwegian national cross-sectional study
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
(1987 to 2008, mean follow-up: 13  6 years) found
valve dysfunction in 22.3% of patients (only 3% se-
vere, mainly aortic stenosis). Anthracycline alone
(n ¼ 177), increased the risk 3-fold (25); this is prob-
ably the first study to show an anthracycline-
associated risk of valve dysfunction, independent of
treatment with cardiac radiation.
Doxorubicin and trastuzumab can cause
chemotherapy-related cardiac dysfunction (CTRCD),
but few patients have standardized follow-up studies
for comprehensive measures of myocardial me-
chanics. In this study (135 patients, 517 echocardio-
grams), changes in ventricular-arterial coupling and
circumferential strain were strongly predictive of
CTRCD: Ea/Eessb and circumferential strain were
most strongly associated with and predictive of
CTRCD (Figure 6), and ventricular-arterial coupling
appears to be a promising new measure to predict
CTRCD (26).
Anthracycline-based chemotherapy can cause
cardiotoxicity, but how soon does the interstitium
get affected? Because elevated myocardial extra-
cellular volume (ECV) is associated with both LV
diastolic and systolic dysfunction, exercise intoler-
ance and mortality, identifying elevated ECV could
help prevent adverse consequences. This study
showed that ECV increases within 3 months after
initiation of chemotherapy, and is most prominent
in participants receiving anthracycline. ECV corre-
lates only weakly with LVEF, end-diastolic volume,
or end-systolic volume (27) and might have addi-
tional value in following-up patients on
chemotherapy.
GLS can detect subtle subclinical dysfunction,
especially in the oncology population, but is often
performed suboptimally. Can training and experience
with the technique improve precision and validity? In
a carefully performed multicenter study of readers
with various degree of experience, GLS had better
interclass correlation coefficients than EF (Figure 7).
Experience improved concordance but precision of
GLS was high for all readers including in those with
none. Training improved assessment of segmental
strain for readers of all level of expertise (28).
CARDIOMYOPATHIC COMPLICATIONS—LV THROMBUS.
CMR can best determine the prevalence of LV
thrombus, but an effective echo algorithm might
allow for selective testing. A 201-patient study (8%
prevalence of LV thrombus) of same-day echo done
according to a tailored protocol and CMR showed that
both noncontrast (35%) and contrast (64%) echo
yielded limited sensitivity for thrombus identified on
delayed enhancement CMR, but echo-measured
noncontrast apical wall motion score was higher
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1889
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 5 Longitudinal Strain and Amyloidosis

A Cardiac CMR, % of LV Segments with LGE in Each Region B

0 20 40 60 80 100
0 80

Histological Amyloid Burden (% of Total Surface Area

Echocardiography, Mean LV-LS by Region (%)

–4
60

with Amyloid Deposits)

–8
40

–12

20
–16

0
–20
–20 –15 –10 –5 0
M-TTR WT-TTR AL
Longitudinal Strain (%)
Free Basal Wall Basal
Patient 1, Patient 2, Patient 3,
Mid-Cavity Apical R2 = 0.31 R2 = 0.60 R2 = 0.69

A B
100 100

80 80
NT-proBNP ≤4000 ng.L–1
Without MACE (%)

Without MACE (%)

60 60
NT-proBNP >4000 ng.L–1
NYHA I-II
40 40
NYHA III-IV
20 20

0 log-Rank test: 12.0; P = 0.001 0 log-Rank test: 6.1; P = 0.0014

0 5 10 15 20 0 5 10 15 20
Follow-Up (Months) Follow-Up (Months)

C
100
Apical strain ≤14.5 %
80
Without MACE (%)

60
Apical strain >14.5 %
40

20

0 log-Rank test: 13.7; P < 0.0001

0 5 10 15 20
Follow-Up (Months)

(Top: A, B) Correlation between regional LVLS and amyloid burden determined by CMR or quantified by histology. (A) Correlation between mean lon-
gitudinal strain in each LV section and the free basal LV wall with the percentage of LV segments exhibiting LGE by CMR. (B) Correlation between amyloid
burden as determined histologically and longitudinal strain in the 3 patients who underwent heart transplantation. (Bottom: A, B, C) Survival analysis
according to prognostic markers. Kaplan-Meier curves for MACE according to the 3 independently predictive variables. Log-rank test p values are given
for each comparison. CMR ¼ cardiac magnetic resonance; MACE ¼ major adverse cardiac event(s); NT-proBNP ¼ N-terminal pro–B-type natriuretic
peptide; NYHA ¼ New York Heart Association. Reprinted with permission from Ternacle et al. (23).
1890 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 6 Longitudinal Patterns of Myocardial Mechanics According to CTRCD

A B
–13 –18

–14 –20

Circumferential Strain (%)

Longitudinal Strain (%)

–15 –22

–16 –24

–17 –26

–18 –28

–19 –30

–20 –32
0

0
00

0
00
10

20

30

40

50

60

70

80

90

10

20

30

40

50

60

70

80

90
10

10
Days Since Cancer Therapy Initiation Days Since Cancer Therapy Initiation

C D
60 1.75

55 1.50

50 1.25
Radial Strain (%)

45 1.00
Ea/Eessb

40 0.75

35 0.50

30 0.25

25 0.00
0

0
00

0
00
10

20

30

40

50

60

70

80

90

10

20

30

40

50

60

70

80

90
10

10

Days Since Cancer Therapy Initiation Days Since Cancer Therapy Initiation

Any CTRCD No Yes

Smoothing splines with point-wise confidence bands for (A) longitudinal strain, (B) circumferential strain, (C) radial strain, and (D) Ea/Eessb.
CTRCD ¼ cancer therapeutics–related cardiac dysfunction. In this robust study, Ea/Eessb, and circumferential strain were strongly associated
with CTRCD while other variables were less so. Reprinted with permission from Narayan et al. (26).

among patients with thrombus (and correlated with
cine-CMR apical function), thus improving overall
performance (AUC: 0.89  0.44) for thrombus (29).
Including apical wall motion improved appropriate
referral for delayed enhancement CMR testing (100%
sensitivity and negative predictive value), while
avoiding further testing in more than one-half of pa-
tients. When to perform CMR to detect LV thrombus
is an unanswered question. In comparison with
myocardial infarction with non-obstructed coronary
arteries (MINOCA), where early CMR is more helpful,
a later CMR study seems to increase the yield for
detecting LV thrombus with CMR (30). The highest
LVT detection rate was obtained in patients in whom
CMR was performed 9 to 12 days after myocardial
infarction (MI), while those having the study in the
first 5 days after a MI may miss a significant number
of eventual LV thrombi necessitating serial studies.
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1891
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 7 Impact of Experience on Strain Measurements

MD Ptrend < 0.001

SD Ptrend = 0.001
CV Ptrend = 0.001
Poverall = 0.007 Poverall = 0.018 Poverall = 0.019

3.0 PAdj = 0.003 PAdj = 0.012 20 PAdj = 0.014

3.0
15
2.0

(%)
2.0
10

1.0
1.0 5

0.0 0.0 0
No Limited Intermed High No Limited Intermed High No Limited Intermed High
n = 13 n = 12 n = 10 n = 23 n = 13 n = 12 n = 10 n = 23 n = 13 n = 12 n = 10 n = 23

With increasing experience, there was a significant trend toward lower mean difference (MD), SD, and coefficient of variation (CV) in global longitudinal systolic strain
(GLS) measurements. High ¼ highly experienced; Intermed ¼ intermediate experience; Limited ¼ limited experience; No ¼ no experience; pAdj ¼ adjusted p value.
Reprinted with permission from Negeshi et al. (28).

IMAGING-GUIDED THERAPY—RANDOMIZED STUDIES. characterized by low voltages on electroanatomic

Advanced echocardiography can help with better mapping, with good sensitivity (76%), good speci-
detection of nonischemic stage B HF, but it is unclear ficity (86%), and very high negative predictive value
whether this translates into improved outcomes. A (95%). This was one of the first studies to show this
randomized trial of 618 patients at risk for HF (care spatial agreement; because CT data is often fused
guided by myocardial deformation and detailed dia- with electroanatomic mapping, this may assist in
stolic function vs. usual care followed by guidance to refining ablation.
primary physicians to initiate treatment with Epicardial fat influences atrial fibrillation (AF)
angiotensin-converting enzyme inhibition and beta- burden and outcomes, but long-term prospective data
adrenoceptor blockade if stage B HF was detected) in disease-free subjects are few. A study of 1,990
showed that strain and diastolic function identified participants without cardiovascular disease on
stage B HF in 71% of the patients with risk factors but computed tomography angiography (CTA) from the
normal EF, with an annualized event rate of 11% (31). prospective population-based Rotterdam Study
While evaluation was associated with a higher inci- cohort found an association of epicardial fat with AF
dence of incidence HF and death, initiation of independent of traditional risk factors, atheroma, left
guideline-based therapies remained suboptimal at atrial size, and fat elsewhere (34). Epicardial fat may
the primary care level, resulting in no difference in mediate AF through mechanisms other than pre-
outcomes in the intention-to-treat analysis despite existing heart disease or by systemic effects of
more detection of early dysfunction. remote adipose tissue.
EP AND IMAGING. Can CMR provide a comprehen-
sive assessment of the heart before pulmonary vein NEWER DIAGNOSTIC MODALITIES
isolation? It looks like it could be a single complete
diagnostic study (32) for assessment of pulmonary Shear wave imaging, a novel ultrasound-based tech-
venous anatomy as well as presence of LA/LAA nique quantifying passive diastolic myocardial stiff-
thrombi thus reducing the number of pre-operative ness (something that cannot be evaluated
tests before pulmonary vein isolation. noninvasively at this time) could be promising in LV
Noninvasive imaging for mapping the VT substrate diastolic dysfunction. In a sheep study, shear wave
(scar) is helpful in the planning and guidance of RF imaging diastolic myocardial stiffness differentiated
ablation but our best test, CMR, may be limited by the noncompliant infarcted from the stunned
devices like implantable cardioverter-defibrillators in myocardium (preserved tissue compliance) when
this population. This study (33) showed that CT with regional systolic myocardial function was similarly
delayed enhancement can detect myocardial scars decreased in both groups (Figure 8). This was the first
1892 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 8 Shear Wave Imaging: A Novel Ultrasound-Based Technique Quantifying Passive Diastolic Myocardial Stiffness

Step 1: Push Generation Step 2: Ultrafast Imaging

A B

Myocardium

Shear
Wave

Acoustic Radiation Force

Stiffness Constant of The End-diastolic End-diastolic Myocardial Stiffness (kPa)

Stress-strain Relationship (Shear Wave Imaging)
(Sonomicrometry) p < 0.01
40.0 18.0
p < 0.05
35.0 16.0 p < 0.05
30.0 14.0

12.0
25.0
10.0
20.0
8.0
15.0
6.0
10.0
4.0
5.0 2.0

0.0 0.0
Initial Reperfused Initial Ischemic Reperfused

(Top) Principle of SWI. (A) Remote shear wave generation: an ultrasonic burst is focused on the myocardium. The acoustic radiation force
generates tissue displacements at the focal zone. (B) Ultrafast imaging: Pulse plane waves are transmitted by the same ultrasonic probe at a
repetition frequency of 10,000 Hz. The pulse echo signals are stored in a computer, and images are beam-formed offline. (Bottom)
Myocardial stiffness after ischemia-reperfusion. Myocardial stiffness is measured by sonomicrometry (left) and shear wave imaging (right) in
stunned (green) and infarcted (pink) animals. Reprinted with permission from Pernot et al. (35).

study (35) to quantify diastolic stiffness during
myocardial ischemia by ultrasonography imaging and
without the need of invasive sensors such as pressure
catheters or sonomicrometer crystals. If proven in
further studies, this could be a very promising
technique.
Reflected ultrasound signal is often significantly
enhanced in infarcted myocardial segments, and a
new scar imaging method based on echocardiography
with ultrasound multipulse scheme can used this to
detect myocardial scar (36). In a proof-of-concept
study, 2-dimensional multipulse echocardiography
reliably detected the presence and site of myocardial
scar, concordant with CMR-LGE at 30 days after
ST-segment elevation myocardial infarction (STEMI),
as well as its absence in negative control subjects.
Echocardiography with ultrasound multipulse
scheme was not as sensitive in the most apical
myocardial segments. Given that it exploits existing
technology with slightly modified settings, this could
offer an easy and cost-effective strategy to detect
myocardial scar.
CT is finding newer uses. One advanced imaging
technique, dual-energy CT, can provide an idea about
material composition. This study asked whether this
ability of dual-energy CT can be used to detect
changes that correlate with serial changes in ECV
fraction on CMR and collagen volume fraction (CVF)
on histology in an animal model of doxorubicin car-
diotoxicity (37). CT ECV and MR ECV values were well
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1893
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 9 Coronary Segment Negative for NIRAF

A C

* C
ps

NIRAF OCT-NIRAF

Lipid Calcium NIRAF

(Distal)

(A) Angiography of the right coronary artery showing nonsignificant coronary disease over the optical coherence tomography near-infrared
autofluorescence (OCT-NIRAF) pullback segment (ps). (B) Two-dimensional NIRAF map demonstrating negligible NIRAF signal. (C) Cross-
sectional OCT-NIRAF image showing normal coronary wall and a calcification (2 o’clock position) with no NIRAF signal detected. (D) Three-
dimensional cutaway rendering of the OCT-NIRAF pullback. (B) Scale bar ¼ 5 mm. (C) Scale bar ¼ 1 mm. *Guidewire shadowing artifact; solid
white circle ¼ side branch. Reprinted with permission from Ughi et al. (38).

correlated with each other (r ¼ 0.88) and with CVF on
histology (CT ECV vs. CVF, r ¼ 0.93; and CMR ECV vs.
CVF; r ¼ 0.96). Dual-energy CT may thus be useful for
characterizing doxorubicin-induced cardiomyopathy
if it can be refined to reduce radiation, and improve
image quality of the iodine map.
New imaging approaches are needed to identify
high-risk atheroma, and novel hybrid imaging can be
more informative for assessing coronary anatomy as
well as risk. An exciting dual-modality intravascular
imaging system (optical coherence tomography and
near-infrared autofluorescence) that can simulta-
neously characterize coronary anatomy and micro-
structure was shown to be clinically feasible in 12
patients (38). Near-infrared autofluorescence signal
localized with a high-risk morphological plaque
phenotype and its focal distribution among lesions
carried meaningful information, making it an inter-
esting endogenous imaging biomarker (Figure 9).
Indocyanine green (ICG)–enhanced near-infrared
fluorescence imaging can illuminate high-risk histo-
logical plaque features and using it with intravascular
1894 JACC: Imaging Editors
Progress in Cardiovascular Imaging
near-infrared fluorescence–optical coherence tomog-
raphy imaging might help target atheroma in pa-
tients. This study from the BRIGHT-CEA (Indocyanine
Green Fluorescence Uptake in Human Carotid Artery
Plaque) trial (39) showed that in patients undergoing
carotid endarterectomy, ICG targets human plaques
exhibiting endothelial abnormalities and can be an
approach to image fundamental biology in coronary
atherosclerosis.
CARDIAC VALVES: THE AORTIC VALVE
AORTIC STENOSIS—PHYSIOLOGY AND DIAGNOSIS
OF TYPICAL AND ATYPICAL VARIANTS. Is a criti-
cally fixed valvular obstruction the main mechanism
of functional impairment in patients with paradoxical
low gradient aortic stenosis? An exercise echocardi-
ography study showed that the aortic valve still has a
fair amount of residual opening reserve, and baseline
indexes of LV valvular and vascular load do not
correlate with functional impairment or exercise-
induced hemodynamics (40). Interestingly, symp-
tomatic patients with PLGAS behaved differently
(increased blood pressure and SV during exercise
despite a fall in vascular resistance) than high-
gradient disease (where the valvular obstruction is
the main impediment).
Transaortic flow rate (FR) may refine prediction of
outcomes better than stroke volume alone given that
it incorporates ejection time. This concept was tested
in 1,661 patients with asymptomatic aortic stenosis
(AS) in the SEAS (Simvastatin and Ezetimibe in Aortic
Stenosis) study (41). Low transaortic FR (in 21% of
patients; 28% of these patients had normal stroke
volume index [SVI]) was associated with lower LV
mass and systemic arterial compliance, but signifi-
cantly more adjusted cardiovascular and all-cause
mortality.
Paradoxical low-flow, low-gradient (LFLG) AS has
low flow and preserved LVEF probably due to
concentric remodeling, impaired LV diastolic filling,
and systolic longitudinal function. Does aortic valve
replacement (AVR) help LV geometry and function in
patients? In the TOPAS (Multicenter Prospective
Study of Low-Flow Low-Gradient Aortic Stenosis)
study subset, AVR improved LV remodeling, longi-
tudinal systolic function, and SVI. Pre-existing severe
diastolic dysfunction prevented the increase in SVI,
making it a marker of negative outcomes. These data
help support the Class IIa recommendation for AVR
in symptomatic patients with paradoxical LFLG se-
vere AS (42).
Dobutamine stress echocardiography is used to
diagnose LFLG-AS, but an increase in heart rate (HR)
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
affects filling time, and thus attenuates an increase in
stroke volume (SV). Would a test less affected by HR,
like transvalvular flow rate, still be diagnostic when
SV is not increased adequately? The answer seems to
be yes (43): more patients showed normalized
FR $200 ml/s despite no significant change in SV, and
FR-guided assessment allowed a more conclusive
assessment of severity of AS than an algorithm based
on SVFR. This may partially explain why some pa-
tients derive prognostic benefit from valve interven-
tion despite a lack of SV reserve. Premature
ventricular beats have compensatory pauses that
allow more vigorous contraction in the subsequent
beat, and this can indicate contractile reserve. Can
post-extra systolic potentiation (PESP) of transaortic
valvular gradients after a premature beat substitute
for DSE? In this study, PESP correlated excellently
with dobutamine-induced transaortic gradients but
not with contractile reserve, suggesting that PESP
could possibly identify true severe LFLG-AS (44).
Larger studies are needed to clarify optimal use.
Is CT or TTE the best way to characterize AS
severity? One of the largest studies (45) to compare
aortic valve area (AVA) measurements by both
showed that underestimation of AVA by TTE (relative
to CT) was more likely for AVA between 0.7 and 1.0
cm 2, and was more common in men. A true minor
axis diameter <1.8 cm was uncommon and should
prompt caution. Discrepancies between AVATTE ,
AVACT , and the heart team final diagnosis were
common but far less when AVA <1.2 cm 2 was used.
TTE and CT require different thresholds of AVA for
defining severe AS.
NATURAL HISTORY/PROGNOSIS IN AS AND WHEN
TO INTERVENE. Increased filling pressures portend
poor prognosis, but better methods than E/e 0 ratio are
in the offing. Early mitral inflow velocity-to-early
diastolic strain rate ratio (E/SRe) surpasses the E/e0
for predicting outcome. In 121 patients with severe AS
scheduled for AVR, pre-operative E/SRe correlated
with E/e 0 , but was a better independent predictor of 5-
year post-operative survival. Future studies will want
to look at this ratio for better predicting the transition
from an asymptomatic state to a symptomatic
state (46).
A comparison of the natural history of the disease
in subgroups with high-gradient AS, LFLG, and
normal-flow low-gradient will be important. This
study shows that patients with LFLG severe AS had
outcomes similar to high-gradient severe AS but
worse compared with normal-flow low-gradient se-
vere AS, supporting the role of SVI in risk stratifica-
tion of low gradient severe aortic stenosis (47).
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
Does the survival benefit associated with AVR
differ based on strata of AS severity? Should discor-
dance between AVA and gradients change the
threshold value to define severe AS (e.g., make it 0.8
cm 2)? Survival rates of 1,710 patients with docu-
mented moderate to severe AS were separated into 4
strata of AS severity (based alternatively on AVA,
indexed AVA, MG, or peak aortic jet velocity [V peak])
were compared using propensity matching (48).
Discordant grading was seen in 30% of patients with
moderate to severe AS and normal ejection fraction/
flow. AVR improved survival when AVA was 0.8 to 1.0
cm 2 even when discordant (AVA #1 cm 2, but mean
gradient <40 mm Hg or Vpeak <4 m/s). Lowering the
AVA threshold for AS severity to 0.8 cm 2 does not
seem to be indicated, at least based on survival after
AVR.
The group from Vienna has had seminal papers in
natural history of mitral regurgitation (MR), and here
they present prospective data (49) on the natural
history and optimal timing of surgery in elderly pa-
tients with severe asymptomatic AS. This group is
unique because onset of symptoms may be missed
given their impaired mobility and they have
increasing comorbidities. A study of 103 consecutive
prospectively followed patients (mean age 77  5
years) with asymptomatic severe AS (peak aortic jet
velocity: 4.7  0.6 m/s) showed impaired mobility in
29%, and when symptoms appeared, they were se-
vere (43% more than New York Heart Association
functional class III), suggesting early symptoms could
be missed in this age group. Event-free survival was
poor (73%, 43%, 23%, and 16% at 1, 2, 3, and 4 years)
and worse with peak velocity $5.0 m/s (21% and 6% at
2 and 4 years). Three-fourths of the patients under-
went AVR with post-operative survival of 89% and
77% after 1 and 3 years, respectively. AS in this age
group calls for particularly close clinical follow-up,
and AVR works well in low to moderate risk-
selected elderly patients.
CARDIAC VALVES: THE MITRAL VALVE
There may be differences in outcomes in women and
men with organic MR, but there are no sex-specific
guideline recommendations. In a comprehensive
pre- and post-operative study, baseline age and EF
were similar, but women seemed to have a smaller
LV/LA and regurgitant volume but higher PA pressure
and more HF symptoms (often the trigger for sur-
gery). However, this paradox disappeared on
normalizing for body size: LV and LA diameters and
regurgitant volume were as severe as in men (50).
Over 10 years of follow-up, women had similar
JACC: Imaging Editors 1895
Progress in Cardiovascular Imaging
survival as men but experienced more HF linked to
worse pre-operative presentation. Imaging that does
not account for body size might inadvertently make
women’s pre-operative presentation appear to be
“benign.”
Effort intolerance in patients with valve stenosis is
often thought to be a mechanical obstruction. This
study in mitral stenosis showed that exercise intol-
erance is predominantly the result of many things,
including restrictive lung function, chronotropic
incompetence, limited stroke volume reserve, and
peripheral factors, and not simply impaired valvular
function (51). Interestingly, transmitral gradient and
mitral valve area were not well correlated with peak
VO2. Patients with MS have ventilatory abnormalities
similar to those reported in HF patients, accounting
for their effort intolerance.
How to identify elevated left ventricular filling
pressure (LVFP) in patients with mitral annular
calcification is a vexing problem. In a prospective
study of 50 patients, E/e 0 was an inaccurate parameter
with moderate or severe mitral annular calcification
(52). A clinical algorithm using mitral E/A and iso-
volumic relaxation time had good specificity (100%)
and positive predictive value (100%), and moderate
sensitivity (81%) and negative predictive value (67%)
for high LVFP. Diagnostic accuracy was 94% in a
validation cohort. The proposed algorithm can clas-
sify most cases (87%), has excellent specificity for
high LVFP, and is simple and obtainable in most
patients.
Is mitral annular disjunction, so common in mitral
valve prolapse (MVP), associated with abnormal
annular dynamics due to decoupling of annular-
ventricular function? Three-dimensional (3D) studies
showed that the disjunctive annulus is decoupled
functionally from the ventricle, leading to paradoxi-
cal annular dynamics with systolic dilatation/expan-
sion and flattening that may require specific
intervention (53). This happens in the presence of
normal LV systolic function assessed by both ejection
fraction and strains, suggesting intrinsic annular ab-
normalities and a decoupled annular function.
Echo and CMR are often discordant in grading MR
severity: one-third of patients classified as severe by
echo are only mild by CMR. One study (54), however,
found no systematic overestimation by echo. Echo-
derived regurgitant volume correlated well with
CMR, but interestingly, an integrated assessment by
echo as recommended by most societies actually
worsens the agreement with CMR. MR severity using
PISA RV alone had a very small bias (of 0.6 ml)
compared with CMR when performed on the same
day. This debate will continue!
1896 JACC: Imaging Editors
Progress in Cardiovascular Imaging
Prognosis in MVP is variable, but are some patients
at risk for sudden cardiac death? A spiked systolic
high-velocity signal $16 cm/s on tissue Doppler,
possibly representing a traction effect, may identify a
group at high risk for a malignant phenotype (55).
Perhaps mechanical traction of the papillary muscles
and posterolateral LV wall is arrhythmogenic.
IMAGING IN STRUCTURAL INTERVENTIONS
TRANSCATHETER INTERVENTION IN AORTIC
VALVE. Features associated with transvalvular aortic
regurgitation (AR) after transcatheter aortic valve
replacement (TAVR) are important to know. In the
Cedars Sinai experience (56), patients with trans-
valvular AR had larger prosthetic expansion, a more
elliptical prosthetic shape at the prosthetic commis-
sure level, and a more antianatomical position (which
was defined as malposition of the prosthetic com-
missures in relation to the native commissures) than
the patients without transvalvular AR. Age and
effective area oversizing were associated with mild or
greater paravalvular AR.
Can one develop a procedure simulation platform
for in vitro TAVR using patient-specific 3D-printed
tissue-mimicking phantoms? A proof-of-concept
study (57) showed feasibility of using 3D-printed
tissue-mimicking phantoms to quantitatively assess
the post-TAVR aortic root strain in vitro. A novel in-
dicator of the post-TAVR annular strain unevenness,
the annular bulge index, outperformed the other
established variables and achieved a high level of
accuracy in predicting post-TAVR paravalvular
leakage in terms of its occurrence, severity, and
location. This is a new frontier: traditional 3D printing
creates patient-specific anatomies, but using 3D
printing as a quantitative tool to study pathophysi-
ology is new and exciting.
TAVR has been used to treat BAV-AS but with het-
erogeneous outcomes. In an international multicenter
study (58), acute and 30-day outcomes were compa-
rable to tricuspid valves except for an excess of new
permanent pacemaker implantation (PPMI) (similar
between balloon- and self-expandable valves). Not
having a baseline CT increased the rates of mild par-
avalvular leak. Identifying a previously neglected
morphology of tricommissural (functional/acquired)
BAV was useful.
Very few studies have studied long-term perfor-
mance of TAVR and SAVR with imaging. The PART-
NER I (Placement of Aortic Transcatheter Valves) trial
(59) longitudinal echo data demonstrate that valve
performance and cardiac hemodynamics are stable
after implantation in both SAPIEN TAVR and SAVR in
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
patients alive at 5 years. AVA and Doppler velocity
index did not change significantly over time, and the
severity of AR did not increase with either prosthesis
type (Figure 10). Both SAPIEN TAVR and SAVR have
good long-term durability and structural integrity.
POST AVR MONITORING AND COMPLICATIONS?
Permanent pacemaker (PPM) is associated with
increased mid- and long-term mortality after surgical
aortic valve replacement. What about its effect on
perioperative mortality? In a study of 40,381 patients
(39,568 SAVR and 813 TAVR), no difference in mortal-
ity between patients with or without PPM was found
after TAVR, but there were fewer patients (60). In the
SAVR group, PPM increased risk of both perioperative
and overall mortality, whereas moderate PPM just
increased perioperative mortality. PPM attenuated
regression of LVH post-operatively, and the impact
on mortality was worse in younger patients <70 years
of age, and/or with coronary artery bypass.
Knowing the layout of the left ventricular outflow
tract (LVOT) and aortic complex might help reduce
bad outcomes during TAVR, and aortic angulation
may be one important parameter. However, study
size may influence the results. In the Cedar Sinai
experience (61), increased aortic root angulation
adversely influences acute procedural success
following SE but not BE TAVR. However, a much
larger study (n ¼ 3,578) from the CoreValve US Clin-
ical Trials (62), did not find that the degree of aortic
angulation had any effect on early clinical outcomes
of self-expanding TAVR.
We published one of the first studies (63) to clarify
the midterm outcomes with hypoattenuated leaflet
thickening (HALT) after TAVR. HALT with reduced
leaflet motion was not uncommon (1.4%, 10.0%, and
14.3% at discharge, 6 months, and 1 year) but was
usually subclinical. HALT area and the degree of
leaflet immobility are correlated, supporting the idea
that HALT could reflect THV thrombosis, but valve
hemodynamics and mid-term outcomes remained
uneventful even without additional anticoagulant
therapy. Because HALT spawned a number of defini-
tions (reduced leaflet motion [RELM], hypoattenua-
tion affecting motion [HAM]), there is a need to
standardize the lexicon and diagnostic pathways. A
paper from the group originally describing this phe-
nomenon (64) created a document for best definitions
and methodology to follow-up on HALT.
A definitive risk model for new PPMI after TAVR
would be useful, especially with newer valves that
still have a high PPMI rate (14.6% in this study from
Cedars). The distribution of calcification in the AVC
predicted new PPMI (NCC-DLZ CA). Right bundle
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1897
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 1 0 Valve Hemodynamics and Left Ventricular Mass Index of TAVR

A B
1.8
40
AV area
1.6 p = 0.41
1.4

Mean Gradient (mm Hg)

n = 84 n = 83 n = 74 n = 66 n = 70 n = 84 30
1.2
AV area index
1.0

0.8 20
n = 79 n = 80 n = 71 n = 63 n = 69 n = 79
0.6
n = 86 n = 77
0.4 DVI 10 n = 83 n = 67 n = 70 n = 86

0.2 n = 84 n = 83 n = 74 n = 66 n = 70 n = 84

0.0
0
FPI 1-Yr 2-Yr 3-Yr 4-Yr 5-Yr FPI 1-Yr 2-Yr 3-Yr 4-Yr 5-Yr

C D
30
300
Absolute Change in Mean Gradient (mm Hg)

Left Ventricular Mass Index (g/m2)

20
p < 0.001
250

10
200
0
150 n = 74
–10 n = 71
n = 64 n = 55 n = 65 n = 74
100
–20

Individual TAVR Patients 50

–30
FPI 1-Yr 2-Yr 3-Yr 4-Yr 5-Yr

(A) Trend in AV area, AV area index, and Doppler velocity index (DVI) from first post-implant (FPI) through 5 years in TAVR patients with paired echocardiograms. (B)
Box plots of the mean aortic valve gradient from FPI through 5 years. (C) The absolute change in mean gradient from FPI to 5 years for each patient. (D) Box plots of
the left ventricular mass index from FPI through 5 years. Box plot center line is the median with whisker lengths extending 1.5 times the interquartile range above Q3
and below Q1. The p values represent paired 2-sample analysis of results at FPI and 5 years. AV ¼ atrioventricular; TAVR ¼ transcatheter aortic valve replacement.
Reprinted with permission from Daubert et al. (59).

branch block, short MS length, and more ventricular value >110.0 mm 3 of the intermediate CT score vol-
device implantation added to the risk of PPMI (65); ume may call for a cerebral embolic protection device
including device depth in the model increased the during TAVR procedures (66).
sensitivity to 94%, specificity to 84%, and negative
predictive value to 99%. TRANSCATHETER INTERVENTIONS IN THE MITRAL
Stroke during TAVR remains a concerning compli- VALVE. There is great interest in predicting small neo
cation, and its mechanism is still unclear (1). Captured LVOT after mitral valve-in-valve procedures. CT is the
debris is a mix of materials such as tissue, thrombus, main technique but a small pilot study using 3D TEE
necrotic core, and calcium. It appears that pre- echo (proximity of mitral valve bioprosthetic struts to
procedural measurement of noncalcified aortic valve the septum [S-Sept] was assessed offline in mid-
plaque volume on CT can help with risk assessment of systole) found a strong association between reduced
ischemic stroke and neurocognitive decline; a cutoff S-Sept values and left ventricular outflow tract
1898 JACC: Imaging Editors
Progress in Cardiovascular Imaging
obstruction (LVOTO). LVOTO incidence was very high
with pre–mitral valve-in-valve S-Sept distances <7.5
mm. Conceptually, S-Sept approximates the pro-
jected short-axis width of the neo-LVOT as previously
described in other imaging modalities and might be a
useful marker (67).
Determining mitral annular (MA) shape and sizing
is important prior to transcatheter mitral valve im-
plantation. This study (68) showed that patients with
MVP had larger MA dimensions (SL [anteroposterior]
expansion) than patients with functional mitral
regurgitation (FMR), and LA dilation was the main
driver in FMR in MVP. Given significant interindi-
vidual variability in D-shaped MA dimensions, a
careful characterization is important for TMVR.
CTA may help with diagnosis of prosthetic valve
dysfunction. A study of 58 prosthetic heart valves age
7.7  5.2 years with an infection rate of 29% showed a
high accuracy (using surgery as the reference stan-
dard) with CTA for detecting prosthetic valve
dysfunction (particularly for the assessment of para-
valvular pathologies [paravalvular leakage, abscess,
pseudoaneurysm, or dehiscence] and identification of
thrombi/pannus). CTA was useful to clarify the cause
of increased transvalvular pressure gradients
(thrombus/pannus) on echocardiography (69).
NOVEL DIAGNOSTIC STRATEGIES. Approximately 7 significantly attenuate plaque progression (74).
million standard CT scans (no ECG gating and wider
slice thickness), are done each year for noncardiac
reasons that contain information on coronary artery
calcium (CAC) that is not often reported or used. A
study of 4,544 community-living individuals suggests
it might be time for us to be doing so! CAC found on 3-
mm ECG-gated CTs showed excellent correlation with
standard 6-mm chest CT (r ¼ 0.93) but with lower
median CAC scores (22 AU vs. 104 AU). Scores on
either scan (Figure 11) similarly predicted all-cause
mortality (70). Breast arterial calcification (BAC) of-
fers a similar opportunity. A study of 292 women with
digital mammography and nongated computed to-
mography showed a strong quantitative association
of BAC with CAC (71). BAC was superior to standard
cardiovascular risk factors and was equivalent to FRS
and PCE (Figure 12).
CORONARY ARTERY DISEASE
PLAQUE CHARACTERIZATION. Sex-specific associa-
tions have been described in coronary artery disease
(CAD), but are they due to per-vessel CAD or some
other differences? A study of 5,632 patients from the
CONFIRM (COronary CT Angiography EvaluatioN For
Clinical Outcomes: An InteRnational Multicenter)
registry (mean age 60  12 years; 37% women)
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
showed that men had more obstructive disease (42%
vs. 26%) and women had more normal coronary ar-
teries (43% vs. 27%). MACE risk strongly correlated
with nonobstructive and obstructive CAD, and there
were no sex-specific patterns predictive of MACE (72).
Anatomic CAD on coronary CTA poses similar risk of
MACE in both women and men.
The presence of high-risk plaque (HRP) features
predicts future ACS, and statins may stabilize the
plaque. Do patients on statin therapy have a lower
prevalence of HRP? The ROMICAT II (Rule Out
Myocardial Infarction/Ischemia Using Computer
Assisted Tomography II) investigators showed that
subjects on statins were less likely to have HRP in-
dependent of obstructive CAD and cardiovascular risk
factors. Statin therapy alters the natural history of
composition and morphology of coronary athero-
sclerosis (73).
CTA allows better study of the temporal changes in
coronary plaque volume and can detect the effect of
lipid-lowering treatments. In a multicenter study of
467 patients undergoing serial coronary CTA, patients
with low-density lipoprotein cholesterol (LDL-C)
below 70 mg/dl displayed a significant attenuation in
plaque progression compared with follow-up LDL-C
levels $70 mg/dl. Strict LDL-C control appeared to
Vascular calcification is complex; macroscopic de-
posits in plaques stabilize, while microcalcific de-
posits may portend plaque rupture. [18 F]-sodium
fluoride positron emission tomography (PET) imaging
can detect the latter. This study validated the rela-
18
tionship between in vivo F-NaF uptake and ex vivo
hydroxyapatite expression within carotid plaque, and
showed that it localized to active microcalcification
(hydroxyapatite expression) rather than the overall
calcification, thus noninvasively identifying active
calcification (75).
18
F-fluorodeoxyglucose (FDG) is increasingly used
to detect plaque inflammation and as a surrogate
endpoint for vascular interventional drug trials, but
18
the best metrics of F-FDG uptake and their repro-
ducibility are debated. This important study assessed
18
5 frequently applied arterial F-FDG uptake metrics
in healthy control subjects, those with risk factors,
and patients with CVD to derive thresholds in each
subject group (Figure 13). They found that FDG met-
rics were reproducible and different between healthy
and diseased subjects, albeit with significant overlap
that limits generalizability. This has important im-
plications for vascular interventional studies (76).
INDUCIBLE ISCHEMIA. Limited testing that avoids
test stacking can improve efficiency, and a method to
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1899
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 1 1 Coronary Artery Calcium From Standard Nongated CT Scans

A B

R
R

3 mm ECG-Gated CT Scans 6 mm Chest CT Scans

and All-Cause Mortality and All-Cause Mortality
Odds Ratios and 95% Confidence Intervals Odds Ratios and 95% Confidence Intervals
CAC
Categories

CAC >300

CAC = 101 - 300

CAC = 1 - 100

CAC = 0 (ref)

1 2 4 8 1 2 4 8

(Top) Illustrative example of the difference in sensitivity between 3-mm electrocardiogram (ECG)-gated computed tomography (CT) scans and 6-mm
chest CT scans in a single slice within an individual. (A) 3-mm ECG-gated CT (Agatston coronary artery calcium [CAC] score ¼ 372); (B) 6-mm chest CT
(Agatston CAC score ¼ 117). (Bottom) Odds ratios and 95% confidence intervals for the associations between 3-mm ECG-gated CT scans and mortality and
6-mm chest CT scans and mortality. *Adjusted for age, sex, diabetes, hypertension, hyperlipidemia, body mass index, smoking, and family history of
cardiovascular disease. Reprinted with permission from Hughes-Austin et al. (70).

enrich test positivity will be important. CAC predicts EVALUATING INTERMEDIATE STENOSIS. Coronary CTA
outcomes, but can it also predict presence of often reports intermediate stenosis, triggering further
myocardial ischemia for tiered testing? A meta- physiological testing. CTA-based fractional flow
analysis of 20 studies (n ¼ 2,123 patients) showed a reserve (FFR) may be the best next step, and local
stepwise increase in the frequency of ischemia ac- workstation-based methods might make it easier to
cording to CAC with very low rates among patients use. However, the specific thresholds for CTA-FFR
with very low CAC score (77). However, CAC values predicting ischemic versus nonischemic FFR
scores $400, although predicting high rates, showed with acceptable confidence are unknown. In one of
wide variability among studies. Zero to low CAC the first studies evaluating the utility of a hybrid
scores were infrequently associated with ischemia diagnostic approach with use of CTA-FFR (using a
and can be incorporated into tiered testing, but in- desk top FFR prototype), 50% with intermediate ste-
termediate to high CAC scores lack sufficient predic- nosis could be confidently triaged into ischemic
tive accuracy. versus nonischemic stenosis. CTA-FFR may be
1900 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

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F I G U R E 1 2 Digital Mammography and Screening for Coronary Artery Disease

1-Specificity
A
1.00

0.75

Sensitivity
0.50
0.7629 0.7092

P = 0.1080
0.25
B
0.00

0.00 0.25 0.50 0.75 1.00

1-Specificity

PCE + BAC PCE

(Left) Examples of breast and coronary arterial calcification. (A) A 48-year-old woman with normal mammogram with BAC ¼ 0 (left) and normal CT scan with CAC ¼
0 (right). (B) A 58-year-old woman with mammogram with BAC ¼ 1 (left) and CT scan with CAC ¼ 2 in the right coronary artery (right). (C) A 54-year-old woman with
mammogram with BAC ¼ 9 (left) and CT scan with CAC ¼ 7 in the left anterior descending coronary artery (right). (D) A 61-year-old woman with mammogram with
BAC ¼ 12 (left) and CT scan with CAC ¼ 12 in the left anterior descending and left circumflex coronary arteries (right). Arrows point to arterial calcification. (Right)
Receiver-operating characteristic curves and C-statistic of PCE and PCEþBAC for the prediction of high-risk CAC 4 to 12. BAC and PCE were equivalent for the
identification of women with CAC >0 and CAC 4 to 12. BAC ¼ breast arterial calcium; PCE ¼ Pooled Cohort Equations; other abbreviations as in Figure 11. Reprinted
with permission from Margolies et al. (71).

superior to methods just evaluating anatomic steno-
sis and may improve testing (78).
Sequential hybrid imaging strategies are becoming
prominent as a way for selective testing. Coronary
CTA has low positive predictive value, and whether
adding PET with higher PPV helps is not clear. In a
study of patients with intermediate probability (n ¼
864), PET myocardial perfusion imaging was per-
formed when CTA showed stenosis and found that
CAD can be excluded by CTA in 53% of patients with
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1901
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F I G U R E 1 3 Vascular Inflammation Thresholds Quantified by 18F-FDG PET Imaging

A 3.0 C 4.5
SUVmax Carotid Arteries

2.6
3.5

SUVmax Aorta
2.0

2.5
1.5

1.0 1.5
Controls Patients CVD Controls Patients CVD
at Risk Patients at Risk Patients

B 3.0 D 4.5
TBRmax Carotid Arteries

2.6
3.5
TBRmax Aorta

2.0

2.5
1.5

1.0 1.5
Controls Patients CVD Controls Patients CVD
at Risk Patients at Risk Patients

300

248
Subjects Needed Per Group

200
183

100

62
46
28
21 16
12
0
5% 10% 15% 20%
Estimated Reduction in TBRmax

Carotid Aorta

(Top) Gradual increase of TBRmax in the carotids and aorta between groups for the carotids (A and B) and aorta (C and D) in healthy control subjects,
patients at CVD risk, and patients with known CVD. The red dashed line represents the 90th percentile value in healthy control subjects. (Bottom)
Estimated sample sizes for vascular intervention studies based on our results. Sample sizes required for studies using TBRmax as the primary endpoint. These
are dependent on the estimated drug effect (ranging between 5% and 20%) and target vessel for imaging (carotid artery or aorta). CVD ¼ cardiovascular
disease; TBRmax ¼ maximum target to background ratio. Reprinted with permission from van der Valk et al. (76).
1902 JACC: Imaging Editors
Progress in Cardiovascular Imaging
good outcome; 49% of the rest can be excluded with
PET (normal perfusion), again with low event rates
similar to no obstructive CAD on coronary CTA.
Sequential approach can allow personalized testing
for CAD (79).
COMPARATIVE EFFICACY OF TESTING. Coronary CTA
has high sensitivity but low specificity, but how it
performs compared with quantitative coronary angi-
ography (QCA) using FFR, the gold standard, is of
interest. A prospective study of 252 patients from 5
countries (FFR þ ve for ischemia in 37%) showed that
CTA and invasive coronary angiography (ICA)
exhibited similar diagnostic performance for the
detection and exclusion of lesion-specific ischemia
(80). Coronary CTA might have a role in replacing ICA
for diagnosing obstructive coronary artery disease in
low- and intermediate-risk patients, but not when
pre-test probability of obstructive CAD is high.
DIAGNOSTIC STRATEGIES FOR CAD. Invasive angi-
ography is often used for detecting coronary artery
stenosis before cardiac valve surgery, but coronary
CTA may be more efficient. A systematic review of 17
studies (n¼1,107 patients) showed that CTA has
excellent sensitivity and negative LR for the detec-
tion of significant coronary stenosis (81).
The ideal screening test for chest pain should
noninvasively define both coronary anatomy and
ischemia. Would such information change the treat-
ing clinician’s decision-making?
Experienced cardiologists were asked to develop
management plan with clinical picture þ CTA alone
and then the same after getting FFR CT data. FFR CT
data changed management plans in 36% of patients
(FFR CT was >0.80 in 30% of patients graded as having
severe stenosis and FFR CT #0.80 in 5% graded as
having stenosis #50%). Availability of FFR CT results
substantially changes how patients with stable chest
pain are labeled and managed (82).
The significance of nonculprit vessel lesions is
often difficult to establish in patients with STEMI.
FFR CT might have a role in detecting lesion-specific
ischemia, but its performance is not known in this
setting. In a first of its kind study (83), CTA with
FFR CT and ICA with FFR were performed 1 month
after STEMI in patients with multivessel disease.
FFR CT was more accurate than CTA alone and was
similar to ICA, but it was only moderately effective
compared with invasive FFR for staged detection of
ischemia in STEMI patients with multivessel disease.
This suboptimal effectiveness, unlike its known effi-
cacy in patients with stable angina, might be due to
the fact that STEMI patients have a smaller vessel
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DECEMBER 2018:1883–914
volume and volume-to-mass ratio than do patients
with stable angina.
FFRCT has good diagnostic performance in trial
conditions, but its utility for real-world testing is un-
known. In a study of nonemergent patients having
CTA in Denmark (n ¼ 1,248, lumen reduction, 30% to
70%), 98% of patients had conclusive FFR CT results,
and implementation of FFRCT for clinical decision-
making influenced downstream diagnostic workflow
(84). FFRCT #0.75 had <10% false positivity, whereas
FFR CT between 0.76 and 0.80 showed much more
false-positive. Patients with FFR CT >0.80 being de-
ferred from ICA have a favorable short-term prognosis.
FFRCT is an exciting technique but requires many
assumptions and alternate methods of calculation
might improve its adoption. A novel method that can
be completed at point-of-care based on boundary
conditions derived from the structural deformation of
coronary lumen and aorta, was feasible, highly
reproducible, and reasonably accurate in detecting
FFR #0.8. This novel FFR CT showed better specificity
and positive predictive value, and incremental
benefit over coronary CTA alone (85).
Value-added CT technologies like CT myocardial
perfusion imaging and FFR CT might attenuate the
limited specificity of CTA. A 2-institution study
looked at the diagnostic performance of CT myocar-
dial perfusion imaging (MPI), CTA FFR, and CT MPI
integrated with CTA FFR with invasive FFR as the
gold standard (86).
CT MPI and CTA FFR were comparable to diagnose
functionally significant CAD, and diagnostic perfor-
mance was better by combining the techniques.
Hybrid approaches are possible because CTA FFR and
dynamic CT MPI provide complementary informa-
tion. A stepwise approach, reserving CT MPI for in-
termediate CTA FFR results (0.74 to 0.85), improved
efficient triage and diagnostic performance.
Does FFR CT predict coronary revascularization and
outcomes and improve efficiency of referral to ICA
after CTA? In a study from the PROMISE (Prospective
Multicenter Imaging Study for Evaluation of Chest
Pain) trial (where FFRCT was measured at a blinded
core lab on patients referred to ICA within 90 days
after CTA) (87), FFR CT was discordant with CTA and
ICA in 30% of the patients. FFRCT of #0.80 was a
significantly better predictor for revascularization or
MACE than severe CTA stenosis; it could decrease
futile ICA (no stenosis $50%) by 44%, and increase
the proportion of ICA leading to revascularization by
24%. Adding FFRCT to an anatomic CTA strategy for
evaluation of stable chest pain could improve the
efficiency of referral.
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
Positron emission tomography (PET) stress
myocardial perfusion is becoming an important test
for CAD, but knowing test-retest precision and daily
biological variability is important for understanding
its clinical utility. These authors found a  10 test-
retest methodological precision of global PET
myocardial perfusion done minutes apart and a  21%
day-to-different-day biological plus methodological
variability. This kind of information is crucial to
optimize stress testing (88). Cadmium-zinc-telluride
technology is thought to be an important advance
over conventional Anger cameras. A systematic re-
view found that cadmium-zinc-telluride MPI has
satisfactory sensitivity for angiographically signifi-
cant CAD, but had suboptimal specificity that calls for
further improvements in technology (89).
MINOCA is being recognized increasingly, and CMR
can identify different underlying etiologies. When to
do CMR for best diagnostic discrimination however is
unclear, and this study in 204 patients showed per-
forming CMR early (within 2 weeks of presentation) in
MINOCA provided the best window of opportunity for
maximizing the diagnostic yield, which is particularly
relevant in acute myocarditis and Takotsubo cardio-
myopathy. CMR established a definitive diagnosis in
70% of patients and had a significant additive effect
on diagnosis and/or clinical management in 66% of
patients, with LGE being the best independent pre-
dictor (90).
Should we worry about an intramural course of a
coronary artery that is found not uncommonly on
CTA? Among 210 patients (22% of the cohort, median
depth 1.9 mm into the myocardium, 40% with a deep
course) with an intramural course of a coronary ar-
tery, the 6-year cumulative event rate (unstable
angina pectoris requiring hospitalization, nonfatal
MI, all-cause mortality) was similar to those without
an intramural course (91). Thus, an intramural course
has a benign outcome if not accompanied by
obstructive CAD.
PROGNOSTICATION, OUTCOMES, AND TAILORED
THERAPY. Do presentation, risk assessment, testing
choices, and results differ by sex in stable symptom-
atic outpatients with suspected CAD? In a study of
10,003 subjects in the PROMISE trial, sex influenced
presentation (women were more likely to have some
risk factors), were thought to have lower risk and low
pre-test probability, had more stress imaging, and
more negative noninvasive test outcomes (92). This
might call for more personalized sex-specific
approaches.
CAC predicts CAD and its outcome, but whether it
can predict noncardiovascular disease, given that it is
JACC: Imaging Editors 1903
Progress in Cardiovascular Imaging
a measure of vascular aging, remains unclear. A study
of 6,814 participants from MESA (Multi-Ethnic Study
of Atherosclerosis) followed for a median of 10.2 years
showed that participants with elevated CAC were at
increased risk of cancer, chronic kidney disease,
chronic obstructive pulmonary disease, and hip frac-
tures (93). Those with CAC ¼ 0 were less likely to
develop common age-related comorbid conditions,
independent of known CVD risk factors, and seem to
be an example of “healthy agers.” Scarce public
health resources could be better directed by such
markers, because 20% of the first non-CVD event
happened in the 10% of patients with CAC >400, and
70% of the events were in those with CAC
>0 (Figure 14).
Because both plaque volume and composition
predict events, changes after therapy might have
important implications. CAC progression might
contain more prognostic information than 1 snapshot
measurement at a given time. Statins, however, affect
CAC differently from plaque, and serial changes in
CAC might or might not have important information.
In a prospective observational study of 5,933 partici-
pants free of CVD, CAC progression was only
modestly associated with CVD outcomes, but this
relationship was no longer significant when including
follow-up CAC in the model (94). Although CAC pro-
gression may carry some prognostic information, this
is largely contained in the last follow-up CAC score.
CAC scoring does not incorporate location and
distributional of calcified plaque—would it be better if
it did? A MESA substudy in 3,262 (50% of the cohort)
individuals with baseline CAC >0 showed that the
number of coronary vessels with CAC significantly
improved CHD and CVD event prediction and net
reclassification, but “diffusivity index” did not
further improve global risk prediction (95). Measures
of CAC distribution add predictive value to the
Agatston CAC score, especially in the intermediate
CAC range (1 to 300).
Do biomarkers influence the incidence and pro-
gression of CAC in asymptomatic middle-aged sub-
jects? The answer seems to be no from a study of 1,227
subjects with 2 CT scans 5 years apart. Of various
biomarkers of calcium-phosphate metabolism (5),
lipid metabolism (4), inflammation (2), kidney func-
tion (3), and myocardial necrosis (cardiac troponin I),
only LDL-C and total cholesterol were associated with
CAC incidence and phosphate with CAC progression,
whereas the 12 other biomarkers had no value (96).
Do exercise habits influence the ability of CAC
scores for predicting clinical risk? Among 10,690
asymptomatic patients undergoing CAC scanning,
CAC ¼ 0 showed low all-cause mortality regardless of
1904 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 1 4 CAC Score Stratum and New Non-CVD Diagnosis

40%
p < 0.001

Proportion of Participants with New Diagnosis 35%

30%

25%
p < 0.001
20%

15% p < 0.001

p < 0.001
10%
p < 0.001 p < 0.05 p < 0.001 p < 0.001
5%

0%
First Cancer CKD Pneumonia COPD DVT/PE Dementia Hip
Non-CVD Fracture
Event
CAC 0 CAC 1-400 CAC >400

40%
36.9%

35%
with Any First Non-CVD Diagnosis
Proportion of Participants

30%

25% 22.5%

20%

15%
11%
10%

5%

0%
CAC = 0 CAC 1-400 CAC >400
CAC = 0 vs CAC >0 CAC >400 vs CAC = 0
Unadjusted HR
0.41 (0.36, 0.45) 4.16 (3.58, 4.84)
(95% CI)
Multivariable
adjusted HR 0.75 (0.65, 0.86) 1.80 (1.48, 2.18)
(95% CI)

(Top) Proportion of participants within each CAC score stratum with any new non-CVD diagnosis and by each specific diagnosis. Pink bars ¼
CAC scores 0, green bars ¼ CAC scores of 1 to 400, and blue bars ¼ CAC scores >400. (Bottom) Proportion of participants with any non-
CVD diagnosis along with unadjusted (Model 1) and multivariable adjusted (Model 5) Cox proportional hazards ratios, adjusted for the
competing risk of fatal coronary heart disease (95% confidence intervals). Multivariable model was adjusted for age (best fit, see Methods
section of Handy et al. [93]), sex, race, socioeconomic status, health insurance status, smoking status, and pack-years of smoking, body
mass index, physical activity, diet, total number of medications used, systolic and diastolic blood pressure, antihypertensive medication use,
total and high-density lipoprotein cholesterol, lipid-lowering medication and aspirin use, and presence of diabetes. CAC ¼ coronary artery
calcium; CKD ¼ chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; CVD ¼ cardiovascular disease; DVT ¼ deep vein
thrombosis; PE ¼ pulmonary embolism. Reprinted with permission from Handy et al. (93).
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
the amount of exercise, but among CAC-positive
subjects, there was a stepwise increase in all-cause
mortality for each reported decrement in exercise,
most pronounced with CAC scores $400. Exercise
may be most protective in patients with more pro-
nounced atherosclerosis (97).
Long-term prognostic value of coronary CTA is well
known, but less so among patients with DM. In a
study of 1,823 patients with DM in the CONFIRM
study with 5-year clinical follow-up, nonobstructive
and obstructive CAD predicted higher rates of all-
cause mortality and MACE at 5 years than in nondia-
betic subjects (98). Interestingly, DM without CAD
had risk comparable to nondiabetic subjects. CTA can
thus predict prognosis in diabetic patients as well as
identify low-risk diabetic subsets.
Does secondhand tobacco smoke (SHTS) exposure
increase atherosclerosis in asymptomatic “never-
smokers”? In a first of its kind study, there was a
significant quantitative dose-response relationship in
never smokers between the extent of SHTS exposure
and the total extent of atherosclerosis manifested by
CTA, independent of conventional risk factors. The
number of major vessels involved as well as
segmental involvement with plaque or stenosis, CAC
score, and the percentage of segments with non-
calcified plaque were affected by SHTS. There may be
a case for regarding SHTS exposure as an important
risk factor (99).
The impact of pericardial fat on myocardial func-
tion and long-term CV prognosis independent of
systemic consequences of adiposity or hepatic fat is
an area of active debate. Among 4,234 participants
enrolled in the MESA study followed-up for a median
12 years, pericardial fat but not hepatic fat was asso-
ciated with a higher rate of incident hard ASCVD.
Pericardial fat is associated with poorer CVD prog-
nosis and LV remodeling independent of insulin
resistance, inflammation, and CT measures of hepatic
fat (100).
TAILORED THERAPY. CAC can fine-tune risk better
and thus can triage primary prevention patients for
statin therapy. In 3,745 subjects (in the Heinz Nixdorf
Recall cohort study) free of CVD or statin therapy,
European Society of Cardiology and American Heart
Association/American College of Cardiology guide-
lines differed in statin recommendation (34% vs.
56%) but prevalence of low CAC score (<100) was
similar in statin recommended patients (59% vs. 62%
for American Heart Association/American College of
Cardiology). Because CAC differentiates the risk for
future events, it can match intensified risk factor
modification to actual risk, thereby avoiding therapy
JACC: Imaging Editors 1905
Progress in Cardiovascular Imaging
in subjects with low coronary atherosclerosis who
have a low 10-year event rate (Figure 15). The popu-
lation attributable utility will possibly be different
depending on the guideline used (101). Non-
obstructive CAD strongly predicts ASCVD events, but
can it refine the pooled cohort equation for statin
therapy that is largely based on risk factors? Using 2
studies (2,295 subjects with nonobstructive CAD in
47%; median follow-up, 49 months; 67 ASCVD
events), these investigators (102) found that adding
nonobstructive CAD information into the pooled
cohort equation resulted in increased statin eligi-
bility. The absence of nonobstructive CAD could
reclassify even high scores toward statin ineligibility.
Nonobstructive CAD improves risk stratification and
statin eligibility therapy across sex and ethnicity
groups.
Detection of calcified coronary plaque could serve
as a motivational tool for physicians and patients to
intensify preventive therapies. A meta-analysis of
11,256 participants suggests that identifying calcified
coronary plaque significantly increases the likelihood
of initiation or continuation of pharmacological and
lifestyle therapies for the prevention of cardiovascu-
lar disease. There was a 2- to 3-fold increase in the
odds for initiation of ASA, statin, and blood pressure
therapy, as well as a >2-fold increase in statin
continuation among those with CAC (103).
TISSUE CHARACTERIZATION IN
HEALTH AND DISEASE
PARAMETRIC IMAGING. Diffuse myocardial fibrosis,
unlike the focal variety, may influence ventricular
remodeling, hemodynamic load, and clinical out-
comes in patients with repaired tetralogy of Fallot. A
good-sized study (n [ 84; median age 23 years)
showed that LV and RV ECV values were positively
correlated with each other and associated with RV
volume overload (not pressure overload) and
arrhythmia (104). ECV might improve risk stratifica-
tion and guide therapeutic interventions in patients
with repaired tetralogy of Fallot (Figure 16).
Few studies have prospectively investigated the
diagnostic and prognostic impact of CMR T1 mapping
and validated it against LV biopsies. A study of T 1
mapping (473 consecutive patients referred for CMR)
with 36 patients having a LV biopsy showed that ECV
accurately reflects the actual amount of extracellular
matrix expansion shown on histology (105). This is an
important study, because it shows that CMR T 1 map-
ping allows quantitative myocardial tissue evaluation
better than with conventional CMR (Figure 17).
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F I G U R E 1 5 Difference in Event Rate by CAC Score in Subjects With Potential Statin Therapy

A ESC Guidelines B AHA/ACC Guidelines

10.4 Years Coronary Event Rate (%)

No Statin Indication Statin Indication No Statin Indication Statin Indication

10.4 Years Coronary Event Rate (%)

14 12
12
10
10
8
8
6
6
4 4

2 2

0 0
0 1 2 ≥3 ≤3 4-5 6-8 ≥9 <2.5 2.5-4.9 5-5.9 6-7.5 7.5-9.9 10-14.9 15-19.9 ≥20
Score ASCVD
N: 363/135/10 168/247/103 51/59/8 47/129/137 N: 437/182/20 78/86/26 Score 62/114/65 36/129/100
380/360/79 140/267/195 36/94/61 19/86/142 247/226/23 116/154/49 105/196/154 36/114/175

CAC = 0 CAC 1-99 CAC ≥100 CAC = 0 CAC 1-99 CAC ≥100

C D
20 No Statin Indication Statin Indication No Statin Indication Statin Indication
10.4 Years CVD Event Rate (%)

20
10.4 Years CVD Event Rate (%)

18 18
16 16
14 14
12 12
10 10
8 8
6 6
4 4
2 2
0 0
0 1 2 ≥3 ≤3 4-5 6-8 ≥9 <2.5 2.5-4.9 5-5.9 6-7.5 7.5-9.9 10-14.9 15-19.9 ≥20
Score ASCVD
N: 363/135/10 168/247/103 51/59/8 47/129/137 N: 437/182/20 78/86/26 Score 62/114/65 36/129/100
380/360/79 140/267/195 36/94/61 19/86/142 247/226/23 116/154/49 105/196/154 36/114/175

CAC = 0 CAC 1-99 CAC ≥100 CAC = 0 CAC 1-99 CAC ≥100

(A and B) Coronary event rate and (C and D) cardiovascular event rate for subjects with and without statin indication according to (A and C) ESC and (B and D) AHA/ACC
guidelines for CAC of 0, 1 to 99, and $100, stratified by SCORE for ESC guidelines and ASCVD score for AHA/ACC guidelines. ACC ¼ American College of Cardiology;
AHA ¼ American Heart Association; ESC ¼ European Society of Cardiology; SCORE ¼ Systematic COronary Risk Evaluation: High & Low cardiovascular Risk Charts.
Reprinted with permission from Mahabadi et al. (101).

Stress CMR is probably the most accurate test for
ischemia at this time, but needs gadolinium. T 1
mapping at rest and during adenosine stress allows
estimation of myocardial blood volume (MBV) as a
comprehensive marker of ischemia. In a proof-of-
principle study, these authors could show for the
first time that T 1 mapping can differentiate normal,
remote, and ischemic myocardium via distinctive
ranges of T1 reactivity to adenosine vasodilatory
stress. Blunted T 1 reactivity in remote myocardium of
CAD patients may help understand its physiology
even when there is no critical flow limiting obstruc-
tion (106).
T 1 mapping parameters in nonischemic dilated
cardiomyopathy might have more prognostic in-
formation than conventional markers of adverse
outcome. In a prospective observational multi-
center longitudinal study of
patients with dilated nonischemic dilated cardio-
myopathy, only native T 1 best predicted all-cause
mortality and HF in adjusted analysis
(Figure 18). This value over traditional prognostic
markers (like function, structure, and LGE), sug-
gests a prominent impact of diffuse myocardial
disease (107).
Hematocrit affects calculation of ECV, and a
method that does not need its concurrent measure-
ment might be advantageous. In a proof-of-concept
study among 427 subjects with a wide range of
health and disease, these authors were able to derive
such a measure (108): synthetic ECV based on the
relationship between native R1blood and Hct that
correlated well with conventional ECV in both the
validation and outcome cohort in terms of outcomes.
This might improve ECV adoption into routine clin-
637 consecutive ical practice.
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018
DECEMBER 2018:1883–914
How to best predict contractile recovery after an MI
is not clear, and ECV of the infarct zone (assessing
severity of myocardial injury), might be better than
LGE (which assesses infarct extent), because it might
better evaluate severity of tissue damage within
infarcted myocardium. In this study (109), ECV had
higher accuracy than LGE extent to predict improved
wall motion, and acute infarct ECV independently
predicted convalescent infarct strain and EF, whereas
LGE could not. It might add particular value in larger
transmural infarcts complementing transmural
infarct extent by LGE.
LATE GADOLINIUM ENHANCEMENT. LGE size in-
fluences AF recurrence following ablation, but tradi-
tional methods have limitations. Using a novel
method (image intensity ratio, which normalizes im-
age intensity by blood pool intensity) in 165 patients
undergoing AF ablation, these authors found that AF
recurrence progressively increased with greater
extent of LGE; LGE #35% had good outcomes,
whereas LGE >35% predicted AF recurrence in the
year after ablation. LGE extent could help triage pa-
tient selection as well as need for more comprehen-
sive ablation (110).
Can CMR, a marker of amyloid infiltration of the
myocardium, help with more precise prognosis in AL
cardiac amyloidosis than biomarker staging? In
multivariate modeling with biomarker stage, global
LGE remained prognostic (hazard ratio: 2.43). Diffuse
LGE provided incremental prognosis over cardiac
biomarker stage in patients with AL cardiac
amyloidosis (111).
What does the published data say about use of LGE
in cardiomyopathies, infiltrative diseases, and hy-
pertrophic cardiomyopathy? A meta-analysis of 7
studies with a total of 425 patients with amyloidosis
and mostly normal EF followed-up for 25 months
showed that endomyocardial biopsy was positive for
amyloidosis in 20%, whereas LGE was present in 73%
of patients (112). LGE-positive patients had increased
overall mortality compared with those without LGE
(pooled odds ratio: 4.96; 95% confidence interval:
1.90 to 12.93; p ¼ 0.001). LGE predicts prognosis
(increased risk of all-cause mortality) in patients with
known or suspected cardiac amyloidosis irrespective
of histopathological diagnosis of amyloidosis on car-
diac biopsy.
What is collectively known about efficacy of LGE
for predicting ventricular tachyarrhythmia risk in
patients with ventricular dysfunction? A meta-
analysis of 19 studies (n ¼ 2,850 patients with 423
arrhythmic events over 2.8 years of follow-up)
showed that the composite arrhythmic endpoint was
8.6% per year with presence of LGE and 1.7% in
JACC: Imaging Editors 1907
Progress in Cardiovascular Imaging
F I G U R E 1 6 ECV and Type of Hemodynamic Load
Multivariable analysis identified abnormally increased LV ECV (>28%) as independently
associated with arrhythmia after adjusting for age and RV mass index.
p = 0.002
50
p = 0.016
p = 0.003
40
30
ECV (%)
20
10
0
Volume Mixed Volume and Pressure
Overload Pressure Load Overload
LV RV
Comparison between left (LV) and right ventricular (RV) extracellular volume fraction
(ECV) and different types of predominant hemodynamic load. Reprinted with permission
from Chen et al. (104).
LGE-negative patients with no differences between
ischemic and nonischemic cardiomyopathy patients.
CMR could improve patient selection for implantable
cardioverter-defibrillators (113).
Predictive value of LGE for adverse events and
death in hypertrophic cardiomyopathy is still being
evaluated. A meta-analysis of 2,993 patients (median
follow-up 36.8 months) showed that LGE was asso-
ciated with an increased risk for total and cardiac
deaths even after adjusting for baseline characteris-
tics; risk was continuous with the extent of LGE.
CMR might allow better targeting of intensive
medical treatment, surveillance, and device implan-
tation (114).
LGE plays an important role in evaluation of pa-
tients with known or suspected cardiac sarcoidosis.
A meta-analysis (760 patients; 3.0  1.1 years of
follow-up; 95% with extracardiac sarcoidosis, and
22% with cardiac involvement) (115) showed that
1908 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 1 7 CMR T 1 Mapping Allows Quantitative Myocardial Tissue Evaluation

A B C
>1500 ms

0 ms

100
CMR-ECV
Lowest Tertile:
≤25.7%
80 Middle Tertile:
25.8 - 28.5%
Highest Tertile:
Event-Free Survival (%)

≥28.6%
60

40

20

20.0 25.0 30.0 35.0

Follow-Up (Months)

(Top) Cardiac magnetic resonance T1 map compared with histology. (A) Native T1 map in a patient with heart failure and preserved ejection
fraction. Extracellular volume by cardiac magnetic resonance T1 mapping was 26.5%. (B) Left ventricular histological specimen of the same
patient scanned with TissueFAXS software. (C) Same specimen after a color-threshold approach was used to visualize and quantify extra-
cellular matrix (30.7%). (Bottom) Kaplan-Meier plot for event-free survival, stratified by tertiles of CMR-ECV. Log-rank test, p ¼ 0.013. ECV
calculation by CMR T1 mapping accurately reflects the actual amount of extracellular matrix expansion by histology and provided evidence
for the prognostic and diagnostic usefulness. CMR-ECV ¼ extracellular volume as determined by cardiac magnetic resonance imaging T1
mapping. Reprinted with permission from Kammerlander et al. (105).

patients with LGE had higher odds for all-cause study with 203 subjects and 37 healthy control sub-
mortality than those without LGE (annualized event jects, extracellular volume of the myocardium
rate of the composite outcome of 12% vs. 1.1%). indexed to body surface area (iECV) correlated well
Tissue characterization has powerful prognostic with diffuse histological fibrosis on myocardial bi-
implications. Progressive myocardial fibrosis prob- opsies. Using iECV and LGE identified 3 groups:
ably is the mechanism for decompensation to HF in normal myocardium (iECV <22.5 ml/m 2), extracellular
aortic stenosis, and CMR might help pinpoint this expansion (iECV $22.5 ml/m 2), and replacement
transition. In a prospective observational cohort fibrosis (presence of midwall LGE) that had
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1909
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

F I G U R E 1 8 Kaplan-Meier Curves for CMR Parameters and All-Cause Mortality in Nonischemic Dilated Cardiomyopathy

A B
1.00 1.00

0.95
0.95
0.90
Survival

Survival
0.90 0.85

0.80
0.85
0.75
2
Chi 19.0 (p < 0.001), HR 5.2 (2.4 – 14.6) Chi2 47.5 (p < 0.001), HR 12.0 (4.9 – 29.6)
0.80 0.70
0 5 10 15 20 25 0 5 10 15 20 25
Time (Months) Time (Months)
Numbers at Risk (Native T1) Numbers at Risk (Native T1)
<2SD (Normal) 313 312 289 222 109 46 <4SD 485 484 448 317 157 54
≥2SD (Abnormal) 324 323 293 214 112 37 ≥4SD 152 150 133 102 55 18
Native T1 Native T1
<2SD (Normal) ≥2SD (Abnormal) <2SD ≥2SD - 4SD ≥4SD - 6SD ≥6SD

C D
1.00 1.00

0.95 0.95
Survival

Survival

0.90 0.90

Chi2 9.2 (p = 0.002), HR 2.0 (1.4 – 6.3) Chi2 2.7 (p = 0.14), HR 3.1 (0.6 – 12.1)
0.85 0.85
0 5 10 15 20 25 0 5 10 15 20 25
Time (Months) Time (Months)
Numbers at Risk (LGE) Numbers at Risk (LVEF)
Absent 466 463 429 316 164 48 >35% 513 511 465 329 166 48
Present 171 171 153 104 48 13 ≤35% 124 123 117 90 47 13
LGE LVEF
Absent Present >35% ≤35%

(A) Native T1 (normal vs. abnormal myocardium, based on >2 SDs above the mean of the normal reference range) (17), (B) native T1 ranked by
2n-times SD (ranks of SD: <2, $2 to 4, $4 to 6, $6) (17), (C) late gadolinium enhancement present versus absent, and (D) left ventricular
ejection fraction <35%. T1 mapping (which detects diffuse myocardial disease) predicts all-cause mortality and a composite HF endpoint of HF
death and HF hospitalization in dilated cardiomyopathy independent of and better than conventional markers of LV function, and
replacement fibrosis (measured by LGE). CMR ¼ cardiac magnetic resonance. Reprinted with permission from Puntmann et al. (107).

increasingly worse myocardial morphology, more How can one predict future repeat episodes in
dysfunction, and greater mortality (Figure 19). This is recurrent pericarditis? LGE might be one good
an interesting classification that needs further eval- answer. In this study, LGE had incremental value over
uation, but it is becoming clear that CMR can probably clinical and laboratory variables (integrated discrim-
optimize timing for intervention (116). ination improvement: 8%; net reclassification
1910 JACC: Imaging Editors JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018

Progress in Cardiovascular Imaging DECEMBER 2018:1883–914

F I G U R E 1 9 CMR Categorization of Myocardial Fibrosis in Aortic Stenosis

T1 Mapping for iECV Late Gadolinium

Measurement Enhancement

Normal
Myocardium
(iECV <22.5 mL/m2)
(N = 71)
No fibrosis
No mid-wall LGE
iECV = 12.7 mL/m2

Extracellular
Expansion
(iECV ≥22.5 mL/m2)
(N = 31)
Diffuse fibrosis
No mid-wall LGE
iECV = 26.1 mL/m2

Replacement
Fibrosis
(N = 37)
Mid-wall LGE
present (red arrows)
iECV = 30.8 mL/m2

A 8 Peak Aortic Velocity B 200 LV Mass (Indexed)

Peak Aortic Velocity (m/s)

7
LV Mass (indexed)

6 150
(g/m2)

5
100
4
3 50
2
P < 0.001 P < 0.0001
1 0
Normal Extracellular Replacement Normal Extracellular Replacement
Myocardium Expansion Fibrosis Myocardium Expansion Fibrosis

C 6 Natural Log (hs Troponin I) D 40 Diastolic Dysfunction

Natural Log (Hs T ni)

4 30
E/e’

2 20

0 10

P < 0.0001 P = 0.04

–2 0
Normal Extracellular Replacement Normal Extracellular Replacement
Myocardium Expansion Fibrosis Myocardium Expansion Fibrosis

E All-Cause Mortality by Group

100
Normal Myocardium
90
Percent Survival

Extracellular Expansion
80
Replacement Fibrosis
70
60
50 Log-rank Test
P = 0.009

0 250 500 750 1000 1250 1500

Days From Recruitment
n = 80 n = 80 n = 80 n = 74 n = 26 n = 24 n=4
n = 38 n = 38 n = 36 n = 32 n = 27 n = 13 n=1
n = 43 n = 41 n = 39 n = 36 n = 24 n=6 n=1

(Top) CMR categorization of myocardial fibrosis in aortic stenosis. Patients with aortic stenosis were categorized into 3 groups based upon
cardiac magnetic resonance (CMR) assessments of fibrosis. (Bottom) Progressive LV decompensation on moving from normal myocardium to
extracellular expansion to replacement fibrosis. On moving from normal myocardium to extracellular expansion and then replacement fibrosis,
there was a stepwise increase in the following measures: (A) the severity of valve narrowing; (B) the degree of hypertrophy; (C) myocardial
injury; (D) left ventricular (LV) performance; and (E) all-cause mortality. hsTni ¼ high-sensitivity troponin I concentration; iECV ¼ indexed
extracellular volume; LGE ¼ late gadolinium enhancement. Reprinted with permission from Chin et al. (116).
JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 12, 2018 JACC: Imaging Editors 1911
DECEMBER 2018:1883–914 Progress in Cardiovascular Imaging

improvement: 36%). Greater extent of LGE meant
shorter time to recurrence as well as a higher recur-
rence rate on follow-up. CMR can thus help decision
making in recurrent pericarditis (117).
CMR is very accurate for MI size and remodeling;
naturally, there is interest in using CMR to reduce
sample size in RCTs. However, there is significant
heterogeneity in the design of RCTs using CMR to
quantify MI size and uncertainty about when to do
the CMR study. An expert group provides guidance
(118)—patient selection (ischemic time <6 h and pre-
PPCI Thrombolysis In Myocardial Infarction flow
grade 0 or 1) can reduce sample size by one-third.
Acute MI size (CMR performed on day 3, 4, or 5)
should be the preferred surrogate endpoint, and 6
months would be the optimal timing for data on both
chronic MI size and LV remodeling. MI size should be
reported as %LV, and studies should provide more
reliable MI size in the control arms for future sample-
size calculation.
OTHER TESTING. Technetium pyrophosphate
PYP) imaging is very important for detecting trans-
thyretin cardiac amyloidoses (ATTR-CA) in patients
with HF, but its role in detecting TTR deposition in
asymptomatic carriers of TTR mutations is unclear. A
study in asymptomatic carriers of TTR mutations
99m
showed that Tc-PYP uptake may be the first
measurable manifestation of
involvement, preceding overt echocardiographic,
cardiac biomarker, or clinical signs. 99m Tc-PYP cardiac
imaging could have a role in early detection of amy-
loid in this population (119). How can one improve
uptake of such imaging? Bisphosphonate scintigraphy
is an excellent agent to diagnose and type cardiac
amyloidosis diagnosis, but is a laborious procedure
especially for frail patients. This study (120) showed
99m
that one could just use early phase Tc-hydroxy-
methylene diphosphonate scintigraphy, because it
matched late-phase findings. Such a change in pro-
tocol could increase its use and cost effectiveness.
It is clear from this compilation that imaging is
growing rapidly and in a healthy manner, with much
provocative science that has the potential to change
how we manage cardiovascular prevention, diag-
nosis, and treatment. We at JACC: Cardiovascular
Imaging strongly believe that disseminating good
ideas in a concise manner helps the field grow and
stay vigorous, and we are looking forward to share
99m
Tc- with you the excitement of new discovery in the next
iteration of this collection.
ADDRESS FOR CORRESPONDENCE: Dr. Y. Chandra-
shekhar, Division of Cardiology, Mail Code: 111c,
University of Minnesota/VAMC, 1 Veterans Drive,
Minneapolis, Minnesota 55417. E-mail: shekh003@
amyloid heart umn.edu.

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