MOLECULAR IMAGING (J WU AND P NGUYEN, SECTION EDITORS)
Molecular Imaging to Monitor Left Ventricular Remodeling
in Heart Failure
Elias Ylä-Herttuala1 & Antti Saraste2,3 & Juhani Knuuti2,3 & Timo Liimatainen4,5 & Seppo Ylä-Herttuala1,6
Published online: 26 February 2019
# The Author(s) 2019
Abstract
Purpose of Review Cardiovascular diseases are the leading cause of deaths worldwide. Many complex cellular and molecular
pathways lead to myocardial remodeling after ischemic insults. Anatomy, function, and viability of the myocardium can be
assessed bymodernmedical imaging techniques by both visualizing and quantifying damages. Novel imaging techniques aim for
a precise and accurate visualization of the myocardium and for the detection of alternations at the molecular level.
Recent Findings Magnetic resonance imaging assesses anatomy, function, and tissue characterization of the myocardium non-
invasively with high spatial resolution, sensitivity, and specificity. Using hyperpolarized magnetic resonance imaging, molecular
and metabolic conditions can be assessed non-invasively. Single photon-emission tomography and positron-emission tomogra-
phy are the most sensitive techniques to detect biological processes in the myocardium. Cardiac perfusion, metabolism, and
viability are the most common clinical targets. In addition, molecular-targeted imaging of biological processes involved in heart
failure, such as myocardial innervation, inflammation, and extracellular matrix remodeling, is feasible.
Summary Novel imaging techniques can provide a precise and accurate visualization of the myocardium and for the detection of
alternations at molecular level.
Keywords Myocardium . Infarction .MRI . HyperpolarizedMRI . PET . SPECT
Introduction
Cardiovascular diseases (CVD) are the leading cause of
death worldwide and consist of a variety of diseases from
cardiac dysfunction to aneurysm rupture [1–3]. In this re-
view, we describe how novel imaging techniques including
magnetic resonance imaging (MRI), hyperpolarized MRI
(hMRI), positron-emission tomography (PET), and single
photon-emission computed tomography (SPECT) tech-
niques can be used to image myocardial infarction (MI)
and myocardial remodeling post-MI. MI develops when re-
duced blood flow and lack of oxygen lead to death of
cardiomyocytes via necrosis, inflammation, replacement
of extracellular space by fibrosis, protein infiltration, and
myocardial disarray [4, 5]. Overall, fibrosis is thought to
be the final common pathway in various myocardial
This article is part of the Topical Collection on Molecular Imaging
* Seppo Ylä-Herttuala
Seppo.Ylaherttuala@uef.fi
Elias Ylä-Herttuala
elias.yla-herttuala@uef.fi
Antti Saraste
antti.saraste@utu.fi
Juhani Knuuti
juhani.knuuti@utu.fi
Timo Liimatainen
timo.liimatainen@oulu.fi
1 A.I. Virtanen Institute for Molecular Sciences, University of Eastern
Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
2 Turku PET Centre, Turku University Hospital and University of
Turku, Turku, Finland
3 Heart Center, Turku University Hospital, Turku, Finland
4 Research Unit of Medical Imaging, Physics and Technology,
University of Oulu, Oulu, Finland
5 Department of Diagnostic Radiology, Oulu University Hospital,
Oulu, Finland
6 Heart Center, Kuopio University Hospital, Kuopio, Finland
Current Cardiovascular Imaging Reports (2019) 12: 11
https://doi.org/10.1007/s12410-019-9487-3
diseases [6]. Intense fibrosis leads to scar formation [7••,
8–11], which further changes the shape and function of the
left ventricle (LV) and can be manifested as dilation and
thinning of the myocardium, hypertrophy of the remote
areas surrounding MI, and overall decline of the heart func-
tion (Fig. 1) [3, 12–14]. All of these features can be accessed
by kinematic imaging over the heart cycle [3].
To imageheart function, ultrasoundandcomputed tomog-
raphy (CT) are applied besides the above mentioned tech-
niques [3, 15, 16]. Nuclear medicine imaging techniques,
namely PET and SPECT, are used to measure changes in
perfusion, metabolism, andmolecular pathways at the cellu-
lar level during the remodeling [3]. Tracer molecule owing a
capability to bind into defined receptor or other molecule
steers radionuclide or other compound which enhances im-
age contrast into target tissue [17]. Although tracers have
been developed forMRI andSPECT, themost sensitive tech-
nique is still PET [3]. To add sensitivity of MRI, novel tech-
niques based on hMRI have been developed which have en-
abled imaging of the cell cycle and cell metabolism [18•].
MRI
Cardiac magnetic resonance imaging (cMRI) contains a
wide variety of options to study cardiac anatomy, function,
infarct scar, and fibrosis and to characterize the myocardium
by relaxation timemapping, perfusion, water diffusion, wall
movement, and myocardial stiffness [19, 20]. cMRI is cur-
rently the golden standard to assess anatomy and function of
the myocardium non-invasively with high spatial resolution
and accuracy [3, 15, 16].
Functional cMRI
The anatomy and functional images from the LVare typically
imaged by acquiring rapidly either with multiple 2D- or 3D-
cine images that are covering the whole heart during more
than 95% of the cardiac cycle [21]. Images allow the accurate
determination of end diastolic volume (EDV) and end systolic
volume (ESV) which are further used to calculate ejection
fraction (EF), stroke volume (SV), and cardiac output (CO)
[3, 12, 15, 16, 22]. Reduced EF together with increased EDV
and decreased myocardial thickness are the clearest signs of
reduced systolic function and remodeling [12, 13, 15, 23, 24].
Additionally, EF and EDV have been shown to increase as a
function of time after MI reperfusion in human [25], swine
[20], and mice [26]. As LV becomes globally thinner, MI scar
tissue expands and causes extra workload in the LV, hypertro-
phy, and expansion of the healthy myocytes to maintain CO
[12, 27]. Recently, texture analysis applied on MRI cine im-
ages was demonstrated to differentiate nonviable and viable
MI areas and remote areas of the myocardium [28]. Texture
analysis finds the patterns and relationships among pixels
from heterogeneities within the imaging target [28].
There are also several other methods to study anatomy and
function of the heart. Bright-blood technique is used for the
detection of hemorrhage in the myocardium [29] whereas
dark-blood technique is used to improve the discrimination
of myocardium and adjacent blood pool revealing small areas
of MI in the endocardium [30]. Myocardial tagging is an im-
aging technique which assesses themotion and deformation of
LV myocardium with good temporal and spatial resolution
[31]. Therefore, myocardial deformation and motion stiffness
caused by MI and fibrosis can be detected by myocardial
Fig. 1 Schematic picture showing gross changes in adverse cardiac remodeling post-MI (adapted with permission from Springer Nature: van den Borne
SW) [14]
11 Page 2 of 13 Curr Cardiovasc Imaging Rep (2019) 12: 11
tagging [32, 33]. Feature tracking is a novel image analysis
technique for myocardial tagging that was shown to be a fea-
sible and robust technique to detect LV motion where data
analysis is faster compared to myocardial tagging [33].
Contrast Agent Imaging: Late Gadolinium
Enhancement and Extracellular Volume
The current gold standard to assess and localize the chronic MI
area in clinics is the contrast agent (CA)–based late gadolinium
enhancement (LGE) technique. Gadolinium (Gd) accumulates
into expanded extracellular space in irreversibly damaged MI
tissue and its washout back to the blood stream is delayed,
which shortens T1 relaxation time in the MI area [7••]. Thus,
Gd accumulation is detected as a delayed hyperintensity in T1-
weighted MR images (Fig. 2) [7••]. Delayed hyperintensity in
the myocardium and signal from blood is hard to distinguish.
To improve contrast between infarct scar and blood in LGE, a
T2 preparation was added between inversion pulse and image
acquisition [34]. Cons of the LGE technique include the inabil-
ity to show the quality of the scar, emphasis on extracellular
water content, and failure to detect diffuse fibrosis and global
changes in the myocardium after the injury [15, 35]. In a recent
myocardial permeability study, measured with albumin-bound
Gd, alternations were associated with remodeling between
acute and chronicMI [36]. T1 mapping before and after contrast
injection together with hematocrit were essential to calculate
the extracellular volume (ECV) [15, 16, 37]. Larger ECV frac-
tions were measured in MI (54 ± 1%) than in remote myocar-
dial tissue (29 ± 2%) [38]. Similar ECV differences between
MI and healthy myocardium (25 ± 3%) have been reported in
the myocardium [39].
ECV technique is a sensitive method to detect the distribu-
tion of the cellular and extracellular interstitial matrix com-
partments [6]. It has been shown to reflect the extent of myo-
cardial fibrosis and has been validated against collagen vol-
ume fraction (Table 1) [40]. It has been reported to agree better
with the collagen volume fraction than the post-contrast T1
alone [41] and to be more accurate in the detection of acute
MI compared to LGE [7••]. Additionally, ECV is used to
evaluate the transmural extent of MI [7••].
Conventional Relaxation Times
Visualization of the myocardial tissue and detection of both
acute and chronic MI can be done without CA. These tech-
niques offer quantitative assessment of the alternations in the
composition of myocardial tissue based on intrinsic water
properties, longitudinal T1 [7••, 42, 43] and transversal T2
relaxations [42, 44], to generate contrast within the myocardi-
um [6]. T1-weighted images are typically used for anatomical
imaging and T2-weighted images for edema and imaging of
transient ischemia (Table 1) [45]. T1 and T2 relaxations can be
mapped by acquiringmultiple relaxation weighted images and
by fitting a curve to signal intensities pixel-by-pixel manner to
form relaxation time maps [35, 44, 46]. Both T1 and T2 map-
ping also allow visualization and quantification of global
changes in the myocardium (Table 1) [11, 44, 46].
T1 relaxation time is elevated during MI development [6,
10, 38, 39, 47] and it has been shown to distinguish between
reversible and irreversible damages in post ST-elevation MI
(STEMI) [22, 48, 49]. In chronic MI, native T1 relaxation
times are lower than in acute MI because edematous and ne-
crotic tissues in the acute MI are replaced by smaller amounts
of expanded extracellular collagen [7••, 50]. Therefore, T1
mapping can be used for diagnostic purposes to detect differ-
ent pathological states in the myocardium (Table 1) [6, 39,
40].
T2 relaxation determines edema via increased T2 relaxation
time resulting from an increased amount of interstitial free
water [28]. Therefore, T2 relaxation time is suitable for the
determination of the area at risk in acute MI [6, 28, 40].
However, T2 suffers from a poor contrast-to-noise ratio com-
pared to T1 and longitudinal rotating frame relaxation time
(T1ρ) [51]. T2* relaxation time can be chosenwhenmyocardial
iron content is used to detect myocardial hemorrhage since
T2* relaxation time is more sensitive for magnetic susceptibil-
ities than T2 due to the accumulated iron content (Table 1) [15,
28, 40, 52].
T1ρ Relaxation Time
Another advanced technique is based on the mapping of a
longitudinal rotating frame relaxation time (T1ρ) which mea-
sures relaxation during a radiofrequency (RF) pulse [42, 53].
T1ρ relaxation is sensitive to slowmolecular motions (range of
0.1 to 10 kHz in vivo compared to fast molecular motions at
Larmor frequency at 10–500MHzwhich are used in T1 and T2
relaxation timemeasurements) [7••]. In general, T1ρ relaxation
time is always between T1 and T2 relaxation times ap-
proaching T2 when spin-lock pulse power nears zero [51].
Increased T1ρ relaxation time associates with increased extra-
cellular volume and fibrotic area in MI [37, 53] and correlates
with LGE in mice (Fig. 2) [7••, 54], pigs [51], and humans
[55] after MI. One limitation of the T1ρ relaxation time map-
ping in clinics is the relatively high specific absorption rate
(SAR) causing tissue heating [7••].
Relaxation Along Fictitious Field
Relaxation along a fictitious field (RAFF) in the nth rotating
frame (RAFFn) is a novel MRI relaxation time technique to
perform rotating frame relaxation time measurements with
less SAR [7••, 56, 57••, 58••]. RAFF takes advantage of the
fictitious magnetic field which is produced by a fast sweep of
the effective RF field [56, 57••]. Advantages of the low SAR
Curr Cardiovasc Imaging Rep (2019) 12: 11 Page 3 of 13 11
become more evident when RAFF in the higher rank (n) ro-
tating frames (RAFFn), an extension of RAFF, is used.
Typically, n varies between 1 and 5 in imaging applications
[56, 57••]. The contrast betweenMI and remote areas has been
demonstrated with RAFFn technique in mice and the MI area
was equally accurately detected as with T1ρ, LGE, and histol-
ogy (Fig. 2) [7••]. TRAFFn relaxation times are also elevated
and more sensitive than T1ρ in the detection of fibrotic area in
the hypertrophic myocardium in mice [59].
Hyperpolarization
A novel imaging technique to measure real-time metabolic ac-
tivity without ionizing radiation is hyperpolarized MRI
(hMRI). The most common technique of hMRI is dynamic
nuclear polarization (DNP). Most often, DNP is based on the
dynamics of the downstream metabolism of [1-13C]-labeled
pyruvate which is the final product of the glycolytic glucose
breakdown [18•]. In healthy myocytes and in aerobic
Fig. 2 Relaxation time maps, LGE, cine, and a corresponding histology
image with sirius red–stained section from the infarcted mouse heart
21 days after infarct. Red arrow indicates the infarct area and black/
white arrow shows the remote control area. B1 homogeneity was
verified to be nominal ± 10% Hz in the area of the whole myocardium
(adapted from Yla-Herttuala E) [7••]
11 Page 4 of 13 Curr Cardiovasc Imaging Rep (2019) 12: 11
conditions, pyruvate is converted to acetyl-CoA and CO2/bi-
carbonate via pyruvate dehydrogenase [18•]. In anaerobic con-
ditions, the lack of oxygen shifts energy conversion to lactate
formation via lactate dehydrogenase [18•]. Imaging [1-13C]-
labeled pyruvate with hMRI is over 10,000 times more sensi-
tive than the conventional MR spectroscopy which makes it
possible to accurately characterize and image low natural abun-
dances ofmetabolic compounds in healthy and ischemic tissues
[18•]. hMRI with DNP has potential to add much more sensi-
tivity and specificity for the characterization of the ischemic
area and effects of the revascularization therapies since DNP
technique reflects energy homeostasis [18•]. Fast T1 decay (~
45 s for [1-13C]-labeled pyruvate) of the substrate limits the
hMRI applications [18•]. Big efforts have been made to make
hMRI available for human use [60] although most hMRI car-
diac imaging studies are still done in experimental animals
[60–63]. In a pig reperfusion model, a significant increase in
lactate level after myocardial reperfusion was found whereas
bicarbonate level remained low after 5 min reperfusion [64]
which clearly demonstrates fast metabolic alternations after re-
perfusion. Supporting these findings, an elevated level of lac-
tate and a decreased level of bicarbonate were found in an
ex vivo infarction study and myocardial reperfusion studies
(Fig. 3) [61, 65, 66]. Moreover, in an in vivo porcine study,
LV wall motion was retained when bicarbonate level returned
back to normal, but LGE was unchanged after reperfusion
(Fig. 3) [62]. Additionally, decreased pH due to increased gly-
colysis and intracellular proton and lactic acid production were
found in ischemic myocardium [18•, 67, 68]. Reduction of the
Krebs cycle flux, where the ladder production from [1-13C]-
pyruvate to different metabolic compounds takes place, was
correlated to the LV systolic dysfunction in rats [69]. Along
with the above myocardium studies, hMRI has been used to
study diabetic cardiomyopathy, fibrosis, hypertrophy and cor-
onary artery disease in animal models, and patients with prom-
ising results [18•, 70].
Other MRI Techniques
Myocardial perfusion gives useful information about cap-
illary blood flow in the myocardium. Myocardial perfu-
sion can be measured without CA by techniques of arte-
rial spin labeling [71] and blood oxygen level-dependent
contrast [15]. CA is used in myocardial angiography,
where blood flow inside coronary arteries can be mea-
sured since the blood flow is alternated in the area of
MI compared to the surrounding heart muscle [72]. CA-
MRA has also been used to determine microvascular ob-
struction in swine acute MI model with high accuracy [22,
71]. Increased ECV, loss of cardiomyocytes and therefore
loss of orientational structure, increases water diffusion in
MI compared to the rest of the myocardium [3] which can
be imaged with the diffusion weighted MRI [73].
Diffusion tractography, [3] measuring the orientation of
cardiomyocytes, has grown in the CMRI field since dif-
fusion tractography was introduced in rat MI model [74];
MI area is disturbing the normal form of crossing helical
fiber architecture of normal myocytes. Bright-blood,
which is gradient-echo based and black-blood, which is
a spin-echo based, T2-weighted sequence, can be used to
assess myocardial structure, acute MI and ischemic areas
with good accuracy in patients [15, 75]. Stiffness of MI
area and the rest of the myocardium is also studied by
MRI elastography where the MI area is discriminated
from the rest of the myocardium by the difference be-
tween the motion stiffness of those areas (MI, 4.6 ±
0.7 kPA; healthy, 3.0 ± 0.6 kPA) [73, 76]. Moreover,
cMRI has an ability to determine with great accuracy mi-
tral valve [77] and aortic valve [78] malfunctions, which
often occur as MI develops and therefore imaging the
function of mitral and aortic valves might give additional
information about the heart’s condition [77].
SPECT and PET
SPECT and PET represent nuclear imaging techniques that
enable mapping of radiotracer concentration and kinetics in
the myocardium with very high sensi t ivi ty [79].
Improvement in PET and SPECT imaging technology has
led to the evolution of imaging beyond the isolated assess-
ment of myocardial perfusion, toward molecular-targeted
imaging of biological processes involved in heart failure,
such as myocardial metabolism, innervation, inflammation,
and extracellular matrix remodeling. PET and SPECT scan-
ners are increasingly integrated with either CT or MRI sys-
tems into PET-CT or PET-MRI hybrid imaging devices,
which facilitate the localization of a molecular signal, by
fusion with high resolution morphologic images [80].
Table 1 Feasibility of conventional parametric mapping methods in
different diseases and tissue characteristics
T2 T2* T1 ECV
AMI Hemorrhage • •• • ??
Edema •• ?? •• •
Necrosis • •• •• ••
Fibrosis Focal/regional* ° ° • ••
Diffuse/global* ?? ° • ••
•• = useable
• = potential
?? = unknown
° = not useable
*Diffuse/global refers to phenomena affecting to the whole myocardium
and focal/regional refers to localized abnormalities in the myocardium
AMI, acute myocardial infarction; ECV, extracellular volume
Curr Cardiovasc Imaging Rep (2019) 12: 11 Page 5 of 13 11
Myocardial Perfusion
Myocardial perfusion imaging with SPECT or PET enables
evaluation of location, extent, severity, and reversibility of myo-
cardial perfusion defects in patients with known or suspected
coronary artery disease (CAD), contributing to the detection of
ischemic etiology of heart failure [81]. In addition to the assess-
ment of relative distribution to the perfusion, PET with radio-
tracer kinetic modeling can be used to quantify myocardial
blood flow (MBF) in absolute terms (mL/g/min) at rest and
during vasodilator stress that allows the computation of coro-
nary flow reserve (CFR) [81]. Quantification of regional MBF
and CFR by PET may identify microvascular dysfunction, bet-
ter characterize the extent and severity of CAD in multi-vessel
disease, detect balanced decreases ofMBF in all major coronary
artery vascular territories, and provide prognostic information
beyond regional myocardial ischemia [82, 83]. Reduced CFR is
a typical feature of a cardiomyopathic heart as a consequence of
microvascular dysfunction even in the absence of epicardial
CAD [84, 85]. Outcome studies have supported microvascular
dysfunction as an independent contributing factor to the symp-
toms and progression of heart failure and reduced CFR was a
predictor of adverse cardiac events in ischemic and dilated car-
diomyopathy [84, 85].
Myocardial Viability
Myocardial viability and scarring can be assessed using per-
fusion imaging using specific viability protocols. In addition,
18F-fluorodeoxyglucose (18F-FDG) PET can be used to de-
tect ischemicmyocardium that is dysfunctional, but viable and
has potential for recovery of the contractile function after re-
vascularization [86]. Viable myocardium shows preserved
18F-FDG uptake, whereas markedly reduced or absent uptake
indicates the presence of scar. A preserved or increased uptake
of 18F-FDG in the presence of reduced myocardial perfusion,
known as flow-metabolism mismatch, is the most commonly
used marker of hibernating myocardium that is capable of
Fig. 3 Short axis imaging after 60-min LAD occlusion in pigs, at baseline
and 1 week post-reperfusion. Color intensity is normalized to pyruvate
seen in the LV cavity. Stunned myocardium (left) demonstrated
normalization of bicarbonate (bic), absence of delayed enhancement
(DE), and normalization of function at 1 week. In the MI (right),
bicarbonate production remained absent at 1 week; lactate (lac) was
only seen in the peri-infarct region (arrow) and delayed enhancement
clearly delineates the MI (adapted with permission from John Wiley
and Sons: Lau AZ) [62]
11 Page 6 of 13 Curr Cardiovasc Imaging Rep (2019) 12: 11
functional recovery after revascularization (Fig. 4). 18F-FDG
PET is a sensitive technique to detect viability and it predicts
functional recovery upon revascularization. A pooled analysis
of 24 studies in 756 patients demonstrated a weighed mean
sensitivity and specificity of 92% and 63%, respectively, for
the detection of regional functional recovery [86].
Retrospective studies have also indicated lower annualized
mortality rates of those with viable myocardium who
underwent revascularization (4%) versus those with viability
who did not undergo revascularization (17%) [88].
The value of 18F-FDG PET in guiding decisions on revas-
cularization assigned 430 heart failure patients with an ejection
fraction below 35% to either management assisted by 18F-FDG
PET imaging or standard care [89]. Although the study overall
showed only a nonsignificant trend toward reduction in cardiac
events for 18F-FDG PETassisted management, 18F-FDG PET
Fig. 4 Myocardial viability study using 18F-fluorodeoxyglucose (18F-
FDG) and myocardial perfusion study at rest using O-15-water. The
patient had 3-vessel obstructive coronary artery disease, contractile
dysfunction in the territory of the left anterior descending (LAD)
coronary artery, reduced left ventricle ejection fraction (35%), and high
surgical risk. Resting perfusion is reduced in the LAD territory (white
line). Viability study shows absence of 18F-FDG uptake in the apex,
but partially preserved uptake elsewhere in the LAD territory indicating
partially preserved viability. VLAvertical long axis, HLA horizontal long
axis, SA short axis (adapted with permission from Springer Nature:
Kiugel M) [87]
Curr Cardiovasc Imaging Rep (2019) 12: 11 Page 7 of 13 11
assisted management improved outcomes in the subgroup of
patients whose treatment adhered to the recommendations by
imaging [89, 90], especially in patients with a large amount of
hibernating myocardium [91]. Similarly, an observational study
evaluating survival benefit from revascularization according to
the extent of ischemic, scarred, and viable myocardium found
survival benefit from revascularization in patients with hiber-
nating myocardium > 10% of the left ventricle [92]. Current
guidelines recommend thatmyocardial revascularization should
be considered in patients with chronic ischemic heart failure
with ejection fraction ≤ 35% in the presence of viable myocar-
dium [93].
Myocardial Metabolism
In addition to 18F-FDG, there are other PET tracers for the
assessment of different aspects of myocardial metabolism [94,
95]. 11C-labeld acetate (11C-acetate) allows robust non-
invasive measurement of myocardial oxygen consumption in
the left and right ventricles independently of the substrate
utilization [94]. This provides the means to estimate the oxy-
gen cost of contractility, the efficiency of myocardial forward
work. The finding of decreased efficiency of myocardial for-
ward work is a consistent and early finding in cardiomyopathy
caused by different etiologies [94]. Myocardial substrate me-
tabolism can be studied in detail by fatty acid analogs, such as
18F-fluoro-6-thia-heptadecanoicacid or 11C-palmitate. The
former reflects myocardial fatty acid utilization, whereas the
latter reflects the flux of fatty acid metabolism through the cell
including lipid pool storage, beta-oxidation, and tricarboxylic
acid cycle [96]. Imaging of myocardial metabolism with PET
has been used for evaluation of many medical and device
therapies on the metabolism of the failing heart [94, 95].
Cardiac Sympathetic Innervation
Cardiac sympathetic imaging provides a non-invasive approach
to assess alterations in cardiac sympathetic nerve function in
cardiomyopathies [96, 97]. Heart failure is associated with an
increased sympathetic tome characterized by increased release
and decreased reuptake of norepinephrine by cardiac sympathet-
ic nerve endings. Currently, cardiac sympathetic function ismost
commonly evaluated by SPECT imaging with 123I-
metaiodobenzylguanidine (123I-MIBG), an iodinated neuro-
transmitter analog [97]. Uptake of 123I-MIBG in the heart is
primarily mediated by the norepinephrine transporter (NET), an
energy-dependent uptake mechanism. Cardiac uptake is usually
measured relative to background mediastinal activity in planar
images (heart-to-mediastinum ratio).Many studies have demon-
strated that cardiac uptake of 123I-MIBG is reduced in individ-
uals with heart failure and indicate that 123I-MIBG can be used
as an independent predictor of heart failure progression and
cardiac mortality [96–99].
11C-Metahydroxyephedrine (11C-HED) is a NET ligand
that has been used for PET imaging of cardiac sympathetic
function. Compared with SPECT, PET imaging provides a
quantitative measure of sympathetic nerve function and iden-
tifies regional heterogeneity of innervation. The extent of re-
duced neural activity assessed with quantitative 11C-HED
PET has been shown to be a predictor of sudden cardiac arrest
independently of EF, infarct volume, symptoms, and natriuret-
ic peptide levels in CAD patients who were candidates for an
implantable cardioverter defibrillator placement for primary
prevention of sudden cardiac death [100]. Despite benefits in
terms of quantification and assessment of regional distribu-
tion, widespread clinical imaging with 11C-HED has been
limited by the short radioactive half-life (20 min) and the need
for an onsite cyclotron. N-[3-Bromo-4-(3-18F-fluoro-
propoxy)-benzyl]-guanidine (LMI1195) is a novel PET tracer
that has been recently evaluated for evaluation of cardiac sym-
pathetic neuronal function inman [101, 102]. LikeMIBG, this
agent is a benzylguanidine analog, but labeled with 18F. 18F
has a radioactive half-life of 120 min that would allow distri-
bution to sites without an onsite cyclotron.
New Tracers for MI and Remodeling
New PET and SPECT tracers targeting the molecular mecha-
nisms underlying repair of myocardial injury have been stud-
ied as potential markers of functional outcome after an acute
MI [103]. Molecular imaging of the cellular mechanisms of
myocardial remodeling can potentially provide new bio-
markers for early detection, risk stratification, and evaluation
of response to therapy in heart failure.
The αvβ3 integrin is a mediator of angiogenesis and its ex-
pression is markedly upregulated in the myocardium after MI
[104, 105]. In addition to the endothelium, it is expressed by both
activated cardiacmyofibroblasts andmacrophages afterMI [105,
106]. Thus, αvβ3 integrin has been studied as a potential target
for imaging angiogenesis and repair of myocardial injury.
Molecular imaging of αvβ3 is based on tracers that contain the
RGD peptide subunit (the arginine-glycine-aspartate motif) that
binds to the activated αvβ3 integrin. Several PET tracers
targeting αvβ3 integrin have been evaluated in experimental
models of MI [104, 106–113] and in patients with MI
[114–116]. Studies have shown increased uptake of RGD-
based radiotracers at the site of infarction as early as 3 days,
peaking at 1–3 weeks after MI. The uptake correlates with an-
giogenesis, infarct scar formation, and adverse remodeling
(Fig. 5). The value of imaging of αvβ3 integrin in predicting
outcome of infarcted tissue after MI and demonstrating effects of
therapies aimed at accelerating repair afterMI, such as angiogen-
ic gene therapy [117], still remains to be studied.
Inflammatory response after MI is another target that has
been studied for predicting functional recovery after MI.
Studies have shown increased myocardial uptake of metabolic
11 Page 8 of 13 Curr Cardiovasc Imaging Rep (2019) 12: 11
markers 18F-FDG [118] and 11C-methionine [119] reflecting
inflammatory activity after recentMI. Uptake of 18F-FDG early
after an acute MI inversely correlated with the degree of func-
tional recovery [119]. Pentixafor is a novel 68Ga-labeled PET
tracer that binds to CXCR4 chemokine receptor mediating leu-
kocytes accumulation at the sites of inflammation [120–122]. In
experimental and human MI, increased pentixafor uptake was
detected by PET in the infarcted tissue early after injury. After
the initial pro-inflammatory phase, cells that promote tissue re-
pair are the major inflammatory cell population in the infarcted
myocardium [123, 124]. Molecular imaging may help to under-
stand time course and contributions of the pro- and anti-
inflammatory mechanisms after MI.
Other radionuclide imaging approaches have been evaluat-
ed to assess molecular mechanisms underlying myocardial
fibrosis, such as activation of matrix metalloproteinases
[125–127] and activation of the renin-angiotensin-
aldosterone system [128, 129]. Molecular imaging with a
radiolabeled ligand of the angiotensin receptor 1, 11C-
KR31173, demonstrated changes in myocardial expression
Fig. 5 Images of myocardial αvβ3 integrin upregulation evaluated by
68Ga-DOTA-RGD PET after experimental myocardial infarction (MI) in
rat. Autoradiographs of cross sections of the left ventricle show increased
tracer uptake (green and red color) in the infarcted myocardium peaking
at 1 week post-MI persisting at 4 weeks post-MI. Infarction is visible in
the corresponding section stained with hematoxylin and eosin (HE).
Micro-PET/CT images show increased tracer uptake in the anterolateral
wall of the left ventricle (arrow) 1 week after infarction (adapted with
permission from Springer Nature: Kiugel M) [87]
Curr Cardiovasc Imaging Rep (2019) 12: 11 Page 9 of 13 11
of angiotensin receptor 1 in a pig model of chronic MI and the
radiotracer was tolerated also in humans [128]. Although new
tracers for imaging MI are in a relatively early stage of devel-
opment, studies have already shown that molecular imaging
of the new targets can clarify pathogenesis of heart failure and
be potentially useful to study effects of therapies.
Conclusion
Anatomy, function, and viability of the myocardium can be
assessed by modern medical imaging techniques by both visu-
alizing and quantifying damages. Novel imaging techniques are
capable of precise and accurate visualization of themyocardium
and detection of alternations at molecular level. Magnetic reso-
nance imaging assesses the myocardium non-invasively with
high spatial resolution and high contrast between myocardium
and blood, cardiac function and tissue characterization of the
myocardium. Molecular and metabolic conditions can also be
assessed non-invasively with novel hyperpolarized magnetic
resonance imaging. Single photon-emission tomography and
positron-emission tomography are the most sensitive tech-
niques to detect biological processes, including cardiac perfu-
sion, metabolism, and viability in the myocardium.
Acknowledgments This study has been supported by the Finnish Academy
Center of Excellence, Instrumentarium Science Foundation, Finnish
Foundation for Cardiovascular Research, and Finnish Heart Foundation.
Funding Information Open access funding provided by University of
Eastern Finland (UEF) including Kuopio University Hospital.
Compliance with Ethical Standards
Conflict of Interest Elias Ylä-Herttuala, Antti Saraste, Juhani Knuuti,
Timo Liimatainen, and Seppo Ylä-Herttuala1declare that they have no
conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Yla-Herttuala S. Angiogennic gene therapy in cardiovascular dis-
eases: dream or vision? Eur Heart J. 2017;38:1365–71.
2. Yla-Herttuala S. Cardiovascular gene therapy: past, present, and
future. Mol Ther. 2017;25:1095–106.
3. Curley D. Molecular imaging of cardiac remodeling after myocar-
dial infarction. Basic Res Cardiol. 2018;113:10.
4. van Slochteren FJ. Advanced measurement techniques of regional
myocardial function to assess the effects of cardiac regenerative
therapy in different models of ischemic cardiomyopathy. Eur
Heart J Cardiovasc Imaging. 2012;13:808–18.
5. Patel N. Contrast – in cardiac magnetic resonance imaging.
Echocardiography. 2018;35:401–9.
6. Mavrogeni S. T1 and T2 mapping in cardiology: “mapping the
obscure object of desire”. Cardiology. 2017;138:207–17.
7.•• Yla-Herttuala E. Quantification of myocardial infarct area based
on TRAFFn relaxation time maps – comparison with cardiovascular
magnetic resonance late gadolinium enhancement, T1ρ and T2
in vivo. J Cardiovasc Magn Reson. 2018;20:34. This study pro-
vides the first myocardial infarction study in vivo done with
TRAFFn relaxation time maps and those results are compared
to other MRI imaging methods.
8. Ertl G. Healing after myocardial infarction. Cardiovasc Res.
2005;66:22–32.
9. Blankesteijn WM. Dynamics of cardiac wound healing following
myocardial infarction: observations in genetically altered mice.
Acta Physiol Scand. 2001;173:75–82.
10. Garg P. Role of T1 mapping and extracellular volume in the as-
sessment of myocardial infarction. Anatol J Cardiol. 2018. https://
doi.org/10.14744/AnatolJCardiol.2018.39586.
11. Baxa J. T1 mapping of the ischemic myocardium: review of po-
tential clinical use. Eur J Radiol. 2016;85:1322–928.
12. Galli A. Postinfarct left ventricular remodeling: a prevailing cause
of heart failure. Cardiol Res Pract. 2016. https://doi.org/10.1155/
2016/2579832.
13. Palazzuoli A. The impact if infarct size on regional and global left
ventricular systolic function: a cardiac magnetic resonance imag-
ing study. Int J Cardiovasc Imaging. 2015;5:1037–44.
14. van den Borne SW. Myocardial remodeling after infarction: the
role of myofibroblasts. Nat Rev Cardiol. 2010;7:30–7.
15. Saeed M. Magnetic resonance imaging for characterizing myocar-
dial diseases. Int J Cardiovasc Imaging. 2017;33:1395–414.
16. Captur G. Cardiac MRI evaluation of myocardial disease. Heart.
2016;102:1429–35.
17. Phelps ME. PET: the merging of biology and imaging into molec-
ular imaging. J Nucl Med. 2000;41:661.
18.• Apps A. Hyperpolarized magnetic resonance for in vivo real-time
metabolic imaging. Heart. 2018;104:1484–91. This review arti-
cle provides great overview about use of hyperpolarized MRI
in vivo.
19. Ghosn MG. Important advances in technology and unique appli-
cations related to cardiac magnetic resonance imaging. Methodist
Debakey Cardiovasc J. 2014;10:159–62.
20. Whitaker J. CardiacMR characterization of left ventricular remod-
eling in a swine model of infarct followed by reperfusion. J Magn
Reson Imaging. 2018;48:808–17. https://doi.org/10.1002/jmri.
26005.
21. Krishnamurthy R. Tools for cardiovascular magnetic resonance.
Cardiovasc Diagn Ther. 2014;4:104–25.
22. Wong DT. The role of cardiac magnetic resonance imaging fol-
lowing acute myocardial infarction. Eur Radiol. 2012;22:1757–
68.
23. Reuben MT. Distal coronary embolization following acute myo-
cardial infarction increases early infarct size and late left ventric-
ular wall thinning in a porcine model. J Cardiovasc Magn Reson.
2015;17:106.
24. Watanabe E. Infarct tissue heterogeneity by contrast-enhanced
magnetic resonance imaging is a novel predictor of mortality in
11 Page 10 of 13 Curr Cardiovasc Imaging Rep (2019) 12: 11
patients with chronic coronary artery disease and left ventricular
dysfunction. Circ Cardiovasc Imaging. 2014;7:887–94.
25. Pokorney SD. Infarct healing is a dynamic process following acute
myocardial infarction. J Cardiovasc Magn Reson. 2012;14:62.
26. Michel L. Real-time pressure-volume analysis of acute myocardial
infarction in mice. J Vis Exp. 2018. https://doi.org/10.3791/57621.
27. Opie LH. Controversies in ventricular remodeling. Lancet.
2006;367:356–67.
28. Larroza A. Texture analysis of cardiac cine magnetic resonance
imaging to detect nonviable segments in patients with chronic
myocardial infarction. Med Phys. 2018;4:1471–80.
29. Payne AR, Berry C, Kellman P, Anderson R, Hsu LY, Chen MY,
et al. Bright-blood T(2)-weighted MRI has high diagnostic accu-
racy for myocardial hemorrhage in myocardial infarction: a pre-
clinical validation study in swine. Circ Cardiovasc Imaging.
2011;4:738–45.
30. Kim HW. Dark-blood delayed enhancement cardiac magnetic res-
onance of myocardial infarction. JACC Cardiovasc Imaging.
2017;11:1758–69. https://doi.org/10.1016/j.jcmg.2017.09.021.
31. Caudron J. Evaluation of left ventricular diastolic function with
cardiac MR imaging. Radiographics. 2011;31:239–59.
32. Shehata ML. Myocardial tissue tagging with cardiovascular mag-
netic resonance. J Cardiovasc Magn Reson. 2009;11:11–55.
33. Khan JN. Comparison of cardiovascular magnetic resonance fea-
ture tracking and tagging for the assessment of left ventricular
systolic strain in acute myocardial infarction. Eur J Radiol.
2015;84:840–8.
34. Fahmy AS. Grey blood late gadolinium enhancement cardiovas-
cular magnetic resonance for improved detection of myocardial
scar. J Cardiovasc Magn Reson. 2018;20:20.
35. Maestrini V. T1 mapping for characterization of intracellular and
extracellular myocardial diseases in heart failure. Curr Cardiovasc
Imaging Rep. 2014;7:9287.
36. Lavin B. MRI with gadofosveset: a potential marker for perme-
ability in myocvardial infarction. Atherosclerosis. 2018;275:400–
8.
37. Kis E. Cardiac magnetic resonance imaging of the myocardium in
chronic kidney disease. Kidney Blood Press Res. 2018;43:134–
42.
38. Klein C. The influence of myocardial blood flow and volume of
distribution on late gd-dtpa kinetics in ischemic heart failure. J
Magn Reson Imaging. 2004;20:588–93.
39. Radenkovic D. T1 mapping in cardiac MRI. Heart Fail Rev.
2017;22:415–30.
40. Messroghli DR. Clinical recommendations for cardiovascular
magnetic resonance mapping of T1, T2, T2* and extracellular
volume: a consensus statement by the society for cardiovascular
magnetic resonance (SCMR) endorsed by the European associa-
tion for cardiovascular imaging (EACVI). J Cardiovasc Magn
Reson. 2017;19:75.
41. Sibley CT. T1 mapping in cardiomyopathy at cardiac MR: com-
parison with endomyocardial biopsy. Radiology. 2012;265:724–
32.
42. Mark Haacke E, et al. Magnetic resonance imaging, physical prin-
ciples and sequence design. 1st ed. Hoboken: A John Wiley And
Sons, Inc.; 1999.
43. Haaf P. Cardiac T1 mapping and extracellular volume (ECV) in
clinical practice: a comprehensive review. J Cardiovasc Magn
Reson. 2016;18:89.
44. Sanz J. Myocardial mapping with cardiac magnetic resonance: the
diagnostic value of novel sequences. Rev Esp Cardiol (Eng Ed).
2016;69:849–61.
45. Aletras AH. Retrospective determination of the area at risk for
reperfused acute myocardial infarction with t2-weighted cardiac
magnetic resonance imaging: histopathological and displacement
encoding with stimulated echoes (dense) functional validations.
Circulation. 2006;113:1865–70.
46. Lota AS. T2 mapping and T2* imaging in heart failure. Heart Fail
Rev. 2017;22:431–40.
47. Graham-Brown MP. Novel cardiac nuclear magnetic resonance
method for noninvasive assessment of myocardial fibrosis in he-
modialysis patients. Kidney Int. 2016;90:835–44.
48. Liu D. CMR native T1 mapping allows differentiation of revers-
ible versus irreversible myocardial damage in ST-segment–eleva-
tion myocardial infarction. Circ Cardiovasc Imaging. 2017.
https://doi.org/10.1161/CIRCIMAGING.116.005986.
49. Tessa C. T1 and T2 mapping in the identification of acute myo-
cardial injury in patients with NSTEMI. Radiol Med. 2018;123:
926–34. https://doi.org/10.1007/s11547-018-0931-2.
50. Kali A. Determination of location, size, and transmurality of
chronic myocardial infarction without exogenous contrast media
by using cardiac magnetic resonance imaging at 3 T. Circ
Cardiovasc Imaging. 2014;7:471–81.
51. Stoffers RH. Assessment of myocardial injury after reperfused
infarction by T1r cardiovascular magnetic resonance. J
Cardiovasc Magn Reson. 2017;19:17.
52. Jackowski C. Postmortem unenhanced magnetic resonance imag-
ing of myocardial infarction in correlation to histological infarc-
tion age characterization. Eur Heart J. 2006;27:2459–67.
53. Sepponen RE. A method for T1 rho imaging. J Comput Assist
Tomogr. 1985;9:1007–11.
54. Mustafa HS. Longitudinal rotating frame relaxation timemeasure-
ments in infarcted mouse myocardium in vivo. Magn Reson Med.
2013;69:1389–95.
55. van Oorschot JWM. Endogenous assessment of chronic myocar-
dial infarction with T1ρ-mapping in patients. J Cardiovasc Magn
Reson. 2014;16:104–12.
56. Liimatainen T. MRI contrasts from relaxation along a fictitious
field (RAFF). Magn Reson Med. 2010;64:983–94.
57.•• Liimatainen T. MRI contrasts in high rank rotating frames. Magn
Reson Med. 2015;73:254–62. This study provides the theoreti-
cal background behind the TRAFFn relaxation time method.
58. Kettunen MI. Low spin-lock field T1 relaxation in the rotating
frame as a sensitive MR imaging marker for gene therapy treat-
ment response in rat glioma. Radiology. 2007;243:796–803.
59. Khan MA. The follow-up of progressive hypertrophic cardiomy-
opathy using magnetic resonance rotating frame relaxation times.
NMR Biomed. 2018;31. https://doi.org/10.1002/nbm.3871.
60. Rider OJ. Clinical implications of cardiac hyperpolarized magnet-
ic resonance imaging. J Cardiovasc Magn Reson. 2013;15:93.
61. Golman K. Cardiac metabolism measured noninvasively by
hyperpolarized 13C MRI. Magn Reson Med. 2008;59:1005–13.
62. Lau AZ. Reproducibility study for free-breathing measurements
of pyruvate metabolism using hyperpolarized (13) C in the heart.
Magn Reson Med. 2013;69:1063–71.
63. Merritt ME. Hyperpolarized 13C allows a direct measure of flux
through a single enzyme-catalyzed step by NMR. Proc Natl Acad
Sci U S A. 2007;104:19773–7.
64. Aquaro GD. Cardiac metabolism in a pig model of ischemia–
reperfusion by cardiac magnetic resonance with hyperpolarized
13C-Pyruvate. IJC Metab Endocr. 2015;6:17–23.
65. Ball DR. Metabolic imaging of acute and chronic infarction in the
perfused rat heart using hyperpolarised [1-13C]pyruvate. NMR
Biomed. 2013;26:1441–50.
66. Oh-Ici D. Hyperpolarized metabolic MR imaging of acute myo-
cardial changes and recovery after ischemia-reperfusion in a
small-animal model. Radiology. 2016;278:742–51.
67. Schroeder MA. Measuring intracellular pH in the heart using
hyperpolarized carbon dioxide and bicarbonate: a 13C and 31P
magnetic resonance spectroscopy study. Cardiovasc Res.
2010;86:82–91.
Curr Cardiovasc Imaging Rep (2019) 12: 11 Page 11 of 13 11
68. Lau AZ. Mapping of intracellular pH in the in vivo rodent heart
using hyperpolarized [1-13C]pyruvate. Magn Reson Med.
2017;77:1810–7.
69. Rubler S. New type of cardiomyopathy associated with diabetic
glomerulosclerosis. Am J Cardiol. 1972;30:595–602.
70. Chong C-R. Metabolic remodelling in diabetic cardiomyopathy.
Cardiovasc Res. 2017;113:422–30.
71. Do HP. Non-contrast assessment of microvascular integrity using
arterial spin labeled cardiovascular magnetic resonance in a por-
cine model of acute myocardial infarction. J Cardiovasc Magn
Reson. 2018;20:45.
72. Ma H. Contrast-enhanced whole-heart coronary MRA at 3.0T for
the evaluation of cardiac venous anatomy. Int J Cardiovasc
Imaging. 2011;27:1003–9.
73. Nquyen C. In vivo contrast free chronic myocardial infarction
characterization using diffusion-weighted cardiovascular magnet-
ic resonance. J Cardiovasc Magn Reson. 2014;16:68.
74. Sosnovik DE. Diffusion spectrum MRI tractography reveals the
presence of a complex network of residual myofibers in infarcted
myocardium. Circ Cardiovasc Imaging. 2009;2:206–12.
75. Payne AR. Bright-blood T2-weighted MRI has higher diagnostic
accuracy than dark-blood short tau inversion recovery MRI for
detection of acute myocardial infarction and for assessment of
the ischemic area at risk and myocardial salvage. Circ
Cardiovasc Imaging. 2011;4:210–9.
76. Arunachalam SP. Regional assessment of in vivo myocardial stiff-
ness using 3Dmagnetic resonance elastography in a porcine mod-
el of myocardial infarction. Magn Reson Med. 2018;79:361–9.
77. Metha NK. Utility of cardiac magnetic resonance for evaluation of
mitral regurgitation prior to mitral valve surgery. J Thorac Dis.
2017;4:S246–56.
78. Quarto C. Late gadolinium enhancement as a potential marker of
increased perioperative risk in aortic valve replacement. Interact
Cardiovasc Thorac Surg. 2012;15:45–50.
79. Bengel FM. Cardiac positron emission tomography. J Am Coll
Cardiol. 2009;54:1–15.
80. Gaemperli O. Cardiac hybrid imaging. Eur Heart J Cardiovasc
Imaging. 2012;13:51–60.
81. Jaarsma C. Diagnostic performance of noninvasive myocardial
perfusion imaging using single-photon emission computed to-
mography, cardiac magnetic resonance, and positron emission to-
mography imaging for the detection of obstructive coronary artery
disease: a meta-analysis. J Am Coll Cardiol. 2012;59:1719–28.
82. Saraste A. PET: is myocardial flow quantification a clinical real-
ity? J Nucl Cardiol. 2012;19:1044–59.
83. Gupta A. Integrated noninvasive physiological assessment of cor-
onary circulatory function and impact on cardiovascular mortality
in patients with stable coronary artery disease. Circulation.
2017;136:2325–36.
84. Neglia D. Prognostic role of myocardial blood flow impairment in
idiopathic left ventricular dysfunction. Circulation. 2002;105:
186–93.
85. Majmudar MD. Quantification of coronary flow reserve in pa-
tients with ischaemic and non-ischaemic cardiomyopathy and its
association with clinical outcomes. Eur Heart J Cardiovasc
Imaging. 2015;16:900–9.
86. Schinkel AF. Hibernating myocardium: diagnosis and patient out-
comes. Curr Probl Cardiol. 2007;32:375–410.
87. Kiugel M. Dimeric [(68)Ga]DOTA-RGD peptide targeting αvβ 3
integrin reveals extracellular matrix alterations after myocardial
infarction. Mol Imaging Biol. 2014;16:793–801.
88. Allman KC. Myocardial viability testing and impact of revascu-
larization on prognosis in patients with coronary artery disease and
left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol.
2002;39:1151–8.
89. Beanlands RS. F-18-Fluorodeoxyglucose positron emission to-
mography imaging-assisted management of patients with severe
left ventricular dysfunction and suspected coronary disease a ran-
domized, controlled trial (PARR-2). J Am Coll Cardiol. 2007;50:
2002–12.
90. Mc Ardle B. Long-term follow-up of outcomes with F-18-
fluorodeoxyglucose positron emission tomography imaging-
assisted management of patients with severe left ventricular dys-
function secondary to coronary disease. Circ Cardiovasc Imaging
2016;9(9). https://doi.org/10.1161/CIRCIMAGING.115.004331.
91. Mielniczuk LM. Does imaging-guided selection of patients with
ischemic heart failure for high risk revascularization improve iden-
tification of those with the highest clinical benefit? Imaging-
guided selection of patients with ischemic heart failure for high-
risk revascularization improves identification of those with the
highest clinical benefit. Circ Cardiovasc Imaging. 2012;5:262–70.
92. Ling LF. Identification of therapeutic benefit from revasculariza-
tion in patients with left ventricular systolic dysfunction: inducible
ischemia versus hibernating myocardium. Circ Cardiovasc
Imaging. 2013;6:363–72.
93. Ponikowski P. ESC guidelines for the diagnosis and treatment of
acute and chronic heart failure: the task force for the diagnosis and
treatment of acute and chronic heart failure of the European
Society of Cardiology (ESC). Eur Heart J. 2016;37:2129–200.
94. Knaapen P. Myocardial energetics and efficiency: current status of
the noninvasive approach. Circulation. 2007;115:918–27.
95. Tuunanen H, Knuuti J. Metabolic remodelling in human heart
failure. Cardiovasc Res. 2011;90:251–7.
96. Juneau D. The role of nuclear cardiac imaging in risk stratification
of sudden cardiac death. J Nucl Cardiol. 2016;23:1380–98.
97. Travin MI. Current clinical applications and next steps for cardiac
innervation imaging. Curr Cardiol Rep. 2017;19:1.
98. Jacobson AF. Myocardial iodine-123 meta-iodobenzylguanidine
imaging and cardiac events in heart failure. Results of the prospec-
tive ADMIRE-HF (AdreView Myocardial Imaging for Risk
Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:
2212–21.
99. Narula J. 123I-MIBG imaging for prediction of mortality and po-
tentially fatal events in heart failure: the ADMIRE-HFX study. J
Nucl Med. 2015;56:1011–8.
100. Fallavollita JA. Regional myocardial sympathetic denervation pre-
dicts the risk of sudden cardiac arrest in ischemic cardiomyopathy.
J Am Coll Cardiol. 2014;63:141–9.
101. Yu M, Bozek J. Evaluation of LMI1195, a novel 18F-labeled
cardiac neuronal PET imaging agent, in cells and animal models.
Circ Cardiovasc Imaging. 2011;4:435–43.
102. Sinusas AJ. Biodistribution and radiation dosimetry of LMI1195:
first-in-human study of a novel 18F-labeled tracer for imaging
myocardial innervation. J Nucl Med. 2014;55:1445–51.
103. Saraste A. PET imaging in heart failure: the role of new tracers.
Heart Fail Rev. 2017;22:501–11.
104. Meoli DF. Noninvasive imaging of myocardial angiogenesis fol-
lowing experimental myocardial infarction. J Clin Invest.
2004;113:1684–91.
105. Sun M, Opavsky MA. Temporal response and localization of
integrins beta1 and beta3 in the heart after myocardial infarction:
regulation by cytokines. Circulation. 2003;107:1046–52.
106. Van den Borne SWM. Molecular imaging of interstitial alterations
in remodeling myocardium after myocardial infarction. J Am Coll
Cardiol. 2008;52:2017–28.
107. Higuchi T. Assessment of alphavbeta3 integrin expression after
myocardial infarction by positron emission tomography.
Cardiovasc Res. 2008;78:395–403.
108. Sherif HM. Molecular imaging of early αvβ3 integrin expression
predicts long-term left-ventricle remodeling after myocardial in-
farction in rats. J Nucl Med. 2012;53:318–23.
11 Page 12 of 13 Curr Cardiovasc Imaging Rep (2019) 12: 11
109. Gao H. PET imaging of angiogenesis after myocardial infarction/
reperfusion using a one-step labeled integrin-targeted tracer 18F-
AlF-NOTA-PRGD2. Eur J NuclMedMol Imaging. 2012;39:683–
92.
110. Knetsch PA. [68Ga]NODAGA-RGD for imaging αvβ3 integrin
expression. Eur J Nucl Med Mol Imaging. 2011;38:1303–12.
111. Laitinen I. Comparison of cyclic RGD peptides for αvβ3 integrin
detection in a rat model of myocardial infarction. EJNMMI Res.
2013;3:38.
112. Menichetti L. MicroPET/CT imaging of αvβ3 integrin via a novel
68Ga-NOTA-RGD peptidomimetic conjugate in rat myocardial
infarction. Eur J Nucl Med Mol Imaging. 2013;40:1265–74.
113. Grönman M. Imaging of αvβ3 integrin expression in experimen-
tal myocardial ischemia with [68Ga]NODAGA-RGD positron
emission tomography. J Transl Med. 2017;15:144.
114. Jenkins WS. Cardiac αVβ3 integrin expression following acute
myocardial infarction in humans. Heart. 2017;103:607–15.
115. Sun Y. Application of (68)Ga-PRGD2 PET/CT for αvβ3-integrin
imaging of myocardial infarction and stroke. Theranostics.
2014;4:778–86.
116. Verjans J. Early molecular imaging of interstitial changes in pa-
tients after myocardial infarction: comparison with delayed
contrast-enhanced magnetic resonance imaging. J Nucl Cardiol.
2010;17:1065–72.
117. Hartikainen J. Adenoviral intramyocardial VEGF-DΔNΔC gene
transfer increases myocardial perfusion reserve in refractory angi-
na patients: a phase I/IIa study with 1-year follow-up. Eur Heart J.
2017;38:2547–55.
118. Rischpler C. Prospective evaluation of 18F-fluorodeoxyglucose
uptake in postischemic myocardium by simultaneous positron
emission tomography/magnetic resonance imaging as a prognostic
marker of functional outcome. Circ Cardiovasc Imaging. 2016;9:
e004316.
119. Thackeray JT. Targeting amino acid metabolism for molecular
imaging of inflammation early after myocardial infarction.
Theranostics. 2016;6:1768–79.
120. Thackeray JT. Molecular imaging of the chemokine receptor
CXCR4 after acute myocardial infarction. JACC Cardiovasc
Imaging. 2015;8:1417–26.
121. Lapa C. [(68)Ga]Pentixafor-PET/CT for imaging of chemokine
receptor 4 expression after myocardial infarction. JACC
Cardiovasc Imaging. 2015;8:1466–8.
122. Rischpler C. Upregulated myocardial CXCR4-expression after
myocardial infarction assessed by simultaneous GA-68 pentixafor
PET/MRI. J Nucl Cardiol. 2016;23:131–3.
123. Nahrendorf M. Monocyte and macrophage heterogeneity in the
heart. Circ Res. 2013;112:1624–33.
124. Frangogiannis NG. The inflammatory response in myocardial in-
jury, repair, and remodelling. Nat Rev Cardiol. 2014;11:255–65.
125. Sahul ZH. Targeted imaging of the spatial and temporal variation
of matrix metalloproteinase activity in a porcine model of
postinfarct remodeling: relationship to myocardial dysfunction.
Circ Cardiovasc Imaging. 2011;4:381–91.
126. Su H. Noninvasive targeted imaging of matrix metalloproteinase
activation in a murine model of postinfarction remodeling.
Circulation. 2005;112:3157–67.
127. Kiugel M. Evaluation of 68Ga-labeled peptide tracer for detection
of gelatinase expression after myocardial infarction in rat. J Nucl
Cardiol. 2018;25:1114–23.
128. Fukushima K. Molecular hybrid positron emission tomography/
computed tomography imaging of cardiac angiotensin II type 1
receptors. J Am Coll Cardiol. 2012;60:2527–34.
129. de Haas HJ. Molecular imaging of the cardiac extracellular matrix.
Circ Res. 2014;114:903–15.
Curr Cardiovasc Imaging Rep (2019) 12: 11 Page 13 of 13 11