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March 2014 - Issue 3
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Reviews
Assessment of Myocardial Viability: A Review
of Current Non Invasive Imaging Techniques
Ahmed Talib1 MBChB, Caroline Cheese1 MBBS, Iqbal Elfigih1 MBBCh, Zainab Hamoudi1
MBChB, Abednego Mnisi1 MBChB, Elias Kangwa1 MBChB, Mohammad Khan Madni1 MBChB,
Michael Y. Henein 1-2 MD PhD FRCP
1 Canterbury Christ Church University, Canterbury, UK
2 Heart Centre and Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
Introduction
Coronary artery disease (CAD) is the most prevalent and
single most common cause of morbidity and mortality1 with
the resulting left ventricular dysfunction (LVD) an important
complication2. Worldwide, CAD accounts for 5.7 million new
cases per year, of these 1.3 million in Europe alone3. In addition,
it imposes a substantial share of health service resources and
expenses, an impaired quality of life, disability and high social
cost3,4. Furthermore, LVD itself has been shown to be a powerful
determinant of survival2, 5.
The once previously held notion that LVD in patients with CAD is
always irreversible has been discounted. Indeed, the damaged
myocardium can be at a state of stunning, defined as a prolonged
contractile dysfunction after a transient acute ischemic insult
and coronary reperfusion6. Myocardial hibernation, reduced
segmental myocardial function at rest and with stress, due to
persistently impaired coronary blood flow, has also been shown
to recover partially or completely after revascularization7. In view
of the evidence for potentially healthy myocardium, a myriad
of invasive and non-invasive diagnostic techniques have been
developed for the identification of myocardial viability. Indeed,
the European Society of Cardiology (ESC) and the European
Association for Cardio-Thoracic Surgery (EACTS) recommend the
detection of myocardial viability a part of the diagnostic work up
for revascularisation, and patients with no evidence for viability
should be discouraged from procedures8.
This review focuses on the scientific analysis of the existing
evidence on the accuracy of the available diagnostic techniques
including echocardiography, single-photon emission computed
tomography (SPECT), positron emission tomography (PET), and
cardiac magnetic resonance imaging (cardiac MRI) in determining
the presence of myocardial viability.
Stress Echocardiography
Introduction
Echocardiography has been routinely used in the assessment
of myocardial viability. There are four techniques employed;
dobutamine stress, myocardial contrast, 2D gray scale
wall motion scoring, tissue Doppler and more recently
adenosine speckle tracking stress echocardiography. Resting
echocardiography highlights diastolic wall thickness of at least 5
mm as a marker of viable myocardium.
The most commonly used criterion to identify viable myocardium
is by detection of contractile reserve. This is achieved by
stress echocardiography using Dobutamine, Adenosine or
Dipyridamole. An infusion of low-dose dobutamine (5–10 mg/
kg/min) is administered which results in increased contractile
function of viable segments whereas nonviable ones do not
show such response. Myocardial viability can also be detected
by using the biphasic response, with enhanced activity at low
dose dobutamine and reduced function (ischaemia) at high dose
dobutamine.
Using intravenous micro-bubble contrast, contrast
echocardiography is able to demonstrate viability qualitatively.
These micro-bubbles are inert gases and stay in the vascular
space and behave like red blood cells in terms of rheology.
Segments that have normal or patchy perfusion are classified as
being viable in contrast to those with no perfusion who are taken
as non-viable9.
Doppler echocardiography uses optimum increase in coronary
flow reserve (CFR) as an additional marker of viability. The
underlying mechanism behind that is the increased myocardial
metabolic demand with stress, which causes dilatation of the
coronary vessels10.
Additional information on myocardial viability can be obtained
from adenosine speckle tracking based myocardial strain imaging.
Usually at rest, there is no significant difference between the
viable and nonviable myocardium strain. With adenosine stress,
viable segments increase their longitudinal strain in contrast to
non-viable ones which remain unchanged15.
Low Dose Dobutamine Stress Echocardiography (LDDE)
The most recent meta-analysis by Schinkel AF et al (2007), of
33 studies (1121 patients); showed that low-dose dobutamine
echocardiography had a cumulative sensitivity and specificity
of 81% and 78% respectively, with a positive predictive value
(PPV) and negative predictive value (NPV) of 75% and 83%
respectively, (P < 0.05). It also found that high-dose dobutamine
echocardiography had a higher sensitivity (83%) and NPV
(85%) than low-dose dose (P < 0.05), whereas specificity and
PPV were comparable [11]. A review by Camici et al (2008)
examined 20 studies for myocardial viability in patients with LV
dysfunction (LVEF ≤45%), and predicted functional recovery
after revascularisation; having shown that LDDE has superior
specificity, lower PPV and similar NPV compared to nuclear
imaging9.
Myocardial Contrast Echocardiography (MCE)
Senior et al (2009) illustrated the accuracy of MCE for the
prediction of myocardial viability, demonstrating a mean sensitivity
of 85% and specificity of 70%12. Also, in the setting of STelevation myocardial infarction (STEMI) a review (2008) showed
that MCE had a high sensitivity for predicting functional recovery
after revascularization, but equivalent specificity compared with
DSE. Finally, MSE and cardiac MRI have been shown comparable
in predicting functional recovery13.
Doppler CFR echocardiography
A study by Djordjevic-Dikic et al (2011) evaluated basal CRF
and measured diastolic deceleration time (DDT) before elective
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angioplasty in patients with prior MI, and demonstrated that the
two measurements can predict myocardial function recovery10. In
a trial format Meimoun et al (2010) examined the prognostic value
of CFR in predicting LV remodelling in acute MI in comparison
to clinical, biochemical, electrocardiogram, and angiographic
parameters, and concluded that CRF is an independent predictor
of LV remodelling. It has been shown that patients with preserved
CFR had better improvement in LV EF, and wall motion score and
a fall in LV end diastolic volume compared to those with reduced
CFR at 6-month follow-up14.
2D speckle tracking stress echocardiography;
Ran et al (2012), in a recent trial assessed patients who had
sustained a MI and EF of 40% (±6%) and showed that using
adenosine stress, radial myocardial strain more than 9.5% had a
sensitivity of 83.9% and a specificity of 81.4% for detecting viable
myocardium, whereas a change of longitudinal strain more than
14.6% displayed a sensitivity of 86.7% and a specificity of 90.2%.
Peak-systolic circumferential strain however, had little effect on
viability assessment15.
Limitation and advantages
The main limitations of echocardiography include; operator
dependence, both in data acquisition, and interpretation,
however, this could easily be overcome by good training and
experience. Adequate acoustic window acquisition is another
potential limitation but has greatly improved by using contrast
agents. The main advantages of stress echocardiography include;
good validity, wide availability, cost effectiveness, lack of ionizing
radiation, and being friendly with implanted devices16.
Prognostic value
The VIAMI-trial (2012), was the first randomized control trial
investigating a viability-guided invasive approach in 261 patients
recruited at least 48 hours after an acute MI who then underwent
LDDE for the detection of viability within 72 hours of MI. Those
with a viable myocardium were randomized to an invasive or
conservative treatment. The primary endpoint was the composite
of death from any cause, recurrent MI and unstable angina at
1-year follow-up. An invasive approach in patients with a high
viability score had a substantial reduction in ischemic events.
The VIAMI-trial supports the concept that viability determines
prognosis17.
Single-Photon Emission Computed
Tomography
Introduction
One of the most popular non-invasive nuclear imaging modalities
used, is Single-Photon Emission Computed Tomography
(SPECT). The main technique involve the administration of a
radioactive tracer such as thallium-201 or Technetium Tc-99m,
with Tc-99m sestamibi being the most widely used in clinical
practice. The most commonly used criterion to identify viable
myocardium is the percentage tracer uptake by the dysfunctional
segments, where a tracer activity of >50% and redistribution
of >10% are used as markers of viability as a consequence of
preserved membrane integrity (detected by thallium SPECT). A
tracer activity of >50% and improvement in tracer uptake after
nitrates administration is also taken as a markers of viability, as
a consequence of preserved mitochondrial function (detected by
technetium SPECT).
Various protocols have been developed to optimise the
information obtained from thallium-201 imaging such as; stressredistribution imaging, late redistribution imaging, thallium-201
re-injection and rest-redistribution imaging 18.
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Rest-redistribution imaging protocol
Rizzllo V. et al (2005) analysis of 22 studies (557 patients) using
Tl-201 rest-redistribution showed an average sensitivity and
specificity of 88% (range 44-100%) and 59% (range 22-92%)
respectively, and PPV 69% and NPV of 80%, for predicting
regional function recovery19; confirming previous meta-analysis by
Bax et al (1997) of 8 studies, which showed a mean sensitivity of
90% and specificity of 54%20. Similar results have recently been
confirmed by Camici et al (2008)9.
Thallium-201 re-injection protocol
Re-injection protocol is an extra value on top of rest-redistribution
results. Rizzllo V. et al (2005) found lower specificity of 50%
having analysed 11 studies (301 patients) and sensitivity of 86%,
with low PPV of 57% and NPV of 83% [19]. Similar results were
demonstrated earlier by Bax et al (1997), based on meta-analysis
of 7 studies where an average sensitivity and specificity of 86%
and 47%, respectively were produced20.
Technetium-99m sestamibi (MIBI)
Rizzllo V. et al (2005) analysis of 20 studies (488 patients)
assessing Technetium-99m sestamibi studies, without the use
of nitrates concluded a lower sensitivity of 81%, but better
specificity of 66%, with PPV of 71% and NPV of 86%19. These
results were similar to those by Bax et al (1997), based on metaanalysis of 7 studies with an average sensitivity and specificity
of 80% (range 73-100%) and 60% (range 35-86%), respectively.
Bax et al (1997) also noticed better results with increased
sensitivity from 81% to 91% (range 88-95%) and specificity of
60 to 88% (range 88-89) when nitrates were used20. Current
practice involves nitrate administration in patients with previous
cardiac events.
Limitation and advantages
The main limitations of SPECT include; higher cost compared to
echocardiography, limited spatial resolution, potential difficulty in
interpreting results in patients with balanced myocardial ischemia
(3-vessel disease) and the risk of radiation. The main advantages
include; extensive validation, increasing availability, good
sensitivity and lower cost compared to PET16.
Prognostic value
Cardiac SPECT viability study results can predict the recovery of
global LV function; 99mTc-sestamibi demonstrated a sensitivity
of 81% and specificity of 60%, thallium re-injection a sensitivity
of 86% and specificity of 47%, thallium rest redistribution a
sensitivity of 90% and specificity of 54%20.
Positron Emission Tomography
Introduction
Cardiac positron emission tomography (cardiac PET) involves the
administration of a tracer, Rubium-82, Ammonium-13, Water-15,
and Fluorine-18 deoxyglucose (18-FDP). Of these various
positron-emitting radiotracers, which are peripherally introduced,
a glucose analogue; Fluorine-18 deoxyglucose (18-FDP), is
the most validated radiotracer for cardiac PET metabolism.
Glucose 11-C, free fatty acid (FFA), and Oxygen are also
metabolism tracers, however glucose is the preferred metabolite
for assessment of ischaemic or hypoxic myocardium18-21. The
most commonly used criterion to identify viable myocardium
is the uptake and metabolism of 18-FDP, which is dependent
on viable myocytes, with viable glucose transporters. Viable
myocardium displays normal perfusion and normal 18F-FDG
uptake, hibernating myocardium displays reduced perfusion and
preserved 18F-FDG uptake but, scarred tissue will display no
perfusion and absent 18F-FDG uptake21-23.
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In order to maximise glucose metabolism, which improves the
quality of the images, a glucose fed state, with an insulin infusion
for diabetics or those with insulin resistance, is established22.
Stress testing is not a requirement for a myocardial viability study
with cardiac PET.
The recent analysis by Schinkel AF et al (2007) of 24 studies
involving 756 patients noted weighted mean sensitivities and
specificities of 92% and 63%, and positive and negative
predictive values of 74% and 87% respectively11. This was
confirmed by another review by DiCarli MF et al (2007), where
weighted mean sensitivities of 90% and specificities of 89% were
reported24. A meta-analysis by Machac J et al (2005) of 8 studies,
involving 800 patients, demonstrated slightly higher sensitivities
and specificities, 93% and 92%, respectively25.
Limitation and advantages
The main limitations of PET include its high cost, limited
availability, and the use of radio-active tracers. The main
advantages include; established validity and excellent sensitivity.
Compared with the SPECT, PET has better spatial and temporal
resolution, with better quality pictures and less radiation. PET is
not limited in patients with devices.
Prognostic value
A meta-analysis by Beanlands et al (1998) of 10 studies involving
1046 patients, found that, the mortality rate was higher in those
who did not undergo revascularization despite a PET scan
confirming significant myocardial viability. The annual death rate
was 4% in those that had revascularization versus 17% in those
who did not undergo revascularization26.
Magnetic Resonance Imaging
Introduction
The use of cardiac MRI (CMR) in the assessment of myocardial
viability is a relatively new concept and therefore does not carry
the same clinical evidence advantage as other imaging techniques
mentioned above21. Despite this, CMR has the potential to
overcome limitations presented with other imaging modalities,
particularly nuclear imaging, and is therefore of particular
interest 27. Three main techniques employed when using CMR in
assessing myocardial viability are; delayed enhancement (DE),
known as late-gadolinium enhancement (LGE), dobutamine stress
(DS) and end-diastolic wall thickness (EDWT)28.
The most commonly used DS and EDWT criterion to identify
viable myocardium is based on the same principles as in
stress echocardiography even the technical dobutamine stress
protocol is not different. Viable myocardium demonstrates an
increase in contractility, whereas non-viable segments remain
unchanged with stress. End-diastolic myocardial thickness is
also a marker for viability27. DE/LGE techniques demonstrate
the status of myocardial perfusion and tissue enhancement by
i.v. administration of gadolinium-chelated contrast. After 5min of
contrast agent, T1-weighted images are acquired which show
regions of myocardial infarction exhibiting high signal intensity
i.e. high contrast enhancement. This hyperenhancment is
related to the interstitial space between collagen fibers, which
is larger in scar tissue/non viable myocardium, than in normal
viable myocardium. This allows the determination of the extent
of transmural disease, which in turn correlates inversely with the
likelihood of functional recovery of the myocardium following
revascularization9.
A meta-analysis by Romero et al (2012), included 24 prospective
trials in 698 patients; 11 studies assessing DE, 9 DS and 4 EDWT.
DE demonstrated the highest sensitivity of 95% with specificity
of 51%, PPV of 69% and NPP of 90% in detecting viable
myocardium. The respective values for DS were 81%, 91%, 93%
and 75%. Similar studies suggested the combination of DE and
DS to offer more reliable results27, 28. Pegg et al (2010), although
only in 33 patients reported an additional predictive value of DE to
myocardial response to CABG30. Prior to this a cohort of 29 trial
patients demonstrated DE-CMR and PET/SPECT were equally
effective in determining myocardial viability31. Several studies have
supported the latter finding and have additionally demonstrated
that DE-CMR is superior to dobutamine stress echocardiography
(DSE) in certain patients, particularly those with poor images or
arrhythmias27.
Limitation and advantages
The main limitations of CMR include; high cost, long study time,
the requirement for breath-holding sequences and restrictions
in patients with implan devices and impaired renal function9, 16,
33
. However, advances in MRI technology are holding promises
to reduce imaging time, increase spatial resolution and adapt to
scan implanted devices9. The main advantages of CMR include
excellent anatomical details using steady state free precision
(SSFP) cine sequences in EDWT, good sensitivity/specificity with
good interobserver/intraobserver agreement in DE imaging, and
excellent sensitivity offered with DS16.
Prognostic value
Gerber et al (2012) included 144 patients with ischemic LV
dysfunction who had undergone DE imaging, then either
received revascularization with PCI or CABG or were managed
conservatively demonstrated good prediction of survival,
which was significantly lower in patients who did not undergo
revascularization33. Furthermore, it has been suggested that
by combining CMR with nuclear imaging additional benefits
are obtained. For example, in patients with intermediate DE
(25-75%) defined by CMR, PET can assess viable myocardium
and determine the likelihood of functional recovery34. The use
of myocardial tagging has also been shown to increase the
efficacy of DS-CMR, increasing its sensitivity and improving the
specificity27.
Combined Technology
Research into manufacturing combined technology is the new
approach to overcome many of the limitations of a single imaging
technique. One of the techniques is to combine PET and CMR.
Whilst CMR defines the transmurality of scars, PET study can
characterize the state of the non-scarred subepicardium and
help refine the likelihood of functional recovery in cases without
too much thickness of scar. By combining the high sensitivity
of PET with the high specificity of CMR, an improved diagnosis
of difficult cases is achieved35, 36. Another technique is using the
SPECT imaging cameras to capture the positrons emission from
fluorine-18 FDG, as a potential means for combining SPECT
and PET. FDG-SPECT compared to other techniques, such as
conventional thallium-201 SPECT with re-injection protocol or
in combination to low dose dobutamine echocardiography has
demonstrated superior predictive values for functional recovery in
studies of patients after revascularisation37, 38, 39.
Conclusion
This review demonstrates the available data, summarised
in the table below, which shows high sensitivity for the
assessment of myocardial viability for all non-invasive imaging
techniques. However, there is a wide range of specificity
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References
Table
Sensitivity Specificity
(%)
(%)
PPV
NPP
Dobutamine Stress
ECHO
81%
78%
75%
83%
SPECT Th 201
Rest-redistribution
Imaging Protocol
88%
59%
69%
80%
SPECT Th 201
Reinjection Protocols
86%
50%
57%
83%
SPECT Tech-99m
Sestamibi without
Nitrates
81%
66%
71%
87%
PET
92%
63%
74%
87%
Dobutamine Stress
MRI
81%
91%
93%
75%
Delayed
Enhancement MRI
95%
51%
69%
90%
varying between 50% and 91%. The recommended approach
to assess myocardial viability begins with either dobutamine
echocardiogphy or radionuclide myocardial perfusion imaging,
depending upon availability and local expertise. Despite cardiac
magnetic resonance (CMR) and positron emission tomography
(PET) scanning have greater sensitivity they may be more
challenging to perform and not as widely available.
The best data on the clinical impact of myocardial viability
assessment comes from a meta-analysis and from two
randomised trials; The Surgical Treatment for Ischemic Heart
Failure (STICH) trial and The Canadian PPAR study40, 41, 42. The
meta-analysis of 24 observational studies by Allman et al of
3088 patients, demonstrated that revascularization compared
to medical therapy, in patients with heart failure and myocardial
viability have a significantly better survival compared to patients
with no viability who did poorly irrespective of therapy40.
However, perhaps contrary to expectation, both The STICH trial
and The Canadian PPAR study reported a lack of association
between the presence or absence of residual myocardial viability
in patients mortality outcome when treatment was allocated
(revascularization vs medical therapy). Several limitations with
potentially confounding effects may explain the seemingly
opposing results, and further trials are necessary to explore this
outcome41, 42. Finally, it is important to note the European Society
of Cardiology (ESC), the European Association for CardioThoracic Surgery (EACTS), and American College of Cardiology/
American Heart Association guidelines for revasculirazation
of heart failure still recommend viability testing as a part of
diagnostic work up8, 43.
Correspondence to:
Ahmed Talib MB ChB
Canterbury Christ Church University
Medway Campus
Rowan Williams Court
30 Pembroke Court
Chatham Maritime
Kent ME4 4UF, UK
Email: [email protected]
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