myocardial viability : Dr. Akif Baig

Assessment
of
Myocardial
Viability
-Dr. Akif Baig
-Moderator: Dr. Siva Shankar

- Multimodality imaging of myocardial viability: an expert consensus document from the European Association of
Cardiovascular Imaging (EACVI), European Heart Journal - Cardiovascular Imaging, Volume 22, Issue 8, August
2021

 Left ventricular (LV) dysfunction remains one
of the best prognostic determinants of survival in
patients with coronary artery disease (CAD)
 It was originally thought that dysfunctional
myocardium after an infarction was irreversibly
damaged
 However, it was later recognized that some of the
involved tissue remained viable and contractility
may be restored with revascularization

 After a myocardial infarction, the myocardium will
usually demonstrate one of 5 pathophysiologies:
 Normal myocardial perfusion and function
 Myocardial ischemia
 Stunned myocardium
 Myocardial hibernation
 Non-viable infarction

 Prompt reperfusion or the presence of
collateral vessels and intact coronary
microvasculature function may preserve
myocardial perfusion
 Ischemia occurs as a result of decreased blood
flow resulting in low ATP production and
subsequent LV dysfunction

Myocardial Stunning
 Myocardial stunning is a reversible state of
regional contractile dysfunction that occurs after
transient ischemia without ensuing necrosis
 Myocardial stunning is believed to play an
important role in persistent contractile dysfunction
seen in acute myocardial infarction patients
after successful reperfusion
 In general, myocardial perfusion is normal and
function recovers relatively quickly

Myocardial Hibernation
 Myocardial hibernation is a state of persistent left
ventricular dysfunction that results from
chronically reduced blood flow or repetitive
stunning without infarction and necrosis
 A downregulation in contractile function at rest
is thought to represent a protective mechanism to
reduce myocardial oxygen requirements and
ensure myocyte survival

 When severe cellular hypoperfusion and damage
occurs, only cellular function that is essential for
survival, such as membrane integrity, is
preserved
 Preserved or increased myocardial glucose
metabolism also occurs during this state

Nonviable myocardium
 If myocardial perfusion is not restored, irreversible
myocardial necrosis can occur
 The goal of viability testing is to determine if a
large portion of dysfunctional myocardium is
nonviable in which case the risks would likely
outweigh benefit of revascularization

General pathophysiological
principles underlying the
imaging of viable and non-
viable myocardium

 Several pathophysiological principles and molecular
targets may be used clinically to identify viable
myocardium
 Viable myocytes are characterized by preserved energy
conversion by mitochondria and maintained membrane
function and action potentials
 Therefore, myocardial viability may be identified by
preserved electrical activity, for instance by endocardial
surface potentials during electrophysiological mapping
studies
 ECG Q waves on the surface ECG are however relatively
non-specific, relating more closely to the subendocardial
extent rather than transmurality of necrosis and many
myocardial segments with Q waves still demonstrate
viability by other methods

 Membrane function is explored by active uptake
of 201Tl and mitochondrial function by
retention of 99Tc-based tracers such as sestamibi
and tetrofosmin
 Active contraction is a definite marker of
preserved myocyte viability
 Dysfunctional segments at rest may or may not
be viable and frequently require further
assessment

 Stunned and hibernating myocardium is
characterized by reduced sensitivity of myofibrils to
calcium, resulting in reduced mechanical efficiency at
rest
 This may be overcome when the intra-cellular calcium
content increases, viable myocardium therefore has
preserved inotropic reserve
 These principles underlie the ability of dysfunctional
viable myocardium to improve contractility after
premature beats, nitrate infusion and more
commonly dobutamine stimulation

 Another feature of viable myocardium is that
resting perfusion is generally preserved or only
mildly reduced, and that hibernating myocardium
displays preserved metabolism with metabolic
preference for glucose over fatty acids in the
fasting state
 These principles underlie the detection of
myocardial viability using single photon emission
computed tomography (SPECT) or positron
emission tomography (PET) perfusion and
metabolic imaging (such as combined NH3 FDG
PET)

 A final method for detecting myocardial viability is
demonstrating the absence of myocyte
necrosis and the absence of replacement fibrotic
tissue
 These principles underlie the detection of
myocardial viability by late-gadolinium
enhancement (LGE) cardiovascular magnetic
resonance (CMR)

Myocardial Viability Testing
 ECG
 2D ECHO
 Contrast ECHO
 Dobutamine Stress ECHO
 Cardiac MRI
 SPECT
 PET

 The ECG is an initial tool in the evaluation of viability
 Absence of pathologic Q‐waves may be suggestive
of viable myocardium and the presence of them may
imply infarct
 Q waves are not specific for myocardial infarct and
are seen in myocardial hypertrophy, WPW, and
rarely hibernating myocardium
 The presence or absence of Q waves information can
be a helpful complementary marker in conjunction
with the other imaging parameters and clinical data to
determine myocardial viability

R wave height in lead V3
 The R wave height of less than 3 mm in lead V3
was 90.3% sensitive for the detection of non
viable myocardium
 The specificity at the same cut-off point was 25%
Journal of Clinical and Diagnostic Research. 2021 Aug, Vol-15(8): OC18-OC21

Sum of R Wave Height in all
Precordial Leads
 When the sum of R wave height in all precordial
leads was <28.5mm
 Sensitivity : 93.2%
 Specificity : 25%
Journal of Clinical and Diagnostic Research. 2021 Aug, Vol-15(8): OC18-OC21

END DIASTOLIC WALL
THICKNESS (EDWT)
 EDWT more than 6 mm has a sensitivity of
94%, albeit with a low specificity of 48% for
detection of myocardial viability
 With EDWT less than 6 mm, less than 5% will be
viable, while with thickness above that viability is
considered to be more than 50%

 Myocardial contrast echocardiography (MCE)
evaluates myocardial microvascular integrity
 Viable myocardium has preserved microvascular
integrity
 Intravenously injected bubble contrast agents lead
to contrast enhancement of dyssynergic but viable
myocardial segments that can be detected with
echocardiography
 Non-viable myocardium does not show significant
enhancement with bubble contrast due to disruption
of the coronary microvasculature.

Categorization of Wall Motion
Hypokinesis is defined as the preservation of some degree of thickening
and inward motion of the endocardium during systole but less than
normal
It has been defined arbitrarily as less than 5 mm of endocardial
excursion
Akinesis is defined as the absence of systolic myocardial thickening
and endocardial excursion
Dyskinesis is the most extreme form of a wall motion abnormality and is
defined as systolic thinning and outward motion or bulging of the
myocardium during systole
A left ventricular segment that is thin and/or highly echogenic
suggests the presence of scar

ECG evidence of ischemia is less reliable during dobutamine infusion than it is
during exercise testing
Thus, neither ST-segment depression nor elevation occurring in the
absence of a wall motion abnormality or typical symptoms is sufficient reason
for terminating the dobutamine infusion

Safety of Dobutamine
 Because of the short half-life of dobutamine, inducible
ischemia can be readily reversed through termination of
the infusion
 In severe cases or when the ischemic manifestations
persist, a short-acting intravenous β blocker (such as
metoprolol or esmolol) is effective
 The most common side effects associated with
dobutamine infusion are minor arrhythmias such as
premature ventricular contractions and atrial arrhythmias
and minor symptoms such as palpitations or anxiety
 Nonsustained ventricular tachycardia occurs in
approximately 3% of patients and generally terminates
spontaneously or can be successfully treated with an
intravenous β blocker

Contraindications
 There are no absolute contraindications to dobutamine
stress testing
 Unstable patients, such as those with uncompensated
heart failure for unstable angina, should rarely be
subjected to stress testing of any kind
 Dobutamine echocardiography has been safely
performed in patients with:
 Recent myocardial infarction
 Extensive left ventricular dysfunction
 Abdominal aortic aneurysm
 Syncope, aortic stenosis
 Hypertrophic cardiomyopathy
 History of ventricular tachycardia, and aborted sudden death

Vasodilators Stress ECHO
 Potent vasodilators such as dipyridamole and
adenosine have been used in conjunction with
echocardiography for the detection of coronary
artery disease
 Unlike dobutamine, these agents work by
creating maldistribution of blood flow, that is, by
preventing the normal increase in flow in areas
supplied by stenotic coronary arteries (Coronary
Steal Phenomenon)

 Adenosine is a potent and short-acting direct
coronary vasodilator
 Dipyridamole is slower acting and its effects result
from inhibition of adenosine uptake
 With both agents, the development of a wall motion
abnormality is predicated on the ability to create
sufficient maldistribution of regional blood flow to
result in an ischemia-induced wall motion abnormality
 Compared with dobutamine, these changes tend to
be more subtle and short-lived

 SPECT imaging provides reliable information on
myocardial perfusion and to some extent cellular
viability
 Viability assessment can be performed either
with:
 99mTc-sestamibi, a lipophilic cationic compound
 99mTc-tetrofosmin, a diphosphine agent; or
 201-thallium

 Both sestamibi or tetrofosmin are transported
passively into the myocyte and are sequestered
within the mitochondria
 Uptake requires negative transmembrane
potentials of sarcolemmal and mitochondrial
membranes
 By contrast, Tl-201 mimics potassium, and is
taken up actively into the myocyte through the
Na-K-ATPase

 The uptake and retention of all three tracers is
dependent on regional blood flow and
sarcolemmal membrane integrity (for thallium)
or mitochondrial membrane integrity (for
sestamibi and tetrofosmin)
 The principles of viability detection by SPECT
mainly rely on demonstrating reversible stress
perfusion defects in dysfunctional segments

 Areas with persistent little or no tracer uptake
indicate non-viable myocardium unlikely to
recover function after revascularization
 Stress can be performed either after physical
exercise or after vasodilation with dipyridamole,
adenosine, or regadenoson
 Rest-only images demonstrating preserved or
only mildly reduced perfusion are also indicative
of myocardial viability

VIABILITY ASSESSMENT WITH THALLIUM-201
SINGLE-PHOTON EMISSION COMPUTED
TOMOGRAPHY MYOCARDIAL PERFUSION
IMAGING
 Tl-201 behaves pharmacokinetically like a
potassium analog
 Myocardial uptake of Tl-201 is an active Na/K
ATPase pump-dependent process, which requires
cell membrane integrity
 Thus, Tl-201 myocardial uptake is an indication of
regional perfusion, which is necessary for tracer
delivery and myocyte membrane integrity and
metabolic activity (ATP production)

 A pivotal characteristic of Tl-201 myocardial
uptake is its redistribution property
 This phenomenon was initially described in the
late 1970s, with reports of stress-induced
myocardial perfusion defects that appeared to
normalize on repeat imaging at different time
intervals

 This property is a consequence of a constant
exchange of the radiotracer between the
myocardial cells, extracellular space and
subsequently the blood pool after the initial
myocardial uptake
 As Tl-201 is washed out of the myocardial cells,
radiotracer uptake from the blood pool continues to
take place
 In areas of decreased perfusion or with diminished
coronary flow, the rate of Tl-201 extraction is
slower than in those with increased or normal
blood flow, leading to perfusion defects in these area
at initial stress imaging, performed 10–15min
following radiotracer injection

 However, over-time, Tl-201 uptake continues in
areas with diminished blood flow, whereas the
radiotracer washes out from areas with normal or
increased initial blood flow
 This constant redistribution of Tl-201 manifest,
on delayed imaging (3–4h following injection),
with resolution of the initial perfusion defect in
areas that appeared to have little or no tracer
activity on initial stress imaging

 As Tl-201 uptake requires sarcolemmal
membrane integrity, resolution or ‘reversibility’ of
perfusion abnormality is considered to represent
myocardial viability

Thallium-201 viability assessment protocols
Stress/4 and 24h delayed redistribution
protocol
 During the 1980s, Tl-201 stress/4 h redistribution became
the standard protocol for assessment of myocardial
ischemia and to predict functional recovery after coronary
revascularization
 However, it was noted that up to half of the segments with
fixed perfusion defects on 4h imaging demonstrated
normalization of perfusion or improvement in function after
revascularization
 This finding suggests that under certain circumstances, Tl-
201 redistribution may take longer than 4 h, and therefore,
delayed imaging at 18–24 h could improve the ability of
the test to predict functional recovery after coronary
revascularization
 These findings led to the use of Tl-201 stress/4 h
redistribution with delayed, 24 h imaging

Rest/4h redistribution imaging
protocol
 Tl-201 rest/4 h redistribution imaging has also
been used and shown to be adequate for
identification of viable segments
 When Tl-201 is injected at resting state, delayed
imaging at 18–24 h does not yield improved
viability detection
 In this setting, the data suggest that a 10%
absolute increase in radiotracer uptake is
indicative of significant viability, which is
predictive of functional improvement after
revascularization

VIABILITY ASSESSMENT WITH TECHNETIUM-99M
SINGLE-PHOTON EMISSION COMPUTED
TOMOGRAPHY MYOCARDIAL PERFUSION
IMAGING
 Following their extraction from the blood, Tc-99m
tracers bind to the mitochondria, and thus results
in a negligible washout or redistribution

FDG-PET (for viability)
• Based on the fact that myocardium utilizes glucose for
metabolism when under effect of ischemia (hence the
ischemic myocardium will show greater uptake than normal
cells)
• Under normal circumstances, it utilizes fatty acids for
energy
• Non-viable myocardium will not show any uptake

 PET viability is a unique modality in its ability to
evaluate myocardial tissue’s metabolic activity
utilizing intracellular-biochemical pathways
 It requires coupling of myocardial perfusion
data with myocardial metabolic assessment
using various radioactive tracers

 Cardiac PET uses N‐13 ammonia or
Rubidium‐82 (82Rb) to assess perfusion and
 F18‐Fludeoxyglucose (18F‐FDG) to evaluate
myocardial glucose metabolism

 At rest, healthy myocardium oxidizes free fatty
acids to produce ATP
 In the setting of myocardial ischemia, there
would be a shift of hibernating myocardial
metabolism from fatty acids to glucose with
upregulation of glucose transporters

 For optimal 18F‐FDG uptake of viable
myocardium, it is crucial to stimulate
endogenous insulin release by appropriate
dietary protocol, oral or IV glucose loading, and
if needed insulin supplementation, to achieve
appropriate serum glucose (100–140 mg/dl)
levels before injecting 18F‐FDG
 Suboptimal patient preparation may yield poor,
non‐diagnostic images

 Preparation of diabetic patients can be
particularly challenging, requiring insulin injection
to overcome myocardial insulin resistance and
may take longer wait times from
injecting 18F‐FDG to image acquisition

 PET imaging is performed about 45–90 min (up to
3 h in diabetics) after injecting approximately
10 mCi (7 mSv) of 18F‐FDG (t ½ 110 min)

 Myocardial uptake of FDG continues to increase,
and blood pool activity to decrease, even after 45
min
 Waiting 90min after the injection of FDG may give
better signal to nose ratio as the blood pool has
less FDG and the myocardial uptake continues to
increase, especially in people with diabetes
 The typical scan duration is typically 10–30min

Mismatch defect seen in the lateral wall with reduced perfusion and normal metabolic

Matched defect seen in the anterior wall with reduced perfusion and metabolic a

 The two methods of viability testing by CMR are
 Contractile reserve assessment using
dobutamine stress and
 Late gadolinium enhancement (LGE) imaging
using gadolinium-based contrast agents (GBCA)
 With the latter being the more common and
preferred technique
2021

 GBCAs are paramagnetic metal compounds that,
when administered intravenously, cannot
penetrate intact myocardial sarcolemma and
accumulate extracellularly in the intravascular
blood pool and within myocardial interstitium
 With LGE imaging, GBCAs are used to index cell
membrane integrity, as living myocardial cells
exclude GBCA when steady-state concentrations
are reached
2021

 In an acute myocardial infarction, GBCA
passively diffuses intracellularly through ruptured
cell membranes and extracellularly in surrounding
necrotic tissue, whereas
 In chronic infarcts GBCA concentrates in
collagenous scar that has replaced necrotic
tissue.
2021

Evaluation of resting function and
wall thickness
 Preserved myocardial wall thickness of more
than 5.5 mm has a good sensitivity of 95%, but
low specificity for detecting myocardial viability on
CMR
 End-diastolic wall thickness of >5.5 mm and cine
systolic wall thickening of >2 mm has
sensitivity and specificity between 85% and 90%
in the prediction of segmental contractile recovery
after revascularization
- Braunwald Textbook of Cardiology

Late-gadolinium enhancement
(LGE)
 It has become the reference standard for the non-
invasive imaging of myocardial scar and focal
fibrosis in both ischaemic heart disease and non-
ischaemic cardiomyopathy
 Clinically used gadolinium-based contrast agents are
distributed into the extracellular space following
intra-venous injection
 They are therefore present in higher concentration in
fibrotic or infarcted myocardium
 This is best observed 10–15 min after contrast
injection, when difference to normal myocardium are
maximized, using the ‘LGE’ technique
2021

 LGE-CMR sequences are timed to selectively null
signal in normal myocardium, which appears black,
whereas areas of scaring with shorter T1 values
appear bright
 LGE-CMR therefore images non-viable myocardium
and infers viability from the absence of enhancement
 If the extent of scar is less as indicated by less than
50% transmural extent of hyperenhancement
indicates viability
 If 4 or more dysfunctional segments show viability, it
has a good sensitivity of 95%, again with low
specificity of 45%
2021

 Advantages of CMR LGE
 High quality of images
 Absence of ionizing radiation
 High prognostic value, and
 Lower costs relative to nuclear imaging
2021

 Disadvantages of CMR-LGE
 Need for gadolinium-based contrast injection, which although
generally safer than iodinated contrast agents, can cause
allergic reactions and anaphylaxis
 Gadolinium-based contrast agents are considered
contraindicated in pregnancy, although a recent study showed
that in the second and third trimesters, CMR can be safely
performed even with contrast
 Finally, LGE shows the expansion of the extracellular matrix,
regardless of whether this is due to collagen, water, or
amyloid infiltration
 As a result, LGE may overestimate the extent of the scar if there is
myocardial oedema, in particular in acute myocardial infarction.
2021

Dobutamine stress CMR
 Like stress echocardiography, the evaluation of
contractile reserve using dobutamine stress CMR can
be used to assess viability
 Infusion of low dose dobutamine (5–10 mcg/kg/min)
induces systolic wall thickening in viable regions of
myocardium but not in irreversibly scarred areas
 Improvement in myocardial thickening of more than 2
mm with low dose dobutamine CMR is indicative of
viability
 If this contractile reserve can be elicited, the
myocardium is more likely to improve after
revascularization

 In addition, low-dose dobutamine can
accurately predict the development of adverse
remodelling following acute myocardial infarction
 With high-dose dobutamine infusion (20–40
mcg/kg/min), the presence of inducible wall
motion abnormalities using cine CMR can trigger
a biphasic response and provides additional
accurate information regarding the presence of
ischaemia and prognosis

 Results suggest that low-dose dobutamine
CMR is superior to both LGE CMR and wall
thickness in predicting recovery after
revascularization
 This is particularly relevant for detecting viability
in patients with intermediate grades of transmural
infarction (up to 75% extent of LGE), but its
sensitivity may be reduced with more severely
impaired baseline LV function and those patients
with fewer than 50% of all myocardial
segments deemed viable may derive less
benefit from revascularization

 Interestingly, there is a strong correlation
between LV ejection fraction (LVEF) measured
during low-dose dobutamine (10 lg/kg/min) and
LVEF 6 months after revascularization
 The combined use of LGE and low-dose
dobutamine stress CMR, has a higher specificity
(91%) and a lower sensitivity (81%) according to
a meta-analysis

 The inotropic response to dobutamine is strongly
associated with abnormalities of fatty acid
metabolism and is likely to depend on the
presence of viable myocardium which has not
undergone severe ultrastructural change with
myofibrillar degeneration which would otherwise
prevent contractile improvement with inotropic
stimulation
 The combination of dobutamine stress with
other CMR sequences can give a more accurate
assessment of both ischaemia and viability, with
the potential to improve diagnostic performance

Keypoints of Cardiac MRI
CMR LGE is currently the reference method for clinical assessment of viability
and indicates myocardial necrosis or chronic scar
Scars with transmurality >50% are considered non-viable, less transmurality of
scar in dysfunctional myocardium is considered viable myocardium
LGE has high specificity for predicting absence of recovery but sensitivity may
be limited particularly in scars with intermediate transmurality (25–75%)
Low-dose dobutamine stress MR may have additional value in such patients
with intermediate transmurality of scar
Stress perfusion CMR also allows evaluation of ischaemia and coronary flow
reserve

Limitations
 High cost
 Limited availability
 Longer imaging time and
 Restrictions in patients with cardiac implantable electronic
devices (CIED)
 Claustrophobia
 Gadolinium enhancement is not suitable in those with low
glomerular filtration rate of below 30 ml per minute

Advantage of MRI over
SPECT/PET
 In single photon emission computed tomography
(SPECT) or positron emission tomography (PET)
imaging, the presence of scar is inferred by the
lack of uptake of myocardial perfusion tracers,
whereas CMR affords the luxury of direct
visualization of scar and normal myocardium
within the same image
 This reduces the likelihood of falsely labeling
viable segments as nonviable due to relatively
low perfusion tracer counts, especially in thinned
walls where tracer counts will inherently be lower

 Nuclear perfusion techniques also lack the excellent spatial resolution of
CMR (1.5 mm vs 10 mm for nuclear) and suffer from ionizing radiation
exposure
 Wagner et al. showed that SPECT is inadequately sensitive in the
detection of subendocardial scar (<50% TEI) compared to CMR in both
human patients and a canine model with histopathologic correlation
 Nearly one half of subendocardial infarcts were missed by SPECT in
human subjects when CMR was used as the reference standard
 Modalities fared identically in the detection of near transmural infarcts
(>75% TEI), but nearly one quarter of infarcts with 50–75% TEI went
undetected by SPECT
 This may result in the converse labeling of nonviable myocardium as
viable.
Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI and routine single photon emission
computed tomography (SPECT) perfusion imaging for the detection of subendocardial myocardial
infarcts: an imaging study. Lancet 2003;361:374–379

 Viability testing appears to be most helpful when
it is uncertain that the myocardial segment in
question is predominantly transmural scar or
otherwise
 If the dysfunctional myocardial segment
possesses relatively preserved thickness with
wall motion no worse than hypokinesis and
absence of Q waves on EKG, it is unlikely that
segment is NVM (scar), precluding need for any
further testing to assess viability

 Viability testing should be tailored to the individual
patient based on several factors including
limitations or contraindications of a particular
study in each patient, local expertise, and
availability
 The degree of LV remodeling and dysfunction
may play a role in deciding which test to perform

 Patients with extreme degrees of LV dilatation
and segmental wall thinning may need an
advanced imaging modality (CMR, PET)
 In patients with mild to moderate degree of LV
dysfunction and remodeling, dobutamine stress
Echo and SPECT imaging may suffice

References
 Braunwald textbook of cardiology
 Feigenbaum echocardiography
 Braunwald intervention cardiology
 Multimodality imaging of myocardial viability:
an expert consensus document from the
European Association of Cardiovascular
Imaging (EACVI), European Heart Journal -
Cardiovascular Imaging, Volume 22, Issue 8,
August 2021

myocardial viability : Dr. Akif Baig

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