Transcript Viability imaging techniques

MYOCARDIAL VIABILITY
CLAUDIA GIDEA, MD
• Viable = myocardial cells that are alive:
– cellular function
– metabolic function
– contractile function
• Viable myocardium:
– contractile myocardium
– hypocontractile myocardium
• Viability  ``contractile recovery``
• Dysfunctional viable myocardium:
– hibernating myocardium
– stunned myocardium
•
The requirements of cellular viability:
– intact sarcolemmal function → to
maintain electrochemical gradients across
the cell membrane
– preserved metabolic activity → to
generate high-energy phosphates
– adequate myocardial blood flow → to
deliver substrate and washout the
metabolites of the metabolic processes
• irrespective of the resting flow → perfusion
reserve (CFR) is always reduced in
dysfunctional but viable myocardium
• CFR is more severely reduced in the
segments with low resting perfusion flow than
in segments with normal resting perfusion
flow
• the severity of CFR reduction → impacts the
ability of dysfunctional but viable myocardium
to improve its contraction on inotropic
stimulation → increased MVO2 and blood
flow
CFR= the ability of a coronary vascular bed to increase
coronary blood flow in response to stimuli that produce a
maximal or near maximal hyperemic response
CFR=maximal hyperemic / resting coronary 
CFR = 2-5 in man
Reactive hyperemia that follows transient coronary
occlusion or the administration of pharmacologic agents
The patterns of chronic LV ischemic
dysfunction
resting
flow
flow
reserve
inotropic metabo structural reversi
lism
changes bility
reserve
Chronic
stunning
N
↓
yes
(+)
no
yes
Transition
phase
N
↓
yes
(+)
mild
yes
Chronic
hybernatio
n
↓
↓↓↓
±
(+)
severe
Delaye
d/inco
mplete
Infarction
↓
↓↓↓
no
(-)
fibrosis
no
Stunned myocardium
• total coronary artery occlusion for 5 to 15
minutes (a period not associated with cell
death)
• abnormality in regional LV wall motion that
persisted for hours or days following
reperfusion
• stunned myocardium
• Key elements of the stunned myocardium
are:
• short-term, total or near total reduction
of coronary blood flow
• reestablishment of coronary blood
flow
• subsequent LV dysfunction of limited
duration
• Hybernating myocardium
• Original concept:
• ↓resting flow (moderate levels of ischemia
for couple of hours)
• adaptive response to ischemia (without
infarction)
• ``short-term`` hibernation
• Hibernating myocardium
• ↓resting flow (moderate levels of ischemia
for ≥ 12hours)
• sub-endocardial necrosis and infarction
• prolong perfusion-contraction matching =
short-term adaptation → ``short-term``
hibernation
• prolong perfusion-contraction matching ≠
long-term adaptation → chronic
hibernation
• repetitive ischemia distal to a severe
stenosis ↔ chronic hibernation →↓resting
flow is a result rather than the cause of
hibernation
• critical relation between the physiological
severity of a coronary stenosis (CFR) and
the developing of viable dysfunctional
myocardium:
– severe physiological coronary stenosis →
chronic hibernation
– less marked physiological coronary
stenosis → chronically stunned
myocardium
• 2 concepts regarding hybernation:
1) downregulation of metabolic and
contractile function
2) repetitive stunning
• Histopathologic abnormalities at the
cellular level demonstrated by biopsies of
the hibernating segments taken at the
time of surgery:
– cellular dedifferentiation and embrionic
phenotype
- substantial loss of myofibrillar content
- cellular swelling
- increased glycogen content
• 23 swine
• 15-min partial occlusion of the LAD using the
primary occluder → acute stunning → then the
hearts were reperfused through a critical stenosis
→ that abolished the hyperemic response to a
20sec occlusion → yet allowed peak LAD flow to
increase above the preocclusion value
• microspheres assess the transmural distribution of
flow:
– at rest
– during a transient total LAD occlusion (collateral flow)
– after adenosine vasodilation
• histological analysis performed
– to identify changes characteristic for hibernating
myocardium
The reduction of resting LAD flow developed despite the fact
that hyperemic flow always exceeded the preocclusion value
at rest (CFR was ~2)
24 hr= sustained stunning; 2 weeks = hibernation
Analog recordings at selected time points from a representative animal from the 2-week group. Dotted
vertical lines depict end diastole and end systole. On day 1, a 15-minute partial LAD occlusion produced
acute stunning. When reperfused with a critical limitation in flow reserve, function remained depressed when
the animals were reevaluated 24 hours later (day 2), but resting flow was normal, consistent with myocardial
stunning. Function continued to be depressed throughout the study, but resting flow became reduced,
consistent with a progression to hibernating myocardium (day 17). Throughout the study, heart rate and
systemic hemodynamics remained constant, with the exception of an increase in LV enddiastolic
pressure. dPLV/dt represents the first derivative of LV pressure.
Serial measurements of LAD
flow and wall thickening in
animals in the 2-week study
protocol. The initial
(triangles) and final
(squares) reactive hyperemic
(RH) flows were reduced by
the stenosis but always
exceeded the preocclusion
baseline flow at the
beginning of the study
(dotted line). LAD wall
thickening was initially
depressed with normal flow,
consistent with chronic
myocardial stunning. After a
critical stenosis was applied
for 8 days, resting flow
(circles) became reduced.
Thus, a critical coronary
stenosis caused a rapid
progression from stunned to
hibernating myocardium with
reductions in resting
flow occurring in the
presence of recruitable flow
reserve.
Reduction in flow were indicative of reduction in tissue
perfusion
Microsphere measurements of resting flow in animals completing the 2-week protocol. Paired
analysis of flow measurements in the LAD and normally perfused remote region were similar
before occlusion (day 1) and in stunned myocardium after 24 hours (day 2). At the end of the
study, LAD flow was significantly lower than flow in normally perfused myocardium
in each myocardial layer. Flow was reduced in each myocardial layer and was consistent
with a progression from stunned to hibernating myocardium.
Endo, Mid, and Epi indicate subendocardial, midmyocardial, and subepicardial samples, and FT
indicates full thickness.
Histopathologic findings of hibernating myocardium in pigs. Light and electron microscopy in hibernating LAD regions (upper
row) were similar to those reported from human biopsy specimens. Both the remote normally perfused myocardium (middle row)
and sham-operated controls (lower row) are shown to contrast the role of regional ischemia versus global factors. Hibernating
myocardium exhibited regional increases in collagen (blue, first column) (Masson’s trichrome stain, 40) as well as myocyte
hypertrophy (second column) (hematoxylin-eosin stain, 600) as a result of apoptosis induced myocyte loss. Changes in collagen
and myocyte size in remote regions were similar to sham controls. In contrast to these regional changes, electron microscopy (
8300) (third column) and periodic acid–Schiff staining ( 600) (fourth column) demonstrated that the myofibrillar loss and glycogen
deposition occurred throughout the left ventricle. Thus the myofibrillar loss and glycogen deposition thought to be
characteristic of hibernating myocardium actually reflect a global phenomenon that is not a direct result of repetitive
ischemia.
Quantitative analysis of myofibrillar volume loss in subendocardial (black bars) and subepicardial (gray bars)
regions. Myofibrillar loss was nearly 4-fold higher in hibernating
myocardium than sham control myocardium. Myofibrillar loss began after 24 hours and increased after 2
weeks. Subepicardial and subendocardial values were similar. Furthermore, measurements in the LAD
region subjected to ischemia were similar to those in the normal region. Thus, myofibrillar loss was global
and was dissociated from regional differences in function and coronary flow reserve.
• Patients with hibernating myocardium → high
mortality rate in the absence of revascularization
Medical
therapy
PET
• cause-specific mortality data are limited
• unclear whether death arise from:
– progressive heart failure (possibly as a
result of progressive cellular degeneration
and fibrosis)
– myocardial infarction (as a result of
unstable plaque in the setting of global LV
dysfunction)
– sudden death (as a result of primary
ventricular tachycardia and/or fibrillation)
Kaplan-Meier survival analysis of pigs with hibernating myocardium. Swine with hibernating myocardium had a
progressive reduction in survival rate as a result of sudden death. There were no deaths in sham-operated
control animals. By use of implantable Reveal Plus loop recorders, the mechanism of sudden death was
usually ventricular tachycardia (VT) degenerating into ventricular fibrillation (VF) (inset). Postmortem analysis
showed that more than 90% of the animals developing sudden death had no pathologic evidence of acute or
healed infarction. Total coronary occlusion and physiologic features consistent with hibernating myocardium
were demonstrated in a subset of animals studied several weeks before sudden death. These data indicate
that the myocardial adaptive response to ischemia may be a double-edged sword. Though regionally
protecting myocytes from acute ischemia, they may lead to a substrate characterized by electrical
instability and a high risk of lethal ventricular arrhythmias.
• in the porcine models of hibernating
myocardium the deaths were almost entirely
suddenly and not preceded by heart failure
• myocardial sympathetic nerves are very
sensitive to reversible ischemia → ``neural
stunning`` → dysinnervation → sudden death
• transmural distribution of norepinephrine
uptake (I-131 MIBG) in hibernating
myocardium → ↓↓ regional NE uptake in
hibernating myocardium with ↓↓↓↓ in the
subendocardium.
C-11 HED and PET → assess the myocardial sympathetic
innervation in vivo
Imaging of sympathetic dysinnervation in hibernating myocardium. Short-axis (upper panel) and horizontal
long-axis (lower panel) views compare metabolic viability with stimulated F-18 2-deoxyglucose (FDG) and
regional myocardial norepinephrine uptake by use of C-11 hydroxyephedrine (11C-HED) in a pig with
hibernating myocardium. Like the reductions in MIBG by ex vivo tissue counting, C-11 HED
uptake was markedly reduced throughout the risk area distal to the LAD stenosis. Viability was confirmed
by FDG as well as postmortem pathologic analysis. These findings demonstrate a C-11 HED/FDG
mismatch in hibernating myocardium indicative of dysinnervated but viable myocardium.
• hibernating myocardium exhibits
inhomogeneity in sympathetic nerve function
that is similar to that seen after myocardial
infarction → promote the development of VT/
Vfib
• cellular alteration in hibernating myocardium
→ spatial inhomogeneity in the
electrophysiological properties of cardiac
myocytes
• Contractile reserve (CR) in hibernating
myocardium
• CR has a lower sensitivity to detect viable
myocardium than nuclear imaging
techniques but higher specificity to predict
functional recovery after coronary
revascularization
• CR depends on the resting flow
• CR is less in hibernating myocardium with
reduced resting flow (32-46% of
hibernating segments) compared to CR in
stunned myocardium with normal resting
flow
• 88% of segments that show ``biphasic
response `` with dobutamine echo had
normal resting perfusion.
• Viability imaging techniques
• Nuclear imaging techniques
– Stress-delayed thallium-201 imaging
– Rest-delayed thallium –201 imaging
– Technetium-99m-labeled sestamibi
imaging
– Positron Emmision Tomography
• Viability imaging techniques
• Echocardiography techniques
– Low dose dobutamine
– Full dobutamine protocol
• MRI
– Delayed contrast enhancement → assess
the microcirculation
– Dobutamine MRI → assess the contractile
reserve
Prediction of functional recovery by
viability testing
Rest –Redistribution Tl
201
Sensitivity Specificity Accuracy
(%)
(%)
(%)
86
58
73
Stress –Redistribution
– Reinjection Tl201
Tc-99m Sestamibi
87
50
66
79
58
69
PET
92
57
76
Dobutamine Echo
81
80
81
• Viability imaging techniques
• Nuclear imaging techniques
– Stress-delayed thallium-201 imaging
– Rest-delayed thallium –201 imaging
– Technetium-99m-labeled sestamibi
imaging
– Positron Emmision Tomography
•
Concept of redistribution:
1) the initial myocardial extraction of the tracer
reflects the distribution of blood flow at the
time of injection
2) the delayed uptake after equilibrium has
been reached is flow independent but it
reflects an intact myocardial cell membrane
and membrane potential
- because delayed uptake is flow
independent, redistribution can still occur
if a myocardial segment is chronically
hypoperfuzed, even when the injection is
performed at rest
• Concept of reinjection:
- tracer reinjection has 2 effects
1) adds more tracer to both normal and
abnormal segments
2) adds more redistribution
49% of fixed
defects
normal Tl201uptake
Tl-201
reinjection
imaging has
an 88%
concordance
with FDG–
PET imaging
Survival free from cardiac events (cardiovascular
death or heart transplantation) in relation to
viability index (V.I.).
Pagley et al
42
27
27
31
The correlation between improvement in regional function after
coronary bypass grafting and assessment of viability by
preoperative rest-redistribution Tl-201 imaging in segments with
severe asynergy (severe hypokinesis, akinesis, or dyskinesis).
62%
54%
23%
• for revascularization to improve LVSF,
the ventricle must be ischemic from a
stenosis in an artery perfusing the
dysfunctional territory (defect reversibility)
• in the setting of a ventricle impaired by
cellular dysfunction related to a
cardiomyopathy despite satisfactory
myocardial Tl-201 uptake, the
revascularization would not be expected
to improve function.
Influence of left ventricular ejection fraction (EF) on survival in patients with coronary artery disease. Data
from the Duke database are shown for patients with normal left ventricular function (left), miId-to-moderate
left ventricular dysfunction (center), and severe left ventricular dysfunction (right). For each subgroup,
survival rates in patients undergoing coronary artery bypass surgery are compared with those in patients
treated medicaIly. Although survival rates are higher with surgery compared with medical therapy across
the spectrum of left ventricular function. the incremental benefit of surgery is greatest in patients with the
most severe left ventricular dysfunction. (From Muhlbaier LH, Pryor DB, RankinjS. et al: Observational
comparison of event-jree survival with medical and surgical therapy in patients with coronary artery
disease. 20 years of follow-up. Circulation 86[5 supplj:II198-204, 1992.)
• Viability imaging techniques
• Nuclear imaging techniques
– Stress-delayed thallium-201 imaging
– Rest-delayed thallium –201 imaging
– Technetium-99m-labeled sestamibi
imaging
– Positron Emmision Tomography
Percentages of segments that were viable in relation to relative
uptake of Tl-201 or Tc-99m-labeled sestamibi. The likelihood of
viability was related to the magnitude of regional activity rather
than the radiotracer used.
• Viability imaging techniques
• Nuclear imaging techniques
– Stress-delayed thallium-201 imaging
– Rest-delayed thallium –201 imaging
– Technetium-99m-labeled sestamibi
imaging
– Positron Emmision Tomography
Summary:
• Medically treated patients with defined viability
by any noninvasive imaging technique have
the lowest survival rate.
• In patients with ischemic cardiomyoptahy,
improvement in HF symptoms and exercise
capacity after revascularization appears to be
at least modestly related to the preoperative
presence and/or extent of dysfunctional but
viable myocardium.
• Viability imaging predicts improvement in regional
and global LV function after revascularization.
• J.M. Canty and J. A. Fallavollita: ``Hybernating myocardium:
From bench to imaging``. J Nucl Cardiol 2005; 12:104-19
• S. Thomas, J. A. Fallavollita, J.M. Canty: ``Dissociation of
regional adaptations to ischemia and global myolysis in an
accelerated swine model of chronic hybernating
myocardium``. Circ Res. 2002; 91: 970-977.
• R.J Gibbson et all: ``Revascularization in severe left
ventricular dysfunction: The role of viability testing``. J Am
Coll Cardiol 2005; 46: 567-74.
• G. R. Heindrickx et all: Stunning and Hibernation: Two faces
of the same disease. J Clin Basic Cardiol 2000;3:141
• M. Travin: Use of myocardial perfusion imaging to assess
viability. J Nucl Cardiol 2000;7:72-80
• Conti, R & all: ACCSAP 2000. Nuclear Section
• Zaret, B & Beller, G :Nuclear Cardiology: State of the art
and future directions. 3rd edition, 2005 by Elsevier.
• Braunwald & all: Heart disease – A textbook of
cardiovascular medicine. Nuclear Cardiology. 6th edition,
2001 by Saunders.
Thank you!