Basics of myocardial viability, stunned and hibernating myocardium and modalities of its assessment, mechanism of each modality and its compatision

1. Dr. Prithvi Puwar
DNB Cardiology
Vijaya Hospital
Chennai
MYOCARDIAL VIABILITY

2. CORONARY ARTERY DISEASE
ACUTE CORONARY SYNDROME
Undergo revascularisation procedures
Improved survival
Increased number of patients
with residual LV dysfunction
undergoing progressive LV
remodeling and congestive heart
failure
Dr Prithvi Puwar

3. Concept was developed in the late 1970’s based on 2
observations:
1. That myocardial dysfunction present before bypass
surgery often reversed after surgery.
2. And that inotropic stimulation with epinephrine caused
transient improvement in regional and global LV
dysfunction in patients with CAD.
Dr Prithvi Puwar

4. In the early 1980s, Rahimtoola et al reviewed the
results of coronary bypass surgery trials and identified
patients with CAD and chronic LVD that improved upon
revascularization.CORNERSTONE FOR ALL FUTURE STUDIES
CASS (coronary artery surgery study ) REGISTRY
Dr Prithvi Puwar

5. Data from the coronary artery surgery study
(CASS) registry for patients with LVEF < 35%
involved 651 patients.
The five year survival was significantly better in
surgical patients (68%) than in the medical group
(54%).
The contrast was even more in patients with LVEF
< 26% whose five year survival was 63% with
surgery, but 43% with medical treatment
Dr Prithvi Puwar

6. Thus came the concept of myocardial
viability and with it came the new terms
such as hibernation and stunning
Dr Prithvi Puwar

7. THE MYOCARDIAL RESPONSE
TO
ISCHEMIC INJURY
Dr Prithvi Puwar

8. Onset of severe ischemia
Aerobic changes to anaerobic
metabolism
Within
seconds
Decrease in the production of high-energy phosphates, namely
adenosine triphosphate (ATP) and phosphocreatine (PCr)
Ultrastructural changes occur  mitochondrial swelling,
loosening of intercellular attachments,
dilation of the sarcoplasmic reticulum and myofibrillar relaxation
Dr Prithvi Puwar

9. within 1 – 2 min of acute onset
The myocardium is functionally
sensitive to ischemia and will
exhibit marked contractile
dysfunction
HOWEVER, these ultrastructural defects are
entirely reversible if reperfusion occurs within 20–
40 min.
Dr Prithvi Puwar

10. Irreversible Injury
Begins in the subendocardial tissue and progresses towards
the
subepicardium.
In humans, it may take as long as 6–12 hr for
complete infarction of the myocardium at risk
the necrotic changes are usually evident, about
4–12 hr after onset
This may include the denaturation of
cytoplasmic proteins, swelling, and enzymatic
digestion of organelles and the sarcolemma.
Dr Prithvi Puwar

11. If tissue is viable  restoration of
normal blood flow.  will improve the
ventricular function
Thus, the patient’s prognosis will also
improve,
• increase in ejection fraction
• systolic and diastolic performance
• exercise capacity
• survival.
Dr Prithvi Puwar

12. Dysfunctional myocardium subtended by
disease coronary artery with limited or
absent scarring that has
POTENTIAL FOR FUNCTIONAL
RECOVERY
Is
Myocardial Viability
Dr Prithvi Puwar

13. Viable myocardium must have the
following characteristics
1. The ability to generate HEP (PCr and ATP)
2. have an intact sarcolemma, in order to maintain
ionic/electrochemical gradients
3. have sufficient perfusion, both for the delivery of
substrates and O2 and for the adequate washout of
potentially noxious metabolites
?
contractilityDr Prithvi Puwar

14. There are two tissue states that exhibit
sustained contractile dysfunction despite
meeting the three criteria
Stunned myocardium
&
Hibernating myocardium
Dr Prithvi Puwar

15. Myocardial stunning
First documented by Heyndrickx et al. in the mid-
1970s
Delayed recovery of regional myocardial
contractile function after reperfusion despite the
absence of irreversible damage and despite
restoration of normal flow
Dr Prithvi Puwar

16. Pathogenesis of stunning
Earlier,
loss of and reduced ability to synthesize high-
energy phosphates,
Impairment of microvascular perfusion,
impairment of sympathetic neural
responsiveness,
reduction in the activity of creatine kinase,
Were believed to be the causes
Dr Prithvi Puwar

17. Presently
There are 2 major hypotheses for myocardial
stunning:
(1) a oxygen-free radical hypothesis
(2) a calcium overload hypothesis
 dysfunction may persist for
hours or for as long as 6 weeks
post-insult
Time-course of myocardial stunning
 both the duration and severity of
ischemia determine the duration
of post-ischemia/reperfusionDr Prithvi Puwar

18. Normal cardiac contraction depends on the maintenance of
calcium cycling and homeostasis.
Brief ischemia followed by reperfusion- accumulation of
calcium and a partial failure of normal beat to beat calcium
cycling - damages Ca2+ pump and ion channels of the
sarcoplasmic reticulum.
This results in the electromechanical uncoupling of energy
generation from contraction that characterizes myocardial
stunning.
Mechanism of contractile dysfunction in stunning
Dr Prithvi Puwar

19. A state of persistently impaired myocardial and left
ventricular function at rest due to reduced coronary
blood flows, which improves after
revascularization.
Hibernating Myocardium
Dr Prithvi Puwar

20. Hibernating myocardium:
 Episodic and/or chronically reduced blood flow, which is
directly responsible for the decrease in the myocardial
contractile function.
 Tissue ischemia and resultant remodeling without necrosis
 Residual contractile reserve in response to inotropic
stimulation (in at least half of clinical cases).
 Recovery of contractile function after successful
revascularization.
Dr Prithvi Puwar

21. Myocardial Hibernation is primarily a clinical
observation
3 mechanisms whereby this may occur
Decreased flow at rest  decreased metabolism 
decreased function Chronically depressed contractile function.
Demand ischemia Recovery  Repeated stunning 
Chronically depressed contractile function.
Genomic trigger for cell survival Survival proteins
produced by antiapoptotic, cytoprotective, and growth-promoting
genes Protection against apoptosis, activation of autophagy
All these mechanisms lead to cell survival in the face of and inspite
of reduced perfusion.
Dr Prithvi Puwar

22. Dr Prithvi Puwar

23. STUNNING AND HIBERNATION
Dr Prithvi Puwar

24. IDENTIFYING VIABLE MYOCARDIUM
Dr Prithvi Puwar

25. The gold standard for the assessment of viability, in the
clinical setting is limited…….
Noninvasive techniques can only identify tissue that
might benefit from revascularization.
Dr Prithvi Puwar

26. Key non invasive methods to identify
viability
1.Echocardiography
2.Single Photon Emission Computed
Tomography (SPECT)
3.Positron Emission Tomography (PET)
4.Cardiac Magnetic Resonance (CMR)
CSI update 2015 chapter 33Dr Prithvi Puwar

27. Echocardiography
-Extremely useful tool
-document the early and late functional
changes at rest,
Stress echocardiography with
dobutamine (DSE) has also been used to
identify viable, yet chronically
dysfunctional myocardium.
Dr Prithvi Puwar

28. DSE:
Basally the hibernating tissue may be hypokinetic ,
akinetic or dyskinetic.
With dobutamine infusion, it may demonstrate a
biphasic response-
at lower doses(5–10mcg/kg/min),
 an improvement in contractile
performance
at higher doses (>15mcg/kg/min)
 Contractility regresses as the
metabolic demand stimulated overwhelms the
tissue’s capacity to respond
Dr Prithvi Puwar

29. Nagueh et al studied the transmural myocardial
biopsies obtained from patients with hibernating
myocardium
Showed that tissue with >17% fibrosis failed to
exhibit contractile reserve when challenged with
low-dose dobutamine
Circulation 1999, 100, 490–496.
Dr Prithvi Puwar

30. In a study by Pagano et al
the technique appeared to underestimate the extent of
viability: 39% of all recovering LV segments failed to exhibit
inotropic contractile reserve.
Heart 1998;79:281-288
Wiggers et al
studied the functional recovery pre- and 6 months post-
revascularization, and showed that low-dose dobutamine
failed to identify 45% of the segments that ultimately
regained function
Am. Heart. J. 2000, 140, 928–936.Dr Prithvi Puwar

31. VIAMI -TRIAL 2005
First RCT
261 pts, taekn 48 hr after AMI, undervent LDE within 72 hrs
of MI
Investigated viability guided invasive approach
Those with viable myocardium – randomized to invasive Vs
conservative approach
Primary endpoint:
All cause death, recurrent MI, USA at 1 yr followup
An invasive approach in patients with a high viability score
had substantial reduction in ischemic eventsDr Prithvi Puwar

32. Value of DSE
Those regions with greater metabolic reserve will likely retain
the ability to respond to an inotropic stimulus while those regions
with profoundly reduced flow—just on the threshold of
viability—will have no ability to respond.
Such regions will therefore appear to be nonviable on a
dobutamine-echocardiography challenge.
Hence dobutamine-echocardiography may be considered
an easily accessible tool however with sub-optimal
sensitivity for the detection of residual tissue viability
Dr Prithvi Puwar

33. Myocardial contrast echocardiography
(MCE)
Intracoronary contrast administration has emerged as a
modality for assessing myocardial perfusion, and it has the
potential to predict myocardial viability.
Basis :-
Myocardial contrast enhancement depends on
an intact microcirculation.
The combination of intravenous MCE and destruction and
replenishment contrast intensity curves have allowed for
the noninvasive quantification of myocardial blood volume
and velocity and, thus, myocardial blood flow.
Dr Prithvi Puwar

34. Left ventricular opacification (LVO) obtained with
microbubbles improves the definition of the LV border.
This provides better quantitation of LV volume by the
Simpson method.
The correlation between LV volume measured with
cardiac magnetic resonance (CMR) and that measured
with echocardiography is better with the use of LVO.
Regional wall motion analysis can also be better with
LVO.
Dr Prithvi Puwar

35. Dr Prithvi Puwar

36. Echocardiography
Main advantages:
• Good validity
• Lack of ionizing radiation
• Possible with implanted devices
Limitations:
• Operator dependance
• Lack of reproducibility (interobserver variability)
• Spatial resolution is low
Dr Prithvi Puwar

37. Single Photon Emission
Computed
Tomography (SPECT)
Dr Prithvi Puwar

38. STANDARD
SPECT IMAGING
DISPLAY
SA
VLA
HLA
Dr Prithvi Puwar

39. SPECT
injection of a gamma-emitting radioisotope
Thallium-201 and Technetium Tc 99m–Labeled Tracers
are the commonly used radionuclides
201Tl is a monovalent cation with biologic properties
similar to those of potassium (major intracellular cation in
muscle and is virtually absent in scar tissue ) 201Tl is a
well-suited radionuclide for differentiation of normal and
ischemic myocardium from scarred myocardium.
The initial myocardial uptake early after intravenous
injection of thallium is proportional to regional blood flow.
Dr Prithvi Puwar

40. 201Tl stress redistribution
The uptake of 201Tl is an energy-dependent
process requiring intact cell membrane integrity,
and the presence of 201Tl implies preserved
myocyte cellular viability.
Imaging is done-
1) immediately following stress, with either
exercise or pharmacologically induced coronary
hyperemia with dipyridamole or adenosine, and
2) after 3–4 hr redistribution of Tl-201
Dr Prithvi Puwar

41. Defects on post-stress images are acquired, indicating
viability.
A defect that persists and appears again on the 3–4 hr images
(i.e., a fixed-defect) may be due to:
(1) markedly reduced regional perfusion,
(2) impaired cellular membrane integrity, inadequate for
the active sequestration of the tracer into the cell,
(3) cell death (acute infarction), or
(4) scar tissue.
INTERPRETATION
Dr Prithvi Puwar

42. INTERPRETATION
Late redistribution images
Acquire a third set of images at 24 hours
This would allow for redistribution of the tracer to very-
ischemic (yet viable) tissue
It has been shown that 22% of fixed defects (at early
redistribution imaging) demonstrate normal Tl-201 uptake
at later redistribution.
This may indicate a poorly perfused, yet viable region
Dr Prithvi Puwar

43. 99mTc-sestamibi and tetrofosmin
They do not share the redistribution properties of
201Tl
BUT their characteristics for predicting improvement
in regional function after revascularization appear to
be similar
Dr Prithvi Puwar

44. Relation between tracer uptake in a dysfunctional territory and the
subsequent probability of functional recovery after revascularization.
Taken from textbook of Braunwald 10th editionDr Prithvi Puwar

45. 1. Severe apical defect
2. Basal and mid inferior and lateral wall defect
Summed rest score (SRS) – Summed stress score (SSS)= SDS
(Difference) represent extent of ischemia
 Fixed defect
Reversibl
e
AN EXERCISE…..
Dr Prithvi Puwar

46. Hage FG et al J Nucl Cardiol. 2010 Jun;17(3):378-89. Epub 2010 Feb 26.
studied 246 consecutive ICM patients with rest-
redistribution gated SPECT thallium-201 MPI.
Size and severity of perfusion defects were assessed by
automated method.
Regions with <50% activity vs normal were considered
nonviable
Dr Prithvi Puwar

47. RESULTS:
•Of the 246 patients, 37% underwent CR within 3 months of MPI.
•Independent predictors of CR included chest pains (OR 2.74) and rest-
delayed transient ischemic dilatation (OR 4.49), while a prior history of
CR or ventricular arrhythmias favored Medical therapy.
•The cohort was followed-up for 41 +/- 30 m
•Survival was better with CR than MT (P < .0001).
•For CR, survival was better for those with a smaller area of nonviable
myocardium (risk of death increased by 5%/1% increase in size of
nonviable myocardium, P = .009) but this was not seen in MT.
•CR had a mortality advantage over MT when the area of nonviable
myocardium was <or=20%LV but not larger.
Dr Prithvi Puwar

48. Positron emission tomography
(PET)
Dr Prithvi Puwar

49. FDG is transported into the cell by the same sarcolemmal
carrier as glucose, where it is phosphorylated to FDG-6-
phosphate by the enzyme, hexokinase.
This unidirectional reaction results in the intracellular
accumulation of FDG-6-phosphate.
Since FDG does not undergo further metabolism, its uptake
is proportional to the overall rate of trans-sarcolemmal
transport and hexokinase phosphorylation of circulating
glucose by the myocardium
MECHANISM
Dr Prithvi Puwar

50. Although fatty acid oxidation stops shortly after the onset
of severe ischemia, the ischemic myocytes will derive
energy from stored glycogen through anaerobic glycolysis.
After glycogen stores have been depleted, the ischemic
myocyte makes extremely efficient use of its meager supply
of circulating glucose.
Even under conditions of extremely diminished glucose
delivery, there is evidence that certain sarcolemmal glucose
transporters are up-regulated to allow for increased uptake
of this substrate
MECHANISM (Contd…)
Dr Prithvi Puwar

51. As there should be no uptake of glucose by infarcted
myocardium—which is metabolically inert—nonviable
myocardium will appear as a region of low-FDG
concentration in such images.
In areas of reversibly injured myocardium, glucose
utilization is normal and even above normal
Thus, stunned or hibernating myocardium may be
indistinguishable from normal tissue in an FDG PET image.
INTERPRETATION
Dr Prithvi Puwar

52. FDG PET in Myocardial Viability- various studies
combined sensitivity and specificity of 88 and 73%,
Dr Prithvi Puwar

53. SPECT VS FDG PET
Brunken et al published data from a comparison of
tomographic thallium images with PET images; 47% of the
irreversible thallium defects were identified as viable on
PET images
Circulation. Nov 1992;86(5):1357-69.
Tamaki et al subsequently confirmed these findings in 2
comparative studies of SPECT and PET in which 38-42%
of the irreversible thallium defects had enhanced FDG
uptake suggestive of viable myocardium.
Am J Cardiol. Oct 15 1989;64(14):860-5
Dr Prithvi Puwar

54. PET
Advantage:
excellent sensitivity
better spatial resolution
less radiation
Limitations:
high cost
availability
need of radioactive tracers
Dr Prithvi Puwar

55. Magnetic resonance Imaging
(CMR)
Dr Prithvi Puwar

56. WHY THE NEED FOR MRI?
Dobutamine echocardiography (DbE) and thallium single-
photon emission computed tomography are widely available.
Dbe - contractile reserve and SPECT  membrane integrity.
SO in a patient with a scar may exhibit small residua of
viable myocardium which is picked up by SPECT , however it is
insensitive to DbE
Hence a smaller scar may respond to DbE
Increasing TES may be associated with poorer contractile
reserve
Dr Prithvi Puwar

57. Gd-DTPA is the most widely available and tested MR
contrast agent.
It is a freely diffusible, extracellular tracer with a molecular
size of 550 Da. This tracer results in contrast enhancement
by reducing the T1 of tissue in a concentration dependent
fashion
the tracer has an excellent safety profile and clearance is
predominantly via glomerular filtration.
Dr Prithvi Puwar

58. Raymond J. Kim, M.D., Edwin Wu, M.D., Allen Rafael, M.D., Enn-Ling Chen, Ph.D., Michele A. Parker, M.S., Orlando
Simonetti, Ph.D., Francis J. Klocke, M.D., Robert O. Bonow, M.D., and Robert M. Judd, Ph.D.
N Engl J Med 2000; 343:1445-1453
ORIGINAL ARTICLE
The Use of Contrast-Enhanced Magnetic Resonance Imaging to Identify Reversible
Myocardial Dysfunction
Gadolinium-enhanced MRI was performed in 50 patients
with ventricular dysfunction before they underwent surgical or
percutaneous revascularization.
The transmural extent of hyperenhanced regions was
postulated to represent the transmural extent of nonviable
myocardium.
The extent of regional contractility at the same locations was
determined by cineMRI before and after revascularization in 41
patients.
Dr Prithvi Puwar

59. AKINETIC SEGMENT
NO SCAR ON MRI
VIABLE
SEGMENT
BECAME FUNCTIONAL
POST
REVASCULARISATION
REVERSIBLE
DYSFUNCTION
Dr Prithvi Puwar

60. AKINETIC SEGMENT
SCAR ON MRI
NON VIABLE
SCAR AND
AKINESIS WAS
PERSISTENT POST
REVASCULARISATION
IRREVERSIBLE
DYSFUNCTION
Dr Prithvi Puwar

61. DIFFERENTIAL DIAGNOSIS OF HYPERENHANCEMENT
ON MRI
Dr Prithvi Puwar

62. Which technique to be availed?
Dr Prithvi Puwar

63. Meta-analysis demonstrating outcome of patients with ischemic
left ventricular dysfunction after viability testing
J Am Coll Cardiol 39:1151, 2002
Picture taken from textbook of Braunwald 10th e
Dr Prithvi Puwar

64. Accuracy of currently available techniques for prediction of functional recovery after
revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease:
comparison of pooled data
A systematic review of all reports on prediction of functional recovery after revascularization in patients with
chronic coronary artery disease
The evidence available thus far indicates that LDDE appears to have the highest
predictive accuracy.
METHODS
CONCLUSIONS
J Am Coll Cardiol, 1997; 30:1451-1460
MODALITIES : Thallium-201 (Tl-201) stress-redistribution-reinjection, Tl-201 rest-redistribution, fluorine-18
fluorodeoxyglucose with positron emission tomography, technetium-99m sestamibi imaging and low dose
dobutamine echocardiography
RESULTS:
Sensitivity for predicting regional functional recovery after revascularization was high for all techniques. The
specificity of both Tl-201 protocols was significantly lower (p < 0.05) and LDDE significantly higher (p <
0.01) than that of the other techniques
Dr Prithvi Puwar

65. MODALITY
SENSITIVITY (%)
MEAN (95% CI)
SPECIFICITY (%)
MEAN (95% CI)
Dobutamine
echocardiography
76 (72-80) 81 (77-84)
Delayed enhancement by
MRI
97 (91-100) 68 (51-85)
FDG PET 89 (85-93) 57 (51-63)
SPECT 89 (84-93) 68 (61-75)
Commonly Used Noninvasive Testing Modalities to Predict
Regional Functional Improvement
Circulation 117:103, 2008.Dr Prithvi Puwar

66. Indication Test Class Level of
Evidenc
e
1. Predicting improvement in
regional and global LV function
after revascularization
Stress/redistribution/reinjection 201Tl I B
I B
Perfusion plus PET FDG imaging I B
Resting sestamibi imaging I B
Gated SPECT sestamibi imaging IIa B
Late 201Tl redistribution imaging (after
stress)
IIb B
2. Predicting improvement in
heart failure symptoms after
revascularization.
Perfusion plus PET FDG imaging IIa B
3. Predicting improvement in
natural history after
revascularization
201Tl imaging (rest-redistribution and
stress/redistribution/reinjection)
I B
Perfusion plus PET FDG imaging I B
Recommendations for the Use of Radionuclide Techniques to Assess Myocardial Viability
J Am Coll Cardiol, 2003;
42:1318-1333
ACC/AHA/ASNC Guidelines
Dr Prithvi Puwar

67. Myocardial Viability
 End Diastolic Thickness
 Contractile reserve (DS MRI)
 DE MRI (Delayed Enhancement MRI)
Dr Prithvi Puwar

68. End Diastolic Thickness
 EDT <5.5 mm in previous MI : criterion for
myocardial necrosis
 In PET these patients very low metabolically
active myocardium
 The sensitivity and specificity of the end-
diastolic thickness for the diagnosis of
myocardial viability resulted to be respectively
72 and 89%.
 In akinetic segments (but with EDT
preserved), 44% of segments found viable in
PETDr Prithvi Puwar

69. Myocardial Viability
DE MRI
 Allows direct or indirect assessment of viability
 Infarct characterization
 In a study, presence of Microvascular obstruction,
Increased LVEDV and Impaired LVEF in MRI are
found to be independent predictors of adverse
events
Dr Prithvi Puwar

70. DE MRI with PET
 Various studies showed good correlation
 Kuhl et al: Inverse correlation between TEI by
DEMRI and segmental glucose uptake by
PET.
 55% of subendocardial infarcts detected by
DEMRI were detected as normal by PET.
 Reason may be the differential metabolism
along the thickness of myocardium was not
taken in PET.
Dr Prithvi Puwar

71. DE MRI and SPECT
 DE MRI is more specific and sensitive
 60 fold more spatial resolution.
 Wagner et al: Histopathology proved 75%
thickness infarcts (all showed infarction in DE
MRI and SPECT)
 But in <50% infarct thickness in HPE, DE MRI
detected infarction in 92% and SPECT in 28%
only.
 Conclusion: DE MRI systemically detects
subendocardial infarcts missed by SPECT
Dr Prithvi Puwar

72. DE MRI and SPECT
 Kitagawa et al: Post revascularisation functional
recovery was better assessed by DE MRI than by
SPECT.
 Sensitivity: 98% vs 90%
 Specificity: 75% vs 54%
Dr Prithvi Puwar

73. Comparing Modalities
Sensitivity Specificity PPV NPV
CMR
Contrast enhanced
Dobutamine stress
Total
97
94
94
68
90
87
73
86
84
93
92
87
Conventional nuclear
99mTc-sestambi
SPECT FDG
201TI rest, reinjection
Total
96
89
86
89
55
86
63
68
74
---
69
73
80
---
85
84
Echocardiography
DSE
DSE SRI
End-diastolic wall thickness
Total
76
82
94
78
81
80
48
78
66
---
53
64
89
---
93
90
PET
PET-FDG67,70,75,79-81
Total
89
89
57
57
73
73
90
90
Dr Prithvi Puwar

74. Symptoms and/or signs of congestive heart failure
with abnormal left ventricular function
(clinical examination and echocardiography)
CAD+
CAD-
Assess myocardial viability
with technique available
Investigate alternative
aetiologies (DCM, valve diseases etc.
No evidence of viability
or viability < 25 % of LV
Presence of significant viability
in segments subtended by
stenotic coronaries
Medical treatment
CRT, ICD, LVAD
Coronary revascularization
by PCI or CABG
CSI update 2015, chapter 33
Dr Prithvi Puwar

75. Dr Prithvi Puwar

76. Take home
 Revascularization should be done early before irreversible myocardial
injury occur
 In patients with ICMP with predominant heart failure symptoms
viability assessment is essential before Revascularization
 More detailed viability studies are needed for accurate prediction of
benefits of revascularization in ICMP
 Survival of patients with HM treated by MM is worse then similar pts.
With non viable treated by MM
Dr Prithvi Puwar

77. THANK YOU
Dr Prithvi Puwar