Dr. Prithvi PuwarDNB CardiologyVijaya Hospital

Chennai

MYOCARDIAL VIABILITY

Dr Prithvi Puwar

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

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

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

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

Thus came the concept of myocardial viability and with it came the new terms such as

hibernation and stunning

Dr Prithvi Puwar

THE MYOCARDIAL RESPONSE TOISCHEMIC INJURY

Dr Prithvi Puwar

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

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

Irreversible InjuryBegins in the subendocardial tissue and progresses towards thesubepicardium.In humans, it may take as long as 6–12 hr for complete infarction of the myocardium at riskthe necrotic changes are usually evident, about 4–12 hr after onsetThis may include the denaturation of cytoplasmic proteins, swelling, and enzymatic digestion of organelles and the sarcolemma.

Dr Prithvi Puwar

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

Dysfunctional myocardium subtended by

disease coronary artery with limited or

absent scarring that has

POTENTIAL FOR FUNCTIONAL RECOVERY

Is

Myocardial Viability

Dr Prithvi Puwar

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

? contractility

Dr Prithvi Puwar

There are two tissue states that exhibit sustained contractile dysfunction despite meeting the three criteria

Stunned myocardium &

Hibernating myocardium

Dr Prithvi Puwar

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

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

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/reperfusion dysfunction

Dr Prithvi Puwar

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

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

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

Myocardial Hibernation is primarily a clinical observation3 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

Dr Prithvi Puwar

STUNNING AND HIBERNATION

Dr Prithvi Puwar

IDENTIFYING VIABLE MYOCARDIUM

Dr Prithvi Puwar

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

Key non invasive methods to identify viability

1.Echocardiography2.Single Photon Emission

Computed Tomography (SPECT)3.Positron Emission Tomography

(PET)4.Cardiac Magnetic Resonance

(CMR)

CSI update 2015 chapter 33

Dr Prithvi Puwar

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

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

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

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 alstudied 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

VIAMI -TRIAL 2005

First RCT261 pts, taekn 48 hr after AMI, undervent LDE within 72 hrs of MIInvestigated 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 events

Dr Prithvi Puwar

Value of DSEThose 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

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

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

Dr Prithvi Puwar

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

Single Photon Emission ComputedTomography (SPECT)

Dr Prithvi Puwar

STANDARD SPECT

IMAGING DISPLAY

SA

VLA

HLA

Dr Prithvi Puwar

SPECTinjection of a gamma-emitting radioisotopeThallium-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

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

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

INTERPRETATION

Late redistribution imagesAcquire 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

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

Relation between tracer uptake in a dysfunctional territory and the subsequent probability of functional recovery after revascularization. 

Taken from textbook of Braunwald 10th edition

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1. Severe apical defect2. Basal and mid inferior and lateral wall defect

Summed rest score (SRS) – Summed stress score (SSS)= SDS (Difference) represent extent of ischemia

Fixed defectReversible

AN EXERCISE…..

Dr Prithvi Puwar

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

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

Positron emission tomography (PET)

Dr Prithvi Puwar

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

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

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

FDG PET in Myocardial Viability- various studies

combined sensitivity and specificity of 88 and 73%,

Dr Prithvi Puwar

SPECT VS FDG PETBrunken 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

PET

Advantage:excellent sensitivitybetter spatial resolutionless radiation

Limitations:high costavailabilityneed of radioactive tracers

Dr Prithvi Puwar

Magnetic resonance Imaging (CMR)

Dr Prithvi Puwar

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

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

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

AKINETIC SEGMENTNO SCAR ON MRI

VIABLE

SEGMENT BECAME FUNCTIONAL POST REVASCULARISATION

REVERSIBLE DYSFUNCTION

Dr Prithvi Puwar

AKINETIC SEGMENTSCAR ON MRI

NON VIABLE

SCAR AND AKINESIS WAS PERSISTENT POST REVASCULARISATION

IRREVERSIBLE DYSFUNCTION

Dr Prithvi Puwar

DIFFERENTIAL DIAGNOSIS OF HYPERENHANCEMENT ON MRI

Dr Prithvi Puwar

Which technique to be availed?

Dr Prithvi Puwar

Meta-analysis demonstrating outcome of patients with ischemic left ventricular dysfunction after viability

testingJ Am Coll Cardiol 39:1151, 2002Picture taken from textbook of Braunwald 10th edition

Dr Prithvi Puwar

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 dataA 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

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

Indication Test Class Level of Evidenc

e1. Predicting improvement in regional and global LV function after revascularization

Stress/redistribution/reinjection 201Tl

I B

I BPerfusion plus PET FDG imaging I BResting sestamibi imaging I BGated SPECT sestamibi imaging IIa BLate 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 ViabilityJ Am Coll Cardiol, 2003; 42:1318-1333

ACC/AHA/ASNC Guidelines

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Myocardial ViabilityEnd Diastolic ThicknessContractile reserve (DS MRI)DE MRI (Delayed Enhancement MRI)

Dr Prithvi Puwar

End Diastolic ThicknessEDT <5.5 mm in previous MI : criterion

for myocardial necrosisIn PET these patients very low

metabolically active myocardiumThe 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 PET

Dr Prithvi Puwar

Myocardial ViabilityDE MRI Allows direct or indirect assessment of

viabilityInfarct characterizationIn 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

DE MRI with PETVarious studies showed good correlationKuhl 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

DE MRI and SPECTDE MRI is more specific and sensitive60 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

DE MRI and SPECTKitagawa 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

Comparing Modalities Sensitivit

ySpecificity PPV NPV

CMR Contrast enhanced Dobutamine stress Total

979494

689087

738684

939287

Conventional nuclear 99mTc-sestambi SPECT FDG 201TI rest, reinjection Total

96898689

55866368

74---6973

80---8584

Echocardiography DSE DSE SRI End-diastolic wall thickness Total

76829478

81804878

66---5364

89---9390

PET PET-FDG67,70,75,79-81

Total8989

5757

7373

9090

Dr Prithvi Puwar

Symptoms and/or signs of congestive heart failure with abnormal left ventricular function(clinical examination and echocardiography)

CAD+CAD-

Assess myocardial viabilitywith technique available

Investigate alternativeaetiologies (DCM, valve diseases etc.

No evidence of viabilityor viability < 25 % of LV

Presence of significant viabilityin segments subtended by

stenotic coronaries

Medical treatmentCRT, ICD, LVAD

Coronary revascularizationby PCI or CABG

angina

CSI update 2015, chapter 33

Dr Prithvi Puwar

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

Dr Prithvi Puwar

THANK YOU