Myocardial Viability: CMR

Thomas H. HauserMD, MMSc, MPH, FACC

Director of Nuclear CardiologyBeth Israel Deaconess Medical Center

Assistant Professor of MedicineHarvard Medical School

Boston, MA

A major teaching hospital of Harvard Medical School

Case

A 79-year-old man with a history of “heart attacks” in 1978 and 1979 presented with increasing dyspnea on exertion over several months. He also noted increasing fatigue over the same time period. He otherwise felt well.

Physical examination revealed a HR of 60 with a BP of 115/65. His lungs were clear. His heart sounds were normal. There was no peripheral edema.

He was referred for a nuclear myocardial perfusion study to further evaluate his symptoms.

Imaging Protocol

• Stress: Prone 99mTc-Sestamibi• Rest: Prone 201Tl

Nuclear Myocardial Perfusion: Slices

Nuclear Myocardial Perfusion: Gated

Nuclear Myocardial Perfusion: LVEF

Case

The nuclear myocardial perfusion study was interpreted as having a large, severe fixed defect involving the LAD territory. The left ventricular cavity size was increased with severe systolic dysfunction due to akinesis in the territory of the defect.

He was referred for cardiac catheterization.

Cardiac Catheterization

Coronary angiography demonstrated left main and 3 vessel disease in a left dominant system. The left main had a discrete, distal 60% stenosis. The LAD was occluded proximally and filled via left to left collaterals. The large ramus branch had a 80% stenosis. The OM branch of the LCX had a tubular 70-80% stenosis. The RCA had a proximal smooth, 70% stenosis and a 70% distal stenosis.

Case

Should the patient be revascularized?

Dysfunctional but Viable Myocardium

Horn HR, Teichholz LE, Cohn PF, Herman MV, Gorlin R. Augmentation of left ventricular contraction pattern in coronary artery disease by an inotropic catecholamine: the epinephrine ventriculogram. Circulation 1974;49:1063-1071

LVEF 32% LVEF 54%

Dysfunctional but Viable Myocardium

• Hibernating– Chronic ischemia or repetitive stunning

– Ultrastructural changes that result in • Disassembly of contractile apparatus

– Recovery in weeks or months after revascularization

• Stunned– Acute ischemia

– No ultrastructural changes

– Recovery in minutes to days after revascularization

CABG in Patients with LV Dysfunction

Chareonthaitawee et al, JACC 2005;46:567

Importance of Viable Myocardium

J Am Coll Cardiol 2002;39:1151

Prevalence of Myocardial Viability

Schinkel et al, J Nucl Med 2007; 48:1135

Evaluation of Viability

Chareonthaitawee et al, JACC 2005;46:567

Evaluation of Viability

• SPECT– 201Tl– 99mTc – 123I Fatty Acids– PET Agents

• PET– 18FDG– 11C Acetate

• Echocardiography– Dobutamine

• CMR– Late gadolinium enhancement (hyperenhancement, delayed

enhancement)– Dobutamine CMR

• 201Tl most commonly used– Several protocols for use

• Stress – redistribution

• Rest – redistribution – Usually imaged 4 to 24 hours after initial injection

– With or without reinjection

» Usually at 4 hours

– Perfusion tracer initially• Ischemia is a sign of viability

– Membrane integrity tracer in the late phase• K analog

– Assesses integrity of membrane and Na-K-ATPase

SPECT

• 99mTc also helpful– Stress – rest protocol

– Perfusion tracer – Ischemia is a sign of viability

– Membrane integrity tracer• Trapped by active mitochondria

SPECT

201Tl Uptake and Recovery of Function

Perrone-Filardi P, Pace L, Pratarto M, et al. Dobutamine echocardiography predicts improvement of hypoperfused dysfunctional myocardium after revascularization in patients with coronary artery disease. Circulation. 1995;91:2556-2565.

Comparison of 201Tl and 99mTc

Udelson JE, Coleman PS, Metherall J, et al. Predicting recovery of severe regional ventricular dysfunction. Comparison of resting scintigraphy with 201Tl and 99mTc-sestamibi. Circulation. 1994;89:2552-2561.

Nuclear Myocardial Perfusion: Slices

Case

Based on the nuclear myocardial perfusion images, revascularization would not be predicted to improve his left ventricular systolic function.

Because he was otherwise a good operative candidate, further evaluation of viability was pursued

PET

• All PET agents (18FDG, 11C acetate) assess cardiac energy metabolism.– 18FDG imaging assesses glucose metabolism

• Ischemic myocardium generally favors glucose utilization

– 11C acetate imaging assesses lipid metabolism

Importance of Good Patient Preparation

• In the assessment of myocardial viability, the quality and utility of the images is highly dependent on appropriate patient preparation– Inadequate patient preparation can lead to spurious

results or images with no diagnostic value

Myocardial Energy Metabolism

• Cardiac myocytes are continuously active– Require efficient use of energy resources

– Require continual repletion of energy substrates• Faced with varying levels in supply

– Flexibility in substrate use

» Glucose

» Free fatty acids

» Amino acids

FDG Uptake and Retention

glut FDG FDG – 6 – P

glycogen

Aerobic Metabolism

Insulin

Acipimox

• Potent inhibitor of peripheral lypolysis– Drastically reduces FFA in blood

• As FFA are the principal alternative energy source for the myocardium, glucose utilization increases– Relatively independent of insulin and glucose levels

• Not FDA approved– Used in Europe

Hyperinsulinemic/Euglycemic Clamp

• Simultaneous infusions of insulin and glucose to increase the insulin level while keeping the glucose level from falling– High insulin

– Normal glucose

– Low FFA

• High myocardial glucose utilization

Glucose Loading

• Provide a large dose of oral or IV glucose• Endogenous production of insulin

– Supplemented with exogenous insulin if needed

– Moderately high insulin

– Normal glucose

– Low FFA

• High myocardial glucose utilization

Srinivasan G, Kitsiou AN, Bacharach SL, et al. [18F]Fluorodeoxyglucose Single Photon Emission Computed Tomography : Can It Replace PET and Thallium SPECT for the Assessment of Myocardial Viability? Circulation. 1998;97:843 - 850.

PET: 18FDG

Dobutamine Echocardiography

Dobutamine Echocardiography

• Low dose dobutamine– Typically paired with high dose dobutamine

– Four typical responses• Biphasic response

• Progressive dysfunction

• Sustained improvement

• No change

Dobutamine Echocardiograpy

Afridi et al, JACC 1998. Group I (n = 85) consisted of patients who had evidence of myocardial viability and subsequently underwent revascularization. Group II (n = 119) consisted of patients with myocardial viability who did not undergo revascularization. Group III (n = 30) consisted of patients who did not have myocardial viability and underwent revascularization. Finally, group IV (n = 84) patients lacked myocardial viability and did not undergo revascularization.

Comparison of Techniques

Chareonthaitawee et al, JACC 2005;46:567

Gd Contrast Kinetics in Myocardium

Circulation, Dec 1996; 94: 3318 - 3326

Delayed Contrast

Enhancement:Bright is Dead

Circulation, Nov 1999; 100: 1992 - 2002

Normal Myocardium

Anterior/Apical Scar

Ischemic CM with Viable Myocardium

Kim et al, N Engl J Med 2000; 343:1445-1453

Prediction of Recovery of Function

• 41 patients imaged before and ~80 days after revasc.

• 78% of segments with no LGE had recovery of function

• 92% of segments with >50% transmural LGE did not recover

• 36% of all segments had an intermediate probability of recovery

Dobutamine CMR

Wellnhofer et al, Circulation 2004;109:2172-2174

Dobutamine CMR

Wellnhofer et al, Circulation 2004;109:2172-2174 Solid = DCMR, dashed both, hatched LGE. Scar cutoff 25%

Case

The patient was referred for CMR.

SSFP Gated Images

Late Gadolinium Enhancement

Case

The CMR study was interpreted as showing a severely increased cavity size and severe systolic dysfunction with transmural/near transmural late gadolinium enhancement of the mid and distal anterior wall, the distal septum, the distal inferior wall and the apex.

He was treated medically and died one year later of complications from a lung mass and progressive congestive heart failure.

Which is Better?: CMR vs. PET

• Cost• Safety• Ease of implementation • Accuracy

Cost

• Cost– Medicare payment (rough estimate of cost to society)

• CMR ~$750

• PET ~$1400

– Hospital margins/physician payments• PET > CMR

• Conclusion: CMR is superior (… if you are the payer)

Safety

• Safety– PET

• Radiation

• Hypoglycemia

– CMR• NSF

• Conclusion: CMR and PET are both generally safe in this patient population

Ease of Implementation

• Patient preparation for FDG PET is arduous

Patient Preparation Protocol for Myocardial Viability Imaging with FDG. 1. When the appointment is scheduled, obtain the following history:

Presence of diabetes Presence of renal insufficiency Presence of allergy to insulin (TRUE allergy only, not adverse reaction)

If the patient is allergic to insulin, it is unlikely that imaging will be successful and an alternative imaging method should be suggested. If the patient has renal insufficiency, the pharmacokinetics of insulin may be altered. Please consult with the imaging physician to determine if this patient preparation protocol should be followed. 2. Instruct patient to fast overnight prior to the procedure. Patients may take their usual medication with the exception of their diabetes medications. Oral diabetes medications should not be taken the morning of imaging. Patients taking insulin should take no regular insulin and half the dose of their usual long acting insulin. 3. Upon patient arrival on the day of imaging:

Place intravenous line Check initial blood sugar (BS)

4. Give glucose according to the following protocol:

Diabetes?

No Yes

Give oral glucose: Give oral glucose BS ?150 50 g BS ?150 25 g BS 151 to 250 25 g BS 151 to 250 12.5 g BS >250 None BS >250 None

5. If the initial BS is >250, then give IV regular insulin according to the protocol below. If oral glucose is given, recheck BS in 30 minutes and then give IV regular insulin according to the same protocol. Give IV regular insulin BS ?140 None BS 141 to 160 1 units BS 161 to 180 2 units BS 181 to 200 3 units BS 201 to 220 4 units BS 221 to 240 5 units BS 241 to 260 6 units BS 261 to 280 7 units BS 281 to 300 8 units BS >300 Notify Physician 6. Check BS every 15 minutes.

If BS is <140, inject FDG If BS continues to rise, give IV regular insulin according to the protocol above and

continue to check BS every 15 minutes If BS is falling but remains elevated, give IV regular insulin at half the dose according

to the protocol above and continue to check BS every 15 minutes If BS remains elevated after 90 minutes, contact the imaging physician

7. Have the patient eat a light meal 15 minutes after injection of FDG. 8. Continue to check BS every 30 minutes after injection of FDG to monitor for hypoglycemia. 9. Begin imaging 60-90 minutes after injection of FDG. 10. After imaging, monitor patient for 30 minutes and obtain BS. If BS >70 then the patient can be discharged. 11. Upon discharge instruct the patient to:

Beware of hypoglycemia. Encourage the patient to have a meal soon after discharge. Resume all prior medications.

If at any time during the protocol there is a question about how to proceed, contact the imaging physician immediately.

CMR: Exellent Spatial Resolution

Wagner et al. Lancet. 2003;361:374

PET: Scar is More Important than Mismatch

• Beanlands et al evaluated 70 patients before and after revasc.

• “Scar” score was the most important predictor of recovery of function– Superior to mismatch score

in both univariate and multivariate analyses

Beanlands et al (PARR-1) JACC 2002;40:1735– 43

PET Only Images Myocardium, Not Scar

Knuesel et al. Circulation. 2003;108:1095

CMR Multicenter Trial

• Lenge et al imaged 183 patients before and ~6 months after revasc.

• 72% of segments with no LGE had recovery of function

• 83% of segments with >50% transmural LGE did not recover

• 21% of all segments had an intermediate probability of recovery

Lenge et al, SCMR 2008

PET Multicenter Trial

• Gerber et al imaged 178 patients before and 2 to 6 months after revasc.

• Endpoint was >5% improvement in LVEF– RVG, echo, LV gram

Gerber et al, Eur Heart J 2001; 22, 1691–1701

PET: Poor Specificity

• Gerber et al also assessed myocardial glucose uptake during hyperinsulinemic-euglycemic clamping

• Large overlap of normal and dysfunctional segments with wide intra- and inter-patient variation

• Probable overlap large overlap of segments that recover and do not recover (data not reported)

Gerber et al, Eur Heart J 2001; 22, 1691–1701

Comparison of FDG and DE-CMR

Knuesel et al. Circulation. 2003;108:1095

Direct Comparison of FDG PET and CMR

• Wu et al imaged 28 patients before and ~20 days after revasc.

• CMR (>50% transmural)– Sensitivity 92%

– Specificity 45%

• PET/SPECT (>50% normalized uptake)– Sensitivity 99%

– Specificity 60%

• ROC analysis showed no significant difference

Wu et al, JNM Vol. 48 No. 7 1096-1103

PET: Fails to Improve Clinical Outcomes

• Beanlands et al randomized 430 patients to FDG PET guided revascularization or standard care

• Primary endpoint was a composite of cardiac death, MI or hospital stay for a cardiac cause at 1 year

• No significant difference in the primary endpoint or survival– Minor effects found in

subgroups

Comprehensive CMR Evaluation

• Structure• Function

– With or without stress

• Flows• Perfusion

– With or without stress

• Scar/Viability• Coronary Anatomy

FDG and MR for Scar/Viability

FDG

• Directly assesses metabolism

• Images viable myocardium

• Established gold standard for determining recovery of function after revascularization

• Clinical trial suggests lack of effect on outcomes

DE-CMR• Directly assesses anatomy • Images both scar and viable

myocardium• Clinically established

established• Superior spatial resolution

compared to FDG• Lower cost• Easier to implement• Part of a comprehensive CMR

evaluation

Summary• Clinical relevance of evaluating myocardial viability• SPECT

– Tl-201

– Tc-99m

• PET– FDG

• Echocardiography– Dobutamine

• CMR– Late gadolinium enhancement

– Dobutamine

• Compared CMR and PET