Myocardial Viability in IHD Which test? What data?

Negar Mousavi, MD MHSc Non-Invasive Cardiovascular Imaging Fellow Oct 19th , 2011

Outline
Case presentation Methods of myocardial viability assessment
DSE PET CMR-LGE

Recent data
STICH trial

Case Presentation (DS)

30 year-old AA male presented to FH with 3 day hx of intermittent CP/diaphoresis PMHx:
T2DM (Diagnosed pre-teen), A1C (2009): 11.4 Hyperlipidemia Smoker (10-15 PY) Father with MI in 40s

EKG on Presentation

LABs
CK 2102 MB 44.1 TnT 1.36 2477 45.7 3.28 3724 49.2 5.49

LHC

TTE

PET

CMR

Hibernation

LV Dysfunction

Repetitive stunning

Myocardial Necrosis

Hibernating myocardium
Concept was developed in the late 1970s based on two observations:
Myocardial dysfunction present before bypass surgery often reversed after surgery. Inotropic stimulation with epinephrine caused transient improvement in regional and global LV dysfunction in patients with CAD.

Ventriculogram with Epinephrine

 Diamond, et al. noted in 1978, ischemic noninfarcted myocardium can exist in a state of function hibernation. This later led to the proposal by Rahimtoola of hibernating myocardium.

Why Assess Viability?

Why Assess Viability?

Despite advances in medical therapy and improvements in myocardial revascularization techniques, the prognosis for patients with ischemic cardiomyopathy remains poor

Beller GA et al. NEJM 2000;343:1488-1490.

Why Assess Viability?

Pts with injured myocardium at risk:
Higher risk of adverse events when treated medically compared to revascularization

Post revascularization:
Improved Regional wall motion abnormality Improved global LV function Improved survival
Wijns W et al. NEJM 1998;339:173-181. Beller GA et al. NEJM 2000;343:1488-1490. Dilsizian V et al. Circulation 1993; 87: 1-20. Marvick TH et al. Lancet 1998;351:815-819. Bax JJ et al. JACC 1997;30:1451-1460. Bax JJ et al. Current Probl Cardiol 2001

CASS Registry
Survival benefit of CABG over Medical Rx. in pts with severe LV dysfunction Benefit of surgery vs. medical Rx. in pts with Angina as opposed to HF symptoms

Alderman et al. Circulation 1983

Cohort Studies of CABG vs. Medical Rx for pts with LVEF < 40%
Bounous et al Alderman et al Vliestra et al Pigott et al Manley et al Faulkner et al Yatteau et al

Impact of Viability Testing on Prognosis

Meta-Analyis of 24 studies (3038 pts) evaluated for viability with non-invasive testing Improved survival in pts with viable myocardium and revascularization
Allman et al. JACC 2002

Methods of Viability Assessment

T1-201/TC99 PET DSE CMR Cell membrane integrity Mitochondria Metabolism Contractile reserve Scar imaging LGE-CMR Contractile reserve Dob-CMR

Dobutamine Stress Echo

Evaluates the inotropic reserve Infusion with low dose dobutamine (2.5 to 5 mcg/kg/min) and increase incrementally while obtaining echo images at each dose An improved contractile response requires at least 50% viable myocytes in a given segment

Response to Dobutamine
Biphasic Initial improvement followed by worsening of wall motion
Viability w/ superimposed ischemia

Worsening Direct deterioration of wall motion without initial improvement

Severe ischemia in an area supplied by a critically stenosed artery

Sustained Improvement Improvement of wall motion without any subsequent deterioration

Subendocardial necrosis

No Change No change throughout the entire study

Transmural scar

DSE Predicts Viability in ICMP

The predictive value of the test is best when there is a biphasic response

Afridi et al. Circ 1995

Dobutamine Stress Echo

Subject to the same limitations of any general ECHO study;
Body habitus contraindication to dobutamine

Sensitivity and Specificity of DSE

Meta-analysis of 28 studies (925 patients)

Sen: 81%

Spec: 80%

PPV: 77%

NPV: 85%

Bax et al. Curr Probl Cardiol 2001

PET Imaging

Cardiac Metabolism
Ischemic Myocardium
Glucose

Normal Myocardium

Fatty Acid
Glycolysis

B Oxidation
Pyruvate

ATP

Cardiac Metabolism
Ischemic Myocardium
Decreased myocardium Metabolism Decreased FFA uptake Increased glucose uptake (FDG)

PET Imaging Protocol

Insulin Gluc

FDG

Image

2-3 Hours

FDG-PET Uptake Pattern

Perfusion FDG Diagnosis

Match

Reduced

Reduced

Scar

Mismatch Reverse Mismatch

Reduced Normal

Normal reduced

Hibernation Stunning

Severity and Extent of Mismatches

Scoring:
Match: Identical scores for perfusion and metabolism Mismatch: At least one score difference

Extent:
Small: 5-10% of LV (1-2 segments) Moderate: 15-20% of LV (2-3 segments) Large: > 20% of LV (at least 4 segments)
Machac et al . J Nucl Cardiol 2006

PET strengths
Perfusion imaging Assessment of ischemia Assessment of myocardial metabolism LV function

What is the accuracy of Nuclear methods for assessing viability?

Comparison of Imaging Techniques

Scar Imaging; LGE-CMR

Scar Imaging; LGE-CMR

Late Gadolinium Enhancement

Kim et al. Circulation 1999

LGE MR Imaging Protocol

Gd injection

Determine TI

Image

10 min

Kinetics of Gadolinium in Myocardium

Thomson et al. Journal of Magnetic Resonance Imaging 2004

LGE MR Imaging Protocol

LGE pattern

LGE pattern

Example

CMR has Superior Spatial Resolution to SPECT

Wagner et al. Lancet 2003

CMR has Superior Spatial Resolution

SPECT

CMR

Histology

Base

Mid-ventricle

Apex

Prognosis
How much hibernating myocardium must be present for an improvement in LVEF after revascularization to become evident?

Prediction of Recovery of Function

Kim R, et al. NEJM 2000

Prediction of Recovery of Function

41 pts imaged pre/post revasc. 78 % of segments with no LGE recovered > 92 % of segments with > 50% LGE did not recover Sensitivity 95% Specificity 72%
Kim R, et al. NEJM 2000

How Does CMR Compare to PET?

r= 0.81, P<.0001

Klein et al. Circulation 2002

 28 pts imaged 20 days pre/post revasc. CMR (DE> 50%)

Sen: 92 % Spec: 45 %

PET/SPECT
Sen: 99 % Spec: 60 %

Roc curve: No significant difference

Wu et al. JNM 2007

Limitations of CMR
NSF Adequate breath-holding Implanted devices Obesity Claustrophobia

Strengths and weaknesses

CMR LV function and Volumes
Ischemia Scar Viability Accuracy

Nucs +++
++++ ++++ ++++ +++

++++
++ +++++ ++ +++

Cost
Safety

Outcome Studies

PARR 2
Objective: assess effectiveness of FDG PET assisted management in patients with severe LV dysfunction and suspected CAD
One year follow up

Outcome: cardiac death, MI, hospitalization for cardiac event

Beanlands et al. JACC 2007

PARR 2 Results
Composite event was 30% in PET arm vs 36% in standard arm (p= 0.16) Hazard ratio for the composite outcome = 0.78 (p=0.15) Hazard ratio for the composite outcome in patients who adhere to PET recommendations: 0.62 (p=0.019) Hazard ratio for cardiac death in patients without recent angiography = 0.4 (p=0.035) Conclusions: For patients who adhere to PET recommendations and in patients without recent angiography, a significant difference was observed

Beanlands et al. JACC 2007

STICH Trial
Hypothesis of viability testing: In patients with CAD and LV dysfunction, assessment of myocardial viability will identify those patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy

STICH Revascularization Hypothesis

Primary endpoint: All-cause mortality Secondary endpoints: Mortality plus cardiovascular hospitalization Cardiovascular mortality Intention-to-treat analysis

Patients randomized in STICH Revascularization Hypothesis

1212

Patients with myocardial viability test

618
Unusable test Timing Poor quality

594

Patients with no myocardial viability test

17
Patients with usable myocardial viability test

611

Patients with no usable myocardial viability test

601

Patients randomized in STICH Revascularization Hypothesis

1212

SPECT n=471

Dobutamine echo n=280

321 150 130

611
Patients with usable myocardial viability test

Patients with no usable myocardial viability test

601
114 487
Nonviable

Viable

Baseline Characteristics

Patients With and Without Myocardial Viability

Viable (n=487) 61 10 Non-Viable (n=114) 61 9

Variable Age

P value NS

Multivessel CAD
Proximal LAD stenosis

73%
64%

73%
70%

NS
NS

Risk score * Previous MI LV ejection fraction (percent) LV end-diastolic volume index (ml/m2)
LV end-systolic volume index (ml/m2)

12.4 8.7 76.6% 28 8 117 37

86 33

12.9 9.3 94.7% 23 9 147 53

116 50

NS <0.001 <0.001 <0.001

<0.001

* Significant covariates in risk model: Age, renal function, heart failure,

ejection fraction, CAD index, mitral regurgitation, stroke

Myocardial Viability and Mortality

1.0 Without viability With viability 0.8
HR 95% CI P 0.64 0.48,0.86 0.003 Risk score LV ejection fraction LV EDVI LV ESVI Myocardial viability Variables associated with mortality Chi-square 33.26 24.80 35.36 33.90 8.54 p <0.001 <0.001 <0.001 <0.001 0.003

Mortality Rate

0.6

0.4

0.2

0.0 0
Without viability With viability 114 487 99 432

1
85 409

2 3 4 Years from Randomization

80 371 63 294 36 188

5
16 102

Myocardial Viability and Cardiovascular Mortality

1.0 Without viability With viability Cardiovascular Mortality Rate 0.8
HR 95% CI P 0.61 0.44,0.84 0.003 Univariate Chi-square p value 8.81 0.003 Multivariable Chi-square 0.91 p value 0.339

0.6

0.4

0.2

0.0 0
Without viability With viability 114 487

1
99 432 85 409

2 3 4 Years from Randomization

80 371 63 294 36 188

5
16 102

Myocardial Viability and Mortality + CV Hospitalization

1.0 Mortality and CV Hospitalization Rate Without viability With viability 0.8
HR 95% CI P 0.59 0.47,0.44 <0.001

0.6

0.4

Multivariable HR 95% CI P Chi-square p value 0.47,0.44 <0.001 value 0.59 Chi-square p 20.27 <0.001 8.60 0.003

Univariate

0.2

0.0 0
Without viability With viability 114 487

1
56 327 41 284

2 3 4 Years from Randomization

34 238 22 166 14 94

5
5 41

Patients with viability tests

601

Patients with myocardial viability

487

114

Patients without myocardial viability

243 MED 49.9%

244

60

54

CABG 50.1%

MED 52.6%

CABG 47.4%

Myocardial Viability and Mortality

Without Viability
1.0 0.8 Mortality Rate 0.6 MED (33 deaths) CABG (25 deaths)

With Viability
MED (95 deaths) CABG (83 deaths)

0.4
0.2 0.0 0 1
51 48

2 3 4 Years from Randomization

44 41 39 41 29 34

5
14 22

6
4 12

0
243 244

1
219 213

2 3 4 5 Years from Randomization

206 203 179 192 146 148 94 94

6
51 51

MED CABG

60 54

Myocardial Viability and Mortality

Without Viability
1.0 0.8 Mortality Rate 0.6 MED (33 deaths) CABG (25 deaths)

With Viability
MED (95 deaths) CABG (83 deaths)

0.4
0.2 0.0 0 1 2 3 4 Years from Randomization N 114 487 Deaths 58 178 5 6 0 1 2 3 4 5 Years from Randomization Interaction P value 6

Subgroup Without viability With viability

HR 0.70 0.86

95% CI 0.41, 1.18 0.64, 1.16

0.25 CABG better 0.5 1 2 MED better

0.528

Interaction of Viability and Treatment on CV Outcomes

Endpoint Mortality Mortality or CV hospitalization CV mortality

Events 236

Treatment As randomized As treated As randomized As treated

p value 0.528 0.962 0.390 0.975

422

187

As randomized
As treated

0.697
0.261

STICH Revascularization Hypothesis

STICH represents the largest report to date relating myocardial viability to clinical outcomes of patients with CAD and LV dysfunction
and is the first to assess these relationships prospectively among patients who were all eligible for CABG as well as optimal medical management alone

STICH Revascularization Hypothesis

STICH results: demonstrate a significant association between myocardial viability and outcome, but this association is rendered non-significant when subjected to a multivariable analysis that includes other prognostic variables. fail to demonstrate a significant interaction between myocardial viability and medical versus surgical treatment with respect to mortality, whether assessed according to treatment assigned (intention to treat) or to the treatment actually received.

STICH Revascularization Hypothesis

Implications of STICH:

In patients with CAD and LV dysfunction, assessment of myocardial viability does not identify patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy

Full report available at www.NEJM.org

Limitations
Lack of viability data on all patients; patients represent a subpopulation of STICH
Analysis limited to SPECT and DE, not PET or cardiac MRI Fundamental differences in viability information provided by SPECT and DE, and differences in analytic methods between the two methods

Role of Ischemia/Viability Assessment in Management Decisions in Patients With LV Dysfunction

Severe CAD Low EF

Primary CHF

Primary Angina

Myocardial Viability

Cardiac Cath

Poor

Good

Poor Targets

Good Targets

Medical Rx

CABG/PTCA

ESC Guidelines

ACC/AHA Guidelines
Noninvasive imaging to detect myocardial ischemia and viability is reasonable in patients with known coronary artery disease and no angina. Noninvasive imaging may be considered (evidence less well established) to define the likelihood of coronary artery disease in patients with HF and left ventricular dysfunction.

Art of predicting functional recovery Things to consider

Presenting symptoms (angina vs HF) Amount of ischemia, viable tissue, scar LV volumes/severity of remodeling Completeness of revascularization and quality of target vessels Time to revascularization ? role of surgical ventricular restoration

In Conclusion
Different imaging methods are looking at different aspects of viability and can provide complimentary information. Nuclear techniques are considered more sensitive and DSE more specific for LVF recovery post-revascularization Assessment of viability prior to CABG is currently recommended in pts with ischemic CMP with EF<35% and no definite angina

In Conclusion
Assessment for hibernation is most relevant in patients with dyspnea rather than angina. Radionuclide myocardial perfusion imaging and Dobutamine echocardiography have similar test performance for the detection of viable myocardium. Thus, the choice may depend upon availability, local expertise, and whether a more sensitive (MPI) or a more specific technique (DSE) is required for predicting recovery of left ventricular function. PET scanning or MRI is usually performed if clarification is required after echocardiography and/or radionuclide myocardial perfusion imaging. However, if readily available, PET scanning is an alternative initial test and MRI is an acceptable alternative to echocardiography when assessment of left ventricular function at rest and during stress is also desired.

Histopathologic Characteristics
Loss of contractile proteins (sarcomeres) without loss of cell volume in a substantial number of cells. Glycogen-rich perinuclear zones adjacent to areas of numerous small mitochondria. Nuclear changes with heterochromatin distributed evenly over the nucleaplasm Substantial loss of sarcoplasmic reticulum.

Why This Is Important

Methods of Viability Assessment