The Pathophysiology of CK Release Following PCI in UA / NSTEMI By C. Michael Gibson MS, MD Chief...

The Pathophysiology of CK Release Following PCI in UA / The Pathophysiology of CK Release Following PCI in UA / NSTEMINSTEMI

By C. Michael Gibson MS, MDBy C. Michael Gibson MS, MD

Chief Academic Officer &Chief Academic Officer &

Director Core Cardiovascular Services Director Core Cardiovascular Services

Harvard Clinical Research InstituteHarvard Clinical Research Institute

Director TIMI Data Coordinating Center, Brigham and Women’s HospitalDirector TIMI Data Coordinating Center, Brigham and Women’s Hospital

Associate Chief of Cardiology for Academic Affairs Associate Chief of Cardiology for Academic Affairs

Interventional Cardiologist Interventional Cardiologist

Beth Israel Deaconess Medical Center Cardiovascular DivisionBeth Israel Deaconess Medical Center Cardiovascular Division

Harvard Medical School Boston MassachusettsHarvard Medical School Boston Massachusetts

The Pathophysiology of CK Release Following PCI in UA / The Pathophysiology of CK Release Following PCI in UA / NSTEMINSTEMI

By C. Michael Gibson MS, MDBy C. Michael Gibson MS, MD

Chief Academic Officer &Chief Academic Officer &

Director Core Cardiovascular Services Director Core Cardiovascular Services

Harvard Clinical Research InstituteHarvard Clinical Research Institute

Director TIMI Data Coordinating Center, Brigham and Women’s HospitalDirector TIMI Data Coordinating Center, Brigham and Women’s Hospital

Associate Chief of Cardiology for Academic Affairs Associate Chief of Cardiology for Academic Affairs

Interventional Cardiologist Interventional Cardiologist

Beth Israel Deaconess Medical Center Cardiovascular DivisionBeth Israel Deaconess Medical Center Cardiovascular Division

Harvard Medical School Boston MassachusettsHarvard Medical School Boston Massachusetts

Crisis in the Mississippi Delta 120 Years AgoCrisis in the Mississippi Delta 120 Years Ago Crisis in the Coronary Artery Delta Today

Crisis in the Coronary Artery Delta Today

Crisis in the DeltaCrisis in the Delta

C. Michael Gibson, M.S., M.D., 2002C. Michael Gibson, M.S., M.D., 2002

0.150.151%1%6%6%In-Hospital DeathIn-Hospital Death

0.0010.00112%12%21%21%CHFCHF

0.0050.00518%18%40%40%ArrhythmiaArrhythmia

Pvalue

PvalueReflowReflow

No Reflow

No Reflow

Ito H, et al. Circulation. 1996;93:1993-1999.Ito H, et al. Circulation. 1996;93:1993-1999.Porter, et al. Am J Cardiol. 1998;82:1173-7.Porter, et al. Am J Cardiol. 1998;82:1173-7.

No ReflowNo Reflow ReflowReflow

Tissue Level Perfusion By Myocardial Tissue Level Perfusion By Myocardial Contrast Echo (MCE) and AMI OutcomesContrast Echo (MCE) and AMI OutcomesTissue Level Perfusion By Myocardial Tissue Level Perfusion By Myocardial

Contrast Echo (MCE) and AMI OutcomesContrast Echo (MCE) and AMI Outcomes

TIMI Myocardial Perfusion (TMP) Grades TIMI Myocardial Perfusion (TMP) Grades TIMI Myocardial Perfusion (TMP) Grades TIMI Myocardial Perfusion (TMP) Grades

0

1

2

3

4

5

6

7

8

6.2%6.2%

4.4%4.4%

2.0%2.0%n = 203n = 203 n = 46n = 46 n = 434n = 434

TMP Grade 3 TMP Grade 3

p = 0.05p = 0.05

Mo

r ta l

ity

( %)

Mo

r ta l

ity

( %)

n = 79n = 79

5.1%5.1%

Gibson et al, Circulation 2000Gibson et al, Circulation 2000

Normal ground glassappearance of blushDye mildly persistent

at end of washout

Normal ground glassappearance of blushDye mildly persistent

at end of washout

Dye strongly persistentat end of washout

Gone by next injection

Dye strongly persistentat end of washout

Gone by next injection

Stain presentBlush persists

on next injection

Stain presentBlush persists

on next injection

No or minimal blushNo or minimal blush

TMP Grade 2 TMP Grade 2 TMP Grade 1 TMP Grade 1 TMP Grade 0 TMP Grade 0

Not All TIMI Grade 3 Flow is Created Equally:Not All TIMI Grade 3 Flow is Created Equally:Not All TIMI Grade 3 Flow is Created Equally:Not All TIMI Grade 3 Flow is Created Equally:

0

1

2

3

4

5

6

Myocardial Perfusion Grade 3




Myocardial Perfusion Grades 0/1

Myocardial Perfusion Grades 0/1

N = 136N = 136 N = 34N = 34 N = 278N = 278

0.7%0.7%

2.9%2.9%

5.4%5.4%

% M

ort

alit

y%

Mo

rtal

ity

P = 0.007P = 0.007

Gibson CM, et al. Circulation. 2000;101:125-130.Gibson CM, et al. Circulation. 2000;101:125-130.

Among Patients. With Successful Lysis, There is a 7 Fold Range in MortalityAmong Patients. With Successful Lysis, There is a 7 Fold Range in Mortality

TIMI 10 B: Independent Predictors of 2 Year MortalityTIMI 10 B: Independent Predictors of 2 Year MortalityTIMI 10 B: Independent Predictors of 2 Year MortalityTIMI 10 B: Independent Predictors of 2 Year Mortality

• TIMI Grade 3 Flow RR 0.61, p=0.047

• TIMI Myocardial Blush RR 0.50, p = 0.038

• TIMI Grade 3 Flow RR 0.61, p=0.047

• TIMI Myocardial Blush RR 0.50, p = 0.038

In a MV model correcting for :

Performance of PCI

Age

Gender

Pulse

Anterior MI

In a MV model correcting for :

Performance of PCI

Age

Gender

Pulse

Anterior MI

Pre-PCI Epicardial and Myocardial Flow Are Independently Associated with 2 Year Mortality

Gibson et al, Circulation 2002, in pressGibson et al, Circulation 2002, in press

12.2

7.4

4.3

0

2

4

6

8

10

12

14

Blush 3 Blush 2 Blush 0/1

12.2

7.4

4.3

0

2

4

6

8

10

12

14

Blush 3 Blush 2 Blush 0/1

30-D

ay M

ort

alit

y (%

)30

-Day

Mo

rtal

ity

(%)

n=4427%n=4427%

n=7244%n=7244%

n=4729%n=4729%

P<0.0001P<0.0001

Stone GW, et al. J Am Coll Cardiol. 2000;35:403A.Stone GW, et al. J Am Coll Cardiol. 2000;35:403A.

Mortality Following Primary Angioplasty is Related to Mortality Following Primary Angioplasty is Related to Tissue Level PerfusionTissue Level Perfusion

Mortality Following Primary Angioplasty is Related to Mortality Following Primary Angioplasty is Related to Tissue Level PerfusionTissue Level Perfusion

0.00030.00030.00030.00031.40 1.40 ±± 0.23 0.231.40 1.40 ±± 0.23 0.231.44 1.44 ±± 0.26 0.261.44 1.44 ±± 0.26 0.261.97 1.97 ±± 0.30 0.301.97 1.97 ±± 0.30 0.30Global wall Global wall motion indexmotion indexGlobal wall Global wall motion indexmotion index

0.010140.010140.010140.010142.00 2.00 ±± 0.47 0.472.00 2.00 ±± 0.47 0.472.00 2.00 ±± 0.59 0.592.00 2.00 ±± 0.59 0.592.67 2.67 ±± 0.33 0.332.67 2.67 ±± 0.33 0.33Regional wall Regional wall motion indexmotion indexRegional wall Regional wall motion indexmotion index

0.05910.05910.05910.05912.13 2.13 ±± 0.63 0.632.13 2.13 ±± 0.63 0.631.89 1.89 ±± 0.24 0.241.89 1.89 ±± 0.24 0.241.56 1.56 ±± 0.38 0.381.56 1.56 ±± 0.38 0.38Coronary flow Coronary flow reservereserveCoronary flow Coronary flow reservereserve

0.00020.00020.00020.00028 8 ±± 17 178 8 ±± 17 1758 58 ±± 58 5858 58 ±± 58 58144 144 ±± 54 54144 144 ±± 54 54MCE (mm)MCE (mm)MCE (mm)MCE (mm)

P valueP value3 (n=10)3 (n=10)2 (n=7)2 (n=7)0/1 (n=8)0/1 (n=8)Blush GradeBlush GradeBlush GradeBlush Grade

Lepper W, et al. J Am Coll Cardiol. 2000;35:397A.Lepper W, et al. J Am Coll Cardiol. 2000;35:397A.

Relationship Between Blush Grade and MCE and Coronary Flow Reserve (CFR) and Wall Motion in AMI PCI Patients

Relationship Between Blush Grade and MCE and Coronary Flow Reserve (CFR) and Wall Motion in AMI PCI Patients

Early Impaired Myocardial Perfusion is Early Impaired Myocardial Perfusion is Associated with Larger SPECT Infarct SizeAssociated with Larger SPECT Infarct Size

Early Impaired Myocardial Perfusion is Early Impaired Myocardial Perfusion is Associated with Larger SPECT Infarct SizeAssociated with Larger SPECT Infarct Size

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

Patients with a closed myocardium (TMPG 0/1) and patients without complete ST resolution (<70%) had larger infarcts.

In a multivariate model, both impaired TMPG and incomplete ST resolution were independently associated with larger infarct size

Patients with a closed myocardium (TMPG 0/1) and patients without complete ST resolution (<70%) had larger infarcts.

In a multivariate model, both impaired TMPG and incomplete ST resolution were independently associated with larger infarct size n=209n=209 n=111n=111

p<0.001p<0.001

0

2

4

6

8

10

12

14

0

2

4

6

8

10

12

14 Median = 13Median = 13

TMPGTMPG ST ResolutionST Resolution

p=0.004p=0.004

Res <70%Res <70% Res >70%Res >70%TMPG 0/1TMPG 0/1 TMPG 2/3TMPG 2/3

n=108n=108 n=113n=113

Median = 7Median = 7



% S

PE

CT

In

farc

t S

ize

Circulation 2002Circulation 2002

3.9%

8.0%9.0%

10.9%

14.9%

20.9%

Normal 1-2* 2-3* 3-5* 5-10* 10*

% Congestive Heart Failure/ Cardiogenic Shock at 30 days

* x upper limit of normal

4.9%5.7%

9.2%

12.6%

14.5%

19.9%

% Death at 6 months

Relationship Between Extent of Myocardial Necrosis and Long-Term Relationship Between Extent of Myocardial Necrosis and Long-Term Morbidity and Mortality After PCIMorbidity and Mortality After PCI

Relationship Between Extent of Myocardial Necrosis and Long-Term Relationship Between Extent of Myocardial Necrosis and Long-Term Morbidity and Mortality After PCIMorbidity and Mortality After PCI

(n=5,681) (n=1,098) (n=294) (n=302) (n=249) (n=211)(n=5,681) (n=1,098) (n=294) (n=302) (n=249) (n=211)

Alexander JH et al. Circulation. 1999; Suppl 1:1-629.

CK-MB levels during hospitalization Normal 1-2* 2-3* 3-5* 5-10* 10*

CK-MB levels during hospitalization

TMPG and Maximum CK-MB 24 Hours Post-stentTMPG and Maximum CK-MB 24 Hours Post-stent

0

5

10

15

20

25

30

35

40

45

TMPG 3 TMPG 0/1/2

0

5

10

15

20

25

30

35

40

45

TMPG 3 TMPG 0/1/2

Max

imu

m C

K-M

B >

2x U

LN

(%

)M

axim

um

CK

-MB

>2x

UL

N (

%)

41.2%41.2%p = 0.002p = 0.002

1/24 14/34

4.2%4.2%

All Patients Have TIMI 3 Flow at Completion of StentingAll Patients Have TIMI 3 Flow at Completion of Stenting

Gibson, Am Heart J 2002Gibson, Am Heart J 2002

TMPG and Maximum CK-MB 24 Hours Post-StentTMPG and Maximum CK-MB 24 Hours Post-StentTMPG and Maximum CK-MB 24 Hours Post-StentTMPG and Maximum CK-MB 24 Hours Post-Stent

0

0.5

1

1.5

2

2.5

0

0.5

1

1.5

2

2.5

Max

imu

m C

K-M

B /

Up

per

Lim

it o

f N

orm

alM

axim

um

CK

-MB

/ U

pp

er L

imit

of

No

rmal

2.23 + 2.702.23 + 2.70

p = 0.01p = 0.01

n = 24n = 24 n = 34n = 34

TIMI Grade 3 Flow: 100%

CTFC 13


CTFC 13


CTFC 17.5


CTFC 17.5

0.78 + 0.600.78 + 0.60

TMPG 3TMPG 3 TMPG 0, 1 , 2TMPG 0, 1 , 2



p=0.02p=0.02

TMPG Post-stent and Composite Events by 48 Hrs & 1 YrTMPG Post-stent and Composite Events by 48 Hrs & 1 YrTMPG Post-stent and Composite Events by 48 Hrs & 1 YrTMPG Post-stent and Composite Events by 48 Hrs & 1 Yr

0

5

10

15

20

25

30

35

TMPG 3 TMPG 0/1/2 TMPG 3 TMPG 0/1/2

0

5

10

15

20

25

30

35

TMPG 3 TMPG 0/1/2 TMPG 3 TMPG 0/1/2

Co

mp

osi

te E

ven

t (%

)C

om

po

site

Eve

nt

(%)

0%0%

17.7%17.7%

0/240/24 6/346/34

p = 0.037p = 0.037

48 Hour Death, MI, Urgent TVR, Thrombotic Bailout

48 Hour Death, MI, Urgent TVR, Thrombotic Bailout

1 Year Death, MI, Urgent TVR1 Year Death, MI, Urgent TVR

p = 0.01p = 0.01

32.4%32.4%

4.2%4.2%

1/241/24 11/3411/34



TMPG & Late Composite Events (30 Days to 1 Year)TMPG & Late Composite Events (30 Days to 1 Year)

0

2

4

6

8

10

12

14

TMPG 3 TMPG 0/1/2

0

2

4

6

8

10

12

14

TMPG 3 TMPG 0/1/2

Co

mp

osi

te E

ven

t 30

Day

s to

1 Y

r (%

)C

om

po

site

Eve

nt

30 D

ays

to 1

Yr

(%)

0%0%

0/240/24

p = 0.134p = 0.134 11.8%11.8%

4/34



Abnormal After Stenting TMPG Is Associated with MRI HyperenhancementAbnormal After Stenting TMPG Is Associated with MRI Hyperenhancement

Ricciardi M et al, Circulation 2001: 103: 2780-2783.Ricciardi M et al, Circulation 2001: 103: 2780-2783.


A Decline in TMPG After Stenting Is Associated with A Decline in TMPG After Stenting Is Associated with Larger Infarct SizesLarger Infarct Sizes

A Decline in TMPG After Stenting Is Associated with A Decline in TMPG After Stenting Is Associated with Larger Infarct SizesLarger Infarct Sizes

Ricciardi, Gibson et al, ACC 2002Ricciardi, Gibson et al, ACC 2002

All patients had normal epicardial TIMI Grade 3 Flow before PCI

12 of 14 patients had normal TMPG 3 before PCI

Only 7 of 14 had normal TMPG 3 after PCI

All patients had normal epicardial TIMI Grade 3 Flow before PCI

12 of 14 patients had normal TMPG 3 before PCI

Only 7 of 14 had normal TMPG 3 after PCI

Mechanisms for Post PCI CK LeakMechanisms for Post PCI CK LeakMechanisms for Post PCI CK LeakMechanisms for Post PCI CK Leak

• Impaired Tissue Perfusion: Validated by TMPG and MRI findings. Secondary to embolization, inflammation, vasospasm, edema etc.

• Abnormal Epicardial Flow: Many CK leaks occur in presence of patent artery and patent sidebranches. Does not account for majority of cases.

• Greater Extent of CAD: May be associated with CK leak, but no biologically plausible reason why it is causally implicated. Simply a confounder.

• Impaired Tissue Perfusion: Validated by TMPG and MRI findings. Secondary to embolization, inflammation, vasospasm, edema etc.

• Abnormal Epicardial Flow: Many CK leaks occur in presence of patent artery and patent sidebranches. Does not account for majority of cases.

• Greater Extent of CAD: May be associated with CK leak, but no biologically plausible reason why it is causally implicated. Simply a confounder.

CM Gibson 2002CM Gibson 2002

Treating the Crisis in the DeltaTreating the Crisis in the DeltaTreating the Crisis in the DeltaTreating the Crisis in the Delta

Background:Dye in artery: yes

Dye in myocardium: no

Background:Dye in artery: yes

Dye in myocardium: no

Background & BlushDye in artery: yes

Dye in myocardium: yes

Background & BlushDye in artery: yes

Dye in myocardium: yes

Subtracted image:Ribs, spine,

diaphragm & arterysubtracted,blush now apparent

Subtracted image:Ribs, spine,

diaphragm & arterysubtracted,blush now apparent

Measuring Tissue Level Perfusion Using ComputersMeasuring Tissue Level Perfusion Using Computers

ESPRIT: Study DesignESPRIT: Study DesignESPRIT: Study DesignESPRIT: Study Design

2,066 patients with non-acute cardiac conditions scheduled for PCI with stent implantation in native coronary vessels pre treated with ASA and thienopyridines

2,066 patients with non-acute cardiac conditions scheduled for PCI with stent implantation in native coronary vessels pre treated with ASA and thienopyridines

Placebo (n=1,024)Placebo (n=1,024)Eptifibatide 180/2/180 (n=1,040)Eptifibatide 180 µg/kg bolus followed by 2

µg/kg/min infusion until hospital discharge or 18-24 hours. A second 180 µg/kg bolus was

administered 10 minutes following the first bolus

Eptifibatide 180/2/180 (n=1,040)Eptifibatide 180 µg/kg bolus followed by 2

µg/kg/min infusion until hospital discharge or 18-24 hours. A second 180 µg/kg bolus was

administered 10 minutes following the first bolus

Heparin 60 U / Kg bolus

Target ACT 200-300 sec







++

++

Elective StentingElective Stenting

Patients enrolled in angiographic substudy at 3 centersPatients enrolled in angiographic substudy at 3 centers

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Co

ron

ary

Flo

w R

eser

veC

oro

nar

y F

low

Res

erve

PlaceboPlacebo Eptifibatide

180/2/180

Eptifibatide

180/2/180

1.28 + 0.41.28 + 0.4

1.78 + 0.951.78 + 0.95

N=27N=27 N=16N=16

P=0.02P=0.02

00

Gra

y p

er s

ecG

ray

per

sec

7.30 + 8.137.30 + 8.13

3.97 + 2.463.97 + 2.46

P=0.05P=0.05


180/2/180

Eptifibatide

180/2/180

N=27N=27 N=18N=18

Coronary Flow ReserveCoronary Flow Reserve Rate of Increase in DSA

Brightness (Gray /sec)

Rate of Increase in DSA

Brightness (Gray /sec)

5

10

5

10

Cir

cum

fere

nce

(cm

)C

ircu

mfe

ren

ce (

cm)

N=24N=24N=32N=32


180/2/180

Eptifibatide

180/2/180

7.2+ 3.27.2+ 3.2

8.5 + 4.08.5 + 4.0P=0.18P=0.18

Rate of Growth in

Blush Circumference

(cm / sec)

Rate of Growth in

Blush Circumference

(cm / sec)

ESPRIT Substudy: ResultsESPRIT Substudy: ResultsESPRIT Substudy: ResultsESPRIT Substudy: Results

Gibson, Am J Cardiol, 2001Gibson, Am J Cardiol, 2001

All Patients Have TIMI Grade 3 Flow at Completion of StentingAll Patients Have TIMI Grade 3 Flow at Completion of Stenting

Integrilin in PCI and Myocardial BlushIntegrilin in PCI and Myocardial Blush

Bigger

Brighter

Faster

Bigger

Brighter

Faster

All Patients Have TIMI Grade 3 Flow at Completion of StentingAll Patients Have TIMI Grade 3 Flow at Completion of Stenting

Gibson, Am J Cardiol, 2001Gibson, Am J Cardiol, 2001

The Pathophysiology of CK Release Following PCI in UA / NSTEMI By C. Michael Gibson MS, MD Chief...

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