the pathophysiology of ck release following pci in ua / nstemi by c. michael gibson ms, md chief...
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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 Grade 3
Myocardial Perfusion Grade 2
Myocardial Perfusion Grade 2
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
Median = 6Median = 6
Median = 14Median = 14
% 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
TIMI Grade 3 Flow: 100%
CTFC 13
TIMI Grade 3 Flow: 100%
CTFC 17.5
TIMI Grade 3 Flow: 100%
CTFC 17.5
0.78 + 0.600.78 + 0.60
TMPG 3TMPG 3 TMPG 0, 1 , 2TMPG 0, 1 , 2
Gibson, Am Heart J 2002Gibson, Am Heart J 2002
All Patients Have TIMI 3 Flow at Completion of StentingAll Patients Have TIMI 3 Flow at Completion of Stenting
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
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 & 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
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
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.
All Patients Have TIMI 3 Flow at Completion of StentingAll Patients Have TIMI 3 Flow at Completion of Stenting
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
Heparin 60 U / Kg bolus
Target ACT 200-300 sec
Heparin 60 U / Kg bolus
Target ACT 200-300 sec
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
PlaceboPlacebo Eptifibatide
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
PlaceboPlacebo Eptifibatide
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