inflammation following percutaneous coronary interventions

Inflammation Following Percutaneous Inflammation Following Percutaneous Coronary InterventionsCoronary Interventions

Rabih R. Azar, MD, MSc, FACCRabih R. Azar, MD, MSc, FACC

Division of CardiologyDivision of Cardiology

Hotel Dieu de France HospitalHotel Dieu de France Hospital


• Inflammation in coronary artery diseaseInflammation in coronary artery disease

• PCI induce systemic inflammationPCI induce systemic inflammation

• Relation between PCI, inflammation and restenosisRelation between PCI, inflammation and restenosis

• Determinant of the inflammatory response following PCIDeterminant of the inflammatory response following PCI

• Anti-inflammatory therapy in the setting of PCIAnti-inflammatory therapy in the setting of PCI

Unstable Plaques are Hot. CRP probably identifies Unstable Plaques are Hot. CRP probably identifies vulnerable plaquesvulnerable plaques

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

S. Angina U.Angina MI

Difference of temp from Difference of temp from background tempbackground temp

Stefanadis. Circ 99;99:1965Stefanadis. Circ 99;99:1965

CRP Is a Risk Factor in Unstable AnginaCRP Is a Risk Factor in Unstable Angina

Liuzzo et al. N Engl J Med. 1994;331:417.

CRP<0.3 mg/dL

(n=11)

CRP≥0.3 mg/dL

(n=20) p-value

Ischemic episodes 1.8±2.4 4.8±2.5 0.004

In-hospital events:

Death 0 2

MI 0 5

Revascularization 2 12

Total 2 (18%) 18 (90%) <0.001

Coronary Angioplasty Induces a Systemic Coronary Angioplasty Induces a Systemic Inflammatory ResponseInflammatory Response

0

5

10

15

20

25

30

PCI Coronary angiography

Baseline

48 hours

Mean CRP Mean CRP mg/Lmg/L

P < 0.001P < 0.001

P = NSP = NS

Azar et al. Am J Cardiol 1997;80:1476-8Azar et al. Am J Cardiol 1997;80:1476-8

Median plasma levels of CRP before and following Median plasma levels of CRP before and following PCIPCI

Gaspardone et al. AJC 1998;82:515Gaspardone et al. AJC 1998;82:515

Event-free survival in patients with normal or Event-free survival in patients with normal or high CRP 72 hours following PCIhigh CRP 72 hours following PCI

Gaspardone et al. Gaspardone et al. AJC 1998;82:515AJC 1998;82:515

Relationship between circulating monocytes and in-Relationship between circulating monocytes and in-stent neointima proliferation following coronary stent neointima proliferation following coronary

stentingstenting

• Coronary stent implantation of 107 patientsCoronary stent implantation of 107 patients

• Blood collected prior to PCI and each of the 7 days Blood collected prior to PCI and each of the 7 days following PCIfollowing PCI

• Moncotye count increased and reached its peak 48 hours Moncotye count increased and reached its peak 48 hours after stent implantationafter stent implantation

• At 6-month follow-up, all patients received angiographic At 6-month follow-up, all patients received angiographic and volumetric intravascular ultrasound analysisand volumetric intravascular ultrasound analysis

Fukuda et al. JACC 2004;43:18-23Fukuda et al. JACC 2004;43:18-23

Relationship between maximum monocyte count and in-Relationship between maximum monocyte count and in-stent neointimal volume after 6-month follow-upstent neointimal volume after 6-month follow-up


Monocyte Activation and Binding to Monocyte Activation and Binding to Endothelial Cells (CD11b-VICAM)Endothelial Cells (CD11b-VICAM)

Leukocyte activation, adhesion and migrationLeukocyte activation, adhesion and migration

Serial changes in CD11b and 8B2 on the surface of PMNs from Serial changes in CD11b and 8B2 on the surface of PMNs from the coronary sinus samples following PCIthe coronary sinus samples following PCI

Inoue et al. Circ 2003;107:1757Inoue et al. Circ 2003;107:1757

PTCA results in platelets activationPTCA results in platelets activation

Serrano et al. J Am Coll Cardiol 1997;29:1276-83Serrano et al. J Am Coll Cardiol 1997;29:1276-83

The shedding of sCD40L during platelets The shedding of sCD40L during platelets stimulationstimulation

Effects of sCD40LEffects of sCD40L

• Initiation of the inflammatory response– Expression of ICAM, VICAM, E-selectin

– Expression of chemokines (IL-6, IL-6, MCP-1)

• Prothrombotic effect– Expression of tissue factor

– Interaction with the GP IIb/IIIa receptor

• Progression of atherosclerosis

Soluble CD40 Ligand is a predictor of restenosis Soluble CD40 Ligand is a predictor of restenosis following PCIfollowing PCI

Cipollone et al. J Am Coll Cardiol 2003;108:2776-2782Cipollone et al. J Am Coll Cardiol 2003;108:2776-2782

Severity of stent inflammation from pathology Severity of stent inflammation from pathology studies according to damage of the arterial wall by studies according to damage of the arterial wall by

stent strutsstent struts

Farb et al. Circulation 1999;99:44-52Farb et al. Circulation 1999;99:44-52

Clinical and procedural correlates with the inflammatory Clinical and procedural correlates with the inflammatory response following PCIresponse following PCI

Condition Correlation

• Vessel treated NO

• Stent vs. balloon NO

• Maximal pressure NO

• No stents NO

• Age NO

• Sex NO

• Baseline CRP YES

Azar et al. Am J Cardiol 1997;80:1476-8Azar et al. Am J Cardiol 1997;80:1476-8

Liuzzo et al. Circulation 1998;98:2370Liuzzo et al. Circulation 1998;98:2370

IMPRESS: Immunosuppressive Therapy for the IMPRESS: Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Prevention of Restenosis After Coronary Artery

Stent ImplantationStent Implantation• Inclusion:

– Single vessel stenting

– CRP < 0.5mg/dL before stenting and > 0.5 mg/dL 72 hours after stenting

• Treatment:

– Randomly assigned, double blinded

– Prednisone: 1 mg/kg for the first 10 days, 0.5 mg/kg day 11-30, 0.25 mg/kg day 31-45

• End-Points:

– 12-month event free survival (death, MI, repeat revascularization) Versaci et al. J Am Coll Cardiol 2002;40:1935Versaci et al. J Am Coll Cardiol 2002;40:1935

Event-free survival according to treatment in patients with Event-free survival according to treatment in patients with CRP > 5 mg/dL 72 hours after PCICRP > 5 mg/dL 72 hours after PCI

Versaci et al. J Am Coll Cardiol 2002;40:1935Versaci et al. J Am Coll Cardiol 2002;40:1935

Abiciximab improves the outcome of PCI: 3-year Abiciximab improves the outcome of PCI: 3-year event-free survival from EPICevent-free survival from EPIC

JAMA 1997;278:478JAMA 1997;278:478

Effect of abciximab use on inflammatory markers’ Effect of abciximab use on inflammatory markers’ rise following PCIrise following PCI

1.6 1.6

0.4

1

0

0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

CRP IL-6 TNF

Placebo

Abciximab

P=0.025P=0.025 P<0.001P<0.001

P=0.12P=0.12

Me

dia

n c

ha

ng

e a

t 48

-ho

ur

Me

dia

n c

ha

ng

e a

t 48

-ho

ur

Lincoff et al. Circ 2001;104:163-167Lincoff et al. Circ 2001;104:163-167

Abciximab decreases detectable CD11b on Abciximab decreases detectable CD11b on neutrophils from patients undergoing PCIneutrophils from patients undergoing PCI

Mickelson et al. J Am Coll Cardiol 1999;33:97-106Mickelson et al. J Am Coll Cardiol 1999;33:97-106

Mean elevations of CRP and IL-6 elevation following Mean elevations of CRP and IL-6 elevation following PCI in controls and in tirofiban usersPCI in controls and in tirofiban users

Azar et al. J Am Coll Cardiol 2003;supl A:1174-189Azar et al. J Am Coll Cardiol 2003;supl A:1174-189

Azar et al. Am Journal Cardiol; January 15, 2005Azar et al. Am Journal Cardiol; January 15, 2005

Effect of tirofiban on sCD40L riseEffect of tirofiban on sCD40L rise(patients in the upper quartile of sCD40L at baseline excluded)(patients in the upper quartile of sCD40L at baseline excluded)


41% inhibition41% inhibition

Statin therapy at the time of PCI confers an early Statin therapy at the time of PCI confers an early and sustained survival benefitand sustained survival benefit

Chan et al. Circulation 2002;105:691-696Chan et al. Circulation 2002;105:691-696

Mortality according to baseline CRP and statins use Mortality according to baseline CRP and statins use following PCIfollowing PCI

3.1

14.8

1.2 1.8

5.6 5.76.3

2.8

0

2

4

6

8

10

12

14

16

1st quartile 2nd quartile 3rd quartile 4th quartile

control

statin

1-ye

ar m

ort

alit

y (%

)1-

year

mo

rtal

ity

(%)

P = NSP = NS P = NSP = NS

P = NSP = NS

P < 0.009P < 0.009

Preprocedural CRPPreprocedural CRPChen et al. Circulation 2003;107:1750-1756Chen et al. Circulation 2003;107:1750-1756

Effects of Statin Therapy on the Rise of Markers of Effects of Statin Therapy on the Rise of Markers of Inflammation and on Platelets Activation Following Inflammation and on Platelets Activation Following

AngioplastyAngioplasty

-64%-64%

P = 0.008P = 0.008

Azar et al. Circulation, supplement, October 2004Azar et al. Circulation, supplement, October 2004


-32%-32%

P = NSP = NS

Statins suppress elevation of hs-CRP following angioplasty Statins suppress elevation of hs-CRP following angioplasty in patients with high levels of hs-CRP at baselinein patients with high levels of hs-CRP at baseline

Azar et al. Circulation, supplement, October 2004Azar et al. Circulation, supplement, October 2004


Statins decrease CD11b expression and CD11b Statins decrease CD11b expression and CD11b dependent adhesion of monocytes to endothelium dependent adhesion of monocytes to endothelium

in patients with hypercholesterolemiain patients with hypercholesterolemia

Weber et al. J Am Coll Weber et al. J Am Coll Cardiol 1997;30:1212Cardiol 1997;30:1212

ConclusionsConclusions

• PCI induce a systemic inflammatory responsePCI induce a systemic inflammatory response

• The amplitude of this response correlates significantly with adverse events The amplitude of this response correlates significantly with adverse events following PCI, especially restenosisfollowing PCI, especially restenosis

• This response depends mainly on the degree of damage inflicted to the arterial wall This response depends mainly on the degree of damage inflicted to the arterial wall (media) and on the degree of plaque inflammation present before PCI(media) and on the degree of plaque inflammation present before PCI

• Anti-inflammatory therapy may be beneficial in patients with high CRP following PCIAnti-inflammatory therapy may be beneficial in patients with high CRP following PCI

• Many drugs proven to be beneficial during PCI exhibit anti-inflammatory activity Many drugs proven to be beneficial during PCI exhibit anti-inflammatory activity which probably contributes to their effectivenesswhich probably contributes to their effectiveness

Non-fatal MI according to baseline CRP and statins Non-fatal MI according to baseline CRP and statins use following PCIuse following PCI

7

8.9

11.713.1

6.75.4

6.3

8.5

0

2

4

6

8

10

12

14


controlstatin

Pre-procedural CRPPre-procedural CRP

1-y

ea

r n

on

- fa

tal M

I (%

)1

-ye

ar

no

n-f

at a

l MI (

%)

P = NSP = NS

P = NSP = NS

P = 0.09P = 0.09 P = 0.167P = 0.167

Revascularisation within 1 year according to Revascularisation within 1 year according to baseline CRP and statins use following PCIbaseline CRP and statins use following PCI

16.4 1618.2

16.716.5

19.421

11.3

0

5

10

15

20

25


control

statin

Pre-procedural CRPPre-procedural CRP

1-y

ea

r re

vas

cula

riza

tio

n r

at e

(%

)1

-ye

ar

rev a

scu

lari

zat i

on

ra

te (

%)

P = NS for allP = NS for all

Effects of tirofiban on CRP and IL-6 elevation following PCIEffects of tirofiban on CRP and IL-6 elevation following PCI

0

0.5

1

1.5

2

2.5

Baseline 24 h 48 h

0

4

8

12

16

20

Baselilne 24 h 48 h

Mean CRP changeMean CRP change

p = NS for allp = NS for all

Mean IL-6 changeMean IL-6 change

p = NS for allp = NS for all

• placeboplacebo

• tirofibantirofiban

Bonz et al. Am Heart J 2003;145:693-9Bonz et al. Am Heart J 2003;145:693-9

Maximum monocyte count following PCI is an Maximum monocyte count following PCI is an independent predictor of in-stent neointimal volume at independent predictor of in-stent neointimal volume at

6-month follow-up6-month follow-up

RegressionRegression p valuep value

coefficientcoefficient

AgeAge 0.0520.052 0.5720.572

Male sexMale sex - 0.003- 0.003 0.9770.977

HTNHTN 0.0090.009 0.9190.919

DiabetesDiabetes 0.0740.074 0.410.41

HyperlipidemiaHyperlipidemia 0.1220.122 0.1710.171

Stent volume immediatelyStent volume immediately

after implantationafter implantation 0.4230.423 <0.0001<0.0001

Maximum monocyte countMaximum monocyte count 0.3240.324 0.00070.0007


The increase in CD11b at 48-hour is positively correlated The increase in CD11b at 48-hour is positively correlated with late lumen loss at 6-month follow upwith late lumen loss at 6-month follow up

Inoue et al. Circ Inoue et al. Circ 2003;107:17572003;107:1757

Leukocyte-platelet complexes increase following Leukocyte-platelet complexes increase following PCIPCI

2

0.2

11

3

0

2

4

6

8

10

12

monocytes neutrophils

baseline

following PCI

% o

f le

uko

cyte

s h

igh

ly b

ou

nd

to

pla

tele

ts%

of

leu

kocy

tes

hig

hly

bo

un

d t

o p

late

lets P<0.05P<0.05

P<0.05P<0.05


Leukocyte-platelet aggregates are associated with Leukocyte-platelet aggregates are associated with increased adverse event rate following PCI increased adverse event rate following PCI


SMC ProliferationSMC Proliferation

MigrationMigration Matrix secretionMatrix secretion

SMC receptors

Mechanism of Neointimal Formation

Arterial injuryArterial injury

Growth Factors & cytokinesGrowth Factors & cytokines

ThrombusThrombus InflammationInflammation

G0 G1 G2

S

M

Smooth muscle cell Smooth muscle cell (SMC)(SMC)

Signal transduction

Cell cycle

Response of CRP and SAA to PTCA according to Response of CRP and SAA to PTCA according to clinical status and baseline markers levelsclinical status and baseline markers levels

Liuzzo et al. Circulation 1998;98:2370Liuzzo et al. Circulation 1998;98:2370

Inflammatory markers measured 24 hours after PCI Inflammatory markers measured 24 hours after PCI are predictor of restenosisare predictor of restenosis

Cipollone et al. J Am Coll Cardiol 2003;108:2776-2782Cipollone et al. J Am Coll Cardiol 2003;108:2776-2782

Sources of Inflammatory MarkersSources of Inflammatory Markers

Risk of MI According to CRP LevelsRisk of MI According to CRP Levels

IMPRESS Study: Clinical OutcomeIMPRESS Study: Clinical Outcome

Prednisone therapy mainly reduces the incidence of TVRPrednisone therapy mainly reduces the incidence of TVR

7

0 0

7

35

2 2

33

0

5

10

15

20

25

30

35

40

Composite Death Non fatal MI TVR

Prednisone

PlaceboEv

ent

rate

(%

)E

ven

t ra

te (

%)

Versaci et al. J Am Coll Cardiol 2002;40:1935Versaci et al. J Am Coll Cardiol 2002;40:1935

Effect of tirofiban on sCD40L rise following PCIEffect of tirofiban on sCD40L rise following PCI


inflammation following percutaneous coronary interventions

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