Dr. Jajang Sinardja, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 24th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com

1. Role of Inflammation
Patophysiology of Acute Coronary Syndrome
Jajang Sinardja

2. Patophysiology of ACS
• Rupture
• Fissure
• Erosion
Abrupt
plaque
changes
SpasmeThrombosis
• UAP
• NSTEMI
• STEMI
ACS
Stable
plaque
Degree of
thrombosis
and
vascular
changes
Role of INFLAMMATION

3. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372

4. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
1. Normal human artery
The most well developed
intimal layer compared to
other species
1. Normal human artery
The most well developed
intimal layer compared to
other species

5. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
2. Endothelial cells recruited
inflammatory cells such as
monocytes and T lymphocytes.
This was activated by risk factors
such as dyslipidemia
2. Endothelial cells recruited
inflammatory cells such as
monocytes and T lymphocytes.
This was activated by risk factors
such as dyslipidemia

6. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
3. Monocytes become
macrophage, then become
lipid-laden foam cells
by engulfing oxydized LDLs.
Then secrete inflammatory
cytokines and growth factors
which caused smooth muscle
cells migration and
proliferation
3. Monocytes become
macrophage, then become
lipid-laden foam cells
by engulfing oxydized LDLs.
Then secrete inflammatory
cytokines and growth factors
which caused smooth muscle
cells migration and
proliferation

7. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
4. As lesion progresses,
inflammatory mediators
cause expression
of tissue factor, a potent
procoagulant, and of
matrix-degrading
proteinases that
weaken fibrous cap of plaque.
4. As lesion progresses,
inflammatory mediators
cause expression
of tissue factor, a potent
procoagulant, and of
matrix-degrading
proteinases that
weaken fibrous cap of plaque.

8. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
5. Fibrous cap ruptures, thrombogenic
lipid core exposed, and coagulation
cascade begin.
If prothrombotic prevail against
fibrinolytic mechanisms, then occlusive
thrombus causing ACS may result
5. Fibrous cap ruptures, thrombogenic
lipid core exposed, and coagulation
cascade begin.
If prothrombotic prevail against
fibrinolytic mechanisms, then occlusive
thrombus causing ACS may result

9. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
6. Thrombus resorbs, healing response
increased collagen and smooth
muscle cells accumulation, lead to
advance fibrous and
calcified plaque, producing symptoms
of stable angina pectoris
6. Thrombus resorbs, healing response
increased collagen and smooth
muscle cells accumulation, lead to
advance fibrous and
calcified plaque, producing symptoms
of stable angina pectoris

10. Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
7. Superficial erosion can cause
mural thrombus, depending of
local prothrombotic and fibrinolytic
balance, can cause acute myocardial
infarction
7. Superficial erosion can cause
mural thrombus, depending of
local prothrombotic and fibrinolytic
balance, can cause acute myocardial
infarction

11. Stable vs Ruptured Plaque

12. Role of Inflammation in
Destabilizing Plaque
Interferon gamma inhibit de novo sinthesis
of interstitial collagen by smooth muscle
cells
Proinflammatory cytokines induce the
expression of enzymes capable of breaking
down the extracellular matrix, and trigger
apoptosis of smooth muscle cells
Inflammatory stimuli activate matrix
metalloproteinase that promoting
desquamative process of endothelial cell
Resulting in thinner and unstable fibrous cap

13. Role of Inflammation in Creating
Thrombogenic Condition
Inflammatory stimuli causing loss of
endothelial cell
Loss of endothelial cell uncover the
thrombogenic subendothelial matrix
Endothelial cells express tissue factor
procoagulant in response to inflammatory
mediators.

14. Role of Inflammation in Creating
Vasospastic Condition
Inflammatory stimuli causing loss of
endothelial cell, which in turn decrease
production of nitric oxide. (Nitrit oxide
not only has vasodilator effect, but also
can impair platelet aggregation)

15. Inflammatory Biomarkers in ACS
Cardiovascular risk stratification
Novel anti-inflammatory therapy
approach

16. Inflammatory Biomarkers in ACS
CRP and Cardiovascular Risk in ACS
Blake GJ, Ridker PM. J Am Coll Cardiol 2003;41: 37S–42S

17. Inflammatory Biomarkers in ACS
Other inflammatory biomarkers in ACS
Blake GJ, Ridker PM. J Am Coll Cardiol 2003;41: 37S–42S

18. Inflammatory Biomarkers in ACS
2012 AHA UA/NSTEMI Guidelines:
◦ Inflammatory biomarkers show promise for
providing additional insights into
pathophysiological of thrombosis, and novel
therapeutic approaches. But..
◦ None of these inflammatory biomarkers have
been adequately studied or validated to be
recommended for routine clinical application
Anderson, et al. Circulation 2013:127:e663-e828

19. How to Suppress Inflammation
Exercise
Dietary modification
Statin

20. How to Suppress Inflammation
Exercise
Dietary modification
Statin
• Increasing nitric oxide production
• Elevating HDL
• Augmenting insulin sensitivity

21. How to Suppress Inflammation
Exercise
Dietary modification
Statin • Altering the pattern of
prostanoid produced
• Activating PPAR-α

22. How to Suppress Inflammation
Exercise
Dietary modification
Statin

23. How Statin Suppress Inflammation
By reducing:
◦ Macrophage number
◦ Matrix metalloproteinase expression
◦ Tissue factor gene expression
◦ Proinflammatory cytokine expression
◦ Leucocyte adhesion molecule expression
◦ Production of reactive oxygen species
Inflammatory cells and mediators

24. How Statin Suppress Inflammation
Statin also increases insterstitial collagen
content, and smooth muscle cell
maturation
So statin suppress inflamation, improves
endothelial function, enhances fibrinolytic
activity, and stabilizes atherosclerotic
plaque
This is the so called ‘pleiotropic’ effects of
statin

25. 30-month follow-up
4160
patients
Patient population:
Hospitalized for
acute MI or high risk
unstable angina
within the preceding
10 days
LDL-C > 125 mg/dl
TC </= 240 mg/dl
Primary end point :All cause death,
MI, unstable angina requiring rehospitalization,
revascularization occuring > 30 days
after randomization or stroke
Double-blind period
Atorvastatin 80 mg/day (n=2063)
Pravastatin 40 mg/day (n=2099)
Study Design
Secondary end point : Change from baseline of
High-sensitivity C-reactive protein
PROVE – IT TIMI 22 TRIAL

26. PROVE – IT TIMI 22 TRIAL
Effect of statins on LDL and CRP
J Am Coll Cardiol 2005;46:1405–10)

27. PROVE – IT TIMI 22 TRIAL
J Am Coll Cardiol 2005;46:1405–10)
CRP effect
LDL effect

28. PROVE – IT TIMI 22 TRIAL
What do we learn?
◦ Inflammation indeed play a pivotal role in the
patophysiology of ACS
◦ Treating inflammation in ACS resulting in a
better cardiovascular outcome
◦ Statin, beyond it’s LDL lowering effect, has
‘pleiotropic’ effect
What is the implication on our daily
practice?

31. Current Guidelines

32. Take home message
Inflammation play an important role in
initiating, progression, and complicating
athero-thrombotic process
Inflammation biomarkers such as CRP
maybe useful for risk stratification and
therapy guidance, but still need further
study

33. Take home message
Exercise, dietary modification, and statin
can suppress inflammation
Statin (especially high dose atorvastatin)
given early in ACS patients result in
significant reduction of CRP (suppress
inflammation) which then translated to
better early cardiovascular outcome.
(Class IB)