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Role of Inflammation
Patophysiology of Acute Coronary Syndrome
Jajang Sinardja
Patophysiology of ACS
• Rupture
• Fissure
• Erosion
Abrupt
plaque
changes
SpasmeThrombosis
• UAP
• NSTEMI
• STEMI
ACS
Stab...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
1. Normal human artery
The mos...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
2. Endothelial cells recruited...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
3. Monocytes become
macrophage...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
4. As lesion progresses,
infla...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
5. Fibrous cap ruptures, throm...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
6. Thrombus resorbs, healing r...
Role of Inflammation in
Atherosclerosis Timeline
Peter Libby. Circulation. 2001;104:365-372
7. Superficial erosion can cau...
Stable vs Ruptured Plaque
Role of Inflammation in
Destabilizing Plaque
Interferon gamma inhibit de novo sinthesis
of interstitial collagen by smooth...
Role of Inflammation in Creating
Thrombogenic Condition
Inflammatory stimuli causing loss of
endothelial cell
Loss of endo...
Role of Inflammation in Creating
Vasospastic Condition
Inflammatory stimuli causing loss of
endothelial cell, which in tur...
Inflammatory Biomarkers in ACS
Cardiovascular risk stratification
Novel anti-inflammatory therapy
approach
Inflammatory Biomarkers in ACS
CRP and Cardiovascular Risk in ACS
Blake GJ, Ridker PM. J Am Coll Cardiol 2003;41: 37S–42S
Inflammatory Biomarkers in ACS
Other inflammatory biomarkers in ACS
Blake GJ, Ridker PM. J Am Coll Cardiol 2003;41: 37S–42S
Inflammatory Biomarkers in ACS
2012 AHA UA/NSTEMI Guidelines:
◦ Inflammatory biomarkers show promise for
providing additio...
How to Suppress Inflammation
Exercise
Dietary modification
Statin
How to Suppress Inflammation
Exercise
Dietary modification
Statin
• Increasing nitric oxide production
• Elevating HDL
• A...
How to Suppress Inflammation
Exercise
Dietary modification
Statin • Altering the pattern of
prostanoid produced
• Activati...
How to Suppress Inflammation
Exercise
Dietary modification
Statin
How Statin Suppress Inflammation
By reducing:
◦ Macrophage number
◦ Matrix metalloproteinase expression
◦ Tissue factor ge...
How Statin Suppress Inflammation
Statin also increases insterstitial collagen
content, and smooth muscle cell
maturation
S...
30-month follow-up
4160
patients
Patient population:
Hospitalized for
acute MI or high risk
unstable angina
within the pre...
PROVE – IT TIMI 22 TRIAL
Effect of statins on LDL and CRP
J Am Coll Cardiol 2005;46:1405–10)
PROVE – IT TIMI 22 TRIAL
J Am Coll Cardiol 2005;46:1405–10)
CRP effect
LDL effect
PROVE – IT TIMI 22 TRIAL
What do we learn?
◦ Inflammation indeed play a pivotal role in the
patophysiology of ACS
◦ Treati...
Current Guidelines
Take home message
Inflammation play an important role in
initiating, progression, and complicating
athero-thrombotic proce...
Take home message
Exercise, dietary modification, and statin
can suppress inflammation
Statin (especially high dose atorva...
Role of Inflammation in Patophysiology of ACS
Role of Inflammation in Patophysiology of ACS
Role of Inflammation in Patophysiology of ACS
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Role of Inflammation in Patophysiology of ACS

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

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Transcript of "Role of Inflammation in Patophysiology of ACS"

  1. 1. Role of Inflammation Patophysiology of Acute Coronary Syndrome Jajang Sinardja
  2. 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. 3. Role of Inflammation in Atherosclerosis Timeline Peter Libby. Circulation. 2001;104:365-372
  4. 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. 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. 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. 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. 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. 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. 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. 11. Stable vs Ruptured Plaque
  12. 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. 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. 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. 15. Inflammatory Biomarkers in ACS Cardiovascular risk stratification Novel anti-inflammatory therapy approach
  16. 16. Inflammatory Biomarkers in ACS CRP and Cardiovascular Risk in ACS Blake GJ, Ridker PM. J Am Coll Cardiol 2003;41: 37S–42S
  17. 17. Inflammatory Biomarkers in ACS Other inflammatory biomarkers in ACS Blake GJ, Ridker PM. J Am Coll Cardiol 2003;41: 37S–42S
  18. 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. 19. How to Suppress Inflammation Exercise Dietary modification Statin
  20. 20. How to Suppress Inflammation Exercise Dietary modification Statin • Increasing nitric oxide production • Elevating HDL • Augmenting insulin sensitivity
  21. 21. How to Suppress Inflammation Exercise Dietary modification Statin • Altering the pattern of prostanoid produced • Activating PPAR-α
  22. 22. How to Suppress Inflammation Exercise Dietary modification Statin
  23. 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. 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. 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. 26. PROVE – IT TIMI 22 TRIAL Effect of statins on LDL and CRP J Am Coll Cardiol 2005;46:1405–10)
  27. 27. PROVE – IT TIMI 22 TRIAL J Am Coll Cardiol 2005;46:1405–10) CRP effect LDL effect
  28. 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?
  29. 29. Current Guidelines
  30. 30. 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
  31. 31. 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)
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