Role of InflammationPatophysiology of Acute Coronary Syndrome

Jajang Sinardja

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

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 arteryThe most well developed intimal layer compared to other species

1. Normal human arteryThe most well developed intimal layer compared to other species

Role of Inflammation in Atherosclerosis Timeline

Peter Libby. Circulation. 2001;104:365-372

2. Endothelial cells recruitedinflammatory cells such asmonocytes and T lymphocytes.This was activated by risk factorssuch as dyslipidemia

2. Endothelial cells recruitedinflammatory cells such asmonocytes and T lymphocytes.This was activated by risk factorssuch as dyslipidemia

Role of Inflammation in Atherosclerosis Timeline

Peter Libby. Circulation. 2001;104:365-372

3. Monocytes become macrophage, then become lipid-laden foam cellsby engulfing oxydized LDLs.Then secrete inflammatorycytokines and growth factorswhich caused smooth muscle cells migration and proliferation

3. Monocytes become macrophage, then become lipid-laden foam cellsby engulfing oxydized LDLs.Then secrete inflammatorycytokines and growth factorswhich caused smooth muscle cells migration and proliferation

Role of Inflammation in Atherosclerosis Timeline

Peter Libby. Circulation. 2001;104:365-372

4. As lesion progresses, inflammatory mediatorscause expression of tissue factor, a potent procoagulant, and of matrix-degrading proteinases that weaken fibrous cap of plaque.

4. As lesion progresses, inflammatory mediatorscause expression of tissue factor, a potent procoagulant, and of matrix-degrading proteinases that weaken fibrous cap of plaque.

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

Role of Inflammation in Atherosclerosis Timeline

Peter Libby. Circulation. 2001;104:365-372

6. Thrombus resorbs, healing responseincreased collagen and smoothmuscle cells accumulation, lead toadvance fibrous and calcified plaque, producing symptomsof stable angina pectoris

6. Thrombus resorbs, healing responseincreased collagen and smoothmuscle cells accumulation, lead toadvance fibrous and calcified plaque, producing symptomsof stable angina pectoris

Role of Inflammation in Atherosclerosis Timeline

Peter Libby. Circulation. 2001;104:365-372

7. Superficial erosion can causemural thrombus, depending oflocal prothrombotic and fibrinolyticbalance, can cause acute myocardialinfarction

7. Superficial erosion can causemural thrombus, depending oflocal prothrombotic and fibrinolyticbalance, can cause acute myocardialinfarction

Stable vs Ruptured Plaque

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

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.

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)

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 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

How to Suppress Inflammation

�Exercise

�Dietary modification

�Statin

How to Suppress Inflammation

�Exercise

�Dietary modification

�Statin

• Increasing nitric oxide production• Elevating HDL• Augmenting insulin sensitivity

How to Suppress Inflammation

�Exercise

�Dietary modification

�Statin • Altering the pattern of prostanoid produced

• Activating PPAR-α

How to Suppress Inflammation

�Exercise

�Dietary modification

�Statin

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

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

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

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

◦ 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?

Current Guidelines

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

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)