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1. Anwar Santoso
Dept. of Cardiology – Faculty of Medicine; University of Indonesia
National Cardiovascular Centre – Harapan Kita Hospital
Jakarta - Indonesia
Pathogenesis of Atherosclerosis:
Challenges to Vulnerable Plaque Concept

2. Outline
• Background
• Pathogenesis of atherosclerosis
• Challenges to vulnerable plaques concept
– Plaque rupture versus plaque erosion
• Summary

3. Background
• Atherosclerosis is a chronic inflammatory disease
of the arterial wall, arising from an imbalance in
lipid metabolism and a maladaptive inflammatory
response.
• Advanced atherosclerotic lesions are further
weakened by pronounced local activity of matrix-
degrading protease as well as immature neo-
vessels sprouting into the lesion
Silvestre-Roig C, et al. Cir Res 2014; 114: 214 – 26; Weber C & Noels H. Nat Med 2011; 17: 1410 - 22

4. Background
• Understanding the pathophysiology of
atherogenesis and the progression of
atherosclerosis have been major goals of
CV research in the last decades
• However, the complex molecular and
cellular mechanisms underlying plaque
destabilization remain largely obscure
Silvestre-Roig C, et al. Cir Res 2014; 114: 214 - 26

5. Atherothrombosis Development
• Atherosclerosis initiation
• Atheroma evolution
• Atherosclerosis complication
• Thrombosis
Libby P. The Vascular Biology. In: 10th ed. Braunwald’s Heart Disease. A Textbook of Cardiovascular Disease. 2015; Elsevier, page 1043

6. Schematic evolution of
atherosclerotic plaque
Libby P. The Vascular Biology. In: 10th ed. Braunwald’s Heart Disease. A Textbook of Cardiovascular Disease. 2015; Elsevier, page 1043

7. Atherosclerosis Initiation
• Extracellular lipid accumulation
• Leucocyte recruitment and retention
• Focality of lesion formation
• Intracellular lipid formation
• Foam cell formation
Libby P. The Vascular Biology. In: 10th ed. Braunwald’s Heart Disease. A Textbook of Cardiovascular Disease. 2015; Elsevier, page 1043

8. Scanning electron micrograph of rabbit aorta receiving
intra venous human LDL-C
Nievelstein PF, et al. Arterioscler Thromb 1991; 11: 1795 - 91

9. Leucocyte extravasation cascade and
monocyte appears to come between EC
Faggiotto A, et al. Arteriosclerosis 1984; 4: 323; Schnoor M, et al. Med of Inflammation 2015; .doi.org/10.1155/2015/946509

10. Reduction of chloride concentration accelerates lipid
accumulation in macrophages (foam cells)
Wu Q-Q, et al. Circ J 2016; 80: 1024 - 33

11. Endothelial-derived foam cell in a late stage of
experimental hypercholesterolemia
Simionescu. M & Sima AV. In: Wick G & Grundtman C. Inflammation and Atherosclerosis 2012. Springer-Verlag

12. Evolution of Atheroma
• Inflammation in atherogenesis
• Smooth cell migration and proliferation
• Smooth muscle death in atherogenesis
• Arterial extracellular matrix
• Angiogenesis in plaque
• Plaque mineralization
Libby P. The Vascular Biology. In: 10th ed. Braunwald’s Heart Disease. A Textbook of Cardiovascular Disease. 2015; Elsevier, page 1043

13. Inflammation represented by sPLA2 in atherosclerosis
Yamamoto K, et. al. Annal Bional Chem 2011; 400: 1829 - 42

14. Membrane Cell Structure

15. Rosenson RS & Hurt-Cameho E . Eur H J 2012; 33: 2899 - 2909
PLA2 enzymatic activity generates harmful lipid products

16. 16
Foam cells in aortic tissues ~ darapladib (LpPLA2 inhibtors)
reduces oxidative stress – inflammation in DM model
Heriansyah T,...Santoso A et. al. Asian Pac J HK Coll Cardiol 2016; 24: 64 - 73

17. Santoso A, Kaniawati M et. al. Int J Angiol 2013; 22: 49 - 54

18. Santoso A, Kaniawati M et. al. Int J Angiol 2013; 22: 49 - 54
Association between age, renal function, inflammation and sPLA2
with Acute Coronary Syndromes
sPLA2 a novel predictor of ACS through inflammation

19. Systemic IL-10 accelerates endothelial recovery and
inhibits VSMC hyperplasia
Verma S, et. al. PLOS One 2016; Jan 25: doi: 10.1371/journal.pone.0147615
IL-10 is an anti-inflammatoric cytokines

20. Fatty streak lesion in a hyperlipidemic hamster
aorta
Simionescu. M & Sima AV. In: Wick G & Grundtman C. Inflammation and Atherosclerosis 2012. Springer-Verlag
A few smooth muscle cells emigrated from or within media

21. In-vivo angiogenesis capacity of EC impaired by MMP8
gene knock-out or inactivation
Fang C, et. al. Cardiovasc Res 2013; 99: 146 – 55
MMP (matrix metallo proteinase) - 8 induces angiogenesis

22. Extracellular protease, oxidative stress and neo-angiogenesis
weaken atherosclerotic lesion
Silvestre-Roig C, et al. Cir Res 2014; 114: 214 – 26

23. Complication of Atherosclerosis
• Arterial stenosis and clinical implication
• Thrombosis and atheroma complication
• Plaque rupture vs plaque erosion
• Athero-thrombosis
Libby P. The Vascular Biology. In: 10th ed. Braunwald’s Heart Disease. A Textbook of Cardiovascular Disease. 2015; Elsevier, page 1043

24. Challenges to the vulnerable concept
 Is the vulnerable plaque and plaque
rupture still a valid concept ?
 Few thin-capped plaques actually
rupture

25. Stable and vulnerable atherosclerotic
plaques
Simionescu. M & Sima AV. In: Wick G & Grundtman C. Inflammation and Atherosclerosis 2012. Springer-Verlag
Stable plaque Vulnerable plaque

26. Plaque rupture in a patient with
ST-elevation MI
Kubo T, et al. J Atheroscler Thromb 2014; 21: 895 – 903

27. Plaque erosion in a patient with
ST-elevation MI
Kubo T, et al. J Atheroscler Thromb 2014; 21: 895 – 903

28. Challenges to the vulnerable concept
Plaque rupture
• 85% of male AMI
Plaque erosion
• 40% of female AMI
• smokers
Davies MJ, et al. Heart 2000; 83: 361 - 6

29. Vulnerable plaque definitions
and assumptions
 Plaque with high probability to rupture or erode
hence provoke thrombosis
 Predictor or MI and stroke
 Similar structural characteristics as plaques with
recent thrombus
Are these assumptions valid?

30. Stone GW, et al. N Eng J Med 2011; 364: 226 - 35
Only 5% of thin-cap fibroatheroma causes events at a
median follow up of 3.4 years (PROSPECT)

31. Challenges to the vulnerable concept
 Thin capped, lipid-rich atheromata most often persist for
years without causing a clinical effect
 Thin-capped, lipid rich atheromata are not solitary, rather
often multiple and affect several arterial beds in the same
individual
 The risk profile of ACS is shifting globally (global burden,
younger patients, more women, more insulin
resistance/DM, more hyper-TG and less LDL-C excess)

32. Challenges to the vulnerable concept
Statin treatment and other preventive
measures have begun to modify
atherosclerotic plaque and clinical setting
Statin treatment is on the remarkable use

33. ACS treatment changes with time

34. Previous Use of Medications on
an Outpatient Basis

35. Raber L. Eur Heart J 2015; 36: 490 – 500

37. Effects of aggressive lipid lowering on
human plaques
Libby P. Eur Heart J 2015; 36: 472 – 474

38. Schematic overview of the traditional view vs
biomechanical view of plaque rupture
Van der Heiden K, et al. Thromb Haemost 2016; 115: doi.org/10.1160/TH15-07-0614
• Cap thickness is more relevant parameter
• Necrotic core is less important

39. The Changing Face of
Acute Coronary Syndromes
Ruff CT and Braunwald E. Nat Rev Cardiol 2011: 8: 140 - 47

40. What the mechanisms behind erosion?

41. Hypothesis:
Mechanisms of superficial erosion

42. Expression of Myeloperoxidase (MPO) in inflammatory
cells within thrombi of plaque erosion and rupture
Ferrante G, et. al. Circulation 2010: 122: 2505 - 13

43. Potential mechanisms of plaque erosion?

44. Potential mechanisms of plaque erosion?

45. EC apoptosis associates with luminal PMN and TLR2
(toll-like receptor) expression only in SMC-rich lesions
Quillard T, et al. Eur Heart J 2015

47. SUMMARY
 Atherosclerosis is a chronic inflammatory disease,
arising from an imbalance in lipid metabolism and a
maladaptive inflammatory response.
 Statin treatment and other preventive measures
have begun to modify atherosclerotic plaque and
clinical setting
 The character of human plaque is changing in the
statin era, human plaque is getting less fatty and
less inflamed

48. SUMMARY
 Recent evidence suggest that TCFA and large lipid
pools actually seldom rupture and cause clinical
events. Multiple “active” plaques often reside in the
coronary and other arteries.
 Our current clinical practices contribute to decline
in STEMI and increase in NSTEMI, and disclose
superficial erosion as a cause of thrombosis

49. Hypothesis generating?
• Perivascular tissue as an entry for atherosclerosis?
• Correlation between plaque erosion and NSTEMI
and STEMI?