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
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
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
42. Expression of Myeloperoxidase (MPO) in inflammatory
cells within thrombi of plaque erosion and rupture
Ferrante G, et. al. Circulation 2010: 122: 2505 - 13
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
46.
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