statins, atherosclerotic plaque

1. PLAQUEPLAQUE
STABILIZATION and REGRESSIONSTABILIZATION and REGRESSION
A new Therapeutic TargetA new Therapeutic Target
Role of High-Dose Statins RegimenRole of High-Dose Statins Regimen
Alexandru Andritoiu
Military Hospital, Craiova, Romania

2. Hypotheses
• The two dominant hypotheses to explain
the discrepancy between the magnitude
of the angiographic and clinical benefit
of cholesterol reduction therapy are:
• plaque stabilization
• improved endothelial function
• One or both mechanisms may play a role
in the clinical benefit seen with the lipid-
lowering therapies.

3. Concept
• The concept of plaque stabilization was first proposed in
the 1990s in an attempt to explain the discrepancy
between the small amount of plaque regression
demonstrated angiographically in many randomized trials
of lipid lowering and the large reduction in clinical events
seen in these trials (Ambrose JA 2002)
• The concept of the vulnerable plaque should be
expanded to include any plaque that is high-risk and prone
to destabilization and thrombosis whether lipid-rich or
proteoglycan-rich.
Ambrose JA - Circulation 2002; Muller JE-JACC 1994

6. Characteristic of Vulnerable Plaque
 increased lipid content
 increased macrophage content
 foam cell and T lymphocyte content
 a reduced collagen and smooth muscle cell content
• Rupture tends to occur at the margins or ‘shoulder
region’ of plaques where the overlying fibrous cap is
necrotic, very thin and extensively infiltrated by
macrophages and adjacent to relatively normal tissue
• The ‘shoulder region’ is the site exposed to the greatest
shear stress

9. The extrinsic features that cause a
vulnerable plaque to rupture
• increased blood pressure
• vasospasm

10. Stabilization of Vulnerable Plaques
• To reduce subsequent events, vulnerable
plaques must remain stable and
quiescent.
• Plaque stabilization may not only reduce
the incidence of acute coronary
syndromes but also prevent the
evolution of plaques to more stenotic
lesions.

11. Atherosclerosis Regression,
Vascular Remodeling, and
Plaque Stabilization
Lloyd W. Klein - J Am Coll Cardiol, 2007; 49:271-273

12. REMODELIG
POSITIVE REMODELING
• early phase of ATS
• luminal size is not
affected by plaque growth
• enlargement of vessel
size
• inflamation, calcification,
medial thinning
• associated with unstable
angina
NEGATIVE REMODELING
• moderate ATS
• no increase in vessel size
• the plaque approaches
the lumen
• associated with stable
angina
STATINS

13. Which Components of the Plaque Are
Most Likely to be Targets of
Pharmacotherapy?
• The lipid pool is a highly accessible target for statin therapy
By increasing cholesterol efflux, an imbalance between the deposition and
removal of vascular cholesterol after endothelial injury may be corrected.
• Fibrous tissue seem to be irreversible despite metabolic manipulation.
However, statins have been shown to diminish smooth muscle cell
accumulation and collagen deposition.
• Calcification seems to be a nonreversible change, but this has not been
formally evaluated.
• Inflammatory reaction in the forms of cellular migration, humoral
substance release, and edema are obviously potential targets.
• Statins decrease inflammation, an effect correlated with clinical benefit

14. Regression and Stabilization:
Is There a Relationship?
• Decreasing endothelial injury, diminishing lipid
content, and altering the cellular elements and
inflammatory milieu in the subendothelial layer
may ameliorate the susceptibility to plaque
rupture.
• Treatment with statins is associated with
constrictive remodeling
• The hyperechogenicity index (composed of
dense fibrous or elastic tissue) increase in
atorvastatin-treated patients, whereas
calcification and hypoechogenic plaque (lipoid,
and necrotic tissue) remained constant.

15. Pleiotropic effects of statins on the vasculaturePleiotropic effects of statins on the vasculature
Clin. Sci. (2003) 105, 251-266Clin. Sci. (2003) 105, 251-266

16. CAD/ACS
• Culprit lesions
• Vulnerable plaque
• Unstable plaque
• Complicated plaque
• Calcium score
• %stenosis
• Occlusion

17. Ray, K. K. et al. - J Am Coll Cardiol 2005;46:1425-1433
"Pathological vascular triad" implicated in acute coronary syndrome

18. Plaque Volume and Necrotic
Core Size Determine the Plaque
Vulnerability
Plaque Hemorrhage Is Associated With
Neointimal Neovascularization and Vasa
Vasorum Proliferation

19. Plaque stabilization in acute
coronary syndromes

20. Imaging of the Vulnerable Plaque

21. Invasive Techniques for Evaluation
of the Atherosclerotic Vulnerable
Plaques
• Angiography
• Angioscopy
• Thermography
• IVUS (+CEUS)
• IVUS elastography
• Optical Coherence Tomography
• Infrared Spectrosopy

22. Noninvasive Techniques for
Evaluation of the Atherosclerotic
Vulnerable Plaques
• US (B mod, CDUS, Power-angio) -3D
• Electron Beam Computed Tomography (EBCT)
• Magnetic Resonance Imaging (MRI)

24. Culprit lesion/Plaque rupture in ACS
Okaki Y et al. Eur Heart J 2011;32:2814-2823

25. Culprit lesion/Stable plaque
images in Stable angina
Okaki Y et al. Eur Heart J 2011;32:2814-2823

26. Plaque-Specific Considerations
The destabilized (disrupted and/or
thrombosed) culprit plaque in a patient
with an acute coronary syndrome requires
a different treatment philosophy and
strategy than plaques that have not
destabilized.

35. High-Dose Lipid-Lowering Therapy and
Long-Term Antithrombotic Therapy for
Destabilized Plaques

37. What Degree of Plaque Regression Has
Been Achieved by Pharmacotherapy?
• REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid
Lowering) trial , median atheroma volume decreased (regressed)
0.4% in the high-dose statin group versus progressed 2.7% in the
moderate-dose group over an 18-month period.
• ASTEROID (A Study to Evaluate the Effect of ROsuvastatin on
Intravascular Ultrasound Derived Coronary Atheroma Burden)
study, 63.6% of patients experienced regression and mean total
atheroma volume decreased 7%, with a 1% decrease in percent
atheroma volume, after 24 months of treatment.
• Intravenous recombinant apolipoprotein A1 Milano administered in 5
weekly infusions showed a 4.1% decrease in total atheroma volume
(p < 0.001).
Although the absolute amount of regression achieved is small,
it may be sufficient to produce clinical benefit

38. REVERSAL – NORMALIZE
Studies (IVUS)
• the more calcified atheromas were
resistant to change, either progression or
regression
• less calcification was a sign of potential for
significant changes over time, either
progression or regression
The findings suggest that the various components of atheroma respond
differently to treatment with medical therapies, and can be used to target
plaques that are likely to respond.

42. IVUS in REVERSAL
• the more calcified atheromas were resistant to
change, either progression or regression.
• less calcification was a sign of potential for significant
changes over time, either progression or regression.
Nicholls SJ et al. JACC 2007;49:263-270
• The findings suggest that the various components of
atheroma respond differently to treatment with medical
therapies, and can be used to target plaques that
are likely to respond.

43. ESTABLISH
Early Statin Treatment in Patients With
Acute Coronary Syndrome trial
• Early statin treatment (Atorvastatin 20 mg)
in patients with ACS resulted in regression
of atherosclerotic lesions 6 months later.
• Plaque volume was reduced 13% from
baseline in the atorvastatin-treated group,
but increased 9% in the control group
(p < 0.03).

45. Rosuvastatin 40 mg (n =694)
Atorvastatin 80 mg (n=691)
Safety Safety Lipids
Safety
IVUS
Lipids
Safety
Lipids
Safety
Safety Safety
Visit:
Week:
1
–4
3
0
4
13
5
26
6
39
7
52
8
65
9
78
10
91
11
104
Screening
Period
2
–2
Rosuva 20 mg
Atorva 40 mg
IVUS
Lipids
Lipids
Randomization
Period
Lipids
Safety
Safety
1385 patients with symptomatic CAD (angiographic stenosis >20%)
LDL-C with (>80 mg/dL) or without (>100 mg/dL) statin use last 4 weeks
Study DesignStudy Design

46. Primary IVUS Efficacy Parameter
Change
Percent
Atheroma
Volume
-1.22
-0.99
P=0.17†
P<0.001*
P<0.001*
Median Change Percent Atheroma Volume
† comparison between groups. * comparison from baseline

47. JAPAN-ACS
Japan Assessment of Pitavastatin and Atorvastatin in
Acute Coronary Syndrome
Pitavastatin 4 mg/d vs Atorvastatin 20 mg/d
OBJECTIVE:
Plaque volum regression
Method: IVUS volumetry
N = 307 pts with ACS + Hyper-Chol + coronary plaque
Takafumi Hiro et al. -JACC 2009;54:293-302
Follow-up: 8-12 months
There were significant correlations between the change in plaque volume and
the change in external elastic membrane (EEM) volume (A), whereas no
significant correlation was observed between the change in plaque volume and
the change in lumen volume (B). The regression of plaque volume was
associated with negative vessel remodeling.

48. TRUTH
Comparison of Arterial Remodeling and Changes in
Plaque Composition Between Patients With Progression
Versus Regression of Coronary Atherosclerosis During
Statin Therapy
Treatment With Statin on Atheroma Regression
Evaluated by Intravascular Ultrasound With Virtual
Histology (TRUTH)
119 patients
2 groups: progessors vs regressors
CONCLUSION:
• Coronary arteries showed negative remodeling during statin-induced plaque
regression.
• The difference in plaque composition between patients with progression and
those with regression of coronary atherosclerosis during statin therapy arose
from the difference in the change in fibrous component.
8-month follow-up

50. Carotid plaque

51. The Prevalence of Carotid Plaques
Pacienti cu
placa;
515; 40%
Pac. fara
placa;
780; 60%
N = 1295 subjects Age 40-90 yrs; M 720: F 575
Andritoiu A, nepubl.

52. The Carotid Plaques Prevalence in
relationship with Age decades
13,79
28,35
43,8
57,14
81,25
0
20
40
60
80
100
40-49 50-59 60-69 70-79 80-89
Ani
Prevalenta%
N =405; Age 40-90 yrs
Andritoiu A, 2009

54. Carotid atherosclerosis and CVRF
Fabris F et al. Stroke. 1994;25:1133-1140

55. Carotid atherosclerosis and CVRF
Fabris F et al. Stroke. 1994;25:1133-1140

56. Carotid plaque

57. Carotid US plaque
Nodular plaque Parietale plaque

58. Vulnerable Carotid Plaque
• Thin fibrous cap
• Ulcerated surface
• Lipidic core
• Hipo/anecogenicity

59. Vulnerable carotid plaque

60. Carotid ulcerated plaque

61. AJNR 2010 31: 1395-1402

63. 15
6
stenoza ocluzie
Prevalenta stenozei si
ocluziei carotidiene
1.15/1000
0.46/1000
Andritoiu A, 2009
N = 1295 subiecti; 40-90 ani; B 720: F 575

64. DD, M, 62yr- RICA stenosis (60%)
ACI inhibitor+AAS+Clopidogrel+Sortis 40 (80) mg o.d
Stenting vs Endarterectomy?
• HBP (175/100 mmHg)
• Cholesterol 216 mg/dl
• LDL-Chol 130 mg/dL
• HDL-Chol 23 mg/dl
• TG 168 mg/dl

65. • In the United States, 90% of carotid intervention
(endarterectomy and stenting) is now for
asymptomatic carotid stenosis.
• Until a modern randomized trial comparing
stenting, endarterectomy and best medical
therapy is carried out, widespread
endarterectomy or stenting of asymptomatic
carotid stenosis for unselected patients with
asymptomatic carotid stenosis should be
regarded as malpractice.

66. J. David Spence
Professor of Neurology and Clinical Pharmacology,
Director, Stroke Prevention & Atherosclerosis Research
Centre (SPARC)-ROBARTS Research Institute
The father of carotid plaque
Plaque area or plaque volume vs. CIMT
Spence J.D., Hackam D.G. Treating Arteries Instead of Risk Factors.
A Paradigm Change in Management of Atherosclerosis. Stroke 2010;41:1193-1199.
20102010 Stroke Innovation AwardStroke Innovation Award

68. Plaque area

69. Plaque volume
3D-Reconstruction

71. RT- elastography
of carotid plaque

72. Neovascularization of
Atherosclerotic Arteries

73. Doyle, B. et al. - J Am Coll Cardiol 2007;49:2073-2080
Role of Vessel Wall Neovascularization in Plaque Growth

74. Contribution of Neovascularization to
Plaque Growth

75. Relation between neovascularization
and unstable plaque
Matsumoto N 2010

76. The plaque neovascularization
and CV risk
Staub D - Stroke 2010

78. CEUS-plaque neovascularization
Staub D - Stroke 2010

79. The plaque neovascularization
and CV risk
Staub D - Stroke 2010

80. Carotid plaque stabilization
and regression

81. Statins in Carotid Atherosclerosis
• Statins may have a direct effect on
atherosclerotic plaques in the carotid arteries.
• Studies have shown that statins reduce the
progression of carotid stenosis in patients
without previous cardiac or cerebrovascular
events and may reduce carotid intima-media
thickness in patients with hypercholesterolemia
or CHD.
• More aggressive cholesterol reduction may have
a greater effect on carotid atherosclerosis.
MacMahon S - Circulation 1998; Smilde TJ - Lancet 2001

82. The Multicenter Atorvastatin Plaque
Stabilization (MAPS) Study
Inclusion Criteria
• Symptomatic carotid stenosis > 70% (NASCET criteria)
• Eligibility for carotid endarterectomy
• Total cholesterol level between 5.83 and 7.64 mmol/L
• Never treated with lipid lowering drugs
Purpose
how different lipid-lowering strategies (non-
statin therapy, low-dose statin and high-
dose statin) affects cellular composition of
carotid plaque over a short-term period of
three months.
University of Padua
Each group received:
atorvastatin 10 mg/day,
atorvastatin 80 mg/day, or
cholestyramine 8 g/day plus
sitosterol 2.5 g/day

84. Ainsworth CD - Stroke 2005
The plaque volume regression
Atorvastatin 80 mg/d -3Mo
Plaque volume regression is real !

86. SPARCL
Stroke Prevention by Agressive Reduction in Cholesterol
Levels
• intense lipid lowering with atorvastatin 80
mg/day reduced the risk of cerebro- and
cardiovascular events in patients with and
without carotid stenosis
• The carotid stenosis group may have greater
benefit
• In the group with carotid artery stenosis,
treatment with atorvastatin 80 mg/day was
associated with a 33% reduction in the risk of
any stroke
Sillesen H,et al - Stroke 2008

88. The answer is: Yes!!!

89. Plaque Stabilization:
Can We Turn Theory into
Evidence?

90. Stabilizing the Destabilized Plaque
• percutaneous intervention
• long-term antithrombotic and
anticoagulant approaches
• high-dose lipid-lowering therapy