1. PLAQUE STABILIZATION
and
REGRESSION
A new Therapeutic Target
The Role of Statins
Alexandru Andritoiu
Military Hospital, Craiova, Romania

2. Lower is better

3. TNT: Baseline and final LDL
cholesterol levels
LDL cholesterol level
Mean baseline LDL
cholesterol levels
(mg/dL)
Final LDL cholesterol
levels (mg/dL)
Atorvastatin 10 mg
(n=5006)
Atorvastatin 80 mg
(n=4995)
98
97
101
77
LaRosa JC et al. - N Engl J Med 2005

4. TNT: Primary efficacy outcomes
Outcome
Atorvastatin
10 mg
(n=5006)
Atorvastatin
80 mg
(n=4995)
Hazard ratio
(95% CI)
p
Total major
cardiovascular
events (%)
10.9
8.7
0.78
(0.69-0.89)
<0.001
•Death from
coronary heart
disease (%)
2.5
2.0
0.80
(0.61-1.03)
0.09
•Nonfatal MI (%)
6.2
4.9
0.78
(0.66-0.93)
0.004
•Resuscitation
after cardiac
arrest (%)
0.5
0.5
0.96
(0.56-1.67)
0.89
•Fatal or nonfatal
stroke (%)
3.1
2.3
0.75
(0.59-0.96)
0.02
LaRosa JC et al. N Engl J Med 2005

5. IDEAL The Incremental Decrease in End points
through Agressive Lipid lowering
High-dose atorvastatin vs usual-dose simvastatin for
secondary prevention after myocardial infarction: the IDEAL
study: a randomized controlled trial.
Results:
• In the IDEAL study, 68 CV events were prevented among 1000 patients
managed with atorvastatin 80 mg compared with those receiving simvastatin
40 mg daily.
• The mean LDL-C level in patients receiving simvastatin 40 mg was 2.7
mmol/L compared with that of 2.1 mmol/L in those receiving atorvastatin 80
mg.
Pedersen TR et al - JAMA. 2005;294(19):2437-45.

6. PROVE IT-TIMI 22
•
In 2005, an analysis of data from
PROVE IT-TIMI 22 showed that
intensive therapy using atorvastatin 80
mg was associated with a significant
reduction in the composite clinical
endpoint (MACE) as early as 30 days
after the acute event compared with
standard-dose pravastatin (40 mg).
•
A trend in favor of intensive therapy was
evident at 15 days after randomization.
J Am Coll Cardiol 2005;46:1405-10
N Engl J Med. 2005;352:20-8

7. PROVE IT-TIMI 22
N Engl J Med. 2005;352:20-8

9. 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 lipidlowering therapies.

10. 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

11. 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.

14. 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

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

16. 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.

17. ACS
• Acute coronary syndromes (unstable
angina, acute myocardial infarction and
sudden cardiac death) result from fissure,
erosion or frank rupture of a vulnerable
atherosclerotic plaque
• An acute coronary syndrome will occur
only if coronary blood flow is reduced
and collateral flow is inadequate

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

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

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

21. 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

22. 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
•

23. 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.

24. ESTABLISH
Early Statin Treatment in Patients With Acute Coronary
Syndrome Trial
• Early statin treatment 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).

25. 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.

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

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

28. Comparative Atorvastatin Pleiotropic
Effects (CAP)
• The primary objective of
the study is to evaluate
the efficacy of
atorvastatin 80 mg daily
as compared to
atorvastatin 10 mg daily
in reducing C-reactive
protein levels over a 26week treatment period
in subjects with
documented coronary
artery disease.
Collaborators (67)
Ma PT, Opgenorth A, Frohlich J, …
Cinteza M, Dimulescu D, Vintila M,
Ahmedzhanov N, Lopatin Y, Dukat A,
Filipova S, Murin J.
Bonnet J, Clin Ther 2008;30(12):2298-313

29. REVERSAL Study - Results
Nissen SE et al. N Engl J Med 2005;352(1):29-38

30. Imaging of the Vulnerable Plaque

31. 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)

33. IVUS Elastography of
Vulnerable Plaque
IVUS (A), elastogram (B), macrophage staining (C), and collagen staining
(D). In the elastogram, a vulnerable plaque is indicated by a high strain on
the surface. In the corresponding histology, a high amount of
macrophages (C) is visible with a thin cap (D) and a lipid pool (LP).
Schaar JA et al. – Circulation 2003;108:2636-2641

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

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

37. 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
STATINS
NEGATIVE REMODELING
• moderate ATS
• no increase in vessel size
• the plaque approaches
the lumen
• associated with stable
angina

39. TRUTH
Treatment With Statin on Atheroma Regression
Evaluated by Intravascular Ultrasound With Virtual
Histology (TRUTH)
Comparison of Arterial Remodeling and Changes in
Plaque Composition Between Patients With Progression
Versus Regression of Coronary Atherosclerosis During
Statin Therapy
119 patients
2 groups: progessors vs regressors
8-month follow-up
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.

40. Neovascularization of
Atherosclerotic Arteries

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

42. Relation between neovascularization
and unstable plaque
Matsumoto N 2010

43. Carotid plaque neovascularization
Feinstein SB - JACC 2006

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

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

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

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

48. Vulnerable carotid plaque

49. Carotid ulcerated plaque

50. Statins and Stroke

51. Statins for Stroke Prevention
Disappointment and Hope
• lack of association between cholesterol levels
and stroke in most epidemiological and
observational studies.
• cholesterol as a risk factor for stroke is
controversial
• the relatively modest effects on stroke
(compared with other stroke prevention
strategies) were obtained primarily in patients
with established CHD, not in ischemic stroke
patients without CHD. The latter constitute the
majority of stroke patients.
Amarenco P – Circulation 2004;109:44-49

52. 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

53. Risk of Hemorrhagic Stroke?
• One concern from observational cohort data is
the possibility of an increased risk of
hemorrhagic stroke with cholesterol-lowering
therapy.
• However, an increase in hemorrhagic stroke was
not observed in the long-term statin secondary
prevention trials that examined hemorrhagic
stroke as a secondary end point.
• The incidence of hemorrhagic stroke was ≤0.5%
in both the placebo and statin-assigned groups.

54. 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

55. 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 (nonstatin therapy, low-dose statin and highdose statin) affects cellular composition of
carotid plaque over a short-term period of
three months.

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

57. Plaque volume regression is real !

60. JAPAN-ACS
Japan Assessment of Pitavastatin and Atorvastatin in
Acute Coronary Syndrome
Pitavastatin 4 mg/d vs Atorvastatin 20 mg/d
N = 307 pts with ACS + Hyper-Chol + coronary plaque
OBJECTIVE:
Plaque volum regression
Method: IVUS volumetry
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.
Takafumi Hiro et al. -JACC 2009;54:293-302

61. The plaque volume regression
Atorvastatin 80 mg/d -3Mo
Ainsworth CD - Stroke 2005

62. Message take home

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

65. 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).

66. IVUS in REVERSAL and NORMALIZE
studies
• 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.
Nicholls SJ et al. JACC 2007;49:263-270

67. Plaque stabilization in acute
coronary syndromes

68. Ambrose JA - 2002