PLAQUE PLAQUE STABILIZATION and STABILIZATION and
REGRESSIONREGRESSIONA new Therapeutic TargetA new Therapeutic Target
Role of High-Dose Statins Role of High-Dose Statins Regimen Regimen
Alexandru AndritoiuMilitary Hospital, Craiova, Romania
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.
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
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
The extrinsic features that cause a vulnerable plaque to rupture
• increased blood pressure
• vasospasm
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.
Atherosclerosis Regression, Vascular Remodeling, and
Plaque Stabilization
Lloyd W. Klein - J Am Coll Cardiol, 2007; 49:271-273
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
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
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.
Pleiotropic effects of statins on the vasculature Pleiotropic effects of statins on the vasculature
Clin. Sci. (2003) 105, 251-266 Clin. Sci. (2003) 105, 251-266
CAD/ACS
• Culprit lesions• Vulnerable plaque• Unstable plaque• Complicated plaque• Calcium score• %stenosis• Occlusion
Ray, K. K. et al. - J Am Coll Cardiol 2005;46:1425-1433
"Pathological vascular triad" implicated in acute coronary syndrome
Plaque Volume and Necrotic Core Size Determine the Plaque
Vulnerability
Plaque Hemorrhage Is Associated With Neointimal Neovascularization and Vasa
Vasorum Proliferation
Plaque stabilization in acute coronary syndromes
Imaging of the Vulnerable Plaque
Invasive Techniques for Evaluation of the Atherosclerotic Vulnerable
Plaques
• Angiography
• Angioscopy
• Thermography
• IVUS (+CEUS)
• IVUS elastography
• Optical Coherence Tomography
• Infrared Spectrosopy
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)
Culprit lesion/Plaque rupture in ACS
Okaki Y et al. Eur Heart J 2011;32:2814-2823
Culprit lesion/Stable plaque images in Stable angina
Okaki Y et al. Eur Heart J 2011;32:2814-2823
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.
High-Dose Lipid-Lowering Therapy and Long-Term Antithrombotic Therapy for
Destabilized Plaques
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
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.
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.
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).
Rosuvastatin 40 mg (n =694)
Atorvastatin 80 mg (n=691)
Safety Safety LipidsSafety
IVUSLipids Safety
LipidsSafety
Safety Safety
Visit:Week:
1–4
30
413
526
639
752
865
978
1091
11104
Screening Period
2–2
Rosuva 20 mg
Atorva 40 mg
IVUSLipids
Lipids
Randomization Period
LipidsSafety
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
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 DesignStudy DesignStudy Design
Primary IVUS Efficacy ParameterPrimary IVUS Efficacy Parameter
Change Percent
Atheroma Volume
-1.22
-0.99
P=0.17†
P<0.001*
P<0.001*
Median Change Percent Atheroma VolumeMedian Change Percent Atheroma Volume
† comparison between groups. * comparison from baseline
JAPAN-ACSJapan 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.
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.
Nozue T et al - Am J Cardiol 2012;109:1247-1253
8-month follow-up
Carotid plaque
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.
The Carotid Plaques Prevalence in relationship with Age decades
13,7928,35
43,857,14
81,25
0
20
40
60
80
100
40-49 50-59 60-69 70-79 80-89
Ani
Pre
vale
nta
%
N =405; Age 40-90 yrsAndritoiu A, 2009
Carotid atherosclerosis and CVRF
Fabris F et al. Stroke. 1994;25:1133-1140
Carotid atherosclerosis and CVRF
Fabris F et al. Stroke. 1994;25:1133-1140
Carotid plaque
Carotid US plaque
Nodular plaque Parietale plaque
Vulnerable Carotid Plaque
• Thin fibrous cap• Ulcerated surface • Lipidic core• Hipo/anecogenicity
Vulnerable carotid plaque
Carotid ulcerated plaque
AJNR 2010 31: 1395-1402
15
6
stenoza ocluzie
Prevalenta stenozei si ocluziei carotidiene
1.15/1000
0.46/1000
Andritoiu A, 2009N = 1295 subiecti; 40-90 ani; B 720: F 575
DD, M, 62yr- RICA stenosis (60%)
ACI inhibitor+AAS+Clopidogrel+Sortis 40 (80) mg o.dStenting vs Endarterectomy?
• HBP (175/100 mmHg)• Cholesterol 216 mg/dl• LDL-Chol 130 mg/dL• HDL-Chol 23 mg/dl• TG 168 mg/dl
• 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.
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
Plaque area
Plaque volume
3D-Reconstruction
RT- elastography of carotid plaque
Neovascularization of Atherosclerotic Arteries
Doyle, B. et al. - J Am Coll Cardiol 2007;49:2073-2080
Role of Vessel Wall Neovascularization in Plaque Growth
Contribution of Neovascularization to
Plaque Growth
Relation between neovascularization and unstable plaque
Matsumoto N 2010
The plaque neovascularization and CV risk
Staub D - Stroke 2010
CEUS-plaque neovascularization
Staub D - Stroke 2010
The plaque neovascularization and CV risk
Staub D - Stroke 2010
Carotid plaque stabilization and regression
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
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
Ainsworth CD - Stroke 2005
The plaque volume regressionAtorvastatin 80 mg/d -3Mo
Plaque volume regression is real !
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
The answer is: Yes!!!
Plaque Stabilization: Can We Turn Theory into
Evidence?
Stabilizing the Destabilized Plaque
• percutaneous intervention
• long-term antithrombotic and anticoagulant approaches
• high-dose lipid-lowering therapy