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