CLINICAL PRACTICE

The role of Rosuvastatin for Plaque stabilization

Angke Widya
St.Borromeus Hospital - Bandung
OUTLINE

 Introduction

 Characterization of coronary atherosclerosis plaque by

imaging modalities

 The role of RosuvaStatin for Plaque stabilization

 INTRODUCTION - CARDIOVASCULAR DISEASE

• CVDs are the number 1 cause of death globally

• An estimated 17.9 million people died from CVDs in 2016, representing 31% of all global deaths 85%
are due to heart attack and stroke.
• Over three quarters of CVD deaths take place in low- and middle-income countries..
• Most cardiovascular diseases can be prevented by addressing behavioural risk factors.
• People with cardiovascular disease or who are at high cardiovascular risk (due to the presence of one
or more risk factors such as hypertension, diabetes, hyperlipidaemia or already established disease)
need early detection and management using counselling and medicines, as appropriate.
The Cardiovascular Disease Continuum

• The basic concept of cardiovascular risk continuum was first

proposed by Dzau and Braunwald as a new paradigm for
cardiovascular disease pathogenesis.
• Cardiovascular risk-factors such as dyslipidemia, hyperten-
sion, DM, Smoking, and obesity  endothelial dysfunction 
acute myocardial infarction or chronic coronary artery disea-
se, left ventricular remodeling  heart failure death.
• Interruption of this chain of events  decrease the morbidity
and mortality associated with cardiovascular disease.
VJ Dzau et al. Circulation 2006;114: 2850-2870
The Cardiovascular Disease Continuum
The Cardiovascular Disease Continuum

 Medical treatments that target ASCVD risk factors have been

proven to reduce adverse events and mortality.
 With respect to reducing mortality, it is especially important to
elucidate the mechanisms of atherosclerotic plaque development
and to identify approaches to stabilize atherosclerotic plaque,
especially “ vulnerable plaque ”.
 Atherosclerosis Timeline

• Atherosclerosis is a chronic disease that invol-

ves the lipid accumulation and inflamma-tion
of the arterial wall.
• Despite great efforts, the pathophysiology is
not fully explained.
• Existent drugs can reduce its progression but
there are no available drugs to prevent from its
complications.
• Atherosclerosis remains the leading global
cause of death

Sacli et al. http://dx.doi.org/10.5772/intechopen.77301

Stenosis prior to myocardial infarction
Most acute coronary events result from the rupture of mildly stenotic plaques

Ahmadi et al. J Am Coll Cardiol 2019;74:1608–17

Velzen et al. Hellenic J Cardiol 2009; 50: 245-263
PLAQUE DISAPPEAR ?

Prof.Dr. Christopher Cannon:

“Making plaque disappear is not possible, but

we can shrink and stabilize it,"
The question is  do I have plaque  Vulnerable or stable
plaque ?

What is the Methods for Identification the Plaques ?

Characteristic of Vulnerable Plaque

Raber L et al. J Am Coll Cardiol Img 2019;12:1518–28

 • WHAT IS PLAQUE STABILIZATION?

• Plaque stabilization is an approach towards altering the structure,

content, or function of the plaque and/or its overlying endothelium to
either prevent or reduce the severity of plaque rupture.
• Once the plaque has disrupted/ eroded with overlying
thrombus, stabilization is possible by percutaneous coronary
intervention
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
syndrome BUT also prevent the evolution of plaques to more stenotic
lesions.
 Characterization of coronary atherosclerosis by intravascular imaging modalities
Imaging of (Vulnerable) Plaque

Invasive Techniques Non-Invasive Techniques

• Invasive coronary angiography • Multi-slice Spiral CT (MSCT)

• intravascular ultrasound ( IVUS) • Magnetic Resonance Imaging ( MRI )
• Virtual histology intravascular ultrasound
(VH IVUS)
• Optical coherence tomography (OCT)
• Intra Coronary angioscopy.
• Intravascular ultrasound palpography
 Characterization of coronary atherosclerosis by
intravascular imaging modalities

• Among all imaging techniques, IVUS and OCT  the closet information to match 
the histology of atherosclerotic plaques.

• Invasive and High cost of these techniques limit their widespread use

• Less Invasive techniques, are more appropriate for prevention or screening purposes

Saremi et al, AJR 2015;204: W249-W260

Coronary Angiography ( CAG )

Coronary angiography is the traditional

gold standard for atherosclerotic plaque
assessment,its assessment is based on
the imaging of arterial lumen stenosis,.

CAG generates a 2-D silhouette of the

arterial lumen and does not image the
vessel wall, the site at which plaque
accumulates.

Dave, et al. Indian Journal of Endocrinology and Metabolism / Nov-Dec 2013 / Vol 17 | Issue 6
IVUS - Plaque type characterization

Attenuated plaque :
correlate with a fibroatheroma containing large necrotic core, with a large lipid pool. Attenuated plaque is
frequently observed at culprit lesion in patients with acute coronary syndrome (ACS)
Echolucent plaque :
a fibroatheroma, but relatively smaller size of necrotic core or lipid pool, culprit lesions in patients with
acute myocardial infarction
Honda, et al. Cardiovasc Diagn Ther 2016;6(4):368-381
IVUS - Plaque type characterization

• Calcified nodule
• Spotty calcification
• Multiple layer appearance

Honda, et al. Cardiovasc Diagn Ther 2016;6(4):368-381

IVUS images – Atheroma area, Remodeling

Nissen SE et al, JAMA 2004 :291: 1071-1080

Virtual Histology IVUS images

Velzen et al. Hellenic J Cardiol 2009; 50: 245-263

 OCT - Plaque type characterization

 A coronary atheromatous plaque becomes unstable on exhibiting a large necrotic lipid

core and a thin fibrotic cap, which is invaded by macrophages.
 Enlargement of the vessel diameter at the site of the plaque and the presence of spotty
calcifications within the plaque.
 It has an excellent spatial resolution of 10-20 µm, which is ten times higher than the
resolution of IVUS ( 100-250 µm )

 OCT is the technique of choice for the measurement of fibrous cap thickness,
assessment of macrophage content and visualization of intracoronary thrombus.
Benedect et al, Journal of Cardiovascular Emergencies 2016;2(4):173-184
Velzen et al. Hellenic J Cardiol 2009; 50: 245-263
OCT - Plaque type characterization

S. Takarada et al. / Atherosclerosis 202 (2009) 491–497

Benedect et al, Journal of Cardiovascular Emergencies 2016;2(4):173-184

COMPUTED TOMOGRAPHIC ANGIOGRAPHY/ MSCT

Two different CT-scan protocols  the assessment of coronary atherosclerosis

Noncontrast CT-scan Coronary CT Angiography/CCTA

CAC score (CACS)

• Luminal stenoses,
 CAC volume • Plaque characteristics, and
 CAC density • Plaque volume.

Cardiovascular events Aengevaeren et al,Circulation. 2020;141:1338–1350

 Coronary artery calcification score - CACS

• Calcification of the coronary arteries and other vascular structures appears to be a

regulated process of mineral deposition, akin to bone formation.
• Noninvasive and invasive imaging modalities, several recent studies have identified
select characteristics of CAC  associated with a lower risk of CVD
• These characteristics  the density of CAC, the pattern of calcification within a plaque,
and the proportion of atherosclerotic plaque that is calcified
• These findings support CAC as a robust, noninvasive surrogate measure of
noncalcified atherosclerosis of the coronary arteries.

Thomas et al. Clinical Cardiology. 2018;41:144–150

 Coronary artery calcification score - CACS

• Calcification of the coronary artery is a complex pathophysiologic process that is

intimately associated with atherosclerosis.
• Early pathologic studies showed CACS to correlate closely with the presence and
extent of atherosclerotic plaque
• More recent in vivo studies  found both high levels of CAC and progression of CAC
to be associated with cardiovascular disease (CVD).
• Early pathologic studies showed CACS to correlate closely with the presence and
extent of atherosclerotic plaque
a progression from a CAC score of zero to a positive CAC score, the score increasing by :
0.5% in the first year, 1.2% in the second year, 5.7% in the third year, 6.2% in the fourth year, and
11.6% in the fifth year
Thomas et al. Clinical Cardiology. 2018;41:144–150
 Coronary artery calcification score - CACS

Absolute CAC Degree of coronary Clinical interpretation

score Score
(Agatston ) artery calcification
0 • No identifiable plaque/absent
0 • Very low risk of future coronary events

1-100 • Discrete 1-100 • Low risk of future coronary events

101-400 • Moderate 101-400 • Increased risk of future

coronary events
> 400 • Accentuated > 400 • Increased probability of
myocardial ischemia
a progression from a CAC score of zero to a positive CAC score, the score increasing by :
0.5% in the first year, 1.2% in the second year, 5.7% in the third year, 6.2% in the fourth year, and
11.6% in the fifth year

Neves PO et al,Radiol Bras. 2017 Mai/Jun;50(3):182–189

CORONARY CT ANGIOGRAPHY / CTA

Plaque characteristics

Calcified plaque Noncalcified plaque mixed plaque

Aengevaeren et al, Circulation. 2020;141:1338–1350

MSCT, VH-IVUS, IVUS, ICA
Coronary plaques in the culprit vessel UAP Px

Pundziute et al. European Heart Journal (2008) 29, 2373–2381

MSCT, VH-IVUS, IVUS, ICA
Coronary plaques in the culprit vessel UAP Px

These observations further

support the hypothesis of a
pan-coronary distribution
of vulnerable plaques

Pundziute et al. European Heart Journal (2008) 29, 2373–2381

MSCT, VH-IVUS, IVUS, ICA
Coronary plaques in the culprit vessel UAP Px

Pundziute et al. European Heart Journal (2008) 29, 2373–2381

 The Plaque Characteristics
COMPUTED TOMOGRAPHIC ANGIOGRAPHY/ MSCT

High Risk Plaque features

identified :
• Positive remodeling,
• Low Hounsfield Unit (HU)
attenuation ( < 30 HU )
• Napkin-ring sign (NRS),
and
• Spotty calcium

MSCT 64 MDCT
 Sensitifitas 94 %
 Spesifisitas 97% L
 NPV 99%
 PPV 87%
comprising a necrotic core covered by a thin cap fibro-atheroma
 The Characteristics of Culprit lesion in ACS
COMPUTED TOMOGRAPHIC ANGIOGRAPHY

The CT characteristics of culprit lesions in ACS include :

• positive vessel remodeling (PR) and
• low-attenuation plaques (LAP). Moyotama, J Am Coll Cardiol 2009;54:49–57
The Characteristics of Culprit lesion in ACS
COMPUTED TOMOGRAPHIC ANGIOGRAPHY

Moyotama, J Am Coll Cardiol 2009;54:49–57

The Characteristics of Culprit lesion in ACS
COMPUTED TOMOGRAPHIC ANGIOGRAPHY

Moyotama, J Am Coll Cardiol 2009;54:49–57

HOW IS ROLE OF INFLAMMATION MARKER ?

Inflammation has been recognized to play an important role in both the initiation and
progression of coronary artery disease  

Several prospective studies  plasma high sensitivity C-reactive protein (hsCRP)

levels,  are a powerful predictor of future myocardial infarction (MI) and cardiac
death among appar ently healthy individuals

The high hsCRP levels have also been reported to be associated with an increased risk of
further coronary events in patients with CAD  

Plasma hsCRP levels were found to be associated with the presence and extent of
coronary stenosis in patients with stable CAD.  
Taniguchi et all. Atherosclerosis 178 (2005) 173–177
VULNERABLE PATIENTS

M. Tomaniak et al. European Heart Journal (2020) 0, 1–10

 Cardiovascular risk for every people
(2019 ESC/EAS Guidelines for the management of dyslipidemias : lipid modification to reduce cardiovascular risk)

Very-high risk People with any of the following:

Documented ASCVD, either clinical or unequivocal on imaging. Documented ASCVD includes previous ACS (MI or unstable angina), stable
angina, coronary revascularization (PCI, CABG, and other arterial revascularization procedures), stroke and TIA, and peripheral arterial
disease. Unequivocally documented ASCVD on imaging includes those findings that are known to be predictive of clinical events, such as
significant plaque on coronary angiography or CT scan (multivessel coronary disease with two major epicardial arteries having >50%
stenosis), or on carotid ultrasound.
DM with target organ damage, or at least three major risk factors, or early onset of T1DM of long duration (>20 years).
Severe CKD (eGFR <30 mL/min/1.73 m2)
A calculated SCORE ≥10% for 10-year risk of fatal CVD
FH with ASCVD or with another major risk factor

High-risk People with:

Markedly elevated single risk factors, in particular TC >8 mmol/L (>310 mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or BP ≥180/110
mmHg.
Patients with FH without other major risk factors.
Patients with DM without target organ damage, with DM duration ≥10 years or another additional risk factor.
Moderate CKD (eGFR 30-59 mL/min/1.73 m2)
A calculated SCORE ≥5% and <10% for 10-year risk of fatal CVD.

Moderate-risk Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors.
Calculated SCORE ≥1 % and <5% for 10-year risk of fatal CVD
Low-risk Calculated SCORE <1% for 10-year risk of fatal CVD

ESC/EAS Guidelines, 2019

HOW CAN PLAQUE STABILIZE ?
Current treatments and future perspectives of plaque stabilization

• Plaque stabilization can be achieved by increasing thickness of

fibrous cap, reducing inflammation in the fibrous cap, and
reducing size of atheromatous core. 

Statin
Pleiotropic effect of Statins

Plaque Stability

Anti-Inflammatory
STATIN
Proportional effects on cause-specific mortality
per 1 mmol/L ( 38.67 mg/dl ) LDL cholesterol reduction

Lancet 2005; 366: 1267–78

The Role of High Intensity Statin

Grundy et al. JACC VOL. 73, No. 24, 2019

The Role of High Intensity Statin

• Numerous large-scale clinical trials have demonstrated anti-

atherosclerotic effects of 3-hydroxy-3-methylglutaryl coenzyme A reduc-
tase inhibitors or Statins for the primary and secondary prevention.
• Statin has the ability to reduce atherosclerotic cardiovascular events and
attenuate disease progression.
• In addition, high-intensity statin has the potential to regress coronary
atheroma in patients with CAD.

Honda,et al. Cardiovasc Diagn Ther 2016;6(4):368-381

The Role of High Intensity Statin
Intensive vs Moderate Statins After Acute Coronary Syndromes 

Each 10% reduction in LDL-C level (15 mg/dL)

approximately  1% reduction in the change in
atheroma volume after 18 months.

REVERSAL study Nissen SE et al. JAMA. 2004;291:1071-1080

The Role of High Intensity Statin
Intensive vs Moderate Statins After Acute Coronary Syndromes 

95 mg/dl

62 mg/dl

PROVE IT–TIMI 22 Canon CP et al,. N Engl J Med 2004;350:1495-504

IVUS STUDIES EXAMINING THE IMPACT OF STATIN THERAPY ON
PLAQUE PROGRESSION/REGRESSION

ASTEROID study COSMOS study japan

- 0.79
- 53.2

130.4

60.8

Takata K et al. Cardiovasc Diagn Ther 2016;6(4):304-321

Takayama T et al. Circ J 2009; 73: 2110 – 2117
 IVUS STUDIES EXAMINING THE IMPACT OF STATIN THERAPY ON
PLAQUE REGRESSION
ASTEROID study

In ASTEROID (western patients), a – 53.2% reduction in LDL-C (to 60.8 ± 20.0

mg/dl) elicited by very high-intensity Rosuvastatin 40 mg/day was accompanied
by a reduction in plaque volume of – 6.7±11.1%.

COSMOS study japan In COSMOS (japan), the results were –38.6% (to 82.9±18.7 mg/dl) elicited by
Rosuvastatin ≤ 20 mg/day and a reduction in plaque volume of – 5.1±14.1%.

Comparable regression of plaque volume with less reduction of LDL-C.

Takata K et al. Cardiovasc Diagn Ther 2016;6(4):304-321
Takayama T et al. Circ J 2009; 73: 2110 – 2117
IVUS STUDIES EXAMINING THE IMPACT OF STATIN THERAPY ON
PLAQUE PROGRESSION/REGRESSION

Nicholls SJ et al. N Engl J Med 2011;365:2078-87.

The Role of Rosuvastatin for Inflammation – JUPITER study
JUPITER investigators :
randomly allocated 11 001 men and 6801 women who
had hsCRP levels 2 mg/L (median 4.2 mg/L) and LDL
cholesterol levels 130 mg/dL (median 108 mg/dL) to either rosuvastatin
20 mg or to placebo. The JUPITER trial was stopped early 1.9 years

RidkerPM.Circ Cardiovasc Qual Outcomes. 2009;2:279-285

The Role of Rosuvastatin for plaque stabilization – ALTAIR study
Effect of Rosuvastatin 2.5 mg vs 20 mg

• high-dose and low-dose rosuvastatin increased plaque stability.

• high-dose rosuvastatin was more effective than lowdose rosuvastatin in
inducing plaque volume regression.
Takayama T, http://dx.doi.org/10.1016/j.amjcard.2016.01.013
Changes in Coronary Plaque Composition in Patients With Acute Myocardial Infarction
Treated With High-Intensity Statin Therapy (IBIS-4)

At 13 months, median LDL decreased from 128 mg/dl to 73.6 mg/dl .

In patients with STEMI treated with high-intensity statin, we found:

• modest but significant increase in FCT
• reduction in macrophage accumulation
Raber L et al. J Am Coll Cardiol Img 2019;12:1518–28
What do the guideline recommend ?
(2019 ESC/EAS Guidelines for the management of dyslipidemias : lipid modification to reduce cardiovascular risk)

ESC/EAS Guidelines, 2019

 Summary

• Atherosclerosis is a systemic disorder that begins early in life and represents a chronic process, with
gradual accumulation of plaque during the course of decades, before its clinical onset in middle age.

• The ultimate progression of atherosclerotic plaque to either flow limiting vascular obstruction (CCS)
or acute exposure (ACS ).

• Non-invasive imaging offers the potential as a screening tool to identify plaques with features of
vulnerability, indicating patients at increased cardiovascular risk.

• It is well known that lowering the LDL-C level with statin is useful in both the primary and secondary
prevention of cardiovascular events.

• Statins have favorable pleiotropic effects on atherosclerosis, including a reduction in lipid volume,
anti-inflammatory activity, and improvement of endothelial function.
 Summary

• Various imaging modalities (IVUS,OCT, Coronary CT angiography) demonstrated that statin

therapies attenuate plaque progression and strengthen plaque stability.

• Difference in the degree and pattern of regression exerted by various statins could be attributed to
differences in plaque tissue characteristics and the patient’s treatment history.

• Changes in plaque volume and lumen volume achieved by statin treatment are greatly influenced
by baseline vascular conditions

• Further reduction of LDL-C with rosuvastatin could induce significant atheroma regression,
supporting
“the lower the better”
• Regressive effect of rosuvastatin on plaque volume is mediated not simply by LDL-C reduction, but by
multiple mechanisms”
THANK YOU