Vulnerable plaques

The majority of coronary thrombi (∼75%) is caused by plaque rupture.1,2 Prototype of the rupture-prone plaque contains a large, soft, lipid-rich necrotic core with a thin and inflamed fibrous cap, so-called thin-cap fibroatheroma (TCFA) (Figure 1).3,4 Other common features include expansive remodelling, large plaque size, plaque haemorrhage, neovascularization, adventitial inflammation, and ‘spotty’ calcifications.4 Thin-cap fibroatheroma caps are usually <65 µm thick.4Figure 2 summarizes factors contributing to the formation of vulnerable plaques. No distinct morphological features have been identified for the erosion-prone plaques, but they are usually rarely associated with expansive remodelling, scarcely calcified, and contain only limited inflammation.2,5

Figure 1

Cross-sectioned coronary artery showing a ruptured thin-cap fibroatheroma. The fibrous cap is very thin near the rupture site (between arrows) and a non-obstructive mural thrombus (asterisks) is bordering the gap in the disrupted cap. A haemorrhage has penetrated from the lumen through the gap into the lipid-rich necrotic core in which the characteristic cholesterol clefts are clearly seen. The lumen contains contrast medium injected postmortem. Overview in inset. Trichrome, staining collagen blue, and thrombus and haemorrhage red.

Figure 1

Cross-sectioned coronary artery showing a ruptured thin-cap fibroatheroma. The fibrous cap is very thin near the rupture site (between arrows) and a non-obstructive mural thrombus (asterisks) is bordering the gap in the disrupted cap. A haemorrhage has penetrated from the lumen through the gap into the lipid-rich necrotic core in which the characteristic cholesterol clefts are clearly seen. The lumen contains contrast medium injected postmortem. Overview in inset. Trichrome, staining collagen blue, and thrombus and haemorrhage red.

Figure 2

Factors contributing to the formation of vulnerable plaques. MCP-1, monocyte chemotactic protein-1; MIF, migration inhibitory factor; TNFα, tumour necrosis factor-α; ILs, interleukins; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases; PDGFs, platelet-derived growth factors; VEGFs, vascular endothelial growth factors; FGFs, fibroblast growth factors; Mφ, macrophages.

Figure 2

Factors contributing to the formation of vulnerable plaques. MCP-1, monocyte chemotactic protein-1; MIF, migration inhibitory factor; TNFα, tumour necrosis factor-α; ILs, interleukins; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases; PDGFs, platelet-derived growth factors; VEGFs, vascular endothelial growth factors; FGFs, fibroblast growth factors; Mφ, macrophages.

Inflammatory cells, cytokines, chemokines, and growth factors

Vulnerable plaques contain monocytes, macrophages, and T-cells. Of the T-cells, CD4+ T-helper (Th) cells are the most prominent.6 T-cells can differentiate into a Th1 phenotype, which secretes and responds to IFN-γ or a Th2 phenotype, which secretes and responds to IL-4, IL-10, and IL-13 (Figure 3). T-cells promote the vulnerability of plaques through their effects on macrophages. Similarly, there are two main plaque macrophage phenotypes: pro-inflammatory M1 macrophages (IFN-γ-induced) and anti-inflammatory or regulatory M2 macrophages (IL-4/IL-13-induced).7

Figure 3

Diverse leucocyte populations in atherosclerotic plaques. Depending on the context of antigen presentation including the cytokine environment, naïve T-cells and macrophages may adopt several phenotypes that are more or less inflammatory. Polarization of the environment is promoted by the positive and negative interactions indicated. Th1, Th2, Treg: T-cell subtypes; M1, M2a, M2c: macrophage subtypes.

Figure 3

Diverse leucocyte populations in atherosclerotic plaques. Depending on the context of antigen presentation including the cytokine environment, naïve T-cells and macrophages may adopt several phenotypes that are more or less inflammatory. Polarization of the environment is promoted by the positive and negative interactions indicated. Th1, Th2, Treg: T-cell subtypes; M1, M2a, M2c: macrophage subtypes.

Cytokines and chemokines important for regulating inflammatory and immune responses are listed in Supplementary material online, Table S1.7–11 The concept that Th1-related pro-inflammatory cytokines drive progression whereas Th2- and regulatory T-cell-related cytokines exert anti-atherogenic effects provides a useful theoretical framework (Figure 3). For an unstable phenotype, IFN-γ, IL-12, and IL-18 seem to be important factors. CCR5 drives Th1-type pro-inflammatory responses and contributes to plaque formation.12 Important players for plaque destabilization are macrophage migration inhibitory factor (MIF)13 and monocyte chemotactic protein-1.14 Of the plaque-stabilizing factors, IL-10 and TGF-β are of the greatest significance.11,15

Extracellular proteases and platelets

Extracellular proteases correlate with changes associated with plaque vulnerability,16 such as macrophage ingress and apoptosis, and loss of collagen and elastin.17,18 Apoptosis of SMCs contributes to weakening of plaques. Knockout models supported a role for matrix metalloproteinases (MMPs)19 and cathepsins20 in plaque rupture, although the effects of MMP inhibitors on plaque stability have been mixed. Recent studies with more selective drugs21 provide new hope that inhibiting proteases or preventing their secretion19 may lead to plaque stabilization.

Platelets contribute to atherogenesis through secretory functions and as modulators of inflammatory responses. Antiplatelet drugs might, therefore, serve as plaque-stabilizing compounds. However, experimental data on antiplatelet drugs are contradictory.22–25 Although antiplatelet drugs have proven benefits in the secondary prevention of CVD, their direct role in plaque stabilization remains unclear.

Endothelial dysfunction, wall stress, and shear stress

Impairment in endothelium-dependent vasodilatation is the clinical hallmark of endothelial dysfunction.26 In atherosclerosis, there is coexistence of segments with normal vasodilatory and abnormal vasoconstrictive responses to acetylcholine. In virtual histology (VH)-intravascular ultrasound (IVUS), segments with endothelial dysfunction have larger plaques and necrotic core areas.27 Under sympathetic activity, dysfunctional endothelium will respond with paradoxical vasoconstriction. The release from platelets of peptides, in particular serotonin and thrombin, leads to further vasoconstriction and perpetuation of the situation.28–31

Shear stress plays a key role during initiation of atherosclerosis.32,33 Recent studies indicate that it also predicts location of advanced lesions.34 Repeated measurements indicate that low shear stress is predictive of not only plaque location, but also of plaque growth.35,36 Role of wall stress in plaque rupture has been increasingly recognized, since it seems to predict plaque rupture better than shear stress.37 The levels of these forces inducing rupture are in the order of ∼150 kPa or ∼1100 mmHg, which have been shown to occur at the shoulder regions.37 In the PREDICTION trial, large plaque burden and low local endothelial shear stress provided independent and additive prediction to identify plaques that develop progressive enlargement and lumen narrowing.38

Angiogenesis

Microvessels increase with plaque progression, are abundant in vulnerable plaques,39 and can contribute to plaque inflammation.40 Fragile microvessels allow extravasation of lipoproteins and red blood cells,41 which contribute to plaque lipids. Whether haemorrhage from neovessels triggers plaque rupture (or vice versa) remains to be demonstrated. Mechanisms regulating plaque angiogenesis involve hypoxia-inducible factor and growth factors, such as VEGFs, PlGF, PDGFs, and FGFs.42 However, the net effect of all these regulators remains unclear. While VEGF is expressed in atherosclerotic lesions,43 patients receiving anti-VEGF antibodies for cancer show increased CVD complications. This finding is compatible with vasculoprotective effect of VEGF, and transient treatment of mice with VEGF has not increased atherosclerosis.44 Whether therapeutic manipulation of angiogenesis can stabilize plaques remains to be investigated.45

Progenitor cells

Clinical studies show correlations of endothelial progenitor cells (EPCs) with atherogenesis,46 suggesting that EPCs may provide protection against atherosclerosis. Recent data, however, question these findings: putative EPCs measured in the clinics have generated mostly inflammatory cells rather than endothelial cells.47 Also, mouse studies tracking endothelial origin in atherogenesis have found rare, if any, contributions from the blood.48

Smoking

Smoking is a major CVD risk factor causing endothelial damages, disturbances in coagulation, and inflammation.49 Stopping smoking is beneficial for plaque stabilization.

Biomarkers, genetic testing, and imaging in the detection of unstable plaques

Biomarkers and genetic testing

Single nucleotide polymorphism and GWAS studies have identified approximately 160 genetic loci that are associated with CVD, MI, and restenosis.50,51 However, there are no data to pinpoint specific genetic signatures to the vulnerable plaque. Although a genetic test to identify patients who carry vulnerable plaques is the ultimate goal, this seems currently unlikely. It seems clear that part of the gene–environment interactions are regulated by epigenetics.52 As chromatin alterations are reversible, epigenetic modifications are amendable to pharmacological interventions, which may provide new treatments for CVD.

Detection of unstable plaques

Plaque burden correlates well with calcification, but is not an indicator of stability. Computerised tomography shows that lesion area in ruptured plaques is larger than in stable lesions.53 Using IVUS, it was found that patients with acute MI had larger plaque area compared with patients with unstable or stable angina. VH-IVUS allows classification of lesions as fibrous, fibrocalcific, fibroatheroma, and TCFAs.54 The definition of IVUS-derived TCFA is a lesion with plaque burden ≥40% and confluent necrotic core ≥10% in direct contact with lumen. VH-IVUS identified the following characteristics as predictors of clinical events5: TCFA, plaque burden ≥70%, and minimum lumen area ≤4 mm2. However, even combining these characteristics resulted in only 18% event rate during 3 years, which illustrates current limitations of imaging techniques.

Optical coherence tomography (OCT) gives a spatial resolution of ≤20 µm allowing more accurate assessment of cap thickness (Figure 4).55 Optical coherence tomography has potential to assess plaque macrophage content. In non-flow-limiting coronary lesions, high-risk plaque characteristics (such as thin fibrous cap, large lipid pools, and microchannels) were associated with plaque progression.56 NIR spectroscopy is another technique designed to identify lipid-containing plaques.57 Emerging imaging techniques utilize MRI markers homing to rupture-prone plaques and markers of macrophage metabolic activity.58 Developing such techniques remains a challenge for the future.59

Figure 4

Serial and corresponding virtual histology and optical coherence tomography. (A) The baseline optical coherence tomography frame (top), the corresponding virtual histology frame (mid), and the quantification of the virtual histology tissue types (bottom). The optical coherence tomography frame shows from 8 to 12 o'clock a fibroatheroma which is composed of a fibrous cap (white arrow) and a necrotic core (asterisk). The corresponding virtual histology frames show also a fibroatheroma (necrotic core-rich plaque in red colour). In (B), the patient was reimaged at 1 year and some plaque changes have been observed. In the optical coherence tomography frame, the fibrous cap became thinner (please note that at baseline, the signal rich area overlying the necrotic core was wider).

Figure 4

Serial and corresponding virtual histology and optical coherence tomography. (A) The baseline optical coherence tomography frame (top), the corresponding virtual histology frame (mid), and the quantification of the virtual histology tissue types (bottom). The optical coherence tomography frame shows from 8 to 12 o'clock a fibroatheroma which is composed of a fibrous cap (white arrow) and a necrotic core (asterisk). The corresponding virtual histology frames show also a fibroatheroma (necrotic core-rich plaque in red colour). In (B), the patient was reimaged at 1 year and some plaque changes have been observed. In the optical coherence tomography frame, the fibrous cap became thinner (please note that at baseline, the signal rich area overlying the necrotic core was wider).

Current treatments and future perspectives of plaque stabilization

Statin therapy

Patients receiving pravastatin 3 months before carotid endarterectomy showed significantly less inflammation and a higher collagen content in carotid plaques, suggesting plaque stabilization.60 The ATROCAP study randomized two-step bilateral carotid endatherectomy patients to atorvastatin or placebo for 4–6 months after the first procedure. Plaques from treated patients showed a trend towards fewer inflammatory cells, whereas no change was observed in controls.61 Results are consistent with pleiotropic, anti-inflammatory effects of statins, which may contribute to the stabilization of plaques.62 Recent experimental finding of plaque stabilization with ezetimide, which lacks pleiotropic effects, lends support to the lipid-lowering therapy per se.63 However, it is not yet possible to discern the contribution of each mechanism to clinical results.

The German Atorvastatin Study demonstrated that hyperechogenicity of plaques significantly increased after 12 months compared with non-statin-based lipid lowering.64 In the ASTEROID65 and SATURN studies,66 aggressive lipid lowering regressed atheroma volume in IVUS. Data from several prospective IVUS trials confirmed significant atheroma regression after LDL reduction67 and the PROVE-IT trial showed lower CVD endpoints after 24 months under intense lipid lowering in ACS patients.68 In addition, the JUPITER study in healthy subjects with LDL <3.4 mmol/L and hs-C-reactive protein above 2 mg/L showed that 20 mg of rosuvastatin significantly reduced major CVD events in this low-risk group.69

Antiplatelet and antihypertensive therapies

Aspirin is effective for CVD secondary prevention, and a major reduction in CVD events was found in the CURE trial, where clopidogrel was added to aspirin in ACS patients.70 However, these agents mostly reduce complications of plaque rupture and may not be plaque-stabilizing agents per se. Whether new platelet inhibitors ticagrelor and prasugrel and platelet thrombin receptor inhibitor vorapaxar have plaque-stabilizing properties remains unknown, although recent meta-analyses have suggested the same benefits in patients with recent ACS.71

Four recent IVUS trials have shown that β-blockers slow the progression of CVD.72 Endothelial function can be improved by renin–angiotensin inhibitors, and HOPE73 and ONTARGET74 trials have shown a larger reduction in CVD events that could be predicted from the reduction in blood pressure, supporting plaque-stabilizing effects.

Other anti-atherosclerotic therapies

HDL-raising therapies

ApoA1-Milano and other HDL-like apoA1 complexes have been shown to regress atherosclerosis possibly via several HDL-related protective mechanisms like reverse cholesterol transport, anti-oxidative activity, endothelial vasoprotection, and reduction of platelet activation.75 HDL also inhibits coagulation cascade. Cholesterol ester transfer protein (CETP) is a plasma protein that catalyses exchange of cholesteryl esters and triglycerides between lipoproteins. Reduction in CETP activity is associated with cholesterol reduction in VLDL and LDL and enrichment of HDL. However, the ILLUMINATE trial with a CETP inhibitor torcetrapib failed due to toxicity.76 New trials with novel CETP inhibitors such as anacetrapib (Supplementary material online, Table S2) are underway, but dal-OUTCOMES trial assessing dalcetrapib has been stopped due to the lack of efficacy.77 Thus, these recent trials and a large Mendelian randomization study78 question the usefulness of HDL-raising therapies, if no simultaneous beneficial changes can be achieved in VLDL or LDL levels.

Niacin/nicotinic acid

With interest in HDL-raising therapies, niacin has been recently re-investigated. Two trials in statin-treated patients with low HDL have shown that modified-release nicotinic acid significantly reduced carotid atherosclerosis,79 and that the use of slow-release niacin significantly reduced carotid intima-media thickness in comparison with statin.80 However, AIM-HIGH and HPS-2-THRIVE trials failed to show any added benefits (Supplementary material online, Table S2), which raises doubts about the usefulness of this approach.

Phospholipase inhibitors

Another approach to reduce plaque inflammation is to inhibit lipoprotein-associated phospholipase A2, which has prevented increase in necrotic core when compared with placebo.81 Two major trials testing this approach are now ongoing (STABILITY and SOLID-TIMI 52 trials).

New approaches

Antagonists against pro-atherogenic chemokine receptor CCR5 and its ligand CCL5 have been developed.82 Migration inhibitory factor is involved in atheroprogression and its inhibition with biologicals or small molecules may be useful for plaque stabilization.13

PCSK9 is involved in hypercholesterolaemia by favouring degradation of LDL receptor.83 Some natural PCSK9 mutations increase its function and cause hypercholesterolaemia, whereas loss-of-function mutations cause hypocholesterolaemia. Therefore, PCSK9 is an attractive target for lowering plasma LDL with potential plaque-stabilizing features. The ODYSSEY OUTCOMES trial is now testing the efficacy of PCSK9 inhibitor in CVD (Supplementary material online, Table S2).

siRNAs against apoB100 have been used to reduce LDL levels.84 Whether this technology will be useful in the prevention of plaque ruptures remains unknown. Innate and adaptive immunity regulates pro-atherogenic inflammation. Immunization of hyperlipidaemic animals with LDL preparations or apoB100 fragments reduces atherosclerosis, suggesting that vaccination may become a potential strategy for the prevention of CVD.85,86

Key points (adapted from Ylä-Herttuala et al.1)

  • Vulnerable plaques are prone to rupture and thrombosis. Two types of vulnerable plaques are rupture-prone and erosion-prone. Prototype of the rupture-prone plaque contains large and soft lipid-rich necrotic core covered by thin and inflamed fibrous cap.

  • Thin-cap fibroatheroma: If the fibrous cap is thin, the plaque is called TCFA. Thin fibrous caps are usually heavily inflamed.

  • Plaque stabilization can be achieved by increasing thickness of fibrous cap, reducing inflammation in the fibrous cap, and reducing size of atheromatous core. Plaques may be stabilized against thrombosis independent of changes in plaque size and luminal obstruction.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This study was supported by ESC Working Group of Atherosclerosis and Vascular Biology.

Conflict of interest: I.H. has received research grants from NWO, CTMM, BMM, and TI Pharma. J.W.J. has received grants from Astellas, Astra-Zeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Genzyme, Medtronic, MSD, Pfizer, Orbus Neich, Novartis, Roche, Servier, Sanofi-Aventis, the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework FP7 Programme. R.K. has received grants from the Netherlands and British Heart Foundations, the CTMM, the BBSRC and EPSRC, the FP7 Programme, and Johnson & Johnson. B.R.K. has received grants from the Swiss National Science Foundation, Fondation Leenaards, and the Fondation Prevot. N.M. has received research grants from Boehringer Ingelheim, GSK, MSD, and Takeda. A.N. has received grants from the British Heart Foundation and the UK National Institute for Health Research. He is also consultant for PlaqueTec. G.P. is a co-founder of Cavadis. C.W. is a shareholder of Carolus Therapeutics, Inc. S.Y.-H has received grants from the Academy of Finland, the Finnish Heart Foundation, and EU FP7 programme grants CliniGene, Baculogenes, BIOMAGSCAR, and BAMI.

Acknowledgements

The invaluable help of Ms Marja Poikolainen in preparing the manuscript is greatly acknowledged.

References

1
Ylä-Herttuala
S
Bentzon
J
Daemen
M
Falk
E
Garcia-Garcia
H
Herrmann
J
Hoefer
I
Jukema
W
Krams
R
Kwak
B
Marx
N
Naruszewicz
M
Newby
A
Pasterkamp
G
Serruys
P
Waltenberger
J
Weber
C
Tokgözoglu
L
Opinion paper, European Society of Cardiology, Working Group of Atherosclerosis and Vascular Biology: stabilisation of atherosclerotic plaques
Thromb Haemost
 , 
2011
, vol. 
106
 (pg. 
1
-
19
)
2
Schaar
JA
Muller
JE
Falk
E
Virmani
R
Fuster
V
Serruys
PW
Colombo
A
Stefanadis
C
Ward Casscells
S
Moreno
PR
Maseri
A
van der Steen
AF
Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece
Eur Heart J
 , 
2004
, vol. 
25
 (pg. 
1077
-
1082
)
3
Falk
E
Shah
PK
Fuster
V
Coronary plaque disruption
Circulation
 , 
1995
, vol. 
92
 (pg. 
657
-
671
)
4
Kolodgie
FD
Burke
AP
Farb
A
Gold
HK
Yuan
J
Narula
J
Finn
AV
Virmani
R
The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes
Curr Opin Cardiol
 , 
2001
, vol. 
16
 (pg. 
285
-
292
)
5
Stone
GW
Maehara
A
Lansky
AJ
de Bruyne
B
Cristea
E
Mintz
GS
Mehran
R
McPherson
J
Farhat
N
Marso
SP
Parise
H
Templin
B
White
R
Zhang
Z
Serruys
PW
A prospective natural-history study of coronary atherosclerosis
N Engl J Med
 , 
2011
, vol. 
364
 (pg. 
226
-
235
)
6
Hansson
GK
Hermansson
A
The immune system in atherosclerosis
Nat Immunol
 , 
2011
, vol. 
12
 (pg. 
204
-
212
)
7
Martinez
FO
Helming
L
Gordon
S
Alternative activation of macrophages: an immunologic functional perspective
Annu Rev Immunol
 , 
2008
, vol. 
27
 (pg. 
451
-
483
)
8
Kleemann
R
Zadelaar
S
Kooistra
T
Cytokines and atherosclerosis: a comprehensive review of studies in mice
Cardiovasc Res
 , 
2008
, vol. 
79
 (pg. 
360
-
376
)
9
Zernecke
A
Weber
C
Chemokines in the vascular inflammatory response of atherosclerosis
Cardiovasc Res
 , 
2010
, vol. 
86
 (pg. 
192
-
201
)
10
Ait-Oufella
H
Taleb
S
Mallat
Z
Tedgui
A
Recent advances on the role of cytokines in atherosclerosis
Arterioscler Thromb Vasc Biol
 , 
2011
, vol. 
31
 (pg. 
969
-
979
)
11
Tedgui
A
Mallat
Z
Cytokines in atherosclerosis: pathogenic and regulatory pathways
Physiol Rev
 , 
2006
, vol. 
86
 (pg. 
515
-
581
)
12
Potteaux
S
Combadière
C
Esposito
B
Lecureuil
C
Ait-Oufella
H
Merval
R
Ardouin
P
Tedgui
A
Mallat
Z
Role of bone marrow-derived CC-chemokine receptor 5 in the development of atherosclerosis of low-density lipoprotein receptor knockout mice
Arterioscler Thromb Vasc Biol
 , 
2006
, vol. 
26
 (pg. 
1858
-
1863
)
13
Zernecke
A
Bernhagen
J
Weber
C
Macrophage migration inhibitory factor in cardiovascular disease
Circulation
 , 
2008
, vol. 
117
 (pg. 
1594
-
1602
)
14
Ylä-Herttuala
S
Lipton
BA
Rosenfeld
ME
Särkioja
T
Yoshimura
T
Leonard
EJ
Witztum
JL
Steinberg
D
Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions
Proc Natl Acad Sci USA
 , 
1991
, vol. 
88
 (pg. 
5252
-
5256
)
15
Potteaux
S
Esposito
B
van Oostrom
O
Brun
V
Ardouin
P
Groux
H
Tedgui
A
Mallat
Z
Leukocyte-derived interleukin 10 is required for protection against atherosclerosis in low-density lipoprotein receptor knockout mice
Arterioscler Thromb Vasc Biol
 , 
2004
, vol. 
24
 (pg. 
1474
-
1478
)
16
Dollery
CM
Libby
P
Atherosclerosis and proteinase activation
Cardiovasc Res
 , 
2006
, vol. 
69
 (pg. 
625
-
635
)
17
Sluijter
JP
de Kleijn
DP
Pasterkamp
G
Vascular remodeling and protease inhibition—bench to bedside
Cardiovasc Res
 , 
2006
, vol. 
69
 (pg. 
595
-
603
)
18
Sluijter
JPG
Pulskens
WPC
Schoneveld
AH
Velema
E
Strijder
CF
Moll
F
de Vries
JP
Verheijen
J
Hanemaaijer
R
de Kleijn
DP
Pasterkamp
G
Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms
Stroke
 , 
2006
, vol. 
37
 (pg. 
235
-
239
)
19
Newby
AC
George
SJ
Ismail
Y
Johnson
JL
Sala-Newby
GB
Thomas
AC
Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes
Thromb Haemost
 , 
2009
, vol. 
101
 (pg. 
1006
-
1011
)
20
Lutgens
SP
Cleutjens
KB
Daemen
MJ
Heeneman
S
Cathepsin cysteine proteases in cardiovascular disease
FASEB J
 , 
2007
, vol. 
21
 (pg. 
3029
-
3041
)
21
Johnson
JL
Devel
L
Czarny
B
George
SJ
Jackson
CL
Rogakos
V
Beau
F
Yiotakis
A
Newby
AC
Dive
V
A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein e-knockout mice
Arterioscler Thromb Vasc Biol
 , 
2011
, vol. 
31
 (pg. 
528
-
535
)
22
Liu
H
Jiang
D
Zhang
S
Ou
B
Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice
Cardiovasc Drugs Ther
 , 
2010
, vol. 
24
 (pg. 
17
-
24
)
23
Afek
A
Kogan
E
Maysel-Auslender
S
Mor
A
Regev
E
Rubinstein
A
Keren
G
George
J
Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice
Microvasc Res
 , 
2009
, vol. 
77
 (pg. 
364
-
369
)
24
Schulz
C
Konrad
I
Sauer
S
Orschiedt
L
Koellnberger
M
Lorenz
R
Walter
U
Massberg
S
Effect of chronic treatment with acetylsalicylic acid and clopidogrel on atheroprogression and atherothrombosis in ApoE-deficient mice in vivo
Thromb Haemost
 , 
2008
, vol. 
99
 (pg. 
190
-
195
)
25
Yamamoto
Y
Yamashita
T
Kitagawa
F
Sakamoto
K
Giddings
JC
Yamamoto
J
The effect of the long term aspirin administration on the progress of atherosclerosis in apoE-/- LDLR-/- double knockout mouse
Thromb Res
 , 
2010
, vol. 
125
 (pg. 
246
-
252
)
26
Herrmann
J
Lerman
A
The endothelium: dysfunction and beyond
J Nucl Cardiol
 , 
2001
, vol. 
8
 (pg. 
197
-
206
)
27
Lavi
S
Bae
JH
Rihal
CS
Prasad
A
Barsness
GW
Lennon
RJ
Holmes
DR
Jr
Lerman
A
Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques
Heart
 , 
2009
, vol. 
95
 (pg. 
1525
-
1530
)
28
Willerson
JT
Golino
P
Eidt
J
Campbell
WB
Buja
LM
Specific platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications
Circulation
 , 
1989
, vol. 
80
 (pg. 
198
-
205
)
29
Golino
P
Piscione
F
Willerson
JT
Cappelli-Bigazzi
M
Focaccio
A
Villari
B
Indolfi
C
Russolillo
E
Condorelli
M
Chiariello
M
Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients
N Engl J Med
 , 
1991
, vol. 
324
 (pg. 
641
-
648
)
30
Weyrich
AS
Solis
GA
Li
KS
Tulenko
TN
Santamore
WP
Platelet amplification of vasospasm
Am J Physiol
 , 
1992
, vol. 
263
 (pg. 
H349
-
H358
)
31
Kaul
S
Padgett
RC
Heistad
DD
Role of platelets and leukocytes in modulation of vascular tone
Ann NY Acad Sci
 , 
1994
, vol. 
714
 (pg. 
122
-
135
)
32
Davies
PF
Polacek
DC
Shi
C
Helmke
BP
The convergence of haemodynamics, genomics, and endothelial structure in studies of the focal origin of atherosclerosis
Biorheology
 , 
2002
, vol. 
39
 (pg. 
299
-
306
)
33
Wentzel
JJ
Whelan
DM
van der Giessen
WJ
van Beusekom
HMM
Andhyiswara
I
Serruys
PW
Slager
CJ
Krams
R
Coronary stent implantation changes 3-D vessel geometry and 3-D shear stress distribution
J Biomech
 , 
2000
, vol. 
33
 (pg. 
1287
-
1295
)
34
Krams
R
Wentzel
JJ
Oomen
JA
Vinke
R
Schuurbiers
JC
de Feyter
PJ
Serruys
PW
Slager
CJ
Evaluation of endothelial shear stress and 3D geometry as factors determining the development of atherosclerosis and remodeling in human coronary arteries in vivo. Combining 3D reconstruction from angiography and IVUS (ANGUS) with computational fluid dynamics
Arterioscler Thromb Vasc Biol
 , 
1997
, vol. 
17
 (pg. 
2061
-
2065
)
35
Samady
H
Eshtehardi
P
McDaniel
MC
Suo
J
Dhawan
SS
Maynard
C
Timmins
LH
Quyyumi
AA
Giddens
DP
Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease
Circulation
 , 
2011
, vol. 
124
 (pg. 
779
-
788
)
36
Chatzizisis
YS
Giannoglou
GD
Shear stress and inflammation: are we getting closer to the prediction of vulnerable plaque?
Expert Rev Cardiovasc Ther
 , 
2010
, vol. 
8
 (pg. 
1351
-
1353
)
37
Teng
Z
Canton
G
Yuan
C
Ferguson
M
Yang
C
Huang
X
Zheng
J
Woodard
PK
Tang
D
3D critical plaque wall stress is a better predictor of carotid plaque rupture sites than flow shear stress: an in vivo MRI-based 3D FSI study
J Biomech Eng
 , 
2010
, vol. 
132
 pg. 
031007
 
38
Stone
PH
Saito
S
Takahashi
S
Makita
Y
Nakamura
S
Kawasaki
T
Takahashi
A
Katsuki
T
Nakamura
S
Namiki
A
Hirohata
A
Matsumura
T
Yamazaki
S
Yokoi
H
Tanaka
S
Otsuji
S
Yoshimachi
F
Honye
J
Harwood
D
Reitman
M
Coskun
AU
Papafaklis
MI
Feldman
CL
Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION Study
Circulation
 , 
2012
, vol. 
126
 (pg. 
172
-
181
)
39
Virmani
R
Kolodgie
FD
Burke
AP
Finn
AV
Gold
HK
Tulenko
TN
Wrenn
SP
Narula
J
Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage
Arterioscler Thromb Vasc Biol
 , 
2005
, vol. 
25
 (pg. 
2054
-
2061
)
40
Eriksson
EE
Intravital microscopy on atherosclerosis in apolipoprotein E-deficient mice establishes microvessels as major entry pathways for leukocytes to advanced lesions
Circulation
 , 
2011
, vol. 
124
 (pg. 
2129
-
2138
)
41
Sluimer
JC
Gasc
JM
van Wanroij
JL
Kisters
N
Groeneweg
M
Sollewijn Gelpke
MD
Cleutjens
JP
van den Akker
LH
Corvol
P
Wouters
BG
Daemen
MJ
Bijnens
AP
Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
1258
-
1265
)
42
Herrmann
J
Lerman
LO
Mukhopadhyay
D
Napoli
C
Lerman
A
Angiogenesis in atherogenesis
Arterioscler Thromb Vasc Biol
 , 
2006
, vol. 
26
 (pg. 
1948
-
1957
)
43
Rutanen
J
Leppänen
P
Tuomisto
T
Rissanen
TT
Hiltunen
MO
Vajanto
I
Niemi
M
Häkkinen
T
Karkola
K
Stacker
SA
Achen
MG
Alitalo
K
Ylä-Herttuala
S
Vascular endothelial growth factor expression in human atherosclerotic lesions
Cardiovasc Res
 , 
2003
, vol. 
59
 (pg. 
971
-
979
)
44
Leppänen
P
Koota
S
Kholova
I
Koponen
J
Fieber
C
Eriksson
U
Alitalo
K
Ylä-Herttuala
S
Gene transfers of VEGF-A, VEGF-B, VEGF-C and VEGF-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-receptor/apolipoprotein B48-deficient mice
Circulation
 , 
2005
, vol. 
112
 (pg. 
1347
-
1352
)
45
Moulton
KS
Heller
E
Konerding
MA
Flynn
E
Palinski
W
Folkman
J
Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice
Circulation
 , 
1999
, vol. 
99
 (pg. 
1726
-
1732
)
46
Werner
N
Kosiol
S
Schiegl
T
Ahlers
P
Walenta
K
Link
A
Böhm
M
Nickenig
G
Circulating endothelial progenitor cells and cardiovascular outcomes
N Engl J Med
 , 
2005
, vol. 
353
 (pg. 
999
-
1007
)
47
Timmermans
F
Plum
J
Yoder
MC
Ingram
DA
Vandekerckhovea
B
Case
J
Endothelial progenitor cells: identity defined?
J Cell Mol Med
 , 
2009
, vol. 
13
 (pg. 
87
-
102
)
48
Hagensen
MK
Shim
J
Thim
T
Falk
E
Bentzon
JF
Circulating endothelial progenitor cells do not contribute to plaque endothelium in murine atherosclerosis
Circulation
 , 
2010
, vol. 
121
 (pg. 
898
-
905
)
49
Teo
KK
Ounpuu
S
Hawken
S
Pandey
MR
Valentin
V
Hunt
D
Diaz
R
Rashed
W
Freeman
R
Jiang
L
Zhang
X
Yusuf
S
INTERHEART Study Investigators
Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study
Lancet
 , 
2006
, vol. 
368
 (pg. 
647
-
658
)
50
Wang
TJ
Gona
P
Larson
MG
Tofler
GH
Levy
D
Newton-Cheh
C
Jacques
PF
Rifai
N
Selhub
J
Robins
SJ
Benjamin
EJ
D'Agostino
RB
Vasan
RS
Multiple biomarkers for the prediction of first major cardiovascular events and death
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2631
-
2639
)
51
Roy
H
Bhardwaj
S
Ylä-Herttuala
S
Molecular genetics of atherosclerosis
Hum Genet
 , 
2009
, vol. 
125
 (pg. 
467
-
491
)
52
Turunen
MP
Aavik
E
Ylä-Herttuala
S
Epigenetics and atherosclerosis
Biochim Biophys Acta
 , 
2009
, vol. 
1790
 (pg. 
886
-
891
)
53
Hoffmann
U
Moselewski
F
Nieman
K
Jang
IK
Ferencik
M
Rahman
AM
Cury
RC
Abbara
S
Joneidi-Jafari
H
Achenbach
S
Brady
TJ
Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography
J Am Coll Cardiol
 , 
2006
, vol. 
47
 (pg. 
1655
-
1662
)
54
Garcia-Garcia
HM
Mintz
GS
Lerman
A
Vince
DG
Margolis
MP
van Es
GA
Morel
MA
Nair
A
Virmani
R
Burke
AP
Stone
GW
Serruys
PW
Tissue characterisation using intravascular radiofrequency data analysis: recommendations for acquisition, analysis, interpretation and reporting
EuroIntervention
 , 
2009
, vol. 
5
 (pg. 
177
-
189
)
55
Kubo
T
Imanishi
T
Takarada
S
Kuroi
A
Ueno
S
Yamano
T
Tanimoto
T
Matsuo
Y
Masho
T
Kitabata
H
Tsuda
K
Tomobuchi
Y
Akasaka
T
Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
933
-
939
)
56
Uemura
S
Ishigami
K
Soeda
T
Okayama
S
Sung
JH
Nakagawa
H
Somekawa
S
Takeda
Y
Kawata
H
Horii
M
Saito
Y
Thin-cap fibroatheroma and microchannel findings in optical coherence tomography correlate with subsequent progression of coronary atheromatous plaques
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
78
-
85
)
57
Brugaletta
S
Garcia-Garcia
HM
Serruys
PW
de Boer
S
Ligthart
J
Gomez-Lara
J
Witberg
K
Diletti
R
Wykrzykowska
J
van Geuns
RJ
Schultz
C
Regar
E
Duckers
HJ
van Mieghem
N
de Jaegere
P
Madden
SP
Muller
JE
van der Steen
AF
van der Giessen
WJ
Boersma
E
NIRS and IVUS for characterization of atherosclerosis in patients undergoing coronary angiography
JACC Cardiovasc Imaging
 , 
2011
, vol. 
4
 (pg. 
647
-
655
)
58
Lamare
F
Hinz
R
Gaemperli
O
Pugliese
F
Mason
JC
Spinks
T
Camici
PG
Rimoldi
OE
Detection and quantification of large-vessel inflammation with 11c-(r)-pk11195 pet/ct
J Nucl Med
 , 
2011
, vol. 
52
 (pg. 
33
-
39
)
59
Wu
JC
Ylä-Herttuala
S
Human gene therapy and imaging: cardiology
Eur J Nucl Med Mol Imaging
 , 
2005
, vol. 
32
 (pg. 
S346
-
S357
)
60
Crisby
M
Nordin-Fredriksson
G
Shah
PK
Yano
J
Zhu
J
Nilsson
J
Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization
Circulation
 , 
2001
, vol. 
103
 (pg. 
926
-
933
)
61
Cortellaro
M
Cofrancesco
E
Arbustini
E
Rossi
F
Negri
A
Tremoli
E
Gabrielli
L
Camera
M
Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study
Thromb Haemost
 , 
2002
, vol. 
88
 (pg. 
41
-
47
)
62
Tuomisto
TT
Lumivuori
H
Kansanen
E
Häkkinen
SK
Turunen
MP
van Thienen
JV
Horrevoets
AJ
Levonen
AL
Ylä-Herttuala
S
Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2
Cardiovasc Res
 , 
2008
, vol. 
78
 (pg. 
175
-
184
)
63
Patel
R
Janoudi
A
Vedre
A
Aziz
K
Tamhane
U
Rubinstein
J
Abela
OG
Berger
K
Abela
GS
Plaque rupture and thrombosis are reduced by lowering cholesterol levels and crystallization with ezetimibe and are correlated with fluorodeoxyglucose positron emission tomography
Arterioscler Thromb Vasc Biol
 , 
2011
, vol. 
31
 (pg. 
2007
-
2014
)
64
Schartl
M
Bocksch
W
Koschyk
DH
Voelker
W
Karsch
KR
Kreuzer
J
Hausmann
D
Beckmann
S
Gross
M
Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease
Circulation
 , 
2001
, vol. 
104
 (pg. 
387
-
392
)
65
Nissen
SE
Nicholls
SJ
Sipahi
I
Libby
P
Raichlen
JS
Ballantyne
CM
Davignon
J
Erbel
R
Fruchart
JC
Tardif
JC
Schoenhagen
P
Crowe
T
Cain
V
Wolski
K
Goormastic
M
Tuzcu
EM
ASTEROID Investigators
Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial
JAMA
 , 
2006
, vol. 
295
 (pg. 
1556
-
1565
)
66
Nicholls
SJ
Borgman
M
Nissen
SE
Raichlen
JS
Ballantyne
C
Barter
P
Chapman
MJ
Erbel
R
Libby
P
Impact of statins on progression of atherosclerosis: rationale and design of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: effect of Rosuvastatin versus AtorvastatiN)
Curr Med Res Opin
 , 
2011
, vol. 
27
 (pg. 
1119
-
1129
)
67
Nicholls
SJ
Tuzcu
EM
Sipahi
I
Grasso
AW
Schoenhagen
P
Hu
T
Wolski
K
Crowe
T
Desai
MY
Hazen
SL
Kapadia
SR
Nissen
SE
Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis
JAMA
 , 
2007
, vol. 
297
 (pg. 
499
-
508
)
68
Cannon
CP
Braunwald
E
McCabe
CH
Rader
DJ
Rouleau
JL
Belder
R
Joyal
SV
Hill
KA
Pfeffer
MA
Skene
AM
Intensive versus moderate lipid lowering with statins after acute coronary syndromes
N Engl J Med
 , 
2004
, vol. 
350
 (pg. 
1495
-
1504
)
69
Ridker
PM
Danielson
E
Fonseca
FA
Genest
J
Gotto
AM
Jr
Kastelein
JJ
Koenig
W
Libby
P
Lorenzatti
AJ
MacFadyen
JG
Nordestgaard
BG
Shepherd
J
Willerson
JT
Glynn
RJ
JUPITER Study Group
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein
N Engl J Med
 , 
2008
, vol. 
359
 (pg. 
2195
-
2207
)
70
Yusuf
S
Zhao
F
Mehta
SR
Chrolavicius
S
Tognoni
G
Fox
KK
Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation
N Engl J Med
 , 
2001
, vol. 
345
 (pg. 
494
-
502
)
71
Oldgren
J
Wallentin
L
Alexander
JH
James
S
Jönelid
B
Steg
G
Sundström
J
New oral angicoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis
Eur Heart J
 , 
2013
, vol. 
34
 (pg. 
1670
-
1680
)
72
Sipahi
I
Tuzcu
EM
Wolski
KE
Nicholls
SJ
Schoenhagen
P
Hu
B
Balog
C
Shishehbor
M
Magyar
WA
Crowe
TD
Kapadia
S
Nissen
SE
Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials
Ann Intern Med
 , 
2007
, vol. 
147
 (pg. 
10
-
18
)
73
Yusuf
S
Sleight
P
Pogue
J
Bosch
J
Davies
R
Dagenais
G
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators
N Engl J Med
 , 
2000
, vol. 
342
 (pg. 
145
-
153
)
74
Yusuf
S
Teo
KK
Pogue
J
Dyal
L
Copland
I
Schumacher
H
Dagenais
G
Sleight
P
Anderson
C
ONTARGET Investigators
Telmisartan, ramipril, or both in patients at high risk for vascular events
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
1547
-
1559
)
75
Shah
PK
Yano
J
Reyes
O
Chyu
KY
Kaul
S
Bisgaier
CL
Drake
S
Cercek
B
High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization
Circulation
 , 
2001
, vol. 
103
 (pg. 
3047
-
3050
)
76
Barter
PJ
Caulfield
M
Eriksson
M
Grundy
SM
Kastelein
JJP
Komajda
M
Lopez-Sendon
J
Mosca
L
Tardif
J-C
Waters
DD
Shear
CL
Revkin
JH
Buhr
KA
Fisher
MR
Tall
AR
Brewer
B
for the ILLUMINATE Investigators
Effect of torcetrapib in patients at high risk for coronary events
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
2109
-
2122
)
77
Schwartz
GG
Olsson
AG
Abt
M
Ballantyne
CM
Barter
PJ
Brumm
J
Chaitman
BR
Holme
IM
Kallend
D
Leiter
LA
Leitersdorf
E
McMurray
JJV
Mundi
H
Nicholls
SJ
Shah
PK
Tardif
J-C
Wright
RS
for the dal-OUTCOMES Investigators
Effects of dalcetrapib in patients with a recent acute coronary syndrome
N Engl J Med
 , 
2012
, vol. 
367
 (pg. 
2089
-
2099
)
78
Voight
BF
Peloso
GM
Orho-Melander
M
Frikke-Schmidt
R
Barbalic
M
Jensen
MK
Hindy
G
Hólm
H
Ding
EL
Johnson
T
Schunkert
H
Samani
NJ
Clarke
R
Hopewell
JC
Thompson
JF
Li
M
Thorleifsson
G
Newton-Cheh
C
Musunuru
K
Pirruccello
JP
Saleheen
D
Chen
L
Stewart
A
Schillert
A
Thorsteinsdottir
U
Thorgeirsson
G
Anand
S
Engert
JC
Morgan
T
Spertus
J
Stoll
M
Berger
K
Martinelli
N
Girelli
D
McKeown
PP
Patterson
CC
Epstein
SE
Devaney
J
Burnett
MS
Mooser
V
Ripatti
S
Surakka
I
Nieminen
MS
Sinisalo
J
Lokki
ML
Perola
M
Havulinna
A
de Faire
U
Gigante
B
Ingelsson
E
Zeller
T
Wild
P
de Bakker
PI
Klungel
OH
Maitland-van der Zee
AH
Peters
BJ
de Boer
A
Grobbee
DE
Kamphuisen
PW
Deneer
VH
Elbers
CC
Onland-Moret
NC
Hofker
MH
Wijmenga
C
Verschuren
WM
Boer
JM
van der Schouw
YT
Rasheed
A
Frossard
P
Demissie
S
Willer
C
Do
R
Ordovas
JM
Abecasis
GR
Boehnke
M
Mohlke
KL
Daly
MJ
Guiducci
C
Burtt
NP
Surti
A
Gonzalez
E
Purcell
S
Gabriel
S
Marrugat
J
Peden
J
Erdmann
J
Diemert
P
Willenborg
C
König
IR
Fischer
M
Hengstenberg
C
Ziegler
A
Buysschaert
I
Lambrechts
D
Van de Werf
F
Fox
KA
El Mokhtari
NE
Rubin
D
Schrezenmeir
J
Schreiber
S
Schäfer
A
Danesh
J
Blankenberg
S
Roberts
R
McPherson
R
Watkins
H
Hall
AS
Overvad
K
Rimm
E
Boerwinkle
E
Tybjaerg-Hansen
A
Cupples
LA
Reilly
MP
Melander
O
Mannucci
PM
Ardissino
D
Siscovick
D
Elosua
R
Stefansson
K
O'Donnell
CJ
Salomaa
V
Rader
DJ
Peltonen
L
Schwartz
SM
Altshuler
D
Kathiresan
S
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Lancet
 , 
2012
, vol. 
380
 (pg. 
572
-
580
)
79
Lee
JM
Robson
MD
Yu
LM
Shirodaria
CC
Cunnington
C
Kylintireas
I
Digby
JE
Bannister
T
Handa
A
Wiesmann
F
Durrington
PN
Channon
KM
Neubauer
S
Choudhury
RP
Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
1787
-
1794
)
80
Taylor
AJ
Villines
TC
Stanek
EJ
Devine
PJ
Griffen
L
Miller
M
Weissman
NJ
Turco
M
Extended-release niacin or ezetimibe and carotid intima-media thickness
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
2113
-
2122
)
81
Serruys
PW
Garcia-Garcia
HM
Buszman
P
Erne
P
Verheye
S
Aschermann
M
Duckers
H
Bleie
O
Dudek
D
Bøtker
HE
von Birgelen
C
D'Amico
D
Hutchinson
T
Zambanini
A
Mastik
F
van Es
GA
van der Steen
AF
Vince
DG
Ganz
P
Hamm
CW
Wijns
W
Zalewski
A
Integrated Biomarker and Imaging Study-2 Investigators
Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque
Circulation
 , 
2008
, vol. 
118
 (pg. 
1172
-
1182
)
82
Koenen
RR
Weber
C
Therapeutic targeting of chemokine interactions in atherosclerosis
Nat Rev Drug Discov
 , 
2009
, vol. 
9
 (pg. 
141
-
153
)
83
Tibolla
G
Norata
GD
Artali
R
Meneghetti
F
Catapano
AL
Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition
Nutr Metab Cardiovasc Dis
 , 
2011
, vol. 
21
 (pg. 
835
-
843
)
84
Akdim
F
Tribble
DL
Flaim
JAD
Yu
R
Su
J
Geary
RS
Baker
BF
Fuhr
R
Wedel
MK
Kastelein
JJP
Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia
Eur Heart J
 , 
2011
, vol. 
32
 (pg. 
2650
-
2659
)
85
Binder
CJ
Chang
M-K
Shaw
PX
Miller
YI
Hartvigsen
K
Dewan
A
Witztum
JL
Innate and acquired immunity in atherogenesis
Nat Med
 , 
2002
, vol. 
8
 (pg. 
1218
-
1226
)
86
Ahmed
T
Karalis
I
Jukema
JW
Emerging drugs for coronary artery disease. From past achievements and current needs to clinical promises
Expert Opin Emerg Drugs
 , 
2011
, vol. 
16
 (pg. 
203
-
233
)

Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

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