RESEARCH ARTICLE

High-density lipoprotein cholesterol as a

therapeutic target for residual risk in patients
with acute coronary syndrome
Yuichi Ozaki1, Atsushi Tanaka1*, Tsuyoshi Nishiguchi1, Kenichi Komukai1,2,
Akira Taruya1, Keisuke Satogami1, Manabu Kashiwagi1, Akio Kuroi1, Yoshiki Matsuo1,
Yasushi Ino1, Hironori Kitabata1, Takashi Kubo1, Takeshi Hozumi1, Takashi Akasaka1
1 Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan, 2 Department
of Cardiovascular Medicine, Hidaka General Hospital, Gobo, Japan

a1111111111 * [email protected]
a1111111111
a1111111111
a1111111111 Abstract
a1111111111

Objective
OPEN ACCESS The current guideline recommends lowering low-density lipoprotein cholesterol (LDL-C) for
Citation: Ozaki Y, Tanaka A, Nishiguchi T, Komukai the primary management of dyslipidemia in patients at high-risk of cardiovascular events.
K, Taruya A, Satogami K, et al. (2018) High-density Patients who have achieved LDL-C levels below the recommended targets may still experi-
lipoprotein cholesterol as a therapeutic target for ence cardiovascular events, suggesting additional therapeutic targets beyond LDL-C. The
residual risk in patients with acute coronary
syndrome. PLoS ONE 13(7): e0200383. https://doi.
aim of this study was to investigate whether high-density lipoprotein cholesterol (HDL-C)
org/10.1371/journal.pone.0200383 levels had an impact on plaque stabilization in patients with acute coronary syndrome
Editor: Sanjoy Bhattacharya, Bascom Palmer Eye
(ACS).
Institute, UNITED STATES

Received: March 13, 2018

Methods
Accepted: June 24, 2018
This study consisted of 90 ACS patients with untreated dyslipidemia. In optical coherence
Published: July 11, 2018
tomography (OCT) analysis, a plaque with fibrous cap thickness ≦160 μm was defined as a
Copyright: © 2018 Ozaki et al. This is an open high-risk plaque. We registered one high-risk plaque per one patient by baseline OCT imag-
access article distributed under the terms of the
ing, and then administrated high-intensity statin. Based on the follow-up OCT results,
Creative Commons Attribution License, which
permits unrestricted use, distribution, and patients whose registered plaque was no longer high-risk plaque were classified into a
reproduction in any medium, provided the original responder group and the remains into a non-responder group.
author and source are credited.

Data Availability Statement: All relevant data are

within the paper and its Supporting Information Results
files.
No differences were observed in the baseline LDL-C and HDL-C levels between the two
Funding: This work was supported in part by
groups. Reduction of LDL-C levels (δ LDL-C: −53 ± 21 mg/dL vs. −42 ± 29 mg/dL, p = 0.036)
Grant-in-Aid for Young Scientists (B), Japan (No.
16K19420). There was no additional external and increase of HDL-C levels (δ HDL-C: 2.5 ± 5.9 mg/dL vs. −0.3 ± 6.7 mg/dL, p = 0.039)
funding received for this study. were greater in the responder group. On multivariate logistic regression analysis, δ LDL-C
Competing interests: The authors have declared levels (OR: 0.956, 95% CI: 0.921–0.993; p = 0.020) and δ HDL-C levels (OR: 1.143; 95%
that no competing interests exist. CI: 1.005–1.300, p = 0.041) were independent contributors for plaque stabilization.

PLOS ONE | https://doi.org/10.1371/journal.pone.0200383 July 11, 2018 1 / 11

 HDL and residual risk

Conclusions
Increase of HDL-C levels is associated with plaque stabilization in patients with ACS. HDL-
C could be a therapeutic target for residual risk management.

Introduction
Today, atherosclerotic cardiovascular disease is the most important public health problem all
over the world. Current guideline for the primary management of dyslipidemia in patients at
high risk of cardiovascular disease recommends lowering low-density lipoprotein cholesterol
(LDL-C) using statin or another anti-dyslipidemic agents [1]. High dose statin therapy has
been provided lower LDL-C levels and plaque stabilization [2]. However, some patients could
still suffer cardiovascular events, even though they have achieved LDL-C levels below the rec-
ommended targets. It should be a question to clarify the residual risk factors that affect the ath-
erosclerotic progression of coronary plaque and result in cardiovascular events. This
clarification must be suggesting additional therapeutic targets beyond LDL-C.
Intravascular optical coherence tomography (OCT) is a suitable method for plaque charac-
terization that has provided a high-resolution imaging [3], and histological studies have dem-
onstrated that OCT can identify the microstructure of atherosclerotic plaque, including
fibrous cap thickness (FCT) and lipid core [4]. Our OCT study demonstrated that not only
LDL-C levels but also high-density lipoprotein cholesterol (HDL-C) levels are associated with
plaque vulnerability [5]. The aim of this study was to investigate the change of HDL-C levels
had an impact on plaque stabilization using OCT in patients with acute coronary syndrome
(ACS).

Materials and methods

Patient population
All 206 consecutive patients with successful percutaneous coronary intervention (PCI) for
ACS (defined as ST-segment elevation acute myocardial infarction, non–ST-segment elevation
myocardial infarction, or unstable angina) who underwent OCT for non-culprit lesion plaque,
and untreated dyslipidemia (defined as serum LDL-C level >100 mg/dl) between March 2014
and February 2016, at Wakayama Medical University Hospital were included. Exclusion crite-
ria were left main coronary artery disease, recommended coronary artery bypass grafting, car-
diogenic shock, renal insufficiency with serum creatinine level >2.0 mg/dl, and current use of
any lipid-lowering therapy according to self-reported or the previous and another hospital
information as possible. This study was in compliance with the Declaration of Helsinki with
regard to investigation in humans, and the protocol for this study was approved by the Ethics
Committee of Wakayama Medical University (IRB #2293). We also obtained written informed
consent from all the participants in this study for participation, medical procedure, and using
of clinical data prior to coronary angiography.

Study protocol
We performed an OCT examination in patients with successful PCI for ACS. The target plaque
for this OCT examination was an intermediate non-culprit lesion plaque. We registered one
high-risk plaque per one patient according to baseline OCT findings of the non-culprit pla-
ques, and then administrated statin within 24 hours after PCI. OCT was performed at baseline

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 HDL and residual risk

and follow-up. Based on the follow-up (10.4 ± 2.1 months) OCT results, we defined the
patients as a responder when the FCT became >160 μm, and the remains were as a non-
responder. δ LDL-C and δ HDL-C levels mean that they were calculated by subtraction base-
line from follow-up levels.

OCT image acquisition and analysis

The OCT images were acquired using frequency-domain OCT (FD-OCT) as previously
described [5]. The FD-OCT imaging system (C7-XRTM/ ILUMIEN OPTISTM, St. Jude Medi-
cal, St. Paul, Minnesota, USA) was used in the present study. Following a Z-offset adjustment,
a FD-OCT image catheter (DragonflyTM/ DragonflyTM JP/ ILUMIEN OPTISTM imaging cath-
eter, St. Jude Medical, St. Paul, Minnesota, USA) was positioned so that its imaging lens was
distal to the culprit lesion over a 0.014-inch conventional angioplasty guide-wire. All OCT
images were obtained using an automatic pullback device traveling at a rate of 20 mm/s. To
flush the coronary artery, contrast media at 37˚C (OmnipaqueTM 350 Injection, Daiichi Phar-
maceutical, Tokyo, Japan) was infused directly through the guiding catheter at a rate of 2.5 to
4.5 mL/s using an auto injector pump (Mark V; Medrad, Pennsylvania, USA). The FD-OCT
images were digitally stored for offline analysis.
The OCT images were analyzed in a blinder fashion using a dedicated offline review system
(St. Jude Medical, St. Paul, Minnesota, USA) at the core laboratory (Department of Cardiovas-
cular Medicine, Wakayama Medical University, Wakayama, Japan). Serial OCT images at
baseline and follow-up were reviewed side by side on the screen, and target plaques were
matched based on the distance from landmarks like side branches and calcifications. OCT
images were analyzed according to Consensus Standards for Acquisition, Measurement, and
Reporting of Intravascular Optical Coherence Tomography Studies [6].
Fibrous cap was identified as a tissue layer, which is signal-rich homogenous region overly-
ing a lipid core characterized by a diffusely bordered, signal-poor region on the OCT image.
Lipid was semi-quantified according to the number of involved quadrants on the cross-sec-
tional OCT image. Cap thickness was measured frame by frame and 3 times for each image to
determine the thinnest site, and the average value was calculated. In this study, thin-cap
fibroatheroma (TCFA) was defined as a plaque with a minimal FCT <65 μm. The lipid arc
was measured on the frame with the largest lipid core by visual screening. Lipid length was cal-
culated from the number of frames with lipid core. Fibrous or fibrocalcific plaques, which lack
a fibrous cap and lipid core, were excluded from analysis. We compared minimum FCT at
baseline with that of follow-up. In OCT analysis, a plaque with FCT less than 160μm was
defined as a high-risk plaque, because our study previously demonstrated that plaque with
FCT less than 160 μm was at risk for plaque disruption [7].

Clinical parameters
The clinical parameters assessed were age, sex, and coronary risk factors, which consisted of
hypertension (blood pressure 140/90 mmHg, and/or a history of taking antihypertensive
medication), diabetes mellitus (fasting plasma glucose 126 mg/dl, casual plasma glucose
200mg/dl, or a diabetic pattern on 75-g oral glucose tolerance test), current smoking, and
family history.

Blood sampling and analysis

Blood samples were collected at baseline and follow-up in the fasting state. Serum samples
were separated by centrifugation, stored at 4˚C, and then analyzed (SRL Co., Ltd., Tokyo,
Japan). Serum total cholesterol, HDL-C, triglyceride, and hemoglobin (HbA1c) levels were

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 HDL and residual risk

measured by enzymatic methods. Serum LDL-C level was calculated using the Friedwald equa-
tion. Serum levels of the inflammatory biomarkers high-sensitivity C-reactive protein (hs-
CRP) were measured by a latex particle-enhanced turbidimetric immunoassay as reported pre-
viously [8].

Statistical analysis
Variables were expressed as mean ± standard deviation, median [interquartile range], or
counts (percentage). Comparisons between two groups were performed using Student’s t,
Mann-Whitney U, or Chi-square test as appropriate. Multivariable logistic regression analysis
was used to determine the contributors for plaque stabilization during follow-up. Age, male
sex, coronary risk factors, δ LDL-C, δ HDL-C, and variables with a p value of <0.1 on the uni-
variate assessment were entered into a multivariable model. Statistical analyses were per-
formed using JMP version 12.2 (SAS Institute, Inc., Cary, North Carolina). A p value <0.05
was considered statistically significant.

Results
Patient population
Among consecutive 206 patients, we excluded 105 patients who had a left main coronary
artery disease (n = 4), recommended coronary artery bypass grafting (n = 6), cardiogenic
shock (n = 5), and renal insufficiency (n = 17). We also excluded 73 patients caused by current
use of lipid-lowering therapy, and then, we finally enrolled 101 patients. During the follow-up
period, 11 patients were excluded due to withdraw consent (n = 4), discontinued study medi-
cation (n = 2), physician’s decision (n = 3), lost to follow-up (n = 1), and adverse event (n = 1).
Ultimately, we analyzed 90 patients for this study as shown in Fig 1.

Patient characteristics and OCT findings

Forty-six patients (51%) were classified into a responder group according to the follow-up
OCT findings. The baseline clinical characteristics of the study subjects are listed Table 1.
There were no significant differences between the two groups. As a matter of course, no differ-
ences were observed in the baseline LDL-C and HDL-C levels. Table 2 shows the number of
patients with statins and other lipid-modifying drugs at follow-up.

Relationship between variation of lipid levels and plaque stabilization

No significant correlations were observed between the change in FCT and both δ LDL-C and δ
HDL-C in overall patients (δ LDL-C; r = -0.176, p = 0.096, δ HDL-C; r = 0.107, p = 0.317,
respectively). There was significant reduction in terms of LDL-C levels during the follow-up
period in the responder group compared to those in the non-responder group (responder:
−53 ± 21 mg/dL vs. non-responder: −42 ± 29 mg/dL, p = 0.036) (Fig 2). Furthermore,
responder group indicated greater increase of HDL-C levels during the follow-up period than
those in non-responder group (responder: 2.5 ± 5.9 mg/dL vs. non-responder: −0.3 ± 6.7 mg/
dL, p = 0.039) (Fig 3).

Predictive factors for plaque stabilization

Multivariate logistic regression analysis demonstrated that δ LDL-C (OR: 0.956, 95% CI:
0.921–0.993; p = 0.020) and δ HDL-C (OR: 1.143; 95% CI: 1.005–1.300, p = 0.041) were inde-
pendent contributors for plaque stabilization. Moreover, no potential determinant for the

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 HDL and residual risk

Fig 1. Study flowchart.

https://doi.org/10.1371/journal.pone.0200383.g001

change in FCT was observed analyzing with only baseline variables including age, gender, cor-
onary risk factor, lipid profiles, and medications (data not shown).

Discussion
To evaluate the association between HDL-C levels and plaque stabilization assessed by OCT is
the focus of this research. In this study, we have demonstrated that not only lowering LDL-C
but also raising HDL-C levels affected on plaque stabilization in patients with ACS.

Lipid component and plaque morphology

It is well known that lowering LDL-C levels using anti-lipidemic agents such as statin lead to
plaque stabilization. A number of clinical trials demonstrated that lowering LDL-C levels
reduced major cardiovascular events [9–11]. Intravascular ultrasound (IVUS) studies revealed
that statins suppress the progression of atherosclerosis or even enable regression of atheroma-
tous plaque [12,13]. Recently, we revealed that significant association between lowering
LDL-C levels using statin and plaque stabilization with the assessment of OCT findings such as
FCT, lipid arch, or macrophage grade [8]. However, in spite of the statin therapy, there
remains a residual risk even in patients with well-controlled LDL-C level. In the Framingham
Heart Study, HDL-C levels had an inverse association with the incidence of coronary artery
disease (CAD), that means HDL-C level was a more potent risk factor for CAD than LDL-C

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 HDL and residual risk

Table 1. Baseline characteristics.

Responder Non-responder p value
Number, n 46 44
Age (years) 65 ± 8 67 ± 10 0.29
Male gender 34 (74) 30 (68) 0.55
Coronary risk factors
Hypertension 27 (59) 24 (55) 0.69
Diabetes mellitus 8 (17) 8 (18) 0.92
Current smoking 21 (46) 20 (46) 0.99
Family history 8 (17) 8 (18) 0.92
Total cholesterol (ml/dL) 201.3 ± 40.7 192.7 ± 24.5 0.22
Triglyceride (mg/dL) 125.4 ± 94.0 122.1 ± 76.7 0.86
LDL-C (mg/dL) 130.4 ± 27.9 123.6 ± 23.6 0.21
HDL-C (mg/dL) 42.8 ± 10.1 44.1 ± 10.2 0.56
HbA1c (%) 6.5 ± 1.8 6.4 ± 1.5 0.87
hs-CRP (mg/dL) 0.15 [0.07–0.46] 0.14 [0.08–0.51] 0.92
Medication
Aspirin 3 (7) 6 (14) 0.31
ACEI or ARB 9 (20) 6 (14) 0.45
β blocker 8 (17) 4 (9) 0.25
CCB 13 (28) 11 (25) 0.73
Insulin 3 (7) 0 (0) 0.24
Target vessel 0.59
LAD 20 (43) 16 (36)
LCX 11 (24) 9 (21)
RCA 15 (33) 19 (43)

Data are presented as mean ± standard deviation, median [interquartile range], or numbers (%).
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HbA1c, hemoglobin A1c; HDL-C, high-density
lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein
cholesterol; RCA, right coronary artery.

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[14]. It was also reported that HDL-C level was a predictive factor of major cardiovascular
events in patients treated with statin [15], even when LDL-C level was <70 mg/dl [16]. Previ-
ously, we demonstrated that HDL-C had an impact on fibrous cap thickening even after
adjustment for LDL-C in patients with ACS using intra-coronary OCT imaging [5]. In the
present study, we also shown that not only lowering LDL-C levels but also raising HDL-C

Table 2. Lipid modifying drugs at follow-up.

Responder Non-responder p value
(n = 46) (n = 44)
Atorvastatin 21 (46) 33 (75) 0.01
Pitavastatin 25 (54) 11 (25) 0.01
Eicosapentaenoic acid 3 (7) 0 (0) 0.11
Ezetimibe 1 (2) 1 (2) 0.98

Data are presented as numbers (%).

There were no significant differences between the two groups in terms of baseline OCT findings of target plaque including FCT, lipid arch, plaque rupture, and intra-
coronary thrombus (data not shown).

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 HDL and residual risk

Fig 2. Comparison of δ LDL-C levels between the 2 groups. δ LDL-C levels in patients with responder group were greater than those in
non-responder group (responder: −53 ± 21 mg/dL vs. non-responder: −42 ± 29 mg/dL, p = 0.036). Data are presented as box and whisker
plots with median and 25th to 75th percentiles (boxes) and 10th to 90th percentiles (whiskers). LDL-C = low-density lipoprotein cholesterol.
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levels had affected the plaque stabilization assessed by OCT in patients with ACS. These results
may suggest that we should consider the additional therapy to reduce cardiovascular events.
Several studies have reported that low HDL-C levels are precious risk factor for CAD, and
HDL-C potentially has various anti-atherogenic properties, including the regulation of reverse
transport of cholesterol from cells from the arterial wall to the liver and steroidogenic organs
[17–20]. The metabolism and a crucial anti-atherogenic function in HLD-C, that means
reverse cholesterol transport, more especially, HDL-C-mediated efflux of cholesterol from
non-hepatic cells and its subsequent delivery to the liver and steroidogenic organs, in which it
is used for the composition of lipoprotein, vitamin D, bile acids, and steroid hormones [18–
20]. It was reported that the ability of HDL-C to promote cholesterol efflux from macrophage
foam cells was strongly and inversely associated with both subclinical atherosclerosis and

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 HDL and residual risk

Fig 3. Comparison of δ HDL-C levels between the 2 groups. δ HDL-C levels in patients with responder group were greater than those in
non-responder group (responder: 2.5 ± 5.9 mg/dL vs. non-responder: −0.3 ± 6.7 mg/dL, p = 0.039). Data are presented as box and whisker plots
with median and 25th to 75th percentiles (boxes) and 10th to 90th percentiles (whiskers). HDL-C = high-density lipoprotein cholesterol.
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obstructive CAD [21]. Take results into consideration in this study, a treatment strategy target-
ing LDL-C with statin may not be sufficient for CAD management. Therapeutic strategies of
lipid treatment that involve additional targets beyond LDL-C reduction are required to
improve clinical outcome and it is necessary to take more notice to modulation of HDL-C sim-
ilar to that of LDL-C.

Study limitations
First, the subjects in this study were administrated different statins including atorvastatin and
pitavastatin, this may affect lipid profile or plaque stabilization. Second, some patients were
administrated additional another anti-lipidemic agents such as eicosapentaenoic acid and

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 HDL and residual risk

ezetimibe. Third, the evaluation of plaque volume is not permitted due to the limited penetra-
tion depth of OCT. Therefore, it is difficult to estimate and quantify the amount of lipids on
OCT, without IVUS. Fourth, we did not perform a 3-vessel assessment, therefore it is possible
that some patients might have a vulnerable plaque in another coronary artery as previously
reported [22]. Fifth, there were many potential confounders might effect on responder status
that were not measured or consider in this analysis. Finally, since this is a single-center study
involving a small sample, a study of larger patient populations from various centers with an
independent core OCT laboratory is required to confirm the results, and our results may not
be applicable to all patients with coronary artery disease because we excluded some patients
with current use of anti-lipidemic treatments, plaques in the left main coronary artery, recom-
mended coronary artery bypass grafting, cardiogenic shock, and renal insufficiency.

Conclusions
As well as reduction of LDL-C levels, increase of HDL-C levels is associated with plaque stabili-
zation assessed by OCT in patients with ACS. HDL-C could be a therapeutic target for residual
risk management.

Supporting information
S1 File. All uploaded data. All data including age, gender, coronary risk factors, target vessels,
laboratory data at baseline and follow-up, and medication were uploaded.
(XLSX)

Acknowledgments
We thank all staff members for the support.

Author Contributions
Conceptualization: Yuichi Ozaki, Atsushi Tanaka, Takashi Akasaka.
Data curation: Yuichi Ozaki, Tsuyoshi Nishiguchi, Kenichi Komukai, Akira Taruya.
Formal analysis: Yuichi Ozaki, Atsushi Tanaka, Tsuyoshi Nishiguchi, Keisuke Satogami, Hir-
onori Kitabata.
Investigation: Yuichi Ozaki, Kenichi Komukai, Manabu Kashiwagi.
Methodology: Yuichi Ozaki, Tsuyoshi Nishiguchi, Kenichi Komukai, Akira Taruya, Keisuke
Satogami, Manabu Kashiwagi.
Project administration: Yuichi Ozaki.
Supervision: Atsushi Tanaka.
Validation: Yuichi Ozaki, Atsushi Tanaka, Akio Kuroi.
Writing – original draft: Yuichi Ozaki.
Writing – review & editing: Yuichi Ozaki, Atsushi Tanaka, Tsuyoshi Nishiguchi, Kenichi
Komukai, Akira Taruya, Keisuke Satogami, Manabu Kashiwagi, Akio Kuroi, Yoshiki
Matsuo, Yasushi Ino, Hironori Kitabata, Takashi Kubo, Takeshi Hozumi, Takashi Akasaka.

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 HDL and residual risk

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