450

ORIGINAL
Lipoprotein (a) is a risk factor of aortic valve calcificationin patients with a risk of atherosclerosis
Munkhtsetseg Tserensonom1, Shusuke Yagi1,2 MD, Takayuki Ise1 MD, Yutaka Kawabata1 MD, Muneyuki Kadota1 MD,
Tomoya Hara1 MD, Kenya Kusunose1 MD, Koji Yamaguchi1 MD, Hirotsugu Yamada1 MD, Takeshi Soeki1 MD,
Tetsuzo Wakatsuki1 MD, and Masataka Sata1 MD
1Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan, 2Department ofCommunity Medicine and Human Resource Development, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

Abstract : Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons.
Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed
tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels
were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single
regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels andnegatively associated with the estimated glomerular filtration rate. No statistical significance was observed forother risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression
analysis revealed that age (P < 0.001), female sex (P < 0.05), Lp(a) (P < 0.01), and hemoglobin A1c (P < 0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a)for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level isa potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023
Keywords : Calcium volume, Aortic stenosis, Lipoprotein

The development of aortic calcification leads to aortic stenosis(AS), which is one of the most common and serious valve diseases in the elderly population (1). Delayed treatment for AS,
including aortic valve replacement (AVR) and transcatheter
aortic valve implantation, results in heart failure and sudden
cardiac death ; thus, the prevention of aortic valve calcification(AVC) is needed, and clinical risk factors for AVC should be identified (2). According to epidemiological research, AS is linked
to common atherogenic risk factors as hypertension, smoking,diabetes, and hyperlipidemia (1). Risk factors for AS overlap
with those for vascular atherosclerosis, such as male sex, hypertension, dyslipidemia, diabetes mellitus, and the coexistenceof atherosclerosis and valvular calcification (3, 4). AS develops
through initial endothelial injury and dysfunction, immune cell
infiltration, the myofibroblastic / osteoblastic differentiation of
valvular interstitial cells (VICs), and subsequent calcification(5). AS is partially caused by the infiltration of lipids and the
production of oxidatively derived products in the aortic valve (6).
However, controlling conventional risk factors has not prevented the development of AS ; thus, residual risk factors for AVC
should be identified. Lipoprotein (Lp) (a), omega 3- and 6-fatty
acids like eicosapentaenoic acid (EPA) / docosahexaenoic acid
(DHA), and oxidized low-density lipoprotein (LDL) are lipid-related candidates of residual risk factors (6-8). However, the mostcontributable risk factor for AVC has not been identified. Thus,
we investigated the residual risk factors for AVC in patients at ahigh risk of atherosclerotic disease.

METHODS
We retrospectively enrolled 2,378 patients who underwent
coronary angiography with computed tomography (CT) becauseof suspicion of coronary artery disease (CAD) or ruling out of
CAD before AVR at the Department of Cardiovascular Medicine
at Tokushima University Hospital between January 2016 andNovember 2022. Figure 1 shows the selection of eligible patientsand the enrollment process. Young AS patients included thoseCoronary CT scan were performed
between January, 2016 and November 2022
(n=2378)
Excluded (n=1466)
Age ˂70
Excluded (n=399)
Lack of laboratory
data (Lp (a), EPA,
DHA, OxLDL, LDL-C)

Received for publication June 19, 2023 ; accepted July 12, 2023.
Address correspondence and reprint requests to Shusuke Yagi,
MD, PhD, Department of Cardiovascular Medicine, Tokushima
University Graduate School of Biomedical Sciences, 3-18-15
Kuramoto-cho, Tokushima 770-8503, Japan and Fax : +81-88-6337894, Email : syagi@tokushima-u.ac.jp

Analysis (n=513)
Figure 1. Flow diagram of the study population.

The Journal of Medical Investigation Vol. 70 2023

The Journal of Medical Investigation Vol. 70 August 2023
with congenital disorders (e.g., bicuspid aortic valve), many ofwhich lacked laboratory data. To explore the influence of Lp(a)on atherosclerotic aortic valve calcification, we enrolled relatively
older patients age 70 and older. Thus, after excluding patients
younger than 70 years of age, to eliminate heterogeneity in the
study population, as well as patients lacking laboratory data on
Lp(a), EPA, oxidized LDL, and LDL-cholesterol (LDL-C), we
finally evaluated the data of 513 patients.
We calculated calcium volume using the commerciallyavailable 3 mensio Structural Heart 10.1 (Pie Medical Imaging ; Maastricht, The Netherlands), which were expressed asmm3. We defined aortic valve calcification as calcification within
the aortic valve leaflets, aortic annulus, or aortic wall, below thesinotubular junction and excluded calcification of the coronary
arteries and mitral annulus from the region of interest (Figure2). A threshold of 650 HU (Hounsfield Unit) was chosen for AVC
assessment in all patients to distinguish between calcium andthe contrast agent (9, 10).
Plasma Lp(a) levels were measured via latex agglutination
immunoassays at a commercial laboratory (SRL ; Tokyo, Japan).
Serum fatty acid composition, including the levels of EPA, DHA,
and arachidonic acid (AA), was measured using gas-liquid chromatography at a commercial laboratory (SRL, Tokyo, Japan).
Oxidized LDL was measured as malondialdehyde-modified LDL
using enzyme-linked immunosorbent assays at a commercial
laboratory (SRL). In addition, other conventional biochemicalparameters, including LDL-C, triglycerides, high-density lipoprotein cholesterol (HDL-C), hemoglobin A1c (HbA1c), and theserum estimated glomerular filtration rate (eGFR), were measured. All laboratory data were collected from blood tests within
1 year of the date of the CT scan.
Because the study was retrospective, written informed consent was not necessary. The study protocol was approved by theTokushima University Hospital Ethics Committee in conformity
with the Helsinki Declaration (No. 3913).

451

STATISTICAL ANALYSES
Continuous variables are defined as mean ± standard deviation, whereas categorical variables are expressed as numbers
and percentages. The patient characteristics classified by thepresence or absence of AVR were compared using the t-test forcontinuous variables and chi-squared test for discrete variables.
After stratification according to age and quartiles of lipid-related
biomarkers, differences in clinical characteristics were determined using one-way analysis of variance. A Pearson correlation
analysis was performed to determine the association between
the calcium volume and biomarkers of AS, including Lp(a). A
multiple regression analysis was used to assess the dependenceof a set of variables on the calcium volume. A receiver operating
characteristic (ROC) curve analysis was performed to determine
the cut-off level for implementation of AVR. Calcium volume
was natural log transformed due to non-normally distributed
parameter for the multiple regression analysis. JMP 10 software(SAS ; Cary, NC, USA) was used to conduct all statistical analyses. P < 0.05 was used to determine statistical significance.

RESULTSA total of 513 individuals highly at risk of atherosclerosis andaged 79.6 ± 6.1 years participated in this study. Representative
cases of AVC are shown in Figure 2. The characteristics of all
patients stratified based on the presence or absence of AVR are
shown in Table 1. The calcium volume and serum Lp(a) level
were significantly higher in patients with AVR than in those
without AVR. The prevalence of elderly age was higher in patients with AVR, and the prevalence of male sex, and the levelsof HbA1c and eGFR were lower in patients with AVR. There wasno difference in the serum levels of triglycerides, HDL-C, LDLC, oxidized LDL, and fatty acid concentrations, including EPA,

Mild

Moderate

SevereCalcium volume
187 mm3

Calcium score 566
Calcium volume
566 mm3

Calcium volume
986 mm3

Figure 2. Representative images of mild, moderate, and severe aortic valve calcification.

Figur

T. Munkhtsetseg, et al. Lp(a) on aortic valve calcification

452

DHA, and AA, as well as the prevalence of statin use between
these two groups.
The level of calcium volume was significantly associated withage and quartiles of Lp(a), but not with the quartiles of oxidized
LDL, EPA, and DHA (Figure 3).
A single regression analysis showed that the calcium volume
was positively associated with age and the Lp(a) level and negatively associated with the eGFR and HbA1c levels. No statistical significance was observed for other risk factors, including

triglyceride, LDL-C, HDL-C, oxidized LDL, EPA, DHA, and AA
levels (Table 2).
The multiple regression analysis revealed that age (P < 0.001),
female sex (P < 0.05), Lp(a) (P < 0.01), and HbA1c (P < 0.01) were
determinants of the calcium volume, but not eGFR (Table 3).
The area under the curve in ROC analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg / dL
(Figure. 4).

Table 1. Clinical characteristics of patients with/without aortic valve replacement
Variables

All patients

AVR(-)AVR (+)

P-value

Number of patients

513

421

92

Age (years)

79.6 ± 6.1

77.9 ± 0.2

87.2 ± 0.5<0.001

Male sex, n (%)

271 (53%)244 (58%)

27 (29%)<0.001

Calcium volume (mm3)113 ± 198

40 ± 6442 ± 13<0.001

Lipoprotein (a) (mg / dL)

17.2 ± 21.0

14.8 ± 0.9

27.7 ± 2.1<0.001eGFR (mL / min / 1.73 m2)

62.0 ± 16.7

64.4 ± 0.7

51.5 ± 1.6<0.001HbA1c (%)

6.1 ± 0.7

6.1 ± 0.1

5.8 ± 0.1

<0.01

Triglyceride (mg / dL)

129.6 ± 70.5

131.8 ± 3.4

119.3 ± 7.3

0.12

HDL-C (mg / dL)

61.1 ± 16.4

61.2 ± 0.8

60.7 ± 1.7

0.82

LDL-C (mg / dL)

105.6 ± 28.9

106.7 ± 1.4

100.5 ± 2.9

0.06

Oxidized LDL (U / I)99.4 ± 34.4

100.5 ± 1.7

94.8 ± 3.6

0.15

Fatty acid concentrations
EPA (μg / mL)

66.7 ± 46.7

67.9 ± 2.3

61.2 ± 4.8

0.22

DHA (μg / mL)

130.6 ± 40.5

130.1 ± 1.9

133.1 ± 4.2

0.52

AA (μg / mL)

194.9 ± 47.4

194.9 ± 2.3

194.9 ± 4.9

0.99

Medication use
Statins, n (%)

240 (47%)

190 (45%)50 (54%)0.14

Ezetimibe, n (%)

32 (6%)

27 (6%)

5 (5%)

0.70

ACEI/ARB, n (%)

178 (35%)129 (31%)49 (53%)<0.001β-blockers, n (%)

185 (36%)154 (37%)

31 (33%)0.54

269 (52%)

210 (50%)59 (63%)0.02

Calcium channel blockers, n (%)
Antidiabetics, n (%)

113 (22%)94 (22%)19 (20%)0.68

Anticoagulants, n (%)

167 (33%)

155 (37%)

12 (13%)<0.001

Antiplatelets, n (%)

248 (48%)

169 (40%)79 (85%)<0.001

Coronary artery disease, n (%)

227 (44%)197 (47%)

30 (32%)0.01

Diabetes mellitus, n (%)

145 (28%)

126 (30%)

19 (20%)0.06

Complications

Data are presented as the median ± standard deviation.
Abbreviations : AVR ; aortic valve replacement ; eGFR, estimated glomerular filtration rate ; HbA1c, hemoglobin
A1c ; TG, triglyceride ; HDL-C, high- density lipoprotein cholesterol ; LDL-C, low- density lipoprotein cholesterol ; EPA, eicosapentaenoic acid ; DHA, docosahexaenoic acid ; AA, arachidonic acid ; ACEI, angiotensin- converting
enzyme inhibitors ; ARB, angiotensin II receptor blockers.

453

The Journal of Medical Investigation Vol. 70 August 2023*

70-74 75-79 80-84 ≧85*

Q1 Q2 Q3 Q4Age(y.o)Lp(a) (mg/dL)
Calcium volume (mm3)

Calcium volume (mm3)

Calcium volume (mm3)

Calcium volume (mm3)

Calcium volume (mm3)Figure 3

Q1 Q2 Q3 Q4
EPA (g/mL)

Q1 Q2 Q3 Q4Oxidized LDL (U/L)

Q1 Q2 Q3 Q4
DHA (g/mL)

Figure 3. Calcium volume stratified by age groups, and stratified by quartiles of Lp(a), oxidized low-density lipoprotein (LDL),
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ; expressed as mean ± standard deviation (*P < 0.001).

Table 2. Single regression analysis for the determinant associationof the calcium volume and risk factors of aortic valve calcification
VariablesβP-valueAge (years)

18.4< 0.001

Lipoprotein (a) (mg / dL)

2.3< 0.001

eGFR (mL / min / 1.73 m2)-2.9

HbA1c (%)
Triglyceride (mg / dL)

Table 3. Multiple regression analysis for the determinant association of the calcium volume and risk factors of aortic valve calcification
β (95% CI)

P-valueAge (years)

0.16 (0.13, 0.19)< .0001

Female sex

0.20 (0.03, 0.36)

0.02< 0.001

Lipoprotein (a) (mg / dL)

0.01 (0.01, 0.02)< 0.01

-28.1

0.02

eGFR (mL / min / 1.73 m2)-0.01 (-0.02, 0.01)

0.08

-0.05

0.66

HbA1c (NGSP%)

0.35 (0.13, 0.58)< 0.01HDL-C (mg / dL)

-0.58

0.27

LDL-C (mg / dL)

-0.47

0.12

Oxidized LDL (U / L)

-0.19

0.45

EPA (μg / mL)

-0.22

0.24

DHA (μg / mL)

0.08

0.70

AA (μg / mL)

0.03

0.86

Abbreviations : eGFR, estimated glomerular filtration rate ; HbA1c,
hemoglobin A1c

1.0

Abbreviations : eGFR, estimated glomerular filtration rate ; HbA1c,
hemoglobin A1c ; HDL-C, high- density lipoprotein cholesterol ;LDL-C, low- density lipoprotein cholesterol ; EPA, eicosapentaenoic
acid ; DHA, docosahexaenoic acid ; AA, arachidonic acid

Sensitivity

0.8
0.6
Lp(a) = 16 mg/dL

0.4

AUC = 0.65
p = <.0001

0.2
0

0

0.2

0.4

0.6

0.8 1.0

1-Specifity
Figure 4. The area under the curve in receiver operating characteristic
analysis of Lp(a) for implementation of AVR.

454

T. Munkhtsetseg, et al. Lp(a) on aortic valve calcification

DISCUSSION
The present study demonstrated that the serum levels of Lp(a)contribute to an increase in AVC in patients at a high risk of
CAD. The result indicates that a high Lp(a) level is a residual
risk factor for AVC in high-risk patients of CAD.
We showed that female sex is a determining factor for calcium
volume. AS shows a female predominance in the Japanese registry (11). This study contained many older female AS patientswith a high calcium volume. This may be due to the longer life
expectancy of women. The skewed prevalence of AS toward older
females in our subjects might have influenced the results. In
addition, we showed that the use of anticoagulants was lower,
but antiplatelet use was higher in patients with than in patients
without AVR. The predominance of antiplatelet use in patientswith AVR was thought to be related to perioperative use in
those with AVR. It has been reported that anticoagulant andantiplatelet use might influence aortic valve calcification (12, 13).
Thus, we could not exclude the possibility of effects of anti-coagulant and anti-platelet use on aortic valve calcification, which wasa limitation of this cross-sectional study.
Lp(a) has been recognized as a risk factor for CAD based onabundant evidence (14) ; however, whether Lp(a) is a risk factor
for AVC has not been established, although some papers havereported that the serum Lp(a) level is a risk factor for AVS (7).
A genome-wide association study showed that LPA single nucleotide polymorphisms were associated with aortic valve calcium,
as evaluated by CT (15). The ASTRONOMER trial showed thatelevated Lp(a) levels were associated with the progression of AS,
as well as the need for AVR (16). Thus, Lp(a) could be a novel
biomarker for AS and a target for the prevention of AS.
The AVS process is as follows : the aortic valve is exposed
to powerful mechanical / shear stress according to the cardiac
output, leading to valvular endothelial cell (VEC) damage,following lipoprotein infiltration, including LDL and Lp(a).
Damaged VECs evoke the extravasation of immune cells into
the interstitium of the valve leaflets and a decreased endothelial
nitric oxide synthase (eNOS) activation. Reduced eNOS induces
the production of reactive oxygen species, which stimulate theoxidation of infiltrated lipids into oxidized LDL and oxidized
phospholipids, resulting in transformation into lysophosphatidylcholine, promoting VIC apoptosis and the release of inflammatory cytokines, such as tumor necrosis factor-α, interleukin(IL)-6, IL-1β, and the receptor activator of nuclear factor kappa
B5. These cytokines activate inflammatory cells, including macrophages and T cells, and lead to the osteogenic differentiation of
VICs, resulting in AVC (17).
Lp(a) is a plasma lipoprotein composed of an LDL-like particle
containing cholesteryl esters and triglycerides as a central core,
which was ringed by many particles, including phospholipids
and free cholesterol. Lp(a) also contains a single apo B-100 molecule linked via a single disulfide bond to a large polymorphic
glycoprotein apo (a) (18). The lipoprotein component apo (a) canbind to exposed fibrin on areas of injured endothelium subjected
to mechanical stress and can easily accumulate in aortic valve
leaflets, leading to a substrate of AVC (19).
In addition, the lysine site of Kringle domain IV type 10 on
Lp(a) is where Lp(a) covalently binds to oxidized phospholipids(oxPLs) in the plasma, contributing to the progression of AVC(20). oxPLs on Lp(a) play a pivotal role in the calcification of VICs
by increasing IL-6 and bone morphogenetic protein 2. Thus,
Lp(a) is susceptible to oxidation and inflammatory and proatherogenic processes (21). The direct effect of oxPL on Lp(a) leading
to valvular inflammation may explain the association between ahigh Lp(a) level and AVC.
n-3 polyunsaturated fatty acids (PUFAs) are anothercandidate for preventing aortic calcification (8). Human stenotic aortic valves have been found to have lower amounts of n-3
PUFAs, and n-3 PUFA therapy has been shown to reduce AVC
in mouse models, improving the hemodynamics of the aortic
valve. A genetic variation in the fatty acid desaturase 1 / 2 locus,
which is responsible for manufacturing the essential enzyme
for synthesizing PUFAs has been linked to AS by genome-wide
association and Mendelian randomization studies (22). It has
been proposed that the proresolving lipid mediator resolvin
E1, derived from the n-3 PUFA EPA, exerts protective effects
against VIC calcification and valvular inflammation throughits receptor ChemR23 (8). In addition, higher systemic levels ofAA, having pro-inflammatory properties, are associated with
AVC (23). However, our results indicate that the serum levels of
n-3 PUFAs and n-6 PUFAs did not contribute to AVC. Furthermore, oxidized LDL is associated with pro-inflammatory andgrowth-stimulating properties and is involved in the initiationand progression of atherosclerosis (6, 24). A previous study
revealed that oxidized LDLs are present in AS valves and colocalize with calcium nodules and inflammatory infiltrates (25).
Additionally, oxidized LDL-C can easily be taken up by macrophages. However, our results indicate that the serum levelsof oxidized LDL did not contribute to AS. This may be due to adiscrepancy between the serum level of oxidized LDL and tissuelevels of oxidized LDL.
Lp(a) is a genetically determined by LDL particle ; however,a reduction in Lp(a) is recommended to reduce cardiovascular
events (26). It is estimated that one in seven cases of AS could be
prevented by marked Lp(a) reduction (27). Clinical studies thatused intensive lipid-lowering therapy with atorvastatin did nothalt the progression of calcific AS or induce its regression (28).
Additionally, proprotein convertase subtilisin kexin 9 (PCSK9)
inhibitors lowered Lp(a) concentrations by approximately 25%,
although clinical trials remain underway (NCT04968509) (29,30). Niacin also reduces Lp(a) levels by approximately 20%.
Although no proven effect on cardiovascular endpoints was
revealed in two major studies (31, 32), niacin could be a currently available agent in Japan. Inclisiran, a small interfering
RNA (siRNA) that inhibits the hepatic synthesis of the PCSK9protein (33), the antisense oligonucleotide AKCEA-APO(a)-LRx(Pelacarsen) that reduces Lp(a) levels by impairing the synthesis of apo(a) (34), and siRNA against apo(a) under phase 2
trials (NCT04270760) may contribute to a potential strategy forpreventing the progression of AS. The development of Lp(a)-lowering agents is awaited, and randomized controlled studies areneeded.

CONCLUSION
The serum Lp(a) level is a potent risk factor for AVC in patients at a high risk of atherosclerosis. Lowering Lp(a) levels may
be a potential strategy for the prevention of AVC. Intervention
studies involving methods of lowering Lp(a) levels are needed toconfirm the results.

ACKNOWLEDGMENTS
This work was supported partially by the Vehicle Racing
Commemorative Foundation (to MS) and the JSPS KAKENHI
Grant (JP22H03069 to MS).

The Journal of Medical Investigation Vol. 70 August 2023
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