Download Percutaneous Coronary Intervention Results in Acute

Percutaneous Coronary Intervention Results in Acute
Increases in Oxidized Phospholipids and Lipoprotein(a)
Short-Term and Long-Term Immunologic Responses to Oxidized
Low-Density Lipoprotein
Sotirios Tsimikas, MD; Herbert K. Lau, PhD; Kyoo-Rok Han, MD;
Brian Shortal, MD; Elizabeth R. Miller, BS; Amit Segev, MD; Linda K. Curtiss, PhD;
Joseph L. Witztum, MD; Bradley H. Strauss, MD, PhD
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Background—This study was performed to assess whether oxidized low-density lipoprotein (OxLDL) levels are elevated
after percutaneous coronary intervention (PCI).
Methods and Results—Patients (n⫽141) with stable angina pectoris undergoing PCI had serial venous blood samples
drawn before PCI, after PCI, and at 6 and 24 hours, 3 days, 1 week, and 1, 3, and 6 months. Plasma levels of
OxLDL-E06, a measure of oxidized phospholipid (OxPL) content on apolipoprotein B-100 detected by antibody E06,
lipoprotein(a) [Lp(a)], autoantibodies to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL), and
apolipoprotein B-100 –immune complexes (apoB-IC) were measured. OxLDL-E06 and Lp(a) levels significantly
increased immediately after PCI by 36% (P⬍0.0001) and 64% (P⬍0.0001), respectively, and returned to baseline by
6 hours. In vitro immunoprecipitation of Lp(a) from selected plasma samples showed that almost all of the OxPL
detected by E06 was bound to Lp(a) at all time points, except in the post-PCI sample, suggesting independent release
and subsequent reassociation of OxPL with Lp(a) by 6 hours. Strong correlations were noted between OxLDL-E06 and
Lp(a) (r⫽0.68, P⬍0.0001). MDA-LDL and Cu-OxLDL autoantibodies decreased, whereas apoB-IC levels increased
after PCI, but both returned to baseline by 6 hours. Subsequently, IgM autoantibodies increased and peaked at 1 month
and then returned to baseline, whereas IgG autoantibodies increased steadily over 6 months.
Conclusions—PCI results in acute plasma increases of Lp(a) and OxPL and results in short-term and long-term
immunologic responses to OxLDL. OxPL that are released or generated during PCI are transferred to Lp(a), suggesting
that Lp(a) may contribute acutely to a protective innate immune response. In settings of enhanced oxidative stress and
chronically elevated Lp(a) levels, the atherogenicity of Lp(a) may stem from its capacity as a carrier of proinflammatory
oxidation byproducts. (Circulation. 2004;109:3164-3170.)
Key Words: angioplasty 䡲 atherosclerosis 䡲 antibodies 䡲 lipoproteins
O
xidized low-density lipoprotein (OxLDL) is present in
atherosclerotic lesions of animal models and humans
and directly influences a multitude of atherogenic responses.1– 4 In animals, OxLDL within plaques is preferentially
depleted in response to regression/antioxidant diets.5–7 In
humans, plaque specimens from carotid and coronary arteries
are significantly enriched in OxLDL1,3 and become depleted
in OxLDL after treatment with statins.8 In particular, unstable
plaques appear to be preferentially enriched in OxLDL,9,10
and OxLDL in plasma has been shown to be associated with
acute coronary syndromes 9,11,12 and endothelial
dysfunction.13,14
In the present study, we measured plasma levels of several
OxLDL markers immediately before and serially up to 6
months after percutaneous coronary intervention (PCI) to
evaluate the role of OxLDL in PCI.
Methods
Patients
The patient cohort was derived from a single-center, prospective
study of 156 patients with stable angina undergoing elective,
uncomplicated PCI.15,16 The study included men (77%); diabetics
(18%); and patients with hypertension (44%), smoking (39%), and
prior myocardial infarction (26%). Balloon angioplasty was per-
Received May 14, 2003; de novo received December 27, 2003; revision received March 4, 2004; accepted March 17, 2004.
From the Department of Medicine, University of California, San Diego (S.T., B.S., E.R.M., J.L.W.); the Department of Internal Medicine, Hallym
University, Seoul, Korea (K.-R.H.); and the Department of Immunology, The Scripps Research Institute (L.K.C.), and the Departments of Medicine and
Laboratory Medicine and Pathobiology (H.K.L) and the Ann and Roy Foss Interventional Research Program, Terrence Donnelly Heart Centre, St
Michael’s Hospital (A.S., B.H.S.), University of Toronto, Ontario, Canada.
Correspondence to Sotirios Tsimikas, MD, Vascular Medicine Program, Department of Medicine, University of California San Diego, 9500 Gilman
Drive, BSB 1080, La Jolla, CA 92093-0682. E-mail [email protected]
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000130844.01174.55
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Tsimikas et al
formed in 69% and stent placement in 31%. Blood samples were
available from 141 patients, and 6-month angiographic follow-up
was performed in 134 (95%) patients. Venous blood in EDTA was
obtained before PCI; immediately after PCI; and 6 hours, 24 hours,
3 days, 1 week, and 1, 3, and 6 months after PCI.
Quantitative and qualitative (smooth, irregular, or ulcerated borders, concentric or eccentric appearance, calcification, thrombus)
coronary angiographic measurements and American Heart Association/American College of Cardiology (AHA/ACC) lesion classification were performed according to previously described criteria.17
OxLDL markers and lipoprotein(a) [Lp(a)] levels were correlated
with angiographic lesion characteristics.
In a control group of 50 patients who underwent diagnostic
coronary angiography without any intervention, plasma samples
were obtained immediately before and after angiography. The
Human Subjects Protection Program at the University of California
San Diego approved this study.
Determination of OxLDL-E06 Levels, OxLDL
Autoantibody Titers, and Apolipoprotein
B-100 –Immune Complexes
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Chemiluminescence ELISA was used to measure OxLDL markers. OxLDL-E06 is a measure of the content of oxidized phospholipids (OxPL) per apolipoprotein (apo) B-100 particle, using
the murine monoclonal antibody E06, which specifically binds to
the phosphorylcholine head group of oxidized but not native
phospholipids (reviewed in Tsimikas et al11 and references
therein). A 1:50 dilution of plasma in PBS is added to microtiter
wells coated with the monoclonal antibody MB47, which specifically binds apoB-100 particles. Under these conditions, a saturating amount of apoB-100 is added to each well, and consequently, an equal number of apoB-100 particles are captured in
each well for all assays. The content of OxPL per apoB-100 is
then determined with biotinylated E06 as previously described.11
Plasma titers of IgG and IgM malondialdehyde (MDA-LDL)
(1:200 plasma dilution) and copper-oxidized LDL (Cu-OxLDL
(1:50 dilution) autoantibodies and apoB-100 –immune complexes
(apoB-IC; labeled LDL-IC previously)11 were measured as previously described.11 Internal controls consisting of high and low
standard plasma samples were included on each microtiter plate to
detect potential variations between microtitration plates. Each
sample was assayed in triplicate, and data are expressed as
relative light units in 100 ms. The intra-assay coefficients of
variation for all assays were 6% to 10%.
OxLDL and Lp(a) in PCI
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apoB-100 by using biotinylated LPA4, E06, and goat anti-human
apoB-100 (Biodesign International), respectively.
Statistical Analysis
Statistical analysis was performed with GraphPad InStat, version
3.02. For changes in OxLDL and Lp(a) levels in the PCI group,
statistical analysis was performed with 1-way ANOVA with either
the parametric Bonferroni multiple comparisons test or nonparametric Kruskal-Wallis tests. For comparison of angiographic characteristics to OxLDL and Lp(a) levels in the PCI group, an unpaired t test
was performed at each time point; for differences in preangiography
and postangiography samples in the control group, a paired t test was
performed. The Mann-Whitney test was used for values that were not
normally distributed. A Spearman correlation was used to determine
relations between OxLDL markers and Lp(a). A value of P⬍0.05
was considered significant.
TABLE 1. Quantitative and Qualitative Angiographic
Characteristics of the Study Cohort
Coronary artery undergoing PCI, %
Left anterior descending artery
56.7
Left circumflex artery
22.4
Right coronary artery
20.9
Quantitative angiographic characteristics, mean⫾SD
Reference diameter, mm
2.8⫾0.54
Lesion length, mm
Before PCI
9.24⫾3.21
After PCI
7.73⫾3.22
At 6 mo
9.40⫾4.04
Minimal lumen diameter, mm
Before PCI
0.86⫾0.33
After PCI
2.12⫾0.70
At 6 mo
1.76⫾0.84
Diameter stenosis, %
Before PCI
69.1⫾10.7
After PCI
29.2⫾13.8
At 6 mo
40.8⫾30.0
Qualitative angiographic characteristics of target lesion
Lp(a) Assay
Plasma Lp(a) levels were measured by a novel chemiluminescent
ELISA with the use of the murine monoclonal antibody LPA4,
which was generated by immunizing mice with human Lp(a) and
screening the hybridomas for antibodies that bound to a synthetic
peptide of apo(a) with sequence TRNYCRNPDAEIRP. LPA4
does not cross-react with plasminogen. For this assay, MB47 (5
␮g/mL) was plated on microtiter well plates to capture apoB-100
in human plasma [1:400 plasma dilution yielded a nonsaturating
amount of Lp(a)] and Lp(a) detected with 50 ␮L of biotinylated
LPA4. This assay correlated well (n⫽500, r⫽0.96, P⬍0.0001)
with a commercially available Lp(a) assay (Diasorin).
AHA/ACC lesion classification, %
A
33.6
B1
39.6
B2
23.1
C
3.7
Lesion surface, %
Smooth
85.0
Irregular
9.0
Ulcerated
6.0
Lesion appearance, %
Determination of Binding of OxPL-E06 to Lp(a)
To determine whether the OxPL-E06 epitope was bound to Lp(a)
versus other apoB-100 – containing lipoproteins, we added increasing
amounts of antibody LPA4 [0- to 20-fold molar excess of
LPA4:Lp(a) in the presence of 0.27 mmol/L EDTA, 0.02% sodium
azide, and 25 ␮mol/L BHT] from 5 patients’ plasma, using samples
from the pre-PCI, immediately post-PCI, 6-hour, 24-hour, and
6-month time points to immunoprecipitate Lp(a). After an overnight
incubation at 4°C, the samples were centrifuged at 14 000 rpm for 30
minutes and 50-␮L aliquots of the supernatants were added to
MB47-coated plates and tested for the presence of Lp(a), OxPL, and
Concentric
69.9
Eccentric
30.1
Calcium, %
Absent
92.8
Present
7.2
Thrombus, %
Absent
98.5
Present
1.5
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Circulation
TABLE 2.
Median (Range) Values of OxLDL Markers and Lp(a) in the PCI Group
Lp(a), mg/dL
June 29, 2004
Before
After
6h
24 h
3d
1 wk
1 mo
3 mo
6 mo
7.0 (0.0–156.7)
9.9 (0.2–180.1)
7.0 (0.1–162.4)
7.3 (0.1–172.8)
7.9 (0.0–144.2)
5.9 (0.0–131.3)
7.3 (0.0–155.9)
7.3 (0.0–175.8)
8.1 (0.5–184.7)
5896 (3238–63 943)
OxLDL-E06
6177 (3249–60 761)
7240 (3251–88 714)
6315 (3331–72 091)
6085 (3277–70 804)
6027 (3339–59 345)
6199 (3149–55 071)
6063 (3459–56 968)
6314 (3611–59 213)
Cu-OxLDL IgM
3935 (1227–54 359)
3714 (890–41 932)
4090 (537–44 180)
3961 (572–40 982)
4007 (213–46 498)
4125 (150–45 729)
4109 (141–42 907)
3999 (736–31 898)
3727 (345–45 729)
Cu-OxLDL IgG
2801 (439—9609)
2691 (5108–9180)
2796 (641–9545)
2768 (546–9815)
2776 (449–8075)
2875 (643–8100)
2880 (543–8325)
2847 (464–13 232)
2846 (811–12 528)
MDA-LDL IgM
9219 (2003–39 665)
8438 (1066–37 396)
8751 (2312–37 419)
8618 (409–41 637)
8996 (678–30 768)
9556 (678–35 990)
8428 (644–38 820)
8350 (919–40 741)
8394 (678–33 094)
MDA-LDL IgG
3286 (1163–17 421)
2955 (728–12 333)
3075 (853–14 660)
3211 (900–15 056)
3394 (1082–11 917)
3397 (895–17 914)
3271 (676–17 604)
3288 (977–14 241)
3200 (894–12 244)
IC IgM
2856 (429–14 822)
2914 (121–20 211)
2770 (475–13 721)
2641 (1220–13 328)
3069 (6–15 017)
3128 (40–12 368)
3037 (140–11 669)
2952 (62–17 729)
2969 (279–13 585)
IC IgG
2970 (933–12 366)
2810 (737–14 144)
2893 (477–14 492)
2664 (911–12 941)
2728 (889–10 426)
3110 (775–13 372)
2985 (1020–10 730)
2843 (980–13 217)
2652 (782–11 511)
Units of OxLDL markers are in relative light units.
Results
Baseline, Postprocedural, and 6-Month
Quantitative and Qualitative Angiographic
Characteristics
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Most lesions were type A and B1, smooth, concentric, and
without significant calcification or thrombus (Table 1).
Absolute Baseline and Follow-Up Values of
OxLDL Markers Lp(a)
Compared with pre-PCI levels, median post-PCI levels of
OxLDL-E06 levels increased significantly [6177 to 7240
relative light units, P⫽0.03] and promptly returned to baseline by 6 hours (Table 2). Similarly, median Lp(a) levels
increased after PCI [7.0 to 9.9 mg/dL, P⫽0.27] but not
significantly and returned toward baseline by 6 hours. A
strong correlation was noted between OxLDL-E06 and Lp(a)
in the plasma samples obtained at all time points (r⫽0.68,
P⬍0.0001, Figure 1). No significant differences were noted
in other markers when evaluated as absolute levels. There
were no significant differences in baseline levels between
patients who had PCI and the angiography-only control group
(n⫽50) in all measures except that the patients who had PCI
had a greater level of IgG-LDL immune complexes
(P⫽0.007) (Tables 2 and 3).
Changes in OxLDL-E06 and Lp(a) Levels
In this patient population, there was a wide baseline variation
in the absolute values of Lp(a) and OxLDL at baseline that
were not normally distributed. Therefore, we expressed each
patient’s changes in OxLDL markers and Lp(a) in response to
PCI as a percent change compared with the pre-PCI samples,
and mean percent changes were calculated for all patients,
which were generally normally distributed. For OxLDL-E06,
there was a 36% mean percent increase after PCI compared
with before PCI (P⬍0.0001), and the post-PCI change was
significantly different from all the other time points
(P⬍0.001, Figure 2). In parallel, Lp(a) levels increased 64%
in the post-PCI time point, which was also statistically
significant from all other time points measured (P⬍0.001).
In contrast, in the angiography-only control group, no
significant changes were noted in OxLDL-E06 or in Lp(a)
levels between the preangiography and postangiography samples (Table 3).
Determination of Binding of Oxidized
Phospholipid Epitopes to Lp(a)
The antibody LpA4 immunoprecipitated ⬇95% of Lp(a) in
each plasma sample at each time point, as expected (Figure
3A). Similar to Lp(a), the majority of E06 epitopes were also
immunoprecipitated at all time points except in the immediate
post-PCI time point, in which only ⬇50% of the total E06
epitopes were associated with Lp(a) (Figure 3B), whereas the
other 50%, because of the design of the assay, are by
necessity on other apoB-containing lipoproteins not associated with Lp(a). However, by 6 hours and consistently for up
to 6 months, nearly all the E06 epitopes are again associated
with Lp(a).
Changes in OxLDL Autoantibodies and ApoB-IC
The mean percent change in Cu-OxLDL and MDA-LDL IgM
titers decreased significantly in the post-PCI sample
(P⬍0.0001 for both) but returned to baseline by 6 hours.
Subsequently, titers increased, peaked at 1 month, and then
returned toward baseline by 6 months (Figure 4, A and B).
TABLE 3. Median (Range) Values of OxLDL Markers and Lp(a)
in the Control Group
Before
Lp(a), mg/dL
16.0 (1.0–108.0)
After
16.0 (1.0–93.0)
OxLDL-E06
6215 (3331–75 883)
6475 (2870–68 202)
MDA-LDL IgM
9086 (2517–38 591)
9027 (1897–36 406)
MDA-LDL IgG
3366 (1247–15 136)
3359 (845–18 602)
IC IgM
2702 (1618–6118)
2364 (278–6512)
IC IgG
2455 (949–18 483)
2474 (836–19 626)
Units of OxLDL markers are in relative light units.
Figure 1. Spearman correlation of OxLDL-E06 and Lp(a) levels
for all patients at all time points.
Tsimikas et al
OxLDL and Lp(a) in PCI
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Relation of Angiographic Variables to
OxLDL Markers
There were no significant associations between OxLDL
markers or Lp(a) and angiographic characteristics, nor were
there significant associations in patients undergoing balloon
angioplasty versus stent placement (data not shown).
Clinical Outcomes
Two patients (1 each in the balloon and stent groups) had
subacute vessel occlusion at day 4 and had a myocardial
infarction. One patient died suddenly at day 7. Six-month
follow-up showed only 1 non–target vessel revascularization
and 35 target vessel revascularizations (33 PCI, 2 CABG)
related to restenosis. No significant differences in OxLDL
markers were noted between patients having nonrestenotic
events and the entire cohort.
Discussion
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Figure 2. Relative changes (mean percent change from pre-PCI
levels) of OxLDL-E06 (A) and Lp(a) (B) after PCI. *P⬍0.001 compared with other time points.
Cu-OxLDL (P⫽0.016) and MDA-LDL (P⬍0.0001) IgG titers also initially decreased in the post-PCI sample but
returned to baseline by 6 hours. Over the ensuing 6 months,
they demonstrated a modest but persistent increase (Figure 4,
C and D). No changes were noted in these markers in the
control group.
There was a reciprocal increase in IgM apoB-IC (P⫽0.021
by ANOVA) and a trend toward an increase in IgG apoB-IC
(P⫽0.099 by ANOVA, Figure 5) after PCI. Interestingly, the
levels returned to baseline by 24 hours and then peaked at 1
to 3 months, in parallel with the elevation in OxLDL
autoantibody titers. By 6 months, the apoB-IC levels had
returned to baseline. No changes were noted in these markers
in the control group.
This study demonstrates for the first time that PCI results in
acute plasma elevations of both OxLDL-E06 and Lp(a).
Plasma oxidized phospholipid epitopes detected by E06
(OxLDL-E06) were predominantly physically associated
with Lp(a) in all samples tested except in the immediate
post-PCI sample, in which they were bound to both non–
Lp(a)-containing apoB-100 particles and Lp(a) but transferred to Lp(a) particles within 6 hours. In addition, a strong
correlation was confirmed between OxLDL-E06 and Lp(a).11
This may have pathophysiological consequences, as such
OxPL have been shown to have a variety of proinflammatory
properties.18,19 In addition, the long-term OxLDL antigen/
autoantibody responses were consistent with OxLDL acting
as an immunogen in patients who were already sensitized by
previous exposure. These observations support the hypothesis
that OxPL are present in disrupted plaques and are released
into the circulation by PCI, where they are bound by
apoB-containing lipoproteins, and preferentially by Lp(a).
Furthermore, they define a novel relation between OxPL and
Lp(a) and suggest new insights into the role of Lp(a) in
normal physiology as well as in atherogenesis.
What is the cause of the rise in OxPL and Lp(a) after PCI?
One possibility is that both OxPL and Lp(a) are derived from
disrupted plaque contents, inasmuch as both have been
previously documented to be enriched in atherosclerotic
lesions in vivo.1–3,5,9,10,20 In fact, recent work in animal
models demonstrates that OxLDL can be imaged noninvasively with radiolabeled oxidation-specific antibodies.2,5 Sev-
Figure 3. Levels of Lp(a) (A), OxLDL-E06
(B), and apoB-100 (C) in plasma after in
vitro precipitation of Lp(a) with increasing
doses of antibody LPA4. Data represent
mean values of samples obtained from 5
patients at indicated time points before
and after PCI. Patients studied had the
highest values of Lp(a) and OxLDL-E06
in the post-PCI sample.
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June 29, 2004
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Figure 4. Relative changes (mean percent change from pre-PCI levels) of Cu-OxLDL IgM (A), MDA-LDL IgM (B), Cu-OxLDL IgG (C), and
MDA-LDL IgG (D) levels after PCI. *P⬍0.001 compared with other time points.
eral studies have clearly documented that PCI results in
plaque compression, redistribution, or disruption, and intimal
and medial dissection; that emptied plaque cavities are noted
in patients with spontaneous plaque rupture; and that placing
stents in patients with unstable angina leads to a marked
reduction in plaque burden, suggesting compression and
embolization of plaque material.21
Another possibility for the rise in plasma content of OxPL
but probably not Lp(a) is a consequence of transient oxidative
stress secondary to ischemia/reperfusion occurring during
PCI causing increased lipid peroxides. Buffon et al22 observed transient (⬍15 minutes’ duration) elevation of free
lipid peroxides in the coronary sinus during balloon occlusion
of the left anterior descending coronary artery. However, in
contrast to our study, in which OxPL were present in the
systemic circulation, lipid peroxides were not present in the
systemic circulation or after PCI of the right coronary artery.
Although the E06 assay does not detect lipid peroxides, it is
possible that lipid peroxides generated secondary to such
ischemia/reperfusion may oxidize phospholipids in the vessel
wall or even in plasma, which would then be subsequently
detected as OxPL (eg, EO6 reactivity) bound to LDL or Lp(a)
in plasma. Further studies are needed to explore this
possibility.
Another possibility for the acute increases in Lp(a) is rapid
synthesis of apo(a) by the liver (possibly by cytokines upregulated during PCI), where it may bind to LDL, creating
Lp(a) particles. Perhaps apo(a) was released from a pre-
formed hepatic pool. For example, it is possible that release
of OxPL from the plaque upregulates liver apo(a) synthesis,
as the apo(a) gene has an IL-6 response element leading to
enhanced transcription,23 similar to the effect of cytokines
that upregulate C-reactive protein synthesis. Patients with the
highest baseline Lp(a) levels had the greatest absolute increases in Lp(a) after PCI. The mean Lp(a) levels rose on
average by ⬇8 mg/dL (from 21.7 to 29.8 mg/dL) before PCI
to after PCI. Assuming a 6-L plasma volume, this suggests
that the absolute plasma Lp(a) content, on average, was
increased by ⬇500 mg during the time it takes to perform
PCI. However, despite the fact that Lp(a) correlates with
angiographic disease and has a predilection for and is
enriched in unstable atherosclerotic plaques,20,24 it seems
unlikely that this amount of Lp(a) is derived from the site of
plaque disruption alone.
What are the clinical consequences of the increased plasma
levels of these substances during PCI? In the present study,
patients with procedural complications were excluded by
definition, and nonrestenotic major adverse cardiac events
were exceedingly low in these patients with stable angina.
However, data from experimental and human13 studies have
suggested that OxLDL and in particular OxLDL-E06,14 as
well as Lp(a), contain vasoactive moieties.25 It is possible that
release of such vasoactive substances during PCI may lead to
vasoconstriction of the microvasculature and no-reflow
phenomenon.
Tsimikas et al
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Figure 5. Relative changes (mean percent change from pre-PCI
levels) of apoB-IC IgM (A) and IgG (B) levels before and after PCI.
The association between OxLDL-E06 and Lp(a) has been
documented only recently,11 and a potential pathophysiological link was provided by demonstrating binding of proinflammatory OxPL by Lp(a) and even covalent adduct formation with apo(a).26 We have recently shown that kringle V of
apo(a) covalently binds ⬇2 moles of OxPL detected by
antibody E06 and that this portion of apo(a) induced IL-8
production by macrophages.26 We recently demonstrated that
both OxLDL-E06 and Lp(a) rise concurrently after acute
coronary syndromes, but unlike the present study, in which
levels increased only after PCI in otherwise uncomplicated
procedures, levels remained elevated up to 3 to 6 months.11 In
the present study, we documented for the first time a transient
disassociation of OxLDL-E06 and Lp(a) in the post-PCI
samples, suggesting that these two compounds are independently generated to some extent but later reassociate. We
have suggested that Lp(a), compared with LDL, preferentially binds such OxPL, and in vitro transfer studies suggest
this hypothesis (Tsimikas, Witztum, unpublished observations). Thus, we suggest that Lp(a) acts as a “sink” for such
OxPL in vivo, providing a mechanism for their transport and
potentially even their degradation, as it has been reported that
Lp(a) contains a high content of platelet-activating factor
acetylhydrolase, which would destroy the proinflammatory
properties of OxPL by removing the oxidized fatty acid.27,28
From these data, we hypothesize that a potential physiological role for Lp(a) may be to protect organisms from oxidative
stress. In this way, it may be part of the innate immune
OxLDL and Lp(a) in PCI
3169
response, similar to C-reactive protein, which has also been
shown to bind OxLDL.29 This would suggest that low levels
of Lp(a) may actually be beneficial. On the other hand, its
atherogenicity may rise from the fact that when plasma levels
of Lp(a) are elevated, an enhanced number of Lp(a) particles
would enter the vessel wall, where Lp(a) is preferentially
bound to the extracellular matrix, and, with its enhanced
content of OxPL, Lp(a) would have profound proinflammatory properties.18
The long-term immunogenic responses to the released
OxLDL are unique observations and confirm that OxLDL
plays a role in initiating immune responses in atherogenesis.30,31 The immediate decline in free autoantibody levels
probably represents acute immune complex formation, as
apoB-IC rose simultaneously. If one assumes that the released
products of OxLDL, such as OxPL measured in our assay, are
proinflammatory and promote endothelial dysfunction, then
the trapping of these epitopes by such autoantibodies may be
beneficial. The long-term increase in IgG and IgM autoantibodies presumably reflects an anamnestic response or synthesis of totally new species of OxLDL antibodies and is
consistent with acute presentation of OxLDL to a previously
sensitized immune system. Whether these long-term responses are protective (or even adverse) is not clear, although
immunization of animals with OxLDL32,33 or pneumococcal
vaccine,34 which results in increased OxLDL autoantibodies,
provides protection against atherosclerosis. However, additional immune mechanisms are probably involved in this
protection, and further research is needed to determine the
role of OxLDL autoantibodies in human disease.30,31
Limitations of this study include the fact that direct capture
and analysis of embolized debris for OxLDL and Lp(a) were
not performed. Thus, the immediate source of increased
levels of OxLDL-E06 and Lp(a) in plasma and the direct
underlying mechanisms responsible for these changes were
not investigated. In addition, the patient cohort was composed
only of patients with stable angina undergoing elective,
uncomplicated procedures with fairly uniform and simple
lesion characteristics; therefore, it is not clear if patients with
complications during PCI would have similar changes.
In conclusion, PCI results in acute elevations of OxLDLE06 and Lp(a) and long-term OxLDL/autoantibody responses. These observations provide impetus for further
studies into the role of OxLDL in plaque disruption, ischemia/reperfusion, and coronary blood flow during PCI and the
physiological role of Lp(a) and its potential atherogenicity.
Acknowledgments
This investigation was supported by National Heart, Lung, and
Blood Institute grant HL-56989 (La Jolla Specialized Center of
Research in Molecular Medicine and Atherosclerosis, E.R.M.,
L.K.C., S.T., J.L.W.). We thank Joseph Juliano for expert technical
assistance.
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Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids
and Lipoprotein(a): Short-Term and Long-Term Immunologic Responses to Oxidized
Low-Density Lipoprotein
Sotirios Tsimikas, Herbert K. Lau, Kyoo-Rok Han, Brian Shortal, Elizabeth R. Miller, Amit
Segev, Linda K. Curtiss, Joseph L. Witztum and Bradley H. Strauss
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Circulation. 2004;109:3164-3170; originally published online June 7, 2004;
doi: 10.1161/01.CIR.0000130844.01174.55
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