© 1999 American Heart Association, Inc.
Vascular Biology |
Increased Systemic Oxidative Stress After Elective Endarterectomy
Relation to Vascular Healing and Remodeling
From the Centro per lo Studio dell’Ipertensione Arteriosa delle Dislipidemie e dell’Aterosclerosi (A.M., M.D.G., S.D.P., F. Costantini, F. Cipollone, D.D.C., F. Chiarelli, F. Cuccurullo), the Department of Medicine and Aging Science, Institute of General Surgery (S.U.), and the Department of Biomedical Science (T.B., F.R.), University "Gabriele D’Annunzio," Chieti, Italy.
Correspondence to Prof Andrea Mezzetti, MD, Padiglione Biologico, IV livello-V Dente, Via Pescara, 66013-Chieti Scalo, Italy. E-mail mezzetti{at}unich.it
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Abstract |
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Abstract—It has been reported that systemic and local redox state may have an important role in the functional and organic changes characterizing the process of vascular response to injury. Carotid endarterectomy to remove atherosclerotic plaque is followed by a long lasting healing and remodeling process that can be carefully followed over time with noninvasive ultrasonography. Plasma vitamin C concentration and native LDL (n-LDL) content in lipid peroxides, vitamin E, ß-carotene, and lycopene as well as LDL susceptibility to peroxidation were assessed in 45 patients undergoing elective endarterectomy for internal carotid stenosis, at baseline, 24 hours, 3 and 15 days, and 1 month after surgery. Serial duplex scans were performed in all patients postoperatively and 3, 6, and 12 months. The changes in far wall thickness (FW) and % renarrowing from postoperatively to 12 months were used as remodeling indices. Plasma antioxidant vitamins and lag-phase showed a sharp and significant decrease during the first 24-hours after surgery remaining unchanged until the third day, whereas, an opposite trend was evidenced for n-LDL content in lipid peroxides and serum ceruloplasmin. After the third day all the parameters returned progressively to baseline within one month from endarterectomy. Interestingly, the n-LDL lipid peroxide content, the serum ceruloplasmin and the plasma vitamin C concentration, measured at 24 and 3 days from surgery, were significantly associated to the change in % renarrowing from postoperatively to 12 months. The higher the LDL content in lipid peroxides, the higher the serum level of ceruloplasmin, the lower the plasma content in vitamin C and the higher the % of vessel renarrowing. In conclusion, carotid endarterectomy with atherosclerotic plaque removal is associated with an acute and prolonged increase in systemic oxidative stress that influences vascular healing and late luminal loss.
Key Words: endarterectomy • LDL oxidation • carotid artery • healing • vascular remodeling • ultrasonography
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Carotid endarterectomy to remove atherosclerotic plaque restores blood flow and reduces the risk of cerebral ischemia.1 This current surgical procedure is followed by a long-lasting healing and remodeling process that in 4% to 22% of patients may induce the development of a recurrent carotid stenosis.1 2
Vascular repair and remodeling is a very complex phenomenon that involves a local intense inflammatory response, smooth muscle cell proliferation and migration, and extracellular matrix production and contraction. Thus it may be considered the vascular manifestation of a general biological response to tissue injury, reflecting the systemic wound-healing process.3 4 5 In this light it has recently been suggested that systemic and local redox states may have an important role in the functional and organic changes that characterize vessel healing and remodeling after invasive therapeutic procedures.6 7 8 In an animal model it has been shown that vascular repair is negatively influenced by a high oxidation state of circulating LDL and benefits from antioxidant vitamin administration.9 Recently, in humans, vascular surgery such as carotid endarterectomy and coronary angioplasty have been found to be associated with a transient increase in systemic oxidative stress.10 11 12 13 To investigate whether changes in systemic and LDL oxidative status may be associated with vascular healing and remodeling after an invasive therapeutic procedure, we chose the model of the internal carotid artery subjected to elective endarterectomy. This artery does not restenose very often to the extent that symptomatic recurrence needs further intervention,14 15 but the healing and remodeling process is easy to study over time with noninvasive ultrasonography.14 15 16
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Methods |
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Patient Selection
Forty-five patients (35 men, 10 women) admitted to the Vascular Surgery Division of The General Hospital of Chieti (Italy) for elective internal carotid endarterectomy were enrolled in the study.
Selection Criteria
Only patients admitted to the hospital with an indication for
monolateral internal carotid endarterectomy were
eligible for the study. Inclusion criteria were patients 
50 years of
age (mean age±SD 63±9 years, range 50 to 75 years); 70% internal
carotid artery stenosis angiographically confirmed; history of
transient ischemic attacks or amaurosis fugax; or a single
nondebilitating stroke. All women were in the postmenopausal state, but
none of them was receiving hormone replacement therapy. Exclusion
criteria were current smoking; vitamin supplements or drugs with known
antioxidant activity taken within 1 month before surgery; diabetes;
previous carotid endarterectomy; impaired
consciousness; serious disabling diseases; prosthetic patch
angioplasty.
Characteristics of Patients Enrolled
Preoperative angiography demonstrated preocclusive lesions in 22
patients (>90%) and a 71% to 90% stenosis in the remaining
23 (Table 1
). All patients were
dyslipidemic (Fredrickson type IIa), and 68% were
pharmacologically well-controlled hypertensives. Ischemic heart
disease was diagnosed in 39% of the patients. None of the patients had
significant peripheral vascular disease. All patients were
receiving prophylactic treatment with aspirin (100
mg/d) and were following the step II American Heart Association
diet throughout the study.
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Follow-Up
The patients were followed up by serial duplex scanning
performed after surgery and at 3, 6, and 12 months after hospital
discharge. Only patients with high-quality B-mode ultrasonographic
images of the proximal internal carotid artery were retained in the
study. Fasting venous blood samples for determination of biochemical
parameters were obtained from all the patients soon before
surgery (baseline) and 24 hours, 3 days, 15 days, and 1 month
after endarterectomy.
This study was approved by the Ethics Committee of the School of Medicine of the University "Gabriele D’Annunzio" of Chieti (Italy). All patients included in this study gave written informed consent.
Carotid Endarterectomy Procedure
A standard elective endarterectomy procedure
was performed under general anesthesia by the same surgeon.
Intraluminal shunts were used for patients with history of stroke,
contralateral internal carotid artery stenosis, or occlusion
with internal stump pressure <50 mm Hg.
Ultrasonographic Carotid Artery Measurements
Real time, B-mode ultrasound was used to evaluate the internal
carotid artery. All examinations were performed by the same trained
sonographer with a Hewlett Packard model 77030A ultrasound imaging
system equipped with a 7.5-MHz transducer. Subjects were examined in
the supine position, with a slight hyperextension of the neck. The
internal carotid arteries were examined in a series of cross-sectional
scans to select the angle of interrogation that would lead to a
perpendicular longitudinal view at the site of the maximal wall
thickness. The same interrogation angle was used for each patient
during follow-up. Each scan was magnified and recorded on
videotape. The indexes of renarrowing were measured from all of these
video recordings by the same scanning physician at the end of
the study period. The videotapes were read in random order, and the
reader was blinded to the name of the patient and the number of the
follow-up visit. In all the patients, the new intima-media thickness of
the far wall (FW) and the percentage of renarrowing were measured after
surgery and at 3, 6, and 12 months after hospital discharge. The FW
thickness corresponds to the averaged value obtained on a 1-cm-long
longitudinal section starting from the flow divider. The parietal
thickness of the far wall was considered the distance from the leading
edge of the first echogenic bright line (lumen–new intima interface)
to the leading edge of the second echogenic line (wall-adventitia
interface).17 All measurements were made at
end-diastole by ECG triggering, with electronic calipers.
Percentage of vascular renarrowing was calculated at the point of
maximal lumen narrowing by dividing the difference of the reference
lumen diameter (RLD) and the minimum lumen diameter (MLD) by the RLD,
with the use of the morphometry software of the echo
unit.17 The MLD was considered the distance between the
leading edge of the new intima-lumen interface of the near wall and the
leading edge of the lumen–new intima interface of the
FW.18 The percent changes in FW thickness and in percent
renarrowing (late luminal loss) from after surgery to 12 months of
follow-up were used as final measures of the vascular healing and
remodeling process. To assess intraobserver variability, 25% of the
scans were randomly selected and reexamined by the scanning physician.
The intraobserver coefficients of variation for FW thickness and
percent renarrowing were 6.9% and 6.4%, respectively.
Laboratory Methods
Serum Lipids and Lipoprotein Assay
Total serum cholesterol and
triglycerides were measured by standard enzymatic
techniques (Chod-Pap MPR1, Boehringer Mannheim). HDL
cholesterol was assessed by immunoturbidimetric technique.
The LDL cholesterol (LDL-C) was calculated by Friedewald’s
formula. Apoprotein AI and apoprotein B were determined by rate
nephelometry.19
Plasma Vitamin C Determination
Plasma vitamin C was immediately assessed by a
spectrophotometric method as previously described.19
LDL Isolation and Oxidation
Blood was drawn into test tubes containing EDTA (2.7
mmol/L). The LDL fraction was isolated by single vertical spin
ultracentrifugation with a discontinuous NaCl/KBr
density gradient as previously reported.20 21 22 LDL protein
and cholesterol were determined by established
methods.23 24
LDL (0.2 mg LDL-C/mL) oxidation was triggered by the addition of 5 µmol/L CuSO4 in phosphate-buffered saline, pH 7.4, 37°C. The lag phase preceding the formation of conjugated dienes was calculated as described previously.25
Lipid Peroxidation in Native LDL
To improve our measurement of native LDL (n-LDL) content in
oxidation products, we used 2 different indirect indexes of lipid
peroxidation.
Lipid peroxidation in n-LDL was assessed by measurement of fluorescent products of lipid peroxidation (FPLPs) and of thiobarbituric acid reactive substances (TBARS). FPLPs essentially reflect the interaction of aldehydic lipid peroxidation products with phospholipids and amino groups of the protein.21 25 26 27 The characteristic of these indicators is that they tend to be long-lived and to remain at the sites of oxidative damage.26 Briefly, an n-LDL sample (1 mL), diluted with PBS to a final protein concentration of 0.5 mg/mL, was mixed with 7 mL chloroform/methanol (2:1 vol/vol) plus water and briefly centrifuged. The lipid-containing phase was removed, dried under a stream of N2 gas at room temperature, resuspended in chloroform (2.5 mL), and exposed to ultraviolet light. Fluorescence values were estimated spectrofluorometrically at 360-nm excitation and 430-nm emission with the use of a Kontron SFM25 spectrofluorometer calibrated with quinine sulfate. Results were expressed as units of relative fluorescence (URF)/mg LDL-C.
The lipid peroxide content of n-LDL was also evaluated fluorometrically as TBARS.21 LDL (100 µg protein) was mixed with 1.5 mL of 0.67% thiobarbituric acid and 1.5 mL of 20% trichloroacetic acid containing 1 mg/mL EDTA. After heating at 100°C for 30 minutes, fluorescent reaction products were estimated spectrofluorometrically at 515-nm excitation and 553-nm emission with the use of a Kontron SFM25 spectrofluorometer. Freshly diluted tetramethoxypropane, which yields malondialdehyde (MDA), was used as a standard, and results were expressed as nanomoles of MDA equivalents per milligram of LDL-C (nmol MDA/mg LDL-C).
LDL Antioxidant Determination
LDL content in vitamin E, ß-carotene, and lycopene were
determined by HPLC as previously reported.20 21 Vitamins
were separated and quantified with the use of a Kontron system 450
equipped with a UV-visible, wavelength-variable Kontron Detector
430. Analysis was performed by isocratic elution. The flow rate
was 1.5 mL/min. The mobile phase, consisting of methanol-butanol-water
(89.5:5:5.5 vol/vol/vol), was premixed and vacuum-filtered through a
0.45-µm polypropylene membrane filter (Whatman) before use.
Autoinjection of 10 µL of organic extract was performed with the use
of a Waters autoinjector (model 717 plus Autosampler) refrigerated at
5°C. The analytical column used was a replaceable Partisphere 5
C18 cartridge (110 mmx4.7 mm ID,
5-µm particle size, Whatman) protected by a guard cartridge
(C18, 5 µm) system and maintained at
45°C. Vitamin E, tocopherol acetate (internal standard),
lycopene, and ß-carotene were detected by the UV-visible
spectrophotometer at different wavelengths programmed for
analysis as follows: at 0 minutes, 290 nm; 4.5 minutes, 280 nm;
15 to 22 minutes, 450 nm. Vitamins were expressed as micrograms per
milligram of LDL-C (µg/mg LDL-C).
Ceruloplasmin Assay
Serum ceruloplasmin concentration was measured by
immunonephelometry with a commercially available kit (QM300, Kallestad
Diagnostics Inc) and expressed as milligrams per liter
(mg/L). The coefficient of variation of ceruloplasmin content for
analytic reproducibility was 2.9%.
Statistical Analysis
Data are reported as mean±SD. An ANOVA for repeated measures
followed by a multiple comparison test (Scheffè’s test) was
performed to test the changes in biochemical and ultrasonographic
parameters measured over time. Simple and multiple linear
regression analyses were also used.
First, the relation between the biochemical parameters of interest measured at different time points (24 hours, 3 days, 15 days, and 1 month) and the indexes of vascular renarrowing measured as the percent change from after surgery to 12 months was tested by use of simple linear regression analysis. Successively, multiple regression analyses were performed to test the association between changes in FW thickness and percent renarrowing from after surgery to 12 months, and changes over a 24-hour and a 3-day period in those biochemical parameters resulted, at the univariate analysis, as being significantly associated with the ultrasonographic indexes. Thus we created 4 different multiple regression models in which changes in FW thickness and percent renarrowing from after surgery to 12 months were, alternatively, the independent variables, and the changes of the biochemical parameters over the 24-hour period or over the 3-day period represented the dependent variables. All models have been adjusted for potential confounders (levels of the biochemical parameters before surgery, body mass index [BMI], age, sex, ischemic heart disease, systolic blood pressure, percent stenosis before surgery, duration of surgery). Statistical analysis was performed with the STATVIEWS 4.5 software (Abacus Concepts Inc) for the Macintosh Performa 5300 computer.
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Results |
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Baseline clinical characteristics and levels of biochemical parameters of the patients enrolled in the study are reported in Table 1
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Ultrasonographic Measurements
The data are reported in Table 2.
The ultrasonographic follow-up was carried out in 42 of the 45 patients
enrolled in the study. Three male patients were excluded because of
poor ultrasonographic images.
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The FW thickness and the percent renarrowing of the internal carotid arteries increased significantly and progressively from after surgery to 12 months. FW increased from 0.88±0.23 to 1.58±0.41 mm (+79%, P<0.001) and percent renarrowing from 17±6.7% to 39±13.5% (+129%, P<0.001).
Time Course of Biochemical Parameters
Native LDL content in vitamin E, lycopene, ß-carotene, the lag
phase, and plasma vitamin C concentration showed a sharp and
significant decrease during the first 24 hours after surgery; these
changes persisted unmodified after 3 days and returned progressively to
baseline within 1 month of the surgical operation (Table 3). An opposite trend was seen for lipid
peroxide n-LDL content (both indexes) and serum ceruloplasmin, which
showed a rapid and significant increase in the first 24 hours, no
change until the third day, and subsequent lowering to initial values
after 1 month. The highest deviations from the baseline (measured at 24
hours) were n-LDL content in lipid peroxides (FPLPs, +53%,
P<0.001; TBARS, +32%, P<0.001, respectively)
and lycopene (-36%, P<0.001), plasma vitamin C (-27%,
P<0.001), and serum ceruloplasmin (+24%,
P<0.001). Lower but significant variations were
recorded for lag-phase duration (-21%, P<0.001),
n-LDL content in ß-carotene (-21%, P<0.001), and
vitamin E (-15%, P<0.001).
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Associations
First, the association between the biochemical variables and
the changes in vascular remodeling indexes were tested in a
univariate fashion. No statistically significant
association was observed between changes (from after surgery to 12
months) in both ultrasonographic indexes of vascular remodeling and
baseline clinical characteristics or biochemical parameters
(such as ceruloplasmin, n-LDL content in FPLPs or TBARS, plasma vitamin
C, and n-LDL content in lipophilic antioxidants). Serum ceruloplasmin,
n-LDL content in lipid peroxides (FPLPs and TBARS), and plasma vitamin
C concentration at 24 hours and 3 days were the only biochemical
parameters significantly associated with the changes in FW
thickness and in percent vascular renarrowing. The higher the lipid
peroxide n-LDL content, the higher the ceruloplasmin serum
concentration, the lower the vitamin C plasma level, and the higher the
percentage of renarrowing (Figures 1 and 2). FW thickness was also positively
related to n-LDL content in lipid peroxides (FPLPs: 24 hours,
r=-0.60, P<0.003; 3 days, r=-0.45,
P<0.04; TBARS: 24 hours, r=-0.49,
P<0.03; 3 days, r=-0.49, P<0.03,
respectively) and serum ceruloplasmin (24 hours, r=-0.70,
P<0.005; 3 days, r=-0.61, P<0.005,
respectively) and inversely related to plasma vitamin C, even if the
last relation did not reach statistical significance (24 hours,
r=-0.37, P<0.08; 3 days, r=-0.40,
P<0.07, respectively). On the basis of these results, we
investigated the association between changes in renarrowing indexes and
changes in these oxidative stress parameters over a 24-hour
and a 3-day period.
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Multiple regression analysis was performed as described
in detail in the Methods section. The final models included only FPLPs,
vitamin C, and ceruloplasmin (Table 4)
and were adjusted for potential confounders (levels of the biochemical
parameters before surgery, BMI, age, sex, ischemic
heart disease, systolic blood pressure, percent
stenosis before surgery, duration of surgery). A higher
increase in FPLPs (ß=2.372; P<0.0001) and ceruloplasmin
(ß=1.959; P<0.0001) over a 24-hour period was
significantly associated with a higher percentage of vascular
renarrowing at 12 months (Table 4). A higher decrease in
vitamin C (ß=-0.536; P=0.019) over a 24-hour period was
significantly associated with a higher percentage of vascular
renarrowing at 12 months (Table 4). This model was able to
explain 
71% (R2=0.708) of the
variation in the change in percent renarrowing over the 12 months. The
changes in these oxidative stress parameters over a 3-day
period showed a slightly more significant association with the change
in percent renarrowing over the 12-month period
(R2=0.712). A weaker association was
found when we used FW thickness as the dependent variable both for
changes in FPLPs, ceruloplasmin, and vitamin C over a 24-hour period
(R2=0.541) and for changes of the same
parameters over a 3-day period
(R2=0.585). This discrepancy between
the two ultrasonographic indexes should be mostly attributed to the
lesser sensitivity of the FW thickness as a measure of remodeling
compared with the percentage of vascular renarrowing. In fact, it is
well known that intimal thickness accounts for only a minor proportion
of the loss in lumen diameter and that the reduction in circumferential
dimension of the entire artery itself constitutes the major cause of
late luminal loss.5 6 On the contrary, the percent
renarrowing, which measures the degree of healing and remodeling as the
percent reduction of the lumen diameter at the site of maximal
narrowing, is expression not only of intima-media thickening but of
vascular contraction or expansion and thus is the most appropriate
index for the follow-up of lesions over a long period of
time.5 6
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Discussion |
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In this study we found that patients undergoing elective endarterectomy have a significant increase in systemic oxidative stress. This enhanced and long-lasting systemic oxidant burden was characterized by the concomitant increase in pro-oxidants and decrease in antioxidant blood levels and is mostly attributable to the inflammatory process after surgery and plaque removal.7 9 28 29 In fact, circulating inflammatory cells such as monocytes and neutrophils adhere to the site of injury, infiltrate the vessel wall, and produce high amounts of reactive oxygen species (ROS).7 28 29 30 Concomitantly, the hepatic production of several proteins is modified with a marked increase in serum level of ceruloplasmin.31 This increase may be caused in part by monocytes, which have recently been shown to be an important source of ceruloplasmin during the inflammatory response.32 Ceruloplasmin is a multifunctional protein that behaves as an acute-phase reactant; it tends to be raised after tissue damage or inflammation and it is a marker of severity of the inflammatory process.33 Moreover, it has recently been shown that intact ceruloplasmin has an important pro-oxidant activity and stimulates cell-mediated and non–cell-mediated LDL oxidation in vitro33 34 by the Haber-Weiss reactions or by a copper ion–dependent mechanism.32 33 These two characteristics might explain the association between ceruloplasmin change over time and vascular remodeling. In addition, plaque removal might release iron and copper in catalytic forms that favor free radical reaction.35 All these events may provide a pro-oxidant environment responsible of a striking increase in local and systemic free radical generation, which affects antioxidant consumption and promotes LDL oxidation. It is generally assumed that the oxidative modification of LDL occurs primarily in the arterial intima because of the many antioxidants present in blood plasma.36 However, we cannot exclude that in the presence of conditions favoring a systemic pro-oxidant/antioxidant imbalance such as the inflammatory process after surgery with plaque removal, a significant LDL oxidation may occur also in blood plasma.
In this regard, a recent study described a transient increase in systemic oxidant burden immediately after carotid endarterectomy, but it was short-lasting and returned to baseline a few minutes after surgery.11 In contrast, our results show a more complex and long-lasting phenomenon that appears to influence the process of vascular healing and repairing.
A major finding of our study was that the increased systemic oxidative stress level detected between the first and the third days after surgery was predictive of late luminal loss. In particular, the multivariate analysis showed that changes in lipid peroxide LDL content, ceruloplasmin, and vitamin C within 24 hours and 3 days of surgery were strong predictors of change in percent renarrowing and FW thickness over the 12 months. The high interindividual variability in the oxidative stress response crucially contributes to explain most of the differences observed in the entity of healing, remodeling, and late lumen loss.
The hypothesis that an excess of systemic ROS and increased LDL oxidative modification may influence the process of vascular healing and remodeling is supported by several animal studies.7 8 9 30 It has been reported that the presence of excess ROS stimulates intimal thickening, directly promoting migration and proliferation of vascular smooth muscle cells.30 Oxidative stress also decreases the effective concentration of nitric oxide in the vessel, which has been reported to have a growth-inhibitory effect on vascular smooth muscle cells, to decrease the expression of adhesion molecules for leukocytes, and to inhibit platelet aggregation.29 Moreover, oxidative cytotoxic products produced by vessel injury may enhance the inflammatory process, impair cellular repair and accelerate cell death, and favor prostaglandin and leukotriene synthesis and platelet aggregation.7 37 38 39 40 The severity of the inflammatory stage might predict the severity of wound healing and therefore the total amount of collagen and matrix formation produced as a result of an injury.3 4 7 Interestingly, a recent study has shown that the acute inflammatory changes peak at 24 hours after endarterectomy and disappear by the fifth day.3 4 All these data strongly support our findings, which attribute to the increase in systemic oxidative stress an important role in promoting and conditioning vascular healing and renarrowing.
Among antioxidants, only plasma vitamin C was inversely and
significantly related to percentage of lumen renarrowing (Figure 2). Our finding could be explained, considering that when free
radicals are formed in an aqueous environment, such as plasma, vitamin
C acts as the primary defense, whereas vitamin E is consumed only when
vitamin C is depleted. Thus in the case of an inflammatory process with
a short acute phase as that induced by
endarterectomy, vitamin C is likely to be more
important than vitamin E in reducing the inflammatory response through
early free radical scavenging.41 In particular, it has
recently been reported that during the inflammatory response,
myeloperoxidase released from activated neutrophils generates
high amounts of an aggressive ROS, mostly hypochlorous acid, which is
efficiently and specifically neutralized by vitamin
C.42 43 It has also been shown that vitamin C but not
vitamin E or probucol protect, in vivo, endothelium
from oxidized LDL–induced leukocyte adhesion and aggregate
formation.44
A further confirmation of our findings comes from recent studies demonstrating that among antioxidants, only probucol45 46 and vitamin C,47 administrated before or immediately after successful percutaneous transluminal coronary angioplasty, were able to significantly attenuate restenosis.
In conclusion, our study shows that surgical procedures to remove atherosclerotic plaque, such as elective carotid endarterectomy, are followed by an acute and long-lasting systemic oxidative stress and that the higher the oxidative stress, the higher the late luminal loss. Moreover, the interindividual variability in the oxidative stress response explains most of the interindividual differences in the entity of vascular remodeling. Finally, our data provide a biological plausibility to the effectiveness of an early treatment with antioxidants, started before any invasive procedure for vascular stenosis, to prevent late renarrowing.
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Acknowledgments |
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The skillful technical assistance given by Corrado Romano and Maria Di Riti is gratefully acknowledged.
Received September 9, 1998; accepted March 24, 1999.
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