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(Circulation. 1996;93:1647-1650.)
© 1996 American Heart Association, Inc.

Articles

Endothelium-Dependent Coronary Vasomotion Relates to the Susceptibility of LDL to Oxidation in Humans

Todd J. Anderson, MD; Ian T. Meredith, MBBS, PhD; François Charbonneau, MD; Alan C. Yeung, MD; Balz Frei, PhD; Andrew P. Selwyn, MD; Peter Ganz, MD

From the Cardiovascular Division (T.J.A., I.T.M., A.C.Y., F.C., A.P.S., P.G.), Brigham and Women's Hospital, Harvard Medical School, Boston; and the Department of Medicine and Biochemistry (B.F.), Boston University School of Medicine, Boston, Mass.

	Abstract

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Background Oxidatively modified LDL has been shown to markedly impair endothelium-dependent dilation in experimental studies. The aim of the present study was to determine the relation between the coronary vasomotor response to the endothelium-dependent agonist acetylcholine and the in vitro susceptibility of LDL to oxidation in patients.

Methods and Results Endothelium-dependent coronary vasomotion in response to acetylcholine (10^-8 to 10^-6 mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56±9 years) after 1 year of therapy with either an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation was determined by measuring the lag phase of conjugated diene formation induced by Cu²⁺. Patients treated with lovastatin and probucol had prolongation of the lag phase (263±64 minutes) compared with diet- (91±22 minutes) or lovastatin and cholestyramine– (118±57 minutes) treated patients (P<.0001). By univariate analysis, the coronary vasomotor response to acetylcholine was significantly related to the lag phase of conjugated diene formation (P=.002), cholesterol-lowering therapy (P=.002), and serum cholesterol (P=.02). By multivariate analysis, the lag phase remained a significant predictor of the acetylcholine vasomotor response, independent of the effect of cholesterol-lowering treatment.

Conclusions In patients treated with lipid-lowering agents, the vasodilator response to acetylcholine is related to the susceptibility of LDL to oxidation. These findings suggest that oxidative stress is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis and hypercholesterolemia.

Key Words: endothelium • endothelium-derived factors • antioxidants • acetylcholine • cholesterol

	Introduction

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Through the release of paracrine factors such as nitric oxide, the healthy endothelium plays an important role in maintaining vascular integrity.^{1 2} Abnormalities in the coronary vasomotor response to acetylcholine, an endothelium-dependent vasodilator, have been observed in patients with atherosclerosis³ or hypercholesterolemia.⁴ Accumulating evidence suggests that oxidative modification of LDL is important in the pathogenesis of atherosclerosis and endothelial dysfunction.⁵ The oxidized form of LDL is markedly more effective than native LDL in impairing the vasorelaxation to acetylcholine.⁶ Lysolecithin, a product formed as a consequence of lipid peroxidation in LDL, may be involved in the development of abnormal arterial vasomotion.⁷ High levels of cholesterol have also been shown to increase endothelial production of oxygen free radicals, which may bind to and inactivate nitric oxide.^{8 9} The relation between coronary vasomotion and LDL oxidation has not been explored in clinical studies. The aim of the present study was to relate coronary vasomotor responses to the endothelium-dependent agonist acetylcholine with the susceptibility of LDL to oxidation in humans.

	Methods

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Patient Population
The study population consisted of a subgroup of 23 patients who had been treated for 1 year as part of a recently reported cholesterol-lowering endothelial function study.¹⁰ In that study of 49 patients, patients treated with 1 year of lovastatin and probucol demonstrated a significant improvement in the coronary vasodilator response to acetylcholine compared with patients treated with diet. Only a trend for improvement was seen with patients treated with an LDL-lowering strategy (lovastatin and cholestyramine), suggesting that the antioxidant properties of probucol may be important. The ability of therapy to protect the LDL particle against oxidation was studied in a subgroup of patients who make up the present study group. Patients were randomized to receive an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). On the subgroup, we performed endothelium-dependent coronary vasomotion studies and a determination of the susceptibility of LDL to oxidation after 1 year of therapy. Details of the inclusion and exclusion criteria for the entire trial have been presented previously.¹⁰

Study Protocol
Written informed consent was obtained from patients before the catheterization procedure in accordance with the guidelines established by the Committee for the Protection of Human Subjects. Patients' long-acting vasoactive medications, including calcium channel blockers, ß-blockers, nitrates, and converting enzyme inhibitors, were discontinued for at least 18 hours before the catheterization. Cholesterol-lowering and antioxidant medications were taken up until the time of the study.

Endothelium-dependent and -independent vasodilation was tested with the use of serial intracoronary infusions of acetylcholine (10^-8 to 10^-6 mol/L) and nitroglycerin (16 µg/min), respectively.^{3 10} Quantitative coronary angiographic images were taken after each intervention.¹⁶ A nonionic contrast medium (Omnipaque) was injected into the left coronary artery at 7 mL/s for a total of 9 mL with a power injector (Medrad) to opacify the coronary artery.

At the time of the follow-up, vasomotion study blood was taken for lipids as well as for the determination of the susceptibility of LDL to oxidation.

Statistical Analysis
Quantitative Coronary Angiography
Technically suitable single-plane angiograms were selected for computer analysis on the basis of a previously described method.¹⁰ An automated edge-detection program was used to search densities and seek inflection points, thus allowing measurement of the segment diameter of the vessel along the length of the selected segment (ImageComm, Quantum IC software). Two segments 8 to 10 mm long were selected for analysis prospectively on the basis of being optimal regions for quantitative angiographic analysis. For analysis, the mean of the responses in the two coronary segments of each patient were used to create an average percent diameter change to acetylcholine (at the highest dose given) and nitroglycerin.

Determination of LDL Oxidation
The susceptibility of LDL to oxidation was determined by the formation of conjugated dienes induced by Cu²⁺ at the follow-up study. Briefly, fresh heparinized plasma was treated with G-25 gel filtration with the use of a rapid column centrifugation technique to remove water-soluble antioxidants. LDL was prepared from plasma with single vertical spin discontinuous density gradient ultracentriguation.¹¹ Isolated LDL was treated with chelex and filtered through a 0.2-µm syringe filter. LDL (0.1 mg of protein/mL) in PBS, pH 7.4, was exposed to Cu²⁺ (2.5 µmol/L) at 37°C. Lipid peroxidation was followed by measurement of diene conjugation at 234 nm. Absorbance was measured with a Hitachi U-2000 spectrophotometer. Absorbance was recorded at 10-minute intervals. Tangents were drawn to the segments of the absorbance curve corresponding to the lag and propagation phases of lipid peroxidation, and the length of the lag phase was determined as the intercept of the two tangents. Previous work has determined that the coefficient of variation for the length of the lag phase is 7.5% with this technique. A longer lag phase demonstrates a decreased susceptibility of the LDL particle to oxidation. In three patients in the lovastatin-plus-probucol group, the lag phase determination was terminated at 250, 250, and 300 minutes, and therefore these conservative values of lag phase were used in the analysis.

The lag phase was chosen because it was believed that this measurement is the most reliable, reproducible, and accepted marker of LDL oxidizability.¹² The lag phase relates to the antioxidant content of LDL, which is primarily what we were trying to alter with the probucol therapy, as has been shown in in vitro experiments.¹³

Statistical Analysis
Differences in the cholesterol indexes and vasomotor responses between baseline and 1-year follow-up values were determined with repeated-measures ANOVA. Differences in cholesterol indexes and the lag phase between the three groups were determined with one-way ANOVA. Linear regression analysis was used to compare the continuous relation between the maximum acetylcholine response and the lipid indexes and lag phase. Predictors of the acetylcholine response were explored with forward stepwise multiple linear regression analysis. Statistical significance was defined as two-sided P<.05. Data are expressed as mean±SD unless otherwise specified.

	Results

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Study Population
The study population consisted of 23 patients who had been treated for 1 year in one of three treatment arms: American Heart Association Step 1 diet (seven patients), lovastatin (mean, 60 mg/d) and cholestyramine (mean, 8 g/d) (seven patients), or lovastatin (mean, 60 mg/d) and probucol (1000 mg/d) (nine patients). There was no difference in the baseline demographics among the three groups. There was a significant decrease in the total and LDL cholesterol levels in both drug-treated groups and a significant decrease in HDL cholesterol in the lovastatin and probucol group compared with baseline (Table 1).

View this table: [in this window] [in a new window]   Table 1. Lipid Profile and Coronary Vasomotion

Coronary Vasomotion
Within the two drug groups, there was an improvement in the vasomotor response to acetylcholine after 1 year of therapy (P<.05). At the follow-up study, vasodilation in response to acetylcholine was restored in patients treated with either lovastatin and cholestyramine or lovastatin and probucol compared with the diet group (Table 1; P<.01), whereas there was no difference in the nitroglycerin responses.

LDL Oxidation
The susceptibility of LDL cholesterol to Cu²⁺-induced oxidation was assessed at the 1-year follow-up. Data from the time of the baseline study were not available. The time of the lag phase of conjugated diene formation was longer in the patients in the lovastatin-and-probucol group compared with the other two groups (Table 2; P<.0001). The lag phase of LDL oxidation in patients in the lovastatin-and-cholestyramine group was not different from that of diet-treated patients.

View this table: [in this window] [in a new window]   Table 2. Susceptibility of LDL to Oxidation

LDL Oxidation and Endothelial Function
The lag time of conjugated diene formation correlated closely with the acetylcholine response (r=.62, P=.002) (Figure). Other univariate predictors of the acetylcholine response included the treatment group (P=.002) and serum cholesterol (P=.02). By multivariate analysis, the lag time remained a significant predictor of the acetylcholine response, even after accounting for the treatment group. The cholesterol level was not a significant predictor in the multivariate model. Importantly, the lag time was predictive of the acetylcholine response, whereas standard lipid indexes, including total, LDL, and HDL cholesterol, apolipoprotein B, the ratio of LDL to apolipoprotein B, and triglycerides, could not be used to predict the response in this group of patients.

View larger version (12K): [in this window] [in a new window]   Figure 1. Relation between endothelium-dependent coronary vasomotion and the lag time to conjugated diene formation after 1 year of therapy. Increased lag time indicates decreased susceptibility to oxidation. Ach indicates acetylcholine. r=.62, P=.002.

	Discussion

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In the present study, we have shown in patients treated with lipid-lowering agents that the coronary vasomotor response to acetylcholine is related to the protection of LDL from oxidation. These findings extend to observations of patients from experimental studies that have shown a close relation between LDL oxidation and endothelial vasodilator dysfunction.

Furchgott and Zawadzki² were the first to demonstrate that the endothelium plays a central role in the control of vascular integrity through the release of factors such as nitric oxide. However, the biological action of nitric oxide is impaired in response to a number of injurious stimuli. LDL was initially shown to rapidly inhibit endothelium-dependent relaxation in vitro.¹⁴ Subsequent studies have suggested that oxidatively modified LDL is a more potent inhibitor of endothelium-dependent vasorelaxation.^{6 7 15} Lysolecithin, a product formed as a consequence of lipid peroxidation in LDL, may interfere with receptor-mediated stimulation of nitric oxide.⁷ Oxidized LDL may also interfere with signal transduction in the release of nitric oxide.¹⁶ Cholesterol has been shown to stimulate endothelial production of oxygen free radicals.⁸ Free radicals not only oxidize lipoproteins in the subintimal space but also directly bind to and inactivate nitric oxide.⁹

In vitro studies have demonstrated that probucol and vitamin antioxidants can improve endothelium-dependent vasorelaxation in arterial segments.^{17 18} This may occur as a result of protection of the LDL particle against oxidation or as a result of reduced oxygen-derived free radicals in the vessel wall.¹⁹

Clinical studies have confirmed that endothelium-dependent vasodilation is impaired in patients with atherosclerosis or hypercholesterolemia.^{3 4} However, the relation between endothelium-dependent vasorelaxation and the susceptibility of LDL to oxidation has not been explored. We recently completed a clinical trial that demonstrated that a combination of cholesterol-lowering and antioxidant therapy for 1 year improves endothelium-dependent coronary vasomotion in patients with atherosclerosis.¹⁰ Patients treated with lovastatin and cholesytramine demonstrated a trend for improvement in vasomotion compared with diet (P=.08), but a clear benefit was seen in the group treated with lovastatin and probucol.¹⁰ This suggested an added benefit from antioxidant therapy.

In the present study, we have shown that treatment with lovastatin and probucol markedly increased the lag phase of conjugated diene formation, indicating reduced susceptibility of LDL to oxidation. Probucol protects LDL from oxidation.²⁰ Improvement in coronary vasomotor response to acetylcholine was related to the degree of protection of LDL from oxidation. The lag phase was a significant predictor of the acetylcholine response, even after accounting for the effects of lipid-lowering treatment. Standard lipid indexes were not related to the vasomotor response in this patient population. Clearly, lovastatin and probucol may have other beneficial effects at the tissue level that lead to an improvement in endothelial function that we are unable to measure. This is confirmed in in vitro studies that have shown that oxidized LDL is an important inhibitor of endothelium-dependent vasorelaxation and that antioxidants may attenuate this dysfunction. This may be one mechanism by which antioxidant therapy exerts a beneficial effect in patients with atherosclerosis.⁵

Study Limitations
Only a small number of patients were studied, and determinations were available only at the follow-up study. However, even with only 23 patients, a significant relation was found between coronary vasomotion and the lag time. Also, the in vitro suspectibility of LDL to oxidation is only one measure of antioxidant effect. We are unable to assess free radical–scavenging effects or important tissue effects of the cholesterol-lowering therapies.

Conclusions
Endothelium-dependent coronary vasomotion is related to the susceptibility of LDL to oxidation. This suggests that the oxidative environment is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis. Antioxidant strategies may exert a beneficial effect on atherosclerosis through an endothelium-dependent mechanism.

	Acknowledgments

 
This study was supported by a Clinical Fellowship of the Alberta Heritage Foundation for Medical Research (Dr Anderson), a National Heart Foundation of Australia Ralph Reader Overseas Research Fellowship (Dr Meredith), NHLBI Clinician-Investigator Development Award 1-K08-HL-02787 (Dr Yeung), NHLBI grant R29-HL-49954-01 (Dr Frei), NHLBI grant R01-HL-38780-05 (Dr Selwyn), and NHLBI Research Career Development Award 1-K04-HL-02566 and NIH grant 5P01-HL-48743 (Dr Ganz). We thank Timi Manion for the determination of LDL oxidation susceptibility. We also thank Danielle Delagrange, MS, and Michael Dyce for expert technical assistance and the cardiac catheterization laboratory staff for their support and enthusiasm.

	Footnotes

 
Reprint requests to Todd J. Anderson, MD, Foothills Hospital, 1403-29th St NW, Calgary, Alberta, Canada T2N 2T9.

Received October 23, 1995; revision received November 9, 1995; accepted November 15, 1995.

	References

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