Background Patients with coronary artery disease and abnormalitiesof serum lipid levels often have endothelial vasodilator dysfunction,which may contribute to ischemic cardiac events. Whether cholesterol-loweringor antioxidant therapy can restore endothelium-dependent coronaryvasodilatation is unknown.
Methods We randomly assigned 49 patients (mean [±SD]serum cholesterol level, 209±33 mg per deciliter [5.40±0.85mmol per liter]) to receive one of three treatments: an AmericanHeart Association Step 1 diet (the diet group, 11 patients);lovastatin and cholestyramine (the low-density lipoprotein [LDL]–loweringgroup, 21 patients); or lovastatin and probucol (the LDL-lowering–antioxidantgroup, 17 patients). Endothelium-dependent coronary-artery vasomotionin response to an intracoronary infusion of acetylcholine (10-8to 10-6 M) was assessed at base line and after one year of therapy.Vasoconstrictor responses to these doses of acetylcholine areconsidered to be abnormal.
Results Treatment resulted in significant reductions in LDLcholesterol levels of 41±22 percent in the LDL-lowering–antioxidantgroup and 38±20 percent in the LDL-lowering group (P<0.001vs. the diet group). The maximal changes in coronary-arterydiameter with acetylcholine at base line and at follow-up were-19 and -2 percent, respectively, in the LDL-lowering–antioxidantgroup, -15 and -6 percent in the LDL-lowering group, and -14and -19 percent in the diet group (P<0.01 for the LDL-lowering–antioxidantgroup vs. the diet group; P = 0.08 for the LDL-lowering groupvs. the diet group). (The negative numbers indicate vasoconstriction.)Thus, the greatest improvement in the vasoconstrictor responsewas seen in the LDL-lowering–antioxidant group.
Conclusions The improvement in endothelium-dependent vasomotionwith cholesterol-lowering and antioxidant therapy may have importantimplications for the activity of myocardial ischemia and mayexplain in part the reduced incidence of adverse coronary eventsthat is known to result from cholesterol-lowering therapy.
Hypercholesterolemia is a health risk, and epidemiologic studieshave shown a link between total cholesterol levels and the riskof cardiac events.1,2 Studies have shown that lowering the levelsof total and low-density lipoprotein (LDL) cholesterol can resultin a decrease in cardiac morbidity and mortality.3,4 Angiographicstudies of coronary arteries have demonstrated a disparity betweenthe decrease in cardiac events and the extent of regressionof coronary-artery lesions. Mechanisms other than the regressionof coronary stenoses may therefore be important in the beneficialeffect of cholesterol lowering.5,6
The healthy endothelium, in part by the release of paracrinefactors such as nitric oxide, has an important role in maintainingvascular integrity.7,8 In vitro studies have shown that LDLcholesterol and, in particular, its oxidized derivative areinjurious to the endothelium.9 Abnormalities in the coronary-arteryvasomotor response to acetylcholine, an endothelium-dependentvasodilator, can be observed in patients with atherosclerosis.10A close relation between abnormalities in lipids and coronary-arteryendothelial dysfunction has also been demonstrated.11,12 However,the benefits of reducing the levels of LDL cholesterol and ofantioxidant therapy in restoring endothelial function have notbeen examined in the clinical setting. In a controlled clinicaltrial, we sought to test the hypothesis that a reduction inLDL cholesterol levels or the combination of such reductionwith antioxidant therapy would improve the impaired endothelium-dependentvasodilator responses seen in the coronary arteries of patientswith atherosclerosis.
Methods
Patient Population
Patients were eligible for the study if they had a total serumcholesterol level before catheterization of 180 to 280 mg perdeciliter (4.7 to 7.2 mmol per liter) and were not receivingcholesterol-lowering medication. Patients were excluded if theyhad uncontrolled hypertension, diabetes mellitus, or heart failure;if they were cigarette smokers; or if they had recently hada myocardial infarction.
Sixty-seven patients were recruited and randomly assigned inapproximately equal numbers to the three treatment groups, afterwhich they underwent base-line evaluation. Complete data, includingthe results of coronary angiography and testing of coronary-arteryvasomotion after one year of follow-up, were available for 49patients, who formed the study population. There was no differencein demographic characteristics, the degree of atherosclerosis,or the base-line vasomotor response between the study populationand the 18 patients who did not complete the protocol.
Study Design
Assessment of Endothelium-Dependent Vasomotion
Written informed consent was obtained from the patients beforecatheterization in accordance with the guidelines establishedby the Committee for the Protection of Human Subjects. Long-actingvasoactive medications taken by the patients, including calcium-channelblockers, beta-blockers, nitrates, and angiotensin-converting–enzymeinhibitors, were discontinued for at least 18 hours before catheterization.
Endothelium-dependent vasomotion was assessed by serial intracoronaryinfusions of acetylcholine (Miochol, Iolab Pharmaceuticals,Claremont, Calif.), with final estimated intracoronary concentrationsof 10-8 to 10-6 M. Endothelium-independent vasomotion was assessedby an infusion of nitroglycerin at 16 µg per minute, accordingto an established protocol.10 Serum lipid concentrations weremeasured in the cardiac catheterization laboratory for all patientsat base line and follow-up, with the patient fasting. Quantitativecoronary angiographic images were obtained after each interventionwith a previously validated method, and at the follow-up studythe patients were studied in the same catheterization laboratorywith the same imaging protocol.
Treatment
After the initial study of coronary vasomotion, the patientswere randomly assigned to receive one of three treatments: anAmerican Heart Association Step 1 diet (the diet group); thesame diet plus lovastatin and cholestyramine (the LDL-loweringgroup); or the same diet plus lovastatin and probucol (the LDL-lowering–antioxidantgroup). There was no blinding with respect to treatment assignments.All the patients received dietary instruction from a registereddietitian. The medications were titrated over the first twomonths to the maximal tolerable doses.
Quantitative Coronary Angiography
Technically suitable single-plane angiograms were selected forcomputer analysis on the basis of a previously described method.10An automated edge-detection program was used to search densitiesand seek inflection points, measuring the diameter of the vesselalong the 8-to-10-mm length of the selected segment (QuantumIC software, ImageComm, Sunnyvale, Calif.). The percentage ofchange in diameter was determined for each dose of acetylcholine,and the maximal constriction was also noted. In the analysis,the average of the responses in two coronary-artery segmentswas calculated for each patient in order to determine an averagepercentage of change in diameter in response to acetylcholineand nitroglycerin. The segments were matched in the follow-upstudy with respect to anatomical determinants, such as sidebranches. The angiograms were coded and digitized by the investigatorsand were analyzed by a single technician who was unaware ofthe patients' treatment assignments and the phase of the study.
Statistical Analysis
The differences between treatment groups in clinical characteristicsand lipid profiles were analyzed by a two-way repeated-measuresanalysis of variance. The primary end point, the average changein the maximal coronary vasomotor response to acetylcholinein two coronary-artery segments, was analyzed by a two-way repeated-measuresanalysis of variance with treatment group and time taken intoaccount. Testing included a Bonferroni correction as appropriate.Linear regression analysis was used to compare the continuousrelation between changes in the response to acetylcholine andchanges in lipid measurements and clinical characteristics.A two-sided P value of less than 0.05 was considered to indicatestatistical significance. Data are expressed as means ±SDunless otherwise specified.
Results
Characteristics of the Patients
The study population consisted of 49 patients, 37 men and 12women, with a mean age of 56±9 years. Eleven patientswere randomly assigned to the diet group, 21 to lovastatin andcholestyramine (the LDL-lowering group), and 17 to lovastatinand probucol (the LDL-lowering–antioxidant group). Thebase-line characteristics of the patients are shown in Table 1.
Table 1. Clinical Characteristics of the Study Patients.
Ninety-two percent of the patients had angiographic evidenceof atherosclerosis. Only 4 patients (8 percent) had smooth coronaryarteries, whereas 2 (4 percent) had irregularities, 24 (49 percent)had single-vessel coronary disease, and 19 (39 percent) haddouble-vessel disease. Atherosclerosis was equally distributedamong the three groups. Coronary angioplasty of a coronary vesselother than the study vessel was performed in 35 patients (71percent) at the time of the base-line vasomotion study.
Clinical Follow-Up
During the treatment phase and before the completion of theone-year follow-up study, 11 patients presented with symptomssuggestive of recurrent ischemia and underwent diagnostic catheterization(3 in the diet group, 2 in the LDL-lowering group, and 6 inthe LDL-lowering–antioxidant group). There was no statisticaldifference among the groups with respect to the proportion requiringtreatment.
Adverse effects attributable to the study medications occurredonly in the patients receiving cholestyramine. Constipationor gastrointestinal upset was severe enough to cause the discontinuationof cholestyramine therapy in four patients, and to cause a decreasein the dose in three. The mean dose of cholestyramine at thefollow-up study was 12 g per day. There were no adverse effectsof lovastatin therapy. The mean doses were 62 mg per day inthe LDL-lowering group and 61 mg per day in the LDL-lowering–antioxidantgroup. The patients in the LDL-lowering–antioxidant groupreceived 500 mg of probucol twice a day without side effects.
Changes in Lipid Profiles
The lipid profiles in the three treatment groups at base lineand at the one-year follow-up are shown in Figure 1. There wereno differences among the three groups in lipid measurementsat base line. The mean decreases in total and LDL cholesterollevels in the LDL-lowering group (23±13 percent and 38±20percent, respectively) and in the LDL-lowering–antioxidantgroup (33±15 percent and 41±22 percent) were significantlydifferent from that in the diet group (P<0.001), but notfrom each other. The mean decrease in high-density lipoprotein(HDL) cholesterol in the LDL-lowering–antioxidant group(21±14 percent) was significantly different from thechanges in both the diet group and the LDL-lowering group (P<0.001).There was no significant change in triglyceride levels frombase line to follow-up in any of the groups.
Figure 1. Mean (±SE) Lipid Levels in the Three Study Groups at Base Line and after One Year of Therapy.
To convert values to millimoles per liter, multiply by 0.02586. Asterisks indicate P<0.001 for the comparison with the diet group; the dagger indicates P<0.001 for the comparisons with the diet group and the LDL-lowering group.
Coronary-Artery Vasomotor Function
At base line there was no significant difference among the threetreatment groups in the vasomotor response of epicardial coronaryarteries to either acetylcholine or nitroglycerin.
For the patients in the LDL-lowering–antioxidant group,the mean maximal change in coronary-artery diameter in responseto acetylcholine was -19±19 percent at base line, ascompared with -2±18 percent at follow-up one year later(negative values indicate coronary vasoconstriction). LDL loweringalso reduced the constrictive response to acetylcholine, from-15±19 percent at base line to -6±18 percent atfollow-up. There was no change in the vasomotor response inthe diet group (-14±19 at base line vs. -19±18percent at follow-up). The improvement in the vasomotor responseto acetylcholine was significantly greater in the LDL-lowering–antioxidantgroup than in the diet group (P<0.01). However, the improvementin vasomotor response in the LDL-lowering group did not differfrom that in the diet group (P = 0.08).
When the analysis incorporated the entire dose–responsecurve (Figure 2 and Figure 3), there was a significant differenceamong the three groups with regard to the change in responseto acetylcholine (P = 0.02). There was more improvement in thedose–response curve to acetylcholine in the LDL-lowering–antioxidantgroup than in the diet group (P = 0.01), but the improvementin the LDL-lowering group did not differ from that in the dietgroup.
Figure 2. Mean (±SE) Change in Coronary-Artery Diameter in Response to Serial Infusions of Acetylcholine at Base Line and after One Year of Therapy in the Three Study Groups.
The improvement in the response from base line to follow-up in the LDL-lowering–antioxidant group was significantly greater than that in the diet group (P<0.05). Negative numbers indicate vasoconstriction.
Figure 3. Mean (±SE) Change in the Vasomotor Response to Acetylcholine after One Year of Therapy in the Three StudyGroups.
The vasodilator response to nitroglycerin, the endothelium-independentdilator, did not differ among the three groups at base lineor after one year of therapy.
Predictors of Improvement in the Response to Acetylcholine
The strongest univariate predictor of improvement in acetylcholine-inducedvasoconstriction was the degree of constriction at base line(r = 0.52, P<0.001). Patients whose coronary arteries hadmore constriction in response to acetylcholine at base linewere more likely to have improvement during the study period.The treatment group was also a strong univariate predictor ofchange in endothelial vasodilator function (r = 0.45, P = 0.006).There was a significant, but moderate, relation between improvementin acetylcholine-induced vasoconstriction and the degree ofreduction in the levels of both total and LDL cholesterol (r= 0.31, P = 0.04).
When stepwise multiple linear regression analysis was used,only the treatment group (P = 0.004) and the response to acetylcholineat base line (P<0.001) were significant predictors in a multivariateanalysis.
Discussion
This randomized, controlled study demonstrated that coronary-arteryendothelial dysfunction, which is characteristic of patientswith hypercholesterolemia and atherosclerosis, can be significantlyimproved by a combination of LDL-lowering and antioxidant therapy.
The endothelium is an important modulator of coronary vasodilationthrough the release of endothelium-derived nitric oxide, andthe response to acetylcholine depends on the integrity of thistissue.8 This endothelium-dependent pathway for nitric oxideis impaired in patients with atherosclerosis,10 probably becauseof the direct injurious effects of elevated levels of LDL cholesterolon the endothelium.11,12 In patients with coronary artery disease,vasoconstrictor responses may play a part in the pathogenesisof ischemia.13 Stenotic lesions have been shown to constrictin response to stimuli such as exercise or mental stress.14,15The responses observed to these stimuli parallel the vasoconstrictionobserved in response to acetylcholine in the same patients,suggesting the presence of an impairment in endothelium-dependentvasodilatation. In atherosclerosis induced by dietary hypercholesterolemia,cholesterol lowering improves vasodilator responses to acetylcholineboth in vitro and in vivo.16,17 In addition, functional improvementhas been shown to precede structural regression.18 Recently,Leung et al. demonstrated in an uncontrolled study that coronary-arteryendothelial function could be improved after six months of therapywith cholestyramine in patients with hypercholesterolemia butwith no angiographic evidence of atherosclerosis.19
The present study has shown that a medical regime combiningaggressive lowering of LDL cholesterol levels with antioxidanttherapy over a one-year period results in significant improvementin endothelium-dependent vasomotor responses to acetylcholine.Complete normalization of the response to acetylcholine wasnot seen, suggesting an attenuation rather than a normalizationof endothelial dysfunction. Whether a longer period of therapywould result in more improvement in the dilator response needsto be tested. It is encouraging to find that endothelial functioncan be significantly improved in patients with only mild hypercholesterolemia.
There is accumulating evidence to suggest that the oxidationof LDL particles is important in the pathogenesis of atherosclerosisand endothelial dysfunction.20 Experimental studies suggesttwo distinct mechanisms that link oxidative stress with impairmentin endothelium-dependent vasodilatation. First, an oxidizedLDL particle is markedly more effective than native LDL in impairingthe vasodilator response to acetylcholine.9,21 Lysolecithin,a product formed as a consequence of lipid peroxidation of LDLparticles, may be involved in the development of abnormal arterialvasomotion.22 Probucol is transported in lipoproteins, whereit acts as a chain-breaking antioxidant and inhibits lipid peroxidationand oxidative modification of LDL particles in vitro.23,24 Simonet al. administered probucol to cholesterol-fed rabbits anddemonstrated that its antioxidant effect improved endothelium-dependentresponses.25 Second, studies by Ohara and colleagues have suggestedthat hypercholesterolemia is a stimulus to the augmented generationof superoxide radicals by the endothelium.26 Superoxide directlyinactivates nitric oxide and may also increase the subsequentoxidation of LDL particles by the formation of peroxynitrite.27A recent in vitro study using isolated rabbit arteries has suggestedthat probucol improves endothelium-dependent vasodilator responsesin the presence of LDL, not only by protecting the LDL particleagainst oxidation, but also perhaps by scavenging oxygen freeradicals in the arterial wall.28
In our study, the patients randomly assigned to the LDL-lowering–antioxidantgroup had significantly better vasomotor responses to acetylcholineafter therapy than did those in the diet group or those treatedwith LDL lowering alone. The relative contributions of the loweringof LDL cholesterol levels and antioxidant therapy cannot beseparated on the basis of our results.
After adjustment for assignment to the LDL-lowering–antioxidantgroup, the remaining predictor of improvement in endothelialfunction was the base-line vasomotor response to acetylcholine.The patients with the most abnormal endothelial function atbase line were likely to show the greatest improvement. Improvementin levels of total or LDL cholesterol was related to improvementin endothelial function in a univariate analysis, but not inthe multivariate model after adjustment for assignment to treatmentgroup. This further suggests that other factors besides cholesterollowering, such as the antioxidant effect of probucol, may bepartly responsible for the improvement in endothelial vasodilatorresponses.
The clinical improvement seen with cholesterol-lowering therapyseems to be disproportionate to the small degree of anatomicalregression of atherosclerotic stenoses that can be achievedby this therapy.5,6 In plaques with large cholesterol pools,the resorption of cholesterol may diminish the propensity ofthe plaque to rupture.6 We suggest that, in addition to thismechanism, a beneficial effect on endothelial function may contributeto the clinically important benefit seen with cholesterol lowering.
About 25 percent of our patients did not complete the study,and there were more dropouts in the diet group than in the othertwo groups. However, there were no significant differences inthe demographic variables, the angiographic burden of atherosclerosis,or the vasomotor responses between these patients and the overallstudy population.
The LDL-lowering–antioxidant strategy was more effectivein restoring endothelial function than was the dietary treatment,which alone had little or no effect on lipid levels. The LDL-loweringregime improved vasomotor responses from base line, but therewas only a trend toward improvement in the LDL-lowering groupas compared with the diet group (P = 0.08). Although the magnitudeof improvement was less in the LDL-lowering group than in theLDL-lowering–antioxidant group, the two results were notsignificantly different. In clinical trials, it is often difficultto prove that one highly effective treatment is superior toanother, given the inherent limitations of the sample in studiesrequiring catheterization and populations less homogeneous thanthose in experimental studies. The relative contributions ofcholesterol lowering and antioxidant effects cannot be ascertainedfrom this study, but the results suggest that the beneficialeffects of probucol outweigh its potentially detrimental HDL-loweringeffects.
In conclusion, a combination of LDL cholesterol–loweringand antioxidant therapy improved endothelium-dependent vasodilatorresponses to acetylcholine in patients with coronary atherosclerosis.This observation may have important clinical implications forthe activity of myocardial ischemia and the reduction of adversecoronary events that is known to occur with cholesterol-loweringtherapy.
Supported by a Clinical Fellowship from the Alberta HeritageFoundation for Medical Research (to Dr. Anderson); a NationalHeart Foundation of Australia Ralph Reader Overseas ResearchFellowship (to Dr. Meredith); a Clinician-Investigator DevelopmentAward (1 K08 HL-02787) from the National Heart, Lung, and BloodInstitute (NHLBI) (to Dr. Yeung); grants (R29 HL-49954-01 andR01 HL-38780-05) from the NHLBI; an NHLBI Research Career DevelopmentAward (1 K04 HL-02566) (to Dr. Ganz); and grants (5P01 HL 48743and NCRR GCRC MO1 RR02635) from the National Institutes of Health.
We are indebted to Dr. Akimi Uehata and Dr. FrançoisCharbonneau for expert assistance with the coronary vasomotionstudies; to John Orav, Ph.D., for statistical assistance; toMs. Timi Manion for the determination of LDL oxidation susceptibility;to Ms. Danielle Delagrange, M.S., Ms. Karen Eddings, B.N., andMr. Michael Dyce for expert technical assistance; and to thestaff members of the cardiac catheterization laboratory fortheir support and enthusiasm.
Source Information
From the Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School (T.J.A., I.T.M., A.C.Y., A.P.S., P.G.), and the Department of Medicine and Biochemistry, Boston University School of Medicine (B.F.) — all in Boston.
Address reprint requests to Dr. Anderson at the Cardiovascular Division, 8th Floor, Foothills Hospital, 1403 29th St. N.W., Calgary, AB T2N 2T9, Canada.
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