Effect of Exercise on Coronary Endothelial Function in Patients with Coronary Artery Disease
Rainer Hambrecht, M.D., Anamaria Wolf, M.D., Stephan Gielen, M.D., Axel Linke, M.D., Jürgen Hofer, B.S., Sandra Erbs, M.D., Nina Schoene, M.D., and Gerhard Schuler, M.D.
Background Studies of the cardioprotective effects of exercisetraining in patients with coronary artery disease have yieldedcontradictory results. Exercise training has been associatedwith improvement in myocardial perfusion even in patients whohave progression of coronary atherosclerosis. We therefore conducteda prospective study of the effect of exercise training on endothelialfunction in patients with coronary artery disease.
Methods We randomly assigned 19 patients with coronary endothelialdysfunction, indicated by abnormal acetylcholine-induced vasoconstriction,to an exercise-training group (10 patients) or a control group(9 patients). To reduce confounding, patients with coronaryrisk factors that could be influenced by exercise training (suchas diabetes, hypertension, hypercholesterolemia, and smoking)were excluded. In an initial study and after four weeks, thechanges in vascular diameter in response to the intracoronaryinfusion of increasing doses of acetylcholine (0.072, 0.72,and 7.2 µg per minute) were assessed. The mean peak flowvelocity was measured by Doppler velocimetry, and the diameterof epicardial coronary vessels was measured by quantitativecoronary angiography.
Results In the initial study, the two groups had similar vasoconstrictiveresponses to acetylcholine. After four weeks of exercise training,coronary-artery constriction in response to acetylcholine ata dose of 7.2 µg per minute was reduced by 54 percent(from a mean [±SE] decrease in the luminal diameter of0.41±0.05 mm in the initial study to a decrease of 0.19±0.07mm at four weeks; P<0.05 for the comparison with the changein the control group). In the exercise-training group, the increasesin mean peak flow velocity in response to 0.072, 0.72, and 7.2µg of acetylcholine per minute were 12±7, 36±11,and 78±16 percent, respectively, in the initial study.After four weeks of exercise, the increases in response to acetylcholinewere 27±7, 73±19, and 142±28 percent (P<0.01 for the comparison with the control group). Coronary blood-flowreserve (the ratio of the mean peak flow velocity after adenosineinfusion to the resting velocity) increased by 29 percent afterfour weeks of exercise (from 2.8±0.2 in the initial studyto 3.6±0.2 after four weeks; P<0.01 for the comparisonwith the control group).
Conclusions Exercise training improves endothelium-dependentvasodilatation both in epicardial coronary vessels and in resistancevessels in patients with coronary artery disease.
The vascular endothelium serves as an important modulator ofvasomotor tone and function by synthesizing and releasing nitricoxide.1 The coronary vascular response to acetylcholine dependson the integrity of the endothelium and the endothelial nitricoxide pathway.2 Coronary atherosclerosis is associated withprogressive impairment of coronary endothelial function. Sinceendothelium-derived nitric oxide is thought to be necessaryto maintain an adequate vascular response to increased blood-flowdemands during exercise, correction of endothelial dysfunctionhas become a goal of therapy. Endothelium-dependent coronaryvasodilatation has been improved by a variety of interventions,including the use of agents such as angiotensin-converting–enzymeinhibitors, ß-hydroxymethylglutaryl–coenzymeA reductase inhibitors, and antioxidants.3,4,5,6
Among the nonpharmacologic therapeutic options for patientswith stable coronary artery disease, regular physical exerciseis known to correct some risk factors for coronary artery diseaseand improve functional work capacity. In patients with symptomaticcoronary artery disease, endurance exercise training has beenshown to attenuate ST-segment depression during exercise7 anddecrease perfusion defects on thallium scanning,8 indicatinga possible increase in myocardial perfusion.
Advocates of exercise training for patients with coronary atherosclerosishave long faced the question of how exercise induces improvementin myocardial perfusion in the absence of any net regressionof epicardial coronary stenoses.9 Recruitment of collateralvessels during maximal exercise is one possible mechanism, butangiographic studies performed in patients at rest have failedto provide support for this hypothesis.10,11
The objective of this study was to determine whether aerobicexercise training has the potential to correct endothelial dysfunctionand improve coronary flow reserve in patients with coronaryartery disease.
Methods
Selection of Patients
Nineteen male patients (age, 70 years) with documented coronaryartery disease were recruited. Patients were eligible for thestudy if they had a hemodynamically important coronary-arterystenosis that required nonsurgical revascularization (percutaneoustransluminal coronary angioplasty) and a noncritical stenosisin another coronary vessel, which thus could be used for testing(the target vessel). To be suitable for testing, the targetvessel had to have signs of endothelial dysfunction, definedas either constriction (a decrease of 5 percent in the meanluminal diameter) or no change (a decrease of <5 percentor no decrease in the mean luminal diameter) in response toacetylcholine. Patients also had to have a symptom-free exercisecapacity of at least 50 W.
To minimize the effect of variables that could influence endothelialfunction, patients with any of the following conditions wereexcluded: diabetes, hypertension (a systolic blood pressureof >160 mm Hg or a diastolic blood pressure of >90 mmHg), hypercholesterolemia (a low-density lipoprotein cholesterollevel of 165 mg per deciliter [4.3 mmol per liter]), cigarettesmoking during the previous three months, ventricular tachyarrhythmias,chronic obstructive pulmonary disease, valvular heart disease,and a left ventricular ejection fraction of less than 40 percent.Patients who had undergone coronary-artery bypass graft surgery,had undergone a mechanical revascularization procedure duringthe previous three months, or had had myocardial infarctionduring the seven days before randomization were also excluded,as were patients with hematologic, renal, or hepatic dysfunction.
Study Protocol
The protocol of this study was approved by the ethics committeeof the University of Leipzig, and written informed consent wasobtained from all patients before randomization. The same testingprotocol was followed both for the initial study and for thefollow-up study at four weeks.
Treatment with any cardiovascular medication was discontinuedfor at least 24 hours before the measurement of coronary endothelialfunction. At base line, patients were given 15,000 U of heparinafter diagnostic coronary angiography or 24 hours after angioplastyin a vessel other than the target vessel, and an 8-French guidingcatheter was used to cannulate the left or right coronary artery.A 2.5-French infusion catheter (Transit Infusion Catheter, Cordis,Miami, Fla.) was then advanced over a 0.014-in. (0.036-cm) guidewire into a nonbranching segment of the target vessel. Thisguide wire contained a 12-MHz, pulsed Doppler ultrasound velocimeter(FlowMAP, Cardiometrics, Endosonics, Rancho Cordova, Calif.).The tip of the guide wire was positioned 1 cm distal to theend of the infusion catheter, close to an anatomical landmarkto facilitate its precise positioning at follow-up. The positionof the tip of the guide wire was documented by cineangiographyat the time contrast medium was injected. The maximal and meanpeak blood-flow velocity measured by the Doppler velocimeterwas continuously recorded throughout the test protocol and drugadministration. For the assessment of coronary blood flow, themean peak velocity was multiplied by the cross-sectional areaof the vessel segment of interest to generate a value for theflow, expressed in milliliters per minute.
Drug Administration
Saline (0.9 percent), acetylcholine (10 mg per milliliter; Dispersa,Germering, Germany), adenosine (3 mg per milliliter; SanofiWinthrop, Munich, Germany), and nitroglycerin (1 mg per milliliter;Schwarz Pharma, Monheim, Germany) were administered throughthe infusion catheter. The agents were given in the followingorder: saline for three minutes (base line); acetylcholine inincreasing doses (0.072, 0.72, and 7.2 µg per minute);saline for three minutes (return to base line); adenosine (2.4mg per minute); saline for five minutes (return to base line);and nitroglycerin (200 µg as an intracoronary bolus).Three-minute intervals were allowed between drug infusions topermit all variables to return to base-line values. Saline,acetylcholine, and adenosine were infused with an infusion pump(Braun, Melsungen, Germany) set to a flow rate of 2 ml per minute.
Quantitative Angiography
Serial coronary angiograms were obtained in the same projectionat the end of each infusion, as follows. A nonionic contrastagent (Xenetrix, Guerbet, Sulzbach, Germany) was manually injectedat low pressure through the guiding catheter. The artery ofinterest was centered and magnified, and then the image wasdigitized for subsequent computer analysis, as previously described.12The mean diameter of a 10-mm segment of interest was measured2 to 3 mm distal to the tip of the Doppler guide wire beforethe infusion of acetylcholine and then after the infusion ofeach successive dose, after the infusion of adenosine, and afterthe administration of nitroglycerin. The response of the segmentwas calculated as the percent change in the mean diameter ofthe segment after the infusion of acetylcholine at each doseas compared with its initial diameter after saline infusion.The mean luminal diameter was determined with the use of anedge-detection algorithm (Medis, Leiden, the Netherlands). Thecontrast-filled distal catheter was used as the standard forcalibration.
Maximal flow-dependent coronary vasodilatation was calculatedby measuring changes in the target-vessel diameter proximalto the tip of the infusion catheter after the administrationof adenosine. Coronary blood-flow reserve was calculated asthe ratio of the mean peak coronary blood-flow velocity afterthe administration of adenosine to the coronary blood-flow velocitywith the patient at rest.13
Follow-Up Studies
Two days after the invasive assessment of endothelial function,patients underwent symptom-limited spirometric testing duringexercise for the determination of peak oxygen uptake. The patientsexercised in the upright position on a calibrated, electronicallybraked bicycle ergometer. The work load was increased everythree minutes in steps of 25 W, beginning at 50 W. The invasiveassessment of endothelium-dependent vasodilatation and exercisetesting were repeated after four weeks.
Exercise-Training Program
After the initial study, patients were randomly assigned toeither an exercise-training group or a physically inactive controlgroup. Patients assigned to exercise training stayed in thehospital for the initial four weeks of the study period. Theywere expected to exercise, under close supervision, six timesper day for 10 minutes (in addition to 5 minutes for warmingup and 5 minutes for cooling down during each session); theyexercised on a bicycle ergometer at 80 percent of the heartrate they had reached during peak oxygen uptake in the initialexercise test. The mean (±SE) heart rate reached duringpeak oxygen uptake in the initial test was 134.4±3.8beats per minute, a value that was influenced by beta-adrenergic–receptorblockade in patients taking a beta-blocker (90 percent of thepatients in this group). Thus, during this four-week period,patients trained at a mean heart rate of 108.3±3.0 beatsper minute.
Patients assigned to the control group resumed treatment withtheir previous medications after the initial study, continuedtheir sedentary lifestyle, and were supervised by their privatephysicians.
Statistical Analysis
All data are expressed as means ±SE. Both the absolutevalues and the percentage changes from base-line values wereused in the statistical analyses; the two types of analysisyielded similar P values. Comparisons within each group andbetween the groups were performed with the use of two-way repeated-measuresanalysis of variance, followed by a post hoc Tukey test. Datawere tested for normal distribution with the Kolmogorov–Smirnovtest and for homogeneity of variances with Levene's test. TheMann–Whitney U test was used to compare the percentagechanges (from the initial study to the follow-up assessmentat four weeks) between the two treatment groups. A P value ofless than 0.05 (by two-tailed testing) was considered to indicatestatistical significance.
Results
Base-Line Characteristics
Nineteen patients were randomly assigned to the exercise-traininggroup (10 patients) or to the control group (9 patients). Inthe initial study, patients in the control group did not differsignificantly from those in the exercise-training group (Table 1).Of the 19 target vessels selected for study, 14 (74 percent)were the left anterior descending coronary artery, 4 (21 percent)the circumflex coronary artery, and 1 (5 percent) the nondominantright coronary artery.
Table 1. Base-Line Characteristics of the Patients at the Time of the Initial Study.
The two groups did not differ significantly with respect tomedical treatment at base line. Patients were taking beta-blockers(90 percent of the patients in the exercise-training group and78 percent of the patients in the control group), angiotensin-converting–enzymeinhibitors (60 percent and 44 percent, respectively), nitrates(30 percent and 56 percent), and calcium antagonists (0 percentand 11 percent). Their treatment did not change during the four-weekperiod before enrollment or during the four-week follow-up period.
Clinical Follow-Up
One patient in the exercise-training group had a temporary third-degreeatrioventricular conduction block during the initial infusionof adenosine. No adenosine was administered to this patientduring the follow-up examination.
During exercise training, the body weight of patients in theexercise-training group remained essentially unchanged (83.4±4kg before training vs. 82.5± 4 kg after training), asdid metabolic variables that might affect endothelial function,including the serum total cholesterol level (193±8 mgper deciliter [5.0± 0.2 mmol per liter] before trainingvs. 193±8 mg per deciliter after training), the low-densitylipoprotein cholesterol level (135±8 mg per deciliter[3.5±0.2 mmol per liter] vs. 128±8 mg per deciliter[3.3±0.2 mmol per liter]), and the serum triglyceridelevel (115±18 mg per deciliter [1.3±0.2 mmol perliter] vs. 106±9 mg per deciliter [1.2±0.1 mmolper liter]) (P not significant for any comparison).
After four weeks of exercise training, peak oxygen uptake duringexercise increased by 12 percent (from 24.0±1.5 to 26.8±1.0ml per kilogram of body weight per minute), whereas no significantchange was observed in the control group (23.3±1.1 vs.23.1±1.1 ml per kilogram per minute, P<0.05 for thecomparison between the groups).
Response to Acetylcholine
In the initial study, patients in the exercise-training andcontrol groups had similar responses to acetylcholine, expressedas the percentage change from base line in the luminal diameterafter the infusion of increasing doses of acetylcholine. Inthe exercise-training group, the mean decreases in the luminaldiameter after infusions of 0.072, 0.72, and 7.2 µg ofacetylcholine per minute were 5.3±1.5, 11.0±2.4,and 15.2±2.2 percent, respectively; in the control group,they were 3.2±1.3, 7.4±1.7, and 10.9±2.1percent (P not significant).
After four weeks of exercise training, the mean vasoconstrictiveresponses to the intermediate dose of acetylcholine (0.72 µgper minute) and the highest dose (7.2 µg per minute) weresignificantly attenuated in comparison with the responses inthe initial study. Coronary-artery constriction was reducedby 48 percent (from 0.29±0.06 to 0.15±0.05 mm)and 54 percent (from 0.41±0.05 to 0.19±0.07 mm)at the respective doses (P<0.05 for the comparison with thepercentage change in the control group, at both doses) (Figure 1and Table 2).
Figure 1. Individual Changes in Coronary-Vessel Luminal Diameter in Response to Acetylcholine at a Dose of 7.2 µg per Minute at the Initial Study and after Four Weeks.
The mean percent change differed significantly between the groups at four weeks (P<0.05 for the comparison with the initial study). Negative values indicate decreases in diameter. Each line represents the change in an individual subject, and the solid circles and bars represent the group means ±SE.
Table 2. Effect of Exercise Training on Coronary-Vessel Diameter.
Exercise training led to significantly greater increases incoronary blood-flow velocity from base line. The increase was96 percent (from 4.6±2.8 cm per second at the initialstudy to 9.0±3.6 cm per second at four weeks) with acetylcholineat a dose of 0.072 µg per minute (P<0.05 for the comparisonwith the change in the control group), 73 percent (from 11.7±4.4to 20.2±3.5 cm per second) at a dose of 0.72 µgper minute (P<0.01 for the comparison with the change inthe control group), and 73 percent (from 21.9±4.2 to37.8±3.6 cm per second) at a dose of 7.2 µg perminute (P<0.01 for the comparison between groups) (Table 3).
Table 3. Effect of Exercise Training on Mean Peak Coronary Blood-Flow Velocity.
After four weeks of exercise training, the change in coronaryblood flow in response to acetylcholine administration increasedin a dose-dependent manner. At the highest dose of acetylcholine,the change in mean coronary blood flow increased from 27±11percent above base line at the initial study to 110±24 percent above base line at four weeks (from 36± 18to 185±38 ml per minute) (P<0.01 for the comparisonbetween groups) (Figure 2).
Figure 2. Individual Changes in Coronary Blood Flow in Response to Acetylcholine at a Dose of 7.2 µg per Minute at the Initial Study and after Four Weeks.
The mean percentage differed significantly between the groups at four weeks (P<0.01). Negative values indicate decreases in coronary blood flow. Each line represents the change in an individual subject, and the solid circles and bars represent the group means ±SE.
In the control group, the changes in vessel diameter and blood-flowvelocity in response to acetylcholine infusion at four weekswere not significantly different from those in the initial study.
Endothelium-Independent Coronary Vasodilatation
The vasodilatory response of the epicardial arteries in responseto the endothelium-independent vasodilator nitroglycerin remainedessentially unchanged after four weeks of exercise training(an increase of 0.27±0.03 mm in luminal diameter beforetraining vs. an increase of 0.28±0.06 mm after training;P not significant). The maximal increase in coronary blood flowcaused by nitroglycerin was 168±23 percent at the initialstudy and 188±33 percent after four weeks of exercisetraining; the difference was not significant, and the effectof nitroglycerin in the control group was similar.
Coronary Blood-Flow Reserve and Flow-Dependent Dilatation
Coronary blood-flow reserve as assessed by adenosine infusion(the mean peak flow velocity after the administration of adenosine,divided by the velocity when the patient was at rest) improvedsignificantly with exercise training (from 2.8±0.2 to3.6±0.2, a 29 percent change; P<0.01 for the comparisonbetween groups). The adenosine-induced change in the diameterof the proximal target-vessel segment (exposed to increasedflow but not directly to adenosine) was measured in all patients,with the exception of one patient in the exercise-training group,in whom a temporary, adenosine-induced third-degree atrioventricularblock developed during the initial study. Exercise trainingled to a significant increase in flow-dependent dilatation (from0.19±0.06 to 0.39± 0.07 mm, a 105 percent change;P<0.01 for the comparison between groups). In the controlgroup, coronary blood-flow reserve and adenosine-induced changesin proximal-vessel diameter after four weeks did not differsignificantly from the results at the initial study.
Discussion
We found that four weeks of vigorous exercise training improvedcoronary endothelial function in patients with asymptomaticcoronary atherosclerosis. Coronary vasoconstriction in responseto acetylcholine was significantly attenuated after exercisetraining, indicating that exercise had beneficial effects onthe endothelium of epicardial conduit vessels. In agreementwith this result was the finding that adenosine-induced flow-dependentvasodilatation after training was markedly improved.
In addition, we found that exercise training was associatedwith increases in agonist-mediated blood-flow velocity and coronaryblood-flow reserve. These findings indicate that in the absenceof clinically significant coronary-artery stenosis, the vasodilatorycapacity of coronary resistance vessels was enhanced.
However, in this study, a four-week period of high-intensityendurance training improved the endothelial response to acetylcholinebut did not restore it to normal levels, suggesting that therestoration of normal endothelial function may require a moreextended exercise-training intervention. In studies of patientswith symptomatic coronary artery disease, long-term exercisetraining was associated with a significant reduction in theincidence and severity of exercise-induced myocardial ischemia.7,9,14It is reasonable to suppose that in these patients myocardialperfusion was augmented after training.
Several mechanisms have been proposed to explain the enhancedmyocardial perfusion in patients with coronary artery diseasewho undertake exercise training. They include regression ofcoronary artery disease, recruitment of coronary collateralvessels, and enhanced blood flow. As regards the first, moststudies have failed to document a net regression of coronarylesions, even with the addition of lipid-lowering strategiesto exercise-training interventions.14 Moreover, a decrease inthe incidence of myocardial ischemia was observed in patientswith progression of stenotic lesions.9 This unexpected resultimplies that improvement in myocardial perfusion may be achievedindependently of changes in coronary lesions.
As regards the second, evidence from studies in animals suggeststhat long-term intensive exercise leads to an improvement incoronary collateralization.15,16 However, angiographic studiesperformed at rest in patients with coronary artery disease didnot substantiate this hypothesis.10 Finally, blood viscositycan be reduced and blood flow can be improved by exercise trainingin healthy subjects and in patients with peripheral vasculardisease.17 However, in patients with coronary artery diseaseand impaired left ventricular function, exercise training didnot have any significant effect on blood viscosity.18 The reasonsfor the differences among these groups in their responses toexercise remain obscure.
None of the proposed mechanisms fully explain the beneficialeffect of regular exercise on myocardial perfusion. However,this does not imply that these mechanisms are irrelevant tothe observed improvement in myocardial perfusion in the exercise-traininggroups. Rather, these mechanisms may have an effect at the levelof another important structure regulating coronary perfusion,the vascular endothelium.
It is conceivable that improved endothelial function and coronaryblood-flow reserve after exercise training reduce stress-inducedmyocardial ischemia despite increases in myocardial oxygen consumption.Our results suggest that it may be impaired endothelium-dependentcoronary vasodilatation on which exercise has the most potenteffect. This hypothesis is consistent with the results of interventionalstudies in patients with hypercholesterolemia. A marked decreasein the serum cholesterol level was associated with a correctionof endothelial dysfunction,5 improvement in myocardial perfusion,19and a decrease in the incidence of myocardial ischemia.6 Becausepatients with the classic risk factors known to affect endothelialfunction (diabetes, hypertension, hypercholesterolemia, andsmoking) were excluded from our study, the study groups do notreflect the typical population of patients with coronary arterydisease.
Exercise training may correct endothelium-dependent vasodilatationof conduit coronary arteries by a variety of mechanisms. First,cell-culture experiments have demonstrated that shear stressaugments the expression of nitric oxide synthase in endothelialcells. This finding is consistent with studies in dogs in whichan increased expression of endothelial nitric oxide synthasewas documented in coronary resistance vessels.20 Second, shearstress induces up-regulation of the cytosolic copper-and-zinc–containingsuperoxide dismutase, a free-radical scavenger. The inactivationof nitric oxide by a vascular superoxide or other reactive oxygenspecies may thereby be attenuated.21 Third, shear-stress–mediatedsuppression of angiotensin-converting enzyme may influence endothelium-dependentrelaxation by affecting local concentrations of bradykinin,since angiotensin-converting enzyme is able to break down bradykinininto its inactive metabolites.22
In our assessment of nitroglycerin-induced, endothelium-independentcoronary vasodilatation, we observed no differences betweenthe exercise-training group and the control group. Short-termexercise training in patients with coronary atherosclerosisdid not seem to alter the responsiveness of smooth-muscle cellsof the coronary vasculature to the exogenous application ofnitric oxide. Haskell and coworkers, however, demonstrated thatthe epicardial coronary arteries of highly trained, middle-agedendurance runners had a significantly greater dilating capacityin response to nitroglycerin than did those of healthy but inactivemen.23 It is conceivable that high-intensity endurance trainingover a long period may be necessary to increase the capacityof coronary vessels for endothelium-independent dilatation amongpatients with coronary atherosclerosis. It is also possiblethat in the present trial, the dose of nitroglycerin infusedwas sufficiently greater than the concentration of reactiveoxygen species that small changes in vascular oxygen radicalshad no detectable effect on nitroglycerin-induced vasodilatation.
Several mechanisms may influence coronary resistance vesselsand the microcirculation after high-intensity exercise training.In studies in animals, it has been conclusively demonstratedthat exercise training is associated with an increase in thetotal cross-sectional area of the vascular bed24 and with enhancedsensitivity of coronary resistance vessels to adenosine25 andother metabolic vasodilators.26 None of these proposed mechanismshave yet been confirmed in humans, however.
In patients with coronary atherosclerosis, exercise trainingpartially improves the endothelial function of large coronaryconduit and resistance vessels. This finding provides a pathophysiologicframework for the elucidation of the positive effects of exerciseon myocardial perfusion and emphasizes the therapeutic potentialof endurance training for patients with stable coronary arterydisease.
The catheters used in this study were provided by A.D. KrauthCardiovascular (Hamburg, Germany).
Source Information
From the University of Leipzig Heart Center, Department of Medicine and Cardiology, Leipzig, Germany.
Address reprint requests to Dr. Hambrecht at the Herzzentrum, Universität Leipzig, Russenstr. 19, 04289 Leipzig, Germany, or at hamr{at}server3.medizin.uni-leipzig.de.
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70 years) with documented coronary artery disease were recruited. Patients were eligible for the study if they had a hemodynamically important coronary-artery stenosis that required nonsurgical revascularization (percutaneous transluminal coronary angioplasty) and a noncritical stenosis in another coronary vessel, which thus could be used for testing (the target vessel). To be suitable for testing, the target vessel had to have signs of endothelial dysfunction, defined as either constriction (a decrease of 
5 percent in the mean luminal diameter) or no change (a decrease of <5 percent or no decrease in the mean luminal diameter) in response to acetylcholine. Patients also had to have a symptom-free exercise capacity of at least 50 W. 
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