652

Effects of Angiotensin-Convertiling Enzyme Inhibition on Exegulse-Indu ced Angina and ST Segment Depression in Patients W!" -I

Afficrovamular Angina

JUAN CARLOS KASKI, MD, FACC, GIUSEPPE ROSANO, MD, STAVROS GAVRIELIDES, MD,

LIJIA CHEN, MDLondon, England, United Kingdom

QpKer. This study was couducRd to test the hypothesis thattoy me inhibition may lessen myocardial

nit patients with microvascular angina.Bc,v,r,gmxd. Patients with syndrome X (angina pectoris, pos-

itive findings on exercise testing and normcnal coronary arterio-gpmw) have a reduced coronary vasadRalor reserve (11microvas-cular mighWI) and may dww an increased sympathetic drive .

enzyme inhibition attenuates sympathetic0womary vawmMexoWnWWWWomn in patients with coronary artery dis-

Mdhods. Ten patients (seven women and three men, mean ageQMN It * 6 pmrl with syndinnne X sod a mWd1weved coronary flowreserve underwent a ran6dommsiumd, sinoublind, crossover, place-Wontrolled study of vie emects of the mqbmuwamvettingewyme

bitor enalapril on angina and exercise-induced STt depression. Assessment was by symptom-limed tread-

min exenise testing amw 2 weeks of treatment with 10 mglday ofensiapril and alter 2 weeks of placebo administration .

Patients with "microvascular angina" (1) or "syndrome X"(2-4) have exertional angina that appears to be caused by anabnormal vasodilator capacity of the coronary microcircula-tion (1,3,5-7) . In these patients, ergonovine can exacerbatelimited coronary flow reserve during pacing in the absence ofepicardial coronary artery spasm (7) . A large proportion ofpatients with syndrome X have rest angina and ischemia-likeST segment depression during ambulatory electrocardio-graphic (ECG) monitoring that is not always preceded by anincrease in heart rate . Therefore, dynamic small vessel

From the Coronary Artery Disease Research Group. Department ofCard al Sciences. St. George's Hospital Medical School, London,England, United Ki*om, This study was presented in abstract form at the65th Annual Scientific Sessions of the American Heart Association, Novem-ber 1992 . Dr. Rosano was sponsored by an Educational Grant from the ItalianMinistry of Health, Rome, Italy and Dr . Gavrielides by an Educational Grantfrom the University of Thessaloniki, Thessaloniki, Greece .

Manuscript received July 30 . 1993 ; revised manuscript received October7. 199-1 , accepted October 14, 1993 .

for mmsnowdkenc : Dr. Juan Carlos Kaski, Coronary ArteryDisease Research Group, Department of Cardiological Sciences, St. George'sHospital Medical School, Cranmer Terrace, London SW17 ORE, England .United Kingdom.

0 1994 by the American College or Cardiology

MCC Vol. 23, No . 3March 1, 1994:652-7

Results. Ali patients had positive findings on exercise testing( :t_- I min ST segment depression and angina) while taking placebo,whereas six patients had a positive test result (four with angina)during enalapril therapy. Total exercise duration and time toI mm of ST segment depression wene prolonged by enWaprill overthose obtained with placebo (mean 779 141 vs . 690 ± 148 s, p =0.006 and d9O al: 204 vs. 415 cc 241 s, p 0 . 7, respectively) . Themagnitude of ST segment depression was also less with enalaprilthan with placebo (mean 1.1 ± 0.4 vs. I .S ± 0.2 mm, p -- 0.004).Heart rate and blood pressure at peak exercise and at 1 man of STdepression were not significantly different during placebo andenalapril treatment.

Conclusions . Angiotensin-converting enzyme inhibition lessensexercise-induced ischemia in patients with syndrome X and mi-crovascular aqlinsl, probably by a direct modulation of coronarymicrovascular tone, which results in an increased myocardialoxygen supply .

(J Am Coll Cardiol 1994,23 :652-7)

constriction has been suggested to play a role in the genesisof angina in these patients (4) . Recently, it has been shown(8) that in patients with microvascular angina the abnormalvasodilator reactivity affects net only the coronary microcir-

culation but also the systemic vasculature .Although coronary blood flow is primarily governed by

autoregulatory mechanisms dependent on myocardial oxy-

gen needs, this primacy of local factors does not negate thefact that neural and humoral influences can play an impor-

tant modulatory role under certain conditions . Studies (9,14)have shown that the renin-angiotensin system is activated inpatients with ischemic heart disease and myocardial infarc-

tion and that endogenous angiotensin II participates in thecontrol of coronary blood flow during transient myocardial

ischemia. However, the pathogenetic mechanisms in these

disorders may be different from those causing syndrome X .Angiotensin-converting enzyme inhibitor drugs increase

coronary blood flow in the presence of an activated renin-angiotensin system. A potential mechanism of action may be

the blockade of tissue angiotensin generation (11) . More-over, angiotensin-converting enzyme inhibition reduces left

ventricular diastolic pressure, systolic pressure and sympa-

0735-1097/94/$7 .00

JACC Vol . 23, No . 3March 1 . 3994 :652-7

thetic drive (12-14), thus reducing myocardial work . Theseeffects may be beneficial in patients with angina pectoris .However, the effects of angiotensin-converting enzyme in-hibition on myocardial ischemia in patients with coronaryartery disease are variable ( 115) .

The observations that the syndrome of microvascularangina is associated with an abnormal dilator response of thecoronary microcirculation and that angiotensin-cone 4rtingenzyme inhibition attenuates sympathetic coronary vaso-constriction in patients with coronary artery diseaseprompted us to examine the effects of angiotensin-converting enzyme inhibition on the exercise response ofpatients with syndrome X .

MethodsPatients. Ten patients (seven women, three men, aged 42

to 65 years, mean age (± SEq 53 4: 6 years) with syndrome Xand microvascular angina were included in the study . Syn-drome X was definek, as typical exertional angina, a positiveexercise test result (ii- I mm of ST segment depression andangina), abnormal coronary blood flow reserve and a com-pletely normal coronary arteriogram . No patient nad leftventricular hypertrophy . Left ventricular mass index rangedfrom 78 to 95 g/m2 in the seven women and from 83 to122 g/m 2 in the three men . Measurements were obtainedaccording to American Society of Echocardiography recom-mendations (16) . Left ventricular wall thickness was calcu-lated as the arithmetic mean of both posterior and interven-tricular septal thickness, and left ventricular mass wascalculated using the method proposed by Troy et al . (17) .Left ventricular hypertrophy was excluded using gender-specific normal limits from the Framingham Heart Study(18) . No patient had systemic hypertension (defined as ablood pressure > 140/90 mm Hg in repeated readings), coro-nary artery spasm, cardiomyopathy, valvular heart diseaseor conduction disturbances . All patients with syndrome Xincluded in the study had episodes of horizontal ordownsloping ST segment depression during 24-h ambulatoryECG monitoring, and seven had reversible regional perfu-sion abnormalities during exercise as assessed by techne-tium-99m hexamibi scans in five and by positron emissiontomography (rubidium-82) in the remaining two . Coronaryblood flow reserve in response to intravenous dipyridamole,assessed by positron emission tomography (oxygen-15-labeled water [19,201) was reduced in all 10 patients (mean2.3 ± 0.3), as found also by Geltman et al . (21) using a similartechnique .

Study protocol. Ethics . The study protocol was ap-proved by the hospital's ethics committee . The nature of thestudy was explained to each subject before written informedconsent was obtained .

Design . We investigated the effects of enalapril (5 mgtwice daily) in a randomized, single-blind, placebo-controlled, crossover study wfth two treatment periods of 2weeks each. The dose of enaiapril (10 mg/day) was chosen

KASKI ET AL .

653EFFECTS OF ENALAPRIL W SYNDROME X

on the basis of recently reported observations (15) in patientswith transient myocardial ischemia . All antianginal medica-tion was discontinued X72 h before the study, with theexception of sublingual nitrates, which were allowed forrelief of anginal attacks . After appropriate washout of pre-vious medications, patients were randomized to receiveeither enalapril or placebo for 2 weeks . After a 1-weekwashout period, patients were crossed over to receive eitherenalapril or placebo for another 2 weeks .

Patients were assessed by symptom-limited exercise tests(modified Bruce protocol) . These tests were carried out 2 hafter drug administration on the last day of each treatmentperiod .

Exercise testing. Before the exercise test and after theECG electrodes were placed on the chest according to astandardized technique, patients were asked to rest in thesitting position for 30 min . They were then invited to standup, and rest heart rate, blood pressure and rate pressureproduct (heart rate x systolic blood pressure expressed inbeats/min x mm Hg) were measured after 2 to 3 min in thestanding position . All patients underwent exercise testingunder standardized conditions . The modified Bruce protocolwas used in all tests ; the end points were a 2-mm depressionof the ST segment, progressive angina or fatigue . Twelve-lead ECG and blood pressure measurements were obtainedduring the control period, at 1-min intervals during exerciseand for 6 min during recovery . After signal averaging, thelevel of the ST segment 80 ms after the J point was measuredin all 12 leads with use of a computer-assisted system (CASEMarquette 12, Marquette Electronics Inc .) . The lead show-ing the most ST segment depression was selected for analy-sis. In patients with positive test results, the duration ofexercise, heart rate and rate-pressure product were mea-sured at 1-nim depression of the ST segment and at peakexercise ; in those with negative test results, the duration ofexercise, heart rate and rate-pressure product were mea-sured at peak exercise only .

Statistical analysis . All data were analyzed withoutknowledge of the patients' treatment . Rest pre-exerciseheart rate, blood pressure and rate-pressure product weremeasured in the upright position in every patient . Thefollowing exercise variables were also measured : total exer-cise time, time to I mm of ST segment depression, heartrate, systolic blood pressure and rate-pressure product atpeak exercise and 1 mm of ST segment depression . Themagnitude of ST segment depression at peak exercise wasalso assessed. Data are presented as mean value ± SD .Student t tests were carried out to compare placebo versusenalapril results as appropriate . AA p value < 0.05 wasconsidered significant .

ResultsAll 10 patients completed the study uneventfully and no

side effects were observed during the relatively short treat-ment period . Routine hematologic and biochemical variables

654

KASKI ET AL.EFFECTS OF ENALAPRIL IN SYNDROME X

150t

100-~

so _1

0

8MR

MR

P-Mum

Sap

Sop

p=OM2

RFP

P.NS

RPP

MR

Sop

RPP

Figure 1. Hemodynamic variables . Bargraphs showing mean values±SD for heart rate (HR), systolic blood pressure (SBP) and rate-pressure product (double product of the heart rate and systolic bloodpressure [RPPI) during treatment with placebo (solid bars) and theangiotensin-converting enzyme inhibitor enalapril (open bars) . Atrest (A) . During treatment with enalapril, systolic blood pressureand the rate-pressure product significantly decreased compared withvalues during placebo treatment . However, reflex tachycardia wasnot observed. At peak exercise (B) and at I mm of ST segmentdepression (C), no significant differences in hemodynamic variableswere observed when placebo and enalapril treatment periods werecompared.

remained unchanged during the study in all patients . Bodyweight did not change significantly when placebo and enal-april treatment periods were compared .

Pre-exerdse rtemodynamic variables . Systolic blood pres-sure at rest was significantly lower with enalapril than withplacebo (125 ± 12 vs . 133 ± 9 mm Hg, p = 0 .009) (Fig . IA) .

JACC Vol. 23, No . 3March 1, 1994:652-7

How.;-er, !art rate was not significantly different withei alapril (b I ± 10 vs . 95 ± 15 beats/min, p = NS) . As a resultof Ns, the rate-pressure product was also significantly lowerwith enalapril than with placebo (Fig . IA) .

Exercise hemodynamics. Systolic blood pressure was notsignificantly different at peak exercise during enalapril andplacebo treatment (177 ± 26 and 183 ± 23 mm Hg, respec-tively, p = NS) . Heart rate and rate-pressure product werealso similar during the two treatment periods (Fig . 1B) .

Similar to results at peak exercise, heart rate, bloodpressure and the rate-pressure product at 1 mm of STsegment depression were not significantly diTerent duringplacebo and enalapril treatment (Fig. 1Q.

Exercise time. Despite similar values for rate-pressureproduct in the two treatment Nriods, exercise time wassignificantly longer with enalapril than with placebo (779 ±141 vs. 690 ± 148 s, respectively, p = 0 .006) (Fig. 2). Timeto 1 mm of ST segment depression was also significantlyprolonged by enalapril (690 ± 204 vs . 485 ± 241 s, p = 0 .007)(Fig. 2). With enalapril, three patients had a 2t20% longerpeak exercise time and six had a atM increase in time toI mm of ST segment depression (Fig. 2) .

ST segment depression . On average, the magnitude of STsegment depression was significantly reduced during treat-ment with the angiotensin-converting enzyme inhibitor enal-april compared with the value recorded during placebotreatment (Fig . 3). All patients had a positive exercise testresult (with angina) during placebo treatment . With enala-pril, four patients had a negative test response (< I mm of STsegment depression and no angina) and two others had aborderline positive test response without angina . Duringtreatment with enalapril, 9 of the 10 patients consistentlyimproved their exercise capacity and had <1 mm of STsegment depression (4 patients) or ST segment depression oflesser magnitude than that during exercise with placebotreatment (Fig . 3) .

DiscussionThe results of our study showed that the angiotensin-

converting enzyme inhibitor enalapril improves exercise-induced angina and ST segment depression in patients withsyndrome X and microvascular angina . During treatmentwith enalapril, 40% of the patients had a negative exercisetest result and, in the group as a whole, exercise durationand time to 1 mm of ST segment depression were signifi-cantly prolonged by enalapril compared with placebo . Whenindividual results are considered, the majority of patientsincreased the time to 1 mm of ST segment depression by2t20% while taking enalapril . The magnitude of ST segmentdepression at peak exercise was also lessened by the admin-istration of enalapril . Patient compliance was good and allpatients completed the study without observed side effectsduring treatment with the angiotensin-converting enzymeinhibitor .

JACC Vol . 23, No . 3March 1, 1994 :652-7

I MM ST R exercise

Figure 2. Exercise time. Exercise time at both I mm of ST segmentdepression (left panel) and at peak exercise (right panel) in individualpatients with syndrome X during placebo and enalapril therapy .While receiving enalapril, three patients had a >_20% increase inexercise time and six had a L-20 decrease in time to I mm of STsegment depression compared with values during the placebo pe-riod . Thick lines indicate patients who did not reach I mm of STsegment depression (negative exercise test result) .

Mechanisms potentially responsible for decreasing exer-cise-induced ischernia. There are different mechanisms bywhich angiotensin-converting enzyme inhibitors can lessenmyocardial ischemia in patients with angina . A reduction ofthe rate-pressure product (22), which in turn results in areduced cardiac work, is one of these . In our patients,enalapril provoked a decrease in rest blood pressure (with-out reflex tachycardia), thus reducing the rest rate-pressureproduct, as previously observed in other studies (23) . How-ever, peak exercise heart rate and rate-pressure productwere not significantly different when placebo and enalaprilwere compared. The decrease of myocardial ischemia inresponse to enalapril therefore occurred in the presence of arate-pressure product at peak exercise that was similar tothat observed while the patients exercised during treatmentwith placebo . This finding suggests that the beneficial effectof enalapril observed in our study could have resulted froma direct modulation of coronary microvascular artery toneby the angiotensin-converting enzyme inhibitor . The role ofthe renin-angiotensin system on modulation of coronaryartery blood flow has not been thoroughly investigateddespite the well known potency of angiotensin II as acoronary vasoconstrictor . The emerging concept that angio-tenMn is produced locally at tissue sites has importantimplications, as local angiotensin concentrations may ex-ceed those of plasma levels and may play an important rolein the tonic control of vascular resistance (24-26) . There isevidence in humans and experimental models that coronary

KASKI ET AL .

655EFFECTS OF ENALAPRIL IN SYNDROME X

nun

Figure 3 . ST segment depression at peak exercise . Individual re-sults of the magnitude of ST segment depression during placebo andenalapril therapy . All patients had a positive exercise test result(2! 1 aim of ST segment depression) during placebo treatment . Withenalapril, four patients had a negative exercise test response . Nineof the 10 study patients showed a reduced magnitude of peakexercise ST segment depression during enalapril therapy comparedwith that during placebo therapy .

vascular resistance is increased by angiotensin 11 (27) . Indifferent models of myocardial ischemia, endogenous angio-tensin 11 exerts intense coronary arteriolar constriction,which can be prevented by pretreatment with angiotensin-converting enzyme inhibitors (28) . However, the nature ofmyocardial ischemia may differ between syndrome X andother coronary syndromes . It has been shown that angioten-sin-converting enzyme inhibition attenuates sympatheticcoronary vasoconstriction in patients with coronary arterydisease (29) . The mechanism appears to be the removal ofthe facilitating influence of angiotensin II on sympatheticmodulation of coronary vasomotor tone (29) . Angiotensin-converting enzyme inhibitors have also been shown toincrease coronary blood flow in patients with heart failureassociated with dilated cardiomyopathy or ischemic heartdisease (30) . Enalapril (or more appropriately, its activemetabolite enalaprilat) is an antagonist of angiotensin 11 inisolated coronary arteries (31) and antagonizes the coronaryvasoconstrictor effect of angiotensin II (32) . These observa-tions suggest that the renin-angiotensin system, when stim-ulated, can exert a direct vasoconstrictor effect on vasculartone and that angiotensin-converting enzyme inhibitors mayplay a beneficial role .

Increased sympathetic drive in patients with syndrome X .An increased sympathetic drive has been suggested to play arole in the genesis of angina in patients with syndrome X(33,34) and an interaction between the sympathetic nervoussystem and the renin-angiotensin system has been docu-mented (35) . Facilitation of sympathetic nerve influences inthe heart by angiotensin 11 contributes to its inotropic actionand possibly to its effects on coronary blood flow (35) .Ganten (35) reported that the effects of sympathetic stimu-lation on isolated perfused heart preparations were signifi-cantly reduced by pretreatment with angiotensin-converting

656 KASKI ET AL.EFFECTS OF ENALAPRIL IN SYNDROME X

enzyme inhibitors . More recently, Perondi et al. (29) ob-served that treatment with captopril resulted in the attenua-tion of sympathetic coronary artery vasoconstriction inpatients with atheromatous coronary artery disease. Thesefindings are of particular relevance in syndrome X, at least inthe subgroup of patients in whom an increased sympatheticdrive plays a pathogenic role. It is also conceivable thatattenuating the effects of the sympathetic nervous system oncardiac contractility could have contributed to the beneficialeffect of angiotensin-converting enzyme inhibition that weobserved in our patients with microvascular angina (13,14) .Experimental evidence (31) suggests that in addition toantagonizing the coronary arteriolar constrictor action ofangiotensin II, angiotensin-converting enzyme inhibitorsalso have cardioprotective properties . Because these agentscan prevent bradykinin breakdown by inhibition of kininaseII and can stimulate prostaglandin production, it has beenpostulated that at least some of the cardiac effects ofangiotensin-converting enzyme inhibition depend on theseproperties (25,35). However, no conclusive evidence isavailable that the effects of angiotensin-converting enzymeinhibition are fully mediated by prostaglandins and bradyki-nin (36) .C ns. The results of our study suggest that angio-

tensin-converting enzyme inhibition lessens exercise-induced angina and ST segment depression in patients withsyndrome X who have a reduced coronary blood flowreserve. The mechanism by which angiotensin-convertingenzyme inhibition exerts its beneficial effect in patients withmicrovascular angina is not yet known, but modulation ofcoronary tone at the microcirculation level may be a poten-tial mechanism . Our findings may help to improve patientmanagement .

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657EFFECTS OF ENALAPRIL IN SYNDROME X

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