Br Heart JT (Supplement) 1994; 72: 52-56

CORONARY ARTERY DISEASE

Effects of ACE inhibitors on coronary

haemodynamics and angina pectoris

M K Davies

Angiotensin II is a potent vasoconstrictor ofboth coronary and peripheral vasculature; itincreases myocardial contractility, promotesmyocardial hypertrophy, and possibly con-tributes to the process of atherosclerosis. Inaddition, the renin-angiotensin system andthe sympathetic nervous system are inter-dependent, each stimulating the activity ofthe other. Angiotensin II enhances the activityof the sympathetic nervous system byfacilitating the release of noradrenalinelA andby interfering with its neuronal reuptake.5 6Angiotensin II has important central andperipheral vagolytic effects.7-'0 Vasodilatationand decreased fluid retention reduce preload,afterload, heart size, and left ventricular wallstress, thereby reducing myocardial oxygendemand. Similarly, reductions in the leftventricular hypertrophy associated with hyper-tension and heart failure and reductions in thepositive inotropic effects of angiotensin IIcould contribute to reduced myocardialoxygen demand. A reduction in sympatheticand increase in parasympathetic tone at restand on exercise, due to inhibition in activity ofboth the renin-angiotensin system and thesympathetic nervous system by angiotensinconverting enzyme (ACE) inhibitors, willreduce heart rate, or the reflex tachycardiausually associated with peripheral vaso-dilatation, and thereby reduce the rate-pressure (double) product. A concurrentreduction in vasoconstriction mediated byangiotensin II at the coronary vascular bedshould result in coronary vasodilatation and animprovement in myocardial oxygen supply.Despite these diverse potential mechanismsaffecting both myocardial oxygen demand andsupply beneficially, a consistent and clinicallysignificant anti-ischaemic effect of ACEinhibition has been difficult to show.ACE inhibitors improve prognosis in all

grades of symptomatic heart failure, reducingmortality from progressive heart failure andsudden death.1 1-14 Sudden death is oftenpresumed to be arrhythmic in origin, butmost patients with heart failure have com-plex ventricular ectopic activity on Holtermonitoring.'5 Although the presence of thesearrhythmias is related to prognosis in somestudies, their predictive accuracy is generallyweak.'2 16-19 There are few large postmortemstudies in heart failure, but the data availablesuggest that the arrhythmias associated withsudden death in these patients are often themanifestation of some intercurrent coronary orpulmonary thrombotic event.19 The reduction

in incidence of sudden death observed afterACE inhibitors in heart failure may be due inpart therefore to a beneficial effect on thecoronary circulation, atherogenesis, or thethrombotic process.20 Both the recent SOLVDtreatment'3 and SAVE2' studies have shown areduction in the rate of recurrent infarction inpatients with heart failure or with impairedleft ventricular function after myocardialinfarction who have been treated with ACEinhibitors. Thus, indirect data are available tosuggest that ACE inhibitors have anti-ischaemic effrects that could account for someof their beneficial therapeutic and prognosticeffects.

Effects ofACE inhibitors in patients withstable anginaThe effects of ACE inhibitors on coronaryvascular tone was studied by Karsch et al in12 patients with coronary heart disease andexertional angina.22 Central haemodynamicmeasurement and coronary angiographywere carried out during control pacing andduring angina induced by rapid atrial pacingbefore and after ACE inhibition with intra-venous captopril. At rest and during ischaemiacaptopril resulted in coronary vasodilatation atthe site of coronary atherosclerotic narrowing,increasing coronary artery diameter by 0 1 mmat rest and by 0-2 mm during ischaemia.These changes were associated with a fallin left ventricular end diastolic pressureand peripheral vasodilatation. Despite thesefavourable haemodynamic changes, however,only one patient experienced a significantreduction in angina, captopril having nosignificant effect on coronary artery diameterin the non-diseased segments. Ikram et al alsoused intravenous captopril and atrial pacing toexamine the effects on angina threshold andsystemic and coronary haemodynamics in 12patients with documented coronary arterydisease.23 Captopril resulted in an increasedtime to angina and increased paced heart ratefor the development of angina, with a trendtowards increased coronary blood flow (229 to296 ml/min, P = 0-1 1) and decreased coronaryvascular resistance (53 to 47 dyn s cm-5/1000,P=0-11).The clinical effects of ACE inhibitors in

angina pectoris were investigated by Gibbset al in 12 patients with chronic stableangina.24 In a two week double blind placebocontrolled study the effects of oral enalapril onangina frequency and treadmill exercise

Department ofCardiology,Selly Oak Hospital,BirminghamM K DaviesCorrespondence to:Dr M K Davies,Department of Cardiology,Selly Oak Hospital,Birmingham B29 6JD.

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Effects ofACE inhibitors on coronary haemodynamics and angina pectoris

testing were determined. Enalapril reducedresting and exercise double product (each byabout 10%) by reducing systolic bloodpressure at rest and on exercise without aneffect on heart rate. In the group as a whole,however, the frequency of angina andconsumption of glyceryl trinitrate was notimproved with enalapril. On formal exercisetesting enalapril increased exercise duration by43 s (from 466 s to 509 s) and exerciseduration to ST segment depression (0 1 mV)by 42 s (from 345 s to 387 s). However,interpatient variability was considerable, withfour patients showing an increase in totalexercise time of more than 20% with enalapriland two patients showing a marked reductionin exercise capacity and an increase in anginafrequency. Thus, although ACE inhibitorsseemed to reduce myocardial ischaemia insome patients, deterioration was evident in alarge proportion.The effects of ACE inhibition on myo-

cardial ischaemic episodes has also beenexamined using ambulatory ST segmentmonitoring over 24 hours. In a study of 11normotensive patients with angiographicallyproved coronary artery disease Thurmann et alshowed that the number of angina attacks andischaemic episodes was not significantlyreduced after treatment with the ACEinhibitor benazepril.25 On formal exercisetesting these patients' exercise double productand maximal exercise induced ST segmentdepression were not improved. Interpatientvariability was again considerable, with sixpatients improving (as assessed by maximalST segment depression) and three patientsmanifesting worsening of ischaemia. In asimilar study by Klein et al in 29 patients withchronic stable angina benazepril did not alterexercise time or improve exercise inducedischaemia.26 Although the number of episodesof ST segment depression on ambulatorymonitoring and the total ischaemic burdenwas reduced from 1549 minutes in the placebogroup to 879 minutes in the benazepril group,these changes were not significant. Benazeprildid not reduce angina frequency or con-sumption of glyceryl trinitrate. In a more recentstudy on 34 patients with chronic stableangina benazepril again failed to improve totalexercise duration or exercise time to STsegment depression of 1 mm.27 On ambulatorymonitoring for 48 hours the number ofepisodes of ST segment depression (>1 mm)did not change significantly, and, althoughthere were falls in total ischaemic burden andthe number of episodes of silent ischaemia,these changes were not significant. How-ever, benazepril treatment resulted in a sig-nificant reduction in the maximal depth ofST segment depression and significantlyaltered the circadian rhythm of myocardialischaemia.The MERCATOR study assessed the

effects of cilazapril on the prevention of angio-graphic restenosis in 595 patients after percu-taneous transluminal coronary angioplasty.28Cilazapril did not improve any objectivevariable on exercise testing (although signifi-

cantly fewer patients developed chest painduring exercise: 74 given placebo v 42 givencilazapril, P = 0-03). In another study of 12patients cilazapril did not improve exercise

29time to angina. Similarly, enalapril did notimprove exercise time to development ofangina in a group of 12 patients with stableangina after one week's treatment.30Thus in chronic stable angina several

studies, each of small numbers of patients,have failed to show a convincing anti-ischaemic effect with ACE inhibitors whetherthis is assessed by symptoms, exercise testing,or ambulatory ST segment monitoring.Although beneficial systemic and coronaryhaemodynamic effects can occur, which mightbe expected to improve myocardial ischaemia,individual patient responses are unpredictableand the use of ACE inhibitors may cause adeterioration in angina in some patients.

Effects ofACE inhibitors on unstableanginaIn patients with unstable angina cardiacsympathetic activity is significantly increasedcompared with that in patients with stableangina. Tritiated noradrenaline infusions inpatients undergoing coronary angiographyshow that cardiac noradrenaline spillover andcoronary sinus noradrenaline concentrationare increased in patients who have hadunstable angina within the preceding threemonths compared with those with stableangina.3' This suggests that the increase insympathetic activity may be sustained andpersist for several months after a period ofunstable angina. A similar increase in cardiacsympathetic overactivity has been shown inanother study of unstable angina, butpersistent abnormalities were not found aspatients with inactive unstable angina (unstableangina occurring 8-12 weeks previously butno angina for at least four weeks) had nochange in cardiac noradrenaline spillovercompared with controls.32 In this study acorrelation was found between the number ofsilent ischaemic episodes or the overallduration of ischaemia and noradrenaline spill-over, suggesting that sympathetic overactivitymight be a determinant of ischaemia, thougha causal relation should not be assumed. Asingle dose of captopril (25 mg by mouth)attenuated sympathetically mediated increasesin coronary vascular resistance induced by thecold pressor test or the diving reflex in a studyof nine patients with coronary artery disease.33The predominant anti-ischaemic effect ofACE inhibitors may reside in their ability toreduce sympathetic tone rather than theinhibition of the other diverse haemodynamicand neuroendocrine effects of angiotensin II.

Effects of ACE inhibitors in patientswith angina and hypertensionACE inhibitors are effective antihypertensiveagents that reduce blood pressure and leftventricular hypertrophy. The reduction inblood pressure is not associated with a reflex

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Davies

tachycardia and therefore reductions in rate-pressure product result. This effect profile is ofpotential benefit in patients with hypertensionand coronary artery disease, a common

association.34 Few studies have examined theeffects of ACE inhibitors on coronary haemo-dynamics in patients with hypertension andcoronary artery disease. Daly et al reported theacute effects of oral captopril in a group ofeight patients." Captopril reduced the rate-pressure product, coronary blood flow, andmyocardial oxygen consumption. Althoughthe only significant change was in the rate-

pressure product, the changes in coronary

blood flow and myocardial oxygen con-

sumption tended to parallel the decrease indouble product.Akhras and Jackson compared the effects of

captopril treatment and placebo in a singleblind study of 18 patients with hypertensionand angina due to coronary artery disease.36Captopril had a significant antihypertensiveeffect, increased the time to ST segmentdepression (1 mm) from 188 s to 364 s, andreduced the maximum ST segment depressionfrom 2-5 mm to 1-2 mm. Exercise durationwas increased from 310 s to 461 s. In additionto these objective criteria of myocardialischaemia, the number of angina attacks was

reduced from 17-6 to 4 0. In another studyperindopril significantly improved exerciseinduced ischaemia in a group of 51 patientswith ischaemic heart disease and hypertensionand reduced angina frequency (from 6 to 2-3per week).37

Effects of ACE inhibitors on coronary

haemodynamics in heart failureIntracoronary enalaprilat was used in a studyof 16 patients with dilated cardiomyopathy todifferentiate between direct coronary effectsand effects secondary to systemic vaso-

dilatation.38 After bilateral coronary infusionenalaprilat increased coronary blood flow by19% and reduced coronary artery resistanceby 18%. This was associated with an increasein coronary sinus oxygen content andpressure. However, enalaprilat also caused a

fall in cardiac index, ejection fraction, and theratio of end systolic stress to end systolicvolume. Thus the coronary vasodilator andnegative inotropic effects were consistent, inthis study, with a reduction in angiotensin IImediated coronary vasoconstriction andpositive inotropic effect. The fall in ejectionfraction and other indices of cardiac functionin this study are opposite to the effectsobserved in the heart failure trials, but in theseinstances the oral administration of the ACEinhibitor results in simultaneous systemicvasodilatation, which offsets any direct adversemyocardial effect.A 20% increase in coronary blood flow

associated with a fall in filling pressures anddouble product occurred in a study of shortterm enalaprilat treatment in patients withsevere congestive heart failure.39 Most studieshave noted, however, that coronary vascularresistance declines somewhat less than the

general systemic vascular resistance duringACE inhibition; as the fall in coronaryperfusion pressure that is, blood pressure-is greater than the fall in coronary resistance,coronary blood flow tends to fall. The reasonwhy coronary resistance falls less than in othercirculations is probably because of auto-regulation in response to reduced myocardialoxygen demand caused by reductions in heartrate, preload, and afterload. Thus, oralcilazapril given short term produced coronaryvasodilatation with a fall in double productand improved myocardial lactate metabolismbut no change in coronary blood flow inpatients with heart failure due to ischaemicheart disease or congestive cardiomyopathy.40A decrease in coronary blood flow (by 13%)after short term oral captopril in 11 patientswith heart failure was found in a study byRouleau et al.4' This decrease was con-siderably less than the decrease in doubleproduct (27%) and myocardial oxygen con-sumption (19%). Similarly, a decrease incoronary blood flow (17%, NS) was observedby Halperin et al without a change in coronaryvascular resistance, but coronary arterio-venous oxygen difference and myocardialoxygen consumption were unchanged,presumably because of the concomitantreductions in preload and afterload.42Measures of global coronary blood flow may

be irrelevant to the problem of angina, inwhich regional flow is far more important.Coronary arteriolar tone is usually low inregions of myocardium subtended by a severeepicardial coronary stenosis and dilatationmay not increase much after ACE inhibition.ACE inhibitors have the potential to reducecoronary vascular resistance in territoriessupplied by normal epicardial coronaryarteries, "stealing" blood away from ischaemiczones43 and worsening regional ischaemia.

Effects ofACE inhibitors on angina inpatients with heart failureIn a double blind placebo controlled crossoverstudy the effects of oral captopril on symptomsand exercise test results were determined in 18patients with chronic heart failure andangina.43 Treatment resulted in a worsening ofangina symptoms as assessed by visualanalogue scores and use of glyceryl trinitrate.Exercise performance tended to deterioratewith ACE inhibition, with an increase in thenumber of patients stopping exercise becauseof developing angina.

Effects of ACE inhibitors on subsequentischaemic events in patients withprevious myocardial infarction, leftventricular dysfunction, or heart failureSeveral clinical trials have shown that ACEinhibitors have beneficial effects on recurrentischaemic events in patients after myocardialinfarction and in patients with chronic leftventricular systolic dysfunction with or with-out heart failure. The results of these studieswith respect to death and recurrent infarction

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Effects ofACE inhibitors on coronary haemodynamics and angina pectoris

is dealt with at greater length by Hall and Ballin this supplement,44 but I will examine theresults of these trials to identify possible effectsof treatment on the occurrence of angina.The SMILE study (survival of myocardial

infarction long-term evaluation) examined theeffects of the ACE inhibitor zofenopril onsubsequent cardiac events in 204 patients aftermyocardial infarction.45 There was a small(non-significant) reduction in mortality at oneyear and the number of fatal reinfarctionswas not reduced, though the incidence waslow in each group (two patients in zofenoprilgroup, two in control group). However, theincidence of early and late recurrence ofangina were both reduced in the ACEinhibitor group (8-9% v 27K1% and 9-8% v217% respectively). In the SOLVD pre-vention trial in patients with asymptomatic leftventricular dysfunction enalapril reduced therelative risk of subsequent unstable angina by140/o.46 47 In the SOLVD treatment trial inpatients with mild to moderate heart failuresimilar results were seen, the relative risk ofdeveloping unstable angina being reduced by27%.13 47

Further objective evidence of a reductionin subsequent ischaemia after myocardialinfarction was obtained in a recent study bySogaard et al in 64 patients followed up for sixmonths.48 Captopril resulted in a reduction inST segment depression on ambulatory moni-toring and on exercise testing. The effects onischaemic indices gradually increased overthe follow up period. A similar effect wasobserved in other ACE inhibitor studies-thatis, SAVE and SOLVD prevention-in whichthe coronary event rates diverged little until12-18 months.Not all studies have shown these beneficial

effects, however. In the Nordic enalaprilexercise trial (a subtrial of CONSENSUS II)exercise testing at one and six months aftermyocardial infarction in 327 patients did notshow any benefit from ACE inhibition withrespect to the frequency of ST segmentdepression or angina as the limitingsymptom.49 A similar study in a smaller group(99 patients) also showed no benefit fromcaptopril treatment on the occurrence ofischaemia on exercise testing at one year.50

Finally, the anti-ischaemic mechanisms ofACE inhibitors may have accounted for andcontributed to the observed improvements insudden death reported in other trials-that is,V-HeFT II-as sudden death may be relatedto ischaemic intercurrent cardiac events(recent myocardial infarction and acutecoronary thrombosis).'9

ConclusionsACE inhibitors should have, at least theor-etically, significant anti-ischaemic properties.ACE inhibitors do have anti-ischaemicproperties in some patients with angina,hypertension, and concomitant coronaryartery disease, as well as in patients with heartfailure due to previous hypertension, con-gestive cardiomyopathy, or ischaemic heart

disease. The main anti-ischaemic effects maybe indirect and related to reductions in leftventricular pressure, cavity size, and wallstress and to concomitant reductions insympathetic tone rather than overriding directprimary effects on coronary haemodynamics.The observed responses are often weak andunpredictable. Coronary steal phenomenamight be important in negating the benefits ofACE inhibition and explain why some patientsdeteriorate in terms of developing ischaemia orangina symptoms.A clear distinction must be made between

the short term effects of ACE inhibitors onischaemia and angina and their potential formodifying the natural history of atheromatousdisease, a much more long term process.

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