eur heart j 1998 forslund 578 87

European Heart Journal (1998) 19, 578–587

Ischaemia during exercise and ambulatorymonitoring in patients with stable angina pectoris

and healthy controls

Gender differences and relationships to catecholamines

L. Forslund, P. Hjemdahl*, C. Held, I. Bjo ¨ rkander, S. V. Eriksson and N. Rehnqvist

Department of Medicine, Danderyd’s Hospital, *Department of Clinical Pharmacology, Karolinska Hospital,Stockholm, Sweden

Aims To evaluate signs of ischaemia and ventriculararrhythmias in relation to gender and sympathoadrenalactivity in patients with stable angina pectoris and healthycontrols.

Material and Methods 809 patients (248 females) withstable angina pectoris, and 50 matched healthy controlsperformed an exercise test and an ambulatory ECG record-ing. Catecholamines were measured in plasma before andimmediately after exercise, and in urine during ambulatoryECG.

Results Male and female patients showed similar fre-quencies of ST-depression, similar blood pressure andcatecholamine responses on exercise testing. Females hadhigher heart rates and were more prone towards silentischaemia. The healthy controls exercised longer andshowed greater adrenaline responses. During ambulatoryECG, the two genders had similar duration of ST-depression, but males had more premature ventricularcomplexes. Females excreted more noradrenaline, and had

higher minimal and maximal heart rates. Prematureventricular complexes were equally common amongpatients and controls, but controls had greater catecho-lamine excretion. Maximal ST-depression during exercisewas positively related to the duration of ST-depressionduring ambulatory ECG for both genders. Exercise timeuntil ST-depression was inversely related to the duration ofST-depression during ambulatory ECG among malepatients only. Catecholamine responses during exercisetesting were more closely correlated to time until chest painthan to signs of ischaemia.

Conclusion Mechanisms behind myocardial ischaemiaand arrhythmias may differ in male and female patients, asfemales seem to be more prone towards silent ischaemia.Ischaemia on exercise correlated to ambulatory ischaemiaamong males only.(Eur Heart J 1998; 19: 578–587)

Key Words: Angina pectoris, exercise testing, ambulatorymonitoring, gender differences, catecholamines.

Introduction

Stable angina pectoris is a clinical condition, whichhas a close relationship with coronary arteriosclerosis.The diagnosis is commonly based on history, and testssuch as exercise tolerance testing and ambulatory ECGmonitoring. These tests are also used to document theseverity of the coronary artery disease and to evaluatethe possible need for coronary angiography, in order toestablish whether revascularization is indicated. Usually,

but not always, significant coronary artery narrowingcan be demonstrated on angiography in patients withstable angina pectoris. Coronary spasm[1] or syndromeX[2] sometimes cause anginal pain in the absence ofangiographically significant stenosis. Silent ischaemiaduring ambulatory ECG is common among patientswith a positive exercise tolerance test[3]. On the otherhand, as many as 30% of patients with angiographicallysignificant coronary stenosis have no signs of ischaemiaor chest pain during exercise tolerance testing[4]. Anginapectoris is thus a complex condition which cannot beevaluated only in terms of a positive coronary angio-gram, a positive exercise tolerance test and/or an ambu-latory ECG. Results from exercise tolerance testing andambulatory ECG may be fairly closely interrelated[5,6],

Revision submitted 30 September 1997, and accepted 13 October1997.

Correspondence: Lennart Forslund, MD, Department of Medicine,Trelleborg’s Hospital, S-231 85 Trelleborg, Sweden.

0195-668X/98/040578+10 $18.00/0 hj970819 ? 1998 The European Society of Cardiology

or show poor correlations[7]. However, such relation-ships have mostly been examined in small studies mainlyconcerning the effects of drug treatment, and in selectedpatient groups (e.g. only patients with positive exercisetolerance tests). There is also limited information ondifferences between male and female patients with stableangina pectoris, although the specificity and sensitivityof exercise tolerance testing appears to be poorer amongfemales[8].

The detrimental effects of catecholamines on theischaemic myocardium are well known and are therationale behind beta-blockade in the treatment ofangina pectoris[9]. In addition, adrenaline may provokepain and signs of ischaemia when infused in patientswith stable angina pectoris[10]. However, relatively littleis known about catecholamine levels in patients withstable angina pectoris during exercise and/or ambu-latory conditions. It is therefore important to studysympathoadrenal activity in relation to chest pain andsigns of ischaemia in such patients.

Ventricular arrhythmias attracted much atten-tion during the 1960s and 1970s, when prematureventricular complexes were found to carry independentprognostic information in patients with ischaemic heartdisease[11]. These studies mainly concerned men whohad suffered a myocardial infarction. Increased sym-pathetic activity was considered to be one of the mostimportant factors provoking arrhythmias. The fact thatbeta-blockade was found to improve the prognosisafter an acute myocardial infarction[12] strengthenedthis opinion. Thus, an evaluation of sympathoadrenalactivity in relation to arrhythmias in stable anginapectoris is also of interest.

The present report evaluated ischaemia andarrhythmias in minimally treated or untreated patientswith stable angina pectoris entering the Angina Prog-nosis Study In Stockholm (APSIS)[13]. For comparison,we studied a matched healthy control group. In thisreport, we focus on differences between male and femalepatients on relationships to sympathoadrenal activity (asassessed by measurements of catecholamines in plasmaand urine) in connection with exercise tolerance testingand ambulatory ECG, respectively, and on relationshipsbetween results from exercise tolerance testing andambulatory ECG.

Methods

The present study is based on identical examinations inpatients taking part in the APSIS study and an age- andsex-matched healthy control group. The study wasapproved by the Ethics Committee of the KarolinskaInstitute, and all participants gave their informed con-sent before entering the study. In order to avoid reboundphenomena or severe deterioration, patients already onbeta-blockers or calcium antagonists received minimaldoses of metoprolol (25–50 mg daily) or verapamil(40 mg twice daily) during a 14 day run-in period. Thus,

55% of the patients were on low-dose metoprolol and15% on low dose verapamil at the time of baselineinvestigations.

Patients

Altogether 1276 patients with suspected angina pectoriswere referred from the Danderyd Hospital or fromprimary care in the catchment area to the HeartResearch Laboratory at the Danderyd Hospital. Basedon medical history and physical examination by acardiologist, 809 patients (248 women) were consideredto fulfil the criteria for inclusion in the APSIS study.

Inclusion criteria were: age <70 years and ahistory of chronic stable angina pectoris according toHeberden[14] i.e. ‘a discomfort of the chest that gives asense of strangling and anxiety, that is usually broughtabout while walking around, and relieved by rest’. Chestpain could present itself as effort-induced, or anginaat rest (i.e. vasospastic, but not unstable), or both.Episodes of chest pain or discomfort should persistlonger than a few seconds, but less than 15 min. Sub-lingual nitrates, when used, should typically provideprompt relief. When in doubt whether the symptomswere of cardiac origin or not, additional examinations(exercise tests, perfusion scintigraphy, radiologicaland/or gastrointestinal investigations) were performed inorder to exclude non-cardiac chest pain.

Exclusion criteria were: myocardial infarctionwithin the last 3 years; anticipated need for revasculariz-ation within 1 month after inclusion; significant valvulardisease or severe congestive heart failure; other severediseases; contraindications to either study drug(metoprolol or verapamil); and risk of poor compliance(e.g. suspected alcohol abuse).

Healthy controls

Fifty healthy subjects (13 females) were recruited via thepopulation registry of Stockholm County. They werematched for sex and birth date with every 16th patient inthe APSIS study, and were invited to participate by astandardized letter. The controls were, for administra-tive reasons, recruited and examined about 2 years laterthan the patients. Subjects who reported signs of diseaseduring a brief telephone interview were excluded. Theremaining subjects were then invited for a closer exami-nation, which included medical history, a thoroughphysical examination, measurements of blood pressureand an ECG recording at rest. Altogether 36 personswere excluded (reasons were health problems orinsufficient veins for platelet function studies), andreplaced by another matched control from the popula-tion registry list. Finally 50 healthy persons wereincluded; they were taking no drugs of any kind, andhad normal resting ECGs and diastolic blood pressures¦90 mmHg.

Ischaemia during exercise and ambulatory monitoring in stable angina pectoris 579

Eur Heart J, Vol. 19, April 1998

Exercise tolerance testing

A symptom-limited exercise test was performed on anelectrically braked bicycle ergometer, with a startingload of 30 W and 10 W increments every min. ExerciseECGs were registered on a Siemens-Elema Sicard 440/440S with an on-line ECG (leads I, II, V5), or aMingograph 740 (both from Siemens–Elema, Solna,Sweden). The Sicard was attached to a Siemens Nixdorfcomputer which produced averaged ECG complexes at60 s intervals. From the Mingograph, on-line paperprint-outs of six chest leads were produced continuouslyat a paper speed of 25 mm . s"1 and every minute a12-lead ECG at a paper speed of 50 mm . s"1 wasregistered. ECG print-outs were surveyed both auto-matically and manually, and analysed for ST-segmentdepressions. Significant ischaemia was considered to bepresent if there was an ST-depression of at least 1 mm,horizontal or downsloping, 80 ms from the J-point in atleast two adjacent leads. Systolic blood pressure wasmeasured every 3rd min throughout the test.

The patients were urged to report chest painimmediately, as well as increases in severity, as assessedby the 10-degree modified Borg scale[15]. Exercise toler-ance testing was stopped when patients were unable tocontinue due to chest pain, general and/or leg musclefatigue or dyspnoea. The healthy subjects were encour-aged to continue until exhaustion (Borg scale for Ratingof Perceived Exhaustion, RPE §17). For safety reasonsthe responsible cardiologist could also stop the test ifthere was a fall in systolic blood pressure (§20 mmHgin one measurement or §10 mmHg in two consecu-tive measurements), a severe ST-segment depression(4–5 mm in at least three leads), or a severe ventriculararrhythmia. The following parameters were registered:exercise duration (s); maximal work load (W); time toonset of chest pain (s); time to 1 mm ST-depression (s);maximum ST-depression (mm).

Subgrouping based on exercise test resultsThe patients were divided into four subgroups, accord-ing to the presence or absence of symptoms and signs ofischaemia on exercise. The first group had ischaemicST-depression without chest pain, or signs of ischaemiaat least 1 min before onset of chest pain (‘delayed anginaor silent ischaemia’). The second group (‘angina andischaemia’) consisted of patients with ST-depressionoccurring simultaneously with or after the onset of chestpain. The third group had chest pain without ST-depression (‘angina only’). The fourth group had neitherST-depression nor chest pain (‘neither-nor’).

Ambulatory ECG recordings

Ambulatory ECG was performed over 24 h with theOxford Medilog system (Oxford Medical EquipmentLtd, Abingdon, U.K.), and analysed for ST-depressionsand ventricular arrhythmias by an Oxford Excelcomputer. The computer analyses were checked

manually for the same parameters. Both the numberof episodes and the total duration (in minutes/24h) ofST-depression, defined as for the exercise test, wereregistered. Events had to last §1 min and be separatedfrom the next event by §1 min. Premature ventricularcomplexes were defined according to Lown[16]. Subjectswith premature ventricular complexes of Lown classesfrom 2 to 5 were analysed together (premature ventricu-lar complexes §2). Tapes from patients with >10premature ventricular complexes/hour were carefullyscrutinized to ascertain that computer classificationswere correct. Only tapes with 17 or more recordedhours of technically acceptable quality were analysed.Registrations covering 17–24 h were extrapolated to24 h.

Catecholamine analyses in plasma and urine

PlasmaVenous blood samples were drawn through an indwell-ing antecubital venous catheter after 15 min of supinerest, and immediately upon resumption of the supineposition after the termination of exercise. Plasmacatecholamine concentrations were analysed by highperformance cation exchange liquid chromatographywith amperometric detection, as described and validatedpreviously[17].

UrineDuring ambulatory ECG, the patients also collectedurine, with separate canisters for day and night urine.The canisters contained sodium metabisulfite (0·5 g/canister), and the urine was acidified to pH 2–3 with 6Nhydrochloride acid before storing aliquots for analysis at"80 )C. Urinary catecholamine concentrations wereanalysed using a methodology similar to that for plasmaanalyses[18]. In order to avoid confounding by samplingerrors with regard to urine volume, the excretionsof catecholamines were adjusted for creatinine ex-cretion. Creatinine was measured by the Jaffe reaction,using a Monarch 2000 autoanalyser (InstrumentationLaboratories, Lexington, MA, U.S.A.).

Statistics

Mean values and standard deviations or mediansand interquartiles are presented unless otherwise noted.Discrete variables were compared by the chi-square testwith Yates’ continuity correction. Group differences incontinuous variables were assessed by two-tailed t-tests.Coefficients for skewness and kurtosis were used to testdeviations from a normal distribution. If the underlyingnormality assumption was violated, a non-parametricmethod was used. Inter-relationships between variableswere analysed by Spearman rank order correlations.Descriptive statistics and graphical methods were usedto characterize the data. Analyses were performed

580 L. Forslund et al.


with the SAS statistical software (SAS Institute Inc.,SAS/STAT version 6, 4th ed. Cary, NC, U.S.A.) and theStatistica= statistical package for PC/Macintosh (StatSoft, Tulsa, OK, U.S.A.). A P value of <0·05 wasconsidered statistically significant.

Results

Demographic data are shown in Table 1. Previousmyocardial infarction (P<0·001), and previous re-vascularization (P<0·01) were more common amongmale than female patients. Patients showing ST-segmentdepression or chest pain only during the recovery phaseof the exercise tolerance test were excluded fromthe analyses concerning exercise tolerance testing andambulatory ECG, as were patients with left bundlebranch block or treatment with cardiac glycosides(n=68).

Exercise tolerance testing (Table 2)

PatientsThe reasons for terminating exercise differed betweengenders (P<0·001), and were (males vs females): chestpain for 30 vs 18%, leg muscle fatigue for 25 vs 30%,dyspnoea for 13 vs 20%, respectively, and general fatiguefor 30% in both genders. Heart rate at maximal workload (Wmax) was lower among males (P<0·01), butsystolic blood pressure did not differ. A greater pro-portion of males compared to females had chest pain (63vs 51%; P<0·01), but significant ST-depression occurredwith equal frequencies (67 vs 71%; ns). Among 157females with significant ST-depression on exercise,80 (51%) reported chest pain, whereas 235 (69%) of341 male patients with significant ST-depression hadchest pain. Thus, females were less likely than males

to experience symptoms with signs of ischaemiaduring exercise testing (P<0·001). Patients on minimalanti-anginal treatment showed lower resting heart rates(63&11 vs 68&11; P<0·001), achieved lower Wmax(114&33 vs 125&39 W; P<0·001) with lower heartrates (121&24 vs 138&21; P<0·001) and hadearlier onset of chest pain (354&163 vs 396&183 s;P<0·01).

Healthy controlsOne male and two females showed asymptomatic ST-depressions considered to be of ischaemic origin duringexercise. All controls terminated the exercise test due togeneral or leg muscle fatigue.

Ambulatory ECG recordings (Table 3)

PatientsSignificant ischaemic ST-changes on ambulatory ECGoccurred in 57% of males and 59% of females (ns).The median duration of ST-depression/24 hours was 4(0;40) min for males and 6 (0;46) min for females (ns).Premature ventricular complexes of Lown grade 2 to 5(premature ventricular complexes §2) occurred in 270patients, 220 (42%) males and 50 (24%) females(P<0·001). The duration of ST-depression in this sub-group of patients was 5 (0;51) min for males and 10(0;90) min for females (ns). Minimally treated patientshad lower minimal and maximal heart rates over 24 h(48&7 vs 49&7; P<0·01 and 127&32 vs 136&22;P<0·001, respectively).

Healthy controlsST-depressions occurred in eight males and five females.Seventeen males and two females had prematureventricular complexes §2.

Table 1 Patients with angina pectoris and healthy control subjects. Demographics atbaseline

Healthycontrols

Allpatients

Malepatients

Femalepatients

No. of subjects 50 809 561 248Age (years) 61&9 59&7 59&8 59&7Body mass index (kg . m"2) 25&3 26&4 26&3 26&4Active smokers (%) 28·0 21·8 24·6 15·3**Ex-smokers (%) 34·0 43·0 48·5 30·7**Diabetes mellitus (%) — 8·5 9·8 5·6History of angina pectorisDuration (years) — 3·7&4·5 3·9&4·7 3·3&3·8

Previous cardiac historyMyocardial infarction (%) — 16·1 20·1 6·9***CABG or PTCA (%) — 5·7 7·3 2·0**History of cardiac decompensation (%) — 6·6 6·2 7·3History of hypertension (%) — 27·1 27·8 25·4

Mean&SD. **P<0·01, ***P<0·001, refers to differences between male and female patients.CABG=coronary artery bypass grafting; PTCA=percutaneous transluminal coronaryangioplasty.



Table 2 Results from exercise tolerance testing in patients with angina pectoris and healthy control subjects. Thedifferences in the number of subjects examined are due to the exclusion of patients with left bundle branch block and ofthose on cardiac glycoside treatment. Furthermore, due to a freezer breakdown, some catecholamine samples weredestroyed

Total no. of subjects Healthy controls50

All patients809

Male patients561

Female patients248

Haemodynamics at restHeart rate (beats . min"1) 64&9 65&12 65&12 66&11SBP (mmHg) 134&19†† 143&21 144&20 142&18DBP (mmHg) 84&10 85&10 86&10 83&10*

Exercise testsNumber of subjects examined 50 731 511 220Exercise duration (s) 795&268††† 595&212 654&212 460&136***Wmax (W) 158&45††† 128&36 138&36 105&23***HR at Wmax (beats . min"1) 153&16††† 127&24 125&24 133&24**SBP at Wmax (mmHg) 173&28 174&32 174&34 171&29

Plasma catecholamines (nmol . l"1)Number of subjects examined 50 581 424 157

AdrenalineAt rest 0·19&0·15 0·18&0·13 0·18&0·13 0·16&0·12**After exercise 0·94&0·77††† 0·66&0·60 0·68&0·62 0·62&0·54

NoradrenalineAt rest 2·14&0·67 2·47&1·20 2·43&1·12 2·44&1·23After exercise 15·1&5·61 13·45&8·00 13·74&8·44 12·66&6·63

Symptoms and signs of ischaemia during exerciseNumber with chest pain (%) 0 433 (59) 321 (63) 112 (51)**Exercise duration until chest pain (s) — 373&172 406&171 278&139***Number with ST-depression (%) 3 (6) 497 (68) 340 (67) 157 (71)Exercise duration until ST depression (s) (420–660)‡ 386&182 423&193 308&121***Max ST depression (mm) (1·0)‡ 2·0&1·1 2·2&1·1 1·7&0·9***

Mean=SD. *P<0·05, **P<0·01, ***P<0·001 refers to differences between male and female patients.††P<0·01, †††P<0·001 refers to differences between patients and healthy controls, †=range. HR=heart rate; SBP=systolic andDBP=diastolic blood pressure; Wmax=maximal work-load.

Table 3 Heart rate, 1 mm ST-depression and premature ventricular complexes (PVCs) during 24 h ambulatory ECGin patients with angina pectoris and healthy control subjects. The table also shows maximal and minimal heart rates andurinary catecholamine excretion during ambulatory ECG. Adrenaline and noradrenaline excretions are adjusted forcreatinine excretion (nmol/mmol creatinine) and are separated into day and night sampling portions. Patients with leftbundle branch blocks and on treatment with cardiac glycosides have been excluded

Healthy controls All patients Male patients Female patients

Number of subjects examined 49 638 473 210Number of subjects with ST-depression (%) 13 (27)††† 395 (58) 271 (57) 124 (59)Number of episodes with ST-depression during 24 h 0 (0;1)††† 1 (0;7) 1 (0;7) 2 (0;9)Duration of ST-depression during 24 h (min) 0 (0;1)††† 4 (0;42) 4 (0;40) 6 (0;46)Number of subjects with (%) PVCsLown grade 1 12 (24) 184 (29) 129 (27) 55 (26)Lown grade §2 19 (39) 270 (42) 220 (47) 50 (24)***

Number of PVCs/24 h 5 (0;31) 9 (0;89) 15 (1;129) 1 (0;35)***Maximum heart rate 130&19 132&22 130&22 137&23***Minimum heart rate 49&6 48&7 48&7 49&7**Adrenaline (day) 5·15&2·48††† 4·06&3·20 4·08&3·55 4·00&2·18Adrenaline (night) 1·27&1·09 1·21&1·79 1·22&2·03 1·19&1·06*Noradrenaline (day) 44·16&17·41††† 35·37&13·55 33·31&13·25 40·13&13·05***Noradrenaline (night) 26·48&14·42††† 18·73&8·39 18·08&8·22 20·25&8·63***

Median (q1;q3) and mean&SD. *P<0·05, **P<0·01, ***P<0·001, refers to differences between male and female patients. †††P<0·001,refers to differences between patients and healthy controls.



Catecholamine analyses

Plasma catecholamine concentrations (Table 2)Adrenaline levels were slightly, but significantly higherin male compared to female patients at rest (P<0·01),but not after exercise; increases from resting to maximalvalues did not differ either. Noradrenaline levels showedno significant gender differences either at rest or afterexercise. In minimally treated patients compared tountreated, noradrenaline at rest was higher (2·58&1·23vs 2·24&1·01; P<0·01) and so was adrenaline afterwork (0·71&0·64 vs 0·60&0·58; P<0·01). Healthy con-trols and patients had similar catecholamine levels atrest, but the controls had a greater adrenaline responseto exercise (P<0·001), probably reflecting their higherWmax and greater relative exertion during the exercisetolerance testing.

Urinary catecholamine excretion during ambulatoryECG (Table 3)Female patients excreted more noradrenaline than malesboth during the day and at night (P<0·001; for both),but showed a slightly lower excretion of adrenaline atnight (P<0·05). The urinary excretion of adrenalineduring the day and of noradrenaline both during the day

and at night were significantly higher among healthycontrols compared to patients. The diurnal variability ofcatecholamine excretion was similar among patients andcontrols, as well as among male and female patients.

Exercise tolerance testing responses vsresults from ambulatory ECG in thedifferent ischaemia groups (Table 4)

Cardiovascular responses to exerciseMale patients with delayed angina or silent ischaemiareached a higher Wmax than males with angina andischaemia (P<0·01) and their maximal ST-depressionwas greater (P<0·001). Heart rate at Wmax was higher(P<0·001) but systolic blood pressure did not differ. Infemales with delayed angina or silent ischaemia, exerciseduration was longer (P<0·05) and maximal ST-depression greater (P<0·05) compared to females withangina and ischaemia, but heart rate and systolic bloodpressure did not differ. In the delayed angina or silentischaemia group, 58% of males and 77% of females hadno chest pain despite signs of ischaemia during exercisetolerance testing (P<0·001).

Table 4 Signs of ischaemia, chest pain, haemodynamics and catecholamines during exercise tolerance testing, andduration of ST-depressions during ambulatory ECG. Patients with left bundle branch blocks and on treatment withcardiac glycosides have been excluded

Delayed angina orsilent ischaemia

(a)

Angina andischaemia

(b)

Angina only(c)

Neither-nor(d) Statistics

Number of males (%) 183 (40) 123 (26) 79 (17) 79 (17)Number of females (%) 94 (47) 50 (25) 29 (14) 28 (14)Exercise duration (s)Males 660&206 594&217 618&181 764&227 d>a,b,c P<0·001

a>b P<0·01Females 483&127 434&136 421&161 487&129 a>b,c P<0·05

d>c P<0·05Heart rate at end of exerciseMales 128&23 117&23 120&23 133&24 a,d>b,c P<0·001Females 137&22 131&24 124&28 132&22

Systolic blood pressure at end of exerciseMales 175&35 175&33 169&31 179&34Females 173&29 170&29 169&31 172&30

Maximal ST-depression during exercise (mm)Males 2·4&1·2 1·9&0·8 a>b P<0·001Females 1·9&1·1 1·5&0·6 a>b P<0·05

Plasma catecholamines after exercise (nmol . l"1)AdrenalineMales 0·72&0·58 0·60&0·53 0·56&0·71 0·74&0·58 a>b;d>b P<0·05

a>c;d>c P<0·01Females 0·69&0·56 0·53&0·46 0·54&0·33 0·72&0·73

NoradrenalineMales 14·3&8·6 12·8&7·0 11·9&6·9 15·2&10·7 a>c;d>c P<0·05Females 14·9&7·8 10·4&4·8 10·6&4·4 12·8&5·5 a>b; P<0·01

Duration of 1 mm ST-depression in min during 24 h ambulatory ECG. Median (q1;q3)Males 14 (0;105) 7 (0;24) 0 (0;30) 0 (0;3) a>b,c P<0·01

* a>d;b>d P<0·001Females 8 (0;69) 9 (0;46) 0 (0;14) 4 (0;25) a>c P<0·01

Mean&SD. *P<0·05 refers to difference between male and female patients in the neither-nor group.



Plasma catecholamine responses to exerciseAfter work, both adrenaline and noradrenaline levelswere higher in males with delayed angina or silentischaemia compared to males with angina and ischaemia(P<0·05) and males with angina only (P<0·01).Noradrenaline after exercise was also higher amongfemales with delayed angina or silent ischaemiacompared to those with angina and ischaemia (P<0·01).

Ambulatory ECG results in different ischaemia groupsMales in the delayed angina or silent ischaemiagroup showed longer duration of ST-depression onambulatory ECG compared to males in other groups. Infemales, the duration of ST-depression differed betweenfemales with delayed angina or silent ischaemia com-pared to those with angina only (P<0·01). In the neither-nor group, the duration of ST-depression duringambulatory ECG was longer in women compared tomen (P<0·05). There were no differences betweenischaemia groups concerning premature ventricularcomplexes in either sex (data not shown).

Correlations between results from exercisetolerance testing and ambulatory ECG

The maximal ST-depression on exercise was positivelycorrelated to the duration of ST-depression duringambulatory ECG in both males and females (r=0·33,P<0·001 and r=0·27, P<0·001, respectively). Thetime until 1 mm ST-depression during exercise was

inversely correlated to the duration of ST-depression onambulatory ECG in men only (r="0·30; P<0·001)(Fig. 1).

Correlations between results from exercisetolerance testing and catecholamine

responses in plasma

The time until chest pain was correlated to increases (i.e.differences between resting and maximal values) ofnoradrenaline in plasma among both male (r=0·30,P<0·001) and female patients (r=0·45, P<0·001). Formales there was also a correlation between time untilchest pain and adrenaline increase (r=0·31, P<0·001).Male patients showed a weak correlation between timeuntil ST-depression and increases in noradrenaline(r=0·16, P<0·01), which could not be found amongfemales (r=0·08, ns).

Correlations between results fromambulatory ECG and catecholamine

excretion

There were no correlations between signs of ischaemiaor premature ventricular complexes during ambulatoryECG, and catecholamine excretion in urine for eithermales or females. Among male patients, maximal heartrates over 24 h showed weak positive correlations to

800

Time until start of ST-depression during ETT

Du

rati

on o

f S

T-de

pres

sion

du

rin

g A

EC

G

1000

600

400

200

200 400 600 800 1200 14000

Figure 1 This shows the relationship between time until start of ST-depression in seconds during exercisetolerance testing (ETT) and the duration of ST-depression in minutes during ambulatory ECG monitoring(AECG) in 306 male patients. The regression line is also shown (r="0·30; P<0·001). Only patients withoutleft bundle branch block or without cardiac glucoside treatment are analysed. Each point does not representthe same number of patients.



noradrenaline excretion both during the day (r=0·15,P<0·01) and at night (r=0·17, P<0·001). Minimal heartrate correlated to noradrenaline excretion during the day(r=0·22, P<0·001) and at night (r=0·21, P<0·001).There was also a weak correlation between minimalheart rates and adrenaline excretion during the day(r=0·14, P<0·01). Among females, minimal heart ratecorrelated to noradrenaline excretion both during theday (r=0·20, P<0·01) and at night (r=0·25, P<0·001).

Discussion

In the present population, with carefully clinicallydiagnosed angina pectoris, chest pain was more commonamong male patients. Signs of ischaemic (i.e. ST-depression), on the other hand, were equally commonamong male and female patients both during exercise,and on ambulatory ECG, i.e. in ‘daily life’. This is inagreement with previous findings in more selectedpatient groups, where the exercise tolerance testing hasbeen shown to be equally specific among women andmen with a positive thallium stress test[19], or angio-graphically documented coronary lesions[20]. Femaleshad more asymptomatic ischaemia on exercise thanmales, but there was no gender difference with regard toST-depression on exercise, during ambulatory ECG, orthe catecholamine responses to exercise. Differencesin pain perception may contribute to the gender differ-ence in symptoms. For example, females with an acutemyocardial infarction appear to wait longer beforegoing to hospital[21], and receive less analgesia duringtreatment for myocardial infarction than men[22].

In a study by Deedwania et al. on 97 male anginapatients[23] exercise time until ST-depression showed aweak but significant inverse relationship to the durationof ambulatory silent ischaemia. We did not recordsymptoms during ambulatory ECG, but we did find arelationship between exercise-induced and ambulatorysigns of ischaemia among male patients. Thus, we areable to confirm the previous results[23] in a larger popu-lation of male patients, but we also found a genderdifference, which may reflect differences in the patho-genesis of myocardial ischaemia in males and females.The present results concerning ambulatory ischaemia vsischaemia on exercise suggests that the two tests arecomplementary when evaluating patients with stableangina pectoris. The influence of minimal baseline treat-ment on results from exercise tolerance testing andambulatory ECG was limited to differences in heartrates, maximal work-load and the occurrence of chestpain during exercise. Plasma noradrenaline at rest andadrenaline after exercise were higher among treatedpatients. These differences are, at least in part, due to thefact that minimally treated patients generally had a moresevere cardiac condition[24].

Amsterdam et al.[25] reported that 42% of 92patients (15 women) had delayed angina or silentischaemia. When using the same criteria we also found

this in 42% of our patients. In addition, we found thatsilent ischaemia during exercise was more commonamong females than males, and that delayed angina orsilent ischaemia on exercise was associated with a greatermaximal ST-depression during exercise tolerance testingin both genders. Lanza et al.[26] recently reported that50% of patients with a negative exercise tolerance testhad ischaemia on ambulatory ECG. Our data do notsupport such a high prevalence of ambulatory ischaemiaamong patients with a normal exercise tolerance test(14% in our study), but indicate that ischaemia is notuncommon in the absence of positive exercise tolerancetesting. Interestingly, the duration of ST-depression dur-ing ambulatory ECG was longer among males com-pared to females with delayed angina or silent ischaemia.These males had greater adrenaline responses to exercisetolerance testing than males with angina and ischaemia,and they also exercised longer. Run-in treatment didnot explain this difference. Whether or not increasedexertion upon exercise might influence the risk of amyocardial infarction in such patients can only bespeculated upon.

Male patients had more complex ventriculararrhythmias (premature ventricular complexes §2) thanfemales on ambulatory ECG, but the arrhythmias werenot related to signs of ischaemia. The healthy controlswere carefully examined before inclusion, and had alower incidence of ischaemic ST-changes than found byothers[27,28]. Nonetheless, they had equally many andsevere premature ventricular complexes, suggesting thatpremature ventricular complexes are a poor indicator ofischaemic heart disease, at least in the absence of heartfailure. The control group was too small to allowmeaningful gender comparisons.

Even though males had a greater number anda higher complexity of premature ventricular com-plexes during ambulatory ECG, females excreted morenoradrenaline both during the day and at night.Catecholamine excretion was higher in the healthy con-trol group, with the exception of adrenaline excretionduring the night. This probably reflects a higher level ofphysical activity among healthy persons. The elevationof catecholamine excretion among female patients is noteasily explained. However, it has been proposed that thecombined stress of employment and household workleads to increased sympathoadrenal activity amongfemales compared to males[29]. As noted above, femalepatients also showed more asymptomatic ischaemia onexercise than males, and it is possible that symptomsrestrict male patients more than female patients.

Opinions concerning the diagnostic accuracy andthe implications of exercise test results have differed,as some studies find good agreement with cor-onary morphology[30,31] whereas others find pooragreement[4,32]. Women have been reported to haveST-depression during exercise without significantatherosclerotic narrowing of epicardial coronary arterieson angiography[33,34], and to have ‘normal’ coronaryarteries[35] more often than men. Exercise testing has ahigh predictive value for coronary atherosclerosis in



patients with typical symptoms, but the predictive valueis low when the symptoms are atypical[34]. The predictivevalue of a negative exercise test may be good in bothsexes[36], or poorer among women[33]; differences inreferral must be taken into account[19]. However, it mustbe kept in mind that myocardial ischaemia is notalways due to anatomical lesions within the coronaryarteries[1,2,37,38]. The present and previous results implythat myocardial ischaemia may not have the samepathogenesis in men and women. Coronary angiographymight be the ‘gold standard’ for risk classification andclinical management of the patients, but it does notreflect all relevant phenomena contributing to anginapectoris. Coronary angiography has its limitations indiagnosing myocardial ischaemia; further diagnostictests are often needed to ascertain the presence ofischaemia in women[39].

Our studies concerning catecholamines reflect‘overall’ sympathetic activity. To detect changes in aspecific organ requires regional studies, which we did notperform. When analysing relationships, we found thatchest pain during exercise showed the closest relation-ship to catecholamine responses to exercise. Signs ofischaemia were not related to catecholamines duringeither exercise or ambulatory ECG. This is of interest asMcCance et al.[10] found that infusion of adrenalineprovoked ischaemic ST-changes in patients with stableangina pectoris, but that chest pain was not provoked tothe same extent. Other interesting findings were thatplasma catecholamine responses to exercise were similarin males and females, suggesting similar relative levels ofexertion, and that females excreted more noradrenalineduring ambulatory ECG despite fewer and less complexpremature ventricular complexes. Adrenaline is amarker of ‘arousal’ and stress, which may correlate wellwith cardiac sympathetic nerve activity[40]. However, wefound no important relationships between plasma orurinary adrenaline and signs of ischaemia in the presentstudy.

Limitations of the studySince the diagnosis of angina pectoris was based onhistory and clinical examinations only, it can be arguedthat some of our patients did not have ischaemic heartdisease. As stated above, however, neither coronaryangiography nor tests such as exercise tolerance testingand ambulatory ECG reveal the whole truth aboutangina pectoris. Selecting patients who only had positiveangiograms, exercise tolerance tests or ambulatoryECGs would have resulted in exclusion of many patientswho were, in fact, suffering from ischaemic heart disease.

ConclusionsIn conclusion, we have described some differencesbetween male and female patients with chronic stableangina pectoris, which might reflect differences in the

mechanisms underlying myocardial ischaemia and ar-rhythmias. Notably, females had more silent ischaemiaon exercise and no relationships between ischaemia onexercise and ischaemia or arrhythmias during ambula-tory monitoring. Only weak relationships were foundbetween results from exercise tolerance testing andambulatory ECG, suggesting that the two tests arecomplementary rather than interchangeable. Overall,sympathoadrenal activity was not related to ischaemia.Future analysis of our results from the long-termfollow-up and prognosis in different patient groups maygive some information on the clinical implications ofthese findings.

We gratefully acknowledge all help and support from ourresearch nurses Inger Bergbom, Ewa Billing, Ann-Marie Ekman,Britt Ryden, and technicians Maud Daleskog, Maj-ChristinaJohansson, Christina Perneby and Wiveka Ring-Persson. We alsothank Per Nasman, at the Royal Institute of Technologyin Stockholm for data management and statistical services andMargret Lundstrom for data entering management.This study was supported by grants from the Swedish Heart,

Lung Foundation, the Foundation of the Serafimer Hospital, theSwedish Society of Medicine, the Karolinska Institute, Knoll AG,Ludwigshafen, Germany and Astra Hassle, Gothenburg, Sweden.

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