Br HeartJ_ 1993;70:346-351

Clinical presentation and functional prognosis insyndrome X

Anoop Chauhan, Paul A Mullins, Suren I Thuraisingham, Michael C Petch,Peter M Schofield

AbstractObjectives-To assess the effect of clini-cal presentation on functional prognosisin patients with syndrome X.Design-A prospective study. PatientswithI syndrome X presenting with unsta-ble angina and stable angina werefollowed up with a questionnaire toexamine their functional state.Patients-41 patients with syndrome Xand unstable angina and 41 patientswith syndrome X and stable angina.Syndrome X was defined as typical angi-nal chest pain, a positive exercise test,and normal coronary angiogram.Setting-Regional cardiothoracic centre.Results-The mean follow up time was 36(range 20-51) months for the unstableangina group and 35 (range 19-51)months for the stable'-angina group. Nopatient was lost to follow up in eithergroup. At follow up 28 patients in the

unstable. a4gina group, were pain freecomparedt with 15 patients in the stableangina group (p = 0.008). Seven patientsin the unstable angina. group had furtherhospital admission wi'th chest pain afterthe, cardiac catheterisation comparedwith 12 patients in the stable anginagroup (NS). Seven patients in the unsta-ble angina- group believed that they hadheart disease compared with 27 in thestable angina group (p < 0.001). 26patients in the unstable ana group butonly eight, patients in the stable anginagroup~were unlimited in their physicalactivity (p < 0.001). 12 patients in theunstable angina group compared with 27patients in the stable angina group wereunable to work normally because ofchest pain (p < 0.001). The mean (SD)duration of symptoms before cardiaccatheterisation was 7-9 (4.7) months inthe unstable angina"group and 13-4 (5.6)months, in the stable angina group

RegUonal Cardiac (p < 0-001). 10- patients in the unstableHospital, Papworth a -group and 24 patients in theEverard, Cambridge - 'stable -angina group still attended hospi-A ChauhanP A Mullins tal outpatient clinics because of chestS I Thuraisingham pain (p = 0 004). 16 patients in the unsta-M C Petch ble angina group and 29 patients in theP M Schofield stable angina group were still taking reg-Correspondence to: ular antianginal medication (p < 0 001).Cardiac Unit, Papworth Conclusions-Patients with syndrome XHospital, Papworth Everard, who present with unstable angina have aCambridge CB3 8RE. significantly better functional prognosisAccepted for publication27 April 1993 -- than those presenting with symptoms of

stable angina. This may reflect differ-ences in underlying pathophysiologicalmechanisms.

(Br HeartJ 1993;70:346-35 1)

Most of the clinical manifestations ofischaemic heart disease are due to a fixed ordynamic obstruction of epicardial coronaryarteries. In more than 10% of patients under-going coronary angiography for the assess-ment of chest pain, however, the coronaryangiogram is normal.1-3 Also, about 10% ofpatients referred for cardiac catheterisationwith the diagnosis of unstable angina havenormal coronary angiograms.45 Thesepatients are said to have angina pectoris withnormal coronary angiograms or Syndrome X.It is now recognised that syndrome X is a het-erogeneous syndrome that encompasses dif-ferent pathophysiological entities.67 It hasbeen shown by many studies that patientswith chest pain and normal coronary arterieshave a normal long term life expectancy.8-0The same studies have also indicated, how-ever, that there is a considerable residualmorbidity with medical, economic, and socialconsequences. Studies of functional statehave shown that many patients with syn-drome X continue to remain significantly lim-ited in activity despite reassurance." 12Differences in the functional state of patientswith syndrome X who present with unstableangina compared with those who present withstable angina have not been reported previ-ously. We investigated the hypothesis thatpatients with syndrome X who present withunstable angina may have a different func-tional prognosis than those presenting withstable symptoms due to differences in under-lying pathophysiological mechanisms. Thismay allow the identification of a subset ofpatients with a worse functional prognosis.

Patients and methodsPATIENTSThe functional state of 41 patients with syn-drome X who presented to PapworthHospital with unstable angina (unstableangina group) and 41 patients with syndromeX who presented with stable angina (stableangina group) was examined prospectively.Patients were recruited into the study duringthe period 1988 to 1991.

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Clinical presentation andfunctional prognosis in syndrome X

PATIENT SELECTIONConsecutive patients with syndrome X pre-senting with unstable angina were

approached for inclusion in the study. Allpatients gave full informed consent. Eachpatient then underwent oesophageal functionstudies. Patients in whom these were abnor-mal were excluded. The remaining patientswere then matched with patients with syn-

drome X presenting with stable angina whohad also undergone oesophageal functionstudies to exclude patients with oesophagealabnormalities.

During the study recruitment period 47patients with syndrome X presented withunstable angina. This constituted 12% of thetotal number of patients presenting with syn-

drome X. Forty six of these consented to beincluded in this study. Five (11%) had an

abnormality on oesophageal function testsand were therefore excluded from the study.A total of 50 patients with syndrome X pre-

senting with stable angina were investigatedby oesophageal function studies. Nine (18%)had an abnormal oesophageal manometryand were therefore excluded. The remaining41 were matched to patients with syndromeX and unstable angina for the follow up

study.

UNSTABLE ANGINA GROUPBecause of their symptoms, these patientswith unstable angina were referred from otherhospitals in the region for urgent coronary

angiography. The cardiac enzymes had beennormal in all patients. There were 20 men

and 21 women in this group.

STABLE ANGINA GROUPThese patients had been referred initially tothe outpatient clinic with a diagnosis ofangina. Their symptoms had continueddespite antianginal medication and they were

subsequently electively admitted for cardiaccatheterisation. There were 16 men and 25women in this group.

DEFINITION OF SYNDROME XSyndrome X was defined as typical anginalchest pain, a positive exercise test, and nor-

mal coronary arteries on angiography as

reviewed by two independent observers. Allpatients underwent an exercise test with a

standard Bruce protocol after all antianginalmedication had been stopped for a minimumof three days. In all patients the exercise testwas performed after the cardiac catheterisa-tion and only those patients with a positiveexercise test were included in the study. Theexercise test was considered to be positive ifthere was horizontal or downsloping ST seg-ment depression of >1 mm for 80 ms afterthe J point. All patients had a normal left ven-tricular function as judged from the echocar-diogram and left ventricular angiogram. Theleft ventricular end diastolic pressure was

normal in all patients. There was no evidenceof muscle bridging on coronary angiography.

DEFINITION OF UNSTABLE ANGINAUnstable angina is a descriptive term for a

spectrum of acute myocardial syndromes thatlie clinically between stable angina andmyocardial infarction. The term, as it is usedin clinical practice, is not precisely definedand many complex classifications have beenproposed based on clinical and angiographiccriteria."I14 In this study unstable angina wasdefined as (a) new angina of one to twomonths duration occurring at low work loadsor rest; (b) crescendo angina defined as anoticeable increase in the frequency or sever-ity of previously stable angina; and (c) pain atrest with electrocardiographic evidence ofischaemia but without evidence of myocardialinfarction. These categories are not mutuallyexclusive. The category of pain at rest wouldinclude some patients with previously mildangina and a noticeable increase in symptoms(crescendo angina) and also patients withpreviously severe angina and a slight increasein symptoms.

ECHOCARDIOGRAPHYAll patients underwent echocardiographicassessment. M mode and cross sectionalassessments of the left ventricular posteriorwall and septal thickness were made.

BLOOD ANALYSISBlood samples were taken for full bloodcount, serum urea and electrolytes, and fast-ing lipids on the morning of their cardiaccatheter study.

OESOPHAGEAL STUDIESAll patients underwent oesophageal manome-try and 24 hour pH studies after their cardiaccatheterisation to exclude an oesophagealcause for chest pain.

EXCLUSION CRITERIAPatients with even minimal coronary arteryirregularities, hypertension, diabetes mellitus,clinical or echocardiographic evidence of leftventricular hypertrophy or valvar heart dis-ease, and abnormalities of oesophageal func-tion were excluded from the study. We alsoexcluded those patients who had a left bundlebranch block on the resting electrocardio-gram or developed one during the exercisetest.

CARDIAC CATHETERISATIONAll patients underwent left heart catheterisa-tion through the percutaneous femoralapproach and left ventriculography and coro-nary arteriography were performed. Analtered perception of pain has been previouslyreported in patients with syndrome X.15-17 Itwas noted during the cardiac catheterisation,whether manipulations of catheters in theaortic root and the left ventricle, and injectionof a 5 ml bolus of contrast medium into theleft and right coronary arteries, produced anychest pain.

FOLLOW UPConsecutive patients who satisfied therelevant criteria were placed in either theunstable angina or stable angina groupdepending on their presentation. The patients

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-Chauhan, Mu/lins, Thuraisingham, Petch, Schofield

Table 1 Patient responses

Questions UA SA p Value*

Do you still have your chest pain?Yes 13 26 0-008No 28 15

Have you been admitted to hospitalbecause of chest pain since yourcardiac catheter?

Yes 7 12 NSNo 34 29

Are you limited in performing yourusual daily activities because of yourchest pain?

Yes 15 33 <0-001No 26 8

Do you still believe that you haveserious heart disease?

Yes 7 27 <0-001No 34 14

At the moment are you unable to workbecause of chest pain?

Yes 12 27 <0-001No 29 14

Are you attending a hospital clinicon a regular basis for your chest pain?

Yes 10 24 0 004No 31 17

Are you taking any regular treatmentfor your chest pain?

Yes 16 29 <0-001No 25 12

*X2 analysis, UA, unstable angina group; SA, stable anginagroup.

were followed up at six monthly intervals witha questionnaire (table 1). The questionnaireinquired about the patient's symptoms, limi-tations, and work capacity. The final assess-

ment was performed in December 1992.Patients were reassured after the cardiac

catheterisation that their heart and coronaryarteries were normal. It was explained tothem that an excellent prognosis was

expected although they might continue toexperience chest pain. It was emphasised tothem that although their heart was normal westill believed in their symptoms and at notime was it suggested that their pain was psy-chosomatic in nature. The referring physi-cians were informed of the normal findings.Patients were also informed that no restric-tion on their physical activity was necessaryand they should try to lead a normal life.

STATISTICAL ANALYSISThe data were compared by X2 analysis,Fisher's exact test, and Student's t test as

appropriate.

ResultsTable 2 shows relevant patient information.

Table 2 Patient variables

Unstable angina Stable anginagroup group(n = 41) (n = 41)

Weight (kg) 77-3 (11-3) 72-5 (10-8)Smokers 18 15Hb (g/dl) 14-1 (1-4) 13-8 (1 1)Plt (10-9) 278 (46) 287 (59)PCV (1/1) 0-42 (0 04) 0-40 (0 04)ESR(mm/h) 11(10) 9(6)Urea (mmol/l) 6-0 (0-9) 6 2 (0 8)Glucose (mmol/l) 4-6 (0-7) 4-9 (1-0)Creatinine (umol/1) 111 (15) 102 (17)Cholesterol (mmoIl/) 6-1 (0 8) 5 9 (0-3)LVEDP (mm Hg) 9 (1-0) 8 (0-8)Previous hysterectomy 2 6

Values are given as means (SD) where appropriate. ESR, ery-throcyte sedimentation rate; Hb, haemoglobin; LVEDP, leftventricular end diastolic pressure; PCV, packed cell volume;Plt, platelets.

Table 3 Exercise test data

Unstable angina Stable anginagroup group(n = 41) (n = 41)

Resting HR (beats/min) 86 (14) 82 (13)Timeto lmmST 8-3 (2 0) 8-0 (1.9)depression (min)RPP at end of stage 1 i25 -(3521) 19 986 (3724)RPP at peak exercise 26 235 (4470) 25 980 (4190)Maximum exercise 9-0 (2-6) 8-8 (2.4)duration (min)

Values are given as means (SD). Differences are not signifi-cant. HR, heart rate; RPP, rate:-pressure product.

In the unstable angina group the mean agewas .47 (range 28-69) years and the mean fol-low up time was 36 (range 20-51) months. Inthe stable angina group the mean age was46-4 (range 29-68) years and the mean dura-tion of follow up was 35 (range 19-51)months. Fifty one percent were women in theunstable angina group compared with 61% inthe stable angina group. There was no signifi-cant difference in the, number of smokersbetween the two groups.

EXERCISE TEST DATATable 3 shows that there was no significantdifference in the mean duration of exercise,time to 1 mm ST segment depression, andthe rate pressure product (heart rate x sys-tolic pressure) at peak exercise between thetwo groups. The resting heart rates of the twogroups were also similar.

FUNCTIONAL FOLLOW UPNo patient was lost to follow up in eithergroup. There were no deaths. The mean(SD) duration of symptoms before cardiaccatheterisation was 7-9 (4 7) months in theunstable angina group and 13-4 (5 6) monthsin the stable angina group (p < 0-001,Student's t test). Table 1 shows the results ofthe responses to the follow up questionnaire.Significantly more patients were completelypain free in the unstable angina group than inthe stable angina group (28 v 15; p = 0008).Seven patients in the unstable angina groupand 12 patients in the stable angina grouphad further hospital admissions with chestpain but this difference was not statisticallysignificant. Details of these admissions wereobtained and showed that none were associ-ated with myocardial infarction. Repeatcoronary angiography was performed in fourof these patients (one in the unstable anginagroup and three in the stable angina group).This again showed normal coronary arteries.

Only seven patients in the unstable anginagroup but 27 patients in the stable anginagroup still believed that they had serious heartdisease (p < 0-001). Twenty six patients inthe unstable angina group but only eightpatients in the stable angina group wereunlimited in their physical activities (p <0-001). Twelve patients were unable to worknormally because of their chest pain in theunstable angina group compared with 27 inthe stable angina group (p < 0-001).Significantly more patients were still attend-ing a medical out patient clinic for their chest

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Clinical presentation andfunctional prognosis in syndromeX

Table 4 Use of antianginal drug

Stabl Unstablangina angina

Antianginal drugs group group p Value*

Nitrates 3 11 0-02fl Blockers 6 9 NSCalcium antagonists 15 28 0 004

*Fisher's exact test.

pain in the stable angina group comparedwith the unstable angina group (24 v 10;p = 0 004).

ANTIANGINAL MEDICATIONSTable 4 shows that 16 patients in the unsta-ble angina group and 29 in the stable anginagroup were still taking antianginal medica-tions (p < 0-001). Patients in the stableangina group were taking significantly more

nitrates (p = 0 02) and calcium antagonists (p= 0 004). There was, however, no significantdifference in the use off, blockers betweenthe two groups.

CHEST PAIN AT CARDIAC CATHETERISATIONThirty two patients in the stable angina groupbut only 12 patients in the unstable anginagroup experienced their usual chest pain atthe time of their cardiac catheterisation on

catheter manipulation or intracoronary injec-tion of a 5 ml bolus of contrast (p < 0.001).At follow up, 24 (71%) of stable angina andeight (67%) of these unstable angina patientsremained considerably limited by their symp-toms (NS).

DiscussionThe term syndrome X was coined by Kemp20 years ago to define patients presentingwith chest pain and normal epicardial coro-

nary arteries.'8 Investigations over the pasttwo decades have not found a specific causefor this syndrome. Many explanations havebeen put forward to explain it, includingsmall vessel abnormalities,'9 coronary artery

spasm,20 cardiomyopathy,2' metabolicabnormalities,22 misinterpretation of the coro-

nary angiograms,2' impaired coronary flowreserve,24 25 oxyhaemoglobin dissociationdefects,26 psychosomatic factors,27'28 alteredpain perception,17-19 increased sympatheticdrive,2 I and endothelial dysfunction.32 Asinvestigations have accumulated more infor-mation, the syndrome has become ever more

confusing. All attempts to find a single patho-physiological mechanism responsible for theclinical presentations and long-term course ofsyndrome X have been confounded. It is nowacknowledged that syndrome X probablyencompasses several pathophysiologicaldiseases.

Previous studies of functional disabilityhave shown that about three quarters ofpatients with syndrome X continue to see a

physician, about half regard their life as

significantly disabled, about half remain or

become unemployed." 12 33 About 75% reportresidual chest pain at follow up. Only about

one third to a half are reassured that they donot have serious heart disease. None of thesestudies has, however, adequately differenti-ated between patients with syndrome X withunstable angina and those with stable angina.Our study has shown significant differences

between the two presentations of syndrome X.The findings in the stable angina group aresimilar to the other long-term studies." 1233 Itis clear, however, from the results that theunstable angina group is behaving differently.Patients with syndrome X presenting withunstable angina have an appreciably shorterduration of symptoms before their cardiaccatheterisation. Many more of these patientsare pain free at follow up, are working nor-mally, and are unlimited in their physicalactivity. The patients with unstable anginaare also less likely to be taking antianginalmedications and attending hospital follow upclinics.

Previously, long-term follow up studieshave shown that the incidence of subsequentmyocardial infarction and sudden cardiacdeath in patients with chest pain and normalcoronary arteries is very low.'834 Our studyalso confirms the good prognosis in patientswith syndrome X. There were no deaths andno patients had a myocardial infarction overthe follow up period.

Studies of oesophageal function hadexcluded patients from the study with abnor-malities of the oesophagus which could havebeen the source of chest pain in some patientswith syndrome X. The age differencebetween the two groups was not significant.Separate analysis of the functional capabilitiesby sex did not show any difference betweenthe men and women. As the underlyingpathophysiology may differ in the three sub-groups of patients classified as having unsta-ble angina the data were analysed to detectany difference in functional outcome betweenthe subgroups. There were no significant dif-ferences.The duration of symptoms before cardiac

catheterisation was shorter in the unstableangina group. This probably reflects a clinicalbias towards earlier referral and investigationof patients thought to have unstable angina.Patients with symptoms that are stable aremore likely to be managed by drug treatmentin the first instance and further investigationsare only performed when the symptoms failto settle.

It is reasonable to hypothesise that just asdifferent subgroups with different underlyingpathophysiological mechanisms many com-prise syndrome X, patients presenting withunstable angina and stable angina may have adifferent functional prognosis due to differ-ences in the underlying mechanisms responsi-ble for the symptoms. Any attempt at thisstage to explain this difference is speculativeas the patients in this study have not beeninvestigated further to assess the presence ofabnormal coronary flow reserve, epicardialcoronary hyperreactivity, or evidence of varia-tions in sympathetic activity. The results ofour study, however, suggest that differences

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Chauhan, Mullins, Thuraisingham, Petch, Schofield

in perception of cardiac pain may be impor-tant in finding the functional outcome.Altered perception of painful stimuli has beenreported in patients with syndrome X. Thismay heighten the perception of anginal chestpain in these patients.15-17 We have alsoshown previously that patients with syndromeX commonly have an exaggerated cardiacsensitivity compared with patients with coro-nary artery disease or valvar heart diseasewith their typical pain provoked by intracar-diac stimulation in the absence of ischaemia.3In this study there was a significant differencein the number of patients reporting theirusual chest pain at the time of their cardiaccatheterisation in the two groups with morepatients complaining of pain in the stableangina group (32 v 12, p < 0 001). This sug-gests that many more patients presenting withstable angina have abnormal cardiac nocicep-tion and this may contribute to the differ-ences in the functional prognosis between thetwo groups. Also, in both groups, mostpatients who reported chest pain at the timeof their catheterisation continued to havesymptoms at follow up suggesting thatpatients who may have an altered pain per-ception tend to remain more symptomaticand functionally limited regardless of theirclinical presentation. This is the first report oflong-term functional prognosis in patientsthought to have altered perception of painand our results lend further support to thetheory that some patients with syndrome Xmay have an altered perception of pain. Thisstudy has also shown, for the first time, a dif-ference in the prevalence of an abnormal per-ception of pain based on clinical presentationin syndrome X. It is tempting to postulatethat the fundamental difference in the under-lying pathophysiological mechanism of thetwo presentations of syndrome X was theprevalence of an abnormal cardiac nocicep-tion. The mechanisms that initiate pain inpatients with syndrome X are not known butmay include changes in heart rate, rhythm,contractility, or loading conditions. It may bethat a lowered pain threshold in the stableangina group leads to chest pain as a result ofthese trigger factors more often and for longercausing their considerable functional morbid-ity.

Recently Rosano et al have suggested thatthe pathogenesis of syndrome X in womenmay be due to a generalised alteration ofvasomotor control, including dysfunction ofthe coronary microcirculation secondary toovarian hormonal deficiency.36 In their studyof 99 patients with syndrome X, 78 werewomen, and 35(44 9%) had had hysterec-tomies. They further investigated 30 womenwith symptoms and signs of ovarian hor-monal deficiency and found them to beseverely hypooestrogenic. In our study onlytwo of the 21 women in the unstable anginagroup and six of the 25 women in the stableangina group had undergone a hysterectomyat the time of their final follow up. We havenot specifically looked for symptoms ofoestrogen deficiency and have not measured

oestrogen concentrations in our study there-fore we cannot comment on the oestrogenstate of all the women patients. It is clear,however, that the number of women with ahysterectomy in our study is considerablylower (eight out of 46, 17%) than thatreported by Rosano et al, and is in fact similarto that of the general population (8%-12%).36An increased sympathetic drive has also

been suggested in patients with syndrome Xby several studies.2931 The resting heart ratewas similar in the two groups in our study.Also, the time to 1 mm ST segment depres-sion, mean exercise duration, and the ratepressure product at the end of stage one andat peak exercise were similar in the twogroups. This suggests that the sympatheticdrive was not significantly different betweenthe two groups and that the functional differ-ences found in our study are unlikely to bedue to significant differences in the sympa-thetic drive. We did not, however, perform 24hour ambulatory electrocardiographic record-ings and did not measure plasma cate-cholamine concentrations to study thespecific role of the sympathetic nervous sys-tem as this was beyond the scope of ourstudy.

There is little objective evidence about theeffect of cardiac medications in patients withsyndrome X. Most patients in all long-termstudies continue to report chest pain and takecardiac medications so there is unlikely to bea large drug effect. There are some reportsthat suggest that propranolol may reducepain.' 10 37 Accordingly, ,B blockers were foundto be the most effective drugs in these studies.It is interesting to note that in our study therewas no significant difference in the use of,fblockers between the two groups. The use ofcalcium antagonists and oral nitrates was sig-nificantly more common in the stable anginagroup. The class of drugs used most com-monly in both groups was the calcium antag-onists. The use of antianginal drugs in ourstudy was significantly higher in the stableangina group, which was also more limitedfunctionally. This difference in the use ofantianginal medications probably reflects thesymptomatic improvement in the unstableangina group. Clearly, patients will tend touse antianginal drugs less if they feel betterand get less chest pain. This may not, how-ever, imply a remission of the underlying dis-ease process. Indeed, Borghi et al have shownin a preliminary study describing the long-term clinical course of syndrome X, thatdespite complete resolution of symptomsmost patients still have ST depression andreversible perfusion abnormalities duringexercise.38

It is well recognised that patients withchest pain and normal coronary angiograms,even if defined by a positive exercise test assyndrome X, are a heterogeneous populationwith regard to the possible underlying patho-physiological cause of their chest pain. Wedid not assess the patients in this study bynuclear perfusion imaging or coronary flowreserve studies. The possibility that there may

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Clinical presentation andfunctional prognosis in syndromeX

have been significant differences betweenthe two groups in terms of an impairedcoronary flow reserve cannot be excluded.

Although the good long-term prognosis inpatients with syndrome X is not in doubt, itis also clear that there remains a significantfimctional disability in many patients. It hasbeen considered previously that syndrome Xdoes not represent a clinical entity but israther a mix of unrelated conditions and thevarious components of this mix cannot beseparated easily by clinical features alone.34 39This study has shown for the first time thatthe clinical presentation of patients with syn-drome may predict outcome with regard totheir functional prognosis. In this studypatients with syndrome X who presentedwith symptoms suggestive of unstableangina had a better functional prognosisthan those patients with syndrome X whopresented with symptoms of stable angina.Given the heterogeneous nature of syn-drome X these differences may be due todifferent underlying pathophysiologicalmechanisms in the two groups. A higherprevalence of an abnormal cardiac nocicep-tion in the stable angina group may beresponsible for their worse functional prog-nosis. The findings of our study provide newclues about syndrome X that may help ourunderstanding of this fascinating entity.Dr A Chauhan is a British Heart Foundation junior researchfellow.

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