BRITISH MEDICAL JOURNAL 11 JANUARY 1975 71

MEDICAL PRACTICE

Hospital Topics

Oesophagoscopy, Biopsy, and Acid Perfusion Testin Diagnosis of "Reflux Oesophagitis"

G. E. SLADEN, R. H. RIDDELL, J. M. T. WILLOUGHBY

British Medical journal, 1975, 1, 71-76

Summary

The results of fibreoptic endoscopy have been assessedretrospectively in 71 patients referred for considerationof the oesophagus as the possible or probable cause oftheir symptoms. Gross endoscopic abnormality wasuncommon but friability of the mucosa was seen in abouthalf of the patients with typical symptoms of "reflux-pain" and a quarter of those without. The combination ofradiological reflux and endoscopic abnormality-that is,true reflux oesophagitis-was seen in only a third of thepatients with typical symptoms though much lesscommonly in those with atypical symptoms. Histologicalabnormality was common but did not relate well tosymptom pattern. The results of the acid perfusion testwere significantly related to symptom pattern thoughoverlap was observed between the two symptomaticgroups. Six of these patients had had or were awaitingsurgery to correct reflux and they all had uniformlypositive findings.This study confirms the value of the acid perfusion test

in clarifying the diagnosis of reflux pain, especially if thesymptoms are difficult to assess. Endoscopy and biopsyadded little further information of diagnostic value andcould probably be reserved for the small minority of

patients who have special problems such as blood lossor dysphagia or where clarification of a radiologicallesion is required.

Introduction

The term "reflux oesophagitis" is usually applied to a well-recognized clinical syndrome with typical symptoms and radio-logical evidence of gastroesophageal reflux. Many patients,however, have atypical symptoms and the radiological findingsmay be difficult to interpret. For example, reflux may be difficultto show even when the symptoms are typical and, conversely,the attribution of atypical symptoms to demonstrable refluxmay be incorrect. These patients are often referred for endo-scopic clarification. We assessed the results of endoscopyretrospectively in a group of such patients, taking into accountthe symptom pattern, radiological findings, and, where available,the results of the acid perfusion test and oesophageal biopsies.

Patients and Methods

The 71 adult patients in this survey were seen as part of a routineupper gastrointestinal endoscopy service provided by G.E.S.and J.M.T.W. from February 1971 to February 1973. Theyall had chronic continuous or intermittent symptoms, and atten-tion had been directed to the oesophagus either by the symptomsor by the radiological finding of a hiatus hernia. Routine uppergastrointestinal radiology had failed to show any abnormality ofthe oesophagus, stomach, or duodenum apart from a slidinghiatus hernia with or without reflux. Patients with otheroesophageal abnormalities such as paraoesophageal hernia,carcinoma, stricture, peptic ulcer, monilial infection, or variceswere excluded.

St. Bartholomew's Hospital, London EClA 7BEG. E. SLADEN, D.M., M.R.C.P., Honorary Senior Lecturer in Gastro-

enterology (Present address: Royal Hospital, Sheffield SI 3SR)R. H. RIDDELL, M.B., M.R.C.PATH., Lecturer in PathologyJ. M. T. WILLOUGHBY, B.M., M.R.C.P., Honorary Lecturer in Gastro-

enterology (Present address: The Lister Hospital, Stevenage, Herts.)

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72

SYMPTOMS

The symptoms were assessed at the time of endoscopy and thecase records were also scrutinized for details of the patient'shistory. The symptom patterns were divided into two groups:typical and atypical. Typical symptoms consisted of pain ordiscomfort confined mainly or wholly to the retrosternal areaassociated with at least one of the following features: a relation-ship to posture with or without regurgitation; aggravation byswallowing--especially, hot liquids-with or without a sensationof blockage; and definite relief by antacids. Atypical symptomsincluded retrosternal discomfort or pain unaccompanied by anyof the three features just mentioned, pain or discomfort mainlyin epigastrium or abdomen, symptoms such as regurgitation orflatulence without actual discomfort, frank or suspected uppergastrointestinal blood loss, or isolated dysphagia unaccompaniedby any other typical feature.

RADIOLOGY

The available x-ray pictures and radiological reports wereassessed at the time of endoscopy and the presence or absenceof radiological reflux noted. Reports describing trivial or dubiousabnormalities were discounted and only unequivocal evidenceof reflux was accepted as positive. In the radiological departmentof St. Bartholomew's Hospital the routine assessment for hiatushernia and reflux involves a downward head tilt in the prone orsemiprone position. More elaborate procedures using bolstersor swallowing water after the barium are not used routinely.

Hiatus hernia was observed in 46 patients, of whom 20 hadevidence of reflux. There was only one patient with reflux in theabsence of a demonstrable hernia. The high incidence of herniareflects patient selection. In line with current thinking' weassumed that the finding of hernia without reflux is of nosymptomatic significance and confined our attention to thepresence or absence of reflux.

ENDOSCOPYInitially the Olympus E.F. oesophagoscope was used, but inthe second year this was replaced by the longer OlympusG.I.F.-D end-viewing instrument. The procedure was performedunder sedation with intravenous diazepam (5-20 mg) after thethroat had been anaesthetized with a lignocaine (2%) gargle.The entire oesophagus was examined carefully and the oeso-phagogastric mucosal junction was clearly identified in mostcases. To reduce observer variation and error to a minimumevidence of oesophagitis was based exclusively on the presenceof friability-that is, spontaneous bleeding or bleeding inducedby gentle brushing. These changes were often slight and observedonly in the distal few centimetres of the oesophagus but werestill regarded as positive. Other changes of inflammation suchas redness, oedema, granularity, and alterations of vascularpattern were considered to be unreliable as criteria in our handsand therefore disregarded. After the oesophagus had been in-spected the rest of the stomach and (with the G.I.F.-D instru-ment) the proximal duodenum were examined to confirm theabsence of other macroscopic abnormalities.

HISTOLOGY

At least two biopsy specimens were taken from the oesophagealmucosa with endoscopic forceps. The specimens were takenfrom macroscopically abnormal areas if present or from differentpoints in the distal 10 cm of an apparently normal oesophagus.Biopsies were not performed routinely at the beginning of thesurvey so histological information was not available on all thepatients. The specimens were placed in 10% formol saline andsubsequently embedded on edge in paraffin wax. Sections

BRITISH MEDICAL JOURNAL 11 JANUARY 1975

5-tm thick were stained with haematoxylin and eosin. Measure-ments of the height of the basal cell layer and the dermal papillaewere taken using an eyepiece micrometer and expressed as apercentage of the total thickness of the mucosa. When the basalcell layer was difficult to delineate the periodic-acid Schiff stain,which left the basal cell layer unstained, was used.The criteria of normality were those of Ismail-Beigi et al.2

A biopsy specimen was considered normal if the basal cell layeroccupied 15% or less and the dermal papillae 67% or less ofthe total mucosal thickness (fig. 1). Initially, if either of these

FIG. 1-Normal oesophageal mucosa.Squ=Mature squamous epithelium. D P=Dermalpapillae. B C L=basal cell layer, which is here onlyone or two cells thick and occupies much less than15% of the epithelium. (H. and E. x 350.)

measurements was greater than this the specimen was consideredabnormal (fig. 2). In five biopsies three or fewer papillae wereobtained, while in the remaining biopsies no specimen wasobtained in which the basal cell height was normal in thepresence of abnormal dermal papillary height. We thereforeconcluded that in small biopsy specimens basal cell heightalone would be an accurate criterion of oesophageal abnormality.In four biopsy specimens an abnormal basal cell height wasfound in the presence of a normal dermal papillary height, butin three of these specimens papillae were scant.The histological features were assessed by R. H. R. without

knowledge ofthe patient's symptoms or endoscopic appearances.

ACID PERFUSION TEST

The acid perfusion test was performed according to a protocolbased on the method of Bennett and Atkinson." A standardpolyvinyl chloride nasogastric (Ryles) tube was passed to mid-oesophagus and the position checked radiologically. Sodiumchloride 0-15 mol/l. was perfused at 10 ml/min by gravity for10 minutes followed by hydrochloric acid 0-1 mol/l. at the samerate for 15 minutes or until symptoms were produced. If nosymptoms were produced the drip rate was increased to 20 ml/min for a further 15 minutes before the result was regarded asnegative. If symptoms were produced at either flow rate theinfusion was replaced by sodium bicarbonate 0-1 mol/l. at thesame rate. After relief of symptoms acid was infused again tocheck that the result was reproducible. The bottles were sus-

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BRITISH MEDICAL JOURNAL 11 JANUARY 1975

pended behind the patient's head so that the solutions could bechanged without his knowledge. The result was consideredpositive if the perfusion of acid, but not saline, reproduced themajor symptom(s) that the patient recognized as his own and ifthese were relieved by alkali. In positive cases the symptoms

were usually reproduced and relieved within 5-10 minutes ofstarting the appropriate perfusion.The production of trivial symptoms not previously recognized

by the patient and the failure to obtain relief by alkali were

regarded as negative results. Two patients experienced definite

x < . c~~~~~~ -b.FIG. 2-Basal cell hyperplasia.Squ== Mature squamous epithelium. D P Dermal papillaencroaching into superficial third of epithelium. B C L=Basal cell layer which is widened and occupies 22% of thetotal epithelium. Slight tangential cutting does not affect thisfigure. L P-=Lamina propria. (H. and E. x 350.)

and typical heartburn, relieved by alkali, which was quite unliketheir own complaints. This was termed a "positive unrelated"response by Bernstein et al.4, and we regarded it as a negativeresponse. In both these patients other findings were uniformlynegative. The procedure was abandoned in four subjects becausethey were unable to tolerate it, and the results were disregardedin two others who were quite unable to give a clear descriptionof their symptoms.

These perfusion tests were not performed by the endoscopist,but the results were assessed afterwards by him. They were

performed by junior hospital staff or medical students accordingto a strict protocol to obviate observer bias.

STATISTICS

The results were analysed by the x2 test (3 x 2 contingency

73

tables), Yates's x2 test (2x2 contingency tables N>50), or

Fisher's test (2 x 2 contingency tables N <50).5 P values equalto or less than 0 05 are quoted. Where no P value is stated itcan be assumed that it was greater than 0 05.

Results

Endoscopy

The incidence of radiological reflux or endoscopic abnormalityor both was appreciably higher in the patients with typicalsymptoms, but this was statistically significant for reflux only(P= 0-01; table I). Only one-third of patients with typicalsymptoms had both reflux and endoscopic change-thatis, true reflux oesophagitis. The endoscopic abnormalities-weremild in most cases, only six patients showing more gross andextensive abnormality. Two patients with atypical symptomshad gross oesophagitis. They had previously had mild dyspepsiabut presented acutely with frank upper gastrointestinal haemor-rhage and little or no pain. If reflux and endoscopic change were

considered together in individual patients there was a statisticallysignificant separation of the two symptomatic groups (P <0-01;table I).

TABLE II-Relation between Presence or Absence of Reflux and EndoscopicAppearances in 71 Patients. Results are Numbers of Patients

Acid Perfusion Test

Successful acid perfusion tests were performed on 48 of the 71patients (table III). In these patients the incidence of refluxand endoscopic abnormality in the two symptomatic groups was

similar to that shown in the whole group. A positive perfusiontest result was obtained in most patients with typical symptomsand in a few of those without. Statistically, the results of the acidperfusion test were significantly related to symptom patternand endoscopic abnormality (P <0-01) (tables III and IV) but notto reflux. If endoscopy and acid perfusion test were consideredtogether in individual patients the symptomatic groups were

significantly separated (P <0 01; table III).

Histological Evidence

Sixty-four interpretable biopsy specimens were available from36 patients, and 16 further specimens were uninterpretable(five were fragmented or inadequate, five were gastric, four hadno basal layer, one was ulcerated, and one was only a blood clot).Lamina propria was present in material from 26 patients.There was a much greater incidence of abnormalities in

biopsy specimens from patients with typical symptoms, but this

failed to reach statistical significance (table V) though significancewas reached in the smaller group in which the acid perfusion

TABLE I-Relation of Symptom Patterns to Endoscopic Appearances and Presence of Radiological Reflux in 71 Patients. Results are Numbers of Patients

Reflux and EndoscopicAbnormalitiest

?resent One Present NeitherPresent9 8 92 16 27

-1

*P =0-01. tP <0-01.

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TABLE IiI-Relation of Symptom Patterns to Endoscopic Appearances. Presence of Radiological Reflux, and Results of Acid Perfusion Test in 48 Patients.Results are Numbers of Patients

Perfusion TestResultst

Positive Negative

14 55 24

Endoscopy Findings and Perfusion TestResultt

Both Positive

82

One Positive Neither Positive

7 46 21

*P=0.05. tP<0-01.

TABLE iV-Relation between Perfusion Test Result, Endoscopic Appearances,and Presence or Absence of Reflux in 48 Patients. Results are Numbers ofPatients

TABLE vi-Relation between Histological Appearances, Presence or Absenceof Reflux, and Endoscopic Appearances in 36 Patients. Results are Numbers ofPatients

Perfusion TestResult

PositiveNegative

No. ofPatients

1929

Reflux

89

NoReflux

1120

Endoscopic Appearances*

Abnormal Normal

10 94 25

*P<0-0l.

test was also carried out (P <0 05; see table VII). Of the 11subjects with normal histological appearances two had typicalsymptoms, one was endoscopically abnormal, one had an abnor-mal acid perfusion test result, but none had reflux. The rela-tionship between histological appearances and both endoscopicabnormality (P <0 05) and radiological reflux (P=005) reachedstatistical significance (table VI).Submucosal polymorphs were present in 10 out of 18 speci-

mens with basal cell hyperplasia in which lamina propria waspresent. In three out of seven further abnormal biopsy specimens,in which no lamina propria was present, polymorphs could beidentified in the dermal papillae. By contrast, in none of the 11normal specimens were polymorphs seen in lamina propria ifpresent or in the dermal papillae. This relationship was statis-tically significant (P< 0-01).When gastric mucosa was obtained on biopsy there is the

possibility that ulcerated oesophageal mucosa had become re-epithelialized from the gastric mucosa. While this would indicateprevious oesophageal disease we ignored it here. Similarly, thesingle ulcerated biopsy specimen was disregarded as its exactsite of origin was not accurately known and no adjacent mucosawas present.

Acid Perfusion Test and HistologyInterpretable information about both the acid perfusion testand histological features was available in 27 patients and thedistribution of abnormal findings was similar to that in theprevious groupings (table VII). Of the 11 patients with typicalsymptoms the acid perfusion test gave a positive result in mostand the histological appearances were abnormal in all. Therelation between symptom pattern and histology was statisticallysignificant in this subgroup (P< 0-05), whereas that betweensymptoms and acid perfusion was not. Only one out of 13patients with a positive acid perfusion test result had normalhistological appearances. This relationship was not statisticallysignificant (table VIII).

Cumulative evidence in relation to symptoms was based on

HistologicalAppearances

No. ofPatients

Reflux*Endoscopic Appearancest

NoReflux Abnormal Normal

Abnormal .. 25 8 17 12 13Normal .. 11 0 11 1 10

*P=005. tP<005.

three criteria (endoscopy, acid perfusion, and histology) and isshown in table VII. The difference between patients positiveon two or three criteria and those positive on one or none wasstatistically significant (P< 0 05).

Discussion

Though the oesophagus was suspected as a possible or probablecause of symptoms in all these patients only six (8&4%) hadendoscopic evidence of severe and extensive oesophagitis. Ofthese six patients two presented with upper gastrointestinalhaemorrhage without pain and minimal previous clinical evidenceof oesophageal reflux. Lesser endoscopic abnormalities wereobserved in about half the patients with typical symptoms ofreflux oesophagitis, but the endoscopic criteria used were possiblytoo strict and might have excluded slighter but significantabnormalities. Other authors describe changes such as rednessand oedema as indicative of mild oesophagitis. We consideredthat such criteria would be liable to considerable observervariation and error but know ofno formal study in which this hasbeen assessed. By analogy with studies of proctitis8 we consideredthat friability would be the most objective criterion. Grosserand unequivocal evidence of oesophagitis, such as stricture orfrank ulceration, was not seen in this series.

Other reports indicate a higher incidence of endoscopicabnormality in patients with typical reflux heartburn,2-4 7but in these and other studies it is apparent that symptoms andendoscopic findings do not always correlate.9 10 The relationprobably depends on the chronicity and severity of symptomsrather than their quality. In a series of 76 patients coming tooperation, presumably with chronic unremitting symptoms,Cocco and Brantigan'1 observed endoscopic abnormality in 69.In six of our patients coming to surgery all had endoscopicabnormality.The histological criteria of oesophagitis were until recently

the classical ones of oedema and hyperaemia with an inflam-matory infiltrate in the lamina propria and possibly subsequentfibrosis.12 As a mononuclear infiltrate is normally seen in the

TABLE v-Relation of Symptom Patterns to Endoscopic Appearances, Presence ofare Numbers of Patients

Radiological Reflux, and Histological Appearances in 36 Patients. Results

-;-

_ _-1-

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BRITISH MEDICAL JOURNAL 11 JANUARY 1975 75

TABLE viI-R'elation of Symptom Patterns to Endoscopic Appearances, Presence of Radiological Reflux, Acid Perfusion Test Results, and Histological Appearancein 27 Patients. Results are Numbers of Patients

*P <0-05.

TABLE ViII-Relation between Acid Perfusion Test Result and HistologicalAppearances in 27 Patients. Results are Numbers of Patients

lamina propria the presence of polymorphs is a useful criterionof inflammation. There may also be ulceration of the surfaceepithelium, with exposure of the capillary channels in the dermalpapillae, accounting for both the hyperaemia and haemorrhageseen endoscopically.

Ismail-Beigi et al.2 described changes in the squamous epi-thelium in 28 out of 33 patients with typical reflux heartburncompared with two out of 21 controls (see Methods). Theyobtained large biopsy specimens by suction, but we were inter-ested in applying these criteria to specimens obtained by fibre-optic instruments. Endoscopic biopsy specimens are small,difficult to orientate, and often contain little lamina propria.Other workers have concluded that they are generally too smallfor conventional histological interpretation.13 In our study,using criteria based on thickness of basal cell layer, 25 out of36 patients were considered to have abnormal biopsy specimens.Of these 20 had other evidence of oesophageal disease (onendoscopy, radiology, acid perfusion test, or a combination ofthese). Of the remaining 11 patients with normal specimens nonehad radiological reflux, one had a positive acid perfusion testresult, and one had endoscopic abnormality. The latter mayreflect the sampling problem found by Ismail-Beigi et al.2 in25% of paired samples. In 21 patients of our series in whom two

or more satisfactory biopsy specimens were obtained onlytwo had discrepant histological appearances. Significant relation-ships were found between histological abnormality and endo-scopic appearance, radiological reflux, and the presence ofpolymorphs in the lamina propria or dermal papillae. We didnot consider it justifiable to submit normal volunteers to endo-scopy to obtain a strictly normal group of oesophageal biopsyspecimens.

Basal cell hyperplasia seems, therefore, to be a sensitive indexof oesophageal abnormality as judged by several other criteria.It may, however, be too sensitive and indicate trivial or inter-mittent reflux of no clinical importance. In the present seriesfive out of 25 patients with abnormal specimens had no otherpositive feature suggestive of oesophageal disease, and yet in allthe basal cell layer accounted for at least 20% of mucosal thick-ness and in four polymorphs were present in the lamina propria.No readjustment of the criteria of Ismail-Beigi et al.2 could bemade to classify these as normal without invalidating therelationship between histology and clinical features in many morepatients. On the other hand, in the absence of basal cell hyper-plasia it seems unlikely that there will be other good evidence ofoesophageal abnormality. In view of evidence suggesting thatcigarette smoking might be a common cause of oesophagealreflux14 a smoking history was obtained retrospectively in 35of the 36 patients with satisfactory histological specimens.Ofthe 25 with abnormal histological appearances 14 were regularsmokers and 11 were non-smokers, and out of the 10 patients

with normal appearances four were smokers and six were non-smokers. (Two patients who smoked very rarely were groupedas non-smokers.) Though abnormal appearances were morecommon in smokers than in non-smokers the difference was notsignificant (P >005).The acid perfusion test has been widely used in the differential

diagnosis of oesophageal and cardiac pain. In several seriesthere has been an extremely close relationship between theresults of acid perfusion and symptoms in patients with typicalheartburn compared with asymptomatic controls.24 15 On theother hand Spencer 16 has reported a potentially misleadinglow incidence ofpositive results in patients with a variety ofotherupper gastrointestinal disorders, but he did not relate theseresults to their actual symptoms. Earlam17 has claimed that theepigastric pain of duodenal ulcer can be reproduced by acidperfusion of the lower oesophagus. We regarded the result aspositive only if the patient's own symptoms were reproduced,and none of these patients had evidence of active peptic ulcer orother conditions at the time of the investigation. The perfusiontest was better than the other criteria in distinguishing patientswith typical and atypical symptoms, in that a clear majorityof patients with typical symptoms had a positive test resultand a clear majority of those with atypical symptoms had a nega-tive result. On the other hand, only half the patients with apositive test result had abnormal endoscopic appearances, where-as most in a smaller group of patients had abnormal histologicalappearances. This latter finding is difficult to interpret becausemore than half the patients with a negative perfusion test resultalso had abnormal histological appearances. Of the five patientswith atypical symptoms and a positive perfusion test two hadendoscopic evidence of oesophagitis and, symptomatically, threehad retrosternal pain and two had epigastric pain associated withregurgitation. Thus, with a few exceptions a positive perfusiontest result was associated with symptomatic or other evidence ofacid reflux. On the other hand, a negative result may notexonerate the oesophagus, as indicated by the five patients withtypical symptoms and a negative result; two had radiologicalreflux, one other had abnormal endoscopic appearances, andonly two had negative findings on all criteria.We did not assess reflux formally and the evidence was based

solely on routine radiological procedures performed by a numberof radiologists. There was a low incidence of reflux in the series(21 out of 71 patients) and among the patients who were positiveon the other criteria (typical symptoms, histology, acid per-fusion, etc), there was no incidence of reflux greater than 50%.On the other hand, the incidence of reflux was very low amongpatients who were negative on the various criteria. All thepatients who had had or were awaiting surgery had free radio-logical reflux. Probably routine radiological examinations asperformed in these patients underestimated the true incidenceof reflux, because in other series reflux has been shown to bepresent by pH probe techniques in most patients with typicalsymptoms or a positive acid perfusion test result or both.2 15 18Negative findings on radiology should not refute a clinicaldiagnosis of reflux pain especially if the diagnosis is supportedby a positive perfusion test result, and repeat radiology may showthe reflux if special attention is paid to its elicitation.

Considering all the evidence our results show that in patientswith the typical reflux heartburnsyndrome macroscopic evidenceof oesophagitis is often minimal or lacking altogether. The acid

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76 BRITISH MEDICAL JOURNAL 11 JANUARY 1975

perfusion test is a useful procedure in patients who give anatypical history, and an unequivocally positive result wouldstrongly support the diagnosis. A negative result would focusattention on other causes of the symptoms, irrespective of theradiological finding of oesophageal reflux. Endoscopic biopsyas used in this study added little information of diagnostic im-portance, perhaps because the criteria of abnormality weresensitive to trivial degrees of reflux. It seems that endoscopy andbiopsy could be reserved for the small group of patients withradiological abnormality, evidence of blood loss, or dysphagia.We thank Dr. A. M. Dawson for encouragement and criticism

and for allowing us to study patients under his care; the manystudents and members of junior hospital staff who helped with theacid perfusion test; the nursing staff of the endoscopy unit; andthe technical staff of the histology de,partment. We thank thesecretaries of the university department of medicine, Royal Hos-pital, Sheffield, for typing the manuscript.

G.E.S. was supported financially by the Wellcome Trust andJ.M.T.W. by the Medical Research Council.

References1 Pope, C. E., Gastroenterology, 1970, 59, 460.2 Ismail-Beigi, F., Horton, P. F., and Pope, C. E., Gastroenterology, 1970,

58, 163.3 Bennett, J. R., and Atkinson, M., Lancet, 1966, 2, 1150.4 Bernstein, L. M., Fruin, R. C., and Pacini, R., Medicine, 1962, 41, 143.5 Langley, R., Practical Statistics, p. 269. London, Pan Books, 1968.6 Skinner, D. B., and Belsey, R. H. R., Journal of Thoracic and Cardio-

vascular Surgery, 1967, 53, 33.Bombeck, C. T., Battle, W. S., and Nyhuss, L. M., Archives of Surgery,

1972, 104, 477.8 Baron, J. H., Connell, A. M., and Lennard Hones, J. E., British Medical

Journal, 1964, 1, 89.9 Tuttle, S. G., Belttarello, A., and Grossman, M. I., Gastroenterology,

1960, 38, 861.10 Skinner, D. B., AmericanJournal of Digestive Diseases, 1966, 11, 771.11 Cocco, A. E., and Brantigan, 0. C., Annals of Surgery, 1969, 169, 857.12 Palmer, E. D., Archives of Pathology, 1955, 59, 51.13 Thomas, E., Hislop, I. G., and Grant, A. K., AmericanJournal of Digestive

Diseases, 1973, 17, 43.14 Stanciu, C., and Bennett, J. R., British Medical_Journal, 1972, 3, 793.15 Benz, L. J., et al., Gastroenterology, 1972, 62, 1.16 Spencer, J., Proceedings of the Royal Society of Medicine, 1972, 65, 30.17 Earlam, R. J., British Medical_Journal, 1970, 4, 714.18 Hadded, J. K., Gastroenterology, 1970, 58, 175.

Contemporary Themes

Pathophysiology of Subendocardial IschaemiaJ. I. E. HOFFMAN, G. D. BUCKBERG

British Medical J7ournal, 1975, 1, 76-79

Summary

Most forms of heart disease cause myocardial damagewhich often is confined to the deep (subendocardial)layer of left ventricular muscle. Much clinical and ex-perimental evidence suggests that subendocardial muscleis prone to ischaemic damage, and a physiologicalmechanism for this vulnerability is described. Fur-thermore, experiments suggest that pressures recordedat cardiac catheterization can help to assess if there issubendocardial ischaemia in a variety of lesions in man.

Introduction

During 1971 in England and Wales cardiovascular diseasescaused half of all deaths, and in those dying under 65 years ofage they caused 42% of all deaths in males and 30% of deaths infemales. Irrespective of the aetiology of the heart disease mostof these deaths were due to damage to and failure of heartmuscle. Until the basic diseases can be prevented doctors canreduce the mortality and morbidity from myocardial failure byearly and accurate diagnosis of the disability and selection ofappropriate medical therapy. Hence it is essential to under-stand the pathophysiology of myocardial failure and, in parti-cular, to appreciate how important a part subendocardialischaemia plays in many types of heart disease.

Cardiovascular Research Institute, School of Medicine, Universityof California, San Francisco, U.S.A.

J. I. E. HOFFMAN, M.D., F.R.C.P., Profesor of PaediatricsG. D. BUCKBERG, M.D., Associate Professor of Surgery

Cardiac damage occurs predominantly in the subendocardialmuscle of the left ventricle. Many myocardial infarcts are sub-endocardial, 2 and patients with angina pectoris but no majorinfarct have subendocardial ischaemia, as shown by electro-cardiography, and areas of necrosis and fibrosis scattered mainlyin subendocardial muscle. Even when the coronary arteries arenormal there may be electrocardiographic and pathologicalevidence of subendocardial ischaemia, as in patients withsevere aortic regurgitation and stenosis,3 4rapid tachycardias,5and complicating acute haemorrhage6 and shock.7 Finally,many who die after open heart surgery for a variety of lesionshave diffuse haemorrhagic necrosis of the left ventricular sub-endocardial muscle.8 9 To explain how these lesions occur andmight be prevented we will discuss the pathophysiology ofcoronary flow, show how animal experiments throw light onthe causes of subendocardial ischaemia, and apply this in-formation to a variety of human diseases.

Physiological Background

When the left ventricle contracts it compresses vessels in itswall and reduces coronary flow. The compressive force isgreatest in subendocardial muscle, where it equals or ex-ceeds pressure in the left ventricular cavity, and falls to nearatmospheric pressure at the epicardial surface.'0 As a re-sult, in systole no blood flows through subendocardial muscle,whereas the outer subepicardial muscle is perfused. In diastole,however, all the muscle is perfused, thus explaining the dom-inant diastolic flow pattern in the left coronary artery (fig. 1 A).When the ventricle works harder and needs more oxygen

and thus more coronary blood flow the coronary vessels dilate,lower vascular resistance, and permit more flow even withunchanged perfusing pressures. If, however, cardiac workincreases until coronary vessels dilate maximally then coronaryflow will depend upon the perfusing pressure, just as flow

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