Postgraduate Medical Journal (July 1976) 52, 438--444.

Non-atheromatous ischaemic heart disease

CELIA M. OAKLEYM.D., F.R.C.P.

Division of Cardiovascular Diseases (Clinical Cardiology),Royal Postgraduate Medical School, Hammersmith Hospital, London WJ2 OHS

THE symptom of angina reports an imbalance be-tween myocardial oxygen need and available myo-cardial blood flow. The overdraft may stem fromincreased demand in structural disease such as aorticstenosis, hypertrophic cardiomyopathy or thyro-toxicosis or from reducedflow and this is not alwaysthe result of obstructive atheroma (Table 1).

TABLE 1. Acquired non-atheromatous coronary arterydisease

Embolism Mitral stenosis (thrombus)Myxoma (tumour)Aortic stenosis (calcium)Infective endocarditisValve prostheses

Ostial stenosis AortitisAfter valve replacementDissection of the aortaIsolated

Coronary dissection MarfanPregnancy

Coronary thrombosis SmokersSpasm

Microvascular disease PolyarteritisAmyloidDiabetes

latrogenic Coronary angiography

Myocardial ischaemia may result from congenitalabnormalities in the origin or distribution of thecoronary arteries. Coronary obstruction may alsodevelop at a young age in some rare hereditary dis-orders such as Hurler's syndrome, homocystinuriaor pseudoxanthoma elasticum. The coronary arteriesmay be the site of embolism; ostial stenosis maycomplicate luetic (or other) aortitis or coronary dis-section; the small coronary arteries may be involvedin certain connective tissue disorders such as poly-arteritis, in amyloid heart disease or in diabetes.Finally, angina or even infarction may develop inthe absence of these disorders and in the demon-strated presence of normal coronary arteries; thisnot so rare phenomenon has attracted increasinginterest now that coronary angiography has becomemore generally available.

Congenital coronary anomaliesAnomalous origin ofa coronary artery

This is a rare disorder. In its most usual form theleft coronary artery arises from the left posterioraspect of the pulmonary artery instead of from theleft coronary sinus of the aorta (Fig. 1). The arterythen emerges from the pulmonary trunk and theaorta to pursue its usual course. Occasionally theanomalously arising vessel represents only onebranch of the left coronary artery, the circumflexor anterior descending then arising normally. Anoma-lous origin of the right coronary artery has also beendescribed but it is much rarer.Anomalous origin of the left coronary artery

results in left ventricular ischaemia or infarction, theextent of this depending on the rate of fall of pul-monary artery pressure after birth and the rapidity

FIG. 1. Anomalous origin of left coronary artery fromthe pulmonary artery in a neonate. Because the pul-monary artery pressure was still high the anomalouscoronary filled after contrast injection into the mainpulmonary artery (anteroposterior projection).

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Non-atheromatous ischaemic heart disease

of development of intercoronary anastomoses withpossibility of blood flow between the normallyarising high-pressure right coronary artery and theanomalously arising low-pressure left coronaryartery. The extent of left ventricular ischaemia alsodepends on coronary dominance. In the presence of aheavily dominant right coronary artery, anomalousorigin of the left coronary artery may be less serious.The usual time of presentation is between 1 and 4

months of age and the mortality is high. Rarely thecondition may be encountered in childhood or evenin adult life. The infant presents with: (1) symptomsof myocardial ischaemia with attacks of screamingand pallor; (2) failure to thrive; or (3) heartfailure.The infant is usually well for the first week or so of

life because at that time the pulmonary artery pres-sure is still high and the anomalous coronary is per-fused at a high pressure albeit with blood of relativelyiow oxygen tension. Persistence of the ductus in thefirst few days of life may also contribute to themaintenance of left ventricular nutrition while it isopen. The development ofleft ventricular failure mayitself contribute towards an uneasy balance by delay-ing the normal fall in pulmonary artery pressure. Itfollows that by the time that the condition is recog-nized the left ventricle has already suffered severe, ifnot fatal, infarction. These infants, by definition, donot possess adequate intercoronary anastomoses, soflow down the anomalous coronary is still antegradefrom the pulmonary artery and treatment is difficult.Logically it should be by reimplantation of theanomalous coronary artery into the aorta. This isdone by removing it together with a cuff of pul-monary artery and implanting it either in the normalsite or, more often, anastomosing it with the sub-clavian artery. The mortality is high because theinfant is already critically ill, the left ventricle havingusually already sustained irreversible damage.The clinical signs are of heart failure often with

mitral regurgitation (Noren et al., 1964). The sys-tolic murmur may be loud and the mitral reflux isattributable to papillary muscle ischaemia but maylead to the mistaken diagnosis of ventricular septaldefect. The ECG is invariably abnormal and usuallyshows evidence of infarction or ischaemia of the leftventricle. Less often there may simply be changes ofa left ventricular disorder which is not specific.

If the intercoronary anastomoses permit adequateretrograde myocardial perfusion into the left coron-ary artery from the right coronary artery and par-ticularly if the territory supplied by the anomalouscoronary is small then the infant may survive with noapparent problem. Both the ECG and left ventricularfunction may be normal or variably abnormaldepending on the amount of left ventricular damagewhich has been sustained. Presentation in childhood

or adult life is then associated with the late develop-ment of a continuous murmur with or without symp-toms and evidence of left ventricular ischaemia.Presentation at this age is attributable to excessiveflow through the intercoronary anastomoses betweenthe high-pressure right coronary circulation and thelow-pressure left coronary circulation. If the run-offincreases then the intercoronary anastomoses whichwere responsible for sustaining the left ventricularmyocardium and life during infancy later on becomeresponsible for the development of secondaryischaemia in the territory of the left coronary artery.Cardiac catheterization may reveal an oxygen step-up in the pulmonary trunk attributable to drainingof blood retrograde from the aorta to the pulmonaryartery through the coronary system. The rightcoronary artery is seen to be greatly enlarged, theleft coronary artery is opacified only via the rightand cannot be intubated from the aorta. At thisstage the correct treatment is ligation of the leftcoronary at its origin from the pulmonary artery.The third, and the rarest form of presentation, is

in adult life with the development of acquiredcoronary artery disease in the single right coronaryartery.

Coronary-cameral and arterio-venous fistulaeSometimes a normally arising coronary artery

develops a fistulous connection with one of thecavities of the heart, most commonly the right ven-tricle or right atrium. The connection with the low-pressure chamber slowly enlarges and a continuousmurmur is often the presenting feature. Eventuallymyocardial ischaemia may develop.

Figure 2 shows a right coronary fistula into theright ventricle in a 20-year-old man who had been ina car accident. A continuous murmur over thecardiac apex was heard after operation for a rupturedspleen and liver and this fistula may have beentraumatic rather than congenital in origin.

Rarely the onset of symptoms may be attributableto atheromatous obstruction otherwise coronary-cameral fistula more often produces no symptomsat all. Thus, a 55-year-old man presenting withangina was found to have a soft continuous murmurmaximal at the right sternal edge in the third andfourth spaces. Coronary angiography revealed himto have a fistula between the sinus node branch ofthe right coronary artery and the right atrium buthis presentation was attributable to the developmentof an atheromatous obstruction of the left anteriordescending coronary artery. Obstruction of thelatter alone may not have produced symptoms hadit not been for the congenital malformation in theother coronary. Both the congenital and the acquireddisorder were successfully treated surgically. Thepatient has lost his angina and has done well.

439

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440 Celia M. Oakley

FIG. 2. Coronary-cameral fistula which may have beenof traumatic origin (see text). The left venticular angio-gram in right anterior oblique projection shows bothcoronary arteries. The left coronary is normal but theright coronary artery is dilated and tortuous. There is afaint 'blush' anteriorly which in other views was shownto be caused by contrast entering the right ventricularchamber from the right coronary artery.

Congenital lengthening and tortuosityThis is an exceedingly rare congenital ab-

normality in which extreme tortuosity of all thecoronary branches is associated with progressivemyocardial ischaemia.

Elongation and tortuosity is also seen in the kinkyhair syndrome (Menke's syndrome) attributable tocopper deficiency.

Hereditary disorders affecting the arterial system andcoronary arteriesMarfan's syndrome

Marfan's syndrome is transmitted by an autosomaldominant gene in which there is a defect in theelastic fibres of connective tissue, associated withusually increased height, skeletal abnormalities,myopia and ectopia lentis, aortic aneurysm, dis-section and rupture, and valvular regurgitation. Thewell known habitus of Marfan's syndrome is notalways present in patients who present with vascularcomplications (McKusick, 1972).

Hurler's syndrome (mucopolysaccharidosis 1)In this disorder (characterized by dwarfism,

skeletal anomalies, a characteristic coarse facies('gargoylism'), clouding of the cornea and lowintelligence) cardiac abnormality commonly de-

velops. This may be caused by deposition ofmucopolysaccharide in valve cusps leading toregurgitation or stenosis, or coronary obstructionmay lead to angina or sudden death (Scheibler et al.,1962).

HomocystinuriaThis condition, which superficially resembles

Marfan's syndrome except for the common associ-ation of mental subnormality, is characterized byarterial thromboses which can lead to angina, infarc-tion and death.

Ehlers-Danlos syndromeThis is a heritable disorder of connective tissue

characterized by hyperextensibility of the skin and avariety of visceral abnormalities which share somefeatures of Marfan's syndrome. There are articularand ligamentous laxity, ectopia lentis and cysticmedial necrosis of the aorta and other arteries leadingto dissection (Beighton, 1969).

Pseudoxanthoma elasticumThis is a disorder which can be recognized clini-

cally by changes in the skin which has a crapy tex-ture and by the well known angioid streaks in theretina. Gastrointestinal haemorrhages, hypertensionand arterial occlusions tend to develop. The firstmanifestation can be angina or infarction in a youngperson and when this occurs this disorder should bethought of and the skin and retinal changes sought.Appearance of the coronary arteries on coronaryangiography is not dissimilar to that in atheromatouscoronary disease and cases have been treated success-fully by coronary by-pass (Bete et al., 1975). Thearteries show increase, fragmentation and calci-fication with sub-endocardial thickening rich in acidmucopolysaccharide. Medial fibrosis develops anddisruption of the internal and external elasticlaminae.

Acquired non-atheromatous coronary diseaseCoronary embolismEmbolism to the coronary arteries is not un-

common. It is a frequent complication of infectiveendocarditis and of sterile thrombotic (marantic)endocarditis and is the major determinant of anginain patients with mitral stenosis. In tumours of theleft atrium (usually myxoma) the presentation canbe with angina or infarction due to embolism oftumour or associated thrombus into a major branchof the coronary arteries.Calcium embolism occurs frequently in calcific

aortic stenosis although it only rarely producesmajor infarction. Angina is one of the expectedsymptoms of aortic stenosis so that angina due tolodgment of particles of calcium in minor branches

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Non-atheromatous ischaemic heart disease 441

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FIG. 3. Acute coronary embolization during selective coronary angiography in a patient with a historyof infarction but who showed no evidence of coronary atheroma or other abnormality except theiatrogenic one. The right anterior oblique view on the left shows the left coronary artery with an abrupttermination of the large calibre obtuse marginal branch of the circumflex. This cut-off appearanceindicates an acute block and the patient developed an infarct. The lateral view on the right showsthe stump of the blocked vessel which should have coursed down the posterolateral free wall of theleft ventricle.

of the coronary branches does not alter the clinicalpicture nor is it usually sufficient to contributematerially to left ventricular dysfunction. The cal-cium can be found in the myocardium on histo-logical examination of most fatal cases of calcificaortic stenosis.One of the causes of death after artificial valve

replacement of the aortic or mitral valve is coronaryembolism and this is particularly likely to occur bydirect extension of thrombus from an aortic valveprosthesis into the ostium of one of the coronaryarteries, usually the left. The end of the cage of theStarr-Edwards prosthesis is one of the sites ofelection for thrombus deposition and from there it isonly a very short distance into one of the coronaryostia.

AortitisIn aortitis due to any cause, ostial stenosis may

develop. It occurs classically in syphilitic aortitis butmay also be seen in aortitis associated with anky-losing spondylitis, rheumatoid arthritis or in Reiter'ssyndrome, in giant cell arteritis, in oriental arteritisand aortitis (Takayashu's syndrome) and as an iso-lated finding. In the latter instance when there is noassociated disorder to alert the physician to thepossibility of ostial stenosis the condition can bemissed both by the inexperienced operator atcoronary angiography and by the pathologist atautopsy. Coronary ostial stenosis also developsearly in hypercholesterolaemia when it is due to

atherosclerosis in the aortic root, a site of pre-dilection and almost of xanthoma formation in thisdisorder. It may develop also as a consequence ofturbulence after replacement of the aortic valve by acaged ball valve prosthesis (Roberts and Morrow,1969) and also in association with supravalvaraortic stenosis.

Coronary dissectionCoronary dissection distinct from or complicating

aortic dissection due to cystic medionecrosis mayoccur in pregnancy, in coarctation, in Marfan'ssyndrome and in Ehlers-Danlos syndrome.

Introgenic coronary diseaseCoronary dissection or embolism can complicate

the investigation of coronary angiography but inexperienced hands the risk should be exceedinglylow (< 1 in 1,000) (Fig. 3).

Connective tissue disordersCoronary artery involvement in the connective

tissue disorders is common. In giant cell arteritis andin polyarteritis the major coronary arteries as wellas branch arteries (visible on coronary angiography)may be affected (Holsinger, Osmundson andEdwards, 1962). In suspected polyarteritis wherethere is evidence of cardiac involvement, coronaryangiography may indeed be justified and revealtypical small aneurysms on branches of the coronarytree.

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Celia M. Oakley

The syndrome of angina and angina-like pain withnormal coronary arteriesCardiac pain may arise from myocardial ischaemia,

from pericarditis or from the aorta in dissection. Itmay occur in heart muscle disease (cardiomyopathy)and aortic stenosis. Angina-like pain may arise fromother viscera particularly from the oesophagus. Inyet other patients none of these explanations seemsto apply and the source and the mechanism of theirangina-like pain continues to be obscure.

CardiomyopathyAngina or angina-like pain is not uncommon in

the primary heart muscle disorders (cardiomyopa-thies). In hypertrophic cardiomyopathy with orwithout obstruction (HOCM), angina is a majorsymptom in many patients and it is explicable by theoverdraft created by a grossly increased muscle massand increased internal cardiac work caused by thefunctional disorder in the face of normal (or evenunusually large) coronary arteries. In dilated (con-gestive) cardiomyopathy angina occurs in about 10%of patients. These are usually patients with advanceddisease in whom the association of cavity dilatationwith consequent increased wall tension, the increasedmuscle mass and the tendency to tachycardia duringexercise together account for the development ofangina. Finally, in primary restrictive cardiomyo-pathy (usually or always due to endocardial fibrosis)cardiac pain is a common mode of presentationalthough its exact genesis is not well understood.

Recurrent pericardial painPericarditis is apt to relapse and the pain to recur.

Pericardial rubs and sizeable effusions may not befound and the patient's description of his pain mayclosely simulate the pain of angina. There may be nohistory of acute pericarditis and the syndrome maybe far less flamboyant than the post-pericardiotomysyndrome or Dressler's post-myocardial infarctionsyndrome in which pain, fever and pericardialeffusion follow cardiac surgery or myocardial infarc-tion respectively. The pain of recurrent pericarditistends to come in bouts separated by symptom-freeintervals of days, weeks or months. During therecrudescence of symptoms the patient may eitherhave persistent pain or pain which comes and goesover the period of a few days. It is not strictly effortrelated but has a pleuritic component which maymake the pain seem to be worse on exercise andcause confusion if the respiratory augmentation isnot determined. The ECG may show non-specificrepolarization changes which, again, may be con-fused with those caused by ischaemia.

Aortic painDissection of the aorta is frequently a cata-

strophic and rapidly fatal event. The pain is extremelysevere and is in the distribution of cardiac pain butoften is with radiation through to the back or downinto the abdomen, these latter two componentsgiving the clue to the source of pain. Rarely, aorticdissection may be subacute and subclinical and inthese patients the pain may simulate angina. Againthe pain will not be strictly effort-related.

Extra-cardiac sources ofpainOesophageal pain caused by acid reflux ('heart-

burn') is common, particularly in women, and canusually readily be differentiated from myocardialischaemia by its burning quality and its relationshipto posture occurring when the patient is lying orsitting or bending over.The pain of achalasia can be very severe and

exactly similar to that of myocardial ischaemia butagain should be distinguished by its lack of relationto effort. Whereas oesophageal pain due to acidreflux can be prevented or relieved by demulcentantacids and avoidance of stooping, the pain ofachalasia is not due to acid and is ill understood.When the above conditions have been excluded

there remains a considerable group of patients inwhom chest pain simulating angina is the only com-plaint. Unlike the majority of patients with angina,many of these patients are young, there is an excessof women over men, risk-related traits such ashyperlipidaemia and high blood pressure are rare butsmoking is common. Sometimes the pain is atypical,lacking a strict relationship to effort, or fluctuatingin severity from day to day. Physical examination,ECG and chest X-ray are all normal. Myocardialbiopsy has been carried out in a group of thesepatients and the biopsies have been normal with noevidence of microvascular disease. Coronary sinuslactate estimation during pacing has usually notshown any evidence of lactate production nor haspain been provoked.

Therapeutic trial, antacids, glyceryl trinitrate andbeta-blockers are cheaper and more relevant thanwholesale prescription of barium meals and chole-cystograms. After all, hiatus hernia and gall-stonesare so common that finding them does not neces-sarily indicate that a diagnosis of the cause of painhas been achieved.

Coronary spasmAlthough these patients are undoubtedly a hetero-

geneous group, coronary spasm now seems to beestablished as a real entity (Oliva, Potts and Pluss,1973). Smoking may be an initiator of coronaryspasm in a predisposed subject and may lead tocoronary thrombosis through its effect also onplatelet aggregation but smoking is probably not anatherogenic agent.

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Non-atheromatous ischaemic heart disease 443

When Prinzmetal first described his 'inverted'angina he was referring to the paradoxical ST seg-ment elevation which accompanied attacks of chestpain. Later he changed the name to variant angina(Prinzmetal et al., 1959), which is the namestill commonly used. Although Prinzmetal's originalcases had atheromatous coronary artery obstruction,it has been found that the same clinical syndrome ismore often associated with coronary arteries whichon angiography are either normal or show onlyminor irregularities due to atheromatous plaguing,often without any significant narrowing of thevessels.

Variant angina differs from angina due to coronaryartery obstruction in its lack of relationship to exer-cise (Macalpin, Kattus and Alvaro, 1973) and itsfailure to respond to beta-blockers. The pain associ-ated with coronary artery obstruction is provokedby an increase in cardiac work and this is the keysymptom which is far more reliable than the patient'sdescription of how the pain feels. The clue is whatbrings on the pain. The pain associated with coronaryspasm is virtually never exercise-provoked becauseexercise is a potent coronary vasodilator. The paincomes on at rest, often wakes the patient at night andmay be longer lasting than the usual anginal pain.Although ST segment elevation on the ECG wasfirst described this is probably a phenomenon whichdepends on the duration of the coronary spasm.Similar ST segment elevation is seen also in impend-ing infarction before the development of the typicalchanges associated with myocardial necrosis. Coron-ary spasm of shorter duration probably produces STsegment depression but better known is the obser-vation that variant angina may be associated withfatal ventricular arrhythmia. It is likely that pro-longed coronary spasm from which the patient doesnot get a fatal dysrhythmia may lead to thrombosisand/or infarction. The manifestation of coronaryspasm may therefore depend on its duration.Does coronary spasm actually happen or is it a

convenient fiction to explain a syndrome which wedo not understand? The evidence, although largelycircumstantial, is compelling. We have the betterdocumented arterial spasm which is responsible forRaynaud's phenomenon and for migraine, and theobservation that angina may frequently be provokedby cold, in individuals with obstructive coronaryatheroma, or by smoking both in these people andin patients with anatomically normal coronaryarteries. This angina is not provoked by effort, iswell relieved by nitrates though not by beta-blockers;spontaneous coronary spasm may be seen duringcoronary angiography when it may be mistaken fororganic coronary disease but it may be reversed bynitrates; nitrates are observed to induce dilatationeven in normal 'non-spastic' coronary arteries and

workers in nitroglycerin factories may get nitrate'withdrawal' at the week-end. There is the provoca-tion of spasm by physical or pharmacological meanssuch as intravenous ergonovine during coronaryangiography.The treatment of coronary spasm consists in

avoiding the known provocateurs particularly smok-ing, the prescription of nitrates ad libitum and aregime of regular incremental physical exercise.Usually the clinical situation improves. Fatal ven-tricular fibrillation in patients with Prinzmetal'svariant angina and anatomically normal coronaryarteries is, however, well known so that the disorderis potentially a serious one. Beta adrenergic blockingdrugs should be avoided.

SmokingAlthough smoking is one of the three major risk-

related traits in patients with coronary atheroma itseems that the habit engenders thrombosis ratherthan atherosclerosis. Smoking increases plateletstickiness, probably through stimulating fatty acidrelease, and nicotine may cause vascular spasm in thepredisposed. The combination of spasm and in-creased platelet stickiness may lead to coronarythrombosis in the absence ofatheroma. The enhancedrisk to smokers is removed with cessation ofsmoking.

AcknowledgmentI am grateful to my colleague, Dr Maurice Raphael,

Senior Lecturer in Diagnostic Radiology, for the angiogramprints.

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HOLSINGER, D.R., OSMUNDSON, P.J. & EDWARDS, J. (1962)The heart in periarteritis nodosa. Circulation, 25, 610.

MACALPIN, R.N., KATTUS, A.A. & ALVARO, A.B. (1973)Angina pectoris at rest with preservation of exercisecapacity. Prinzmetal's variant angina. Circulation, 47, 946.

McKUSICK, V.A. (1972) Heritable Disorders of ConnectiveTissue, 4th Edn, pp. 292-371. C. V. Morby, St Louis.

NOREN, B.R., RAGHIB, G., MOLLER, J.H., AMPLATZ, K.,ADAMS, P., JR & EDWARDS, J.E. (1964) Anomalous originof the left coronary artery from the pulmonary trunk withspecial reference to the occurrence of mitral insufficiency.Circulation, 30, 171.

OLIVA, P.B., Porrs, D.E. & PLUSS, R.G. (1973) Coronaryarterial spasm in Prinzmetal angina. Documentation bycoronary angiography. New England Journal of Medicine,288, 745.

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444 Celia M. Oakley

ROBERTS, W.L. & MORROW, A.G. (1969) Late postoperativefindings following cardiac valve replacement with Starr-Edwards prosthesis. In: Prosthetic Heart Valves (Ed. byL. A. Brewer), p. 384. Charles C. Thomas, Springfield,Illinois.

SCHEIBLER, G.C., LORINCZ, A.E., BROGDON, B.G. & KROVETZ,L.J. (1962) Cardiovascular manifestations of Hurler'ssyndrome. Circulation, 26 (Suppl.), 782.

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heart disease.Non-atheromatous ischaemic

C. M. Oakley

doi: 10.1136/pgmj.52.609.3381976 52: 338-344 Postgrad Med J

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