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Postgrad Med J: first published as 10.1136/pgmj.67.783.4 on 1 January 1991. Downloaded from Postgrad Med J (1991) 67, 4 - 8 ) The Fellowship of Postgraduate Medicine, 1991

Leading Article and myocardial with normal coronary M.E. Bourke and D.L.H. Patterson Cardiac Department, Whittington Hospital, Highgate Hill, London N19 SNF, UK. Introduction Coronary ischaemic syndromes, including chest imbalance between myocardial supply and suggestive of angina pectoris, and document- demand might be abnormal haemoglobin oxygen ed , in the presence of angio- dissociation, as in poisoning.6 graphically normal , have been Classic angina pectoris usually indicates myocar- the subject of much attention. In contrast to dial ischaemia, secondary to obstructive coronary atheromatous coronary the patho- artery disease. It can arise when myocardial physiology ofsuch conditions is poorly understood ischaemia is due not to reduction ofcoronary and the mechanisms underlying myocardial ischae- flow, but to other mechanisms such as increased mia in these circumstances have been the cause ofa cardiac work as in aortic ; altered blood great deal of conjecture and controversy. oxygen content in severe anaemia; rheological abnormalities of the blood in hypergammaglobin-

aemia or, as described in this issue of the Journal, by copyright. Myocardial infarction due to thyrotoxicosis.'5 In Europe, approximately 10% ofpatients refer- A small percentage of patients presenting with red to cardiac units for assessment ofchest pain are myocardial infarction are found to have found on diagnostic to have angiographically normal epicardial coronary arter- no angiographic evidence of significant coronary ies. The is high in certain subsets of artery disease.'6 It is important to appreciate that myocardial infarction patients, such as the very coronary angiograms only visualize coronary young,' especially those infarcting during or fol- arteries of greater than 400 gAm diameter. The lowing severe physical ,2 and in young majority will have a non-cardiac cause for their http://pmj.bmj.com/ women during pregnancy or using oral contracep- symptoms and in many cases careful reassessment tives and .3 Documented myocardial and investigation will reveal a musculoskeletal, infarction in the presence of normal coronary oesophageal or psychological cause.'7 It may be arteries has been reported in thyrotoxicosis; both difficult to determine whether -related true and factitious,4 temporally related to symptoms are a cause or consequence of the use,5 after acute exposure to carbon monoxide,6 current . In a small minority of patients and in patients with viral .7 This issue of there will still be a clinical suspicion that symptoms the Journal contains a case report on a multisystem are due to myocardial ischaemia. on September 23, 2021 by guest. Protected leading to myocardial infarction without evidence of coronary artery involvement.8 Amongst suggested mechanisms are defects in Coronary clotting factors and activity,9"10 coronary artery ," with rapid spontaneous In 1959 Prinzmetal et al. introduced the concept of lysis,'2 coronary emboli' and small vessel disease.'3 epicardial artery spasm causing the specific clinical In cases of chronic Chagas' disease, where syndrome, 'variant angina', which is characterized there is parasympathetic ganglion destruction it is by angina at rest with elevated ST segments on postulated that transitory sympathetic overdrive electrocardiogram (ECG).'8 Now it is thought that causes myocardial infarction.' In these cases the this mechanism may play a role in other aspects of coronary arteries are not only free ofatheroma but ischaemic heart disease. Spasm can be detected in indeed are larger in comparison to hypertensive angiographically normal segments, or may be and normal patients. Another cause of an extreme superimposed on an atherosclerotic - 'dynamic coronary stenosis'. Unfortunately the Correspondence: D.L.H. Patterson, M.D., F.R.C.P. literature has become confused because the term Received: 6 September 1990 coronary spasm is often applied to any situation of Postgrad Med J: first published as 10.1136/pgmj.67.783.4 on 1 January 1991. Downloaded from

NORMAL CORONARY ARTERIES AND ISCHAEMIC SYNDROMES 5 increased coronary vasomotor tone. It should be symptoms. Many patients have a poor response to confined to a situation of focal coronary constric- long acting nitrate therapy, and a good response to tion sufficient to cause transient coronary occlu- calcium antagonists. The incidence ofsudden death sion, which gives rise to attacks ofischaemic pain at in patients with documented coronary artery rest. spasm is unknown. Since episodes of complete Although various neural'9 and humoral202' and ventricular are known mechanisms have been proposed, the genesis of to occur during coronary artery spasm, it may be coronary spasm is as yet undefined. Maseri and his that some patients have died as a result of these co-workers postulate a focal hyperreactivity to a rhythm disturbances. Overall the prognosis of a variety of coronary vasoconstrictive stimuli acting patient with severe coronary and on different receptors.22 It has been observed that in coronary artery spasm depends upon the degree of variant angina, coronary spasm usually occurs at atherosclerosis.29,30 the site ofatheromatous plaques,23 but the fact that such plaques are common and classical variant Syndrome X angina rare, suggests that some additional factor other than the presence of plaque is required. In a The term Syndrome X was first used by Kemp3' in large study of patients with chronic coronary 1973 in an editorial discussion of a paper by ischaemic syndromes other than variant angina, Arbogast and Bourassa,32 who performed pacing Bertrand et al.24 showed that when stenosis existed studies in patients with chest pain and normal there was no correlation between the degree of coronary arteries and showed ST depression dur- underlying stenosis and the occurrence of spasm. ing atrial pacing. No mention was made ofexercise- Bertrand could demonstrate ergonovine-induced induced ST segment changes in these patients. The angina in only 4% of those with chronic stable authors designated their patient cohort as group X. angina and 6% with old myocardial infarction. In The phrase was later popularized by Opherk et al.33 contrast 20% ofpatients with recent infarction and The term has been widely used, but with a lack of 30% ofthose experiencing angina at rest developed agreed hard diagnostic criteria. This has resulted in by copyright. focal coronary occlusion in response to ergono- a confusing picture as each study has used it own vine. It may be that in these acute situations there is terms of reference, making comparisons very a focal hyperreactivity to coronary vasoconstrictor difficult. agents. Less than 1% of those who present to a cardiac Recent studies have shown that vasoactive com- unit with possible angina, and in whom a non- pounds affect segments of the human coronary cardiac cause has been excluded, will fulfil the circulation differentially.22 This has implications in diagnostic criteria of a tight, albeit empirical, the pathophysiology of both focal coronary artery definition of Syndrome X:34 (a) typical angina on spasm and of 'Syndrome X', which has been effort; (b) positive exercise test; (c) no demonstrable http://pmj.bmj.com/ suggested to be due to a more diffuse disturbance of coronary stenosis; (d) no other obvious cause, such coronary blood flow. Intracoronary injection of as , valve disease or overt cardio- organic nitrates causes marked dilatation ofepicar- myopathy. Even applying these strict criteria will dial vessels, suggesting a resting coronary motor not give an infallible diagnosis, since, for instance tone. In contrast these doses have little affect on exercise testing has its limitations. total coronary blood flow, implying little effect on An alternative approach to the diagnosis is to use intramural resistance vessels. displays a conceptual definition, i.e. inducible ischaemia in the opposite pattern, with a marked distal dilating the absence of large coronary artery stenosis or on September 23, 2021 by guest. Protected effect but relatively minor actions on the epicardial haemodynamic overload. This approach intro- vessels. duces practical problems because ofthe difficulty in Studies ofthe effects ofintracoronary infusion of demonstrating ischaemia unequivocally. various endogenous vasoactive substances, includ- Several studies have used the demonstration of ing calcitonin gene related peptide,25 neuropeptide stimulation ofanaerobic metabolism as evidence of y,26 acetylcholine27 and substance P,28 point to a ischaemia. This is a specific but not sensitive heterogeneity of responses within the human cor- marker. In studies of patients with postulated onary circulation, and may allow some pharma- Syndrome X, 12-100% demonstrated myocardial cological intervention of coronary blood flow lactate production in response to pacing or dipyrid- regulation. It is difficult to validate their relevance amole infusion.34'35 to the pathophysiology of conditions under con- A fall in coronary sinus oxygen saturation in sideration here. response to increased workload, as induced by The clinical course of patients with documented pacing, provides an alternative indirect mark of coronary artery spasm is variable. Some have a ischaemia and indicates a level ofenergy consump- chronic course characterized by recurrent angina at tion beyond the limits ofautoregulation offlow. In rest, others develop spontaneous remission of normal subjects, coronary sinus oxygen saturation Postgrad Med J: first published as 10.1136/pgmj.67.783.4 on 1 January 1991. Downloaded from 6 M.E. BOURKE & D.L.H. PATTERSON

falls transiently as pacing rate is increased but emia, demonstrated significantly reduced hypera- returns to normal with autoregulation within 20 emia and higher vascular resistance in patients with seconds. Crake et al.36 demonstrated that in microvascular angina than in the control group. It patients with atheromatous coronary artery is postulated that patients with Syndrome X appear disease coronary sinus oxygen falls with the onset to have an impairment of vasodilator reserve that of ischaemia, as measured by pacing-induced ST affects not only the but also segment depression, and remains low, continuing their peripheral arterial bed. to fall with further increases in pacing rate. Ten Several studies have reported an excellent prog- patients with Syndrome X were also studied, two of nosis for patients with angiographically normal whom had responses almost identical to those of coronary arteries, regardless ofthe aetiology ofthe obstructive . The others chest pain. The largest study of 1,977 consecutive showed normal coronary sinus oxygen responses, patients with either normal coronary arteries or raising the possibility that their pain might not 'insignificant coronary artery disease' showed a reflect myocardial ischaemia. 98% 10 year survival with a 2% ofmyocardial A number of studies have attempted to evaluate infarction at 10 years for patients with normal left ventricular function in patients with Syndrome coronary arteries. Patients in both groups con- X. Arbogast and Bourassa's original paper demon- tinued to have symptoms that resulted in frequent strated no change in left ventricular function hospitalizations, use, and employment during induced by atrial pacing in patients.32 disability. Almost 50%, in any given year of Levy et al.37 measuring pulmonary artery diastolic follow-up, could not perform activities of high pressure, demonstrated that, in contrast to the metabolic requirement. Although these patients haemodynamic changes that occur during myocar- are at low risk of death many remain functionally dial ischaemia in coronary artery disease, chest impaired for years.42 pain and ST segment changes in patients with In Kemp's study the 6 year survival was no Syndrome X are not associated with impaired left different from that ofan asymptomatic age and sex ventricular function. In contrast, other studies38 matched cohort.'7 However, in most long term by copyright. show regional wall motion abnormalities, shorten- series the clinical characteristics of the patients ing of diastolic time and raised left ventricular have not been adequately described. Groups with end-diastolic pressures during stress by pacing and oesophageal, musculoskeletal and psychosomatic exercise testing. causes have not been excluded. Opherk et al.43 There have been several studies demonstrating characterized a group of 40 Syndrome X patients an impaired rise in coronary blood flow in response with abnormal flow responses to dipyridamole; at a to atrial pacing in patients with Syndrome X. In mean follow-up of 4 years, all patients were alive, Cannon's studies38 patients developing their typical and symptom status was unchanged in most. No chest pain during atrial pacing demonstrated signi- patient had a spontaneous improvement or remis- http://pmj.bmj.com/ ficantly lower great cardiac flow and higher sion ofsymptoms. It must be noted that 15 ofthese calculated coronary resistance compared with 40 patients had conduction abnormalities on their those without pacing-induced chest pain. The chest ECG during exercise, of these 5 developed persis- pain group also demonstrated significantly higher tent , and 6 progressed lactate production and abnormalities ofleft ventri- towards a dilated . It is possible cular systolic and diastolic function suggestive of that the abnormality responsible for limited cor- myocardial ischaemia. These and other similar onary flow reserve in this subgroup is different from studies are consistent with a hypothesis that some that with normal ECGs. Many patients with con- on September 23, 2021 by guest. Protected patients with chest pain and angiographically nor- duction abnormalities on ECG, at rest or during mal epicardial arteries have dynamic abnormalities exercise, do not enjoy the same benign prognosis of the coronary microcirculation. This abnormal with respect to ventricular function. vasodilator capacity or may result Epidemiological studies of patients with chest in angina pectoris and myocardial ischaemia. This pain and normal coronary arteries are reassuring has been termed microvascular angina. with regard to mortality, but do indicate con- If Syndrome X is due to small vessel disease, a siderable long term morbidity and medical/social pathogenesis is as yet unknown. No evidence of a and economic consequences. An alternative aetio- structural abnormality of small arteries has ever logy should be sought for the chest pain by history, been found, except in a small group of atypical examination and appropriate investigation. With patients who may have early cardiomyopathy.39 firm diagnosis ofa non-cardiac cause these patients Conversely there is evidence that microvascular can be effectively managed. angina may give rise to cardiomyopathy.40 Treatment ofthe small group ofpatients remain- Studies offorearm vasodilator reserve in normo- ing with a diagnosis of microvascular angina is tensive patients with microvascular angina,4' which difficult. Glyceryl trinitrate is helpful for short term measured hyperaemic response to forearm ischa- relief of pain in most cases. Many, but not all, Postgrad Med J: first published as 10.1136/pgmj.67.783.4 on 1 January 1991. Downloaded from

NORMAL CORONARY ARTERIES AND ISCHAEMIC SYNDROMES 7

respond to calcium channel blockers. Beta-block- small vessels. It may be that aminophylline ers can sometimes be of benefit, possibly by blockade of adenosine receptors blunts excessive reducing myocardial oxygen demand.44 Intraven- arteriolar dilatation thus preventing this maldis- ous aminophylline has recently been demonstrated tribution. It remains to be seen whether oral to increase effort tolerance, improve symptoms and aminophylline preparations can confer the same abolish ischaemic ST segments during exercise in benefit. Since the condition of Syndrome X has patients with Syndrome X.45 It is suggested that a been so poorly defined it is not surprising that there transmural steal phenomenon occurs whereby have been no adequate clinical trials of treatment there is a maldistribution of coronary flow due to for the condition. an abnormally elevated resistance upstream of the

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