Saturday 2 April
CORONARY VASOSPASM IN ANGINA PECTORIS A. MASERI A. PESOLA M. MARZILLI
S. SEVERI O. PARODI
A. L’ABBATE A. M. BALLESTRA G. MALTINTI D. M. DE NES A. BIAGINI
C.N.R. Clinical Physiology Laboratory and Istituto di Patologia Medica I, University of Pisa, Italy
Coronary angiography was performed during 34 anginal attacks in thirty patients admitted because of recurrent angina at rest. Nineteen (seventeen with S-T segment elevation and two with S-T depression) had angiograms during a spontaneous attack, eleven (nine with S-T elevation and two with S-T depression) during an attack induced by intravenous ergonovine maleate. Control coronary angioSummary
grams showed a wide range of atherosclerotic obstruction, from normal vessels to severe triple-vessel disease. During the anginal attack, all patients with S-T segment elevation had vasospasm localised to one of the major branches, often resulting in complete occlusion. Attacks with S-T segment depression were seen only in patients with double or triple vessel disease, and here the vasospasm generally affected coronary branches without causing complete occlusion. When appropriately searched for, vasospastic angina seems to be common.
Introduction Lathaus and Gardner,! Osler,2Gallavardin,3 and several other clinicians suggested on clinical grounds that coronary vasospasm might be a cause of angina pectoris. But this "functional" hypothesis fell into disrepute when nearly all anginal patients proved at necropsy to have severe "organic" coronary-artery atherosclerotic obstructions.4 The notion then arose that coronaryartery stenosis sets a fixed limit to the possible increase of coronary blood-flow, and that angina ensues whenever oxygen supply is short of myocardial metabolic demand. Prominent cardiology textbooks5 went further by stating that the only variable capable of determining an acute imbalance between demand and supply was an excessive increase of myocardial demand-a concept which has so far conditioned medical and surgical therapy of angina. This unilateral concept was challenged, however, when the attacks of angina at rest were shown not to be preceded by any detectable increase of the haemodynamic indices determining myocardial oxygen consumption.6-9 This was true not only of anginal attacks with S-T elevation on the
1977
electrocardiogram (the "variant" form of angina of PrinzmetallO 11) but also of attacks with s-T depression.12 Furthermore, radioisotopic myocardial perfusion studies have revealed that variant angina" and also angina at rest with s-T depression 14 are associated with a severe reduction of blood-flow to a region of the myocardium. These findings strongly suggest that coronary vasoconstriction contributes to the genesis of these anginal attacks at rest. So far, angiographic records of coronary-artery vasospasm have been made more by chance than by design,15-20 and sceptics suggest that the spasm may have been induced by the catheter.21The direct therapeutic implications of vasospasm as a cause of angina have led us to undertake a systematic angiographic study of the possible functional alterations of coronary arteries during episodes of angina and their relation to the site and extent
of atherosclerotic lesions.
Patients and Methods We studied
males and two 63 years, admitted to our coronary1976 with frequent, recurrent attacks
thirty patients, twenty-eight
females, aged from 24
to
unit from 1973 to of angina at rest (see accompanying table). In nineteen patients we were able to perform coronary angiography during a spontaneous episode. The s-T segment changes were transient elevation in seventeen and transient depression in two. Thirteen of these patients had angina during routine angiography (but the catheter was introduced into the coronary ostium after the onset of s-T segment changes). In the other six, we placed, the catheter below the renal arteries and waited 20-90 minutes for an anginal episode. Since April, 1975, we have also performed coronary angiograms during episodes of angina induced.by intravenous injection of ergot derivatives.zz z3 We believe that this investigation was not notably more hazardous than the simple coronary arteriography in patients who had spontaneous attacks during the procedure. We used the smallest dose capable of inducing angina (ascertained earlier in the coronary-care unit). The findings influenced our decisions about medical versus surgical care
management. CORONARY ANGIOGRAPHY DURING ANGINAL
*Arrows indicate direction of
s-T
segment
8014
ATTACK*
change.
714 In four patients with s-T segment elevation, ergonovine maleate 0.05-0.2 mg was injected after angiographic study of a spontaneous episode, to see whether the two types of attack differed angiographically. In eleven patients angiograms were obtained only during attacks induced by intravenous ergonovine maleate; during these attacks nine had s-T segment elevation and two had s-T segment depression. Selective coronary arteriography was performed by the Judkins techniques after premedication with 10 mg of diazepam, 6-8 ml of 76% ’Renografin’ being injected. Drug therapy was stopped the day before angiography. In particular, nitroglycerin was not given immediately before coronary angiography. Left and right coronary angiograms were recorded on 35 mm film at 30 frames per sec in the two obliques and in the lateral projections. On the basis of the angiographic findings, additional projections were secured by rotating the patient in the plywood cradle. The vessel to be injected was selected according to the electrocardiographic leads showing the s-T segment changes. Whenever possible, several contrast injections were made during the anginal attack. Additional injections were made after termination of the attack by sublingual nitroglycerin. In all cases nitroglycerin relieved the angina, and the pro-
cases). In these four patients the angina was accompanied by s-T segment elevation, and angiography during the attacks showed a spasm which, at least during one phase, completely occluded the vessel involved (fig. 1); otherwise it produced diffuse narrowing and poor and delayed distal filling and run-off. In two of these patients a second attack was produced by ergonovine maleate injection but there were no electrocardiographic or angiographic differences, in the site or extent of vasospasm, between drug-induced and spontaneous attacks.
volvement.
Group 2.-Nine patients had single-vessel disease (75% or greater lumen reduction); they were eight men and one woman, aged from 46 to 63 years. In all of them, the contrast injections performed during the anginal attack (which was always accompanied by s-T segment elevation) revealed a diffuse spasm of the stenotic vessel. Seven had complete occlusion with no distal dye-progression. In one of these patients the anginal attack was reproduced by an ergonovine maleate injection and angiography showed diffuse vessel narrowing with poor and delayed filling and run-off, whereas during the spontaneous attack the vessel had been completely occluded at the site of the organic stenosis with no distal filling. In three of these patients the attack was induced by ergonovine maleate injection. Group 3.-Nine male patients, aged 41 to 62 years,
Group 1.-Four patients, three males and one to 62 years, showed only coronary wall irregularities (two cases) or had normal vessels (two
had double-vessel disease. In seven the attacks were accompanied by s-T segment elevation: in six of these, spasm occluded the severely diseased left anterior des-
cedure gave rise to no complications. Results
The thirty patients were divided into four groups according to the degree of coronary atherosclerotic in-
female, aged from 24
Fig. I-Angiograms of a woman aged 24. A, control; B, during spontaneous anginal attack, showing only faint opacification of the middle third of the anterior descending artery. Corresponding 12-lead electrocardiograms are on top of the cine frames.
715
cending artery; in one, the spasm occluded
the right corwhich was in stenosed its proximal 75% onary artery, attack was two the In third. patients accompanied by s-T the in one the first on anterior leads: segment depression with stenosis 90% proximal during the septal branch, reduced in lumen with attack, seemed diffusely delayed filling and run-off, and there was diffuse narrowing also of the anterior descending artery and its branches; in the second, with left coronary injection, the distal filling of the right coronary, which was completely occluded at its middle third by an organic stenosis, became barely visible with some narrowing of all left coronary branches. In three of these patients, two with s-T segment elevation and one with s-T segment depression, the anginal attack was induced by ergonovine. Group 4.-Eight male patients, aged 45 to 63 years, had triple-vessel disease. The attack was accompanied by s-T segment elevation in six, and depression in antero-lateral leads in two. During the attack, five of those with s-T segment elevation had a transient complete vessel occlusion (fig. 2). A patient with s-T segment elevation on the anterior and diaphragmatic leads had a pronounced increase in the organic stenosis, with diffuse narrowing and delayed filling and run-off of the middle and distal segments of the anterior descending and middle circumflex arteries. In the two patients with s-T segment depression, during attacks one had strikingly reduced filling and delayed run-off of the proximally
occluded left anterior descending artery and of its branches via collaterals from the right coronary, and the other had diffuse narrowing of the branches of the left coronary artery without delayed filling and run-off (fig. 3). In six patients, five with s-T segment elevation and one with depression, the attack was provoked by ergonovine maleate. In one patient, ergonovine maleate induced a more severe and a greater proximal extension of the vessel occlusion than had been observed in a spontaneous attack. As judged by the Friesinger scoring system,25 patients had no consistent differences in severity of coronary atherosclerosis between the vessel liable to vasospasm and the other vessels. After sublingual nitroglycerin, the electrocardiogram always reverted to its previous state, the pain disappeared, and the spasm was no longer visible; often the vessels seemed more dilated than they had been before the attack.
Discussion These findings provide objective evidence that the transmural reduction of myocardial perfusion seen during episodes of angina at rest with s-T segment elevation 12 13 is caused by localised, severe coronary-artery vasospasm. The hypothesis that vasospasm may sometimes be induced mechanically by a catheter21 is not relevant to this group of patients since the catheter was
Fig. 2_angiograms of a man aged 60 with typical angina on exertion and triple-vessel disease. A, angiogram after no
opacification
nitroglycerin showing a double severe stenosis of anterior descending beyond the middle anterior descending artery.
artery;
B, angiogram during a spontaneous attack showing
716
Fig. 3-Angiograms of a hyperftnsive man aged 54 with triple-vessel disease. A, control, showing severe stenosis of the left main stem; B, during an attack induced by ergonovine maleate, showing diffuse reduction of the lumen of all the branches, notably of the distal circumflex.
introduced into the coronary ostium after the onset of angina and because the spasm was observed only when
(and
on
all occasions
when) arteriography
was
performed during the ischaemic episode. In patients with "variant" angina, the vessels subject to spasm showed remarkable variations in the severity of atherosclerosis-from normal lumen to multiple, greater than 90%, stenosis. Also, in vessels with severe atherosclerotic stenosis the spasm was not limited to the site of obstruction but seemed to extend proximally and distally from it. In the patients with single-vessel disease the spasm involved the vessel with atherosclerotic stenosis ; in patients with double or triple vessel disease the degree of atherosclerotic stenosis in the vessel affected by spasm was not different from that in the other vessels. The facts that, during attacks, the s-T segment changes were nearly always in the same electrocardiographic leads and that spasm was always seen in the same vessel suggest that some local factor is present; however, this factor is not necessarily a subcritical atherosclerotic obstruction, as postulated by Prinzrnetal et a!.,’" and the existence of angina with "normal" coronary arteriograms26 27 -and even with normal coronaries at necropsy2g-may not represent the paradox that it has seemed to some
workers.29
30
patients with angina at rest and s-T segment depression, our invariable finding of severe coronary For the
least two vessels, with collaterals, suggests the possibility of a variable extension of subendocardial ischxmia which does not reach the epicardium because of the presence of the collaterals and/or of a lesser intensity or diffusion of the ‘r vasospasm. Since, during continuous monitoring,’ episodes of s-T segment elevation and depression were observed in the same leads on different attacks in the same patients, it is reasonable to assume that the variations in the s-T segment changes reflect only a variable degree of ischaemia. The nature of the stimuli responsible for vasospasm probably varies in different patients and in the same patient at different times. Circulating substances such as ergot derivatives 22 23 or substances released from platelets,3’ on the one hand, and stimulation of nervous receptors with an alpha-type response,32-34 on the other, seem capable of inducing constriction of the large coronary-artery branches. Once locally initiated, the excitatory stimuli may be propagated in the smooth-muscle tissue,35 accounting for the diffuseness of the vasospasm. The demonstration of coronary vasospasm as a cause of angina must lead to reconsideration of the prevailing concept that angina can only be due to an excessive increase of myocardial metabolic demands in the presence of a reduced, fixed limitation of coronary blood-supply. This pathogenetic mechanism may well apply to patients
atherosclerosis numerous
occluding
at
717
angina is stable, occurring at a more-or-less fixed level of heart activity, but not necessarily to patients with unstable or "preinfarction" angina. Coronary bypass surgery is unlikely to represent the ideal treatment for patients with vasospastic angina, since the spasm seems to involve the vessels over a long segment. Such treatment may be indicated only for patients withtypical angina of effort, caused by critical coronary stenosis, in whom exercise tolerance is considerably limited. As to the medical treatment, reduction of myocardial oxygen consumption is not the only possible
A RETROSPECTIVE ANALYSIS OF BLOOD-LEAD IN MENTALLY RETARDED CHILDREN
whose
approach. syndrome of vasospastic angina is apparently and may overlap substantially with angina induced by excessive increase of myocardial demand in the presence of a fixed potential supply. In fact, angina at The
common
with s-T segment elevation-a reasonable indicator of vasospastic angina-seems to be present in over 10% of all patients admitted to our centre for diagnostic or therapeutic evaluation of chest pain.36 37 The overall prevalence of vasospastic angina may well be considerably higher, since (1) "variant" angina may be triggered also by exertion;36-39 (2) patients with variant angina at rest may have classic effort-induced angina with typical s-T segment depression in the same leads which show s-T segment elevation at rest, or in different leads;36 37 and (3) vasospastic angina can be accompanied also by s-T segment depression. We believe that, in diagnosis, therapy, and research, the possibility of a vasospastic origin for angina must now be taken into proper consideration. rest
Requests for reprints should be addressed to A. M., Clinica del C. N. R., Via Savi, 8, Pisa, Italy.
Fisiologia
REFERENCES 1. Fothergill, J. M. The Heart and its Diseases. Philadelphia, 1879. 2. Osler, W. Lancet, 1910, i, 839. 3. Gallavardin, L. Lyon méd. 1933, 151, 217. 4. Blumgart, H. L., Schlesinger, M. J., Davis, D. Am. Heart J. 1940, 19, 1. 5. Friedberg, L. K. Disease of the Heart. Philadelphia, 1966. 6. Guazzi, M., Polese, A., Fiorentini, C., Magrini, F., Bartorelli, C. Br. Heart J. 1971, 33, 84. 7. Maseri, A., Pesola, A., Mimmo, R., Chierchia, S., L’Abbate, A. Circulation, 1975, 52, suppl. ii, p. 89 (abstr.). 8. Guazzi, M., Polese, A., Fiorentini, C., Magrini, F., Olivari, M. T., Bartorelli, C. Br. Heart J. 1975, 37, 401. 9. Maseri, A., Mimmo, R., Chierchia, S., Marchesi, C., Pesola, A., L’Abbate, A. Chest, 1975, 68, 625. 10. Prinzmetal, M., Kennamer, R., Merliss, R., Wada, J. Am. J. Med. 1959, 27, 375. 11. Prinzmetal, M., Ekmekei, A., Kennamer, R., Kwoezynski, J. K., Shubin, H., Toyoshima, H. J. Am. med. Ass. 1960, 174, 1791. 12 Chierchia, S., Marchesi, C., Maseri, A. in International Workshop on Angina Pectoris (edited by A. Maseri, G. Klassen, and M. Lesh). New York (in the press). 13. Masen, A., Parodi, O., Severi, S., Pesola, A. Circulation, 1976, 54, 280. 14. Parodi, O., Severi, S., Maseri, A., Biagini, A. in International Workshop on Angina Pectons (edited by A. Maseri, G. Klassen, and M. Lesh). New York (in the press). 15. Dhurandhar, R. W., Watt, D. L., Silver, M. D., Trimble, A. S., Adelman, A. G. Am. J. Cardiol. 1972, 30, 902. 16. Oliva, P. V., Potts, D. E., Pluss, R. G., New Engl. J. Med. 1973, 288, 745. 17. Froment, R., Normand, J., Amiel, L. Arch. Mal. Coeur, 1973, 66, 755. 18. Kerin, N., McLeod, C. Br. Heart J. 1974, 36, 244. 19. Rose, F. J., Johnson, A. D., Carleton, R. A. Chest, 1974, 66, 719. 20. Applefield, M. M., Ronan, J. A., Jr, ibid. p. 721. 21. O’Reilly, R. J., Spellberg, D. R., King, T. W. Radiology, 1970, 95, 305. 22 Clark, D. A., Quint, R. A., Bolen, J. Am. J. Cardiol. 1975, 35, 127 (abstr.). 23. Heupler, F., Brondfit, W., Siegel, W. Circulation, 1975, 52, suppl. ii, p. 37. 24 Judkins, M. P. Radiol. Clins N. Am. 1968, 6, 467. 25. Friesinger, G. C., O’Neal, H. J., Ross, R. S. in Coronary Heart Disease (edited by M. Kaltenbach and P. Lichtlen). Frankfurt, 1972. 26. Kemp, H. G., Elliot, W. C., Gorlin, R. Trans. Ass. Am. Physns, 1967, 80, 59. 27. Cheng, T. O., Bashour, T., Kelser, G. A. Circulation, 1973, 47, 476. 28. Auzepy, Ph., Blondeau, M., Albessard, F. Arch. Mal. Coeur, 1974, 67, 1107.
MICHAEL R. MOORE PETER A. MEREDITH ABRAHAM GOLDBERG
University of Glasgow Department of Materia Medica, Stobhill General Hospital, Glasgow G21 3UW Blood-lead concentrations were measured retrospectively in the blood contained on cards used for testing for phenylketonuria in the first two weeks of life. Cards which belonged to 80 of a group of 77 children with mental retardation of unknown ætiology and 77 controls were identified. Of 77 usable cards, 41 were from mentally retarded children and 36 were from controls; 24 mental-retardation/ control pairs were found. There was a highly significant trend towards higher blood-lead concentrations in the mentally retarded children. Water-lead concentrations in the maternal home during pregnancy correlated with blood-lead concentrations in the mentally retarded children. These results reinforce the probable association between lead exposure during pregnancy and the development of mental retardation of otherwise unknown
Summary
ætiology. Introduction SINCE 1966 all children born in Scotland have been tested for phenylketonuria by means of the Guthrie test.’ In this test, blood-samples obtained by a heel stab in the first 2 weeks of life are spotted on absorbent cards (r.K.u. cards) and are analysed for phenylalanine in the Bacteriology Laboratories at Stobhill General Hospital in Glasgow. These cards are stored under dry conditions. Punched disc techniques may be used to measure accurately blood-lead in blood absorbed on to filter paper.23 We decided to examine the blood-lead status in the first 2 weeks of life of the 77 children with mental retardation of unknown aetiology (i.e., no evidence of other causes such as perinatal assault, hypoxia, induction of labour, prematurity, or post-maturity) and their paired controls identified by Beattie et al. in their investigation of the role of exposure to lead in water supplies in the aetiology of mental retardation.
Materials and Methods The children in this
29.
study were those identified as explained
Likoff, W., Segal, B. L., Kasparian, H. F. New Engl. J. Med. 1967, 276,
1063. 30. James, T. N. Circulation, 1973, 42, 476. 31. Ellis, E. F., Oelz, O., Jackson Roberts, L., Payne, N. A., Sweetman, B. J., Nies, A. S., Oates, J. A. Science, 1976, 193, 1135. 32. Yasue, H., Touyama, M., Kato, H., et al. Am. Heart J. 1976, 91, 148. 33. Bassenge, E., Holtz, J., Restoff, W. in International Workshop on Angina Pectoris (edited by A. Maseri, G. A. Klassen, and M. Lesh). New York (in the press). 34. Feigl, E. O., Mohrman, D. E. ibid. 35. Bohr, D. F. Circulation Res. 1973, 32, 665. 36. Maseri, A., Mimmo, R., Chierchia, S., Pesola, A., Parodi, O., Seven, S. G. Ital. Cardiol. 1976, 6, 13. 37. Maseri, A., Seven, S., Chierchia, S., Parodi, O., Biagini, A. in International Workshop on Angina Pectoris (edited by A. Maseri, G. A. Klassen, and M., Lesh). New York, (in the press). 38. Fortuin, N. J., Friesinger, G. C. Am. J. Med. 1970, 49, 459. 39. Bobba, P., Vecchio, C., Di Guglielmo, V., Montemartini, C., Salerno, J., Casari, A. Cardiol. prat. 1971, 12, 337.
CORONARY VASOSPASM IN ANGINA PECTORIS A. MASERI A. PESOLA M. MARZILLI
S. SEVERI O. PARODI
A. L’ABBATE A. M. BALLESTRA G. MALTINTI D. M. DE NES A. BIAGINI
C.N.R. Clinical Physiology Laboratory and Istituto di Patologia Medica I, University of Pisa, Italy
Coronary angiography was performed during 34 anginal attacks in thirty patients admitted because of recurrent angina at rest. Nineteen (seventeen with S-T segment elevation and two with S-T depression) had angiograms during a spontaneous attack, eleven (nine with S-T elevation and two with S-T depression) during an attack induced by intravenous ergonovine maleate. Control coronary angioSummary
grams showed a wide range of atherosclerotic obstruction, from normal vessels to severe triple-vessel disease. During the anginal attack, all patients with S-T segment elevation had vasospasm localised to one of the major branches, often resulting in complete occlusion. Attacks with S-T segment depression were seen only in patients with double or triple vessel disease, and here the vasospasm generally affected coronary branches without causing complete occlusion. When appropriately searched for, vasospastic angina seems to be common.
Introduction Lathaus and Gardner,! Osler,2Gallavardin,3 and several other clinicians suggested on clinical grounds that coronary vasospasm might be a cause of angina pectoris. But this "functional" hypothesis fell into disrepute when nearly all anginal patients proved at necropsy to have severe "organic" coronary-artery atherosclerotic obstructions.4 The notion then arose that coronaryartery stenosis sets a fixed limit to the possible increase of coronary blood-flow, and that angina ensues whenever oxygen supply is short of myocardial metabolic demand. Prominent cardiology textbooks5 went further by stating that the only variable capable of determining an acute imbalance between demand and supply was an excessive increase of myocardial demand-a concept which has so far conditioned medical and surgical therapy of angina. This unilateral concept was challenged, however, when the attacks of angina at rest were shown not to be preceded by any detectable increase of the haemodynamic indices determining myocardial oxygen consumption.6-9 This was true not only of anginal attacks with S-T elevation on the
1977
electrocardiogram (the "variant" form of angina of PrinzmetallO 11) but also of attacks with s-T depression.12 Furthermore, radioisotopic myocardial perfusion studies have revealed that variant angina" and also angina at rest with s-T depression 14 are associated with a severe reduction of blood-flow to a region of the myocardium. These findings strongly suggest that coronary vasoconstriction contributes to the genesis of these anginal attacks at rest. So far, angiographic records of coronary-artery vasospasm have been made more by chance than by design,15-20 and sceptics suggest that the spasm may have been induced by the catheter.21The direct therapeutic implications of vasospasm as a cause of angina have led us to undertake a systematic angiographic study of the possible functional alterations of coronary arteries during episodes of angina and their relation to the site and extent
of atherosclerotic lesions.
Patients and Methods We studied
males and two 63 years, admitted to our coronary1976 with frequent, recurrent attacks
thirty patients, twenty-eight
females, aged from 24
to
unit from 1973 to of angina at rest (see accompanying table). In nineteen patients we were able to perform coronary angiography during a spontaneous episode. The s-T segment changes were transient elevation in seventeen and transient depression in two. Thirteen of these patients had angina during routine angiography (but the catheter was introduced into the coronary ostium after the onset of s-T segment changes). In the other six, we placed, the catheter below the renal arteries and waited 20-90 minutes for an anginal episode. Since April, 1975, we have also performed coronary angiograms during episodes of angina induced.by intravenous injection of ergot derivatives.zz z3 We believe that this investigation was not notably more hazardous than the simple coronary arteriography in patients who had spontaneous attacks during the procedure. We used the smallest dose capable of inducing angina (ascertained earlier in the coronary-care unit). The findings influenced our decisions about medical versus surgical care
management. CORONARY ANGIOGRAPHY DURING ANGINAL
*Arrows indicate direction of
s-T
segment
8014
ATTACK*
change.
714 In four patients with s-T segment elevation, ergonovine maleate 0.05-0.2 mg was injected after angiographic study of a spontaneous episode, to see whether the two types of attack differed angiographically. In eleven patients angiograms were obtained only during attacks induced by intravenous ergonovine maleate; during these attacks nine had s-T segment elevation and two had s-T segment depression. Selective coronary arteriography was performed by the Judkins techniques after premedication with 10 mg of diazepam, 6-8 ml of 76% ’Renografin’ being injected. Drug therapy was stopped the day before angiography. In particular, nitroglycerin was not given immediately before coronary angiography. Left and right coronary angiograms were recorded on 35 mm film at 30 frames per sec in the two obliques and in the lateral projections. On the basis of the angiographic findings, additional projections were secured by rotating the patient in the plywood cradle. The vessel to be injected was selected according to the electrocardiographic leads showing the s-T segment changes. Whenever possible, several contrast injections were made during the anginal attack. Additional injections were made after termination of the attack by sublingual nitroglycerin. In all cases nitroglycerin relieved the angina, and the pro-
cases). In these four patients the angina was accompanied by s-T segment elevation, and angiography during the attacks showed a spasm which, at least during one phase, completely occluded the vessel involved (fig. 1); otherwise it produced diffuse narrowing and poor and delayed distal filling and run-off. In two of these patients a second attack was produced by ergonovine maleate injection but there were no electrocardiographic or angiographic differences, in the site or extent of vasospasm, between drug-induced and spontaneous attacks.
volvement.
Group 2.-Nine patients had single-vessel disease (75% or greater lumen reduction); they were eight men and one woman, aged from 46 to 63 years. In all of them, the contrast injections performed during the anginal attack (which was always accompanied by s-T segment elevation) revealed a diffuse spasm of the stenotic vessel. Seven had complete occlusion with no distal dye-progression. In one of these patients the anginal attack was reproduced by an ergonovine maleate injection and angiography showed diffuse vessel narrowing with poor and delayed filling and run-off, whereas during the spontaneous attack the vessel had been completely occluded at the site of the organic stenosis with no distal filling. In three of these patients the attack was induced by ergonovine maleate injection. Group 3.-Nine male patients, aged 41 to 62 years,
Group 1.-Four patients, three males and one to 62 years, showed only coronary wall irregularities (two cases) or had normal vessels (two
had double-vessel disease. In seven the attacks were accompanied by s-T segment elevation: in six of these, spasm occluded the severely diseased left anterior des-
cedure gave rise to no complications. Results
The thirty patients were divided into four groups according to the degree of coronary atherosclerotic in-
female, aged from 24
Fig. I-Angiograms of a woman aged 24. A, control; B, during spontaneous anginal attack, showing only faint opacification of the middle third of the anterior descending artery. Corresponding 12-lead electrocardiograms are on top of the cine frames.
715
cending artery; in one, the spasm occluded
the right corwhich was in stenosed its proximal 75% onary artery, attack was two the In third. patients accompanied by s-T the in one the first on anterior leads: segment depression with stenosis 90% proximal during the septal branch, reduced in lumen with attack, seemed diffusely delayed filling and run-off, and there was diffuse narrowing also of the anterior descending artery and its branches; in the second, with left coronary injection, the distal filling of the right coronary, which was completely occluded at its middle third by an organic stenosis, became barely visible with some narrowing of all left coronary branches. In three of these patients, two with s-T segment elevation and one with s-T segment depression, the anginal attack was induced by ergonovine. Group 4.-Eight male patients, aged 45 to 63 years, had triple-vessel disease. The attack was accompanied by s-T segment elevation in six, and depression in antero-lateral leads in two. During the attack, five of those with s-T segment elevation had a transient complete vessel occlusion (fig. 2). A patient with s-T segment elevation on the anterior and diaphragmatic leads had a pronounced increase in the organic stenosis, with diffuse narrowing and delayed filling and run-off of the middle and distal segments of the anterior descending and middle circumflex arteries. In the two patients with s-T segment depression, during attacks one had strikingly reduced filling and delayed run-off of the proximally
occluded left anterior descending artery and of its branches via collaterals from the right coronary, and the other had diffuse narrowing of the branches of the left coronary artery without delayed filling and run-off (fig. 3). In six patients, five with s-T segment elevation and one with depression, the attack was provoked by ergonovine maleate. In one patient, ergonovine maleate induced a more severe and a greater proximal extension of the vessel occlusion than had been observed in a spontaneous attack. As judged by the Friesinger scoring system,25 patients had no consistent differences in severity of coronary atherosclerosis between the vessel liable to vasospasm and the other vessels. After sublingual nitroglycerin, the electrocardiogram always reverted to its previous state, the pain disappeared, and the spasm was no longer visible; often the vessels seemed more dilated than they had been before the attack.
Discussion These findings provide objective evidence that the transmural reduction of myocardial perfusion seen during episodes of angina at rest with s-T segment elevation 12 13 is caused by localised, severe coronary-artery vasospasm. The hypothesis that vasospasm may sometimes be induced mechanically by a catheter21 is not relevant to this group of patients since the catheter was
Fig. 2_angiograms of a man aged 60 with typical angina on exertion and triple-vessel disease. A, angiogram after no
opacification
nitroglycerin showing a double severe stenosis of anterior descending beyond the middle anterior descending artery.
artery;
B, angiogram during a spontaneous attack showing
716
Fig. 3-Angiograms of a hyperftnsive man aged 54 with triple-vessel disease. A, control, showing severe stenosis of the left main stem; B, during an attack induced by ergonovine maleate, showing diffuse reduction of the lumen of all the branches, notably of the distal circumflex.
introduced into the coronary ostium after the onset of angina and because the spasm was observed only when
(and
on
all occasions
when) arteriography
was
performed during the ischaemic episode. In patients with "variant" angina, the vessels subject to spasm showed remarkable variations in the severity of atherosclerosis-from normal lumen to multiple, greater than 90%, stenosis. Also, in vessels with severe atherosclerotic stenosis the spasm was not limited to the site of obstruction but seemed to extend proximally and distally from it. In the patients with single-vessel disease the spasm involved the vessel with atherosclerotic stenosis ; in patients with double or triple vessel disease the degree of atherosclerotic stenosis in the vessel affected by spasm was not different from that in the other vessels. The facts that, during attacks, the s-T segment changes were nearly always in the same electrocardiographic leads and that spasm was always seen in the same vessel suggest that some local factor is present; however, this factor is not necessarily a subcritical atherosclerotic obstruction, as postulated by Prinzrnetal et a!.,’" and the existence of angina with "normal" coronary arteriograms26 27 -and even with normal coronaries at necropsy2g-may not represent the paradox that it has seemed to some
workers.29
30
patients with angina at rest and s-T segment depression, our invariable finding of severe coronary For the
least two vessels, with collaterals, suggests the possibility of a variable extension of subendocardial ischxmia which does not reach the epicardium because of the presence of the collaterals and/or of a lesser intensity or diffusion of the ‘r vasospasm. Since, during continuous monitoring,’ episodes of s-T segment elevation and depression were observed in the same leads on different attacks in the same patients, it is reasonable to assume that the variations in the s-T segment changes reflect only a variable degree of ischaemia. The nature of the stimuli responsible for vasospasm probably varies in different patients and in the same patient at different times. Circulating substances such as ergot derivatives 22 23 or substances released from platelets,3’ on the one hand, and stimulation of nervous receptors with an alpha-type response,32-34 on the other, seem capable of inducing constriction of the large coronary-artery branches. Once locally initiated, the excitatory stimuli may be propagated in the smooth-muscle tissue,35 accounting for the diffuseness of the vasospasm. The demonstration of coronary vasospasm as a cause of angina must lead to reconsideration of the prevailing concept that angina can only be due to an excessive increase of myocardial metabolic demands in the presence of a reduced, fixed limitation of coronary blood-supply. This pathogenetic mechanism may well apply to patients
atherosclerosis numerous
occluding
at
717
angina is stable, occurring at a more-or-less fixed level of heart activity, but not necessarily to patients with unstable or "preinfarction" angina. Coronary bypass surgery is unlikely to represent the ideal treatment for patients with vasospastic angina, since the spasm seems to involve the vessels over a long segment. Such treatment may be indicated only for patients withtypical angina of effort, caused by critical coronary stenosis, in whom exercise tolerance is considerably limited. As to the medical treatment, reduction of myocardial oxygen consumption is not the only possible
A RETROSPECTIVE ANALYSIS OF BLOOD-LEAD IN MENTALLY RETARDED CHILDREN
whose
approach. syndrome of vasospastic angina is apparently and may overlap substantially with angina induced by excessive increase of myocardial demand in the presence of a fixed potential supply. In fact, angina at The
common
with s-T segment elevation-a reasonable indicator of vasospastic angina-seems to be present in over 10% of all patients admitted to our centre for diagnostic or therapeutic evaluation of chest pain.36 37 The overall prevalence of vasospastic angina may well be considerably higher, since (1) "variant" angina may be triggered also by exertion;36-39 (2) patients with variant angina at rest may have classic effort-induced angina with typical s-T segment depression in the same leads which show s-T segment elevation at rest, or in different leads;36 37 and (3) vasospastic angina can be accompanied also by s-T segment depression. We believe that, in diagnosis, therapy, and research, the possibility of a vasospastic origin for angina must now be taken into proper consideration. rest
Requests for reprints should be addressed to A. M., Clinica del C. N. R., Via Savi, 8, Pisa, Italy.
Fisiologia
REFERENCES 1. Fothergill, J. M. The Heart and its Diseases. Philadelphia, 1879. 2. Osler, W. Lancet, 1910, i, 839. 3. Gallavardin, L. Lyon méd. 1933, 151, 217. 4. Blumgart, H. L., Schlesinger, M. J., Davis, D. Am. Heart J. 1940, 19, 1. 5. Friedberg, L. K. Disease of the Heart. Philadelphia, 1966. 6. Guazzi, M., Polese, A., Fiorentini, C., Magrini, F., Bartorelli, C. Br. Heart J. 1971, 33, 84. 7. Maseri, A., Pesola, A., Mimmo, R., Chierchia, S., L’Abbate, A. Circulation, 1975, 52, suppl. ii, p. 89 (abstr.). 8. Guazzi, M., Polese, A., Fiorentini, C., Magrini, F., Olivari, M. T., Bartorelli, C. Br. Heart J. 1975, 37, 401. 9. Maseri, A., Mimmo, R., Chierchia, S., Marchesi, C., Pesola, A., L’Abbate, A. Chest, 1975, 68, 625. 10. Prinzmetal, M., Kennamer, R., Merliss, R., Wada, J. Am. J. Med. 1959, 27, 375. 11. Prinzmetal, M., Ekmekei, A., Kennamer, R., Kwoezynski, J. K., Shubin, H., Toyoshima, H. J. Am. med. Ass. 1960, 174, 1791. 12 Chierchia, S., Marchesi, C., Maseri, A. in International Workshop on Angina Pectoris (edited by A. Maseri, G. Klassen, and M. Lesh). New York (in the press). 13. Masen, A., Parodi, O., Severi, S., Pesola, A. Circulation, 1976, 54, 280. 14. Parodi, O., Severi, S., Maseri, A., Biagini, A. in International Workshop on Angina Pectons (edited by A. Maseri, G. Klassen, and M. Lesh). New York (in the press). 15. Dhurandhar, R. W., Watt, D. L., Silver, M. D., Trimble, A. S., Adelman, A. G. Am. J. Cardiol. 1972, 30, 902. 16. Oliva, P. V., Potts, D. E., Pluss, R. G., New Engl. J. Med. 1973, 288, 745. 17. Froment, R., Normand, J., Amiel, L. Arch. Mal. Coeur, 1973, 66, 755. 18. Kerin, N., McLeod, C. Br. Heart J. 1974, 36, 244. 19. Rose, F. J., Johnson, A. D., Carleton, R. A. Chest, 1974, 66, 719. 20. Applefield, M. M., Ronan, J. A., Jr, ibid. p. 721. 21. O’Reilly, R. J., Spellberg, D. R., King, T. W. Radiology, 1970, 95, 305. 22 Clark, D. A., Quint, R. A., Bolen, J. Am. J. Cardiol. 1975, 35, 127 (abstr.). 23. Heupler, F., Brondfit, W., Siegel, W. Circulation, 1975, 52, suppl. ii, p. 37. 24 Judkins, M. P. Radiol. Clins N. Am. 1968, 6, 467. 25. Friesinger, G. C., O’Neal, H. J., Ross, R. S. in Coronary Heart Disease (edited by M. Kaltenbach and P. Lichtlen). Frankfurt, 1972. 26. Kemp, H. G., Elliot, W. C., Gorlin, R. Trans. Ass. Am. Physns, 1967, 80, 59. 27. Cheng, T. O., Bashour, T., Kelser, G. A. Circulation, 1973, 47, 476. 28. Auzepy, Ph., Blondeau, M., Albessard, F. Arch. Mal. Coeur, 1974, 67, 1107.
MICHAEL R. MOORE PETER A. MEREDITH ABRAHAM GOLDBERG
University of Glasgow Department of Materia Medica, Stobhill General Hospital, Glasgow G21 3UW Blood-lead concentrations were measured retrospectively in the blood contained on cards used for testing for phenylketonuria in the first two weeks of life. Cards which belonged to 80 of a group of 77 children with mental retardation of unknown ætiology and 77 controls were identified. Of 77 usable cards, 41 were from mentally retarded children and 36 were from controls; 24 mental-retardation/ control pairs were found. There was a highly significant trend towards higher blood-lead concentrations in the mentally retarded children. Water-lead concentrations in the maternal home during pregnancy correlated with blood-lead concentrations in the mentally retarded children. These results reinforce the probable association between lead exposure during pregnancy and the development of mental retardation of otherwise unknown
Summary
ætiology. Introduction SINCE 1966 all children born in Scotland have been tested for phenylketonuria by means of the Guthrie test.’ In this test, blood-samples obtained by a heel stab in the first 2 weeks of life are spotted on absorbent cards (r.K.u. cards) and are analysed for phenylalanine in the Bacteriology Laboratories at Stobhill General Hospital in Glasgow. These cards are stored under dry conditions. Punched disc techniques may be used to measure accurately blood-lead in blood absorbed on to filter paper.23 We decided to examine the blood-lead status in the first 2 weeks of life of the 77 children with mental retardation of unknown aetiology (i.e., no evidence of other causes such as perinatal assault, hypoxia, induction of labour, prematurity, or post-maturity) and their paired controls identified by Beattie et al. in their investigation of the role of exposure to lead in water supplies in the aetiology of mental retardation.
Materials and Methods The children in this
29.
study were those identified as explained
Likoff, W., Segal, B. L., Kasparian, H. F. New Engl. J. Med. 1967, 276,
1063. 30. James, T. N. Circulation, 1973, 42, 476. 31. Ellis, E. F., Oelz, O., Jackson Roberts, L., Payne, N. A., Sweetman, B. J., Nies, A. S., Oates, J. A. Science, 1976, 193, 1135. 32. Yasue, H., Touyama, M., Kato, H., et al. Am. Heart J. 1976, 91, 148. 33. Bassenge, E., Holtz, J., Restoff, W. in International Workshop on Angina Pectoris (edited by A. Maseri, G. A. Klassen, and M. Lesh). New York (in the press). 34. Feigl, E. O., Mohrman, D. E. ibid. 35. Bohr, D. F. Circulation Res. 1973, 32, 665. 36. Maseri, A., Mimmo, R., Chierchia, S., Pesola, A., Parodi, O., Seven, S. G. Ital. Cardiol. 1976, 6, 13. 37. Maseri, A., Seven, S., Chierchia, S., Parodi, O., Biagini, A. in International Workshop on Angina Pectoris (edited by A. Maseri, G. A. Klassen, and M., Lesh). New York, (in the press). 38. Fortuin, N. J., Friesinger, G. C. Am. J. Med. 1970, 49, 459. 39. Bobba, P., Vecchio, C., Di Guglielmo, V., Montemartini, C., Salerno, J., Casari, A. Cardiol. prat. 1971, 12, 337.
